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Investigations into novel (per)fluoromethylations of organic molecules
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Content
Investigations into Novel (Per)fluoromethylations of
Organic Molecules
By
Vinayak Krishnamurti
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2021
Copyright 2021 Vinayak Krishnamurti
ii
Dedication
I dedicate this dissertation to my parents
Dr. Hemalatha Krishnamurti and Dr. Ramesh Krishnamurti
“The best gift is a good education” – Dr. Hemalatha Krishnamurti
iii
Acknowledgements
There are so many to whom I owe a world of gratitude for their support in helping me achieve my
academic goals. First and foremost, I would like to thank my PhD advisor Dr. Surya Prakash for giving me
the incredible chance to prove myself as a researcher and student mentor by accepting me as his graduate
student. You taught me much about the world of academia and research. Beyond all that, you have always
been a wonderful role model, always pushing your students to be better scientists and better people. I
will always remember with utmost fondness the long and fun days as a graduate student in your lab, and
our meandering discussions on every topic under the stars. One could not ask for a better teacher and
mentor, and I consider myself lucky to have been under your tutelage.
I sincerely thank Dr. Robert Anizfeld for his constant support and guidance: both inside the lab
and out. He has been there for me in very crucial times, and if not for his selflessness my PhD experience
would not be what it was. You taught me a lot about maintaining perspective on the practical aspects of
research, and how to find value in chemistry beyond academic interests.
I thank Dr. Thomas Mathew for teaching me various lab techniques. You have been a great moral
support and teacher over the years. Your advice and encouragement have been great enablers of my
academic progress. I owe Dr. Alain Goppert a lot of gratitude. At the drop of a hat, you have always been
ready to assist me in utilizing equipment that I am not familiar with. You always go above and beyond to
ensure that the other students and I in the lab have access to the things we need. Thank you, Jessie May,
for always being so kind in helping us order supplies and reagents, book air tickets for conferences, and
taking such a personal interest in all our well-beings. Your thoughtfulness really makes this lab a better
place and the group is very lucky to have you. A big thank you to USC chemistry, the Loker Hydrocarbon
Research Institute, the Morris-Smith foundation, and the Berg foundation for financial support during my
iv
PhD program. I am grateful to Dr. Nicos A. Petasis, Dr. Chao Zhang, Dr. Ralph Haiges, Dr. Barry Thompson
and Dr. Katherine Shing for being on my screening and qualifying exam committees.
I would like to thank my collaborators and friends over the years for the amazing experiences. You
all made it a life well lived and gave me memories I will always cherish. Of course, special thanks go to my
friend and collaborator Colby Barrett. Mentoring you and working alongside you has been an absolute
pleasure, and our late nights in the lab will always be some of my fondest memories. You have really
helped me grow as a chemist and a researcher. As a friend, you set the bar too high with your
thoughtfulness and kindness. Here’s something only you would appreciate: *incoherent thanking noises*.
Overflowing thanks and love to my partner Xanath Ispizua Rodriguez. Our relationship blossoming
alongside my professional growth has been the most wonderful experience. Your unconditional support
and love are something I can never thank you enough for. You challenge me intellectually and make me
want to be better every day. As I close this chapter of my professional life and begin the next, I am
reassured knowing you are by my side.
My family has always been my biggest support. Harini Krishnamurti, you are truly a source of
comfort and good vibes. You, my sister, have been my best friend since before I can remember, and I am
truly lucky to have a sister as wonderful and you are. Growing up as your brother has made me a better
man and I can never thank you enough for that. And finally, and most importantly, thank you Dr.
Hemalatha Krishnamurti and Dr. Ramesh Krishnamurti (or as I call you, Amma and Appa) for giving me a
truly privileged life. The two of you will always be my home, and it is without a doubt your constant
guidance and love which has gently guided me along the river of life. Appa, you are probably the smartest
person I will ever meet, yet also the humblest. I aspire to your sense of duty and commitment. You are
the most affectionate father I have ever seen. Really, I have you to thank for kindling my interest in
Chemistry with our fun discussions. Amma, you have always been my confidante. At every stage of my
life, you have been there to nurture me, protect me and teach me right from wrong. From driving me
v
home from the train station every day to reading my textbooks out loud to me when I did not want to
study, you have been there for me at every stage of my life. There is no one who knows me as well as you
do. I sincerely thank you Amma and Appa, and I hope I have done you proud.
vi
Table of Contents
Page Number
Dedication ............................................................................................................................................... ii
Acknowledgements ................................................................................................................................ iii
List of Tables ........................................................................................................................................... ix
List of Figures .......................................................................................................................................... x
List of Schemes ....................................................................................................................................... xi
Permissions ........................................................................................................................................... xv
Abstract ................................................................................................................................................ xvi
Chapter 1: Introduction ........................................................................................................................... 1
1.1 The Trifluoromethyl, Difluoromethyl and Monofluoromethyl Groups ............................ 1
1.2 Silicon-Based Reagents in (Per)fluoromethylation Reactions .......................................... 6
1.2.1 Trifluoromethyltrimethylsilane in Trifluoromethylation Reactions ..................... 7
1.2.2 Trifluoromethylsilanes in Difluoromethylenation Reactions ................................ 8
1.2.3 Halodifluoromethylsilanes in Difluoromethylenation Reactions ....................... 15
1.2.4 (Arylsulfanyl)difluoromethylsilanes in Difluoromethylenation Reactions .......... 20
1.2.5 (Arylsulfonyl)difluoromethylsilanes in Difluoromethylenation Reactions ......... 26
1.2.6 (Phosphonodifluoromethyl)silanes in Difluoromethylenation Reactions .......... 31
1.2.7 (Carbonyldifluoromethyl)silanes in Difluoromethylenation Reactions .............. 40
1.3 FBSM and its Application to Monofluoromethylation Strategies ................................... 46
Chapter 2: Direct Difluorination-Hydroxylation, Trifluorination and C(sp
2
)–H Fluorination
of Enamides ......................................................................................................................... 62
2.i Introduction ..................................................................................................................... 62
2.ii Results and Discussion .................................................................................................... 64
2.iii Conclusion ....................................................................................................................... 72
2.iv Experimental Section ....................................................................................................... 73
General .............................................................................................................. 73
Synthesis of Benzamide Starting Materials ....................................................... 73
vii
Synthesis and NMR Spectroscopic Data of Benzamide Starting Materials ........ 75
Synthesis and NMR Spectroscopic Data of Enamide Starting Materials ........... 77
General Procedures for Gem-Difluorination of Isoindolinones ......................... 89
Evaluation of the Effect of Initial Water Content on
Dehydration/Oxyfluorination Sequence ............................................................ 92
Synthesis and NMR Spectroscopic Data of Difluorinated Products ................... 95
Synthesis and NMR Spectroscopic Data of Fluoro-Olefin Derivatives ............. 114
General Procedure for the Synthesis of Trifluorinated Derivatives 2-4 .......... 118
Synthesis and NMR Spectroscopic Data of Trifluorinated Derivatives 2-4 ...... 119
Procedure for the Enantioselective Thiol Addition using Catalyst A ............... 123
Chapter 3: C(sp
2
)–H Trifluoromethylation of Enamides using TMSCF 3: Access to
Trifluoromethylated Isoindolinones, Isoquinolinones, 2-Pyridinones
and Other Heterocycles ..................................................................................................... 126
3.i Introduction .................................................................................................................. 126
3.ii Results and Discussion .................................................................................................. 129
3.iii Mechanistic Investigations ........................................................................................... 135
3.iv Conclusion .................................................................................................................... 144
3.v Experimental Section .................................................................................................... 144
General ............................................................................................................ 144
Synthesis and NMR Spectroscopic Data of Starting Materials ........................ 145
General Procedures for C(sp
2
)–H Trifluoromethylation .................................. 160
Synthesis and NMR Spectroscopic Data of Products ....................................... 161
Attempted Trifluoromethylation of 3-methyl-1-phenylpyridin-2(1H)-one ..... 178
Chapter 4: Siladifluoromethylation and Deoxo-Trifluoromethylation of P
V
–H Compounds
with TMSCF 3: Routes to P
V
–CF 2-Transfer Reagents and P–CF 3 Compounds ...................... 179
4.i Introduction .................................................................................................................. 179
4.ii Results and Discussion .................................................................................................. 182
4.iii Mechanistic Hypothesis ................................................................................................ 187
4.iv Conclusion .................................................................................................................... 196
4.v Experimental Section ..................................................................................................... 197
viii
General Information ........................................................................................ 197
Synthesis and Characterization of Starting Materials ..................................... 197
Synthesis and Characterization of Products .................................................... 203
Attempted Carbene Insertion into Disilanes and Silyl Hydrides ...................... 218
Chapter 5: Aqueous Base Promoted O-Difluoromethylation of Carboxylic Acids with TMSCF 2Br:
Bench-top Access to Difluoromethyl Esters ....................................................................... 222
5.i Introduction ........................................................................................................................... 222
5.ii Results and Discussion ........................................................................................................... 225
5.iii Conclusion ............................................................................................................................. 229
5.iv Experimental Section ............................................................................................................. 229
General information ........................................................................................ 233
Synthesis and Characterization of Difluoromethyl Esters ............................... 230
Chapter 6: Regioselective Monofluoromethylation of Aryliodonium Salts using
Fluorobis(phenylsulfonyl)methane (FBSM) ......................................................................................... 249
6.i Introduction ........................................................................................................................... 249
6.ii Results and Discussion ........................................................................................................... 253
6.iii Future Directions ................................................................................................................... 257
6.iv Conclusion ............................................................................................................................. 258
References ........................................................................................................................................... 259
ix
List of Tables
Page number
Table 2.1 Optimization table for the base-mediated difluorination reaction ....................................... 65
Table 2.2 Optimization table for the acid-mediated difluorination reaction ........................................ 69
Table 2.S1 Effect of varying amounts of water on the relative ratio of products ................................. 93
Table 2.S2 Evaluation of various chiral Brønsted acid catalyst for enantioselective thiol addition .... 122
Table 3.1 Optimization table ............................................................................................................... 130
Table 3.2 Control Experiments ............................................................................................................ 135
Table 3.S1 Full optimization table ....................................................................................................... 159
Table 4.1 Select optimization studies on diethyl phosphonate (4-1a) ................................................ 183
Table 4.2 Siladifluoromethylation of P
V
–H compounds ...................................................................... 184
Table 4.3 Deoxo-trifluoromethylation of secondary phosphine oxides using TMSCF 3 ....................... 186
Table 4.4 Demonstration of the prepared phosphonodifluoromethylsilanes as reagents
and the effect of the phosphorous substituents on the stability of the product ............... 196
Table 4.S1 Full optimization table ....................................................................................................... 201
Table 5.1 Optimization experiments on 5-1a ...................................................................................... 224
Table 5.2 Substrate scope .................................................................................................................... 226
Table 5.3: O-difluoromethylation of biologically relevant carboxylic acids ......................................... 228
Table 6.1 Optimization table using diphenyliodonium trifluorocaetate (6-1a-TFA) ........................... 254
Table 6.2 Optimization table using phenyl(trimethoxyphenyl)iodonium
trifluoroacetate (6-1a-TMBTFA) ......................................................................................... 255
Table 6.3 Optimization table using diphenyliodonium triflate (1a-OTf) ............................................. 256
x
List of Figures
Page Number
Figure 2.S1
19
F NMR after 2 h of entries 1-4 from table 2.S1 ................................................................ 94
Figure 2.S2
19
F NMR of entries 5 and 9 from table 2.S1 ........................................................................ 94
Figure 2.S3 Proposed Transition State Model for Stereochemical Outcome ...................................... 125
Figure 3.1 Examples of relevant APIs containing the enamide functionality ...................................... 127
Figure 3.2 Difference between pyridinones and other enamide-heterocycles ................................... 128
Figure 3.3 Reagents employed in the direct trifluoromethylation of enamides ................................. 128
Figure 3.4 Proposed reaction pathway ............................................................................................... 129
Figure 3.5 Reaction scope of the C(sp
2
)–H trifluoromethylation ........................................................ 132
Figure 3.6 Proposed Mechanism ......................................................................................................... 143
Figure 4.1 Extensive use of P
V
CF 2TMS reagents: Mostly limited to diethyl phosphonate
Derivatives ......................................................................................................................... 180
Figure 4.2 Reported syntheses of siladifluoromethyl phosphorous compounds ................................ 181
Figure 4.3 Predicted reaction pathway leading to product 4-2 ........................................................... 182
Figure 4.4 Prior art on the synthesis of trifluoromethylphosphines ................................................... 185
Figure 4.5 Plausible reaction pathways ............................................................................................... 195
Figure 5.1 Prior art on the direct difluoromethylation of carboxylic acids .......................................... 223
Figure 5.2 Mechanistic hypothesis ...................................................................................................... 224
xi
List of Schemes
Scheme 1.1a Select examples of pharmaceuticals containing the trifluoromethyl (–CF 3) group ........... 1
Scheme 1.1b Examples of active pharmaceutical ingredients containing the CF 2 group ........................ 2
Scheme 1.1c Some monofluoromethyl compounds that are used as therapeutics ............................... 2
Scheme 1.2a Reported bioisosteric replacements with different monofluoro-, difluoro- and
Trifluoromethyl groups ...................................................................................................... 3
Scheme 1.2b Comparisons of methyl, monofluoromethyl, difluoromethyl, and trifluoromethyl
Moieties ......................................................................................................................................... 4
Scheme 1.2c Calculated energy difference between singlet and triplet difluorocarbene ...................... 5
Scheme 1.3 Mechanism of fluoroalkanide release via nucleophilic addition of an activator
to perfluoroalkylsilanes .................................................................................................................... 6
Scheme 1.4 Representative types of trifluoromethylation reactions ..................................................... 7
Scheme 1.5 [2+1] cycloaddition of TMSCF 3-derived difluorocarbene with alkenes and alkynes ............ 8
Scheme 1.6 (Sila)difluoromethylation of C nucleophiles ........................................................................ 9
Scheme 1.7 N-difluoromethylation using trifluoromethylsilanes ......................................................... 11
Scheme 1.8 Difluoromethylation of chalcogen nucleophiles using TMSCF 3 ................................................................. 12
Scheme 1.9 (Sila)difluoromethylation of P
V
–H nucleophiles promoted by Li
+
...................................... 13
Scheme 1.10 CF 2 carbene insertion into Sn–H bonds ........................................................................... 13
Scheme 1.11 Difluoromethylenation reactions using TMSCF 3 .............................................................. 14
Scheme 1.12 Pentafluoroethylation and tetrafluoroethylation using TMSCF 3-derived
Tetrafluoroethene ........................................................................................................... 14
Scheme 1.13 C—H bromination of difluoromethylphenyldimethylsilane ............................................ 15
Scheme 1.14 Reduction-silylation of dibromodifluoromethane ........................................................... 16
Scheme 1.15 TMSCF 3 as a feedstock of TMSCF 2Br ................................................................................ 16
Scheme 1.16 Difluorocyclopropenation using TMSCF 2Br ...................................................................... 17
Scheme 1.17 Difluoromethylene insertion into ketones ...................................................................... 17
Scheme 1.18 CF 2 carbene triggered ring expansion .............................................................................. 17
Scheme 1.19 Nucleophilic C-difluoromethylation with Ph 3P=CF 2 .......................................................................................... 18
Scheme 1.20 Difluoromethylation of diverse nucleophiles using TMSCF 2Br ........................................ 19
Scheme 1.21 TMSCF 2Br in multi-component reactions ........................................................................ 20
xii
Scheme 1.22 Access to phenyl (trimethylsilyl)difluoromethyl thioether .............................................. 21
Scheme 1.23 Siladifluoromethylthioethers as potent pronucleophiles ................................................ 23
Scheme 1.24 More nucleophilic reactions of TMSCF 2SPh ..................................................................... 24
Scheme 1.25 Scaffolds accessed via the nucleophilic addition-radical desulfurization strategy .......... 25
Scheme 1.26 PhSeCF 2TMS as a reagent ................................................................................................ 26
Scheme 1.27 Access to sulfonylfluoroalkylsilanes ................................................................................. 27
Scheme 1.28 Nucleophilic difluoromethylation of C(sp
2
) electrophiles ................................................ 28
Scheme 1.29 Nucleophilic difluoromethylation of C(sp
3
) electrophiles ................................................ 29
Scheme 1.30 In situ generated [CuCF 2SO 2Ph] as a reactive intermediate ............................................ 30
Scheme 1.31a Using PhSO 2CF 2TMS to synthesize an electrophilic PhSO 2CF 2 transfer reagent ............ 30
Scheme 1.31b Monofluoromethylation using silane reagents ............................................................. 31
Scheme 1.32 Preparations of phosphadifluoromethylsilanes ............................................................... 32
Scheme 1.33 Nucleophilic phosphono(di)fluoromethylation ............................................................... 33
Scheme 1.34 Nucleophilic P
V
CF 2-transfer .............................................................................................. 34
Scheme 1.35 Recent transition metal-free transfers of silane-derived
phosphonodifluoromethide to electrophiles ................................................................... 35
Scheme 1.36 Transition metal-mediated transfer of –CF 2P(O)(OR) 2 ................................................................................... 37
Scheme 1.37 Recent metal-mediated phosphonodifluoromethylations .............................................. 39
Scheme 1.38 First preparations and uses of [Si]CF 2C(O)R compounds ................................................. 40
Scheme 1.39 Nucleophilic difluoromethylation reactions .................................................................... 41
Scheme 1.40 Metal-mediated transfers of the CF 2CO 2R anion ............................................................. 42
Scheme 1.41 Difluoromethylations promoted by transition metals ..................................................... 44
Scheme 1.42 FBSM as a masked nucleophile ........................................................................................ 47
Scheme 1.43 Phosphine-catalyzed FBSM addition to a,b-unsaturated compounds ............................ 48
Scheme 1.44 Addition of FBSM to arynes, alkynes and a,b-unsaturated ketones ............................... 49
Scheme 1.45: Chiral monofluoromethylation of a,b-unsaturated ketones with FBSM ........................ 50
Scheme 1.46 Asymmetric monofluoromethylation of a,b-unsaturated aldehydes and ketones ......... 50
Scheme 1.47 b-monofluoromethyl ketones via chiral primary amine catalysis ................................... 52
Scheme 1.48 I
V
mediated oxidative monofluoromethylation ............................................................... 52
Scheme 1.49 Enantioselective monofluoromethylation of indole derivatives ..................................... 52
Scheme 1.50 Preparation of fluoroindanes and fluorochromanols ...................................................... 53
Scheme 1.51 Enantioselective Pd-catalyzed allylic monofluoromethylation ........................................ 53
xiii
Scheme 1.52 Enantioselective Ir-catalyzed monofluoromethylation of allylic carbonates .................. 54
Scheme 1.53 Chiral ligand-assisted Pd-catalyzed a-fluoromethylation ................................................ 54
Scheme 1.54 Ir-catalyzed synthesis of allylic fluorides ......................................................................... 55
Scheme 1.55 Nucleophilic monofluoromethylation of primary alkyl halides ....................................... 55
Scheme 1.56 Stereospecific deoxymonofluoromethylation of secondary alcohols .............................. 56
Scheme 1.57 Epoxide ring-opening with FBSM ..................................................................................... 56
Scheme 1.58 Monofluoromethylation of amines by phase-transfer catalysis ...................................... 57
Scheme 1.59 Synthesis of b-monofluoromethyl amines through Mannich-type intermediate ............ 57
Scheme 1.60 Radical monofluoromethylation of olefins using FBSM-I ................................................ 58
Scheme 1.61 Allylic monofluoromethylation of alkynes ....................................................................... 58
Scheme 1.62 Monofluoromethylation of conjugated dienes ................................................................ 58
Scheme 1.63 Electrophilic alkynylation of FBSM ................................................................................... 58
Scheme 1.64 Enantioselective monofluoromethylation of MBH-carbonates ....................................... 59
Scheme 1.65 Trifluoromethide-promoted monofluoromethylation ..................................................... 59
Scheme 1.66 Li
+
-promoted FBSM addition to aldehydes ...................................................................... 60
Scheme 1.67 Monofluoroolefination using FBSM ................................................................................. 60
Scheme 1.68 Dehydrogenative monofluoromethylation of amines ..................................................... 60
Scheme 1.69 Silylation of fluorobis(phenylsulfonyl)methane (FBSM) .................................................. 61
Scheme 2.1 Naturally occurring and FDA-approved isoindolinones ..................................................... 63
Scheme 2.2 Proposed reaction pathway ............................................................................................... 63
Scheme 2.3 Selected N-F reagents for electrophilic fluorination .......................................................... 64
Scheme 2.4 Various fluorinated products observed during optimization ............................................. 64
Scheme 2.5 Substrate scope for the base-mediated synthesis of 2-2 under strictly
anhydrous conditions ........................................................................................................ 67
Scheme 2.6 Proposed reaction pathway for an acid-mediated synthesis of 2-2 .................................. 68
Scheme 2.7 Substrate scope for the acid-mediated synthesis of 2-2 under bench-top conditions ..... 70
Scheme 2.8 C(sp
2
)–H olefinic fluorination of isoindolinones ................................................................ 71
Scheme 2.9 1,2,2-trifluorination of isoindolinones ............................................................................... 71
Scheme 2.10 Asymmetric chemical elaboration of 3-hydroxy-3-difluoroalkylisoindolin-1-ones .......... 72
Scheme 2.S1. Observed CF 2-containing species and their hydrolysis to 2-2n ....................................... 92
xiv
Scheme 6.1 Approaches to access monofluoromethyl compounds via direct fluorination ................ 250
Scheme 6.2 Prior art on the synthesis of monofluoromethylarenes via
monofluoromethylation of functionalized arenes .......................................................... 251
Scheme 6.3 This work: direct nucleophilic monofluoromethylation of aryliodonium salts ................ 252
Scheme 6.4 Proposed diaryliodonium salts to probe counter anion effects ...................................... 257
Scheme 6.5 Alternative monofluoromethylation reagents to contrast with FBSM ............................ 258
xv
Permissions
Chapter 1: Adapted/reprinted with permission from:
- X. Ispizua-Rodriguez, C. Barrett, V. Krishamurti and G. K. Surya Prakash, in The Curious World of Fluorinated
Molecules, ed. K. Seppelt, Elsevier, 2021, vol. 6, pp. 117–218. https://doi.org/10.1016/B978-0-12-819874-
2.00012-6
- V. Krishnamurti, C. Barrett and G. K. S. Prakash, in Emerging Fluorinated Motifs, John Wiley & Sons, Ltd,
2020, pp. 477–549. https://doi.org/10.1002/9783527824342.ch17
- X. Ispizua-Rodriguez, V. Krishnamurti, M. Coe and G. K. Surya Prakash, Org.Synth., 2019, 96, 474–493.
10.1002/0471264229.os096.29
Chapter 2: Adapted/reprinted with permission from: Munoz, S. B.; Krishnamurti, V.; Barrio, P.; Mathew, T.; Prakash,
G. K. S. Org. Lett. 2018, 20, 4, 1042–1045. doi: https://doi.org/10.1021/acs.orglett.7b03994. Copyright (2018)
American Chemical Society
Chapter 3: Reproduced from: Krishnamurti, V.; Munoz, S., B.; Ispizua-Rodriguez, X.; Vickerman, J.; Mathew, T.;
Prakash, G. K. S Chem. Commun., 2018, 54, 10574-10577. doi: https://doi.org/10.1039/C8CC04907F. with permission
from The Royal Society of Chemistry
Chapter 4: Adapted/reprinted with permission from: Krishnamurti, V.; Barrett, C.; Prakash, G. K. S Org. Lett. 2019,
21, 5, 1526–1529. doi: https://doi.org/10.1021/acs.orglett.9b00381. Copyright (2019) American Chemical Society
Chapter 5: Adapted/reprinted with permission from: Krishnamurti, V.; Barrett, C.; Ispizua-Rodriguez, X.; Coe, M.;
Prakash, G. K. S. Org. Lett. 2019, 21(23), 9377–9380. https://doi.org/10.1021/acs.orglett.9b03604. Copyright
(2019) American Chemical Society]
xvi
Abstract
Fluorinated organic matter has become an integral part of our society. It is found in materials,
drugs, and numerous other substances which influence and elevate the human condition. In stark contrast
to its overwhelming utility, organofluorine compounds are almost absent in nature. This makes
organofluorine chemistry a purely synthetic field. As a graduate student in the Prakash Lab at the Loker
Hydrocarbon Research Institute, my research focused on the development of efficient routes to
fluorofunctionalize organic molecules of pharmaceutical and agricultural relevance.
The first two chapters of this work detail new routes to access fluorine-containing N-heterocyclic
molecules. The next three chapters look at novel difluoromethylenation reactions using silane-derived
difluorocarbene. Finally, the thesis winds up with a discussion of preliminary studies into a novel synthesis
of monofluoromethyl arenes.
1
Chapter 1: Introduction
1.1 The Trifluoromethyl, Difluoromethyl and Monofluoromethyl Groups
Fluoroalkyl groups have long piqued the interest of scientists in no small part due to the
interesting properties imparted by them to molecules crucial to the modern era.
1–3
Despite methods
available for the installation of fluorine and fluorine-containing groups, there is a sustained need for new
fluorofunctionalization methodologies primarily because fluorine-containing organic molecules are rare
in nature and are not usually involved in life-sustaining processes. In the context of biology,
(per)fluoromethyl groups have attracted immense attention by virtue of their varied in-vivo physical and
chemical properties.
4–7
Schemes 1.1a (–CF 3), 1.1b (–CF 2–), and 1.1c (–CFH–) showcase select examples of
biologically relevant molecules containing fluorinated methyl groups.
Scheme 1.1a Select examples of pharmaceuticals containing the trifluoromethyl (–CF 3) group
S
O
NH
HN
N N
O
OH
Me
Me
Roniciclib
(antineoplastic)
O
H
N
Cl
O
F
F
F
F F
F
Efavirenz
(antiretroviral)
H
N O
F
F
F
Fluoxetine
(antidepressant)
N
N
S
H
2
N
O
O
F
F
F
Celecoxib
(NSAID)
F
F
F
O
MeO
N
Me
OMe
H
N
NH
2
Me
Tafenoquine
(antimalarial)
2
Scheme 1.1b Examples of active pharmaceutical ingredients containing the CF 2 group
Scheme 1.1c Some monofluoromethyl compounds that are used as therapeutics
Monofluoromethylated drugs are uncommon, probably due to the limited number of
monofluoromethylation methods available,
8
whereas trifluoromethyl and difluoromethyl compounds are
more widely utilized. Trifluoromethyl compounds have received the most attention in regards to their
biological activity, with the earliest reports from the early 1900s.
9
Compounds having difluoromethyl or
F F
N
HN
N
H
O
NHCO
2
Me
i
Pr
N
N
H
N
H
O
i
Pr
MeO
2
CHN
Ledipsvir
(in clinical trials)
O P
F
2
C
O
O
P O
O
O
P O
O
O
O
N
NH
O
O
OH
Metabolically stable
nucleotide analogues
CF
2
O
OH
HO
N
N
NH
2
O
Gemcitabine
(anticancer activity)
O
OH
OH
F
2
C C
4
H
9
(H
2
C)
3
COOH
16,16- Difluoro PGE1
(Antiplatelet drug)
Cl
O
O
Et
Cl F
N
N
N
O
HF
2
C
Carfentrazone-ethyl
(Herbicide)
H
2
N
CF
2
H
H
2
N
O
OH
Eflorithine
(Treats sleeping sickness,
excess facial hair)
CO
2
Me
S
O
O
N
H
O
N
H
N
N
O
O
CF
2
H
CF
2
H
Primisulfuron-methyl
(Herbicide)
H
N
CN
O
O
F
F
Fludioxonil
(Fungicide)
H
2
N
N
N
O
Afloqualone
(clinical sedative)
F
3
C
CF
3
O F
Sevofluran
(anesthetic)
O
F
F
HO
O
O
O
S
F
Fluticasone
(analgesic)
F
3
difluoromethylene groups are currently the most sought after however, owing (in part) to the many
studies on their bioisosteric behavior with thioethers, alcohols, thiols and other biologically active
structures.
10–13
See below some examples of groups which have been subject to bioisosteric replacement
with CF 3,
14,15
CF 2H
11–13
and CFH 2
8
groups.
Scheme 1.2a Reported bioisosteric replacements with different mono-, di- and trifluoromethyl groups
The seemingly subtle structural differences between the different fluoromethyl groups have a
great impact on the properties they impart to bioactive molecules. A molecule’s lipophilicity, metabolic
stability, and binding affinity can be fine-tuned by changing the number of fluorine atoms on the
fluoromethyl group (Scheme 1.2b). By increasing the number of fluorine atoms, the methyl group
becomes increasingly inductively electron withdrawing. Of the fluoromethyl anions, the trifluoromethyl
anion is the most stable.
16
Yet, its persistence is less than that of the methyl anion. This is because
fluoromethyl anions exist in equilibrium with the corresponding carbene and fluoride, and this equilibrium
is not possible in the case of the methyl anion as hydride is a poor leaving group.
H
H
H
OH
H
H
F
H
H
Me
H
H
NO
2
H
H
SH
H
H
NH
2
H
H
aminomethyl hydroxymethyl methyl ethyl nitromethyl methylthiol
N
H
O
Me
F
H
F
S
H
O
H O
H
S
thiomethyl methoxy amine thiol alcohol aldehyde
Me
H
Me Me
F
F
F
NO
2
Cl
tert-butyl iso-propyl nitro chloride
Me Me
Me
4
Scheme 1.2b Comparisons of methyl, monofluoromethyl, difluoromethyl, and trifluoromethyl moieties
The use of TMSCF 3 in particular must be highlighted in this context as a potent
difluoromethylenation reagent. Trifluoromethide, which can be generated as discussed earlier, is known
to decompose into difluorocarbene and fluoride as shown in Scheme 1.2b. This type of dissociation leads
to the formation of singlet difluorocarbene. The singlet form is energetically favored over the triplet form;
a trend observed amongst halocarbenes but uncommon among non-halogenated carbenes. The singlet
carbene is reported to be 56.6 kcal/mol lower in energy than the triplet state (Scheme 1.2c). This stability
is attributed to the propensity of the fluorine atoms to donate electron density into the empty orbital of
the singlet carbene. While discussing carbenes, it is important to remember that the conversion of a
singlet to triplet carbene (or vice-versa) constitutes a forbidden transition and is therefore unattainable
in practice.
H H
H
F H
H
F F
H
F F
F
increasing electronegativity
H H
H
F H
H
F F
H
F F
F
increasing steric bulk
~
F F
F
H H
H
F H
H
F F
H
increasing H-bond donor ability
F H
H
F F
H
F F
F
H H
H
anion persistence
H H
H
F H
H
F F
H
F F
F
increasing lipophilicity
F X
X
X X
+ F
—
(per)fluoromethyl anion in equilbrium with
a carbene and fluoride
5
Scheme 1.2c Calculated energy difference between singlet and triplet difluorocarbene
These immense differences between their individual stabilities and properties make a unified
method for their incorporation rather challenging. Furthermore, a common source or mode of production
for all these groups has not been developed. For example, among the corresponding fluoroalkyl silanes,
TMSCF 3 is a good source of trifluoromethide, which affords the CF 3 anion even with mild activators. On
the other hand, TMSCF 2H requires harsher modes of activation, and TMSCFH 2 has not successfully been
used as a reagent for monofluoromethylation. Herein lies the need for specialized methods for the
incorporation of each of these (per)fluoromethyl groups into target substrates. The next two subsections
of this chapter will focus on two of the most widely utilized reagent systems for (per)fluoromethylation:
Silanes and sulfones.
F
F
F
F
triplet state
singlet state
= 56.6 kcal/mol
6
1.2 Silicon-Based Reagents in (Per)fluoromethylation Reactions
17
Scheme 1.3 Mechanism of fluoroalkanide release via nucleophilic addition of an activator to
perfluoroalkylsilanes
The simple activation conditions and ease of handling of tetrahedral silicon-based reagents have
elevated them to the forefront of fluorofunctionalization methodologies. Utilization of
perfluoroalkylsilanes usually involves an activation step wherein a pentacoordinate silicate intermediate
is formed upon nucleophilic addition of an activating species (X
–
) to the silicon atom (Scheme 1.3). This
pentacoordinate complex is in equilibrium with the disproportionation product: the
bis(perfluoroalkyl)silicate. Either one of the perfluoroalkyl silicates can afford the perfluoroalkyl anion
with concomitant collapse into the silane form. This liberated anion has been shown to be the active
perfluoroalkylating species.
16,18,19
R
F
Si
R R
R
Si
X
R
F
R
R
R
+ X
—
— X
—
active fluoroalkylating species
—
R
F
Si
X
X
R
R
R Si
R
F
R
F
R
R
R
1/2
(disproportionation)
+
Si
X
R
F
R
R
R
Si
R
F
R
F
R
R
R
X
Si
R R
R
R
F
Si
R R
R
Perfluoroalkylsilane
7
1.2.1 Trifluoromethyltrimethylsilane in Trifluoromethylation Reactions
Trifluoromethylation using silicon reagents offers one of the mildest routes to access medicinally
and industrially relevant trifluoromethylated compounds. The first examples in this class of molecules
were synthesized in 1984 by Ruppert and coworkers using CF 3Br as the source of the CF 3 unit.
20
Since its
initial use as a reagent by Prakash and coworkers in 1989,
21,22
there has been an explosion in the number
of reactions employing TMSCF 3 (commonly called the Ruppert-Prakash reagent) as a source of
trifluoromethide. Over the last three decades, this popularity has spawned a number of comprehensive
reviews and books focused on the use of TMSCF 3 and other trifluoromethylsilanes in trifluoromethylation
protocols.
23–25
See Scheme 1.4 for some representative examples.
Scheme 1.4 Representative types of trifluoromethylation reactions
TMSCF
3
R
1
R
2
O
R
1
HO
R
2
CF
3
R
Br
R
CF
3
[O]
Nu
—
Nu CF
3
8
1.2.2 Trifluoromethylsilanes in Difluoromethylenation Reactions
The use of [Si]–CF 3 compounds for the single-step installation of a CF 2 group has only recently
been explored experimentally. This section will focus on developments in the use of these [Si]–CF 3
compounds as reagents to install difluoromethylene groups into organic molecules.
Scheme 1.5 [2+1] cycloaddition of TMSCF 3-derived difluorocarbene with alkenes and alkynes
In its singlet electronic configuration, the electrophilicity of silane-derived difluorocarbene has
been harnessed for the difluoromethylenation of a set of compositionally variant molecules. TMSCF 3 was
first used as a difluorocarbene source in 2011 by Prakash, Hu, and coworkers (Scheme 1.5).
26
A
combination of TMSCF 3 and NaI at 65˚C was found highly effective in generating gem-
difluorocyclopropanes and propenes from alkenes, proceeding via a [2+1] cycloaddition reaction between
the alkene and the in situ-generated difluorocarbene. At lower temperatures, catalytic TBAT was also
found to facilitate this chemistry, generating the products in excellent yields. Both internal and terminal
alkynes were demonstrated as being potent substrates under the NaI-initiated conditions. Moderate to
excellent yields of the gem-difluorocyclopropenes were obtained.
R
2
R
1
R
3
R
4
TMSCF
2
F
NaI (cat.)
65˚C R
2
R
1
R
3
R
4
F F
(78% — 85%)
TMSCF
2
F
TBAT (cat.)
0˚C
(22% — 83%)
TMSCF
2
F
NaI (cat.)
65˚C
F F
(68% — 99%)
(R
1
= aryl)
(R
2
= alkyl, aryl)
(R
3
= H, alkyl)
(R
4
= H, aryl)
R
1
R
2
R
1
R
2
(R
1
= aryl, alkyl)
(R
2
= aryl, alkyl, H)
9
Scheme 1.6 (Sila)difluoromethylation of C nucleophiles
A direct a-siladifluoromethylation of a-(di)substituted carbonyl compounds was published by
Mikami and coworkers in 2014 (Scheme 1.6-a).
27
The lithium enolates formed as a consequence of a-
X
O
R
1
R
2
1) LiHMDS (1 equiv)
2) MeLi (1 equiv)
3) TMSCF
3
(5 equiv)
-78˚C
X
O
CF
2
TMS
R
1
R
2
(X = O, N, C)
(R
1
= alkyl, carbonyl)
(R
2
= alkyl)
(35% — 94%)
a.
X
O
R
1
X
O
R
1
CF
2
TMS
O
N
O
R
O Ph
O
N
O
R
O Ph
TMSF
2
C
(R
1
= aryl)
(X = N, C)
(34% — 99%)
(43% — 71%)
Ar
O
Ar
N(alkyl)
2
O
1)
n
BuLi (1 — 2 equiv)
-78˚C
2) TMSCF
3
(1 — 1.2 equiv)
-78˚C
O
CF
2
TMS
N(alkyl)
2
O
Ar
Ar
FG
PG—O
FG
PG—O
CF
2
TMS
(20% — 50%)
(29% — 57%)
Ph
OR
Ph Ph
RO
Ph Ph Ph
+
(R = C(O)N(
i
Pr)
2
)
RO
CF
2
TMS
CF
2
TMS
(50%) (18%)
R H
(R = aryl, silyl)
R CF
2
TMS
(37% — 68%)
b.
c.
Ar
1
Ar
2
OR
Ar
1
Ar
2
Ar
3
1) LDA
HMPA (2.0 equiv)
2) TMSCF
3
Ar
1
Ar
2
OR
Ar
1
Ar
2
Ar
3
CF
2
TMS
CF
2
TMS
(77% — 95%)
(71% — 94%)
10
deprotonation adjacent the carbonyl unit were found to react with TMSCF 3, producing –CF 2TMS-
containing products in moderate to good yields. Interestingly, the authors proposed a reaction route not
involving difluorocarbene, instead invoking a C–F bond activation by lithium as the vector for this reaction.
Two years later, the authors disclosed methods for the siladifluoromethylation of carbon nucleophiles
having various hybridizations (Scheme 1.6-b).
28
(Diarylmethane)carbamates were selected as model
substrates for the C(sp
3
)–H siladifluoromethylation. Deprotonation with
n
BuLi followed by the addition of
TMSCF 3 at -78˚C formed –CF 2TMS products in moderate yields. A variant of the above substrates with a
b-styryl group in place of one of the aryl groups was also found to undergo difluoromethylation at the g-
carbon. A small amount of the a-difluoromethylated product was also observed. A similar strategy with
modified stoichiometry produced ortho-siladifluoromethylarenes from moderate conversions of the
corresponding O-protected phenols. Terminal alkynes afforded the difluoromethyl products in moderate
yields, with either arenes or bulky silane groups on the other terminus of the alkyne moiety. Possibly
inspired by the works of Mikami and coworkers, Ji et al. developed a siladifluoromethylation of di- and
triarylmethanes using TMSCF 3 (Scheme 1.6-c).
29
Even though the same lithium-promoted deprotonation-
siladifluoromethylation strategy was applied in this procedure, this work differentiates itself from its
predecessors in that including HMPA as an additive was found to be crucial to obtain high yields of the
desired compounds. Both cyclic and acyclic di- and triarylmethanes produced the desired products in good
yields, with the conditions tolerating halides, nitriles and other reactive groups. The detection of TMSF
led the authors to propose that a difluorocarbene intermediate is involved in the reaction.
The difluoromethylation of N-centered nucleophiles with trifluoromethylsilanes has been
demonstrated. In 2014, Prakash et al. divulged a difluoromethylation of imidazoles and benzimidazoles
using TMSCF 3 under near-neutral conditions (Scheme 1.7).
30
The N-difluoromethyl products could be
obtained in moderate to excellent yields under both conventional heating and microwave irradiation. A
11
modest library of N-difluoromethyl imidazoles was prepared. The authors also reported the N-
difluoromethylation of theophylline, forming mixtures of N-difluoromethyl caffeine and N-
difluoromethylmethyl isocaffeine. Furthermore, the difluoromethylation of a ligand for an amyloid b-
peptide inhibitor complex was prepared in moderate yield.
Scheme 1.7 N-difluoromethylation using trifluoromethylsilanes
Chalcogens (specifically S and Se), potentially owing to their soft nucleophilic character, have been
demonstrated as potent nucleophiles in reactions with TMSCF 3. In 2015, Prakash and coworkers
delineated a direct difluoromethylation of lithium thiolates (Scheme 1.8-a).
31
The addition of TMSCF 3 to
the thiolates yields a mixture of RSCF 2TMS and RSCF 2H, which is fully converted to the proto-desilylated
product, RSCF 2H, upon addition of aqueous fluoride. Aromatic thiols generally provided higher yields of –
SCF 2H products than aliphatic thiols, with the latter group only providing moderate yields. The authors
also demonstrated a one-pot procedure for the nucleophilic transfer of the (p-tolylsulfonyl)difluoromethyl
group to benzaldehyde to provide the silyl ether product in good yield. Then in 2019, the authors
published a report on the incorporation of the CF 2 unit into disulfide and diselenide bonds (Scheme 1.8-
b). A combination of LiOtBu and LiCl was found to be the optimal system for producing singlet CF 2 carbene
from TMSCF 3 and its subsequent incorporation into Se–Se bonds, transforming diaryl diselenides into
difluoromethylene diselenoacetals in good yields. Under slightly modified silane activation conditions,
N
N
N
N
O
O
N
H
N
R
2
R
1
N
H
N
R
2
TMSCF
3
LiI
Microwave irridiation
OR
conventional heating
N
N
R
2
R
1
N
N
R
2
R
1
R
1
CF
2
H
CF
2
H
CF
2
H
N
N
N
N
O
O
difluorocaffeine difluoroisocaffeine
CF
2
H
12
diaryl disulfides were also found to be viable substrates, affording the corresponding –SCF 2S– products in
moderate to good yields.
Scheme 1.8 Difluoromethylation of chalcogen nucleophiles using TMSCF 3
The success of siladifluoromethyl phosphonates as reagents
32,33
led Prakash and coworkers to
develop a direct P–H siladifluoromethylation of phosphonates and phosphine oxides (Scheme 1.9).
34
First,
the substrates are deprotonated with a lithium base. The lithium-stabilized P-centered anion is then
treated with TMSCF 3, affording siladifluoromethyl- and difluoromethylphosphonates in moderate to
excellent yields. Dialkyl phosphonates worked best under these reaction conditions, with the products
obtained in high yields. Aryl and alkyl phosphine oxides displayed condition-dependent divergent
reactivity with TMSCF 3, predicated by the amount of Li
+
in the solution. While higher loadings result in the
formation of the (sila)difluoromethyl products, lower lithium concentrations resulted in a novel deoxo-
trifluoromethylation protocol. The reaction was shown to proceed via difluorocarbene, and the discussed
divergent reactivity stems from a common reaction intermediate.
a.
1) LiH, LiBF
4
2) TMSCF
3
R—SH [R—SCF
2
TMS] R—SCF
2
H
aqueous F
—
R = aryl, alkyl
R = aryl (53% — 83%)
R = alkyl (51% — 71%)
SH
1) 4 Å molecular sieves, LiH, LiBF
4
2) TMSCF
3
3) PhCHO
S
C
F
2
OTMS
Ph
(68%)
b.
Ar
Se
Se
Ar
LiOtBu (1 equiv)
TMSCF
3
, LiCl
Ar
Se
C
F
2
Se
Ar
Ar
S
S
Ar
LiOtBu (3 equiv)
TMSCF
3
Ar
S
C
F
2
S
Ar
(63% — 94%) (25% — 71%)
13
Scheme 1.9 (Sila)difluoromethylation of P
V
–H nucleophiles promoted by Li
+
Tin hydrides have also been used as nucleophiles to trap difluorocarbene. Prakash and coworkers
showed that TMSCF 3-derived difluorocarbene could insert into a Sn–H bond, yielding
difluoromethylstannanes in moderate to good yields (Scheme 1.10). Using the prepared
tributyl(difluoromethyl)stannane, cross-coupling reaction systems with aryl iodides and b-styryl halides
were established.
Scheme 1.10 CF 2 carbene insertion into Sn–H bonds
The difluoromethylenation of carbon centers has been performed using TMSCF 3. Hu and
coworkers showcased a sequential trifluoromethylation-fluoride elimination on diazo compounds, from
which gem-difluoromethyl alkenes were obtained in moderate to good yields (Scheme 1.11-a).
35,36
CuCF 3
is presumed to be the active trifluoromethylating species. An elimination of CuF then results in the
formation of the desired compounds. Prakash and coworkers then developed a Wittig-type reaction to
transform aldehydes and ketones into 1,1-dilfuoroalkenes (Scheme 1.11-b).
37
TMSCF 3-derived
difluorocarbene was proposed to react with triphenylphosphine to form the corresponding
difluoromethyl ylide in situ, which then performs a deoxygenation-difluoromethylenation on the carbonyl
group with the production of triphenylphosphine oxide as a byproduct. The aldehyde-derived products
P
H
O
R
R
1) LiH, LiCl
2) TMSCF
3
P
CF
2
TMS
O
R
R
P
CF
2
H
O
R
R
(48% — 99%) (40% — 83%)
1) LiH, no additional Li
+
2) TMSCF
3
P
CF
3
R
R
(55% — 62%)
(R)
3
Sn—H
TMSCF
3
CaI
2
(R)
3
Sn—CF
2
H
(R = alkyl, aryl) (54% — 86%)
14
were obtained in moderate to excellent conversions. Ketones were found to be less compatible
substrates, providing low conversions to the desired alkenes.
Scheme 1.11 Difluoromethylenation reactions using TMSCF 3
Scheme 1.12 Pentafluoroethylation and tetrafluoroethylation using TMSCF 3-derived tetrafluoroethene
Hu and coworkers found a two-pot solution for the production and utilization of hazardous
tetrafluoroethene by the dimerization reaction of singlet CF 2 carbene generated from TMSCF 3 (Scheme
1.12).
38
The tetrafluoroethene gas was bubbled into a solution of phenanthroline, copper(I) chloride, and
CsF, which results in the formation of a [(phen)Cu–C 2F 5] species (path A). The reaction of this copper
species with aryl iodides produced pentafluoroethylarenes in excellent yields. Replacing CsF with sodium
phenoxide resulted in the formation of the oxycupration product [PhOCF 2CF 2Cu(phen)] (path B), which
was then reacted with 4-nitro-1-iodobenzene to yield the cross-coupling product. Alternatively, the in situ
generated tetrafluoroethene was reacted with phenols, thiols and imidazoles under basic conditions to
R
1
R
2
N
2
a.
CuI (5 mol %), CsF (5 mol %)
TMSCF
3
, rt
R
1
R
2
CF
2
(R
1
= aryl)
(R
2
= aryl, alkyl)
(31% — 82%)
R
1
R
2
O
b.
TMSCF
3
PPh
3
, LiI
R
1
R
2
CF
2
(R
1
= aryl, vinyl)
(R
2
= H, aryl, alkyl)
(22% — 90%)
F F
F
TMSCF
3
F
NaI (5 mol %)
sealed tube, 70 ˚C
1) CuCl, phen
rt, 10 min
2) 30˚C, 3h
[(phen)CuCF
2
CF
2
F]
KOH
Nu—H
Nu—CF
2
CF
2
H
(64% — 92%)
(Nu—H = imidazoles, thiols, phenols)
PhONa
[PhOCF
2
CF
2
Cu(phen)]
CsF
path A
path B
path C
15
produce O-, S-, and N-(1,1,2,2-tetrafluoroethyl) compounds (path C). The authors later developed a one-
pot procedure for the in situ generation of [CuCF 2CF 3] from TMSCF 3, which was also reacted with aryl
iodides.
39
Boutureira and coworkers developed an extension of this work using [CuCF 2CF 3] for the
pentafluoroethylation of (hetero)aryl and vinyl halides, without the addition of phenanthroline.
40
1.2.3 Halodifluoromethylsilanes in Difluoromethylenation Reactions
Halodifluoromethylsilanes have been mostly used as sources of difluorocarbene, though their
reactions also include radical and nucleophilic siladifluoromethylation. TMSCF 2Br is the most widely
utilized silane of this type and has received much attention in the past decade. The first report on a
bromodifluoromethylsilane dates back to 1981. Fuchikami and Ojima synthesized
(bromodifluoromethyl)phenyldimethylsilane (PhMe 2SiCF 2Br) in 74% yield by performing a radical
bromination of PhMe 2SiCF 2H with NBS (Scheme 1.13).
41
Prakash and coworkers developed the first
synthesis of TMSCF 2Br via an aluminum-mediated silylation reaction of CF2BrCl with TMSBr in N-
methylpyroldinone.
42
An alternative synthesis by Broicher and Geffken utilized CF 2Br 2 in combination with
tris(diethylamino)phosphine. Subsequent treatment of the thus formed difluoromethylphosphonium
species with a halosilane produces TMSCF 2Br in low yields (Scheme 1.14).
43
A similar approach substituting
the phosphine for magnesium metal as the reducing agent provided very low yields of TMSCF 2Br.
44
Furthermore, a Cl/Br exchange was demonstrated between TMSCl and TMSCF 2Br to give TMSCF 2Cl
quantitatively.
42
Alternative syntheses which bypass the need for handling dibromodifluoromethane have
also been developed, driven by the ever-decreasing availability of CF 2Br 2.
43
Scheme 1.13 C—H bromination of difluoromethylphenyldimethylsilane
Si
CF
2
H
Me
Me
NBS
Si
CF
2
Br
Me
Me
16
Scheme 1.14 Reduction-silylation of dibromodifluoromethane
Scheme 1.15 TMSCF 3 as a feedstock of TMSCF 2Br
TMSCF 3, which can be prepared from fluoroform, is currently the most facile starting material for
the preparation of TMSCF 2Br (Scheme 1.15). TMSCF 2H can be conveniently prepared by a NaBH 4-mediated
reduction of TMSCF 3.
45
TMSCF 2H can in turn be converted to TMSCF 2Br using either NBS
46
or aqueous
HBr/H 2O 2 in the presence of light.
47
Hu and coworkers showed that TMSCF 2Br is quickly accessed by the
reaction between TMSCF 2H and BBr 3 in two minutes.
46,47
R 3SiCF 2X compounds are most commonly
exploited as difluorocarbene reagents, and are often preferred over other classes of reagents due to their
ease of activation and compatibility with water.
48
Surprisingly, the oldest examples of their utilization only
date back about a decade or so. Hu and coworkers reported the first difluorocyclopropanation of alkenes
with TMSCF 2Br-derived difluorocarbene in a patent from 2009 (Scheme 1.16).
49
Further work by the same
group improved the yields of the transformation.
50,46
Br BrF
2
C
i) P(NEt
2
)
3
ii) TMSBr
10% yield
TMS CF
2
Br
i) Al
0
ii) TMSBr
55% yield
CF
3
TMS
i) NaBH
4
ii) NaBr, H
2
O
2
H
2
SO
4
, hv
56% yield
TMS CF
2
Br
i) NaBH
4
ii) NBS
53% yield
BBr
3
, 2 minutes
52% yield
17
Scheme 1.16 Difluorocyclopropanation using TMSCF 2Br
Scheme 1.17 Difluoromethylene insertion into ketones
Scheme 1.18 CF 2 carbene triggered ring expansion
Later work built upon these reactions by applying them to enol ethers. Dilman and coworkers
used TMSCF 2Br for a difluoromethylene insertion reaction between the α and β-carbons of O-silyl enol
ethers (Scheme 1.17).
51
It is postulated that the first step of this reaction is a difluorocyclopropanation
reaction at the enol ether. Subsequently, treatment with an acid cleaves the bond between the α and β-
carbons. This system generates gem-difluoro ketones in moderate to excellent yields. Further work
expanded the scope of this reaction to include enolizable esters.
51,52
Chang and Song et al. further
explored this reaction paradigm in indanones (Scheme 1.18) and 2-cyclopentenones
53
, and then in acyclic
enolizable vinyl ketones.
54
Difluorocarbene has also been used to install the difluoromethyl group into
molecules. Being electrophilic in nature, nucleophilic substrates are the most compatible reactive
partners. An appropriate Lewis base facilitator can install the –CF 2– unit nucleophilically into electrophiles
as well. An example of the latter strategy was developed by Dilman and coworkers, wherein
R
1
R
2
R
3
R
4
R
1
R
2
R
3
R
4
F
2
C
TMSCF
2
Br
43% to 89% yields
R
1/2/3/4
= H, Aryl, Alkyl, vinyl
R
1
O
R
2
R
3
i) TMSOTf, NEt
3
ii) TMSCF
2
Br
iii) HBr/AcOH
R
1
C
F
2
O
R
2
H
R
3
O
R
2
R
1
TMSCF
2
Br, TBAB, TBAF (cat)
70% to 90% yield
OH
F
R
1
R
2
18
triphenylphosphine was used as a Lewis base to form an ylide intermediate with CF 2 carbene (Scheme
1.19). The authors added in situ-generated Ph 3P=CF 2 to ketones,
55
nitro alkenes,
55
and carboxylic acid-
derived acyl chlorides
56
. The phosphonium intermediates were subsequently dephosphorylated under
appropriate conditions to provide the desired products.
Scheme 1.19 Nucleophilic C-difluoromethylation with Ph 3P=CF 2
The addition of difluorocarbene to nucleophiles is the most common approach for electrophilic
difluoromethylation. This approach has been applied to C,
57,58
N,
46,59
O,
60,61
P and S nucleophiles
46
(Scheme
1.20). This strategy has also been used in multi component reactions, where an electrophilic and
nucleophilic coupling partner are “stitched together” using CF 2 carbene, facilitating the rapid synthesis of
complex scaffolds containing an internal –CF 2– moiety.
62
Alternatively, the CF 2 carbene can be added on
on the end of the coupling reaction between the coupling partners, forming a terminal difluoromethyl
unit (Scheme 1.21).
63
TMS CF
2
Br
PPh
3
Ph
3
P CF
2
R
1
O
R
2
R
1
O
Cl
R
1
R
2
NO
2
R
1
R
2
TMSO CF
2
—PPh
3
R
1
CF
2
—PPh
3
TMSO CF
2
—PPh
3
R
1
R
2
N
Ph
3
P—F
2
C
O
OTMS
aq. KOH
Pyridine, H
2
O
i) TMSCl, MeOH
ii) Pyridine, H
2
O
R
1
R
2
HO CF
2
H
R
1
CF
2
H
HO CF
2
H
R
1
R
2
HF
2
C
NO
2
19
Scheme 1.20 Difluoromethylation of diverse nucleophiles using TMSCF 2Br
TMSCF 2Br has seen use in a multitude of other reactions, including deoxo-difluoroolefination of
carbonyl compounds,
64
difluoromethylenation of diazo compounds,
65,66
and zinc-mediated nucleophilic
siladifluoromethylation of electrophiles.
67–76
EWG X
R
2
O
R
3
H
TMSCF
2
Br
Ar
OR’
O
R
3
CF
2
H
(66% — 99%)
Ar
NRR’
O
R
3
CF
2
H
(43% — 86%)
OR’
O
R
3
CF
2
H
(64% — 94%)
’’R
O
S
Ar
R
3
CF
2
H
(77% — 98%)
EtO
O
O
O
carbon nucleophiles
R OH
oxygen nucleophiles
R
O
CF
2
H
(42% — 95%)
R OCF
2
H
O
(38% — 90%)
R SH
sulfur nucleophiles
R
S
CF
2
H
(61% — 99%)
Ph
S
CF
2
H
(61%)
O O
N
N
CF
2
H
R
1
R
2
R
3
(31% – 49%)
N
N
N
CF
2
H
(81%)
N
N
N
N
CF
2
H
Ph
(70%)
N
N
R
1
R
2
CF
2
H
R
3
(14% — 93%)
nitrogen nucleophiles
N
H
R
2
R
1
P
O
R R
H
phosphorous nucleophiles
P
O
R CF
2
H
R
(50% — 82%)
20
Scheme 1.21 TMSCF 2Br in multi-component reactions
1.2.4 (Arylsulfanyl)difluoromethylsilanes in Difluoromethylenation Reactions
The distinct and characteristic biological properties of sulfides and fluorinated compounds led to
their inevitable coalescence.
77
Perhaps motivated by initial discoveries of their potential for treating HIV
78
and the ability of the sulfide unit to serve as a handle for further structural elaboration, numerous
methods have been developed for the direct installation of the alkyl- and arylthiodifluoromethyl unit R–
SCF 2. Thiodifluoromethylsilanes have been used for over a decade as stable pronucleophiles for the
generation of (thio)difluoromethide ions under mild activation conditions (alkoxide or fluoride). The first
reported synthesis of a member of this class of molecules was developed by Prakash and coworkers in
2003 (Scheme 1.22-a). Phenyl bromodifluoromethyl thioether afforded (trimethylsilyl)difluoromethyl
phenyl thioether in 86% yield upon treatment with Mg
0
and TMSCl at room temperature.
79
Recently,
Prakash and coworkers delineated a method for the direct siladifluoromethylation of lithium thiolates
using TMSCF 3, thereby adding the CF 2TMS unit in one reaction step (Scheme 1.22-b).
31
R
1
N
R
2
H
CS
2
K
2
CO
3
R
1
N
R
2
S
S
TMSCF
2
Br
R
1
N
R
2
S
SCF
2
H
(35% — 89%)
Ph
S
O
ONa
Ar
SH
LiI
LiI, NaH
TMSCF
2
Br
R
O
H
TBAF
TBAF
Ph
S
C
F
2
O O
OH
R
Ar
S
C
F
2
OH
R
(59% — 93%)
(71% — 99%)
21
Scheme 1.22 Access to phenyl (trimethylsilyl)difluoromethyl thioether
In 2003, Prakash and coworkers disclosed the first use of this silane for the nucleophilic
difluoromethylation of aldehydes and ketones (Scheme 1.23-a). Using a catalytic amount (10 mol %) of
TBAT, O-silyl-a-difluoromethyl carbinols were obtained, which were then desilylated to produce the
desired products in good yields. The reactive intermediate was proposed to be
(phenylthio)difluoromethide. Substituting diphenyl disulfide in place of the ketone/aldehyde resulted in
the formation of bis(phenylthio)difluoromethane in 85% yield. Alternatively, using methyl benzoate as the
substrate yields the corresponding a,a-difluoro ketone in low yield. Pohmakotr et al. used these
difluoromethyl alcohols, as prepared by Prakash’s method, as substrates for the synthesis of gem-
difluoroalkenes.
80
Flash vacuum pyrolysis of the carbinols yielded the corresponding gem-difluoroalkenes
in moderate to good yields (70% – 79%).
A complementary method to the fluoride-induced (phenylthio)difluoromethylation protocol of
Prakash and coworkers is the Lewis acid-catalyzed procedure developed by the groups of Toru and Shibata
(Scheme 1.23-b).
81
Using Cu(OAc) 2 as the activator of the carbonyl compound, 4-nitrobenzaldehyde
underwent facile difluoromethylation, affording the b-(phenylthio)-b,b-difluoro alcohol in 60% yield. In
2007, Hu and coworkers published a report on the stereoselective difluoromethylation and subsequent
radical cyclization of sulfinylimines (Scheme 1.23-c).
82
Initial efforts were focused on the transfer of the
PhSCF 2 unit to chiral sulfinylimines. The use of 0.5 equivalents of TBAT promoted the nucleophilic
a.
SCF
2
Br
Mg
0
TMSCl
SCF
2
TMS
b.
SH
1) LiH, LiBF
4
2) TMSCF
2
F
SCF
2
TMS
(86%)
(83%)
SCF
2
H
aq. fluoride
or TBAF
22
(phenylsulfonyl)difluoromethylation, providing yields between 30% and 89% in excellent diastereomeric
ratios of 99:1. The thus obtained products then underwent a desulfurization-allylation at the N atom using
allyl bromide and potassium carbonate. The newly formed N-allyl (phenylthio)difluoromethyl products,
upon reduction with tributyltin hydride and AIBN, afforded gem-difluorocyclopentanes. This reaction
likely proceeds via a radical desulfurization at the CF 2–S bond, generating a difluorinated carbon radical.
Addition of this radical species to the allyl group results in the formation of 3-methyl-azacyclopentanes in
moderate yields. An extension of the above strategy was developed by Pohmakotr et al. in 2007 (Scheme
1.23-d).
83
When a-keto esters were used as substrates, 2-(phenylsulfanyl)difluoromethyl-2-hydroxy
esters were formed in 74% - 91% upon
n
Bu 3SnH/AIBN-mediated desulfurization. Using g-keto esters as the
starting materials yielded gem-difluoro-g-butyrolactones in good yields upon reductive desulfurization.
Toulgoat et al. developed a multistep procedure to synthesize sulfonyl fluorides and lithium sulfonates
using (trimethylsilyl)difluoromethyl phenyl sulfide (Scheme 1.23-e).
84
First, the silane was reacted with
sulfur dioxide using CsF to activate the Si center. The thus formed Cesium
(phenylsulfonyl)difluoromethylsulfinate is then oxidized to the sulfonyl fluoride by Selectfluor
®
. Finally,
treatment of the sulfonyl fluorides with LiOH yields the desired sulfonates. Further investigations on this
reaction were performed by Sanchez et al. in 2011.
85
The authors expanded the scope of the
aforementioned synthetic pathway. The lithium sulfonates obtained from this procedure were then
evaluated as electrolytes. Dilman and coworkers have also performed a nucleophilic
(phenylsulfanyl)difluoromethylation of bromomethylpinacolborane, wherein the PhSCF 2 anion adds to
the primary C–Br bond in a (presumably) S N2 fashion.
86
23
Scheme 1.23 Siladifluoromethylthioethers as potent pronucleophiles
R
1
R
2
O
a.
1) TMSCF
2
SPh
TBAT (10 mol %)
2) TBAF, H
3
O
+ CF
2
SPh
OH
R
1
R
2
(R
1
= aryl, alkyl)
(R
2
= H, aryl, alkyl)
(77% — 91%)
Ph
S
S
Ph
TMSCF
2
SPh
TBAT (10 mol %)
Ph
S
C
F
2
S
Ph
Ph O
O
1) TMSCF
2
SPh
TBAT (10 mol %)
2) TBAF, H
3
O
+
(85%)
Ph CF
2
SPh
O
(28% — 41%)
(Depending on the solvent used)
H
O
b.
1) TMSCF
2
SPh
Cu(OAc)
2
/dppe
2) H
3
O
+
(60%)
O
2
N
c.
TMSCF
2
SPh
TBAT (50 mol %)
(30% — 89%)
(d.r. ≥ 99:1)
t
Bu
S
N
O
R
t
Bu
S
N
H
O
R
CF
2
SPh
1) HCl, MeOH
2) Allyl bromide
K
2
CO
3
(61% — 78%)
N
H
R
CF
2
SPh
(R = alkyl, aryl)
Bu
3
Sn—H
AIBN
N
H
F
F
R
N
H
F
F
R
(major) (minor)
(43% — 75% combined)
R
O
d.
TMSCF
2
SPh
TBAF (10 mol %)
OEt
O
R
OEt
O
HO CF
2
SPh Bu
3
Sn—H
AIBN
R
OEt
O
HO CF
2
H
(77% — 98%) (74% — 91%)
R
O
OEt
O
TMSCF
2
SPh
TBAF (10 mol %)
R
OEt
O
HO CF
2
SPh
p-TsOH
O
O
R
CF
2
SPh
Bu
3
Sn—H
AIBN
O
O
R
CF
2
H
(72% — 93%)
(74% — 85%)
e.
RSCF
2
TMS
CsF, SO
2
-40˚C to rt
RSCF
2
SO
2
—
Cs
+
RSCF
2
SO
2
F
N
N
F
Cl
[BF
4
]
—
[BF
4
]
—
LiOH
RSCF
2
SO
3
—
Li
+
(51% — 98%)
(32% — 79%)
CF
2
SPh
OH
O
2
N
24
Scheme 1.24 More nucleophilic reactions of TMSCF 2SPh
The first S N2 reaction between silane-derived (phenylthio)difluoromethide and primary alkyl
bromides was demonstrated in 2008 (Scheme 1.24-a).
87
Hu and coworkers found that a combination of
CsF and 15-crown-5 was required to obtain excellent yields of the difluoromethyl thioethers. Interestingly,
alkyl iodides were found to be less effective substrates, affording low conversions to the desired
difluoromethylated product. Cyclic imides have also been established as potent electrophiles in coupling
with the (phenylthio)difluoromethyl anion (Scheme 1.24-b).
88
Bootwicha et al. synthesized cyclic a-
hydroxy-a-(phenylsulfanyl)difluoromethyl amides in good to excellent yields, which were then reduced
a.
RCH
2
—Br
TMSCF
2
SPh
CsF, 15-crown-5
RCH
2
—CF
2
SPh
(84% — 94%)
b.
TMSCF
2
SPh
TBAF
(50% — 95%)
N
O
O
R N
O
R
HO
CF
2
SPh
n
Bu
3
SnH
AIBN
(R = —Me,
—Bn, —CO
2
Et)
(R = )
N
O
R
HO
CF
2
H
N
O
HO
F
F
alkyl
(66% — 86%)
(45% — 87%)
c.
1) TMSCF
2
SPh
TBAF
2) HCl, H
2
O
(60% — 93%)
R
1
O
R
2
R
1
R
2
HO CF
2
SPh
n
Bu
3
SnH
AIBN
F
F
HO
R
1
R
2
(56% — 87%)
d.
TMSCF
2
SPh
TBAF
O
CO
2
Et
R
n
m CO
2
Et
R
n
m
CF
2
SPh
HO
n
Bu
3
Sn—H
AIBN
m
HO
CO
2
Et
n
F
F
R
Pb(OAc)
4
I
2
, hv
O
O
m
I CO
2
Et
n
F
F
R
(50% — 78%)
(+/-)
cis + trans: (78% — 98%)
alkyl
25
with
n
Bu 3SnH and AIBN.
88
When the exocyclic N-substituent was a methyl, benzyl, or ester group, the
products underwent desulfurization followed by intermolecular H atom transfer yielding difluoromethyl
compounds. The adduct of (phenylsulfanyl)difluoromethyl anion with N-allyl imides underwent radical
cyclization upon desulfurization, leading to the formation of 3,3-difluoro-1-azacyclopentanes in moderate
to good yields (Scheme 1.24-b). An analogous approach was applied to g-ene-ketones, affording gem-
difluorocyclopentanes in moderate yields (Scheme 1.24-c).
89
The same group then used a similar approach
for the synthesis of gem-difluorinated macrocyclic lactones.
90
First, the
(phenylsulfanyl)difluoromethylsilane is activated by TBAF or TBAT, with concomitant addition of the anion
to the ketone group of the substrate. Subsequent treatment with AIBN and tributyltin hydride causes a
desulfurization-cyclization sequence, leading to the formation of a bicycloalkanol. A combination of
Pb(OAc) 4 and I 2 under light irradiation caused the cleavage of the bridging bond, forming macrocycles in
good yields (Scheme 1.24-d).
Scheme 1.25 Scaffolds accessed via the nucleophilic addition-radical desulfurization strategy
N
O
PO
PO
OH
F
F
Me
n = 1,2
+
N
O
PO
PO
OH
F
F
n = 1,2
Me
dihydroxypyrrolizidines and indolizidines
CF
2
H
H
H O
R
3,3‐difluoro‐2‐propanoylbicyclo[3.3.0]octanes
O
O
R
HF
2
C
α,β‐unsaturated-γ‐butyrolactones
N
F
F
R
n = 1,2
n
(HO)
polyhydroxypyrrolizidines and ‐indolizidines
H H
R
OH
F F
H H
linear triquinanes Z
O
R
2
OH
F
F
polycyclic cage compound
R CF
2
H
O
ketones
O
N
OMe
CF
2
SPh
R
isobenzofurans
R
1
R
2
N
R
2
HO
F F
R
3
hydroxyindolones
26
Scheme 1.26 PhSeCF 2TMS as a reagent
The same group then extended this nucleophilic addition-radical cyclization methodology to a
host of similar substrates, forming gem-difluorinated asymmetric dihydropyrrolizidines and
indolizidines,
91
spiro-g-butyrolactones,
92
g-difluoromethylated-g-lactams,
93
3,3-difluoro-2-
propanylbicyclo[3.3.0]octanes,
94
g-difluoromethyl-a,b-unsaturated-g-butyrolactones,
95
and a host of
other relevant macrocycles and pharmaceutically relevant molecular cores (Scheme 1.25).
96–103
Similar to
its sulfur analogue, ((phenylselanyl)difluoromethyl)trimethylsilane has been prepared from the reaction
of CF 2Br 2 with sodium phenylselenolate, followed by silylation with TMSCl. It has been demonstrated as a
pronucleophile for the difluoromethylation of aldehydes and non-enolyzable ketones (Scheme 1.26).
104
The products were obtained in moderate to excellent yields.
1.2.5 (Arylsulfonyl)difluoromethylsilanes in Difluoromethylenation Reactions
Sulfones, by virtue of their electrophilicity and oxidation state, are very capable stabilizers of a-
carbanions via resonance. Silyldifluoromethylsulfones serve as powerful reagents for the transfer of a
‘masked’ difluoromethyl group. The sulfonyl group has been shown to be cleavable by a radical
desulfurization process, forming internal and terminal difluoromethyl compounds. Access to these silanes
is currently limited to very few methods. The first method involves reduction of bromodifluoromethyl
phenyl sulfide with Mg
0
, with concomitant silylation using TMSCl. Subsequent oxidation yields the desired
silane in good yield (Scheme 1.27-a).
105
An alternative synthesis can be performed using
R
1
R
2
O
(R
1
= H, alkyl)
(R
2
= Aryl, alkyl)
PhSeCF
2
TMS, TBAF
4 Å molecular sieves
R
1
R
2
HO CF
2
SePh
(37% — 91%)
27
(phenylsulfonyl)difluoromethane via
n
BuLi-mediated deprotonation and subsequent silylation by TMSCl
(Scheme 1.27-b).
106
Scheme 1.27 Access to sulfonylfluoroalkylsilanes
Fluorobis(phenylsulfonyl)methyltrimethylsilane was prepared in large scale by Prakash and
coworkers. First, fluorobis(phenylsulfonyl)methane (FBSM) was prepared via a multiscale procedure
starting from phenyl chloromethyl sulfide. After a Cl-F exchange reaction using KF and 18-crown-6, Oxone
®
was added which resulted in the formation of phenyl fluoromethyl sulfone. Deprotonation with KHMDS
followed by an addition elimination reaction of phenylsulfonyl fluoride yielded FBSM in high conversions.
Next, a deprotonation-silylation sequence using NaH and TMSCl was employed, yielding the target silane
in moderate yields.(Scheme 1.27-c).
107
The first use of a sulfonyldifluoromethylsilane can be traced back to 2003, when Hu and coworkers
published a TBAF-initiated difluoromethylation of aldehydes and ketones.
106
a-
(Phenylsulfonyl)difluoromethyl carbinols were furnished in good yields (Scheme 1.28-a). Desulfurization
SCF
2
Br
a.
1) Mg
0
2) TMSCl
SCF
2
TMS mCPBA SO
2
CF
2
TMS
SO
2
CF
2
H
b.
SO
2
CF
2
Li
TMSCl
SO
2
CF
2
TMS n
BuLi
S
c.
Cl
KF
18-crown-6
CH
3
CN, reflux
S F
Oxone
®
S F
O
O
1) PhSO
2
F
2) KHMDS, -78˚C
3) 4 M HCl
Ph
S
F
S
Ph
O
O O
O
1) NaH
2) TMSCl
TMSCF(SO
2
Ph)
2
28
of these products was performed via a reductive process utilizing Mg
0
in an acetic acid-sodium acetate
mixture.
Scheme 1.28 Nucleophilic difluoromethylation of C(sp
2
) electrophiles
The Hu group later published a similar difluoromethylation of a-amino carbonyl compounds, obtaining a-
difluoromethyl-b-amino alcohols (Scheme 1.28-b).
108
An attempted fluoride-initiated, chiral ammonium
salt-catalyzed, asymmetric, nucleophilic fluoroalkylation of aldehydes produced the desired alcohols in
good yields but with low enantiomeric excesses (Scheme 1.28-c).
109
Despite nucleophilic fluoroalkylation
generally being intolerant to acidic conditions, Kosobokov et al. were able to design a
phenylsulfonyldifluoromethylation of imines using an acidic fluoride (Scheme 1.28-d).
110
The reaction of
R
1
R
2
O
a.
TMSCF
2
SO
2
Ph
[(
n
Bu)
4
)N]
+
F
—
R
1
CF
2
SO
2
Ph
OH
R
2
b.
H
O
R
NBn
2
CF
2
SO
2
Ph
R
NBn
2
OH
(72% — 92%)
Mg
0
R
1
CF
2
H
OH
R
2
AcOH/NaOAc
c.
H Ar
O OH
chiral ammonium salt
N
HO
N
F
—
CF
3
Ar
d.
N
R
2
R
1
HN
R
2
R
1
CF
2
SO
2
Ph
1) CF
3
COOH/KHF
2
2) TMSCF
2
SO
2
Ph
Initiator
e. N
R
1
R
1
R
2
MeOTf
N
R
1
R
1
R
2
TfO
—
N
R
1
R
1
R
2
CF
2
SO
2
Ph
(50% - 92%) (80% — 91%)
(64% — 91%)
(low ee: < 50%)
(70% — 85%)
(64% — 94%)
1) [
n
Bu
4
N]
+
[Me
3
SiF
2
]
—
TMSCF
2
SO
2
Ph
2) [
n
Bu
4
N]
+
F
—
TMSCF
2
SO
2
Ph
chiral ammonium salt
CF
2
SO
2
Ph
TMSCF
2
SO
2
Ph
KF
29
KHF 2 and trifluoroacetic acid formed HF in situ, which then protonated the substrate to generate the
active iminium electrophile. Upon addition of the silane, the desired a-difluoromethyl amines were
obtained in moderate to excellent isolated yields. Upon N-methylation with methyl triflate,
dihydroisoquinolines react with in situ generated PhSO 2CF 2 anion to form a-CF 2-containing N-heterocycles
in good to excellent yields (Scheme 1.28-e).
111
Scheme 1.29 Nucleophilic difluoromethylation of C(sp
3
) electrophiles
Sulfonyldifluoromethyl anions, first demonstrated to be good nucleophiles by Prakash and
coworkers,
112
have been added to C(sp
3
)-centered electrophiles. The first instance of this type of reaction
utilizing a (phenylsulfonyl)difluoromethylsilane was reported by Hu and coworkers in 2010 (Scheme 1.29-
a).
113
An S N2 reaction was performed on primary alkyl iodides, from which difluoromethyl alkanes were
formed in moderate to good yields. These compounds were then transformed into difluoroalkenes, which
could be further fluorinated (electrophilic fluorination) to yield trifluoromethyl compounds. Later on, the
same authors worked on a difluoromethylation of N,N-acetals (Scheme 1.29-b).
114
Moderate to good
yields of products could be obtained from acid treatment of the substrate and subsequent addition of
TMSCF 2SO 2Ph and KF. Dilman and coworkers prepared (phenylsulfonyl)difluoromethyl boronic acid in 55%
I
alkyl
a.
PhO
2
SF
2
C
alkyl
b. N
N
1) CF
3
COOH
2) TMSCF
2
SO
2
Ph
Initiator
N
CF
2
SO
2
Ph
c.
Br B
O
O
PhO
2
SF
2
C B
O
O
(51% — 84%)
(51% — 84%)
TMSCF
2
SO
2
Ph
CsF
15-crown-5
TMSCF
2
SO
2
Ph
KF
(55%)
30
isolated yield from the reaction of TMSCF 2SO 2Ph and KF with bromomethyl pinacolborane (Scheme 1.29-
c).
115
Copper (phenylsulfonyl)difluoromethide is proposed to be a reactive intermediate generated in situ
from the reaction of CuI, (phenylsulfonyl)difluoromethyltrimethylsilane, and CsF.
116
This species reacts
with propargyl chlorides to form allenes, and with alkynyl halides to form internal alkynes (Scheme 1.30).
Scheme 1.30 In situ generated [CuCF 2SO 2Ph] as a reactive intermediate
A more recent application of this fluoroalkylsilane was detailed by Billard and coworkers. The
silane was treated with DAST, and then stirred overnight with aniline to afford
(benzenesulfonyl)difluoromethanesulfenamide in moderate yield (Scheme 1.31a).
117
This compound was
then used to perform electrophilic (benzenesulfonyl)difluoromethylthiolation of C–H nucleophiles. The
only example of a bis(sulfonyl)fluoromethane-derived silane was prepared by Prakash and coworkers via
initial NaH-mediated deprotonation and then silylation by TMSCl (Scheme 1.31b).
107
The reagent thus
prepared was used with sub-stoichiometric CsF to carry out a monofluoromethylation of aldehydes and
ketones. The difluoromethyl carbinols were obtained in excellent yields.
Scheme 1.31a Using PhSO 2CF 2TMS to synthesize an electrophilic PhSO 2CF 2 transfer reagent
R
1
R
2
Cl
CuI
Cu CF
2
SO
2
Ph C
R
1
R
2
CF
2
SO
2
Ph
X R
(X = Cl, Br, I)
PhO
2
SF
2
C R
CsF
TMSCF
2
SO
2
Ph
S
CF
2
TMS
O O
1) DAST
2) PhNH
2
S
C
F
2
O O
S
(60%)
at 10 g scale
N
H
31
Scheme 1.31b Monofluoromethylation using silane reagents
1.2.6 (Phosphonodifluoromethyl)silanes in Difluoromethylenation Reactions
The introduction of phosphorous-containing fluorinated groups has received prolonged interest
owing to the unique properties imparted to molecules possessing them.
118
Among them, as will be evident
from the following discussion, the difluoromethylphosphonate unit is the most explored. The synthesis of
phosphonodifluoromethyltrimethylsilanes has been explored in a cursory manner, with few available
methods to create these versatile synthons. The archetypical synthetic route is comprised of an Arbuzov
reaction between triethyl phosphite and dibromodifluoromethane, resulting in the formation of the
oxidized phosphorous species: diethyl bromodifluoromethylphosphonate (Scheme 1.32-a).
119,120
Reduction/lithiation of the C–Br bond and subsequent silylation of the generated anion produces diethyl
(trimethylsilyl)difluoromethylphosphonate in good yield. The limited availability of Halons (a consequence
of the Montreal Protocol) inspired the development of Halon-free access to these silanes. Diisopropyl
(trimethylsilyl)difluoromethylphosphonate was prepared in moderate yield by Lequeux and coworkers via
a direct fluorination procedure (Scheme 1.32-b).
121
In the first step, diisopropyl
(methylthio)methylphosphonate undergoes oxidative C(sp
3
)–H chlorination with SO 2Cl 2. Chlorine-fluorine
exchange is performed using Et 3N·3HF. Finally, sequential treatment with
n
BuLi and TMSCl produces the
target silane. A more recent approach uses commercially available TMSCF 3 as a source of both the CF 2 and
TMS units. This method involves an initial deprotonation of a disubstituted phosphonate or phosphine
oxide, after which TMSCF 3 is added to perform a formal siladifluoromethylation in one reaction step. The
R
1
R
2
O
TMSCF(SO
2
Ph)
2
CsF
R
1
R
2
HO CF(SO
2
Ph)
2
(R
1
= H, aryl)
(R
2
= aryl)
(64% — 99%)
32
procedure extends the scope of available phosphadifluoromethylsilanes to not only novel dialkyl
phosphonates, but diaryl and dialkyl phosphine oxides as well (Scheme 1.32-c).
Scheme 1.32 Preparations of phosphadifluoromethylsilanes
The first recorded use of a phosphonodifluoromethylsilane can be found in the 1982 report by
Obayashi and Kondo on the synthesis of 1,1-difluoro-2-hydroxyphosphonates (Scheme 1.33-a).
122
Catalytic cesium fluoride initiated the reaction between aromatic aldehydes and the silane reagent,
affording the corresponding phosphonodifluoromethyl O-silyl compounds. The desired alcohols were
generated via acid hydrolysis of the O–TMS bond. In 1994, Burton and coworkers synthesized 1-
14
C
labelled 2,2-difluoroethene, from the thermal decomposition of the product formed as a result of the
reaction between
14
C-formaldehyde and diethyl (trimethylsilyl)difluoromethylphosphonate (Scheme
1.33-b), as a means to enable research on the metabolism of difluoroethene.
123
Silicon-based mono- and
difluoromethyl phosphonate pronucleophiles were used in the synthesis of mono- and difluoromethyl
analogues of phosphate-containing substrates
124
for sn-glycerol-3-phosphate dehydrogenase (Scheme
1.33-c).
125
Interestingly, the monofluoro and methylene analogues displayed similar behaviors under the
biological testing conditions, whereas the difluoromethylene version behaved significantly differently.
These silicon reagents have also been applied to the synthesis of other biologically relevant ligands using
similar processes.
126,127
The groups of Toru and Shibata collaboratively designed a Lewis acid-catalyzed
P EtO
OEt
EtO
(1) CF
2
Br
2
(2) BuLi or M
0
(M
0
= Li, etc)
(3) TMSCl
P EtO
CF
2
TMS
EtO
O
P
i
PrO
CH
2
SCH
3
i
PrO
O
(1) SO
2
Cl
2
(2) Et
3
N—3HF
(3)
n
BuLi
(4) TMSCl
P
i
PrO
CF
2
TMS
i
PrO
O
a.
b.
c. P R
H
R
O
(1) LiH, LiCl
(2) TMSCF
3
P R
CF
2
TMS
R
O
(42%)
(R = alkyl, aryl, alkoxy) (29% — 99%)
(62%)
33
protocol for the direct nucleophilic phosphonodifluoromethylation of aldehydes (Scheme 1.33-d).
128
Cu(OAc) 2 was found to be the most effective catalyst among those screened, affording the desired b-
phosphonodifluoromethyl alcohol in 78% yield. The complementarity of this approach to the
fluoride/base initiated procedure of Obayashi and Kondo
122
is noteworthy.
Scheme 1.33 Nucleophilic phosphono(di)fluoromethylation
In 2009, Beier and coworkers expanded on the work of Obayashi and Kondo, applying the silicon-
based pronucleophile to a host of aldehydes and ketones.
33
Catalytic KF, catalytic or stoichiometric K 2CO 3,
and catalytic TBAT were each shown to be effective activators for the phosphonodifluoromethylation of
benzaldehyde (Scheme 1.34-a). This procedure was then applied to other aldehydes and ketones as well.
The silyl ethers thus derived were further treated with an initiator (either CsF or TBAT) and one equivalent
Ar—CHO
TMSCF
2
P(O)(OEt)
2
CsF (cat.)
Ar
OTMS
CF
2
P(O)(OEt)
2
a.
H
3
O
+
Ar
OH
CF
2
P(O)(OEt)
2
H—
14
CHO
TMSCF
2
P(O)(OEt)
2
CsF (cat.)
H
2
14
C
OTMS
CF
2
P(O)(OEt)
2
b.
Δ
CsF
H
2
14
C
F
F
O
O
OTf
n
BuLi
TMSCl
THF, -78 ˚C
c.
Br
2
FC
P
O
OEt
OEt
P
O
OEt
OEt
F
TMS
Li
(1)
-78 ˚C
(2) LiOEt-EtOH, 0 ˚C
(3) aq. NH
4
Cl
P
O
OEt
OEt
F
O
O
O
P
O
O
O
F
BrF
2
C
P
O
OEt
OEt
n
BuLi
TMSCl
THF, -78 ˚C
TMSF
2
C
P
O
OEt
OEt
O
O
O
(1)
-78 ˚C
(n-Bu)
4
N
+
F
—
(cat.)
3 Å Molecular Sieves
(2) aq. NaHCO
3
C
F
2
P
O
OEt
OEt
O
O
OH
C
F
2
P
O
O
O
O
(38% — 84%)
(63%)
(30%)
(1) TMSCF
2
P(O)(OEt)
2
Cu(OAc)
2
(10 mol %)
(2) H
3
O
+
d.
O
2
N
O
O
2
N
OH
CF
2
P(O)(OEt)
2
(78%)
OH
OH
34
of an aldehyde. A phospha-brooke rearrangement (C to O migration of the phosphonate group) occurs,
and 2,2-difluoro-1-phosphonato-3-ols are obtained in moderate to high yields (Scheme 1.34-b).
Scheme 1.34 Nucleophilic P
V
CF 2-transfer
The paper also showcased a nucleophilic CF 2 homologation of aldehydes by using two equivalents of
aldehyde (Scheme 1.34-c). The in situ generated phosphonodifluoromethyl carbinol reacted with a second
equivalent of aldehyde, forming an O-phosphoranyl-2,2-difluoro-1,3-diol. Dilman and coworkers
delineated an acidic fluoride-mediated phosphonodifluoromethyl transfer to imines (Scheme 1.34-d).
110
The strategy involves the in situ-generation of the active electrophile: the iminium ion. Upon displacement
of the phosphonodifluoromethide moiety from the silane, it adds to the electrophilic iminium carbon to
TMSCF
2
P(O)(OEt)
2
initiator
a)
O OTMS
CF
2
P(O)(OEt)
2
(100%)
initiator = KF (100 mol %)
K
2
CO
3
(100 mol %)
K
2
CO
3
(1 mol %)
TBAT (1 mol %)
1) TMSCF
2
P(O)(OEt)
2
TBAT or CsF initiator
2) H
2
O
R
O
(R = alkyl, aryl)
R
PO
C
F
2
OH
R
H
TMSCF
2
P(O)(OEt)
2
TBAT or CsF initiator
R
O
R
OTMS
CF
2
P(O)(OEt)
2
(R = alkyl, aryl)
(R
2
= H, Me)
R
3
CHO
TBAT or CsF initiator
H
2
O R
(EtO)
2
(O)PO
C
F
2
OH
R
3
R
2 R
2
R
2
b)
Ph
N
TMSCF
2
P(O)(OEt)
2
KHF
2
, CF
3
COOH
Ph
HN
CF
2
P(O)(OEt)
2
N
R
3
TMSCF
2
P(O)(OEt)
2
KHF
2
, CF
3
COOH
R
2
N
R
3
R
3
R
1
R
2
R
3
R
1
CF
2
P(O)(OEt)
2
(30%)
(71% — 84%)
e)
TMSCF
2
P(O)(OEt)
2
KF, rt
B Br
O
O
B (EtO)
2
(O)PF
2
C
O
O
c)
d)
35
produce the desired amine in moderate yield. An S N2 reaction on bromomethyl pinacolborane was
devised by Dilman and coworkers, producing the desired phosphonodifluoromethyl compound in
moderate yield (Scheme 1.34-e).
115
Scheme 1.35 Recent transition metal-free transfers of silane-derived phosphonodifluoromethide to
electrophiles
An example of nucleophilic phosphonodifluoromethylation of an electrophile formed in situ by
oxidation of the substrate can be found in a paper by Xu, Wang, and coworkers (Scheme 1.35-a).
129
DDQ
(EtO)
2
P(O)CF
2
TMS
CsF, DDQ
rt
N
Ph
N
Ph
CF
2
P(O)(OEt)
2
(72%)
a.
(1) (EtO)
2
P(O)CF
2
TMS
TMSOK, Bu
4
NCl
-40 ˚C or -60 ˚C
(2) sat. aq NH
4
Cl
b.
N
S
O
t-Bu
R
1
H
HN
S
O
t-Bu
R
1
CF
2
P(O)(OEt)
2
(81% — 94%)
d.r. 99:1
(EtO)
2
P(O)CF
2
TMS
TMAF
rt, 18h
c.
O
O
2
N
O
NO
2
CF
2
P(O)(OEt)
2
(69% — 82%)
d.
e.
O
P
H
R
R
(1) LiH, LiCl
(2) TMSCF
2
F
TMSCF
2
P(O)(R)
2
O
2
N
O
O
2
N
OTMS
CF
2
P(O)(OR)
2
Cs
2
CO
3
(R = —OEt, —Oi-Pr,
—OCH
2
CH(CH
3
)
2
CH
2
O—
—p-C
6
H
4
NMe
2
)
TMSCF
2
P(O)(OEt)
2
KOAc (10 mol %)
18-crown-6
R
1
R
2
O
R
1
R
2
TMSO
CF
2
P(O)(OEt)
2
(R
1
= alkyl) (33% — 83%), R
2
= aryl
(83% — 98%), R
2
= —C(O)NR’R’’
(50% — 87%), R
2
= H, —C≡C—, —CH=CH—
36
was found to be the optimal reagent for the oxidation of the amine starting material to the corresponding
iminium ion, which then accepts the phosphorous-containing nucleophile. The product was furnished in
72% yield. Das and O’Shea published the first report of an asymmetric phosphonodifluoromethylation of
N-tert-butanesulfinyl imines, wherein the desired products were formed diastereoselectively in excellent
yields (Scheme 1.35-b).
130
The Poisson group disclosed a synthesis of a sugar-derived CF 2-containing
phosphate analog via a Michael addition of silane-derived phosphonodifluoromethide to 2-nitroglycals
(Scheme 1.35-c).
131
In 2016, Zhou and coworkers published an 18-Crown-6/KOAc-mediated
phosphonodifluoromethylation of ketones (Scheme 1.35-d).
132
Both enolizable and non-enolizable
ketones were compatible with the procedure. Aryl alkyl ketones underwent smooth conversion to the
desired alcohols. Vinyl alkyl ketones and alkynyl alkyl ketones also provided a-phosphonodifluoromethyl
alcohols in good yields. In 2019, Prakash and coworkers published an alternative and scalable synthesis of
phosphonodifluoromethylsilanes, using commercially available TMSCF 3 and either secondary
phosphonates or secondary phosphine oxides (Scheme 1.35-e). The thus synthesized reagents were then
nucleophilically transferred to aldehydes in good yields, and the resultant compounds were found to have
varying hydrolytic stabilities depending on the nature of the substituents on the P atom.
34
Phosphonofluoroalkylsilanes have also been extensively exploited in chemistry utilizing transition
metals. In particular, the use of [Cu–CF 2P(O)(OR) 2] as a reactive intermediate has received much attention.
The first such example was presented by Qing et al. in 2012 (Scheme 1.36-a). Using CuI with
phenanthroline as a stabilizing ligand, [Cu–CF 2P(O)(OR) 2] was generated in situ from the silane
pronucleophile, and then used in an oxidative cross-coupling reaction with terminal alkynes, affording
fluoroalkylated internal alkynes in moderate to good yields.
133
The direct ipso-
phosphonodifluoromethylation of aryl boronic acids has been demonstrated, employing a stoichiometric
amount of CuTc/phenanthroline and diethyl trimethylsilyldifluoromethylphosphonate (Scheme 1.36-
37
b).
134
AgCO 3 served as an oxidant for the transformation, while pyridine was the optimal base. The desired
products were furnished in moderate to good yields. Poisson and coworkers delineated a novel coupling
reaction between aryl diazonium salts and silane-derived [CuCF 2P(O)(OEt) 2], yielding
phosphonodifluoromethylarenes in moderate to good yields (Scheme 1.36-c).
135
Scheme 1.36 Transition metal-mediated transfer of –CF 2P(O)(OR) 2
(EtO)
2
P(O)CF
2
TMS
CsF
H
2
O (45 equiv)
0 ˚C to rt
e.
N
2
R
1
OR
2
O
CuCl
CuSCN
R
1
OR
2
O
R
1
OR
2
O
P(O)(OEt)
2
F
SCF
2
P(O)(OEt)
2
R a.
TMSCF
2
P(O)(OR’)
2
CuI/phenanthroline
t-BuOK, DDQ, -15 ˚C
R CF
2
P(O)(OR’)
2
R b.
TMSCF
2
P(O)(OR’)
2
CuTc/phenanthroline
AgCO
3
, pyridine
4 Å molecular sieves
45 ˚C
B(OH)
2
R
CF
2
P(O)(OR’)
2
I
R
X
R
I X R
R
Ar I
Ar
X
(X = OTf, BF
4
)
d.
CuSCN, CsF
TMSCF
2
P(O)(OEt)
2
0 ˚C to rt, 16h
R
CF
2
P(O)(OEt)
2
Ar CF
2
P(O)(OEt)
2
R CF
2
P(O)(OEt)
2
(56% — 99%)
(18% — 72%)
f.
TMSCF
2
P(O)(OEt)
2
AgOTf, KF
80 ˚C, 24h
CF
2
P(O)(OEt)
2
(40%)
R
c.
TMSCF
2
P(O)(OR’)
2
CuSCN, CsF
N
2
+
BF
4
—
R
CF
2
P(O)(OR’)
2
38
The very same authors then published a synthesis of diverse P
V
CF 2–containing alkynes, arenes,
and alkenes (Scheme 1.36-d).
136
Symmetric hypervalent iodine reagents were used as potent oxidative
coupling partners to react with CuSCN-derived [Cu–CF 2P(O)(OR) 2], showing good functional group
tolerance while providing phosphonodifluoromethylarenes, alkynes, and alkenes in moderate yields.
Radical trapping experiments suggest that a radical pathway is not at play; the authors attributed the
reactivity to a Cu(I) - Cu(III) redox cycle. The authors then explored a divergent reactivity of
TMSCF 2P(O)(OEt) 2 with a-diazocarbonyl compounds based on the identity of the copper salt employed
(Scheme 1.36-e).
137
The use of CuCl afforded a-fluorovinylphosphonates in good to excellent yields.
Interestingly, the phosphonate group was always found syn to the ester group of the starting material.
Substituting CuCl for CuSCN led to the formation of phosphonodifluoromethylthio compounds in
moderate yields. A silver-mediated procedure has been developed for the direct C–H
phosphonodifluoromethylation of arenes (Scheme 1.36-f).
138
Besset and coworkers devised a novel electrophilic phosphonodifluromethylthiolation reagent,
synthesized from the CsF mediated reaction of S-cyano-N-mesitylthiohydroxylamine with
TMSCF 2P(O)(OEt) 2 (Scheme 1.37-a).
139
The reagent was then used to functionalize C–H, S–H, and N–H
bonds under mild reaction conditions. Adding to the slew of available copper-mediated
phosphonodifluoromethylthiolations, the Poisson group delineated a method for the addition of the
SCF 2P(O)(OEt) 2 group onto a-bromoketones (Scheme 1.37-b).
140
The products were furnished in good
yields. Notably, heterocycles and aryl halide moieties were tolerated. All the findings by the Poisson group
on the reactions of [CuCF 2P(O)(OEt) 2] with various substrates were also reported cumulatively in a full
paper, with an expanded substrate scope and more elaborate descriptions of reactivity trends.
141
The
reactivity of disulfides and aryl iodides with [CuCF 2P(O)(OEt) 2] is also discussed. Their later work focused
on the transmetalation from the widely utilized, in situ-generated, copper complex to a palladium(II)
39
catalyst (Scheme 1.37-c).
142
This system, employing a catalytic amount of palladium(II), was then used in
a cross-coupling reaction with aryl iodides, generating phosphonodifluoromethyl arenes in moderate
yields. Finally, Trost et al. published an asymmetric difluoromethylation of allyl fluorides, catalyzed by a
Pd(II) species (Scheme 1.37-d).
143
The product was obtained in 77% yield in an enantiomeric ratio of 80:20.
Scheme 1.37 Recent metal-mediated phosphonodifluoromethylations
a.
NH
CuSCN, CsF
TMSCF
2
P(O)(OEt)
2
60%
4.4 mmol scale
NCS
HN
SCF
2
P(O)(OEt)
2
(Het)Ar—H
R
1
O
R
2
R
1
O
R
2
SCF
2
P(O)(OEt)
2
(Het)Ar—SCF
2
P(O)(OEt)
2
HN
SCF
2
P(O)(OEt)
2
NH
2
(56% — 91%)
(44% — 72%)
(56% — 91%)
R SH RS
SCF
2
P(O)(OEt)
2
(55% — 86%)
b.
CuSCN
TMSCF
2
P(O)(OEt)
2
CsF, H
2
O
R
O
Br
R
O
SCF
2
P(O)(OEt)
2
(28% — 73%) R = (het)aryl, alkyl
c. (Het)Ar I
PdCl
2
(PPh
3
)
2
(5 mol %)
CuCF
2
P(O)(OEt)
2
[generated from
TMSCF
2
P(O)(OEt)
2
,
CsF and CuCl]
(Het)Ar CF
2
P(O)(OEt)
2
(38% — 80%)
Ph
F
TMSCF
2
P(O)(OEt)
2
[CpPd(ƞ
3
—C
3
H
5
)] (6 mol %)
Ligand (7 mol %)
Ph
CF
2
P(O)(OEt)
2
(77%)
(e.r. 80:20)
d.
O O
N
N N
N
Ph
Ph
Ph
Ph
ligand
40
1.2.7 (Carbonyldifluoromethyl)silanes in Difluoromethylenation Reactions
The first record of a (carbonyldifluoromethyl)silane can be found in a patent from 1998.
144
A year
later, an electrochemical synthesis of hexyl (trimethylsilyl)difluoroacetate was developed by Uneyama et
al. via a defluorination of trifluoromethyl ketones (Scheme 1.38-a). Using a lead electrode with
n
Bu 4NBr
as the electrolyte, a mixture of the desired O-silyl and C-silyl compounds was obtained. A thermally
induced silyl migration from the O atom to the CF 2 carbon at 50˚C afforded only the C-silyl product. The
product was then used as a reagent for the difluoromethylation of a host of electrophiles in moderate to
excellent yields. In 2000, Clavel et al. reported a molar-scale electrosynthesis of ethyl-2,2,-dilfuoro-2-
trimethylsilylacetate (Scheme 1.38-b).
145
Using HMPA or DMPU as a cosolvent produced the desired
reagent in 85% or 81% isolated yield, respectively. This compound was then transferred to a set of C(sp
2
)
electrophiles with moderate to good conversions.
Scheme 1.38 First preparations and uses of [Si]CF 2C(O)R compounds
Siladifluoroacetate ethyl ester was used to prepare CF 2-containing precursors of 3,3-
difluoroazetidinones.
146
The activation of this silane was later performed with catalytic LiOAc by
Mukaiyama and coworkers for the difluoromethylation of an N-tosyl aldimine, with the CF 2-containing
F
3
C
O
O(
n
hex)
+ 2e
—
TMSCl (excess)
50˚C, 3h
a.
TMSF
2
C
O
O(
n
hex)
(68%)
E—F
2
C
O
O(
n
hex)
(45 % — 92%)
R
1
O
R
2
R
1
= aryl, alkoxy, alkyl
R
2
= aryl, alkyl, H, Cl
= E
ClF
2
C
O
OEt
2.2 F/mol
Al
0
NBu
4
Br
TMSCl (excess)
rt
b.
TMSF
2
C
O
O(Et)
(81% —85%)
molar scale
E—F
2
C
O
O(
n
hex)
(38% — 85%)
R
1
O
R
2
R
1
= aryl, alkyl
R
2
= aryl, alkyl, H, alkoxy, Cl, F
= E
41
amine formed in 85% yield.
147
In 2013, Dilman and coworkers synthesized a CF 2CO 2Et-containing
pinnacolborane derivative through an S N2 reaction at the C–Br bond of bromomethyl pinacolborane
(Scheme 1.39-a).
115
TMSCF 2CO 2NR 2 reagents have been used in an oxidation-difluoromethylation
procedure by Chen et al. where DDQ was the oxidant and CsF was chosen as the silane’s activator (Scheme
1.39-b).
129
Scheme 1.39 Nucleophilic difluoromethylation reactions
a. TMSCF
2
CO
2
Et
KF, rt
(59%)
O
B
O
Br
O
B
O
CF
2
CO
2
Et
b. TMSCF
2
CO
2
R
CsF, DDQ
[R = dialkylamine, alkoxy]
(75% — 90%)
N
Ar
FG
N
Ar
FG
CF
2
CO
2
R
c.
R
2
R
1
O
R
1
= aryl, alkyl, H
R
2
= vinyl, alkyl, aryl
1) TMSCF
2
CONR
2
TBAT (10 mol %)
[R = alkyl]
2) 2M aq. HCl, MeOH/THF
R
2
R
1
HO CF
2
CONR
2
(21% — quantitative)
R
2
R
1
N
S
t
Bu
O
R
1
CF
2
CONR
2
NH R
2
S
t
Bu
O
(52% — 91%)
d.
R Br
OR
Ar
O
Br
TMSCF
2
CO
2
Et
CuSCN, CsF
R = alkyl, aryl
R CF
2
CO
2
Et
OR
Ar
O
CF
2
CO
2
Et
(60% — 90%)
(27% — 66%)
e.
alkyl
O
TIPS
TMSCF
2
CONEt
2
CuCN, KF, -40˚C
alkyl
TIPS
CF
2
CONEt
2
(57% — 70%)
(ee: 92% — 99%)
S
O
O
OMe
42
An S N2-type reaction at a Se–CN bond was used in the preparation of an electrophilic-type
difluoromethylation reagent by Billard and coworkers.
A similar reagent for electrophilic
difluoromethylthiolation was generated from an S N2-type reaction at a S–Cl bond.
150
Silane-generated
amidodifluoromethide has been added to aldehydes, ketones and chiral sulfinylimines (Scheme 1.39-c).
151
Catalytic loadings of TBAF effectively initiated the auto-catalytic reaction, forming aldol-type products and
Mannich-type products in good isolated yields. An NHC has also been used to facilitate a similar addition
to aldehydes, forming difluoromethyl carbinols in good yields.
152
A one-pot difluoromethylthiolation
protocol was devised by Xu et al. in 2017 which employed CuSCN and TMSCF 2CO 2Et for the in situ
generation of EtO 2C–F 2C
–
, which then performed an S N2 reaction on primary alkyl bromides (Scheme 1.39-
d).
153
A copper-mediated S N2-type reaction on secondary propargyl sulfonates was demonstrated to
produce the difluoromethylated products in good ee. with inversion of stereochemistry (Scheme 1.39-e).
Scheme 1.40 Metal-mediated transfers of the CF 2CO 2R anion
a. Ar—I ArCF
2
CO
2
Et
TMSCF
2
CO
2
Et
CuI, KF, 60 ˚C
(41% — 88%)
K
3
CO
3
MeOH/H
2
O
[ArCF
2
CO
2
H]
F
—
DMF OR NMP
> 170˚C
ArCF
2
H
(57% — 84%)
b.
1) MeI, 100˚C
2) TMSCF
2
CO
2
Et
CuI, KF, 60 ˚C
(22%, 32%)
CF
2
CO
2
Et
Y
X
N
Y
X
N
N
i
Pr
i
Pr
X = CN, NO
2
Y = Me, OMe
c.
TMSCF
2
CO
2
Et
AgF
C
6
F
14
, 100˚C
combined yields:
(41% — 68%)
N
FG
N
N
N
i
Pr
i
Pr
FG
N
N
i
Pr
i
Pr
N
FG
N
N
i
Pr
i
Pr
+
R
F
R
F
R
F
R
F
= CF
2
CO
2
Et
d.
R
1
R
2
TMSCF
2
CO
2
Et
AgOTf, PhI(OAc)
2
, NaOAc
Hantzsch ester, rt
R
1
R
2
CF
2
CO
2
Et
R
1
= alkyl
R
2
= alkyl, H
(51% — 82%)
e. Ar—Br
TMSCF
2
CO
2
NR
2
[Pd
0
] (1 mol %)
KF, 100 ˚C
R = Me, Et,—(CH
2
)
2
O(CH
2
)
2
—
Ar
CF
2
CO
2
NR
2
(66% — 93%)
43
TMSCF 2C(O)(OEt) has been used as in a copper-mediated cross-coupling reaction with aryl iodides
(Scheme 1.40-a).
154
In 2011, Amii and coworkers prepared a series of difluoromethyl arenes via a multi-
step process. First, the silane was reacted with KF and CuI to (potentially) form the Cu–R F species, which
then does an oxidative addition at the C Ar–I bond. Reductive elimination results in difluoromethyl arenes
prepared in good to excellent yields. A solvolysis-decarboxylation sequence was employed to remove the
ester functionality and produce a CF 2H unit, thus producing terminal difluoromethyl molecules. An
extension of this work to halopyridines was later published by the same authors in 2012.
155
The
ethoxycarbonyldifluoromethylation of aromatic triazines reported by Hafner and Bräsein took two
functionalized aromatic substrates and transformed them into CF 2-containing arenes, albeit in low yields
(Scheme 1.40-b).
156
The strategy employed the “masked-iodide” behavior of triazo compounds, which
form aryl iodides readily on treatment with methyl iodide. The aryl iodide thus formed is the oxidative
cross-coupling partner. Alternatively, O-difluoromethylated triazines can be prepared from the reaction
of triazines with this silane and silver(I) fluoride (Scheme 1.40-c).
157
Performing the reaction at elevated
temperatures (100˚C) in C 6F 14 produced mixtures of mono- and di-ortho difluoromethylated triazo arenes
in moderate yields. TMSCF 2CO 2Et has also been used to conduct a regioselective
hydrodifluoromethylation of terminal alkenes (Scheme 1.40-d).
158
The procedure utilizes PIDA as the
oxidant and NaOAc as the base. A Hantzsch ester was selected as the hydrogen atom source, furnishing
the products in moderate to good yields. Hao and coworkers were also able to apply the procedure to
quinine and estrone derivatives. The amide analogue of this silane (TMSCF 2CO 2NEt 2) found use as an
optimal difluoromethylation reagent for the palladium-catalyzed formation of aryldifluoromethyl arenes
in good yields from aryl bromides (Scheme 1.40-e).
159
The methodology tolerates a variety of reactive
handles for further functionalization of the derived products. Transformations of the CF 2CONEt 2 moiety
were also showcased. A similar reaction using catalytic Cu(OAc) (20 mol %) was published by the same
group (Hartwig and coworkers) in 2016.
160
44
Scheme 1.41 Difluoromethylations promoted by transition metals
The direct C–H difluoromethylation of arenes can be performed using TMSCF 2COR reagents
utilizing silver salts as oxidants (Scheme 1.41-a). Hao and coworkers used a system of AgOTf, KF, and
a.
R R
CF
2
COOEt
TMSCF
2
CO
2
Et
AgOTf, KF
reflux, 16 h
b. TMSCF
2
CO
2
Et
AgNO
3
, NaOAc
PhI(OAc)
2
(41% — 96%)
N
PG
O
alkyl
FG FG
N
PG
O
alkyl
CF
2
CO
2
Et
(38% — 96%)
c.
TMSCF
2
CONEt
2
CuSO
4
DMSO, 140˚C
FG
(40% — 93%)
COOH
FG
CF
2
CONEt
2
d.
TMSCF
2
CO
2
Et
AgF, O
2
(25% — 85%)
FG FG
O F
CO
2
Et
e.
NC
FG FG
N
FG FG
TMSCF
2
CO
2
Et
Ag
2
CO
3
, PhI(OAc)
2
NaOAc, K
2
CO
3
(21% — 70%)
CF
2
CO
2
Et
f.
R
NHBOC
R
NHBOC
OH
TMSCF
2
CO
2
Et
KF, AgOTf
LiOTf, Selectfluor
2-fluoropyridine
EtOAc/PhCF
3
(40%, 57%) (R = Ph,
i
Pr)
g.
TMSCF
2
CO
2
Et
KF, AgOTf
LiOTf, Selectfluor
2-fluoropyridine
EtOAc/PhCF
3
(40%, 57%) (R = Ph,
i
Pr)
N
S O O
Ar
O
FG
H
N
FG
O
Ar
CF
2
CONR
2
EtO
2
CF
2
CO
45
TMSCF 2C(O)R for the direct difluoromethylation of arenes.
138
The regioselectivity of this transformation is
modest, controlled by the electronics of the aryl ring. An analogous approach was then used to synthesize
CF 2 containing oxindoles (Scheme 1.41-b).
161
Later work by Wang et al. synthesized the amide analogues
of the above compounds using catalytic loadings of a silver(I) salt and PIDA as the oxidant system.
162
The
developed difluoromethylation-cyclization cascade produced difluoromethylene-containing products in
moderate to excellent yields. Control experiments with TEMPO suggest that a difluoromethyl radical
initiates the cascade reaction. A copper sulfate-mediated decarboxylative amidodifluoromethylation of
a,b-unsaturated carboxylic acids, also invoking a difluoromethyl radical, was shown to yield
difluoromethyl alkenes (Scheme 1.41-c).
163
As shown by Cai and coworkers, AgF facilitates the 1-carboxyl-
1-fluoroolefination of non-activated alkenes using TMSCF 2CO 2Et (Scheme 1.41-d).
164
The proposed
reaction mechanism involves an initial radical difluoromethylation step, followed by a 1,2-elimination of
HF to form the alkene unit. Difluoromethyl phenanthridines have been synthesized from the silver(I)
mediated reaction of TMSCF 2COOEt with 2-isocyanatobiaryl systems via a radical difluoromethylation-
cyclization sequence (Scheme 1.41-e).
165
An oxidative synthesis of difluoromethyl ethers has been studied
on two substrates by Qing and coworkers (Scheme 1.41-f).
166
Their method provides the two
difluoromethyl ethers in moderate yields. Liu et al. developed a radical cascade reaction wherein CuBr
facilitated the reaction between TMSCF 2CONR 2 and N-(arylsulfonyl)acrylamides to form difluoromethyl
amides (Scheme 1.41-g).
167
The transformation proceeds via an initial radical difluoromethylation,
followed by an aryl migration from the sulfone to the newly formed C-radical. Recently, an example of a
palladium-catalyzed asymmetric difluoromethylation of allyl fluorides can be found in the work of Trost
and coworkers. An allyl difluoromethylated product was produced in 72% yield with an enantiomeric ratio
of 89:11.
143
46
1.3 FBSM and its Application to Monofluoromethylation Strategies
Monofluoromethylation is an important transformation that has been employed as a strategy to
introduce fluoroalkyl functionalities into molecules.
168,169
Among known strategies for the introduction of
a fluoromethyl group into a target molecule, nucleophilic monofluoromethylation stands out as an
important approach in which a fluoroalkyl anion is generated and reacted with a suitable electrophile.
Fluorobis(phenylsulfonyl)methane (FBSM) has been widely employed as a pronucleophile given that the
electron-withdrawing nature of the phenylsulfonyl groups increases the acidity of the proton on the
adjacent carbon atom, making its deprotonation facile and giving rise to a resonance-stabilized
fluoromethide species
170
that can react with several electrophiles. This compound was first synthesized
by Shibata et al., through the electrophilic fluorination of bis(phenylsulfonyl)methane
171
and was later on
used as a nucleophilic monofluoromethylating reagent. Prakash and coworkers envisioned a large-scale
procedure to synthesize FBSM in reagent quantities.
172
The present addendum discloses the
transformations available employing FBSM as a monofluoromethylation reagent (Scheme 1.42). It is
important to note that Fluoroalkyl sulfones such as FBSM are one of the most diverse and versatile classes
of compounds for the introduction of perfluoroalkyl groups. Their syntheses
173
and utilization
77,174,175
have
therefore received much attention. For a comprehensive review of fluorinated sulfones and sulfoxides
and their applications in synthetic chemistry, see the enclosed reference.
176
This section serves an
introduction to FBSM and the types of reactions performed by it.
47
Scheme 1.42 FBSM as a masked nucleophile
Michael Reactions are one of the most important synthetic avenues to impart structural
complexity to organic molecules. The acidity of FBSM enables its facile deprotonation even when using
mild bases, with the resultant anion being a good nucleophile which has been reacted with a variety of
Michael acceptors, furnishing C-protected monofluoromethyl compounds. One of the earliest of such
transformations was performed by Prakash and coworkers in 2008 (Scheme 1.43).
177
The authors
prepared and screened a variety of fluoro(phenylsulfonyl)methanes, with the third substituent being a
phenylsulfonyl, nitro, cyano, ester or ketone group. In reactions with a,b-unsaturated compounds,
trimethylphosphine was found to be the most efficient catalyst, furnishing the desired products in
F
S S
O
O
O
O
H
R
H
PhO
2
S SO
2
Ph
F
R R
PhO
2
S SO
2
Ph
F
O
O
H
R
SO
2
Ph
PhO
2
S
F
R
OH
PhO
2
S
SO
2
Ph
F
R
2
OH
R
1
F
SO
2
Ph
SO
2
Ph
N
R
1
R
2
SO
2
Ph
SO
2
Ph
F
R
OBz
SO
2
Ph
F
R
Addition to alkenes
R
O
R
O
S
n
2 and S
n
2’
R
BocO
O
O
Enantioselective
substitution
R
O
H
Sp
2
hybridized
electrophiles
O
R
1
R
2
Epoxide ring opening
R
1
NH
R
2
+
H
H
O
Mannich type reaction
R H
O
Monofluoro olefination
Michael reaction
R
R'
O
R
PhO
2
S
SO
2
Ph
F O
R'
48
moderate to excellent yields (Scheme 1.43-a). The reaction is proposed to proceed via initial addition of
the electron-rich phosphine to the electrophilic carbon of the Michael acceptor, producing the active
base: a b-phosphonio enolate. Note that analogous intermediates are well documented in the Morita-
Baylis-Hillman reaction. Deprotonation of FBSM by the formed base, followed by subsequent attack of
the newly-formed nucleophile at the C–P
+
carbon results in the formation of the desired products, along
with the regeneration of the phosphine catalyst (Scheme 1.43-b). Shortly after this seminal work, Hu and
coworkers investigated FBSM-type molecules as pronucleophiles in the fluoromethylation of a,b-
unsaturated ketones, arynes, and alkynes.
178
Each transformation provided a mixture of products, with
the ratio of formed species dependent on the hardness/softness of the nucleophile (Scheme 1.44).
Scheme 1.43 Phosphine-catalyzed FBSM addition to a,b-unsaturated compounds
EWG EWG
R(PhO
2
S)FC
(54% - 91%)
EWG
H—CF(SO
2
Ph)R
EWG
R(PhO
2
S)FC
R
1
O
cat. PMe
3
, rt
R
1
O
F
PhO
2
S
R
2
H—CF(SO
2
Ph)R
2
(64% - 93%)
K
2
CO
3
, rt
PMe
3
Me
3
P
O
R
O
R
Me
3
P
O
R
SO
2
Ph
PhO
2
S
F
H
SO
2
Ph
PhO
2
S
F
Me
3
P
R
O
F
PhO
2
S
SO
2
Ph
O
R
a.
b.
49
Scheme 1.44 Addition of FBSM to arynes, alkynes and a,b-unsaturated ketones
A reaction system for the long-elusive chiral monofluoromethylation came from the 2008 work
by Shibata and coworkers, wherein FBSM was used as a pronucleophile in an asymmetric 1,4-addition to
a,b-unsaturated ketones, with the stereochemistry set by a Cinchona alkaloid-derived ammonium salt.
179
Generally high (ee: 84% – 98%) enantiomeric excesses were observed along with good yields. Further
functionalization at the carbonyl group was demonstrated via a NaBH 4-mediated reduction, keeping the
phenylsulfonyl groups intact. Following this, oxidation to restore the carbonyl group results in
simultaneous desulfurization, forming a monofluoromethyl group. Alternatively, a Mg
0
-mediated
reduction of the alcohol results in desulfurization to yield the monofluoromethyl derivative (Scheme
1.45).
R
1
O
R
2
H—CXY(SO
2
Ph)
base
R
1
R
2
HO
PhO
2
S
X
Y
R
1
R
2
+
O
X SO
2
Ph
Y
TMS
R
OTf
R
SO
2
Ph
F SO
2
Ph
H—CF(SO
2
Ph)
2
CsF
(60% - 90%)
H—CF(SO
2
Ph)(C(O)Ph)
CsF
R
SO
2
Ph
(70% - 95%)
Ph
O
F
R
2
R
1
O R
1
O
R
2
SO
2
Ph PhO
2
S
F
H—CF(SO
2
Ph)
2
CsOH H
2
O
(60% - 90%)
CsOH H
2
O
H—CF(C(O)Ph)(SO
2
Ph)
R
2
PhO
2
S
H
F
R
1
Ph O
O
(45% - 88%)
50
Scheme 1.45: Chiral monofluoromethylation of a,b-unsaturated ketones with FBSM
Scheme 1.46 Asymmetric monofluoromethylation of a,b-unsaturated aldehydes and ketones
Chiral enamine catalysis has been extensively employed in the asymmetric functionalization of
aldehydes and ketones (Scheme 1.46). In 2009, the Wang group documented an asymmetric conjugate
addition of FBSM to enals, catalyzed by a chiral proline derivative.
180
The active electrophile, the in situ-
formed a,b-unsaturated iminium ion; is trapped by FBSM to form a b-substituted enamine. Subsequent
hydrolysis of the enamine (loss of the proline derivative) affords the desired products in moderate to good
yields and in excellent enantiomeric excess. Adding to the slew of enantioselective fluoromethylations of
Michael Acceptors, Córdova and coworkers added FBSM to 1,2-enals using chiral proline-type catalysts,
181
similar to the work of Wang and coworkers.
180
The authors used an –OTMS-containing catalyst in place
of an –OTBS-containing one, generating the desired monofluoromethyl compounds in good yields. At the
Ar
O
R
H—CF(SO
2
Ph)
2
Cs
2
CO
3
, -40
o
C, 1-2 days
Ar
O
R
F
SO
2
Ph
SO
2
Ph
(56% - 90%)
NaBH
4
Ar R
F
SO
2
Ph
SO
2
Ph
(98%)
HO
Mg
0
Ar R
F
H
(50%)
HO
H
PCC
Ar R
F
H
H
(97%)
O
H—CF(SO
2
Ph)
2
R
CHO
N
H
Ph
O[Si]
Ph
R O
SO
2
Ph PhO
2
S
F
NaBH
4
R
SO
2
Ph PhO
2
S
F
OH
cat.
(17% - 83%)
(84% - 95%)
Wang et al., [Si] = TBS
Cordova et al. [Si] = TMS
Rios et al. [Si] = TMS (64% - 96%)
51
same time, Rios and coworkers also published a near-identical synthesis of b-monofluoromethyl
aldehydes.
182
Another method for the enantioselective conjugate addition of FBSM to a,b-unsaturated ketones
comes in the form of the 2009 paper by Kim and coworkers, wherein chiral primary amine catalysts were
used to steer the stereochemical outcome of the reaction towards one enantiomer (Scheme 1.47).
183
The
thus formed products were obtained in moderate stereoselectivity and good to excellent yields.
Noteworthy is the work of Hu and coworkers on the reversibility of 1,2-additions of FBSM across a,b-
unsaturated carbonyl compounds, wherein the formation of 1,4-adducts was observed following the
disappearance of the 1,2-adducts.
184
Despite iminium catalysis being widespread in organic chemistry, the
converse process had not been studied (the conversion of an enamine to an iminium ion). That is, until
the 2011 paper by Zhang et al., wherein in situ-generated enamines were oxidized by a hypervalent iodine
compound (IBX) (Scheme 1.48). The thus formed iminium ions were then reacted with FBSM, generating
b-fluoromethyl compounds, which were then reduced to the corresponding alcohols using NaBH 4.
185
An
in situ-generated iminium ion, stemming from the desulfurization of an indole derivative, has been used
as an electrophile in reactions with FBSM. In this work by Shibata and coworkers, the monofluoromethyl
indole derivatives were prepared in excellent yields and generally displayed high enantiomeric excess
(Scheme 1.49).
186
As in previous work, radical desulfurization proceeds with retention of stereochemistry.
Finally, in a collaborative effort, the labs of Yang and Rios jointly developed a cascade reaction for the
synthesis of fluoroindane and fluorochromanol derivatives.
187
The cascade begins with a conjugate
addition of FBSM to the iminium ion born as a consequence of condensation between the aldehyde and
the chiral amine. Upon the occurrence of a second Michael reaction, the fluoroindane is formed. Using
(2-hydroxy)cinnamic acids results in the formation of fluorochromanols (Scheme 1.50).
52
Scheme 1.47 b-monofluoromethyl ketones via chiral primary amine catalysis
Scheme 1.48 I
V
mediated oxidative monofluoromethylation
Scheme 1.49 Enantioselective monofluoromethylation of indole derivatives
S N2’ chemistry offers a viable route to obtain functionalized allylic compounds. The application of
this concept to FBSM pronucleophile has facilitated the synthesis of various b,g-unsaturated-a-
fluoromethyl compounds. The first transformation of this type was disclosed collaboratively by Shibata
and Toru in 2006 (Scheme 1.51).
171
The authors perform an enantioselective allylic
R
R
PhO
2
S
SO
2
Ph
catalyst
R'
O
N
OMe
NH
2
N
F O
R'
(85% - 93%)
catalyst
H—CF(SO
2
Ph)
2
R
O
H—CF(SO
2
Ph)
2
IBX
cat.
N
H
Ph
OTMS
Ph
IBX
I
O
O
O
HO
R
PhO
2
S
SO
2
Ph
F
O
NaBH
4
R
PhO
2
S
SO
2
Ph
F
OH
(51% - 69%)
N
H
SO
2
Tol
R
Ar
N
OH
N
t-Bu
t-Bu
Br
-
catalyst
N
H
R
Ar
H—CF(SO
2
Ph)
2
Cs
2
CO
3
SO
2
Ph
SO
2
Ph
F
(74% - 98%)
53
monofluoromethylation of allyl acetates using FBSM in combination with a palladium catalyst and chiral
ligand, producing the desired allyl monofluoromethanes in moderate to good yields with high
enantioselectivities.
Scheme 1.50 Preparation of fluoroindanes and fluorochromanols
Scheme 1.51 Enantioselective Pd-catalyzed allylic monofluoromethylation
An analogous reaction catalyzed by iridium in place of palladium was devised by Liu et al., wherein
FBSM-containing terminal alkenes were prepared in excellent yields with good enantioselectivity (Scheme
1.52).
188
The authors then proceeded to apply their methodology to the synthesis of monofluoromethyl
ibuprofen, which was found to have enhanced analgesic properties
189
O
R’
CHO
R R
(57% - 75%)
H—CF(SO
2
Ph)
2
N
H
OTMS
Ph
Ph cat.
SO
2
Ph
PhO
2
S
F
O
O
R’
OH
CHO
R
R
(50% - 75%)
H—CF(SO
2
Ph)
2
N
H
OTMS
Ph
Ph cat.
O OH
SO
2
Ph PhO
2
S
F
R
O
R
O
Cs
2
CO
3
(1.1 equiv)
CH
2
Cl
2
, 0
o
C, 6h
R R
PhO
2
S SO
2
Ph
F
(22% - 92%)
O
N PPh
2
iPr
(S)-PHOX
H—CF(SO
2
Ph)
2
(S)-PHOX (5 mol%)
[{Pd(C
3
H
5
)Cl}
2
] (2.5 mol%)
54
Scheme 1.52: Enantioselective Ir-catalyzed monofluoromethylation of allylic carbonates
As part of an investigation into the potency of phosphine-imidazoline ligands when applied to
allylic substitution reactions, FBSM was reacted with an allylic acetate to generate the allyl-
monofluoromethyl compound in good yield with excellent ee.
190
Mei et al. discovered that the optimal
catalyst for this system was h
3
-allyl palladium(II)chloride dimer, and a series of axially-chiral BINAP-type
ligands were found suitable for the transformation (Scheme 1.53). Finally, Hartwig and coworkers
developed a method for the production of tertiary allylic fluorides from tri-substituted alkene derivatives
(Scheme 1.54).
191
Catalyzed by an iridium species, the reaction system provided the desired products in
moderate to excellent yields.
Scheme 1.53 Chiral ligand-assisted Pd-catalyzed a-fluoromethylation
R O O
O
H—CF(SO
2
Ph)
2
[Ir(COD)Cl]
2
(2 mol%)
(S, S, S
a
)-ligand (4 mol%)
Cs
2
CO
2
(2.5 equiv)
DCM, rt
R
SO
2
Ph
PhO
2
S
F
R
SO
2
Ph
PhO
2
S
F
+
Major
(28% - 96%)
Minor
O
O
P N
(S, S, S
a
)-ligand
O
O
H—CF(SO
2
Ph)
2
[(η
3
-C
3
H
5
PdCl)
2
] (5 mol%)
ligand (10 mol%)
CsCO
3
(1.1 equiv)
MeCN, rt, 12h PhO
2
S SO
2
Ph
F
PPh
2
N
N
S
O
O
O
2
N
ligand
(83%)
55
Scheme 1.54 Ir-catalyzed synthesis of allylic fluorides
In 2009, Prakash and coworkers developed a base mediated monofluoromethylation of primary
alkyl halides using FBSM as the pronucleophile.
192
The results of this chemistry are substrate-dependent.
Where aliphatic alkyl halides produced the expected S N2 product, benzyl halides afforded
monofluoroolefins instead, which facilitates the synthesis of b-fluorostyrenes (Scheme 1.55).
Scheme 1.55 Nucleophilic monofluoromethylation of primary alkyl halides
Mitsunobu chemistry has been used extensively in the deoxygenative functionalization of primary
and secondary alcohols. In 2007, Prakash and coworkers delineated a DIAD/PPh 3-mediated
deoxygenation-monofluoromethylation of secondary alcohols, producing monofluoromethyl compounds
in good to excellent yields (Scheme 1.56).
193
In the case of enantiopure alcohols, the transformation
proceeds with inversion of stereochemistry at the chiral alcohol carbon. Epoxide ring-opening reactions
have seen use primarily in the synthesis of b-substituted alcohols. One approach to b-monofluoromethyl
alcohols was disclosed by Hu and coworkers in 2006.
194
On deprotonation with n-BuLi, FBSM was reacted
with various epoxides, of which the corresponding monofluoromethane derivatives were obtained in
good to excellent yields (Scheme 1.57).
F
O
O
F
F
F
Na—CF(SO
2
Ph)
2
catalyst (8 mol%)
THF, rt, 24h
PhO
2
S
F
SO
2
Ph
F
Ph
(56%)
O
O
P
N
Ir
BF
4
-
catalyst
R—X
H—CF(SO
2
Ph)
2
K
2
CO
3
DMF, rt
PhO
2
S SO
2
Ph
F R
R
H—CF(SO
2
Ph)
2
Cs
2
CO
3
MeCN
R
F
SO
2
Ph
X
56
Scheme 1.56 Stereospecific deoxymonofluoromethylation of secondary alcohols
Scheme 1.57 Epoxide ring-opening with FBSM
The propensity of FBSM to behave as a pronucleophile has encouraged its implementation in
multicomponent reactions. The first such system was developed by Shibata and coworkers in 2007, which
allowed for the synthesis of b-monofluoromethyl amines starting from b-sulfonyl amines and using a
chiral phase transfer catalyst (Scheme 1.58). The products were furnished in good to excellent yields. In
2013, Prakash and coworkers presented a Mannich-type reaction between an aldehyde, a secondary
amine, and FBSM, producing a variety of monofluoromethyl amines in moderate to good yields.
195
The
addition of NaH as a base was required for challenging substrates (Scheme 1.59).
O N
O
N O
O
DIAD
R
1
R
2
OH
H—CF(SO
2
Ph)
2
PPh
3
, DIAD
benzene, rt
R
1
R
2
PhO
2
S SO
2
Ph
F
HO
H
H—CF(SO
2
Ph)
2
PPh
3
, DIAD
benzene, rt
H
PhO
2
S
SO
2
Ph
F
Mg
0
, MeOH
0
o
C
H
F
(60% - 90%)
(58%) (67%)
H—CF(SO
2
Ph)
2
O
R
1
i) n-BuLi Et
2
O, -78ºC
ii) F
3
B OEt
2
iii)
HO
R
2
R
2
CF(SO
2
Ph)
2
R
1
(10% - 78%)
57
Scheme 1.58 Monofluoromethylation of amines by phase-transfer catalysis
Scheme 1.59 Synthesis of b-monofluoromethyl amines through Mannich-type intermediate
Fluoroiodobis(phenylsulfonyl)methane (FBSM-I) has been prepared by a deprotonation-
iodination sequence developed by Prakash and coworkers (Scheme 1.60),
196
and this methodology was
later used by Shibata and coworkers in developing novel halogen-bonding catalysts.
197
In Prakash’s work,
the iodomethane derivative was demonstrated to be a viable radical monofluoromethylation reagent,
affording the desired monofluoromethyl products in good to excellent yields. A palladium-catalyzed
allylation of FBSM was later developed by Hu and coworkers.
198
Mediated by HOAc, this method furnished
the linear products in high yields and excellent regioselectivity (Scheme 1.61). In 2009, Shibata and
coworkers devised a synthesis of monofluoromethyl allenes from 2-halo-1,3-dienes and FBSM, catalyzed
by a palladium species.
199
The desired allenes were synthesized in excellent yields (Scheme 1.62). A
transition metal-free, chiral ammonium salt catalyzed, electrophilic alkynylation method was developed
by Kamlar et al., yielding alkynyl monofluoromethanes in high yields (Scheme 1.63).
200
R SO
2
Ph
NHBoc
H—CF(SO
2
Ph)
2
phase transfer cat. (5 mol%)
CsOH H
2
O (1.2 equiv)
CH
2
Cl
2
, -80
o
C, 24h - 48h
R
NHBoc
SO
2
Ph
PhO
2
S
F
(70% - 98%)
N
H
HO
N
O
Cl
-
phase transfer cat.
R
1
NH
R
2
+
H H
O
CH
2
Cl
2
, 12h
N
R
1
R
2
SO
2
Ph
SO
2
Ph
F
(41% - 97%)
H—CF(SO
2
Ph)
2
NaH (0 - 1 equiv)
58
Scheme 1.60 Radical monofluoromethylation of olefins using FBSM-I
Scheme 1.61 Allylic monofluoromethylation of alkynes
Scheme 1.62 Monofluoromethylation of conjugated dienes
Scheme 1.63 Electrophilic alkynylation of FBSM
Morita-Baylis-Hillman (MBH) products have been extensively used as versatile synthons for the
introduction of molecular complexity in substrates of interest. The first fluoromethylation of an MBH-
carbonate was reported by Shibata and coworkers in 2011, wherein FBSM was used as a nucleophilic
I
2
, Cs
2
CO
3
CH
3
CN, rt
R
I—CF(SO
2
Ph)
2
Et
3
B
Air, CH
2
Cl
2
R
I F
PhO
2
S
PhO
2
S
DBU
Toluene
0
o
C, 3h
H
R
H
PhO
2
S SO
2
Ph
F
(94%)
(15% - 75%) (38% - 68%)
I—CF(SO
2
Ph)
2
H—CF(SO
2
Ph)
2
+
Pd(PPh
3
)
4
(5-10 mol%)
HOAc (50 mol%)
1,4-Dioxane
100
o
C, 12h
R
1
R
2
F
PhO
2
S
SO
2
Ph
(50% - 91%)
H—CF(SO
2
Ph)
2
R
1
R
2
R
2
R
1
R
3
Br H—CF(SO
2
Ph)
2
Pd-cat
base
C R
1
R
2
R
3
Mg
MeOH
C R
1
R
3
F
SO
2
Ph
SO
2
Ph
F
(52% - 70%) (42% - 90%)
+
I
O
O
catalyst (10 mol%)
Toluene
rt, 16h
SO
2
Ph
PhO
2
S
F
TMS
Catalyst
(70%)
N
O OH
N
H—CF(SO
2
Ph)
2
59
monofluoromethyl source (Scheme 1.64).
201
The use of a axially chiral anthraquinone allowed the authors
to obtain allyl-fluoromethyl compounds in moderate to good yields, with high enantioselectivity. Similar
work is reported by Yang et al.
202
Later, Shibata conducted a similar transformation, wherein the base
used to deprotonate FBSM was trifluoromethide generated in situ from (trifluoromethyl)trimethylsilane
(TMSCF 3) (Scheme 1.65).
203
Scheme 1.64 Enantioselective monofluoromethylation of MBH-carbonates
Scheme 1.65 Trifluoromethide-promoted monofluoromethylation
FBSM has been added to C(sp
2
) electrophiles. In 2011, Hu and coworkers disclosed an addition of
FBSM to aldehydes, mediated by Li
+
coordination (Scheme 1.66).
204
The nature of the cation was found
essential in facilitating the addition, as Na
+
and K
+
bases did not produce favorable results. The desired
monofluoromethyl carbinols were obtained in excellent yields. Further elaboration on this type of
chemistry was presented by the same group, two years later. Synthesized by the above method,
204
monofluoromethyl carbinols were transformed into monofluoroolefins through step-wise treatment with
benzyl chloride and then LiHMDS. The olefins were predominantly obtained in the Z configuration, and in
R
BocO
O
O
H—CF(SO
2
Ph)
2
(DHQD)
2
AQN (10 mol%)
toluene, 50
o
C
O
O
H
R
SO
2
Ph
PhO
2
S
F
O O
O O
N N
O O
N N
(DHQD)
2
AQN
(58% - 72)
F
O
O
TMSCF
3
(3.0 equiv)
H—CF(SO
2
Ph)
2
(DHQD)
2
AQN (10 mol%)
CH
2
Cl
2
, 0
o
C, 24h
O
O
PhO
2
S
F
SO
2
Ph
60
good yields (Scheme 1.67).
205
A DIAD-mediated a-fluoromethylation of tertiary amines is reported by Hu
and coworkers, via a dehydrogenative coupling of the amines with FBSM (Scheme 1.68).
206
The reaction
is postulated to involve an iminium ion intermediate, which is the active electrophile for reaction with
FBSM. The monofluoromethyl products were obtained in moderate to excellent yields.
Scheme 1.66 Li
+
-promoted FBSM addition to aldehydes
Scheme 1.67 Monofluoroolefination using FBSM
Scheme 1.68 Dehydrogenative monofluoromethylation of amines
Perfluoroalkylsilanes have been extensively used as sources of nucleophilic fluoroalkyl species.
The deprotonation-silylation of fluorobis(phenylsulfonyl)methane (FBSM), as conducted by Prakash et al.,
provides access to a reagent that requires mild activation for nucleophilic monofluoromethylation of
carbonyl compounds (Scheme 1.69).
107
R
O
H
H—CF(SO
2
Ph)
LiHMDS
CH
2
Cl
2
, -78
o
C
Li
O
R
S
S
F O
O
Ph
O
O
Ph
CF
3
COOH
CH
2
Cl
2
, -94
o
C
R
OH
PhO
2
S
SO
2
Ph
F
(85% - 95%)
R H
O
+
i) LiHMDS, THF, -78
o
C, 30 min
ii) BzCl, THF, -78
o
C, 3h
iii) LiHMDS, THF, 0
o
C, 1h
R
OBz
SO
2
Ph
F
(40% - 86%)
H—CF(SO
2
Ph)
2
R
2
R
1
N
R
3
DIAD
DMF, 50
o
C, 3h
R
2
R
1
N
R
3
SO
2
Ph
SO
2
Ph
F
O N
O
N O
O
DIAD
(39% - 95%)
H—CF(SO
2
Ph)
2
61
Scheme 1.69 Silylation of fluorobis(phenylsulfonyl)methane (FBSM)
i) NaH (1.5 equiv), THF, 0
o
C
ii) TMSCl (2.0 equiv), 0
o
C
(43%)
TMS—CF(SO
2
Ph)
2
H—CF(SO
2
Ph)
2
62
Chapter 2: Direct Difluorination-Hydroxylation, Trifluorination and C(sp
2
)–H
Fluorination of Enamides
2.i Introduction
When I first joined The Prakash Group (then called the Olah-Prakash group) as a graduate student
in 2016, I was quickly drawn into evolving research field of gem-difluorinated organic molecules as
emerging motifs in therapeutics and agrochemicals.
12,13,207
Of Interest to me was the lack of novel,
substrate-specific methods for introducing difluoromethyl groups into organic molecules without using
transition metal-based catalysts. The simplest conceptualization of adding a –CF 2– group to an organic
scaffold would be a direct difluorination of an alkene/alkyne functional group. A seminal example of this
concept is the reaction of Olah’s reagent (pyridine-x.HF complex) with alkynes, delineated by Olah and
coworkers.
208
Our group had recently published a synthesis of isoindolin-1-ones:
209
N-conjugated
heterocycles which are found in many naturally occurring and designed compounds of synthetic and
applicative value (see Scheme 2.1), and while there are many methods for their synthesis,
209–216
their
fluorofunctionalization was much less explored.
91,93
The advent of electrophilic/radical fluorinating reagents (primarily N–F reagents) has given
chemists new tools for direct fluorination.
217,218
Drawing inspiration from this new reaction paradigm, and
further driven by my Research Advisor’s longstanding interest in organofluorine and heterocyclic
chemistry,
209,219
my colleagues and I set out to develop a direct gem-difluorination-hydroxylation protocol
for the construction of b-difluoro-a-functionalized isoindol-1-ones. Inspired by Toste and coworkers’
direct oxyfluorination of enamides,
220
we envisaged the reaction pathway pictured in Scheme 2.2. After
fluorination of the parent compound 2-1, the increased acidity of the a-proton (H α) in the proposed a-
63
fluoroiminium intermediate 2-I1 could undergo facile deprotonation to yield 2-3. Another equivalent of
N–F reagent could then react with the formed alkene unit, generating iminium carbocation 2-I2.
Depending on the choice of nucleophile used, diverse difluorinated products can be obtained.
Scheme 2.1 Naturally occurring and FDA-approved isoindolinones
Scheme 2.2 Proposed reaction pathway
MeO
MeO
N
O
O
O
MeO
OMe
NH
O
O
O
Me
2
N
N
N
N
O
O
O
N
N
N
Cl
N
O
N
N
Cl
R
O
Lennoxamine Fumaridine
Eszopiclone Pagoclone
N
O
Ar
R N
O
Ar
R
N—F reagent
F
H
B
—
N
O
Ar
R
F
N—F reagent
N
O
Ar
R
F
F
Nu
—
N
O
Ar
R
F
F
Nu
2-I1 2-3 2-1
2-I2
2-2
64
2.ii Results and Discussion
To validate this hypothesis, isoindolinone 2-1a was selected as a model substrate and reacted
with several electrophilic fluorine sources (N–F reagents, Scheme 2.3) under varied reaction conditions.
Table 2.1 summarizes pivotal trials in the optimization process. Initial studies using Selectfluor I (2.0 equiv)
as the electrophilic fluorine source and K 2CO 3 (1.2 equiv) as the base in anhydrous MeCN, afforded product
2-2a in 45% yield (Table 2.1, trial 1).
Scheme 2.3 Selected N-F reagents for electrophilic fluorination
Scheme 2.4 Various fluorinated products observed during optimization
The selectivity toward 2-2a was rather poor, with varying quantities of monofluorinated and
trifluorinated derivatives observed (2-4a and 2-5a respectively) being formed (See Scheme 2.4 for
structures of all fluorinated products observed).
15
Performing the reaction in the presence of 3 Å
molecular sieves, inhibited the formation of 2-5a and afforded 2-2a and 2-4a in 24% and 63% yield
respectively (trial 2). Using 3.2 equivalents of Selectfluor I provided 2-4a in 80% yield. A similar result was
obtained when the reaction was conducted with Selectfluor I (2 equiv) in the presence of anhydrous KF (1
N
N
F
Cl
2(BF
4
-
) N
N
F
Cl
2(PF
6
-
)
PhO
2
S
N
F
SO
2
Ph
N
F
TfO
-
N
F TfO
-
Selectfluor I Selectfluor II NFSI
N-fluoropyridinium triflates
N
O
Ar
F
2-3a
N
O
Ar
F
F
OH
2-2a
N
O
Ar
F
F
F
2-4a
N
O
Ar
F
OH
2-5a
N
O
Ar
2-1a
65
equiv) as an external fluoride source (Table 1, entries 3 and 4). Selectfluor II was then tested against the
standard reaction conditions, providing very good selectivity for product 2-2a, with no 2-4a detected.
Table 2.1 Optimization table for the base-mediated difluorination reaction
a
trial F source
(equiv)
Base Time
(hours)
Yield (%)
b
2-2a 2-4a 2-5a
1
c,d
Selectfluor I (2.0) K 2CO 3 1 45 40 13
2 Selectfluor I (2.0) K 2CO 3 1 24 63 3
3 Selectfluor I (3.2) K 2CO 3 1 15 80 0
4 Selectfluor I (2.0) K 2CO 3 1 14 80 0
5 Selectfluor II (2.2) K 2CO 3 0.5 90 0 0
6 NFSI (2.2) K 2CO 3 12 <5% 0 0
7 N-fluoropyridinium triflate (i) (2.2) K 2CO 3 12 No reaction of starting material
8 N-fluoropyridinium triflate (ii) (2.2) K 2CO 3 12 No reaction of starting material
[a]
Reactions were carried out with 2-1a (0.25 mmol) and 3 Å molecular sieves (250 mg).
[b]
Determined by
19
F NMR using
fluorobenzene internal standard.
[c]
CH 3CN (0.05 M) was used
[d]
Reaction performed in the absence of molecular sieves. n.d = not
detected
These results suggest that the formation of 2-4a is via fluoride abstraction from the
tetrafluoroborate counter anion of Selectfluor I by the very electrophilic iminium carbocation, rather than
the N—F bond being the source of fluoride. Though PF 6
-
can release fluoride under certain conditions, the
ability of Selectfluor II to selectively afford 2-2a could be rationalized by the relative Lewis acidity strength
N
O
Ar
F
2-3a
N
O
Ar
F
F
OH
2-2a
N
O
Ar
F
F
F
2-4a
N
O
Ar
F
OH
2-5a
N
O
Ar
2-1a
66
of BF 3 vs PF 5 (fluoride ion affinity of 83.1 kcal/mol for BF 3 vs 94.9 kcal/mol for PF 5).
221
NFSI and N-
fluoropyridinium triflates (i) and (ii) (see Scheme 2.3) were also tested, but were not as efficient. With
optimized conditions for compound 2-2a (trial 5), we set out to investigate the scope of the base-
mediated 1-hydroxylation-2,2-difluorniation reaction.
The results of this investigation are tabulated in Scheme 2.5. Product 2-2a was obtained from the
model substrate 2-1a in 90% yield. An acidic N–H bond in the substrate does not impede the reaction
progress, as can be seen in example 2-2b which proved even more suitable than the model substrate. This
result was encouraging when considering that a large number of isoindolinone natural products and drugs
have N–H bonds, which increases the method’s applicability in late-stage functionalization. A benzyl
substituent on the N (R 2 = Bn) however decreased the yield to 79% (2-2c). This decrease was somewhat
surprising, with our initial considerations being focused on potential steric effects. This later seemed
unlikely as we believe the steric effects experienced by the b-carbon of the enamide moiety due to the N-
benzyl group should not be significant due to the distance between the groups. To further probe the
effects of N-substitution on the reaction outcome, substrate 2-1d with a N–Ph unit was subjected to the
model conditions. A lower yield (61%) of the product was obtained. Considering the examples 2-2a to 2-
2d, it appears that as the electron withdrawing ability of the N-substituent increases, the yield of the
product decreases. To further verify this trend further, attempts to synthesize compound 2-2e were
conducted. Compound 2-1e containing an N-methoxy group, arguably the most electron-withdrawing N-
substituent we tested, gave us no corresponding difluorinated product (2-2e). This information ties in well
with the proposed reaction pathway (Scheme 2.2). The loss of reactivity with consequential drop in
product yield can be explained by a decrease in the stability of the carbocation intermediates 2-I1 and 2-
I2. After developing an understanding of the influence of N-substitution on the reaction outcome, we
investigated the electronic effects of varied substitution in the aryl group R 3 in the structure 2-1 on the
67
outcome of the reaction. As can be seen from examples 2-2f to 2-2j, the nature of the aryl group
substituent in R 3 does not significantly impact the yield or selectivity of the reaction. The same holds true
for examples 2-2l to 2-2n, which have electronically different functional groups on the phenylene unit of
the isoindol-1-one core.
[a] Reactions performed using 0.25 mmol of substrate. See Experimental Section for full details.
Scheme 2.5 Substrate scope for the base-mediated synthesis of 2-2 under strictly anhydrous conditions
N
O
R
2
R
3
R
1
Selectfluor II (2.2 equiv)
K
2
CO
3
(1.2 equiv)
3 Å molecular sieves (10% w/V)
CH
3
CN, rt, 0.5 hours
N
O
R
2
F
R
1
HO
R
3
F
N
O
Me
F
HO
F
2-2a: 90%
N
O
H
F
HO
F
2-2b: 95%
N
O
F
HO
F
2-2c: 79%
N
O
F
HO
F
2-2d: 61%
N
O
F
HO
F
2-2e: 0%
OMe
N
O
Me
F
HO
F
2-2f: 85%
OMe
N
O
Me
F
HO
F
2-2g: 80%
CF
3
N
O
Me
F
HO
F
2-2h: 85%
F
N
O
Me
F
HO
F
2-2i: 89%
Br
N
O
Me
F
HO
F
2-2j: 78%
N
O
F
HO
F
N
2-2k: 81%
N
O
Me
F
HO
F
2-2l: 73%
N
O
Me
F
HO
F
2-2m: 88%
O
F
3
C
Cl
N
O
Me
F
HO
F
2-2n: 84%
Me
2-1 2-2
68
Water has a very adverse effect on the reaction. Even in flame-dried vials and with 10%
weight/volume of molecular sieves, the 2-fluoro-1-hydroxy product (product 2-5) was observed in yields
ranging from 5% to 25% and could not be suppressed further. We then realized that the alcohol byproduct
2-5 should undergo an acid promoted E 1 reaction to form alkene 2-3, characteristic of a tertiary alcohol
having an a proton (Scheme 2.6). Compound 2-3 should then be able to react with another equivalent of
the N—F reagent to form the desired b-difluoroiminium carbocation 2-I2. Subsequent quenching with
water would yield product 2-2. This hypothesis was tested with substrate 2-1b (Table 2.2) using Selectfluor
I as the fluorinating reagent. Phosphoric acid was found to be a suitable candidate for the reaction,
although it required 40 hours for the reaction to go to completion (trial 9). Trifluoroacetic acid on the
other hand provided comparable results in just four hours (trial 10). Both boron trifluoride monohydrate
(trial 11) and triflic acid (trial 12), however, were not suitable, providing an unresolvable spectrum with
no clear indication of the product. This result is comparable to the base-mediated synthesis of 2-1b,
prompting us to explore the applicability of this trifluoroacetic acid-mediated method on isoindolinones
2-1a to 2-1n (Scheme 2.7).
Scheme 2.6 Proposed reaction pathway for an acid-mediated synthesis of 2-2
N
O
R
3
R
2
R
1
N—F reagent
N
O
R
3
R
2
R
1
F
H
2
O
N
O
R
3
R
2
R
1
F
OH
H
+
N
O
R
3
R
2
R
1
F
2-1 2-I1 2-5 2-3
N
O
R
3
R
2
R
1
F
2-I2
N—F
reagent
F
H
2
O
N
O
R
3
R
2
R
1
F
2-2
F
OH
69
Like the base-mediated method, the yield from this method was decreased with increasing
electronegativity of the N-substituent (Scheme 2.7). Unlike the previous method however, the presence
of electron-withdrawing groups in the R 3 group or the 1,2-phenylene units of the isoindolinone ring led to
decreased product yields. Interestingly, 2-2f having an electron-donating methoxy group gave a lower
yield of the corresponding product than 2-2g with a trifluoromethyl group. We attribute the difference to
the likely protonation of the methoxy group, the corresponding oxonium-type species of which would be
a stronger electron-withdrawing group than the –CF 3 group.
Table 2.2 Optimization table for the acid-mediated difluorination reaction
a
trial
a
F source
(equiv)
Acid/base Time
(hours)
Yield (%)
b
2-2a 2-4a 2-5a
9 Selectfluor I (2.2) H 3PO 4 40 94 0 0
10 Selectfluor I (2.2) CF 3COOH 4 95 0 0
11 Selectfluor I (2.2) BF 3-H 2O 2 Complex mixture of products
12 Selectfluor I (2.2) TfOH 2 Complex mixture of products
[a]
Reactions were carried out with 2-1b (0.25 mmol) and 3 Å molecular sieves (250 mg).
[e]
H 2O (100 mL was added after 1 h at 50
o
C. See Experimental Section for full details. TFA = trifluoroacetic acid, TfOH = trifluoromethanesulfonic acid.
Satisfactorily, the ketone group of 2-1j was tolerated and no side-reaction as observed. Even the
pyridyl-substituted containing 2-2k was obtained in moderate yield, although it required mild heating to
50
o
C for a long period (60 hours). The electron withdrawing nature of the pyridinium species formed upon
protonation of the pyridine ring is the likely reason for its stubbornness to react under the developed
conditions. Later, we found that the amount of H 2O present in the system at the onset of the reaction
must be within certain limits for the success of the reaction. The experimental section details a study of
the effect of varying amounts of added water on the reaction outcome. By reducing the amount of
70
Selectfluor I from 3 equivalents to 1 equivalent under acidic conditions, we were able to generate and
isolate monofluoroolefin products 2-3 as mixtures of E and Z geometric isomers (Scheme 2.8).
[a] Reactions performed using 0.25 mmol of substrate. See Experimental Section for full details.
Scheme 2.7 Substrate scope for the acid-mediated synthesis of 2-2 under bench-top conditions
What is most interesting about these products is the geometric isomer ratio in which they are
formed. In all cases, the Z isomer is the predominant form. Just looking at the products, this result seems
counterintuitive from a purely steric perspective. While we don’t have a sound explanation for why this
change in ratio of isomers is observed, it is interesting, nonetheless. Adding potassium fluoride to our
N
O
R
2
R
3
R
1
Selectfluor 1 (3.0 equiv)
CF
3
COOH (10 equiv)
CH
3
CN, rt - 65
o
C
N
O
R
2
F
R
1
HO
R
3
F
N
O
F
HO
F
2-2a: 95%
N
O
H
F
HO
F
2-2b: 97%
N
O
F
HO
F
2-2c: 80%
N
O
F
HO
F
2-2d: 0%
N
O
F
HO
F
2-2e: 0%
OMe
N
O
F
HO
F
2-2f: 65%
OMe
N
O
F
HO
F
2-2g: 71%
CF
3
N
O
F
HO
F
2-2h: 83%
F
N
O
F
HO
F
2-2i: 66%
Br
N
O
F
HO
F
2-2j: 76%
N
O
F
HO
F
N
2-2k: 55%
N
O
F
HO
F
2-2l: 0%
N
O
F
HO
F
2-2m: 74%
O
F
3
C
Cl
N
O
F
HO
F
2-2n: 84%
71
base-mediated conditions also allowed us to access 1,2,2-trifluorinated isoindolinones in good yields
(Scheme 2.9).
Scheme 2.8 C(sp
2
)–H olefinic fluorination of isoindolinones (See Experimental Section for full details)
Scheme 2.9 1,2,2-trifluorination of isoindolinones (See Experimental Section for full details)
Since iminium ion intermediates are widely invoked as synthons for structural diversification,
222–
224
we believed that showing the applicability of our furnished products 2-2 as iminium ion precursors
N
O
R
2
R
3
R
1
N
O
R
2
R
3
R
1
F
Selectfluor I (1 equiv)
CF
3
COOH (10 equiv)
CH
3
CN, air
50
O
C to 80
O
C
NH
O
F
NH
O
F
N
O
F
N
O
F
MeO
2-3s
98% (Z:E = 4:1)
2-3t
98% (Z:E = 4:1)
2-3u
98% (Z:E = 4:1)
2-3v
98% (Z:E = 4:1)
N
O
Me
Ar
N
O
Me
Ar
F
F
F
Selectfluor II (2.5 equiv)
KF (2 equiv)
3 A molecular sieves
MeCN, rt, 0.5 h
N
O
Me R
2
F
F
F
N
O
Me R
2
F
F
F
N
O
Me R
2
F
F
F
2-1 2-4
2-4w 2-4x 2-4y
CF
3
OMe
72
would greatly enhance the impact of our work. Our investigations showed that catalyst A (shown below)
promotes the enantioselective addition of p-methoxythiophenol (PMP-SH) in moderate yield and high
enantiomeric excess (Scheme 2.10).
22
In contrast to previously reported methodologies using 3-
hydroxyisoindolin-1-one derivatives as substrates for chiral BINOL-derived phosphoric acid-catalysis, 2b
required the use of the more acidic triflimide derivative A.
23
This may be due to the electron withdrawing
nature of the gem-difluoro unit, which would make the neighboring –OH group less basic and therefore
require a stronger acid for its protonation. The destabilization of the resultant iminium carbocation may
also be an inhibiting factor.
Scheme 2.10 Asymmetric chemical elaboration of 3-hydroxy-3-difluoroalkylisoindolin-1-ones
2.iii Conclusion
In this project, we developed novel methods for various fluorofunctionalizations of isoindolin-1-
ones. Two complementary methods for 2,2-difluorination-1-hydroxylation under basic and Brønsted
acidic conditions were developed. By reducing the amount of Selectfluor in the acidic condition, olefinic
C(sp
2
)–F products were obtained. The addition of KF to our base-mediated conditions afforded 1,2,2-
trifluoro products. The utility of the obtained products was further demonstrated with the synthesis of an
enantioenriched N,S-aminal.
NH
O
HO
F
F
catalyst A (10 mol %)
PMP—SH (5 equiv)
DCM, 50
o
C
NH
O
F
F
S PMP
(60%, 93% ee)
O
O
P
O
NHTf
catalyst A
73
2.iv Experimental Section
General
Unless otherwise mentioned, all the chemicals were purchased from commercial sources and
used without further purification. Acetonitrile (MeCN) was distilled from P 2O 5 and stored over molecular
sieves in a Strauss flask under N 2. Flash column chromatography was performed to isolate products with
suitable eluent as determined by TLC.
1
H,
13
C, and
19
F spectra were recorded on 400 MHz or 500 MHz
Varian NMR spectrometers.
1
H NMR chemical shifts were determined relative to Chloroform-d as the
internal standard at δ 7.26.
13
C NMR shifts were determined relative to Chloroform-d at δ 77.16 ppm.
19
F
NMR chemical shifts were determined relative to CFCl 3 at δ 0.00. IR data was recorded on a JASCO FT/IR-
4600 infrared spectrometer. Mass spectra were recorded on a high-resolution mass spectrometer, EI or
ESI mode. HPLC analyses were performed using a JASCO PU-2089 Plus chromatographer equipped with
an MD-2010 detector. Flash chromatographic purification of compounds was performed using a Biotage,
Isolera One, accelerated chromatographic isolation (ACI) automated flash column chromatogram.
Electrophilic fluorinating reagents I, III, IV and V are commercially available and were used as received. F-
TEDA-PF 6 was prepared according to a reported procedure.
225
All alkynes used in the synthesis of
isoindolinones were from commercial sources and used as received. Finely ground 3 Å molecular sieves
were activated by heating in a furnace at 300
o
C for 24 h.
Synthesis of Benzamide Starting Materials
Unless otherwise stated, benzoic acid and benzamide starting materials, were obtained from
commercial sources and used as received without further purification. The following benzamides were
synthesized according to the reported procedures, and their spectra matched the reported values: 2-iodo-
N-methylbenzamide,
209
2-iodo-N-benzylbenzamide,
226
2-iodo-N-phenylbenzamide,
227
2-iodo-N-
methoxybenzamide.
228
74
Unless otherwise stated, the benzamides were synthesized according to the following procedure.
Synthesis of 2-iodo-N-benzylbenzamide (representative procedure):
2-iodobenzoic acid (11 mmol, 2.73 g) was weighed into a 250 mL round bottom flask
equipped with a magnetic stir bar and 25 mL of dry dichloromethane (DCM) was added
by syringe under a stream of nitrogen. To this stirring suspension, SOCl 2 (13.2 mmol, 960 µL) and two
drops of anhydrous dimethylformamide (DMF) were added sequentially by syringe and stirred at room
temperature until a clear solution formed, which indicated full formation of the acyl chloride. The resulting
solution was concentrated to half volume under reduced pressure and cooled down to 0
˚
C with an
ice/water bath. To this solution, benzylamine (64 mmol, 7.0 ml) was added slowly at 0˚C. Upon complete
addition of benzylamine, the mixture was allowed to warm up to room temperature and stirring was
continued for 1 hr. The solid formed was recovered by filtration, washed with cold DCM (15 mL) and cold
water (15 mL). This solid was then dried under high vacuum overnight, affording analytically pure 2-iodo-
N-benzylbenzamide as a white crystalline powder (78% yield, 2.93g). The
1
H NMR shifts obtained were in
agreement with the reported values.
226
R
I
OH
O
SOCl
2
R
I
Cl
O
R
I
NHR’
O
R’NH
2
I
O
N
H
Bn
75
Synthesis and NMR Spectroscopic Data of Benzamide Starting Materials
4-chloro-2-iodo-N-methylbenzamide
4-chloro-2-iodobenzoic acid (11 mmol, 3.12 g) was weighed into a 250 mL round
bottom flask equipped with a magnetic stir bar and 25 mL of dry dichloromethane
(DCM) was added by syringe under a stream of nitrogen. To this stirring suspension, SOCl 2 (13.2 mmol,
960 µL) and two drops of anhydrous dimethylformamide (DMF) were added sequentially by syringe and
stirred at room temperature until a clear solution formed, which indicated full formation of the acyl
chloride. The resulting solution was concentrated to half volume under reduced pressure and cooled
down to 0
˚
C with an ice/water bath. To this solution, 40% aqueous MeNH 2 (64 mmol, 5.0 mL) was added
slowly at 0˚C. Upon complete addition of the amine, the mixture was allowed to warm up to room
temperature and stirring was continued for 1 hr. The solid formed was recovered by filtration, washed
with cold DCM (15 mL) and cold water (15 mL). This solid was then dried under high vacuum overnight,
affording analytically pure 4-chloro-2-iodo-N-benzylbenzamide as a white crystalline powder (m.p.122-
124˚C) (74% yield, 2.41 g).
1
H NMR (399 MHz, Chloroform-d) δ 7.87 (dd, J = 1.8, 0.5 Hz, 1H), 7.38 – 7.35
(m, 1H), 7.33 (d, J = 8.2 Hz, 2H), 5.73 (s, 2H), 3.02 (d, J = 5.0 Hz, 2H).
13
C NMR (100 MHz, Chloroform-d) δ
169.1, 140.6, 139.2, 136.1, 129.0, 128.5, 92.6, 26.8. HRMS EI
+
(M) calculated for C 8H 7NOICl = 294.92612,
found = 294.92517. FT/IR ( n max (neat) cm-1): 3373, 3194, 1627, 1608, 1584, 1468, 1400, 1372, 1267, 1220,
1148, 11021013, 891, 826, 778, 698, 636, 593, 559, 459.
2-iodo-5-methylbenzamide
2-iodo-5-methylbenzoic acid (11 mmol, 2.88 g) was weighed into a 250 mL round bottom flask equipped
with a magnetic stir bar and 25 mL of dry dichloromethane (DCM) was added by syringe under a stream
of nitrogen. To this stirring suspension, SOCl 2 (13.2 mmol, 960 µL) and two drops of anhydrous
Cl I
N
H
O
76
dimethylformamide (DMF) were added sequentially by syringe and stirred at room
temperature until a clear solution formed, which indicated full formation of the acyl
chloride. The resulting solution was concentrated to half volume under reduced pressure and cooled
down to 0
˚
C with an ice/water bath. To this solution, 14.8 M aqueous NH 4OH (64 mmol, 4.32 mL) was
added slowly at 0˚C. Upon complete addition of the amine, the mixture was allowed to warm up to room
temperature and stirring was continued for 1 hr. The solid formed was recovered by filtration, washed
with cold DCM (15 mL) and cold water (15 mL). This solid was then dried under high vacuum overnight,
affording analytically pure 2-iodo-5-methylbenzamide as a white crystalline powder (m.p. 128-130˚C)
(81% yield, 2.41 g).
1
H NMR (399 MHz, Chloroform-d) δ 7.75 (d, J = 8.08 Hz, 1H), 7.31 (dt, J = 1.59, 0.79 Hz,
1H), 6.94 (ddq, J = 8.12, 2.17, 0.68 Hz, 1H), 5.77 (s, 2H), 2.32 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ
171.0, 140.9, 140.1, 138.6, 132.7, 129.5, 88.0, 21.0. HRMS-EI
+
(M) calculated for C 8H 8NOI = 260.96509,
found = 260.96565. FT/IR (n max (neat) cm-1): 3373, 3194, 1627, 1608, 1584, 1468, 1400, 1372, 1220, 1148,
1014, 891, 826, 778, 698, 636, 593, 574, 559, 459.
2-iodo-N,5-dimethylbenzamide
2-iodo-N,5-dimethylbenzoic acid (11 mmol, 2.88 g) was weighed into a 250 mL round
bottom flask equipped with a magnetic stir bar and 25 mL of dry dichloromethane (DCM)
was added by syringe under a stream of nitrogen. To this stirring suspension, SOCl 2 (13.2 mmol, 960 µL)
and two drops of anhydrous dimethylformamide (DMF) were added sequentially by syringe and stirred at
room temperature until a clear solution formed, which indicated full formation of the acyl chloride. The
resulting solution was concentrated to half volume under reduced pressure and cooled down to 0
˚
C with
an ice/water bath. To this solution, 40% aqueous MeNH 2 (64 mmol, 5.0 mL) was added slowly at 0˚C. Upon
complete addition of the amine, the mixture was allowed to warm up to room temperature and stirring
was continued for 1 hr. The solid formed was recovered by filtration, washed with cold DCM (15 mL) and
I
N
H
O
I
NH
2
O
77
cold water (15 mL). This solid was then dried under high vacuum overnight, affording analytically pure 2-
iodo-N,5-dimethylbenzamide as a white crystalline powder (m.p.126-127˚C) (84% yield, 2.54 g).
1
H NMR
(399 MHz, Chloroform-d) δ 7.70 (dd, J = 8.1, 1.3 Hz, 1H), 7.22 (s, 1H), 6.91 (dd, J = 7.6, 1.2 Hz, 1H), 5.73 (s,
1H), 3.01 (d, J = 5.0 Hz, 3H), 2.30 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 170.2, 142.3, 139.7, 138.6,
132.2, 129.4, 88.4, 26.9, 21.0. HRMS-EI
+
(M) calculated for C 9H 10NOI = 274.98074, found = 274.98133.
FT/IR (n max (neat) cm-1): 3230, 2922, 1640, 1588, 1539, 1456, 1401, 1313, 1262, 1157, 1131, 1035, 1007,
890, 821, 796, 770, 709, 667, 592, 562, 456.
Synthesis and NMR Spectroscopic Data of Enamide Starting Materials
Isoindolinone starting materials 1a-1o were prepared according to reported procedures
209,229,230
and their
spectral data matched those previously reported.
209,229,230
(Z)-3-benzylidene-2-methylisoindolin-1-one (2-1a)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.0 mg), CuCl (0.2
mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3 mmol,
967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and sealed
with a septum. Outside the glovebox, phenylacetylene (3.0 mmol, 330 µL) and degassed water (4 mL)
were added sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil bath
preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down
to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad
of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further extracted
with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
a EtOAc/ Hexanes system (gradient from 0% - 25%). The combined fractions were concentrated on a rotary
N
O
78
evaporator to afford the product 1a (82% yield, 385.9 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.86 (dt, J
= 7.5, 1.0 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.5, 1.2 Hz, 1H), 7.49 (td, J = 7.5, 0.9 Hz, 1H), 7.42 –
7.37 (m, 2H), 7.37 – 7.30 (m, 3H), 6.79 (s, 1H), 3.04 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1,
138.1, 136.3, 134.9, 132.0, 129.8, 129.1, 128.6, 128.2, 127.6, 123.3, 119.4, 106.7, 30.7. This data
corresponds to the previously reported structure.
(Z)-3-benzylideneisoindolin-1-one (2-1b)
Inside an argon glovebox, 2-iodobenzamide (2 mmol, 494.1 mg), CuCl (0.2 mmol, 19.8
mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3 mmol, 967 mg) and
Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and sealed with a septum.
Outside the glovebox, phenylacetylene (3.0 mmol, 330 µL) and degassed water (4 mL) were added
sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil bath preheated to
130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down to room
temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad of Celite.
The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further extracted with
EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
a EtOAc/ Hexanes system (gradient from 0% - 25%). The combined fractions were concentrated on a rotary
evaporator to afford the product Obtained as a pale-yellow solid (70% yield, 309.8 mg).
1
H NMR (399 MHz,
Chloroform-d) δ 8.03 (s, 1H), 7.89 (dt, J = 7.5, 1.0 Hz, 1H), 7.80 (dt, J = 7.8, 0.9 Hz, 1H), 7.69 – 7.62 (m, 1H),
7.53 (td, J = 7.5, 1.0 Hz, 1H), 7.44 (d, J = 4.4 Hz, 4H), 7.36 – 7.29 (m, 1H), 6.57 (s, 1H).
13
C NMR (100 MHz,
Chloroform-d) δ 169.4, 138.4 , 135.0 , 133.1 , 132.3 , 129.3 , 129.2 , 128.8 , 128.7 , 127.8 , 123.6 , 119.9,
106.2 . The chemical shift corresponding to the N–H varies significantly with sample concentration. Data
NH
O
79
reported here corresponds to a concentration of 10 mg/mL. This data corresponds to the previously
reported structure.
(Z)-2-benzyl-3-benzylideneisoindolin-1-one (2-1c)
Inside an argon glovebox, N-benzyl-2-iodobenzamide (2 mmol, 674.3 mg), CuCl (0.2
mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3 mmol,
967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and sealed
with a septum. Outside the glovebox, phenylacetylene (3.0 mmol, 330 µL) and
degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then
placed in an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was
allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered
through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH
and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine,
dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 10%). The combined fractions were
concentrated on a rotary evaporator to afford the product 1a (82% yield, 385.9 mg). Obtained as a beige
solid (64% yield, 398.6 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.94 (dd, J = 7.5, 1.0 Hz, 1H), 7.75 (dd, J =
7.7, 1.0 Hz, 1H), 7.63 (td, J = 7.7, 1.1 Hz, 1H), 7.53 (td, J = 7.4, 1.0 Hz, 1H), 7.29 – 7.22 (m, 3H), 7.10 – 7.02
(m, 5H), 6.72 (s, 1H), 6.53 (dd, J = 7.0, 1.3 Hz, 2H), 4.94 (s, 2H).
13
C NMR (100 MHz, Chloroform-d) δ 169.2,
138.6 , 136.9 , 134.7 , 134.5 , 132.2 , 129.8 , 129.2 , 128.2 , 128.1 , 128.0 , 127.5 , 126.8 , 126.5 , 123.7 ,
119.6 , 107.7 , 45.0 . This data corresponds to the previously reported structure.
(E)-3-benzylidene-2-phenylisoindolin-1-one (2-1d)
N
O
80
Inside an argon glovebox, N-phenyl-2-iodobenzamide (2 mmol, 646.3 mg), CuCl (0.2
mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3 mmol,
967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and sealed
with a septum. Outside the glovebox, phenylacetylene (3.0 mmol, 330 µL) and degassed water (4 mL)
were added sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil bath
preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down
to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad
of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further extracted
with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
a EtOAc/ Hexanes system (gradient from 0% - 25%). The combined fractions were concentrated on a rotary
evaporator to afford the product Obtained as a pale-yellow solid (60% yield, 356.8 mg).
1
H NMR (399 MHz,
Chloroform-d) δ 7.96 (dt, J = 7.5, 0.9 Hz, 1H), 7.91 – 7.83 (m, 1H), 7.68 (td, J = 7.6, 1.1 Hz, 0H), 7.56 (dd, J
= 7.5, 0.9 Hz, 1H), 7.10 – 7.05 (m, 5H), 7.02 – 6.92 (m, 1H), 6.94 – 6.89 (m, 2H), 6.88 – 6.84 (m, 2H), 6.84
(s, 1H). This data corresponds to the previously reported structure.
(E)-3-benzylidene-2-methoxyisoindolin-1-one (2-1e)
Prepared by adapting a reported procedure.
7
A flame dried Schlenk flask was charged
with N-methoxybenzamide (2 mmol, 302.4 mg), Pd(OAc) 2 (5 mol %, 22.5 mg) and 1,4-
benzoquinone (20 mol %, 43.2 mg). Subsequently this flask was evacuated and backfilled
with O 2 three times (balloon). Acetic acid (22 mL) was then added and the reaction mixture was heated
to 50˚C in an oil bath. Subsequently, styrene (4 mmol, 460 µL) was added to this mixture, and the flask
was kept under O 2 atmosphere (balloon). After this, the reaction mixture was place into a pre-heated oil
bath at 110˚C and stirred for 20 hours. This mixture was concentrated using rotary evaporator and the
N
O
OMe
N
O
81
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%).
Obtained as a yellow-oil in 45% yield (226.2 mg).
1
H NMR (399 MHz, Chloroform-d)
δ 7.85 (ddd, J = 7.5,
1.3, 0.7 Hz, 1H), 7.51 – 7.41 (m, 6H), 7.41 – 7.35 (m, 2H), 6.77 (s, 1H), 4.11 (s, 3H).
13
C NMR (100 MHz,
Chloroform-d) δ 161.1, 134.5, 132.1, 131.9, 131.5, 129.7, 129.5, 128.8, 128.2, 128.0, 123.4, 123.1, 110.1,
64.4. This data corresponds to the previously reported structure.
(Z)-3-(4-methoxybenzylidene)-2-methylisoindolin-1-one (2-1f)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide
(3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial
and sealed with a septum. Outside the glovebox, 4-methoxyphenylacetylene (3 mmol, 389µL) and
degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then
placed in an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was
allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered
through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH
and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine,
dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 25%). The combined fractions were
concentrated on a rotary evaporator to afford the product Obtained as a pale-yellow solid (91% yield,
483.0 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.85 (dt, J = 7.5, 1.0 Hz, 1H), 7.73 (dt, J = 7.8, 0.9 Hz, 1H),
7.58 (td, J = 7.5, 1.2 Hz, 1H), 7.48 (td, J = 7.5, 0.9 Hz, 1H), 7.31 – 7.24 (m, 2H), 6.95 – 6.91 (m, 2H), 6.74 (s,
1H), 3.85 (s, 3H), 3.07 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1, 159.2, 138.3, 135.8, 131.9, 131.1,
128.9, 128.6, 127.1, 123.3, 119.3, 113.8, 106.6, 55.5, 30.7. This data corresponds to the previously
reported structure.
N
O
OMe
82
(Z)-2-methyl-3-(4-(trifluoromethyl)benzylidene)isoindolin-1-one (2-1g)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide
(3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial
and sealed with a septum. Outside the glovebox, 4-trifluoromethylphenylacetylene (3 mmol, 489 µL) and
degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then
placed in an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was
allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered
through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH
and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine,
dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 15%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as a pale-yellow solid (73% yield,
443 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.87 (dd, J = 7.6, 1.0 Hz, 1H), 7.75 (dd, J = 7.7, 1.0 Hz, 1H),
7.68 – 7.59 (m, 3H), 7.52 (tt, J = 7.5, 7.5, 1.1 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 3.03 (s, 3H).
13
C
NMR (100 MHz, Chloroform-d) δ 169.0, 138.8, 137.9, 137.6, 132.9 (d, J = 218.2 Hz), 130.1 , 129.6 (q, J =
32.7 Hz), 129.6 , 128.6, 125.2 (q, J = 3.8, 3.7, 3.7 Hz), 124.2 (q, J = 272.0 Hz), 123.5, 119.5, 30.8 .
19
F NMR
(282 MHz, Chloroform-d) δ -63.1 (s, 3F). This data corresponds to the previously reported structure.
(Z)-3-(4-fluorobenzylidene)-2-methylisoindolin-1-one (2-1h)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide
(3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial
N
O
CF
3
N
O
F
83
and sealed with a septum. Outside the glovebox, 4-fluorophenylacetylene (3 mmol, 344 µL) and degassed
water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then placed in
an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to
cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through
a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further
extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over
MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 15%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as an off-white powder (74% yield,
375 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.85 (dt, J = 7.6, 0.6 Hz, 1H), 7.72 (dt, J = 7.7, 0.8 Hz, 1H),
7.59 (td, J = 7.8, 0.6 Hz, 1H), 7.49 (td, J = 7.4, 0.8 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.12 – 7.05 (m, 2H), 6.71 (s,
1H), 3.02 (s, 1H).
13
C NMR (100 MHz, Chloroform-d) δ 169.0, 162.2 (d, J = 247.6 Hz), 138.0 , 136.6 , 132.1
, 131.4 (d, J = 8.0 Hz), 130.8 (d, J = 3.5 Hz), 129.2 , 128.6 , 123.3 , 119.3 , 115.3 (d, J = 21.6 Hz), 105.4 , 30.7.
19
F NMR (376 MHz, Chloroform-d) δ -114.4 – -114.6 (m). This data corresponds to the previously reported
structure.
(Z)-3-(4-bromobenzylidene)-2-methylisoindolin-1-one (2-1i)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide
(3 mmol, 967 mg) 4-bromophenylacetylene (3 mmol, 543 mg) and Cs 2CO 3 (6 mmol,
1955 mg) were placed in a crimp-top vial and sealed with a septum. Outside the glovebox, degassed water
(4 mL) was added by syringe under a stream of nitrogen. The vial was then placed in an oil bath preheated
to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down to room
temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad of Celite.
N
O
Br
84
The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further extracted with
EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
a EtOAc/ Hexanes system (gradient from 0% to 15%). The combined fractions were concentrated on a
rotary evaporator to afford the product. Obtained as an off-white powder (83% yield, 522 mg).
1
H NMR
(399 MHz, Chloroform-d) δ 7.85 (dd, J = 7.6, 1.1 Hz, 1H), 7.72 (dd, J = 7.7, 0.7 Hz, 1H), 7.60 (t, J = 7.6 Hz,
1H), 7.54 – 7.47 (m, 3H), 7.22 (d, J = 8.6 Hz, 2H), 6.65 (s, 1H), 3.03 (s, 4H).
13
C NMR (100 MHz, Chloroform-
d) δ 169.0 , 138.0 , 136.9 , 133.9 , 132.1 , 131.4 , 129.3 , 128.5 , 123.4 , 121.7 , 119.4 , 105.0 , 30.8 (C–Br
carbon not detected).This data corresponds to the previously reported structure.
(3-(4-acetylbenzylidene)-2-methylisoindolin-1-one (2-1j)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide
(3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top
vial and sealed with a septum. Outside the glovebox, 4-acetylphenylacetylene (3 mmol, 433 mg) and
degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then
placed in an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was
allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered
through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH
and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine,
dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 30%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as a beige solid (82% yield, 455 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.86 (dt, J = 7.5, 1.0 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.5,
N
O
COMe
85
1.2 Hz, 1H), 7.49 (td, J = 7.5, 0.9 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.37 – 7.30 (m, 3H), 6.79 (s, 1H), 3.04 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1, 138.1, 136.3, 134.9, 132.0, 129.8, 129.1, 128.6, 128.2, 127.6,
123.3, 119.4, 106.7, 30.7. This data corresponds to the previously reported structure.
2-benzyl-3-(pyridin-2-ylmethylene)isoindolin-1-one (2-1k)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl (0.2
mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3
mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and
sealed with a septum. Outside the glovebox, 2-ethynylpyridine (3 mmol, 309 mg, 303 µL) and degassed
water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then placed in
an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to
cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through
a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further
extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over
MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 40%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as an off-white powder (m.p.137-
140˚C) in (64% yield, 400 mg). Obtained in a Z:E ratio of 10:1. This mixture was used in the following
difluorination step. Shifts reported correspond to the major Z-isomer
1
H NMR (399 MHz, Chloroform-d) δ
8.64 (ddd, J = 4.9, 2.0, 1.0 Hz, 1H), 7.93 (dq, J = 7.4, 1.1 Hz, 1H), 7.75 (dq, J = 7.8, 1.0 Hz, 1H), 7.62 (tt, J =
7.6, 1.3 Hz, 1H), 7.54 (tt, J = 7.6, 1.2 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.17 – 7.12 (m, 1H), 7.03 (ddt, J = 6.8, 5.4,
1.2 Hz, 4H), 6.63 (s, 1H), 6.60 – 6.55 (m, 2H), 5.39 (s, 2H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1, 154.1,
149.0, 138.8, 137.3, 136.4, 136.0, 132.3, 129.6, 128.3, 128.1, 126.7, 126.4, 125.4, 123.8, 121.8, 119.7,
106.0, 45.2. HRMS-ES
+
(M+) Calculated for C 21H 16ON 2 = 312.12627, found = 312.12686. FT/IR (n max (neat)
N
O
N
86
cm-1): 3034, 2921, 1694, 1654, 1612, 1584, 1558, 1497, 1472, 1455, 1433, 1399, 1361, 1349, 1300, 1277,
1247, 1226, 1208, 1187, 1153, 1118, 1097, 1076, 1030, 981, 968, 956, 951, 903, 849, 816, 793, 777, 746,
734, 718, 692, 685, 645, 615, 574, 552, 516, 459, 432, 419.
(Z)-2-benzyl-3-benzylidene-6-(trifluoromethyl)isoindolin-1-one (2-1l)
Inside an argon glovebox, N-benzyl-2-bromo-5(trifluoromethyl)benzamide (2
mmol, 810 mg), CuCl (0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-
tetrabutylammonium bromide (3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg)
were placed in a crimp-top vial and sealed with a septum. Outside the glovebox, phenylacetylene (3 mmol,
330 µL) and degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The
vial was then placed in an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction
mixture was allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was
then filtered through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution
of NH 4OH and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed
with brine, dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was
purified by flash chromatography using a EtOAc/ Hexanes system (gradient from 0% to 25%). The
combined fractions were concentrated on a rotary evaporator to afford the product. Obtained as an off-
white powder (m.p.171-174˚C) (71% yield, 539 mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.23 – 8.21 (m,
1H), 7.97 – 7.65 (m, 2H), 7.37 – 7.20 (m, 3H), 7.15 – 6.97 (m, 5H), 6.82 (s, 1H), 6.56 – 6.47 (m, 2H), 4.96 (s,
2H).
13
C NMR (100 MHz, Chloroform-d) δ 167.8, 141.4, 136.5, 134.0, 133.5, 131.5 (q, J = 33.1 Hz), 129.7,
129.0 (q, J = 3.5 Hz), 128.6, 128. 2, 128.2, 128.0, 127.0, 126.5, 123.9 (q, J = 272.4 Hz), 121.1 (q, J = 4.0 Hz),
120.3, 110.1, 45.2.
19
F NMR (376 MHz, Chloroform-d) δ -62.8 (s, 1F). HRMS-ES
+
(M) Calculated for
C 23H 16ONF 3 = 379.11840, found = 379.11816. FT/IR (n max (neat) cm-1): 3030, 1692, 1653, 1598, 1505, 1473,
N
O
F
3
C
87
1443, 1397, 1361, 1344, 1304, 1290, 1263, 1216, 1158, 1114, 1096, 979, 956, 939, 908, 859, 834, 812,
762, 743, 696, 677, 616, 597, 522, 502, 457.
(Z)-3-benzylidene-5-chloro-2-methylisoindolin-1-one (2-1m)
Inside an argon glovebox, 4-chloro-2-iodo-N-methylbenzamide (2 mmol, 591 mg),
CuCl (0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium
bromide (3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-
top vial and sealed with a septum. Outside the glovebox, phenylacetylene (3 mmol, 330 µL) and degassed
water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then placed in
an oil bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to
cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through
a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further
extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over
MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/ Hexanes system (gradient from 0% to 15%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as a pale-yellow powder (m.p.138-
142˚C) (69% yield, 372 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.78 (ddd, J = 8.0, 1.5, 0.6 Hz, 1H), 7.72
(td, J = 1.6, 0.6 Hz, 1H), 7.46 (dt, J = 8.1, 1.7 Hz, 1H), 7.40 (ddt, J = 9.4, 6.2, 1.7 Hz, 2H), 7.36 – 7.31 (m, 3H),
6.76 (s, 1H), 3.02 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 168.0, 139.7, 138.5, 135.3, 134.4, 129.8,
129.5, 129.0, 128.3, 127.9, 124.6, 119.9, 107.8, 30.8. HRMS-ES+ (M) Calculated for C 16H 12ONCl =
269.06074, found = 269.06011. FT/IR (n max (neat) cm
-1
): 2922, 1709, 1612, 1447, 1434, 1310, 1259, 1131,
1098, 1073, 1040, 1024, 822, 768, 688, 655, 604, 542, 492.
(Z)-3-benzylidene-2,6-dimethylisoindolin-1-one (2-1n)
N
O
Cl
88
Inside an argon glovebox, 2-iodo-N,5-dimethylbenzamide (2 mmol, 550.2 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3
mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and
sealed with a septum. Outside the glovebox, phenylacetylene (3 mmol, 330 µL) and degassed water (4
mL) were added sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil bath
preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down
to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad
of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further extracted
with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
a EtOAc/ Hexanes system (gradient from 0% to 15%). The combined fractions were concentrated on a
rotary evaporator to afford the product. Obtained as an off-white powder (m.p.134-135˚C) (71% yield,
354 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.65 (dq, J = 1.6, 0.8 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.42 –
7.28 (m, 6H), 6.72 (s, 1H), 3.02 (s, 3H), 2.48 (s, 3H).
13
C NMR (126 MHz, CHLOROFORM-D) δ 169.2, 139.4,
136.4, 135.7, 135.1, 133.1, 129.9, 128.9, 128.2, 127.5, 123.5, 119.2, 105.9, 30.7, 21.7. HRMS-ES+ (M)
Calculated for C 17H 15ON = 249.11537, found = 249.11519. FT/IR (n max (neat) cm-1): 3025, 2945, 1692, 1652,
1598, 1494, 1443, 1430, 1380, 1333, 1304, 1217, 1114, 1026, 956, 836, 777, 745, 697, 645, 616, 519, 420.
(Z)-3-benzylidene-6-methylisoindolin-1-one (2-1o)
Inside an argon glovebox, 5-methyl-2-iodobenzamide (2 mmol, 522 mg), CuCl (0.2
mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3 mmol,
967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and sealed
with a septum. Outside the glovebox, phenylacetylene (3 mmol, 330 µL) and degassed water (4 mL) were
added sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil bath
N
O
NH
O
89
preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down
to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad
of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH 4OH and further extracted
with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
a EtOAc/ Hexanes system (gradient from 0% to 30%). Obtained as an off-white powder (68% yield, 320
mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.03 (s, 1H, NH), 7.69 – 7.65 (m, 2H), 7.46 (s, 1H), 7.43 (d, J = 4.4
Hz, 4H), 7.33 – 7.27 (m, 1H), 6.49 (s, 1H), 2.49 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1, 139.8,
135.8, 135.3, 133.5, 133.3, 129.4, 129.0, 128.5, 127.7, 123.9, 119.8, 105.3, 21.8. This data corresponds to
the previously reported structure.
General Procedures for Gem-Difluorination of Isoindolinones
(I = Selectfluor I, II = Selectfluor II)
Method A (basic, anhydrous conditions); representative procedure: Inside an argon glovebox, the
isoindolinone derivative 1 (0.25 mmol), K 2CO 3 (1.2 eq, 41.5 mg), finely ground, activated (350
o
C for 24h)
3 Å molecular sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame dried
crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous MeCN
(2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half an hour at
room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and filtered
N
O
R
2
R
1
N
O
R
2
R
1 R
3
Method A:
II (2.2 equiv)
K
2
CO
3
(1.2 equiv)
3 Å mol. sieves
MeCN, rt, 30 min
2
F
F
OH Method B:
I (3.0 equiv)
MeCN
TFA (10 equiv)
H
2
O
rt-65
o
C
R
3
1
2-1
2-2
90
through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the product was
extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer was
separated, dried under MgSO 4 and the product was purified by flash column chromatography using a
gradient of the appropriate solvent system, usually EtOAc/Hexanes. The combined fractions were then
concentrated by rotary evaporation to afford difluorinated products 2-2.
**Note on method A: Strictly anhydrous conditions are necessary to obtain high yields of CF 2-products 2-
2 by method A. Water present in the system, gives rise to increasing amounts of monofluoro derivatives
2-5. Anhydrous K 2CO 3 was purchased from Sigma Aldrich and used as received. F-TEDA-PF 6, II was
prepared as previously reported,
1
dried under high vacuum at 40 ˚C for 24 hours, and kept in an argon
glove box for several months without signs of decomposition.
Method B (aqueous, Brønsted acidic conditions); representative procedure:
On the benchtop, the isoindolinone derivative 2-1 (0.25 mmol) and Selectfluor I (F-TEDA-BF 4) (3 equiv, 266
mg) were weighed into a screw-cap glass vial equipped with a with a magnetic stir bar. Subsequently,
reagent grade (dry-solv®) MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at
room temperature, the vial was opened and trifluoroacetic acid (10 equiv, 191 μl) was added via
micropipette. The resulting mixture was stirred at the temperature for the time indicated below (see
below for each particular product). After this time, H 2O (100 L) was added and stirring was continued at
the same temperature for the time indicated. Consumption of monofluoro derivatives 2-5 and
2-
1
2-
5
2-
2
91
appearance of CF 2-products 2-2 could be conveniently monitored by
19
F NMR spectroscopy. After
completion, the solution was neutralized using aqueous NaHCO 3 (sat), the product was extracted with
EtOAc (3 times, 10 mL) and washed with brine. The organic layer was separated, dried under MgSO 4,
concentrated under reduced pressure and the products were purified by flash column chromatography
(EtOAc/Hexanes gradient). The combined fractions were concentrated by rotatory evaporation to afford
products 2-2.
**Note on method B: The rate of formation of CF 2-products 2, via a dehydration/oxyfluorination sequence
of monofluoro derivatives 2-5 is greatly affected by the amounts of H 2O present at the onset of the
reaction. As it is expected for a dehydration process, large amounts of water present at the onset,
significantly suppress this process, leading to sluggish reactions and recovery of monofluoro products 2-
5. Thus, is of critical importance to add H 2O (100 L) only after the dehydration of derivative 2-5 has
ensued (although in some cases the dehydration step is completed in shorter times, the addition of H 2O
was done after 3-4 h in all cases for consistency; see below for a study on the effect of water using
substrate 2-1n). After the addition of H 2O, continued stirring of this reaction mixture is required to effect
hydrolysis of other CF 2-containing species formed during the course of the reaction.
92
Evaluation of the Effect of Initial Water Content on Dehydration/Oxyfluorination Sequence
Isoindolinone derivative 2-1n (0.25 mmol, 62.3 mg), and Selectfluor, F-TEDA-BF 4, I (3 equiv, 266 mg) were
weighed into a screw-cap glass vial equipped with a with a magnetic stir bar. Subsequently, solvent (2.5
mL) was added by syringe. After stirring this mixture for 15 min at room temperature, trifluoroacetic acid
(10 equiv, 191 μl) was added via micropipette. The resulting mixture was stirred at room temperature and
samples were taken and the
19
F NMR spectra was recorded in neat solvent system (unlocked) and the
relative ratios of products were determined (Scheme S1 and Table S1).
Scheme 2.S1. Observed CF 2-containing species and their hydrolysis to 2-2n
In this study, when using MeCN:H 2O (1:0; v:v) other CF 2-containing products including the trifluorinated
derivative 3n and CF 2-containing derivative 2n’ were detected by
19
F NMR (Table S1, entry 1). We
tentatively assign derivative 2n’ as either the trifluoroacetate derivative or the acetamido derivative, this
latter arising from a Ritter-type reaction of MeCN on the corresponding difluoroiminium ion. Upon
addition of H 2O (100 uL) to the reaction mixture, the signal corresponding to 3n immediately disappeared
(table S1, entry 9), indicating its hydrolysis, whereas 2n’ required further stirring under this aqueous acidic
93
condition (Scheme S1, Fig. S1 and Fig. S2). In addition, in the cases where water was present at the onset,
the monofluoro derivative 4n remained even after 12 h (table S1, entries 10-13). From these results it can
be seen that water present at the onset has a detrimental effect has in the dehydration of derivatives 4.
Thus, the reactions using method B were performed by adding water only after 3-4 h of reaction with
trifluoroacetic acid .
Table 2.S1 Effect of varying amounts of water on the relative ratio of products.
entry time MeCN:H 2O Ratio 2n:2n':3n:4n
1 2 h 1:0 10:6.1:6:0
2 2 h 100:1 0:0:0:1
3 2 h 50:1 0:0:0:1
4 2 h 25:1 0:0:0:1
5 4 h
1:0
10:7.1:3.7:not
detected
6 4 h 100:1 0:0:0:1
7 4 h 50:1 0:0:0:1
8 4 h 25:1 0:0:0:1
9
4 h
a
1:0
a
10:5.6:0:0
10 12 h 1:0 10:5:0:0
11 12 h 100:1 0:0:0:1
12 12 h 50:1 0:0:0:1
13 12 h 25:1 0:0:0:1
a
H 2O 100 µL was added to the reaction mixture
94
Figure 2.S1
19
F NMR after 2 h of entries 1-4 from table 2.S1
Figure 2.S2
19
F NMR of entries 5 and 9 from table 2.S1
A) Entry 5 of table S1 (MeCN:H 2O, 1:0; V:V):
19
F NMR spectrum after 4 h. B) Entry 9 of table S1:
19
F NMR
spectrum after addition of H 2O (100 L)
Spectra of 2h
(entries 1-4)
in
Chloroform-d
400 MHz
Spectrum of 2h
(entry 5) in
Chloroform-d
Taken at 400
MHz
Spectrum of 2h
(entry 9) in
Chloroform-d
Taken at 400
MHz
95
Synthesis and NMR Spectroscopic Data of Difluorinated Products
2-methyl-3-(difluoro(phenyl)methyl)-3-hydroxyisoindolin-1-one (2-2a)
Method A: Inside an argon glovebox, the isoindolinone 2-1a (0.25 mmol, 58.8 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame dried
crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 15%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2a in 90% yield (65 mg) as an off-white
solid.
Method B: On the benchtop, the isoindolinone derivative 2-1a (0.25 mmol, 58.8 mg) and Selectfluor (F-
TEDA-BF 4) I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 3 hours at 50
o
C After this time, H 2O (100 µL) was added and stirring was continued at the same
temperature for 1 h (overall reaction time: 4 h). After this time, complete disappearance of monofluoro
derivative 2-5a was observed by
19
F NMR spectroscopy. Upon cooling down to room temperature, the
solution was diluted with EtOAc (5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic
layer was separated, and the product was further extracted with EtOAc (3 times, 10 mL). The organic layer
N
O
F
OH
F
96
was washed with brine and the combined organic layer was dried under MgSO 4, concentrated under
reduced pressure and the residue was purified by flash column chromatography (EtOAc/Hexanes gradient
from 0% to 15%). The combined fractions were the concentrated by rotatory evaporation. The product 2-
2a was isolated as an off-white solid (m.p. 151-152˚C) in 95% yield, 68.7 mg.
1
H NMR (500 MHz,
Chloroform-d) δ 7.54 (d, J = 7.3 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 7.3 Hz,
1H), 7.32 (d, J = 7.5 Hz, 1H), 7.29 – 7.22 (m, 4H), 3.84 (s, 1H), 2.96 (s, 3H).
13
C NMR (151 MHz, Chloroform-
d) δ 168.1, 142.1, 132.5 (t, J = 25.4 Hz), 132.1(5), 132.1, 130.8, 130.7, 128.0, 126.6 (t, J = 6.4 Hz), 124.00,
123.4, 120.6 (t, J = 255.3, 254.5 Hz), 90.6 (t, J = 30.3 Hz), 25.7 (t, J = 2.8 Hz).
19
F NMR (470 MHz, Chloroform-
d) δ -103.1 (d, J = 251.2 Hz, 1F), -108.5 (d, J = 251.3 Hz, 1F). HRMS-ES
+
(M+H
+
) Calculated. for C 16H 14NO 2F 2
= 290.0993, found = 290.1004. FT/IR (n max (neat) cm-1): 3212, 1661, 1615, 1473, 1451, 1428, 1391, 1271,
1246, 1225, 1148, 1118, 1077, 1058, 1032, 1012, 942, 925, 887, 823, 755, 696, 664, 624, 588, 551, 472.
3-(difluoro(phenyl)methyl)-3-hydroxyisoindolin-1-one (2-2b)
Method A: Inside an argon glovebox, the isoindolinone 2-1b (0.25 mmol, 55.3 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame dried
crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 25%). The combined fractions were
NH
O
F
OH
F
97
then concentrated by rotary evaporation to afford the product 2-2b in 95% yield (65 mg) as an off-white
powder.
Method B: On the benchtop, the isoindolinone derivative 2-1b (0.25 mmol, 55.3 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 µL) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 2-5 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc
(5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated, and the
product was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and
the combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 25%). The
combined fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder
(m.p.123-124˚C) in 97% yield, 67mg.
1
H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J = 7.5 Hz, 1H), 7.63 –
7.59 (m, 1H), 7.56 – 7.50 (m, 4H), 7.47 (d, J = 7.3 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 6.32 (s, 1H), 3.55 (s, 1H).
13
C
NMR (100 MHz, Chloroform-d) 169.0, 143.2, 133.1, 132.2 (t, J = 25.6 Hz), 131.6, 130.9, 130.9, 128.3, 127.2
(t, J = 6.4 Hz), 124.1, 124.0, 119.6 (dd, J = 252.7, 251.9 Hz), 88.1 (t, J = 33.9 Hz).
19
F NMR (376 MHz,
Chloroform-d) δ -107.8 (d, J = 248.8 Hz, 1F), -109.3 (d, J = 248.9 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for
C 15H 12NO 2F 2 = 276.0836, found = 276.0826. FT/IR (n max (neat) cm-1): 3327, 2921, 1693, 1677, 1590, 1496,
1471, 1391, 1292, 1165, 1140, 1115, 1076, 1052, 1030, 995, 979, 949, 910, 784, 761, 740, 697, 612, 514,
418.
98
2-benzyl-3-(difluoro(phenyl)methyl)-3-hydroxyisoindolin-1-one (2-2c)
Method A: Inside an argon glovebox, the isoindolinone 2-1c (0.25 mmol, 77.9 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame
dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 10%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2c in 79% yield (72 mg) as an off-white
powder.
Method B: On the benchtop, the isoindolinone derivative 2-1c (0.25 mmol, 77.9 mg) and Selectfluor I (F-
TEDA-BF 4) (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 L) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 4 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc (5
mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated and the product
was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and the
combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the residue
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 10%). The combined
N
O
F
OH
F
99
fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder (m.p.181-
182˚C), in 80% yield (73 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.71 – 7.67 (m, 1H), 7.53 – 7.49 (m, 2H),
7.41 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 6.8 Hz, 2H), 7.32 – 7.28 (m, 2H), 7.25 – 7.20 (m, 3H), 7.15 (d, J = 7.8 Hz,
2H), 5.14 (d, J = 15.3 Hz, 1H), 4.57 (d, J = 15.2 Hz, 1H), 2.90 (s, 1H).
13
C NMR (126 MHz, Chloroform-d) δ
168.2 , 142.2 , 138.0 , 132.4 (t, J = 25.4 Hz), 132.2 , 132.0 , 130.8 , 130.7 , 128.8 (t, J = 13.4 Hz), 128.6 ,
127.9 , 127.5 , 126.8 (t, J = 6.3 Hz), 124.1 , 123.6 , 120.8 (t, J = 256.1 Hz), 91.4 (t, J = 30.5 Hz), 44.0 (t, J =
2.6 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -102.1 (d, J = 251.0 Hz, 1F), -107.7 (d, J = 250.8 Hz, 1F). HRMS-
ES
+
(M+H
+
) Calcd. for C 22H 18NO 2F 2 = 366.1306, found = 366.1297. FT/IR (n max (neat) cm-1): 3241, 2926,
1678, 1601, 1494, 1470, 1435, 1408, 1328, 1276, 1203, 1164, 1110, 1074, 1060, 1010, 967, 927, 904, 819,
758, 693, 667, 626, 604, 528, 417.
3-(difluoro(phenyl)methyl)-3-hydroxy-2-phenylisoindolin-1-one (2-2d)
Method A: Inside an argon glovebox, the isoindolinone 2-1d (0.25 mmol, 74.3 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame
dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 7%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2d in 61% yield (54 mg) as an off-white
powder (m.p.189-190˚C).
N
O
F
OH
F
100
Method B: On the benchtop, the isoindolinone derivative 2-1d (0.25 mmol, 74.3 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 µL) was added and stirring was
continued at 65
o
C for 60 hours, however, even after this time, no difluorinated product could be detected
by
19
F NMR.
1
H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.62 (m, 1H), 7.55 – 7.48 (m, 2H), 7.40 – 7.37 (m,
2H), 7.36 – 7.29 (m, 4H), 7.24 (d, J = 7.1 Hz, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 4.16 (s, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 167.4, 141.7, 135.5, 132.6, 132.4 (t, J = 25.3 Hz), 131.9, 131.0, 130.6,
128.8, 128.2, 127.7(2), 127.7(0), 127.1 (dd, J = 7.5, 5.5 Hz), 124.5, 124.0, 120.3 (t, J = 254.7 Hz), 92.4 (t, J =
30.9 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -100.6 (d, J = 251.1 Hz, 1F), -106.7 (d, J = 251.3 Hz, 1F). HRMS-
ES
+
(M+H
+
) Calcd for C 21H 16NO 2F 2 = 352.1149, found = 352.1156. FT/IR (n max (neat) cm-1): 3070, 2921,
1670, 1595, 1492, 1468, 1451, 1378, 1270, 1240, 1161, 1118, 1087, 1060, 1011, 926, 833, 754, 717, 698,
667, 584, 543, 511.
3-(difluoro(phenyl)methyl)-3-hydroxy-2-methoxyisoindolin-1-one (2-2e)
In the case of isoindolinone 2-1e, both the acid and base mediated methods were unsuccessful in
furnishing the desired product.
3-(difluoro(4-methoxyphenyl)methyl)-3-hydroxy-2-methylisoindolin-1-one (2-2f)
Method A: Inside an argon glovebox, the isoindolinone 2-1f (0.25 mmol, 66.3
mg), K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å
molecular sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed
into a flame dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled,
N
O
F
OH
F
OMe
101
anhydrous acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was
stirred for half an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc
(10 mL) and filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate
and the product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The
organic layer was separated, dried under MgSO 4, concentrated under reduced pressure and the product
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined
fractions were then concentrated by rotary evaporation to afford the product 2-2f in 85% yield (68 mg) as
an off-white powder.
Method B: On the benchtop, the isoindolinone derivative 2-1f (0.25 mmol, 66.3 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 L) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 4 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc (5
mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated and the product
was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and the
combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the residue
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined
fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder (m.p.150-
151˚C) in 65% yield (52mg).
1
H NMR (399 MHz, CHLOROFORM-D) δ 7.57 – 7.53 (m, 1H), 7.50 (td, J = 7.5,
1.4 Hz, 1H), 7.44 (td, J = 7.4, 1.2 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.7 Hz,
2H), 3.85 (s, 1H), 3.78 (s, 3H), 2.96 (t, J = 1.5 Hz, 3H).
13
C NMR (126 MHz, Chloroform-d δ 168.4 , 161.1 ,
142.5 , 132.0 , 131.8 , 130.5 , 128.2 (t, J = 6.3 Hz), 124.8 (t, J = 25.9 Hz), 124.1 , 123.1 , 120.5 (t, J = 255.5
102
Hz), 113.2 , 90.8 (t, J = 30.8 Hz), 55.4 , 25.7 (t, J = 2.2 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -101.8 (d, J
= 250.0 Hz, 1F), -107.4 (d, J = 250.2 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for C 17H 16NO 3F 2= 320.1098, found =
320.1093. FT/IR (n max (neat) cm-1): 3274, 2935, 1694, 1613, 1516, 1469, 1420, 1371, 1307, 1283, 1252,
1179, 1146, 1124, 1070, 1047, 1024, 1002, 956, 907, 828, 788, 753, 698, 646, 606, 569, 526, 474.
3-(difluoro(4-(trifluoromethyl)phenyl)methyl)-3-hydroxy-2-methylisoindolin-1-one (2-2g)
Method A: Inside an argon glovebox, the isoindolinone 2-1g (0.25 mmol, 75.8
mg), K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å
molecular sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed
into a flame dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled,
anhydrous acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was
stirred for half an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc
(10 mL) and filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate
and the product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The
organic layer was separated, dried under MgSO 4, concentrated under reduced pressure and the product
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined
fractions were then concentrated by rotary evaporation to afford the product 2-2g in 80% yield (71 mg)
as an off-white powder.
Method B: On the benchtop, the isoindolinone derivative 2-1g (0.25 mmol, 75.8 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 µL) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
N
O
F
OH
F
CF
3
103
derivative 2-5 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc
(5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated, and the
product was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and
the combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The
combined fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder
(m.p.158-159˚C) in 71% yield (63 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 8.2 Hz, 2H), 7.47 –
7.42 (m, 3H), 7.42 – 7.36 (m, 2H), 7.14 (d, J = 7.5 Hz, 1H), 4.94 (s, 1H), 2.77 (s, 3H).
13
C NMR (126 MHz,
Chloroform-d) δ 168.4, 141.9, 136.5 (t, J = 25.7 Hz), 132.8 (q, J = 32.7 Hz), 132.2, 131.7, 130.9, 127.6 (t, J =
6.4 Hz), 125.0 (q, J = 3.7 Hz), 124.0, 123.7 (q, J = 272.6 Hz), 123.4, 119.7 (dd, J = 257.0, 253.7 Hz), 90.6 (t, J
= 29.9 Hz), 25.8 (t, J = 2.6 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -63.5 (d, J = 253.3 Hz, 1F), -103.8 (d, J
= 253.3 Hz, 1F), -108.8 (d, J = 253.8 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for C 17H 13F 5NO 2 = 358.0866, found =
358.0867. FT/IR (n max (neat) cm-1): 3233, 1669, 1620, 1478, 1432, 1415, 1394, 1323, 1245, 1165, 1108,
1065, 1016, 953, 865, 835, 777, 745, 698, 625, 603, 545, 470.
3-(difluoro(4-fluorophenyl)methyl)-3-hydroxy-2-methylisoindolin-1-one (2-2h)
Method A: Inside an argon glovebox, the isoindolinone 2-1h (0.25 mmol, 63.3 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame
dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
N
O
F
OH
F
F
104
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 15%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2h in 85% yield (65 mg) as an off-white
powder.
Method B: On the benchtop, the isoindolinone derivative 2-1h (0.25 mmol, 63.3 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 µL) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 2-5 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc
(5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated, and the
product was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and
the combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 15%). The
combined fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder
(m.p.162-163˚C) in 83% yield (63.7 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.53 – 7.49 (m, 1H), 7.48 (dt,
J = 7.4, 1.3 Hz, 1H), 7.46 – 7.41 (m, 1H), 7.28 – 7.23 (m, 3H), 6.97 (t, J = 8.7 Hz, 2H), 4.08 (s, 1H), 2.90 (s,
1H).
13
C NMR (126 MHz, Chloroform-d) δ 168.1, 164.0 (d, J = 251.2 Hz), 142.0, 132.2, 132.0, 130.9, 129.0
(dt, J = 8.6, 6.3 Hz), 128.6 (td, J = 26.0, 3.3 Hz), 123.9 (d, J = 2.3 Hz), 123.5, 120.2 (dd, J = 256.6, 254.2 Hz),
115.2 (d, J = 22.0 Hz), 90.6 (t, J = 30.3 Hz), 25.7 (t, J = 2.6 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -102.5
(d, J = 251.9 Hz, 1F), -107.8 (d, J = 252.0 Hz, 1F), -110.0 – -110.1 (m, 1F). HRMS-ES
+
(M+H
+
) Calcd. for
C 16H 12O 2F 3N = 307.11331, found = 307.11312. FT/IR (n max (neat) cm-1): 3224, 3059, 1670, 1613, 1511,
105
1471, 1433, 1401, 1357, 1323, 1274, 1245, 1227, 1156, 1117, 1066, 1024, 1015, 941, 913, 880, 863, 835,
761, 746, 697, 624, 562, 520, 413.
3-((4-bromophenyl)difluoromethyl)-3-hydroxy-2-methylisoindolin-1-one (2-2i)
Method A: Inside an argon glovebox, the isoindolinone 2-1i (0.25 mmol, 78.6 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame
dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2i in 89% yield (82 mg) as an off-white
powder.
Method B: On the benchtop, the isoindolinone derivative 2-1i (0.25 mmol, 78.6 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 µL) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro-
derivative 4 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc (5
mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated and the product
N
O
F
OH
F
Br
106
was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and the
combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the residue
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined
fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder (m.p.155-
157˚C) in 66% yield (61 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.54 – 7.48 (m, 3H), 7.46 (d, J = 7.3 Hz,
1H), 7.44 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.10 (s, 1H), 2.91 (d, J = 1.8 Hz, 3H).
13
C NMR (126 MHz,
Chloroform-d) δ 168.0, 141.7, 132.1, 131.8, 131.5 (t, J = 25.8 Hz), 131.1, 130.8, 128.3 (t, J = 6.3 Hz), 125.3
(t, J = 2.1 Hz), 123.8, 123.4, 120.0 (dd, J = 256.7, 254.2 Hz), 90.3 (t, J = 30.0 Hz), 25.6 (t, J = 2.5 Hz).
19
F NMR
(376 MHz, Chloroform-d) δ -103.3 (d, J = 252.1 Hz, 1F), -108.6 (d, J = 252.3 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd.
for C 16H 13BrF 2NO 2 = 368.00977, found = 368.00876. FT/IR (n max (neat) cm-1): 3224, 2924, 1681, 1614,
1598, 1477, 1428, 1388, 1272, 1221, 1150, 1126, 1072, 1051, 1035, 1008, 950, 938, 917, 833, 798, 764,
730, 704, 673, 623, 598, 554, 486, 468, 429.
3-((4-acetylphenyl)difluoromethyl)-3-hydroxy-2-methylisoindolin-1-one (2-2j)
Method A: Inside an argon glovebox, the isoindolinone 2-1j (0.25 mmol, 69.3
mg), K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å
molecular sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed
into a flame dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled,
anhydrous acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was
stirred for half an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc
(10 mL) and filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate
and the product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The
organic layer was separated, dried under MgSO 4, concentrated under reduced pressure and the product
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined
N
O
F
OH
F
COMe
107
fractions were then concentrated by rotary evaporation to afford the product 2-2j in 78% yield (65 mg) as
an off-white powder.
Method B: On the benchtop, the isoindolinone derivative 2-1j (0.25 mmol, 69.3 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 µL) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 2-5 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc
(5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated, and the
product was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and
the combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The
combined fractions were the concentrated by rotatory evaporation. Obtained as an off-white powder
(m.p.149-150˚C) in 76% yield (63mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.84 (d, J = 8.1 Hz, 2H), 7.56 (d,
J = 7.0 Hz, 1H), 7.51 (tt, J = 7.7, 1.4 Hz, 1H), 7.47 (tt, J = 7.5, 1.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.32 (d, J =
7.5 Hz, 1H), 3.77 (s, 1H), 3.00 (s, 3H), 2.58 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 197.4, 167.9, 141.7,
138.7, 136.9 (t, J = 25.8 Hz), 132.3, 132.1, 131.1, 127.8, 127.1 (t, J = 6.2 Hz), 123.9, 123.6, 120.2 (t, J =
255.6, 255.1 Hz), 90.4 (t, J = 29.4 Hz), 26.9, 25.8 (t, J = 2.6 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -103.6
(d, J = 252.4 Hz, 1F), -108.8 (d, J = 252.1 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for C 18H 16NO 3F 2 = 332.1098, found
= 332.1089. FT/IR (n max (neat) cm-1): 3252, 2920, 2683, 1612, 1467, 1427, 1407, 1384, 1359, 1301, 1273,
1244, 1219, 1194, 1158, 1121, 1087, 1074, 1038, 1009, 952, 909, 831, 755, 699, 668, 634, 606, 589, 547,
516, 501, 484, 470, 417.
108
2-benzyl-3-(difluoro(pyridin-2-yl)methyl)-3-hydroxyisoindolin-1-one (2-2k)
Method A: Inside an argon glovebox, the isoindolinone 2-1k (0.25 mmol, 78.1 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame dried
crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 30%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2k in 81% yield (74 mg) as an off-white
powder.
Method B: On the benchtop, the isoindolinone derivative 2-1k (0.25 mmol, 78.1 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at 65
o
C. After this time, H 2O (100 L) was added and stirring was continued at the same
temperature for 60 h. After this time, small amounts of monofluoro derivative 2-5 was still observed by
19
F NMR spectroscopy and no further heating to afford higher conversions was pursued. The reaction
mixture was then diluted with EtOAc (5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The
organic layer was separated, and the product was further extracted with EtOAc (3 times, 10 mL). The
organic layer was washed with brine and the combined organic layer was dried under MgSO 4,
concentrated under reduced pressure and the residue was purified by flash column chromatography
N
O
N
F
OH
F
109
(EtOAc/Hexanes gradient from 0% to 30%). The combined fractions were the concentrated by rotatory
evaporation. Obtained as an off-white powder (m.p.194-195˚C) in 55% yield (50mg).
1
H NMR (500 MHz,
Chloroform-d) δ 8.60 (d, J = 4.9 Hz, 1H), 8.46 (s, 1H), 7.89 – 7.86 (m, 1H), 7.59 – 7.48 (m, 4H), 7.39 (ddd, J
= 7.7, 4.8, 1.3 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.10 – 7.07 (m, 2H), 6.96 – 6.91 (m, 2H), 4.71 (d, J = 16.4 Hz,
1H), 4.30 (d, J = 16.4 Hz, 1H), 1.25 (s, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 169.6, 153.1 (dd, J = 31.9,
25.9 Hz), 147.6, 142.7, 138.2, 137.7, 132.5, 132.0, 130.6, 128.1, 126.8, 126.6, 125.9, 124.6 (d, J = 5.1 Hz),
123.5, 121.6 (dd, J = 5.6, 3.4 Hz), 114.0 (t, J = 251.9 Hz), 92.4 (dd, J = 30.6, 27.9 Hz), 43.3.
19
F NMR (470
MHz, Chloroform-d) δ -97.1 (d, J = 265.4 Hz, 1F), -114.0 (d, J = 265.0 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for
C 21H 17F 2N 2O 2 = 367.1258, found = 367.1257. FT/IR (n max (neat) cm-1): 2918, 2848, 1684, 1597, 1574, 1493,
1465, 1431, 1395, 1336, 1290, 1200, 1139, 1105, 1059, 1005, 943, 870, 787, 749, 693, 647, 622, 521, 421.
2-benzyl-3-(difluoro(phenyl)methyl)-3-hydroxy-6-(trifluoromethyl)isoindolin-1-one (2-2l)
Method A: Inside an argon glovebox, the isoindolinone 2-1l (0.25 mmol, 94.9 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame
dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 10%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2l in 73% yield (79 mg) as an off-white
powder (m.p.196-197˚C).
N
O
F
OH
F
F
3
C
110
Method B: On the benchtop, the isoindolinone derivative 2-1l (0.25 mmol, 94.9 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at
room temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting
mixture was stirred for 4 hours at 65
o
C. After this time, H 2O (100 L) was added and stirring was
continued at the same temperature for 60 h. After this time, no difluorinated product 2-2l could be
observed by
19
F NMR spectroscopy and no further efforts were pursued.
1
H NMR (600 MHz, Chloroform-
d) δ 7.92 (dt, J = 1.6, 0.7 Hz, 1H), 7.72 (ddd, J = 7.9, 1.7, 0.8 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.35 – 7.32
(m, 3H), 7.31 – 7.27 (m, 3H), 7.26 – 7.22 (m, 2H), 7.21 (d, J = 7.1 Hz, 2H), 5.03 (d, J = 15.4 Hz, 1H), 4.46 (d,
J = 15.4 Hz, 1H), 3.67 (s, 1H).
13
C NMR (151 MHz, Chloroform-d) δ δ 166.7, 145.5, 137.5, 133.4 (q, J = 33.1
Hz), 132.9, 132.0 (t, J = 25.4 Hz), 131.0, 129.1 (q, J = 3.6 Hz), 128.7, 128.5, 128.2, 127.8, 126.8 (t, J = 6.3
Hz), 124.9, 123.5 (q, J = 272.9 Hz), 120.9 (q, J = 3.9 Hz), 120.4 (t, J = 255.7 Hz), 91.5 (t, J = 30.8 Hz), 44.2
(t, J = 2.4 Hz).
19
F NMR (564 MHz, Chloroform-d) δ -63.2(s, 3F), -102.9 (d, J = 251.6 Hz, 1F), -107.0 (d, J =
251.8 Hz, 1F). HRMS-ES
+
(M
+
) Calcd. for C 23H 16F 5NO 2 = 433.11012, found = 433.11060. FT/IR (n max (neat)
cm-1): 3159, 2923, 1668, 1631, 1496, 1451, 1406, 1369, 1321, 1282, 1233, 1167, 1132, 1102, 1084,
1061, 1021, 977, 935, 925, 905, 880, 860, 839, 788, 773, 764, 756, 727, 693, 667, 647, 596, 526, 468,
410.
5-chloro-3-(difluoro(phenyl)methyl)-3-hydroxy-2-methylisoindolin-1-one (2-2m)
Method A: Inside an argon glovebox, the isoindolinone 2-1m (0.25 mmol, 67.4
mg), K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å
molecular sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed
into a flame dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled,
anhydrous acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was
N
O
F
OH
F
Cl
111
stirred for half an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc
(10 mL) and filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate
and the product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The
organic layer was separated, dried under MgSO 4, concentrated under reduced pressure and the product
was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined
fractions were then concentrated by rotary evaporation to afford the product 2-2m in 88% yield (71 mg)
as an off-white powder.
Method B: On the benchtop, the isoindolinone derivative 2-1m (0.25 mmol, 67.4 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 L) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 2-5 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc
(5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated, and the
product was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and
the combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The
combined fractions were the concentrated by rotatory evaporation. Obtained as an pale-yellow powder
(m.p.182-184˚C) in 74% yield (60mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.42 (t, J = 7.3 Hz, 1H), 7.37 –
7.26 (m, 6H), 7.21 (s, 1H), 4.53 (s, 1H), 2.91 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 167.1, 143.7,
138.4, 132.0 (t, J = 25.3 Hz), 130.9, 130.8 (t, J = 1.8 Hz), 130.1, 128.0, 126.6 (t, J = 6.4 Hz), 124.5 (t, J = 1.9
Hz), 124.2, 120.0 (dd, J = 256.4, 254.3 Hz), 90.2 (t, J = 30.7 Hz), 25.7 (t, J = 2.5 Hz).
19
F NMR (376 MHz,
Chloroform-d) δ -104.0 (d, J = 251.7 Hz, 1F), -107.9 (d, J = 251.5 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for
112
C 16H 13ClF 2NO 2 = 324.0603, found = 324.0602. FT/IR (n max (neat) cm-1): 3159, 2923, 1668, 1631, 1496, 1451,
1439, 1406, 1369, 1321, 1301, 1282, 1233, 1204, 1167, 1132, 1102, 1084, 1073, 1055, 1021, 977, 935,
925, 905, 880, 860, 839, 788, 773, 756, 727, 693, 667, 647, 596, 526, 468, 410.
3-(difluoro(phenyl)methyl)-3-hydroxy-2,6-dimethylisoindolin-1-one (2-2n)
Method A: Inside an argon glovebox, the isoindolinone 2-1n (0.25 mmol, 62.3 mg),
K 2CO 3 (1.2 equiv, 41.5 mg), finely ground, activated (350
o
C for 24h) 3 Å molecular
sieves (250 mg) and F-TEDA-PF 6, II (2.2 equiv, 260 mg) were weighed into a flame
dried crimp-top vial equipped with a magnetic stir bar. Outside the glovebox, freshly distilled, anhydrous
acetonitrile (2.5 ml) was then added under nitrogen flow via a syringe and the mixture was stirred for half
an hour at room temperature. Subsequently, the reaction mixture was diluted with EtOAc (10 mL) and
filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL) and subsequently washed with brine. The organic layer
was separated, dried under MgSO 4, concentrated under reduced pressure and the product was purified
by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The combined fractions were
then concentrated by rotary evaporation to afford the product 2-2n in 84% yield (64 mg) as an off-white
powder.
Method B: On the benchtop, the isoindolinone derivative 2-1n (0.25 mmol, 62.3 mg) and Selectfluor, F-
TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a screw-cap glass vial equipped with a with a magnetic
stir bar. Subsequently, MeCN (2.5 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 191 μl) was added via micropipette. The resulting mixture was
stirred for 4 hours at room temperature. After this time, H 2O (100 mL) was added and stirring was
continued at the same temperature for 16 h. After this time, complete disappearance of monofluoro
derivative 2-5 was observed by
19
F NMR spectroscopy. The reaction mixture was then diluted with EtOAc
N
O
F
OH
F
113
(5 mL) and poured into saturated aqueous NaHCO 3 (15 mL). The organic layer was separated and the
product was further extracted with EtOAc (3 times, 10 mL). The organic layer was washed with brine and
the combined organic layer was dried under MgSO 4, concentrated under reduced pressure and the
residue was purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 20%). The
combined fractions were the concentrated by rotatory evaporation. Obtained as a pale-yellow powder
(m.p.158-159˚C) in 84% yield (64 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.40 – 7.35 (m, 1H), 7.31 – 7.21
(m, 6H), 7.10 (d, J = 7.7 Hz, 1H), 4.17 (s, 1H), 2.91 (s, 3H), 2.34 (s, 3H).
13
C NMR (126 MHz, Chloroform-d)
δ 168.3, 140.9, 139.3, 132.7, 132.6 (t, J = 25.3 Hz), 132.0, 130.4, 127.8, 126.6 (t, J = 6.4 Hz), 123.6, 123.5,
120.3 (dd, J = 256.2, 253.9 Hz), 90.4 (t, J = 30.1 Hz), 25.6 (t, J = 2.6 Hz), 21.4.
19
F NMR (376 MHz, Chloroform-
d) δ -103.0 (d, J = 250.9 Hz, 1F), -108.7 (d, J = 250.9 Hz, 1F). HRMS-ES
+
(M+H
+
) Calcd. for C 17H 16NO 2F 2 =
304.1149, found = 304.1157. FT/IR (n max (neat) cm-1): 3214, 1673, 1617, 1470, 1451, 1437, 1404, 1377,
1318, 1277, 1167, 1136, 1101, 1081, 1061, 1042, 1013, 967, 930, 910, 877, 827, 770, 702, 668, 626, 573,
541, 525, 494, 472, 447, 430, 417.
1-gram scale reaction (2-2a)
Method B: On the benchtop, the isoindolinone derivative 2-1a (4.25 mmol, 999.9 mg)
and Selectfluor, F-TEDA-BF 4, I (3 equiv, 266 mg) were weighed into a flame-dried
round-bottom flask equipped with a with a magnetic stir bar and rubber septum.
Subsequently, MeCN (43 mL) was added by syringe. After stirring this mixture for 15 min at room
temperature, trifluoroacetic acid (10 equiv, 3.3 mL) was added via syringe. The resulting mixture was
stirred for 4 hours at 50
˚
C After this time, H 2O (100 mL) was added and stirring was continued at the same
temperature for 1 h (overall reaction time: 5 h). Upon cooling down to room temperature, the solution
was diluted with EtOAc (25 mL) and poured into saturated aqueous NaHCO 3 (50 mL). The organic layer
was separated, and the product was further extracted with EtOAc (3 times, 10 mL). The organic layer was
N
O
F
OH
F
114
washed with brine and the combined organic layer was dried under MgSO 4, concentrated under reduced
pressure and the residue was purified by flash column chromatography (EtOAc/Hexanes gradient from
0% to 15%). The combined fractions were the concentrated by rotatory evaporation. The product 2a was
isolated as an off-white solid (m.p. 151-152˚C) in 93% yield, 1.14 g.
Synthesis and NMR Spectroscopic Data of Fluoro-Olefin Derivatives
3-(fluoro(phenyl)methylene)isoindolin-1-one (2-5s)
On the benchtop, the isoindolinone derivative 2-1s (0.25 mmol, 55.3) and F-TEDA-BF 4, I
(1.05 eq, 93 mg) were weighed into a glass vial with a screw-cap with a magnetic stir bar.
Acetonitrile (2.5 ml) was added and the solution was stirred at room temperature for 1
hour. After this, trifluoroacetic acid (10 equiv, 191 mL) was added by syringe, and the
reaction mixture was stirred at 50
˚
C for 23 h. On cooling, the solution was neutralized with NaHCO 3. The
product was extracted with EtOAc (3 times, 10 mL), followed by washing with brine. The combined organic
layer was dried over MgSO 4 and concentrated by rotary evaporation to yield the product (98% yield, 59
mg) without need for further purification. NMR analysis shows only the presence of an inseparable
mixture of isomers with no other impurities. Obtained as an off-white powder (m.p.182-186˚C) in 98%
yield (59mg). (Inseparable mixture of geometric isomers in a 5:1 (Z:E) ratio as determined by proton and
fluorine NMR). Major isomer was assigned as the Z-isomer based on the
19
F NMR chemical shift and its
comparison with (Z) 3u . Reported shifts are from major isomer (Z) 2-3s for clarity.
1
H NMR (400 MHz,
Chloroform-d) δ 8.68 (s, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.71 – 7.63 (m, 2H), 7.56 – 7.50 (m, 3H), 7.46 (td, J =
7.4, 1.2 Hz, 1H), 7.39 (td, J = 7.5, 1.3 Hz, 1H), 7.34 (dt, J = 7.7, 1.1 Hz, 1H).
13
C NMR (126 MHz, Chloroform-
d) δ 166.8, 144.2 (d, J = 252.8 Hz), 134.7 (d, J = 6.6 Hz), 132.9, 132.0, 130.9 (d, J = 2.0 Hz), 130.2 (d, J = 23.3
Hz), 129.5 (d, J = 2.9 Hz), 129.2 (d, J = 5.2 Hz), 129.0, 124.2, 121.6 (d, J = 1.9 Hz), 119.4 (d, J = 20.8 Hz).
19
F
NH
O
F
115
NMR (376 MHz, Chloroform-d) δ -103.16 (s, 1F).
19
F NMR shift if the MINOR isomer: (376 MHz,
Chloroform-d) δ -128.26 (s, 1F). HRMS-ES
+
(M) Calculated for C 15H 10ONF = 239.07464, found = 239.07454.
FT/IR (n max (neat) cm-1): 3181, 3056, 1698, 1612, 1532, 1495, 1471, 1446, 1371, 1357, 1307, 1267, 1200,
1179, 1127, 1090, 1053, 1023, 908, 800, 757, 689, 641, 588, 544, 535, 477, 422, 408.
3-(fluoro(phenyl)methylene)-6-methylisoindolin-1-one (2-3t)
On the benchtop, the isoindolinone derivative 2-1t (0.25 mmol, 58.8) and F-TEDA-BF 4, I
(1.05 eq, 93 mg) were weighed into a glass vial with a screw-cap with a magnetic stir bar.
Acetonitrile (2.5 ml) was added and the solution was stirred at room temperature for 1
hour. After this, trifluoroacetic acid (10 equiv, 191 mL) was added by syringe, and the
reaction mixture was stirred at 50
˚
C for 23 h. On cooling, the solution was neutralized with NaHCO 3. The
product was extracted with EtOAc (3 times, 10 mL), followed by washing with brine. The combined organic
layer was dried over MgSO 4 and concentrated by rotary evaporation to yield the product (98% yield, 59
mg) without need for further purification. NMR analysis shows only the presence of an inseparable
mixture of isomers with no other impurities. Obtained as an off-white powder (m.p.192-197˚C) in 97%
yield (61mg). (Inseparable mixture of geometric isomers in a 4:1 (Z:E) ratio as determined by
1
H and
19
F
NMR). Major isomer was assigned as the Z-isomer based on the
19
F NMR chemical shift and its comparison
with Z-3u and Z-3v . Reported shifts are from major isomer (Z) 2-3b for clarity.
1
H NMR (400 MHz,
Chloroform-d) δ 7.93 (br. s, 1H), 7.72 – 7.69 (m, 1H), 7.68 – 7.64 (m, 1H), 7.64 – 7.60 (m, 1H), 7.55 – 7.48
(m, 3H), 7.25 – 7.18 (m, 2H), 2.43 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 166.5, 143.6 (d, J = 250.9
Hz), 139.6 (d, J = 2.4 Hz), 134.1, 133.2, 130.7 (d, J = 2.0 Hz), 129.9, 129.4 (d, J = 3.2 Hz), 129.0, 126.7 (d, J =
5.2 Hz), 124.4, 121.4 (d, J = 2.0 Hz), 119.3 (d, J = 20.7 Hz), 21.6 (d, J = 3.1 Hz).
19
F NMR (376 MHz,
Chloroform-d) δ -105.1 (s, 1F).
19
F NMR shift if the MINOR isomer: (376 MHz, Chloroform-d) δ -129.38 (s,
1F). HRMS-ES
+
(M) Calculated for C 16H 12ONF = 253.09029, found = 253.09035. FT/IR (n max (neat) cm-1):
NH
O
F
116
3154, 3054, 1693, 1486, 1446, 1400, 1382, 1351, 1316, 1294, 1258, 1221, 1139, 1091, 1074, 1040, 1022,
926, 823, 791, 768, 700, 685, 655, 641, 617, 554, 546, 510, 463, 437, 410.
(Z)-3-(fluoro(phenyl)methylene)-2-methylisoindolin-1-one ((Z) 2-3u)
On the benchtop, the isoindolinone derivative 2-1u (0.25 mmol, 58.8 mg) and F-TEDA-BF 4,
I (1.05 eq, 93 mg) were weighed into a glass vial with a screw-cap with a magnetic stir bar.
Acetonitrile (2.5 ml) was added and the solution was stirred at room temperature for 1
hour. After this, trifluoroacetic acid (10 equiv, 191 µL) was added by syringe, and the
reaction mixture was stirred at 80
˚
C for 23 h. On cooling, the solution was neutralized with NaHCO 3. The
product was extracted with EtOAc (3 times, 10 mL), followed by washing with brine. The combined organic
layer was dried over MgSO 4 and concentrated by rotary evaporation. Purified by flash column
chromatography (EtOAc/Hexanes gradient from 0% to 15% to yield the product as an off-white powder
(m.p.125-128˚C) in 90% combined yield (57 mg) of geometrical isomers in a 2:1 (Z:E) ratio as determined
by
19
F NMR. The two isomers could be separated by flash column chromatography. The stereochemistry
(Z) was assigned based on the observed coupling of the fluorine atom with the N-methyl protons).
1
H NMR
(399 MHz, Chloroform-d) δ 7.85 (ddt, J = 7.6, 1.3, 0.6 Hz, 1H), 7.66 – 7.61 (m, 2H), 7.59 – 7.51 (m, 3H), 7.38
(td, J = 7.5, 0.9 Hz, 1H), 7.28 – 7.21 (m, 1H), 6.83 (ddt, J = 8.0, 2.1, 0.8 Hz, 1H), 3.64 (dd, J = 5.4, 2.0 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 166.7, 144.7 (d, J = 258.0 Hz), 134.8 (d, J = 7.5 Hz), 131.6, 131.4, 131.0
(d, J = 2.8 Hz), 130.4 (d, J = 2.2 Hz), 129.5 (d, J = 5.6 Hz), 129.2 (d, J = 1.8 Hz), 128.7 (d, J = 1.8 Hz), 123.6,
121.5 (d, J = 1.5 Hz), 121.4 (d, J = 14.2 Hz), 29.7 (d, J = 10.7 Hz, (CH 3 C–F coupling).
19
F NMR (376 MHz,
Chloroform-d) δ -103.4 (q, J = 5.7 Hz, (CH 3) H–F coupling, 1F). HRMS-ES
+
(M+H
+
) Calculated for C 16H 13ONF
= 254.0981, found = 254.0983. FT/IR (n max (neat) cm-1): 3057, 3022, 2955, 29202850, 1698, 1474, 1443,
1428, 1376, 1338, 1302, 1242, 1210, 1192, 1162, 1085, 1066, 1038, 1017, 945, 918, 850, 762, 689, 639,
614, 549, 479, 435, 420.
N
O
F
117
(E)-3-(fluoro(phenyl)methylene)-2-methylisoindolin-1-one ((E)-3u)
(m.p.65-66˚C)
1
H NMR (500 MHz, Chloroform-d) δ 8.06 (dt, J = 7.8, 1.1 Hz, 1H), 7.90
(dq, J = 7.6, 0.9 Hz, 1H), 7.64 (tt, J = 7.6, 1.0 Hz, 1H), 7.56 (dddd, J = 6.3, 3.3, 1.6, 0.8 Hz,
2H), 7.53 – 7.48 (m, 4H), 2.90 (d, J = 0.7 Hz, 3H).
13
C NMR (126 MHz, Chloroform-d) δ
168.1 (d, J = 1.8 Hz), 146.9 (d, J = 247.5 Hz), 135.7 (d, J = 2.5 Hz), 132.6, 131.2, 131.0, 130.6 (d, J = 2.7 Hz),
130.4 (d, J = 2.4 Hz), 130.2 (d, J = 2.7 Hz), 129.1 (d, J = 1.9 Hz), 128.5 (d, J = 1.3 Hz), 124.5 (d, J = 15.9 Hz),
123.5, 30.7.
19
F NMR (376 MHz, Chloroform-d) δ -110.1 (s, 1F). HRMS-ES
+
(M+H
+
) Calculated for C 16H 13ONF
= 254.0981, found = 254.0981. FT/IR (n max (neat) cm-1): 3054, 2919, 2849, 1700, 1678, 1493, 1472, 1443,
1427, 1368, 1339, 1303, 1240, 1208, 1190, 1156, 1060, 1040, 1021, 966, 920, 823, 763, 720, 687, 639,
625, 614, 549, 473, 418.
(Z)-3-(fluoro(phenyl)methylene)-2-methylisoindolin-1-one (2-3u)
On the benchtop, the isoindolinone derivative 2-1u (0.25 mmol, 66.3 mg) and F-TEDA-
BF 4, I (1.05 eq, 93 mg) were weighed into a glass vial with a screw-cap with a magnetic
stir bar. Acetonitrile (2.5 ml) was added and the solution was stirred at room temperature
for 1 hour. After this, trifluoroacetic acid (10 equiv, 191 µL) was added by syringe, and
the reaction mixture was stirred at 80
˚
C for 23 h. On cooling, the solution was neutralized with NaHCO 3.
The product was extracted with EtOAc (3 times, 10 mL), followed by washing with brine. The combined
organic layer was dried over MgSO 4 and concentrated by rotary evaporation. Purified by flash column
chromatography (EtOAc/Hexanes gradient from 0% to 15%). Obtained as an off-white powder (m.p.131-
134˚C) in 90% combined yield (64 mg) of geometrical isomers in a 3:1 (Z:E) ratio as determined by
19
F
NMR. The stereochemistry (Z) was assigned based on the observed coupling of the fluorine atom with the
N-methyl protons). Minor isomer could not be isolated. Shifts reported correspond to the major isomer
N
O
F
N
O
F
MeO
118
(Z) 3u.
1
H NMR (400 MHz, Chloroform-d) δ 7.84 (dt, J = 7.6, 1.0 Hz, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.37 (td, J
= 7.3, 0.9 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.04 (dd, J = 7.9, 1.0 Hz, 2H), 6.87 (ddd, J = 7.9, 1.9, 0.8 Hz, 1H), 3.92
(s, 3H), 3.63 (dd, J = 5.4, 1.1 Hz, 3H).
13
C NMR (101 MHz, Chloroform-d) δ 166.5, 161.5 (d, J = 2.2 Hz), 144.7
(d, J = 258.4 Hz), 134.9 (d, J = 7.3 Hz), 131.8 (d, J = 14.3 Hz), 129.3 (d, J = 5.6 Hz), 123.7, 123.5, 123.4, 121.3,
120.7, 120.6, 114.4 (d, J = 9.4 Hz), 55.4, 29.5 (d, J = 11.2 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -101.3
(q, J = 4.9 Hz, 1F).
19
F NMR shift if the MINOR isomer: (376 MHz, Chloroform-d) δ -108.0 (s, 1F). HRMS-ES
+
(M+H
+
) Calculated for C 17H 15O 2NF = 284.1087, found = 284.1078. FT/IR (n max (neat) cm-1): 2916, 2850,
1697, 1606, 1511, 1472, 1424, 1309, 1242, 1175, 1036, 1027, 837, 815, 766, 694, 681, 577, 544, 507, 476,
445.
General Procedure for the Synthesis of Trifluorinated Derivatives 2-4
Note: F-TEDA-BF 4 (I) contains intrinsic amounts of H 2O. Best yields of trifluorinated derivatives 2-4 are
obtained by pre-drying I under high vacuum over a P 2O 5 trap for at least 24 h at room temperature. Drying
the substrates 2-1 in a similar manner is highly recommended. In this way, large amounts of hydroxy-
derivatives 2-2 and 2-5 could be avoided, offering good selectivity for 2-4. In addition, pre-treatment of
all reactants/reagents with molecular sieves is highly recommended. The obtained trifluorinated products
2-5, may be stored in a glovebox without appreciable decomposition, however they slowly hydrolyze to
difluorinated products 2-2 if left on the bench top.
119
Synthesis and NMR Spectroscopic Data of Trifluorinated Derivatives 2-4
3-(difluoro(phenyl)methyl)-3-fluoro-2-methylisoindolin-1-one (2-4w)
Inside an argon glovebox, the isoindolinone derivative 2-1w (0.25 mmol, 58.8 mg),
K 2CO 3 (1.5 equiv, 51.8 mg), anhydrous KF (2.0 equiv, 29 mg) and finely ground,
activated (300
o
C for 24 h) 3 Å molecular sieves (250 mg) were weighed into a flame-
dried crimp-top vial equipped with a magnetic stir bar. Into a second flame-dried crimp-top vial was added
Selectfluor, I (2.5 equiv, 221.5 mg) and 3 Å molecular sieves (250 mg). Outside the glovebox, anhydrous
acetonitrile (1 ml) was then added to both vials under nitrogen flow via a syringe and both vials were
stirred for 30 min. After this pre-drying process, the contents of the vial containing I were transferred in
one portion to the vial containing substrate 2-1w, K 2CO 3 and KF. Subsequently, this mixture was stirred
for 30 min at room temperature, after which, the contents were diluted with EtOAc and filtered through
a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the product was extracted
with EtOAc (3 times, 10mL). The organic layer was subsequently washed with brine, separated, dried
under MgSO 4 and purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 10%).
The combined fractions were concentrated by rotary evaporation to afford 2-4w (80% yield, 58 mg) as a
white solid (m.p.82-84˚C).
1
H NMR (399 MHz, Chloroform-d) δ 7.74 – 7.67 (m, 1H), 7.54 (ddt, J = 6.5, 3.7,
1.8 Hz, 2H), 7.46 – 7.36 (m, 2H), 7.33 (d, J = 4.1 Hz, 4H), 3.12 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ
168.1 (d, J = 2.6 Hz), 138.3 (d, J = 17.6 Hz), 132.6, 131.9, 131.8 (t, J = 25.1 Hz), 131.7, 131.2, 128.4, 126.5
(td, J = 6.4, 1.6 Hz), 124.4 (d, J = 3.2 Hz), 123.7, 119.2 (td, J = 255.2, 35.4 Hz), 102.9 (dt), 26.2.
19
F NMR (376
MHz, Chloroform-d) δ -104.3 (dd, J = 258.1, 17.1 Hz, 1F), -108.1 (dd, J = 258.0, 15.0 Hz, 1F), -150.7 (t, J =
16.0 Hz, 1F). HRMS EI
+
Calculated for C 16H 12F 3NO (M
+
) = 291.08710, found = 291.08726. FT/IR (n max (neat)
cm-1): 3058, 2955, 1725, 1699, 1675, 1653, 1647, 1613, 1587, 1559, 1494, 1456, 1442, 1427, 1427, 1368,
N
O
F
F
F
120
1338, 1302, 1280, 1243, 1211, 1180, 1162, 1106, 1085, 1066, 1043, 1017, 958, 944, 908, 889, 837, 761,
700, 672, 639, 616, 549, 509, 749, 440, 420.
3-(difluoro(4-(trifluoromethyl)phenyl)methyl)-3-fluoro-2-methylisoindolin-1-one (2-4x)
Inside an argon glovebox, the isoindolinone derivative 2-1x (0.25 mmol, 75.8 mg),
K 2CO 3 (1.5 equiv, 51.8 mg), anhydrous KF (2.0 equiv, 29 mg) and finely ground,
activated (300
o
C for 24h) 3 Å molecular sieves (250 mg) were weighed into a
flame-dried crimp-top vial equipped with a magnetic stir bar. Into a second flame-dried crimp-top vial was
added Selectfluor, I (2.5 equiv, 221.5 mg) and 3 Å molecular sieves (250 mg). Outside the glovebox,
anhydrous acetonitrile (1 ml) was then added to both vials under nitrogen flow via a syringe and both vials
were stirred for 30 min. After this pre-drying process, the contents of the vial containing I were transferred
in one portion to the vial containing substrate 2-1x, K 2CO 3 and KF. Subsequently, this mixture was stirred
for 30 min at room temperature, after which, the contents were diluted with EtOAc and filtered through
a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the product was extracted
with EtOAc (3 times, 10 mL). The organic layer was subsequently washed with brine, separated, dried
under MgSO 4 and purified by flash column chromatography (EtOAc/Hexanes gradient from 0% to 10%).
The combined fractions were concentrated by rotary evaporation to afford 2-4x as a pale-yellow oil (73 %
yield, 65.5 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.75 – 7.72 (m, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.59 –
7.56 (m, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.41 – 7.36 (m, 1H), 3.14 (t, J = 1.7 Hz, 3H).
13
C NMR (100 MHz,
Chloroform-d) δ 168.0, 137.8 (dd, J = 17.7, 1.6 Hz), 135.5 (td, J = 26.7, 1.2 Hz), 133.3 (q, J = 33.0 Hz), 132.8
(d, J = 1.7 Hz), 132.0 (d, J = 1.8 Hz), 131.9, 127.2 (td, J = 6.4, 1.8 Hz), 125.5 (q, J = 3.8 Hz), 124.3 (d, J = 2.9
Hz), 124.1, 123.5 (q, J = 272.8 Hz), 118.7 (td, J = 255.9, 36.3 Hz), 102.6 (ddd, J = 224.6, 31.8, 30.4 Hz), 26.3
(t, J = 2.8 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -63.6 (s, 3F), -104.6 (dd, J = 260.5, 17.2 Hz, 1F), -108.3
(dd, J = 260.5, 14.6 Hz, 1F), -150.6 (t, J = 15.9 Hz, 1F). HRMS EI+ Calculated for C 17H 12F 6NO (M
+
) = 360.08229,
N
O
F
F
F
CF
3
121
found = 360.08244. FT/IR (n max (neat) cm-1): 3086, 2960, 1731, 1470, 1428, 1412, 1364, 1323, 1300, 1275,
1170, 1127, 1090, 1071, 1052, 1012, 961, 923, 915, 835, 820, 758, 690, 673, 663, 631, 598, 540, 475, 468,
456, 440, 419.
3-(difluoro(4-methoxyphenyl)methyl)-3-fluoro-2-methylisoindolin-1-one (2-4y)
Inside an argon glovebox, the isoindolinone derivative 1-4y (0.25 mmol, 66.3
mmol), K 2CO 3 (1.5 equiv, 51.8 mg), anhydrous KF (2.0 equiv, 29 mg) and finely
ground, activated (300
o
C for 24h) 3 Å molecular sieves (10 wt %, 250 mg) were
weighed into a flame-dried crimp-top vial equipped with a magnetic stir bar. Into a second flame-dried
crimp-top vial was added F-TEDA-BF 4 (2.5 equiv, 221.5 mg) and 3 Å molecular sieves (250 mg). Outside
the glovebox, anhydrous acetonitrile (1 ml) was then added to both vials under nitrogen flow via a syringe
and both vials were stirred for 30 min. After this pre-drying process, the contents of the vial containing I
were transferred in one portion to the vial containing substrate 1-4y, K 2CO 3 and KF. Subsequently, this
mixture was stirred for 30 min at room temperature, after which, the contents were diluted with EtOAc
and filtered through a short plug of celite. A saturated NaHCO 3 solution was added to the filtrate and the
product was extracted with EtOAc (3 times, 10mL). The organic layer was subsequently washed with brine,
separated, dried under MgSO 4 and purified by flash column chromatography (EtOAc/Hexanes gradient
from 0% to 15%). Obtained as a colorless oil (65 % yield, 52 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.74
– 7.69 (m, 1H), 7.58 – 7.52 (m, 2H), 7.45 – 7.38 (m, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H),
3.80 (s, 3H), 3.12 (t, J = 1.7 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 168.2 (d, J = 2.4 Hz), 161.6 (t, J =
1.7 Hz), 138.5 (dd, J = 17.6, 1.8 Hz), 132.5 (d, J = 1.6 Hz), 132.0, 131.6 (d, J = 1.9 Hz), 128.0 (td, J = 6.4, 1.7
Hz), 124.4 (d, J = 3.5 Hz), 123.8 (t, J = 25.7 Hz), 123.7, 119.4 (td, J = 255.1, 35.5 Hz), 113.7, 102.9 (ddd, J =
224.0, 33.5, 31.4 Hz), 55.5, 26.2 (t, J = 2.7 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -103.1 (dd, J = 257.1,
17.5 Hz, 1F), -106.9 (dd, J = 257.0, 15.8 Hz, 1F), -150.6 (t, J = 16.6 Hz, 1F). HRMS EI+ (M
+
) Calculated for
N
O
F
F
F
OMe
122
C 17H 14F 3NO 2 = 321.09766, found = 321.09737. FT/IR (n max (neat) cm-1): 3079, 2949, 1727, 1672, 1614,
1516, 1478, 1366, 1309, 1281, 1254, 1178, 1126, 1085, 1039, 960, 910, 829, 759, 682, 639, 633, 597, 562,
536, 488, 455, 442, 419.
Table 2.S2 Evaluation of various chiral Brønsted acid catalyst for enantioselective thiol addition
Entry catalyst temperature (ºC) time (h) conversion (%)
1 TRIP-OH rt 24 0
2 9-Anthryl-OH rt 24 0
3 TRIP-NHTf rt 24 0
4 9-Anthryl-NHTf (cat A) rt 24 25
5 9-Anthryl-NHTf (cat A) 50 12 100
NH
O
CF
2
Ph
OH
Chiral
catalyst
DCM,
Temperature
time
NH
O
Ph
S
F
F
OMe
BINOL Phosphoric acid derived:
TRIP-OH= Ar = 2,4,6-(iPr)
3
-C
6
H
2
; X = OH
9-anthryl-OH = Ar = 9-anthryl; X = OH
Triflimide Derived:
TRIP-NHTf= Ar = 2,4,6-(iPr)
3
-C
6
H
2
; X = NHTf
(Cat A) 9-anthryl-OH = Ar = 9-anthryl; X = NHTf
SH
OMe
+
O
P
O
O
X
Ar
Ar
Tf = trifluoromethanesulfonyl
2b (+)6
123
Procedure for the Enantioselective Thiol Addition using Catalyst A
In a crimp-top vial, the isoindolinone (14 mg, 0.05 mmol) and catalyst A (4 mg, 10 mol %) were added and
the vial was evacuated and filled with nitrogen (3 times). Subsequently, DCM (1 mL) and p-
methoxythiophenol, PMP–SH (31 µL, 0.25 mmol, 5 equiv) were subsequently added. The reaction mixture
was then introduced into a pre-heated oil bath at 50 ºC and stirred overnight at that temperature. Solvents
were then removed and the crude reaction mixture subjected to flash chromatography purification on
silica gel using mixtures of hexane:ethyl acetate as eluent (5:1-2:1).
(S)-3-(difluoro(phenyl)methyl)-3-((4-methoxyphenyl)thio)isoindolin-1-one (+)
The title compound was synthesized following the procedure shown above using 14
mg, 0.05 mmol of the isoindolinone to afford the product as a white solid (m.p.207-
209˚C) (12 mg, 0.03mmol, 60%).
1
H NMR (300 MHz, Chloroform-d): 7.74 (1H, d, J =
7.8 Hz), 7.53 (1H, ddd, J = 7.8, 6.6, 2.0 Hz), 7.34-7.10 (7H, m), 7.08-6.87 (m, 2H), 6.64-
6.39 (m, 2H), 6.29 (br s, 1H), 3.62 (s, 3H).
13
C NMR (125 MHz): 169.2, 161.5, 143.8,
139.4, 132.7 (t, J = 22.5 Hz), 131.6, 130.9, 129.9, 128.2, 127.2 (t, J = 6.3 Hz), 125.1, 123.8, 123.0 (t, J =
253.5), 118.0, 114.6, 77.2 (t, J = 30 Hz), 55.6;
19
F NMR (282 MHz, Chloroform-d): -99.2 (1F, d, J = 248.5 Hz),
-100.4 (1F, d, J = 248.6 Hz). HRMS-ES
+
(M+H
+
) Calculated for C 22H 18F 2NO 2S = 398,1026, found = 398,1021.
IR (n max cm
-1
) 3884, 3072, 1697, 1589, 1439, 1248. The enantiomeric excess of the product was determined
by HPLC: Phenomenex amylose-1 (25 cm x 0.46 cm column), hexane:isopropanol 80:20 (v:v) as eluent and
flow = 2 ml/min.: t R major= 9.4 min, t R minor = 13.3 min. [α] D
25
= +22.0 (c 1.0; CHCl 3).
NH
O
S
CF
2
Ph
OMe
124
HPLC Chromatogram of (rac) N/S-aminal
HPLC Chromatogram of (+)6
125
Figure 2.S3 Proposed Transition State Model for Stereochemical Outcome.
Regarding the stereochemical outcome, we propose that the reaction proceeds through a transition state
analogous to the one recently reported by Gredičak in agreement with Simon and Goodman’s model, thus
we tentatively assign (+) product as the S enantiomer. The corresponding N-Me analogue was subjected
to the aforementioned reaction conditions affording the addition product as a racemate, implying the
participation of hydrogen bonding with the N–H moiety in the enantiodifferentiating transition state.
231
126
Chapter 3: C(sp
2
)–H Trifluoromethylation of enamides using TMSCF
3
: access to
trifluoromethylated isoindolinones, isoquinolinones, 2-pyridinones and other
heterocycles
3.i Introduction
Our paper on the gem-difluoromethylation of isoindolinones (see Chapter 2), encouraged us to explore
the reactivity of the enamide moiety towards other fluorine-containing electrophiles. Our group’s
development of the Ruppert-Prakash reagent (TMSCF 3) as a mild source of trifluoromethide
21,22
and the
range of transformations inspired by it
232
led us to look into how we could use this silane to oxidatively
add a –CF 3 group to the enamide functionality. Enamides are found in many naturally occurring substances
and designed pharmaceuticals. They are also quintessential synthetic intermediates in the preparation of
heterocycles, chiral amines and amides.
233–235
This chapter describes our efforts on performing an
oxidative C(sp
2
)–H trifluoromethylation of pyridinones, isoindolinones and isoquinolinones, which are all
important classes of enamide-containing heterocycles (Figure 3.1). Interestingly, the nucleophilic center
of a pyridinone is unlike that of an enamide, despite the structural similarities. See Figure 3.2 for the
differences between pyridinones and other enamide-containing heterocycles.
Since the early 1900s, researchers have been interested in the modified biological activity
bestowed upon APIs (active pharmaceutical ingrediants) and pharmaceutical building blocks by the
addition of a trifluoromethyl group.
9
The potential for novel therapeutics and material with enhanced
properties has birthed an ever-increasing demand for new trifluoromethylation procedures.
3–6,207
Modern
efforts can be divided based on the nature of the reactive –CF 3 moiety into electrophilic/radical,
236-237
and
127
nucleophilic
21,22,232
trifluoromethylation reactions. Of these categories, electrophilic trifluoromethylation
is relatively newer, and its development has permitted hitherto unknown transformations on nucleophilic
substrates. This is in stark contrast to nucleophilic trifluoromethylation, which operates on electrophilic
substrates.
Figure 3.1 Examples of relevant APIs containing the enamide functionality.
NH
OMe
MeO
O
O
O
Me
2
N
S
O O
OH O
N
H
S
N
N
Ph
O
N
OMe
MeO
O
O
O
N
S
O
O OH
H
H
N
Phg
N
N
O
O
HO
O
Fumaridine Meloxicam Pirfenidone
8-Oxoberberine Cefalexin
(Phg = phenylglycine)
(S)-Camptothecin
128
Figure 3.2 Difference between pyridinones and other enamide-heterocycles
Figure 3.3 Reagents employed in the direct trifluoromethylation of enamides
There are few reported methods to directly trifluoromethylate enamides. Togni’s reagent and
Umemoto’s reagent have been used to perform electrophilic trifluoromethylations of the nucleophilic b-
carbon of enamides.
238–240
Despite their demonstrated reactivity, the practicality of these reagents is
limited by their high cost and sensitivity to ambient conditions (they tend to be shock sensitive
241
). 2-
pyridinones can be trifluoromethylated using an in-situ generated trifluoromethyl radical obtained from
reagents III, IV, V, VI or VII (See Figure 3.3), either with oxidants like XeF 2 or a combination of an oxidant
with expensive additives like Rh, Ru, Ir catalysts.
242–250
Oxidative trifluoromethylation has been proposed
NH
O
N
O
R
1
R
2
H
N
O
R
nucleophilic carbon
2-pyridinone isoindolin-1-one isoquinolin-1-one
nucleophilic carbon
nucleophilic carbon
E
+
(electrophile)
E
+
(electrophile)
E
+
(electrophile)
NH
O
E
N
O
R
1
R
2
E
N
O
R
E
I
O
O
CF
3
S
CF
3
BF
4
—
CF
3
SO
2
Cl
III
CF
3
SO
2
Na
IV
CF
3
I
V
(CF
3
CO
2
)O
VI
CF
3
CO
2
H / XeF
2
VII
I II
129
as a feasible alternative to these specialized reagent systems, wherein a CF 3
–
source first generates a
trifluoromethide ion which is subsequently oxidized by an external oxidant (Figure 3.4).
23
TMSCF 3 was
chosen as our CF 3
–
source since it is an inexpensive and readily-available reagent. Figure 3.4 depicts our
proposed reaction pathway. Upon reaction with an activator (such as KF), TMSCF 3 releases
trifluoromethide. A ligand exchange at the oxidant forms the electrophilic trifluoromethylating complex
3i 1. Homolytic cleavage of this species produces an electrophilic trifluoromethyl radical, which would react
with the nucleophilic b-carbon of the enamide moiety. Subsequent oxidation of the thus formed radical
species will result in the formation of product 3-2.
Figure 3.4 Proposed reaction pathway
Our mechanistic hypothesis provides insight into a possible competing reaction which would
negatively impact the desired transformation. The choice of activator is crucial, since it must react faster
with TMSCF 3 than with the oxidant. Fluorides were chosen due to their lowered tendency to get oxidized.
3.ii Results and Discussion
TMSCF
3
KF
[KCF
3
]
I
R
X X
I
R
X CF
3
+ KX
(oxidant)
3i
1
3i
1
bond homolysis I
R
X
CF
3 +
CF
3
N
O
R
N
O
R
H CF
3
3
O
3
O
N
O
R
CF
3
3-2
X
—
130
Isoindolinone 3-1a was selected as our model substrate for optimization studies, the results of which are
summarized in Table 3.1.
See the Experimental Section for a full optimization table with all performed
trials. The combination of diacetoxyiodobenzene (PIDA), TMSCF 3 and KF was successful in producing the
desired trifluoromethylated product 3-2a. However, the conversion to 3-2a was only 22% (trial 1).
Substituting PIDA with bis(trifluoroacetoxy)iodobenzene (PIFA) increased the reaction yield to 42% of 3-
2a (trial 2). This result contrasts with previous reports of analogous systems with other nucleophilic
substrates wherein switching the oxidant from PIDA to PIFA decreased the yield or gave no conversion to
product.
251,252
Lowering the loadings of PIFA and KF to 1.5 equivalents each increased the yield (trial 4).
Table 3.1 Optimization table
a
trial Solvent Oxidant
(equiv)
TMSCF 3
(equiv)
KF
(equiv)
Additive
(equiv)
Yield
(%)
b
1 CH 3CN PIDA (2) 4 4 - 22
2 CH 3CN PIFA (2) 4 4 - 42
3 CH 3CN PIFA (2) 2 2 - 52
4 CH 3CN PIFA (1.5) 1.5 1.5 - 52
5 CH 3CN PIFA (1.5) 1.5 1.5 CuCl (0.1) 59
6 CH 3CN PIFA (1.5) 1.5 1.5 Cu(OTf) 2 (0.1) 56
7 CH 3CN PIFA (1.5) 1.5 1.5 Fe(OAc) 2 (0.1) 7
8 CH 3CN PIFA (1.5) 1.5 1.5 ZnCl 2 (0.1) 30
9 CH 3CN PIFA (1.5) 1.5 1.5 Cu(OAc) 2 (0.1) 62
10 CH 3CN PIFA (1.5) 2.0 1.5 Cu(OAc) 2 (0.3) 73
11 CH 3CN PIFA (1.5) 1.5 1.5 Cu(OAc) 2 (1.0) 39
a
Conditions: 3-1a (0.25 mmol), solvent (2.5 mL), 0.1 equiv of additive unless otherwise specified, room temperature for 1h.
b
Yield of 3-2a determined by
19
F NMR spectroscopy using PhCF 3 as internal standard. PIFA = bis(trifluoroacetoxy)iodobenzene;
PIDA = diacetoxyiodobenzene; 3-2a was obtained as a (3:1) mixture of E:Z isomers in all cases.
N
O
Me N
O
Me
oxidant
KF
TMSCF
3
conditions
F
3
C
3-1a 3-2a
131
Assuming that our reaction proceeds via the formation of an in situ Togni-type reagent (with an
I
III
—CF 3 bond), we drew inspiration from prior studies wherein redox-active and/or Lewis acidic additives
proved beneficial for the reaction outcome when Togni’s reagent was the trifluoromethylation reagent.
238,253
Trials 5 to 11 were performed to screen for potential additives. Adding 10 mol% of Cu(I)Cl slightly
increased the yield to 59% of 3-2a, while equal loadings of Cu(OTf) 2, Fe(OAc) 2 or ZnCl 2 gave diminished
yields. In contrast, Cu(OAc) 2 provided the highest conversion of 62% 3-2a (trial 9). Subsequent
optimization revealed that 2 equiv of TMSCF 3 and 0.3 equiv of Cu(OAc) 2 afforded 3-2a in 73% yield, while
conducting the reaction in the presence of 1 equiv Cu(OAc) 2 significantly inhibited the formation of 3-2a
(trials 10 and 11 respectively).
Next, we explored the generality of our C(sp
2
)–H trifluoromethylation conditions (Figure 3.5). In
general, N–H groups were not tolerated. This is likely because the acid-base reaction between the in-situ
formed trifluoromethide and the N–H proton is kinetically more facile than the desired outcome. Aryl-
substituted isoindolinones responded well, affording trifluoromethylated products 3-2a to 3-2d in good
isolated yields (63 - 73%) as mixtures of E:Z isomers in a 4:1 to 3:1 ratio. A slightly decreased yield was
observed in 3-2c, possessing an electron-withdrawing CF 3-group. Isoindolinone 3-1e produces the 1,2-
hydroxytrifluoromethylation product 3-2e in 40% yield. Compounds 2f, 2g and 2h required higher loadings
of the reagents to be produced in good yields. The difference in steric environments between the exocyclic
alkene of the isoindolinone and the endocyclic alkene of the isoquinolinones may be the reason for this
difference in reactivity. The bromo substituent in example 2h was found amenable to the reaction
conditions, allowing for downstream chemical elaborations.
132
Figure 3.5 Reaction scope of the C(sp
2
)–H trifluoromethylation
a
b
3:1 ratio of E:Z isomers.
c
4:1 ratio of E:Z isomers.
d
KF (3 equiv), PIFA (3 equiv) and TMSCF 3 (4.5 equiv) was used.
e
A second
portion of KF (1.5 equiv), PIFA (1.5 equiv) and TMSCF 3 (2 equiv) was added after 1 h. See Experimental Section for complete
experimental details. Bn = benzyl
R
2
N
R
1
O
H
R
3
N
O
R
1
R
2
R
2
N
R
1
O
CF
3
R
3
N
O
R
1
R
2
F
3
C
KF (1.5 equiv)
PIFA (1.5 equiv)
Cu(OAc)
2
(0.3 equiv)
TMSCF
3
(2.0 equiv)
CH
3
CN (0.1M)
3-1 3-2
N
O
Me
F
3
C
N
O
Me
F
3
C
N
O
Me
F
3
C
N
O
Me
F
3
C
N
O
Me
Me
F
3
C
CF
3
OMe
OH
3-2a
73%
b
3-2b
61%
b
3-2c
69%
b
3-2d
63%
c
3-2e
40%, d.r = 4:1
isoindolinones
N
O
Me
CF
3
N
O
Ph
CF
3
N
O
Me
CF
3
Br
isoquinolinones
3-2f
54%
d
3-2g
44%
d
3-2h
55%
d
N
F
3
C
O
Me
3-2i
73%
N
F
3
C
O
3-2j
78%
N
F
3
C
O
3-2k
79%
OMe
N
F
3
C
O
3-2l
50%
N
F
3
C
O
3-2m
66%
Ac
N
F
3
C
O
3-2n
70%
NO
2
N
F
3
C
O
3-2o
48%
CHO N
F
3
C
O
3-2p
68%
BnO
N
F
3
C
O
3-2q
44%
Me
2-pyridinones
N
Ac
CF
3
Ph
N
Ac H
H
CF
3
S
N
CF
3
COOEt
N
N
O
Me
O
N
N
CF
3
3-2r
77%
d
3-2s
0%
3-2t
32%
e
3-2u
56%
e
O
O
miscellaneous
OR OR
133
As stated earlier (Figure 3.2), pyridinones display different reactivity from other heterocyclic
enamides. Under the optimized reaction conditions, N-methyl- and N-phenyl-2-pyridinone (1i and 1j,
respectively) provided high yields of the corresponding 3-trifluoromethyl products (73% and 78%,
respectively). Since N–H bonds were not tolerated under the reaction conditions, we tested various N
protecting groups. N-Bn (3-2l) and N-paramethoxyphenyl (3-2k) groups remained unaltered after the
reaction ran its course. Subsequently, several N-aryl 2-pyridinones were subjected to the optimized
conditions. Nucleophilic trifluoromethylation did not occur at the aldehyde or ketone group of 3-2m and
3-2o, only furnishing the desired product with very good chemoselectivity. These results are notable, as
they allow for further product functionalization.
The electron withdrawing N-phenyl substituents in examples 3-2m to 3-2o decreased the yield
(48-58%). Fortunately, the yields could be successfully increased by adding a second portion of reagents
to the initial reaction mix. Benzyloxy-substituted 2-pyridinone 3-1p afforded the corresponding product
in 68% yield. A trifluoromethylated analogue of pirfenidone (a drug used for the treatment of idiopathic
pulmonary fibrosis) was produced in 44% yield using this procedure (3-2q). Reaction with a tetralone-
derived enamide afforded 3-2r in a good isolated yield (77%). Noteworthy is the absence of oxidation
leading to aromaticity in the N-containing ring. Our success with substrate scope expansion encouraged
us to apply our method to medicinally active N-heterocycles. Our first target was benzosultams, which
have a sulfone group in place of a carbonyl group. We believed that these molecules should be similar
enough to our carbonyl-containing enamides to display comparable reactivity. Benzothiazine-1,1-dioxide
derivatives were particularly interesting, as they are found in a variety of pharmaceutical compounds such
as oxicams: non-steroidal anti-inflammatory drugs (NSAIDs) including Meloxicam, Piroxicam,
Ampiroxicam, etc. Gratifyingly, benzothiazine dioxide 3-1t afforded the expected CF 3-substituted product
3-2t in a synthetically useful yield. Though these results could certainly be improved, the successful
134
preparation of 3-2t without affecting the ester functionality
29
should be highlighted as it enables a
subsequent amidation step, which would be required in the preparation of trifluoromethyl piroxicam and
meloxicam.
30
Trifluoromethyl-caffeine 3-2u was obtained in 56% isolated yield.
135
3.iii Mechanistic Investigations
To gain insight into the mechanism of this reaction, a series of control experiments were conducted. The
results of these trials are summarized in Table 3.2.
Table 3.2 Control Experiments
a
(above: standard conditions)
entry substrate variation from standard conditions yield of 2 (%)
1 [1a] with BHT (1 equiv) [2a] <1
b
2 [1a] with TEMPO (1 equiv)
[2a] <1
b
+ TEMPO-CF3
(54)
3
no
substrate
with TEMPO (1 equiv) TEMPO-CF3 (70)
4 [1i] Cu(OAc)2 (1 equiv), no PIFA [2i] not detected
5 [1i]
PIFA (1.5 equiv) added to entry 4 after 1 h and stirred further for
1 h
[2i] 2
b
(6)
b,d
6 [1i] (phen)CuCF3 (1.5 equiv) instead of TMSCF3, KF, Cu(OAc)2 [2i] 9
b
a
Standard conditions: Unless otherwise indicated, substrate 1a or 1i (0.25 mmol) PIFA (1.5 equiv), KF (1.5 equiv), TMSCF 3 (2
equiv), Cu(OAc) 2 (0.3 equiv), MeCN (0.1 M), rt, 1h.
b
Based on substrate.
c
Based on TEMPO.
d
After 24 h of reaction.
R
2
N
R
1
O
H
R
3
N
O
R
1
R
2
R
2
N
R
1
O
CF
3
R
3
N
O
R
1
R
2
F
3
C
KF (1.5 equiv)
PIFA (1.5 equiv)
Cu(OAc)
2
(30 mol %)
TMSCF
3
(2.0 equiv)
CH
3
CN (0.1M)
3-1 3-2
OR OR
136
Table 3.2 entry 1: To probe the involvement of a radical reaction pathway in the developed conditions,
BHT was used as a radical inhibitor. In an argon glovebox, starting material 1a (0.1 mmol, 23.5 mg, 1 equiv),
PIFA (1.5 equiv, 64.5 mg), KF (1.5 equiv, 8.7 mg), Cu(OAc) 2 (30 mol %, 5.5 mg) and 2,6-di-tert-butyl-4-
methylphenol (BHT) (0.1 mmol, 22 mg) were weighed into an oven-dried crimp-top vial equipped with a
stir bar. The vial was sealed with a septum and brought outside the glovebox. Subsequently, CH 3CN (1 mL)
and TMSCF 3 (2 equiv, 30 µL) were added in quick succession to the vial by syringe under a stream of N 2.
The mixture was then stirred at room temperature for 1 hour. After this time, benzotrifluoride (PhCF 3) (10
uL, 0.081 mmol) was added as internal standard (δ -63.7), and the mixture was then analyzed directly by
19
F NMR (unlocked). The product (E)-3-2a was formed in less only 0.3% (δ -54.7) and the observed were
residual Me 3SiCF 3 (δ -67.8), CF 3H (δ -80.4) and Me 3SiF (δ -158). The corresponding Z-isomer (δ -51.5) was
not observed. The complete inhibition of the reaction indicates the possibility of a radical pathway.
137
Table S2 entry 2: To further probe the involvement of a radical pathway, TEMPO was used as a radical
inhibitor. In an argon glovebox, starting material 1a (0.1 mmol, 23.5 mg, 1 equiv), PIFA (1.5 equiv, 64.5
mg), KF (1.5 equiv, 8.7 mg), Cu(OAc) 2 (30 mol %, 5.5 mg) and 2,2,6,6-Tetramethyl-1- piperidinyloxyl
(TEMPO) (0.1 mmol, 15.6 mg) were weighed into an oven-dried crimp-top vial equipped with a stir bar.
The vial was sealed with a septum and brought outside the glovebox. Subsequently, CH 3CN (1 mL) and
TMSCF 3 (2 equiv, 30 µL) were added in quick succession to the vial by syringe under a stream of N 2. The
mixture was then stirred at room temperature for 1 hour. After this time, benzotrifluoride (PhCF 3) (10 uL,
0.081 mmol) was added as internal standard (δ -63.7), and the mixture was then analyzed directly by
19
F
NMR (unlocked). The product (E) 3-2a was formed in only 0.1% (δ -54.7) and the corresponding Z-isomer
(δ -51.5) was not observed. The main fluorine-containing compounds observed were TEMPO-CF 3 adduct
formed in 54% yield, (δ -56.5), CF 3H (δ -80.4) and Me 3SiF (δ -158.0).
138
Table 3.2 entry 3: It is possible that the formation of TEMPO-CF 3 adduct could proceed via nucleophilic
attack by the trifluoromethyl anion on a TEMPO-derived oxoammonium intermediate. TEMPO-derived
oxoammonium ion could form upon reduction of the substrate by the TEMPO radical. Furthermore, our
reaction conditions have the possibility of producing an equivalent of trifluoroacetic acid, which would
also facilitate the aforementioned oxidation of TEMPO radical. To eliminate the possible influence of the
substrate on the formation of TEMPO-CF 3, the reaction was conducted with TEMPO but in the absence of
the substrate. In an argon glovebox, PIFA (1.5 equiv, 64.5 mg), KF (1.5 equiv, 8.7 mg), Cu(OAc) 2 (30 mol %,
5.5 mg) and 2,2,6,6- Tetramethyl-1-piperidinyloxyl (TEMPO) (0.1 mmol, 15.6 mg) were weighed into an
oven-dried crimp-top vial equipped with a stir bar. The vial was sealed with a septum and brought outside
the glovebox. Subsequently, CH 3CN (1 mL) and TMSCF 3 (2 equiv, 30 µL) were added in quick succession to
the vial by syringe under a stream of N 2. The mixture was then stirred at room temperature for 1 hour.
After this time, benzotrifluoride PhCF 3 (10 uL, 0.081 mmol) was added as internal standard (δ -63.7), and
the mixture was then analyzed directly by
19
F NMR (unlocked). In this case the TEMPO-CF 3 adduct (δ -56.5)
formed in a higher yield of 64%, along with small amounts of CF 3H (δ -80.4) and Me 3SiF (δ -158)
139
Table 3.2 entry 4: To rule out the possibility of Cu(OAc) 2 serving as the oxidant for CF 3- anion, a control
experiment was performed using stoichiometric amounts of this salt, in the absence of PIFA. In an argon
glovebox, Cu(OAc) (1 equiv, 0.25 mmol, 45.4 mg), KF (1.5 equiv, 22 mg) were weighed into an oven-dried
crimp-top vial equipped with a stir bar. The vial was sealed with a septum and brought outside the
glovebox. Subsequently, CH 3CN (2.5 mL), 3-1i (0.25 mmol, 24.5 uL) and TMSCF 3 (2 equiv, 75 µL) were
added in quick succession to the vial by syringe under a stream of N 2. A deep-blue solution formed, and
this mixture was then stirred at room temperature for 1 hour. After this time, trifluoromethoxybenzene,
PhOCF 3 (20 uL, 0.16 mmol) was added as internal standard (δ -58.0), and the mixture was then analyzed
directly by
19
F NMR (unlocked). In this case, no product 2i could be detected. The only fluorine-containing
species observed were PhOCF 3 (δ -58.0 ppm), unreacted TMSCF 3 (δ -66.7) TMSF (δ -154), CF 3H (δ -79.2),
and several signals which were assigned to [CuCF 3] species (δ -26.1, δ -31.1 and δ -40.1).
140
Table 3.2 entry 5: Upon observing various Cu(CF 3) x species, we explored the role of Cu(OAc) 2 as an
additive. To test for the intermediacy of a Cu(CF 3) x species, the deep-blue solution obtained from entry 4,
was transferred via syringe under a stream of N 2, to a crimp-top vial containing PIFA (1.5 equiv, 161 mg)
and this mixture was further stirred at room temperature for 1h. After this time, the contents were then
analyzed by
19
F NMR. Product 3-2i was formed in only 2% (δ -65.6), and several [CuCF 3] species remained
unreacted (δ -28.8, δ -40.4). The yield increased to 6% after 24h.
(1h of reaction time)
141
(24h of reaction time)
Table 3.2 entry 6: To further rule out the involvement of a Cu(CF 3) x species in our oxidative
trifluoromethylation protocol, we synthesized and utilized (phen)CuCF 3 (reported as a well-defined
complex) in place of our TMSCF 3, KF, and Cu(OAc) 2 combination. In an argon glovebox, (phen)CuCF 3 (1.5
equiv, 0.375 mmol, 117.3 mg) and PIFA (1.5 equiv, 161 mg) were weighed into an oven-dried crimp-top
vial equipped with a stir bar. The vial was sealed with a septum and brought outside the glovebox.
Subsequently, CH 3CN (2.5 mL) and 3-1i (0.25 mmol, 24.5 uL) were added in quick succession to the vial by
syringe under a stream of N 2. A vigorous reaction ensued, and a light-green precipitate formed (likely an
oxidation of Cu(I) reagent by PIFA). Upon stirring this mixture for 1h at room temperature,
trifluoromethoxybenzene, PhOCF 3 (20 uL, 0.16 mmol) was added as internal standard (δ -58.0), and the
mixture was then analyzed directly by
19
F NMR (unlocked). In this case, 2i (δ -65.6) was formed in only 9%
yield. Small amounts of [CuCF 3] (δ -28.2), CF 3H δ -79.5 (d, 79 Hz), TMSF and two unidentified fluorine-
142
containing species (-62.7 ppm (dd, J = 116.8, 34.8 Hz) and -8.0 ppm (s)) were detected. No increased in
yield of 3-2i was observed after 24h.
(1h of reaction time)
Based on the results obtained from the control experiments and previous literature reports, it is
likely that the active trifluoromethylating species is a CF 3 radical derived from TMSCF 3. At this point it is
not known whether this is a free radical species or a Cu-associated radical. Though several [CuCF 3] species
have been detected during the course of our investigations, it is likely that they do not play a dominant
role for the oxidative C–H trifluoromethylation to occur. In addition, we have established that PIFA is an
essential component for the reaction, as Cu(II) in stoichiometric amounts was ineffective for the desired
transformation (Table S2, entry 4). Furthermore, our initial investigations showed that [Cu] salts are not
strictly necessary as the reaction also proceeds in a metal-free manner, albeit with diminished yields
143
(Table S1, entries 1-10). Based on these observations, we proposed the following as a possible reaction
pathway (Scheme S2).
(An analogous pathway for enamides is depicted below)
Figure 3.6 Proposed Mechanism
Upon activation by fluoride, CF 3-release from TMSCF 3 followed by ligand exchange with PIFA,
furnishes intermediate [I] which could give rise to CF 3 radical and iodosyl radical [II] via I(III)–CF 3 homolytic
cleavage (initiation). Reaction of CF 3 radical with substrates leads to a carbon centered radical which is
then oxidized to a carbocation (or iminium ion in the case of enamides) by either Cu(II) (with concomitant
generation of Cu(I) ions) or species [II] (with concomitant generation of Ph–I and CF 3COO
-
). Subsequent
deprotonation of this carbocation species furnishes the desired trifluoromethylated product. In addition,
TMSCF
3
KF, PIFA
F
3
C I OCOCF
3
Ph
I
III
—CF
3
bond
homolysis
(initiation)
I
Ph
OCOCF
3
F
3
C
(-PhI, -CF
3
COO—)
N
O
R CF
3
Cu(I) Cu(II)
N
O
R CF
3
OR
[O]
[O]
N
O
R
H
CF
3
B
— N
O
R CF
3
R
4
N
O
R
3
R
2
R
1
H
F
3
C
R
4
N
O
R
3
R
2
R
1
CF
3
Cu(II) Cu(I)
SET
or
[O]
R
4
N
O
R
3
R
2
R
1
CF
3
H
(deprotonation)
R
4
N
O
R
3
R
2
R
1
CF
3
H
144
intermediate [I] can also give rise to CF 3 radical, Ph–I and CF 3COO- upon single electron transfer (SET)
process from Cu(I); this in turn, regenerates Cu(II), thus closing the catalytic cycle. Though the reaction
also proceeds in a metal-free fashion, we surmised that the enhanced yields of trifluoromethylated
products observed in the presence of catalytic amounts of Cu(II), could be due to the inhibition of side
polymerization reactions by reversible binding of Cu(II) to the carbon-centered radical. Such a scenario
has been described for other copper catalyzed oxidations.
Together, these results lend support to our hypothesis of a trifluoromethyl radical being the active
trifluoromethylating species.
3.iv Conclusion
In conclusion, we developed an efficient method for the direct C(sp
2
)–H trifluoromethylation of
enamides using TMSCF 3 as an accessible CF 3 source. Under our oxidative conditions, a series of hitherto
unknown CF 3-containing isoindolinones, isoquinolinones and 2-pyridinones were prepared. The
applicability of this protocol in the preparation of trifluoromethyl analogues of active pharmaceutical
ingredients 3-2q, 3-2t and 3-2u (pirfenidone, caffeine and benzothiazine dioxide derivatives)
demonstrates its potential for the late-stage trifluoromethylation of analogous compounds.
3.v Experimental Section
General
Unless otherwise mentioned, all the chemicals were purchased from commercial sources and used
without further purification. Acetonitrile (MeCN) was distilled from P 2O 5 and stored over molecular sieves
145
in a Strauss flask under N2. Flash column chromatography was performed to isolate products with suitable
eluent as determined by TLC.
1
H,
13
C, and
19
F spectra were recorded on 400 MHz or 500 MHz Varian NMR
spectrometers.
1
H NMR chemical shifts were determined relative to Chloroform-d as the internal standard
at δ 7.26.
13
C NMR shifts were determined relative to Chloroform-d at δ 77.16.
19
F NMR chemical shifts
were determined relative to CFCl 3 at δ 0.00. Mass spectra were recorded on a high-resolution mass
spectrometer, EI or ESI mode. Starting materials isoindolinones (3-1a to 3-1d),
254,255
3-1e,
256
isoquinolinones (3-1f to 3-1h),
257–259
2-pyridones (3-1j to 3-1k and 3-1m to 3-1q),
260
1l,
261
enamides
1r,
262,263
and 1s
263
benzosultam 1t
264–266
were synthesized according to reported procedures. N-Methyl-2-
pyridone 1i, 5-Methyl-1-phenyl-2-(1H)-pyridone (pirfenidone, 1q) and anhydrous pyridine were
purchased from Sigma-Aldrich and used as received. Copper complex, (phen)CuCF 3 was purchased from
STREM Chemicals and used as received. 4-hydroxy-2-methyl-2H- benzo[e][1,2]thiazine 1,1-dioxide and
caffeine were purchased from AK Scientific and used as received.
Synthesis and NMR Spectroscopic Data of Starting Materials:
(Z)-3-benzylidene-2-methylisoindolin-1-one (3-1a)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.0 mg), CuCl (0.2
mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3 mmol,
967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and sealed with
a septum. Outside the glovebox, phenylacetylene (3.0 mmol, 330 mL) and degassed water (4 mL) were
added sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil bath
preheated to 130 ̊C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool down
to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short pad
of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH
4
OH and further extracted
N
O
146
with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over MgSO 4 and
concentrated under reduced pressure. The resulting residue was purified by flash chromatography using
an EtOAc/hexanes system (gradient from 0% - 25%). The combined fractions were concentrated on a
rotary evaporator to afford the product 3-1a (82% yield, 385.9 mg).
1
H NMR (500 MHz, Chloroform-d) δ
7.86 (dt, J = 7.5, 1.0 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.5, 1.2 Hz, 1H), 7.49 (td, J = 7.5, 0.9 Hz,
1H), 7.42 – 7.37 (m, 2H), 7.37 – 7.30 (m, 3H), 6.79 (s, 1H), 3.04 (s, 3H).
13
C NMR (100 MHz, Chloroform-d)
δ 169.1, 138.1, 136.3, 134.9, 132.0, 129.8, 129.1, 128.6, 128.2, 127.6, 123.3, 119.4, 106.7, 30.7.
(Z)-2-methyl-3-(4-(trifluoromethyl)benzylidene)isoindolin-1-one (3-1b)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3
mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and
sealed with a septum. Outside the glovebox, 4-trifluoromethylphenylacetylene (3 mmol, 489 mL) and
degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then
placed in an oil bath preheated to 130 ̊C and stirred for 30 min. Subsequently, the reaction mixture was
allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered
through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH4OH
and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine,
dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using an EtOAc/hexanes system (gradient from 0% to 15%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as a pale-yellow solid (73% yield,
443 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.87 (dd, J = 7.6, 1.0 Hz, 1H), 7.75 (dd, J = 7.7, 1.0 Hz, 1H),
7.68 – 7.59 (m, 3H), 7.52 (tt, J = 7.5, 7.5, 1.1 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 3.03 (s, 3H).
13
C
NMR (100 MHz, Chloroform-d) δ 169.0, 138.8, 137.9, 137.6, 132.9 (d, J = 218.2 Hz), 130.1 , 129.6 (q, J =
N
O
CF
3
147
32.7 Hz), 129.6 , 128.6, 125.2 (q, J = 3.8, 3.7, 3.7 Hz), 124.2 (q, J = 272.0 Hz), 123.5, 119.5, 30.8 .
19
F NMR
(282 MHz, Chloroform-d) d -63.1 (s, 3F)
(Z)-3-(4-methoxybenzylidene)-2-methylisoindolin-1-one (3-1c)
Inside an argon glovebox, N-methyl-2-iodobenzamide (2 mmol, 522.1 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide
(3 mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial
and sealed with a septum. Outside the glovebox, 4-methoxyphenylacetylene (3 mmol, 389 mL) and
degassed water (4 mL) were added sequentially by syringe under a stream of nitrogen. The vial was then
placed in an oil bath preheated to 130 ̊C and stirred for 30 min. Subsequently, the reaction mixture was
allowed to cool down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered
through a short pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH4OH
and further extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine,
dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using a EtOAc/hexanes system (gradient from 0% to 25%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as a pale-yellow solid (91% yield,
483.0 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.85 (dt, J = 7.5, 1.0 Hz, 1H), 7.73 (dt, J = 7.8, 0.9 Hz, 1H),
7.58 (td, J = 7.5, 1.2 Hz, 1H), 7.48 (td, J = 7.5, 0.9 Hz, 1H), 7.31 – 7.24 (m, 2H), 6.95 – 6.91 (m, 2H), 6.74 (s,
1H), 3.85 (s, 3H), 3.07 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1, 159.2, 138.3, 135.8, 131.9, 131.1,
128.9, 128.6, 127.1, 123.3, 119.3, 113.8, 106.6, 55.5, 30.7.
(Z)-3-benzylidene-2,6-dimethylisoindolin-1-one (3-1d)
N
O
OMe
148
Inside an argon glovebox, 2-iodo-N,5-dimethylbenzamide (2 mmol, 550.2 mg), CuCl
(0.2 mmol, 19.8 mg), PPh 3 (0.6 mmol, 157 mg), n-tetrabutylammonium bromide (3
mmol, 967 mg) and Cs 2CO 3 (6 mmol, 1955 mg) were placed in a crimp-top vial and
sealed with a septum. Outside the glovebox, phenylacetylene (3 mmol, 330 µL) and degassed water (4
mL) were added sequentially by syringe under a stream of nitrogen. The vial was then placed in an oil
bath preheated to 130˚C and stirred for 30 min. Subsequently, the reaction mixture was allowed to cool
down to room temperature and diluted with EtOAc (10 mL). This mixture was then filtered through a short
pad of Celite. The resulting filtrate was poured into 10 mL of a 0.1 M solution of NH4OH and further
extracted with EtOAc (3 times, 15 mL). The organic layers were combined, washed with brine, dried over
MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by flash
chromatography using an EtOAc/hexanes system (gradient from 0% to 15%). The combined fractions were
concentrated on a rotary evaporator to afford the product. Obtained as an off-white powder (m.p.134-
135˚C) (71% yield, 354 mg).
1
H NMR (500 MHz, Chloroform-d) δ 7.65 (dq, J = 1.6, 0.8 Hz, 1H), 7.62 (d, J =
7.9 Hz, 1H), 7.42 – 7.28 (m, 6H), 6.72 (s, 1H), 3.02 (s, 3H), 2.48 (s, 3H).
13
C NMR (126 MHz Chloroform-
d) δ 169.2, 139.4, 136.4, 135.7, 135.1, 133.1, 129.9, 128.9, 128.2, 127.5, 123.5, 119.2, 105.9, 30.7,
21.7. HRMS-ES+ (M) Calculated for C 17H 15ON = 249.11537, found = 249.11519. FT/IR (m max (neat) cm
-1
):
3025, 2945, 1692, 1652, 1598, 1494, 1443, 1430, 1380, 1333, 1304, 1217, 1114, 1026, 956, 836, 777, 745,
697, 645, 616, 519, 420.
(E)-2-benzyl-3-ethylideneisoindolin-1-one (3-1e)
This starting material was prepared following a previously reported procedure and
spectral data matches the reported values.
1
H NMR (399 MHz, Chloroform-d) δ 7.95
(d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (td, J = 7.6, 1.3 Hz, 1H), 7.54 – 7.47 (m,
1H), 7.33 – 7.21 (m, 5H), 5.47 (q, J = 7.6 Hz, 1H), 5.01 (s, 2H), 2.13 (d, J = 7.5 Hz, 3H).
N
O
Me
N
O
Me
149
2-methylisoquinolin-1(2H)-one (3-1f)
Step 1: Adapted from a reported method. To a crimp-top microwave vial charged with
1-chloroisoquinoline (6 mmol, 654 mg), 6M HCl (15.0 mL) was added under air. The
vial was then heated in the microwave reactor to 180˚C for 40 minutes. The vial was allowed to cool down
to room temperature, the solid removed by vacuum filtration and washed with cold water and diethyl
ether, followed by drying under vacuum. Isoquinolin-1(2H)-one was obtained as a white solid (702 mg,
81% yield).
1
H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.79 – 7.56 (m, 2H), 7.57
– 7.35 (m, 1H), 7.25 – 6.99 (m, 1H), 6.54 (d, J = 7.2 Hz, 1H).
Step 2: The synthesis was performed according to a reported procedure. In an argon glovebox, the above
obtained white solid (Isoquinolin-1(2H)-one, 3.91 mmol, 568 mg) and anhydrous K 2CO 3 (2 equiv, 1081 mg)
were weighed into an oven-dried vial. Anhydrous methanol (5 mL) followed by MeI (2 equiv, 487 µL), was
added via syringe under N 2. The mixture was stirred for 22 hours at reflux temperature. After
concentrating the resultant mixture under reduced pressure, the residue was dissolved in water and
extracted with CHCl 3 three times. The combined organic layers were dried over MgSO 4 and purified by
silica gel chromatography (gradient of 0 – 50% EtOAc in hexanes). The required fractions were
concentrated under reduced pressure to afford 2-methylisoquinolin-1(2H)-one (3-1f) as a white solid
(89% yield, 554 mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.44 (d, J = 8.1 Hz, 1H), 7.63 (ddd, J = 8.2, 7.0, 1.3
Hz, 1H), 7.54 – 7.42 (m, 2H), 7.07 (d, J = 7.3 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H), 3.61 (s, 3H).
2-phenylisoquinolin-1(2H)-one (3-1g)
Prepared according to a reported procedure. To a crimp-top vial charged with
isoquinolin- 1(2H)-one (6.89 mmol, 1.0 g), CuI (10 mol %, 127.6 mg) and K 2CO 3 (1 equiv,
0.925 g), DMF (8 mL) and PhI (2 equiv, 1.5 mL) were added by syringe under N 2. The mixture was stirred
N
O
N
O
150
at 150 ˚C for 6 hours. The vial was then allowed to cool down to room temperature and the mixture
diluted with EtOAc (13 mL). NH 4OH (0.1 M aqueous solution, 25 mL) was added, the layers separated, and
the aqueous layer was extracted with EtOAc (10 mL) two more times. The combined organic layer was
washed with brine, dried over MgSO 4 and concentrated under reduced pressure. Column chromatography
(gradient of 0 % to 20 % EtOAc in hexanes) afforded 1f as a white solid (71 % yield, 1.08 g)
1
H NMR (399
MHz, Chloroform-d) δ 8.48 (d, J = 8.1 Hz, 1H), 7.68 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H), 7.58 – 7.48 (m, 4H),
7.46 – 7.39 (m, 3H), 7.19 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H).
13
C NMR (100 MHz, Chloroform-d) δ
162.1, 141.5, 137.2, 132.7, 132.3, 129.4, 128.4, 128.2, 127.3, 127.0, 126.7, 126.1, 106.3. This data matches
reported values.
7-bromo-2-methylisoquinolin-1(2H)-one (3-1h)
Step 1: Adapted from a reported method.4 To a crimp-top microwave vial charged with
7-bromo-1-chloroisoquinoline (6 mmol, 1455 mg), 6M HCl (15.0 mL) was added under air. The vial was
then heated in the microwave reactor to 180˚C for 40 minutes. The vial was allowed to cool down to room
temperature, the solid removed by vacuum filtration and washed with cold water and diethyl ether,
followed by drying under vacuum. 7- bromoisoquinolin-1(2H)-one was obtained as a yellow solid (1155
mg, 86% yield).
1
H NMR (399 MHz, DMSO-d 6) δ 11.43 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 8.5, 2.2
Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 6.8, 5.8 Hz, 1H), 6.57 (d, J = 6.9 Hz, 1H). These data matched
the reported values. Step 2: Adapted from a reported procedure.6 In an argon glovebox, the above
obtained yellow solid (7-bromoisoquinolin-1(2H)-one, 3.91 mmol, 568 mg) and anhydrous K 2CO 3 (2 equiv,
1081 mg) were weighed into an oven-dried vial. Anhydrous methanol (5 mL), followed by MeI (2 equiv,
487 µL), was added via syringe under N2. The mixture was stirred for 22 hours at reflux temperature. After
concentrating the resultant mixture under reduced pressure, the residue was dissolved in water and
N
Br
O
Me
151
extracted with CHCl 3 three times. The combined organic layers were dried over MgSO4 and purified by
silica gel chromatography (gradient of 0 – 50% EtOAc in hexanes). The appropriate fractions were
concentrated under reduced pressure to afford 7-bromo-2-methylisoquinolin-1(2H)-one (3-1h) as a white
solid (89% yield, 554 mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.57 (dt, J = 2.1, 0.6 Hz, 1H), 7.71 (dd, J =
8.5, 2.1 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.45 (dd, J = 7.3, 0.7 Hz, 1H), 3.60 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 161.6, 135.9, 135.4, 133.0, 130.5, 127.7, 127.6, 120.8, 105.5, 37.3.
HRMS ESI+ (M+H+) calculated for C 10H 9NOBr = 237.9868, found = 237.9868. FT/IR (m
-1
max (cm
-1
)) 3417,
1086, 2919, 2849, 1646, 1612, 1590, 1543, 1489, 1438, 1409, 1394, 1380, 1348, 1315, 1290, 1245, 1209,
1184, 1158, 1128, 1066, 967, 957, 889, 828, 787, 757, 722, 705, 692, 596, 567, 519, 493, 466.
1-phenylpyridin-2(1H)-one (3-1j)
Prepared according to a reported procedure. To a crimp-top vial charged with pyridin-2(1H)-
one (13.4 mmol, 1.27 g), CuI (10 mol %, 255.2 mg) and K 2CO 3 (1 equiv, 1.85 g), DMF (16 mL)
and PhI (2 equiv, 3 mL) were added by syringe under N 2. The mixture was stirred at 150 ˚C for 6 hours.
The vial was then allowed to cool down to room temperature and the mixture diluted with EtOAc (25 mL).
NH 4OH (0.1 M aqueous solution, 50 mL) was added, the layers separated, and the aqueous layer was
extracted with EtOAc (15 mL) two more times. The combined organic layer was washed with brine, dried
over MgSO 4 and concentrated under reduced pressure. The residue thus obtained was washed with
hexanes, passed through a pad of silica using EtOAc followed by washing the silica pad with additional
EtOAc (15 mL) to collect residual product. Upon removal of EtOAc, the solid obtained was recrystallized
by dissolving the residue in a minimal amount of hot EtOAc, cooling it to room temperature and then
adding hexanes (slowly, excess), followed by vacuum filtration to afford the product as a pale-yellow solid
(70 % yield, 1.60 g).
1
H NMR (400 MHz, Chloroform-d) δ 7.54 – 7.46 (m, 2H), 7.44 – 7.36 (m, 4H), 7.33 (ddt,
J = 6.9, 2.1, 0.6 Hz, 1H), 6.66 (dt, J = 9.3, 0.7 Hz, 1H), 6.24 (td, J = 6.7, 1.3 Hz, 1H). This data matches that
N
O
152
of previous reports.
1-(4-methoxyphenyl)pyridin-2(1H)-one (3-1k)
Following a known procedure.7 To an oven-dried crimp-top vial charged with 2-
hydroxypyridine (1.34 mmol, 127.4 mg), K2CO3 (1.34 mmol, 185.2 mg), 4-iodoanisole
(2.68 mmol, 646 mg) and CuI (10 mol %, 25.5 mg), DMF (2 mL) was added by syringe. The mixture was
stirred at 150 ˚C in an oil bath overnight (16 hours), following which the vial was allowed to cool down to
room temperature. The contents were diluted with NH 4OH (0.1 M, 50 mL) and the product was extracted
using EtOAc (3 times, 15 mL each). The organic layers were combined, washed with brine and dried over
MgSO 4. The extract was purified by column chromatography (gradient of 0% to 50% EtOAc in hexanes) to
afford the product as a white solid (60 % yield, 161 mg) 1H NMR (399 MHz, Chloroform-d) δ 7.38 (dddd, J
= 9.3, 6.6, 2.1, 0.5 Hz, 1H), 7.34 – 7.28 (m, 3H), 7.02 – 6.96 (m, 2H), 6.65 (ddd, J = 9.3, 1.4, 0.7 Hz, 1H), 6.24
– 6.18 (m, 1H), 3.85 (s, 3H). The NMR data matches reported values.
1-benzylpyridin-2(1H)-one (3-1l)
Prepared according to a reported procedure. To a mixture of 2-hydroxypyridine (761 mg,
8 mmol, 1 equiv), and potassium carbonate (2.76 g, 20 mmol, 2.5 equiv) in acetone was
added benzyl bromide (1.19 mL, 10 mmol, 1.25 equiv) and the mixture was heated at reflux for 20h. It
was then cooled to room temperature and the solids were filtered off and washed with acetone. The
filtrate was concentrated in vacuo, and the residue was partitioned between water and chloroform. The
aqueous layer was further extracted with chloroform, and the organic layers were gathered, dried over
magnesium sulfate and evaporated to dryness. The resulting yellow oil was purified by flash
chromatography using ethyl acetate/petroleum ether (1:2 to 1:1) as eluent. The product was obtained as
a white solid (1.30 g, 88%).
1
H NMR (399 MHz, Chloroform-d) δ 7.37 – 7.23 (m, 7H), 6.62 (ddd, J = 9.2, 1.4,
N
O
OMe
N
O
153
0.7 Hz, 1H), 6.13 (td, J = 6.7, 1.4 Hz, 1H), 5.15 (s, 2H). The spectral data matches the previously reported.
1-(4-acetylphenyl)pyridin-2(1H)-one (3-1m)
Adapted from a known procedure. To an oven-dried crimp-top vial charged with 2-
hydroxypyridine (1.34 mmol, 127.4 mg), K 2CO 3 (1.34 mmol, 185.2 mg), 4-
iodoacetophenone (2.68 mmol, 659.4 mg) and CuI (10 mol %, 25.5 mg), DMF (2 mL)
was added by syringe. The mixture was stirred at 150 ˚C in an oil bath overnight (16 hours), following
which the vial was allowed to cool down to room temperature. The contents were diluted with NH 4OH
(0.1 M, 50 mL) and the product was extracted using EtOAc (3 times, 15 mL each). The organic layers were
combined, washed with brine and dried over MgSO 4. The extract was purified by column chromatography
(gradient of 0% to 40% EtOAc in hexanes) to afford the product as a yellow solid (40 % yield, 114.0 mg).
m.p.: 159-160 ˚C.
1
H NMR (400 MHz, Chloroform-d) δ 8.08 (dt, J = 8.8, 2.3 Hz, 2H), 7.52 (dt, J = 8.9, 2.2 Hz,
2H), 7.41 (ddd, J = 9.3, 6.6, 2.1 Hz, 1H), 7.33 (ddd, J = 6.9, 2.1, 0.8 Hz, 1H), 6.67 (ddd, J = 9.3, 1.3, 0.8 Hz,
1H), 6.28 (td, J = 6.7, 1.3 Hz, 1H), 2.64 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 197.0, 162.1, 144.7,
140.2, 137.3, 136.8, 129.5, 126.9, 122.2, 106.4, 26.8. HRMS EI+ (M+H+) Calculated for C 13H 10NO 2 =
214.0868, found = 214.0866.
1-(4-nitrophenyl)pyridin-2(1H)-one (3-1n)
Prepared according to a reported procedure. To an oven-dried crimp-top vial charged
with 2-hydroxypyridine (1.34 mmol, 127.4 mg), K 2CO 3 (1.34 mmol, 185.2 mg), 4-
Iodonitrobenzene (2.68 mmol, 667.3 mg) and CuI (10 mol %, 25.5 mg), DMF (2 mL) was added by syringe.
The mixture was stirred at 150 ˚C in an oil bath overnight (16 hours), following which the vial was allowed
to cool down to room temperature. The contents were diluted with NH 4OH (0.1 M, 50 mL) and the product
was extracted using EtOAc (3 times, 15 mL each). The organic layers were combined, washed with brine
N
O
O
N
O
NO
2
154
and dried over MgSO 4. The extract was purified by column chromatography (gradient of 0% to 50% EtOAc
in hexanes) to afford the product as a yellow solid (90 % yield, 268 mg).
1
H NMR (400 MHz, Chloroform-d) δ 8.37 (dt, J = 9.1, 2.8, 2.2 Hz, 2H), 7.63 (dt, J = 9.0, 2.8 Hz, 2H), 7.44
(ddd, J = 9.4, 6.6, 2.1 Hz, 1H), 7.33 (ddd, J = 6.9, 2.1, 0.8 Hz, 1H), 6.68 (ddd, J = 9.4, 1.3, 0.8 Hz, 1H), 6.32
(td, J = 6.8, 1.2 Hz, 1H). The NMR data matches reported values.
3-(2-oxopyridin-1(2H)-yl)benzaldehyde (3-1o)
Adapted from a reported procedure. To an oven-dried crimp-top vial charged with 2-
hydroxypyridine (1.34 mmol, 127.4 mg), K 2CO 3 (1.34 mmol, 185.2 mg), 3-
Iodobenzaldehyde (2.68 mmol, 621.8 mg) and CuI (10 mol %, 25.5 mg), DMF (2 mL) was added by syringe.
The mixture was stirred at 150 ˚C in an oil bath overnight (16 hours), following which the vial was allowed
to cool down to room temperature. The contents were diluted with NH 4OH (0.1 M, 50 mL) and the product
was extracted using EtOAc (3 times, 15 mL each). The organic layers were combined, washed with brine
and dried over MgSO 4. The extract was purified by column chromatography (gradient of 0% to 50% EtOAc
in hexanes) to afford the product as an off-white solid (46 % yield, 123 mg) m.p.: 121-122 ˚C
1
H NMR (500
MHz, Chloroform-d) δ 10.04 (s, 1H), 7.93 (dq, J = 7.3, 1.4 Hz, 1H), 7.90 (s, 1H), 7.72 – 7.69 (m, 1H), 7.66 (t,
J = 7.7 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.36 – 7.32 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.28 (tt, J = 6.8, 1.2 Hz, 1H).
13C NMR (126 MHz, Chloroform-d) δ 191.0, 162.2, 141.8, 140.3, 137.6, 137.5, 132.7, 130.2, 129.8, 127.4,
122.2, 106.5. HRMS ESI+ (M+H+): calculated for C 12H 10NO 2 = 200.0712, found = 200.0719.
4-(benzyloxy)-1-phenylpyridin-2(1H)-one (3-1p)
Adapted from a reported procedure. To a crimp-top vial charged with 4-
(benzyloxy)pyridin-2(1H)-one (5.26 mmol, 1.08 g), CuI (10 mol %, 102 mg) and K 2CO 3
(1 equiv, 741 mg), DMF (8 mL) and PhI (2 equiv, 1.2 mL) were added by syringe under N 2. The mixture was
N
O
BnO
N
O
CHO
155
stirred at 150 ˚C for 6 hours. The vial was then allowed to cool down to room temperature and the mixture
diluted with EtOAc (40 mL). NH 4OH (0.1 M aqueous solution, 100 mL) was added, the layers separated,
and the aqueous layer was extracted with EtOAc (25 mL) two more times. The combined organic layer
was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The extract was
purified by column chromatography (gradient of EtOAc in hexanes 0% - 60%) and the appropriate fractions
were concentrated to afford the product as a white solid (61 % yield, 907 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 7.50 – 7.45 (m, 2H), 7.44 – 7.34 (m, 8H), 7.23 (d, J = 7.3 Hz, 1H), 6.15 – 5.99 (m, 2H), 5.05
(s, 2H). The NMR data matches reported values.
3-methyl-1-phenylpyridin-2(1H)-one
This substrate was used to probe the selectivity towards the 3-position in this class of
substrates. Prepared by adapting a reported procedure. To a crimp-top vial charged with
3-methylpyridin-2-ol (5.36 mmol, 660 mg), CuI (10 mol %, 102 mg) and K 2CO 3 (1 equiv, 741 mg), DMF (8
mL) and PhI (2 equiv, 1.2 mL) were added by syringe under N 2. The mixture was stirred at 150 ˚C overnight
(16 hours). The vial was then allowed to cool down to room temperature and the mixture diluted with
EtOAc (40 mL). NH 4OH (0.1 M aqueous solution, 100 mL) was added, the layers separated, and the
aqueous layer was extracted with EtOAc (25 mL) two more times. The combined organic layer was washed
with brine, dried over MgSO 4 and concentrated under reduced pressure. The extract was purified by
column chromatography (gradient of EtOAc in hexanes 0% - 30%) and the required fractions were
concentrated to afford the product as a white solid (81 % yield, 804 mg).
1
H NMR (399 MHz, Chloroform-
d) δ 7.50 – 7.43 (m, 2H), 7.42 – 7.35 (m, 3H), 7.28 – 7.24 (m, 1H), 7.24 – 7.20 (m, 1H), 6.15 (t, J = 6.8 Hz,
1H), 2.19 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 162.8, 141.4, 137.0, 135.4, 130.9, 129.2, 128.3,
126.7, 105.6, 17.4. NMR data matched reported value
N
O
156
N-(3,4-dihydronaphthalen-1-yl)-N-methylacetamide (3-1r)
Step 1 (oxime synthesis): Adapted from a reported procedure. A mixture of 1-tetralone (2.9
g, 20 mmol), hydroxylamine hydrochloride (2.2 g, 31.2 mmol), and 83% EtOH soln in water
(8.7 mL) was placed in a crimp- top vial with a magnetic stir bar. Freshly ground sodium
hydroxide (4 g, 100 mmol) was added in portions under air. The vial was capped and heated to reflux for
15 minutes with occasional shaking to facilitate mixing. After this, the vial was allowed to cool to room
temperature. The contents were poured into a soln of HCl in water (~1.5 M), enough to quench residual
NaOH. The precipitate was suction filtered, washed thoroughly with water, and dried under vacuum to
give the crude oxime as a light brown solid (2.80 g, 87% yield), which was used without further purification
for the next step.
1
H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.07 – 7.73 (m, 1H), 7.32 – 7.13 (m, 3H),
2.83 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.4, 5.6 Hz, 2H), 1.89 (p, J = 6.4 Hz, 2H). Step 2: Performed according to
a reported procedure. To an oven-dried crimp-top vial equipped with a magnetic stir bar charged with (E)-
3,4- dihydronaphthalen-1(2H)-one oxime (1.13 g, 7 mmol), THF (0.5 g, 9.4 mL, 7 mmol) was added by
syringe. To this stirring solution, acetic anhydride (1.32 mL, 14 mmol) and acetic acid (1.2 mL, 21 mmol)
were added by syringe, followed by purging the vial with N 2 for 20 minutes. Subsequently, iron (II) acetate
(2.4 g, 14 mmol) was added, and the reaction vial was recapped. The mixture was heated at 65 ̊C and
stirred for 16 hours. The mixture was then poured into a 250 mL separatory funnel with 20 mL water and
neutralized with 1 g sodium bicarbonate (solid). The aqueous solution was extracted with EtOAc (3 x 20
mL). The combined organic layers were washed with saturated NaHCO 3 (20 mL) and brine (20 mL), dried
with MgSO 4, filtered, and concentrated in vacuo. The extract was purified by flash chromatography
(gradient of 0% -30%% EtOAc in hexanes) and N-(3,4-dihydronaphthalen-1- yl)acetamide was obtained
(554 mg) as an orange solid. The solid was dissolved in EtOAc (~30 mL) and stirred with activated charcoal
for ~1 hour. Charcoal was removed by vacuum filtration through celite washing with EtOAc. Concentration
of the filtrate yielded N-(3,4-dihydronaphthalen-1-yl)acetamide in 31% yield (400 mg).
1
H NMR (500 MHz,
N
Ac
157
Chloroform-d) (mixture of rotamers) δ 7.24 – 7.06 (m, 4H), 6.81 (s, 1H), 6.68 (s, 0.37H), 6.44 (t, J = 4.9 Hz,
0.75H), 5.97 (s, 0.25H), 2.84 (t, J = 8.2 Hz, 1H), 2.76 (t, J = 7.9 Hz, 3H), 2.46 – 2.33 (m, 3H), 2.17 (s, 3H), 1.96
(s, 1H). The NMR data matches reported values. Step 3: Performed according to a reported procedure. To
an oven-dried, sealed crimp-top vial charged with N-(3,4-dihydronaphthalen-1-yl)-N-methylacetamide (1
mmol, 187.2 mg), and NaH (1.5 equiv, 36 mg) cooled to 0 ˚C, 3 mL of dry DMF was added slowly by syringe
under N 2. The resulting suspension was stirred at 0 ˚C for 10 min, followed by addition of MeI (2 equiv)
dropwise. The solution was warmed to room temperature and stirred for 16 hours. Excess sodium hydride
was quenched by adding 1 mL of water at 0 ˚C. The solution as diluted with 50 mL of water, the organic
layer extracted with ethyl acetate three times (15 mL each). The combined organic layer was concentrated
under reduced pressure and N-(3,4-dihydronaphthalen- 1-yl)-N-methylacetamide (3-1r) was isolated by
flash column chromatography (gradient of 30 % EtOAc in hexanes) as a white solid (95 % yield, 190 mg).
1
H NMR (400 MHz, Chloroform-d) δ 7.24 – 7.17 (m, 3H), 7.04 – 7.01 (m, 1H), 5.99 (t, J = 4.6 Hz, 1H), 3.13
(s, 3H), 2.85 (td, J = 8.3, 7.6, 4.3 Hz, 2H), 2.49 – 2.38 (m, 2H), 1.97 (s, 3H). The NMR data matches the
reported values.
N-methyl-N-(1-phenylvinyl)acetamide (3-1s)
To a 250 mL 2-neck flask (fitted with a condenser) charged with MeMgBr (18 mmol, 3M soln in
Et 2O, 6 mL) in Et 2O (50 mL), a solution of PhCN (17 mmol, 1.75 mL) in Et 2O (20 mL) was added
dropwise at 0 ˚C. The solution was refluxed overnight (16 h) at 45 ˚C. A solution of Ac 2O (17 mmol, 1.607
mL) in Et 2O (20 mL) was added dropwise to the resulting solution at 0 ˚C. This solution was refluxed for 8
hours. At room temperature, MeOH was added till all the precipitate dissolved. 85 mL of a 1:1 mixture of
EtOAc:H 2O was added and the organic layer was separated. The aqueous layer was extracted with EtOAc
(3 times, 20 mL each time). The combined organic layers were dried over MgSO 4, concentrated under
reduced pressure and 1s was obtained as a white solid (62 % yield, 1.67 g) following column
Ph
NH
O
158
chromatography (gradient of 0% to 25% EtOAc in hexanes). The spectral data matches reported values.
Ethyl 2-methyl-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3-1t)
Step 1: Adapted from a reported procedure.15 To an oven dried crimp-top vial charged with 4-hydroxy-
2-methyl- 2H-benzo[e][1,2]thiazine 1,1-dioxide (2 mmol, 566 mg), DCM (20 mL), pyridine (2 equiv, 330 µL)
were added sequentially at room temperature, followed by Tf 2O (1.2 equiv, 400 µL) at 0 ˚C). The mixture
was stirred at 0 ˚C for 10 mins, the ice bath was removed, and then the mixture was stirred for an
additional 24 hours. Next, the contents of the vial were poured into water (60 mL) and an extraction with
DCM was performed (10 mL, three times). The organic layers were combined, dried over MgSO 4 and the
product was purified by silica gel chromatography (gradient of 0 % - 25 % EtOAc in hexanes). The
appropriate fractions were combined, and the product was obtained as an off-white solid (m.p.: 105-106
˚C), (92 % yield, 764 mg).
1
H NMR (399 MHz, Chloroform-d) δ 7.93 – 7.90 (m, 1H), 7.85 – 7.82 (m, 1H), 7.83
– 7.70 (m, 2H), 4.45 (q, J = 7.2 Hz, 2H), 3.22 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).
13
C NMR (100 MHz, Chloroform-
d) δ 160.0, 138.0, 133.8, 132.7, 132.0, 129.2, 127.4, 124.7, 122.9, 118.4 (q, J = 321.3 Hz), 63.6, 36.2, 14.00.
19
F NMR (376 MHz, Chloroform-d) δ -73.3 (s, 3F). HRMS EI+ (M + Na+) Calculated for NaC 13H 12F 3NO 7S 2 =
437.9905, found = 437.9897. FT/IR (m
-1
max cm-1): 1648, 1603, 1558, 1452, 1441, 1403, 1381, 1339, 1308,
1271, 1229, 1170, 1144, 1118, 1065, 1043, 1021, 929, 883, 867, 832, 806, 784, 769, 726, 648, 611, 572,
561, 524, 508, 506, 487, 468, 452, 437, 417, 405.
Step 2: Adapted from reported procedures.16,17 To an oven-dried crimp-top vial charged with triflate 1t’
(1.84 mmol, 764 mg), Pd(OAc) 2 (2 mol %, 8.3 mg) and PPh 3 (2 mol %, 9.7 mg), DMF (10 mL) and Et 3SiH (2.5
equiv, 705 µL) were added sequentially by syringe. The mixture was stirred at 60 ˚C for 24 hours. The
mixture was then diluted with EtOAc (75 mL) and washed with NaHCO3, water and brine (75 mL each).
The organic layer was dried over MgSO 4, filtered and concentrated to afford a brown solid. The solid was
washed with hexanes (2 mL, 2 times), re-dissolved in CHCl 3 and then concentrated under reduced pressure
159
to afford the product 3-1t as a light-brown solid (65 % yield, 320 mg). m.p.: 103 – 105 ˚C.
1
H NMR (500
MHz, Chloroform-d) δ 7.94 – 7.86 (m, 1H), 7.68 – 7.62 (m, 2H), 7.57 (s, 1H), 7.57 – 7.53 (m, 1H), 4.38 (q, J
= 7.2 Hz, 2H), 3.26 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 162.5, 133.9, 133.6,
132.4, 130.9, 130.7, 129.3, 122.7, 122.5, 62.3, 36.5, 14.4. FT/IR (m
-1
max cm
-1
): 1720, 1613, 1475, 1443,
1426, 1375, 1363, 1331, 1310, 1302, 1286, 1226, 1170, 1144, 1133, 1073, 1058, 1013, 965, 919, 902, 880,
867, 776, 770, 737, 730, 686, 587, 559, 513, 482, 472, 460, 435, 407. HRMS EI+ (M) Calculated for
C 12H 13NO 4S = 267.05653, found = 267.05567.
Table 3.S1 Full optimization table
a
Entry Solvent Oxidant
(equiv)
TMSCF 3
(equiv)
KF
(equiv)
Additive Yield
(%)
b
1 CH 3CN PIDA (2) 4 4 - 22
2 CH 3CN PIFA (2) 4 4 - 42
3 MeOH PIFA (2) 4 4 - 0
4 PhCH 3 PIFA (2) 4 4 - 0
5 THF PIFA (2) 4 4 - 15
6 EtCN PIFA (2) 4 4 - 17
7 CH 3CN PIFA (2) 2 2 - 52
8 CH 3CN PIFA 1.5 1.5 - 52
9
c
CH 3CN PIFA 1.5 1.5 - 29
10
d
CH 3CN PIFA 1.5 1.5 - 26
11 CH 3CN PIFA 1.5 1.5 CuCl 59
12 CH 3CN PIFA 1.5 1.5 Cu(OTf) 2 56
13 CH 3CN PIFA 1.5 1.5 Fe(OAc) 2 7
160
14 CH 3CN PIFA 1.5 1.5 ZnCl 2 30
15 CH 3CN PIFA 1.5 1.5 Cu(OAc) 2 62
16
e
CH 3CN PIFA 2.0 1.5 Cu(OAc) 2 73
17
f
CH 3CN PIFA 1.5 1.5 Cu(OAc) 2 39
18 CH 3CN PIFA 1.5 1.5 Cu(MeCN) 4PF 6 29
19 CH 3CN PIFA 1.5 1.5 Cu(MeCN) 4BF 4 36
a
Conditions: 1a (0.25 mmol), solvent (2.5 mL), 0.1 equiv of additive unless otherwise specified, room temperature for
1h.
b
Yield determined by 19F NMR spectroscopy using PhCF3 as internal standard.
c
Reaction performed at 0 ˚C.
d
Reaction
performed at 80 ˚C. e 0.3 equiv of additive.
f
1 equiv of additive. PIFA = bis(trifluoroacetoxy)iodobenzene; PIDA =
diacetoxyiodobenzene. 2a was obtained as a (3:1) mixture of E:Z isomers in all cases
General Procedures for C(sp
2
)–H Trifluoromethylation
Method A
In an argon glovebox, starting material 1 (0.25 mmol), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg)
and Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial equipped with a stir
bar. The vial was sealed with a septum and brought outside the glovebox. Subsequently, CH 3CN (2.5 mL)
and TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by syringe under a stream of N2.
The mixture was then stirred at room temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and
extracted with EtOAc three times (3 mL each time). The combined organic layers were dried over MgSO 4,
and the compound was isolated by column chromatography using appropriate solvent system.
Method B
In an argon glovebox, starting material 1 (0.25 mmol), PIFA (3 equiv, 322.6 mg), KF (3 equiv, 43.6 mg) and
Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial equipped with a stir bar.
The vial was sealed with a septum and brought outside the glovebox. Subsequently, CH 3CN (2.5 mL) and
161
TMSCF3 (4.5 equiv, 165 µL) were added in quick succession to the vial by syringe under a stream of N 2.
The mixture was then stirred at room temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and
extracted with EtOAc three times (3 mL each time). The combined organic layers were dried over MgSO 4,
and the compound was isolated by column chromatography using appropriate solvent system.
Method C
In an argon glovebox, starting material 1 (0.25 mmol), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg)
and Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial (vial 1) equipped with
a stir bar. Into a second vial, also equipped with a stir bar (vial 2), PIFA (1.5 equiv, 161.3 mg) and KF (1.5
equiv, 21.8 mg) were charged. Both vials were then sealed with a septum and brought outside the
glovebox. Subsequently, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL) were added in quick succession by
syringe to vial 1 under a stream of N2. The mixture was then stirred at room temperature for 1 hour. After
this time, this solution was transferred into vial 2, followed by addition of TMSCF 3 (2 equiv, 75 µL) by
syringe. *Note: To ensure full transfer of the contents, a small amount of CH 3CN (0.5 mL) was used to
wash vial 1, and then transferred to vial 2. This mixture was further stirred at room temperature for an
additional 1 hour, then diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL
each time). The combined organic layers were dried over MgSO 4, and the compound was isolated by
column chromatography using appropriate solvent system
Synthesis and NMR Spectroscopic Data of Products
Note: in the case of products 3-2a to 3-2d, geometrical isomers where assigned based on the observed C–
F coupling (quartet) between the N–Me and CF 3 groups present in the Z-isomer. Such coupling was not
seen in the E-isomer.
162
2-methyl-3-(2,2,2-trifluoro-1-phenylethylidene)isoindolin-1-one (3-2a)
Prepared following general method A. In an argon glovebox, (Z)-3-benzylidene-2-methylisoindolin-1-one
(3-1a) (0.25 mmol, 58.8 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6
mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75
µL) were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL
each time). The combined organic layers were dried over MgSO 4, and the compound was isolated by
column chromatography (gradient of 0% - 8% EtOAc in hexanes). The two isomers (E:Z = 3:1, determined
by
19
F NMR) were obtained in a combined yield of 66% (50 mg) as a white solid. Shifts of major isomer (E)-
3-2a):
1
H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J = 7.2 Hz, 1H), 7.90 – 7.88 (m, 1H), 7.67 (t, J = 7.1 Hz,
1H), 7.59 (t, J = 7.5 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.36 – 7.33 (m, 2H), 2.59 (s, 3H).
13
C NMR (100 MHz,
Chloroform-d) δ 168.6, 143.2 (q, J = 3.2 Hz), 134.2, 133.1 (q, J = 2.2 Hz), 132.9, 131.9, 130.7, 129.9, 129.3,
128.4, 125.5 (q, J = 7.7 Hz), 124.3 (q, J = 272.7 Hz), 123.5, 111.4 (q, J = 33.7 Hz), 31.0.
19
F NMR (470 MHz,
Chloroform-d) δ -54.3 (s, 3F). HRMS EI+ (M) Calculated for C 17H 12ONF 3 = 303.08710, found = 303.08762.
m.p.: 119-122 ˚C. Shifts of minor isomer (Z)-3-2a:
1
H NMR (500 MHz, Chloroform-d) δ 7.81 (d, J = 7.5 Hz,
1H), 7.59 – 7.51 (m, 1H), 7.54 – 7.47 (m, 2H), 7.40 – 7.34 (m, 3H), 7.12 (t, J = 7.8 Hz, 1H), 5.73 (d, J = 8.1,
0.8 Hz, 1H), 3.58 (q, J = 2.9 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) δ 169.0, 141.8 (q, J = 3.7, 3.2 Hz),
137.2, 133.8 (q, J = 2.6 Hz), 132.4, 131.6, 130.2, 129.6, 129.4, 129.2, 125.2, 123.5, 123.2 (q, J = 272.1 Hz),
110.7 (q, J = 33.8 Hz), 30.2 (q, J = 7.3 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -50.8 (q, J = 2.6 Hz, 3F).
HRMS EI+ (M) Calculated for C 17H 12ONF 3 = 303.08710, found = 303.08762. m.p.: 111-112 ˚C.
2-methyl-3-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethylidene)isoindolin-1-one (3-2b)
Prepared following general method A. In an argon glovebox, (Z)-2-methyl-3-(4-
(trifluoromethyl)benzylidene)isoindolin-1-one (3-1b) (0.25 mmol, 75.8 mg), PIFA (1.5 equiv, 161.3 mg), KF
163
18
ma x 11 6
(1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial. Under
N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by syringe. The
mixture was then allowed to stir at room temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and
extracted with EtOAc three times (3 mL each time). The combined organic layers were dried over MgSO 4,
and the compound was isolated by column chromatography (gradient of 0% - 8% EtOAc in hexanes). The
two inseparable isomers (E:Z = 4:1, determined by
19
F NMR) were obtained in a combined yield of 60%
(56 mg) as a yellow solid. Only shifts of the major isomer reported for clarity. (E-2b)
1
H NMR (399 MHz,
Chloroform-d) δ 8.19 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.72 – 7.68 (m, 3H), 7.61 (td, J = 7.4, 0.9
Hz, 1H), 7.50 (d, J = 7.7 Hz, 2H), 2.59 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 168.4, 144.1 (q, J = 3.3
Hz), 137.1, 134.0, 134.0, 133.1, 132.5, 132.4 (q, J = 7.9 Hz), 131.5 (q, J = 32.9 Hz), 131.1, 129.7, 125.6 (q, J
= 7.6 Hz), 125.4 (q, J = 3.7 Hz), 123.9 (q, J = 272.4 Hz), 123.8 (q, J = 272.4 Hz), 31.3.
19
F NMR (470 MHz,
Chloroform-d) δ -54.0 (s, 3F), -63.3 (s, 3F). 19F NMR of minor isomer (Z-2b) (470 MHz) δ -50.2 (q, J = 2.3
Hz, 3F), -63.2 (s, 3F). HRMS EI+ (M) Calculated = 371.07447, found = 371.07434. FT/IR (l
-1
cm
-1
): 1718,
1617, 1589, 1473, 1449, 1430, 1409, 1370, 1322, 1293, 1272, 1198, 1160, 1103, 1065, 1029, 1020, 979,
938, 927, 868, 839, 815, 802, 771, 750, 701, 679, 664, 631, 601, 556, 521, 480, 457, 453, 406.
2-methyl-3-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethylidene)isoindolin-1-one (3-2c)
Prepared following general method A. In an argon glovebox, (Z)-2-methyl-3-(4-
(trifluoromethyl)benzylidene)isoindolin-1-one (3-1c) (0.25 mmol, 66.3 mg), PIFA (1.5 equiv, 161.3 mg), KF
(1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial. Under
N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by syringe. The
mixture was then allowed to stir at room temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and
extracted with EtOAc three times (3 mL each time). The combined organic layers were dried over MgSO 4,
and the compound was isolated by column chromatography (gradient of 0% - 8% EtOAc in hexanes). The
164
two isomers (E:Z = 4:1) were obtained in a combined yield of 69% (57 mg) as a white solid. Shifts of the
major isomer (E)-3-2c:
1
H NMR (400 MHz, Chloroform-d) δ 8.17 (dt, J = 8.1, 0.7 Hz, 4H), 7.88 (ddd, J = 7.4,
1.4, 0.7 Hz, 1H), 7.66 (td, J = 7.7, 1.4 Hz, 1H), 7.57 (td, J = 7.4, 0.9 Hz, 1H), 7.27 – 7.23 (m, 2H), 6.96 – 6.91
(m, 2H), 3.86 (s, 3H), 2.63 (s, 3H).
13
C NMR (101 MHz, Chloroform-d) δ 168.6, 160.3, 143.3 (q, J = 3.1 Hz),
134.3, 133.2, 132.8, 130.6, 129.9, 125.5 (q, J = 7.7 Hz), 125.1 (q, J = 2.3 Hz), 124.4 (q, J = 272.6 Hz), 123.4
(q, J = 2.6 Hz), 113.9, 111.1 (q, J = 33.6 Hz), 55.5, 31.0.
19
F NMR (376 MHz, Chloroform-d) δ -54.9 (s, 3F).
HRMS EI+ (M) Calculated = 333.09766, found = 333.09806. FT/IR (l
-1
cm
-1
): 1696, 1652, 1605, 1574, 1510,
1471, 1456, 1424, 1395, 1342, 1326, 1292, 1240, 1173, 1087, 1029, 972, 953, 941, 887, 829, 814, 770,
741, 720, 692, 634, 612, 588, 560, 539, 515, 505, 474, 456, 418, 408. m.p.: 131-133 ˚C. Shifts of the minor
isomer (Z)-3-2c:
1
H NMR (399 MHz, Chloroform-d) δ 7.80 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.28 (d,
J = 8.7 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 5.87 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.56 (q,
J = 2.9 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 169.1, 160.6, 141.9 (q, J = 2.9 Hz), 137.4, 133.0, 132.4,
130.1, 129.2, 125.8 (q, J = 2.3 Hz), 125.2, 123.5, 123.3 (q, J = 272.0 Hz), 114.8, 110.4 (q, J = 33.6 Hz), 55.6,
30.3 (q, J = 7.2 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -51.5 (q, J = 2.9 Hz, 3F). HRMS EI+ (M) Calculated
for C 18H 14NO 2F 3 = 333.09766, found = 333.09806. FT/IR ( l
-1
max cm
-1
): 1696, 1652, 1605, 1574, 1510, 1471,
1456, 1424, 1395, 1342, 1326, 1292, 1240, 1173, 1087, 1029, 972, 953, 941, 887, 829, 814, 770, 741, 720,
692, 634, 612, 588, 560, 539, 515, 505, 474, 456, 418, 408. m.p: 119-122 ˚C.
2,6-dimethyl-3-(2,2,2-trifluoro-1-phenylethylidene)isoindolin-1-one (3-2d)
Prepared following general method A. In an argon glovebox, (Z)-3-benzylidene-2,6-dimethylisoindolin-1-
one (1d) (0.25 mmol, 62.3 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %,
13.6 mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv,
75 µL) were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL
165
ma
x
each time). The combined organic layers were dried over MgSO4, and the compound was isolated by
column chromatography (gradient of 0% - 8% EtOAc in hexanes). The two isomers (E:Z = 5:1) were
obtained in a combined yield of 64% (51 mg) as a white solid. Shifts of major isomer:
1
H NMR (399 MHz,
Chloroform-d) 8.05 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.44 – 7.39 (m, 3H), 7.36 – 7.32
(m, 2H), 2.57 (s, 3H), 2.49 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 168.7, 143.3 (q, J = 3.2 Hz), 141.4,
133.8, 133.2 (q, J = 2.3 Hz), 132.0, 131.6, 130.1, 129.2, 128.4, 125.3 (q, J = 7.6 Hz), 124.4 (q, J = 272.6 Hz),
123.7, 110.6 (q, J = 33.6 Hz), 30.9, 21.5.
19
F NMR (376 MHz, Chloroform-d) δ -54.4 (s, 3F). HRMS EI+ (M):
calculated for C 18H 14ONF 3 = 317.10275, found = 317.10220. FT/IR ( l
-1
max cm
-1
): 1722, 1705, 1610, 1490,
1468, 1443, 1428, 1366, 1327, 1288, 1275, 1202, 1176, 1150, 1101, 1038, 1030, 997, 983, 961, 944, 899,
879, 826, 791, 771, 755, 714, 700, 671, 650, 620, 599, 556, 526, 504, 471, 456, 447, 432, 416. m.p: 110-
112 ˚C.
Shifts of minor isomer:
1
H NMR (399 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.57 – 7.43 (m, 3H), 7.36 (d, J =
8.4 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 5.58 (d, J = 8.2 Hz, 1H), 3.56 (q, J = 2.8 Hz, 3H), 2.34 (s, 3H).
13
C NMR
(100 MHz, Chloroform-d) δ 169.1, 142.0 (q, J = 2.9 Hz), 140.8, 134.6, 134.0 (q, J = 2.3 Hz), 133.3, 131.7,
129.5, 129.4, 129.3, 125.0, 123.7, 123.3 (q, J = 271.9 Hz), 109.9 (q, J = 33.9 Hz), 30.2 (q, J = 7.3 Hz), 21.4.
19
F NMR (376 MHz, Chloroform-d) δ -50.5 (q, J = 2.89 Hz, 3F). FT/IR ( l
-1
cm
-1
): 1721, 1617, 1580, 1488,
1464, 1443, 1377, 1275, 1200, 1174, 1149, 1102, 1036, 995, 944, 924, 896, 880, 819, 789, 754, 713, 699,
683, 642, 620, 600, 557, 521, 511, 481, 453, 442, 420, 409. HRMS EI+ (M): calculated for C 18H 14ONF 3 =
317.10275, found = 317.10220. m.p: 124-125 ˚C.
2-benzyl-3-hydroxy-3-(1,1,1-trifluoropropan-2-yl)isoindolin-1-one (3-2e)
Prepared using general method A, implementing a modification in the work-up procedure. In an argon
glovebox, (E)-2-benzyl-3-ethylideneisoindolin-1-one (3-1e) (0.25 mmol, 63 mg mg), PIFA (1.5 equiv, 161.3
mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top
166
ma
x
vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by
syringe. The mixture was then allowed to stir at room temperature for 1 hour. After this time, the mixture
was diluted with EtOAc (5 mL) and HCl (1M, 5ml) was added to the reaction mixture. The layers were
separated and the aqueous layer was further extracted with EtOAc (3 mL x 3). The combined organic layers
were washed with water (10 mL), brine (10 mL) and dried over MgSO 4 and evaporated to dryness under
reduced pressure. The residue was further purified by column chromatography using a gradient of 0% -
10% EtOAc in hexanes. Obtained as an inseparable mixture of diastereomers in a 4:1 ratio. White solid,
40% yield, 33 mg. **Note: If basic work-up (NH 4OH) is implemented, large amounts of N-
benzylphthalimide and lower yields of 2e are obtained. Shifts of major isomer reported for clarity.
1
H NMR
(399 MHz, Chloroform-d) δ 7.84 (dd, J = 7.2, 1.5 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.5, 1.4 Hz,
1H), 7.57 – 7.54 (m, 1H), 7.48 (d, J = 7.7 Hz, 2H), 7.35 – 7.27 (m, 3H), 4.75 (d, J = 15.3 Hz, 1H), 4.62 (d, J =
15.2 Hz, 1H), 3.08 – 2.94 (m, 1H), 2.65 (s, 1H), 0.62 (d, J = 7.1 Hz, 3H). In order to observe signal
corresponding to CF3 group due to concentration,
13
C Shifts of the diastereomeric mixture is reported:
13
C
NMR (100 MHz, Chloroform-d) δ 167.8, 167.2, 144.6, 143.6, 138.1, 137.7, 132.7, 132.2, 131.7, 131.4,
130.3, 129.7, 129.1, 128.9, 128.8, 128.8, 128.7, 127.8, 127.6, 126.7 (q, J = 280.1 Hz), 125.7 (q, J = 280.4
Hz), 123.9, 123.6, 123.3, 92.0 (q, J = 1.4 Hz), 89.6 (q, J = 1.9 Hz), 43.9 (q, J = 26.2 Hz), 43.8 (q, J = 25.4 Hz),
42.9, 42.4, 10.1 (q, J = 2.3 Hz), 9.7 (q, J = 2.5 Hz). 19F NMR (376 MHz, Chloroform-d) δ -64.7 (d, J = 9.6 Hz,
3F). 19F Shift of minor isomer: δ -68.5 (d, J = 8.3 Hz). HRMS ES+ calculated for C 18H 15F 3NO (M-OH+) =
318.1106; found = 318.1155. FT/IR (l
-1
cm-1): 3260.56, 2359.96, 2338.27, 1680.18, 1613.64, 1352.82,
1264.59, 1181.67, 1139.24, 1065.00, 1010.52, 957.002, 911.683, 832.113, 745.835, 710.158
2-methyl-4-(trifluoromethyl)isoquinolin-1(2H)-one (3-2f)
Prepared following general method B. In an argon glovebox, 2-methylisoquinolin-1(2H)-one (0.25 mmol,
39.8 mg), PIFA (3 equiv, 322.6 mg), KF (3 equiv, 43.6 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into
167
3
ma
x
an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (4.5 equiv, 165 µL) were added in
quick succession to the vial by syringe. The mixture was then allowed to stir at room temperature for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 7% EtOAc in hexanes). The product was obtained in 54% yield (31 mg)
as a white solid m.p: 91-93 ˚C.
1
H NMR (500 MHz, Chloroform-d) δ 8.49 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.8
Hz, 1H), 7.74 (t, J = 7.3 Hz, 1H), 7.62 – 7.55 (m, 2H), 3.66 (s, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 162.4,
133.5 (q, J = 7.3 Hz), 133.1, 132.1, 128.5, 128.0, 125.8, 124.0 (q, J = 271.5 Hz), 123.5 (q, J = 2.3 Hz), 106.8
(q, J = 32.0 Hz), 37.7.
19
F NMR (376 MHz, Chloroform-d) δ -61.4 (s, 3F). FT/IR (l
-1
cm
-1
): 3018, 3047, 2956,
2925, 1660, 1637,
1609, 1559, 1494, 1457, 1403, 1350, 1319, 1297, 1262, 1195, 1145, 1104, 1075, 990, 934, 898, 870, 835,
793, 764, 754, 707, 691, 662, 623, 545, 537, 498, 460, 439, 432, 421, 408. HRMS EI+ (M): calculated for
C 11H 8ONF 3 = 227.05580, found = 227.05635.
2-phenyl-4-(trifluoromethyl)isoquinolin-1(2H)-one (3-2g)
Prepared following general method B. In an argon glovebox, 2-phenylisoquinolin-1(2H)-one (0.25 mmol,
55.3 mg), PIFA (3 equiv, 322.6 mg), KF (3 equiv, 43.6 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into
an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (4.5 equiv, 165 µL) were added in
quick succession to the vial by syringe. The mixture was then allowed to stir at room temperature for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 7% EtOAc in hexanes). The product was obtained in 44% yield (32 mg)
as a colorless oil.
1
H NMR (500 MHz, Chloroform-d) δ 8.54 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.80
(t, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.43
168
3
ma
x
(d, J = 7.6 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 161.7, 140.6, 133.6, 133.4 (q, J = 7.3 Hz), 132.0,
129.7, 129.1, 129.0, 128.4, 126.9, 126.3, 124.1 (q, J = 271.0 Hz), 123.6 (q, J = 2.3 Hz), 107.2 (q, J = 32.1 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -61.5 (s, 3F). FT/IR (l
-1
cm
-1
): 1673, 1645, 1605, 1596, 1558, 1490,
1456, 1404, 1359, 1326, 1282, 1256, 1219, 1182, 1143, 1110, 1070, 1037, 976, 896, 799, 770, 757, 743,
706, 694, 667, 626, 585, 455, 408. HRMS ES+ (M+H+): calculated for C 16H 10F 3NO = 290.0793, found =
290.0798.
7-bromo-2-methyl-4-(trifluoromethyl)isoquinolin-1(2H)-one (3-2h)
Prepared following general method B. In an argon glovebox, 7-bromo-2-methylisoquinolin- 1(2H)-one
(0.25 mmol, 59.5 mg), PIFA (3 equiv, 322.6 mg), KF (3 equiv, 43.6 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were
weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (4.5 equiv, 165 µL) were
added in quick succession to the vial by syringe. The mixture was then allowed to stir at room temperature
for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 8% EtOAc in hexanes). The product was obtained in 55% yield (42 mg)
as a white solid. m.p: 180-183 ˚C.
1
H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 2.2 Hz, 1H), 7.83 (dd, J =
8.7, 2.2 Hz, 1H), 7.66 (dd, J = 8.8, 1.8 Hz, 1H), 7.58 (s, 1H), 3.65 (s, 3H).
13
C NMR (126 MHz, Chloroform-d)
δ 161.0, 136.2, 133.7 (q, J = 7.2 Hz), 131.1, 130.6, 127.1, 125.1 (q, J = 2.2 Hz), 124.8 (q, J = 270.9 Hz), 122.1,
106.3 (q, J = 32.4 Hz), 37.6.
19
F NMR (470 MHz, Chloroform-d) δ -61.5 (s, 3F). FT/IR (l
-1
cm-1): 1663, 1643,
1598, 1574, 1542, 1488, 1441, 1415, 1363, 1347, 1315, 1264, 1248, 1191, 1160, 1102, 1074, 1004, 941,
928, 904, 820, 810, 788, 754, 714, 703, 673, 640, 605, 549, 544, 535, 497, 465, 446, 419, 410. HRMS EI+
(M): calculated for C 11H 7ONF 3Br = 304.96631, found = 304.96716.
169
1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one (3-2i)
Prepared following general method A. In an argon glovebox, PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8
mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5
mL), pyridin-2(1H)-one (0.25 mmol, 24.5 µL) and TMSCF 3 (2 equiv, 75 µL) were added in quick succession
to the vial by syringe. The mixture was then allowed to stir at room temperature for 1 hour, diluted with
0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The combined organic layers
were dried over MgSO 4. Subsequently the organic layer was concentrated, and hexanes were added to
precipitate a solid. The supernatant was discarded, and to the solid residue further dried under vacuum
to yield 3-2i as a brown solid in 73% yield (32 mg).
1
H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.1 Hz,
1H), 7.52 (d, J = 6.9 Hz, 1H), 6.25 (t, J = 7.0 Hz, 1H), 3.60 (s, 3H).
19
F NMR (376 MHz, Chloroform-d) δ -66.5
(s, 3F). The NMR data matches reported values.
1-gram scale reaction: In an argon glovebox, PIFA (1.5 equiv, 3.96 g), KF (1.5 equiv, 534.5 mg), Cu(OAc) 2
(30 mol %, 501.3 mg) were weighed into an oven-dried 250 ml round bottom flask equipped with a
magnetic stir bar. To the sealed flask, under N 2, CH 3CN (92 mL), pyridin-2(1H)-one (9.2 mmol, 895 µL), and
TMSCF 3 (2 equiv, 1.36 mL) were added in quick succession by syringe. The mixture was then allowed to
stir at room temperature for 1 hour, diluted with 0.1M NH 4OH (200 mL) and extracted with EtOAc three
times (60 mL each time). The combined organic layers were dried over MgSO 4. Subsequently the organic
layer was concentrated, and to the residue hexanes was added (150 mL) and a solid precipitated. This
flask was kept in a freezer (-20 ˚C) overnight (16 h). The supernatant was discarded, and the solid residue
washed with hexanes (two times, 20 mL each time) and dried under vacuum to yield 2i as a brown solid
in 60% yield (982 mg).
1
H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.1 Hz, 1H), 7.52 (d, J = 6.9 Hz, 1H),
6.25 (t, J = 7.0 Hz, 1H), 3.60 (s, 3H).
19
F NMR (376 MHz, Chloroform-d) δ -66.5 (s, 3F). The NMR data
matches reported values.
170
12 max 9
3
1-phenyl-3-(trifluoromethyl)pyridin-2(1H)-one (3-2j)
Prepared following general method A. In an argon glovebox, 1-phenylpyridin-2(1H)-one (3-1j) (0.25 mmol,
42.8 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc)2 (30 mol %, 13.6 mg) were weighed
into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL) were added in
quick succession to the vial by syringe. The mixture was then allowed to stir at room temperature for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 78% yield (47 mg)
as a white solid. m.p: 63-64 ˚C.
1
H NMR (500 MHz, Chloroform-d) δ 7.82 (d, J = 7.1 Hz, 1H), 7.57 (d, J = 7.0
Hz, 1H), 7.53 – 7.48 (m, 2H), 7.47 – 7.42 (m, 1H), 7.41 – 7.36 (m, 2H), 6.32 (t, J = 7.0 Hz, 1H).
13
C NMR (126
MHz, Chloroform-d) δ 158.3, 142.0, 139.9, 139.4 (q, J = 5.1 Hz), 129.5, 129.2, 126.6, 122.7 (q, J = 271.9
Hz), 121.7 (q, J = 30.9 Hz), 104.1.19F NMR (470 MHz, Chloroform-d) δ -66.5 (s, 3F). HRMS ES+ (M+H+)
Calculated = 240.0636, found = 240.0628. FT/IR (l
-1
cm
-1
): 1667, 1611, 1592, 1552, 1491, 1457, 1374, 1315,
1293, 1270, 1253, 1154, 1122, 1078, 1054, 1038, 1021, 1001, 972, 966, 947, 942, 918, 865, 837, 798, 774,
758, 722, 691, 642, 607, 582, 539, 530, 518, 480, 455, 431, 413, 405.
1-(4-methoxyphenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (3-2k)
Prepared following general method C. In an argon glovebox, 1-(4-methoxyphenyl)pyridin-2(1H)-one (3-
1k) (0.25 mmol, 50.3 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6
mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75
µL) were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour. The solution was then transferred to another crimp-top vial charged with PIFA
(1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF 3 (2 equiv, 75 µL) [vial
was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution was stirred for 1
171
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 79% yield (53 mg)
as a brown solid.
1
H NMR (399 MHz, Chloroform-d) δ 7.81 (dd, J = 7.4, 1.1 Hz, 0H), 7.55 (dd, J = 6.8, 2.2
Hz, 1H), 7.32 – 7.30 (m, 1H), 7.29 (dd, J = 2.3, 0.5 Hz, 1H), 7.01 – 6.99 (m, 1H), 6.98 (dd, J = 2.3, 0.5 Hz, 1H),
6.29 (t, J = 7.0 Hz, 1H), 3.85 (d, J = 0.4 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d) δ 159.9, 158.5 (d, J = 1.5
Hz), 142.3, 139.3 (q, J = 5.0 Hz), 132.7, 127.7, 122.8 (q, J = 271.9 Hz), 121.8 (q, J = 30.9 Hz), 114.7, 104.0,
55.7.
19
F NMR (376 MHz, Chloroform-d) δ -66.5 (s, 3F). HRMS ES+ Calculated for C 13H 11F 3NO 2 (M+H+) =
270.0736; found = 270.0816. FT/IR (l
-1
cm
-1
): 3109, 3057, 3012, 2940, 2848, 1663, 1596, 1248, 1121, 1074,
1026, 815.
1-benzyl-3-(trifluoromethyl)pyridin-2(1H)-one (3-2l)
Prepared following general method A. In an argon glovebox, 1-benzylpyridin-2(1H)-one (1l) (0.25 mmol,
46.3 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed
into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL) were added in
quick succession to the vial by syringe. The mixture was then allowed to stir at room temperature for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 50% yield (31 mg)
as a brown solid.
1
H NMR (399 MHz, Chloroform-d) δ 7.72 (dd, J = 7.1, 2.2 Hz, 1H), 7.48 (dd, J = 6.9, 2.1
Hz, 1H), 7.40 – 7.30 (m, 5H), 6.21 (t, J = 7.0 Hz, 1H), 5.17 (s, 2H).
13
C NMR (100 MHz, Chloroform-d) δ 158.6,
141.2, 138.8 (q, J = 5.0 Hz), 135.5, 129.2, 128.7, 128.6, 122.8 (q, J = 271.7 Hz), 121.0 (q, J = 30.9 Hz), 104.3,
52.3.
19
F NMR (376 MHz, Chloroform-d) δ -66.5 (s, 3F). HRMS ES
+
Calculated for C 13H 11F 3NO (M+H
+
) =
254.0787; found = 254.0826. FT/IR (V-1 cm-1): 3085, 3063, 1661, 1602, 1560, 1453, 1391, 1314, 1186,
172
1124, 1077, 1058, 961, 865.
1-(4-acetylphenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (3-2m)
Prepared following general method C. In an argon glovebox, 1-(4-acetylphenyl)pyridin-2(1H)-one (3-1k)
(0.25 mmol, 53.3 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg)
were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL)
were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour. The solution was then transferred to another crimp-top vial charged with PIFA
(1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF3 (2 equiv, 75 µL) [vial
was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution was stirred for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 61% yield (43 mg)
as a white solid (m.p: 121-123 ˚C).
1
H NMR (500 MHz, Chloroform-d) δ 8.08 (d, J = 8.1 Hz, 2H), 7.84 (d, J =
7.0 Hz, 1H), 7.55 (dd, J = 6.8, 2.1 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 6.36 (t, J = 7.0 Hz, 1H), 2.64 (s, 3H).
13
C
NMR (126 MHz, Chloroform-d) δ 196.9, 158.0, 143.5, 141.2, 139.7 (q, J = 4.9 Hz), 137.4, 129.6, 127.0,
122.6 (q, J = 271.9 Hz), 122.1 (q, J = 31.0 Hz), 104.6, 26.9.
19
F NMR (470 MHz, Chloroform-d) δ -66.6 (s, 3F).
HRMS ES
+
(M+H
+
) Calculated for C 14H 11NO 2F 3 = 282.0742, found = 282.0743. FT/IR (l
-1
cm
-1
): 1671, 1615,
1598, 1582, 1558, 1507, 1449, 1411, 1378, 1361, 1315, 1266, 1152, 1115, 1073, 1055, 1031, 962, 864,
845, 758, 732, 686, 624, 592, 582, 533, 480, 467, 429, 418, 404.
1-(4-nitrophenyl)-3-(trifluoromethyl)pyridin-2(1H)-one (3-2n)
Prepared following general method C. In an argon glovebox, 1-(4-nitrophenyl)pyridin-2(1H)-one (3-1k)
(0.25 mmol, 54.1 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg)
173
were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL)
were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour. The solution was then transferred to another crimp-top vial charged with PIFA
(1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF 3 (2 equiv, 75 µL) [vial
was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution was stirred for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 40% EtOAc in hexanes). The product was obtained in 55% yield (39 mg)
as a pale-yellow solid. m.p: 157-159 ˚C.
1
H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J = 8.2 Hz, 2H), 7.87
(d, J = 7.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 7.0, 2.0 Hz, 1H), 6.41 (t, J = 7.0 Hz, 1H).
13
C NMR
(126 MHz, Chloroform-d) δ 157.7, 147.8, 144.8, 140.7, 140.0 (q, J = 5.1 Hz), 127.9, 124.9, 122.4 (q, J =
272.1 Hz), 122.4 (q, J = 31.4 Hz), 105.0.
19
F NMR (470 MHz, Chloroform-d) δ -66.6 (s, 3F). HRMS ES+ (M+H+)
Calculated for C 12H 8N 2O 3F 3 = 285.0487, found = 285.0485. FT/IR (l
-1
cm
-1
): 3122, 3090, 1667, 1615, 1553,
1516, 1495, 1450, 1419, 1376, 1348, 1311, 1275, 1256, 1157, 1124, 1111, 1075, 1056, 1032, 1015, 953,
867, 853, 811, 801, 778, 753, 733, 694, 663, 604, 534, 515, 497, 445, 420.
3-(2-oxo-3-(trifluoromethyl)pyridin-1(2H)-yl)benzaldehyde (3-2o)
Prepared following general method A. In an argon glovebox, 3-(2-oxopyridin-1(2H)-yl)benzaldehyde (3-1l)
(0.25 mmol, 49.8 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg)
were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL)
were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL
each time). The combined organic layers were dried over MgSO 4, and the compound was isolated by
174
ma
x
19
ma x 15 2 3
column chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 48% yield
(32 mg) as a colorless liquid.
1
H NMR (500 MHz, Chloroform-d) δ 10.06 (s, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.92
(s, 1H), 7.86 (d, J = 7.0 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.59 (dd, J = 6.9, 2.0 Hz, 1H), 6.38 (t, J = 7.0 Hz, 1H).
13
C
NMR (126 MHz, Chloroform-d) δ 190.8, 158.1 (q, J = 1.2 Hz), 141.3, 140.6, 139.8 (q, J = 5.1 Hz), 137.7,
132.6, 130.5, 130.3, 127.3, 122.5 (q, J = 272.0 Hz), 122.1 (q, J = 31.2 Hz), 104.7.
19
F NMR (470 MHz,
Chloroform-d) δ -66.6 (s, 3F). HRMS ES
+
(M+H
+
) Calculated for C 13H 9NO 2F 3 = 268.0585, found = 268.0581.
FT/IR (l
-1
cm
-1
): 1668, 1612, 1601, 1554, 1482, 1454, 1374, 1318, 1278, 1122, 1043, 966, 921, 897, 863,
762, 731, 708, 691, 645, 598, 534, 475, 448, 438, 416, 409.
4-(benzyloxy)-1-phenyl-3-(trifluoromethyl)pyridin-2(1H)-one (3-2p)
Prepared following general method C. In an argon glovebox, 4-(benzyloxy)-1-phenylpyridin-2(1H)-one
(0.25 mmol, 69.3 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2 (30 mol %, 13.6 mg)
were weighed into an oven-dried crimp- top vial. Under N 2, CH 3CN (2.5 mL) and TMSCF 3 (2 equiv, 75 µL)
were added in quick succession to the vial by syringe. The mixture was then allowed to stir at room
temperature for 1 hour. The solution was then transferred to another crimp-top vial charged with PIFA
(1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF 3 (2 equiv, 75 µL) [vial
was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution was stirred for 1
hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each time). The
combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 68% (59 mg) yield
as a white solid (m.p: 166-168 ˚C).
1
H NMR (500 MHz, Chloroform-d) δ 7.48 – 7.44 (m, 3H), 7.43 – 7.41 (m,
5H), 7.39 – 7.35 (m, 1H), 7.35 – 7.30 (m, 2H), 6.17 (d, J = 7.9 Hz, 1H), 5.28 (s, 2H).
13
C NMR (126 MHz,
Chloroform-d) δ 167.1, 159.5, 141.7, 139.9, 135.1, 129.4, 129.0, 129.0, 128.7, 126.9, 126.8, 123.7 (q, J =
273.7 Hz), 104.1 (q, J = 30.0 Hz), 95.2, 71.4.
19
F NMR (470 MHz, Chloroform-d) δ -57.9 (s, 3F). HRMS ES
+
175
(M+H
+
) Calculated = 346.1055, found = 346.1057. FT/IR (l
-1
cm
-1
): 1660, 1605, 1593, 1535, 1475, 1455,
1444, 1360, 1325, 1273, 1249, 1220, 1172, 1160, 1134, 1099, 1079, 1053, 1038, 1029, 1001, 970, 910,
829, 790, 781, 768, 756, 736, 728, 694, 667, 645, 617, 583, 555, 536, 517, 495, 478, 448, 432, 425, 414,
404.
5-methyl-1-phenyl-3-(trifluoromethyl)pyridin-2(1H)-one (3-2q, Pirfenidone analog)
Prepared following general method C. In an argon glovebox, 5-methyl-1-phenylpyridin-2(1H)-one
(Pirfenidone, 3-1q) (0.25 mmol, 46.3 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2
(30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and
TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by syringe. The mixture was then
allowed to stir at room temperature for 1 hour. The solution was then transferred to another crimp-top
vial charged with PIFA (1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF 3
(2 equiv, 75 µL) [vial was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution
was stirred for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each
time). The combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 30% EtOAc in hexanes). The product was obtained in 44% (28 mg) yield
as a white solid.
1
H NMR (399 MHz, Chloroform-d) δ 7.69 (d, J = 2.2 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.46 –
7.40 (m, 1H), 7.40 – 7.36 (m, 2H), 7.35 (s, 1H), 2.17 (d, J = 1.1 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d)
δ 157.7, 141.9 (q, J = 5.0 Hz), 140.1, 139.5, 129.5, 129.0, 126.7, 122.8 (q, J = 271.9 Hz), 121.1 (q, J = 30.7
Hz), 113.2, 17.1.
19
F NMR (376 MHz, Chloroform-d) δ -66.4 (s, 3F). HRMS ES
+
Calculated for C 13H 11F 3NO
(M+H
+
) = 254.0787; found = 254.0826. FT/IR (l
-1
cm
-1
): 3061, 2926, 2855, 2361, 2338, 1678, 1618, 1550,
1492, 1373, 1334, 1255, 1129, 914.
N-methyl-N-(2-(trifluoromethyl)-3,4-dihydronaphthalen-1-yl)acetamide (3-2r)
176
Prepared following general method B. In an argon glovebox, N-(3,4-dihydronaphthalen-1-yl)-N-
methylacetamide (3-1o) (0.25 mmol, 59.5 mg), PIFA (3 equiv, 322.6 mg), KF (3 equiv, 43.6 mg), Cu(OAc) 2
(30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL) and
TMSCF 3 (4.5 equiv, 165 µL) were added in quick succession to the vial by syringe. The mixture was then
allowed to stir at room temperature for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with
EtOAc three times (3 mL each time). The combined organic layers were dried over MgSO 4, and the
compound was isolated by column chromatography (gradient of 0% - 8% EtOAc in hexanes). The product
was obtained in 77% yield (52 mg) as a colorless oil.
1
H NMR (500 MHz, Chloroform-d) δ 7.34 (t, J = 7.4 Hz,
1H), 7.31 – 7.21 (m, 2H), 7.14 (d, J = 7.7 Hz, 1H), 3.11 (s, 3H), 2.94 (t, J = 8.4 Hz, 2H), 2.63 (t, J = 8.2 Hz, 2H),
1.92 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 170.4, 141.9 (q, J = 3.9 Hz), 137.3, 130.5, 130.4, 128.3,
127.7, 124.4 (q, J = 29.3 Hz), 124.2, 123.5 (q, J = 273.1 Hz), 35.8 (q, J = 1.8 Hz), 26.9, 22.5 (q, J = 2.7 Hz),
21.3.
19
F NMR (470 MHz, Chloroform-d) δ -64.2. HRMS EI+ (M): calculated for C 14H 14ONF 3 = 269.10275,
found = 269.10252. FT/IR (l
-1
cm
-1
): 1743, 1652, 1634, 1576, 1559, 1472, 1455, 1430, 1372, 1345, 1318,
1287, 1273, 1235, 1121, 1158, 1115, 1082, 1037, 1026, 977, 949, 864, 828, 778, 755, 737, 720, 667, 625,
541, 489, 468, 465, 435, 420, 405.
Ethyl 2-methyl-4-(trifluoromethyl)-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3-2t)
Prepared following general method C. In an argon glovebox, ethyl 2-methyl-2H- benzo[e][1,2]thiazine-3-
carboxylate 1,1-dioxide (1q) (0.25 mmol, 66.8 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg),
Cu(OAc) 2 (30 mol %, 13.6 mg) were weighed into an oven-dried crimp-top vial. Under N 2, CH 3CN (2.5 mL)
and TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by syringe. The mixture was then
allowed to stir at room temperature for 1 hour. The solution was then transferred to another crimp-top
vial charged with PIFA (1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF 3
(2 equiv, 75 µL) [vial was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution
177
3
ma
x
was stirred for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each
time). The combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0 % - 20 % EtOAc in hexanes). The product was obtained as a viscous,
colorless oil (32 % yield, 27 mg).
1
H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.1 Hz, 1H), 7.76 (d, J =
8.3 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.32 (s, 3H), 1.42 (t, J =
7.2 Hz, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 161.4, 132.5, 131.7, 130.3, 129.4, 126.2 (q, J = 2.9 Hz),
125.3 (q, J = 272.4 Hz), 122.1, 117.1 (q, J = 2.8 Hz), 110.4 (q, J = 32.6 Hz), 63.7, 33.0, 13.9.
19
F NMR (376
MHz, Chloroform-d) δ -55.8 (s, 3F). FT/IR (l
-1
cm
-1
): 2985, 2923, 2850, 1739, 1604, 1593, 1480, 1467, 1443,
1350, 1327, 1287, 1235, 1209, 1119, 1084, 1060, 1009, 944, 909, 856, 838, 802, 764, 747, 724, 694, 681,
644, 626, 583, 555, 502, 462,455. HRMS ESI
+
(M+H
+
): calculated for C 13H 13F 3NO 4S = 336.0517, found =
336.0510.
1,3,7-trimethyl-8-(trifluoromethyl)-3,4,5,7-tetrahydro-1H-purine-2,6-dione (3-2u)
Prepared following general method C. In an argon glovebox, 1,3,7-trimethyl-3,4,5,7-tetrahydro-1H-
purine-2,6-dione (1m) (0.25 mmol, 48.5 mg), PIFA (1.5 equiv, 161.3 mg), KF (1.5 equiv, 21.8 mg), Cu(OAc) 2
(30 mol %, 13.6 mg) were weighed into an oven-dried crimp- top vial. Under N 2, CH 3CN (2.5 mL) and
TMSCF 3 (2 equiv, 75 µL) were added in quick succession to the vial by syringe. The mixture was then
allowed to stir at room temperature for 1 hour. The solution was then transferred to another crimp-top
vial charged with PIFA (1.5 equiv, 161.3 mg) and KF (1.5 equiv, 21.8 mg), followed by addition of TMSCF 3
(2 equiv, 75 µL) [vial was washed with 0.5 mL CH 3CN to ensure complete transfer of material]. The solution
was stirred for 1 hour, diluted with 0.1M NH 4OH (10 mL) and extracted with EtOAc three times (3 mL each
time). The combined organic layers were dried over MgSO 4, and the compound was isolated by column
chromatography (gradient of 0% - 50% EtOAc in hexanes). The product was obtained in 56% yield (37 mg)
as a white solid.
1
H NMR (400 MHz, Chloroform-d) δ 4.15 (q, J = 1.2 Hz, 3H), 3.59 (s, 3H), 3.42 (s, 3H).
19
F
178
NMR (376 MHz, Chloroform-d) δ -62.9 (q, J = 1.3 Hz, 3F). This data matches previous reports.
Attempted trifluoromethylation of 3-methyl-1-phenylpyridin-2(1H)-one
In the case of 2-pyridinones, selectivity toward the 3-position was always observed. Following general
method C, the trifluoromethylation of a substrate in which this position was blocked such as in 3-methyl-
1-phenylpyridin-2(1H)-one afforded only traces of CF 3-containing products, as detected by GC-MS. No
efforts to isolate these products were undertaken.
N
O
Ph method C
N
O
Ph
CF
3
179
Chapter 4: Siladifluoromethylation and deoxo-trifluoromethylation of P
V
–H
compounds with TMSCF
3
: routes to P
V
–CF
2
-
transfer reagents and P–CF
3
compounds
4.i Introduction
After exploring the fluorofunctionalizations of enamides, we turned our attention towards the
synthesis of organoperfluoroalkylsilanes. Despite the widespread use of perfluoroalkylsilanes as pro-
nucleophiles in organic reactions, methods for their synthesis are rather underdeveloped and limited to a
few traditional syntheses. Of initial interest to us was the synthesis of a bis(silyl)difluoromethane; a
molecule which we believed could be used as a [CF 2]
2–
equivalent. Our initial investigations revolved
around attempts to insert a difluoromethylene group into symmetric disilanes. Later efforts focused on a
difluorocarbene addition to a deprotonated hydrosilane, and while the concept appeared feasible in
theory, we were unable to successfully prepare the target molecule using that approach. The full
optimization table for these unsuccessful attempts are included in the experimental section of this
chapter. These attempts serve as an entry into the thought process behind the development of this
project: a direct siladifluoromethylation of phosphonates and phosphine oxides via a base-mediated
reaction of TMSCF 3 with the P—H bond of the phosphorous substrate.
The difluoromethylene moiety is a demonstrated bioisostere of ethereal oxygens, carbonyls,
secondary amides and methylene groups, that also demonstrates lipophilic hydrogen bond donor
properties.
13,207,267
This property has inspired a plethora of gem-difluorination
255,268,269
and
difluoromethylation
270–272
protocols. A prime example of –CF 2– bioisosterism is the use of –CF 2P
V
groups
in creating metabolically stable, bioactive molecules,
127,273–277
especially nucleoside mono-/di-/tri-
180
phosphate analogues.
278–281
A unified route to obtain these compounds is using
phosphonodifluoromethylsilanes, which can be activated by nucleophilic activators to afford a
phosphonodifluoromethide precursor under mild conditions. This has unsurprisingly promoted their use
in reactions with electrophiles
32,33,81,122,130
and in transition metal-mediated cross-coupling
reactions
129,133,135,141
(Figure 4.1) to produce a variety of fluorinated analogues with potentially divergent
chemical and physical properties.
Figure 4.1 Extensive use of P
V
CF 2TMS reagents: Mostly limited to diethyl phosphonate derivatives.
What is surprising is that despite the fact that variability of P
V
substituents can potentially
influence chemical/physical properties, examples demonstrating such variations are scarce. Known
reagent preparations have been generally limited to –OEt and –Oi-Pr derivatives. Furthermore, despite
the associated hazards, limited availability and requirement of an additional silylation step,
282,283
they are
routinely accessed from the controlled substance CF 2Br 2
119,284
(Halon 1202): a class I ozone depleting
R
CF
2
P(O)(OEt)
2
OH
P
O
EtO CF
2
TMS
EtO
R N
H
S
O
t-Bu
CF
2
P(O)(OEt)
2
Invaluable reagent for
phosphadifluoromethylation
CF
2
P(O)(OEt)
2
CF
2
P(O)(OEt)
2
R
variety of P
V
CF
2
-
containing products
ref. [10]
ref. [9]
Electrophiles
imines, enamines
aldehydes, ketones
P
O
EtO CF
2
EtO
CF
2
P(O)(OEt)
2
R
NH
R
R
CF
2
P(O)(OEt)
2
OH
R'
[Cu
I
], [Pd
0
], [Pd
II
]
Ar-I, Ar-B(OH)
2
tetrahydroisoquinolines
Cross-coupling
N
CF
2
P(O)(OEt)
2
Ar
CF
2
P(O)(OEt)
2
X
activation
(fluoride
alkoxide
carbonate)
R
RC CH
E
2
+
Electrophile
P
O
EtO CF
2
E
1
EtO
E
1
+
Electrophile
F
2
C
E
2
E
1
(dephosphorylation)
[CF
2
2-
] equivalent
P
O
EtO CF
2
TMS
EtO
(desilylation)
181
chemical and one of the most toxic fluorobromocarbon known. Another approach involves C(sp
3
)–H
chlorination of diisopropyl ((methylthio)methyl)phosphonate with thionyl chloride, chlorine-fluorine
exchange (with 3HF-Et 3N), activation with n-BuLi, and silylation (Figure 4.2).
121
P
V
-CF 2H compounds have
been prepared using TMSCF 2Br.
285
Figure 4.2 Reported syntheses of siladifluoromethyl phosphorous compounds
TMSCF 3 can be a source of nucleophilic –CF 3
21,22
and –C 2F 5,
38
and electrophilic singlet CF 2
carbene.
24
It can be prepared from fluoroform
286
and is safer and cheaper than many other
fluoroalkylation reagents. Using TMSCF 3 to add –CF 2TMS to nucleophiles has garnered appreciable
interest, allowing direct synthesis of less accessible difluoromethylsilanes from a single –CF 2– and TMS–
source. The seminal work of Mikami and coworkers on the siladifluoromethylation of boron
287
and sp
3
,
sp
2
, and sp carbon
28
centered nucleophiles is a prime example. An HMPA-mediated
siladifluoromethylation of di-/triarylmethanes is also reported.
29
Our group had also just recently detailed
a synthesis of S
II
–CF 2H compounds, via S
II
–CF 2TMS intermediates.
31
Our aim in this investigation was to
develop a novel method for the direct siladifluoromethylation of P
V
—H compounds, using the safe and
relatively inexpensive TMSCF 3 as both the source of the TMS— and the –CF 2—units.
Towards this goal, we envisioned the reaction pathway depicted in Figure 4.3. First, the phosphine
oxide substrate would be deprotonated by the chosen base to form the anion, which would be in
equilibrium with its tautomer 4-i 1. This molecule could then react with TMSCF 3 to release an equivalent
of trifluoromethide and form one equivalent of 4-i 2. The trifluoromethide released should, given the right
P
CF
2
TMS
O
RO
RO
P
X
O
RO
RO
(i) CF
2
Br
2
, (ii) TMSCl
(R = Et, X = H)
OR
(i) SO
2
Cl
2
(ii) 3HF NEt
3
(iii) n-BuLi (iv) TMSCl
(R = iPr, X = CH
2
SCH
3
)
182
set of conditions, decompose to form fluoride and difluorocarbene. Trapping of the thus formed
difluorocarbene by 4-i 2 produces the ylide type intermediate 4-i 3. The rearrangement of this molecule via
an [1,3] retro phospha-brooke rearrangement would furnish product 4-2. Alternatively, silylation by as
additional equivalent of TMSCF 3 could also produce the desired product after deprotection of the O—TMS
group.
Figure 4.3 Predicted reaction pathway leading to product 4-2
4.ii Results and Discussions
Optimization trials (Table 4.1) were performed using 4-1a. Note that Table 4.1 only contains the
most representative experiments of the optimization process. Further details on all the experiments
performed can be found in the Experimental Section of this chapter Among the bases screened, alkali
metal hydrides proved most effective, affording 4-2a in 66% yield (trial 2, 3). Amide and alkoxide bases
proved less effective for this substrate, with appreciable decomposition of 4-1a observed. At constant
stoichiometry of the reagents, no reaction was observed in THF, Et 2O, hexanes or MeCN as solvents.
DMPU promoted full consumption of TMSCF 3, but the uncontrollable reaction rate yielded none of the
desired product 4-2a. Binary solvent systems of DMF mixed with either THF, hexanes, MeCN, or Et 2O did
P
OTMS
R
R
O
R
R
P
CF
2
TMS
4-2
4-i
2
TMSCF
3
CF
3
-
F
-
+ :CF
2
Li
+
LiF
O
R
R
P
CF
2
TMS
4-i
3
4-i
1
O
P
H
R
R
O
P
Li
R
R
P
OLi
R
R
LiH
P
V
-P
III
tautomerism
4-1
TMSCF
3
183
not produce favorable results. Our working hypothesis was that the reaction proceeded through a
difluorocarbene intermediate; therefore, utilizing lithium or sodium salts could accelerate decomposition
of [CF 3]
–
to difluorocarbene. Interestingly upon substituting LiI with NaCl in DMF, 4-2a was not observed.
Instead, the hitherto unknown 4-3a was formed selectively (trial 5), highlighting the need for Li
+
.
28
The
combination of LiH and LiCl afforded 4-2a in near-quantitative yields (trial 9) when using 4 equivalents of
TMSCF 3. At this point in time, the reason behind the need for excess TMSCF 3 is unclear. The method was
extended to a series of phosphonates and phosphine oxides (table 4.2).
a
Table 4.1 Select optimization studies on diethyl phosphonate (4-1a)
trial
a
salt
e
base
e
TMSCF 3
(equiv)
NMR yield (%)
b
4-2a 4-3a 4-4a
1 LiI LiOtBu 2.5 22 0 11
2 LiI LiH 2.5 66 0 0
3 LiI NaH 2.5 66 0 0
4
c
LiI - 2.5 0 0 0
5 NaCl NaH 2.5 0 89 3
6 NaI NaH 2.5 5 24 5
7 LiCl NaH 2.5 73 4 2
8 LiCl LiH 2.5 84 0 0
9
d
LiCl LiH 4.0 99 0 0
a
Unless specified, trials were performed using 1a (0.5 mmol), in DMF (0.2 M).
b
Based on
19
F NMR using fluorobenzene (0.5 mmol)
as internal standard.
c
LiBF 4 (1.2 equiv) was added.
d
Reaction was performed in DMF (0.4 M).
e
1.2 equiv
P
H
O
EtO
EtO
P
CF
2
TMS
O
EtO
EtO
(i) base, salt
solvent, rt
10 mins
(ii) TMSCF
3
30 mins, rt
4-1a 4-2a
P
C
F
2
O
EtO
EtO
N
OTMS
4-3a
P
CF
2
H
O
EtO
EtO
4-4a
+ +
184
Phosphonate 4-2a, used extensively in phosphadifluoromethylation reactions,
9-10
was obtained in
near-quantitative yield (99%) (Table 4.2). To investigate steric effects at the P atom, 4-1b with an isopropyl
group in the place of an ethyl group was subjected to the developed conditions and furnished 4-2b in
excellent yield (89%). Even the egregiously sterically encumbered 1c underwent facile transformation to
2c (94%). At 20 mmol scale, 4-2a (83%, 4.3 g) and 4-2b (63%, 3.6 g) were obtained in high yields,
demonstrating scalability and applicability in bulk reagent synthesis.
a
Table 4.2 Siladifluoromethylation of P
V
–H compounds
a
Reactions performed with 0.5 mmol of 4-1. Yields in parentheses determined by
19
F NMR of reaction mix with PhF (0.5 mmol) as
internal standard. *20 mmol of 4-1.
b
2.5 equiv TMSCF 3.
c
2.0 equiv LiO
t
Bu, 2.0 equiv LiCl.
d
4.0 equiv LiCl.
P
CF
2
TMS
O
O
O
P
CF
2
TMS
O
O
O
P
CF
2
TMS
O
O
O
P
CF
2
TMS
O
4-2a
99%, 83%*
4-2b
89%, 63%*
,b
4-2c
94%
c
4-2d
73%
P
CF
2
TMS
O
N
4-2e
20% (48%)
c
O
P
O
H
R
R
(i) LiH (1.2 equiv), LiCl (1.2 equiv)
DMF (0.4 M), 10 - 30 min, rt
(ii) TMSCF
3
(4.0 equiv), rt, 10 - 30 mins
P
O
CF
2
X
R
R
O
O
P
CF
2
H
O
4-4f
73%
d
(83%)
MeO
MeO
P
CF
2
H
O
4-4i
29% (40%)
4-1 4-2: X=TMS, 4: X=H
P-O bond tolerance
P-N bond tolerance P-C(sp
2
) bond tolerance
P-C(sp
3
) bond tolerance
P
CF
2
H
O
H
H
P
CF
2
TMS
O
Me
2
N
Me
2
N
4-4g
55%
d
4-2h
40% (48%)
185
Though reagents 4-2a, 4-2b and 4-2c enable steric variability at the P atom, the cleavable alkoxy
groups may limit applicability in some scenarios. Cyclic phosphonate 4-2d was prepared in excellent yield
(73%) as a potentially more stable reagent. Diphenyl- and dibenzyl phosphonate, however, did not
produce the corresponding products 4-2, possibly due to the enhanced leaving group ability of the
corresponding aryloxy and benzyloxy groups when compared to the alkoxy groups. To investigate
tolerance of P–N bonds, bis(diethylamino)phosphine oxide (4-1e) was subjected to the reaction condition,
and phosphonamidate 4-2e was isolated. Diarylphosphine oxides 4-4f and 4-4g were prepared in good to
excellent yields (55% and 73%) as a mixture of the corresponding P
V
–CF 2TMS and P
V
–CF 2H compounds
and were therefore isolated as the corresponding P
V
–CF 2H products. Interestingly, the most electron-rich
phosphine oxide 4-2h was obtained selectively as the P
V
–CF 2TMS compound (40%). The greater electron
density at the P atom, leading to a less stable anion upon desilylation, may be responsible for this
heightened stability. A similar reaction with bis(4-(trifluoromethyl)phenyl)phosphine oxide did not
produce any significant amount of product 4-2. It appears that electron-deficient aryl units are not
compatible with this procedure. Difluoromethyl dialkyl phosphine oxide 4-4i was obtained in 29% yield.
During the screening process, we noticed new signals in the
19
F NMR spectra of the crude samples
when the concentration of lithium was decreased. Isolation and characterization of the new mystery
compounds led us to discover that slight modifications to our developed conditions favored the formation
of diaryl trifluoromethylphosphines! This result is the first ever example of a tandem deoxygenation
fluorofunctionalization using a fluoroalkyl silane.
Figure 4.4 Prior art on the synthesis of trifluoromethylphosphines
P
H
O
RO
RO
Cu(I)/TMSCF
3
OR
[R
2
S-CF
3
]
+
X
-
P
CF
3
O
RO
RO
P
OR
RO
RO
CF
3
Br
P
X
R
R
TMSCF
3
cat. CsF
P
CF
3
R
R
P
CF
3
R
R
I
III
-CF
3
186
Furthermore, methods to access trifluoromethyl phosphines are very scarce, and rely on pre-
formed electrophilic trifluoromethylation reagents and ozone-depleting substances (Figure 4.4). P
V
–CF 3
compounds have been synthesized using CF 3Br in an Arbuzov-type reaction.
288
P–H trifluoromethylation
has been shown using TMSCF 3 with (a) dialkyl phosphonates and copper(I),
289
(b) P
III
–X compounds (X = F,
NEt 2, OPh) and CsF.
290
Electrophilic-type trifluoromethylation with a Yagupolskii-Umemoto-type/Togni’s
reagent is also reported.
291,292
The exclusion of LiCl from the standard conditions for substrate 4-1i
transformed it into the corresponding trifluoromethyl phosphine 4-5i in 62% yield (Table 4.3) which
underwent slow oxidation in air. Similarly, 4-5j was obtained in good yield (47%, 62% by NMR). These
results demonstrate a divergence in reactivity under similar conditions, dictated by the amount of LiCl
present. Finally, 4-5g was obtained (50%) as an air stable solid.
Table 4.3 Deoxo-trifluoromethylation of secondary phosphine oxides using TMSCF 3
a,b
a
Reactions performed with 0.5 mmol of 4-1. Yields in parentheses determined by
19
F NMR of reaction mix with PhF (0.5 mmol)
as internal standard. *20 mmol of 1.
b
2.5 equiv TMSCF 3. **Oxidized for easy isolation.
e
1.2 equiv LiCl added.
P
P
CF
3
O
P
R
R
H
i) LiH (1.2 equiv)
DMF, rt, 30 mins
ii) TMSCF
3
(4.0 equiv)
rt, 30 mins
P
R
R
CF
3
4-5i**
62% (62%)
4-5g
50% (55%)
4-5j**
,e
47% (62%)
4-1 4-5
O
CF
3
P
O
CF
3
H
3
C(H
2
C)
5
H
3
C(H
2
C)
5
187
4.iii Mechanistic Hypothesis
(Product key)
To elucidate a potential reaction pathway and probe the intermediates involved in out process,
we performed a series of control experiments described below.
Control 0: Standard conditions
Initially, we performed ‘blank’ trials to identify the reaction component responsible for activation
of TMSCF 3. On stirring LiCl with TMSCF 3 in DMF for 30 minutes (Control 1), no reaction was observed, with
full retention of TMSCF 3. Substituting LiH in place of LiCl (Control 2) did not show any reaction either, with
all 4 equivalents of TMSCF 3 remaining. Even with both LiH and LiCl together (Control 3), no reaction was
observed in 30 minutes. This suggests that within the timescale of this reaction, neither LiH nor LiCl can
noticeably activate TMSCF 3. Control 4 shows that without base, 4-1a cannot react with TMSCF 3.
P
H
O
EtO
EtO
P
CF
2
TMS
O
EtO
EtO
P
C
F
2
O
EtO
EtO
NMe
2
OTMS
P
CF
2
H
O
EtO
EtO
1a 2a 3a 4a
Ph
Ph
T
Ph
CF
2
Ph
CT
4-1a (1 equiv)
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M)
TMSCF
3
(4 equiv), rt, 30 mins
4-2a (99%) Control 0
188
Quenching 4-i 1 with TMSCl before adding TMSCF 3 (Control 5) suggests that 4-i 1is required for significant
activation of TMSCF 3, due to the presence of a large amount of 4-i 2 left unreacted.
Control 5: Quenching 4-i 1with TMSCl affords little product. 4-i 1is likely the activator of TMSCF 3
no 4-1a and 4-T
i) LiCl (1.2 equiv)
DMF (0.4 M)
TMSCF
3
(4 equiv), rt, 30 mins
4 equiv TMSCF
3
left unreacted
Control 1
no 4-1a and 4-T
i) LiH (1.2 equiv)
DMF (0.4 M)
TMSCF
3
(4 equiv), rt, 30 mins
4 equiv TMSCF
3
left unreacted
Control 2
no 4-1a and 4-T
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M)
TMSCF
3
(4 equiv), rt, 30 mins
4 equiv TMSCF
3
left unreacted
Control 3
4-1a
i) LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii)TMSCF
3
(4 equiv), rt, 30 mins
4-1a and TMSCF
3
left unreacted
Control 4
4-1a
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii)TMSCl (1 equiv)
iii)TMSCF
3
(4 equiv), rt, 30 mins
4
-
2a (23%) Control 5
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
0.27
0.46
1.00
0.72
10.38
-132 -130 -128 -126 -124 -122 -120 -118 -116 -114 -112
f1 (ppm)
0.46
1.00
PhF (m)
-113.7
2a (d)
-130.3
J(90.3)
189
Control 5:
31
P NMR shows a large amount of unreacted (EtO) 2P-OTMS
However, pre-stirring LiH and LiCl in DMF followed by addition of TMSCF 3 resulted in significant
decomposition of TMSCF 3 to TMSF (Control 6). DMF will slowly decompose with alkali metal hydrides to
produce small amounts of formaldehyde and dimethylamide (or dimethylamine in the presence of trace
water). This trial shows that the small amount of dimethylamide formed reacts with TMSCF 3, making it a
potential activator of this system.
Repeating this experiment with 4-T (Control 7) resulted in 89% of 4-CT
293
being formed. This shows that
not only is TMSCF 3 activated under these conditions, but there is facile formation of difluorocarbene as
well. However, this still does not answer the question of what the actual activator in our reaction system
is. We always have a Bronsted acidic species (4-1) in our actual trials, the deprotonation of which should
-90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140
f1 (ppm)
31P NMR (CDCl3) at 162 MHz
115 120 125 130 135 140
f1 (ppm)
(EtO)2P(O)TMS (s)
127.1
Control 6
no 4-1a and 4-T
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
TMSCF
3
(4 equiv), rt, 30 mins
2.7 equiv TMSF
formed
190
be a faster reaction than the decomposition of DMF by LiH. Since we always use 1.2 equiv of LiH in our
trials, Control 0 does not provide any information about the true activator. Our assumption that the acid-
base reaction between 4-1a and LiH must be faster than the reaction of LiH with DMF is based on the
observation of effervescence observed immediately on addition of 4-1a to a suspension of LiH in DMF,
and the fact that within 30 minutes, LiH does not appear to noticeably react with DMF (Control 2). Keeping
in mind this assumption, we performed Control 8, with only 0.5 equiv of LiH. Having twice the amount of
4-1a relative to LiH should ensure that all the LiH is consumed before it has any time to appreciably
decompose any DMF. Interestingly, we observed 81% conversion to 4-2a + 4-4a, though 0.5 equiv LiH
should have only provided 50%. Accounting for the larger-than-usual amount of fluoroform observed, it
is quite possible that in this case, the remaining 30% of 4-1a was deprotonated by CF 3
-
formed from
TMSCF 3 reacting with 4-1 i. All these experiments suggest that the activator for TMSCF 3 is I4-1 i .
Control 7: CF 2 carbene trapped by alkene T
4-T (1 equiv)
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii) TMSCF
3
(4 equiv), rt, 30 mins
4-CT (89%)
Control 7
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
1.77
1.00
C T
T M S F
C F 3 H
T M S C F 3
P h F
-130 -125 -120 -115
f1 (ppm)
1.77
1.00
CT (t)
-129.5
J(10.3)
A (m)
-113.7
u n i d e n t i f i e d p e a k
191
Next, we were interested in testing for the potential intermediacy of a difluorocarbene electrophile, which
could react with intermediate II. TMSCF 2Br is known to afford CF 2 carbene under very mild reaction
conditions.
285
Performing Control 9 with only 1 equiv of TMSCF 2Br provided a total CF 2 incorporation of
30%.
Control 8: Base as limiting reagent. No hydride left to decompose DMF. Reaction proceeds via activation
of TMSCF 3 by 4-1 i
4-1a (1 equiv)
i) LiH (0.5 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii) TMSCF
3
(4 equiv), rt, 30 mins
4-2a + 4-4a (81%)
Control 8
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
0.09
1.53
1.00
C F 3 H
T M S F
P h F
2 a
4 a
-140 -136 -132 -128 -124 -120 -116 -112
f1 (ppm)
0.09
1.53
1.00
PhF (m)
-113.7
2a (d)
-130.3
J(89.9)
4a (dd)
-136.4
J(89.6, 47.6)
T M S C F 3
Control 9
4-1a (1 equiv)
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii) TMSCF
2
Br (1 equiv), rt, 30 mins
4-2a (25%)
+
4-4a (5%)
192
Control 9: CF 2 incorporation observed with TMSCF 2Br; a milder difluorocarbene source
Finally, to confirm the intermediacy of difluorocarbene, we ran a competition reaction with 4-1a and 4-T
(Control 10).
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
0.09
0.50
1.00
0.62
T M S F
C F 2 B r H
P h F
2 a
4 a
-140 -136 -132 -128 -124 -120 -116 -112
f1 (ppm)
0.09
0.50
1.00
4a (dd)
-136.4
J(90.2, 47.8)
PhF (m)
-113.7
2a (d)
-130.2
J(90.5)
4-1a (1 equiv)
+
4-T (1 equiv)
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii) TMSCF
3
(4 equiv), rt, 30 mins
4-2a + 4-4a (70%)
+
4-CT (30%)
Control 10
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
0.12
1.30
0.60
1.00
T M S F
2 a
C T
P h F
C F 3 H
T M S C F 3
4 a
-140 -135 -130 -125 -120 -115
f1 (ppm)
0.12
1.30
0.60
1.00
CT (t)
-129.5
J(10.5)
2a (d)
-130.3
J(89.6)
PhF (m)
-113.7
4a (dd)
-136.4
J(89.7, 47.9)
193
Control 10: Competition reaction between 4-1a and 4-T for further evidence of CF 2 carbene intermediate
Interestingly, the total CF 2 incorporation was very similar in reactions with just 4-2a (Control 0, 99% CF 2
incorporation), just 4-T (Control 7, 89% CF 2 incorporation) and both 4-2a and 4-T (Control 10, 100% CF 2
incorporation). This suggests that both reactions proceed via CF 2 carbene.
After establishing the intermediacy of a CF 2 carbene, we were interested in looking into whether CF 2
carbene can react with 4-i 2. In Control 11, 4-i 1 is quenched with TMSCl to pre-form intermediate 4-i 2.
Addition of the mild carbene source TMSCF 2Br afforded total CF 2 incorporation of 53% into 4-i 2,
demonstrating that 4-i 2 can trap the CF 2 electrophile.
Control 11: Reaction of 4-i 2 with TMSCF 2Br provides the corresponding P
V
-CF 2TMS product
4-1a (1 equiv)
i) LiH (1.2 equiv)
LiCl (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii) TMSCl (1 equiv), rt, 10 mins
iii)TMSCF
2
Br (1 equiv), rt, 30 mins
4-2a + 4-4a (53%) Control 11
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
0.07
0.07
0.97
1.00
0.39
-136.62
-136.49
-136.38
-136.26
-130.32
-130.08
-113.74
-113.73
-113.72
-113.71
-113.70
-113.68
-113.68
-113.67
-113.66
-72.30
-72.14
-140 -135 -130 -125 -120 -115 -110
f1 (ppm)
0.07
0.97
1.00
PhF (m)
-113.7
4a (dd)
-136.4
J(89.8, 47.7)
2a (d)
-130.2
J(89.7)
194
As a demonstration of intermediate 4-i 2 being the point of divergence between path 1 and path 2, 4-i 2
was formed from 4-1i and reacted with TMSCF 3 to afford the product Bn 2P–CF 3. This is in stark contrast
with the results of Control 11, wherein 4-5a was not observed.
Control 12: 4-i2 (derived from 4-1i) reacts with TMSCF 3 to produce Bn 2P–CF 3, showing common
intermediate for both paths
Based on our mechanistic investigations, we envision that the divergent reactivity results from differences
in the mode of reaction of intermediate 4-i 2 with TMSCF 3. In path 1, we propose that intermediate 4-i 2 is
formed by silylation of 4-i 1 with TMSCF 3. This releases CF 3
-
that will decompose in the presence of excess
Li+ to produce electrophilic difluorocarbene. Trapping of difluorocarbene by 4-i 2 may result in the ylide-
intermediate 4-i 3, which could undergo an intra- or intermolecular silylation at the CF 2 carbon to afford
4-1i (1 equiv)
i) LiH (1.2 equiv)
DMF (0.4 M), rt, 30 mins
ii) TMSCl (1 equiv), rt, 10 mins
iii)TMSCF
3
(4 equiv), rt, 30 mins
Bn
2
P-CF
3
(26%) Control 12
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
19F NMR (CDCl3) at 376 MHz
2.08
0.13
0.12
1.00
1.40
4.89
0.79
-120 -110 -100 -90 -80 -70 -60 -50
f1 (ppm)
1.00
1.40
4.89
0.79
Bn2P-CF3 (d)
-57.3
J(50.9)
PhF (m)
-113.9
195
product 4-2. In contrast, path 2 may be a consequence of an additional silylation of 4-i 2 by another
equivalent of TMSCF 3, producing either the oxonium trifluoromethide 4-i 4 or trifluoromethylphosphorane
4-i 5. Similar to the mechanism of deoxygenation (reduction) of phosphine oxides using hexachlorodisilane,
a reductive elimination of TMS 2O would produce compound 5.
Figure 4.5 Plausible reaction pathways
As a demonstration of their synthetic utility, 4-2a, 4-2b, 4-2d and 4-2h were reacted with 4-6sm
to produce P
V
CF 2– compounds 4-6 (Table 4.4). Interestingly, the stability of the O–TMS bond depends on
the identity of the R groups at P. 4-6a and 4-6b were readily formed. 4-6’d underwent slower hydrolysis
under the same conditions, producing a mixture of O–H and O–TMS compounds. 4-6h was unreactive to
the hydrolytic conditions. The difference in stability to the basic, aqueous conditions reinforces the
importance of variability at the P atom in tuning the chemical properties of these molecules.
P
OTMS
R
R
O
R
R
P
CF
2
TMS
4-2 4-i
2
TMSCF
3
CF
3
—
F
-
+ :CF
2
Li
+
LiF
O
R
R
P
CF
2
—
TMS
4-i
3
P
TMS
CF
3
R
R
OTMS
TMS
2
O
P
CF
3
R
R
4-5
4-i
5
4-i
1
O P
H
R
R
O P
Li
R
R
P
LiO
R
R
4-i
1
LiH
path 1: siladifluoromethylation
path 2: deoxo-trifluoromethylation
P
V
-P
III
tautomerism
P
OTMS
R
R
4-i
2
TMSCF
3
P
O
R
R
4-i
4
TMS
TMS
CF
3
—
4-1
196
a
Table 4.4 Demonstration of the prepared phosphonodifluoromethylsilanes as reagents and the effect of
the phosphorous substituents on the stability of the product
a
Unoptimized, isolated yields. See Experimental Section for full experimental details. TMS may be fully cleaved on prolonged
stirring.
4.iv Conclusion
In this project, we developed a method for siladifluoromethylation of dialkyl phosphonates and
secondary phosphine oxides with TMSCF 3. The siladifluoromethylation products could serve as
nucleophilic P
V
–CF 2– transfer reagents. Multi-gram scale reactions to prepare the reagents is also
demonstrated. Condition-dependent divergent reactivity under our developed conditions was
demonstrated by the additional formation of trifluoromethylphosphines, by varying the concentration of
lithium ions in solution. Both one-pot transformations are operationally simple and employ inexpensive
materials. Mechanistic investigations suggest that the divergent reactivity originates from a common
intermediate, with Li
+
concentration directing the chemoselectivity.
Ar
E = 4-nitro-
benzyldehyde
4-6a: 96%
4-6d: 77% (TMS:H = 2:1)
4-6b: 72%
C
F
2
HO
P
O
OEt
OEt
Ar C
F
2
HO
P
O
Oi-Pr
Oi-Pr
Ar C
F
2
TMSO
P
O
O
O
4-6h: 86%
Ar C
F
2
TMSO
P
O NMe
2
NMe
2
Ar =
O
2
N
4-6sm
O
P
RO CF
2
TMS
RO
i) Aldehyde E
Cs
2
CO
3
30 min, rt
4-2
ii) H
2
O/EtOAc
(1:1)
120 min, rt
RO
RO
O
P
OTMS
C
F
2
Ar
4-6’
RO
RO
O
P
OX
C
F
2
Ar
X = H OR TMS
4-6
Proto-desilylation depends on R 4-2 as pro-nucleophiles
Ar C
F
2
HO
P
O
O
O
197
4.v Experimental Section
General Information
Unless otherwise mentioned, all the chemicals were purchased from commercial sources and
used without further purification. N,N-dimethylformamide (DMF) was distilled from CaH 2 under N 2 and
stored over activated 3 Å molecular sieves in a Strauss flask. Where applicable, flash column
chromatography was performed to isolate the compounds, with a suitable eluent determined by TLC.
Solid starting materials were dried under high vacuum (< 0.1 Torr) with a P 2O 5 trap prior to use.
1
H,
13
C,
19
F and
31
P spectra were recorded on 400 MHz or 500 MHz Varian NMR spectrometers.
1
H NMR chemical
shifts were determined relative to CHCl 3 as the internal standard at δ 7.26 ppm.
13
C NMR shifts were
determined relative to Chloroform-d at δ 77.16 ppm.
19
F NMR chemical shifts were determined relative
to CFCl 3 at δ 0.00 ppm.
31
P NMR chemical shifts were determined relative to D 3PO 4 in D 2O at δ 0.00 ppm.
Mass spectral data were recorded on a high-resolution mass spectrometer, EI or ESI mode.
Synthesis and Characterization of Starting Materials
Phosphonates 4-1a to 4-d and phosphine oxide 4-1g were purchased from commercial sources
and used as received.
4-1e: bis(diethylamino)phosphine oxide
Adapted from a reported procedure.
294,295
To a flame dried, two-neck flask (50 mL) equipped
with a magnetic stir bar and air condenser and charged with N,N,N',N',N'',N''-
hexaethylphosphanetriamine (8.2 mL, 30 mmol) [(Et 2N) 3P], THF (15.6 mL) and water (650 µL, 36 mmol)
O
P
N
N
H
198
were sequentially added via syringe under N 2. The solution was refluxed for 4 h. The stopper was then
removed while maintaining reflux temperature and stirred for 20 mins, effectively removing THF and
diethylamine, and 4-1e was isolated by distillation under N 2 (b.p 80 – 90 at 0.1 mm Hg) as a colorless liquid
in 20 % yield (1.18 g). The NMR data matches previous reports.
294
1
H NMR (400 MHz, Chloroform-d) δ 6.66
(d, J = 570.2 Hz, 1H), 3.05 – 2.88 (m, 8H), 1.01 (td, J = 7.0, 3.0 Hz, 12H).
4-1f: bis(4-methoxyphenyl)phosphine oxide
Adapted from a reported procedure.
296
To a flame-dried, three-neck flask (250 mL)
charged with Mg (2.5 g, 102.5 mmol, 3.3 equiv) and equipped with a condenser,
magnetic stir bar and additional funnel, THF (48 mL) was added via syringe under N 2.
To the above suspension, 1-bromo-4-methoxybenzene (12.8 mL, 102.5 mmol, 3.3 equiv) was added
dropwise as a solution in THF (20 mL), following which the suspension was stirred for 4 hours at room
temperature. The flask was then cooled to 0 ˚C, and a solution of diethyl phosphonate (4 mL, 1 equiv, 31.1
mmol) in THF (8 mL) was added dropwise. The solution was stirred for 18 h at room temperature, cooled
to 0 ˚C, and treated; dropwise; with 0.1 M HCl (80 mL). MTBE (80 mL) was added, the mixture was stirred,
and then the organic layer was decanted and filtered through celite. The process was repeated two more
times with MTBE (15 mL each time) and the organic layers were combined. The remaining reaction
mixture was centrifuged, the top-layer liquid was decanted and filtered through celite. The above process
was repeated two more times with MTBE (15 mL each time). All the organic layers were combined, dried
over MgSO 4, filtered and concentrated. The crude residue was purified by silica gel column
chromatography (DCM) to afford analytically pure 4-1f as a white solid in 39% yield (3.1 g). The NMR data
matches previous reports.
296
1
H NMR (399 MHz, Chloroform-d) δ 8.03 (d, J = 477.0 Hz, 1H), 7.61 (ddd, J =
13.1, 8.6, 1.6 Hz, 4H), 7.00 (dt, J = 8.8, 1.9 Hz, 4H), 3.85 (s, 6H).
13
C{
1
H} NMR (100 MHz, Chloroform-d) δ
163.0 (d, J = 2.1 Hz), 132.8 (d, J = 13.0 Hz), 123.7, 114.6 (d, J = 13.9 Hz), 55.5.
O
P
H
OMe
MeO
199
4-1h: bis(4-(dimethylamino)phenyl)phosphine oxide
Adapted from a reported procedure.
297
To a flame-dried, three-neck flask (250 mL)
charged with Mg (1.3 g, 54 mmol, 3.3 equiv) and equipped with a condenser, magnetic
stir bar and additional funnel, THF (32 mL) was added via syringe under N 2. To the above
suspension, 1-bromo-4-(dimethylamino)benzene (21.6 mL, 54 mmol, 3.3 equiv) was added dropwise as a
solution in THF (20 mL), following which the suspension was stirred for 4 hours at room temperature. A
solution of diethyl phosphonate (2.1 mL, 1 equiv, 16.5 mmol) in THF (5 mL) was added dropwise. The
solution was stirred for 4 h at room temperature and treated (dropwise) with 0.1 M HCl (40 mL). The
mixture was filtered through celite, the organic layer was separated, and the crude product was extracted
with DCM (35 mL, three times) from the aqueous layer. The combined organic layers were dried over
MgSO 4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (gradient
of 40% - 100% EtOAc in hexanes, followed by flushing with 10% MeOH in EtOAc) to afford analytically pure
4-1h as a white solid in 51% yield (2.4 g). [Note: low solubility in hexanes, EtOAc and MeOH resulted in 4-
1h being collected in ~ 2 L of eluent. Recrystallization may provide better results]. The NMR data matches
previous reports.
298
1
H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 471.1 Hz, 1H), 7.50 (dd, J = 13.0, 8.9
Hz, 4H), 6.71 (dd, J = 9.0, 2.2 Hz, 4H), 3.01 (s, 12H).
4-1i: dibenzylphosphine oxide
Adapted from a reported procedure.
299
To a flame-dried, three-neck flask (250 mL)
charged with Mg (1.9 g, 76 mmol, 3.3 equiv) and equipped with a condenser, magnetic stir
bar and additional funnel, Et 2O (10 mL) was added via syringe under N 2. To the above
suspension, benzyl bromide (13 g, 76 mmol, 3.3 equiv) was added dropwise as a solution in Et 2O (60 mL),
following which the reaction mixture was stirred for 30 mins at room temperature. A solution of diethyl
O
P
H
N
N
O
P
H
200
phosphonate (3.2 mL, 1 equiv, 25 mmol) in Et 2O (20 mL) was added dropwise. The solution was stirred for
30 mins at room temperature and treated (dropwise) with 0.1 M HCl (40 mL). The reaction mixture was
filtered through celite, the organic layer was separated, and the crude product was extracted with DCM
(35 mL, three times) from the aqueous layer. The combined organic layers were dried over MgSO 4, filtered,
and concentrated. The crude residue was purified by silica gel chromatography (gradient of 40% - 100%
EtOAc in hexanes) to afford analytically pure 4-1i as a white solid in 55% yield (3.2 g). The NMR data
matches previous reports.
299
1
H NMR (399 MHz, Chloroform-d) δ 7.40 – 7.30 (m, 4H), 7.34 – 7.26 (m, 2H),
7.25 – 7.17 (m, 4H), 7.59 – 6.34 (m, 1H), 3.27 – 3.09 (m, 4H).
13
C{
1
H} NMR (100 MHz, Chloroform-d) δ
131.0 (d, J = 7.3 Hz), 129.7 (d, J = 5.8 Hz), 129.3 (d, J = 2.9 Hz), 127.5 (d, J = 3.3 Hz), 35.3 (d, J = 60.2 Hz).
4-1j: di(n-hexyl)phosphine oxide
Adapted from a reported procedure.
299
To a flame-dried, three-neck flask (250 mL)
charged with Mg (1.9 g, 76 mmol, 3.3 equiv) and equipped with a condenser, magnetic
stir bar and additional funnel, THF (15 mL) was added via syringe under N 2. To the above suspension, n-
hexyl bromide (10.7 mL, 76 mmol, 3.3 equiv) was added dropwise as a solution in THF (60 mL), following
which the reaction mixture was stirred for 30 mins at room temperature. A solution of diethyl
phosphonate (3.2 mL, 1 equiv, 25 mmol) in THF (20 mL) was added dropwise. The solution was stirred for
30 mins at room temperature and treated (dropwise) with 0.1 M HCl (40 mL). The reaction mixture was
filtered through celite, the organic layer was separated, and the crude product was extracted with DCM
(35 mL, three times) from the aqueous layer. The combined organic layers were dried over MgSO 4, filtered,
and concentrated to afford analytically pure 4-1j as a white solid in 51% yield (2.8 g). The NMR data
matches previous reports.
299
1
H NMR (500 MHz, Chloroform-d) δ 6.85 (d, J = 445.8 Hz, 1H), 1.87 – 1.51 (m,
8H), 1.48 – 1.35 (m, 4H), 1.33 – 1.25 (m, 8H), 0.91 – 0.84 (m, 6H).
O
P
H H
3
C(H
2
C)
5
H
3
C(H
2
C)
5
201
Table 4.S1 Full optimization table
Trial Solvent
Co-
solvent
SM
concentration
(M)
Activator
(Lithium
source)
(eq)
Base/additive
(eq)
Time:
step
1
(min)
TMSCF3
NMR
yield of
4-2a
(%)
1 DMF - 0.2 LiI (1.2) LiOtBu (1.2) 10 2.5 22+10
2 DMF - 0.2 LiI (1.2) LiH (1.2) 10 2.5 66
3 DMF - 0.2 LiI (1.2) LDA (1.2) 10 2.5 16
4 DMF - 0.2 LiI (1.2) KOtBu (1.2) 10 2.5 0
5 DMF - 0.2 LiI (1.2) KHMDS (1.2) 10 2.5 0
6 DMF - 0.2 LiI (1.2) LiBF4 (1.2) 10 2.5 0
7 DMF - 0.2 LiI (1.2) NaH (1.2) 10 2.5 66
8 DMF - 0.2 LiI (1.2) CaH2 (1.2) 10 2.5 0
9 DMF - 0.2 LiI (1.2) NaOtBu (1.2) 10 2.5 0
10 THF - 0.2 LiI (1.2) LiH (1.2) 10 2.5 0
11 Hexanes - 0.2 LiI (1.2) LiH (1.2) 10 2.5 0
12 Et2O - 0.2 LiI (1.2) LiH (1.2) 10 2.5 0
13 DCM - 0.2 LiI (1.2) LiH (1.2) 10 2.5 0
14 MeCN - 0.2 LiI (1.2) LiH (1.2) 10 2.5 0
15 DMF - 0.2 LiI (0.1) LiH (1.2) 10 2.5 2
16 DMF - 0.2 NaI (1.2) NaH (1.2) 10 2.5 5+9
17 DMF - 0.2
NaCl
(1.2) NaH (1.2) 10 2.5 0+3
202
18 DMF - 0.2 LiCl (1.2) NaH (1.2) 10 2.5 76+3
19 DMF - 0.2 LiI (1.2) LiOtBu (1.2) 10 2.5 22+10
20 DMF Hexanes 0.2 LiI (1.2) LiH (1.2) 10 2.5 71+14
21 DMF THF 0.2 LiI (1.2) LiH (1.2) 10 2.5 58+6
22 DMF Et2O 0.2 LiI (1.2) LiH (1.2) 10 2.5 47+7
23 DMF - 0.2
NaCl
(1.2) LiH (1.2) 10 2.5 5+0
24 DMF - 0.2 NaI (1.2) LiH (1.2) 10 2.5 28+4
25 DMF - 0.2 LiCl (1.2) LiH (1.2) 10 2.5 70+0
26 DMF - 0.2 LiCl (1.2) LiH (2.0) 10 2.5 90+0
27 DMF - 0.2 LiCl (2.0) LiH (1.2) 10 2.5 45+11
28 DMF - 0.2 LiCl (1.2) LiH (1.2) 10 1.2 60+0
29 DMF - 0.2 LiCl (1.2) LiH (1.2) 10 2 56+0
39 DMF - 0.2 LiCl (1.2) LiH (2.0) 10 2.5 30
40 DMF - 0.4 LiCl (1.2) LiH (2.0) 10 2.5 57
41 DMF - 0.2 LiCl (2.0) LiH (2.0) 10 2.5 20
42 DMF - 0.2 LiCl (1.2) LiH (1.2) 10 2.5 30
43 DMF - 0.4 LiCl (1.2) LiH (1.2) 10 2.5 61
44 DMF - 0.4 LiCl (1.2) LiH (1.2) 10 4 73
45 DMF - 0.4 LiCl (1.2) LiH (2.0) 10 4 75
46 DMF - 0.4 LiCl (2.0) LiH (2.0) 10 4 49
47 DMF - 0.4 LiCl (1.2) LiH (1.2) 10 4 76
48 DMF - 0.4 LiCl (1.2) LiH (2.0) 10 4 76
49 DMF - 0.8 LiCl (1.2) LiH (1.2) 10 4 51
50 DMF - 0.8 LiCl (1.2) LiH (2.0) 10 4 49
51 DMF - 0.8 LiI (1.2) LiH (1.2) 10 4 38
203
Synthesis and Characterization of Products
4-2a: diethyl (difluoro(trimethylsilyl)methyl) phosphonate
In an Argon glovebox, LiH (1.1 equiv, 4.4 mg) and LiCl (1.2 equiv, 25.4 mg) were weighed
into an oven-dried 5 mL crimp-top vial equipped with a magnetic stir-bar, and the vial
was sealed. Under an atmosphere of N 2, DMF (0.4 M, 1.25 mL) and 4-1a (0.5 mmol, 64 µL) were
sequentially added by syringe. The resultant mixture was stirred for 10 mins at room temperature,
followed by addition of TMSCF 3 (4 equiv, 295 µL) dropwise by syringe under a N 2 atmosphere and
subsequent stirring of the resultant mixture for 30 mins at room temperature. The vial was opened, and
3 mL of n-pentane was added. The biphasic mixture was agitated, the n-pentane layer was decanted, and
the process was repeated two times (3 mL each time). The n-pentane layers were washed with water (5
mL), combined, filtered to remove small suspended particulates, and concentrated by rotary evaporation
to afford analytically pure 4-2a as a colorless liquid in 99% isolated yield (128 mg). The obtained spectra
match previous reports.
33
1
H NMR (500 MHz, Chloroform-d) δ 4.06 (p, J = 7.1 Hz, 4H), 1.19 (t, J = 7.0 Hz,
6H), 0.08 (s, 9H).
13
C{
1
H} NMR (126 MHz, Chloroform-d) δ 126.5 (td, J = 271.6, 165.3 Hz), 63.5 (d, J = 6.8
Hz), 16.1 (d, J = 5.4 Hz), -4.8 (t, J = 2.5 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -131.2 (d, J = 92.1 Hz).
31
P{
1
H} NMR (202 MHz, Chloroform-d) δ 9.6 (t, J = 92.2 Hz).
52 DMF - 0.8 LiI (1.2) LiH (2.0) 10 4 36
53 DMF - 0.4 - LiH (1.2) 10 4 24
54 DMF - 0.4 LiCl (1.2) - 10 4 0
55 DMF - 0.4 LiCl (1.2) LiH (1.2) 10 4 69
56 DMF - 0.4 LiCl (1.2) LiH (1.2) 0 4 84
57 DMF - 0.4 LiCl (1.2) LiH (1.2) 10 4 80
O
P
CF
2
TMS
O
O
204
20 mmol scale reaction: In an Argon glovebox, LiH (1.1 equiv, 176.0 mg) and LiCl (1.2 equiv, 1.02 g) were
weighed into an oven-dried two neck flask (250 mL flask) equipped with a magnetic stir-bar and sealed
with rubber septa. Under an atmosphere of N 2, dry DMF (0.4 M, 50 mL) and 4-1a (20 mmol, 2.56 mL) were
sequentially added by syringe. The resultant mixture was stirred for 10 mins at room temperature,
followed by dropwise addition of TMSCF 3 (4 equiv, 11.8 mL) by addition funnel under a N 2 atmosphere,
washing the funnel with 2 mL DMF, and subsequent stirring of the resultant mixture for 30 mins at room
temperature. The vial was opened, and 50 mL of n-pentane was added. The biphasic mixture was agitated,
stirred for 5 mins at room temperature, the n-pentane layer was decanted, and the process was repeated
two times (50 mL each time). The combined n-pentane layer was washed with water (50 mL), filtered to
remove small suspended particulates, and concentrated by rotary evaporation to afford analytically pure
4-2a in 83% isolated yield (4.32 g).
Tips while scaling up:
1. To prevent proto-desilylation of 4-2a, oven drying the flask is essential. Additionally, it can be
flame dried under reduced pressure to remove trace water.
2. Adequate venting (while still under inert gas) must be allowed during the addition of 4-1a due to
the evolution of H 2 gas. Add 4-1a slowly.
3. Agitation of the n-pentane/DMF mixture was done by gently shaking the sealed flask, which
causes a very slight pressure build-up. Venting the reaction vessel prior to unsealing it is
recommended.
4. Letting the product sit over water for extended periods may cause proto-desilylation.
205
4-2b: diisopropyl (difluoro(trimethylsilyl)methyl) phosphonate
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg) and LiCl (1.2 equiv, 25.4 mg) were weighed
into an oven-dried 5 mL crimp-top vial equipped with a magnetic stir-bar, and the vial
was sealed. Under an atmosphere of N 2, DMF (0.4 M, 1.25 mL) and 4-1b (0.5 mmol, 84
µL) were sequentially added by syringe. The resultant mixture was stirred for 10 mins at room
temperature, followed by addition of TMSCF 3 (2.5 equiv, 185 µL) (dropwise) by syringe under a N 2
atmosphere and subsequent stirring of the resultant mixture for 15 mins at room temperature. The vial
was opened, and 3 mL of n-pentane was added. The biphasic mixture was agitated, the n-pentane layer
was decanted, and the process was repeated two times (3 mL each time). The n-pentane layers were
washed with water (5 mL), combined, filtered to remove small suspended particulates, and concentrated
by rotary evaporation to afford analytically pure 4-2b in 89% isolated yield (128 mg). The obtained spectra
match previous reports.
121
1
H NMR (399 MHz, Chloroform-d) δ 4.84 (dq, J = 12.8, 6.4 Hz, 2H), 1.37 (dd, J
= 6.2, 2.0 Hz, 12H), 0.26 (s, 9H).
19
F NMR (376 MHz, Chloroform-d) δ -131.8 (d, J = 92.5 Hz).
31
P NMR (162
MHz, Chloroform-d) δ 8.1 (tt, J = 92.5, 7.1 Hz). FT-IR (cm
-1
) 2981, 2940, 1664, 1468, 1454, 1378, 1376,
1251, 1178, 1143, 1103, 992, 900, 886, 845, 753, 638, 605, 540, 472. HRMS ESI
+
(M+H
+
) C 10H 24F 2O 3PSi =
299.0846.
20 mmol scale reaction: In an Argon glovebox, LiH (1.2 equiv, 211 mg) and LiCl (1.2 equiv, 1.02 g) were
weighed into an oven-dried two-neck flask (250 mL flask) equipped with a magnetic stir-bar and sealed
with rubber septa. Under an atmosphere of N 2, dry DMF (0.4 M, 50 mL) and 4-1b (20 mmol, 3.36 mL) were
sequentially added by syringe. The resultant mixture was stirred for 10 mins at room temperature,
followed by dropwise addition of TMSCF 3 (2.5 equiv, 7.38 mL) by addition funnel under a N 2 atmosphere,
washing the funnel with 2 mL DMF, and subsequent stirring of the resultant mixture for 30 mins at room
temperature. The vial was opened, and 50 mL of n-pentane was added. The biphasic mixture was agitated,
O
P
CF
2
TMS
O
O
206
stirred for 5 mins at room temperature, the n-pentane layer was decanted, and the process was repeated
two times (50 mL each time). The combined n-pentane layer was washed with water (50 mL), filtered to
remove small suspended particulates, and concentrated by rotary evaporation to afford analytically pure
4-2b in 63% isolated yield (3.63 g).
4-2c: di-tert-butyl (difluoro(trimethylsilyl)methyl) phosphonate
In an Argon glovebox, LiOtBu (3.0 equiv, 80 mg) and LiCl (2.0 equiv, 42.4 mg) were
weighed into an oven-dried 5 mL crimp-top vial equipped with a magnetic stir-bar, and
the vial was sealed. Under an atmosphere of N 2, DMF (0.4 M, 1.25 mL) and 4-1c (0.5
mmol, 101 µL) were sequentially added by syringe. The resultant mixture was stirred for 10 mins at room
temperature, followed by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2
atmosphere and subsequent stirring of the resultant mixture for 30 mins at room temperature. The vial
was opened, and 3 mL of n-pentane was added. The biphasic mixture was agitated, the n-pentane layer
was decanted, and the process was repeated two times (3 mL each time). The n-pentane layers were
washed with water (5 mL), combined, filtered to remove small suspended particulates, and concentrated
by rotary evaporation to afford analytically pure 4-2c in 94% isolated yield (149 mg).
1
H NMR (399 MHz,
Chloroform-d) δ 1.55 (s, 18H), 0.25 (s, 9H).
13
C{
1
H} NMR (100 MHz, Chloroform-d) δ 125.8 (td, J = 269.8,
171.3 Hz), 72.4 (d, J = 9.3 Hz), 30.3, -4.4.
19
F NMR (376 MHz, Chloroform-d) δ -130.7 (d, J = 94.9 Hz).
31
P{
1
H}
NMR (162 MHz, Chloroform-d) δ 11.8 (t, J = 95.6 Hz). FT-IR (cm
-1
) 2981, 2934, 1661, 1475, 1459, 1395,
1371, 1267, 1251, 1168, 1095, 1038, 993, 920, 846, 754, 688, 602, 545, 496, 468. HRMS-ESI
+
(M+H
+
)
C 12H 28F 2O 3PSi = 317.0705.
O
P
CF
2
TMS
O
O
207
4-2d: 2-(difluoro(trimethylsilyl)methyl)-5,5-dimethyl-1,3,2-dioxaphosphinane 2-oxide
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg), LiCl (1.2 equiv, 25.4 mg) and 4-1d (0.5
mmol, 101 mg) were weighed into an oven-dried 5 mL crimp-top vial equipped with a
magnetic stir-bar, and the vial was sealed. Under an atmosphere of N 2, DMF (0.4 M,
1.25 mL) was added by syringe. The resultant mixture was stirred for 30 mins at room temperature,
followed by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2 atmosphere and
subsequent stirring of the resultant mixture for 20 mins at room temperature. The vial was opened, and
3 mL of n-pentane was added. The biphasic mixture was agitated, the n-pentane layer was decanted, and
the process was repeated two times (3 mL each time). The n-pentane layers were washed with water (5
mL), combined, filtered to remove small suspended particulates, and concentrated by rotary evaporation
to afford analytically pure 4-2d as a colorless liquid in 73% isolated yield (99 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 4.33 (d, J = 10.3 Hz, 2H), 4.02 (ddt, J = 17.2, 10.9, 1.1 Hz, 2H), 1.33 (s, 3H), 0.90 (s, 3H),
0.28 (s, 9H).
13
C{
1
H} NMR (101 MHz, Chloroform-d) δ 129.4 (td, J = 273.8, 155.6 Hz), 78.9 – 78.6 (m), 32.7
(d, J = 8.7 Hz), 22.1, 20.6 (d, J = 1.1 Hz), -4.5 – -4.6 (m).
19
F NMR (376 MHz, Chloroform-d) δ -128.9 (d, J =
89.3 Hz).
31
P NMR (162 MHz, Chloroform-d) δ -0.1 (t, J = 89.3 Hz). FT-IR (cm
-1
) 2972, 2904, 1670, 1472,
1408, 1375, 1290, 1253, 1210, 1095, 1051, 1012, 994, 956, 918, 850, 831, 751, 666, 615, 589, 514, 484,
462. HRMS-ESI
+
(M+H
+
) C 9H 20F 2O 3PSi = 273.0906.
4-2e: tert-butyl P-(difluoro(trimethylsilyl)methyl)-N,N-diethyl phosphonamidate
In an Argon glovebox, LiOtBu (2.0 equiv, 80.1 mg) and LiCl (2 equiv, 42.4 mg) were
weighed into an oven-dried 5 mL crimp-top vial equipped with a magnetic stir-bar, and
the vial was sealed. Under an atmosphere of N 2, DMF (0.4 M, 1.25 mL) and 4-1e (0.5
mmol, 96 mg) were sequentially added by syringe. The resultant mixture was stirred for 30 mins at room
temperature, followed by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2
O
P
CF
2
TMS
O
O
O
P
CF
2
TMS
N
O
208
atmosphere and subsequent stirring of the resultant mixture for 15 mins at room temperature. The vial
was opened, and 3 mL of n-pentane was added. The biphasic mixture was agitated, the n-pentane layer
was decanted, and the process was repeated two times (3 mL each time). The n-pentane layers were
washed with water (5 mL), combined, filtered to remove small suspended particulates, and concentrated
by rotary evaporation to afford analytically pure 4-2h in 20% yield (32 mg).
1
H NMR (399 MHz, Chloroform-
d) δ 3.35 – 3.04 (m, 4H), 1.52 (s, 9H), 1.13 (t, J = 7.1 Hz, 6H), 0.25 (s, 9H).
13
C{
1
H} NMR (126 MHz,
Chloroform-d) δ 128.2 (ddd, J = 277.3, 267.1, 157.0 Hz), 83.9 (d, J = 9.9 Hz), 39.3 (d, J = 4.2 Hz), 30.7 (d, J =
4.1 Hz), 14.0, -3.9 (t, J = 2.5 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -128.7 (dd, J = 392.8, 72.7 Hz), -131.2
(dd, J = 392.6, 99.9 Hz).
31
P NMR (162 MHz, Chloroform-d) δ 11.0 (ddp, J = 101.3, 72.9, 9.6 Hz). FT-IR (cm
-
1
) 2979, 2935, 1661, 1467, 1371, 1298, 1241, 1211, 1164, 1082, 1030, 994, 962, 920, 846, 795, 752, 703,
665, 635, 601, 545, 510, 498, 457. HRMS (M+H
+
) calculated = 316.1673, found = 316.1669.
4-4f: (difluoromethyl)bis(4-methoxyphenyl)phosphine oxide
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg), LiCl (4.0 equiv, 84.8 mg) and 4-1f (0.5
mmol, 131.1 mg) were weighed into an oven-dried 5 mL crimp-top vial equipped
with a magnetic stir-bar, and the vial was sealed. Under an atmosphere of N 2, DMF
(0.4 M, 1.25 mL) was added by syringe. The resultant mixture was stirred for 30 mins at room temperature,
followed by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2 atmosphere and
subsequent stirring of the resultant mixture for 20 mins at room temperature. The vial was then opened,
the mixture transferred to an 8 dram vial, rinsing with DMF (1 mL), and stirred while a 1 M aqueous
solution of potassium carbonate (1.0 mL) was added slowly. The mixture was then left to stir at r.t.
overnight (16 h). To the mixture was then added 1 M HCl (3 mL). This was extracted with EtOAc (3 x 4 mL).
Each 4 mL extract layer was washed with 1 M HCl (10 mL), the combined organic extracts were dried with
Na 2SO 4, and after decanting from the drying agent the solvent was removed in vacuo. The crude material
P
CF
2
H
O
MeO
MeO
209
was purified by column chromatography (gradient of 0% - 100% EtOAc in hexanes) to afford analytically
pure 4-4f in 73% isolated yield (114 mg) as a pale-yellow oil. The obtained spectra matched previous
reports.
285
1
H NMR (400 MHz, Chloroform-d) δ 7.76 (dd, J = 11.2, 8.9 Hz, 4H), 7.01 (dd, J = 9.0, 2.4 Hz, 4H),
6.26 (td, J = 49.3, 22.0 Hz, 1H), 3.84 (s, 6H).
13
C{
1
H} NMR (101 MHz, Chloroform-d) δ 163.6 (d, J = 3.0 Hz),
134.1 (d, J = 11.0 Hz), 117.6 (d, J = 109.5 Hz), 115.5 (td, J = 265.7, 105.7 Hz), 114.6 (d, J = 13.3 Hz), 55.5.
19
F
NMR (376 MHz, Chloroform-d) δ -132.8 (dd, J = 69.6, 49.3 Hz). FT-IR (cm
-1
) 2950, 2842, 1595, 1568, 1503,
1461, 1442, 1409, 1293, 1257, 1201, 1178, 1120, 1083, 1044, 1023, 831, 803, 764, 720, 667, 572, 535,
460. HRMS ESI
+
(M+H
+
) C 15H 15F 2O 3P = 313.0810.
4-4g: (difluoromethyl)diphenylphosphine oxide
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg), LiCl (4.0 equiv, 84.8 mg) and 4-1g (0.5
mmol, 101.1 mg) were weighed into an oven-dried 5 mL crimp-top vial equipped with a
magnetic stir-bar, and the vial was sealed. Under an atmosphere of N 2, DMF (0.4 M, 1.25
mL) was added by syringe. The resultant mixture was stirred for 30 mins at room temperature, followed
by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2 atmosphere and subsequent
stirring of the resultant mixture for 20 mins at room temperature. The vial was opened, and the solution
was diluted with EtOAc (3 mL), followed by of 1M HCl (10 mL). The organic layer was separated, and the
product was extracted from the aqueous layer two more times (3 mL each time). The combined organic
layers were dried over MgSO 4, filtered, concentrated by rotary evaporation, and purified by column
chromatography (gradient of 0% - 55% EtOAc in hexanes) to afford analytically pure 4-4g as a white solid
in 56% isolated yield (71 mg). The obtained spectra matched previous reports.
300
1
H NMR (399 MHz,
Chloroform-d) δ 7.93 – 7.79 (m, 4H), 7.69 – 7.60 (m, 2H), 7.60 – 7.46 (m, 4H), 6.34 (td, J = 49.1, 22.3 Hz,
1H).
13
C{
1
H} NMR (100 MHz, Chloroform-d) δ 133.5 (d, J = 3.0 Hz), 132.2 (dt, J = 9.6, 1.4 Hz), 129.1 (d, J =
O
P
CF
2
H
210
12.3 Hz), 126.5 (d, J = 102.1 Hz), 115.4 (td, J = 266.2, 104.6 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -132.6
(dd, J = 70.1, 49.0 Hz).
31
P{
1
H} NMR (162 MHz, Chloroform-d) δ 22.5 (t, J = 69.8 Hz).
4-2h: (difluoro(trimethylsilyl)methyl)bis(4-(dimethylamino)phenyl)phosphine oxide
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg), LiCl (1.2 equiv, 25.4 mg) and 4-1h
(0.5 mmol, 144.1 mg) were weighed into an oven-dried 5 mL crimp-top vial
equipped with a magnetic stir-bar, and the vial was sealed. Under an atmosphere
of N 2, DMF (0.4 M, 1.25 mL) was added by syringe. The resultant mixture was stirred for 30 mins at room
temperature, followed by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2
atmosphere and subsequent stirring of the resultant mixture for 50 mins at room temperature. The
biphasic mixture was agitated, the n-pentane layer was decanted, and the process was repeated two
times (4 mL each time). The n-pentane layers were washed with water (10 mL), combined and
concentrated in vacuo. Then, EtOAc (4 mL) was added to the reaction mixture (remaining DMF layer)
followed by 1 M HCl (8 mL). The organic layer was decanted and washed with 1 M HCl (10 mL). The DMF-
water fraction was extracted again with EtOAc (4 mL, two times) and the combined EtOAc layers were
concentrated in vacuo. Both the hexanes and EtOAc layers contained the product. The combined crude
residue was purified by silica gel chromatography (gradient of 0% to 75% EtOAc in hexanes) to afford 4-
2h as a white solid (m.p: 146-150 ˚C) in 40% yield (83 mg).
1
H NMR (400 MHz, Chloroform-d) δ 7.79 – 7.69
(m, 4H), 6.71 (dd, J = 9.2, 2.6 Hz, 4H), 3.00 (s, 12H), 0.07 (s, 9H).
13
C{
1
H} NMR (101 MHz, Chloroform-d) δ
152.7 (d, J = 2.4 Hz), 133.7 (d, J = 10.4 Hz), 130.3 (td, J = 280.7, 76.1 Hz), 113.9 (d, J = 108.3 Hz), 111.3 (d, J
= 12.5 Hz), 40.0, -3.7.
19
F NMR (376 MHz, Chloroform-d) δ -126.3 (d, J = 71.3 Hz).
31
P{
1
H} NMR (162 MHz,
Chloroform-d) δ 26.5 – 25.3 (m). FT-IR (cm
-1
) 3084, 2959, 2899, 2815, 1594, 1543, 1517, 1446, 1363, 1298,
1248, 1231, 1204, 1187, 1107, 1056, 1000, 974, 960, 941, 845, 819, 808, 774, 763, 749, 720, 649, 628,
606, 577, 536, 521, 510, 493, 477, 458. HRMS ESI
+
(M+H
+
) C 20H 30F 2N 2OPSi = 411.1827.
P
O
CF
2
TMS
N
N
211
4-4i: dibenzyl(difluoromethyl)phosphine oxide
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg), LiCl (1.2 equiv, 25.4 mg) and 4-1i (0.5
mmol, 115 mg) were weighed into an oven-dried 5 mL crimp-top vial equipped with a
magnetic stir-bar, and the vial was sealed. Under an atmosphere of N 2, DMF (0.4 M, 1.25
mL) was added by syringe. The resultant mixture was stirred for 30 mins at room temperature, followed
by addition of TMSCF 3 (4 equiv, 295 µL) (dropwise) by syringe under a N 2 atmosphere and subsequent
stirring of the resultant mixture for 20 mins at room temperature. The vial was opened, and its contents
transferred to an 8 dram vial (washed with 1 mL DMF). To the stirred solution was slowly added aqueous
K 2CO 3 solution (1M, 2 mL), and the resultant solution was stirred overnight (16 h). 1M HCl (3 mL) was
added. The product was extracted with EtOAc (4 mL, three times), with each extracted layer being washed
with 1M HCl (10 mL). The organic layers were combined and concentrated in vacuo, and the crude residue
was purified by column chromatography (gradient of 0% to 30% EtOAc in hexanes) to afford 4-4i as a
white solid (m.p. 94 – 97 ˚C) in 29% isolated yield (40 mg).
1
H NMR (400 MHz, Chloroform-d) δ 7.34 – 7.20
(m, 10H), 5.84 (td, J = 48.8, 20.5 Hz, 1H), 3.33 – 3.12 (m, 4H).
13
C NMR (101 MHz, Chloroform-d) δ 130.0
(d, J = 5.3 Hz), 129.2 (d, J = 2.6 Hz), 129.1 (d, J = 8.2 Hz), 127.7 (d, J = 3.0 Hz), 114.2 (td, J = 264.6, 96.5 Hz),
32.4 (d, J = 60.7 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -137.4 (dd, J = 67.7, 48.7 Hz).
31
P NMR (202 MHz,
Chloroform-d) δ 36.3 (t, J = 67.9 Hz). FT-IR (cm
-1
) 3087, 3063, 3030, 2953, 2915, 2849, 1960, 1601, 1587,
1495, 1454, 1410, 1399, 1328, 1240, 1229, 1201, 1186, 1123, 1076, 1063, 1029, 918, 843, 830, 817, 800,
770, 731, 697, 577, 563, 483, 459. HRMS-ESI
+
(M+H
+
) C 15H 16F 2OP = 281.0898.
4-5g: diphenyl(trifluoromethyl)phosphine
In an Argon glovebox, LiH (1.1 equiv, 4.4 mg) and 4-1g (0.5 mmol, 101 mg) were weighed
into an oven-dried 5 mL crimp-top vial equipped with a magnetic stir-bar, and the vial was
sealed. Under N 2, DMF (1.25 mL) was added by syringe, and the suspension was stirred for
P
CF
3
P
CF
2
H
O
212
30 mins. Next, TMSCF 3 (4 equiv, 295 µL) was added by syringe (dropwise), and the solution was stirred for
30 mins at room temperature. The vial was opened, and 3 mL of EtOAc was added. The biphasic mixture
was agitated, the organic layer was decanted, and the process was repeated two times (3 mL EtOAc each
time). The organic layers were washed with water (5 mL), combined, concentrated by rotary evaporation
and the crude product was purified by column chromatography (hexanes) to afford analytically pure 4-5g
as a white solid in 50% yield (118 mg). The NMR data matches previous reports.
301
1
H NMR (400 MHz,
Chloroform-d) δ 7.63 – 7.57 (m, 4H), 7.50 – 7.41 (m, 6H).
19
F NMR (470 MHz, Chloroform-d) δ -55.6 (d, J =
73.7 Hz).
4-5i: dibenzyl(trifluoromethyl)phosphine oxide
In an Argon glovebox, LiH (1.2 equiv, 4.4 mg) and 4-1i (0.5 mmol, 115.1 mg) were
weighed into an oven-dried 5mL crimp-top vial equipped with a magnetic stir bar. The
vial was sealed, and DMF (0.4M, 1.25 mL) was added by syringe under N 2. The resulting
mixture was stirred for 30 mins at room temperature, followed by dropwise addition of TMSCF 3 (4 equiv,
295 µL). The mixture was stirred for 15 minutes at room temperature. The vial was opened, and 3 mL of
EtOAc was added. The solution was poured into aqueous HCl (1M, 8 mL). The biphasic mixture was
agitated, the EtOAc layer was decanted, and the process was repeated two times (3 mL each time). The
organic layers were washed with water (10 mL), combined and concentrated by rotary evaporation. The
crude product was re-dissolved in CHCl 3 (8 mL), and mCPBA (1 equiv, accounting for purity of reagent) was
added portion-wise with stirring. The mixture was stirred for 1.5 hours at room temperature, following
which a saturated solution of K 2CO 3 (8 mL) was added. The organic layer was decanted and washed
sequentially with water (10 mL) and HCl (1M, 10 mL). CHCl 3 (5 mL) was added again, and the extraction
procedure was repeated two times. The combined organic layers were concentrated, and the crude
residue was purified by silica gel chromatography (gradient of 0% to 15% EtOAc in hexanes) to afford
P
O
CF
3
213
analytically pure 4-5i as a white solid (m.p 111-112 ˚C) in 62% yield (93 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 7.35 – 7.27 (m, 6H), 7.26 – 7.22 (m, 4H), 3.44 – 3.22 (m, 4H).
13
C{
1
H} NMR (126 MHz,
Chloroform-d) δ 130.1 (d, J = 5.6 Hz), 129.1 (d, J = 2.5 Hz), 128.2 (d, J = 8.1 Hz), 127.9 (d, J = 3.2 Hz), 123.0
(qd, J = 319.3, 123.7 Hz), 33.1 (d, J = 62.6 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -70.9 (d, J = 78.0 Hz).
31
P NMR (202 MHz, Chloroform-d) δ 36.4 (qp, J = 78.6, 14.5 Hz). FT-IR (cm
-1
) 3087, 3063, 3033, 2944, 2906,
2890, 1602, 1585, 1495, 1455, 1403, 1234, 1182, 1162, 1128, 1110, 1068, 1030, 923, 914, 852, 830, 823,
774, 763, 742, 728, 695, 619, 593, 568, 539, 527, 476, 456. HRMS ESI
+
(M+H
+
) C 15H 14F 3OP = 299.0846.
4-5j: dihexyl(trifluoromethyl)phosphine oxide
In an Argon glovebox, LiH (1.2 equiv, 4.8 mg), LiCl (1.2 equiv, 25.4 mg) and 4-1j (0.5
mmol, 109 mg) were weighed into an oven-dried, crimp-top vial equipped with a
magnetic stir bar. The vial was sealed, and DMF (0.4M, 1.25 mL) was added by syringe under N 2. The
resulting mixture was stirred for 30 mins at room temperature, followed by dropwise addition of TMSCF 3
(4 equiv, 295 µL). The mixture was stirred for 30 minutes at room temperature. The vial was opened, and
3 mL of EtOAc was added. The solution was poured into aqueous HCl (1M, 8 mL). The biphasic mixture
was agitated, the EtOAc layer was decanted, and the process was repeated two times (4 mL EtOAc each
time). The organic layers were washed with water (10 mL), combined and concentrated by rotary
evaporation. The crude product was re-dissolved in CHCl 3 (8 mL), and mCPBA (1 equiv, accounting for
purity of reagent) was added in portions. The mixture was stirred for 2 hours at room temperature,
following which an aqueous solution of K 2CO 3 (1M, 8 mL) was added. The organic layer was decanted and
washed sequentially with water (10 mL) and HCl (1M, 10 mL). CHCl 3 (5 mL) was added again, and the
extraction procedure was repeated two times. The combined organic layers were concentrated, and the
crude residue was purified by silica gel chromatography (gradient of 0% to 18% EtOAc in hexanes) to afford
analytically pure 4-5j as a colorless oil in 47% yield (67 mg).
1
H NMR (400 MHz, Chloroform-d) δ 2.00 –
P
CF
3
O
H
3
C(H
2
C)
5
H
3
C(H
2
C)
5
214
1.81 (m, 4H), 1.73 – 1.61 (m, 4H), 1.46 – 1.37 (m, 4H), 1.33 – 1.25 (m, 8H), 0.92 – 0.82 (m, 6H).
13
C{
1
H}
NMR (101 MHz, Chloroform-d) δ 123.29 (qd, J = 318.7, 120.1 Hz), 31.19, 30.69 (d, J = 14.3 Hz), 25.62 (d, J
= 65.6 Hz), 22.42, 20.70 (d, J = 4.5 Hz), 14.04.
19
F NMR (376 MHz, Chloroform-d) δ -72.54 (d, J = 78.5 Hz).
31
P{
1
H} NMR (202 MHz, Chloroform-d) δ 44.48 (q, J = 78.6 Hz). FT-IR (cm
-1
) 2956, 2929, 2872, 2858, 2357,
2341, 1462, 1401, 1379, 1353, 1292, 1248, 1234, 1184, 1119, 1005, 979, 808, 713. HRMS ESI
+
(M+H
+
)
C 13H 27F 3OP = 287.1759.
NMR data of Side-product 4-3a:
NMR yield = 89%.
1
H NMR (399 MHz, Chloroform-d) δ 4.61 (dd, J = 16.7, 8.5 Hz, 1H),
4.40 – 4.13 (m, 4H), 2.41 – 2.29 (m, 6H), 1.42 – 1.29 (m, 6H), 0.17 (s, 9H).
13
C NMR {
1
H}
(100 MHz, Chloroform-d) δ 118.9 (ddd, J = 277.2, 264.2, 208.5 Hz), 86.2 (ddd, J = 28.0, 22.4, 18.8 Hz), 64.7
– 64.1 (m), 40.2 (dd, J = 4.6, 1.4 Hz), 16.6 (dd, J = 7.9, 5.7 Hz), 0.2.
19
F NMR (376 MHz, Chloroform-d) δ -
110.9 (ddd, J = 303.1, 102.1, 8.5 Hz), -126.8 (ddd, J = 303.0, 97.0, 16.7 Hz).
31
P NMR {
1
H} (162 MHz,
Chloroform-d) δ 6.7 (dd, J = 102.2, 97.0 Hz).
4-6a: diethyl (1,1-difluoro-2-hydroxy-2-(4-nitrophenyl)ethyl)phosphonate
In an Argon glovebox, 4-nitrobenzaldehyde (4-6sm)(0.5 mmol, 75.5 mg) and
Cs 2CO 3 (1.2 equiv, 195 mg) were weighed into an oven-dried, crimp-top vial
equipped with a magnetic stir bar and sealed. DMF (1 mL) and 4-2a (2.0 equiv, 260 mg) were added by
syringe under N 2. The mixture was stirred for 1 hour at room temperature. The reaction mixture was
poured into a biphasic mixture of EtOAc and water (1:1 V:V, 6 mL each of EtOAc and H 2O) and stirred for
2 hours under air. The organic layer was decanted, and the aqueous layer was extracted with EtOAc (2
times, 4 mL each time). The organic layers were combined, washed with water (4 mL) and saturated
aqueous K 2CO 3 (4 mL) and concentrated. The residue was purified by silica gel column chromatography
P
O
C
F
2
OTMS
N
EtO
EtO
OH
C
F
2
P
O
O
O
O
2
N
215
(gradient of 0% to 40% EtOAc in hexanes) to afford 4-6a as a pale-yellow solid (m.p: 116-119 ˚C) in 96%
isolated yield (162 mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.23 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H),
5.34 – 5.14 (m, 1H), 5.05 (s, 1H), 4.33 – 4.20 (m, 4H), 1.38 – 1.30 (m, 6H).
13
C {
1
H} NMR (100 MHz,
Chloroform-d) δ 148.3, 142.4 (dd, J = 6.8, 2.1 Hz), 129.2, 123.3, 117.8 (ddd, J = 273.7, 265.5, 207.1 Hz),
72.6 (ddd, J = 26.5, 21.5, 14.3 Hz), 65.5 (dd, J = 24.8, 7.2 Hz), 16.4 (t, J = 4.9 Hz).
19
F NMR (376 MHz,
Chloroform-d) δ -113.5 (ddd, J = 306.2, 98.3, 4.8 Hz), -126.3 (ddd, J = 306.4, 103.7, 21.4 Hz).
31
P {
1
H} NMR
(162 MHz, Chloroform-d) δ 6.1 (dd, J = 103.8, 98.4 Hz). FT-IR (cm
-1
) 3264, 2991, 2917, 2851, 2357, 2333,
1611, 1600, 1524, 1491, 1478, 1442, 1416, 1391, 1369, 1346, 1274, 1238, 1181, 1158, 1084, 1058, 1041,
1012, 963, 862, 819, 797, 763, 728, 690, 675, 647, 603, 557, 520, 512, 469. HRMS ESI
+
(M+H
+
) C 12H 16F 2NO 6P
= 340.0774.
4-6b: diisopropyl (1,1-difluoro-2-hydroxy-2-(4-nitrophenyl)ethyl)phosphonate
In an Argon glovebox, 4-nitrobenzaldehyde (4-6sm)(0.5 mmol, 75.5 mg) and
Cs 2CO 3 (1.2 equiv, 195 mg) were weighed into an oven-dried, crimp-top vial
equipped with a magnetic stir bar and sealed. DMF (1 mL) and 4-2b (2.0 equiv, 290 mg) were added by
syringe under N 2. The mixture was stirred for 1 hour at room temperature. The reaction mixture was
poured into a biphasic mixture of EtOAc and water (1:1 V:V, 6 mL each of EtOAc and H 2O) and stirred for
2 hours under air. The organic layer was decanted, and the aqueous layer was extracted with EtOAc (2
times, 4 mL each time). The organic layers were combined, washed with water (4 mL) and saturated
aqueous K 2CO 3 (4 mL) and concentrated. The residue was purified by silica gel column chromatography
(gradient of 0% to 40% EtOAc in hexanes) to afford 4-6b as a pale-yellow solid (m.p: 130-131 ˚C) in 72%
isolated yield (132 mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.23 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H),
5.25 – 5.14 (m, 1H), 4.92 – 4.80 (m, 2H), 4.71 (s, 1H), 1.41 – 1.27 (m, 12H).
13
C {
1
H} NMR (100 MHz,
Chloroform-d) δ 148.3, 142.2 (d, J = 6.7 Hz), 129.3, 123.2, 117.1 (ddd, J = 272.6, 266.9, 207.6 Hz), 75.1 (dd,
OH
C
F
2
P
O
O
O
O
2
N
216
J = 26.0, 7.4 Hz), 73.5 – 72.3 (m), 24.2 (dd, J = 7.2, 3.5 Hz), 23.8 (dd, J = 25.6, 5.0 Hz).
19
F NMR (376 MHz,
Chloroform-d) δ -114.8 (ddd, J = 304.4, 96.6, 4.7 Hz), -127.3 (ddd, J = 304.3, 104.8, 21.2 Hz).
31
P {
1
H} NMR
(162 MHz, Chloroform-d) δ 4.5 (dd, J = 104.9, 96.5 Hz). FT-IR (cm
-1
) 3303, 2982, 2928, 2876, 2852, 1608,
1592, 1490, 1466, 1454, 1388, 1378, 1347, 1318, 1247, 1201, 1174, 1164, 1143, 1101, 1090, 991, 900,
889, 869, 860, 819, 791, 751, 730, 695, 611, 569, 528, 468, 473, 457. HRMS ESI
+
(M+H
+
) C 14H 20F 2NO 6P =
368.1081.
4-6d: 2-(1,1-difluoro-2-(4-nitrophenyl)-2-((trimethylsilyl)oxy)ethyl)-5,5-dimethyl-1,3,2-
dioxaphosphinane 2-oxide
In an Argon glovebox, 4-nitrobenzaldehyde (4-6sm)(2 equiv, 0.5 mmol, 75.5
mg) and Cs 2CO 3 (1.0 equiv, 0.25 mmol, 195 mg) were weighed into an oven-
dried, crimp-top vial equipped with a magnetic stir bar and sealed. A solution and 4-2d (0.25 mmol, 70
mg) in DMF (0.5 mL) was added by syringe under N 2. The mixture was stirred for 1 hour at room
temperature. The reaction mixture was poured into a biphasic mixture of EtOAc and water (1:1 V:V, 6 mL
each of EtOAc and H 2O) and stirred for 2 hours under air. The organic layer was decanted, and the aqueous
layer was extracted with EtOAc (2 times, 4 mL each time). The organic layers were combined, washed with
water (4 mL) and saturated aqueous K 2CO 3 (4 mL) and concentrated. The residue was purified by silica gel
column chromatography (gradient of 0% to 40% EtOAc in hexanes) to afford 4-6d as a pale-yellow oil in
52% isolated yield (55 mg). The corresponding O–H product was obtained as a yellow solid in 25% yield
(17 mg). The overall yield of this transformation was 77% (52% OTMS + 25% OH products).
1
H NMR (399
MHz, Chloroform-d) δ 8.23 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 5.35 – 5.20 (m, 1H), 4.39 (d, J = 10.8
Hz, 1H), 4.24 (d, J = 11.0 Hz, 1H), 4.01 (ddd, J = 29.7, 19.1, 11.2 Hz, 2H), 1.34 (s, 3H), 0.90 (s, 3H), 0.10 (s,
9H).
13
C NMR {
1
H} (100 MHz, Chloroform-d) δ 148.4, 143.0 (dd, J = 5.9, 2.7 Hz), 129.4, 123.3, 119.6 (ddd,
J = 273.9, 265.9, 202.7 Hz), 79.0 (ddd, J = 9.5, 7.3, 2.3 Hz), 73.7 (ddd, J = 27.1, 21.0, 14.3 Hz), 32.6 (d, J =
O
P
O
O
C
F
2
TMSO
O
2
N
217
8.4 Hz), 22.1, 20.5, 0.0.
19
F NMR (376 MHz, Chloroform-d) δ -113.3 (ddd, J = 304.7, 98.5, 6.2 Hz), -123.2
(ddd, J = 304.7, 104.0, 19.9 Hz).
31
P {
1
H} NMR (162 MHz, Chloroform-d) δ -3.0 (dd, J = 104.0, 98.3 Hz).
HRMS ESI
+
(M+H
+
) C 16H 24F 2NO 6PSi = 424.1199.
The above experiment also yielded the corresponding O–H product as a yellow solid in 25% yield (17 mg)
4-6h: (1,1-difluoro-2-(4-nitrophenyl)-2-((trimethylsilyl)oxy)ethyl)bis(4-
(dimethylamino)phenyl)phosphine oxide
In an Argon glovebox, 4-nitrobenzaldehyde (4-6sm) (2 equiv, 0.2 mmol,
32.6 mg), Cs 2CO 3 (1.0 equiv, 0.1 mmol, 32.6 mg) and 4-2h (0.1 mmol, 41
mg) were weighed into an oven-dried, crimp-top vial equipped with a
magnetic stir bar and sealed. DMF (0.5 mL) was added by syringe under N 2. The mixture was stirred for 1
hour at room temperature. The reaction mixture was poured into a biphasic mixture of EtOAc and water
(1:1 V:V, 6 mL each of EtOAc and H 2O) and stirred for 2 hours under air. The organic layer was decanted,
and the aqueous layer was extracted with EtOAc (2 times, 4 mL each time). The organic layers were
combined, washed with water (4 mL) and saturated aqueous K 2CO 3 (4 mL) and concentrated. The residue
was purified by silica gel column chromatography (gradient of 0% to 40% EtOAc in hexanes) to afford 4-
6h as a yellow solid (m.p: 52-54 ˚C) in 52% isolated yield (55 mg).
1
H NMR (399 MHz, Chloroform-d) δ 8.03
(d, J = 8.6 Hz, 2H), 7.75 (t, J = 9.9 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.48 (t, J = 9.8 Hz, 2H), 6.72 (d, J = 9.1 Hz,
2H), 6.56 (d, J = 9.1 Hz, 2H), 5.47 (dd, J = 16.7, 9.4 Hz, 1H), 3.02 (s, 6H), 2.94 (s, 6H), -0.08 (s, 9H).
13
C NMR
(100 MHz, Chloroform-d) δ 152.7 (dd, J = 17.2, 2.6 Hz), 148.0, 144.4 (t, J = 3.1 Hz), 133.5 (td, J = 11.2, 10.8,
2.5 Hz), 129.7, 120.9 (ddd, J = 279.6, 271.1, 104.3 Hz), 113.3 (dd, J = 114.3, 96.4 Hz), 111.2 (dd, J = 15.1,
13.0 Hz), 73.2 (ddd, J = 26.9, 21.4, 13.4 Hz), 40.0 (d, J = 13.7 Hz), -0.0.
19
F NMR (376 MHz, Chloroform-d) δ
-115.0 (ddd, J = 299.7, 79.9, 8.9 Hz), -119.5 (ddd, J = 299.9, 79.9, 16.4 Hz).
31
P NMR (162 MHz, Chloroform-
d) δ 27.3 (t, J = 80.4 Hz). FT-IR (cm
-1
) 2955, 2921, 2850, 1595, 1519, 1445, 1365, 1345, 1299, 1252, 1231,
NO
2
P
OTMS
O
Me
2
N
Me
2
N
C
F
2
218
1194, 1165, 1110, 1060, 1026, 1015, 1001, 994, 873, 843, 811, 775, 751, 731, 649, 628, 606, 573, 539,
501, 456. HRMS ESI
+
(M+H
+
) C 27H 34F 2N 3O 4PSi = 562.2134.
Attempted Carbene Insertion Into Disilanes and Silyl Hydrides
The following pages summarize in table form our various unsuccessful attempts to perform
difluorocarbene insertion chemistry into various silicon compounds. This data is presented in the hopes
that it can be useful to another graduate student in possibly similar research pursuits.
219
1 Et
2
O (0.1M) LDA (1.2) HMPA (2) 4 -78 10 rt 20
numerous unidentifyable
fluorinated products
2 Et
2
O (0.1M) LDA (1.2) - 4 -78 10 rt 20 TMSCF
3
, TMSF, CF
3
H
3 THF (0.1M) MeLi (1.6M) in Et
2
O (1.2) HMPA (2) 4 -78 30 rt 18
TMSCF
3
, TMSF, CF
3
H, -81.9, -
129.6, -135.8, -140.0, -139.2, -
157.8, -158.1
4 THF (0.1M) MeLi (1.6M) in Et
2
O (1.2) - 4 -78 30 rt 18 unreacted TMSCF
3
5 THF (0.1M) MeLi (1.6M) in Et
2
O (2) HMPA (2) 3 -78 30 rt 18
-60.6 (d), TMSCF
3
, CF
3
H,
TMSF
6 THF (0.1M) MeLi (1.6M) in Et
2
O (3) HMPA (2) 3 -78 5 rt 18
-60.6 (d), TMSCF
3
, CF
3
H,
TMSF
7 THF (0.1M) MeLi (1.6M) in Et
2
O (4) HMPA (2) 3 -78 5 rt 18
-60.6 (d), TMSCF
3
, CF
3
H,
TMSF
8 DMF (0.1M) - LiI (2) 4 rt 10 - 24 TMSCF
3
, CF
3
H, TMSF
9 DMF (0.1M) KOtBu (1.5) LiI (2) 4 rt 10 - 24
-58.7 (s), TMSCF
3
, CF
3
H,
TMSF
10 DMF (0.1M) KHMDS (1.5) LiI (2) 4 rt 10 - 24 -75.7 (s), -78.7 (s), -77.4 (s)
11 hexanes (0.1M) LiN(SO
2
CF
3
)
2
(1.2) - 4 rt 10 - 48 unreacted TMSCF
3
12 hexanes (0.1M) - LiOTf (1.2) 4 rt 10 - 48 unreacted TMSCF
3
13 hexanes (0.1M) LiNMe
2
(1.2) - 4 rt 10 - 48 unreacted TMSCF
3
14 hexanes (0.1M) LiN(SO
2
CF
3
)
2
(1.2 ) - 4 rt 10 - 23 unreacted TMSCF
3
15 hexanes (0.1M) - LiI (1.2) 4 rt 10 - 23 unreacted TMSCF
3
16 hexanes (0.1M) LiHMDS (1.2) - 4 rt 10 - 23 unreacted TMSCF
3
17 hexanes (0.1M) LDA (1.2) - 4 rt 10 - 23 unreacted TMSCF
3
18 hexanes (0.1M) LiH (1.2) - 4 rt 10 - 23 unreacted TMSCF
3
19 hexanes (0.1M) LiOtBu (1.2) - 4 rt 10 - 23 unreacted TMSCF
3
start
temperature
(celcius)
Time before addition of
TMSCF
3
(minutes)
warm-to
temperature (celcius)
reaction
time (hours)
Reaction mix: observed
species by NMR
TMSCF
3
(equiv)
Additive (equiv) Base
Solvent
(concentration)
Using (MeO)
3
SiH (limiting reagent)
trial
220
221
trial
Solvent
(concentration)
Base Additive (equiv)
TMSCF
3
(equiv)
start
temperature
(celcius)
Time before the
addition of TMSCF
3
(minutes)
warm-to
temperature (celcius)
reaction
time (hours)
Reaction mix: observed
species by NMR
1 DMF (0.1) MeLi (1.6M) in Et
2
O (1.2) HMPA (2) 4 0 15 rt 3
-58.8 (s), TMSCF
3
, -67.1 (s), -
73.9 (s), -74.4 (s), -77.34 (s),
CF
3
H, -79.4, -81.1, -139.7, -
153.0, TMSF, -179.6
2 MeCN (0.1)
MeLi (1.6M) in Et
2
O (1.2
equiv)
HMPA (2) 4 0 15 rt 3 CF
3
H
3 THF (0.1)
MeLi (1.6M) in Et
2
O (1.2
equiv)
HMPA (2) 4 0 15 rt 3
-60.6 (s), TMSCF
3
, CF
3
H, -
79.3, TMSF
4 HMPA (0.1)
MeLi (1.6M) in Et
2
O (1.2
equiv)
- 1.2 0 15 rt 24 CF
3
H
5 THF (0.1) KF (3) LiI (1.2) 2 rt 10 - 24 no peaks observed
6 THF (0.1) KF (3)
LiI (1.2), HMPA
(2)
2 rt 10 - 24
-6.6 (s), -60.6 (s), TMSCF
3
,
CF
3
H, TMSF
7 HMPA (0.1) KF (3) LiI (1.2) 2 rt 10 - 24 CF
3
H, TMSF
8 THF (0.1) TMAF (3) LiI (1.2) 2 rt 10 - 24 -79.2 (s)
9 THF (0.1) TMAF (3)
LiI (1.2), HMPA
(2)
2 rt 10 - 24 -52.9, -54.7, CF
3
H, TMSF
10 HMPA (0.1) TMAF (3) LiI (1.2) 2 rt 10 - 24
TMSCF
3
, CF
3
H, -140.1 (s),
TMSF
11 HMPA (0.125) MeLi (1.6M) in Et2O (0.9) - 1.2 0 15 rt 5 -59.6 (s), CF
3
H, TMSF
12 DMPU (0.125) MeLi (1.6M) in Et2O (1.9) - 1.2 0 15 rt TMSCF
3
, TMSF
Using (Me)
3
Si-Si(Me)3
trial
Solvent
(concentration)
Base Additive (equiv)
TMSCF
3
(equiv)
start
temperature
(celcius)
Time before the
addition of TMSCF
3
(minutes)
warm-to
temperature (celcius)
reaction
time (hours)
Reaction mix: observed
species by NMR
1 THF (0.1) Li (2.7) - 1.5 rt 15 - 2.5 no peaks observed
2 THF (0.1) Li (2.7) - 1.5 rt
15 (for addn of TMSCl,
TMSCF
3
from start)
- 2.5 no peaks observed
3 THF (0.1) Li (2.7) - 1.5 rt 0 - 2.5 no peaks observed
Using Me
3
SiCl
222
Chapter 5: Aqueous Base Promoted O-Difluoromethylation of Carboxylic Acids
with TMSCF
2
Br: Bench-Top Access to Difluoromethyl Esters
5.i Introduction
Our success with the synthesis of siladifluoromethylphosphonates and
siladifluoromethylphosphine oxides prompted me to consider more elaborate transformations invoking
difluorocarbene. While perusing the literature, I stumbled across an interesting reaction paradigm:
difluorocarbene has been used for the deoxygenation-fluorofunctionalization of organic molecules! The
first reaction of this type was reported by Hine and Porter in 1960.
302
The only other report of this nature
comes from Hu, Qing, and Shen,
303
wherein difluorocarbene generated from CF 2Br 2 and Zn
0
was
demonstrated to perform a tandem deoxygenation-gem-difluorination of ketones, yielding
difluoroalkanes. It seemed likely that a milder and more reactive source of difluorocarbene like TMSCF 2Br
would be able to display comparable reactivity. We then performed a number of trials to explore the
possibility of this reaction. During the exploratory phase, we stumbled across a very interesting result.
When sodium acetate was used as an activator for TMSCF 2Br, we observed small amounts of the
corresponding difluoromethyl ester (difluoromethyl acetate), meaning that we had performed a direct
electrophilic difluoromethylation of the conjugate base of a carboxylic acid. Excited by this preliminary
result, we began looking for related transformations in the literature and found that there were very few
methods for the synthesis of difluoromethyl esters. The lack of general synthetic methods to synthesize
difluoromethyl esters was surprising when considering the abundance of carboxylic acids in nature and in
pharmacologically relevant molecules. One reported approach uses fluorosulfonyldifluoroacetic acid at
room temperature with metal carboxylates to form the corresponding difluoromethyl esters in moderate
to good yields, with SO 2 and CO 2 as undesirable byproducts.
304
Another report describes a
223
difluoromethylation using Ph 3P
+
–CF 2–COO
–
, wherein triphenylphosphine and carbon dioxide are
byproducts.
305
The reaction of benzoic acid with (trifluoromethyl)trimethyl tin has been shown to yield
difluoromethyl benzoate.
306
Owing to the inherent toxicity of SO 2, and the incompatibility of PPh 3 and tin
compounds in the context of cell biology, an alternative and sustainable difluoromethylation approach is
desirable. Difluorodiazirine, a gaseous and explosive compound, can produce –CF 2– esters from the
corresponding carboxylic acids.
307
Figure 5.1 Prior art on the direct difluoromethylation of carboxylic acids
As previously discussed, silicon reagents, by virtue of their mild activation conditions
21,24,33,114
and
non-toxic byproducts, provide one such alternative. Among the various reagents to release
difluorocarbene, TMSCF 2Br stands out owing to its availability, effectiveness, and compatibility with
aqueous reaction systems.
285
Using TMSCF 2Br to perform a difluoromethylation of carboxylic acids would
be a facile, accessible and safe method to synthesize difluoromethyl esters. Based on our previous
experience with difluorocarbene chemistry,
34,308
we envisioned a reaction system wherein the carbene
generated from TMSCF 2Br would react with a carboxylate anion, yielding a difluoromethyl carboxylate
upon protonation (Scheme 5.1).
R
O O
CF
2
H
F
C
F
N
N
hv
Ph
3
PCF
2
CO
2
R OH
Xylene Pyrolysis
R OH
O
O
Sn
CF
3
OH
O
S
O
O
F
F F
R OM
O
MeCN
R OH
O
224
Figure 5.2 Mechanistic hypothesis
Table 5.1 Optimization experiments on 5-1a
Trial
a
Base
(equiv)
Solvent
b
TMSCF2Br
(equiv)
5-2a
(%)
c
1 NaOtBu (1.1) triglyme 2 44
2 KOtBu (1.1) triglyme 2 39
3 KOtBu (1.1) CH 3CN 2 58
4 K 2CO 3 (1.1) CH 3CN 2 27
5 KOH (1.1) CH 3CN 2 48
6 KOH (2.2) DMF 2 10
7 KOH (2.2) CH 3CN 2 72
8
d
KOH (2.2) CH 3CN 2 72
9
d
KOH (2.2) CH 3CN 3 69
10
d
KOH (2.2) CH 3CN 4 66
a
Reactions performed with 0.5 mmol of 5-1a.
b
0.4 M concentration of 5-1a in solvent.
c
Yield determined by
19
F NMR using
fluorobenzene as internal standard.
d
100 µL of H 2O added.
R OH
O
R O
O
TMSCF
2
Br
KOH
KOH
CF
2
K
R O
O
CF
2
R O
O
CF
2
H
H
+
225
5.ii Results and Discussion
Substrate 5-1a was chosen as the model substrate for optimization studies. Sodium tert-butoxide
(trial 1) and potassium tert-butoxide (trial 2) proved mildly effective in facilitating this transformation in
triglyme. Performing the reaction in acetonitrile increased the amount of difluoromethyl benzoate (5-2a)
observed (trial 3). Of the bases screened, KOH worked the best, with 72% of 5-2a detected (trial 5). DMF
was found to be ineffective in promoting the chemistry, with a severely diminished yield of 5-2a (trial 6).
It was found that higher loadings of KOH resulted in higher yields, with the maximum being 72% of 5-2a
observed when 2.2 equivalents of KOH were used (trial 7). To remove the variability in the system by virtue
of water absorbed by the hygroscopic KOH, 100 µL of water were added to the system, and the yield
remained unchanged (trial 8). With the optimal base and solvent system determined, efforts were made
to determine the optimal amount of TMSCF 2Br required in this system. Higher loadings of TMSCF 2Br (trials
9 and 10) did not afford increased yields. For a full table of optimization trials, see the Experimental
Section.
The optimum conditions were then applied to a series of carboxylic acids (Table 5.2). The model
substrate 5-1a afforded 5-2a in 72% yield by
19
F NMR and was isolated in 41% yield. The reduced isolated
yield may be attributed to the volatility of the product. Similarly, 5-2b was isolated in 65% yield (87% by
NMR). Haloarenes are tolerant to the reaction conditions, as is demonstrated by 5-2c and 5-2d, which
were isolated in high yields. Compound 5-2e, bearing the electron-donating 4-OMe substituent, was
obtained in good yield. Despite the facile nature of difluorocarbene cyclopropanation reactions with
alkenes, substrate 5-1f, containing a 4-vinyl group, gave none of the difluorocyclopropane product, instead
providing only the desired difluoromethyl ester 5-2f.
26,285
226
Table 5.2 Substrate scope
a
a
Reactions performed at 1 mmol scale for isolated yields. Yields in parentheses determined by
19
F NMR at 0.25 mmol reaction
scale.
b
3 equiv TMSCF 2Br
R
OH O
MeCN (2.5 mL)
H
2
O (0.4 mL)
rt, air, 30 min
R
O O
(ii) TMSCF
2
Br (2 equiv)
rt, air, 2h
R
O O
F
F
O O
O
O O
Et
O O
O O
F
F
F
F
F
F
F
F
F
3
C CF
3
O
O
F
F
O
O
F
F
O O
F
F
5-2e
74% (82%)
5-2b
65% (87%)
5-2f
70% (71%)
5-2k
55% (85%)
5-2j
79% (96%)
5-2l
24% (52%)
O O O O
I F
F
Br F
F O O
F
F
5-2a
41% (72%)
5-2c
90% (98%)
5-2d
86% (95%)
Cl
O
O
5-2i
78% (92%)
(1 mmol)
(i) KOH (2.2 equiv)
Aromatic and aliphatic difluoromethyl esters
5-2h
47% (49%)
F F
O
S
F
F
5-2n
61% (75%)
O O
F
F
5-2g
77% (83%)
OH
O
O
F
F
5-2m
84% (85%)
S
S
O O
O O
F F
S
S
HO O
O O
F F
+
F
F
5-2o
5-2o’
65%
b
(78%) combined yield
227
Similarly, the terminal alkyne unit on 5-2g was left untouched; no difluorocyclopropene was
observed. This exquisite selectivity could be advantageous in the O-difluoromethylation of complex
carboxylic acids. An electron deficient ester, 5-2h, with two trifluoromethyl groups, was obtained in
moderate yield. Among the aryl carboxylic acids (5-1a to 5-1h), it appears that the yield is directly related
to the electron density on the aryl ring: electron-donating groups enhance the yield, while electron-
withdrawing groups diminish the yield. Under the optimized conditions, 4-chlorocinnamic acid saw high
conversion to 5-2i. Aliphatic carboxylic acids were also tested under the optimized conditions.
Difluoromethyl 4-phenylbutanoate 5-2j was formed with excellent conversion. The phenyl acetic acid
derivative 5-2k was obtained in a slightly lower yield than the phenyl butyric acid derivative 5-2j, possibly
due to the stronger withdrawing effect of the phenyl group in 5-2k by virtue of proximity to the carboxylic
acid group. 1-Adamantyl carboxylic 5-1l acid was derivatized in moderate yields, despite the strong
electron-donating effect of the adamantyl group. Strong steric repulsion may be responsible for this
diminished yield. Aliphatic alcohols, despite their propensity to react with CF 2 carbene,
309
were found to
be tolerant to the conditions: 5-2m was furnished from mandelic acid in 84% yield, with none of the
difluoromethyl ether observed. Thiocarboxylic acid ester 5-2n was prepared in 75% conversion, with the
carbene showing a preference for the S atom over the O atom (inferred from
19
F NMR and IR data, see the
Supporting Information document). Finally, disulfide containing 5-1o produced a 1:1 mixture of 5-2o and
5-2o’, with <4% formation of the gem-difluoromethyl dithioacetal (the product of :CF 2-insertion into the
S—S bond).
308
As stated previously, carboxyl groups can be found in a number of FDA approved drugs and other
biologically relevant molecules. To test the applicability of this method on more complex molecules, acids
1p–1u were subjected to the reaction conditions (Table 5.3). Ibuprofen (5-1p) furnished 5-2p in high
conversion. Ketoprofen (5-1q) was transformed to the corresponding difluoromethyl ester (5-2q) in
228
excellent yield. Notably, the ketone functionality in 5-1q was left untouched; i.e. neither the
bromodifluoromethyl carbinol from nucleophilic bromodifluoromethylation
32
nor the difluoroalkane
resulting from deoxo-gem-difluorination at the carbonyl group
33,34
were observed.
Table 5.3: O-difluoromethylation of biologically relevant carboxylic acids
Reactions performed at 1 mmol scale using standard reaction conditions.
a
conducted at 0.5 mmol scale.
b
3 equivalents of
TMSCF 2Br.
Naproxen 5-1r furnished 5-2r in good yield. Ester 5-2s was prepared from Boc-protected leucine
in good yield, with retention of the Boc group despite the ability of difluorocarbene to replace the tert-
butyl group, generating an O-difluoromethyl carbamate.
35
Furthermore, the unprotected amino acid
phenylalanine (5-1t) furnished 5-2t in moderate yield, with no evidence of the N—CF 2H product,
demonstrating applicability to even unprotected primary amines. Under the optimized conditions, salicylic
acid (5-1u) formed a mixture of products, by virtue of competing O-difluoromethylation at the carboxylic
iPr
O
O
F
F
5-2p
63% (89%)
From Ibuprofen
O O
F
F
Ph
O
*
O
O
5-2q
87%
From Ketoprofen
5-2r
67% (71%)
From Naproxen
O
O
O
5-2u
38% (50%)
b
HO
H
N
Boc
O
O F
F
5-2s
64%
a
(79%)
From N-Boc-L-Leucine
F
F
Biologically relevant difluoromethyl esters
O O
F
F
O
F
F
From salicylic acid
5-2u’
(31%)
+
F F
+
H
2
N
O
O
F
F
Ph
5-2t
42% (50%)
From L-phenylalanine
229
acid and alcohol functionalities. Increasing the loading of TMSCF 2Br to 3 equivalents resulted in an easily
separable 5:3 (5-2u:5-2u’) mixture of the mono- and di-substituted products, with an 81% overall
conversion of 5-1u to the mixture of products.
5.iii Conclusion
Reports on difluoromethyl esters are scarce. This chapter presents an aqueous, base-mediated
method to access these potentially valuable compounds under accessible bench-top conditions using the
commercially available reagent TMSCF 2Br. The procedure is compatible with a number of commonly
encountered functional groups. Emphasis must be placed on the tolerance of alkenes, alkynes, primary
amines and disulfides under the reaction conditions, since these groups are otherwise expected to react
with difluorocarbene. Our direct application of this method to active pharmaceutical ingredients and
amino acids demonstrates the applicability of this methodology in late-stage functionalization.
5.iv Experimental Section
General Information
Unless otherwise specified, all materials were purchased from commercial sources and used
without further purification. The handling of reagents and the reaction setup were conducted under air
with no precautions to exclude moisture or oxygen. TMSCF 2Br was purchased from Synquest Laboratories
and used as received. Anhydrous DriSolv® acetonitrile (Millipore Sigma) was used in all trials. Repetition
of the synthesis of 2a with reagent grade (non-anhydrous) acetonitrile gave comparable results. Where
applicable, flash column chromatography on silica gel was performed with either a manual column or a
230
Biotage autocolumn with UV detector (254 nm and 280 nm detection) for product isolation with a
hexanes/EtOAc eluent system.
1
H,
13
C, and
19
F spectra were recorded on 400 MHz, 500 MHz, or 600 MHz
Varian NMR spectrometers.
1
H NMR chemical shifts were determined relative to CHCl 3 as the internal
standard at δ 7.26 ppm.
13
C NMR shifts were determined relative to Chloroform-d at δ 77.16.
19
F NMR
chemical shifts were determined relative to CFCl 3 at δ 0.00. NMR yields were determined via
19
F spectral
analysis of neat reaction mixture aliquots after adding a known quantity of a fluorinated internal standard:
PhF or PhOCF 3. Mass spectral data were recorded on a high-resolution mass spectrometer (QTOF), EI or
ESI mode. IR data were recorded on a JASCO FT/IR spectrometer.
Synthesis and Characterization of Difluoromethyl Esters
Difluoromethyl benzoate (5-2a):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with KOH
(123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and benzoic acid 5-1a (122
mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was then sealed with a crimp
top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water (0.40 mL), and the mixture
was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was then added, and the
reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction mix was diluted with
DCM (5 mL), and water (8 mL) was added. The organic layer was removed, the aqueous layer was extracted
twice more with DCM (2 x 5 mL), and the organic extracts were washed individually with brine (10 mL).
The combined organics were dried with Na 2SO 4, decanted, and concentrated in vacuo. The crude product
was dry loaded on silica gel for purification by flash column chromatography with an eluent system of
hexanes/EtOAc. The desired product eluted in pure hexanes. The appropriate fractions were combined
and concentrated in vacuo to give 5-2a (71 mg, 41% yield) as a colorless liquid. Note: due to its moderate
231
volatility, care must be taken when evaporating the solvent to avoid product loss.
1
H NMR (500 MHz,
Chloroform-d) δ 8.10 (dd, J = 8.4, 1.4 Hz, 2H), 7.71 – 7.63 (m, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 71.1
Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -91.9 (d, J = 70.9 Hz).
13
C {
1
H} NMR (101 MHz, Chloroform-d)
δ 162.8 (t, J = 3.3 Hz), 134.9, 130.5, 128.9, 127.4, 113.1 (t, J = 257.8 Hz). FT-IR (n
-1
cm
-1
) 3731, 3034, 2349,
2312, 1764, 1589, 1435, 1360, 1243, 1134, 1077, 1023, 934, 860, 783, 744, 705, 656, 553. HRMS (ESI
+
)
m/z calculated for C 8H 7F 2O 2 [M+H]
+
: 173.0409; found 173.0411 (1.16 ppm).
Difluoromethyl 4-ethylbenzoate 5- (2b):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with KOH
(123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 4-ethylbenzoic acid 5-
1b (150 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was then sealed with
a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water (0.40
mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was
then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction mix
was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined organics
were dried with MgSO 4, filtered, and concentrated in vacuo. The crude product was dry loaded on silica
gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The desired
product eluted in pure hexanes. The appropriate fractions were combined and concentrated in vacuo to
give 5-2b (130 mg, 65% yield) as a colorless liquid.
1
H NMR (500 MHz, Chloroform-d) δ 8.03 – 7.98 (m, 2H),
7.32 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 71.3 Hz, 1H), 2.74 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).
19
F NMR
(376 MHz, Chloroform-d) δ -91.8 (d, J = 71.5 Hz).
13
C {
1
H} NMR (101 MHz, Chloroform-d) δ 162.8 (t, J = 3.3
Hz), 152.1, 130.7, 128.5, 124.8, 113.1 (t, J = 257.2 Hz), 29.2, 15.2. FT-IR (n
-1
cm
-1
) 3073, 3032, 2968, 2937,
2877, 2353, 2308, 1765, 1610, 1588, 1568, 1507, 1470, 1435, 1418, 1359, 1261, 1241, 1180, 1146, 1077,
232
1223, 927, 851, 784, 777, 741, 645, 551, 419. HRMS (ESI
+
) m/z calculated for C 10H 11F 2O 2 [M+H]
+
: 201.0722;
found 201.0719 (1.49 ppm).
Difluoromethyl 2-iodobenzoate (5-2c):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 2-iodobenzoic
acid 5-1c (248 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was then
sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water (0.40
mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was
then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction mix
was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, the aqueous layer was extracted twice more with DCM (2 x 5 mL), and the organic extracts were
washed individually with H 2O (10 mL). The combined organics were dried with Na 2SO 4, decanted, and
concentrated in vacuo. The crude product was dry loaded on silica gel for purification by flash column
chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in pure hexanes.
The appropriate fractions were combined and concentrated in vacuo to give 5-2c (268 mg, 90% yield) as a
yellow liquid.
1
H NMR (400 MHz, Chloroform-d) δ 8.02 – 7.94 (m, 1H), 7.77 – 7.71 (m, 1H), 7.49 – 7.39 (m,
2H), 7.29 (t, J = 70.7 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -92.1 (d, J = 70.8 Hz).
13
C {
1
H} NMR (126
MHz, Chloroform-d) δ 161.4 (t, J = 3.5 Hz), 135.4, 134.5, 132.6, 128.2, 127.6, 123.5, 113.0 (t, J = 258.9 Hz).
FT-IR (n
-1
cm
-1
) 3032, 2961, 2934, 2910, 2872, 2857, 1763, 1717, 1587, 1571, 1510, 1469, 1434, 1362,
1282, 1240, 1130, 1073, 1020, 960, 860, 778. HRMS (ESI
-
) m/z calculated for C 8H 5F 2IO 2 [M]
-
: 297.9302;
found 297.9289 (4.36 ppm).
233
Difluoromethyl 2-bromobenzoate (5-2d):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 2-
bromobenzoic acid 5-1d (201 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The
vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by
water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00
mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the
reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic
layer was removed, the aqueous layer was extracted twice more with DCM (2 x 5 mL), and the organic
extracts were washed individually with H 2O (10 mL). The combined organics were dried with Na 2SO 4,
decanted, and concentrated in vacuo. The crude product was dry loaded on silica gel for purification by
flash column chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in 3%
EtOAc in hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5-2d (216
mg, 86% yield) as a yellow liquid.
1
H NMR (400 MHz, Chloroform-d) δ 8.01 – 7.96 (m, 1H), 7.77 – 7.72 (m,
1H), 7.49 – 7.39 (m, 2H), 7.29 (t, J = 70.6 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -92.1 (d, J = 70.2 Hz).
13
C {
1
H} NMR (126 MHz, Chloroform-d) δ 161.4 (t, J = 3.4 Hz), 135.4, 134.5, 132.6, 128.2, 127.6, 123.5,
113.0 (t, J = 258.9 Hz). FT-IR (n
-1
cm
-1
) 3072, 3033, 2969, 2938, 2348, 2323, 2313, 2164, 2131, 2123, 2115,
1667, 1606, 1588, 1570, 1511, 1468, 1435, 1361, 1281, 1241, 1132, 1022, 960, 922, 861, 781, 743, 701,
651. HRMS (ESI
-
) m/z calculated for C 8H 5F 2BrO 2 [M]
-
: 249.9441; found 249.9434 (2.80 ppm).
234
Difluoromethyl 4-methoxybenzoate (5-2e):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with KOH
(123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 4-methoxybenzoic
acid 5-1e (152 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was then sealed
with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water
(0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol)
was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction
mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined organics
were dried with Na 2SO 4, decanted, and concentrated in vacuo. The crude product was dry loaded on silica
gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The desired
product eluted in 6% EtOAc in hexanes. The appropriate fractions were combined and concentrated in
vacuo to give 5-2e (166 mg, 82% yield) as a pale yellow liquid.
1
H NMR (400 MHz, Chloroform-d) δ 8.07 –
8.02 (m, 2H), 7.28 (t, J = 71.4 Hz, 1H), 6.98 – 6.94 (m, 2H), 3.89 (s, 3H).
19
F NMR (376 MHz, Chloroform-d)
δ -91.7 (d, J = 71.5 Hz).
13
C {
1
H} NMR (126 MHz, Chloroform-d) δ 164.9, 162.4 (t, J = 3.2 Hz), 132.8, 119.6,
114.3, 113.1 (t, J = 256.8 Hz), 55.7. FT-IR (n
-1
cm
-1
) 3249, 3073, 3033, 2994, 2737, 2710, 2625, 2586, 2522,
2348, 2322, 2305, 2164, 2148, 2121, 1765, 1605, 1510, 1436, 1360, 1318, 1244, 1170, 1135, 1076, 1024,
918, 847, 745, 696, 654. HRMS (ESI
+
) m/z calculated for C 9H 9F 2O 3 [M+H]
+
: 203.0514; found 203.0516 (1.48
ppm).
235
Difluoromethyl 4-vinylbenzoate (5-2f):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with KOH
(123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 4-vinylbenzoic acid 5-
1f (148 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was then sealed with a
crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water (0.40
mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was
then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction mix
was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined organics
were dried with MgSO 4, filtered, and concentrated in vacuo. The crude product was dry loaded on silica
gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The desired
product eluted in 3% EtOAc in hexanes. The appropriate fractions were combined and concentrated in
vacuo to give 5-2f (139 mg, 70% yield) as a pale yellow glass.
1
H NMR (400 MHz, Chloroform-d) δ 8.03 (d,
J = 8.4 Hz, 6H), 7.49 (d, J = 8.2 Hz, 5H), 7.31 (t, J = 71.2 Hz, 1H), 6.76 (dd, J = 17.6, 10.9 Hz, 4H), 5.91 (d, J =
17.6 Hz, 2H), 5.45 (d, J = 10.9 Hz, 2H).
19
F NMR (376 MHz, Chloroform-d) δ -91.8 (d, J = 71.1 Hz).
13
C {
1
H}
NMR (101 MHz, Chloroform-d) δ 162.5 (t, J = 3.2 Hz), 143.8, 135.8, 130.8, 126.5, 117.8, 113.1 (t, J = 257.6
Hz). FT-IR (n
-1
cm
-1
) 3732, 3075, 3034, 1764, 1607, 1589, 1435, 1361, 1264, 1242, 1024, 989, 913, 857, 776,
740, 707, 653, 552, 471, 445. HRMS (ESI
+
) m/z calculated for C 10H 8F 2O 2Li [M+Li]
+
: 205.0647; found
205.0639 (3.90 ppm).
Difluoromethyl 3-ethynylbenzoate (5-2g):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 3-
ethynylbenzoic acid 5-1g (146 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The
236
vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by
water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00
mmol) was then added, and the reaction mix was stirred at r.t. for 20 hours [Note: the reaction was
complete after the standard 2 hours, as determined by
19
F NMR, but for convenience the reaction mixture
was left to stir overnight.]. The vial was then opened, the reaction mix was diluted with DCM (5 mL), and
saturated aqueous NH 4Cl (8 mL) was added. The organic layer was removed, and the aqueous layer was
extracted twice more with DCM (2 x 5 mL). The combined organics were dried with MgSO 4, filtered, and
concentrated in vacuo. The crude product was dry loaded on silica gel for purification by flash column
chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in 5% EtOAc in
hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5-2g (151 mg, 77%
yield) as a colorless liquid.
1
H NMR (400 MHz, Chloroform-d) δ 8.19 (t, J = 1.6 Hz, 1H), 8.05 (dt, J = 8.0, 1.4
Hz, 1H), 7.75 (dt, J = 7.9, 1.4 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 70.8 Hz, 1H), 3.17 (s, 1H).
19
F NMR
(376 MHz, Chloroform-d) δ -91.8 (d, J = 70.9 Hz).
13
C {
1
H} NMR (101 MHz, Chloroform-d) δ 162.0 (t, J = 3.3
Hz), 138.0, 134.0, 130.5, 129.1, 127.8, 123.4, 113.0 (t, J = 259.1 Hz), 82.0, 79.1. FT-IR (n
-1
cm
-1
) 3304, 2926,
2853, 1752, 1712, 1602, 1578, 1480, 1429, 1360, 1266, 1184, 1061, 998, 910, 813, 746, 659, 519, 420.
HRMS (ESI
+
) m/z calculated for C 10H 7F 2O 2 [M+H]
+
: 197.0409; found 197.0416 (3.55 ppm).
Difluoromethyl 3,5-bis(trifluoromethyl)benzoate (5-2h):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 3,5-
bis(trifluoromethyl)benzoic acid 5-1h (258 mg, 1 equiv, 1.00 mmol) under an air
atmosphere. The vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added,
followed quickly by water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309
µL, 2.00 equiv, 2.00 mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial
237
was then opened, the reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was
added. The organic layer was removed, and the aqueous layer was extracted twice more with DCM (2 x 5
mL). The combined organics were dried with MgSO 4, filtered, and concentrated in vacuo. The crude
product was dry loaded on silica gel for purification by flash column chromatography with an eluent system
of hexanes/EtOAc. The desired product eluted in pure hexanes. The appropriate fractions were combined
and concentrated in vacuo to give 5-2h (145 mg, 47% yield) as a colorless liquid.
1
H NMR (600 MHz,
Chloroform-d) δ 8.53 (s, 2H), 8.18 – 8.17 (m, 1H), 7.34 (t, J = 70.1 Hz, 1H).
19
F NMR (470 MHz, Chloroform-
d) δ -63.6 (s, 2F), -91.8 (d, J = 69.7 Hz, 6F).
13
C {
1
H} NMR (126 MHz, Chloroform-d) δ 160.5 (hept, J = 3.5
Hz), 133.1 (q, J = 34.4 Hz), 130.5 (q, J = 3.8 Hz), 129.8, 128.2 (hept, J = 3.6 Hz), 122.8 (q, J = 274.4 Hz), 113.0
(t, J = 260.9 Hz). FT-IR (n
-1
cm
-1
) 3731, 3097, 3075, 3034, 2354, 2349, 2309, 1766, 1589, 1435, 1365, 1278,
1241, 1132, 1081, 1024, 920, 847, 765, 744, 700, 680, 554, 438. HRMS (ESI
+
) m/z calculated for C 10H 4F 8O 2Li
[M+Li]
+
: 315.0238; found 315.0252 (4.44 ppm).
Difluoromethyl (E)-3-(4-chlorophenyl)acrylate (5-2i):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was
charged with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to
addition) and (E)-3-(4-chlorophenyl)acrylic acid 5-1i (183 mg, 1 equiv, 1.00
mmol) under an air atmosphere. The vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50
mL) was added, followed quickly by water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br
(406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was then added, and the reaction mix was stirred at r.t. for 2
hours. The vial was then opened, the reaction mix was diluted with DCM (5 mL), and water (8 mL) was
added. The organic layer was removed, the aqueous layer was extracted twice more with DCM (2 x 5 mL),
and the organic extracts were washed individually with brine (10 mL). The combined organics were dried
with Na 2SO 4, decanted, and concentrated in vacuo. The crude product was dry loaded on silica gel for
238
purification by flash column chromatography with an eluent system of hexanes/EtOAc. The desired
product eluted in 5% EtOAc in hexanes. The appropriate fractions were combined and concentrated in
vacuo to give 5-2i (181 mg, 78% yield) as a colorless solid (m.p. = 58-62°C).
1
H NMR (400 MHz, Chloroform-
d) δ 7.77 (d, J = 16.0 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.42 – 7.34 (m, 2H), 7.19 (t, J = 71.1 Hz, 1H), 6.38 (d, J =
16.0 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -91.9 (d, J = 70.9 Hz).
13
C {
1
H} NMR (126 MHz,
Chloroform-d) δ 162.4 (t, J = 3.3 Hz), 147.5, 137.6, 132.0, 129.8, 129.5, 115.6, 112.7 (t, J = 257.3 Hz). FT-IR
(n
-1
cm
-1
) 3095, 3040, 3033, 2967, 2934, 1767, 1744, 1685, 1633, 1589, 1567, 1412, 1436, 1407, 1362,
1325, 1307, 1275, 1241, 1207, 1075, 1066, 977, 943, 864, 817, 758, 549, 490. HRMS (ESI
+
) m/z calculated
for C 10H 7ClF 2O 2Li [M+Li]
+
: 239.0257; found 239.0254 (1.26 ppm).
Difluoromethyl 4-phenylbutanoate (5-2j):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was
charged with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to
addition) and 4-phenylbutanoic acid 5-1j (164 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial
was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water
(0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol)
was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction
mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined organics
were dried with Na 2SO 4, decanted, and concentrated in vacuo. The crude product was dry loaded on silica
gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The desired
product eluted in 6% EtOAc in hexanes. The appropriate fractions were combined and concentrated in
vacuo to give 5-2j (169 mg, 79% yield) as a pale yellow liquid.
1
H NMR (500 MHz, Chloroform-d) δ 7.30 (t,
J = 7.5 Hz, 2H), 7.24 – 7.20 (m, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.05 (t, J = 71.1 Hz, 1H), 2.69 (t, J = 7.5 Hz, 2H),
239
2.46 (t, J = 7.4 Hz, 2H), 2.01 (p, J = 7.5 Hz, 2H).
19
F NMR (470 MHz, Chloroform-d) δ -92.4 (d, J = 71.3 Hz).
13
C {
1
H} NMR (101 MHz, Chloroform-d) δ 169.7 (t, J = 2.8 Hz), 140.8, 128.7, 128.6, 126.4, 112.4 (t, J = 257.5
Hz), 34.9, 33.2, 25.8. FT-IR (n
-1
cm
-1
) 3731, 3680, 3541, 3524, 3508, 3069, 3031, 2994, 2973, 2935, 2906,
2878, 2321, 2312, 2157, 2123, 1663, 1589, 1568, 1495, 1435, 1361, 1280, 1241, 1071, 917, 744, 700.
HRMS (ESI
+
) m/z calculated for C 11H 13F 2O 2 [M+H]
+
: 215.0878; found 215.0878 (0.00 ppm).
Difluoromethyl 2-phenylacetate (5-2k):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 2-
phenylacetic acid 5-1k (136 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The
vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by
water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00
mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the
reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic
layer was removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined
organics were dried with Na 2SO 4, decanted, and concentrated in vacuo. The crude product was dry loaded
on silica gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The
desired product eluted in 5% EtOAc in hexanes. The appropriate fractions were combined and
concentrated in vacuo to give 5-2k (102 mg, 55% yield) as a pale yellow liquid.
1
H NMR (400 MHz,
Chloroform-d) δ 7.40 – 7.27 (m, 5H), 7.06 (t, J = 70.8 Hz, 1H), 3.75 (s, 2H).
19
F NMR (376 MHz, Chloroform-
d) δ -92.4 (d, J = 70.8 Hz).
13
C {
1
H} NMR (101 MHz, Chloroform-d) δ 167.9 (t, J = 2.7 Hz), 131.8, 129.5, 129.0,
127.9, 112.5 (t, J = 258.9 Hz), 40.8. FT-IR (n
-1
cm
-1
) 3070, 3033, 1768, 1588, 1496, 1434, 1361, 1283, 1241,
1077, 1024, 960, 929, 744, 697. HRMS (ESI
+
) m/z calculated for C 9H 8F 2O 2Li [M+Li]
+
: 193.0647; found
193.0648 (0.52 ppm).
240
Difluoromethyl (3r,5r,7r)-adamantane-1-carboxylate (5-2l):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with KOH
(123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and (3r,5r,7r)-
adamantane-1-carboxylic acid 5-1l (180 mg, 1 equiv, 1.00 mmol) under an air atmosphere.
The vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly
by water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv,
2.00 mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened,
the reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic
layer was removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined
organics were dried with MgSO 4, filtered, and concentrated in vacuo. The crude product was dry loaded
on silica gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The
desired product eluted in 10% EtOAc in hexanes. The appropriate fractions were combined and
concentrated in vacuo to give 5-2l (55 mg, 24% yield) as a pale yellow oil.
1
H NMR (400 MHz, Chloroform-
d) δ 7.04 (t, J = 71.6 Hz, 1H), 2.05 (s, 3H), 1.95 – 1.92 (m, 6H), 1.79 – 1.66 (m, 6H).
19
F NMR (376 MHz,
Chloroform-d) δ -92.5 (d, J = 71.6 Hz).
13
C {
1
H} NMR (101 MHz, Chloroform-d) δ 173.8 (t, J = 2.3 Hz), 112.9
(t, J = 256.9 Hz), 41.0, 38.2, 36.3, 27.7. FT-IR (n
-1
cm
-1
) 2957, 2933, 2909, 2855, 1768, 1756, 1717, 1685,
1507, 1455, 1367, 1217, 1134, 1076, 1047, 977, 903, 771, 726, 538. HRMS (ESI
+
) m/z calculated for
C 12H 16F 2O 2Na [M+Na]
+
: 253.1011; found 253.1018 (2.77 ppm).
Difluoromethyl 2-hydroxy-2-phenylacetate (5-2m):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged
with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 2-
hydroxy-2-phenylacetic acid 5-1m (152.2 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was
then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water
OH
OCF
2
H
O
241
(0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 μL, 2.00 equiv, 2.00 mmol)
was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction
mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, the aqueous layer was extracted twice more with DCM (2 x 5 mL), and the organic extracts were
washed individually with H 2O (10 mL). The combined organics were dried with MgSO4, decanted, and
concentrated in vacuo. The crude product was dry loaded on silica gel for purification by flash column
chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in 40% EtOAc in
hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5-2m (171 mg, 84%
yield) as a colorless liquid.
1
H NMR (399 MHz, Chloroform-d) δ 7.52 – 7.44 (m, 2H), 7.40 (qd, J = 3.7, 1.9
Hz, 3H), 7.15 (t, J = 70.1 Hz, 1H), 3.78 (s, 1H).
13
C NMR (100 MHz, Chloroform-d) δ 170.7 (t, J = 2.7 Hz),
140.2, 128.7, 128.5, 127.3, 112.9 (t, J = 261.8 Hz), 81.3.
19
F NMR (376 MHz, Chloroform-d) δ -91.9 (d, J =
70.1 Hz). FT-IR (n
-1
cm
-1
) 3534, 2352, 2184, 2033, 2011, 1769, 1492, 1359, 1215, 1191, 1133, 1090, 1058,
969, 934, 820, 805, 756, 696, 674, 492, 415. HRMS (ESI
+
) m/z calculated for C 9H 8F 2O 3 [M+H]
+
: 203.0514;
found 203.0511 (1.58 ppm).
S-(difluoromethyl) benzothioate (5-2n):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with KOH
(123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) under an air atmosphere.
The vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added,
followed quickly by water (0.40 mL) and benzothioic S-acid 5-1n (138 mg, 118 µL, 1 equiv, 1.00 mmol), and
the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was then added,
and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction mix was diluted
with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was removed, and
the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined organics were dried with
O SCF
2
H
242
Na 2SO 4, decanted, and concentrated in vacuo. The crude product was dry loaded on silica gel for
purification by flash column chromatography with an eluent system of hexanes/EtOAc. The desired
product eluted in pure hexanes. The appropriate fractions were combined and concentrated in vacuo to
give5- 2n (115 mg, 61 %) as a pale pink liquid.
1
H NMR (400 MHz, Chloroform-d) δ 7.93 – 7.87 (m, 2H),
7.69 – 7.64 (m, 1H), 7.56 – 7.46 (m, 2H), 7.50 (t, J = 55.2 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -99.9
(d, J = 55.2 Hz).
13
C {
1
H} NMR (100 MHz, Chloroform-d) δ 187.4 (t, J = 3.3 Hz), 135.7 (t, J = 2.5 Hz), 134.9,
130.5, 129.2, 128.9, 127.8, 120.7 (t, J = 270.8 Hz). FT-IR (n
-1
cm
-1
) 1754, 1682, 1597, 1579, 1448, 1292,
1208, 1178, 1075, 1056, 892, 788, 769, 682, 645. HRMS (ESI
+
) m/z calculated for C 8H 7F 2OS [M+H]
+
:
189.0180; found 189.0186 (3.17 ppm).
[The regiochemistry of this compound was assigned using IR and
19
F NMR data, which were in agreement
with previous reports of thioesters:
NMR: Org. Chem. Front., 2018, 5, 2163-2166
IR: Beilstein J. Org. Chem. 2015, 11, 1265–1273.]
5-2o: bis(difluoromethyl) 2,2'-disulfanediyldibenzoate
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (246 mg, 4.40 equiv., 4.40 mmol) (ground just prior to addition) and 2,2'-
disulfanediyldibenzoic acid 5-1o (306.4 mg, 1 equiv, 1.00 mmol) under an air
atmosphere. The vial was then sealed with a crimp top septum cap. At r.t. MeCN (5.0
mL) was added, followed quickly by water (0.80 mL), and the mixture was stirred for
30 minutes. TMSCF 2Br (640 μL, 4.00 equiv, 4.00 mmol) was then added, and the reaction mix was stirred
at r.t. for 2 hours. The vial was then opened, the reaction mix was diluted with DCM (10 mL), and saturated
aqueous NH 4Cl (30 mL) was added. The organic layer was removed, the aqueous layer was extracted twice
more with DCM (2 x 10 mL), and the organic extracts were washed individually with H 2O (20 mL). The
S
S
OCF
2
H
O
HF
2
CO
O
243
combined organics were dried with MgSO 4, decanted, and concentrated in vacuo. The crude product was
dry loaded on silica gel for purification by flash column chromatography with an eluent system of
hexanes/EtOAc. The desired product eluted in 40% EtOAc in hexanes. The appropriate fractions were
combined and concentrated in vacuo to give 5-2o (247 mg, 65% yield) as a colorless liquid.
1
H NMR (399
MHz, Chloroform-d) δ 8.17 (dd, J = 7.9, 1.5 Hz, 2H), 7.78 (dd, J = 8.2, 1.1 Hz, 2H), 7.53 (td, J = 7.4, 1.4 Hz,
2H), 7.35 (t, J = 70.8 Hz, 2H), 7.32 (ddd, J = 7.8, 7.3, 1.1 Hz, 2H).
13
C NMR (100 MHz, Chloroform-d) δ 162.3
(t, J = 3.4 Hz), 142.1, 135.0, 132.6, 126.3, 126.2, 124.4, 113.0 (t, J = 259.0 Hz).
19
F NMR (376 MHz,
Chloroform-d) δ -91.2 (d, J = 70.8 Hz). FT-IR (n
-1
cm
-1
) 3411, 3317, 3182, 2978, 2924, 2851, 1707, 1656,
1597, 1454, 1411, 1284, 1179, 1074, 952, 707, 432. HRMS (ESI
+
) m/z calculated for C 16H 10F 4O 4S 2 [M+H]
+
:
407.0029; found 407.0011 (4.42 ppm).
Difluoromethyl (S)-2-(4-isobutylphenyl)propanoate (5-2p):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was
charged with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to
addition) and (S)-2-(4-isobutylphenyl)propanoic acid 5-1p (206 mg, 1 equiv,
1.00 mmol) under an air atmosphere. The vial was then sealed with a crimp top septum cap. At r.t. MeCN
(2.50 mL) was added, followed quickly by water (0.40 mL), and the mixture was stirred for 30 minutes.
TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was then added, and the reaction mix was stirred at
r.t. for 2 hours. The vial was then opened, the reaction mix was diluted with DCM (5 mL), and saturated
aqueous NH 4Cl (8 mL) was added. The organic layer was removed, and the aqueous layer was extracted
twice more with DCM (2 x 5 mL). The combined organics were dried with MgSO 4, filtered, and
concentrated in vacuo. The crude product was dry loaded on silica gel for purification by flash column
chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in 10% EtOAc in
hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5-2p (161 mg, 63%
O
OCF
2
H
244
yield) as a colorless oil.
1
H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H),
7.20 (t, J = 71.2 Hz, 1H), 3.96 (q, J = 7.1 Hz, 1H), 2.66 (d, J = 7.2 Hz, 2H), 2.13 – 1.98 (m, 1H), 1.73 (d, J = 7.3
Hz, 3H), 1.10 (d, J = 6.7 Hz, 6H).
19
F NMR (470 MHz, Chloroform-d) δ -91.9 (dd, J = 179.2, 71.3 Hz, 1F), -92.9
(dd, J = 179.2, 71.1 Hz, 1F).
13
C {
1
H} NMR (126 MHz, Chloroform-d) δ 171.0 (t, J = 2.7 Hz), 141.4, 135.7,
129.8, 127.3, 112.7 (t, J = 257.9 Hz), 45.2, 45.0, 30.3, 22.4, 18.0. FT-IR (n
-1
cm
-1
) 3403, 3072, 3032, 2992,
2967, 2347, 2308, 2129, 2121, 1763, 1667, 1607, 1589, 1511, 1435, 1362, 1317, 1281, 1242, 1130, 1079,
1023, 744, 649. 416. HRMS (ESI
+
) m/z calculated for C 14H 19F 2O 2 [M+H]
+
: 257.1348; found 257.1351 (1.17
ppm).
Difluoromethyl 2-(3-benzoylphenyl)propanoate (5-2q):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was
charged with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to
addition) and 2-(3-benzoylphenyl)propanoic acid 5-1q (254 mg, 1 equiv, 1.00 mmol) under an air
atmosphere. The vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added,
followed quickly by water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309
µL, 2.00 equiv, 2.00 mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial
was then opened, the reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was
added. The organic layer was removed, and the aqueous layer was extracted twice more with DCM (2 x 5
mL). The combined organics were dried with MgSO 4, filtered, and concentrated in vacuo. The crude
product was dry loaded on silica gel for purification by flash column chromatography with an eluent system
of hexanes/EtOAc. The desired product eluted in 5% EtOAc in hexanes. The appropriate fractions were
combined and concentrated in vacuo to give 5-2q (265 mg, 87% yield) as a colorless oil.
1
H NMR (500 MHz,
Chloroform-d) δ 7.82 – 7.78 (m, 2H), 7.76 – 7.71 (m, 2H), 7.63 – 7.58 (m, 1H), 7.56 – 7.46 (m, 4H), 7.05 (t,
J = 70.9 Hz, 1H), 3.89 (q, J = 7.2 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H).
19
F NMR (470 MHz, Chloroform-d) δ -92.2
Ph
O
O
OCF
2
H
245
(dd, J = 179.0, 71.0 Hz, 1F), -92.7 (dd, J = 178.7, 71.5 Hz, 1F).
13
C {
1
H} NMR (126 MHz, Chloroform-d) δ
196.3, 170.4 (t, J = 2.8 Hz), 138.7, 138.4, 137.4, 132.8, 131.6, 130.2, 129.7, 129.4, 129.1, 128.5, 112.6 (t, J
= 258.9 Hz), 45.2, 18.0. FT-IR (n
-1
cm
-1
) 3731, 3508, 3074, 3034, 2993, 1767, 1659, 1589, 1435, 1362, 1281,
1242, 1131, 1079, 1022, 913, 742, 705, 649. HRMS (ESI
+
) m/z calculated for C 17H 15F 2O 3 [M+H]
+
: 305.0984;
found 305.0983 (0.33 ppm).
Difluoromethyl (S)-2-(6-methoxynaphthalen-2-yl)propanoate (5-2r):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was
charged with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to
addition) and (S)-2-(5-methoxynaphthalen-2-yl)propanoic acid 6-1r (230
mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial was then sealed with a crimp top septum cap.
At r.t. MeCN (2.50 mL) was added, followed quickly by water (0.40 mL), and the mixture was stirred for 30
minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv, 2.00 mmol) was then added, and the reaction mix was
stirred at r.t. for 2 hours. The vial was then opened, the reaction mix was diluted with DCM (5 mL), and
saturated aqueous NH 4Cl (8 mL) was added. The organic layer was removed, and the aqueous layer was
extracted twice more with DCM (2 x 5 mL). The combined organics were dried with MgSO 4, filtered, and
concentrated in vacuo. The crude product was dry loaded on silica gel for purification by flash column
chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in 5% EtOAc in
hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5-2r (188 mg, 67%
yield) as a beige solid (m.p. = 61-64°C).
1
H NMR (400 MHz, Chloroform-d) δ 7.74 (t, J = 8.0 Hz, 2H), 7.70 –
7.66 (m, 1H), 7.40 (dd, J = 8.5, 1.9 Hz, 1H), 7.19 (dd, J = 8.9, 2.5 Hz, 1H), 7.14 (d, J = 2.6 Hz, 1H), 7.07 (t, J =
71.0 Hz, 1H), 3.98 – 3.91 (m, 4H), 1.65 (d, J = 7.1 Hz, 3H).
19
F NMR (376 MHz, Chloroform-d) δ -91.9 (dd, J
= 179.0, 71.1 Hz, 1F), -92.8 (dd, J = 178.9, 71.1 Hz, 1F).
13
C {
1
H} NMR (126 MHz, Chloroform-d) δ 170.9 (t,
J = 2.7 Hz), 158.0, 134.1, 133.5, 129.4, 129.0, 127.6, 126.4, 125.8, 119.4, 112.7 (t, J = 258.1 Hz), 105.7,
O
O
OCF
2
H
246
55.2, 45.2, 17.9. FT-IR (n
-1
cm
-1
) 2990, 2941, 1770, 1630, 1604, 1505, 1485, 1453, 1438, 1392, 1379, 1348,
1325, 1267, 1227, 1173, 1096, 1079, 1055, 1026, 928, 855, 820, 791, 761, 458, 420. HRMS (ESI
+
) m/z
calculated for C 15H 15F 2O 3 [M+H]
+
: 281.0984; found 281.0986 (0.71 ppm).
Difluoromethyl (tert-butoxycarbonyl)-L-leucinate (2s):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged
with KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and (tert-
butoxycarbonyl)-L-leucine 5-1s (116 mg, 1 equiv, 0.50 mmol) under an air
atmosphere. The vial was then sealed with a crimp top septum cap. At r.t. MeCN (1.25 mL) was added,
followed quickly by water (0.20 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (203 mg, 155
µL, 2.00 equiv, 1.00 mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial
was then opened, the reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was
added. The organic layer was removed, and the aqueous layer was extracted twice more with DCM (2 x 5
mL). The combined organics were dried with Na 2SO 4, decanted, and concentrated in vacuo. The crude
product was dry loaded on silica gel for purification by flash column chromatography with an eluent system
of hexanes/EtOAc. The desired product eluted in 10% EtOAc in hexanes. The appropriate fractions were
combined and concentrated in vacuo to give 5-2s (90 mg, 64% yield) as a colorless oil.
1
H NMR (400 MHz,
Chloroform-d) δ 7.07 (t, J = 70.8 Hz, 1H), 4.82 (d, J = 6.2 Hz, 1H), 4.40 – 4.25 (m, 1H), 1.83 – 1.69 (m, 1H),
1.70 – 1.60 (m, 1H), 1.60 – 1.51 (m, 1H), 1.44 (s, 9H), 0.97 (d, J = 2.0 Hz, 3H), 0.96 (d, J = 1.9 Hz, 3H).
19
F
NMR (376 MHz, Chloroform-d) δ -91.1 (dd, J = 178.5, 71.3 Hz, 1F), -93.2 (dd, J = 178.4, 70.3 Hz, 1F).
13
C
{
1
H} NMR (101 MHz, Chloroform-d) δ 170.0 (t, J = 2.7 Hz), 155.5, 112.6 (t, J = 259.4 Hz), 80.7, 40.7, 28.4,
24.9, 22.9, 21.7. FT-IR (n
-1
cm
-1
) 3443, 3412, 3404, 3319, 3009, 2964, 2936, 2874, 1780, 1708, 1503, 1455,
1389, 1366, 1272, 1253, 1219, 1164, 1066, 959, 928, 769, 666, 579, 493, 423. HRMS (ESI
+
) m/z calculated
for C 12H 22F 2NO 4 [M+H]
+
: 282.1511; found 282.1504 (2.48 ppm).
Boc
H
N
O
OCF
2
H
247
Difluoromethyl phenylalaninate (5-2t)
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and
phenylalanine 5-1t (165.2 mg, 1 equiv, 1.00 mmol) under an air atmosphere. The vial
was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly by water
(0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 μL, 2.00 equiv, 2.00 mmol)
was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened, the reaction
mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic layer was
removed, the aqueous layer was extracted twice more with DCM (2 x 5 mL), and the organic extracts were
washed individually with H 2O (10 mL). The combined organics were dried with MgSO4, decanted, and
concentrated in vacuo. The crude product was dry loaded on silica gel for purification by flash column
chromatography with an eluent system of hexanes/EtOAc. The desired product eluted in 80% EtOAc in
hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5-2t (90 mg, 42%
yield) as a colorless liquid.
1
H NMR (399 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.38 – 7.28 (m, 3H), 7.18 – 7.12
(m, 2H), 7.08 (dd, J = 70.2, 69.6 Hz, 1H), 5.91 (s, 1H), 5.05 (dt, J = 7.8, 6.0 Hz, 1H), 3.44 – 3.01 (m, 2H).
13
C
NMR (100 MHz, Chloroform-d) δ 167.7 (dd, J = 3.2 Hz), 134.4, 129.3, 129.1, 127.9, 112.5 (dd, J = 261.5,
260.0 Hz), 51.6, 37.0.
19
F NMR (376 MHz, Chloroform-d) δ -90.7 (dd, J = 178.4, 70.9 Hz), -93.1 (dd, J = 178.5,
69.6 Hz). FT-IR (n
-1
cm
-1
) 2961, 2353, 2039, 2009, 2005, 1779, 1685, 1493, 1258, 1088, 1020, 869, 796, 759,
677. HRMS (ESI
+
) m/z calculated for C 10H 11F 2NO 2 [M+H]
+
: 216.0514; found 203.0511 (1.58 ppm).
H
2
N
O
O
F
F
Ph
248
Difluoromethyl 2-hydroxybenzoate (5-2u):
An oven dried 5 mL crimp top vial equipped with magnetic stir bar was charged with
KOH (123 mg, 2.20 equiv., 2.20 mmol) (ground just prior to addition) and 2-
hydroxybenzoic acid (5-1u) (138 mg, 1 equiv, 1.00 mmol) under an air atmosphere.
The vial was then sealed with a crimp top septum cap. At r.t. MeCN (2.50 mL) was added, followed quickly
by water (0.40 mL), and the mixture was stirred for 30 minutes. TMSCF 2Br (406 mg, 309 µL, 2.00 equiv,
2.00 mmol) was then added, and the reaction mix was stirred at r.t. for 2 hours. The vial was then opened,
the reaction mix was diluted with DCM (5 mL), and saturated aqueous NH 4Cl (8 mL) was added. The organic
layer was removed, and the aqueous layer was extracted twice more with DCM (2 x 5 mL). The combined
organics were dried with MgSO 4, filtered, and concentrated in vacuo. The crude product was dry loaded
on silica gel for purification by flash column chromatography with an eluent system of hexanes/EtOAc. The
desired product eluted in 7% EtOAc in hexanes. The appropriate fractions were combined and
concentrated in vacuo to give 5-2u (71 mg, 38% yield) as a yellow oil.
1
H NMR (500 MHz, Chloroform-d) δ
9.94 (s, 1H), 7.88 (dd, J = 8.0, 1.7 Hz, 1H), 7.56 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.30 (t, J = 70.4 Hz, 1H), 7.03
(dd, J = 8.4, 1.1 Hz, 1H), 6.99 – 6.90 (m, 1H).
19
F NMR (470 MHz, Chloroform-d) δ -91.9 (d, J = 70.5 Hz).
13
C
{
1
H} NMR (126 MHz, Chloroform-d) δ 166.6 (t, J = 3.6 Hz), 162.7, 137.8, 130.5, 120.0, 118.2, 112.6 (t, J =
259.8 Hz), 110.1. FT-IR (n
-1
cm
-1
) 3300, 3145, 3031, 2961, 2934, 2912, 2873, 2857, 2370, 2349, 2314, 1772,
1701, 1616, 1579, 1511, 1484, 1465, 1390, 1365, 1296, 1249, 1210, 1121, 1067. HRMS (ESI
+
) m/z
calculated for C 8H 7F 2O 3 [M+H]
+
: 189.0358; found 189.0361 (1.58 ppm).
HO
O OCF
2
H
249
Chapter 6: Regioselective monofluoromethylation of aryliodonium salts using
fluorobis(phenylsulfonyl)methane (FBSM)
Shortly after our success in developing new difluoromethylation reactions, we were invited to
author a review on the syntheses and uses of fluorobis(phenylsulfonyl)methane: a pronucleophile for the
generation of a protected monofluoromethyl group.
310
Our literature compilation revealed that there are
very few methods to access monofluoromethyl arenes, and fewer still involving the addition of a
monofluoromethyl group. Further encouraging this new venture into monofluoromethyl compounds was
a mini review article by Reichel and Karaghiosoff on the need for new monofluoromethylation
procedures,
8
specifically reagent systems which can regioselectively fluoromethylate target molecules.
6.i Introduction
The incorporation of the monofluoromethyl group into biologically active molecules to impart
modified physicochemical properties to them is an emerging trend within the scientific community.
8
The
monofluoromethyl group has been successfully utilized as a bioisostere of numerous functionalities
including –CH 3, –CH 2OH, –CH 2NH 2, –C 2H 5, –CH 2NO 2 and –CH 2SH.
207,311,312
This increasing demand for
monofluoromethyl compounds has been met with the development of a plethora of monofluorination
strategies, wherein a single fluorine atom is added to the molecule.
313
See the enclosed references for
examples.
189,314,315
This strategy follows straightforward reaction pathways: 1) a deprotonation followed
by electrophilic fluorination or 2) the addition of H–F across an alkene unit.
250
Scheme 6.1 Approaches to access monofluoromethyl compounds via direct fluorination
On the other hand, monofluoromethylation strategies offer the added advantage of being able to
extend the carbon skeleton of the molecule by one carbon atom. Monofluoromethylarenes constitute an
important class of pharmacologically relevant fluorinated structures and have been the focus of many
recent synthetic studies. Numerous transition metal-mediated monofluoromethylation reactions have
been published (Scheme 6.2). The first reaction of this type was presented by Suzuki and coworkers in
2009, wherein fluoroiodomethane was used as a source of the monofluoromethyl unit (Scheme 6.2 a).
316
Phenyldifluoromethane was produced in 57% yield from the Pd catalyzed reaction of phenylboronic acid
with iodofluoromethane. It is important to note that the authors use 40 equivalents of phenylboronic
acid, which renders the method impractical. Qing and coworkers later delineated a Pd(II)-catalyzed cross-
coupling reaction of aryl boronic acids with ethyl bromofluoroacetate (Scheme 6.2 b).
317
Zinc
monofluoromethylsulfinate was demonstrated by Baran and coworkers as a potent source of
monofluoromethyl radical for the C(sp
2
)—H monofluoromethylation of N-heterocycles under oxidative
conditions (Scheme 6.2 c).
318
Hu and workers later published a (2-pyridylsulfonyl)fluoromethylation of
iodoarenes (Scheme 6.2 d).
319
(2-pyridylsulfonyl)fluoroiodomethane was used as the
monofluoromethylation reagent, which was first reduced by zinc metal to form the zinc-fluoromethyl
complex. Subsequent addition of copper iodide produced the active fluoromethylating species [Cu—
CFH—SO2—2Py], which reacts with the aryl iodide to furnish the desired product. A similar approach was
later published by Hu wherein a benzoyl derivative of the sulfone reagent was used (Scheme 6.2 e).
320
EWG EWG EWG EWG
F
base
EWG EWG
electrophilic
fluorination
reagent
1)
H
+
F
—
source
2)
R
2
R
1
R
4
R
3
R
2
R
1
R
4
R
3
F H
251
Scheme 6.2 Prior art on the synthesis of monofluoromethylarenes via monofluoromethylation of
functionalized arenes
I F
+ B
O
O
(40 equiv)
[Pd
2
(dba)
3
]/P(o-CH
3
C
6
H
4
) (1:6)
K
2
CO
3
, DMF, 5 min, 60 oC
(57%)
F
a.
b. B
OH
OH
R
+
F
Br
OEt
O
Pd(OAc)
2
(5 mol %), PPh
3
(20 mol %)
K
3
PO
4
3H
2
O, toluene (0.1 M)
100
o
C, 3 h
R
F
O
OEt
c. het
+
O
Zn
O
O
CFH
2
CFH
2
O
O
O H
aq. solvent
het CFH
2
d.
I
R
1
+
I S
F
O O
N
Et
2
Zn, CuI
R
1
S
F
O O
N
e.
I
R
1
+
F S
O O
N
NaHCO
3
CuTc (30 mol %)
R
1
S
F
O O
N
O R
f.
B
R
1
OH
OH
+ H
2
CFBr
NiCl
2
DME (5 mol %)
phenanthroline (5 mol %)
DMAP (10 mol %)
K
2
CO
3
(2.0 equiv)
DME/dioxane, 70
o
C
R
1
F
g.
B
R
1
+ CH
2
FI
Pd
2
(dba)
3
(5 mol %)
P(o-toluene)
3
(20 mol %)
H
2
O (5 equiv), Cs
2
CO
3
(1.5 equiv)
R
1
F
O
O
h.
F
O
OEt
+
[RuCl
2
(p-cymene)]
2
(5 mol %)
Pd(PPh
3
)
4
, 90
o
C, 1,4-dioxane
X N
R
Br
X N
R
CH
2
F
i.
I
R
1
+
NiI
2
(10 mol %), ligands
Mn, DMAc, 40
o
C
R
1
F
I
F
Bn
Bn
j.
R
+
[Ru(p-cymene)Cl
2
)]
2
(5 mol %)
Na
2
CO
3
(2 equiv), AgNTf
2
(20 mol %)
N-Ac-L-Iso (30 mol %)
Ar, DCE, 150
o
C, 48 h
BrHCFCO
2
Et (3 equiv)
R
1
R
2
I
F
Bn
H
N
R
2
OMe
N
OMe
CO
2
Et
F
252
Bromofluoromethane (Scheme 6.2 f) and iodofluoromethane (Scheme 6.2 g) have been
employed in transition metal catalyzed reactions with aryl boron compounds, furnishing
monofluoromethylarenes.
321,322
A similar report from Wang and coworkers employs
(phenylsulfonyl)fluoroiodomethane as the monofluoromethyl source.
323
The groups of Wang and
Ackermann developed meta-selective monofluoromethylation procedures using ethyl
bromofluoroacetate (Scheme 6.2 h).
324,325
1-Iodo-1-fluoro-2-phenylethane has been used as a
fluoromethyl source in reactions with iodoarenes and ketoximes (Scheme 6.2 i and j).
326,327
It is evident
that there are no reported transition metal-free syntheses of arylfluoromethanes. Such a method would
provide great cost benefits by bypassing the need for expensive and toxic metal catalysts and ligands.
Furthermore, the need for strictly anhydrous conditions in these methods poses practicality and
accessibility issues. Our goal was the development of an accessible, cost-effective and transition metal-
free synthesis of these valuable compounds. We relied on the rich history of aryliodonium salts, which
have been used as electrophilic arylation reagents for the arylation of nucleophiles. These reagents are
conveniently prepared via bench-top procedures from the corresponding iodoarene.
328–330
We envisioned
a straightforward reaction pathway wherein a nucleophilic masked monofluoromethyl unit could react
with the electrophilic aryliodonium salt to form the desired product (See Scheme 6.3).
Scheme 6.3 This work: direct nucleophilic monofluoromethylation of aryliodonium salts
X I Ar
2
Ar
1
X Y
F
X
Y
F
Ar
1
X,Y = removable groups for the stabilization of the anion
253
6.ii Results and Discussions
Our initial studies utilized fluorobis(phenylsulfonyl)methane as the nucleophilic
fluoromethylation reagent. The enhanced acidity of the compound allows for its deprotonation under
mild conditions. Diphenyliodonium trifluoroacetate (6-1a-TFA) was chosen as the model substrate. Table
6.1 summarizes the optimization experiments performed on 6-1a-TFA. With one equivalent of FBSM and
1.2 equivalents of K 2CO 3 in toluene with 30 mol % of TBACl (tetrabutylammonium chloride), only 10% of
the desired product 6-2a was obtained at 100
o
C (trial 1). Substituting toluene with DMF afforded 9% of
6-2a (trial 2). Acetonitrile was found to be an even less compatible solvent, furnishing only 6% of the
desired product (trial 3). Even in the presence of the phase transfer reagent TBACl, no conversion of 6-1a-
TFA to the desired product was observed in water (trial 4). Increasing the temperature of the reaction to
120
o
C proved detrimental to the reaction outcome when using K 2CO 3 (trial 5). However, when Cs 2CO 3
was used at 120
o
C in place of K 2CO 3, 6-2a was produced in 41% yield highlighting the importance of Cs
+
in the reaction (trial 6). Running trial 6 in DMF instead of toluene only afforded 25% of 6-2a (trial 7). In
acetonitrile, the yield dropped further down to 7% (trial 8). Running the reaction in water with sub-
stoichiometric loading of TBACl produced 21% of the desired product (when considering the amount of
unreacted FBSM) (trial 9). At this point, it appears that polar, coordinating solvents are unfavorable for
this monofluoromethylation procedure. Since these reactions are run at high temperatures, highly
coordinating and nucleophilic solvents like DMF and MeCN could react with and decompose the
aryliodonium salt. This would explain why a weakly coordinating aprotic solvent like toluene is more
suitable for the transformation. At 120
o
C, 1.2 equivalents of Cs 2CO 3 as the base facilitated a smooth
reaction between the substrate 6-1a-TFA and 2 equivalents of FBSM, yielding 6-2a in 72% yield by
19
F NMR
(trial 10). Interestingly, increasing the equivalents of FBSM to 2.5 decreased the yield to 57% (trial 11). At
this stage of the project, it is unclear as to what causes the drop in yield with higher loadings of FBSM.
254
Table 6.1 Optimization table using diphenyliodonium trifluorocaetate (6-1a-TFA)
a
a
Reactions performed at 0.5 mmol scale.
To extend the utility of this method, non-symmetric diaryliodonium salt 6-1a-TMBTFA was used
as the substrate. See table 6.2 for an overview of the exploratory process. With 1.2 equivalents of FBSM,
48% of the desired product was observed (trial 1). Decreasing the temperature to 100
o
C reduced the yield
to 25% (trial 2), with a large amount of FBSM left unreacted.
I
—
OCOCF
3
conditions
S S
F
Ph Ph
O
OO
O
SO
2
Ph
SO
2
Ph
F
6-1a-TFA 6-2a
FBSM
255
Table 6.2 Optimization table using phenyl(trimethoxyphenyl)iodonium trifluoroacetate (6-1a-TMBTFA)
a
a
Reactions performed at 0.5 mmol scale. NMR yield determined using fluorobenzene as an internal standard
Increasing the reaction time at 100
o
C from 1 hour to 2 hours did not improve the yield noticeably
(trial 3). Next, equivalents of base were varied. Higher loading of base decreased the yield of the reaction
notably (trials 4 and 5), as did decreasing the amount of base added (trial 6). Under conditions similar to
trial 1, when FBSM was used as the limiting reagent (0.7 equivalents), only 33% of 6-2a was observed (trial
I
—
OCOCF
3
conditions
S S
F
Ph Ph
O
OO
O
SO
2
Ph
SO
2
Ph
F
6-1a-TMBTFA
6-2a
FBSM
OMe
OMe MeO
256
7). Lowering the ratio of FBSM to 6-1a-TMBTFA afforded comparable yields to trial 7 with no significant
improvement. The addition of 18-C-6 offered a slightly higher conversion to 6-2a as compared to trial 1
(see trial 9). Cu(II)SO 4.5H 2O however was not a suitable additive, severely impacting the reaction yield as
shown in trial 10. The addition of TBACl did not improve yields either. Finally, NaH was found to be an
incompatible base for the transformation (trial 13).
Table 6.3 Optimization table using diphenyliodonium triflate (1a-OTf)
a
a
Reaction performed at 0.5 mmol scale
The reaction parameter we tested next was the nature of the counteranion of the aryliodonium
salt and its effect on the reaction outcome. Table 6.3 summarizes our efforts in using diphenyliodonium
triflate as the substrate. We observed that unlike 6-1a-TFA, 6-1a-OTf was not compatible with Cs 2CO 3.
The carbonate base was therefore replaced with NaH. In the case of 6-1a-OTf, the reaction yield was
capped at 58%. Adding over 1.2 equivalents of FBSM did not improve the reaction yield significantly. The
current working hypothesis is that a more strongly bound anion imparts greater stability to the iodonium
I
TfO
—
conditions
S S
F
Ph Ph
O
O O
O
SO
2
Ph
SO
2
Ph
F
6-1a-OTf 6-2a
FBSM
257
salt. Accordingly, the triflate anion imparts less stability to the iodonium complex 6-1a than
trifluoroacetate. Nonetheless, with the appropriate choice of base, 6-2a can be obtained from 6-1a-OTf
in moderate yield.
6.iii Future Directions
These results demonstrate the feasibility of a transition metal-mediated synthesis of masked
monofluoromethyl arenes. Going forward, further tolerance of different counter-anions will be tested.
Scheme 6.4 shows the structures of other classes of diaryliodonium salts that will be tested in the same
manner as the ones discussed above. The molecules have been organized in order of decreasing
coordination strength of the anion with the iodonium center. If the previously observed trend holds true,
a more coordinating anion should provide higher yields of the desired product, and the yields should be
in order of yield 6-1a-OMs > yield 6-1a-OTs > yield 6-1a-BF4 > yield 6-1a-PF6.
Scheme 6.4 Proposed diaryliodonium salts to probe counter anion effects
After we determine the optimal anion for the transformation, efforts will be focused on finding
the optimal monofluoromethylation reagent. Scheme 6.5 shows the structures that will be investigated
and whose results will be compared to the yields obtained from FBSM.
I
—
OSO
2
Me
6-1a-OMs
I
—
OSO
2
(p-C
6
H
4
CH
3
)
6-1a-OTs
I
BF
4
—
6-1a-BF
4
I
PF
6
—
6-1a-PF
6
258
Scheme 6.5 Alternative monofluoromethylation reagents to contrast with FBSM
Upon determining the optimal anion and monofluoromethyl source, functional group tolerance
will be tested. Finally, biologically relevant molecules will be subjected to this methodology.
6.iv Conclusion
This work will be the first transition metal-free synthesis of monofluoromethyl arenes. The
method utilized readily available chemicals, and the syntheses of the required reagents can be performed
in large scale with commodity chemicals. Current results indicate the feasibility of a metal-free approach.
Future work will investigate the impact of the identity of the iodonium salt and the
monofluoromethylation reagent on the reaction outcome.
F
S O O
O
F
S O O
N
O
F
S O O
N
S
O
O
N
F
O
O
S
S
O
O
O
O
F
F
S
S
O
O
FDBzM
BzPySM FB2-PSM
cFBSM FTSM
BzPhSM
259
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Abstract (if available)
Abstract
Fluorinated organic matter has become an integral part of our society. It is found in materials, drugs, and numerous other substances which influence and elevate the human condition. In stark contrast to their overwhelming utility, organofluorine compounds are almost absent in nature. This makes organofluorine chemistry a purely synthetic field. As a graduate student in the Prakash Lab at the Loker Hydrocarbon Research Institute, my research focused on the development of efficient routes to fluorofunctionalize organic molecules of pharmaceutical and agricultural relevance. The first two chapters of this work detail new routes to access fluorine-containing N-heterocyclic molecules. The next three chapters look at novel difluoromethylenation reactions using silane-derived difluorocarbene. Finally, the thesis winds up with a discussion of preliminary studies into a novel synthesis of monofluoromethyl arenes.
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Krishnamurti, Vinayak
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Investigations into novel (per)fluoromethylations of organic molecules
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College of Letters, Arts and Sciences
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Doctor of Philosophy
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Chemistry
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04/16/2021
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carboxylic acids,difluoromethyl,enamides,fluorine,fluorofunctionalization,methodology,monofluoromethyl,OAI-PMH Harvest,phosphonates,trifluoromethyl
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methodology
monofluoromethyl
phosphonates
trifluoromethyl