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Harnessing fluorinated C1 nucleophilic reagents for the direct fluoroalkylation of ubiquitous C(sp2)-X and C(sp)-H centers
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Harnessing fluorinated C1 nucleophilic reagents for the direct fluoroalkylation of ubiquitous C(sp2)-X and C(sp)-H centers
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Content
Harnessing fluorinated C1 nucleophilic reagents for the direct fluoroalkylation of
ubiquitous C(sp2)-X and C(sp)-H centers
By
XANATH ISPIZUA RODRIGUEZ
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 2023
Copyright 2023 XANATH ISPIZUA RODRIGUEZ
ii
Dedication
This dissertation is dedicated to my parents, Iñaki Ispizua Gil and Xanath Rodriguez Vega for
their unconditional love and support.
“It's the questions we can't answer that teach us the most. They teach us how to think. If you
give a man an answer, all he gains is a little fact. But give him a question and he'll look for his
own answers.”
― Patrick Rothfuss, The Wise Man's Fear
iii
Acknowledgements
First and foremost, I would like to express my gratitude and admiration to my mentor, Prof. G.K.
Surya Prakash. I will be forever grateful for his guidance, his kindness and fatherly advice. I am
so incredibly lucky to have pursued my graduate studies in his group where I was encouraged to
fully explore my scientific curiosity and where I grew not only as a scientist, but also as a person.
Thank you, Prof. Prakash, for always looking out for your students, and for providing a safe and
collaborative environment for people to reach their full potential. Your wisdom and kind-
heartedness will always be an example for everyone that crosses your path. I would also like to
acknowledge Prof. Francisco Valero, without whom I wouldn’t be at USC in the first place. Thank
you for your commitment to support and advocate for students from Mexico, and for your initiative
to increase diversity at the university. It is professors like you that make a difference in the world.
I also want to thank Professor Juan Rodrigo Salazar for being so instrumental in my academic
journey, for teaching me all the foundations of organic chemistry and for introducing me to
research by taking me under his wing. It is because of you that I decided to pursue research and
for that, I’m forever grateful. Thank you for being a mentor and a friend. I want to thank Professor
Rodolfo Álvarez Manzo not only for his tough classes and insightful conversations, but for
spending the summer before I left for my Ph.D. teaching me advanced inorganic chemistry so
that I could be well prepared. You are an outstanding professor and friend.
A special thank you to my best friend, collaborator, colleague, and husband, Dr. Vinayak
Krishnamurti. Your unwavering support, love, and care got me through the toughest times.
Without you by my side, I wouldn’t have been able to be so productive and motivated. You are a
blessing in my life, and I continue my journey reassured that my soulmate will be holding my hand
along the way. A big thank you to my friend Colby Barret. You made this chapter of my life so fun
iv
and enjoyable. Thank you for being there for me in so many different capacities. You, Vinayak
and I will always be “The three musketeers” as Prof. Prakash would call us.
I would like to thank Prof. Chao Zhang for being a member of all my committees and for asking
me the hardest chemistry questions, always challenging me to look further. Thank you to Dr.
Thomas Matthew for being so supportive, so kind, and helpful throughout my studies. I also want
to acknowledge Dr. Robert Aniszfeld, Dr. Alain Goeppert and Dr. Patrice Batamack for always
lending me a helping hand with a kind smile. Thank you to the LHI staff Jessy May, Carole Phillips,
David Hunter, Michele Dea, and Gloria Canada. It is because of you that the labs run smoothly,
and I’m thankful for all your hard work. My gratitude goes towards USC chemistry department,
the Loker Hydrocarbon Research Institute, and the Gilead Foundation for their financial support
during my Ph.D. I would also like to acknowledge past members of the group, and my lab mates
and friends at USC. Ziyue, Matt, Alex, Van, Aleique, CJ, Raktim, Naz, Daniel, JP, Vicente,
Antonio. Thank you for being there for me, for discussing chemistry, exchanging chemicals with
me, and for being someone to vent with when life got stressful. A special thanks to my friends
back home for bearing with me during my Ph.D: Charly, Poshi, Dany, Angela, Muñoz, Bibbins,
Mich, Jorge, Dani, Nico, and many others, I love and appreciate you always. Thank you for not
allowing the distance and hectic life situations to weaken our bond. I want to acknowledge my
own mentors and my undergraduate students for helping me grow and learn how to be a better
scientist. Moreover, thank you to my first friend and roommate in Los Angeles, Brandon Simpson.
You became my brother and made my first year in a new country unforgettable.
Thank you to my parents-in-law, Dr. Hemalatha Krishnamurti and Dr. Ramesh Krishnamurti, and
sister-in-law (Manii) Harini Krishnamurti. Your love, acceptance, and support mean the world to
me (and thank you for proof-reading my thesis). Finally, the biggest thank you to my family. My
dear parents, Xanath and Iñaki. I don’t have enough words to thank you for always believing in
me, supporting me, picking me up when I was down, and for raising me to be a strong but kind
woman. You two are my biggest motivation and I hope I’ve done you proud. Thank you for always
v
working tirelessly to provide me the best life possible and for making sure I had the best education.
Mamá, you are a true example of a strong, intelligent, and compassionate human. You are my
best friend and I aspire to be half the woman you are. Papá, you are my biggest cheerleader, my
role model, and my confidante. Thank you for your continuous teachings and enormous heart.
This is a chapter we all close together, for this was a group effort. My team, thank you for
everything.
vi
Table of Contents
Dedication ...................................................................................................................................... ii
Acknowledgements ...................................................................................................................... iii
List of Schemes: ......................................................................................................................... viii
List of Tables: ............................................................................................................................... xi
List of Figures: ............................................................................................................................. xii
List of Images: ............................................................................................................................ xiii
List of equations: ........................................................................................................................ xiv
Permissions: ................................................................................................................................ xv
Abstract: ..................................................................................................................................... xvi
Preface: Research overview ..................................................................................................... xviii
List of publications: ...................................................................................................................... xx
CHAPTER 1: INTRODUCTION .................................................................................................... 1
1.1 The fluorine atom. Introduction and relevance of fluorine in the pharmaceutical context ... 1
1.2 Monofluoromethylation strategies ....................................................................................... 5
1.3 Difluoromethylation strategies .......................................................................................... 18
1.4 Trifluoromethylation strategies ......................................................................................... 65
CHAPTER 2: Copper-mediated Synthesis of Trifluoromethyl ketones from Carboxylic Acids
by Cross-Coupling with Acyloxyphosphonium Ions .................................................................... 73
2.1 Introduction and prior art in the synthesis of trifluoromethyl ketones ............................... 73
2.2 Optimization of the trifluoromethylation reaction .............................................................. 75
2.3 Substrate scope: aliphatic and aromatic trifluoromethyl ketones. CF3- containing
active pharmaceutical ingredients .......................................................................................... 81
2.4 Mechanistic studies .......................................................................................................... 83
2.5 Conclusion ........................................................................................................................ 94
2.6 Experimental data ............................................................................................................. 94
CHAPTER 3: Copper/Zinc-mediated Synthesis of difluoromethyl ketones via
Acyloxyphosphonium Ions and catalytic approach ................................................................... 105
3.1 Introduction and prior art in the synthesis of difluoromethyl ketones .............................. 105
3.2 Optimization difluoromethylation reaction ....................................................................... 107
3.3 Substrate scope: difluoromethyl ketones. CF2H-containing active pharmaceutical
ingredients ............................................................................................................................ 110
3.4 Mechanistic considerations ............................................................................................ 113
vii
3.5 Conclusion ...................................................................................................................... 115
3.6 Experimental data ........................................................................................................... 115
CHAPTER 4: Copper-catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl
Acetylenes and their Applications in Intramolecular Cyclization and cycloaddition reactions
for the Preparation of CF2H-Heterocycles ................................................................................ 129
4.1 Introduction and prior art in the synthesis of difluoromethyl alkynes .............................. 129
4.2 Optimization of the difluoromethylation reaction ............................................................. 132
4.3 Substrate scope of difluoromethyl alkynes form terminal and silyl acetylenes ............... 134
4.4 Mechanistic considerations and proposal ....................................................................... 137
4.5 Derivatization reactions with difluoromethyl alkynes ...................................................... 138
4.6 Tandem difluoromethylation-intramolecular cyclization .................................................. 139
4.6.1 Prior art on the synthesis of 2-CF2H indoles ............................................................ 139
4.6.2 Optimization of the tandem difluoromethylation-intramolecular cyclization ............. 141
4.6.3 Mechanistic considerations of the tandem difluoromethylation-intramolecular
cyclization ......................................................................................................................... 150
4.7 Conclusion ...................................................................................................................... 152
4.8 Experimental Data .......................................................................................................... 153
CHAPTER 5: Direct synthesis of monofluoromethyl ketones from carboxylic acids
derivatives and fluoromethyl anion surrogates ......................................................................... 181
5.1 Introduction and prior art in the synthesis of fluoromethyl ketones ................................ 181
5.2 Optimization of the fluoromethylation reaction with FBSM ............................................. 185
5.3 Desulfonylation reaction: challenge of the magnesium mediated reduction ................... 194
5.4 Preliminary studies of the reaction with FBDT ................................................................ 199
5.5 Mechanistic considerations ............................................................................................ 199
5.6 Conclusion and outlook .................................................................................................. 200
5.7 Experimental data ........................................................................................................... 200
References: .............................................................................................................................. 212
viii
List of Schemes:
• Scheme A: Chemistry with carboxylic acids…………………………………………………... xviii
• Scheme B: Copper catalysis………………………………………………….......................... xix
• Scheme C: Carbene chemistry …………………………………………………...................... xix
• Scheme 1.1: Reagents for monofluoromethylation of C, N, S, or O centers………………… 6
• Scheme 1.2: Large-scale synthesis of FBSM…………………………………………………... 6
• Scheme 1.3: FBSM as a masked nucleophile………………………………………………….. 7
• Scheme 1.4: Addition of FBSM derivatives to Michael acceptors……………………………. 8
• Scheme 1.5: Pd or Ir catalyzed fluoromethylation with FBSM………………………………… 10
• Scheme 1.6:
SN2 reactions with FBSM (a) and reactions of FBSM with secondary
alcohols and epoxides (b) …………………………………………………........... 11
• Scheme 1.7: Synthesis of b-monofluoromethyl amines……………………………………….. 12
• Scheme 1.8: Addition of FBSM to Morita-Baylis-Hillman carbonates………………………... 13
• Scheme 1.9: Nucleophilic addition of fluoromethyl phenyl sulfone (A) and FBDT (B)……... 13
• Scheme 1.10: Electrophilic fluoromethylation with halofluoromethane derivatives………….. 15
• Scheme 1.11: Fluoromethylation with monofluoromethylsulfoxinium salts…………………… 16
• Scheme 1.12: Radical monofluoromethylation with EBFA.……………………………………... 17
• Scheme 1.13: Radical fluoromethylation of O,S, N and P-nucleophiles………………………. 17
• Scheme 1.14: Difluoromethylation strategies…………………………………………………..... 19
• Scheme 1.15: Mechanism of fluoroalkyl silane activation for the release of fluoroalkanide… 20
• Scheme 1.16: Synthesis of (difluoromethyl)trimethylsilane…………………………………….. 21
• Scheme 1.17:
First approaches for the difluoromethylation of carbonyl compounds with
TMSCF2H …………………………………………………................................... 22
• Scheme 1.18: Synthesis of b-amino-a-(difluoromethyl)alcohols and 1,2-difluoromethyl diols 23
• Scheme 1.19: Difluoromethylation of enolizable ketones……………………………………….. 24
• Scheme 1.20: Synthesis of Ethyl difluoropyruvate and applications…………………………... 24
• Scheme 1.21: Regioselective difluoromethylation of heterocycles…………………………….. 25
• Scheme 1.22: Synthesis of –CF2H indazoles…………………………………………………..... 26
• Scheme 1.23: Nucleophilic difluoromethylation of S-centers…………………………………… 27
• Scheme 1.24: Nucleophilic difluoromethylation of sulfides and disulfides……………………. 28
• Scheme 1.25: Difluoromethylation of Se–CN bonds…………………………………………….. 29
• Scheme 1.26: Difluoromethylation of ditellurides………………………………………………… 29
• Scheme 1.27: Nucleophilic difluoromethylation promoted by potassium tert-pentoxide…….. 31
• Scheme 1.28: Copper-promoted difluoromethylation of aryl iodides…………………………... 32
• Scheme 1.29: [(SIPr)AgCF2H]-catalyzed difluoromethylations………………………………… 33
• Scheme 1.30: Sandmeyer difluoromethylation of aryldiazonium salts………………………… 34
• Scheme 1.31: Copper-mediated oxidative difluoromethylation………………………………… 35
• Scheme 1.32: Copper and palladium catalyzed difluoromethylation reactions………………. 37
• Scheme 1.33: Bromination of TMSCF2—H bonds………………………………………………. 38
• Scheme 1.34: Difluoromethylation of carbonyl compounds with PhMe 2CF2H……………….. 39
• Scheme 1.35: Preparation of (pentafluoroethyl)trimethyl silane (TMSC2F5)………………….. 40
ix
• Scheme 1.36: Synthesis of a-pentafluoroethyl carbinols……………………………………….. 40
• Scheme 1.37:
Pentafluoroethylation of carbonyls, thiocarbonyls, imines and inorganic
molecules with TMSCF2CF3…………………………………………………........ 42
• Scheme 1.38: SN2 reaction with alkyl (pseudo)halides…………………………………………. 43
• Scheme 1.39: Regioselective pentafluoroethylation of (hetero)cycles………………………… 44
• Scheme 1.40: (C)sp
2
–X
bond pentafluoroethylation (I) ………………………………………… 46
• Scheme 1.41: Indirect pentafluoroethylation with –C2F5 borate salts………………………….. 47
• Scheme 1.42: Nucleophilic pentafluoroethylation of sulfur compounds………………………. 48
• Scheme 1.43: First syntheses and uses of [Si]CF2C(O)R compounds………………………... 49
• Scheme 1.44: Nucleophilic difluoromethylation reactions………………………………………. 50
• Scheme 1.45: Metal-mediated transfers of the –CF2CO2R anion……………………………… 51
• Scheme 1.46: Difluoromethylenation reactions promoted by transition metals………………. 52
• Scheme 1.47:
Nucleophilic difluoromethylation with sulfones, sulfoximines and
phosphonates………………………………………………….............................. 54
• Scheme 1.48:
Electrophilic difluoromethylation with sulfones, sulfoximines, and
hypervalent iodine reagents…………………………………………………......... 56
• Scheme 1.49: Generation of difluorocarbene form TMSCF3 and TMSCF2Br………………… 57
• Scheme 1.50: Cyclopropa(e)nation reactions with halodifluoromethylsilanes………………... 58
• Scheme 1.51: Reaction of TMSCF2Br with enolizable compounds……………………………. 59
• Scheme 1.52:
Select examples of the difluoromethylation of nucleophiles and electrophiles
with of TMSCF2Br…………………………………………………........................ 60
• Scheme 1.53:
(Sila)difluoromethylation of C-nucleophiles, chalcogens and other
heteroatoms with TMSCF3…………………………………………………........... 61
• Scheme 1.54: Transition-metal catalyzed synthesis of difluoromethyl compounds………….. 62
• Scheme 1.55: Radical difluoromethylation and photocatalysis………………………………… 64
• Scheme 1.56: trifluoromethylation strategies…………………………………………………...... 66
• Scheme 1.57: Nucleophilic trifluoromethylation of electrophiles with TMSCF3………………. 67
• Scheme 1.58: Nucleophilic trifluoromethylation of electrophiles with fluoroform……………... 68
• Scheme 1.59: Preparation of Cu-CF3 complexes………………………………………………... 70
• Scheme 1.60: Electrophilic and oxidative trifluoromethylation of nucleophiles………………. 71
• Scheme 2.1: Synthesis of trifluoromethyl ketones via acyloxyphosphonium ions………….. 73
• Scheme 2.2:
Prior art on the synthesis of trifluoromethyl ketones from carboxylic acid
derivatives………………………………………………….................................... 75
• Scheme 2.3: Deoxygenative trifluoromethylation of carboxylic acids reaction scope……… 81
• Scheme 2.4:
Possible ionic pathway in comparison to SET pathway to access
trifluoromethyl ketones…………………………………………………................. 83
• Scheme 2.5: Control competition experiment for esterification with phenol………………… 84
• Scheme 2.6: Competition experiments for deoxygenative trifluoromethylation…………….. 89
• Scheme 2.7: Generation of CuCF3 species…………………………………………………...... 92
• Scheme 3.1: Synthesis of difluoromethyl ketones via acyloxyphosphonium ions………….. 105
• Scheme 3.2:
Prior art on the synthesis of Difluoromethyl ketones from carboxylic acid
derivatives………………………………………………….................................... 107
x
• Scheme 3.3:
Deoxygenative synthesis of difluoromethyl ketones from carboxylic acid
derivatives: copper mediated and catalytic methods…………………………… 112
• Scheme 3.4: Mechanistic hypothesis for the synthesis of difluoromethyl ketones…………. 115
• Scheme 4.1: Synthesis of difluoromethyl alkynes……………………………………………… 129
• Scheme 4.2: Prior art on the synthesis of difluoromethyl alkynes……………………………. 131
• Scheme 4.3: Substrate scope of difluoromethyl alkynes………………………………………. 135
• Scheme 4.4: Mechanistic proposal for the difluoromethylation of terminal acetylenes…….. 138
• Scheme 4.5: Unoptimized tandem difluoromethylation-cyclization…………………………… 139
• Scheme 4.6: Prior art of the synthesis of 2-CF2H indoles……………………………………... 141
• Scheme 4.7: Mechanistic proposal for the tandem difluoromethylation/cyclization………… 151
• Scheme 4.8: N-Benzyl and N-methyl substituted compounds……………………………….. 152
• Scheme 5.1: Synthesis of monofluoromethyl ketones…………………………………………. 181
• Scheme 5.2: Possible mechanisms for the irreversible inhibition of cysteine with MFMK…. 182
• Scheme 5.3: Prior art in the synthesis of monofluoromethyl ketones………………………... 183
• Scheme 5.4: Prior art in the addition of FBSM and FBDT to carbonyl electrophiles……….. 184
• Scheme 5.5:
Only report for the synthesis of bis(phenylsulfonyl) monofluoromethyl ketone
(2) …………………………………………………............................................... 187
• Scheme 5.6: Proposed mechanism for the reductive desulfonylation reaction with Mg …... 196
• Scheme 5.7:
Proposed mechanism for the reductive desulfonylation reaction with tin
hydride…………………………………………………...………………………….. 198
• Scheme 5.8: Proposed mechanism for the synthesis of MFMK……………………………… 200
xi
List of Tables:
• Table 1.1: Asymmetric monofluoromethylation with FBSM and chiral catalysts… 9
• Table 2.1: Copper sources and base optimization…………………………………. 76
• Table 2.2: Effect of TMSCF3 and CuI loading………………………………………. 77
• Table 2.3: Effect of [Cu] concentration………………………………………………. 77
• Table 2.4: Effect of PPh3/NBS loading and solvent system on selectivity for 2a.. 78
• Table 2.5:
Direct Deoxygenative Trifluoromethylation of Carboxylic Acids: Effect
of Reaction Parameters (selected trials) ……………………………….. 79
• Table 2.6: Determination of Relative Ratio of A':B' from GC-FID Data…………... 85
• Table 2.7: Data obtained from the competition experiments performed…………. 88
• Table 3.1: Optimization of the synthesis of difluoromethyl ketones …………….. 109
• Table 4.1: Optimization of the difluoromethylation reaction……………………….. 133
• Table 4.2: Reactions with propargyl alcohol derivatives…………………………… 137
• Table 4.3: Cycloaddition reactions………………………………………………….... 139
• Table 4.4: Optimization of the difluoromethylation reaction with TMSCF2H…….. 143
• Table 4.5:
Optimization of the difluoromethylation reaction with
(DMPU)2Zn(CF2H)2…………..........……..........……..........……............. 147
• Table 5.1: Screening of carbonyl electrophiles……………………………………... 185
• Table 5.2: Screening of bases with benzoic anhydride……………………………. 186
• Table 5.3: Optimization of the monofluoromethylation reaction with FBSM……... 190
• Table 5.4: Optimization of the desulfonylation reaction with magnesium………... 194
• Table 5.5: Preliminary results on the tin-mediated desulfonylation………………. 197
• Table 5.6: Optimization of the monofluoromethylation reaction with FBDT……… 199
xii
List of Figures:
• Figure 1.1: Fluorinated pharmaceuticals with 1,2 and 3 fluorine atoms…………. 4
• Figure 2.1: Biologically and synthetically relevant trifluoromethyl ketones……… 74
• Figure 2.2:
Hammett Plot of the reaction of [CuCF3] with substituted
acyloxyphosphonium ions; relative rates of formation of CF3-
ketones versus s …………………………………………………………. 84
• Figure 3.1: Biologically and synthetically relevant difluoromethyl ketones............ 106
• Figure 3.2:
neat
19
F NMR of the reaction mixture employing naphthoic acid (full
spectrum) ……………………………………………….......................... 114
• Figure 4.1: Alkyne-containing pharmaceuticals and API’s………………………… 130
• Figure 4.2: Trend observed with different copper loadings……………………….. 134
• Figure 4.3:
19
F NMR spectrum of reaction performed with cyclopropyl
acetylene…………………………………………………........................ 178
• Figure 4.4:
19
F NMR spectrum of reaction performed with prop-2-yn-1-
ylbenzene………………………………………………….......................
179
• Figure 5.1 NMR of isolated compound (2):
1
H and
19
F NMR: -139.9 ppm........... 188
• Figure 5.2 Effects of the solvent polarity in the reaction outcome……………….. 193
• Figure 5.3 Effects of the reaction time in the outcome……………………………. 193
• Figure 5.4 Effects of the temperature in the reaction outcome…………………... 193
• Figure 5.5 Effects of the concentration in the reaction outcome…………............ 193
xiii
List of Images:
• Image 2.1:
GC-FID Chromatogram of Reaction Mixture from Control
competition experiment……………………………………………………. 86
• Image 2.2:
Chromatogram of authentic phenyl benzoate A’ (ret time 7.5 min)
and authentic phenyl 4-methoxybenzoate B’ (at 8.6 min) using n-
dodecane (ret time 5.6 min) as internal standard………………………. 86
• Image 2.3
19
F NMR Spectrum of competition experiment 1 (H vs OMe)…………. 89
• Image 2.4:
19
F NMR Spectrum of competition experiment 2 (Br vs Me)…….......... 90
• Image 2.5
19
F NMR Spectrum of competition experiment 1 (Br vs H)……………. 90
• Image 2.6:
19
F NMR Spectrum of competition experiment 1 (CF3 vs H)……......... 91
• Image 2.7:
[CuCF3] species’
19
F NMR spectrum after 15 min at room
temperature: a) full spectrum, b) expansion of CF3 region,
c) expansion of CF2CF3…………………………………………………… 93
• Image 2.8:
[CuCF3] species’
19
F NMR spectrum after 30 min at room
temperature: a) full spectrum, b) expansion of CF3 region, c)
expansion of CF2CF3………………………………………………………. 93
• Image 2.9:
[CuCF3] species’
19
F NMR spectrum after 50 min at room
temperature: a) full spectrum, b) expansion of CF3 region, c)
expansion of CF2CF3………………………………………………………. 94
• Image 4.1:
Visual representation of the reaction set-up for General procedure
A…………………………………………………........................................ 161
• Image 4.2:
Visual representation of the reaction set-up for General procedure
B…………………………………………………........................................ 162
• Image 5.1:
19
F NMR spectra before and after the desulfonylation reaction……..... 195
• Image 5.2:
19
F NMR spectra before and after the desulfonylation reaction 2…......
197
• Image 5.3: Sample
19
F NMR spectrum of the fluoromethylation reaction………….
211
xiv
List of equations:
• Equation 2.1: Calculation of relative ratio………………………………………………..
85
xv
Permissions:
• Chapter 1: Adapted/reprinted with permission from:
- Ispizua-Rodriguez, X. Barrett, C. Krishamurti, V. and Prakash, G.K.S. 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
- Ispizua-Rodriguez, X. Krishnamurti, V. Coe, M. and Prakash, G.K.S. Discussion Addendum for:
Fluorobis(phenylsulfonyl) methane (FBSM). Org. Synth., 2019, 96, 474-493.
https://doi.org/10.1002/0471264229.os096.29
• Chapter 2 and 3: Reproduced from:
Ispizua-Rodriguez, X. Munoz, S. Krishnamurti, V. Mathew, T. and Prakash, G.K.S. Direct
Synthesis of Tri/Difluoromethyl Ketones from Carboxylic Acids via Cross-Coupling with
Acyloxyphosphonium Ions. Chem. Eur. J., 2021, 27, 1–7.
https://doi.org/10.1002/chem.202102854.
• Chapter 4: Reproduced from:
- Ispizua-Rodriguez, X. Krishnamurti, V. Carpio, V. Barrett, C. Prakash, G.K.S. Copper-Catalyzed
Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes. J. Org. Chem. 2023, 88,
2, 1194–1199. https://doi.org/10.1021/acs.joc.2c02799.
xvi
Abstract:
As stated in the title, this dissertation will discuss my research conducted on the development of
synthetic methods to exploit the potential of fluorinated nucleophiles for the functionalization of
organic molecules. Having been immersed in the world of fluorine as a part of the Prakash group,
my research was focused on developing novel and alternative methodologies to introduce this
unique element into organic backbones, providing access to fluorofunctionalized products. The
preface section of this dissertation provides an overview of my research in organofluorine
chemistry that is mainly divided into three categories: (i) Fluorination and perfluoroalkylation of
carboxylic acid derivatives for the synthesis of fluorinated carbonyl compounds, (ii) Copper-
catalyzed perfluoroalkylation of C-H(sp) and C-H(sp
2
) centers, and (iii) Difluoromethylation of -N,
-O and -C nucleophiles with difluoro/dihalocarbene. Chapter 1 will provide insight into the impact
that fluorinated compounds have had in several fields of society, with emphasis in the
pharmaceutical and medicinal realms. This chapter will also include an overview of some of the
available reagents and methodologies to access fluorinated and perfluoroalkyl organic molecules
via monofluoro, difluoro, and trifluoromethylation reactions that follow either nucleophilic,
electrophilic, or radical pathways. Chapter 2 will focus on the synthesis of trifluoromethyl ketones
from activated carboxylic acids utilizing the Ruppert-Prakash reagent (TMSCF3) and copper (I) as
a trifluoromethylating system. The scope and applicability of the method are discussed, as well
as the mechanistic proposal derived from control and competition experiments. Chapter 3 will
further demonstrate the pluripotency of acyloxyphosphonium ions by utilizing them to prepare
difluoromethyl ketones employing a difluoromethyl zinc reagent and copper catalysis. Two
methods are provided for the synthesis of these compounds where copper acts as either a
promoter or a catalyst in the reaction. The same difluoromethyl zinc reagent was used to develop
the work discussed in Chapter 4, which describes the preparation of difluoromethyl alkynes from
terminal and silyl acetylenes. The scope of the method is demonstrated by the synthesis of
multiple CF2H-alkynes bearing diverse functionalities, including analogs of pharmaceutically
xvii
relevant compounds. The applicability of the protocol is further exemplified by both, the
preparation of 2-CF2H indoles via a tandem difluoromethylation/cyclization reaction of
ethynylanilines, and the synthesis of heterocycles via cycloaddition reactions. Chapter 5 will
discuss the work conducted in the synthesis of monofluoromethyl ketones from carboxylic acid
derivatives and fluoroalkyl anion surrogates. This chapter demonstrates the first addition-
elimination reaction of FBSM (fluorobis(phenylsulfonyl)methane) to carbonyl electrophiles to
prepare bis(phenylsulfonyl)fluoromethyl ketones. The full optimization of the reaction is analyzed,
and the preliminary results in the magnesium-mediated reductive desulfonylation are discussed.
This chapter includes the outlook and future work needed to apply the method to structurally
diverse substrates. All chapters demonstrate the power of spectrometric and spectroscopic
techniques to elucidate the structural composition of novel compounds. Nuclear Magnetic
Resonance (NMR), Infrared Spectrophotometry (IR), High-Resolution Mass Spectrometry
(HRMS), and Gas Chromatography coupled to Mass Spectrometry (GC-MS) were the main
techniques utilized to resolve the structure of the prepared molecules, and their structural data is
provided in the experimental section of each chapter.
xviii
Preface: Research overview
The research I conducted during my Ph.D. studies can be summarized in three general
categories: (i) Fluorination and perfluoroalkylation of carboxylic acid derivatives for the synthesis
of fluorinated carbonyl compounds (Scheme A), (ii) Copper-catalyzed perfluoroalkylation of C-H
sp and C-H sp
2
centers (Scheme B), and (iii) Difluoromethylation of -N, -O and -C nucleophiles
with difluoro/dihalocarbene (Scheme C).
Scheme A: (i) Fluorination and perfluoroalkylation of carboxylic acid derivatives for the synthesis of fluorinated
carbonyl compounds
{
{
R O
O
PPh
3
I
R CF
3
O
2
R OH
O
Carboxylic acids
Acyloxyphosphonium ions
CF
3
-ketones
Org. Lett. 21(6), 2019: 1659–63 Chem.Eur. J. 2021,27, 15908–13 Chem.Eur. J. 2021,27, 15908–13
3HF • Et
3
N
DCM, rt, 2h
R
O
SO
2
Ph
PhO
2
S
F
R
O
F
a-fluoromethyl
ketones
FBSM
MeCN
R O
O
II
Acid anhydrides
R
O
Manuscript under preparation
CuCF
2
H
DCM, rt, 1h
CuCF
3
THF, rt, 1h
(A) (B) (C) (D)
R CF
2
H
O
3
CF
2
H-ketones
R F
O
Acyl fluorides
1
xix
Scheme B: (ii) Copper-catalyzed perfluoroalkylation of C-H sp and C-H sp
2
centers
Scheme C: (iii) Difluoromethylation of N, O and C nucleophiles with difluoro/dihalocarbene
TMSCF
3
/KF/ PIFA
Cu(OAc)
2
MeCN
1h, rt
N
O
R
1
F
3
C
R
2
or
R
1
R
2
N
O
R
3
R
4
F
3
C
CF
2
H
R
R
BrCF
2
P(O)(OEt)
2
Ni/ Cu/ dtbpy
K
2
CO
3
1,4-Dioxane, 80°C, 5h
P
F F
OEt
O
OEt
Cu
Copper catalysis
L2Zn(CF2H)2
CuBr/base
oxidant
DMF, 80ºC
b-trifluoromethyl
enamides
b-trifluoromethyl
pyridones
Phosphonodifluoromethyl
arenes
Difluoromethyl
alkynes
Chem. Commun., 54, 2018, 10574-77 Chem.Eur. J. 2022, e202200457
J. Org. Chem. 2023, 88, 2, 1194–1199
CF
2
H
Difluoromethyl
indoles
N
R
(E) (F) (G)
F X
R
2
R
1
R
4
R
3
TMSCF
2
Br
N
C
N
H
C
R
R
N
R
O
N
R
O
R
O O
F
F
CF
2
Difluorocarbene
Difluoromethyl
esters N-CF
2
H and O-CF
2
H
pyridones
Difluoromethyl
formimidamides
F F
F F
F
F
Org. Lett. 2019, 21, 23, 9377–80
Org. Lett. 23(16), 2021, 6494–6498 J. Fluor. Chem, 2022, 261–262, 110023
KOH
MeCN
rt, air, 2h
NaO
t
-Bu
triglyme
-15 ºC, 1h
Na
2
CO
3
MeCN
60ºC, 1h
Na
2
CO
3
BF
3
-etherate
MeCN, 60
o
C, 1h
FX
2
C(O)OEt
CFX
Dihalocarbene
Bromo/chloro
fluorocyclopropanes
NaOEt
DCM, rt, 1h
Org. Lett. 2022, 24, 29, 5417–5421
(H) (I) (K) (J)
xx
From the works shows above in Schemes A-C, this thesis will only cover transformations (B),
(C), (D), and (G) in depth.
List of publications:
1. Krishnamurti, V. Munoz, S. Ispizua-Rodriguez, X. Vickerman, J. Mathew, T. and Prakash,
G.K.S. C(sp
2
)–H Trifluoromethylation of enamides using TMSCF3: access to trifluoromethylated
isoindolinones, isoquinolinones, 2-pyridinones, and other heterocycles. Chem. Commun., 2018,
54, 10574-10577.
2. Munoz, S. Dang, H. Ispizua-Rodriguez, X. Mathew, T. and Prakash, G. K.S. Direct Access to
Acyl Fluorides from Carboxylic Acids using a Phosphine/Fluoride Deoxyfluorination Reagent
System. Org. Lett., 2019, 21, 6, 1659–1663.
3. Ispizua-Rodriguez, X. Krishnamurti, V. Coe, M. and Prakash, G.K.S. Discussion Addendum
for: Fluorobis(phenylsulfonyl) methane (FBSM). Org. Synth., 2019, 96, 474-493.
4. Krishnamurti, V. Barrett, C. Ispizua-Rodriguez, X. Coe, M. and Prakash, G.K.S. Aqueous
Base Promoted O-Difluoromethylation of Carboxylic Acids with TMSCF2Br: Bench-Top Access to
Difluoromethyl Esters. Org. Lett., 2019, 21, 23, 9377–9380.
5. Ispizua-Rodriguez, X. Barrett, C. Krishnamurti, V. and Prakash, G.K.S. Silicon-based
difluoromethylations, difluoromethylenations, pentafluoroethylations, and related
fluoroalkylations. In The Curious World of Fluorinated Molecules, Seppelt, K, Ed. In Progress in
Fluorine Science; Elsevier, Vol 6, 2021, 117-218
6. Zhu, Z. Krishnamurti, V. Ispizua-Rodriguez, X. Barrett, C. and Prakash, G.K.S.
Chemoselective N- and O-Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones
with TMSCF2Br. Org. Lett., 2021, 23, 16, 6494–6498.
7. Ispizua-Rodriguez, X. Munoz, S. Krishnamurti, V. Mathew, T. and Prakash, G.K.S. Direct
Synthesis of Tri/Difluoromethyl Ketones from Carboxylic Acids via Cross-Coupling with
Acyloxyphosphonium Ions. Chem. Eur. J., 2021, 27, 1–7.
xxi
8. Knieb, A. Krishnamurti, V. Ispizua-Rodriguez, X. Prakash, G.K.S. Nickel and Copper
catalyzed ipso-Phosphonodifluoromethylation of Arylboronic Acids with BrCF2P(O)(OEt)2 for the
Synthesis of Phosphonodifluoromethylarenes. Chem.Eur. J. 2022, 28, e202200457
9. Barrett, C. Krishnamurti, V. Ispizua-Rodriguez, X. Zhu, Z. Koch, C.J. Prakash, G.K.S. gem-
Halofluorocyclopropanes via [2+1] cycloadditions of in situ generated CFX carbene with alkenes.
Org. Lett. 2022, 24, 29, 5417–5421
10. Zhu, Z, Xu, Y, Krishnamurti, V. . Koch, C.J. Ispizua-Rodriguez, X. Barrett, C. Prakash,
G.K.S. J. Fluor. Chem. 2022, 261–262, 110023
11. Ispizua-Rodriguez, X. Krishnamurti, V. Carpio, V. Barrett, C. Prakash, G.K.S. Copper-
Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes. J. Org. Chem.
2023, 88, 2, 1194–1199
12. Ispizua-Rodriguez, X. Direct synthesis of monofluoromethyl ketones from carboxylic acids
derivatives and fluoromethyl anion surrogates (Under development).
1
CHAPTER 1: INTRODUCTION
The objective of this chapter is to provide an introduction to fluorine chemistry and to highlight the
relevance of fluorine in the medicinal chemistry context. This section will discuss the most salient
aspects of the structural and chemical properties of fluorine-containing molecules, as well as
some of the different strategies employed to access these compounds. The focus will primarily
be on the existent methodologies for the mono-, di- and trifluoromethylation of organic molecules
through nucleophilic, electrophilic, and radical pathways.
1.1 The fluorine atom. Introduction and relevance of fluorine in the pharmaceutical context
“Fluorine, a small atom with a big ego” - G.K.S. Prakash. Fluorine, in addition to being the most
abundant halogen on earth, it is the most electronegative atom in the periodic table. This particular
property greatly influences carbon-fluorine bonds (C—F) making them polarized yet strong
linkages; in fact, fluorine forms the strongest bonds with carbon in organic chemistry
1
.
Fluorinated compounds have several important applications in diverse areas of current society
such as development of pharmaceuticals and radiopharmaceuticals, biological probes, production
of materials, manufacturing of innovative refrigerants, and synthesis of agrochemicals.
2–4
In the
medicinal chemistry context, numerous research studies are currently taking place to prepare
fluorinated compounds of biological interest. The reason for this being that the introduction of one
or more fluorine atoms can favorably impact the physicochemical properties of organic molecules
such as boiling point, melting point,
5
intramolecular interactions,
6
structural conformation,
7
and
pKa.
8
Thus, directly influencing the binding mode, lipophilicity, selectivity, metabolic stability,
bioavilability, binding affinity, and pharmacokinetic profile of a molecule.
9
Despite the widespread
successful applications of fluorinated compounds, they are scarce in nature and most of them
have to be made in a laboratory. Unlike other halogenated metabolites, biological systems rarely
produce fluorine-containing compounds due to fluorine directly interfering with some of their
2
internal mechanisms.
3
However, modern medicine has harnessed the potential of those biological
interactions with fluorine and developed powerful therapeutics. Successful examples of life-saving
medication that have fluorine in their structure are depicted in Figure 1.1.
10–27
Risperidone
(Risperdal) is a medication that targets dopaminergic, serotonergic, and adrenergic receptors,
enabling the effective treatment of psychotic disorders such as schizophrenia.
28
Also in the
context of psychiatry, the discovery of Prozac (fluoxetine) which is used to treat clinical
depression, anxiety, and other disorders was a major breakthrough that revolutionized the mental-
health industry.
29
This amine bound to a (trifluoromethyl)phenoxy core (Figure 1.1) serves as a
selective serotonin-reuptake inhibitor, thus increasing the availability of serotonin in the brain.
29
In the context of oncology, a multitude of fluoro-(hetero)arenes have found an application in
treating different types of cancer. Although some have shown more efficacy, safety, and tolerance
than others, the discovery of these pharmaceuticals is undoubtedly, of outmost importance.
Cancer has been found in human remains that are more than 2500 of years old. Nowadays, with
approximately more than 18 million cases of cancer per year around the globe, this disease is a
public health problem and it is the second leading cause of death worldwide.
30
Luckily, the marked
decline of mortality rates in the past years showcases the tremendous progress in the
development of successful treatments and therapeutics,
31
including the recently approved (2022)
monoclonal antibody crosslinked to a topoisomerase I inhibitor, trastuzumab deruxtecan (Figure
1.1).
32
In a similar context, cardiovascular diseases occupy the first place as leading cause of
death worldwide, thus many efforts have been put towards the treatment of heart diseases and
blood pressure-related conditions.
33
Nitroglycerin was the first substance used to treat tightness
and pain in the chest. Interestingly, this pro-drug was also vastly employed as an explosive, and
the discovery of its controlled detonation (which later translated into the development of
dynamite), was the reason for Alfred Nobel’s fortune.
34
Many years after dynamite, came the
statin drugs. The discovery of this class of cholesterol-lowering compounds is regarded as the
biggest moneymaker to date for the pharmaceutical industry. Lipitor (atorvastatin) (Figure 1.1) is
3
a synthetic statin used to treat hypercholesterolaemia, a condition that leads to coronary artery
diseases.
35
As an interesting fact, rabbits became the ideal animal model to study human high
cholesterol levels after a Japanese veterinarian discovered that a bunny in its colony had
significantly higher cholesterol than the rest. This rabbit, and the ones that followed, enabled the
understanding of the physiopathology of coronary artery diseases and the biology of cholesterol.
This accidental; discovery was groundbreaking for its time. As Jie Jack Li very eloquently wrote it
in his book Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use,
“After all, one could not just use people with this genetic defect as human guinea pigs!”.
34
In
addition to these overwhelmingly prevalent conditions, there are other widespread life-threatening
diseases that have been successfully prevented and/or treated through the development of
fluorinated pharmaceuticals. The Human Immunodeficiency Virus, otherwise known as HIV, is a
retrovirus that causes Acquired Immunodeficiency Syndrome (AIDS), a lifelong condition that has
taken around 40 million lives.
36
This infection severely compromises the health and life of
individuals, especially those in marginalized groups and communities with little to no access to
healthcare.
37
Understanding and tackling the physiopathology of the infection has represented a
challenge for many years due to the virus’ ability to bypass the body’s immune system. Luckily,
the discovery of antiretroviral drugs has translated into a decrease of mortality and has
decelerated the progression of the disease. Efavirenz (Figure 1.1) is an HIV-1 specific, non-
nucleoside reverse transcriptase inhibitor
38
that has shown excellent efficacy in the treatment of
this condition. The synthesis of this compound proceeds via an aryl trifluoromethyl ketone that
serves as the source of the CF3 group in the resulting stereogenic quaternary carbon center.
13,39
Also containing a trifluoromethyl group is the drug Januvia (Sitagliptin) (Figure 1.1), an effective
and highly selective DPP-4 inhibitor used for the treatment of type 2 diabetes.
40
Diabetes is a
serious disease that overall affects nearly 10% of the world’s population (men and women). With
three main types of diabetes (type 1 diabetes, type 2 diabetes mellitus and gestational diabetes
mellitus)
41
these conditions affect all age groups and they are characterized by the loss of control
4
of glucose concentrations in the blood, potentially leading to more severe problems such as organ
malfunction and neuropathy issues.
42
Figure 1.1: Fluorinated pharmaceuticals with 1,2 and 3 fluorine atoms
Further discoveries in modern fluorine-containing pharmaceuticals include anesthetics. Looking
back into the history of anesthetics it is noticeable that since the first anesthetic was introduced
in the 1800, none of the compounds contained fluorine in their structure. It wasn’t until the 1950’s
when the non-flammable gas halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) was discovered
that most of the volatile anesthetics thereafter contained at least 1 fluorine atom in their structure.
The advantages of introducing fluorine included decreased flammability, decreased toxicity and
N
N
O
N
O
N
F
Risperdal
®
(Janssen)
Antipsychotic
F
NH
Cl
N
N
O
OMe
N
O
Iressa
®
(AstraZeneca)
Cancer (lung)
N
N
CF
3
S
O
O
Celebrex
®
(Pfizer)
NSAID
N
S
O
O
Lipitor
®
(Pfizer)
Cholesterol
F
OH
OH
O
O
O
H
N
Ph
3
Cl
N
H
O
O
F
3
C
Efavirenz Sustiva
®
(DuPont)
HIV treatment
F
3
C
O
H
N
Prozac
®
(Eli Lilly & Co.)
antidepressant
HN
N
O
O
H H
OH
H
O
HO
CF
3
Viroptic
®
(GSK)
herpes (eyes)
S
N
NH
2
O
F
3
C
Rilutek
®
(Sanofi)
sclerosis
N
N
NH
2
H H
OH
H
O
HO
Gemzar
®
(Eli Lilly & Co.)
chemotherapy
F
F
O
Tibsovo
®
(Servier Pharmaceuticals LLC)
leukemia
N
NC
N
O
N
O
N
F
O NH
F F
Cl
Vaniqa
®
(Allergan Pharmaceutical)
trypanosomiasis
NH
2
HF
2
C
OH
O
H
2
N
N
HN
S
O
N
MeO
MeO
O
CF
2
H
Pantoprazole
®
(Wyeth/Pfizer)
proton pump inhibitor (PPI)
O
CF
2
H
t-Bu
Inhibitor of AgAChE
Malaria’s main vector
N
H
N
O
O
F
5-fluorouracil
chemotherapy
F O F
3
C
CF
3
Sevoflurane
General anesthetic
N
N
O
F
H
2
N
Afloqualone
muscle‐relaxant
and sedative
F
F
F
NH
2
N
O
N
N
N
CF
3
Januvia
®
(Merck)
anti-diabetic medication
O
O
OH
N
O
N
F
NH
O
O
NH
O
HN
O NH
O
H
N
O
N
H
O
(H
2
C)
5
N
O
O
S
trastuzmab
O
CF
3
O
O
N
N
NO
2
Pretomanid
pulmonary tuberculosis
2
Trastuzumab deruxtecan
Cancer (breast or gasric)
5
increased stability of adjacent C-H bonds.
43
Sevofluroane (Figure 1.1) is an inhalable anesthetic
discovered in the 70’s and nowadays it is one of the most employed volatile anesthetics used in
surgical procedures due to the rapid recovery experienced by patients, potentially due to the
compound’s decreased solubility in the blood compared to other drugs from the same class.
44
Many other examples of antibiotics, analgesics, anti-parasitic drugs, and antivirals serve to
demonstrate and highlight the importance of the introduction of fluorine into pharmaceuticals.
The field of organofluorine chemistry has a long-standing history and its development was
accelerated during the 1930’s. Since then, a wide array of reagents has been developed for the
synthesis of C—F bonds.
45
Among all the strategies to introduce one or more fluorine atoms into
molecules, perfluoroalkylation methodologies (transfer of a CFX group) have gained a lot of
traction in recent years. A summary of general strategies for the mono, -di, and
trifluoromethylation of organic compounds will be discussed next.
1.2 Monofluoromethylation strategies
The installation of monofluoromethyl building blocks into organic molecules is an underexplored
perfluoroalkylation strategy compared to its di- and trifluoromethylation counterparts. The
bioisosteric properties of monofluoromethyl compounds are evidenced in fluorinated analogues
of methyl and hydroxyl groups in bioactive molecules.
46,47
The introduction of a single fluorine
atom is often applied to either modify potency or influence the metabolism of bioactive
compounds. Currently the nucleophilic, electrophilic, and radical monofluoromethylation
strategies available to access these desirable fluoroorganics are commonly carried out utilizing
sulfone-based reagents that are sources of the CFH2 unit either as a carbanion
(monofluoromethide) or as a radical, with or without the aid of transition metals to create C—C or
C—X (X= O, N, S) bonds (Scheme 1.1).
48–65
6
Scheme 1.1: Reagents for monofluoromethylation of C, N, S, or O centers
Among these reagents, 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 in the CFH unit, making its deprotonation facile and giving rise
to a resonance- stabilized fluoromethide species.
66
This compound was first synthesized by
Shibata et al., through the electrophilic fluorination of bis(phenylsulfonyl)methane
50
and was later
on used as a nucleophilic monofluoromethylating reagent. Prakash and coworkers envisioned a
large-scale procedure to synthesize FBSM in reagent quantities (Scheme 1.2).
67
Scheme 1.2: Large-scale synthesis of FBSM
S
O
O
F
S
O
O
F
S
O
O
R
S
O
O
F N
N
N
N
t
Bu
S
O
O
F Zn
2
S
O
O
F
Cl S
O
O
F
Na
Nucleophilic monofluoromethylation
Radical monofluoromethylation
Electrophilic monofluoromethylation
S
O
O
F
S
O
O
R
H
F
H
Monofluoromethylated compounds
F
H
H
I
18
F
H
H
I
F
H
H
Cl F
H
H
Br
S
F
BF
4
S
O
N
F
X
X
S
O
N
F
Ts
OEt
O
F
Br
S
F
3
C
O
O
F
O
BF
4
*
F S
Ph
O O
F
S
Ph
O
O
S
Ph
O
O
Cl S
Ph
1. KF, 18-crown-6 (10 mol%)
CH
3
CN, relfux, 120 h
2. Oxone MeOH, H
2
O
1. KHMDS, THF, -78 ºC
2. 4M HCl F
S
Ph
O O
7
In 2020 our group published a comprehensive review that covers the transformations available
employing FBSM as a monofluoromethylation reagent.
51
Scheme 1.3: FBSM as a masked nucleophile
These reactions include Michael reactions, substitution reactions, Mitsunobu-type chemistry,
epoxide ring-opening, multicomponent reactions, additions to alkenes and alkynes, addition to
Morita-Baylis-Hillman products, among others (Scheme 1.3). The use of this reagent for the
preparation of monofluoromethyl ketones and carbinols will be covered more in depth in Chapter
5. Examples of the utilization of FBSM as a Michael donor are extensive due to the utility and
importance of Michael reactions on the synthesis of structurally complex organic molecules. The
acidity of FBSM enables its facile deprotonation even when using mild bases, with the resultant
anion being a good nucleophile that has been reacted with a variety of Michael acceptors,
furnishing C-protected monofluoromethyl compounds. Scheme 1.4.A-C showcases the
trimethylphosphine catalyzed addition of FBSM derivatives (where X= phenylsulfonyl, nitro,
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'
8
cyano, ester or ketone) to a,b-unsaturated compounds which proceeds via the formation of a b-
phosphonio enolate.
68
Similarly, methods for the fluoromethylation of a,b-unsaturated ketones,
arynes, and alkynes with FBSM-type pronucleophiles have also been developed employing
different bases.
69
(Scheme 1.4.C-E).
Scheme 1.4: Addition of FBSM derivatives to Michael acceptors
On the other hand, asymmetric monofluoromethylation represents a bigger challenge and it has
been traditionally achieved by employing amine-based chiral catalysts. A good example of this
is the utilization of FBSM as a pronucleophile in an asymmetric 1,4-addition to a,b-unsaturated
ketones by employing either a Cinchona alkaloid-derived ammonium salt
70
or a chiral quinoline-
based amine catalyst.
71
Both methods successfully direct the stereochemical outcome of the
reaction primarily towards one enantiomer, thus exhibiting good enantiomeric excesses along
with good yields (Table 1.1.A,B).
72
The obtained monofluoromethyl ketones can be further
reduced to the carbinols via a NaBH4-mediated reduction, keeping the phenylsulfonyl groups
intact. Alternatively, with most FBSM-containing compounds, reductive-desulfurization can be
performed in order to yield the monofluoromethyl derivatives. Similarly, Cinchona alkaloids
catalysts have been employed in the reaction of FBSM with in situ generated iminium ions to yield
monofluoromethyl indole derivatives with high enantiomeric excess (Table 1.1.C).
73
Furthermore,
R
SO
2
Ph
F
SO
2
Ph
CsF
R
4
R
5
O
R
1
O R
2
SO
2
Ph
SO
2
Ph
F
CsOH H
2
O
R
1
O
R
3
R
2
R
2
, R
3
: H, alk, Ar
R
1
R
2
O
X
SO
2
Ph
F
H—CFX(SO
2
Ph)
EWG
EWG
R(PhO
2
S)FC
EWG
EWG
R(PhO
2
S)FC
K
2
CO
3
, rt
TMS
FG
OTf
cat. PMe
3
, rt
or
LHMDS
A)
B)
C)
D)
E)
9
enamines derived from chiral amines such as proline have also been extensively used in
asymmetric catalysis due to their ability to produce the target compounds with high selectivity and
enantiomeric excess. The asymmetric conjugate addition of FBSM to enals, catalyzed by a chiral
silyl-proline derivative (Table 1.1.D)
74
proceeds via formation of an a,b-unsaturated iminium ion;
this electrophile reacts with FBSM in order to form a b-substituted enamine. Subsequent
hydrolysis of the enamine (loss of the proline derivative) affords the desired b-monofluoromethyl
aldehydes, which can be further reduced to the primary alcohols with NaBH4.
74–76
The utility of
silyl-proline catalysts has also been demonstrated in conjugate addition/cyclization cascade
reactions to prepare fluoroindanes and fluorochromanol derivatives (Table 1.1.E,F).
77
This
reaction follows a similar mechanism to the cinchona alkaloid, where the first step is the in situ
formation of an iminium ion that will later react with the fluoromethyl anion. A second Michael
reaction in the same pot yields the target compounds.
Table 1.1: Asymmetric monofluoromethylation with FBSM and chiral catalysts
H—CF(SO
2
Ph)
2
N
H
Ph
O[Si]
Ph
cat.
Wang et al., [Si] = TBS
Cordova et al. [Si] = TMS
Rios et al. [Si] = TMS
N
MeO
NH
2
N
2) NaBH
4
1) IBX
2) NaBH
4
cat.
N
H
Ph
OTMS
Ph
R
SO
2
Ph PhO
2
S
F
HO
N
H
SO
2
Tol
R
Ar
N
OH
N
t-Bu
t-Bu
Br
-
N
H
R
Ar
SO
2
Ph
SO
2
Ph
F
O
X
CHO
R
R
N
H
OTMS
Ph
Ph
cat.
SO
2
Ph
PhO
2
S
F
O
O
R’
OH
CHO
R
R
N
H
OTMS
Ph
Ph
cat.
O OH
SO
2
Ph PhO
2
S
F
Catalyst
R
1
O
R
H
O
R
R
1
R
F
SO
2
Ph
SO
2
Ph HO
R
SO
2
Ph
SO
2
Ph
F
R
SO
2
Ph
SO
2
Ph
F
O
H R
1
O
R
H
O
R
HO
N
OMe
OH
N
F
3
C
CF
3
CF
3
F
3
C
X
1)
Substrate Catalyst Product
S P
A)
B)
C)
D)
E)
F)
G)
Substrate Catalyst Product
10
Finally, a novel approach for the oxidative monofluoromethylation of aldehydes was developed in
2011 via in situ conversion of an enamine to an iminium ion with the use of hypervalent iodine
reagents. In this case, IBX (2-Iodoxybenzoic acid) acted as the oxidant to form the iminium ions
that were then reacted with FBSM, generating b-fluoromethyl compounds, The corresponding
carbinols can be obtained upon treatment with NaBH4 (Table 1.1.G).
78
Moreover, the versatility of FBSM has been demonstrated in the preparation of diverse b,g-
unsaturated-a-fluoromethyl compounds via nucleophilic substitution. Enantioselective allylic
monofluoromethylation of allyl acetates using FBSM in combination with palladium or iridium
catalysts and chiral ligands, produce the desired allyl monofluoromethanes in an SN2’ fashion with
high enantioselectivities. (Scheme 1.5).
79–81
Some of the produced compounds have even been
found to have enhanced biological activity.
82
These allylic fluorides can also be accessed utilizing
the sodium salt of FBSM and an iridium catalyst, as demonstrated by Hartwig and coworkers
(Scheme 1.5).
83
Scheme 1.5: Pd or Ir catalyzed fluoromethylation with FBSM
Also, in the realm of nucleophilic substitution with FBSM, alkyl halides can be converted to their
corresponding monofluoromethyl derivatives via an SN2 reaction. As demonstrated by Prakash
O
N PPh
2
iPr
(S)-PHOX
O
O
P N
(S, S, S
a
)-ligand
PPh
2
N
N
S
O
O
O
2
N
ligand 1
O
O
P
N
Ir
BF
4
-
Ir-catalyst
R
O
R
2
R
3
O
X
R R
PhO
2
S SO
2
Ph
F
(22% - 92%)
R
SO
2
Ph
PhO
2
S
F
Major
(28% - 96%)
R R
2
PhO
2
S SO
2
Ph
F
(83%)
PhO
2
S
F
SO
2
Ph
F
Ph
(56%)
F
S S
O
O
O
O
(S)-PHOX (5 mol%)
[{Pd(C
3
H
5
)Cl}
2
] (2.5 mol%)
[Ir(COD)Cl]
2
(2 mol%)
(S, S, S
a
)-ligand (4 mol%)
[(η
3
-C
3
H
5
PdCl)
2
] (5 mol%)
ligand 1 (10 mol%)
Na—CF(SO
2
Ph)
2
Ir-catalyst (8 mol%)
11
and coworkers, aliphatic alkyl halides indeed produce the expected SN2 product, whereas benzyl
halides afford monofluoroolefins instead which enables access to b-fluorostyrenes (Scheme
1.6.A).
84
Scheme 1.6: SN 2 reactions with FBSM (a) and reactions of FBSM with secondary alcohols and epoxides (b)
As delineated in Scheme 1.2, FBSM is also employed in deoxygenative monofluoromethylation
reactions via Mitsunobu-type intermediates
85
and epoxide opening reactions.
86
These
transformations enable access to tertiary fluoromethyl compounds and b-CHF compounds,
respectively (Scheme 1.6-B). As reported by Shibata and coworkers, b-monofluoromethyl amines
have been prepared through the enantioselective monofluoromethylation of in situ generated
prochiral imines with FBSM.
87
In this work, cinchona alkaloids act as both the chiral phase transfer
agents, as well as the catalysts. This Mannich-type reaction was also exploited by Prakash and
coworkers to develop a multicomponent system with an aldehyde, a secondary amine, and FBSM,
producing a variety of monofluoromethyl amines in moderate to good yields (Scheme 1.7).
88
Additionaly, a dehydrogenative coupling of the amines with FBSM and DIAD (Diisopropyl
azodicarboxylate) via an iminium ion intermediate also affords b-monofluoromethyl amines.
PhO
2
S SO
2
Ph
F R
F
SO
2
Ph
X
Alk X
K
2
CO
3
Cs
2
CO
3
R
1
R
2
OH
PPh
3
, DIAD
R
1
R
2
PhO
2
S SO
2
Ph
F
O
R
1
n-BuLi Et
2
O, -78ºC
F
3
B OEt
2
HO
R
2
R
2
R
1
SO
2
Ph
SO
2
Ph
F
R R
H—CF(SO
2
Ph)
2
H—CF(SO
2
Ph)
2
H—CF(SO
2
Ph)
2
H—CF(SO
2
Ph)
2
A)
B)
12
Scheme 1.7: Synthesis of b-monofluoromethyl amines
As discussed earlier, FBSM can be easily deprotonated to yield a monofluoromethide equivalent
that can be transferred to various electrophiles. However, functionalization of the resulting anion
is also a strategy to prepare FBSM-derived reagents such as
Fluoroiodobis(phenylsulfonyl)methane (FBSM-I). This compound developed by Prakash and
coworkers (Scheme 19)
89
can be employed as a radical monofluoromethylation reagent that can
be transferred to alkenes. Similarly, this concept was later used by Shibata and coworkers to
develop a novel class of halogen-bonding catalysts.
90
FBSM can also be transferred to other sp
2
electrophiles such as alkynes
91
and dienes
92
with the aid of palladium catalysis or via metal-free
chiral ammonium catalysts.
93
Morita-Baylis-Hillman carbonates are another class of substrates
that are known to be activated alkenes and that have been reported to efficiently yield allyl-
fluoromethyl compounds with anthraquinone-derived chiral catalysis (Scheme 1.8)
94,95
Lastly, the
addition reaction of FBSM to C(sp
2
) electrophiles is a powerful tool to access diverse
monofluoromethylated carbinols and the prior art on this specific chemistry will be covered in
Chapter 5.
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
H
N
R
2
H H
O
CH
2
Cl
2
, 12h
N
R
1
R
2
SO
2
Ph
SO
2
Ph
F
(41% - 97%)
NaH (0 - 1 equiv)
F
S S
O
O
O
O
Ph Ph
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
13
Scheme 1.8: Addition of FBSM to Morita-Baylis-Hillman carbonates
The rest of the sulfone-based reagents depicted in Scheme 1.1 function in a similar manner to
FBSM: the deprotonation of the CHF unit gives rise to a fluoromethide species that can be
transferred to a multitude of electrophiles. Examples of the chemistry conducted with these
sulfones is depicted in Scheme 1.9. Fluoromethyl phenyl sulfone has been used for the
stereoselective synthesis of α-monofluoromethylamines employing sulfinylimines as the
substrates (Scheme 1.9.A).
48
Similarly, 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT) can
be easily deprotonated and transferred to aldehydes yielding the 1,2-addition products (Scheme
1.9.B). Conjugated aldehydes can also undergo 1,4-addition followed by a second 1,2-addition of
FBDT. This reagent serves as a less sterically hindered alternative to FBSM due to the lack of
reversibility in addition reactions.
53
Scheme 1.9: Nucleophilic addition of fluoromethyl phenyl sulfone (A) and FBDT (B)
The literature on electrophilic and radical monofluoromethylation strategies is less extensive than
the nucleophilic counterpart. Fluoromethanol was the first reagent for electrophilic
monofluoromethylation, developed by Olah and coworkers in 1952. This compound was first
utilized to prepare benzyl fluoride from benzene and ZnCl2 as a Lewis acid under strictly
O O
O O
N N
O O
N N
(DHQD)
2
AQN
R
LG
O
O
Morita-Baylis-Hillman carbonates
H—CF(SO
2
Ph)
2
(DHQD)
2
AQN (10 mol%)
O
O
H
R PhO
2
S
SO
2
Ph
F
R O
O
PhO
2
S
F
SO
2
Ph
H—CF(SO
2
Ph)
2
(DHQD)
2
AQN (10 mol%)
TMSCF
3
or
S
N
O
R= alkyl, aryl
R
H
S
N
H
O
R’
S
O
O
F
F SO
2
Ph
NH
2
’R
F H
H
S
S
O
O
O
O
F
H
O
R
H
HO
R
S
S
O
O
O
O
F
H
OH
R
F
H
H
R= alkyl, aryl
A)
B)
14
anhydrous conditions (Scheme 1.10.A).
96
Years after that discovery, several metal-free
electrophilic fluoromethylation protocols utilizing methylene halides such as chloro-, bromo-, and
iodofluoromethane were developed, including protocols to synthesize
18
F-labeled fluoromethyl-
containing compounds that are utilized for positron emission tomography (PET).
97
The
development of these methods enabled access to O-, S-, and N-monofluoromethyl compounds,
as well expanded the scope of fluoromethylation reactions (Scheme 1.10.B).
60,98
However, the
formation of new C-C bonds via electrophilic fluoromethylation still proved daunting. Utilizing
chlorofluoromethane, Prakash and coworkers synthesized S-(monofluoromethyl)diarylsulfonium
tetrafluoroborate which enabled the fluoromethylation of carbon and phosphorous nucleophiles,
thus overcoming this long-standing synthetic challenge (Scheme 1.10.C).
63
In recent years, more
protocols have been developed to employ halofluoromethanes to create new C-C bonds with the
aid of transitions metal chemistry. Scheme 1.10.D showcases selected examples where boronic
acids and boronic esters have successfully been transformed into their corresponding
monofluoromethyl arene equivalents using Pd and Ni catalysts.
99–102
Similarly, copper catalysts
are used effectively in the borylfluoromethylation of alkenes to prepare branched fluoromethyl
alkanes.
103
More recently, Pace and coworkers developed an elegant method to prepare various
fluoromethyl -O, -S -N, -P, and -Se compounds via a metal free monofluoromethylation reaction
with iodofluoromethane.
104
However, given the ozone-depleting potential that has been linked to
the use of halofluorocarbons,
105
the Montreal protocol has prompted their regulation. Thus, efforts
have been put into the synthesis of alternative electrophilic fluoromethylation reagents with the
goal of affixing the CFH2 unit in a more practical manner. Fluoromethyl sulfonates are a class of
reagents used to circumvent the direct use of methylene halides in fluoromethylation reactions
and they have been successfully employed to produce O-, S-, and N-monofluoromethyl
compounds.
97
More specifically, oxygen nucleophiles can be selectively functionalized with a new
class of monofluoromethylsulfoxinium salts developed by Shibata and coworkers in 2011
(Scheme 1.11).
64
15
Scheme 1.10: Electrophilic fluoromethylation with halofluoromethane derivatives
S
F
BF
4
F
H
H
Cl
S
Na
2) NBS, MeOH
3) Tf
2
O
1,2,3,4-tetramethylbenzene
NaBF
4
F
H
H P
BF
4
P-nucleophiles
F
H
H
N
Me
Me
BF
4
O
O
F
H
H
S
F
S
O
O O
O
F
H H
O-nucleophiles N-nucleophiles C-nucleophiles
F
H
H
S
S-nucleophiles
F
H
H
N O
F
H H
O-nucleophiles N-nucleophiles
F
H H
S
S-nucleophiles
t
Bu
N
F
H
H
Cl R XH
Base
solvent
HO
F
F
H
H
ZnCl
2
40 ºC — 50 ºC
A)
B)
C)
D)
Nu
F
H
R
Y
B(R)
X R
(Suzuki, 2009)
(Wang, 2015)
(Hu, 2015)
(Zhang, 2015)
H pinacol
SO
2
Ph or
CO
2
Et
(OH)
2
R
R
BR'
F
H H
CuBr
JohnPhos
LiOt-Bu
Cat.
[Ni(acac)
2
]
Pd
2
(dba)
3
Pd(dppf)Cl
2
Pd
2
(dba)
3
]
H pinacol
Y
I
I
I
Br H
(OH)
2
NiCl
2
•DME
Metal Cat.
F
H
H
CFH
2
I
B
2
mpd
2
Fluoromethanol
O,N, and S
Sulfonium reagent
Pd and Ni catalyzed
D) Cu catalyzed
16
Although this reagent is described as an electrophilic fluoromethylation reagent that theoretically
produces a fluoromethyl cation equivalent, relative energy calculation studies suggest that the
process might involve a radical •CFH2 species instead. Monofluoromethyl cations are proposed
to show preference toward C nucleophiles, whereas the radical counterpart is described as having
more affinity for oxygen centers. Due to these compounds’ undeniable selectivity for O
nucleophiles over C nucleophiles when reacted with ketoesters, the proposed mechanism for
these transformations involves a radical-like SET process (Scheme 1.11).
106
Nonetheless, the
electrophilic alkylation mechanism is not completely ruled out for all processes.
Scheme 1.11: Fluoromethylation with monofluoromethylsulfoxinium salts
Radical monofluoromethylation reactions are even more unexplored in comparison to the
previously discussed transformations. Ethyl bromofluoroacetate (EBFA) is commonly described
as a protected monofluoromethylation reagent that is inexpensive and readily available.
Monofluoromethyl (hetero)aromatic compounds have been successfully prepared via transition
metal catalysis employing EBFA and boronic acids
101
or aryl iodides
107
(Scheme 1.12.A). The
monofluoromethyl unit can be obtained after decarboxylation of the –COOEt group. Similarly,
work has been conducted to achieve visible light-promoted alkylation with EBFA and subsequent
decarboxylation to afford monofluoromethylated phenanthridine derivatives via fluoroalkylation-
S
O
N
F
Me
Me
R
O
O
O
R
R
1
F
H
H
BF
4
F
H
H
O
S
R
3
O
O
F
O
O-nucleophiles
Base
R
O
O
O
R
R
1
S
Ph
O
N
F
Me
Me
R O
O
O
R
R
1
S
Ph
O
N
F
Me
Me
R O
O
O
R
R
1
S
Ph
O
N
H
2
C
F
Me
Me
R
O
O
O
R
R
1
F
H
H
O selecvity vs C selectivity
17
cyclization of isocyanides. Among other complementary reports
108
, visible light has also been
employed in the development of a method to selectively prepare 2-CFH2 indoles,
benzothiophenes and benzofurans (Scheme 1.12.B).
Scheme 1.12: Radical monofluoromethylation with EBFA
Radical fluoromethylation of (hetero)atoms was reported in 2014 with N-Tosyl-S-fluoromethyl-S-
phenylsulfoximine.
109
This reagent is proposed to produce a radical anion via a SET process from
the nucleophile, yielding the active •CH2F species that would later form a second radical anion.
The transfer of one electron from the newly form radical anion to the sulfoximine would then yield
the desired monofluoromethyl compound (Scheme 1.13).
Scheme 1.13: Radical fluoromethylation of O,S, N and P-nucleophiles
Het
OEt
O
F
Br
Het
COOEt F
X
X
(Wang, 2015)
(Hartwig, 2017)
(OH)
2
Cat.
[Ni(acac)
2
]
I
[Pd-Cinnamyl)Cl]
2
Zn
X
X
F
COOEt
Het
H H
F
X: O,S,N
NC
OEt
O
F
Br
N
F
H H
fac-Ir(ppy)
3
hv
B
A) B)
S
O
N
Ts
Nü
F
H
H
Nü
S
O
N
F
Ts
F
H
H
F
H
H
Nü
S
O
N
F
Ts
Nü
Nu H
Base, heat
F
H
H
Nü
O
Ph
F
H
H
N
F
H
H
N
P
F H
H
O
Ph Ph
S
Ph
F
H
H
Ar
F
H
H
O
O
O,S, N and P-nucleophiles
S
O
N
F
Ts
[1]
[1]
[1]
18
This works illustrates a plausible mechanism for the formation of monofluoromethyl radicals from
this sulfoximine salt. However, the analogous reaction with the trifluoromethyl sulfoximine reagent
and a nucleophile does not afford the expected trifluoromethyl compound. Instead, this reagent
affords the trifluoromethyl product when reacted with electrophiles not nucleophiles, which lends
credence to the hypothesis
109
that the number of fluorine atoms directly affects the philicity and
reactivity of the formed species. Sulfinate salts are another category of stable and versatile
reagents that perform radical monofluoromethylation reactions.
110
Among these, zinc
111
and
sodium
112
sulfinate reagents can be easily prepared in multigram scale and are stable
compounds that allow the formation of radical species. Lastly, the generation of fluorinated
radicals from fluorinated sulfonyl chlorides
58,113
has been reported. An approach for the utilization
of fluoromethanesulfonyl chloride to enable a radical cyclization, followed by an oxidation of a
cyclized radical intermediate via photoredox catalysis has been documented an presented as a
strategy to access 2-oxindoles from N-Arylacrylamides.
58
This sub-section has provided a brief
overview of the type of monofluoromethylation strategies available to affix the fluoromethyl unit to
organic compounds. Next, the difluoromethylation strategies will be discussed.
1.3 Difluoromethylation strategies
The difluoromethyl group has been progressively more studied during the last decade due to the
unique properties that this functionality can impart to molecules. The CF2H moiety has been
described as a lipophilic bioisostere of thiol (SH) and amine (NHR) groups due to their similar
hydrogen bond acidity.
114
However, the ability of this group to hydrogen bond is also strongly
dependent of the chemical environment and substituents on the rest of the molecule.
115
Among
the techniques available for introducing a CF2 unit onto molecules, nucleophilic
difluoromethylation is one of the most popular approaches, very often carried out using
perfluoroalkyl silanes or reagents with S and P centers (Scheme 1.14.i).
116–124
Radical
difluoromethylation and electrophilic direct difluoromethylation are also widely employed
19
techniques.
125–131
Radical methods often employ difluorohalons as reagents, as well as sulfone
and carbonyl-based precursors (Scheme 1.14.ii). On the other hand, electrophilic
difluoromethylation is commonly achieved by employing hypervalent sulfur or iodine reagents as
the ones depicted in Scheme 1.14.iii.
Scheme 1.14: Difluoromethylation strategies
Similarly, difluoromethylenation through difluorocarbene insertion serves as a common tool to
access CF2-containing synthons (Scheme 1.14.iv).
132–134
The reagents used to produce
difluorocarbene in situ usually are initial sources of difluorohalomethide (
—
CF2X) which then
dissociates into difluorocarbene and halogen anion (:CF2 +
—
X). Lastly, direct fluorination of
monofluoromethyl compounds or, defluorination of trifluoromethyl compounds have also been
described as strategies to access CF2 compounds (Scheme 1.14.v)
135
. Many of the
aforementioned methods involve the use of transition metals to prepare organometallic reagents,
or in situ M-CF2H species that act as the active partners in cross coupling reactions. Some of the
most commonly encountered organometallic species containing a CF2H moiety are shown in
Scheme 1.14.vi.
136–140
Given the vast number of strategies available to introduce a difluoromethyl
(i) Nucleophilic difluoromethylation (ii) Radical difluoromethylation
(iii) Electrophilic difluoromethylation
(iv) Difluorocarbene mediated difluoromethylenation
(v) Defluorination or fluorination
R
X
R
X
C
F
F
R
F
F F F F
H
R R
H
F F F H
H
R
Ar
S
CF
2
H
O
O
TMSCF
2
H
CF
2
H P
O
EtO
OEt
TMSCF
2
SPh
Ph
S
CF
2
H
O
NTBS
TMSCF
3
TMSCF
2
Br CF
2
Ph
3
P
TMSCF
2
CO
2
Et
(vi) Difluoromethyl-transition metal species
Cu-CF
2
H Ag-CF
2
H Zn-CF
2
H Pd CF
2
Sn-CF
2
H
X HF
2
C
O
Cl
S
CF
2
Br
O
O
Cl
F F
H I
F F
H
X= OH, COCF
2
H, Cl
CF
3
H
Ar
S
CF
2
Br
O
O
R
E
R
E
CF
2
H
CF
2
R
F
F
R
X
F
F
E E
Nu R
S
CF
2
H
BF
4
O I
PhO
2
SF
2
C
S
CF
2
SO
2
Ph
R
R
HCF
2
Cl
COO
-
X
R R
X
or
R
CF
2
R
CF
2
R
R
X
CF
2
R
or
CF
2
R
CF
2
R Nu
R
or
20
group into a wide variety of organic compounds, this sub-section will be mainly focusing on some
methods that employ silane-based reagents with or without the aid of transitions metals, and a
few -S and -P based reagents. Silicon-based reagents have been tremendously successful in the
field of nucleophilic fluoroalkylation due to their ease of handling and mild activation. The reactivity
of perfluoroalkylsilanes usually involves an activation step wherein a pentacoordinate silicate
intermediate is formed upon nucleophilic addition of an anionic activator to the silicon atom
(Scheme 1.15). This silicate complex [B] is in equilibrium with a bis(perfluoroalkyl)silicate [D] and
either one of the perfluoroalkylsilicates can afford the perfluoroalkyl anion with concomitant
formation of the silane form (species [E] and [A]). This newly formed anion has been shown to be
the active perfluoroalkylating species.
134,141–143
For a comprehensive literature compilation on
difluoromethylenation, pentafluoroethylation, and related fluoroalkylation reactions using silicon
reagents, refer to our book chapter in The Curious World of Fluorinated Molecules, Volume 6 -
1st Edition.
123
Scheme 1.15: Mechanism of fluoroalkyl silane activation for the release of fluoroalkanide
One of the most widely used –CF2H-silanes is (difluoromethyl)trimethylsilane (TMSCF2H) which
can be easily prepared by the reduction of the Ruppert-Prakash reagent (TMSCF3) with sodium
borohydride (NaBH4) in diglyme (Scheme 1.16.a.).
144
Another accessible approach consists of a
Si
R
F
R
R
R
Si
R
F
R
R
R
X
Si
X
R
R
R
X
Si
R
F
R
R
R
R
F
[A] [B] [C] [D]
R
F
Si
X
R
R
R
[E]
Si
R
F
R
R
R
[A]
R
F
= CF
2
X, CF
3
, CFXY
active fluoroalkylating
species
disproportionation
21
Mg-mediated reduction and desulfonylation/silylation of PhSO2CF2H at 0º C (Scheme 1.16.b.).
144
Other methodologies are available however, the former two are considerably the most employed.
Scheme 1.16 Synthesis of (difluoromethyl)trimethylsilane
Nucleophilic difluoromethylation of carbonyl compounds is one of the most straightforward ways
to access dilfluoromethyl carbinols, however, the activation of (difluoromethyl)trimethylsilane has
proven to be more challenging than that of the parent trifluoromethylating Ruppert-Prakash
reagent, by virtue of its higher Si–CFnX bond order.
145
In 1995, Fuchikami and Hagiwara
demonstrated the difluoromethylation of a couple of carbonyl compounds by activating TMSCF2H
under harsh conditions.
145
It wasn’t until 2011 that Hu and coworkers described a direct
nucleophilic difluoromethylation of aldehydes, imines and non-enolizable ketones using
TMSCF2H as a difluoromethide source. The choice of activator (CsF or
t
BuOK) was largely
dependent on the nature of the substrate and the choice of solvent.
146
In the same year, Igumonov
and coworkers found that TMSCF2H in presence of a nucleophilic catalyst such as CsF could
afford the products of the difluoromethylation of aldehydes and ketones (Scheme 1.17 a and b).
After a 16-year-gap, the long-elusive direct difluoromethylation using TMSCF2H had finally been
set in motion. The efforts to synthesize difluoromethyl carbinols were further developed by the
activation of TMSCF2H with phosphazenes based on previous evidence on activation of silylated
reagents with Lewis bases.
147
Catalytic amounts of the phosphazine base
t
Bu-p4 afforded the
expected a–CF2H alcohols from aromatic aldehydes and non-enolizable ketones in moderate to
excellent yields (Scheme 1.17.c). Aliphatic aldehydes showed the lowest conversions, whereas
Si Me
Me
Me
F
F
F
NaBH
4
diglyme, 20—25 ºC
70%
Si Me
Me
Me
F
F
H
Mg/Me3SiCl
DMF, 0 ºC
76%
Si Me
Me
Me
F
F
H
PhSO
2
CF
2
H
(a)
(b)
22
aromatic and heterocyclic aldehydes proved to be the most suitable substrates for this
methodology.
Scheme 1.17: First approaches for the difluoromethylation of carbonyl compounds with TMSCF 2H
In 2015 a nucleophilic addition of TMSCF2H-derived difluoromethide to a-imino ketones and diaryl
1,2-diketones by two different methods (a and b) was reported (Scheme 1.18).
148
The resulting
b-amino-a-(difluoromethyl)alcohols were selectively obtained after the sodium borohydride-
promoted reduction of the intermediate imine (and in some cases concomitant desilylation). In the
same way two a-hydroxydifluoromethyl ketones were prepared in good and excellent yields and
were further reduced to their corresponding 1,2-diols in high yields.
time
1-3 days (Igoumnov, 2011)
(Hu, 2011) 9h/ 1h
Additive
-
TBAF
R
1
R
2
O
R
1
= alkyl, aryl
R
2
= H, alkyl
1) TMSCF
2
H
CsF, DMF
rt, time
2) Additive
R
1
R
2
HF
2
C OH
(70% — 85%)
yields
(50% — 96%)
S
N
O
t
BuOK
THF, -78ºC-rt
R= alkyl, aryl
R
H
S
N
H
O
R’
CF
2
H
TMSCF
2
H
R
1
R
2
O
R
1
= aryl
R
2
= aryl
R
1
R
2
HF
2
C OH
(95%, 97%)
(68% — 91%)
a)
b)
R
1
H
O
R
1
= alkyl, aryl
1) TMSCF
2
H
t
Bu-P
4
DMF, rt
0.5h — 3h
2) H
3
O
+
R
1
R
2
HF
2
C OH
R
1
R
2
O
R
1
, R
2
= aryl
R
1
CF
2
H
OH
N
P N N
N
P(NMe
2
)
3
P(NMe
2
)
3
t-Bu
(Me
2
N)
3
P
t
Bu-P
4
(42% — 99%)
(43% — 46%)
c)
23
Scheme 1.18: Synthesis of b-amino-a-(difluoromethyl)alcohols and 1,2-difluoromethyl diols
Enolizable ketones can also be successfully transformed into their corresponding carbinols. Using
HMPA as an additive with the goal of stabilizing the silicate intermediate which was proposed to
be more reactive towards ketones than the parent pentacoordinate silicate, this method afforded
difluoromethyl alcohols in generally good yields. It was also proposed that excess fluoride was
needed to suppress the enolization side-reactions.
149
Although highly enolizable ketones proved
to be poor substrates, acyclic ketones, 5-7-membered cyclic ketones, as well as aryl and
[hetero]aryl ketones were conveniently converted (Scheme 1.19.a). Shortly after, Hu and
coworkers introduced the concept of a hypervalent silicon intermediate as part of the proposed
mechanism in the difluoromethylation of enolizable ketones. The aforementioned silicate was
stabilized with 18-crown-6 (and Cs
+
as the countercation) and further characterized by NMR
spectroscopy. The reactivity of the pre-generated pentacoordinate silicate species was
demonstrated by reacting it with challenging substrates such as enolizable ketones, which
smoothly underwent difluoromethylation (Scheme 1.19.b.). Based on this successful result, the
group developed a catalytic procedure that involves the in situ formation of the above-mentioned
species to obtain tertiary difluoromethyl alcohols from enolizable ketones and other carbonyl
compounds in moderate to excellent yields.
143
Ar
O
NR
Ar
O
O
Ar
HF
2
C
HO Ar
NHR
HF
2
C
OH
Ar
Ar
OH
(+/-)
1) TMSCF
2
H
activator
solvent
T ºC, 12h
2) NaBH
4
EtOH
rt, 12h
DMF or THF
Activator
CsF or
t
BuOK
a)
b)
t
BuOK
solvent
THF
T ºC
rt or -78
-78
(30% — 65%)
(89% — 91%)
24
Scheme 1.19: Difluoromethylation of enolizable ketones
Due to the prior success observed in the activation of TMSCF2H with alkoxide bases, Mikami and
coworkers envisioned the synthesis of ethyl difluoropyruvate as the electrophile and
difluoromethyl group source for the catalytic and enantioselective synthesis of tertiary alcohols
and oxetenes. Ethyl difluoropyruvate was prepared by employing TMSCF2H as the
difluoromethide source and diethyl oxalate as the starting material. The resulting product from the
nucleophilic reaction is the hydrated form, which can further be hemiacetalized and dehydrated
to obtain the desired ethyl difluoropyruvate.
150
Scheme 1.20: Synthesis of ethyl difluoropyruvate and applications
Direct difluoromethylation approaches with TMSCF2H have also been significantly applied to
other interesting substrates. This is demonstrated by the utilization of perfluoroalkyl/aryl silanes
in the regioselective functionalization of heterocyclic N-oxides.
151
The activation of
Pre-generated [Me
3
Si(CF
2
H)
2
]- [(18-crown-6)Cs]
+
1) CsF
18-crown-6
TMSCF
2
H
DME, rt
overnight
2) TBAF, rt, 1h
3) HCl, rt, 1h
R
1
O
R
2
Si
CF
2
H
CF
2
H
Me
Me
Me
(18-crown-6)Cs
R
1
OH
R
2
CF
2
H
R
1
, R
2
= aryl, alkyl
R
1
, R
2
= aryl, alkyl
Key intermediate
(37% — 98%)
R
1
O
R
2
R
1
, R
2
= aryl, alkyl
1) TMSCF
2
H
CsF
HMPA
rt, 18h
2) TBAF
R
1
R
2
R
1
, R
2
= aryl, alkyl
HO
CF
2
H
(18% — 95%)
a)
b)
OEt CO
2
Et
O
1) TMSCF
2
H
EtOK
t
BuOK
THF, rt, 1h
2) EtOH
distillation P
2
O
5
HF
2
C CO
2
Et
O
(63%)
Difluoropyruvate
CO
2
Et
HO CF
2
H
R R
1
CO
2
Et
O
CF
2
H
*
*
Tertiary Alcohols
Oxetenes
25
(difluoromethyl)trimethylsilane with an alkoxide base at low temperatures resulted in the selective
difluoromethylation of the 2-position, generating –CF2H-containing quinolines in moderate yields
(Scheme 1.21.A). In the same fashion, Nagase et. al. reported a method to selectively prepare
4-perfluoroalkyl heterocycles employing tris(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)borane
as the bulky Lewis acid for the quinoline-borane complexes, and perfluoroalkylsilanes.
152
The
activation of TMSCF2H with CsF in DMF led to a proposed ionic intermediate that undergoes
aromatization by successive oxidation with PIFA to furnish 4-(difluoromethyl)quinoline as the
major product, along with a small amount of the 2-susbtituted quinoline as a by-product (Scheme
1.21.B.).
Scheme 1.21: Regioselective difluoromethylation of heterocycles
This selective perfluorofunctionalization of heterocycles approach was also applied in the silver
mediated C-H bond activation of phenanthridines and 1,10-phenanthrolines with TMSCF2H. 1,10-
Phenanthrolines were reacted with (difluoromethyl)trimethylsilane in the presence of
t
BuOK and
AgCl, with successive treatment with NCS to selectively afford their corresponding 2-
difluoromethylated analogues in moderate to good yields. This is the first report of 2-
N
X
O
R
X= H, S-Alkyl
R= FG
TMSCF
2
H
t
BuOK
3Å MS
THF
-20 ºC, 50 min
N
X
R
X= H, S-Alkyl
R= FG
CF
2
H
(15% — 52%)
N
(F
3
C--4C
6
F
4
)
3
B
1) TMSCF
2
H
CsF
DMF/ MS 4Å
0ºC — rt ,5h
2) PIFA
25 ºC, 3h
3) MeOH
65ºC, 2h
N
CF
2
H
1 example
(56%)
R
(32% — 78%)
N
R
1
H
R
N
R
1
CF
2
H
N
R
N
R
1
H
TMSCF
2
H
AgOAc
t
BuOK
oxidant
solvent
rt, overnight
(i) phenanthridines
(ii) phenanthrolines
N
R
N
R
1
CF
2
H
(20% — 73%)
A) B)
C)
tetraglyme
oxidant
PIFA
solvent
dioxane NCS
(i)
(ii)
AgX
AgOAc
AgCl
26
perfluoroalkylated 1,10-phenanthrolines. Moreover, phenanthridines were selectively
difluoromethylated under similar conditions, employing AgOAc as the mediator and PIFA as the
oxidant that enables the aromatization of the intermediate addition product. It was proposed that
the use of a silver salt facilitates the nucleophilic addition of the difluoromethyl anion formed from
the silane, by virtue of the coordination with a nitrogen atom (Scheme 1.21.C).
137
An alternative
approach to access perfluoroalkylated heterocycles is installing the perfluoroakyl moiety during
the construction of the scaffold. Such approach was taken by Nazaré and coworkers for the
synthesis of 3-perfluoroakyl-2H-indazoles. The protocol describes the preparation of one 3-
(difluoromethyl)-2-phenyl-2H-indazole via difluoromethylation of the corresponding
nitrobenzaldimine. Subsequential cyclization yields the title compound in 61% yield (Scheme
1.22).
153
Scheme 1.22: Synthesis of –CF 2H indazoles
Nucleophilic difluoromethylation of sulfur and selenium centers is another important approach to
access possibly useful synthetic blocks.
154
Gooßßen and coworkers described a copper
thiocyanate-catalyzed protocol to generate difluoromethyl thioethers from alkyl and aryl
thiocyanates utilizing TMSCF2H as the pronucleophile (Scheme 1.23.A.i). Inspired by the
excellent conversions observed, they envisaged a one-pot protocol for the thiocyanation-
difluoromethylation of other C-electrophiles. Primary alkyl halides were chosen as the substrates
to generate a diverse group of alkyl-thioethers (Scheme 1.23.A.ii). The method consists of an in-
situ generation of the alkyl thiocyanides from NaSCN with subsequent displacement of the
cyanide group by nucleophilic Cu-CF2H-derived –CF2H. The same difluoromethylthiolating
approach was slightly modified in order to generate aryl difluoromethyl thioethers from
R
R= FG
O
NO
2
R
1
C
6
H
4
—NH
2
EtOH
reflux, 2h
R
N
NO
2
R
1
TMSCF
2
H
TBAT
THF
rt, 30 min
R
R= FG
N
H
NO
2
R
1
CF
2
H
(14% )
R
N
N
R
1
CF
2
H
R= FG
(61% )
SnCl
2
-2H
2
O
EtOH
75 ºC, 5h
27
arenediazonium salts. Initially, aryl thiocyanates were generated by a Sandmeyer reaction. Upon
concentration of the reaction mixture, the difluoromethylating solution was added to the crude
residue to generate the desired products in good to excellent yields (Scheme 1.23.A.iii).
155
Shortly after, the same group reported another one-pot procedure for the AlCl3-catalyzed
thiocyanation-trifluoro and difluoromethylation cascade of electron-rich arenes by C–H bond
activation. In this method, the electrophile was chosen to be N-thiocyanatosuccinimide (NTS)
which is readily available and can be prepared from succinimide and NaSCN.
156
It was found that
arenes with high nucleophilicity underwent the thiocyanation step smoothly, whereas less
nucleophilic substrates did not undergo electrophilic aromatic substitution. The in situ formed aryl-
thiocyanates were successfully difluoromethylated to afford aryl difluoromethyl thioethers in good
yields (Scheme 1.23.B).
Scheme 1.23: Nucleophilic difluoromethylation of S-centers
In 2016, a metal-free direct difluoromethylation of sulfur-containing molecules was disclosed by
Han et. al, where disulfides and phenylsulfanyl (pseudo)halides were converted to the
corresponding difluoromethyl thioethers and/or di(arylsulfanyl)difluoromethanes.
157
Two protocols
to obtain either one of the products from symmetric aryl or alkyl disulfides were proposed. The
Alkyl LG
LG= Br, OMs
R SCN
R= Alkyl, aryl
X
N
2
X= C, N
R
BF
4
1) Additives
time
temperature
2) TMSCF
2
H
CuSCN
CsF
Solvent
rt, 12h
time
NaSCN
—
CuSCN
Solvent
Additives T ºC
CsCO
3
— DMF —
(i)
(ii)
(iii)
(i)
(ii)
(iii)
NaSCN 2 h 60—110 DMF
1 h rt
MeCN/
DMF
R SCF
2
H
(72% — 99%)
(61% — 98%)
(61% — 95%)
Alkyl SCF
2
H
X
SCF
2
H
R
H
1) NTS, AlCl
3
MeCN, rt, 12h
2) TMSCF
2
H
CuSCN, CsF
DMF
rt, overnight
SCF
2
H
R
R
R= FG
R= FG
(53% — 88%)
A)
B)
28
use of CsF as the initiator results in the generation of difluoromethyl thioethers, while using
t
BuOK
as the activator produces the difluoromethyl dithioacetals, both in moderate to excellent yields
(Scheme 1.24.A.i). On the other hand, a mixture of products can be obtained from the
nucleophilic difluoromethylation of phenylsulfanyl (pseudo)halides. The ratio of products can be
tuned depending on the choice of leaving group and initiator. Activating the silane with cesium
fluoride favors the formation of phenyl(difluoromethyl) thioether, whereas the use of
t
BuOK
renders molecule b (Scheme 1.24.A.ii) as the major product.
Scheme 1.24: Nucleophilic difluoromethylation of sulfides and disulfides
Later that year, a similar methodology was developed to access di(alkyl/aryl) difluoromethyl
disulfides from TMSCF2H and CsF in NMP, albeit with shorter reaction times.
158
The protocol
tolerates a good range of functional groups and produces the desired compounds in moderate to
excellent yields (Scheme 1.24.B). The approaches to access perfluoroalkyl-selenium-containing
compounds are more scarce and typically involve, either the pre-installation of a selenium atom
in the starting materials and successive nucleophilic or radical perfluoroalkylation, or
perfluoroalkyl selenolation of various electrophiles.
159
In 2016, a method was devised to introduce
the SeCF2H moiety into Aryl C–H bonds (Scheme 1.25.A).
160
The electrophilic aromatic
R
S
S
R
R = aryl, alkyl
R S CF
2
H
R S CF
2
S R
R = aryl, alkyl
(40% — 95%)
R = aryl
(40% — 90%)
R
S
S
R
R = alkyl
TMSCF
2
H
CsF
NMP
0ºC —rt
16 h
R
1
S
S
R
1
R
1
= (Het)Aryl
R
S
CF
2
H
R = alkyl
R
1
S
CF
2
H
R
1
= (Het)Aryl
(34% — 82%)
(49% — 99%)
A)
b)
(i)
TMSCF
2
H
CsF
t
BuOK
S
X
X = Cl, SO
2
Ph, CN
Path 1
Path 2
S
CF
2
H
S
C
F
2
S
a
b
Cl
SO
2
Ph
CN
34% 5%
47% 8%
43% 2%
a b
1% 55%
1% 87%
2% 1%
a b
Path 2 Path 1
CsF t
BuOK
(iI)
29
substitution is carried out by the in situ species formed from the oxidative chlorination of
benzyldifluoromethyl selenide, which in turn is prepared from the nucleophilic difluoromethylation
of (selenocyanatomethyl)benzene with TMSCF2H. The work by Dong et. al. describes a similar
nucleophilic difluoromethylation of selenocyanates with TMSCF2H to access difluoromethyl
(aryl/alkyl) selanes in moderate to high yields, employing an alkoxide base as the activator for the
silane (Scheme 1.25.B).
141
More recently (2020) Lu et. al. reported a photocatalytic approach for
the difluoromethylselenolation of aromatic amines with Se-(difluoromethyl)4-
methylbenzenesulfonoselenoate (TsSeCF2H) which was prepared by reacting TMSCF2H and
(selenocyanatomethyl)benzene, and was further treated with 4-toluenesulfinate (TsNa) (Scheme
1.25.C).
161
Scheme 1.25: Difluoromethylation of Se–CN bonds
An example of TMSCF2H being employed as a pronucleophile to functionalize tellurium centers
can be found in the work by Togni and coworkers where they show the synthesis of a
difluoromethyl telluride in 33% yield (Scheme 1.26). This transformation could enable access to
electrophilic –CF2H reagents.
162
Scheme 1.26: Difluoromethylation of ditellurides
Se
N
TMSCF
2
H
CsF
THF
0ºC —23ºC
15 h
Se
F
F
Difluoromethylselenolation
1) SO
2
Cl
2
THF
0ºC 45 min
2) R—ArH
THF, 0ºC — 23ºC
R Ar SeCF
2
H
2 examples
(92%)
R—SeCN
TMSCF
2
H
t
BuOK
THF
0 ºC, / 24h
or rt/ 6h
R—SeCF
2
H
R= aryl, alkyl
R= aryl, alkyl
(54% — 94%)
A)
B)
S
1) TMSCF
2
H
TBAF
THF
2) SOCl
2
, DCM
TsNa, DCM
BnSeCN
O
O
SeCF
2
H
C)
Te
Te
O
O
O
HF
2
C Te
O
TMSCF
2
H
CsF
DMF
rt, overnight
(33%)
30
Recent difluoromethylation approaches utilizing TMSCF2H as a source of nucleophilic –CF2H
were described by Pace and coworkers in 2019. In an effort to synthesize difluoromethyl ketones
(DFMKs) from Weinreb amides,
163
the group first performed a base screening to select the optimal
initiator for the reaction with an epimerizable Weinreb amide. Activation with
t
BuOK resulted in
moderate conversion with unavoidable optical impurities, whilst the use of a more hindered base
like potassium amylate (
t
pentOK) afforded the product in excellent yield with no epimerization. A
quality of the procedure that is worth noting is the lack of enolization in substrates with acidic
protons, which opens the possibility for a wider substrate scope. The methodology tolerates a
broad set of functionalities, affording 36 DFMKs in good to excellent yields (Scheme 1.27.A). In
addition, the synthetic utility of the obtained products was shown. A similar approach was applied
by the same group in the difluoromethylation of isocyanates and iso(thio)cyanates and to generate
a,a-difluoromethyl oxoamides and the unprecedented thioamides, respectively. Potassium tert-
amylate was again used as the activator to generate the nucleophilic species from TMSCF2H and
under their optimized conditions, a set of aromatic and aliphatic a,a-difluoromethyl amides were
obtained in excellent yields (Scheme 1.27.B). The sulfur-analogues were also prepared in high
yields, tolerating potentially electrophilic functionalities and giving rise to a new class of motifs
(a,a-difluoromethylthioamides) with potential synthetic applications.
164
31
Scheme 1.27. Nucleophilic difluoromethylation promoted by potassium tert-pentoxide
(Difluoromethyl)trimethylsilane has also been widely employed in combination with catalytic or
stoichiometric amounts of transition metals to selectively functionalize a wide variety of
substrates. The first approach was reported by Hartwig and coworkers in 2012 where copper
iodide was used as the promoter for the difluoromethylation of aryl iodides with TMSCF2H and
CsF. It was proposed that the reaction proceeded via the in situ formation of ligand-free CuCF2H
as the difluoromethylating entity, which is readily converted to the cuprate Cu(CF2H)2
-
. The latter
has been described as a stable reservoir of the active neutral species.
165
This methodology has
been extensively applied to obtain difluoromethylarenes from electron rich and electron-neutral
aryl iodides, however, electron poor iodoarenes are not effectively converted under these
conditions. Recognizing the situation at hand, Qing and coworkers described a procedure to
prepare –CF2H-aryl and heteroaryl compounds from electron-poor aryl iodides utilizing a
TMSCF2H/CuCl/1,10-phenanthroline system in DMF at room temperature. b-styryl iodides were
also subjected to the reaction conditions producing their corresponding allylic-CF2H derivatives
with retention of stereochemistry.
166
Both previously disclosed difluoromethylation procedures are
complementary and offer efficient ways to access –CF2H-containing arenes (Scheme 1.28).
a)
b)
R N
O
R = aryl, alkyl
OMe
OMe
N
C
S
R
R = aryl, alkyl
N
C
O
R
R = aryl, alkyl
R CF
2
H
O
R = aryl, alkyl
(73% — 96%)
N CF
2
H
S
R = aryl, alkyl
(83% — 95%)
H
R
N CF
2
H
O
R = aryl, alkyl
(80% — 91%)
H
R
TMSCF
2
H
t
pentOK in c-hex
THF, 0 ºC, 1h or 4h
NHCl
4
(aq.)
c)
32
Scheme 1.28: Copper-promoted difluoromethylation of aryl iodides.
The first catalytic approach to access difluoromethyl arenes using TMSCF 2H was disclosed by
Shen and coworkers who envisioned a bimetallic Pd/Ag system which involves two catalytic
cycles with two key transmetalation steps. The group first assessed the ability of a palladium (II)
pre-catalyst to from the difluoromethylated complex that would undergo reductive elimination at
high temperatures to yield the desired Ar-CF2H product. It was established that an L-type
bidentate ligand exchange between the pre-catalyst’s ligand to DPPF, upon reaction with
TMSCF2H, forms the complex that more effectively undergoes reductive elimination. The next
step was to evaluate whether the chosen coinage metal could generate a stable –CF2H complex
that would further undergo transmetalation of the difluoromethyl group to Pd. The precursor
chosen for this stage was the [(SIPr)AgCl] complex that smoothly generates the silver-
difluoromethyl analogue 1a (Scheme 1.29) upon reaction with TMSCF2H. Once all the key
intermediates for every step of the predicted catalytic cycle were identified and characterized, the
scope of the reaction was investigated. The one pot procedure furnishes the desired
difluoromethyl arenes from aryl iodides and bromides in moderate to excellent yields, tolerating a
broad variety of functional groups
167
(Scheme 1.29.a.).
I
TMSCF
2
H
Cu
I
Activator
solvent
T (ºC), time
CF
2
H
R R
Activator
CuI
CsF
CuCl/phen
t
BuOK
Solv.
NMP
DMF
Cu
I
T ºC
120
rt
(Hartwig, 2012)
(Qing, 2014)
R= EDG, EWG
time
24h
24h
33
Scheme 1.29: [(SIPr)AgCF 2H]-catalyzed difluoromethylations
The kinetic studies performed showed that the presence of the silver catalyst promotes a faster
transmetalation reaction than the one that takes place between the silane and palladium,
therefore establishing its role in transferring the difluoromethyl group. With that information in
hand, the group expanded their investigations with the [(SIPr)AgCF2H] complex and further
utilized it as the difluoromethylating agent to prepare difluoromethylated alkenes from
vinyl(pseudo)halides (i,ii,iii)
168
or from iodonium triflates (iv)
169
, difluoromethyl arenes from
diaryliodonium salts (v)
169
, –CF2H diazo compounds from aryldiazonium salts (vi)
169
and
difluoromethyl ketones from acyl chlorides (vii)
169
in high yields (Scheme 1.29.b). This isolable
and stable silver complex prepared from TMSCF2H offers an alternative to conduct base-sensitive
(63% — 99%) (58% — 91%)
R= Alkyl, aryl
R
CF
2
H
R
CF
2
H
R
1
R
2
R, R
1
, R
2
= Alkyl, aryl
(63% — 98%)
R
CF
2
H
R
1
R
2
R, R
1
, R
2
= Alkyl, aryl
R CF
2
H
O
R = alkyl, aryl
N
2
CF
2
H
R= FG
R
CF
2
H
R = Aryl
CF
2
H
R
R = FG
(68% — 93%) (71% — 94%)
(74% — 90%) (55% — 93%)
R
N
N
Ag Cl
TMSCF
2
H
t
BuOM
THF
rt, 1.5h —4h
N
N
Ag CF
2
H
(SIPr)AgCl
(IPr)AgCl
(SIPr)AgCF
2
H (1a)
(IPr)AgCF
2
H (1b)
X
Pd(dba)
2
/DPPF
20 mol% [(SIPr)AgCl]
TMSCF
2
H, NaO
t
Bu
dioxane or toluene
80ºC, 4h — 6h
CF
2
H
R
X= Br, I
R
(58% — 96%)
a)
b)
(i) (ii) (iii) (iv) (v)
(vi) (vii)
34
reactions in neutral conditions, as well as many other transformations.
170–172
Another popular
approach to access difluoromethyl arenes is the Sandmeyer difluoromethylation of (hetero)aryl
diazonium salts reported by Goossen and coworkers.
173
Unlike other copper-promoted
difluoromethylation reactions, the copper salt that favors this reaction is copper thiocyanate, which
generates CuCF2H upon addition of TMSCF2H and CsF. The reaction furnishes difluoromethyl
aryl and heteroaryl compounds in moderate to excellent yields (Scheme 1.30), with the exception
of iodo and carboxylate-substituted arenes, which are not tolerated by the reaction conditions and
fail to give the desired products.
Scheme 1.30: Sandmeyer difluoromethylation of aryldiazonium salts
TMSCF2H has also been used to access difluoromethylated alkynes through a copper-mediated
oxidative procedure that allows direct C–H bond activation. Zhu et. al described CuCF2H ⇌
[CuCF2H)2]
-
as the organometallic entities that are generated in the reaction mixture. It was
proposed that such difluoromethyl copper species generate an intermediate that upon oxidation
with 9,10-phenanthraquinone, undergo reductive elimination to afford terminal –CF2H-alkynes in
moderate to good yields. This approach will be evaluated again in Chapter 4 of this dissertation
(Scheme 1.31.A).
174
The same group applied a similar approach to prepare difluoromethyl-
heteroarenes through the generation of CuCF2H in situ from TMSCF2H and CuCN, demonstrating
that utilizing the same oxidant, difluoromethyl oxazoles, oxadiazoles, thiazoles, thiophenes,
imidazoles, and other heterocycles (Scheme 1.31.B) can be prepared.
X
N
2
TMSCF
2
H
CuSCN
CsF
DMF, 40ºC
X
CF
2
H
R
X= C, N
R= FG
R
(38% — 96%)
BF
4
DMF, rt, 12h
Cu—CF
2
H
35
Scheme 1.31: Copper-mediated oxidative difluoromethylation
The use of copper as either a promoter or as a catalyst for difluoromethylation reactions with
TMSCF2H prevails as a useful strategy due to the reactive nature of the presumed intermediates
formed in situ. However, such reactivity renders them unstable and non-isolable, which poses a
disadvantage for mechanistic studies. In 1996, Brauer and coworkers reported that
difluoromethylcopper is thermally unstable and susceptible to oxidation, which results in the
disproportionation to Cu
0
and the inactive tetrakis(difluoromethyl)cuprate
III
. Cis and trans
difluoroethylene as well as tetrafluoroethane are other products generated from the
decomposition of Cu(CF2H).
175
With these considerations in mind, Sanford and coworkers
visualized the preparation of a L–Cu–CF2H complex that could be stabilized by a suitable ligand
in order to make it isolable. Due to the properties that NHC carbenes possess as electronically
and sterically stable units, they are widely used as ancillary ligands in organometallic chemistry.
Their ability to act as sigma donors facilitates the formation stable complexes with a wide variety
of transition metals.
176
Taking inspiration from the previous literature on (NHC)MX complexes (M=
metal, X=perfluoroalkyl) the Sanford group developed a method to prepare two stable and isolable
R H
TMSCF
2
H
CuI
t
BuOK
9,10-phenanthraquinone
DMF, 0ºC to rt
R CF
2
H
O
O
9,10-phenanthraquinone
(45% — 75%)
X
R
Z
Y
H
TMSCF
2
H
CuCN
9,10-phenanthraquinone
t
BuOK
NMP
rt/ 6h
X
R
Z
Y
CF
2
H
R= FG
X,Y, Z = N,C,S,O
R= FG
X,Y, Z = N,C,S,O
(48% — 87%)
N
O R
H
N
O R
CF
2
H
(52% — 87%)
R= aryl, alkyl
R= aryl, alkyl
or or
A)
B)
36
mononuclear (NHC)Cu(CF2H) complexes by varying the substituents in the carbene ligand. The
most sterically hindered (NHC)CuCl (NHC = 2-IPr, 2-SIPr) precursors displayed the best reactivity
when mixed with TMSCF2H and the resulting (NHC)Cu(CF2H) complexes showed the longest
stability (Scheme 1.32.a.V) thus, they were successfully isolated and fully characterized. Based
on the remarkable success with generating the aforementioned complexes, the group developed
a procedure to prepare difluoromethylarenes from iodoarenes and stoichiometric amounts of (2-
iPr)Cu(CF2H). The reaction furnished the expected products in moderate to excellent yields, which
led Sanford and coworkers to propose a (2-iPr)Cu(CF2H)-catalyzed cross coupling reaction of aryl
iodides with TMSCF2H. Based on the notions that fluoride activators promote the transmetalation
from the silicon center to the transition metal complex, and that high temperatures are needed for
the oxidative addition (which is considered the slow step of the reaction with Cu) the catalytic
protocol was established as depicted in Scheme 1.32.a.ii. obtaining the difluoromethylated
products in moderate to excellent yields.
177
In order to expand the scope of the aryl halide-
substrates used for difluoromethylation reactions with perfluoroalkylsilanes, the same group
developed two comparable palladium-catalyzed procedures for the difluoromethylation of
chloroarenes and bromoarenes with (difluoromethyl)trimethylsilane and sterically hindered
phosphorous-based ligands. Method A employs 3 mol % of the Pd
0
precursor and 4.5 mol % of
the dialyklbiarylphosphine BrettPhos to generate the corresponding –CF2H-Aryl products from -
bromo and chloroarenes in moderate to good yields (Scheme 1.32.b.A), with a few unreactive
exceptions (di-ortho substituted arenes). Alternatively, method B utilizes 5 mol % of the
monodentate phoshpine-Pd
0
complex Pd(PtBu3)2, that along with TMSCF2H, they generate the
products in overall good yields
178
(Scheme 1.32.b.B).
37
Scheme 1.32: Copper and palladium catalyzed difluoromethylation reactions
An important application of (difluoromethyl)trimethylsilane is its use as a precursor to generate
other functionalized perfluoroalkylsilanes. Ojima and Fuchikami reported the synthesis of
PhMe3SiCF2Br as the brominated analog of (difluoromethyl)phenyldimethylsilane and
demonstrated the ease of the radical bromination of a CF2-H bond with a geminal silyl group.
179
In a 2012 report by the Struchkova group, TMSCF2H was brominated employing sodium bromide
in a water/hydrogen peroxide system irradiated with light to afford (bromodifluoromethyl)trimethyl
silane (TMSCF2Br) and was further used to prepare difluoro(trimethylsilyl)-acetonitrile
(TMSCF2CN) (Scheme 1.33.a.) which served as a source of cyanodifluoromethyl for reactions
with carbonyl compounds, imines, and enamines. N-bromosuccinimide is also a suitable
X
R
X= Cl, Br
R= FG
CF
2
H
R
X= Cl (<5% — 90%) A
(25% — 78%) B
X= Br (47% — 95%) A
(36% — 77%) B
Method A or B
TMSCF
2
H
3-5 mol% Pd
0
P ligand
CsF
dioxane
T ºC, 16h–36h
Pd(dba)
2
Pd(PtBu
3
)
2
OMe
MeO PCy
2
i
Pr
i
Pr
i
Pr
—
Pd
0
P ligand
BrettPhos
T ºC
100
120
A
B
BrettPhos
N N
R R
Cu
Cl
1)
t
BuONa
THF
rt, 1h
2) TMSCF2H
shake 10 s
still for 1h
N N
R R
Cu
CF
2
H
R = 1-
i
Pr
1-IMes
1-IPr
1-SIPr
R = 2-
i
Pr
2-IMes
2-IPr
2-SIPr
(0%)
(0%)
(51%)
(82%)
R-Ar-I
toulene
90 ºC, 20h
CF
2
H
R
R= FG (40% — 98%) (i)
I
R
R= FG
10 mol% IPrCuCl
TMSCF2H
CsF
3:1 dioxane : toluene
120 ºC, 20h
(44% — 92%) (ii)
Stoichiometric (i)
Catalytic (ii)
a)
b)
(V)
38
brominating agent to prepare TMSCF2Br from TMSCF2H in dichloromethane at high temperature,
as reported by Hu and coworkers in 2013 (Scheme 1.33.c.).
180
Scheme 1.33: Bromination of TMSCF 2—H bonds
(Difluoromethyl)dimethylphenylsilane is an organosilicon compound similar to TMSCF2H that was
first synthesized in 1981. The halogen exchange reaction between (chloro)dimethylphenylsilane
and lithium generate phenyldimethylsilyllithium as an intermediate, which yields the expected
compound upon reaction with chlorodifluoromethane (Scheme 1.34).
179
The first use of this
compound for nucleophilic difluoromethylation reactions was reported by Hagiwara and
Fuchikami in 1995. It was found that potassium fluoride in DMF served as the appropriate system
to efficiently activate the perfluoroalkylsilane, however, in order to successfully perform the
difluoromethylation of the substrates, the reaction had to be carried out at high temperatures. In
this way, aromatic and aliphatic aldehydes and ketones were converted to their corresponding
difluoromethyl carbinols in moderate to good yields (Scheme 1.34.A) setting the precedent for
nucleophilic difluoromethylation of carbonyl compounds with this and other related
difluoromethylsilanes.
145
The second report that involves the use of this reagent as a source of
difluoromethide was discussed earlier in this chapter where Hu and coworkers performed a direct
nucleophilic difluoromethylation of aldehydes, imines and non-enolizable ketones. Under their
conditions, one substrate was successfully converted to its difluoromethyl analogue in a
comparable yield to when TMSCF2H was used as a source of difluoromethide (Scheme
1.34.B).
146
Although this reagent has proven its utility in nucleophilic difluoromethylation reactions,
a)
c)
Si Me
Me
Me
F
F
H Si Me
Me
Me
F
F
Br
NaBr
H
2
SO
4
H
2
O
2
water
hv
NBS
CH
2
Cl
2
, 90ºC
Si Me
Me
Me
F
F
CN
conditions
(80%) b)
39
its activation is more challenging thus, it has not been as extensively used as the analogous
trimethylsilyl version.
Scheme 1.34: Difluoromethylation of carbonyl compounds with PhMe 2CF 2H
Similar perfluoroalkylsilanes have been prepared, where the dilfuoromethylene unit is attached to
another perfluoroalkyl group, instead of a hydrogen atom. These reagents have been employed
for nucleophilic difluoroalkylation reactions that install longer fluorinated carbon chains. One
example of this is the pentafluoroethylation of organic molecules. The first report of the synthesis
and application of a silane similar to the Ruppert-Prakash reagent (TMSCF3), but with a longer
perfluoroalkyl chain, can be traced back to 1989. In that year, Ruppert and coworkers published
a patent that described the synthesis of (pentafluoroethyl)trimethylsilane (TMSC2F5 or
TMSCF2CF3) from (chloro)trimethylsilane and iodopentafluoroethane, promoted by a
tris(dialkylamino)phosphine (Scheme 1.35).
181
Subsequent distillation and condensation afforded
the title compound in 75% yield. Simultaneously, Prakash and coworkers developed a method to
obtain TMSCF2CF3 under similar conditions from bromopentafluoroethane and
(chloro)trimethylsilane, which was published in 1991.
182
Si
Me
Me
F
F
Si Cl
Me
Me
(35%)
Li
THF
PhMe
2
SiLi
ClCF
2
H
R
1
H
O
R
1
= alkyl, aryl
KF (5-50 mol%)
DMF
100 ºC
R
1
H
R
1
= alkyl, aryl
HF
2
C
OH
CsF
DMF, rt, 9h
TBAF, rt, 1h
Si
Me
Me
F
F
A)
B)
40
Scheme 1.35: Preparation of (pentafluoroethyl)trimethyl silane (TMSC 2F 5)
These protocols opened the door to a new spectrum of possibilities to access compounds with
perfluoroalkyl (CnF2n+1) motifs. The chemical behavior exhibited by this silane is analogous to
other perfluoroalkylsilanes. It can be effectively activated by stoichiometric or catalytic amounts
of fluoride to yield a pentafluoroethide equivalent to perform nucleophilic substitutions, and it can
react with transition metals to generate isolable or in situ complexes for further functionalizations.
A few examples of the utilization of this reagent will be discussed next. Early reports demonstrated
that TMSCF2CF3 could readily convert carbonyl compounds into the corresponding a-
pentafluoroethyl carbinols by fluoride activation in an aprotic polar solvent
181
(Scheme 1.36.A.).
Scheme 1.36: Synthesis of a-pentafluoroethyl carbinols
Me
3
Si Cl
1) ICF
2
CF
3
butyronitrile
-20 ºC
2) [(Et
2
N)
3
P]
add whithn 45 min
-20 ºC to -25 ºC
3) stirr 5h at -15
4) condense in cold trap
(75%)
Me
3
Si CF
2
CF
3
Me
3
Si Cl
1) benzonitrile
-30 ºC
2) BrCF
2
CF
3
evaporate into soln.
-60 ºC
3) [(Et
2
N)
3
P]
4) -60 ºC 1h — rt 24h
(65%)
Me
3
Si CF
2
CF
3
a)
b)
Me
O
TMSCF
2
CF
3
KF
tetraglyme
20 — 30 ºC
18 h
Me
i
Bu
OTMS F
3
CF
2
C
t
BuO
O
O
t
Bu
TMSCF
2
CF
3
TBAF (10 mol%)
THF
reflux
6 — 15 h
TMSO
CF
2
CF
3
t
BuO
O
O
t
Bu
O
HO
O
OH
HO
CF
2
CF
3
1) TMSCF
2
CF
3
TBAF (cat)
THF
0 ºC
2) TBAF in THF
rt, 5h
R
1
R
2
CF
2
CF
3
HO
R
1
R
2
O
R
1
= H, alkyl, aryl
R
2
= aryl, alkyl (81% — 86%)
a)
b)
c)
41
The Geffken and the Prakash groups individually reported methodologies for the
pentafluoroethylation of carbonyl compounds with TMSCF2CF3. In the first protocol, dibutyloxalate
was reacted with different perfluoroalkylsilanes in the presence of catalytic fluoride, in order to
generate the monosubstituted-silylated products that were further converted to the
pentafluoroethyl-diols upon hydrolysis (Scheme 1.36.b.).
183
Similarly, Prakash and coworkers’
method described the activation of TMSCF2CF3 with catalytic fluoride to afford the
pentafluoroethyl analogues of a set of alkyl and aryl ketones and aldehydes in good yields
(Scheme 1.36.c.).
182
The vast majority of the metal-free approaches for the nucleophilic
pentafluoroethylation of carbonyl
182,184–194
, thiocarbonyl
195,196
and imine
187,197–199
compounds with
TMSCF2CF3 consists on the activation of the silane with an appropriate fluoride source in a
suitable solvent for the subsequent transfer of –C2F5 to the electrophilic center. The work done in
this area is extensive and has enabled access to a wide variety of relevant molecules. Scheme
1.37.A portrays the general reaction pathways for the aforementioned transformation, and
selected examples of a-pentafluoroethyl compounds are shown. This approach has also been
applied with inorganic substrates, enabling access to small perfluoroalkylated molecules with
industrial applications. Shreeve and Singh demonstrated the applicability of TMSCF2CF3 in the
pentafluoroethylation of either nitrosyl chloride (NOCl) or an equimolar mix of nitric oxide (NO)
and nitrogen dioxide (NO2) to access perfluoronitrosoalkanes in high yields. Sulfur dioxide and
carbon dioxide were also separately subjected to the reaction conditions, affording their
corresponding cesium salt. The treatment of cesium (pentafluoroethane)sulfinate with anhydrous
HCl gas yielded the sulfinic acid, also prepared by Yagupolskii and coworkers
200
. Similarly, the
same treatment afforded pentafluoropropionic acid from C2F5CO2
-
Cs
+
(Scheme 1.37.B).
201
42
Scheme 1.37 Pentafluoroethylation of carbonyls, thiocarbonyls, imines and inorganic molecules with TMSCF 2CF 3
F
3
CF
2
C
OH
F
3
CF
2
C
OH F
3
CF
2
C
OH
(Gassman, 1994)
OH
CF
2
CF
3
(65%)
OH
CF
2
CF
3
(42%)
(Kitazume, 1995)
R
1
CF
2
CF
3
HO
(83% — 85%)
R
1
= H, alkyl
(Shreeve, 2002)
F
3
CF
2
C S-alkyl
S
(Yagupolskii, 2004)
F
3
CF
2
C S-alkyl
S
(Portella, 2006)
(72% — 84%)
(95%)
R R
2
X
X = O, S, N-PG
R = H, alkyl, aryl
R
2
= H, alkyl, aryl, etc
TMSCF
2
CF
3
fluoride
solvent
T ºC
R R
2
X = O, S, N-PG
R = H, alkyl, aryl
R
2
= H, alkyl, aryl, etc
Y = H, TMS
YX CF
2
CF
3
—
F sources
Solvents
KF THF
TMAF Tetraglyme
TBAF
DMF
CsF NMP
DME
MeCN
F
3
CF
2
C Ph
O
(Portella, 2011)
(50%)
R R
1
R= alkyl, aryl, OR
3
R
2
= H, alkyl, aryl
TMSO CF
2
CF
3
R
HN
CF
2
CF
3
Ts
R= alkyl, aryl
(Mukaiyama, 2006)
R
1
HN
CF
2
CF
3
R
2
NHBz
R
1
, R
2
= H, alkyl, aryl
(Dilman, 2008)
R
1
R
2
CF
2
CF
3
HO
(81% — 86%)
(Prakash, 1991)
(89% — 98%)
O
CF
2
CF
3
CF
2
CF
3
XO
F
3
CF
2
C
X= H, TMS, PR
(67% — 87%)
(Tyrra, 2008)
OH
Me
3
Si
CF
2
CF
3
(73%)
(Tilley, 2011)
O
Ph
i
PrO
F
3
CF
2
C
OH
(65% — 66%)
(Yamamoto, 2017)
O
O
CF
2
CF
3
(68% — 77%)
(Amii, 2018)
R
X
CF
2
CF
3
X = O, S, N-PG
R = alkyl, aryl, etc
Or
(64% — 99%) (35% — 92%) (91%)
R
1
OH
F
3
CF
2
C
O
O
R
(95%) [95:5]
(Tang, 2015)
N O
N
O O
N
Cl O
S
O O
C O O
ONCF
2
CF
3
ONCF
2
CF
3
S
O F
3
CF
2
C
O F
3
CF
2
C
Cs
Cs
TMSCF
2
CF
3
CsF
glyme
-196 ºC — 25 ºC
TMSCF
2
CF
3
CsF
glyme
-196 ºC — 25 ºC
HCl
1h, rt
HCl
1h, rt
S
O F
3
CF
2
C
OH
O F
3
CF
2
C
OH
O
O
A) Pentafluoroethylation of carbonyls, thiocarbonyls, and imines
B) Pentafluoroethylation of inorganic molecules
43
Direct nucleophilic pentafluoroethylation with TMSCF2CF3 can also transform (C)sp
3
-
electrophiles, such as alkyl (pseudo)halides, into the perfluoroalkyl analogues. Primary alcohols
can be turned into their corresponding alkyl triflates which, upon treatment with the activated
silane, yield the pentafluoroalkanes through C—C bond formation. A representative example of
such transformation was reported by Sevenard et. al. where liquid crystals were synthesized in
good yields employing this strategy (Scheme 1.38.a.).
202
Primary alkyl iodides and bromides have
also been subjected to pentafluoroethylation conditions successfully producing a variety of
pentafluoroalkanes by activating TMSCF2CF3 with a crown ether and Cs
+
as the cation (Scheme
1.38.b).
203
It is worth noting that only primary alkyl halides undergo the desired transformation,
given that secondary and tertiary starting materials produce the corresponding alkene, as well as
pentafluoroethane, as major products.
Scheme 1.38: SN 2 reaction with alkyl (pseudo)halides
In 2003, Dilman and coauthors delineated a methodology to fluorofunctionalize a bromomethyl
borane by the intermediacy of a borate salt that results from the interaction of boron with the
perfluoroalkyl nucleophile. It was demonstrated that upon brief heating, the corresponding
pentafluoroethyl-substituted pinacolborane could be generated in high yields (Scheme 1.38.c).
204
In view of the applicability of (pentafluoroethyl)trimethylsilane for nucleophilic perfluoroakylation,
C
3
H
7
H
H
CH
2
CF
2
CF
3
C
3
H
7
H
H
CH
2
OTf
TMSCF
2
CF
3
TMAF
monoglyme
2h at -30 ºC
1.5 h to reach 0 ºC
Alkyl X
X= I, Br
TMSCF
2
CF
3
[Cs(15-crown-5)
2
]F
monoglyme
—18 ºC to rt
16 h
Alkyl CF
2
CF
3
Alkyl—X Yield or major product
1º
2º
3º
(78% — >98%)
alkene and HC
2
F
5
alkene and HC
2
F
5
B Br
O
O
TMSCF
2
CF
3
KF
DMF
18h, rt
B
Br
O O
CF
2
CF
3
50 ºC
1h — 1.5 h
B F
3
CF
2
C
O
O
(80%)
(a)
(b)
(c)
(71%)
44
its use has been extended to other substrates such as aromatic and (hetero)aromatic systems.
Transition metal-free approaches to fluorofunctionalize aromatic rings usually involve pre-
activation of the substrate. As mentioned in section 2.3, Larionov and coworkers described the
regioselective perfluoroalkylation of heterocyclic N-oxides, among which the pentafluoroethylation
reaction with TMSCF2CF3 was included (Scheme 1.39.a).
151
Pentafluoroethyl quinolines and iso-
quinolines were obtained as a result of the base mediated protocol.
Scheme 1.39. Regioselective pentafluoroethylation of (hetero)cycles
Sterically hindered boranes are also employed as Lewis acids for selective functionalizations.
Scheme 1.39.b. illustrates the work by Nagase and coworkers for the generation of 4-
(pentafluoroethyl)quinoline from a quinoline-borane complex, TMSCF2CF3 and an oxidant.
152
A
very interest approach to nucleophilic perfluoroalkylation or arenes was reported in 2017 by
Yagupolskii’s group. The method involves the activation of the arene p-system by virtue of
coordination with a chromium complex (Cr(CO)3), generating a type of Mesenheimer adduct upon
N
O
R
R= FG, H
TMSCF
2
CF
3
t
BuOK
3Å MS
THF
-20 ºC, 50 min
N
R
R= FG, H
CF
2
CF
3
(55% — 86%)
N
B(C
6
F
4
-4-CF
3
)
3
1) TMSCF
2
CF
3
TBAT
AcOEt/ MS 4Å
—40ºC, 11h
2) PIFA
25 ºC, 3h
N
CF
2
CF
3
1 example
(90%)
N
Me
1) TMSCF
2
CF
3
TFA
KHF
2
DMPU
dIoxane
24ºC, 24h
2) PIDA
25 ºC, 2h
N
Me
CF
2
CF
3
H
R
R= H, FG
Cr(CO)
3
1) TMSCF
2
CF
3
2) oxidant
DME
—60 ºC — rt, 4h
CF
2
CF
3
R
R= H, FG
(54% — 95%)
(a)
(b)
(c)
(d)
1 example
(83%)
N
Me
CF
2
CF
3
Si
F
O
Me
Me
Me
H
T.S.
N
N
45
reaction with the nucleophilic perfluoroalkyl anion. The ability of tricarbonyl chromium to stabilize
the negative charge in the cyclohexadienyl derivative renders it a suitable activating agent for
aromatic compounds. Subsequent oxidation of the h
5
-cyclohexadienyl)Cr(CO)3 intermediate
produces –CF3CF2-containing arenes in moderate to good yields,
205
as depicted in Scheme
1.39.c. A more recent approach by Kanai and Kuninobu describes a one-step –silane and
heterocycle activation by the in situ generation of hydrogen fluoride (HF) from trifluoroacetic acid
and potassium bifluoride (KHF2). Such dual activation was proposed to proceed through the
formation of a 6-membered transition state where the reactivity of the silane is enhanced by
means of coordination to DMPU, forming an hexacoordinate silicate. The subsequent nucleophilic
attack of CnF2n+1 at the 2-position of the N-heteroaromatic compound, which was simultaneously
activated by HF, generates another intermediate that undergoes facile oxidation to afford 2-
(perfluoroethyl)quinolines (Scheme 1.39.d).
206
On the other hand, the first 1,4 Michael-type
addition of a pentafluoroethyl nucleophile to a conjugated system was reported in 2003 where
fluoroaklylchromones were converted to the corresponding pentafluoroethylated trimethylsilyl
ethers through a 1,4-addition.
207
In a preliminary study, the selectivity of the 1,4-addition over the
1,2-addition (generation of the a-pentafluoroethylsilyl ether) was tuned by changing the
temperature, as shown in Scheme 1.40.a. Further studies determined that the nature of the
preinstalled pefluoroalkyl group also influences the selectivity due to steric hindrance.
208
C(sp
2
)–
X perfluoroalkylation of non-aromatic substrates is another attractive transformation to prepare
fluorinated analogues that in most cases, proceeds through the generation of a nucleophilic
perfluoroalkyl species. Electron deficient alkenes such as malononitriles proved to be efficient
Michael acceptors for the –C2F5 anion to generate a b-pentafluoroethyl-substituted malononitrile
in excellent yield, under basic conditions
209
(Scheme 1.40.b). A similar approach that also
employed sodium acetate as an activator for (pentafluoroethyl)trimethylsilane, performs the
transformation of 2-nitrocinnamates into their b-perfluoroalkyl analogues. The
46
pentafluoroethylated product in Scheme 1.40.c was obtained as a high yielding mix of
diastereoisomers and the applicability of these type of compounds as fluorinated amino acid
precursors was demonstrated by reduction of the nitro group into the corresponding Boc-
protected amine.
Scheme 1.40: (C)sp
2
–X
bond pentafluoroethylation (I)
Activated allyl fluorides have also served as electrophiles for nucleophilic pentafluoroalkylation.
In this approach, Shibata and coworkers applied the kinetic resolution strategy to obtain an
enantioenriched allyl fluoride [A] and an enantioenriched perfluoroalkyl allyl compound [B] upon
the reaction of a racemic allyl fluoride with perfluoroalkyl silanes and a chiral organic catalyst. The
resulting pentafluoroethylated product in Scheme 1.40.d was obtained with excellent
enantioselectivity and with 53% conversion of the starting material. The mechanistic proposal
comprises the activation of the silane by the allyl fluoride motif and the consequent formation of
an electrophilic E-alkene intermediate, upon reaction of the terminal olefin with the chiral catalyst.
O
R
OSiMe
3
R
F
CF
2
CF
3
O
R
O
R
F
O
R
OSiMe
3
R
F
F
3
CF
2
C TMSCF
2
CF
3
TBAF (cat)
THF
0 ºC , 4h
• —30 ºC: 82 — 18
• 0 ºC: 77 — 23
• 25 ºC: 72 — 28
Ph
CN
CN
TMSCF
2
CF
3
AcONa
DMF
rt , 3h
Ph
CN
CN
CF
2
CF
3
(97%)
t-Bu
NO
2
CO
2
Me
TMSCF
2
CF
3
AcONa
DMF
rt , 3h
Ph
NO
2
CO
2
Me
CF
2
CF
3
(88%)
dr= 1.2 : 1
MeO
2
C
F
Ph
*
MeO
2
C
CF
2
CF
3
Ph
TMSCF
2
CF
3
(DHQD)
2
PHAL
MS (4Å)
1,4-dioxane/THF
0ºC, 40h
(52%)
(+)-[A]; 99% ee (46%)
(a) (b)
(c)
(d)
H
H
[B]
[A]
MeO
2
C
F
Ph
(R)-[B]; 94% ee (45%)
F F
R R
TMSCF
2
CF
3
[equiv.]
TBAF [equiv.]
THF
25ºC
0.5h —1h
F CF
2
CF
3
R R
F
3
CF
2
C CF
2
CF
3
R R
(40% — 83%)
(35% — 82%)
(i)
(ii)
TMSCF
2
CF
3
2.5 equiv
(i)
(ii)
TBAF
1.2 equiv
5.0 equiv
2.0 equiv
(e)
47
Such intermediate undergoes nucleophilic addition of a pentafluoroethide equivalent at the sp
2
carbon, thus enantioselectively generating the desired compound.
210
As previously discussed,
alkenes are ideal substrates for nucleophilic functionalization, however, the perfluoroalkylation of
C—F bond in gem-difluoroalkenes is a particularly interesting transformation. In 2015, Jin et. al.
outlined a protocol for the preparation of mono and bis pentafluoroethylated alkenes from
substituted difluoroethenes and TMSCF2CF3. The selectivity towards the monosubstituted product
can be tuned by simply reducing the equivalents of silane and TBAF. In the same way, higher
amounts of the perfluroalkylating mixture affords the bis –C2F5 product (Scheme 1.40.e).
211
Nucleophilic pentafluoroethylation has also been made possible through the use of isolable borate
salts as the source of pentafluoroethide. Kolomeitsev and coworkers developed a method to
successfully synthesize perfluoroalkyltrialkoxyborates (CnFnB(OR)3
-
X
+
) from trialkoxyboranes and
TMSCnF2n+1.
212
In addition, it was demonstrated that these isolable salts can be turned into their
corresponding boronic esters upon dealkoxylation (Scheme 1.41.b).
Scheme 1.41: Indirect pentafluoroethylation with –C 2F 5 borate salts
Ph CF
2
CF
3
OH
(93%)
via borate salt
MeOTf, MeTs,
MsCl, Me
3
SiCl
solvent
CF
3
CF
2
B(OR)
2
R= Me, Et
(92%)
O
H
(i)
DMF, 50 ºC, 1h
B(OR)
3
R= Me, Et
TMSCF
2
CF
3
KF
THF or glyme
20 ºC, 4h
then 50 ºC, 4h
[CF
3
CF
2
B(OR)
3
]
—
K
+
(98%)
R= Me, Et (i)
X
X = I, Br
R= FG, H
R
(i)
CuI/Phen
THF, 60 ºC
24h
CF
2
CF
3
X = I, Br
R= FG, H
R
(73% — 95%)
(a)
(b)
(c)
48
One of the most popular uses of perfluoroalkyltrialkoxyborates has been as reactants for indirect
perfluoroalkylation from organosilicon reagents. Potassium trimethoxy(pentafluoroethyl)borate
was prepared by Dilman and coworkers to produce a-pentafluoroethyl carbinols from non
enolizable carbonyl compounds
213
(Scheme 1.41.a). Similarly, Amii and coworkers demonstrated
the utility of the same borate salt in the catalytic pentafluoroethylation of aryl halides
214
(Scheme
1.41.c). Moreover, nucleophilic pentafluoroethylation of S atoms provides direct access to
synthetically useful molecules such as fluoroalkyl thioethers, as showcased by Petrov in 2006
(Scheme 1.42.a.).
215
Scheme 1.42 Nucleophilic pentafluoroethylation of sulfur compounds
A ring opening reaction with pentafluoroethide produced the desired product in 48%. In 2008,
Ferry et. al. created (in situ) perfluoroalkyl analogues of the popular deoxygenation-fluorination
SCF
2
CF
3
CF
3
F
2
C
S
C(CF
3
)
2
TMSCF
2
CF
3
CsF or KF
THF
—10 ºC to 25 ºC
(48%)
N S
F
F
F
(DAST)
1) TMSCF
2
CF
3
DIEA
N S
F
CF
2
CF
3
F RNH
2
R
NH
SCF
2
CF
3
Et
N
S—CF
2
CH
3
(R = alkyl, aryl)
Et
N
Ar
in situ
C
2
F
5
—sulfinamidines
C
2
F
5
—sulfanylamides
(22%)
(20% — 66%)
S
SMe
Ph
R
OCONMe
2
TMSCF
2
CF
3
CsF
DME
rt , 24h
SMe
S R
Ph
CF
2
CF
3
R= Me, Et
Me = (83%) (86/14 E/Z)
Et = (90%) (88/12 E/Z)
TMSCF
2
CF
3
i
PrNEt
DCM
N S
F
F
F
(DAST)
N S
F
CF
2
CF
3
F
in situ
DCM
40 ºC — 70 ºC
overnight
R
O
EWG
R
O
EWG
SCF
2
CF
3
(a)
(b)
(c)
(d)
49
reagent DAST, which reacted with anilines forming sulfinamidines in moderate to good yields. For
some substrates, the formation of N-trifluoromethylthiolato anilines predominates over the
formation of the sulfinamidines (Scheme 1.42.b).
216
Pentafluoroethylation of a dithioester
produces high yields of the corresponding ketene dithioacetals, as described by Portella and
coworkers (Scheme 1.42.c).
217
Contrary to the expected reaction pathway of addition at the
thiocarbonyl carbon, the anion is found to add to the S atom of the thiocarbonyl moiety, with the
ultimate loss of the carbamate group from the substrate. Pentafluoroethylation of DAST was
performed by Shibata and coworkers in 2016 using TMSCF2CF3. Using this DAST derivative, the
pentafluoroethylation of active methylene compounds was achieved under mild conditions
(Scheme 1.42.d).
218
In addition to the difluoromethylsilanes already discussed, there is another
class of silanes widely used for dilfuoromethylenations where the –CF2 unit is formally ‘protected’
by a removable group that can be cleaved via decarboxylation, reductive desulfurization, among
other strategies. Trimethylsilyldifluoromethyl ester derivatives were first synthesized in the 1990’s
when hexyl (trimethylsilyl)difluoroacetate was prepared via an electrochemical defluorination of
trifluoromethyl ketones (Scheme 1.43.a.). The obtained product was then employed for the
difluoromethylation of electrophiles. Shortly after, ethyl-2,2,-dilfuoro-2-trimethylsilylacetate was
synthesized using HMPA or DMPU (Scheme 1.43.b).
219
This compound was then transferred to
carbonyl electrophiles with moderate to good conversions.
Scheme 1.43 First syntheses and uses of [Si]CF 2C(O)R compounds
+ 2e
-
TMSCl (excess)
50˚C, 3h
TMSF
2
C
O
OR
R= (
n
hex) R= Et
TMSF
2
C
O
O(
n
hex) TMSF
2
C
O
OEt
(45 % — 92%)
2.2 F/mol
Al, NBu
4
Br
TMSCl (excess), rt
(38% — 85%)
C
F
2
O
OEt
R
1
HO
R
C
F
2
O
O(
n
hex)
R
1
HO
R
a) b)
50
This compound and some amide-containing derivatives have seen wider applications in
nucleophilic reactions such as in the preparation of [CF2]-containing precursors of 3,3-
difluoroazetidinones.
220
The [CF2CO2Et] unit of ethyl-2,2,-dilfuoro-2-trimethylsilylacetate has also
been transferred to bromomethyl pinnacolborane through an SN2 reaction at the C–Br bond
(Scheme 1.44.A).
221
Another application was a one-pot difluoromethylthiolation which employed
NaSCN and TMSCF2CO2Et to generate the reactive species in situ [EtOC(O)F2C
--
], which then
performed an SN2 reaction on primary alkyl bromides (Scheme 1.44. E and F).
222
Scheme 1.44 Nucleophilic difluoromethylation reactions
On the other hand, TMSCF2CO2NR2 reagents where R= alkyl have been used in an oxidative
difluoromethylation protocol to prepare CF2-containing isoquinolines (Scheme 1.44.B).
223
Silane-
derived amidodifluoromethide has also been added to carbonyl compounds (Scheme 1.44.C)
and chiral sulfinylimines (Scheme 1.44.D).
224
In this work, catalytic TBAF enabled the formation
of aldol-type compounds and Mannich-type products in good isolated yields. Secondary propargyl
sulfonates have also been reacted with an amine-containing difluorosilane derivative in an SN2
fashion to prepare the difluoromethylated products with good ee. and with inversion of
TMSF
2
C
O
OR
O
B
O
CF
2
CO
2
Et
N
Ar
CF
2
CO
2
R
R
2
R
1
HO CF
2
CONR
2
R
1
CF
2
CONR
2
H
N
R
2
S
t
Bu
O
R CF
2
CO
2
Et
Ar
O
CF
2
CO
2
Et
alkyl
TIPS
Et
2
NOCF
2
C
O
B
O
Br
N
Ar
FG
R
2
R
1
O
R
2
R
1
N
S
t
Bu
O
R
Br
Ar
O
Br
alkyl
PMPO
2
SO
TIPS
pinacol borane
aldehydes, ketones
alkyl bromides
isoquinoline
chiral sulfinylimines
propargyl sulfonates
alkyl bromides
A)
B)
C)
E)
G)
D.
F)
51
stereochemistry (Scheme 1.44.G). TMSCF2CO2Et has also been used in combination with
transition metals such as silver, palladium, and copper Scheme 1.45.A.
225
showcases a copper-
mediated cross-coupling reaction with aryl iodides to prepare difluoromethylarenes in good to
excellent yields. The authors of this work further demonstrated a solvolysis-decarboxylation
sequence to afford the unprotected [CF2H] unit. An extension of this work to halopyridines was
later published by the same authors in 2012.
226
TMSCF2CO2Et has also been used to conduct an
oxidative hydrodifluoromethylation of terminal alkenes with PIDA (diacetoxyiodo)benzene) as the
oxidant and NaOAc as the base. (Scheme 1.45.B).
227
In this case, a Hanstzsch ester was
selected as the hydrogen atom source to furnish the products in moderate to good yields.
Aromatic triazines have also been successfully transformed into their difluoromethyl derivatives
via ethoxycarbonyldifluoromethylation with this same reagent. Scheme 1.45.C
228
showcases the
functionalized arenes obtained via the in situ formation of aryl iodides upon treatment with methyl
iodide.
Scheme 1.45 Metal-mediated transfers of the –CF 2CO 2R anion
Alternatively, the same triazine starting materials can be converted into ortho-difluoromethylated
triazines upon treatment with the silane and silver(I) fluoride (Scheme 1.45,D.).
229
Performing the
CF
2
CO
2
Et
Y
X
(X = CN, NO
2
)
(Y = Me, OMe)
AgF
C
6
F
14
, 100˚C
N
FG
N
N
i
Pr
i
Pr
CF
2
CO
2
Et
[Pd
0
], KF, 100 ˚C
Br Ar
TMSCF
2
COONR
2
CF
2
COONR
2
Ar
B)
E)
TMSF
2
C
O
OEt
I Ar
CF
2
CO
2
Et
Ar
R
1
R
2
R
1
R
2
CF
2
CO
2
Et
CuI, KF, 60 ˚C
AgOTf, PIDA, NaOAc
Hantzsch ester, rt
A)
TMSF
2
C
O
OEt
1) MeI, 100˚C
2) CuI, KF, 60 ˚C
C)
D)
2-CF
2
CO
2
Et
2,6-CF
2
CO
2
Et
N
N
N
i
Pr
i
Pr
N
N
N
i
Pr
i
Pr
R
Y
X
52
reaction at elevated temperatures (100 ˚C) in C6F14 provided mixtures of mono- and di-ortho
difluoromethylated triazoarenes. The amide analogue of this silane (TMSCF 2CO2NEt2) found use
as a difluoromethylation reagent in combination with a palladium catalyst to transform aryl
bromides intro difluoromethyl(arenes) (Scheme 1.45.E).
230
The protocol exhibited good tolerance
across a variety of reactive handles for further functionalization reactions. A similar transformation
to prepare aryldifluoroamides from aryl iodides was also developed by the same group in 2016.
231
To finalize exemplifying the utility and versatility of perfluoroalkylsilanes for difluoromethylenation
reactions, Scheme 1.46 showcases the diverse difluoromethylenation reactions promoted by
silver or copper catalysts. Following a different pathways than direct nucleophilic
difluoromethylenations, the difluoromethylation of arenes
232
and other heterocycles can be
successfully achieved with TMSCF2CO2Et and a silver catalyst to afford the [CF2H] containing
arenes after subsequent decarboxyllation.
Scheme 1.46 Difluoromethylenation reactions promoted by transition metals
TMSF
2
C
O
OEt
A)
B)
C)
G)
D)
F)
R
CF
2
CO
2
Et
FG
N
PG
O
alkyl
CF
2
CO
2
Et
FG
CF
2
CONEt
2
FG
O F
CO
2
Et
N
FG FG
CF
2
CO
2
Et
R
NHBoc
EtO
2
CF
2
CO
H
N
FG
O
Me
Ar
CF
2
CONR
2
E)
R
N
PG
O
alkyl
Ar
COOH
FG
NC
FG
FG
R
BocHN
HO
Ar
N
S
O
O
Ar
O
Me
Ar
[Ag]
[Ag]
[Cu]
[Ag]
[Ag]
[Ag]
[Cu]
53
Additionally, [CF2] containing oxindoles,
233
and their amide analogues,
234
can be prepared through
a difluoromethylation-cyclization cascade. This powerful combination of ethyl-2,2,-dilfuoro-2-
trimethylsilylacetate and silver salts has also been applied to prepare difluoromethyl
phenanthridines,
235
and difluoromethyl ethers.
236
Similarly, copper salts can be utilized with the
amide derivative of the silane to facilitate the difluoroacetamidation of acrylamides,
237
and the
decarboxylative amidodifluoromethylation of a,b-unsaturated carboxylic acids, yielding
difluoromethylalkenes (Scheme 1.46).
238
As depicted in Scheme 1.14, nucleophilic difluoromethylation can also be achieved
through the utilization of sulfur and phosphorous-based compounds. Aryl difluoromethylsulfones
have been extensively used in the preparation of various difluoromethylated organic
compounds.
239
The versatility of these reagents render them useful to introduce the –CF2 unit into
organic molecules through multiple pathways (nucleophilic, electrophilic, carbene). Difluoromethyl
phenyl sulfone
239
along with trimethylsilyl and pyridyl
240
derivatives have been well studied and
reacted with a variety of electrophiles. Dilfuoro(phenylsulfonyl) carbinols can be prepared through
the reaction of difluoromethyl phenyl sulfone with ketones and aldehydes. The analogous reaction
can also be performed with the pyridyl derivative.
240
Similarly, alkyl and alkynyl electrophiles,
acetals and imines can undergo sulfonodifluoromethylation to selectively afford the CF2-
containing derivatives (Scheme 1.47.A). As exemplified by previous reactions discussed in this
chapter, reductive desulfurization of the prepared compounds can afford the terminal
difluoromethyl group. Hu and coworkers have also reported difluoromethyl sulfoximines, such as
(R)-N-tert-butyldimethylsilyl-S-fluoromethyl-S-phenylsulfoximine as effective reagents for the
challenging nucleophilic difluoromethylation of carbonyl compounds. In comparison to their
previously reported tosyl-substituted sulfonimidoyl sulfoximine (PhSO(NTs)CF2), the reduced
nucleofugality of the TBS group in this particular sulfoximine enables the nucleophilic transfer of
the reagent to C(sp
2
) electrophiles without decomposition.
120
Chiral difluoromethyl alcohols can
54
be prepared effectively with this reagent, and further reductive desulfoximination yields
enantiomerically enriched difluoromethyl alcohols (Scheme 1.47.B).
Scheme 1.47: Nucleophilic dilfuoromethylation with sulfones, sulfoximines and phosphonates
Exploring the area of difluoromethylenation with phosphorous-based reagents, Prakash and Beier
developed a protocol for the nucleophilic difluoromethylation of aldehydes and ketones with
S
CF
2
H
O
O
CF
2
H P
O
EtO
OEt
Ph
S
CF
2
H
O
NTBS
S
CF
2
H
O
O
N
R
1
H
N
R
2
S
t
Bu
O
PhO
2
S
F F
PhO
2
S
F F
PhO
2
S
F F
Ar
F
2
C
Ar
PhO
2
S
F F
R
O
B
O
PhO
2
S
F F
PhO
2
S
F F
OH
Ar
SO
2
Ph
F
F
Ar
N
X
PhO
2
S
F F
N
TMS
S
CF
2
H
O O
HO
Ar
P(O)(OEt)
2
F F
R HO
Ar
H
F F
R O
Ar
R
MeONa/MeOH
A)
B)
C)
F
2
C P
O
EtO
OEt
TMS
HN
CF
2
P(O)(OEt)
2
R
2
N
R
3
R
3
R
1
CF
2
P(O)(OEt)
2
R
OTMS
CF
2
P(O)(OEt)
2
R
2
Ph
N
N
R
3
R
3
R
1
R
2
R
O
R
2
R
OP(O)(OEt)
2
C
F
2
OH
R
3
R
2
R
3
CHO
HO
Ar
F F
R O
Ar
R
Ph
S
O NH
KHMDS, THF
12 M HCl -98ºC
Mg, NaOAc
HOAc, H
2
O
HO
Ar
F F
R
H
D)
a.
b.
c.
55
diethyl (difluoromethyl)phosphonate.
118
A seen with other methods that install a ‘protected’ group,
the resulting (phosphono)difluoromethyl carbinol can undergo reductive cleavage to afford the
free difluoromethyl group (Scheme 1.47.C). Similarly, the syntheses of silylated derivates of this
phosphonate have been explored, giving rise to (phosphono)difluoromethylsilanes. Much like
diethyl (difluoromethyl)phosphonate, phosphonodifluoromethyltrimethylsilane (TMSCF2P(O)
OEt2) has been employed in the reaction with aldehydes, affording the corresponding
phosphonodifluoromethyl O-silyl ethers (Scheme 1.47.D.a)
241
242
243
These compounds can react
with a second equivalent of aldehyde to afford an homologated CF 2-bridged product. Among the
other electrophiles that this pronucleophile can be added to, the asymmetric addition of this
phosphonodifluoromethide to imines and enamines is noteworthy (Scheme 1.47.D.b and c).
Addition of the anion to in situ formed iminium ions via oxidation of amines is a strategy that has
been employed to afford a-functionalized amines.
223
Additionally, the asymmetric addition of the
phosphonodifluoromethyl anion to chiral compounds such as N-tert-butanesulfinyl imines,
produces difluoromethylamines diastereoselectively.
244
As discussed earlier in this chapter,
difluoromethylation strategies follow different mechanisms depending on the substrate and the
reagents’ phylicity. The literature and methods available for electrophilic difluoromethylation are
significantly less extensive than the nucleophilic counterpart. The first reports of reagents for the
direct transfer of a CF2 groups onto nucleophiles were inspired by previous reports on
trifluoromethylsulfonium salts. In 2007 Prakash and Olah envisioned the synthesis of S-
(difluoromethyl)dibenzothiophenium triflate and S-(difluoromethyl)diphenylsulfonium
tetrafluoroborate as efficient reagents for the electrophilic difluoromethylation of a variety
nucleophiles (Scheme 1.48.A).129 The use of S-(difluoromethyl)sulfonium salts can also achieve
C-selective electrophilic difluoromethylation of β-ketoesters, malonates, and dicyanoalkenes with
no O-dilfuoromethylation observed.245 Another sulfur-based electrophilic reagent developed by
Prakash and coworkers in N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium
56
tetrafluoroborate which can also successfully effect the difluoromethylation of carbon, oxygen,
sulfur, nitrogen and phosphorous centers.
246
Scheme 1.48: Electrophilic dilfuoromethylenation with sulfones, sulfoximines, and hypervalent iodine reagents
Lastly, hypervalent iodine reagents have been popular reagents of choice for perfluoroalkylation
reactions. The discovery of (phenylsulfonyl)difluoromethylated hypervalent iodine reagents
enabled the development of new electrophilic protocols for the (phenylsulfonyl)difluoromethylation
of -S and -O chalcogens.
239
The hypervalent iodine salt shown in Scheme 1.48.B can be reacted
with unsaturated carboxylic acids which, with the aid of copper, undergo a decarboxylative
functionalization. Structural variations of this reagent afford similar compounds that can
S
CF
2
SO
2
Ph
R
R
O
R
1
R
2
OR
3
O
NC
NC R
2
H
R
1
R
2
O
R
1
R
2
OR
3
O
NC
NC R
2
R
1
R
2
F
SO
2
Ph
F
F
F
SO
2
Ph
A) Sulfonium and sulfoximinium salts
O
I
PhO
2
SF
2
C
R
2
R
1
O
OH R
2
R
1
SO
2
Ph
F F
R
2
R
1 R
3
R
4
OH
O
•
O
OH
R
2
R
1 R
3
R
4
F F
SO
2
Ph
F
SO
2
Ph
F
CuF
2
•2H
2
O
TMEDA
H
2
O/DCE
CuF
2
•2H
2
O
1,4-dioxane
H
2
O
CuCl
2
•2H
2
O
1,4-dioxane
H
2
O
B) Hypervalent iodine salts
O
R
1
R
2
OR
3
O
F
SO
2
Ph
F
S
CF
2
H
X
R
O
R
3
R
2
R
1
O
CF
2
H
C-selective
P CF
2
H
Ph
Ph
Ph
CF
2
H N
R
R
R
X
X
N-selective
P-selective
CF
2
H S R
S-selective
S
O
N
CF
2
H
Ts
O-selective
57
selectively functionalize thiols,
130
and C-H bonds of (hetero)arenes to produce the corresponding
(phenylsulfonyl)difluoromethylated compounds.
131
Also, in the realm of electrophilic difluoromethylation reactions are those that proceed via CF 2
carbene. Difluorocarbene is a singlet carbene, which means that it has an empty p-orbital to
accept electrons from a nucleophile, making it intrinsically electrophilic.
247
Difluorocarbene can be
generated in various ways: dehydrohalogenation of halodifluoromethanes or deprotonation of
fluorform,
248,249
thermolysis of halodifluoroacetates,
250
thermal decomposition of
perfluorocyclopropanes,
251
among others. Recently, one very popular approach is the use of
fluorinated silanes for the generation of difluorocarbene due to their mild activation conditions,
and widespread availability. The Ruppert-Prakash reagent (TMSCF3) is a well-known source of -
CF3 group for trifluoromethylation reactions.
252
However, being such a versatile reagent, under
the right conditions it is also a source of difluorocarbene, presumably via fluoride elimination from
trifluoromethide (Scheme 1.49.A).
253,254
The brominated derivative of the Ruppert-Prakash
reagent, (bromodifluoromethyl)trimethylsilane (TMSCF2Br) is another widely used silane for this
purposes given that the dissociation of the bromodifluoromethyl anion into bromide and
difluorocarbene enables access to this electrophilic species (Scheme 1.49.B).
Scheme 1.49: Generation of difluorocarbene from TMSCF 3 and TMSCF 2Br
R
X
R
X
C
F
F
F
F
R
X
F
F
E E
C
F
F
Si CF
3
Me
Me
Me
A
Si Me
Me
Me
A
CF
3
F
C
F
F
Si CF
2
Br Me
Me
Me
A
Si Me
Me
Me
A
CF
2
Br
Br
• Difluorocarbene generation from TMSCF
3
• Difluorocarbene generation from TMSCF
2
Br
58
This reagent can be easily synthesized from TMSCF 2H as previously depicted in Scheme 1.33
(Bromination of TMSCF2—H bonds) among other methods, and its activation usually requires
very mild conditions.
123
The earliest report of a halodifluoromethylsilane being used as a
difluorocarbene source was in 2009, when Hu and coworkers reacted TMSCF2Cl with alkenes to
prepare gem-difluorocyclopropanes via a concerted [2+1] cycloaddition of the singlet :CF2 with
the π system of the alkene (Scheme 1.50.a).
255
Later on, TMSCF2Br was shown to undergo the
same reaction with these substrates, as well as alkynes, with higher efficiency and wider
functional group tolerance than TMSCF2Cl (Scheme 1.50.b).
180
Scheme 1.50: Cyclopropa(e)nation reactions with halodifluoromethylsilanes
This cycloaddition reaction with TMSCF 2Br has also been applied to enolizable systems such as
ketones and esters (Scheme 1.51). An example of this reaction with ketones involved the
formation of a silyl enol ether intermediate which later reacts with difluorocarbene to form a
difluorocyclopropyl alcohol. The ring opening reaction of this intermediate is promoted by heat
and provides the homologated dilfuoromethyl ketones as shown in Scheme 1.51.a. Similarly,
enolizable esters can undergo deprotonation to afford the corresponding difluorocyclopropyl
intermediates, which spontaneously ring open to give the α-difluoromethyl product. A crucial
difference with these substrates is that the bond that breaks in the ring opening reaction differs
Si CF
2
Br Me
Me
Me
R
3
R
2
R
1
R
R
2
R
1
R
3
R
2
R
1
R
R
2
R
1
F F
F F
C
F
F
Si CF
2
Cl Me
Me
Me
or
TBACl TBAB
Si CF
2
Cl Me
Me
Me
R
3
R
4
R
1
R
2
F F
(R,R
1
)C=C(R
3
,R
4
)
a)
b)
59
from the one in the reaction with ketones, thus affording α-siladifluoromethyl esters rather than
the homologation product (Scheme 1.51.b).
256
Scheme 1.51: Reaction of TMSCF 2Br with enolizable compounds
Reactions with TMSCF2Br-derived difluorocarbene have also been applied to prepare
monofluoroolefination products via fluoride elimination,
257
difluoroolefins from diazo
compounds,
258
and terminal -C and O-difluoromethyl compounds.
259
Excellent reviews are
available to cover the scope of these transformations.
260,261
Examples of the utilization of
TMSCF2Br to install a CF2H group lie not only in the electrophilic transfer of the carbene to
nucleophiles (Scheme 1.52.a), but in the preparation of ylides to nucleophilically transfer the CF2
unit to a variety of electrophilic substrates
261
(Scheme 1.52.b). This particular approach enables
the utilization of difluorocarbene for nucleophilic difluoromethylation reactions, in addition to the
well-known electrophilic transfer and insertion reactions.
262,263
Si CF
2
Br Me
3
O
R
1
R
3
R
2
H
O
R
1
R
3
R
2
TMS
O
R
1
R
3
R
2
TMS
F
F
O
R
1
R
3
R
2
F F
O
EtO
H
R
1
H
O
EtO
R
1
TMS
O
EtO
R
1
TMS
F
F
O
EtO
R
1
F
F
TMS
a) Homologation of enolizable ketones
b) Siladilfuoromethylation of esters
TMSOTf, Et
3
N
O
R
1
R
3
R
2
H
O
R
1
R
3
R
2
F F
Si CF
2
Br Me
3
TMSCl, LDA
O
EtO
H
R
1
H
O
EtO
R
1
F
F
TMS
60
Scheme 1.52: Select examples of the difluoromethylation of nucleophiles and electrophiles with of TMSCF 2Br
In a similar way to TMSCF2Br, TMSCF3 has enabled access to difluorocyclopropanes and
propenes via cycloaddition reactions with olefins and alkynes
253
. The utilization of this silane as a
nucleophilic CF3 transfer agent has been the primary goal for over three decades, thus the
employment of TMSCF3 as a CF2 surrogate has repurposed and expanded its utility for broader
applications. The activator of choice to achieve these transformations is generally sodium iodide
or a lithium salt due to the cations’ affinity for fluoride, thus promoting the dissociation of
trifluoromethide into carbene and F.
253,254
It has been postulated that the success and selectivity
observed in difluoromethylenation reaction with TMSCF3, when employing sodium iodide is also
due to a predominantly ionic interaction of Na+ cation with the CF3 anion generated from the
starting silane. This interaction favors the efficient generation of difluorocarbene, with sodium
being the fluoride acceptor after a-elimination from the anion. Similar mechanisms have been
postulated for the generation of singlet :CF2 from TMSCF3 utilizing other activators, however, the
strength of the interaction between the cation from the ionic activator and
--
CF3 determines the
path that the carbene generation will follow.
253
The exploration of carbene generation from
Si CF
2
Br Me
Me
Me
Ph
3
P CF
2
PPh
3
Ph
3
P
F
F
DMPU
O
R
1
R
2
O
R
1
OH
NO
2
R
2
R
1
R
1
R
2
HO
CF
2
H
R
1
O
CF
2
H
NO
2
R
2
R
1
CF
2
H
OH
R
1
R
3
R
2
O
R
1
R
3
R
2
CF
2
H
C
F
F
Si CF
2
Br Me
Me
CF
2
Br Br
Me
SH
R
1
R
3
R
2
S
R
1
R
3
R
2
CF
2
H
N
H
N
N
N
CF
2
H
R R CF
2
H
a) Difluoromethylation of nucleophiles b) Difluoromethylation of electrophiles
61
TMSCF3 has resulted in the publication of numerous methodologies for the
(sila)difluoromethylation of C-nucleophiles with multiple substrates ranging from arenes and
vinylic compounds, to -C(sp) and -C(sp
2
) compounds.
264–266
Singlet difluorocarbene generation
from TMSCF3 has also been extensively applied for the terminal CF2H installation onto
chalcogens and other heteroatoms (S,N,O,Se,P).
267–270
(Scheme 1.53).
Scheme 1.53: (Sila)difluoromethylation of C-nucleophiles, chalcogens and other heteroatoms with TMSCF 3
In addition to the direct nucleophilic and electrophilic difluoromethylation routes discussed, the
installation of the CF2 group is effectively achieved through cross coupling reactions that utilize a
reactive handle in the starting material. Very good reviews that encompass the latest reports of
these transformations are available.
140
In this section, selected examples of transition metal-
promoted/catalyzed cross coupling difluoromethylation reactions will be briefly discussed due to
C
F
F
Si CF
3
Me
Me
Me
CF
3
F
O
X
R
2
R
1
O
X
R
2
R
1
CF
2
TMS
C
F
2
TMS
OPG OPG
R
R
F
2
C
TMS
R
OR
Ar
R
OR
Ar
CF
2
TMS
N
H
N
N
N
CF
2
H
OH
R
1
R
3
R
2
O
R
1
R
3
R
2
CF
2
H
SH
R
1
R
3
R
2
S
R
1
R
3
R
2
CF
2
H
Ar
S
S
Ar
Ar
S S
Ar C
F
2
Ar
Se
Se
Ar
Ar
Se Se
Ar C
F
2
P
O
R
1
H
R
2
P
O
R
1
C
F
2
R
2
TMS
62
their relevance to chapters 3 and 4 of this dissertation. As previously discussed, the synthesis of
difluoromethylarenes has been successfully achieved by subjecting aryl iodides to the reaction
with a traditionally nucleophilic CF 2H source in the presence of a copper salt. Scheme 1.28
depicted earlier in this section showcased the work conducted by Hartwig and coworkers,
165
and
Qing and collaborators
166
independently in the use of TMSCF2H and a copper salt to prepare
these compounds. Other important methodologies include the work by Prakash and coworkers
where the combination of tributyl(difluoromethyl)stannane (nBu-Sn-CF2H) and copper iodide
effectively perform a direct ipso difluoromethylation of aryl iodides and β-styryl halides (Scheme
1.54.a).
139
Vicic
136
and Mikami
138
independently reported the use of a new difluoromethyl zinc
reagent [(DMPU)2Zn(CF2H)2] in combination with a copper catalyst to perform the
difluoromethylation of aryl halides (Scheme 1.54.b (i) and (ii). Additionally, the Ritter group
reported the catalytic decarbonylative difluoromethylation of aroyl chlorides employing the same
reagent (Scheme 1.54.c).
271
Scheme 1.54: Transition-metal catalyzed synthesis of difluoromethyl compounds
This versatile zinc reagent can be used in combination with a transition metal to create reactive
difluoromethylating species in situ that can directly and, in most cases, catalytically
I
X
Ar
CF
2
H
X
Ar SnCF
2
H nBu
3
a) Difluoromethyl arenes with CF
2
H stannane
R
3
Sn CF
2
H Cu CF
2
H Cu (CF
2
H)
2
CF
2
H Ar
X
Ar
X: Br, I, OTf
CF
2
H
Ar
(dppf)Ni(COD), rt
CuI, 60 ºC
X: I
Zn
DMPU
DMPU
CF
2
H
CF
2
H
b) Difluoromethyl arenes with ZnCF
2
H
[Ox]
X: H or TMS
R
1
R
X
R
1
R
CF
2
H
CuBr
Zn
DMPU
DMPU
CF
2
H
CF
2
H
PPh
3
/NBS/CuI
R OH
O
R CF
2
H
O
d) Difluoromethyl ketones and alkynes with ZnCF
2
H
R
2
Zn CF
2
H Cu CF
2
H Cu (CF
2
H)
2
CF
2
H R
(i)
(ii)
Ar
CF
2
H
Ar Cl
O
Zn
DMPU
DMPU
CF
2
H
CF
2
H
c) Difluoromethyl arenes with ZnCF
2
H and Pd
Pd(dba)
2
RuPhos
R
2
Zn CF
2
H XPd
II
CF
2
H
CF
2
H Ar
Ar-COCl
CO
63
difluoromethylate substrates such as aryl iodides, bromides, and triflates. Chapter 3 and 4 of this
dissertation describe the use of [(DMPU)2Zn(CF2H)2 in combination with a copper salt to
effectively difluoromethylate carboxylic acids
272
and terminal or silyl alkynes
273
to produce their
corresponding CF2H analogues (Scheme 1.54.d). In all of these transformations, the in situ
generation of a more reactive M-CF2H species is postulated. When copper is used, it is proposed
that the a thermally unstable [Cu-CF2H] is immediately formed, which then produces a more stable
intermediate cuprate [Cu(CF2H)2]
−
, which in turn has been described as a stable reservoir of
reactive [Cu(CF2H)].
165,274
To finalize this section, the principle of radical difluoromethylation reactions can be summarized
in Scheme 1.55. The difluoromethyl reagent of choice is reduced by one electron via a catalyst,
to in situ generate a CHF2 radical. The subsequent propagation of the reaction involves the
formation of a radical anion, and a second SET step affords the corresponding difluoromethylation
product. Further steps might be involved, depending on the nature of the system and the species
participating. Metalsulfinate salts, such as zinc difluoromethanesulfinate,
275
and sodium
difluoromethanesulfinate,
59
are efficient sources of the CF2H radical species that allow the
functionalization of C-H bonds, as well as thiols and other heteroatoms (Scheme 1.55.b.i and
ii).
276,277
As seen in the monofluoromethylation section of this chapter, Prakash and coworkers
synthesized the difluoromethyl equivalent of the sulfonium reagent presented earlier in Scheme
1.10. S-(difluoromethyl)diarylsulfonium tetrafluoroborate (sulfonium reagent in Scheme 1.55.b.iii)
enabled the fluoromethylation of nitrogen, oxygen, and phosphorous nucleophiles, presumably
via difluoromethyl radical formation.
129
Photocatalysis is also a very efficient way of conducting
radical difluoromethylation in a variety of compounds. In these cases, photoredox cycles involve
the use of a metal-based or organic photocatalyst (PC).
64
Scheme 1.55: Radical difluoromethylation and photocatalysis
General photoredox pathways
PC* PC
+1
Oxidative
Quenching
Cycle
PC
hv
PC* PC
-1
Reductive
Quenching
Cycle
PC
hv
R CF
2
H
HF
2
C
R X R X
R X CF
2
H
a) CF
2
H radical coupling
S
H
B
B
CHF
2
Ph
3
P Br
B
B
Ar CF
2
H Ar
[Zn](SO
2
CF
2
H)
2
tBuOOH
TFA
Ar
S
CF
2
H
Ar
CHF
2
S
O
Ph
NTs
TIPSO
R
1
R
3
R
2
O
R
1
R
3
R
2
CF
2
H
facIr(ppy)
3
B
B
CHF
2
S
Ar
Ph
BF
4
Ar
N
N O
R
1
R
2
R
3
Ar
N
N O
R
1
R
2
R
3
CF
2
H
B
B
NaSO
2
CF
2
H
AgNO
3
K
2
S
2
O
8
S
H
R R
S
CF
2
H
R R
b) Radical difluoromethylation
S
CF
2
H
BF
4
CF
2
H P
BF
4
P-nucleophiles
CF
2
H
N
R
R
R
BF
4
S
O
CF
2
H
O-nucleophiles
N-nucleophiles
Nu
iii. Sulfonium reagent
i. Zinc sulfinate
ii. Sodium sulfinate
O
O
Ar
c) Photochemical radical difluoromethylation
Substrate Reagent Light/ PC Product
N N
Ph
Ph Ph
Ph
65
Such catalysts will undergo an electron transfer process (excitation) in which they can either act
as an oxidants (reductive quenching cycle) or reductants (oxidative quenching cycle) depending
on the substrate involved in the reaction (Scheme 1.55.c). The resulting species can then
undergo a second single electron oxidation/reduction, returning the catalyst to its original
oxidation state.
278,279
Multiple difluoromethylating reagents have been used with this
photochemical principle to prepare a variety of CF2H compounds. Examples of this include the
radical difluoromethylation of aromatic thiols with (difluoromethyl)triphenylphosphonium
bromide,
280
the synthesis of α-difluoromethyl ketones from enol silanes via radical generation from
a difluoromethylsulfonamide,
281
the synthesis of CF2H- quinoxalinones via sulfonium salt and
organic catalyst (Scheme 1.55.c)
282
among other important photoredox protocols.
283
1.4 Trifluoromethylation strategies
Trifluoromethylation of organic compounds is arguably one of the most exploited
perfluoroalkylation reactions used in late-stage functionalization of organic compounds. The
trifluoromethyl group is bioisosteric to alkyl groups such as ethyl and even isopropyl, although
CF3 is considerably smaller. The replacement of a methyl group for a trifluorinated analogue can
sometimes improve the biological activity, and even modify the selectivity and binding affinity,
depending of the biological target being tested.
284,285
In the past few decades, a plethora of
methods have become available to perform this chemical transformation in a variety of ways; The
direct nucleophilic trifluoromethylation of carbon centers and different heteroatoms is performed
by utilizing a source of trifluoromethide (
—
CF3) which then will react with an electrophile to afford
the desired compound.
252,286–289
Among the reagents depicted in Scheme 1.56.i, TMSCF3, also
known as the Ruppert-Prakash reagent, is a widely utilized organosilane to prepare
trifluoromethyl-containing molecules due to its versatility, safe handling, and affordability.
182,252
Prakash and coworkers’ pioneering work in nucleophilic trifluoromethylation catalyzed the growth
and popularity of this transformation. Similarly, pioneering work by Umemoto and coworkers in
66
electrophilic trifluoromethylation kickstarted the preparation of a variety of chalcogen-based
reagents (X= S, Se, Te) that can afford an equivalent of trifluoromethyl cation (
+
CF3) in order to
functionalize C,N,O, and S nucleophiles (Scheme 1.56.ii).
290–292
The direct generation of a
trifluoromethyl radical is also an endeavor being pursued since the early 1970’s and it is achieved
through chemical or photocatalyzed methods that enable the formation of C—C bonds through
the formation of highly reactive species.
293–296
Although some reagents are typically used to
enable a particular type of trifluoromethylation reaction, the introduction of oxidants and/or
transition metals can tune the philicity of the trifluoromethyl species. In this way, TMSCF3 can be
used for electrophilic trifluoromethylations,
297
Umemoto’s and Togni’s reagents have been
employed in radical transformations,
298
and some fluorohalons can either be used for nucleophilic
or radical transformations, depending on the conditions used. Transition metals and metalloids
can facilitate trifluoromethylation reactions either through the formation of highly active metal-
perfluoroalkyl species like the ones shown in Scheme 1.56.iv, or as catalysts for electron transfer
processes.
299–302
Scheme 1.56: Trifluoromethylation strategies
(i) Nucleophilic trifluoromethylation
(iii) Radical trifluoromethylation
(ii) Electrophilic trifluoromethylation
TMSCF
3
HCF
3
F
3
C X
O
F
3
C N
O
R
3
Si
X
F
3
C
S
OR
O
ICF
3
/ TDAE
F
3
C
S
S
CF
3
R
1
R
2
X
CF
3
R
1
R
2
S
CF
3
R
1
R
2
O
O
CF
3
R
1
R
2
I
CF
3
O
R
1
R
S
CF
3
N
X
O
C F
I
F
F F
3
C
N
S
O
O
X
N
O
F
3
C
S O
S
(CH
2
)
2
Ph
CF
3
Cu CF
3
Zn
CF
3
Sn
CF
3
Ag
C Br
Br
F
F
(iv) Transition-metal-CF
3
species
CF
3
Mn CF
3
Fe CF
3
Ni
CF
3
Ge
CF
3
Pt
CF
3
Cd CF
3
Mo CF
3
Ti
CF
3
CF
3
CF
3
CF
3
M
67
Given the extent of the trifluoromethylation methodologies available in the literature,
303
this
section will briefly cover selected examples of nucleophilic, electrophilic, and cross-coupling
trifluoromethylations with widely used reagents such as TMSCF3, fluoroform, Togni’s reagent,
among others depicted in Scheme 1.56. In addition to its use as a difluorocarbene source,
TMSCF3 is most well known for being a safe, effective, and cost-efficient way to prepare
trifluoromethyl compounds due to the mild activation conditions generally required and its
commercial availability.
Scheme 1.57: Nucleophilic trifluoromethylation of electrophiles with TMSCF 3
TBAF TBAT
TMAF CsF
n
Bu
3
P
PPh
3
Py
Common ionic and non-ionic initiators
MeCN THF
H
2
O DME
CH
2
Cl
2
DMPU
DMF
Common solvents
TASF KO
t
Bu
DMSO
DFTPS
TMSCF
3
Initiator
R X
O
X= Aryl, alkyl, H
Me SiMe
3
O
F
3
C OR
O
activated esters
silyl ketones
R Cl
O
R
S
X
O O
Ar
R X
HO CF
3
R O
CF
2
TMS
F
3
C OR
HO CF
3
R CF
3
O
R
S
CF
3
O
O
CF
3
Ar
acyl chlorides
S-electrophiles
arenes
(i)
(ii)
(iii)
(iv)
(v)
(vi)
CF
3
HN
’R
R
S
R
Se
CF
3
R
Disulfides
(viii)
(vii)
(ix)
S
R
S
CF
3
R
Se
R
Diselenides
Se
R
N
’R
R
CF
3
F
3
C
NH
2
Ar
Imines
Arly nitriles
CN
Ar
(x)
68
This reagent has been used to trifluoromethylate a broad variety of electrophiles (Scheme 1.57)
among which aldehydes and ketones are widely employed,
304
yielding the corresponding
trifluoromethyl carbinols (Scheme 1.57.i). Acylsilanes have also been employed as electrophiles
for the synthesis of difluoroeneoxysilanes with tetrabutylammonium difluorotriphenylstannate
(Scheme 1.57.ii).
305
The product form the nucleophilic addition to the acyl compounds undergoes
a Brook rearrangement and subsequent fluoride elimination, after which the desired product is
formed. Acid halides are another class or carbonyl compounds that has been transformed into
both the trifluoromethyl ketone and trifluoromethyl carbinol derivatives employing TMSCF3
(Scheme 1.57.iv).
182
Trifluoromethylation of sulfur and selenium electrophiles is also achievable
(Scheme 1.57.v, viii, viii),
288,306
as well as the direct functionalization of imines and nitriles,
producing their corresponding a or b-trifluoromethyl amines (Scheme 1.57.ix, x). As an
alternative to TMSCF3, fluoroform (CF3H) has proven to be an efficient source of trifluoromethide
when treated with an appropriate base. CF3H is a greenhouse gas that is produced as a by-
product from Teflon manufacturing and other industrial processes.
307
Scheme 1.58: Nucleophilic trifluoromethylation of electrophiles with fluoroform
HCF
3
R R'
F
3
C
OH
Borates
Silanes
Elemental sulfur
Ketones
Aldehydes
Esters
Benzyl halides
Si R CF
3
R
R
B R CF
3
R
R
X
HO
3
S CF
3
R
CF
3
O
H OR
F
3
C
OH Formates
CF
3
Ar
CF
3
R
Alkynes
69
The long-elusive transfer of the trifluoromethyl group from this gas was successfully performed
by Prakash and coworkers, and later applied by others, thus enabling the functionalization of
silicon, boron, sulfur, and carbon centers in a variety of organic solvents (Scheme 1.58).
307,308
Fluoroform and (trifluoromethyl)trimethylsilane are also employed in the synthesis of transition
metal complexes that have been widely utilized in a variety of cross-coupling reactions. Cu-CF3
stands as the most successful trifluoromethyl-metal complex to effectively functionalize a wide
variety of compounds. This complex was first identified by Burton and coworkers in what they
describe as a pregenerative route to trifluoromethyl copper via in situ metathesis of
(trifluoromethyl)cadmium or -zinc and a copper salt (Scheme 1.59.A). The reagent is produced
in situ and its utility is demonstrated through the preparation of trifluoromethylated products.
309
Since then, isolable and well-defined trifluoromethylcopper complexes have been prepared. Vicic
and coworkers prepared and characterized Cu(I)−CF3 complexes with N-Heterocyclic carbene
(NHC) as a ligand (Scheme 1.59.B). The route involves the addition of TMSCF 3 to copper tert-
butoxide-(NHC) precursors which readily react to yield (NHC)Cu−CF3 complexes.
310
1,10-
Phenanthroline-CuCF3 is another widely used, and commercially available stable complex first
isolated by Hartwig and coworkers. This complex was prepared from TMSCF3 and was then
shown to react with a large range of aryl halides to yield the trifluoromethyl(arene) compounds
(Scheme 1.59.C).
311
Similarly, Grushin and coworkers have shown that the preparation of a solid
and air-stable [(Ph3P)3Cu(CF3)] can be achieved from copper fluoride, triphenylphosphine and
TMSCF3. This complex serves as a trifluoromethylating agent and a convenient starting material
for the synthesis of other CuCF3 complexes (Scheme 1.59.D).
312
The same group elegantly
reported the direct cupration of fluoroform, via reacting a copper halide with an alkoxide base in
a polar solvent. The resulting alkoxycuprates readily react with CF3H at room temperature to give
CuCF3 derivatives (Scheme 1.59.E).
313
70
Scheme 1.59: Preparation of Cu-CF 3 complexes
The preparation of electrophilic trifluoromethylation reagents can also be done via TMSCF 3 by
either employing oxidative conditions,
297
or by preparing stable and isolable reagents. Hypervalent
iodine reagents are widely used in organic chemistry due to their diverse reactivity and
commercial availability. The reactivity and general behavior of λ
3
-iodanes is largely based on the
nature of the bond between the iodine center and any “X” atom. Loosely bound atoms result in
the iodine center having a distinct positive charge.
314
Therefore, the enhanced electrophilic
properties of ArIX2 compounds stems from this property. Togni and coworkers envisioned the
preparation of an electrophilic trifluoromethylation reagent by treating different iodine compounds
with TMSCF3.
292,315
The resulting compounds 1 and 2 shown in Scheme 1.60.a, commonly known
[CuOtBu)]
4
1) 1,10-phenanthroline
benzene, rt 30 min
2) TMSCF
3
, rt, 18h
Cu CF
3
N
N
KOtBu
DMF
CuCl
K[(DMF)][Cu(O
t
Bu)
2
]
CF
3
H
3HF•Et
3
N
Cu CF
3
DMF, rt
CF
2
Br
2
2 Cd or Zn
BrCdCF
3
Cd(CF
3
)
2
CuBr
-80 ºC — rt
Cu CF
3
A) Burton, (1986)
E) Grushin, (2011)
CuF
2
•H
2
O
PPh
3
, MeOH
reflux in air
TMSCF
3
Cu
CF
3
PPh
3
PPh
3
Ph
3
P
D) Grushin, (2011)
(NHC) Cu
O
O
t
Bu
t
Bu
Cu (NHC)
Cu CF
3
N
N
2 TMSCF
3
THF
B) Vicic, (2008)
C) Hartwig, (2011)
71
Scheme 1.60: Electrophilic and oxidative trifluoromethylation of nucleophiles
I
F
3
C
O
O
I
F
3
C
O
I
F
3
C
O
O
I F
3
C
O
O
Zn
I
CF
3
O
O
Zn HO
R
I
F
3
C
O
O
Zn
O
R
I OH
O
HO
R
X
X
HX
HX
ZnX
2
1 2
1
From TMSCF
3
I
O O
F
3
C
O
CF
3
O
I F
3
C O
CF
3
O
TMSCF
3
KF
PIFA
CF
3
TMSCF
3
I TFA TFA
I CF
3
TFA
CF
3
Homolysis
+
I CF
3
TFA
I TFA
CF
3
(i)
(ii)
(iii)
(iv)
[I]
[II]
[III] [IV]
R
1
R
N R
2
O
R
3
CF
3
H
R
1
R
N R
2
O
R
3
F
3
C
H
[B]
[A]
Cu(I) Cu(II)
SET
or III
R
1
R
N R
2
O
R
3
F
3
C
H
R
1
R
N R
2
O
R
3
F
3
C
H
BH4
[C] [D]
R
1
R
N R
2
O
R
3
F
3
C
[E]
R SH R S
2
CF
3
R P
R
P
2
CF
3
R
X R
R P
R
P
2
CF
3
R
X R
R N
R
N
2
OH R
R
O
CF
3
NH
2
2
NH
R
HN
NH
R
CF
3
a) Eelectrophilic trifluoromethylation with Togni’s reagents
b) Oxidative trifluoromethylation with TMSCF
3
(i)
(ii)
(iii)
(iv)
(v)
72
as Togni’s reagents, are widely employed to electrophilically transfer the CF3 unit to different
nucleophiles. An example of this is the preparation of trilfluoromethyl alcohols employing Togni’s
reagent 2 in the presence of a Lewis acid. The mechanistic proposal suggests that a
carboxylate/iodonium complex is formed upon the treatment of the reagent with a zinc(II) salt. A
ligand exchange occurs upon addition of the alcohol, and the resulting species undergoes
reductive elimination to yield the desired CF3-alcohol. These reagents have also been widely
employed for the electrophilic trifluoromethylation of sulfur, nitrogen, oxygen, phosphorous
centers.
316
Similarly, TMSCF3 can react with hypervalent iodine reagents such as
(bis(trifluoroacetoxy)iodo)benzene (PIFA), in situ to create a trifluoromethyl-iodine bond that upon
homolytic cleavage, yields a trifluoromethyl radical. Prakash and coworkers demonstrated the
utility of this approach by preparing an array of b-trifluoromethyl enamides via an oxidative
difluoromethylation process in the presence of copper (Scheme 1.60.b).
297
73
CHAPTER 2: Copper-mediated Synthesis of Trifluoromethyl ketones from
Carboxylic Acids by Cross-Coupling with Acyloxyphosphonium Ions
Scheme 2.1: Synthesis of trifluoromethyl ketones via acyloxyphosphonium ions
This chapter will cover the discussion and analysis of the developed transformation that utilizes
an acyloxyphosphonium ion as the active electrophile, conveniently generated in situ from a
carboxylic acid substrate by utilizing commodity chemicals. The role of L-Cu-CF3 as the proposed
reactive intermediate and the utility of the reaction system are also discussed. The
chemoselectivity and tolerance to a variety of important functional groups is highlighted, as well
as the late-stage functionalization of carboxylic acid active pharmaceutical ingredients and
pharmaceutically relevant compounds. Lastly, the mechanistic studies performed are analyzed in
depth in order to provide accurate conclusions regarding the system’s reactivity. (Chem. Eur. J.,
2021, 27, 1–7, 10.1002/chem.202102854).
2.1 Introduction and prior art in the synthesis of trifluoromethyl ketones
As discussed in the previous chapter, due to the unique properties that fluoroorganics possess,
they have attracted the attention of the synthetic organic, materials and biological sciences in
recent years.
317,318
And among them, the trifluoromethyl (–CF3) group stands as a valuable moiety
for tuning the lipophilicity and bioavailability of drug-like molecules resulting in a high prevalence
in agrochemicals and APIs. In this same context, the keto- motif is a quintessential functional
group in organic chemistry. This moiety is ubiquitous in naturally occurring compounds, materials,
and active pharmaceutical ingredients (APIs) alike. Moreover, ketones are versatile handles for
PPh
3
[1.4 equiv]
NBS [1.5 equiv]
THF/MeCN
0
o
C - rt, 1h, N
2
R OH
O
1
R CF
3
O
[CuCF
3
]
2
R = aryl, alkyl
[1.0 equiv]
R OPPh
3
O
Via:
X
I
CuI [2.0 equiv]
TMSCF
3
[2.5 equiv]
CsF [1.5 equiv]
74
a wide variety of chemical transformations.
319,320
Thus, streamlined access to ketones from readily
available starting materials is a prevalent goal in organic chemistry. More specifically,
perfluoroalkyl ketones are highly valuable compounds, owing in part to their enhanced
electrophilicity and their general versatility as synthetic intermediates.
321–323
In addition,
trifluoromethyl and difluoroalkyl (-CF2R) ketones have proven highly valuable in medicinal
chemistry (Figure 2.1).
324
Figure 2.1: Biologically and synthetically relevant trifluoromethyl ketones
The synthesis of these valuable compounds dates back to early reports that describe the Friedel-
Crafts trifluoroacetylation of aromatics in moderate to low yields and with limited reaction
scope.
325,326
Direct trifluoroacetylation of organometallic reagents (ArLi or RMgX) has been
reported.
327–330
However, these transformations exhibit poor functional group tolerance and
produce undesired double addition by-products even if temperature (-78
o
C), stoichiometry and
order of addition of reagents are carefully controlled. To circumvent these limitations, multistep
sequences are employed as alternatives (Scheme 2.2).
331–333
Carboxylic acids are widely
encountered in naturally occurring compounds, pharmaceuticals, and materials. They stand as
one of the most accessible feedstocks for various synthetic targets.
[13]
The utilization of these
compounds and their derivatives to produce ketones is arguably the most straightforward
approach for their synthesis. In this context, CF3-ketones have been prepared via nucleophilic
CF
3
O
MeO
2
S
Zifrosilone
(AChE inhibitor)
Me
3
Si
N
O
CF
3
F
(COX-2 inhibitor)
CF
3
H
N
O
O
Ph
Histone deacetylase inhibitor
CF
3
O
Cl
NHR
Intermediate in
Efavirenz synthesis
CF
3
O Br
F
Intermediate in the synthesis of
rheumatoid arthritis lead
(Merck)
(Boehringer Ingelheim)
CF
3
O
R
Precursors for the
synthesis of CF
3
carbinols
75
trifluoromethylation of methyl esters,
289,334,335
acyl chlorides,
336,337
and Weinreb amides
338
(Scheme 2.2). Skrydstrup
demonstrated that the same Weinreb amides can be generated in-situ
from aryl electrophiles via Pd-catalyzed aminocarbonylation, and subsequently used to access
CF3-ketones.
Scheme 2.2: Trifluoromethyl ketones from carboxylic acid derivatives
In 2021, Chen reported a method to access the target compounds from carboxylic acids via mixed
trifluoroacetic anhydrides at elevated temperatures.
339
Similarly, a method to prepare enantio-rich
tertiary alpha-CF3 ketones via nickel-catalyzed reductive cross-coupling was published a year
after.
340
The majority of these methods have limitations in scope, cost of reagents, and/or
practicality of the reaction setup (cryogenic temperatures, multistep sequences, and long reaction
times) in conjunction with the need to pre-synthesize and isolate the acyl electrophiles.
Thus, the development of efficient protocols to access CF 3-ketones directly from carboxylic acids
is a highly warranted endeavor. In this chapter an efficient approach for the synthesis of CF3
ketones directly from carboxylic acids via acyloxyphosphonium ions I is described (Scheme 2.1).
2.2 Optimization of the trifluoromethylation reaction
Based on our previous work on deoxyfluorination of carboxylic acids via acyloxyphosphonium
ions I, where we synthesized acyl fluorides by employing 3HF-Et3N as a source of anhydrous and
acidic fluoride ion,
341
we surmised that a nucleophilic CF3 source could efficiently intercept
intermediate I to yield the desired trifluoromethyl ketone 2. The first parameters that were
optimized were the copper salts, as well as the base to activate TMSCF3. Copper iodide gave the
R
O
Cl
R
O
CF
3
R
O
OH R
O
OMe
(i) TMSCF
3
/F
-
(ii) H
3
O
+
R
O
N
OMe
(i) TMSCF
3
/ CsF
(ii) TBAF, H
2
O
Yagupolskii, (2007) Olah & Prakash (1998) Leadbeater, (2012)
(R= Ar, Alk) (R= Ar)
AgCF
3
Chen, (2021)
(CF
3
CO)
2
O, DMAP
TMSCF
3
/CsF
120ºC, 15h.
Ph
CF
3
Br
2
Chen (2022)
76
best results and as shown in Table 2.1, other copper salts were not effective at forming the active
trifluoromethyl copper species. No [CuCF3] could be detected by
19
FNMR when CuCl was used,
while CuBr and CuSCN resulted in lower yields of the [CuCF3] species. Additionally, as expected,
formation of acyl thiocyanate takes place when CuSCN is used. Similarly, CsF proved to be the
best base of choice for this system.
Table 2.1. Copper sources and base optimization
Reaction conditions: (i) Cu salt, base and TMSCF 3 in MeCN at rt for 10 min under Ar (ii) Naphthoic acid (0.25 mmol),
PPh 3 (1 equiv), NBS (1.1 equiv) in MeCN (2.5 mL), 0
o
C to rt, 15 min. After this time, Cu-containing mixture was then
added to solution of I and stirred 1 h, rt.
a
Yields determined by
19
F NMR analysis.
Next, we evaluated the optimal stoichiometry of copper and TMSCF3 to effectively generate
CuCF3 in solution Entries 1-4 in Table 2.2 demonstrate that an excess of TMSCF3 favors the
PPh
3
[1.0 equiv]
NBS [1.1 equiv]
MeCN
0
o
C - rt, 15 min
R OH
O
1
R CF
3
O
[CuCF
3
]
2
R = naphtyl
[1.0 equiv]
R F
O
R OPPh
3
O
Via:
X
I
Cu source [1.2 equiv]
TMSCF
3
[2.5 equiv]
Base [1.2 equiv]
MeCN, 10 min, rt
Entry [Cu] Base (equiv) 2a Yield (%)
a
RCOF Yield (%)
a
1 CuCl KF 20 n.d
2 CuBr KF 15 n.d
3 CuI KF 0 n.d
4 (MeCN) 4CuBF 4 KF 0 n.d
5 (MeCN) 4CuPF 6 KF 0 n.d
6 CuCl CsF trace n.d
7 CuBr CsF 20 n.d
8 CuI CsF 60 16
9 CuSCN CsF 40 n.d
10 CuI Cs 2CO 3 0 n.d
11 CuI
t
BuOK 5 n.d
77
reaction. Similarly, we determined the optimal concentration of the trifluoromethylating mixture
wherein the copper salt is the limiting reagent (Table 2.3).
Table 2.2. Effect of TMSCF 3 and CuI loading
Entry TMSCF 3 (equiv) CuI (equiv) 2a Yield (%)
a
RCOF, Yield (%)
a
1 1.5 1.5 40 27
2 2 1.5 51 21
3 2 2.0 54 27
4 2.5 2.0 70 15
Reaction conditions: (i) CuI, CsF (1.5 equiv) and TMSCF 3 in MeCN (0.66 mL) at rt for 10 min under Ar (ii) Naphthoic
acid (0.25 mmol), PPh 3 (1 equiv), NBS (1.1 equiv) in MeCN (2.5 mL), 0 ºC to rt, 15 min. After this time, Cu-containing
mixture was then added to solution of I and stirred 1 h, rt.
a
Yields determined by
19
F NMR analysis.
Table 2.3. Effect of [Cu] concentration
Entry [Cu] (M), mL of MeCN 2a Yield (%)
a
RCOF, Yield (%)
a
1 0.75 M, 0.66 mL 70 15
2 0.3M, 1.6 mL 53 5
3 0.1M, 5 mL 48 n.d
PPh
3
[1.0 equiv]
NBS [1.1 equiv]
MeCN
0
o
C - rt, 15 min
R OH
O
1
R CF
3
O
[CuCF
3
]
2
R = naphtyl
[1.0 equiv]
R F
O
R OPPh
3
O
Via:
X
I
CuI [x equiv]
TMSCF
3
[y equiv]
CsF[1.5 equiv]
MeCN, 10 min, rt
PPh
3
[1.0 equiv]
NBS [1.1 equiv]
MeCN
0
o
C - rt, 15 min
R OH
O
1
R CF
3
O
[CuCF
3
]
2
R = naphtyl
[1.0 equiv]
R F
O
R OPPh
3
O
Via:
X
I
CuI [1.5 equiv]
TMSCF
3
[2.5 equiv]
CsF [1.5 equiv]
MeCN [conc], 10 min, rt
78
Reaction conditions: (i) CuI (1.5 equiv), CsF (1.5 equiv) and TMSCF 3 (2.5 equiv) in MeCN at rt for 10 min under Ar (ii)
Naphthoic acid (0.25 mmol), PPh 3 (1 equiv), NBS (1.1 equiv) in MeCN (2.5 mL), 0 ºC to rt, 15 min. After this time, Cu-
containing mixture was then added to solution of I and stirred 1 h, rt.
a
Yields determined by
19
F NMR analysis.
After optimizing the parameters to find the best conditions for the preparation of [CuCF3] solution,
we moved on to optimizing the generation of the acyloxyphosphonium ion in order to achieve
complete selectivity for our desired compound 2a, over the acyl fluoride by-product. Table 2.4
showcases the effect of increasing the amounts of PPh3 and NBS, as well as the effects of a
mixed solvent system. Given that the preparation of ion I is done under air, we hypothesized that
having an excess of bromophosphonium ion (PPh3-Br
+
) helps trap adventitious water that could
potentially interfere with the organometallic species that are added later in the reaction. Therefore,
we found that 1.4 and 1.5 equivalents of PPh3 and NBS, respectively, along with a mixed solvent
system of MeCN/THF afforded the highest yield and complete selectivity. In the case of aliphatic
substrates,
Table 2.4. Effect of PPh 3/NBS loading and solvent system on selectivity for 2a
Entry Solvent 1 (0.1M) PPh 3/NBS (equiv) 2a Yield (%)
a
RCOF, Yield (%)
a
1 MeCN 1/1.1 70 15
2 Dioxane 1/1.1 70 6
3 MeCN 1.4/1.5 65 6
4 THF 1.4/1.5 80 0
[a]
Reaction conditions: (i) CuI (2 equiv), CsF (1.5 equiv) and TMSCF 3 (2.5 equiv) in MeCN (0.66 mL) at rt for 10 min
under Ar (ii) Naphthoic acid (0.25 mmol), Ph 3P, NBS, in solvent I (2.5 mL), 0 ºC to rt, 15 min. After this time, Cu-
containing mixture was then added to solution of I and stirred 1 h, rt.
[b]
Yields determined by 19F NMR analysis.
best results were obtained when I was prepared in DCM instead of THF. After extensive
optimization, the desired deoxytrifluoromethylation of 2-naphthoic acid was achieved in 80% yield
PPh
3
[x equiv]
NBS [y equiv]
solvent 1
0
o
C - rt, 15 min
R OH
O
1
R CF
3
O
[CuCF
3
]
2
R = naphtyl
[1.0 equiv]
R F
O
R OPPh
3
O
Via:
X
I
CuI [2.0 equiv]
TMSCF
3
[2.5 equiv]
CsF [1.5 equiv]
MeCN [0.75M], 10 min, rt
79
by first preparing a solution of I, formed in situ from naphthoic acid, PPh3 (1.4 equiv), and NBS
(1.5 equiv) in THF. This solution was then added to [CuCF3]
generated in 10 min from TMSCF3
(2.5 equiv), CuI (2.0 equiv), and CsF (1.5 equiv) in MeCN. Table 2.5 showcases selected
optimization trials that summarize the most important variations in the reaction’s parameters.
Control reactions established that using catalytic amounts of CuI resulted in the formation of large
amounts of acyl fluoride
341
(Table 2.5, entry 2). Substituting CsF by either KF or
t
BuOK is
detrimental to the outcome of the reaction (Table 2.5, entries 3-4), and as mentioned before, the
use of different copper salts (CuBr, CuCl, CuSCN) dramatically decreased the yield (Table 2.5,
entries 5-7). The use of a binary mixture of THF:MeCN is critical to achieve product selectivity.
Though modest yields of 2a can be obtained in MeCN as a single solvent, contamination with the
acyl fluoride by-product is unavoidable (Table 2.5, entry 8). Addition of pre-formed (phen)CuCF3
311
either in THF or MeCN to a THF-solution of I proved less effective than the use of “ligand-free”
[CuCF3] generated under the standard conditions (Table 2.5, entries 9-10). An explanation for
these results could be the reported a-fluoride elimination from [CuCF3] species, including
(phen)CuCF3, which results in the formation of acyl fluoride by-product as well as homologated
species [CuCF2CF3].
Table 2.5. Direct Deoxygenative Trifluoromethylation of Carboxylic Acids: Effect of Reaction Parameters (selected
trials).
Entry Deviations from “standard conditions” Yield 2a (%) Yield RCOF (%)
1 none 80 0
2 As above but 10% CuI 0
50
3 KF instead of CsF 0 0
PPh
3
[1.4 equiv]
NBS [1.5 equiv]
THF/MeCN
0
o
C - rt, 1h, N
2
R OH
O
1
R CF
3
O
[CuCF
3
]
2
"standard conditions"
R = aryl, alkyl
[1.0 equiv]
R F
O
R OPPh
3
O
Via:
X
I
CuI [2.0 equiv]
TMSCF
3
[2.5 equiv]
CsF [1.5 equiv]
80
4
t
BuOK, instead of CsF 10 0
5 CuBr instead of CuI 30 0
6 CuCl instead of CuI 0 0
7 CuSCN instead of CuI 45 0
8 MeCN instead THF: MeCN 63 15
9 (phen)CuCF 3 (1.5 equiv) in MeCN 30 27
10 (phen)CuCF 3 (1.5 equiv) in THF 55 0
11 TCCA or NCS instead of NBS 0 0
12 2-Napth-COCl as electrophile 0 5
13 2-Napth-COBr as electrophile 60 30
Yields as determined by
19
F NMR spectroscopy using PhOCF 3 as internal standard (average of two runs). TCCA =
trichloroisocyanuric acid; NCS = N-chlorosuccinimide.
Alternative oxidants such as TCCA
342
and NCS are inefficient for the generation of 2a (Table 2.5,
entry 11). Furthermore, the use of an acyl chloride as the electrophile was unsuccessful, while
acyl bromide afforded a modest yield (60%) of the target ketone, along with significant acyl fluoride
contamination. In previous reports, our group has demonstrated the intermediacy of
acyloxyphosphonium I as opposed to acyl bromides. Acyl bromide formation does not take place
under our reaction conditions, as demonstrated by an experiment we conducted where we
unsuccessfully attempted the preparation of 2-naphthoyl bromide under our reaction conditions.
Our results coincide with previous reports that demonstrate that appreciable amounts of acyl
bromides are only obtained from carboxylic acids, PPh3 and NBS in dioxane under reflux.
343
These results highlight the importance of employing acyloxyphosphonium electrophiles I for the
success of the transformation. In addition to their demonstrated superior reactivity, the ease of
generation of I from widely available RCOOH, PPh3 and NBS is a significant advantage of the
protocol. Unlike their acyl chloride counterparts, the number of commercially available acyl
bromides is severely limited. In contrast, the parent carboxylic acids are indisputably widely
available.
81
2.3 Substrate scope: aliphatic and aromatic trifluoromethyl ketones. CF3- containing active
pharmaceutical ingredients
The results of the deoxytrifluoromethylation of various carboxylic acids demonstrate the synthetic
scope of the transformation, showcased in Scheme 2.3. As mentioned earlier, 2-napthoic acid
afforded 2a in 65% isolated yield and 80% conversion by
19
F NMR. Product 2b containing an
electron-donating substituent (p-methoxy) was isolated in 70% yield (99% by
19
F NMR).
Scheme 2.3: Deoxygenative Trifluoromethylation of Carboxylic Acids. Isolated yields. Yields in parentheses as
determined by
19
F NMR using an internal standard.
b
Ketone:hydrate molar ratio
MeO
2a
65% (80%)
2b
70% (99%)
2f
56% (83%)
2d
70% (99%)
O
CF
3
O
CF
3
O
CF
3
O
CF
3
I
Br
2e
60% (99%)
O
CF
3
O
CF
3
2k
40%(42%)
HO
O
CF
3
2c
70%(90%)
2j
45% (60%) (3:1)
[b]
2g
73%
(77%)
(5:3)
[b]
O
CF
3
CF
3
O
MeO
2l
78% (82%)
From Ibuprofen
CF
3
O
O
Aromatic and Aliphatic CF
3
-Ketones
Active pharmaceutical ingredients
From Naproxen
2n
65% (69%)
CF
3
O
2i
52%(54%)
Cl
2h
67%
O
CF
3
R OH
O
1
R CF
3
O
2
standard conditions
[CuCF
3
]
R OPPh
3
O
X
Via:
NC
O
CF
3
2m
51% (60%)
O
CF
3
OH
Br
From 5-Br Salicylic Acid
HOOC
unsuccesful
substrate:
triptycene-9-carboxylic
acid
R CF
3
OH
2'
CF
3
Not observed I
82
Notably, the transformation exhibits distinctive chemoselectivity towards the –COOH moiety over
the phenolic –OH. This is demonstrated by the successful preparation of 2c in 70% yield without
esterification.
344
The excellent chemoselectivity of this protocol is further illustrated by the
quantitative deoxytrifluoromethylation (by
19
F NMR) of 2d and 2e bearing iodo- and bromo-
functionalities, respectively. In these cases, no evidence of aromatic trifluoromethylation is
observed.
345
The alkene unit of 4-vinylbenzoic acid remained unchanged when it was subjected
to the reaction conditions, and the product 2f was obtained in 83% yield. Furthermore, the a-b-
unsaturated carboxylic acids, 4-chlorocinnamic acid and (Z)-cycloundec-1-ene-1-carboxylic acid
afforded 2h and 2i, respectively, without any evidence of conjugate addition;
346
a feature typical
of organocuprate chemistry. Product 2g was prepared in 73% yield as a 5:3 mixture of the ketone
and hydrate forms, without any 1,2-addition at the 4-acetyl group. Similarly, cyano-substituted 2j
also afforded a mixture of ketone and hydrate. This hydration is typical of CF3-ketones containing
electron-withdrawing substituents.
347
The developed protocol is sensitive to steric factors, with
only a modest yield of the target product obtained when 1-adamantanecarboxylic acid was used
(2k, 40% yield). This steric influence was further confirmed by the incompatibility of sterically
encumbered triptycene-9-carboxylic acid. This stands as a limitation of the current protocol.
Synthetic application of this methodology is illustrated by the late-stage functionalization of active
pharmaceutical ingredients bearing a carboxylic acid motif. Anti-inflammatory drugs (NSAIDs)
naproxen and ibuprofen were successfully converted to the corresponding CF3-ketones 2l and 2n
in 78% and 65% yield, respectively. Similarly, 2m was obtained from 5-bromosalicylic acid in a
modest yield (51%) without compromising the Ar–OH or Ar–Br functionalities.
344,345
Notably, the
present protocol occurs at room-temperature without the formation of bistrifluoromethylation
products 2’.
348
We surmise that this observation is likely a result of the utilization of [CuCF3] as
the nucleophilic
–
CF3 source; organocopper reagents are generally reluctant to engage in 1,2-
additions. This, constitutes a major advantage over previous methods.
338,339
83
2.4 Mechanistic studies
Mechanistic aspects of this transformation deserve further consideration. After formation of
bromophosphonium ion A, a fast reaction takes place to afford acyloxyphosphonium ion I. Though
these intermediates are well established acyl electrophiles in conventional amidation and
esterification reactions, their reactivity toward redox-active organometallic species is not well
understood. While it is reasonable to assume that similar acylation via ionic pathway is operative
when nucleophilic [CuCF3] is used, we felt compelled to further corroborate this hypothesis and
study more in-depth the behavior of species I toward redox-active species such as [CuCF3].
Considering the redox-active nature of copper, and reports of phosphoranyl radical b-scission into
acyl radicals,
349
a possible alternative pathway where acyl radicals arise from an SET event (1e-
reduction) from Cu(I) to species I, giving rise to phosphoranyl radicals was also pondered
(Scheme 2.4).
Scheme 2.4: Possible ionic pathways in comparison to SET pathway to access trifluoromethyl ketones
To gain insights into the mechanisms, the kinetic substituent effects of the aroyl transfer from I
were evaluated through competition experiments employing para-substituted benzoic acids and
in-situ prepared [CuCF3]. The Hammett plot built from these data exhibits good linearity and a
positive slope (ρ = +0.997), in line with the results expected from an acylation via ionic pathway,
and directly opposite to that expected for nucleophilic benzoyl radicals
350
(Figure 2.2).
R CF
3
O
R OPPh
3
O
X
I
31
P NMR
! -5 ppm
PPh
3
NBS
N
O
O
or
—
Br
X =
Br PPh
3
31
P NMR
! 31.5 ppm
A
X
R COOH
31
P NMR
! 45.2 ppm
[Cu
I
CF
3
]
O=PPh
3
31
P NMR
! 27 ppm
[Cu
I
X]
SET
[Cu
III
CF
3
]
R OPPh
3
O
R
O
Phosphoranyl
radical
[Cu
II
CF
3
]
Ionic
pathway
A
SET
pathway
B R
O
Br
not formed
not supported
by experiments
84
Figure 2.2. Hammett Plot of the reaction of [CuCF 3] with substituted acyloxyphosphonium ions; relative rates of
formation of CF 3-ketones versus s
The trials conducted to build the Hammett plot consisted of a series of competition experiments
between CuCF3 and two distinct electrophiles. But first, a control experiment for the competitive
esterification of two electrophiles with phenol was conducted in order to establish a benchmark
for comparison with our deoxygenative trifluoromethylation chemistry (Scheme 2.5).
Scheme 2.5: Control competition experiment for esterification with phenol
To set up this experiment, acyloxyphosphonium ions Ia and Ib were generated separately in an
identical manner as in general method I for CF3-ketone synthesis described in subchapter 2.2,
using 0.25 mmol or each acid, except that anhydrous dichloromethane (1 mL for each) was used.
This concentration and solvent afford optimal results in the previously reported esterification
protocol.
343
The two separately generated solutions of Ia and Ib were mixed. Subsequently, this
mixture comprised of Ia and Ib in 2mL DCM, was added quickly in one portion under argon, to a
O
OPPh
3
H
O
OPPh
3
MeO
Ia Ib
PhOH [1.0 equiv]
Pyridine [1.0 equiv]
DCM
rt, 1h
O
OPh
H
O
OPh
MeO
B’ A’
2.15
1.0
85
solution of PhOH (0.25 mmol, 23.5 mg, 1 equiv) and anhydrous pyridine (0.25 mmol, 19.8 mg, 1
equiv) in DCM (1 mL), which had been prepared in an oven-dried, screwcap 4mL vial equipped
with a stir-bar and septum. This mixture was stirred at room temperature for 1h, after which time,
n-dodecane (50 uL, 0.22 mmol) was added as internal standard (IS) using a microsyringe.
Subsequently, this mixture was poured into pentane (20 mL), resulting in precipitation of insoluble
OPPh3, succinimide and pyridinium hydrobromide. Filtration of this suspension through a plug of
celite, afforded a clear solution that was directly subjected to GC-FID analysis (Image 2.1). The
relative ratio of A’ vs B’ was calculated by comparing the P/IS area ratios for each product
according to the formula shown below in Equation 2.1 where P corresponds to either product A’
or product B’, and IS to internal standard.
!
:
"
#$
=
%&'% )
!
%&'% #$
!
:
"
#$
=
%&'% *
!
%&'% #$
"/#$ )!
"/#$ *!
=
)
!
*!
Equation 2.1. Calculation of relative ratio
Table 2.6. Determination of Relative Ratio of A':B' from GC-FID Data
Product A' (7.55 min)
Phenyl benzoate
Product B' (8.58 min)
Phenyl 4-methoxybenzoate
n-dodecane IS
(5.68 min)
Area 1859.44885 866.62885 3865.70947
P/IS 0.48101102 0.2241836
A' : B' molar ratio 0.48/0.22 = 2.15
Note that absolute yields are unnecessary for our purposes. Identity of products A’ and B’ was
confirmed by recording the GC-FID chromatogram of authentic phenyl benzoate (A’) and phenyl
4-methoxybenzoate (B’) (Image 2.2).
86
Image 2.1: GC-FID Chromatogram of Reaction Mixture from Control competition experiment
Image 2.2: Chromatogram of authentic phenyl benzoate A’ (ret time 7.5 min) and authentic phenyl 4-methoxybenzoate
B’ (at 8.6 min) using n-dodecane (ret time 5.6 min) as internal standard.
The results of this control trial show a rate enhancement (2.15 fold) for reaction of benzoic acid-
derived electrophile Ia when compared to p-anisic acid-derived electrophile Ib, which is in accord
with what is expected from a reaction proceeding via ionic pathway. Next, for the purpose of the
deoxygenation-trifluoromethylation competition experiments, the stoichiometry of the reactions
was adjusted to generate a maximum of 1.0 equivalent of [CuCF3] and bromophosphonium ion.
Generation of larger amounts of [CuCF3], which occurs under the optimized conditions, and
O
OPh
H
O
OPh
MeO
B’ A’
2.15
1.0
O
OPh
MeO
B’
1.0
H
3
C CH
3
10
O
OPh
H
A’
H3C CH3
10 H3C CH3
10
O
OPh
MeO
B’
87
generation of larger amounts of bromophosphonium ion, were avoided as it would have rendered
the results of a competition experiment less meaningful. The procedure followed in competition
experiments 1-4 (Scheme 2.6) is illustrated with the example of OMe vs H (Scheme 2.6.1) as
follows: (a) For the generation of Ia and Ib, on the bench top, benzoic acid (0.25 mmol, 30.5 mg,
1.0 equiv) and PPh3 (0.25 mmol, 65.6 mg, 1.0 equiv) were charged into an oven-dried screw cap
vial (4 mL size) equipped with a stir bar. Anhydrous THF (2.5 mL) was added, and this suspension
was placed in ice for 2 min. Subsequently, NBS (0.275 mmol, 49 mg, 1.1 equiv) pre-weighed into
a small vial, was added as a solid in one portion. The vial was closed using a screw cap equipped
with a septum, gently swirled to wash down all solid NBS, and placed in an ice bath for 2 min
while stirring. Subsequently, the vial was taken out of the ice bath, connected to an argon balloon
using a syringe, and a vent needle was attached to allow continuous purging with argon. Stirring
was continued for additional 15 min at room temp under a continuous stream of Ar, resulting in a
bright yellow solution of acyloxyphosphonium ion Ia. In a separate oven-dried, screw cap vial
acyloxyphosphonium ion Ib was simultaneously generated in an identical manner but using p-
anisic acid (0.25 mmol, 38 mg, 1.0 equiv) instead of benzoic acid. (b) For the [CuCF3] generation,
inside an N2 glovebox, CsF (0.25 mmol, 37.9 mg, 1 equiv) and CuI (0.375 mmol, 71.4 mg, 1.5
equiv) were accurately charged into a flame-dried crimp-top vial (5 mL size), equipped with a stir
bar. The vial was then sealed and brought outside the glovebox. Anhydrous, MeCN (0.5 mL) and
TMSCF3 (0.5 mmol, 74 uL, 2 equiv) were added sequentially to the vial under a stream of Ar
(balloon). This suspension was stirred at room temperature for 10 min, resulting in a beige
precipitate and a brown supernatant. (c) For the CF3-ketone formation: After generation of Ia and
Ib in separate vials (15 min for both), the needle outlet was removed from both vials, and still
under Argon, the solution of Ib, was taken up into a syringe and transferred to vial containing Ia
and stirred for 1 min. Mixing these two species results in no observable changes. This bright-
yellow, homogeneous mixture was kept stirring, while the [CuCF3] suspension was taken into a 3
mL syringe and protected under a blanket (2mL) of Argon. This [CuCF3] suspension was then
88
added dropwise to the mixture of Ia and Ib and the mixture was further stirred at room temperature
for 1h. After this time, PhOCF3 (20 uL, 0.15 mmol) was added as internal standard and the mixture
vigorously stirred for 2 min. Stirring was stopped and after all solids had settled, an aliquot (0.6
mL) of the brown supernatant was taken into a screw-cap NMR tube under an atmosphere N2 for
19
F NMR analysis. In all cases, in addition to CF3-ketones, the following species were observed
by
19
F NMR in varying amounts:
CF 3Br δ = -9.54
CF 3CF 2H δ = -86.2 br.s, 3F, -140.4 d J = 51.5 Hz, 2F
[Cu(CF 3) 4]
-
δ = -34.1
CF 3H δ = -78.9
Ph 3PF 2 δ = -40.08 d, J = 667.7 Hz
TMS-F δ = -157.4
TMSCF 3 δ = -66.9
small amounts of CF 3CF 2-containing byproducts
Scheme 2.6 shows the competition experiments conducted between different combinations of
benzoic acid, and para-Br, CF3, and CH3 substituted derivatives. Additionally, Images 2.3—2.6
show the
19
F NMR spectra of the reaction media with PhOCF 3 as an internal standard. The relative
integrations of the peaks were used to calculate the ratios shown in Table 2.7.
Experiment Pairs Ratio
X kX/kH s value log(kX/kH)
Experiment 1 OMe/H 1.0/1.7 OMe 0.59 -0.27 -0.23045
Experiment 2 Me/Br 1.0/2.27 Me 0.80 0.17 -0.09835
Experiment 3 Br/H 1.81/1.0 H 1.0 0 0
Experiment 4 CF 3/H 3.59/1.0 Br 1.81 0.23 0.257679
CF 3 3.59 0.54 0.555094
Table 2.7: Data obtained from the competition experiments performed.
89
Scheme 2.6: Competition experiments for deoxygenative trifluoromethylation
Image 2.3:
19
F NMR Spectrum of competition experiment 1 (H vs OMe)
O
OPPh
3
H
O
OPPh
3
MeO
Ia Ib
[CuCF
3
] [1.0 equiv]
THF/MeCN
rt, 1h
O
CF
3
H
O
CF
3
MeO
IIb IIa
1.7
1.0
Experiment 1
O
OPPh
3
Br
O
OPPh
3
Me
Ic Id
[CuCF
3
] [1.0 equiv]
THF/MeCN
rt, 1h
O
CF
3
Br
O
CF
3
Me
IId IIc
2.27
1.0
Experiment 2
O
OPPh
3
Br
O
OPPh
3
H
Ic Ia
[CuCF
3
] [1.0 equiv]
THF/MeCN
rt, 1h
O
CF
3
Br
O
CF
3
H
IIa IIc
1.81
1.0
Experiment 3
O
OPPh
3
F
3
C
O
OPPh
3
H
Ie Ia
[CuCF
3
] [1.0 equiv]
THF/MeCN
rt, 1h
O
CF
3
F
3
C
O
CF
3
H
IIa IIe
3.59
1.0
Experiment 4
1)
2)
3)
4)
90
Image 2.4:
19
F NMR Spectrum of competition experiment 2 (Br vs Me)
Image 2.5:
19
F NMR Spectrum of competition experiment 1 (Br vs H)
91
Image 2.6:
19
F NMR Spectrum of competition experiment 1 (CF 3 vs H)
The qualitative results obtained from the competition experiments show that electron-withdrawing
substituents increased the rate of reaction, whereas electron-donating substituents decreased the
rate of reaction. Good linearity was observed for the plot versus s values (s- or s + were not
evaluated). The Hammett plot shown in Figure 2.2 was constructed using σ-values which gave ρ
= +0.997. The positive slope of the Hammett plot is in line with the results expected from an
acylation via ionic pathway and are directly opposed to the ones for nucleophilic benzoyl radicals,
in which the reverse trend (i.e. negative ρ value) would be expected.
350
Although more studies
are necessary to fully elucidate the mechanism of the trifluoromethylation step (I → CF3-ketone),
taken together, the results of the control experiments, as well as the previous mechanistic studies
on acylation of organocopper reagents, strongly argue in favor of an ionic pathway and do not
support intermediacy of acyl radicals in this deoxygenative trifluoromethylation using
acyloxyphosphonium ions I. Still, whether the nucleophilic substitution reaction of [CuCF3] and I,
92
proceeds via nucleophilic substitution by copper (i.e., oxidative addition to generate a Cu(III)
species), or nucleophilic substitution by carbon, remains to be determined.
Finally, because of the dynamic non-trivial behavior in solution and speciation
351
of [CuCF3], we
were interested in studying the nature of the “ligand-free” [CuCF3] formed in MeCN from
TMSCF3/CsF/CuI under the optimized conditions. For this experiment, inside an N2 glovebox, CuI
(0.5 mmol, 96 mg, 2 equiv) and CsF (0.375 mmol, 57 mg, 1.5 equiv) were accurately charged into
a screw-cap NMR tube. The tube was tightly capped and brought outside the glovebox.
Anhydrous, freshly distilled MeCN (0.65 mL), PhOCF3 internal standard (20 uL, 0.15mmol) and
TMSCF3 (0.625 mmol, 93 uL, 2.5 equiv) were added sequentially to the NMR tube under a stream
on Argon. This suspension was agitated using a vortex at room temperature for 10 min. Evolution
of a gas, presumably TMS-F was observed immediately upon addition of TMSCF3 and ceased
after 10 min. This mixture was then analyzed by
19
F NMR. Spectra was recorded after 15 min
(Image 2.7), 30 min (Image 2.8) and 50 min (Image 2.9). After conducting
19
F NMR spectroscopic
studies, the major components of the mixture were tentatively assigned as heteroleptic cuprate
[Cu(CF3)(I)]
–
with small amounts of homoleptic cuprate [Cu(CF 3)2]
–
and solvent ligated
(MeCN)CuCF3 appearing at -30.8, -30.9, and -26.7 ppm (br. s), respectively (Scheme 2.7).
Scheme 2.7: Generation of CuCF 3 species
A Schlenk-type equilibrium is likely taking place between [CuI2]
–
and both above-mentioned -ate
complexes. Importantly, all three [CuCF3] species are expected to be competent species to
engage acyl electrophiles I and afford trifluoromethyl ketones.
TMSCF
3
CuI CsF
MeCN [0.65 mL]
rt, 10 min
[0.625 mmol] [0.5 mmol] [0.375 mmol]
[Cu(CF
3
)(I)]
–
[Cu(CF
3
)
2
]
–
CuCF
3
CuCF
2
CF
3
93
Image 2.7: [CuCF 3] species’
19
F NMR spectrum after 15 min at room temperature: a) full spectrum, b) expansion of
CF 3 region, c) expansion of CF 2CF 3
Image 2.8: [CuCF 3] species’
19
F NMR spectrum after 30 min at room temperature: a) full spectrum, b) expansion of
CF 3 region, c) expansion of CF 2CF 3
a) Full spectrum
b) Expansion of CF
3
region
c) Expansion of CF
2
CF
3
region
b) Expansion of CF
3
region
c) Expansion of CF
2
CF
3
region
a) Full spectrum
94
Image 2.9: [CuCF 3] species’
19
F NMR spectrum after 50 min at room temperature: a) full spectrum, b) expansion of
CF 3 region, c) expansion of CF 2CF 3
2.5 Conclusion
This chapter covered the development of a direct deoxygenative Cu-mediated trifluoromethylation
reaction of carboxylic acids. Key to the success of this transformation was the use of
acyloxyphosphonium ions I as acyl electrophiles, which are conveniently and readily prepared in
situ from the corresponding carboxylic acids and commodity chemicals (PPh3, NBS). Salient
features of these protocols include the use of extremely mild reaction conditions (room
temperature) and short reactions times (1h). Wide functional group compatibility is exemplified by
tolerance to enolizable ketones, ethers, nitriles, phenols, aryl iodides and various heterocyclic
functionalities, representing a clear advantage that this process holds over prior synthetic routes.
2.6 Experimental data
2.6.1 General procedure I for the deoxygenative trifluoromethylation of carboxylic acids
On the bench-top, the corresponding carboxylic acid (0.25 mmol, 43 mg, 1.0 equiv) and PPh3
(0.35 mmol, 91.8 mg, 1.4 equiv) were weighed into an oven-dried screw cap vial (5 mL size, vial
b) Expansion of CF
3
region
a) Full spectrum
c) Expansion of CF
2
CF
3
region
95
1), equipped with a stir bar. Anhydrous THF (2.5 mL) was added (anhydrous DCM is used for
aliphatic acids instead of THF), and this suspension was placed in an ice batch for 2-3 min.
Subsequently, N-bromosuccinimide, (0.375 mmol, 66.7 mg, 1.5 equiv) which was pre-weighed
into a small vial, was added as a solid in one portion. The vial was re-capped, gently swirled to
wash down all solid NBS and this mixture was stirred in the ice bath for 2 min. After this time, the
vial is taken out of the ice bath and stirred 13 min at room temp for a total reaction time of 15 min.
During this time, inside an Ar glovebox, CuI (0.5 mmol, 96 mg, 2 equiv) and CsF (0.375 mmol, 57
mg, 1.5 equiv) were accurately charged into a separate flame-dried crimp-top vial (5 mL size),
equipped with a stir bar. The vial was then sealed and brought outside the glovebox. Anhydrous,
freshly distilled MeCN (0.65 mL) and TMSCF3 (0.625 mmol, 93 uL, 2.5 equiv) were added
dropwise to the vial under a stream of nitrogen and this suspension was stirred (500 rpm) at room
temperature for 10 min (vial 2). *Note: Because this is a heterogeneous mixture, it is important to
maintain all the solids at the bottom of the vial to maximize efficiency of [CuCF3] formation.
Washing down all solids when adding MeCN through the walls of vial 2 is useful for this purpose.
TMSCF3 is best added dropwise directly to the liquid phase, avoiding sliding through the walls.
Furthermore, for best results, splashing this reaction mixture should be avoided. After formation
of acyloxyphosphonium species is completed in vial 1 (15 min), this mixture was taken up using
a 5-mL syringe and quickly transferred in one portion to vial 2 containing [CuCF3] under a stream
of nitrogen. To ensure full transfer, contents of the vial were washed with additional fresh
anhydrous THF (0.5 mL) and transferred to vial 2. This mixture was stirred at room temperature
for 1 h. After this time, internal standard (PhOCF3, 20 uL, 0.15 mmol) was added as using a
micropipette. This mixture was stirred for 1 min and the stirring was stopped to allow undissolved
solids to settle at the bottom (2-3 min). The supernatant was then analyzed directly by
19
F NMR
spectroscopy, and the yield was determined by comparing the relative integration of internal
standard PhOCF3 (
19
F NMR -58 ppm) with that of the trifluoromethyl ketone.
96
2.6.2 Isolation of trifluoromethyl ketones
Unless otherwise stated, the following representative procedure was used for the synthesis and
purification of trifluoromethyl ketone products 2. Two separate vials are needed. On the bench-
top, the corresponding carboxylic acid 1 (0.5 mmol, 1 equiv) and triphenylphosphine, PPh3 (0.7
mmol, 1.4 equiv, 184 mg) were charged into an oven-dried screw-cap vial equipped with a
magnetic stir bar. After this, anhydrous tetrahydrofuran, THF or dichloromethane, DCM (for
aliphatic substrates) (0.1M, 5 mL) was added, the vial was capped, and this mixture was then
cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (0.75 mmol, 1.5 equiv,
134 mg) was added as a solid in one portion, the vial was re-capped, and the mixture was kept
in the ice-bath for two minutes. After this time, the ice-bath was removed, and this solution was
further stirred for a total of 15 min (Vial 1). During this time, inside an Ar glovebox, copper iodide,
CuI (1 mmol, 2 equiv, 192 mg), and cesium fluoride, CsF (0.75 mmol, 1.5 equiv, 114 mg) were
accurately charged into a flame-dried crimp-top vial (5 mL size), equipped with a stir bar. The vial
was then sealed and brought outside the glovebox. Anhydrous, freshly distilled acetonitrile MeCN
(1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL) were added dropwise to the vial under a
stream on dry nitrogen and this suspension was stirred (500 rpm) at room temperature for 10 min
(Vial 2). Note: maintaining all the solids at the bottom of the vial maximizes efficiency of [CuCF3]
formation. After vial 1 and vial 2 had been stirred for 15 and 10 minutes, respectively at room
temperature, the content of vial 1 was quickly transferred in one portion to vial 2 containing CuCF3,
using a 5 mL syringe, under a stream of nitrogen. Fresh anhydrous THF (0.5 mL) was added to
vial 1 to wash down the remaining contents and then transferred to vial 2 using the syringe. This
mixture was further stirred for 1 h at room temperature. After this time, the vial was opened, and
the reaction mixture was diluted with pentane (10 mL), and the mixture was stirred for 2 min. After
this time, the mixture is passed through a short pad of celite (3 cm thick x 3 cm diameter).
Subsequently, the celite pad was further washed with pentane (10 mL) or an appropriate mixture
of solvent (see below for each case). The filtrate was then purified by column chromatography
97
using an appropriate solvent system. The appropriate fractions were collected and concentrated
under reduced pressure to afford the target trifluoromethyl ketones 2. *Note: For highly volatile
products, loss due to evaporation is diminished by applying a maximum vacuum of 450 Torr at 35
ºC.
2.6.3 Characterization data of trifluoromethyl ketones
2,2,2-trifluoro-1-(naphthalen-2-yl)ethan-1-one (2a)
The title compound was obtained following the general procedure I, using 2-
naphthoic acid (0.5 mmol, 86 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg), THF
(0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg) MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane (10 ml). The filtrate was then purified by column chromatography (DCM/pentane
5%) to obtain a pale-yellow oil which solidified upon standing. 65% isolated yield (72.8 mg); 80%
by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.08 (dd, J = 8.7, 0.6 Hz,
1H), 8.02 (dd, J = 8.2, 0.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.70 (ddd, J
= 8.2, 6.9, 1.3 Hz, 1H), 7.63 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -71.2
(s, 3F). These data match the previously reported structure.
352
2,2,2-trifluoro-1-(4-methoxyphenyl)ethan-1-one (2b)
The title compound was obtained following the general procedure I, using p-
anisic acid (0.5 mmol, 76 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg), THF (0.1M,
5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75 mmol, 1.5
equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL). Purified by
filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug with pentane
(15 ml). The filtrate was then purified by column chromatography (5% DCM/pentane) to obtain a
O
CF
3
MeO
O
CF
3
98
yellow solid in 70% isolated yield (71 mg); 99% by
19
F NMR spectroscopy.
1
H NMR (400 MHz,
CDCl3) δ 8.18 – 7.94 (m, 2H), 7.11– 6.81 (m, 2H), 3.91 (s, 3H).
19
F NMR (376 MHz, CDCl3) δ -
71.4 (s, 3F). These data match the previously reported structure.
352
2,2,2-trifluoro-1-(4-hydroxyphenyl)ethan-1-one (2c)
The title compound was obtained following the general procedure I, using 4-
hydroxybenzoic acid (0.5 mmol, 69 mg PPh3 (0.7 mmol, 1.4 equiv, 184 mg),
THF (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane (10 ml). The filtrate was then purified by column chromatography (DCM/pentane
5%) to obtain a pale-yellow oil in 70% isolated yield (66.5 mg); 90% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.10 – 7.93 (m, 2H), 7.06 – 6.86 (m, 2H), 6.09 (s, 1H).
19
F NMR (376
MHz, CDCl3) δ -71.41 (s, 3F).These data match the previously reported structure.
353
2,2,2-trifluoro-1-(2-iodophenyl)ethan-1-one (2d)
The title compound was prepared following the general procedure I, using 2-
iodobenzoic acid (0.5 mmol, 124 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg), THF
(0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane (10 ml). The filtrate was then purified by column chromatography (DCM/pentane
5%) to obtain a yellow oil in 70% isolated yield (105 mg); 99% by
19
F NMR spectroscopy.
1
H NMR
(400 MHz, CDCl3) δ 8.10 (ddd, J = 8.0, 1.2, 0.4 Hz, 1H), 7.76 – 7.69 (m, 1H), 7.51 (ddd, J = 7.9,
7.4, 1.2 Hz, 1H), 7.33 – 7.24 (m, 1H).
19
F NMR (376 MHz, CDCl3) δ -72.88 (s, 3F). These data
match the previously reported structure.
352
HO
O
CF
3
O
CF
3
I
99
1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one (2e)
The title compound was prepared following the general procedure I, using 4-
bromobenzoic acid (0.5 mmol, 100.5 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg),
THF (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane (10 ml). The filtrate was then purified by column chromatography (DCM/pentane
5%) to obtain a colorless oil in 60% isolated yield (76 mg); 99% by
19
F NMR spectroscopy.
1
H
NMR (400 MHz, CDCl3) δ 8.01 – 7.83 (m, 2H), 7.78 – 7.53 (m, 2H).
19
F NMR (376 MHz, CDCl3)
δ -72.0 (s, 3F). These data match the previously reported structure.
352
2,2,2-trifluoro-1-(4-vinylphenyl)ethan-1-one (2f)
The title compound was obtained following the general procedure I, using 4-
vinylbenzoic acid (0.5 mmol, 74.1 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg),
THF (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane (10 ml). The filtrate was then purified by column chromatography (100% pentane)
to obtain a pale-yellow oil in 56% isolated yield (56 mg); 83% by
19
F NMR spectroscopy.
Decreased isolated yield was due to high volatility of this compound.
1
H NMR (400 MHz, CDCl3)
δ 8.04 (d, J = 8.1 Hz, 2H), 7.73 – 7.36 (m, 2H), 6.78 (dd, J = 17.6, 10.9 Hz, 1H), 5.96 (d, J = 17.6
Hz, 1H), 5.50 (d, J = 10.9 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -71.83 (s, 3F). These data match
the previously reported structure.
354
Br
O
CF
3
O
CF
3
100
1-(4-acetylphenyl)-2,2,2-trifluoroethan-1-one (2g) and 1-(4-(2,2,2-trifluoro-1,1-
dihydroxyethyl)phenyl)ethan-1-one (2g’)
The title compounds were obtained following the general
procedure I, using 4-acetylbenzoic acid (0.5 mmol, 82.1 mg),
PPh3 (0.7 mmol, 1.4 equiv, 184 mg), THF (0.1M, 5mL), NBS
(0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75 mmol, 1.5 equiv, 114
mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL). Purified by filtration
through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug with pentane and
DCM (10 ml). The filtrate was then purified by column chromatography (0%—25%—50%
EtOAc/pentane) to obtain a mixture of ketone 2g and hydrate 2g’ as a brown solid in 73%
combined isolated yield (5:3 molar ratio, respectively) (86 mg); 77% yield 2g by
19
F NMR
spectroscopy. Hydration occurs during work-up and silica purification.
1
H NMR (400 MHz, CDCl3)
δ 8.10 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.7 Hz, 2H), 2.60 (s, 3H). 2g
19
F NMR (376 MHz, CDCl3) δ
-72.17, (s, 3F). 2g’
1
H NMR (400 MHz, CDCl3) 8.04 (d, J = 7.9 Hz, 2H) 7.77 (d, J = 8.1 Hz, 2H),
5.37 (s, 2H), 2.55 (s, 3H). 2g’
19
F NMR (376 MHz, CDCl3) -84.87, (s, 3F). These data match the
previously reported structure.
352
(E)-4-(4-chlorophenyl)-1,1,1-trifluorobut-3-en-2-one (2h)
The title compound was obtained following the general procedure I, using
chlorocinnamic acid (0.5 mmol, 91.3 mg), PPh3 (0.7 mmol, 1.4 equiv, 184
mg), DCM (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg),
CsF (0.75 mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv,
186 uL). The title compound was not isolated due to its inherent volatility. 67% by
19
F NMR
spectroscopy.
355
O
CF
3
O
CF
3
O
HO OH
Cl
O
CF
3
101
(Z)-1-(cycloundec-1-en-1-yl)-2,2,2-trifluoroethan-1-one (2i)
The title compound was obtained following the general procedure I, using Z-
cycloundec-1-ene-1-carboxylic acid (0.5 mmol, 98 mg), PPh3 (0.7 mmol, 1.4 equiv,
184 mg), DCM (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2
equiv, 192 mg), CsF (0.75 mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and
TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL). Purified by filtration through a short pad of celite (3 cm
thick x 3 cm diameter), washing the plug with pentane (10 ml). The filtrate was then purified by
column chromatography (100% hexanes) to obtain a colorless oil in 52% isolated yield (64.5 mg);
54% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 6.86 (t, J = 7.8 Hz, 1H), 2.53 (dt, J
= 12.0, 6.0 Hz, 4H), 1.68 (p, J = 5.5 Hz, 2H), 1.56 (p, J = 5.7 Hz, 2H), 1.40 – 1.14 (m, 10H).
13
C
NMR (126 MHz, CDCl3) δ 181.36 (q, J = 32.4 Hz), 152.80 (q, J = 4.19, Hz), 136.53, 116.62 (q, J
= 292.6 Hz), 28.11, 27.40, 27.00, 26.56, 26.36, 25.36, 24.97, 24.55, 22.43.
19
F NMR (376 MHz,
CDCl3) δ -69.7, (s, 3F). HRMS-EI
+
(M
+
H
+
HCOO
-
) Calcd. for [C
13
H
20
F
3
O]
+
[HCOO]
-
= 295.1516,
found = 295.1507 (2.37 ppm). FT/IR (n
max (neat) cm-1): 1943, 1778, 1704, 1450, 1307, 1187,
115, 1022, 902
4-(2,2,2-trifluoroacetyl)benzonitrile (2j) and 4-(2,2,2-trifluoro-1,1-
dihydroxyethyl)benzonitrile (2j’)
The title compounds were obtained following the general procedure I,
using 4-cyanobenzoic acid (0.5 mmol, 74 mg), PPh3 (0.7 mmol, 1.4
equiv, 184 mg), THF (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv,
192 mg), CsF (0.75 mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol,
2.5 equiv, 186 uL). Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter),
washing the plug with DCM (10 ml). The filtrate was then purified by column chromatography (5%
EtOAc/DCM) to obtain a mixture of ketone 2j and hydrate 2j’ as a yellow oil in 45% combined
CF
3 O
NC
CF
3
HO OH
NC
O
CF
3
+
102
isolated yield [3:1] (47mg). 60% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.24 –
8.11 (m, 2H), 7.91 – 7.81 (m, 2H). 2j
19
F NMR (376 MHz, CDCl3) δ -72.3, (s, 3F). 2j’
1
H NMR (400
MHz, CDCl3) 7.78 – 7.70 (m, 2H), 7.53 – 7.39 (m, 2H). 2j’
19
F NMR (376 MHz, CDCl3) -85.0, (s,
3F). These data match the previously reported structure.
352
1-((3r,5r,7r)-adamantan-1-yl)-2,2,2-trifluoroethan-1-one (2k)
The title compound was obtained following the general procedure I, using 1-
adamantanecarboxylic acid (0.5 mmol, 90.1 mg), PPh3 (0.7 mmol, 1.4 equiv, 184
mg), DCM (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg),
CsF (0.75 mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv,
186 uL). Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing
the plug with pentane (10 ml). The filtrate was then purified by column chromatography (pentane
100%) to obtain 2k as a brown solid in 40% isolated yield (46.5 mg). 42% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 2.27 – 2.01 (m, 3H), 2.00 – 1.88 (m, 6H), 1.83 – 1.66
(m, 6H).
19
F NMR (376 MHz, CDCl3) δ -72.6 (s, 3F). These data match the previously reported
structure.
356
1,1,1-trifluoro-3-(6-methoxynaphthalen-2-yl)butan-2-one (From Naproxen) (2l)
The title compound was obtained following the general procedure I, using
Naproxen (0.5 mmol, 115 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg), DCM
(0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane and DCM (10 ml). The filtrate was then purified by column chromatography
(DCM/pentane 5%) to obtain a white solid in 78% isolated yield (110 mg); 82% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.61
O
CF
3
CF
3
O
MeO
103
(s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 7.12 (s, 1H), 4.33 (q, J = 7.0 Hz, 1H),
3.92 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H).
13
C NMR (126 MHz, CDCl3) δ 192.01 (q, J = 33.5 Hz),
158.07, 134.08, 131.76, 129.30, 128.97, 127.83, 127.00, 125.99, 119.43, 115.90 (q, J = 293.8
Hz), 105.60, 55.32, 47.13, 17.97.
19
F NMR (376 MHz, CDCl3) δ -76.8 (s, 3F). HRMS-EI
-
(M
-
H
-
)
Calcd. for C15H12F3O2
-
= 281.0795, found = 281.0806. FT/IR (n
max (neat) cm-1):1913, 1835, 1751,
1604, 1457, 1392, 1265, 1207, 1153, 1025, 971, 906, 856, 817. M.P: 57-59 ºC
1-(5-bromo-2-hydroxyphenyl)-2,2,2-trifluoroethan-1-one (From 5-Br Salicylic acid) (2m)
The title compound was obtained following the general procedure I, using 5-
bromosalicylic acid (0.5 mmol, 108.5 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg),
THF (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF (0.75
mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186 uL).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with pentane and DCM (10 ml). The filtrate was then purified by column chromatography (100%
pentane) to obtain 2m as a yellow oil in 51% isolated yield (68 mg); 60% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 7.91 (s, 1H), 7.71 (d, J = 5.5 Hz, 1H),
7.01 (d, J = 9.1 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -71.0 (s, 3F).These data match the
previously reported structure.
357
1,1,1-trifluoro-3-(4-isobutylphenyl)butan-2-one (From Ibuprofen) (2n)
The title compound was obtained following the general procedure I, using
ibuprofen (0.5 mmol, 103.15 mg), PPh3 (0.7 mmol, 1.4 equiv, 184 mg),
DCM (0.1M, 5mL), NBS (0.75 mmol, 1.5 equiv, 134 mg), CuI (1 mmol, 2 equiv, 192 mg), CsF
(0.75 mmol, 1.5 equiv, 114 mg), MeCN (0.75M, 1.3 mL) and TMSCF3 (1.25 mmol, 2.5 equiv, 186
uL). Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the
plug with pentane and DCM (10 ml). The filtrate was then purified by column chromatography
O
CF
3
OH
Br
CF
3
O
104
(DCM/pentane 5%) to obtain 2n as a colorless oil in 65% isolated yield (84mg); 69% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.28 – 7.20 (m, 2H), 7.13 (d, J = 1.9 Hz, 2H), 4.17 (q,
J = 7.0 Hz, 1H), 2.46 (d, J = 7.0 Hz, 2H), 2.02 – 1.67 (m, 1H), 1.51 (d, J = 6.9 Hz, 3H), 0.90 (dd,
J = 6.7, 2.2 Hz, 6H).
13
C NMR (126 MHz, CDCl3) δ 192.26 (q, J = 33.4 Hz), 141.80, 134.10, 129.99,
127.88, 116.05 (q, J = 293.5 Hz), 47.01, 45.15, 30.30, 22.47, 18.06.
19
F NMR (376 MHz, CDCl3)
δ -76.9 (s, 3F). HRMS-EI
-
(M
-
H
-
) Calcd. For C
14
H
16
F
3
O
-
= 257.1159, found = 257.1158. FT/IR
(n
max (neat) cm-1):1754, 1708, 1511, 1457, 1376, 1203, 1153, 1010, 964, 906, 844.
105
CHAPTER 3: Copper/Zinc-mediated Synthesis of difluoromethyl ketones via
Acyloxyphosphonium Ions and catalytic approach
Scheme 3.1: Synthesis of difluoromethyl ketones via acyloxyphosphonium ions
In a similar fashion to Chapter 2, this chapter discusses a novel approach to access a wide array
of difluoromethyl ketones utilizing an acyloxyphosphonium ion I (Scheme 3.1) as the active
electrophilic intermediate. In this case the transmetalation reaction between difluoromethyl zinc
reagent and copper (I) salts enables the formation of highly reactive intermediates that allow the
preparation of the target compounds in excellent yields. The great chemoselectivity and tolerance
exhibited by the reaction is discussed, and the late-stage functionalization of pharmaceutical
ingredients and commercially available therapeutics is examined. Unlike the system discussed in
Chapter 2, this reagent system allows for lower loadings of copper, enabling the development of
a catalytic reaction, which is also analyzed in this chapter (Chem. Eur. J., 2021, 27, 1–7,
10.1002/chem.202102854).
3.1 Introduction and prior art in the synthesis of difluoromethyl ketones
As previously stated in Chapter 1, the difluoromethyl unit has gained a lot of attention for its
potential applications in the synthetic and biological chemistry arenas. Recent investigations have
revealed that the –CF2H group can exhibit either an enhanced, similar, or decreased lipophilicity
profile when compared to carbinols, thiols, and methylarenes, respectively.
114,115,358
These
properties, along with the weak hydrogen-bond donor ability similar to that of thiols and anilines,
can be used to rationally design properties of APIs. Accordingly, significant effort has been
R OH
O
1
R CF
2
H
O
3
PPh
3
(1.4 equiv)
NBS (1.5 equiv)
(DMPU)
2
Zn(CF
2
H)
2
1.5 equiv
Method A: 1.2 equiv CuI
Method B: 10 mol% CuI
DCM, 0
o
C - rt, 1h, N
2
R = aryl, alkyl
[1.0 equiv]
R OPPh
3
O
Via:
X
I
106
devoted toward efficient synthesis of CF2-containing compounds in recent years. Just like the
trifluoromethyl ketones described in Chapter 2, difluoromethyl ketones are highly valuable
compounds that have newly found applications in the synthesis of biologically active compounds
(Figure 3.1).
Figure 3.1: Biologically and synthetically relevant difluoromethyl ketones
More specifically, difluorinated ketones have been described as inhibitors of proteases involved
in different physiopathological pathways due to their proven ability to form stable tetrahedral
adducts, just like their trifluorinated counterparts.
23,324
However, the preparation of these
compounds is far less explored as the synthetic methods available are limited. Electrophilic a-
difluorination
359–361
of carbonyl compounds or their derivatives, oxidation of a-difluoromethyl
alcohols,
362
and hydrodefluorination
363,364
of CF3 ketones, are typical approaches. Methods to
access CF2H-ketones from carboxylic acid derivatives are even more scarce.
169,263,365,366
The
reaction of acyl chlorides with Ph3P=CF2
263
or (NHC)Ag(CF2H),
169
as well as the reaction of
Weinreb amides with PhSCF2TMS
365
or TMSCF2H under Barbier-type conditions
163
are the only
available methods that hitherto employ acyl electrophiles in nucleophilic difluoromethylations. Pd-
catalyzed cross-coupling of aryl boronic acids with difluorocarbene
367
and N-difluoroacetyl
Z-Val
N
H
Ph
O
F F
H
N
Ph
Val-Z
HIV Protease inhibitor
(Abbott)
O
CF
2
H
O
N
O
NH
O
H
N
O
Elastase inhibitor
O
F F
OH
O
GABA
B
agonist
O
CF
2
H
t-Bu
Inhibitor of AgAChE
(Malaria’s main vector)
O
CF
2
H
Inhibitor of AgAChE
(Malaria’s main vector)
N
N
iPr
107
glutarimide
368
(prepared in low yield from difluoroacetic acid) are two recent alternatives.
However, elevated temperatures and/or prolonged reaction times are required and only three
examples of CF2H-ketones were provided in one case (Scheme 3.2).
Scheme 3.2: Difluoromethyl ketones from carboxylic acid derivatives
Thus, the development of efficient protocols to access CF2H-ketones directly from widely available
carboxylic acids is a worth-while venture. In this chapter, an efficient approach for the synthesis
of CF2H ketones directly from carboxylic acids via acyloxyphosphonium ions I is described
(Scheme 3.1).
3.2 Optimization difluoromethylation reaction
In pursuit of valuable difluoromethyl ketones, a deoxygenative difluoromethylation of carboxylic
acids was developed. Initial efforts towards the generation of [CuCF2H]
139,165,166,177
from TMSCF2H
under conditions compatible with I were met with limited success. In previous experiments, we
established that donor amide solvents such as DMF, DMA and NMP are incompatible with highly
electrophilic I and, historically, the generation of [CuCF2H] from TMSCF2H is commonly achieved
in such media. One exception for this is a report on (NHC)CuCF2H preparation in THF/alkoxide
system.
177
Thus, the first experiment showcased on entry 1 of Table 3.1 employing TMSCF2H
and CsF as an activator was conducted in acetonitrile in an attempt to circumvent the potential
incompatibility of I with other solvents. Unfortunately, the experiment proved unsuccessful.
Consequently, a different source of the -CF2H unit was selected. (DMPU)2Zn(CF2H)2 also referred
R
O
Cl
(i) Ph
3
P=CF
2
(ii) Pyridine, H
2
O
R
O
CF
2
H
R
O
N
Me
OMe
TMSCF
2
H
t-PentOK
THF, 0
o
C, 4h
Dilman, (2017)
Pace, (2019)
Ar-B(OH)
Pd/PCy
3
[cat.]. Et
3
N
Amgoune, (2020)
N
O
O
CF
2
H
O
Made from
HCF
2
COOH
(44% yield)
DMF, 80ºC, 16h
(R= Ar, Alk)
108
to as the Vicic-Mikami reagent has been described as a stable source of CF2H in various
difluoromethylation reactions.
136,138,369
In combination with copper I salts, this reagent has enabled
the formation of C-C bonds to install a difluoromethyl moiety onto molecules of interest. However,
the cross-coupling reaction with acyl electrophiles hadn’t been explored before the development
of this methodology. Parting from the known preparation of electrophile I from the reaction of an
in situ prepared bromophosphonium ion with a carboxylic acid,
341
we set out to test whether a
well-defined phosphonium salt would behave is a similar way (Table 3.1, entry 2). PyBroP
(Bromotripyrrolidinophosphonium hexafluorophosphate) was selected as the phosphonium
reagent to be added to a solution of carboxylic acid 1b to potentially generate
acyloxyphosphonium intermediate I. However, upon addition of this solution to a mixture of
(DMPU)2Zn(CF2H)2 and CuI the reaction mixture darkened, and less than 1% of the product was
obtained after 1h. Following a similar approach to the one employed to prepare trifluoromethyl
ketones in Chapter 2, acyloxyphosphonium ion I was prepared from triphenylphosphine (PPh3)
and N-bromosuccinimide (NBS). This solution was then added to a DCM solution off
(DMPU)2Zn(CF2H)2 and reacted for an hour. Variations in the concentration and the stoichiometry
of the reaction components did not afford any product (Table 3.1, entries 3-6). However, upon
the addition of 1.2 equivalents of copper iodide to the difluoromethyl zinc reagent solution, product
3a was obtained in 57% yield (Table 3.1, entry 7). This result demonstrated the stability of
(DMPU)2Zn(CF2H)2 under these conditions and points towards the formation of highly reactive
copper species in solution. The
19
F NMR spectrum of this reaction mixture evidenced the
formation of difluoromethylcopper species that matched the reported chemical shifts
corresponding to bis(difluoromethyl)cuprate [Cu(CF2H)2]
-
and the oxidized tetramer [Cu(CF2H)4]
-
.
Building up from this result, different solvents were screened for both, the preparation of
phosphonium ion I, and the difluoromethylating mixture. Employing acetonitrile (MeCN) for both
solutions proved to be detrimental for the reaction (Table 3.1, entry 8). Similarly, preparing I in
dichloromethane (DCM) while dissolving the difluoromethyl zinc reagent and copper mixture in
109
THF, and vice versa did not improve the reaction conversion (Table 3.1, entries 9 and 11).
Utilizing THF for both solutions resulted in a slight increase in yield, but no significant improvement
was observed. Realizing that the highest conversion was achieved by employing DCM for both
steps, we decided to optimize the reaction stoichiometry. Increasing both the equivalents of PPh3
and NBS showed a substantial increase in yield (Table 3.1, entry 14). Similarly, increasing the
equivalents of the difluoromethylzinc reagent afforded a moderate higher yield, but not substantial
enough to justify the large excess of reagent. Upon further optimization, we found that pre-
dissolving the solid mixture of (DMPU)2Zn(CF2H)2 and CuI in the reaction solvent drastically
reduced the yield. Therefore, we were please to find that adding a solution of I to a dry mixture of
(DMPU)2Zn(CF2H)2 and CuI increased the conversion to 85%. Ultimately, we determined that 3a
can be successfully prepared as follows. Adding a DCM solution of benzoic acid-derived
acyloxyphosphonium ion I to a solid mixture of (DMPU)2Zn(CF2H)2 (1.5 equiv) and CuI (1.2 equiv)
afforded 3a in 94% yield in one hour, as determined by
19
F NMR (Table 3.1, entry 18). These
optimized conditions highlight the potential of I to serve as a pluripotent intermediate to access a
wide variety of products.
Table 3.1. Optimization of the synthesis of difluoromethyl ketones
a
Entry Solvent
1 [M]
Phosphorous-
based reagent
NBS
[equiv]
Solvent
2 [M]
L 2Zn(CF 2H) 2
[equiv]
CuI
[equiv]
Additive
[equiv]
Time h Yield %
b
1 THF
[0.1]
PPh 3 [1.4 eq] 1.5 MeCN
[0.75]
- 2 CsF
[1.5 eq]
1h 0
TMSCF 2H
[2.5 eq]
PPh
3
[1.0 equiv]
NBS [1.1 equiv]
MeCN
0
o
C - rt, 15 min
R OH
O
[1.0 equiv]
R OPPh
3
O
Via:
X
I 1b
R CF
2
H
O
3a
1h, rt
R: Ph
(DMPU)
2
Zn(CF
2
H)
2
[1.2 equiv]
CuI [1.2 equiv]
110
2 DMF
[0.1]
PyBroP - DMF
[0.75]
1.2 1.2
i
Pr 2NEt 1h 1
3 DCM
[0.1]
PPh 3 [1.4 eq] 1.5 DCM
[0.75]
1.2 - - 1h 0
4 DCM
[0.1]
PPh 3 [1.0 eq] 1.1 DCM
[0.75]
1.2 - - 1h 0
5 DCM
[0.1]
PPh 3 [1.0 eq] 1.1 DCM
[0.75]
1.2 - - 24h 0
6 DCM
[0.5]
PPh 3 [1.0 eq] 1.1 DCM
[0.75]
1.2 - - 1h 0
7
c
DCM
[0.1]
PPh 3 [1.0 eq] 1.1 DCM
[0.75]
1.2 1.2 - 1 h 57
8
c
MeCN
[0.1]
PPh 3 [1.0 eq] 1.1 MeCN
[0.75]
1.2 1.2 - 1 h 52
9
c
DCM
[0.1]
PPh 3 [1.0 eq] 1.1 THF
[0.75]
1.2 1.2 - 1 h 32
10
c
THF
[0.1]
PPh 3 [1.0 eq] 1.1 THF
[0.75]
1.2 1.2 - 1 h 49
11
c
THF
[0.1]
PPh 3 [1.0 eq] 1.1 DCM
[0.75]
1.2 1.2 - 1 h 30
12
c
THF
[0.1]
PPh 3 [1.0 eq] 1.1 DMF
[0.75]
1.2 1.2 - 1 h trace
(<5%)
13
c
THF
[0.1]
PPh 3 [1.0 eq] 1.1 MeCN
[0.75]
1.2 1.2 - 1 h 40
14
c
DCM
[0.1]
PPh 3 [1.4 eq] 1.5 DCM
[0.75]
1.2 1.2 - 1h 70
15
c
DCM
[0.1]
PPh 3 [1.4 eq] 1.5 DCM
[0.75]
2.4 1.2 - 1h 76
16
c
DCM
[0.1]
PPh 3 [1.4 eq] 1.5 - 1.2 1.2 - 1h 85
17
d
DCM
[0.1]
PPh 3 [1.4 eq] 1.5 - 2.4 10%
mol
- 1h 69
18
d
DCM
[0.1]
PPh 3 [1.4 eq] 1.5 - 1.2 1.2 - 1h 94
[a]
Optimized conditions: To a solution of benzoic acid 1b (0.15 mmol, 1 equiv) and PPh 3 in DCM, solid NBS was added
at 0
o
C. After stirring for 15 min at room temperature, this solution (vial 1) was added to vial 2 containing a mixture of
(DMPU) 2Zn(CF 2H) 2 and CuI and stirring was continued for 1 h;
[b]
Determined by
19
F NMR spectroscopy;
[c]
the mixture
of (DMPU) 2Zn(CF 2H) 2 and CuI was dissolved [0.75M] and stirred for 30 min prior to the addition of solution in vial 1.
[d]
no pre-stirring of the mixture of (DMPU) 2Zn(CF 2H) 2 and CuI.
3.3 Substrate scope: difluoromethyl ketones. CF2H-containing active pharmaceutical ingredients
The reaction scope of the deoxydifluoromethylation reaction was studied with a variety of
carboxylic acids, and we found that 2-naphthoic acid smoothly affords 3b in 97% isolated yield.
Benzoic acids bearing electron-donating and electron-withdrawing groups are well tolerated
under the optimized conditions and were converted to the target products (3c-3g) in good (66-
85%) yields. 4-Bromobenzoic acid smoothly afforded 3d in 85% isolated yield, while 2-
iodobenzoic acid gave rise to 3e in 66% isolated yield along with a small amount (<16%) of 1-(2-
111
(difluoromethyl)phenyl)-2,2-difluoroethan-1-one, arising from aromatic difluoromethylation
138
of
3e in the presence of excess difluoromethylzinc and CuI. This result is in contrast with the
deoxytrifluoromethylation of the same substrate, wherein aromatic trifluoromethylation was not
observed. Efforts to improve the selectivity towards 3e by decreasing the amount of
difluoromethylzinc reagent were not pursued. Substrates bearing methyl ester and aldehyde
functionalities were shown to be compatible under the present protocol, producing 3f and 3g,
respectively, without any addition to the carbonyl group. In the case of a-phenylcinnamic acid, the
corresponding product 3h was isolated in 68% yield. Traces of a by-product tentatively assigned
to be the 1,4-addition product was observed in the reaction mixture (detected by
19
F NMR and
GC-MS). Contrasting with the deoxygenative trifluoromethylation reaction in Chapter 2 where
conjugate addition is not observed, we surmise that the traces of a by- product likely arising from
–CF2H conjugate addition is promoted by the presence of Lewis-acidic ions such as Zn(II).
370
Aliphatic carboxylic acids were also suitable for the transformation and successfully afforded the
corresponding CF2H-ketones 3i-3l in moderate to good (43-76%) isolated yields (Scheme 3.3).
The applicability of our deoxydifluomethylation protocol was demonstrated by the late-stage
functionalization of several FDA-approved drugs. In this context, febuxostat, indomethacin, and
probenecid all smoothly furnished the corresponding CF2H-ketone derivatives 3m-3o in 70%-89%
isolated yields. These results demonstrate our method’s compatibility with nitriles, sulfonamides,
and carboxamides, as well as heterocyclic functionalities such as indole and thiazole. Control
experiments showed that [Cu] was essential for the acylative cross-coupling reaction to proceed
(Table 3.1, entries 3-6).
This observation is in line with well-established organozinc
chemistry,
366,371–375
in which a metal catalyst, usually Pd (Negishi
373
or Fukuyama
374
couplings) or
Cu
366,375
is required to promote cross-coupling with acyl electrophiles, while uncatalyzed reactions
are reported futile.
366
112
Scheme 3.3:
(a)
Deoxygenative synthesis of difluoromethyl ketones from carboxylic acid derivatives: copper mediated
and catalytic methods
(a)
Isolated yields. Yields in parentheses as determined by
19
F NMR with the aid of an internal
standard.
(b)
Contains ArCF 2H by-product.
Gratifyingly, catalytic amounts of CuI (10 mol%) can be employed to obtain the desired
difluoromethyl ketones (Scheme 3, Method B) albeit with diminished yields. It must be noted
however, that besides employing catalytic amounts of CuI (10 mol%), no other modifications were
made to obtain yields up to 74% (3b) as determined by
19
F NMR spectroscopy. These preliminary
unoptimized results demonstrate the feasibility of a catalytic protocol.
O
CF
2
H
O
CF
2
H
O
CF
2
H
I
3b
A: 97% (99%)
B: (74%)
3a
A: 70%(94%)
3e
A: 66%(84%)
b
MeO
O
CF
2
H
3c
A: 82% (84%)
B: (48%)
O
CF
2
H
O
H
3g
A: 73% (85%)
B: (26%)
CF
2
H
O
Ph
Ph
CF
2
H
O
3i
A: 76%(81%)
B: (66%)
3h
A: 68% (73%)
Br
O
CF
2
H
3d
A: 85%( 94%)
B: (60%)
N
O
Cl
MeO
HF
2
C
O
N
S
O
CF
2
H
CN
O
iBu 3m
A: 89% (99%)
B: (60%)
3n
A: 70% (99%)
CF
2
H
O
S
N
O
O
3o
A: 76% (97%)
B: (63%)
Aromatic and Aliphatic CF
2
H-Ketones
Active pharmaceutical ingredients
O
CF
2
H
O
MeO
3f
A: 74%(77%)
B: (50%)
From febuxostat From indomethacin From probenecid
O CF
2
H
O
O
2
N
CF
2
H
O
3j
A: 64% (70%)
3k
A: 43% (50%)
R OH
O
R OPPh
3
O
1
R CF
2
H
O
3
PPh
3
(1.4 equiv)
NBS (1.5 equiv)
(DMPU)
2
Zn(CF
2
H)
2
1.5 equiv
Method A: 1.2 equiv CuI
Method B: 10 mol% CuI
Via:
I
3
X
"Standard Conditions"
DCM, 0
o
C-RT, 1h
Ph
CF
2
H
O
3l
B: (39%)
113
3.4 Mechanistic considerations
Unlike Chapter 2 where ligand-free Cu-CF3 experiments were conducted in order to understand
the multiple species that could be created under our optimized conditions, the same experiments
could not be conducted for this specific transformation due to CuCF2H reported lower stability in
non-coordinating solvents such as DCM. However, based on previous reports,
138,165,166,369
the
formation of [CuCF2H] species as the active difluoromethylating species from (DMPU) 2Zn(CF2H)2
and CuI is also postulated here. To confirm the formation of the different cuprates, we conducted
the following experiment: On the bench-top, naphthoic acid (0.25 mmol, 1 equiv, 43.04 mg) and
triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. After this, anhydrous dichloromethane, DCM
(0.1M, 2.5 mL) was added, the vial was capped, and this mixture was then cooled to 0 ºC using
an ice-bath. Subsequently, N- bromosuccinimide, NBS (0.375 mmol, 1.5 equiv, 66.7 mg) was
added as a solid in one portion, the vial was re-capped, and the mixture was kept in the ice-bath
for two minutes. After this time, the ice-bath was removed, and this solution was further stirred for
15 min (Vial 1). During this time, Inside an Ar glovebox, copper iodide, CuI (0.3 mmol, 1.2 equiv,
57.13 mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg) were accurately charged
into a flame-dried crimp-top vial (5 mL size), equipped with a stir bar. The vial was then sealed
and brought outside the glovebox. After the completion of the 15 minutes of stirring of vial 1, the
content was transferred in one portion to vial 2, using a 5mL syringe. Fresh anhydrous DCM (240
uL) was added to vial 1 to wash down the remaining contents and then transferred to vial 2 using
the syringe. This mixture was further stirred for 1 h at room temperature. Once this time
concluded, internal standard, difluoromethoxybenzene (0.083 mmol, 10uL, -82.7 ppm (d) 74.2
Hz)) was added. The
19
F NMR spectrum in Figure 3.2 shows a doublet at -117.1 ppm of 49.9 Hz
which, according to literature, was assigned to tetrakisdifluoromethyl cuprate
138
([Cu(CF2H)4]
-
)
born from the oxidation or disproportionation of (bis)difluoromethylcopper(I) [Cu(CF2H)2]-.
Similarly, Figure 3.2 shows distinctive signals at δ -139.2 (d) 56.63Hz, and d -165.6 (m) that
114
coincide with the decomposition products 1,1,2,2-tetrafluoroethane (HF2C-CF2H) and
difluoroethylene (FHC=CFHF), respectively. These byproducts have been previously identified
and their formation from difluoromethylcopper(I) species has been reported.
165,369
Figure 3.2: neat
19
F NMR of the reaction mixture employing naphthoic acid (full spectrum)
Based on these observations, we propose the reaction mechanism depicted in Scheme 3.4.
The transmetalation between (DMPU)2Zn(CF2H)2 and the copper salts occurs rapidly, producing
the thermally unstable Cu(I)CF2H which rapidly forms the two-coordinate cuprate [Cu(CF2H)2]
-
which
has been described as a more stable reservoir of difluoromethide.
165
Consequently, after
the formation of acyl electrophile I from the carboxylic acid and the mixture of NBS and PPh3, we
propose an ionic mechanism where the substitution at the acyl carbon can be effected by either
the difluoromethyl species directly, or through oxidative ligation of [CuCF2H], followed by the
subsequent reductive elimination that would yield compound 3.
115
Scheme 3.4:
Mechanistic hypothesis for the synthesis of difluoromethyl ketones
3.5 Conclusion
This chapter encompassed the development and application of a direct deoxygenative
difluoromethylation reaction of carboxylic acids utilizing a heterobimetallic system of
(DMPU)2Zn(CF2H)2 and CuI. A copper mediated and a copper catalyzed method were presented
as useful alternatives to existing protocols to prepare these valuable compounds. The developed
method exhibits wide functional group tolerance as demonstrated by the preparation of
compounds with vinyl, ester, aldehyde, and alkyl moieties, as well as the synthesis of
difluoromethyl analogues of commercially available FDA-approved pharmaceuticals.
3.6 Experimental data
3.6.1 General procedure A for the deoxygenative difluoromethylation using (DMPU)2Zn(CF2H)2
R
O
OPPh
3
PPh
3
Br
X
PPh
3
NBS
(-succinimide)
I
A
X
N
O O
X =
[Cu
I
]
(i) Nucleophilic Substitution by Copper
(- OPPh
3
)
31
P NMR
δ 45.2 ppm (R = Ph)
31
P NMR
δ 31.5 ppm
PhCOOH
[CF
2
HCu
I
]
R
O
[Cu
III
]X
CF
2
H
R
O
Br
R
O
OPPh
3
X
oxidative
addition
reductive
elimination R
O
CF
2
H
(ii) Nucleophilic Substitution by Carbon
I
X [Cu
I
]
(- OPPh
3
)
[CF
2
HCu
I
]
R
O
OPPh
3
X
I
X
addition-
elimination
[CuCF
2
H]
or Br
-
+
[CuCF
2
H]
[CuCF
2
H] =
(solvent)CuCF
2
H
[CuCF
2
H(X)]
-
[Cu(CF
2
H)
2
]
-
or
3
CuX
L
2
Zn(CF
2
H)
2
[CuCF
2
H]
L
2
Zn(CF
2
H)X
[Cu(CF
2
H)
2
]]
-
[Cu(CF
2
H)
4
]]
-
[Ox]
116
*Note: (DMPU)2Zn(CF2H)2 was synthesized according to Vicic’s reported procedure.
136
As most
organozinc reagents, this compound is moisture sensitive and slowly decomposes. The following
representative procedure for the synthesis of 3 was used (Method A). Two separate vials are
needed. On the bench-top, the corresponding carboxylic acid (0.15 mmol, 1 equiv) and
triphenylphosphine, PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg) were charged into an oven-dried screw-
cap vial equipped with a magnetic stir bar. After this, anhydrous dichloromethane, DCM (0.1M,
1.5 mL) was added, the vial was capped, and this mixture was then cooled to 0 ºC using an ice-
bath. Subsequently, N-bromosuccinimide, NBS (0.225 mmol, 1.5 equiv, 40.04 mg) was added as
a solid in one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two
minutes. After this time, the ice-bath was removed, and this solution was further stirred for 15 min
(Vial 1). During this time, Inside an Ar glovebox, copper iodide, CuI (0.18 mmol, 1.2 equiv, 34.28
mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34 mg) were accurately charged into a
flame-dried crimp-top vial (5 mL size), equipped with a stir bar. The vial was then sealed and
brought outside the glovebox. After the completion of the 15 minutes of stirring of vial 1, the
content was transferred in one portion to vial 2, using a 5mL syringe. Fresh anhydrous DCM ( 240
uL) was added to vial 1 to wash down the remaining contents and then transferred to vial 2 using
the syringe. This mixture was further stirred for 1 h at room temperature. Once this time
concluded, internal standard, difluoromethoxybenzene (0.083 mmol, 10uL) was added, the
mixture was stirred for 1 min and then stirring stopped to allow the undissolved solids to settle at
the bottom. The supernatant was then analyzed by
19
F NMR spectroscopy. The yield was
determined by comparing the relative integration of internal standard (difluoromethoxybenzene,
19F NMR -82.7 ppm) with the difluoromethyl ketone 3. For some substrates the NMR yield
R OH
O
1
R CF
2
H
O
3
PPh
3
(1.4 equiv)
NBS (1.5 equiv)
(DMPU)
2
Zn(CF
2
H)
2
1.5 equiv
Method A: 1.2 equiv CuI
Method B: 10 mol% CuI
DCM, 0
o
C - rt, 1h, N
2
R = aryl, alkyl
[1.0 equiv]
R OPPh
3
O
Via:
X
I
117
determination was done at a 0.15 mmol scale, in which case 10 uL of standard represent 55.55%
of the theoretical yield.
3.6.2 Isolation of dfluoromethyl ketones
Unless otherwise stated, the following representative procedure was used for the synthesis and
purification of difluoromethyl ketone products 3. Two separate vials are needed. On the bench-
top, the corresponding carboxylic acid (0.25 mmol, 1 equiv) and triphenylphosphine, PPh3 (0.35
mmol, 1.4 equiv, 91.8 mg) were charged into an oven-dried screw-cap vial equipped with a
magnetic stir bar. After this, anhydrous dichloromethane, DCM (0.1M, 2.5 mL) was added, the
vial was capped, and this mixture was then cooled to 0 ºC using an ice-bath. Subsequently, N-
bromosuccinimide, NBS (0.375 mmol, 1.5 equiv, 66.7 mg) was added as a solid in one portion,
the vial was re-capped, and the mixture was kept in the ice-bath for two minutes. After this time,
the ice-bath was removed, and this solution was further stirred for 15 min (Vial 1). During this
time, Inside an Ar glovebox, copper iodide, CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and
(DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg) were accurately charged into a flame-dried
crimp-top vial (5 mL size), equipped with a stir bar. The vial was then sealed and brought outside
the glovebox. After the completion of the 15 minutes of stirring of vial 1, the content was
transferred in one portion to vial 2 containing, using a 5mL syringe. Fresh anhydrous DCM (240
uL) was added to vial 1 to wash down the remaining contents and then transferred to vial 2 using
the syringe. This mixture was further stirred for 1 h at room temperature. After this time, the vial
was opened, and the reaction mixture was diluted with DCM (10 mL), and the mixture was passed
through a short pad of celite (3 cm thick x 3 cm diameter). Subsequently, the celite pad was further
washed with DCM (15 mL). The filtrate was then purified by column chromatography (dry loading
a 3g loader) using the appropriate ratio of hexanes/dichloromethane and the residue concentrated
under reduced pressure to afford pure product. When evaporating the lowest pressure used was
200 Torr and the temperature of the bath set at 35 ºC.
118
3.6.3 General procedure B for the catalytic deoxygenative difluoromethylation using
(DMPU)2Zn(CF2H)2
On the bench-top, the corresponding carboxylic acid 1 (0.15 mmol, 1 equiv) and
triphenylphosphine, PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg) were charged into an oven-dried screw-
cap vial equipped with a magnetic stir bar. After this, anhydrous dichloromethane, DCM (0.1M,
1.5 mL) was added, the vial was capped, and this mixture was then cooled to 0 ºC using an ice-
bath. Subsequently, N-bromosuccinimide, NBS (0.225 mmol, 1.5 equiv, 40.04 mg) was added as
a solid in one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two
minutes. After this time, the ice-bath was removed, and this solution was further stirred for 15 min
(Vial 1). During this time, Inside an Ar glovebox, copper iodide, CuI (0.015 mmol, 10 mol%, 3 mg),
and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34 mg) were accurately charged into a flame-
dried crimp-top vial (5 mL size), equipped with a stir bar. The vial was then sealed and brought
outside the glovebox. After the completion of the 15 minutes of stirring of vial 1, the content was
transferred in one portion to vial 2, using a 5mL syringe. Fresh anhydrous DCM ( 240 uL) was
added to vial 1 to wash down the remaining contents and then transferred to vial 2 using the
syringe. This mixture was further stirred for one hour at room temperature. Once this time
concluded, internal standard, difluoromethoxybenzene (0.075 mmol, 9uL) was added, the mixture
was stirred for 1 min and then stirring stopped to allow the undissolved solids to settle at the
bottom. The supernatant was then analyzed by
19
F NMR spectroscopy. The yield was determined
by comparing the relative integration of internal standard (difluoromethoxybenzene,
19
F NMR -
82.7 ppm) with the difluoromethyl ketone 3.
119
3.6.4 Characterization data of difluoromethyl ketones
2,2-difluoro-1-phenylethan-1-one (3a)
General Method A: using benzoic acid (0.25 mmol, 1 equiv, 30.53 mg) and
triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M, 2.5 mL),
NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg),
and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short pad
of celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was then
purified by column chromatography (15% DCM/hexanes) to obtain a pale-yellow oil in 70%
isolated yield (27.3 mg).
1
H NMR (400 MHz, CDCl3) δ 8.12 – 8.04 (m, 2H), 7.72 – 7.63 (m, 1H),
7.58 – 7.47 (m, 2H), 6.30 (t, J = 53.5 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -122.5 (d, J = 53.7
Hz, 2F). These data match the previously reported structure.
[14]
2,2-difluoro-1-(naphthalen-2-yl)ethan-1-one (3b)
General Method A: using naphthoic acid (0.25 mmol, 1 equiv, 43.04 mg)
and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and
(DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short pad of
celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was then
purified by column chromatography (15% DCM/hexanes) to obtain a beige solid in 97% isolated
yield (50 mg).
1
H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.14 – 8.04 (m, 1H), 8.04 – 7.99 (m, 1H),
7.97 – 7.92 (m, 1H), 7.92 – 7.87 (m, 1H), 7.71 – 7.64 (m, 1H), 7.63 – 7.56 (m, 1H), 6.41 (t, J =
53.5 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -121.7 (d, J = 53.7 Hz, 2F). These data match the
previously reported structure.
[14]
General Method B (catalytic CuI): using naphthoic acid (0.15 mmol, 1 equiv, 26 mg) and
triphenylphosphine, PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225
O
CF
2
H
O
CF
2
H
120
mmol, 1.5 equiv, 40.04 mg), CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225
mmol, 1.5 equiv, 95.34 mg). Internal standard, difluoromethoxybenzene (0.075 mmol, 9uL) Crude
reaction mixture
19
F NMR (376 MHz) δ -124.6 (d, J = 53.8 Hz, 2F), 74% NMR yield.
2,2-difluoro-1-(4-methoxyphenyl)ethan-1-one (3c)
General Method A, using 4-methoxybenzoic acid (0.25 mmol, 1 equiv, 38.03
mg) and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and
(DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short pad of
celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was then
purified by column chromatography (20% DCM/hexanes) to obtain a colorless oil in 82% isolated
yield (39.2 mg).
1
H NMR (400 MHz, CDCl3) δ 8.37 – 7.86 (m, 2H), 7.09 – 6.75 (m, 2H), 6.25 (t, J
= 53.7 Hz, 1H), 3.90 (s, 3H) .
19
F NMR (376 MHz, CDCl3) δ -121.9 (d, J = 53.7 Hz, 2F). These
data match the previously reported structure.
[14]
General Method B (catalytic CuI): using 4-methoxybenzoic acid (0.15 mmol, 1 equiv, 23 mg)
PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv, 40.04
mg), CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34
mg). Internal standard, difluoromethoxybenzene (0.075 mmol, 9uL). Crude reaction mixture
19
F
NMR (376 MHz) δ -124.6 (d, J = 53.3 Hz, 2F), 48% NMR yield.
1-(4-bromophenyl)-2,2-difluoroethan-1-one (3d)
General Method A: using 4-bromobenzoic acid (0.25 mmol, 1 equiv, 50.2 mg)
and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and
(DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short pad of
celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was then
MeO
O
CF
2
H
3c
A: 82% (84%)
B: (48%)
Br
O
CF
2
H
121
purified by column chromatography (15% DCM/hexanes) to obtain a yellow oil in 85% isolated
yield (50 mg).
1
H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 2H), 7.75 – 7.54 (m, 2H), 6.24 (t,
J = 53.4 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -122.0 (d, J = 53.9 Hz, 2F). These data match the
previously reported structure.
[14]
General Method B (catalytic CuI): using 4-bromobenzoic acid (0.15 mmol, 1 equiv, 30 mg) PPh3
(0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv, 40.04 mg),
CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34 mg).
Internal standard, difluoromethoxybenzene (0.075 mmol, 9uL).
19
F NMR (376 MHz, unlocked) δ -
125.0 (d, J = 53.0 Hz, 2F), 60% NMR yield.
2,2-difluoro-1-(2-iodophenyl)ethan-1-one (3e) and 1-(2-(difluoromethyl)phenyl)-2,2-
difluoroethan-1-one (3e’)
The title compounds were obtained following the general method II-A,
using 2-iodobenzoic acid (0.25 mmol, 1 equiv, 62 mg) and
triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M, 2.5 mL), NBS (0.375
mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and (DMPU)2Zn(CF2H)2 (0.375
mmol, 1.5 equiv, 159 mg). Purified by filtration through a short pad of celite (3 cm thick x 3 cm
diameter), washing the plug with DCM (10 ml). The filtrate was then purified by column
chromatography (15% DCM/hexanes) to obtain an oil in 83% combined isolated yield [4:1] =
3e:3e’ (44mg). Mixture of products 3e and 3e’as a result of almost identical polarity. Major product
3e
19
F NMR (376 MHz, CDCl3) δ -123.09 (d, J = 53.3 Hz). Minor product 3e’
19
F NMR (376 MHz,
CDCl3) δ -114.48 (d, J = 55.2 Hz), -121.94 (dd, J = 53.7, 2.0 Hz). Major product 3e
1
H NMR (400
MHz, CDCl3 8.09 – 7.98 (m, 1H), 7.71 – 7.66 (m, 1H), 7.54 – 7.45 (m, 1H), 7.29 – 7.21 (m, 1H),
6.31 (t, J = 53.6 Hz, 1H). Minor product 3e’
1
H NMR: All the signals from the minor product were
resolved but one. (See spectrum below).
O
CF
2
H
I
+
O
CF
2
H
CF
2
H
122
methyl 4-(2,2-difluoroacetyl)benzoate (3f)
General Method A: using mono-Methyl terephthalate (0.25 mmol, 1 equiv,
45.04 mg) and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg),
DCM (0.1M, 2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol,
1.2 equiv, 57.13 mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by
filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug with DCM
(10 ml). The filtrate was then purified by column chromatography (15% DCM/hexanes) to obtain
a white solid in 74% isolated yield (40 mg).
1
H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H),
8.14 (d, J = 8.0 Hz, 2H), 6.29 (t, J = 53.4 Hz, 1H), 3.97 (s, 3H).
19
F NMR (376 MHz, CDCl3) δ -
122.4 (d, J = 53.3 Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ 187.42 (t, J = 25.9 Hz), 165.98, 135.53,
134.64 (t, J = 2.1 Hz), 130.16, 129.74 (t, J = 2.4 Hz), 111.32 (t, J = 260.9 Hz), 52.82. These data
match the previously reported structure.
[15]
General Method B (catalytic CuI): using mono-Methyl terephthalate (0.15 mmol, 1 equiv, 24.6
mg) PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv,
40.04 mg), CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv,
95.34 mg). Internal standard, difluoromethoxybenzene (0.075 mmol, 9uL).
19
F NMR (376 MHz,
unlocked) δ -125.3 (d, J = 53.1 Hz, 2F), 50% NMR yield.
4-(2,2-difluoroacetyl)benzaldehyde (3g)
General Method A: using 4-formylbenzoic acid (0.25 mmol, 1 equiv, 37.53 mg)
and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M, 2.5
mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and
(DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a pad of celite
(3 cm thick x 3 cm), washing the plug with DCM (10 ml). The filtrate was then purified by column
chromatography (15% DCM/hexanes) to obtain a white solid in 73% isolated yield (64 mg).
1
H
NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.31 – 8.16 (m, 2H), 8.10 – 7.97 (m, 2H), 6.29 (t, J = 53.3
O
CF
2
H
O
H
O
CF
2
H
O
MeO
123
Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -122.3 (d, J = 53.4 Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ
191.44, 187.38, 140.16, 135.58, 130.39 (t, J = 2.5 Hz), 130.01, 111.36 (t, J = 253.8 Hz). HRMS-
EI
+
(M
+
H
+
HCOO
-
) Calcd. for [C9H7O2F2]
+
[HCOO]
-
= 231.0464, found = 231.0457. FT/IR (n
max
(neat) cm-1) 1951.61, 1835.90, 1689.34, 1519.63, 1423.21, 1307.50, 1268.93, 1226.50, 1126.22,
1064.51, 975.804, 875.524. MP: 109-11 ºC
General Method B (catalytic CuI): using 4-formylbenzoic acid (0.15 mmol, 1 equiv, 24.6 mg)
PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv, 40.04
mg), CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34
mg). Internal standard, difluoromethoxybenzene (0.075 mmol, 9uL). Crude reaction mixture
19
F
NMR (376 MHz) δ -122.3 (d, J = 53.4 Hz, 2F), 26% NMR yield.
(E)-1,1-difluoro-3,4-diphenylbut-3-en-2-one (3h)
General Method A: using a-Phenylcinnamic acid (0.25 mmol, 1 equiv, 56.1mg)
and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M, 2.5
mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13
mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short
pad of celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was
then purified by column chromatography (18% DCM/hexanes) to obtain a colorless oil in 68%
isolated yield (44 mg).
1
H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.46 – 7.41 (m, 3H), 7.31 – 7.27
(m, 1H), 7.23 – 7.17 (m, 4H), 7.10 – 7.06 (m, 2H), 6.12 (t, J = 53.7 Hz, 1H).
19
F NMR (376 MHz,
CDCl3) δ -122.9 (d, J = 53.7 Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ 188.17 (t, J = 23.9 Hz), 144.26
(t, J = 3.0 Hz), 136.05, 134.26, 133.78, 131.39, 130.40, 129.72, 129.23, 128.62, 128.45, 110.01
(t, J = 252.8 Hz). HRMS-EI
+
(M
+
) Calcd. for C
16
H
12
F
2
O = 258.0856, found = 258.0866. FT/IR (n
max
(neat) cm-1) 1689, 1596, 1496, 1446, 1388, 1330, 1268, 1218, 1157, 1064, 906.
CF
2
H
O
124
1,1-difluoro-5-phenylpentan-2-one (3i)
General Method A: using 4-phenylbutanoic acid (0.25 mmol, 1 equiv, 41.05
mg) and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM
(0.1M, 2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13 mg), and
(DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short pad of
celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was then
purified by column chromatography (100% EtOAc) to obtain a colorless oil in 76% isolated yield
(40 mg).
1
H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.4 Hz, 2H), 7.28 – 7.19 (m, 1H), 7.18 (d, J =
7.6 Hz, 2H), 5.66 (t, J = 54.0 Hz, 1H), 2.68 (m, J = 7.4, 3.8 Hz, 4H), 2.17 – 1.76 (m, 2H).
19
F NMR
(376 MHz, CDCl3) δ -127.5 (d, J = 53.9 Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ 206.95, 165.80,
135.36, 130.00, 129.57 (t, J = 2.5 Hz), 111.15 (t, J = 254.1 Hz), 52.64, 30.91, 22.64. These data
match the previously reported structure.
[16]
General Method B (catalytic CuI): using 4-phenylbutanoic acid (0.15 mmol, 1 equiv, 24.6 mg)
PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv, 40.04
mg), CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34
mg). Internal standard, difluoromethoxybenzene (0.075 mmol, 9uL). Crude reaction mixture
19
F
NMR (376 MHz) δ -127.5 (d, J = 54.0 Hz, 2F), 66% NMR yield.
1,1-difluoro-4-phenoxybutan-2-one (3j)
General Method A: using 3-phenoxypropanoic acid (0.25 mmol, 1 equiv, 41.54
mg) and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13
mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short
pad of celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was
then purified by column chromatography (45% DCM/hexanes) to obtain an oil in 64% isolated
yield (32 mg).
1
H NMR (400 MHz, CDCl3) δ 7.29 (m, J = 7.9 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H), 6.90
CF
2
H
O
O CF
2
H
O
125
(d, J = 8.4 Hz, 2H), 5.78 (t, J = 53.8 Hz, 1H), 4.31 (t, J = 6.2 Hz, 2H), 3.16 (t, J = 6.0 Hz, 2H).
19
F
NMR (376 MHz, CDCl3) δ -128.0 (d, J = 53.9 Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ 197.23 (t, J
= 26.9 Hz), 158.22, 129.52, 121.30, 114.56, 109.69 (t, J = 252.6 Hz), 61.45, 36.18. HRMS-EI
+
(M
+
) Calcd. for C10H10F2O2 = 200.0649, found = 200.0646. FT/IR (n
max (neat) cm-1) 1928, 1835,
1747, 1704, 1592, 1496, 1392, 1342, 1303, 1242, 1168, 1072, 906.
1,1-difluoro-3-(4-nitrophenyl)propan-2-one (3k)
General Method A: using 4-nitrophenylacetic acid (0.25 mmol, 1 equiv,
45.3 mg) and triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg),
DCM (0.1M, 2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv, 57.13
mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through a short
pad of celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate was
then purified by column chromatography (65% DCM/hexanes) to obtain a white solid in 42%
isolated yield (23 mg).
1
H NMR (400 MHz, CDCl3) δ 8.59 – 7.87 (m, 2H), 7.47 (dd, J = 8.6, 5.9
Hz, 2H), 6.32 (t, J = 55.2 Hz, 1H), 5.30 (s, 2H).
19
F NMR (376 MHz, CDCl3) δ -122.0 (d, J = 55.2
Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ 171.09, 130.36, 129.62, 124.02, 123.82, 116.16 (t, J =
252.4 Hz), 40.41. HRMS-EI
+
(M
+
) Calcd. for C9H8F2NO3 = 216.0467, found = 216.0477.
1,1-difluoro-3-phenylpropan-2-one (3l)
General Method B (catalytic CuI): using phenylacetic acid (0.15mmol,
20.42mg), PPh3 (0.21 mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS
(0.225 mmol, 1.5 equiv, 40.04 mg), CuI (0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2
(0.225 mmol, 1.5 equiv, 95.34 mg). Internal standard, difluoromethoxybenzene (0.075 mmol,
9uL). Crude reaction mixture
19
F NMR (376 MHz) δ -129.4 (d, J = 53.6 Hz, 2F).
[14]
CF
2
H
O
O
2
N
CF
2
H
O
126
5-(5-(2,2-difluoroacetyl)-4-methylthiazol-2-yl)-2-isobutoxybenzonitrile (3m)
General Method A: using febuxostat (0.25 mmol, 1 equiv, 79.09) and
triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv,
57.13 mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through
a short pad of celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate
was then purified by column chromatography (40% DCM/hexanes) to obtain a yellow solid 89%
isolated yield (75 mg).
1
H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 2.3 Hz, 1H), 8.16 (ddd, J = 8.9,
2.3, 0.6 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.07 (t, J = 53.9 Hz, 1H), 3.92 (d, J = 6.5 Hz, 2H), 2.83
(d, J = 0.6 Hz, 3H), 2.21 (dt, J = 13.3, 6.7 Hz, 1H), 1.10 (d, J = 6.7 Hz, 6H).
13
C NMR (126 MHz,
CDCl3) δ δ 181.28, 170.42, 166.24, 163.22, 133.08, 133.04, 132.71, 132.66, 125.49, 122.35,
115.31, 112.89, 109.96 (t, J = 254.6 Hz), 103.44, 75.97, 29.86, 28.31, 19.19.
19
F NMR (376 MHz,
CDCl3) δ -122.7 (d, J = 53.9 Hz, 2F). HRMS-EI
+
(M
+
H
+
) Calcd. for C17H17F2N2O2S
+
= 351.0973,
found = 351.0977. FT/IR (n
max (neat) cm-1): 1943, 1793, 1743, 1673, 1604, 1504, 1427, 1369,
1322, 1295, 1234, 1126, 1064, 1010, 833. MP: 98-100 ºC
General Method B (catalytic CuI): using febuxostat (0.15 mmol, 1 equiv, 48 mg) PPh3 (0.21
mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv, 40.04 mg), CuI
(0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34 mg). Internal
standard, difluoromethoxybenzene (0.075 mmol, 9uL). Crude reaction mixture
19
F NMR (376
MHz) δ -125.0 (d, J = 53.7 Hz, 2F), 60% NMR yield.
N
S
O
CF
2
H
C
O
N
127
3-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1,1-difluoropropan-2-one (3n)
from indomethacin
General Method A: using indomethacin (0.25 mmol, 1 equiv, 89.44) and
triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv,
57.13 mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg).
Purified by filtration through a short pad of celite (3 cm thick x 3 cm diameter), washing the plug
with DCM (10 ml). The filtrate was then purified by column chromatography (75% DCM/hexanes)
to obtain a yellow solid 70% isolated yield (68 mg).
1
H NMR (400 MHz, CDCl3) δ 7.74 – 7.62 (m,
2H), 7.53 – 7.43 (m, 2H), 6.87 (dd, J = 9.0, 0.6 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.68 (dd, J =
9.0, 2.5 Hz, 1H), 5.81 (t, J = 53.8 Hz, 1H), 4.01 (d, J = 1.2 Hz, 2H), 3.82 (s, 3H), 2.35 (s, 3H).
13
C
NMR (126 MHz, CDCl3) δ δ 195.96 (t, J = 26.5 Hz), 168.34, 156.26, 139.59, 136.91, 133.78,
131.34, 130.95, 130.33, 129.31, 115.19, 111.98, 109.86 (t, J = 253.0 Hz), 109.67, 100.96, 55.80,
32.42, 13.45.
19
F NMR (376 MHz, CDCl3) δ -127.1 (d, J = 53.8 Hz, 2F). HRMS-EI
+
(M
+
H
+
) Calcd.
for C20H17ClF2NO3
+
= 392.0860, found = 392.0857. FT/IR (n
max (neat) cm-1): 1943, 1793, 1743,
1673, 1604, 1504, 1427, 1369, 1322, 1295, 1234, 1126, 1064, 1010, 833. MP: 93-95 ºC
4-(2,2-difluoroacetyl)-N,N-dipropylbenzenesulfonamide (3o) from Probenecid
General Method A: using probenecid (0.25 mmol, 1 equiv, 71.34) and
triphenylphosphine, PPh3 (0.35 mmol, 1.4 equiv, 91.8 mg), DCM (0.1M,
2.5 mL), NBS (0.375 mmol, 1.5 equiv, 66.7 mg), CuI (0.3 mmol, 1.2 equiv,
57.13 mg), and (DMPU)2Zn(CF2H)2 (0.375 mmol, 1.5 equiv, 159 mg). Purified by filtration through
a short pad of celite (3 cm thick x 3 cm diameter), washing the plug with DCM (10 ml). The filtrate
was then purified by column chromatography (70% DCM/hexanes) to obtain a white solid in 76%
isolated yield (61 mg).
1
H NMR (400 MHz, CDCl3) δ 8.23 – 8.14 (m, 2H), 7.98 – 7.86 (m, 2H),
6.28 (t, J = 53.3 Hz, 1H), 3.20 – 3.05 (m, 4H), 1.65 – 1.45 (m, 4H), 0.86 (t, J = 7.4 Hz, 6H).
19
F
N
O
Cl
MeO
HF
2
C
O
CF
2
H
O
S
N
O
O
128
NMR (376 MHz, CDCl3) δ -122.3 (d, J = 53.3 Hz, 2F).
13
C NMR (126 MHz, CDCl3) δ 186.75 (t, J
= 26.4 Hz), 145.89, 133.85 (t, J = 2.1 Hz), 130.29 (t, J = 2.5 Hz), 127.43, 111.22 (t, J = 254.2 Hz),
49.97, 21.97, 11.12. FT/IR (n
max (neat) cm-1): 2965.98, 2943.32, 2876.31, 2361.89, 2004.16,
1716.82, 1338.84, 1155.63, 1088.14, 1060.17, 989.786, 875.524, 557.809. HRMS-EI
+
(M+H
+
)
Calcd. for C14H20F2NO3S
+
= 319.1048, found = 319.1051
General Method B (catalytic CuI): using probenecid (0.15 mmol, 1 equiv, 42.8 mg) PPh3 (0.21
mmol, 1.4 equiv, 55.1 mg), DCM (0.1M, 1.5 mL), NBS (0.225 mmol, 1.5 equiv, 40.04 mg), CuI
(0.015 mmol, 10 mol%, 3 mg), and (DMPU)2Zn(CF2H)2 (0.225 mmol, 1.5 equiv, 95.34 mg). Internal
standard, difluoromethoxybenzene (0.075 mmol, 9uL). Crude reaction mixture
19
F NMR (376
MHz) δ -125.1 (d, J = 53.2 Hz, 2F), 63% NMR yield.
129
CHAPTER 4: Copper-catalyzed Synthesis of Difluoromethyl Alkynes from
Terminal and Silyl Acetylenes and their Applications in Intramolecular Cyclization
and cycloaddition reactions for the Preparation of CF2H-Heterocycles
Scheme 4.1: Synthesis of difluoromethyl alkynes
An efficient method for the direct C(sp)–H difluoromethylation of terminal alkynes and the
desilylation-difluoromethylation of trimethylsilyl-acetylenes is disclosed. The copper-catalyzed
transformation provides access to a wide range of structurally diverse CF 2H-alkynes in very good
yields, utilizing a (difluoromethyl)zinc reagent and an organic oxidant. The synthetic utility of these
difluoromethylacetylenes is further demonstrated by the synthesis of a 2-difluoromethylindole
through a tandem difluoromethylation/intramolecular cyclization reaction, as well as other
derivatization reactions. The difluoromethylation of important synthons and bioactive API’s is also
established. (J. Org. Chem. 2023, 88, 2, 1194–1199, 10.1021/acs.joc.2c02799).
4.1 Introduction and prior art in the synthesis of difluoromethyl alkynes
Amongst the various strategies to introduce fluorine atoms into molecules, the development of
difluoromethylation protocols is on the rise and has been of interest for several recent
investigations.
140,376–379
The difluoromethyl group has been described as a lipophilic bioisostere
of thiol (–SH) and amino (–NHR) groups due to their similar hydrogen bond acidity, and as a less
lipophilic bioisostere to the –CH3 group.
114,115
Reportedly, the hydrogen bond donor capabilities
of the –CF2H moiety are heavily influenced by the chemical environment of a given compound.
Cu
I
L
2
Zn(CF
2
H)
2
[Ox]
X: H or TMS
R
1
R
X
R
1
R
CF
2
H
93% – 22%
• Catalytic Cu
• Good yields
• Wide substrate scope
• Bio-relevant substrates
• Chemoselective
• 23 examples
Ar
Alk
Ar
Alk
130
These properties make the difluoromethyl group an attractive moiety to tune the physicochemical
properties of bioactive compounds. In this context, the alkynyl moiety is a widely preva-lent
functionality in natural products and compounds with biological applications.
380–382
Synthetically,
CºC triple bonds are employed as useful synthons for clickable tags and biomarkers via
cycloaddition reactions to form triazoles, pyrazoles, and other heterocycles.
383–386
Additionally,
they serve as important synthetic intermediates, and are also present in several life-saving
medications (Figure 4.1).
Figure 4.1: Alkyne-containing pharmaceuticals and API’s
Fluoroalkyl alkynes have similarly been described as valuable building blocks, making methods
for their efficient preparation highly sought-after. However, there are only a handful of methods
available in the literature to prepare difluoromethylacetylenes directly from their parent terminal
alkynes, and most protocols for their synthesis proceed via a difluorocarbene intermediate. The
difluoromethylation of propynyl alcohols with Freon-22 (CHF2Cl) as a difluorocarbene source was
demonstrated in 1996 by Konno and coworkers..
387
More recently, this ozone-depleting gas has
been used alongside a palladium catalyst to prepare CF2H-alkynes.
388
In this same vein,
TMSCF2Br,
132
an α-difluoromethyl sulfoximine,
389
and fluoroform
265,390
have also been used as a
N
N
N
H
N
O
Tirasemtiv (troponin activator) Noretynodrel (1st birth control)
O
HO
MeO
O
O
MeO
N
N
HN
Erlotinib (cancer treatment)
Tirabrutinib (hematological malignancies)
N
N
NH
2
N
N
O
O
N O
HIV-1 RT inhibitor
N
NH
O
O
O
OH
Linagliptin (Diabetes type 2)
N
N
O
O
N
N
N
NH
2
N
N
131
difluorocarbene precursors for the preparation of these compounds, however, these display
limited substrate scopes or moderate yields (Scheme 4.2).
Scheme 4.2: Prior art on the synthesis of difluoromethyl alkynes
Despite the rich chemistry of organocopper compounds
391
and the proven ability of Cu-acetylides
to act as alkyne-transfer agents,
392
the reports of the use of copper chemistry for these endeavors
are very scarce. Burton’s work on the reaction between in situ prepared CuCF2H and alkynyl
halides, along with Qing’s oxidative difluoromethylation of terminal alkynes with TMSCF2H and
stoichiometric CuI are the only two reports (Scheme 4.2).
274,393
Therefore, we envisioned the
preparation of CF2H-alkynes employing catalytic loadings of copper and (DMPU)2Zn(CF2H)2 as
the difluoromethyl source (which can be prepared by a halon-free approach).
394
Our previous
experience working with this heterobimetallic system
272
led us to hypothesize that under mild
oxidative conditions, the in situ formed difluoromethyl-copper species could yield the desired
compounds from either terminal or silyl alkynes.
{
R
X
X: H, Cl, I, Li
R
CF
2
H
R: Ar, Alk
(I) Prior art on the synthesis of difluoromethyl alkynes
(II) This work
Cu
I
L
2
Zn(CF
2
H)
2
[Ox]
X: H or TMS
R
1
R
X
R
1
R
CF
2
H
42% – 92%
Ar
Alk
Ar
Alk
TMSCF
2
H
Cu
[1.0] or
CuCF
2
H, -55ºC
TMSCF2Br
t
BuOK
PhMe
CF
3
H excess
t
BuOK [10.0]
or LHMDS
HCF
2
Cl
n-BuLi
or Pd
S
CF
2
H Ph
O NTs
132
4.2 Optimization of the difluoromethylation reaction
To test this hypothesis, we selected 4-Cl-phenylacetylene 1a as the model substrate for the
optimization process. The effects of multiple modifications of the reaction conditions were
evaluated and summarized in Table 4.1. The desired difluoromethylated product 2a was obtained
in 87% yield with 3.0 equivalents of LiO
t
Bu as the base, 2.0 equivalents of the difluoromethyl zinc
reagent, 40 mol% of CuBr and 1.2 equivalents of 9,10-phenanthrenequinone as the oxidant
(Table 4.1, entry 1). The use of 1 or 3 equivalents of KO
t
Bu instead of LiO
t
Bu at -15 or at room
temperature, afforded lower conversions by
19
F NMR even after 18 hours of reaction (Table 4.1,
entries 2, 3 and 4). Similarly, modifying the copper loadings and identity of the copper salts did
not improve the yield of 2a (Table 4.1, entry 5, 6 and 7). Reducing the copper loadings did not
improve the yield, however, it showcased the feasibility of performing the reaction with 5 mol%
CuBr if lower loadings are desired, obtaining the target compound in 64% yield (Table 4.1, entry
10). The trend observed with different copper loadings, ranging from 5% to 100% CuBr is depicted
in the graph in Figure 4.2. Conducting the reaction at room temperature (18h) after setting it up
at -15 ˚C resulted in a moderate but lower yield (Table 4.1, entry 11). The
19
F NMR spectrum of
this trial shows the presence of unidentified species that aren’t observed at higher temperatures,
which may suggest the reaction doesn’t go to completion at room temperature. Changing the
reaction time to 4 or 6 hours did not afford the same results as it did in 8 hours. (Table 4.1, entries
12, 13 and 14). Finally, the absence of either the oxidant (9,10-phenanthrenequinone) or copper
did not afford any product (Table 4.1, entry 15).
133
Table 4.1: Optimization of the difluoromethylation reaction
(a)
Entry Cu [mol%] Base
[equiv.]
L2Zn(CF2H)2
[equiv]
9,10-PQ
[equiv.]
T ºC Solvent [M] Time
h
Yield 2a
%
[b]
1 CuBr [0.40] LiOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 87
2 CuBr [0.40] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 77
3 CuBr [0.65] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to rt DMF [0.108] 18 66
4 CuBr [0.65] KOtBu
[1.0]
[2.0] [1.2] -15 ºC to rt DMF [0.108] 18 17
5 CuBr [0.65] LiOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 78
6 CuCl [0.65] LiOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 18
7 CuBr [100] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to rt DMF [0.108] 18 73
8 CuBr [0.15] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 68
9 CuBr [0.10] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 62
10 CuBr [0.05] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 64
11 CuBr [0.65] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to rt to
80 ºC
DMF [0.108] 18/4
[c]
72
12 CuBr [0.65] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 4/4
[d]
42
13 CuBr [0.65] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 6 58
14 CuBr [0.65] KOtBu
[3.0]
[2.0] [1.2] -15 ºC to 80 ºC DMF [0.108] 8 77
15 CuBr [0.40] LiOtBu
[3.0]
[2.0] - -15 ºC to 80 ºC DMF [0.108] 8 0
* The highlighted cells represent the variables changed in each trial.
[a]
Reaction conditions: CuBr, alkyne [1a], and
base in 0.5mL of DMF -15 ºC, 10 min. Add (DMPU) 2Zn(CF2H) 2 in 0.2 mL of DMF, -15 ºC, 10 min. Add 9,10-
phenanthrenequinone in 0.8mL of DMF, -15 ºC, 10 min. Warm up to room temperature, then place in a bath at 80 ºC
CF
2
H
Cl
H
Cl
CuBr
base
L
2
Zn(CF
2
H)
2
[2 equiv.]
9,10-PQ [1.2 equiv
DMF 0.1M
-15ºC—80ºC, 8h
[1a] [2a]
134
for 8h.
[b]
Yields determined by
19
F NMR analysis using PhOCF 2H as an internal standard.
[c]
After warming up to rt, the
reaction was left stirring overnight and then transferred to the bath at 80 ºC for an additional 4h.
[d]
After warming up to
rt, the reaction was left stirring for 4h and then transferred to the bath at 80 ºC for an additional 4h.
Figure 4.2: Trend observed with different copper loadings
4.3 Substrate scope of difluoromethyl alkynes form terminal and silyl acetylenes
With the optimized conditions in hand, we explored the scope of the difluoromethylation reaction.
Scheme 4.3 depicts the extent of the method’s applicability. (Haloaryl)acetylenes provided the
expected compounds in excellent yields, as exemplified by product 2a from the model substrate,
3,5-difluorophenyl compound 2b and compound 2c. Notably no difluoromethylarene by-product
was observed in these cases
395
and the synthesis of 2a was successfully performed at ~10x the
scale, giving comparable yield. Ethers were amenable to the reaction conditions, regardless of
substitution pattern furnishing compounds 2d (72%), 2e (66%) and 2f (76%) in good yields.
Similarly, 4-ethynylbiphenyl 1g yielded compound 2g with good conversion (75%). The method
similarly tolerates both electron-rich and electron-deficient substrates, affording the target
compounds in comparable yields. Substrate 1h furnished compound 2h (91%) in excellent yield
and compounds containing ester and nitrile substituents afforded compounds 2i, 2j in good yields
without any side reactions. ortho-Substituted 2k (86%) was also afforded in excellent conversion
by
19
F NMR suggesting that sterics may not impede the reaction. 2-naphthylalkyne 1l was
smoothly converted to the difluoromethyl derivative 2l in good yield. Furthermore, example 2m
135
(72%) showcases the method’s tolerance to primary amines, and example 2n (72%)
demonstrates the applicability of the method to substrates with pyridyl moieties. Aliphatic alkynes
were also found to be successful substrates under these conditions. The difluoromethylation of 1-
decyne produced compound 2p in moderate yield. Cyclopropyl acetylene was also subjected to
the reaction conditions, yielding 56% of compound 2o by
19
F NMR. Next, 3-Chloro-3-methyl-1-
butyne afforded compound 2q in moderate yield.
Scheme 4.3: Substrate scope of difluoromethyl alkynes
From terminal alkynes X: H
Cl CF
2
H
[2a]
Br CF
2
H
[2c]
EtO CF
2
H
[2d]
MeO CF
2
H
[2e]
Ph CF
2
H
[2g]
(75%) 64%
[2b]
CF
2
H
(92%) 78%
F
F
CF
2
H
F
3
C
[2h]
(91%) 80%
CF
2
H
MeO
[2f]
(76%) 63%
[2i]
(74%) 60%
CF
2
H
O
MeO
CF
2
H
[2k]
(86%) 70%
Me
CF
2
H
[2l]
(61%) 50%
NC CF
2
H
[2j]
(67%) 56%
[2m]
(72%) 65%
H
2
N
CF
2
H
N
CF
2
H
[2n]
(72%) 63%
CF
2
H
[2o]
(56%)
c
CH
3
CF
2
H
[2p]
(47%) 40%
CF
2
H
[2s]
(44%) 40%
Si CF
2
H
[2t]
(63%) 52%
MeO
From silylated alkynes X: TMS
CF
2
H
[2r]
(42%) 36%
Pharmaceuticals and API’s scaffolds
(87%) 80%
(71%) 64%
(73%) 70%
b
(72%) 60% (66%) 60%
Linagliptin analogue precursor
N
N
O
O
N
N
CF
2
H
N
NH
2
N
N
MeO
O
O
MeO
N
N
HN
Erlotinib analogue
N
N
N
H
N
O
From Tirasemtiv
CF
2
H
CF
2
H
[2u]
[2v]
[2w]
H
R
H
O
Unsuccessful substrates
[F1] [F2]
(A)
(B)
(C)
(i)
(93%) 90%
Cl
CF
2
H
[2q]
(22%)
c
(69%) 61%
(70%) 60%
CF
2
H
R
X
R
CuBr [40 mol%]
LiO
t
Bu [3.0 equiv]
(DMPU)
2
Zn(CF
2
H)
2
[2.0 equiv]
9,10-PQ [1.2 equiv]
DMF [0.1M]
-15 ºC—80 ºC
[1] [2]
Standard conditions
X: H, TMS
136
(a)
[1] (0.15 mmol), LiOtBu (3.0 equiv), CuBr (40 mol%), (DMPU) 2Zn(CF 2H) 2 (2.0 equiv), 9,10-phenanthrenequinone
(1.2 equiv). Set up at -15 ˚C — 80 ˚C for 8 hours. Yields in parentheses determined by
19
F NMR spectroscopy, using
internal standard (PhOCF 2H).
(b)
Scaled-up reaction: 2 mmol.
(c)
Not isolated due to volatility, observed by
19
F NMR.
This lower yield may be attributed to the formation of an allene via chloride elimination.
396
(Trimethylsilyl)alkynes have been described in the literature as synthetic alternatives to terminal
alkynes, especially in cases where volatility and handling are problematic. We were interested in
testing the compatibility of these compounds with our method. We were pleased to find that TMS-
phenylacetylene was converted to the difluoromethyl derivative 2r in a yield comparable to that
obtained with other Cu-mediated methods with terminal alkynes.
274,393
The desilylation-
difluoromethylation of compound 1s also afforded 2s in moderate yield. Further synthetic
applicability of the method was demonstrated by example 2t in which the triisopropylsilyl group
remained untouched, furnishing TIPS-CºCCF2H in good yield (Scheme 4.3.B). The retention of
the more sterically encumbered silane may be of significance in further applications of this
compound . The method was further applied for the preparation of difluoromethyl analogues of
biologically relevant compounds (Scheme 4.3.C). Example 2u was prepared in 93% yield as a
precursor of a CF2H-analogue of Linagliptin, a successful diabetes medication. This example also
showcases the feasibility of difluoromethylating N-propargyl theophylline derivatives with this set
of conditions. Example 2v contains a scaffold based on Erlotinib, a cancer-treating therapeutic.
This difluoromethyl analogue was smoothly furnished in 60% yield. Lastly, 2w, prepared in 69%
yield from Tirasmetiv, contains an imidazo[4,5-b]pyrazinone scaffold commonly encountered in
small molecules that target muscle weakness caused by neurogenic diseases.
397,398
Throughout
the exploration of the substrate scope, we encountered two limitations of the method. Compounds
with scaffolds like F1 or F2 were not able to undergo difluoromethylation under these conditions
(Scheme 2.i), and instead, 1,1,2,2-tetrafluoroethane {
19
F NMR (CDCl3) d -139 (d, 55Hz)} was
formed as the major product (see experimental section). During this exploration process, we
137
wanted to test whether substrates derived from propargyl alcohols could lead to a different result
from the one obtained with substrates F1 and F2. Unfortunately, we found that substrates subject
to a-elimination did not yield the desired compounds. Table 4.2 depicts the 3 different substrates
tested, including propargyl alcohol and derivatives from 1-phenylpropargyl alcohol. Tosylated
compound TS1 underwent conversion with very low yield probably due to spontaneous formation
of an allene by-product upon elimination of the tosylate. Similarly, the reaction with propargyl
tosylhydrazone PH1 resulted in a complex mix of species observed by
19
F NMR with only trace
amounts of the target compound formed.
Table 4.2: Reactions with propargyl alcohol derivatives
Substrate Expected product Yield (%)
P1
0%
TS1
7%
PH1
<1%
4.4 Mechanistic considerations and proposal
The proposed reaction pathway for the presented transformation is primarily based on the
reported activity of perfluoroalkylcopper species with terminal alkynes,
393
as well as prior art on
1) CuBr [40 mol%]
LiO
t
Bu [3 equiv]
DMF 0.5 mL
2) L
2
Zn(CF
2
H)
2
[2 equiv.]
DMF 0.2 mL
3) 9,10-PQ [1.2 equiv]
DMF 0.8 mL
-15ºC—80ºC, 8h
X
H
R
X
CF
2
H
R
OH
H
OH
CF
2
H
O
H
Ts
O
CF
2
H
Ts
HN
H
R
H
N
Ts HN
CF
2
H
R
H
N
Ts
138
[Cu-CF2H] species generation from the Vicic-Mikami reagent and copper (I) salts.
136,138
As seen
in Scheme 4.4, the in situ-formed difluoromethylcopper species can react with alkyne [1] to form
intermediate difluoromethylcopper acetylide [a] in the presence of a base and can then be
oxidized to intermediate [b]. Upon reductive elimination from this intermediate, the desired
compound [2] is released along with the regenerated catalyst.
Scheme 4.4: Mechanistic proposal for the difluoromethylation of terminal acetylenes
4.5 Derivatization reactions with difluoromethyl alkynes
The utility of the synthesized difluoromethylalkynes was exemplified by the preparation of CF2H-
triazoles 4a and 4b, and a (difluoromethyl)dihydro-epoxynaphthalene 5a. The [3+2] click reaction
between difluoromethyl alkyne 2k and benzyl azide yielded a mixture of the two regioisomers in
50% yield (Table 4.2). Similarly, compound 5a was obtained as a product from the [4+2] Diels-
Alder cycloaddition between compound 2a and 1,3-diphenylisobenzofuran (Table 4.3). This
derivatization reaction was carried out quantitatively, smoothly affording compound 5a as the first
example of this kind of Diels-Alder adducts
399
with difluoromethylalkynes.
Table 4.3: Cycloaddition reactions
H
[1]
CuX
(DMPU)
2
Zn(CF
2
H)
2
[CuCF
2
H]
(DMPU)
2
Zn(CF
2
H)X
Cu
L
CF
2
H
CF
2
H
Base
Base-H
Mechanistic
proposal
[a]
[2]
R
R
R
[Ox]
[Ox]
Cu
L
CF
2
H
[b]
R
X
L
139
Reagents Product Yield
Benzyl azide +2l
CF2H triazole
[4b]
a
from [2l]: 1.2:1.0 (50%)
1,3-diphenylisobenzofuran +2a
CF2H epoxy-dihydronaphthalene
[5a]
b
from [2a]: (quant.) 77%
(a)
Regioisomers obtained in a 1.2:1.0 ratio. Isomer 4b isolated in 50% yield.
(b)
Obtained by heating a toluene solution
of alkyne 2a and 1,3-diphenylisobenzofuran at 100 ºC for 36 h.
Furthermore, we extended the developed methodology to explore the selective synthesis of 2-
difluoromethylindoles through a tandem difluoromethylation-intramolecular cyclization process.
Slightly modified conditions were applied to 2-ethynylaniline derivative 1x, affording 2-
difluromethylindole 3 in 68% yield (Scheme 4.5). The in-depth exploration of this transformation
will be discussed in section 4.6 of this chapter.
Scheme 4.5: Unoptimized tandem difluoromethylation-cyclization
4.6 Tandem difluoromethylation-intramolecular cyclization
4.6.1 Prior art on the synthesis of 2-CF2H indoles
We envisioned that a similar protocol as the one developed to prepare CF2H-alkynes could be
applied to selectively prepare 2-difluoromerthyl indoles. Indoles are a class of heterocycles that
is widely prevalent in naturally occurring compounds such as neurotransmitters (serotonin), and
N
N N
Bn
CF
2
H
O
Ph
CF
2
H
Ph
Cl
N
H
N
CF
2
H
Ts
Ts
[1x] [3]
CuBr [65 mol%]
KO
t
Bu [3.0 equiv]
LiH/TMSCl
(DMPU)
2
Zn(CF
2
H)
2
[2.0 equiv]
9,10-P-Q [1.2 equiv]
DMF [0.1M]
-15 ºC—80 ºC (68%)
140
amino acids (tryptophan) as well as pharmaceuticals (indomethancin). Fluorinated indole
derivatives have also been described as promising cores for the development of bioactive
compounds due to their broad scope of physiological activity.
400
These compounds are commonly
obtained through either direct functionalization of the indole core, fluorination of an acyclic
derivative, or through cyclization and/or cycloaddition reactions. The selective C-2
functionalization of indoles has been traditionally achieved by blocking the C-3 position and
employing a radical CF2 source to undergo photoredox catalysis with the aid of Cu, Rh, Ir, Ru or
Ni catalysts.
401,402
These processes often involve a second decarboxylation step to afford the
terminal CF2H moiety (Scheme 4.6.A). Another common strategy is the installation of directing
groups in the nitrogen atom in order to enhance the reactivity and selectivity of the process.
403
A
commonly employed N-directing group is 2-pyrimidyl and it has been extensively use for this
purpose (Scheme 4.6.B).
403–406
In addition to direct C2-functionalization, cycloaddition
intramolecular cyclization reactions have been performed to selectively access 2-difluoromethyl
indoles. In 2004, Konno and coworkers reported a palladium-catalyzed annulation of fluorinated
alkynes with substituted 2-iodoanilines.
407
In this work, one example of a difluoromethyl indole is
prepared with complete regioselectivity (Scheme 4.6.C), whereas the trifluoromethyl indoles were
prepared as a mixture of C2/C3 regioisomers. Unfortunately, no other substrates were explored
for the difluoromethyl derivatives. On the other hand, intramolecular cyclization approaches
include the Grignard reaction of N-[2-(bromo/chloroalkyl)phenyl]imidoyl chlorides with magnesium
reported by Wang and coworkers,
408
and the Michael addition of a fluorinated alkyne and a
haloaniline, followed by a copper-catalyzed intramolecular annulation reported by Cao in 2014
(Scheme 4.6.D).
409
141
Scheme 4.6: Prior art of the synthesis of 2-CF 2H indoles
Considering that our group has developed an efficient and applicable protocol for the synthesis of
difluoromethylalkynes, we hypothesized that the method could be extended to the selective
synthesis of 2-difluoromethyl indoles through a tandem difluoromethylation-intramolecular
cyclization of 2-ethynylanilines. This approach would circumvent the disadvantage of poor
regioselectivity found in cycloaddition and intermolecular reactions, as well as provide an alternative
to methods that employ a substituted indole core with other reactive positions blocked.
4.6.2 Optimization of the tandem difluoromethylation-intramolecular cyclization
Initially, before attempting to apply the conditions found for the sysnthesis of difluoromethylalkynes,
the synthesis of 2-difluoromethylindoles was attempted employing TMSCF2H as a difluoromethide
source. However, the reaction proved to be very challenging, even after extensive optimization
(Table 4.4). Based on prior work on the oxidative difluoromethylation of alkynes with TMSCF2H,
393
N
R
1
X
X: 2-Pym
R
X: H
R
1
: alkyl, H
R: FG
BrCF
2
Y
Ir or Ru cat.
Blue LEDs
Y=CO
2
Et, HPPh
3
Radical CF
2
R
source
Cu/Rh/Ni
ligand
X
N
R
R
2
R
1
R: FG
X: I
R
1
, R
2
: H
X: Alk-Br
R
1
, R
2
: Alkyl-CF
2
H
Mg, THF
or
CuBr, K
2
CO
3
DMSO, 60ºC
RC CCF
2
H
Pd, ligand
Et
3
N, DMF
80ºC, 8h
C2-Difluoromethyl indoles
N
H
CF
2
H
Functionalization Cyclization
R
A) B) C) D)
142
we envisioned that employing a 2-ethynylaniline as the optimizing substrate could lead to the
subsequent intramolecular cyclization reaction after the initial functionalization. Early experiments
with unprotected anilines did not yield the desired results. Thus, the aniline moiety was protected
with a tosyl group. To test whether this change would be favorable for the reaction, we selected
substrate 1x as the optimizing substrate and combined it with copper iodide, potassium tert-butoxide
and 9,10-phenanthrenequinone in one pot. To this vial DMF was added, and the reaction cooled
down to 0 ºC. Lastly, TMSCF2H was added to the chilled solution and the reaction mix was left at
room temperature overnight. This first experiment yielded no results, however, changing the order
of addition of the components resulted in 13% yield of the desired compound (Table 4.4, entry 2).
However, adding TMSCF2H last resulted in 0% conversion (Table 4.4, entry 3). We quickly realized
that adding the oxidant at the right time had a significant effect on the substrate conversion. Entry 4
in Table 4.4 showcases the lack of conversion when the oxidant was added after leaving the reaction
stirring overnight, and even after increasing the temperature to 120 ºC no product was observed. On
the other hand, adding the oxidant last during the set-up of the reaction did show evidence of the
formation of 3a (Table 4.4, entry 5). Throughout the optimization process other variables were
changed in order to study their influence on the reaction yield. Employing different bases, different
copper salts and changing the loadings did not afford higher conversions (Table 4.4, entries 6,7,8,9,
and 10). Although temperature has a significant impact on the reaction, none of the aforementioned
variations at either -15 ºC or -30 ºC resulted in an increased conversion. The addition of 1,10-
phenanthroline as a stabilizing ligand did not afford the desired compound either (Table 4.4, entry
11) and substituting 9,10-phenanthrenequinone as the oxidant for DDQ was also detrimental for the
reaction (Table 4.4, entry 12). The
19
F NMR of the crude reaction mixtures showed the formation of
large quantities of difluoromethane (CF2H2), despite the solvent being distilled and all the other
components thoroughly dried. We hypothesized that the in situ generated difluoromethide could be
deprotonating the sulfonamide of substrate 1x. To circumvent this issue, LiH was chosen as the
base to deprotonate the sulfonamide moiety before mixing it with the other components at low
143
temperatures (Table 4.4, entries 13 and 14). Unfortunately, these experiments did not afford the
expected results.
Table 4.4: Optimization of the difluoromethylation reaction with TMSCF2H
(a)
Entry
[M]
[equiv]
Base
[equiv]
Additive
Time 1
h
CF2H
[equiv]
Oxidant
[equiv]
T ºC
Solvent
[M]
Time
2 h
Yield
%
1
b
CuI [1] KO
t
Bu [3] - 10 min
TMSCF2H
[2]
9,10-PQ
[1.2]
0 ºC to rt DMF [0.2] 16 0
2
c
CuI [1] KO
t
Bu [3] - 10 min
TMSCF2H
[2]
9,10-PQ
[1.2]
0 ºC to rt
DMF
[0.15]
16 13
3
d
CuI [1] KO
t
Bu [3] - 10 min
TMSCF2H
[2]
9,10-PQ
[1.2]
0 ºC to rt DMF [0.3] 16 0
4 CuI [1] KO
t
Bu [3] - 10 min
TMSCF2H
[2]
9,10-PQ
[1.2] after
17h
0 ºC/120
DMF
[0.15]
16 0
5 CuI [1] KO
t
Bu [3] - 10 min
TMSCF2H
[2]
9,10-PQ
[1.2] after
17h
0 ºC to rt
DMF
[0.08]
17 6
6 CuI [1]
TMEDA
[1]
- 10 min
TMSCF2H
[2]
9,10-PQ
[1.2]
0 ºC to rt
DMF
[0.08]
17 0
7 CuI [1]
Cs2CO3
[2]
- 10 min
TMSCF2H
[2]
9,10-PQ
[1.2]
0 ºC to rt
DMF
[0.08]
17 0
8
CuBr
[0.65]
CsF [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF
[0.08]
18 0
9
CuBr
[0.65]
K-
amylate
[3]
LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF
[0.08]
18 0/0
CuX
Base
Additive
TMSCF
2
H
Oxidant
solvent
T ºC, time
[1x] [3a]
N
H
N
CF
2
H
Ts
R
144
10 CuBr [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10 min,
0ºC
TMSCF2H
[3]
9,10-PQ
[1.2]
-15 ºC to
rt
DMF
[0.11]
18 0
11 CuI [1] KO
t
Bu [3]
1,10-
Phenanthroline
[1]/KOtBu [1]
20 min
TMSCF2H
[2]
9,10-PQ
[1.2]
0 ºC/120
DMF
[0.15]
16 0
12 CuI [1] KO
t
Bu [3] - 10 min
TMSCF2H
[2]
DDQ [1.2] 0 ºC to rt
DMF
[0.08]
17 0
13 CuI [1] KO
t
Bu [3] LiH [1]
10
min/15
min
TMSCF2H
[2]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF [0.1] 21 0
14
e
CuI [1] KO
t
Bu [3] LiH [1]
10
min/15
min
TMSCF2H
[2]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF [0.1] 21 0
15 CuI [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[2]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF [0.1] 21 0
16
f
CuI [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[2]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF [0.1] 21 0
17
g
CuI [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF
[0.08]
3 21
18 CuI [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF
[0.08]
17 26
19 CuI [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMPU
[0.08]
17 0
20 CuI [1] KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC for
5h
DMF
[0.08]
5 0
21
CuBr
[0.65]
KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt to 80
ºC
DMF
[0.08]
18 11
22
CuBr
[0.65]
KO
t
Bu [4] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF
[0.08]
18 3
145
23
h
CuBr
[0.65]
KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt to 80
ºC
DMF
[0.08]
18/4 3
24
CuI [1]/
1,10-
phen [1]
KO
t
Bu [3] LiH [2]/TMSCl [1]
10
min/15
min
TMSCF2H
[3]
9,10-PQ
[1.2]
-30 ºC to
rt
DMF
[0.08]
18 0/0
(b)
TMSCF 2H was added to a suspension of substrate/ copper/base/oxidant at 0 ºC
(c)
Substrate was added to
copper/base/TMSCF 2H in solution at 0 ºC (10 min). Next, oxidant was added at 0 ºC.
(d)
TMSCF 2H was added to a
suspension of copper/base at 0ºC (10 min). Next, substrate was added at 0ºC (10 min). lastly, oxidant was added at
the same temperature.
(e)
A solution of substrate/additive/base was added to copper at -30ºC. Next, TMSCF 2H was
added, followed by oxidant. (f) TMSCF 2H added from the beginning.
(g)
TMSCF 2H was added to a suspension of
copper/base at -30 ºC. next a solution of substrate/additive was added to the pot. Lastly, oxidant was added.
(h)
the
reaction was left to stir at rt overnight, then, placed in a bath at 80 ºC for 4h.
We then hypothesized that the deprotonated sulfonamide could be protected in-situ with TMSCl to
avoid re-protonation and thus circumventing the issue. Therefore, distilled TMSCl was added to the
vial containing 1x and LiH at 0 ºC and the resulting solution transferred to a pot containing the metal,
the base and TMSCF2H. While conducting this experiment it became evident that the addition of
TMSCF2H at the right time also had a significant impact on the outcome of the reaction. Adding
TMSCF2H form the onset of the reaction or after the transfer of the solution of 1x is detrimental and
large amounts of tetrafluoroethene were detected instead of the desired compound (Table 4.4, entry
16). Gratifyingly, the addition of TMSCl to a cooled solution of 1x and LiH and the subsequent
transfer of this solution to a pre-stirred suspension of [Cu]/base and TMSCF2H at -30 ºC, followed
by the oxidant afforded 21% of the desired compound in 3 hours ( Table 4.4, entry 17). Increasing
the reaction time by stirring the reaction overnight at room temperature increased the yield to 26%
(Table 4.4, entry 18). Exchanging DMF for DMPU as the reaction solvent did not afford any
conversion and reducing the reaction time proved to be unproductive as well. Unfortunately, further
variations in the reaction conditions, changes in the stoichiometry and/or the nature of the
components did not afford higher conversions. Realizing the challenging nature of the transformation
at hand, a different source of the CF2H unit was chosen to test whether the reaction would proceed
more efficiently.
146
Given the recent success we had preparing difluoromethylalkynes with (DMPU)2Zn(CF2H)2 we
decided to conduct a preliminary experiment where (DMPU)2Zn(CF2H)2 was combined with copper
iodide, potassium tert-butoxide and 9,10-phenanthrenequinone in one pot and then the substrate
[1x] was added to the mix in 500 uL of DMF. Delightfully, this experiment yielded 16% conversion
as determined by
19
F NMR (Table 4.5, entry 1). Elevating the temperature of the reaction to 120 ºC
proved to be detrimental to the reaction yield (Table 4.5, entry 2). Incorporating the additives
previously tested in the optimization with TMSCF2H and switching the order of addition resulted in
the formation of 14% and 13% of the uncyclized product and the 2-CF2H indole 3a, respectively
(Table 4.5, entry 3). This result indicated that the difluoromethylation of the ethynyl moiety is indeed
a crucial step that possibly precedes the cyclization. Adding (DMPU)2Zn(CF2H)2 as a solution in
DMF to a solution of copper, base and substrate 1x proved to be much more efficient than weighing
it as a solid from the beginning, affording compounds 3a in 33% conversion as determined by
19
F
NMR (Table 4.5, entry 4). This trial also showed a reduction in the formation of disproportionation
byproducts from potential [Cu-CF2H] species formed in solution. Changing both the identity and
amount of the copper salt employed, drastically affected the yield of the transformation; switching
from CuI to CuBr resulted in an increased yield, even after only 3 hours at rt (Table 4.5, entry 5)
and this yield was further increased to 52% by conducting the reaction overnight. Meanwhile,
employing CuCl resulted in a significant decreased yield (Table 4.5, entry 7). Similarly, employing
65 mol% CuBr proved to be far superior to employing 40 mol%, 20 mol%, 1.0 equivalent or 2.0
equivalents (Table 4.5, entries 8,9,10 and 11). Similarly, employing 1.0 equivalent of CuBr along
with 9,10-phenanthroline as a potentially stabilizing ligand for the dilfuoromethylcopper species did
not significantly change the reaction outcome (Table 4.5, entry 12). Also, in these trials the effects
of temperature control were tested. Setting up the reaction at room temperature resulted in a very
low yield (Table 4.5, entry 13) possibly due to the thermal instability of the initial difluoromethyl-
copper species formed in solution. Setting up the reaction at -15 ºC, then stirring at room temperature
for 2 hours and then placing the reaction in a bath at 80 ºC for 4h did not increase the yield of 3a
147
(entry 10). We found that running the reaction at room temperature overnight and then placing it in
a bath at 80 ºC afforded a modest yield. Additionally, the crude
19
F NMR spectrum of these reactions
showed complete disappearance of the uncyclized product. On the other hand, heating up the
reaction at 140 ºC resulted in a lower conversion (Table 4.5, entry 14). We concluded that although
the difluoromethylation reaction can proceed at room temperature, moderately heating up the
reaction provides the energy required to promote the intramolecular cyclization and possibly other
steps of the cycle. Replacing 9,10-PQ as the oxidant for either DDQ of PIFA (Table 4.5, entries 15
and 16) resulted in the appearance of new unknown signals in the crude reaction NMR spectrum
and did not improve the reaction yield. Meanwhile, lowering the loading of base to 1.5 equivalents
or doubling the equivalents of (DMPU)2Zn(CF2H)2 independently, afforded moderate conversion of
3a but did not improve the conditions (Table 4.5, entries 17 and 18). Moreover, NMP proved to be
inferior to DMF for this transformation (entry 19). Finally, taking the highest yielding reaction
conditions and omitting LiH from the set up afforded compound 3a in 37% along with increased
amount of tetrafluoroethane (entry 20). Ultimately, the highest possible yield was obtained
employing 2.0 and 1.0 equivalents of lithium hydride and TMSCl respectively to conduct the
deprotonation-silylation at 0 ºC. The following additions were performed at -15 ºC employing 65
mol% of copper bromide, 3.0 equivalents of KOtBu, 2.0 equivalents of the difluoromethyl zinc
reagent, and 9,10-PQ as the oxidant. The reaction was carried out in DMF and was heated to 80 ºC
for 4h after being stirred overnight to afford compound 3a in 68% yield (Table 4.5, entry 21).
Table 4.5: Optimization of the difluoromethylation reaction with (DMPU) 2Zn(CF 2H) 2
(a)
CuX
Base
Additive
(DMPU)
2
Zn(CF
2
H)
2
Oxidant
solvent
T ºC, time
[1x] [3a]
N
H
N
CF
2
H
Ts
R
148
Table 4.5 symbols
Component Substrate 1x Metal (DMPU)2Zn(CF2H)2 Base Oxidant Additives
Symbol [1x] [M] [Zn] [B] [Ox] [AD]
Solutions/
Mixtures
[M]/[B] together as
solids
[1x] and [AD] in 500 uL [M]/[Zn]/[B] together as
solids
Symbol (A) (B) (i)
E
[M]
[equiv]
[AD]
Time
1 [h]
[ZnCF2H]
[equiv]
[Ox]
[equiv]
T ºC
Solvent
[M]
Time
2 [h]
Yield
%
b
Order of addition
1 CuI [1] - - [2]
9,10-
PQ
[1.2]
0 ºC
to rt
DMF
[0.3]
16 16
[M]/[Zn]/[B]/[Ox] together as
solids, add [1x] in 500 uL
DMF
2 CuI [1] - - ([2]
9,10-
PQ
[1.2]
0ºC/1
20
DMF
[0.3]
16 0
[M]/[Zn]/[B]/[Ox] together, add
[1x] in 500 uL DMF
3 CuI [1]
LiH
[2]/TMSCl
[1]
15
min
for 1x
sol'n
[2]
9,10-
PQ
[1.2]
0 ºC
to rt
DMF
[0.11]
17 14/13
[M]/[Zn]/[B] together as solids
(i). Separately, stir [1x] and
[AD] in 500 uL15 min (B),
cool to 0ºC. Add sol’n (B) to
mix (i). Add [Ox] in 800 uL
4 CuI [1]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt
DMF
[0.1]
18 33
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL
5
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt
DMF
[0.1]
3 27
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10, rt for 3h
6
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt
DMF
[0.1]
18 52
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL
7 CuCl [1]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt
DMF
[0.1]
18 18
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10 min, rt for
18h
8
CuBr
[40%]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 17
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10 min, rt for
18h, then 80ºC for 4h
9
CuBr
[20%]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 23
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10 min, rt for
18h, then 80ºC for 4h
149
10 CuBr [1]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
10-2h-
4h
18
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10, rt for 2h
then 80 for 4h.
11 CuBr [2]
LiH
[2]/TMSCl
[1]
¤ 1
0
m
i
n
,
0
º
C
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 26%
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B).
Add (B) to mix (A). Add [Zn]
in 0.2 uL at -15, 10 min. Add
[Ox] in 800 uL. Stir at -15ºC
for 10 min, rt for 18h, then
80ºC for 4h
12
CuBr [1]/
1,10-
phen [1]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18 33
[M]/[B]/Phenanthroline in 400
uL together. Separately, stir
[1x] and [AD] in 500 uL 10
min at 0ºC (B), cool to 15ºC.
Add (B) to mix (A). Add [Zn]
in 0.2 uL at -15, 10 min. Add
[Ox] in 800 uL. Stir at -15ºC
for 10 min, rt for 18h
13
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
rt
DMF
[0.1]
18 7
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10 min, rt for
18h
14
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
140º
C
DMF
[0.1]
18/4
0% /
11%
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B).
Add (B) to mix (A). Add [Zn]
in 0.2 uL at -15, 10 min. Add
[Ox] in 800 uL. Stir at -15ºC
for 10 min, rt for 18h, then
140ºC for 4h
15
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
DDQ
[1.2]
-15
ºC to
rt
DMF
[0.1]
18 3
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10, rt for 18h
16
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
PIFA
[1.2]
-15
ºC to
rt
DMF
[0.1]
18 16
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10 min, rt for
18h
17
c
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 32%
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B),
cool to 15ºC. Add (B) to mix
(A). Add [Zn] in 0.2 uL at -15,
10 min. Add [Ox] in 800 uL.
Stir at -15ºC for 10 min, rt for
18h, then 80ºC for 4h
18
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[4]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 42%
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B).
Add (B) to mix (A). Add [Zn]
in 0.2 uL at -15, 10 min. Add
150
[Ox] in 800 uL. Stir at -15ºC
for 10 min, rt for 18h, then
80ºC for 4h
19
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
NMP
[0.1]
18/4 25
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B).
Add (B) to mix (A). Add [Zn]
in 0.2 uL at -15, 10 min. Add
[Ox] in 800 uL. Stir at -15ºC
for 10 min, rt for 18h, then
80ºC for 4h
20
CuBr
[0.65]
No LiH/
TMSCl [1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 37%
[M]/[Zn] together as solids.
[1x]/[B] and [AD] in 500 uL at
0ºC, 10 min. Add that solution
to dry [M]/[Zn] at -15, 10 min.
rt, 18h, then 80ºC for 4h
21
CuBr
[0.65]
LiH
[2]/TMSCl
[1]
10
min,
0ºC
[2]
9,10-
PQ
[1.2]
-15
ºC to
rt to
80 ºC
DMF
[0.1]
18/4 68
[M]/[B] together as solids (A).
Separately, stir [1x] and [AD]
in 500 uL 10 min at 0ºC (B).
Add (B) to mix (A). Add [Zn]
in 0.2 uL at -15, 10 min. Add
[Ox] in 800 uL. Stir at -15ºC
for 10 min, rt for 18h, then
80ºC for 4h
(a)
Optimized conditions: CuBr [40 mol %] and KOtBu [3.0 equiv] in vial 1(Mix A). Starting material [1x] [0.15 mmol] and
LiH [2.0 equiv] dissolved in 0.2 mL of DMF, cooled down to 0 ºC and then TMSCl [ 2.0 equiv] was added dropwise and
left to stir for 10 min (Vial 2, solution B). Solution B in vial 2 was added to mix A in vial 1 at -15ºC and stirred for 10 min.
Next, (DMPU) 2Zn(CF 2H) 2 [2.0 equiv] was added in 0.2mL at -15 ºC to vial 1. After 10 minutes, 9,10-
phenanthrenequinone [1.2 equiv] was added to vial 1 and the resulting mixture stirred at -15 ºC for 10 minutes, then
room temperature for 18 h and then 80 ºC for 4h.
(b)
determined by
19
F NMR yield.
(c)
KO
t
Bu [1.5]
4.6.3 Mechanistic considerations of the tandem difluoromethylation-intramolecular cyclization
Based on the results of our optimization we propose a plausible pathway for the transformation that
could explain the roles that the additives play in the reaction. A seen in Scheme 4.7, the first step is
proposed to be the deprotonation-silylation effected by LiH and TMSCl. Even though the optimization
process evidenced the feasibility of the reaction without LiH or TMSCl (albeit in lower yields), judging
from the increasing amounts of difluoromethane formed in the absence of these additives, we
concluded that difluoromethide is engaged in the acid-base reaction with one of the intermediates,
thus causing the overall yield of the reaction to be substantially lower.
151
Scheme 4.7: Mechanistic proposal for the tandem difluoromethylation/cyclization
The newly formed intermediate [A] could now undergo oxidative difluoromethylation at the terminal
alkynyl unit to yield the uncyclized intermediate [B] (observed by
19
F NMR). The subsequent pi
coordination of copper leads to the formation of intermediate [C]. This intermediate can then undergo
cyclization and further protonation to afford compound [3] (Scheme 4.7). Prior literature has
described species [i] and indolium species [ii] as potential intermediates in intramolecular cyclization
reactions where the aniline is not deprotonated before the cyclization step (Scheme 4.7, pathway
b). In these cases, the nature of the R group greatly influences the nucleophilicity of the nitrogen
atom in the aniline core. To test whether this nucleophilicity had any influence on our system, we
prepared substrates [1y] and [1z] (Scheme 4.8).
N
TMS
Ts
H
N
TMS
Ts
CF
2
H
N
Ts
CF
2
H
Cu
X
N
CF
2
H
Ts
Cu
X
N
CF
2
H
Ts
[A]
[B] [C]
[D]
[1x]
N
H
Ts
H
Δ
R
R
R
R
R
R
LiH + TMSCl
Base
Mechanistic
proposal
(Pathway a)
[3]
‘[CuCF
2
H]’
CuX
L
2
Zn(CF
2
H)
2
[CuCF
2
H]
L
2
Zn(CF
2
H)X
[Cu(CF
2
H)
2
]
-
Ox
H
N
R
CF
2
H
Cu
X
[i]
R
N
CF
2
H
R
Cu
X
[ii]
R
H
(Pathway b)
152
Scheme 4.8: N-Benzyl and N-methyl substituted compounds
Under our optimized conditions, both substrates failed to give compounds [3] and instead afforded
difluoromethylated intermediates [Y-B] and [Z-B]. These results indicated that the benzyl aniline unit
of substrate [1y] cannot undergo deprotonation by any base present in the reaction to afford
intermediate [C]. The outcome of these reactions is also indicative of the inability of both substrates
to undergo pathway b (Scheme 4.7), thus substantiating the need for a more nucleophilic nitrogen
center for the cyclization step which is realized by the deprotonation of the N-H bond. Ultimately,
compound [3-Y] was obtained by heating isolated intermediate [Y-B] in an aqueous medium with a
copper catalyst, as shown in Scheme 4.8.C.
4.7 Conclusion
In conclusion, an efficient protocol for a direct difluoromethylation of silyl and terminal alkynes, using
catalytic copper and a difluoromethyl(zinc) reagent, was developed. This protocol enables facile
access to a wide assortment of substituted aromatic and aliphatic alkynes, tolerating a broad range
of functionalities. The relevance of this method is further accentuated by its applicability to the
N
Me
Me
H
[1z]
N
H
Bn
H
[Z-B]
N
Me
Me
CF
2
H
[1y]
N
H
Bn
CF
2
H
[Y-B]
N
H
Bn
CF
2
H
Cu(OAc)
2
KO
t
Bu
DMF/H
2
O
120ºC
N
CF
2
H
Bn
[3-Y]
N
CF
2
H
R
[3]
standard
conditions
standard
conditions
N
CF
2
H
R
[3]
[Y-B]
A)
B)
C)
153
preparation of a difluoromethyl analogue of Tirasemtiv, among other medicinally relevant scaffolds.
Additionally, the prepared CF2H alkynes were utilized in [3+2] and [4+2] cycloaddition reactions to
prepare difluoromethyl triazoles and an ortho-substituted difluoromethyl arene. Lastly, the
developed methodology was modified to perform a tandem difluoromethylation-cyclization reaction
to prepare a highly valuable 2-difluoromethylindole and the mechanistic aspects of this
intramolecular process were briefly explored.
4.8 Experimental Data
4.8.1 Procedure for the synthesis of starting material F2
Adapted from a reported procedure (Li, 2018).
410
To an oven-dried crimp-top vial equipped with a
stir bar were added 1-phenylprop-2-yn-1-ol (5 mmol), DDQ (5 mol%), Fe(NO3)3 •9 H2O (10 mol%),
and 10 mL of dichloroethane. The vial was sealed, equipped with an air balloon and the reaction
was stirred at 60 ºC overnight. The resulting solution was diluted with ethyl acetate, washed with
water, brine, and the organic layer was dried with anhydrous MgSO 4. The solvent was
concentrated under reduced pressure and the crude was purified by column chromatography
using hexanes as the eluent to afford 1-phenylprop-2-yn-1-one [1k] in 40% isolated yield (260
mg) as a yellow solid.
1
H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.4 Hz,
1H), 7.51 (t, J = 7.6 Hz, 1H), 4.01 – 2.77 (m, 1H). These data match the reported structural data.
410
4.8.2 Procedure for the synthesis of starting material 1t
H
OH
H
O DDQ (5 mol%)
Fe(NO
3
)
3
• 9H
2
O (10 mol%)
air
DCE [0.5M]
F2
154
Adapted from a reported procedure for the synthesis of N-propargyl amines.
411
To a solution of
theophylline (2 mmol, 360 mg), CuI (8 mol%, 0.16 mmol, 30 mg), and Et3N (1.3 equiv, 2.6. mmol,
279 uL), in THF (0.24M, 9 mL) was added 3-chloro-3-methyl-1-butyne (1.3 equiv, 2.6 mmol, 225
uL). The mixture was left to stir overnight. After the reaction was completed (confirmed by GC-
MS: [M
+
H]
+
= 247.2, 10.66 min), the solvent was evaporated, the residue washed with NaHCO3,
extracted with EtOAc (x3), washed with brine and dried with MgSO4. The residue was purified by
column chromatography utilizing an eluent mix of 30% EtOAc in hexanes to afford compound 1t
in 96% yield (473 mg) as an off-white powder.
1
H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 3.61 (s,
3H), 3.43 (s, 3H), 2.84 (s, 1H), 2.05 (s, 6H).
4.8.3 Procedure for the synthesis of starting material 1u
Adapted from reported procedures: In a flame-dried pressure tube, 0.5 mmol of 4-chloro-6,7-
dimethoxyquinazoline (112 mg) were charged, and butanol (0.083M, 6mL) was added. To this
suspension, 3-ethynylaniline (1.1 equivalents, 0.55 mmol, 65 uL) was added and the tube sealed
with the screw cap. The tube was then placed in the oil bath at 120 ºC and left to react overnight.
The solution was cooled down and the precipitate was filtered out, washed with cold water and
then diethyl ether to afford N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine 1u in 91% yield
Cl
N
N
O
O
Me
Me
N
H
N
N
N
O
O
Me
Me
N
N
CuI (8 mol%)
Et
3
N
THF
1t
N
N
Cl
N
N
HN MeO
MeO
MeO
MeO
3-ethynylaniline [1.1 equiv]
Butanol [0.083 M] 6mL
reflux (120ºC) 18h
1u
155
(139 mg) as a beige fluffy solid
1
H NMR (400 MHz, dmso-d6) δ 11.34 (s, 1H), 8.86 (s, 1H), 8.29
(s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.7
Hz, 1H), 7.33 (s, 1H), 4.29 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). These data match the reported
structural data.
412
4.8.4 Procedure for the synthesis of starting material 1x
In an argon glove box, the corresponding 2-iodoaniline (3 mmol), Pd(PPh3)2Cl2 (2 mol%, 0.06
mmol) and CuI (4 mol%, 0.12 mmol) were added to 20 mL oven-dried crim-top vial equipped with
a stir bar. The vial was sealed and brought outside the glove box and then 10 mL of THF were
added to the vial followed by Et3N (3.0 equiv, 9.0 mmol) and trimethylsilylacetylene (1.5 equiv,
4.5 mmol) at 23 ºC. This mixture was stirred at this temperature for 3 h and then it was quenched
with saturated aqueous NH4Cl. The aqueous layer was extracted with diethyl ether and the
combined organic layers were washed sequentially with 0.1 N HCl (10 mL), water, brine, and then
dried over anhydrous MgSO4. The solvent was evaporated, and the residue was dissolved in THF
(15 mL) and tetrabutylammonium fluoride (TBAF 5mL) was added dropwise. The reaction mixture
was then stirred at 23 °C for 1 h and then it was quenched with saturated aqueous NH4Cl. The
aqueous layer was extracted with diethyl ether and the combined organic layers were washed
sequentially with water, brine, and then dried over anhydrous MgSO4. The solvent was
evaporated, and the residue was redissolved in dichloromethane (DCM) and subjected to the next
step without further purification. Tosyl chloride (1.2 equiv, 3.6 mmol) and pyridine ( 4.0 equiv, 12
mmol) were added to the redissolved residue and the mixture was stirred at 23 ºC for 3 h and
N
H
H
Ts
N
I
H
H
N
H
H
1) TMS
CuI, Et
3
N
Pd(PPh
3
)
2
Cl
2
THF, RT, 3h
2) THF
TBAF
dropwise, rt, 1h
H
TsCl
Pyridine
DCM
rt, 1h
[1x]
156
then it was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with
diethyl ether and the combined organic layers were washed sequentially with 0.1 N HCl (10 mL),
water, brine, and then dried over anhydrous MgSO4. The solvent was evaporated, and the residue
was purified by flash column chromatography. Compound 1x was obtained in 70% yield (570 mg)
as a light-yellow powder.
1
H NMR (500 MHz, CDCl3) δ 7.77 – 7.70 (m, 2H), 7.63 (d, J = 8.3 Hz,
1H), 7.37 (dd, J = 7.7, 1.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.1 Hz, 1H), 7.24 (s, 1H),
7.05 (td, J = 7.6, 1.2 Hz, 1H), 3.40 (s, 1H), 2.41 (s, 3H) These data match the reported structural
data.
413
4.8.5 Procedure for the synthesis of starting material N3
In a flame-dried vial equipped with a stir bar, sodium azide (15 mmol, 975 mg) and 10 mmol of
benzyl bromide (1.19 mL) were charged. Next, the vial was sealed, and 6.2 mL were added. The
resulting suspension was left stirring at room temperature for 24h. After that time, the reaction
was diluted with water and extracted with diethyl ether (X3), washed with brine, dried with
magnesium sulfate, and the solvent evaporated to afford 1.04 mg of benzyl azide [N3] as a clear
liquid.
414
4.8.6 Procedure for the synthesis of starting material TS1
Br
10 mmol
N
3
NaN
3
[1.5 equiv]
DMF [1.6M]
rt, 24h
80% [N
3
]
OH
H
1) TsCl
ether
-5ºC
2) KOH
-5ºC, 1h
rt, 4h
[1]
O
H
Ts
TS1
157
In a dried round-bottom flask, propargyl alcohol (0.560 g, 10 mmol) and p-toluenesulfonyl chloride
(2.28 g, 24 mmol) were dissolved in diethyl ether (20 mL) at − 5°C. Then, KOH (5.6 g, 100 mmol)
was added to the reaction mixture in portions. The reaction was further stirred at − 5°C for 1 h.
After that time, the mixture was left stirring at room temperature for 4 h. Then, the mixture was
poured into cold water (15 mL). The aqueous layer was extracted with diethyl ether (2 × 20 mL)
and washed with brine (1 × 20 mL). The combined organic extract was dried over anhydrous
Mg2SO4, filtered, and the solvent evaporated afford a brown goo in 95% yield.
415
4.8.7 Procedure for the synthesis of starting material PH1
Propargyl hydrazide PH1 was prepared in low yield by adapting a reported procedure: To a
nitromethane/water (10:1, 22 mL) solution of 1,3-diphenyl-2-propyn-1-ol (1 a; 1.0 g, 4.8 mmol), p-
toluenesulfonyl hydrazide (2.7 g, 14.5 mmol), and tetrabutylammonium hydrogensulfate (0.16 g,
0.48 mmol) at room temperature was added gallium triflate (248 mg, 0.48 mmol). The reaction
mixture was stirred for 10 h at 40 °C and then poured into saturated NaHCO3 (100 mL). The
organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers
were combined and dried over anhydrous MgSO4. The solvent was evaporated under reduced
pressure and the residue was purified by column chromatography on silica gel eluting with
CHCl3/hexane (5:1) to give 1-(p-tosylhydrazino)-3-phenyl-2-propyn-1-ylbenzene as an off-white
powder in 12% yield.
416
HN
H
Ph
OH
H
Ph
H
N
Ts
PPh
3
DEAD
TsNHNH
2
THF, 0ºC
PH1
158
4.8.8 Procedure for the synthesis of starting material 1y
To a solution of 2-iodoaniline (0.657g, 3 mmol) and benzaldehyde (0.430 uL, 4.2 mmol) in toluene
(5 mL) was was added acetic acid (0.15 M) and the mixture heated to reflux for 6h with a Dean-
Stark apparatus. Then the reaction mix was cooled to room temperature and then to 0 ºC and
NaBH4 (2.0 equiv.) was added portion-wise to the stirring reaction mixture at 0°C. After stirring for
12 h at room temperature, the mixture was quenched with saturated NaHCO3. The organic layer
was extracted with ethyl acetate 3 times and the extracts were washed with brine, dried with
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography.
417
After
combining the product of two syntheses, in an Argon glove box, N-benzyl 2-iodoaniline (3 mmol),
Pd(PPh3)2Cl2 (2 mol%, 0.06 mmol) and CuI (4 mol%, 0.12 mmol) were added to 20 mL oven-dried
crim-top vial equipped with a stir bar. The vial was sealed and brought outside the glove box and
then 10 mL of THF were added to the vial followed by Et3N (3.0 equiv, 9.0 mmol) and
trimethylsilylacetylene (1.5 equiv, 4.5 mmol) at 23 ºC. This mixture was stirred at this temperature
for 3 h and then it was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted
with diethyl ether and the combined organic layers were washed sequentially with 0.1 N HCl (10
mL), water, brine, and then dried over anhydrous MgSO4. The solvent was evaporated, and the
residue was dissolved in THF (15 mL) and tetrabutylammonium fluoride (TBAF 5mL) was added
dropwise. The reaction mixture was then stirred at 23 °C for 1 h and then it was quenched with
saturated aqueous NH4Cl. The aqueous layer was extracted with diethyl ether and the combined
organic layers were washed sequentially with water, brine, and then dried over anhydrous MgSO4.
N
H
H
Bn
N
I
H
H
N
I
H
Bn
1) C
6
H
5
CO
AcOH
Toluene
130 ºC
Dean-Stark App.
2) NaBH
4
1) Pd(PPh
3
)
2
Cl
2
TMS-acetylene
CuI
Et
3
N
THF, 23ºC
2) TBAF
THF
1y
159
The solvent was evaporated, and the residue was purified by flash column chromatography.
Compound 1y was obtained in 80% yield as a brown solid. These data match the reported
structural data.
1
H NMR (400 MHz, CDCl3) δ 7.39 – 7.33 (m, 5H), 7.31 – 7.27 (m, 1H), 7.17 (ddd,
J = 8.7, 7.4, 1.6 Hz, 1H), 6.63 (td, J = 7.5, 1.1 Hz, 1H), 6.57 (dd, J = 8.3, 1.1 Hz, 1H), 4.43 (d, J =
5.1 Hz, 2H), 3.40 (s, 1H).
418
4.8.9 Procedure for the synthesis of starting material 1z
2-Iodoaniline (657 mg, 3 mmol), K2CO3 (1 g, 7.5 mmol) and iodomethane (561 u L, 9 mmol) in 3
mL CH3CN were stirred under reflux for 12 h. When the reaction was done, the mixture was
treated with water, extracted with DCM (2 × 15 mL). The organic layers were collected, dried over
anhydrous MgSO4and filtered. The solvents were evaporated, and the residue purified by silica
gel column chromatography eluting with Hexane/EtOAc (5%) giving the target compound N,N-
dimethyl-2-iodoaniline 1z in 95% yield.
1
H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.6, 1.8 Hz,
1H), 7.32 – 7.24 (m, 1H), 6.93 (dd, J = 8.4, 1.3 Hz, 1H), 6.88 (ddt, J = 8.7, 6.4, 1.2 Hz, 1H), 3.41
(d, J = 2.1 Hz, 1H), 2.93 (d, J = 2.1 Hz, 6H). These data match the reported structural data.
419
4.8.10 General procedure A for the synthesis of difluoromethylalkynes, NMR yield determination
and Isolation
N
H
Me
Me
N
I
H
H
N
I
Me
Me
MeI
CH
3
CN
Reflux, 12h
1) Pd(PPh
3
)
2
Cl
2
TMS-acetylene
CuI
Et
3
N
THF, 23ºC
2) TBAF
THF, 23
1z
160
In an argon glove box, the corresponding alkyne [1] (0.15 mmol), LiO
t
Bu (0.45 mmol, 3 equiv.)
and CuBr (0.06 mmol, 40 mol%) were weighed into an oven-dried crim-top vial equipped with a
stir bar (vial 1). Then, a separate oven-dried crim-top vial was charged with (DMPU)2Zn(CF2H)2
(0.3 mmol, 2 equiv.) without a stir bar (vial 2). Next, 9,10-phenanthrenequinone (0.18 mmol, 1.2
equiv.) was added to a third oven-dried crim-top vial without a stir bar (vial 3). The three vials
were sealed and brought outside the glove box. Under a constant stream of N2, 0.8 mL of DMF
were added to vial 3 and the vial was put in the ultra-sound bath to ensure complete dissolution
of 9,10-phenanthrenequinone in the solvent. Meanwhile, under a constant stream of N2, 0.5 mL
of DMF were added to vial 1. This vial was then placed in an ethylenegycol/water bath with a
cooling coil (-15 ºC) for 10 minutes. During that time, 0.2 mL of DMF were added to vial 2 and the
vial was vortexed to dissolve the solid. After ten minutes had passed, the contents of vial 2 were
carefully added to vial 1 at -15 ºC with a needle. This mixture was left at this temperature for 10
minutes. Finally, vial 3 was removed from the ultrasound bath and the solution was transferred
slowly to vial 1 at -15 ºC. The final mixture was left in the bath for an additional 10 minutes before
allowing it to warm-up to room temperature and was then placed in an oil bath at 80 ºC for 8
hours. After this time, the reaction was allowed to cool down and difluoromethoxybenzene
(PhOCF2H 0.075 mmol, 50%, 9uL) was added to the vial. The supernatant was then analyzed
directly by
19
F NMR spectroscopy, and the yield was determined by comparing the relative
integration of internal standard PhOCF2H (
19
F NMR -82.7 ppm (d) 74Hz) with that of the
difluoromethyl alkyne. The contents of the NMR tube and reaction vessel were combined and
quenched with sat. NH4Cl and extracted with diethyl ether. The organic layer was washed
CF
2
H
R
1
X
R
1
1) CuBr [40 mol%]
LiO
t
Bu [3 equiv]
DMF 0.5 mL
2) L
2
Zn(CF
2
H)
2
[2 equiv.]
DMF 0.2 mL
3) 9,10-PQ [1.2 equiv]
DMF 0.8 mL
-15ºC—80ºC, 8h
[1] [2]
L: DMPU
9,10-phenanthrenequinone
9,10-PQ
O
O
161
consecutively with water, brine, dried with anhydrous MgSO4 and concentrated under reduced
pressure. The residue was purified using flash chromatography with the appropriate eluent mix
(see below for each case).
*Note: the slow transfer of the solutions into vial 1 must be done carefully to avoid a sudden rise
in the temperature
Image 4.1: Visual representation of the reaction set-up for General procedure A
4.8.11 General procedure B for the synthesis of difluoromethyl indoles, NMR yield determination
and Isolation
In the Ar glove box, the corresponding N-(2-ethynylaryl)-4-methylbenzenesulfonamide 3 (0.15
mmol) and LiH (0.3 mmol, 2.0 equiv, 2.0 mg) were weighed into an oven-dried crim-top vial
equipped with a stir bar (vial 1). Next CuBr (0.15 mmol, 1.0 equiv, 14 mg) and KO
t
Bu (0.45 mmol,
3.0 equiv, 51 mg) were added to a second vial (vial 2). Then, a separate oven-dried crimp-top vial
N
H
N
CF
2
H
Ts
Ts
1) CuBr [65 mol%]
KO
t
Bu [3.0 equiv]
2) LiH/TMSCl [2/1 equiv]
3) (DMPU)
2
Zn(CF
2
H)
2
[2.0 equiv]
4) 9,10-P-Q [1.2 equiv]
DMF [0.1M]
-15 ºC—rt— 80 ºC
18h
[1x] [3a]
162
was charged with (DMPU)2Zn(CF2H)2 (0.3 mmol, 2 equiv, 127 mg) without a stir bar (vial 3). Lastly,
a fourth vial was charged with 9,10-phenanthrenequinone (0.18 mmol, 1.2 equiv, 37 mg) (vial 4).
The four vials were sealed and brought outside the glove box. Under a constant stream of N 2, 0.8
mL of DMF were added to vial 4 and the vial was put in the ultra-sound bath to ensure complete
dissolution of 9,10-phenanthrenequinone in the solvent. Meanwhile, vial 1 was placed in an ice
bath and under a constant stream of N2, 0.5 mL of DMF were added. The newly formed
suspension was allowed to reach 0 ºC and then chlorotrimethylsilane (TMSCl) (0.15 mmol, 1
equiv, 19 uL) was added and the solution stirred at 0 ºC for 10 minutes. After this time, this solution
in vial 1 was added to vial 2 and this vial was then placed in an ethylenegycol/water bath with a
cooling coil (-15 ºC) for 10 minutes. During that time, 0.2 mL of DMF were added to vial 3 and the
vial was vortexed to dissolve the solid. After ten minutes had passed, the contents of vial 3 were
carefully added to vial 1 at -15 ºC with a needle. This mixture was left at this temperature for 10
minutes. Finally, vial 4 was removed from the ultrasound bath and the solution was transferred
slowly to vial 1 at -15 ºC. The final mixture was left in the bath for an additional 10 minutes before
taking it out and allowed to stir at room temperature overnight. Then, the vial was then placed in
an oil bath at 80 ºC.
Image 4.2: Visual representation of the reaction set-up for General procedure B
4.8.12 Scaled-up synthesis of 1-chloro-4-(3,3-difluoroprop-1-yn-1-yl)benzene [2a]
163
In an argon glove box, 1-chloro-4-ethynylbenzene 1a (2 mmol, 373 mg), LiO
t
Bu (3 equiv, 480
mg) and CuBr (40 mol%, 115 mg) were weighed into an oven-dried crimp-top vial equipped with
a stir bar (vial 1). Then, a separate oven-dried crim-top vial was charged with (DMPU)2Zn(CF2H)2
(2 equiv, 1.7 g) without a stir bar (vial 2). Next, 9,10-phenanthrenequinone (1.2 equiv, 500 mg)
was added to a third oven-dried crimp-top vial without a stir bar (vial 3). The three vials were
sealed and brought outside the glove box. Under a constant stream of N2, 12 mL of DMF were
added to vial 3 and the vial was put in the ultra-sound bath to ensure complete dissolution of 9,10-
phenanthrenequinone in the solvent. Meanwhile, under a constant stream of N2, 5 mL of DMF
were added to vial 1. This vial was then placed in an ethylene glycol/water bath with a cooling coil
(-15 ºC) for 10 minutes. During that time, 3 mL of DMF were added to vial 2 and the vial was
vortexed to dissolve the solid. After ten minutes had passed, the contents of vial 2 were carefully
added to vial 1 at -15 ºC with a needle. This mixture was left at this temperature for 10 minutes.
Finally, vial 3 was removed from the ultrasound bath and the solution was transferred slowly to
vial 1 at -15 ºC. The final mixture was left in the bath for an additional 10 minutes before allowing
it to warm-up to room temperature and was then placed in an oil bath at 80 ºC for 8 hours. After
this time, the reaction was allowed to cool down and difluoromethoxybenzene (PhOCF2H 1.0
mmol, 50%, 120.1 uL) was added to the vial. The supernatant was then analyzed directly by
19
F
NMR spectroscopy, and the yield was determined by comparing the relative integration of internal
standard PhOCF2H (
19
F NMR -82.7 ppm (d) 74Hz) with that of the difluoromethyl alkyne. The
contents of the NMR tube and reaction vessel were combined and quenched with sat. NH4Cl and
extracted with diethyl ether. The organic layer was washed consecutively with water, brine, dried
with MgSO4 and concentrated under reduced pressure.
4.8.13 Procedure for the [3+2] cycloaddition reaction with benzyl azide
164
Adapted from a reported procedure.
420
In an argon glovebox, difluoromethyl alkyne 2k (0.1 mmol,
30 mg) and CuCl (5 mol%, 0.5 mg) were added to a microwave-safe vial equipped with a stir bar.
The vial was sealed, brought outside the glovebox, and 1 mL of glycerol was carefully added with
a syringe. This thick heterogeneous mixture was vigorously mixed with a vortex for 5 minutes.
Next, benzyl azide (0.09 mmol, 12uL) was added via microsyringe and the mixture vortexed again
for one minute. The sealed vial was placed in the microwave reactor with the following
parameters: pre-stirring: 2 minutes, time: 1.5 hours, temperature: 100 ºC. After the completion of
the reaction the vial was opened, and the thick homogeneous mixture extracted with DCM (5 mL
X 5). The organic layer was then washed with water, brine, and dried with magnesium sulfate.
The mixture of isomers [4a] and [4b] was purified with column chromatography utilizing a mixture
of ethyl acetate/hexanes.
4.8.14 Procedure for the [4+2] cycloaddition reaction with 1,3-diphenylisobenzofuran
Adapted from a reported procedure.
421
In a crimp top vial equipped with a stir bar, 1,3-
diphenylisobenzofuran (0.805 mmol, 218 mg) and compound [2a] (0.8 mmol, 149 mg) were
dissolved in 1mL (0.8M) of toluene. The vial was capped and placed in a bath at 100 ºC for 36h.
CF
2
H N
3
N N
N
glycerol (1 mL)
MW
100 ºC,1.5 h
Bn
1.2 :1.0 (50%)
[2k] [N
3
]
R
1
R
2
[4a] = R
1
: Napth, R
2
: CF
2
H
[4b] = R
1
: CF
2
H R
2
: Napth [1.1 equiv] [1.0 equiv]
CF
2
H
Toluene [0.8M]
100ºC
36h [2a]
[1.0 equiv] [1.05 equiv]
[4+2]
[5a]
(quant.) 70%
Cl
O
Ph Ph
O
Ph
CF
2
H
Ph
Cl
165
After this time, the solvent was evaporated under reduced pressure and the title compound
obtained with column chromatography utilizing a mixture of 2% ethyl acetate in hexanes.
4.8.15 Characterization data of difluoromethyl alkynes
1-chloro-4-(3,3-difluoroprop-1-yn-1-yl)benzene 2a
The title compound was obtained following the general procedure A, using 1-
chloro-4-ethynylbenzene 1a (0.15 mmol, 21mg), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes
as the mobile phase to obtain a yellow waxy solid in 80% isolated yield (22.4 mg). (87% by
19
F
NMR spectroscopy). Scaled-up procedure: 70% isolated yield; 73% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.52 – 7.40 (m, 2H), 7.40 – 7.30 (m, 2H), 6.41 (t, J = 54.9 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -105.68 (d, J = 54.5 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ
136.6, 133.5 (t, J = 2.6 Hz), 129.1, 118.4, 104.2 (t, J = 232.4 Hz), 87.3, 80.7 (t, J = 34.0 Hz).
These data match the reported structural data.
388
1-(3,3-difluoroprop-1-yn-1-yl)-3,5-difluorobenzene 2b
The title compound was obtained following the general procedure A, using
1-ethynyl-3-(trifluoromethyl)benzene 1b (0.15 mmol, 18 uL), CuBr (40 mol%,
8.6 mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg),
9,10-phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column
chromatography using hexanes as the mobile phase to obtain fine white needles in 78% isolated
yield (22 mg); 92% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.12 – 7.01 (m, 2H),
6.95 – 6.84 (m, 1H), 6.38 (t, J = 54.6 Hz, 1H).
13
C{1H} NMR. (126 MHz, CDCl3) δ 162.8 (dd, J =
250.5, 12.8 Hz), 122.6 (t, J = 11.5 Hz), 115.6 – 115.2 (m), 106.6 (t, J = 25.2 Hz), 103.9 (t, J =
Cl
CF
2
H
CF
2
H
F
F
166
233.2 Hz), 86.0 – 85.6 (m), 81.4 (t, J = 34.4 Hz).
19
F NMR (376 MHz, CDCl3) -106.6 (d, J = 54.9
Hz, 2F), -108.3 (m, 2F). FT/IR (v max (neat) cm-1): 3019, 1426, 1213, 921, 823, 746, 667, 564,
500, 466. Anal. Calcd. for C9H4F4: C, 57.46 H, 2.14. found: C, 57.828; H, 2.07. M.P 144—146 ºC
1-bromo-4-(3,3-difluoroprop-1-yn-1-yl)benzene 2c
The title compound was obtained following the general procedure A, using
1-bromo-4-ethynylbenzene 1c (0.15 mmol, 27 mg), CuBr (40 mol%, 8.6
mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-
phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column
chromatography using hexanes as the mobile phase to obtain a waxy solid in 64% isolated yield
(22 mg); 71% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.55 – 7.49 (m, 2H), 7.38
(d, J = 8.3 Hz, 2H), 6.40 (t, J = 54.9 Hz, 1H).
19
F NMR (376 MHz, CDCl3) -106.24 (d, J = 54.8 Hz,
2F). These data match the reported structural data.
393
1-(3,3-difluoroprop-1-yn-1-yl)-4-ethoxybenzene 2d
The title compound was obtained following the general procedure A, using 1-
ethoxy-4-ethynylbenzene 1d (0.15 mmol, 22 uL), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes
as the mobile phase to obtain a clear oil in 60% isolated yield (18 mg); 72% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.49 – 7.42 (m, 2H), 6.86 (dd, J = 8.9, 2.1 Hz, 2H),
6.40 (t, J = 55.4 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H).
19
F NMR (376 MHz,
CDCl3) δ -105.03 (d, J = 55.3 Hz, 2F).
13
C{1H} NMR. (126 MHz, CDCl3) δ 160.5, 133.9 (t, J = 2.6
Hz), 114.7, 111.7 (t, J = 3.4 Hz), 104.5 (t, J = 231.3 Hz), 89.0 (t, J = 7.4 Hz), 78.8 (t, J = 33.7 Hz),
63.7, 14.8. FT/IR (v max (neat) cm-1): 2983, 2937, 2249, 2222, 2191, 1675, 1604, 1571, 1509,
Br
CF
2
H
EtO
CF
2
H
167
1477, 1372, 1291, 1249, 1175, 1083, 1024, 972, 921, 826, 808, 643, 613, 550, 518, 453. HRMS
(EI+) m/z [M]
+
Calcd. for C11H10F2O= 196.0704, found 196.0699
1-(3,3-difluoroprop-1-yn-1-yl)-4-methoxybenzene 2e
The title compound was obtained following the general procedure A, using
1-methoxy-4-ethynylbenzene 1e (0.15 mmol, 19 uL), CuBr (40 mol%, 8.6
mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-
phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column
chromatography using hexanes as the mobile phase to obtain a clear oil in 60% isolated yield (16
mg); 66% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.6 Hz, 2H), 6.94
– 6.80 (m, 2H), 6.40 (t, J = 55.3 Hz, 1H), 3.83 (s, 3H).
13
C{1H} NMR. (126 MHz, CDCl3) δ 161.0,
133.9 (t, J = 2.6 Hz), 114.3, 111.9 (t, J = 3.3 Hz), 104.5 (td, J = 231.5, 1.1 Hz), 88.9 (t, J = 7.4
Hz), 78.9 (t, J = 33.9 Hz), 55.5.
19
F NMR (376 MHz, CDCl3) δ -105.09 (d, J = 55.5 Hz, 2F). These
data match the reported structural data.
393
1-(3,3-difluoroprop-1-yn-1-yl)-3-methoxybenzene 2f
The title compound was obtained following the general procedure A, using
1-ethynyl-3-methoxybenzene 1f (0.15 mmol, 20mg), CuBr (40 mol%, 8.6
mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-
phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column
chromatography using hexanes as the mobile phase to obtain a clear oil in 63% isolated yield (17
mg); 76% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.25 – 7.21 (m, 1H), 7.11 –
7.06 (m, 1H), 7.00 (s, 1H), 6.97 – 6.92 (m, 1H), 6.38 (t, J = 55.1 Hz, 1H), 3.78 (s, 3H).
19
F NMR
(376 MHz, CDCl3) δ -105.82 (d, J = 55.1 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 159.4, 129.8,
MeO
CF
2
H
CF
2
H
MeO
168
124.8 (t, J = 2.7 Hz), 120.9 (t, J = 3.2 Hz), 116.9 (t, J = 2.7 Hz), 116.9, 104.3 (t, J = 232.1 Hz),
88.4 (t, J = 7.4 Hz), 79.6 (t, J = 33.9 Hz), 55.4. These data match the reported structural data.
249
4-(3,3-difluoroprop-1-yn-1-yl)-1,1'-biphenyl 2g
The title compound was obtained following the general procedure A, using 4-
ethynyl-1,1'-biphenyl 1g (0.15 mmol, 27 mg), CuBr (40 mol%, 8.6 mg), LiO
t
Bu
(3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2
equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes as
the mobile phase to obtain an off-white solid in 64% isolated yield (22 mg); 75% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.64 – 7.57 (m, 6H), 7.50 – 7.43 (m, 2H), 7.43 – 7.34
(m, 1H), 6.44 (t, J = 55.1 Hz, 1H).
19
F NMR (376 MHz, CDCl3) -105.7 (d, J = 54.9 Hz, 2F). These
data match the reported structural data.
393
1-(3,3-difluoroprop-1-yn-1-yl)-3-(trifluoromethyl)benzene 2h
The title compound was obtained following the general procedure A, using
1-ethynyl-3-(trifluoromethyl)benzene 1h (0.15 mmol, 22 uL), CuBr (40
mol%, 8.6 mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-
phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column
chromatography using hexanes as the mobile phase to obtain an oil 80% isolated yield (26 mg);
91% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.69 (t, J = 8.2 Hz,
2H), 7.51 (dt, J = 16.4, 7.8 Hz, 1H), 6.42 (t, J = 54.7 Hz, 1H).
19
F NMR (376 MHz, CDCl3) -63.1 (s,
3F), -106.2 (d, J = 54.7 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 135.3 (dq, J = 2.7, 1.3 Hz),
129.3, 129.2, 129.2 – 129.0 (m), 126.9 (q, J = 3.8 Hz), 123.5 (q, J = 268.8 Hz), 104.0 (t, J = 232.8
Hz), 96.8, 86.6 (t, J = 7.4 Hz), 81.2 (t, J = 34.2 Hz). FT/IR (v max (neat) cm-1): 2927, 2855, 2198,
CF
2
H
Ph
CF
2
H
F
3
C
169
1727, 1646, 1431, 1358, 1328, 1299, 1270, 1167, 1093, 1016, 802, 760, 693, 577, 509, 489, 456.
HRMS (EI+) m/z [M]
+
Calcd. for C10H5F5 =220.0311, found 220.0316.
Methyl 4-(3,3-difluoroprop-1-yn-1-yl)benzoate 2i
The title compound was obtained following the general procedure A, using
1 methyl 4-ethynylbenzoate 1i (0.15 mmol, 24mg), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes
as the mobile phase to obtain a yellow solid in 60% isolated yield (19 mg); 74% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.3, 1.7 Hz, 2H), 7.59 (dd, J = 8.3, 1.9
Hz, 2H), 6.42 (t, J = 54.8 Hz, 1H), 3.94 (s, 3H).
19
F NMR (376 MHz, CDCl3) δ -106.6 (d, J = 54.7
Hz, 2F). These data match the reported structural data.
393
4-(3,3-difluoroprop-1-yn-1-yl)benzonitrile 2j
The title compound was obtained following the general procedure A, using
4-ethynylbenzonitrile 1j (0.15 mmol, 19 mg), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using 2%—3%
ethyl acetate in hexanes as the mobile phase to obtain a light yellow liquid in 56% isolated yield
(15 mg); 67% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.99 – 7.53 (m, 4H), 6.42
(t, J = 54.5 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -107.1 (d, J = 54.5 Hz, 2F). These data match
the reported structural data.
393
CF
2
H
MeO
O
NC
CF
2
H
170
1-(3,3-difluoroprop-1-yn-1-yl)-2-methylbenzene 2k
The title compound was obtained following the general procedure A, using 1-
ethynyl-2-methylbenzene 1k (0.15 mmol, 17.4 uL ), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes
as the mobile phase to obtain a yellow oil in 70% isolated yield (17.4 mg) with 91% purity due to
the extremely similar polarity to the homocoupling byproduct; 86% by
19
F NMR spectroscopy.
1
H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.30 – 7.23 (m, 1H),
7.20 (t, J = 7.8 Hz, 1H), 6.47 (t, J = 55.2 Hz, 1H), 2.47 (s, 3H).
19
F NMR (376 MHz, CDCl3) δ -
105.3 (d, J = 55.4 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 141.2, 132.6 (t, J = 2.7 Hz), 130.1,
129.7, 125.7, 125.6, 104.3 (t, J = 233.0, 231.3 Hz), 87.4, 81.1, 20.4. FT/IR (v max (neat) cm-1):
3752, 2927, 1373, 1214, 1114, 1085, 1035, 769, 741, 629. Anal. Calcd. for C10H8F2= , C, 72.28;
H, 4.85; found C, 72.12; H, 4.451.
2-(3,3-difluoroprop-1-yn-1-yl)naphthalene 2l
The title compound was obtained following the general procedure A, using
2-ethynylnaphthalene 1l (0.15 mmol, 23 mg), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes
as the mobile phase to obtain a fine light yellow solid in 50% isolated yield (15.2 mg); 61% by
19
F
NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.12 – 8.04 (m, 1H), 7.87 – 7.79 (m, 3H), 7.61
– 7.47 (m, 3H), 6.47 (t, J = 55.1 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -105.6 (d, J = 55.0 Hz, 2F).
These data match the reported structural data.
249
CF
2
H
Me
CF
2
H
171
2-(3,3-difluoroprop-1-yn-1-yl)naphthalene 2m
The title compound was obtained following the general procedure A, using
2-ethynylnaphthalene 1m (0.15 mmol, 16 uL), CuBr (40 mol%, 8.6 mg), LiO
t
Bu (3.0 equiv, 36
mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2 equiv, 37 mg) and
DMF (0.1M, 1.5 mL). Purified by column chromatography using 5% ethyl acetate in hexanes as
the mobile phase to obtain a light yellow oil in 65% isolated yield (16.2 mg); 72% by
19
F NMR
spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 7.14 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.82
(d, J = 2.3 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.39 (t, J = 55.2 Hz, 1H), 3.73 (s, 2H).
19
F NMR (376
MHz, CDCl3) δ -105.6 (d, J = 54.9 Hz, 2F). These data match the reported structural data.
393
2-(3,3-difluoroprop-1-yn-1-yl)pyridine 2n
The title compound was obtained following the general procedure A, using 2-
ethynylpyridine 1n (0.15 mmol, 15 uL), CuBr (40 mol%, 8.6 mg), LiO
t
Bu (3.0
equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2 equiv, 37
mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using 5% ethyl acetate in
hexanes as the mobile phase, keeping the flow at no more than 30mL/min to avoid
phenanthrenequinone from co-eluting. The compound was obtained in 63% isolated yield as an
oil (14.4 mg); 72% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.82 – 8.44 (m, 1H),
7.84 – 7.62 (m, 1H), 7.62 – 7.44 (m, 1H), 7.43 – 7.33 (m, 1H), 6.42 (t, J = 54.4 Hz, 1H)..
19
F NMR
(376 MHz, CDCl3) δ -107.5 (d, J = 54.2 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 135.7, 135.3,
129.3, 129.1, 126.9 (t, J = 3.5 Hz), 104.0 (t, J = 232.8 Hz), 86.6, 80.9 (d, J = 69.4 Hz). HRMS
(EI+) m/z [M+H]
+
Calcd. for C8H6F2N=154.0466, found 154.0468. These data match the reported
structural data.
388
CF
2
H
H
2
N
N
CF
2
H
172
(3,3-difluoroprop-1-yn-1-yl)cyclopropane 2o
The title compound was obtained following the general procedure A, using
ethynylcyclopropane 1o (0.15 mmol, 13 uL), CuBr (40 mol%, 8.6 mg), LiO
t
Bu (3.0
equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2 equiv, 37
mg) and DMF (0.1M, 1.5 mL). Due to the compounds’ inherent volatility, traditional isolation was
not feasible. See section 2.12
1,1-difluoroundec-2-yne 2p
The title compound was obtained following the general procedure A, using dec-
1-yne 1p (0.15 mmol, 27 uL), CuBr (40 mol%, 8.6 mg), LiO
t
Bu (3.0 equiv, 36
mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2 equiv, 37 mg) and
DMF (0.1M, 1.5 mL). Purified by column chromatography using hexanes as the mobile phase to
obtain a colorless liquid in 40% isolated yield (11.3 mg); 47% by
19
F NMR spectroscopy.
1
H NMR
(400 MHz, CDCl3). δ 6.16 (tt, J = 55.5, 1.5 Hz, 1H), 2.31 – 2.22 (m, 2H), 1.54 (ddt, J = 16.9, 14.9,
7.3 Hz, 2H), 1.47 – 1.20 (m, 10H), 0.93 – 0.84 (m, 3H).
19
F NMR (376 MHz, CDCl3) δ -104.41 (dt,
J = 55.4, 5.7 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 104.0 (t, J = 230.8 Hz), 91.0 (t, J = 7.2
Hz), 72.3 (t, J = 33.5 Hz), 31.9, 29.2, 29.1, 28.9, 27.8 (t, J = 2.3 Hz), 22.8 (d, J = 3.1 Hz), 18.5 (t,
J = 2.6 Hz), 14.2. These data match the reported structural data.
422
4-chloro-1,1-difluoro-4-methylpent-2-yne 2q
The title compound was obtained following the general procedure A, using 3-
Chloro-3-methyl-1-butyne 1q (0.15 mmol, 17 uL), CuBr (40 mol%, 8.6 mg), LiO
t
Bu
(3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2
equiv, 37 mg) and DMF (0.1M, 1.5 mL). Due to the compounds’ inherent volatility, it was not
isolated.
CF
2
H
CH
3
CF
2
H
Cl
CF
2
H
173
(3,3-difluoroprop-1-yn-1-yl)benzene 2r
The title compound was obtained following the general procedure A, using
trimethyl(phenylethynyl)silane 1r (0.15 mmol, 30 uL), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using
hexanes.The compound was obtained as a pale yellow liquid in 36% isolated yield (8 mg); 42%
by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3). δ 7.52 (d, J = 7.5 Hz, 2H), 7.42 (d, J = 7.3
Hz, 1H), 7.41 – 7.34 (m, 2H), 6.42 (t, J = 55.1 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ-106.41 (d,
J= 55.2 Hz, 2F). These data match the reported structural data.
393
2-(3,3-difluoroprop-1-yn-1-yl)-6-methoxynaphthalene 2s
The title compound was obtained following the general procedure A, using
2-ethynyl-6-methoxynaphthalene 1s (0.15 mmol, 38 mg), CuBr (40 mol%,
8.6 mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-
phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column
chromatography using pentane as the mobile phase. The compound was obtained as a beige
solid in 40% isolated yield (14 mg); 44% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ
7.99 (s, 1H), 7.71 (t, J = 8.2 Hz, 2H), 7.49 (dd, J = 8.6, 1.6 Hz, 1H), 7.19 (dd, J = 9.0, 2.5 Hz, 1H),
7.12 (d, J = 2.5 Hz, 1H), 6.46 (t, J = 55.2 Hz, 1H), 3.94 (s, 3H).
19
F NMR (376 MHz, CDCl3) δ -
105.3 (d, J = 55.2 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 159.1, 135.2, 132.9 (t, J = 2.9 Hz),
129.7, 128.6 (t, J = 2.4 Hz), 128.2, 120.0, 114.7 (t, J = 3.2 Hz), 105.9, 104.5 (t, J = 231.7 Hz),
89.3 (t, J = 7.5 Hz), 79.5 (t, J = 33.9 Hz), 55.5. These data match the reported structural data.
249
CF
2
H
CF
2
H
MeO
174
(3,3-difluoroprop-1-yn-1-yl)triisopropylsilane 2t
The title compound was obtained following the general procedure A, using
ethynyltriisopropylsilane 1t (0.15 mmol, 34 uL), CuBr (40 mol%, 8.6 mg),
LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 127mg), 9,10-phenanthrenequinone
(1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by column chromatography using pentane
as the mobile phase. The compound was obtained as a yellow oil in 52% isolated yield (18 mg);
63% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 6.17 (t, J = 54.8 Hz, 1H), 1.36 –
1.17 (m, 3H), 1.14 – 1.04 (m, 18H).
19
F NMR (376 MHz, CDCl3) δ -105.8 (d, J = 54.8 Hz, 2F).
265
7-(5,5-difluoro-2-methylpent-3-yn-2-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione 2u
The title compound was obtained following the general procedure A, using
1,3-dimethyl-7-(2-methylbut-3-yn-2-yl)-3,7-dihydro-1H-purine-2,6-dione
1u (0.15 mmol, 37 mg), CuBr (40 mol%, 8.6 mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2
(2.0 equiv, 127mg), 9,10-phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL).
Purified by column chromatography using 30% ethyl acetate in hexanes as the mobile phase.
The compound was obtained as a pale-yellow solid in 90% isolated yield (40 mg); 93% by
19
F
NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.31 (t, J = 54.3 Hz, 1H), 3.61 (d,
J = 1.0 Hz, 3H), 3.43 (d, J = 0.9 Hz, 3H), 2.09 (s, 6H).
19
F NMR (376 MHz, CDCl3) δ -107.5 (d, J =
54.1 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 154.2, 151.3, 151.1, 139.9, 106.7, 103.3 (t, J =
233.9 Hz), 88.4 (t, J = 7.1 Hz), 78.1 (t, J = 34.7 Hz), 55.4, 29.9, 29.4, 28.6. FT/IR (v max (neat)
cm-1): 3144, 30001, 2947, 2925, 2853, 2361, 2276, 2245, 1695, 1652, 1593, 1536, 1467, 1436,
1392, 1372, 1338, 1283, 1247, 1223, 1112, 1039, 1010, 970, 910, 787, 761, 743, 701, 624, 515.
Anal. Calcd. for C13H14F2N4O2: C, 52.7; H, 4.76; N, 18.91; found: C, 53.047; H, 4.668; N,18.54
M.P: 107—110 ºC
Si CF
2
H
N
N
O
O
N
N
CF
2
H
175
N-(3-(3,3-difluoroprop-1-yn-1-yl)phenyl)-6,7-dimethoxyquinazolin-4-amine 2v
The title compound was obtained following the general procedure A,
using N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine 1v (0.15
mmol, 46 mg), CuBr (40 mol%, 8.6 mg), LiO
t
Bu (3.0 equiv, 36 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv,
127mg), 9,10-phenanthrenequinone (1.2 equiv, 37 mg) and DMF (0.1M, 1.5 mL). Purified by
column chromatography using 40% ethyl acetate in hexanes and recrystallized from hot
chloroform. The compound was obtained in 60% isolated yield (xx mg) as a beige powder; 70%
by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.01 (d, J = 2.3 Hz, 1H),
7.89 – 7.78 (m, 1H), 7.66 (s, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.10 (s, 1H),
6.61 (t, J = 54.7 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H).
19
F NMR (376 MHz, CD3OD) δ -106.0 (d, J =
54.6 Hz, 2F).
13
C{1H} NMR (126 MHz, CD3OD) δ 158.3, 156.7, 153.6, 151.3, 147.4, 140.9, 130.2,
128.6 (d, J = 2.7 Hz), 126.8 (d, J = 2.7 Hz), 125.5, 121.4 (t, J = 3.2 Hz), 110.6, 106.9, 105.9 (t, J
= 230.1 Hz), 102.3, 88.9 (t, J = 7.2 Hz), 80.8 (t, J = 34.0 Hz), 56.8, 56.6.FT/IR (vmax (neat) cm-
1) 3644, 3407, 3335, 3124, 3020, 2940, 2838, 2762, 2239, 2068, 2026, 1992, 1629, 1581, 1538,
1513, 1474, 1433, 1384, 1314, 1289, 1252, 1220, 1187, 1168, 1146, 1077, 991, 928, 893, 845,
783, 737, 678, 658, 626, 587, 549, 504. Anal. Calcd. for C19H15F2N3O2: C, 64.22; H, 4.26; N,
11.83; Found: C, 63.91; N, 11.72; H, 4.11. M.P: 108 —112 ºC.
6-(3,3-difluoroprop-1-yn-1-yl)-1-(pentan-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one
2w
The title compound was obtained following the general procedure A, using
6-ethynyl-1-(pentan-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one 1w (0.10 mmol, 24 mg),
CuBr (40 mol%, 5.7 mg), LiO
t
Bu (3.0 equiv, 24 mg), (DMPU)2Zn(CF2H)2 (2.0 equiv, 85 mg), 9,10-
phenanthrenequinone (1.2 equiv, 25 mg) and DMF (0.1M, 1.0 mL). Purified by column
chromatography using 15%—20% ethyl acetate in hexanes as the mobile phase. The compound
N
N
N
H
N
O
CF
2
H
O
O N
N
HN
CF
2
H
176
was obtained as a dark green solid in 61% isolated yield (17 mg); 69% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 6.45 (t, J = 54.5 Hz, 1H), 4.30 (tt, J = 10.4, 5.4 Hz, 1H),
2.20 (ddt, J = 17.0, 14.3, 7.5 Hz, 2H), 1.90 (dp, J = 13.9, 7.2 Hz, 2H), 0.87 (t, J = 7.4 Hz, 6H).
19
F
NMR (376 MHz, CDCl3) δ 107.2 (d, J = 54.5 Hz, 2F).
13
C{1H} NMR (126 MHz, CDCl3) δ 153.8,
139.7, 139.7 (t, J = 2.4 Hz), 138.2, 127.5 (t, J = 3.3 Hz), 104.0 (t, J = 233.3 Hz), 85.3 (t, J = 7.3
Hz), 80.7 (t, J = 34.3 Hz), 58.1, 25.1, 11.2 FT/IR (v max (neat) cm-1): 3133, 3059, 2969, 2877,
2781, 2238, 1719, 1615, 1587, 1477, 1432, 1369, 1289, 1271, 1228, 1161, 1092, 1040, 967, 913,
892, 878, 827, 798, 753, 675, 659, 591, 493, 471, 457. Anal. Calcd. for C13H14F2N4O: C, 55.71;
H, 5.03; N, 19.99; found: C, 55.729; H, 5.275; N, 19.906. M.P: 134—137 ºC
2-(difluoromethyl)-1-tosyl-1H-indole 3
The title compound was purified by column chromatography using 15% ethyl acetate in hexanes
as the mobile phase. The compound was obtained as a waxy yellow solid
in 60% isolated yield (29 mg); 68% by
19
F NMR spectroscopy.
1
H NMR δ
8.10 (dd, J = 8.7, 1.1 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.44 – 7.36 (m,
1H), 7.37 (t, J = 54.5 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.08 (s, 1H), 2.35 (s,
3H).
19
F NMR (376 MHz, CDCl3) δ -111.88 (d, J = 55.1 Hz).
13
C{1H} NMR (126 MHz, CDCl3) δ
145.5, 136.9, 135.0, 133.1, 130.0, 128.2, 127.2 (t, J = 1.1 Hz), 126.4, 124.1, 122.3, 114.5, 111.6
(t, J = 6.2 Hz), 109.3 (t, J = 235.9 Hz), 21.7. FT/IR (v max (neat) cm-1): 3784, 3710, 3583, 3325,
3155, 2924, 2858, 2322, 2256, 2117, 1994, 1909, 1724, 1674, 1596, 1450, 1377, 1242, 1173,
1092, 1034, 906, 814. HRMS (EI+) m/z [M]
+
Calcd. for C16H13F2NO2S
+
= 321.0630, found:
321.0643
N
CF
2
H
Ts
177
1-benzyl-5-(difluoromethyl)-4-(naphthalen-2-yl)-1H-1,2,3-triazole 4b
The title compound was obtained following the procedure in section 2.9. Only
one isomer was isolated from the 1.0 : 1.2 mixture in 27% isolated yield (9.1
mg) as a yellow solid.
1
H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.94 (d, J =
8.5 Hz, 1H), 7.88 (q, J = 4.6 Hz, 2H), 7.52 (dt, J = 7.2, 3.8 Hz, 2H), 7.40 – 7.28 (m, 5H), 6.88 (t, J
= 52.5 Hz, 1H), 5.77 (s, 2H).
19
F NMR (376 MHz, CDCl3) δ-111.4 (d, J = 52.5 Hz, 2F).
13
C{1H}
NMR (126 MHz, CDCl3) δ 134.5, 133.5, 133.3, 129.0, 128.8, 128.4, 128.1, 127.9 (d, J = 3.4 Hz),
127.1, 126.9, 126.5, 125.7, 108.4 (t, J = 236.3 Hz), 54.2 (t, J = 1.3 Hz).
(1R,4R)-2-(4-chlorophenyl)-3-(difluoromethyl)-1,4-diphenyl-1,4-dihydro-1,4-
epoxynaphthalene 5a
The title compound was obtained following the procedure in section 2.10,
Purified by column chromatography using 2% ethyl acetate in hexanes as
the mobile phase. The compound was obtained as a light orange solid in
77% isolated yield (17 mg); 99% by
19
F NMR spectroscopy.
1
H NMR (400 MHz, CDCl3) δ 8.06 –
7.94 (m, 2H), 7.53 (dq, J = 9.9, 3.5, 3.0 Hz, 6H), 7.49 – 7.42 (m, 1H), 7.40 – 7.34 (m, 3H), 7.28
(d, J = 8.4 Hz, 2H), 7.20 – 7.11 (m, 2H), 6.97 – 6.89 (m, 2H), 6.17 (dd, J = 56.2, 53.1 Hz, 1H).
19
F
NMR (376 MHz, CDCl3) δ -106.82 (dd, J = 319.5, 55.9 Hz, 1F), -119.17 (dd, J = 319.6, 53.0 Hz,
1F).
13
C{1H} NMR (126 MHz, CDCl3) δ 161.6 (t, J = 10.5 Hz), 151.3, 149.4, 145.6 (t, J = 25.3 Hz),
135.1, 134.2, 133.0, 130.5, 129.2, 129.0, 128.9, 128.8, 128.6, 128.0 (t, J = 1.8 Hz), 126.1, 125.6,
121.6, 121.5, 112.4 (t, J = 234.0 Hz), 94.4, 93.1. FT/IR (v max (neat) cm-1): 3522, 3060, 2923,
2169, 2020, 1947, 1907, 1805, 1676, 1592, 1488, 1449, 1375, 1347, 1308, 1228, 1185, 1089,
1016, 866, 833, 749. 699, 595, 502. Anal. Calcd. for C29H19ClF2O: C, 76.23; H, 4.19, found: C,
76.234; H, 4.213. M.P: 58—63 ºC
N N
N
Bn
HF
2
C
O
Ph
CF
2
H
Ph
Cl
178
4.8.16
19
F NMR of the reaction with cyclopropyl acetylene
The reaction was set up following general procedure A, utilizing cyclopropyl acetylene [1o] as the
substrate. The analysis of the supernatant by
19
F NMR spectroscopy (Figure S1) shows the
formation of the desired compound in 56% conversion at -104.1 ppm, along with the by-products
always observed in crude reaction mixes. Attempts to isolate and/or distill this compound were
unsuccessful due to significant loss of the product because of volatility.
Figure 4.3:
19
F NMR spectrum of reaction performed with cyclopropyl acetylene
4.8.17
19
F NMR spectrum of unsuccessful substrates
The reaction was set up following general procedure A, utilizing either prop-2-yn-1-ylbenzene, 1-
phenylprop-2-yn-1-one, methyl or ethyl propiolate as the substrate. The analysis of the
supernatant by
19
F NMR spectroscopy shows large amounts of tetrafluoroethane as the major
product, along with other difluoromethyl-copper oxidation and disproportionation by-products
(Figure S2).
369
No difluoromethyl alkyne was detected in any case.
179
Figure 4.4:
19
F NMR spectrum of reaction performed with prop-2-yn-1-ylbenzene
4.8.18 Experiments with 5 mol% copper bromide
Due to the moderate yield obtained with lower copper loadings during the optimization stage, we
decided to investigate the behavior of select substrates with 5 mol % of copper bromide.
Substrates 1a, 1e, 1j, 1k, 1h, 1i and 1p were subjected to the reaction conditions employing 5
mol % copper bromide, as shown in the scheme below:
Cl CF
2
H
[2a]
MeO CF
2
H
[2e]
CF
2
H
[2k]
a: (86%)
Me
NC CF
2
H
[2j]
a: (67%)
CH
3
CF
2
H
[2p]
a: (47%)
a: (87%)
b: (64%) b: (39%) b: (35%)
b: (20%)
a: (66%)
b: (34%)
CF
2
H
F
3
C
[2h]
a: (91%)
[2i]
a: (74%)
CF
2
H
O
MeO
b: (21%) b: (49%)
CuBr method a: [40 mol%]
method b: [5 mol%]
180
These experiments show a reduction in yield of roughly 20% to 70% (determined by
19
F NMR)
depending on the nature of the substrate. However, since moderate yields are still obtained in all
cases, we believe these results might be of interest for future investigations.
181
CHAPTER 5: Direct synthesis of monofluoromethyl ketones from carboxylic acids
derivatives and fluoromethyl anion surrogates
Scheme 5.1: Synthesis of monofluoromethyl ketones
Further exploiting the ubiquity and pluripotency of carboxylic acids derivatives as reactive handles
to prepare fluorinated compounds, this chapter will discuss the development of a method for the
synthesis of monofluoromethyl ketones from carboxylic acid anhydrides. In this work, FBSM and
FBDT serve as fluoromethide surrogates to afford the (arylsulfonyl)fluoromethyl ketones upon
treatment with a base. The subsequent reductive desulfonylation, although still posing a
challenge, is expected to afford the unprotected fluoromethyl ketones. The transformation and
the scope are under current development in order to explore the extent of this methodology.
5.1 Introduction and prior art in the synthesis of fluoromethyl ketones
In Chapter 2 and 3 the relevance and biological applications of trifluoromethyl and difluoromethyl
ketones were discussed. In a similar fashion, monofluoromethyl ketones (MFMK) are highly
valuable compounds that have proven bioactivity and applications in enzymatic inhibition.
423
A
prime example of the application of fluoromethyl ketones is in the synthesis of peptides bearing a
C-terminal monofluoromethyl ketone unit (peptidyl-MFMK). This class of peptides has been
employed as probes for biological targets, whose activity can be modified by binding to drugs
(also called druggable enzymatic targets).
424
Particularly, peptidyl-MFMK have been employed in
the inhibition of serine, but mostly cysteine proteases in order to study their proteolytic activity
and to help elucidate their role in several infirmities. The success observed with MFMK in
R
O
O
R
O
S
O
O
S
F
O
O
O
R
H
H
F
O
R
R= aryl, alkyl
S S
O
O
O
O
F
FBSM or FBDT
• Bench-top method
• 3 components
• Air stable
• Facile access to
fluorosulfonyl and
monofluoromethyl
ketones
X
X
182
enzymatic inhibition is generally attributed to these compounds’ ability to act as alkylating agents,
thus irreversibly binding to the thiol residue of cysteine forming a thioether adduct as seen in
Scheme 5.2. Two possible mechanisms are postulated for this interaction: The first one being an
SN
2
reaction via fluoride elimination, and the second one involving the formation of a thiohemiketal
[i] via nucleophilic addition of the thiolate to the ketone’s sp
2
carbon. The subsequent formation
of a sulfonium intermediate [ii] is concomitant with loss of a fluoride and the successive
rearrangement of the 3 member ring affords the thioether adduct B (Scheme 5.2).
423
Scheme 5.2: Possible mechanisms for the irreversible inhibition of cysteine with MFMK
Monofluoromethyl ketones have also found applications as synthetic intermediates and building
blocks to prepare more structurally diverse molecules.
425,426
Prior art on the synthesis of
monofluoromethyl ketones includes the Finkelstein halogen exchange from bromomethyl
precursors (Scheme 5.3.a),
427–429
the electrophilic decarboxylative fluorination of β-Ketoacids with
NFSI (Scheme 5.3.b),
430
the dehydroxylative fluorination of alcohols with sulfuryl fluoride
(Scheme 5.3.c),
431
a protocol for the electrophilic fluorination of diketones with selectfluor
(Scheme 5.3.d),
432
the acylation of lithium fluoromethide with Weinreb amides (Scheme 5.3.e),
56
and the desilylative hydrolysis of 2-fluoroenol silyl ethers
363
(Scheme 5.3.f). Although these
R
O
F
H
H
Cys
S
R
O
H H
Cys
S
Irreversible
enzymatic inhibitors
R
O
F
H
H
Cys
S
R OH
H
H
Cys S
F
R
O
H
H
Cys S
SN
2
Via sulfonium
[A]
[B]
[A] [i] [ii]
183
methods have successfully enabled access to these highly desirable compounds, some protocols
suffer from lack of functional group compatibility, production of unstable intermediates, and/or
utilization of expensive and hazardous chemicals.
Scheme 5.3: Prior art in the synthesis of monofluoromethyl ketones
Thus, we envisioned a method for the preparation of monofluoromethyl ketones utilizing
fluoromethyl anion surrogates, and accessible carboxylic acid anhydrides. As discussed in
Chapter 1, FBSM is a masked monofluoromethide equivalent that can be easily installed onto
electrophiles.
51
Only few reports exists of the monofluoromethylation of carbonyl compounds with
this reagent and its derivatives. The first report on the synthesis of monofluoromethyl carbinols
from FBSM and aldehydes was reported by Hu and coworkers.
433
Their work describes the
essential role that the counter-cation has in stabilizing the reversible carbinolate intermediate
through a coordination complex (Scheme 5.4.A).
433
The quenching of the intermediate with a
Brönsted acid successfully yields the desired fluoromethyl alcohols in good yields. Analogously,
{
R
O
X
R
1
X= Br
KF
18-C-6
MeCN
X= COOH
NFSI
CsCO
3
MeCN/H
2
O
X= OH
SO
2
F
2
Et
3
N
MeCN
X= C(O)R
Selectfluor
R
O
F
R
1
R= H, Ar, alk
X= MeN(OR)
ICH
2
F
MeLi • LiBr
THF/ Et
2
O
-78ºC
!-fluoromethyl ketones
X= CF
2
Mg/TMSCl
—
F/H
2
O
or H
3
O
+
a) b) c) d) e) f)
184
Prakash and coworkers reported the synthesis of the silyl-derivative of FBSM (TMSCF(SO2Ph)2)
and its transfer to aldehydes and ketones as an effective way to prepare fluoromethyl alcohols.
In this work, the self-quenching of the intermediate occurs via a Lewis acid (TMS), resulting in a
fluoromethyl silyl-carbinol. These silyl ethers are obtained in good yields and can further undergo
desilylation to afford the monofluoromethyl alcohols (Scheme 5.4.B).
434
Scheme 5.4: Prior art in the addition of FBSM and FBDT to carbonyl electrophiles
Similarly, Shibata and coworkers envisioned the synthesis of a less sterically hindered sulfonyl
fluoromethane reagent to circumvent the challenges presented when adding a bulky nucleophile
to carbonyl electrophiles. These authors hypothesized that the reversibility of the addition reaction
observed in previous reports could be due to the steric hindrance cause by the two phenylsulfonyl
groups of FBSM. Consequently, the preparation of FBDT resulted in the successful preparation
of fluoromethyl alcohols at room temperature in good yields. The subsequent reductive
desulfonylation with samarium iodide yields the unprotected alcohols (Scheme 5.4.C).
53
R
O
H
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%)
F
S S
O
O
O
O
Ph Ph
R
O
R’ CsF (20 mol%)
THF, rt, 4h
Mg
R
OTMS
SO
2
Ph
SO
2
Ph
F
(85% - 95%)
F
S S
O
O
O
O
Ph Ph
TMS
’R
R
OH
SO
2
Ph
F
’R AcOH
R
OH
F
’R
Na/Hg
MeOH
A)
B)
S S O
O
O
O
F
H
O
R
H
HO
R
S
S
O
O
O
O
F
H
OH
R
F
DABCO
Toluene, rt 1d
SmI
2
THF/MeOH
-60 ºC — -40ºC
C)
(73% - 95%)
185
5.2 Optimization of the fluoromethylation reaction with FBSM
As previously mentioned, the addition of a bulky anion to Csp
2
electrophiles such as aldehydes
tends to be reversible,
433
therefore, we sought out to test how would this addition proceed with
carbonyl compounds containing a removable group. We envisioned that careful choice of the
nucleofuge would be crucial for the reaction to proceed. To test our hypothesis, a series of
carboxylic acid derivatives were screened. FBSM was reacted with the corresponding electrophile
in the presence of lithium hydride and after stirring overnight, an internal standard was added,
and an aliquot was analyzed by
19
F NMR. To our surprise, neither benzoyl chloride, nor the acyl
fluoride or the acyloxyphosphonium ion shown in Table 5.1 yielded any amount of compound 2.
The acid anhydride however, produced a small amount of a compound with a signal at -139 ppm
by
19
F NMR. Given that the fluorine NMR chemical shift of compound 2 is not reported, we decided
to explore this result further.
Table 5.1: Screening of carbonyl electrophiles
Utilizing benzoic anhydride as a starting material, we screened a series of organic and inorganic
bases in the potential fluoromethylation reaction. We were pleased to find that the reaction with
cesium carbonate produced 29% of the same compound found at -139 ppm by
19
F NMR (Table
5.2, entry 1). Previous literature on the synthesis of fluoromethyl carbinols with FBSM and its
1.- Initial screening: carbonyl electrophiles
F
O
Cl
O
OPPh
3
O
Benzoyl fluoride 1a Benzoyl chloride 1b Benzoic anydride SM1 Acyloxyphosphonium ion
1d
O
O
TFA mixed anhydride 1e
CF
3
O
X
O
FBSM
LiH
DCM
rt, 18h
0% of 2
1
2
0% of 2 0% of 2 0% of 2* evidence of of 2
at -139 ppm (
19
F NMR)
S
O
O
S
F
O
O
O
R
O
O Ph
O
F
186
derivatives
433,434
has shown the important role that the counter cation plays in the formation of a
stable intermediate. Consequently, given that we initially saw evidence of reactivity when
employing LiH, we decided to test lithium bis(trimethylsilyl)amide (LiHMDS) and LiOH. Although
evidence of the potential formation of 2 was observed with LiHMDS, the conversion was
significantly lower with this reagent (Table 5.2, entry 2) whereas the reaction with LiOH did not
provide any results (Table 5.2, entry 3). The use of the non-nucleophilic base DBU increased the
conversion to 41%, with concomitant formation of very small amounts of benzoyl fluoride (Table
5.2, entry 4). The use of other organic bases such as triethylamine and DABCO did not improve
the conversion (Table 5.2, entries 5 and 6).
Table 5.2: Screening of bases with benzoic anhydride
E
Base [1.2
equiv]
FBSM unreacted
[equiv]
2 (%)
r-MFMK
(%)
Other
1 Cs 2CO 3 >1.0 29 <1 Acyl fluoride < 1%
2 LiHMDS >1.0 10 0 –
3 LiOH >1.0 0 0 –
4 DBU >1.0 41 0 Acyl fluoride < 1%
5 Et 3N >1.0 0 <1 –
6 DABCO >1.0 4 <1 –
7 n-Bu 4NOH >1.0 0 <1 –
8 K 2CO 3 >1.0 54 <1 –
(a)
Conditions: 0.15 mmol [1.0 equiv] of anhydride 1 and the base [1.2. equiv] are dissolved in 1.0 mL of DCM. To this
solution, 2.0 equivalents of FBSM in 500 uL of DCM are added and the solution is left to stir at room temperature
overnight. Add 7 uL of PhF (50% of 0.15 mmol) [δ-113.15 (s)].
Prakash and coworkers have shown that n-Bu4NOH is an adequate base to obtain a persistent
a-fluorobis(phenylsulfonyl)methide ion for crystallographic purposes.
66
Unfortunately, under these
conditions the ammonium base did not yield the expected results. Finally, we screened potassium
O
O
O
F
S S
O
O
O
O
Ph Ph
O
F
SO
2
Ph
SO
2
Ph
base 1.2 equiv
CH
2
Cl
2
[0.1 M]
rt, overnight
SM1
FBSM 2 r-MFMK
O
F
19
F NMR (CDCl
3
)=
δ -168.8 (d) 45Hz (1F) ~ δ - 139 (s) 1F ~ δ - 230 (t 47Hz, 1F)
187
carbonate as the base. We were pleased to find that the compound at -139 ppm in the
19
F NMR
was obtained in 54% conversion (Table 5.2, entry 8). In order to confirm the identity and
spectroscopic data of the obtained compound, we sought out to synthesize the target molecule
by following a reported procedure for the electrophilic fluorination of a phenylsulfonyl ketone.
435
This work showed the synthesis of gem-bisarylthio enamines and further demonstrates their
applicability in the preparation of halogenated phenylsulfonyl ketones in three steps, however the
fluorine NMR data is not provided. Additionally, this report is the only one available to prepare this
type of bis(phenylsulfonyl)fluoromethyl ketone. First we prepared acetophenone oxime (a)
following a reported procedure.
436
The crude product was then acetylated to afford acetyl oxime
(b). The obtained compound was then recrystallized and used to prepare the following gem-
bisarylthio enamine (c). An acid mediated hydrolysis of the enamine afforded
bis(phenythio)ketone (d) and the subsequent oxidation with hydrogen a peroxide/acid mixture
produced the sulfonyl ketone derivative (e).
Scheme 5.5: Only report for the synthesis of bis(phenylsulfonyl) monofluoromethyl ketone (2)
Finally, the deprotonation/electrophilic fluorination of this compound afforded the target
compound (2) in an overall yield of 30% (Scheme 5.5). The spectroscopic analysis of this
compound revealed that the fluorine chemical shift of this isolated compound matched the one
O
N
OH Py
EtOH
NH
2
OH•HCl
60 ºC, 1 h
N
O
Ac
Ac
2
O
DMAP
Py
rt, 1 h
NH
2
CuI (20 mol%)
NaI (10 mol%)
MeCN (0.1M)
90 ºC, 16 h
Ph S S Ph
MeOH
1M HCl
50ºC, 24h
SPh
SPh
SPh
SPh
O
SO
2
Ph
SO
2
Ph
O
1) H
2
O
2
(30% in H
2
O)
AcOH
2 h, rt
2) overnight, 50 ºC
tBuOK, rt 20 min
Selectfluor
DMF,
rt, 1 h
S
O
O
S
F
O
O
O
(a) (b) (c)
(d) (e)
(2)
(30%)
1
2
3
5
6
4
188
observed in the preliminary optimization studies (Figure 5.1) with a broad singlet observed at
139.9 ppm. With this information in hand, we decided to proceed with the optimization trials
employing a fluorine-labeled substrate SM2 (-102.5 ppm
19
F NMR) to track the reactants and
products by
19
F NMR analysis.
Figure 5.1: NMR of isolated compound (2):
1
H and
19
F NMR: -139.9 ppm
SM2 (4-fluorobenzoic anhydride) was prepared and subjected to the same reaction conditions as
benzoic anhydride SM1 in Table 5.3. The spectroscopic analysis of the crude reaction showed
47% formation of the broad singlet at -139 ppm corresponding to the fluoromethyl unit of product
2 and 61% of the 4-fluorophenyl unit. Realizing that the integration of the fluorine signals was not
representative of the yield due to the broadness of the most up-field signal, we calculated a ratio
between both percentages. The average ratio obtained by dividing the %yield of the signal at -
101 ppm (61) by the %yield of the signal at -139 ppm (47) was 1.29. This calculation was
performed for every other optimization trial as a guide to determine the conversion to product 2.
We then proceeded to test whether a more polar solvent would increase the yield. The reaction
conducted in THF at 0 ºC showed a slight decrease in the yield (Table 5.3, entry 3) whereas
utilizing a mixture of DCM and acetonitrile (MeCN) to dissolve the starting material showed no
conversion at all (Table 5.3, entry 4). Utilizing only MeCN for the solvolysis of SM2 was also
unsuccessful, and heating the reaction mix to 40 ºC did not afford any product. Other ineffective
189
modifications included employing DBU as the base at 0 ºC or room temperature, and the use of
Na2CO3 as the base in a mixture of DCM/MeCN at 0 ºC (Table 5.3 entries 6 to 8). The use of
potassium tert-butoxide produced 49/29% of the expected product (Table 5.3, entry 9). Based
on the work by Yang and coworkers in the nickel-catalyzed coupling of carboxylic acid
anhydrides
437
we attempted to adapt the reported conditions to our method. The results evidenced
the formation of compound 2 in only 22/17% yield, although the mechanism of this transformation
is unclear (Table 5.3, entry 10). Attempts to utilize a copper salt as a catalyst, or silver nitrate as
a vehicle to form a stable silver benzoate byproduct, did not afford any conversion of the SM
(Table 5.3, entries 11 and 12). Returning to our highest yielding conditions in entry 2, we wanted
to test how conducting the reaction at room temperature with 1.5, 2.0 and 3.0 equivalents of
K2CO3 would affect the conversion. The yield of these trials was lower, however the difference
between using 2.0 or 3.0 equivalents of base was minimal (Table 5.3, entries 13 to 16). The
addition of dimethylaminopyridine (DMAP) as an additive to aid in the acylation of the nucleophilic
species
438
did not afford the expected product (Table 5.3, entry 17). Utilizing the conditions with
2.0 equivalents of K2CO3 we decided to test how the polarity of the solvent would alter the yield
given the insolubility of potassium carbonate in dichloromethane. Taking the reported polarity
index values into consideration (Toluene=2.4, DCM=3.1, THF=4.0, MeCN= 5.8, DMF= 6.4)
439
we
screened these solvents under the reaction conditions (Table 5.3, entries 18 to 21). Among the
solvents screened, the reaction conducted in acetonitrile showed the highest conversion
(68/53%), followed by DCM (61/47%), THF (53/41%) and toluene (35/26%) whereas the use of
DMF resulted in no conversion of the starting material. The graph shown in Figure 5.2 showcases
the trend observed with different solvents. Given that the a-fluorobis(phenylsulfonyl)methide ion
resulting from the deprotonation of FBSM can be quenched by a proton source, we wanted to
assess whether the moisture content in the reaction affected the results given that the method is
conducted in the bench top. The addition of water as a co-solvent to acetonitrile significantly
decreased the yield (Table 5.3, entry 22) confirming that excessive water content is detrimental
190
for the reaction. Based on these results, we selected MeCN as the solvent and we then tested
two other carbonate salts (Na2CO3, Cs2CO3) and LiO
t
Bu. As initially observed in the experiment
conducted with a mixture of solvents (entry 8), Na2CO3 did not afford any product in only
acetonitrile. Meanwhile, Cs2CO3 and LiO
t
Bu afforded lower conversions (Table 5.3, entries 23
and 25).
Table 5.3: Optimization of the monofluoromethylation reaction with FBSM
(a)
E
FBSM
[equiv]
Base
[equiv]
Solvent
1 [M]
SM
Solvent
2
T ºC Additives
Set-up
times
Time
% -101
ppm
(4-F)
(b)
% -139
ppm
(bs)
(b)
1 [1.2]
K2CO3
[1.2]
DCM
[0.15]
SM1 - 23 ºC - - 18h n/a 54
2 [1.2]
K2CO3
[1.2]
DCM
[0.15]
SM2 - 23 ºC - - 18h 61 47
3 [1.2]
K2CO3
[1.2]
THF
[0.15]
SM2 -
0 ºC
to rt
- - 18h 58 41
4
(c)
[1.2]
K2CO3
[1.2]
DCM
(1mL)
SM2
DCM
(1mL)/
MeCN
(0.6mL)
0 ºC
to rt
-
10
min/5
min
6h 0 0
5
(c)
[1.2]
K2CO3
[1.2]
DCM
(1mL)
SM2
MeCN
[0.1]
(0.5mL)
0 ºC
to 40
ºC
-
10
min/5
min
6h 0 0
6 [1.2]
DBU
[1.2]
DCM
[0.15]
SM2 - 23 ºC -
18h 0 0
7 [1.2]
DBU
[1.2]
THF
[0.15]
SM2 -
0 ºC
to rt
- - 6h 0 0
8
(c)
[1.2]
Na2CO3
[1.2]
DCM
(1mL)
SM2
MeCN
[0.1]
(0.5mL)
0 ºC
to rt
-
10
min/5
min
6h 0 0
9 [1.2]
KOtBu
[1.2]
DCM
[0.15]
SM2 - 23 ºC - - 18 49 29
~ δ - 139 (s) 1F
δ - 101 (s) 1F
δ -102.5 (m) (2F)
O
O
O
F
S S
O
O
O
O
Ph Ph
O
F
SO
2
Ph
SO
2
Ph
Base
Solvent
T ºC
time
SM2
FBSM 2
19
F NMR (CDCl
3
)=
δ -168.8 (d) 45Hz (1F)
F
F F
191
10
(d)
[1.2]
K3PO4
[3.0]
Toluene
[0.2M]
0.75ml
SM2 - 50 ºC
Ni cat
[5%]/ PCy
[1.5%]
- 18 22 17
11 [1.2]
K2CO3
[1.2]
DCE
[0.15]
SM2 - 23 ºC
CuBr
[10%]
- 4h 0 0
12 [1.2]
K2CO3
[1.2]
DCE
[0.15]
SM2 - 23 ºC Ag2CO3 - 18 0 0
13 [1.2]
K2CO3
[1.2]
DCM
[0.15]
SM2 - 23 ºC - - 18h 31 20
14 [1.2]
K2CO3
[1.5]
MeCN
[0.15]
SM2
23 ºC
- 18h 8 5
15 [1.2]
K2CO3
[2.0]
DCM
[0.15]
SM2 - 23 ºC - - 18h 29 20
16 [1.2]
K2CO3
[3.0]
DCM
[0.15]
SM2 - 23 ºC - - 18h 29 22
17 [1.2]
K2CO3
[2.0]
DCM
[0.15]
SM2
DMAP
[1.0]
23 ºC - - 18h 0 0
18 [1.2]
K2CO3
[2.0]
THF
[0.15]
SM2 - 23 ºC - - 18h 53 41
19 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 23 ºC - - 18h 68 53
20 [1.2]
K2CO3
[2.0]
DMF
[0.15]
SM2 - 23 ºC - - 18h 0 0
21 [1.2]
K2CO3
[2.0]
Toluene
[0.15]
SM2 - 23 ºC - - 18h 35 26
22 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2
WATER
(50uL)
23 ºC - - 18h 18 14
23 [1.2]
Cs2CO3
[2.0]
MeCN
[0.15]
SM2 - 23 ºC - - 18h 14 10
24 [1.2]
Na2CO3
[2.0]
MeCN
[0.15]
SM2 - 23 ºC - - 18h 0 0
25 [1.2]
LiO
t
Bu
[2.0]
MeCN
[0.15]
SM2 - 23 ºC - - 18h 27 21
26 [1.0]
K2CO3
[2.0]
MeCN
[0.15]
SM2
[1.2]
- 23 ºC - - 18h 69 53
27 [1.0]
K2CO3
[2.0]
MeCN
[0.15]
SM2
[2.0]
- 23 ºC - - 18h 24 17
28 [1.0]
K2CO3
[2.0]
MeCN
[0.15]
SM2
[1.5]
- 23 ºC - - 18h 35 30
29 [1.2]
K2CO3
[2.0]/
[0.5]
MeCN
[0.15]
SM2
1eq/
SM2
0.5
eq
- 23 ºC -
18h/
6h
24h 61 54
30 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 23 ºC - - 6h 3 0
31 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 23 ºC - - 3d 29 25
32 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 50 ºC - - 18h 24 19
192
33 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 35 ºC - - 18h 59 49
34 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 0 ºC - - 18h 44 36
35 [1.2]
K2CO3
[2.0]
MeCN
[0.15]
SM2 - 15 ºC - - 18h 80 68
36 [1.0]
K2CO3
[2.0]
MeCN
[0.15]
(1mL)
SM2 - 15 ºC - - 18h 68 59
37 [1.2]
K2CO3
[3.0]
MeCN
[0.15]
SM2 - 15 ºC - - 18h 74 63
38 [1.2]
K2CO3
[2.0]
MeCN
[0.075M]
(2mL)
SM2 - 15 ºC - - 18h 23 19
39 -[1.2]
K2CO3
[2.0]
MeCN
[0.2]
(750uL)
SM2 - 15 ºC - - 18h 42 38
(a)
bs= broad singlet. Unless otherwise specified, FBSM [1.2 equiv], base [1.2 equiv] and SM [0.15 mmol] were weighed
into a vial, solvent was added, and the reaction left to stir at a given temperature for a determined time.
(b)
Yields
determined by
19
F NMR using PhF as an internal standard.
(c)
FBSM and the base were weighed into a vial, Solvent 1
was added and placed in a bath at 0 ºC (10 min). The SM was weighed in a separate vial, solvent 2 added and the
solution transferred to vial 1 (5 min @ 0 ºC). The reaction was left at rt for 6h.
(d)
Ni cat= Ni(PPh 3) 2Cl 2
During the course of the optimization, we kept observing unreacted FBSM in the crude
19
F NMR,
consequently we tested whether inverting the stoichiometry of the reaction would result in the
complete or partial consumption of FBSM. Entries 26 to 28 showcase the effects of utilizing 1
equivalent of FBSM instead of 1.2 and varying the equivalents of the acid anhydride. Interestingly,
when 1.2 equivalents of anhydride are used, the result is the same as when the stoichiometry is
directly inverted (1.2 eq of FBSM/ 1.0 eq SM2). Increasing the amount of SM2 to 1.5 or 2.0
equivalents resulted in a decreased yield. In an attempt to completely consume FBSM, we also
added a second portion of base and SM2 after stirring overnight (Table 5.3, entry 29). Even
though the yield was not drastically decreased, around half an equivalent of FBSM was still
unreacted. Another parameter that we wanted to test was the time of the reaction. Stirring
overnight (18h) had thus far resulted in the highest conversion, whereas stopping the reaction at
6h or 72h resulted in insignificantly lower yields (Table 5.3, entries 30 and 31). The graph shown
in Figure 5.3 showcases the trend observed with different reaction times. Next, we decided to
193
screen different temperatures (0 ºC, 15 ºC, 35 ºC and 50 ºC) to assess how this parameter affects
the reaction and how the results compare to the ones obtained at room temperature (23 ºC).
Figure 5.2: Effects of the solvent polarity in the
reaction outcome
Figure 5.3: Effects of the reaction time in the outcome
Figure 5.4: Effects of the temperature in the reaction
outcome
Figure 5.5: Effects of the concentration in the reaction
outcome
Among the temperatures screened, 15 ºC afforded the target compound in 80/68% yield as seen
in Table 5.3, entry 35 (see experimental section for
19
F NMR spectrum). The graph shown in
Figure 5.4 showcases the trend observed with different temperatures. Utilizing the best
temperature (15 ºC) we varied the equivalents of base (3.0) and FBSM (1.0), finding that the
yields, although good, were still lower. Finally, the effects of the reaction concentration were
evaluated, finding that more dilute (0.075M) or more concentrated (0.2M) reaction mixtures did
not improve the yield of 2 (Table 5.3, entries 38 and 39). The graph shown in Figure 5.5 depicts
35
29
53
68
0
TOL (2.4) DCM
(3.1)
THF (4.0) MeCN
(5.8)
DMF
(6.4)
% yield
Polarity index
Solvent polarity @ 23 ºC
3
68
29
6 18 72
% yield
hours
Time variation @ 23 ºC
44
80
68
59
24
0 15 22 35 50
% yield
ºC
Temperature trend
42
80
23
0.20 0.15 0.075
% yield
[M]
Concentration @ 15 ºC
194
the effects of the concentration in the reaction outcome. With these results in hand, we proceeded
to screen different conditions for the reductive desulfonylation of compound 2 in order to afford
the unprotected monofluoromethyl ketone.
5.3 Desulfonylation reaction: challenge of the magnesium mediated reduction
Initial attempts to isolate the monofluoromethyl ketone 2 from the unreacted FBSM proved
challenging. Chromatographic separation resulted in the co-elution of both compounds due to
their extremely similar polarity. In spite of this hurdle, we proceeded with the reductive
desulfonylation tests after light treatment of the reaction mix.
Magnesium in methanol has proven to be an efficient method for desulfonylation reactions and a
safe alternative to the use of sodium amalgam and other reductants.
440
Previous reports that
employ FBSM for fluoromethylation reactions perform these magnesium-mediated reductions
effectively to afford the fluoromethyl compounds.
51
With this information, we prepped our crude
reaction mix by filtering it through a celite plug and evaporating the solvent. The residue was then
redissolved in dry methanol and the reductive conditions were screened (Table 5.4).
Table 5.4: Optimization of the desulfonylation reaction with magnesium
(a)
E Mg
0
[equiv.] MeOH [v] Additives T ºC Time Observations
1 11.0 1 mL
1,2-dibromoethane
[0.619 mmol]
rt 3h Complete reduction of [2] to [I]
2 11.0 1 mL - 0 1h Complete reduction of [2] to [I]
3 2.0 1 mL - -10 1h Complete reduction of [2] to [I]
4 1.0 1 mL - -20 1h Complete reduction of [2] to [I]
(a)
Granulated magnesium was used in the glove box and drySolv methanol was added in the fume hood.
F
O
F
Me
O
F
Mg
0
/ MeOH
S
O
O
F
S
O
Ph
O
S
F
Ph
O
O
O
F
[3] [I] [II]
δ: -102 (s, 4-F)
δ: -210.67 (t, J =47.2Hz) δ: -105 (s, 4-F)
δ: -229 (t, J = 46.9 Hz)
δ: - 139 (s) 1F
δ: - 101 (s) 1F
[2]
195
The analysis of the first reduction trial revealed the appearance of two new signals by
19
F NMR
at around -105 ppm (m) and a triplet at -211 ppm, as well as the disappearance of both the broad
singlet at -139 ppm and the signal at -101 ppm (Image 5.1). Given that the triplet signal was too
downfield to belong to compound [3],
441
we performed a chromatographic isolation to confirm the
identity of the newly formed species. From the reaction mix we were able to isolate 4-
fluoroacetophenone [I] and fluoromethyl phenylsulfone [II]. This result indicated that the reduction
conditions were too harsh, cleaving the fluorine-carbon bond and resulting in complete reduction
of compound [2] to compound [I].
Image 5.1:
19
F NMR spectra before and after the desulfonylation reaction
The proposed mechanism for the reductive desulfonylation is depicted in Scheme 5.6. Two single
electron transfer processes mediated by magnesium are needed per sulfonyl group present in
the molecule.
442
These steps result in the formation of ketyl species [ib] and [ig] after protonation
with MeOH, which subsequently get reduced to anionic intermediates [ic] and [ih], respectively.
Similarly, the cleavage of the C-F bond is proposed to be facilitated by a two electron transfer
process since magnesium has shown to be effective in the reductive successive defluorination of
perfluoroalkyl ketones.
363
The ketyl intermediate [ik] undergoes a b-elimination to afford
196
benzophenone [I]. In an attempt to circumvent this issue, we conducted another trial with excess
magnesium and without 1,2-dibromoethane. This experiment also resulted in the complete
reduction of compound [2]. Decreasing the amounts of magnesium to a small excess [2.0 equiv],
or a stoichiometric amount [1.0 equiv] and conducting the reactions at lower temperatures (-10
and -20 ºC) to tame the reactivity did not afford compound [3] and resulted in complete reduction.
Scheme 5.6: Proposed mechanism for the reductive desulfonylation reaction with magnesium
Although effective desulfonylation of other FBSM-containing substrates has been demonstrated
in the past, the cleavage of carbon-fluorine bonds is highly dependent on thermodynamic and
structural factors.
443
It is a possibility that the reduction potential of bis(phenylsulfonyl)
fluoromethyl ketones is higher than those of other molecules containing bis(phenylsulfonyl)
fluoromethyl units. Further investigations into the reduction potential of these compounds are
S
O
Ph
O
S
F
Ph
O
O
O
F
S
O
Ph
O
S
F
Ph
O
O
O
F
Mg
MeO—H
S
O
Ph
O
S
F
Ph
O
O
HO
F
Mg
S
O
Ph
O
S
F
Ph
O
O
HO
F
S
F
Ph
O
O
HO
F
S
F
Ph
O
O
O
F
Mg
S
F
Ph
O
O
O
F
MeO—H
S
F
Ph
O
O
HO
F
Mg
S
F
Ph
O
O
HO
F
F
OH
F
F
O
F
SET
SET
[2]
[3]
F
O
F
MeO—H
F
OH
F
Mg
F
OH
F
Mg
OH
F
O
F
SET
Mg
[I]
[ia] [ib] [ic]
[id] [ie] [if] [ig]
[ih] [ii] [ij]
[ik] [il] [im]
197
needed to establish an efficient system for the desulfonylation of compound [2]. However, based
on a report by Wnuk and coworkers
444
on the tin-mediated desulfonylation of of α-fluoro esters,
we conducted an experiment utilizing a crude reaction mix, tributyl tin hydride (tBuSnH), and
AIBN as a radical initiator (Table 5.5). We were delighted to find that under these unoptimized
conditions, the desired fluoromethyl ketone [3] was obtained and observed by
19
F NMR (Image
5.2).
Table 5.5: Preliminary results on the tin-mediated desulfonylation
E
n
Bu-SnH Toluene [v] AIBN T ºC Time Observations
1 1.3 equiv 500 uL 15 mol% 115 1h
Disappearance of [2],
appearance of signals
corresponding to [3]
Image 5.2:
19
F NMR spectra before and after the desulfonylation reaction 2
F
O
F
Me
O
F
S
O
O
F
S
O
Ph
O
S
F
Ph
O
O
O
F
[3] [I] [II]
δ: -102 (s, 4-F)
δ: -210.67 (t, J =47.2Hz) δ: -105 (s, 4-F)
δ: -229 (t, J = 46.9 Hz)
δ: - 139 (s) 1F
δ: - 101 (s) 1F
[2]
1)
n
BuSnH
toluene [0.2M]
Ar
2) AIBN [15 mol%]
relfux, 1h
198
This result indicates that the tin radical presumed to be formed in situ is better suited to reduce
this kind of compounds. Scheme 5.7 showcases the proposed mechanism where the radical
initiator promoted the formation of a Sn-based radical that can effect the generation of a radical
anion (step 1 and 2). The subsequent elimination of a phenyl sulfonyl radical produces a tin
enolate (step 3) that can undergo protonation by the in situ formed sulfinic acid (step 4). The
resulting compound can undergo steps 1 to 4 again to yield the desired ketone [3].
Scheme 5.7: Proposed mechanism for the reductive desulfonylation reaction with tin hydride
SnH
Sn
n
Bu
O
2
S
S
O
O
SnH nBu
Sn nBu
S
OH
O
O
F
O
2
S
Ph
O
F
1)
n
BuSnH [1.35 equiv]
toluene [0.2M]
degass Ar (30 min)/5 min
2) AIBN [15 mol%]
relfux (~115 ºC)
1h
O
2
S
F
Ph
F
O
F
O
2
S
Ph
O
2
S
F
Ph
n
BuSn
O
F
O
2
S
Ph
O
2
S
F
Ph
n
B
u
O
F
O
2
S
F
Ph
n
BuSn
O
F
O
2
S
F
Ph
n
BuSn
step 1
step 2 step 3 step 4
O
F
O
2
S
F
Ph
steps 1–4
[3]
[2]
199
5.4 Preliminary studies of the reaction with FBDT
As mentioned in section 5.1 FBDT is considered to be a less sterically hindered phenylsulfonyl-
fluoromethylation reagent.
53
To test whether its reaction with acid anhydrides was feasible, we
conducted a few preliminary experiments utilizing a similar system to the one created for the
FBSM reaction. Employing potassium carbonate in MeCN at room temperature did not afford any
product whit FBDT (Table 5.6, E1). Replacing K2CO3 for potassium tert-butoxide at either 15 ºC
or room temperature was also unsuccessful. Conducting the reaction with DABCO as the base
showed evidence of the formation of a compound at -101 ppm by
19
F NMR. This result will be
explored further in order to optimize this transformation.
Table 5.6: Optimization of the monofluoromethylation reaction with FBDT
(a)
E
FBSM
[equiv]
Base
[equiv]
Solvent [M] SM T ºC Time
% -101
ppm
(4-F)
(b)
% -139
ppm
(bs)
(b)
FBDT-E1
FBDT
[1.2]
K2CO3
[2.0]
MeCN [0.15]
(1mL)
SM2 23 ºC 18h 0 0
FBDT-E2
FBDT
[1.2]
KO
t
Bu
[2.0]
MeCN [0.15]
(1mL)
SM2 15 ºC 18h 0 0
FBDT-E3
FBDT
[1.2]
KO
t
Bu
[2.0]
MeCN [0.15]
(1mL)
SM2 23 ºC 18h 0 0
FBDT-E4
FBDT
[1.2]
DABCO
[2.0]
MeCN [0.15]
(1mL)
SM3 23 ºC 18h 3 0
5.5 Mechanistic considerations
The mechanistic proposal for the fluoromethylation of acid anhydrides follows a traditional
nucleophilic addition pathway. The pronucleophile is deprotonated by the base, generating the
sulfonyl fluoromethide species that then would react with the electrophile. The addition-elimination
~ δ - 138 to -140 (s) 1F
δ - 100 to -101 (s) 1F
δ -102.5 (m) (2F)
O
O
O
Base
Solvent
T ºC
time
SM2 FBDT
4
19
F NMR (CDCl
3
)=
δ -165.6 (d) 51.7Hz (1F)
F
F
S
S
O
O
O
O
F
O
F
F
S
S
O
O
O
O
200
reaction proceeds via elimination of a benzoate unit, yielding the monofluoromethyl ketone
(Scheme 5.8).
Scheme 5.8: Proposed mechanism for the synthesis of MFMK
5.6 Conclusion and outlook
This work establishes a precedent for the synthesis of bis(phenylsulfonyl)fluoromethyl ketones in
a single step from carboxylic anhydrides and FBSM. The developed methodology thus far enables
access to these protected precursors in a mild and cost-effective fashion. The outlook for this
synthetic work includes the exploration of the substrate scope, as well as the optimization of the
reductive desulfonylation in order to prepare monofluoromethyl ketones. Another challenge to
overcome is the complete separation of the product from unreacted FBSM due to their very similar
polarities. The reaction with FBDT will also be explored to provide an alternative synthesis of
phenylsulfonyl ketones with another fluoromethyl anion surrogate.
5.7 Experimental data
5.7.1 Procedure for the synthesis of starting material 1a
On the bench-top, benzoic acid 1 (1 equiv, 0.5 mmol) and triphenylphosphine, PPh3 (2 equiv, 1
mmol, 262.3 mg) and anhydrous DCM (5 mL) were charged into an oven-dried screw-cap vial
equipped with a magnetic stir bar. The vial was capped, and this mixture was then cooled to 0 ºC
X
S
O
O
S
F
O
O
O
S S
O
O
O
O
F
X
X
S S
O
O
O
O
F
X
H
O
O
PhF
O
F
S
S
O
O
O
O
F
X
O
O
PhF
O
F
F
F-Ph-COO
F
O
OH
O
1 1a
1) PPh
3
[2.0 equiv]
NBS [2.1 equiv]
DCM [0.1 M]
0 ºC - rt, 15 min
2) 3HF • Et
3
N [2.0 equiv]
DCM, rt, 2h
201
using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1 equiv, 1.05 mmol, 187 mg) was
added as a solid in one portion, the vial was re-capped, and the mixture was kept in the ice-bath
for two minutes. After this time, the ice-bath was removed, and this solution was further stirred for
15 min. After this time, the vial was opened and 3HF-Et3N (2 equiv, 1 mmol, 163 uL) was added
via micropipette. This mixture was stirred further for 2 h at room temperature. After this time, the
vial was opened, and the reaction mixture was diluted with hexanes (20 mL), and the mixture was
stirred for 10 min. During this time, large amounts of succinimide and triphenylphosphine oxide
precipitate, which are then removed by passing the mixture through a short pad of silica (2 cm
thick x 3 cm diameter). Subsequently, the silica pad was further washed with hexanes. The filtrate
was then concentrated under reduced pressure to afford pure product 1a as a colorless oil in 65%
isolated yield (40.5 mg) without the need of further purification.
1
H NMR (400 MHz, CDCl3) δ 8.06
(dd, J = 8.6, 1.2 Hz, 2H), 7.68 (ddt, J = 7.9, 7.1, 1.3 Hz, 1H), 7.53 – 7.46 (m, 2H).
19
F NMR (376
MHz, CDCl3) δ 17.6 (s, 1F). These data match the previously reported structure.
445
5.7.2 Procedure for the synthesis of starting material 1d
The acyloxyphosphonium ion 1d was prepared according to a reported procedure
341
and used in
solution immediately after. On the bench-top, 4-fluorobenzoic acid 1 (1 equiv, 0.5 mmol) and
triphenylphosphine, PPh3 (2 equiv, 1 mmol, 262.3 mg) and anhydrous DCM (5 mL) were charged
into an oven-dried screw-cap vial equipped with a magnetic stir bar. The vial was capped, and this
mixture was then cooled to 0 ºC using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1
equiv, 1.05 mmol, 187 mg) was added as a solid in one portion, the vial was re-capped, and the
mixture was kept in the ice-bath for two minutes. After this time, the ice-bath was removed, and
O
O
PPh
3
F
OH
O
F
1
PPh
3
[2.0 equiv]
NBS [2.1 equiv]
DCM [0.1 M]
0ºC — rt
2 min- 15 min
1d
Br
202
this solution was further stirred for 15 min. This solution was used for the subsequent reaction with
FBSM.
5.7.3 Procedure for the synthesis of starting material 1e
The mixed anhydride 1e was prepared according to a reported procedure
446
in deuterated solvent
and used in solution. Under a stream of argon, 4-fluorobenzoic acid 1 (2.0 mmol), trifluoroacetic
anhydride (2 mmol) and 1 mL of CDCl3 were added to an over-dried crimp-top vial. The mixture
was stirred at room temperature under argon, for 5 minutes. The formation of the mixed anhydride
was established by NMR and the solution used for the next reaction with FBSM.
5.7.4 Procedure for the synthesis of starting material SM2
To an oven-dried round bottom flask equipped with a stir bar were added tosyl chloride (0.5 equiv,
2.5 mmol, 477 mg), 4-fluorobenzoic acid 1 (5 mmol, 701 mg), K2CO3 (1.5 equiv, 5.5 mmol, 760
mg) and DrySolv acetonitrile (0.2M, 25 mL). The reaction mix was stirred for 24h at room
temperature. After this time, DCM was added to the reaction mix, stirred and filtered. The organic
layer was dried with anhydrous MgSO4, filtered, and the solvent evaporated to afford 4-
fluorobenzoic anhydride SM1 in 95% yield as a white solid. The solid was further dried over P2O5
OH
O
F
F
3
C O
O
CF
3
O
O
O
F
CF
3
O
CDCl
3
5 minutes
1
1e
[1.0 equiv]
O
O O
F F
OH
O
F
1
TsCl
K
2
CO
3
MeCN
24 h
SM2
203
overnight.
1
H NMR (400 MHz, CDCl3) δ 8.33 – 7.85 (m, 4H), 7.25 – 7.17 (m, 4H).
19
F NMR (376
MHz, CDCl3) δ -102.07 (td, J = 8.3, 4.1 Hz). These data match the reported structural data.
447
5.7.5 Procedure for the screening of bases with benzoic anhydride SM1 and NMR yield
determination
On the bench-top, benzoic anhydride SM1 (0.15 mmol),and the corresponding base (1.2 equiv,
0,18 mmol) were added and suspended in 1 mL of DCM. Next, FBSM (1.2 equiv, 0.18 mmol,
xxmg) in 500 uL of DCM was added and the solution was left to stir at room temperature overnight.
After this time, 7 uL of fluorobenzene (PhF) were added (50% of 0.15 mmol) [δ-113.15 (s)] and
an aliquot analyzed by
19
F NMR.
5.7.6 Synthesis of bis(phenylsulfonyl) monofluoromethyl ketone (2) from bisphenylthio enamines
Step 1 and 2:
To an oven-dried round bottom flask was added a solution of acetophenone (22.0 mmol, 2.4g)
and pyridine (61.8 mmol, 5.0 mL) in EtOH (10 mL). Next, NH2OH•HCl (33.0 mmol, 2.29 g) was
added in one portion and the reaction mixture was stirred at 60 ºC for 1h. Upon completion of the
reaction, water was added, and the reaction extracted twice with ethyl acetate. The organic layers
were washed with 1N aqueous HCl, brine, and dried over anhydrous MgSO 4. The solvent was
removed in vacuo to give oxime (a). The crude oxime was combined with acetic anhydride (4.2
O
O
O
F
S S
O
O
O
O
Ph Ph
O
F
SO
2
Ph
SO
2
Ph
base 1.2 equiv
CH
2
Cl
2
[0.1 M]
rt, overnight
SM1
FBSM 2
O
N
OH Py
EtOH
NH
2
OH•HCl
60 ºC, 1 h
N
O
Ac
Ac
2
O
DMAP
Py
rt, 1 h
(a) (b) (x)
204
mL) and catalytic DMAP (0.002 equiv, 5 mg) in pyridine (10 mL). The mixture was stirred at room
temperature for one hour. After this time, the reaction mixture was treated by water and ethyl
acetate. The organic layers were collected and washed with 1N aqueous HCl, brine, dried over
anhydrous MgSO4, and filtered. The solvent evaporated to afford he crude product which was
purified by recrystallization from ethyl acetate-hexane to afford (E)-1-phenylethan-1-one O-acetyl
oxime (b) as white crystals.
436
Step 3:
The pure acetyl oxime (1 mmol) was added to an oven-dried crimp-top vial in an Ar glovebox. To
this vial was also added diphenyl disulfide (1 mmol, 2.0 equiv, 436 mg), CuI (38 mg, 0.20 mmol)
and NaI (15 mg, 0.10 mmol). The vial was brought outside the glovebox and acetonitrile (1.0 mL)
was added under a nitrogen stream. The mixture was stirred for 16 h at 90 ⁰C. After this time, the
reaction mix was cooled to room temperature, and concentrated under educed pressure. The
desired gem-bisphenylthioenamine (c) was purified by silica-gel column chromatography for the
next step.
Step 4:
NH
2
CuI (20 mol%)
NaI (10 mol%)
MeCN (0.1M)
90 ºC, 16 h
Ph S S Ph
SPh
SPh
(c)
N
O
Ac
(b)
MeOH
1M HCl
50ºC, 24h
SPh
SPh
O
(d)
NH
2
SPh
SPh
(c)
205
Bis(phenylthiol)enamine (c) (33.5 mg, 0.10 mmol) was added to an oven-dried vial and dissolved
in methanol (2mL). To this solution, 1 M HCl (2.7 mL, 2.74 mmol) solution was added, and the
mixture was stirred at 50 ºC for 24 h and then evaporated under reduced pressure. The residue
was purified by preparative TLC on silica gel eluting with hexanes/ethyl acetate (10:1) to give 1-
phenyl-2,2-bis(phenylthio)ethan-1-one (d). The mass of this compound was confirmed by GC-MS
Step 5:
To a solution of compound (d) (0.1 mmol, 33.6 mg) in AcOH (0.2 mL) was added H2O2 (0.15 mmol,
30% in H2O). The reaction mixture was stirred for 2 h at room temperature and then overnight at
50 °C. The mixture was then cooled to room temperature and concentrated under educed
pressure. The residue was purified by preparative TLC on silica gel eluting with hexanes/ethyl
acetate (1:1) to give sulfonyl ketone (e).
Step 6:
1-Phenyl-2,2-bis(phenylsulfonyl)ethan-1-one (e) (0.1 mmol, 40.0 mg) was dissolved in 1 mL DMF
and KO
t
Bu (202 mg, 0.3 mmol) was added in one portion. The reaction was stirred at room
temperature for 20 min. After this time, a solution of Selectfluor (637 mg, 0.3 mmol) in 1 mL DMF
was added slowly. The reaction mixture was then stirred at room temperature for 1 h. The reaction
SO
2
Ph
SO
2
Ph
O
1) H
2
O
2
(30% in H
2
O)
AcOH
2 h, rt
2) overnight, 50 ºC
(e)
SPh
SPh
O
(d)
tBuOK, rt 20 min
Selectfluor
DMF,
rt, 1 h
S
O
O
S
F
O
O
O
(2)
(30%)
SO
2
Ph
SO
2
Ph
O
(e)
206
was then quenched with water (15 mL) and extracted with EtOAc (10 mL×3). The combined
organic layers were washed with water, brine, and dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by preparative TLC on silica gel eluting with
hexanes/ethyl acetate (2:1) to give compound (2) in 30% yield as an off-white solid.
1
H NMR (400
MHz, CDCl3) δ 8.01 – 7.88 (m, 4H), 7.72 (td, J = 7.4, 1.3 Hz, 2H), 7.62 (d, J = 7.9 Hz, 2H), 7.59 –
7.48 (m, 5H), 7.40 – 7.29 (m, 2H). The proton spectrum data matched the reported structure.
435
19
F NMR (376 MHz, CDCl3) δ -139.90 (s, 1H).
5.7.7 Synthesis of FBSM
Step 1:
In an argon glove box, spray-dried potassium fluoride (152 mmol, 2.0 equiv, 8.80 g), and 18-
crown-6 (7.6 mmol, 0.1 equiv, 2.01 g) were added to an oven-dried round-bottom flask equipped
with a stir bar. The flask was sealed with a rubber septum and brought outside the glove box.
Anhydrous acetonitrile (50 mL) and chloromethyl phenyl sulfide (76.0 mmol, 1.0 equiv, 10.2 mL)
were then added successively to the flask by syringe under a stream of nitrogen. A reflux
condenser fitted with a nitrogen inlet adaptor is then attached and the apparatus is flushed with
nitrogen three times. The reaction mixture was heated to reflux in an oil bath at 102 °C for 120 h.
After this time, the reaction mixture was cooled in an ice bath, diluted with ice water (50 mL) and
transferred to a separatory funnel. The mixture was extracted with dichloromethane (4 x 25 mL,
and the combined organic layers were washed with water (30 mL), dried over anhydrous MgSO4,
and filtered. The solvent was evaporated under reduced pressure to give crude fluoromethyl
phenyl sulfide as a brown oil that was directly used for the next step.
F S
Ph
O O
Cl S
Ph
1. KF, 18-crown-6 (10 mol%)
CH
3
CN, relfux, 120 h
2. Oxone MeOH, H
2
O
F
S
O
O
S
O
O
KHMDS, THF, -78 ºC
2. 4M HCl
F
S
Ph
O O
1.
(a)
(b) (c)
207
Step 2:
Oxone® (190 mmol KHSO5, 2.6 equiv, 116.80 g) was added to a 1-L round-bottomed flask
equipped with a magnetic stir bar followed by distilled water (175 mL). The flask was then
equipped with an addition funnel containing a solution of crude fluoromethyl phenyl sulfide (10.20
g, 72 mmol, 1.0 equiv) in methanol (175 mL) and placed in an ice bath. The methanolic solution
was added dropwise over 1 h, The reaction mixture was allowed to slowly warm to room
temperature and stirred for an additional 12 h. The solvent was evaporated under reduced
pressure to give a residue with a large amount of insoluble white precipitate, which was removed
by filtration. The funnel was rinsed with dichloromethane (2 x 30 mL) and the filtrate transferred
to a 250-mL separatory funnel. After layer separation, the aqueous layer was further extracted
with dichloromethane. The organic layers were combined, washed with water, dried over
anhydrous MgSO4, filtered, and concentrated to 40 mL of a pale-yellow solution. The solution was
filtered through a plug of silica and further washed with dichloromethane to give a clear solution.
The solvent was evaporated under reduced pressure and the residue placed under vacuum to
give a light-yellow oil, which slowly solidifies at room temperature under vacuum. The solid was
recrystallized in hot hexanes to afford colorless crystals over 15 min, which were filtered and
washed with cold (0 °C) hexanes (2 x 10 mL) giving fluoromethyl phenyl sulfone (b) (92%).
Step 3:
Potassium hydride (163 mmol, 2.7 equiv, 21.80 g, 30% wt in oil) was added to an oven-dried 250-
mL round-bottomed flask, equipped with a stir bar and sealed with a rubber septum. The flask
was evacuated and purged with nitrogen three times and then placed in an ice bath. Excess oil is
removed as follows. Anhydrous hexanes (20 mL) (Note 24) are added to the flask via syringe.
The mixture is gently stirred for 10 min and allowed to stand unstirred for another 10 min before
the removal of the hexanes-oil solution with a syringe. The hexanes-oil solution is added dropwise
to an isopropyl alcohol solution. This washing procedure is repeated two more times. Anhydrous
208
THF (130 mL) is then added and hexamethyldisilazane (195 mmol, 3.2 equiv, 40.9 mL) is then
added portion-wise to the stirred solution via syringe over a period of 20–30 min. The hydrogen
evolution ceased within 15 min after the addition. The ice bath was removed, and the reaction
mixture was allowed to stand without stirring for 30 min at room temperature. An oven dried 500-
mL round-bottomed flask equipped with a stir bar was charged with fluoromethyl phenyl sulfone
(b) (61.2 mmol, 1.0 equiv, 10.66 g). The flask is sealed with a rubber septum and purged with
nitrogen three times. Benzenesulfonyl fluoride (61.2 mmol, 1.0 equiv, 7.37 mL) and anhydrous
tetrahydrofuran (40 mL) were added successively via syringe. The flask was cooled in a dry ice-
acetone bath (–78 °C) and the KHMDS solution in tetrahydrofuran prepared above is added
dropwise via cannula over 30 min. During the addition, the reaction mixture becomes brownish,
cloudy, and viscous. After 30 min at –78 °C, the reaction mixture was quenched by transfer via
cannula over 30 min to another 500-mL round-bottomed flask under a nitrogen atmosphere
containing a stirred solution of 4M HCl (185 mL). The resultant mixture appears was extracted
with dichloromethane and the combined organic layers were washed with brine (50 mL), dried
over anhydrous MgSO4, and filtered. The solvent was evaporated under reduced pressure and
further dried under vacuum to afford crude fluorobis(phenylsulfonyl)methane (c) as a colorless
solid (95%) which was recrystallized in methylene chloride and hexanes. The resulting white
precipitate was collected and rinsed with 25 mL cold DCM/hexanes (1:1, v/v; 0 °C) and allowed
to air dry on the funnel for 15 min and then placed on a vacuum line for 15 min to afford pure (c).
1
H NMR (400 MHz, CDCl3) δ 8.06 – 7.88 (m, 4H), 7.77 (ddt, J = 8.7, 7.1, 1.3 Hz, 4H), 7.68 – 7.56
(m, 4H), 5.71 (d, J = 45.8 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -168.71 (d, J = 45.7 Hz, 1F). The
data matched the reported structure
5.7.8 Synthesis of FBDT
Step 1:
209
To a suspension of benzene-1,2-dithiol (7.11 g, 50 mmol), cesium carbonate (24.40 g, 75 mmol)
and anhydrous DMF (120 mL) was added dropwise bromochloromethane (9.60 g, 75 mmol) under
nitrogen. The resulting mixture was stirred and then heated at 110 °C for 2 h. The mixture was
then poured into water (150 mL) and the aqueous layer was extracted with DCM (2 × 100 mL).
The combined organic layer was dried over anhydrous MgSO4. The solvent was evaporated under
reduced pressure and the residue was purified by column chromatography with n-hexane to give
the product DT-1 as a yellow oil.
Step 2:
To a mixture of XIR10-FBDT-1 (4.63 g, 30 mmol) in glacial acetic acid (48.61 mL), was added
hydrogen peroxide (21.11 mL, 30% w/w in water) dropwise at room temperature. The reaction
mixture was stirred at room temperature for 2 h, and then warm up to 50 °C for 15 h. The solvent
was removed under reduced pressure and the residue was recrystallized from EtOH. The product
BDT was obtained as a white solid (5.48 g, 83.7% yield).
1
H NMR (400 MHz, CDCl3) δ 8.02 (t, J =
4.6 Hz, 2H), 7.95 (dd, J = 6.0, 3.0 Hz, 2H), 4.71 (s, 2H).
Step 3:
SH
SH
S
S
CH
2
ClBr [1.5 eq]
Cs
2
CO
3
[1.5 eq]
DMF [0.4M]
107-110ºC
2h
DT-1
S
S
S
S
O
O
O
O
1) AcOH [0.6M]
H
2
O
2
[1.42M of 30% in H
2
O]
dropwise. rt, 2h
2) 50ºC, 15h
DTO-2
210
To a solution of 1,3-benzodithiole-1,1,3,3-tetraoxide (1.0 g, 4.58 mmol), selectfluor (1.70g, 4.81
mmol), tetrabutylammonium bromide (147.6 mg, 0.458 mmol) in CH3CN (10 ml) and THF (10 ml)
1N NaOH aq. (4.81 ml, 4.81 mmol) was added at 0 ºC. The reaction mixture was stirred at 50 C
for 17 h. The reaction mixture was quenched with 1N HCl and extracted with CH2Cl2. The
combined organic phase was washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by column chromatography on silica gel
(CH2Cl2/n-hexane = 1/2) to give FBDT (644.9 mg, 60%) as white solid.
1
H NMR (400 MHz, CDCl3)
δ 8.08 – 7.96 (m, 4H), 5.91 (d, J = 51.5 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -165.63 (d, J =
51.7 Hz, 1F).
5.7.9 General method for the synthesis of monofluoromethyl ketone 2
On the bench-top, 4-fluorobenzoic anhydride SM2 (0.15 mmol), K2CO3 (1.2 equiv, 0,18 mmol),
and FBSM (1.2 equiv, 0.18 mmol, 57 mg) were added to a vial equipped with a stir bar and the
vial was placed in an ethylene glycol/water bath at 15 ºC. Then, 1.5 mL of DCM were added, and
the solution was left to stir at this temperature overnight. After this time, 14 uL of fluorobenzene
(PhF) were added (0.15 mmol) [δ-113.15 (s)] and an aliquot analyzed by
19
F NMR.
S
S
O
O
O
O
S
S
O
O
O
O
F
1) Selectfluor [1.05 eq]
TBAB [10 mol%]
MeCN [0.5M]
THF [0.5M]
1N NaOH
0ºC
2) 50ºC, 17h
FBDT
O
O
O
F
S S
O
O
O
O
Ph Ph
O
F
SO
2
Ph
SO
2
Ph
K
2
CO
3
1.2 equiv
CH
2
Cl
2
[0.1 M]
15 ºC, 18 h
SM2
FBSM 2
F
F
F
211
Image 5.3: Sample
19
F NMR spectrum of the fluoromethylation reaction
212
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Abstract (if available)
Abstract
As stated in the title, this dissertation will discuss my research conducted on the development of synthetic methods to exploit the potential of fluorinated nucleophiles for the functionalization of organic molecules. Having been immersed in the world of fluorine as a part of the Prakash group, my research was focused on developing novel and alternative methodologies to introduce this unique element into organic backbones, providing access to fluorofunctionalized products. The preface section of this dissertation provides an overview of my research in organofluorine chemistry that is mainly divided into three categories: (i) Fluorination and perfluoroalkylation of carboxylic acid derivatives for the synthesis of fluorinated carbonyl compounds, (ii) Copper- catalyzed perfluoroalkylation of C-H(sp) and C-H(sp2) centers, and (iii) Difluoromethylation of -N, -O and -C nucleophiles with difluoro/dihalocarbene. Chapter 1 will provide insight into the impact that fluorinated compounds have had in several fields of society, with emphasis in the pharmaceutical and medicinal realms. This chapter will also include an overview of some of the available reagents and methodologies to access fluorinated and perfluoroalkyl organic molecules via monofluoro, difluoro, and trifluoromethylation reactions that follow either nucleophilic, electrophilic, or radical pathways. Chapter 2 will focus on the synthesis of trifluoromethyl ketones from activated carboxylic acids utilizing the Ruppert-Prakash reagent (TMSCF3) and copper (I) as a trifluoromethylating system. The scope and applicability of the method are discussed, as well as the mechanistic proposal derived from control and competition experiments. Chapter 3 will further demonstrate the pluripotency of acyloxyphosphonium ions by utilizing them to prepare difluoromethyl ketones employing a difluoromethyl zinc reagent and copper catalysis. Two methods are provided for the synthesis of these compounds where copper acts as either a promoter or a catalyst in the reaction. The same difluoromethyl zinc reagent was used to develop the work discussed in Chapter 4, which describes the preparation of difluoromethyl alkynes from terminal and silyl acetylenes. The scope of the method is demonstrated by the synthesis of multiple CF2H-alkynes bearing diverse functionalities, including analogs of pharmaceutically relevant compounds. The applicability of the protocol is further exemplified by both, the preparation of 2-CF2H indoles via a tandem difluoromethylation/cyclization reaction of ethynylanilines, and the synthesis of heterocycles via cycloaddition reactions. Chapter 5 will discuss the work conducted in the synthesis of monofluoromethyl ketones from carboxylic acid derivatives and fluoroalkyl anion surrogates. This chapter demonstrates the first addition-elimination reaction of FBSM (fluorobis(phenylsulfonyl)methane) to carbonyl electrophiles to prepare bis(phenylsulfonyl)fluoromethyl ketones. The full optimization of the reaction is analyzed, and the preliminary results in the magnesium-mediated reductive desulfonylation are discussed. This chapter includes the outlook and future work needed to apply the method to structurally diverse substrates. All chapters demonstrate the power of spectrometric and spectroscopic techniques to elucidate the structural composition of novel compounds. Nuclear Magnetic Resonance (NMR), Infrared Spectrophotometry (IR), High-Resolution Mass Spectrometry (HRMS), and Gas Chromatography coupled to Mass Spectrometry (GC-MS) were the main techniques utilized to resolve the structure of the prepared molecules, and their structural data is provided in the experimental section of each chapter.
Linked assets
University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Ispizua Rodriguez, Xanath
(author)
Core Title
Harnessing fluorinated C1 nucleophilic reagents for the direct fluoroalkylation of ubiquitous C(sp2)-X and C(sp)-H centers
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Degree Conferral Date
2023-05
Publication Date
05/01/2023
Defense Date
04/25/2023
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
carboxylic acids,catalysis,copper,difluoromethylation,fluorine,fluoroalkylation,ketones,OAI-PMH Harvest,organofluorine chemistry,transition metal,trifluoromethylation
Format
theses
(aat)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Prakash, Surya (
committee chair
), Valero Cuevas, Francisco (
committee member
), Zhang, Chao (
committee member
)
Creator Email
ispizuar@usc.edu,xispizua@gmail.com
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-oUC113091232
Unique identifier
UC113091232
Identifier
etd-IspizuaRod-11746.pdf (filename)
Legacy Identifier
etd-IspizuaRod-11746
Document Type
Dissertation
Format
theses (aat)
Rights
Ispizua Rodriguez, Xanath
Internet Media Type
application/pdf
Type
texts
Source
20230501-usctheses-batch-1034
(batch),
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA
Repository Email
cisadmin@lib.usc.edu
Tags
carboxylic acids
catalysis
copper
difluoromethylation
fluorine
fluoroalkylation
ketones
organofluorine chemistry
transition metal
trifluoromethylation