Close
About
FAQ
Home
Collections
Login
USC Login
Register
0
Selected
Invert selection
Deselect all
Deselect all
Click here to refresh results
Click here to refresh results
USC
/
Digital Library
/
University of Southern California Dissertations and Theses
/
Controlled heteroatom functionalization of carbon-carbon bonds by aerobic oxidation
(USC Thesis Other)
Controlled heteroatom functionalization of carbon-carbon bonds by aerobic oxidation
PDF
Download
Share
Open document
Flip pages
Contact Us
Contact Us
Copy asset link
Request this asset
Transcript (if available)
Content
Controlled Heteroatom Functionalization of Carbon-Carbon Bonds by
Aerobic Oxidation
by
William John Richards
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)
August 2024
© Copyright 2024 by William J. Richards, 2024. All rights Reserved.
ii
Dedication
To my loving and supportive wife Dr. Van Do and her family
To my parents Jim and Angela
To my sister Katie
To my best friend Danny
In loving memory of my cat Dewey
iii
Acknowledgments
I would like to first express my appreciation for my advisor and mentor, Professor
Valery V. Fokin. The knowledge and experience I have gained from Valery has been
invaluable and has directly contributed to my success as a chemist. These past 5 years
have not been the easiest, but I will be forever grateful for the guidance and support he
has provided. I have grown as a person and am leaving USC a better chemist and person
largely thanks to you.
I would also like to thank the rest of my committee members: Professor Travis
Williams, Professor Jahan Dawlaty, Professor Chao Zhang, and Professor Danniel
McCurry for their time and advise throughout my time at USC. I would also like to thank
Professor Christina Zavaleta who agreed to serve on my dissertation committee when I
had to rush to meet a deadline to graduate.
Thanks to all former and current Fokin group members, especially to Dr.
Shubhangi Aggarwal who brought me onto her project and mentored me. Without her
help, my PhD experience would have been very different with much less success. I would
also like to thank Dr. Joice Thomas who took me under his wing in my first year giving me
a lot more confidence for my remaining time than I would have otherwise had. A special
thanks to Kevin Varges, Joshua Ibs, and Rudra Pursaud who have been very fun to talk
to as well as a source of support. Our conversations never ceased to entertain and having
you all there made the years very enjoyable. I can’t imagine going through a PhD without
your support.
iv
I would also like to thank the friends that I have gained at USC. Dr. CJ Kosh, Dr.
Keying Chen, Dr. Bryce Tappan, and Dr. Carlos Navarro. The time spent out of lab with
them was very helpful as it gave a very good balance to social activities and lab activities.
They also provided interesting perspectives to problems in the lab due to all of their
difference expertise.
Last but not least, I will forever be grateful to my wife Van who has given me
endless love and support. I would have not gotten through the program as well if at all
without her. I would also like to thank my parents and sister who have also given me their
love and support. I would not be the person I am today without them.
v
Table of Contents
Dedication..................................................................................................................................ii
Acknowledgments.....................................................................................................................iii
List of Tables.............................................................................................................................. ix
List of Figures .............................................................................................................................x
List of Schemes ........................................................................................................................ xii
Abstract..................................................................................................................................xviii
Chapter 1. Heteroatom Functionalization of Small Organic .......................................................1
1.1 Introduction........................................................................................................................1
1.2 Radical Chemistry ..............................................................................................................2
1.2.1 Radical Structure and Reactivity....................................................................................3
1.2.2 Radical Formation ........................................................................................................7
1.2.3 Examples of Radicals in Synthesis.................................................................................9
1.3 Ketenimine Chemistry.......................................................................................................15
1.3.1 Ketenimine Structure and Reactivity............................................................................17
1.3.2 Synthesis of Ketenimines ............................................................................................18
1.3.3 Ketenimines in Organic Synthesis................................................................................24
1.4 Copper Catalyzed C–H Functionalization...........................................................................32
1.4.1 Advantages of Copper Catalyst ...................................................................................32
1.4.2 Reactivity of Copper ...................................................................................................33
1.4.3 Reactions with Copper ...............................................................................................34
1.5 Conclusion.......................................................................................................................42
1.6 References .......................................................................................................................42
Chapter 2. C-I Bond Activation of Synthesized α-Iodoamidines leading to α-Hydroxyamidines
Through Aerobic Oxidation .......................................................................................................51
2.1 Introduction......................................................................................................................51
2.2 Reaction Inspiration, Design and Background ....................................................................53
2.3 Reaction Optimizations.....................................................................................................55
2.3.1 Iodine Source Screening .............................................................................................57
2.3.2 Base Screening...........................................................................................................58
2.3.3 Solvent Selection........................................................................................................60
2.3.4 Proton Source Screening.............................................................................................61
vi
2.3.5 Additives Screening ....................................................................................................62
2.3.6 Temperature Screening ...............................................................................................66
2.3.7 Atmosphere Screening ...............................................................................................67
2.4 Understanding the Role of Oxygen .....................................................................................67
2.4.1 Water under N2 atmosphere ........................................................................................68
2.4.2 Testing for low energy triplet state................................................................................69
2.4.3 Testing for SET mechanism..........................................................................................70
2.4.4 Testing for singlet oxygen (1O2).....................................................................................72
2.4.5 Testing for autoxidation with triplet oxygen (3O2) ...........................................................73
2.5 Substrate Scope ...............................................................................................................76
2.6 Mechanism Proposal ........................................................................................................80
2.7 Further Reactivity of Lithiated Ketenimine and Hydroxy Product..........................................81
2.8 C-H Activation Through Radical Initiation ...........................................................................83
2.9 C-I Bond Study with Different Lewis Bases .........................................................................84
2.10 Conclusion .....................................................................................................................87
2.11 References .....................................................................................................................88
Chapter 3. Copper-Catalyzed C-H Oxidation using ambient Air: A Selective Oxygenase Type
Reactivity .................................................................................................................................94
3.1 Introduction......................................................................................................................94
3.2 Reaction Discovery ...........................................................................................................97
3.2.1 Initial Mass Spectrometry Observations ......................................................................97
3.2.2 Initial electrochemistry experiments ...........................................................................98
3.3 Reaction Optimization ......................................................................................................99
3.3.1 Catalyst Screen to Develop Oxo Conditions...............................................................100
3.3.2 Solvent Screening to Develop a High Selectivity Condition Towards Oxo Product.........102
3.3.3 Additives Screening to Develop High Selectivity Condition Towards Oxo Product.........103
3.3.4 Optimizing Hydroxy Selectivity Condition...................................................................105
3.4 Reactions Control...........................................................................................................106
3.4.1 Oxygen Effect ...........................................................................................................106
3.4.2 Copper Effect...........................................................................................................108
3.5 Structural Limitations of Starting Material ........................................................................111
3.5 Kinetic Profiles for the Oxygenation of the Sultam.............................................................113
3.5.1 Kinetic Profile of the Oxo Reaction.............................................................................114
vii
3.5.2 Kinetic Profile Done with Optimized Hydroxy Conditions ............................................115
3.6 Competition Reaction with added Product in the Oxo Condition .......................................116
3.7 Substrates Scope............................................................................................................118
3.8 Mechanism Proposal ......................................................................................................122
3.9 Conclusion.....................................................................................................................123
3.10 References ...................................................................................................................123
Chapter 4. Reactivities of SO2F Triazoles................................................................................126
4.1 Introduction....................................................................................................................126
4.2 Reaction Discovery .........................................................................................................128
4.3 Reaction Exploration.......................................................................................................130
4.3.1 Fluorosulfonylating Reagent Screen ..........................................................................130
4.4.2 Solvent Screening.....................................................................................................133
4.4.3 Base Screening.........................................................................................................134
4.4.4 Base Equivalents Screening ......................................................................................135
4.4.5 Temperature Screening .............................................................................................136
4.4.6 Concentration Screen...............................................................................................136
4.4.7 Order of Addition ......................................................................................................137
4.5 Alternate Route for SO2F-Containing Carbene Product .....................................................138
4.5.1 Synthesis of Sulfonyl Imidazole Triazole.....................................................................139
4.5.2 Synthesis of the Sulfonyl Imidazole Triazole through Rhodium Carbenes ....................140
4.5.3 Methylated Sulfonyl Imidazole Triazole and Rhodium Chemistry.................................142
4.6 The Utilization of Ketenimine from SO2F Triazole...............................................................143
4.6.1 Amine Screen for Amidine Formation ........................................................................143
4.6.2 Fluorosulfonylating Reagent Screening......................................................................144
4.7 N-heterocyclic Carbene Formation..................................................................................145
4.7.1 NHC Species Synthesis Optimization ........................................................................145
4.7.2 NHC on Iridium Complex ..........................................................................................145
4.8 Conclusion.....................................................................................................................147
4.9 References .....................................................................................................................147
Chapter 5. Procedures and Characterization .........................................................................151
5.1 Iodine Project (Chapter 2)................................................................................................151
5.1.1 Synthesis of Starting Materials ..................................................................................151
5.1.2 Optimization Studies ................................................................................................159
viii
5.1.3 Procedures for Controls............................................................................................161
5.1.4 Substrate Scope.......................................................................................................172
5.1.5 Post Functionalization ..............................................................................................190
5.1.6 Scaled up synthesis for α-hydroxyamidine 2.28..........................................................194
5.1.7 NMRs for chapter 2...................................................................................................196
5.2 Copper Project (Chapter 3)..............................................................................................262
5.2.1 Optimization ............................................................................................................262
5.2.2 Synthesis of Starting Materials for Controlled Experiments.........................................269
5.2.3 Condition Controlled Experiments ............................................................................272
5.2.4 Structural Controlled Experiments ............................................................................277
5.2.5 Kinetic Profile for the Oxygenation of the Sultam........................................................278
5.2.6 Competition Reaction with added Products with Oxo Conditions ...............................280
5.2.7 Synthesis of Sultams ................................................................................................280
5.2.8 Substrate Scope.......................................................................................................293
5.2.9 NMRs for Chapter 3 ..................................................................................................309
5.3 Fluorosulfonyl Triazole (Chapter 4)...................................................................................361
5.3.1 Synthesis of Starting Material....................................................................................361
5.3.2 Synthesis of Fluorosulfonyl Triazole...........................................................................363
5.3.3 Synthesis of Sulfonyl Imidazole Triazole.....................................................................369
5.3.4 Sulfonyl Imidazole used in Rhodium Chemistry .........................................................371
5.3.5 Synthesis of Methylated Sulfonyl Imidazole Triazole...................................................372
5.3.6 Methylated Sulfonyl Imidazole in Rhodium Chemistry................................................373
5.3.7 Synthesis of Amidines from SO2F Triazoles ................................................................373
5.3.8 Synthesis of Carbene 4.8 ..........................................................................................373
5.3.9 Synthesis of Carbene 4.7 Complexes ........................................................................374
5.3.10 NMRs for Chapter 4 ................................................................................................375
5.3.11 References.............................................................................................................399
Bibliography ...........................................................................................................................401
ix
List of Tables
Table 2.1. Optimization for the α-hydroxyamidine synthesis.......................................... 57
Table 4.1. Optimization of sulfonyl imidazole triazole synthesis. ................................. 140
Table 4.2. Conditions tried for the rhodium reactions. ................................................. 141
x
List of Figures
Figure 1.1. Comparison of the reactive forms of carbon showing reactive radicals with
an unpaired electron as a neutral species....................................................................... 4
Figure 1.2. A) Examples of structures that have similar structures to ketenimines. B)
The 90° angle between the substituent on the C and N terminus of the ketenimines.
C) The equilibrium the ketenimine isomers are in. ........................................................ 18
Figure 2.1. Examples of sterically stabilized and push-pull stabilized radicals.............. 52
Figure 2.2. Sulfonyl amide general structure along and some examples of their
presence in biological active drug molecules ................................................................ 53
Figure 2.3. A) Formation of the iodoamidine from the lithiated ketenimine B) Synthesis
of oxygenated amidines from similar rhodium carbene systems. .................................. 55
Figure 2.4. An example of a LC-MS DAD chromatogram showing many reaction
species.......................................................................................................................... 56
Figure 2.5. Substrate scope for the oxygenated amidine with various amines,
sulfones, and aryl groups. ............................................................................................. 76
Figure 2.6. Varies conditions that tried to initiate the radical oxidation with none
working.......................................................................................................................... 83
Figure 2.7. 13CNMRs showing the ppm shift of the benzylic carbon for benzyl iodide.
...................................................................................................................................... 87
Figure 3.1. A) General oxygenase type reaction. B) Examples of oxygenase type
reactions. C) Oxygenase type reaction with sulfonyl amides. ....................................... 96
Figure 3.2. A) General reaction scheme for the oxygenation of the sultam products.
B) The chromatograms of both APCI and ESI runs for the sultams showing the
oxygenated species. C) The same observations also shown with different electronic
conditions...................................................................................................................... 97
Figure 3.3. Air and current showing a positive correlation to oxygenated species
forming in APCI experiments......................................................................................... 98
Figure 3.4. GC-FID chromatogram shows starting sultam, hydroxy product, and oxo
product peaks can be visualized at distinct retention time and magnitude. ................. 100
Figure 3.5. Catalyst screen bar graph showing CuCl2 was the best catalyst and
copper metal was required. ......................................................................................... 100
Figure 3.6. Solvent screening showed the strong correlation between high yielding
product and selectivity towards hydroxy in smaller aprotic alcohols............................ 102
xi
Figure 3.7. Additive screening shows that ligands can inhibit the reaction to some
extent and bases can promote the formation of oxo product 3.2, while acids can
promote the hydroxy product 3.3................................................................................. 103
Figure 3.8. Optimization of the hydroxy product from oxo product optimization study
based off of observations from the oxo optimization. .................................................. 105
Figure 3.9. A) Reaction performed with only catalyst, MeOH, and starting material. B)
Reaction performed with added water. B) Reaction performed with both water and
lithium carbonate......................................................................................................... 114
Figure 3.10. Reaction profile for the hydroxy optimized conditions. ............................ 116
Figure 3.11. Competition experiments in order to observe product formation effect on
the reaction. ................................................................................................................ 118
Figure 3.12. Comparison of the APCI studies done with t-Bu and benzyl derivatives
showing no conversion with a benzyl group and limited conversion with a t-Bu group.
.................................................................................................................................... 119
Figure 3.13. Substrates scope for this reaction showing both hydroxy and oxo
conditions.................................................................................................................... 121
Figure 4.1. Examples of structures possible with SO2F groups................................... 128
Figure 4.2. NOESY experiments to show the relative stereochemistry of the imidazole
addition by-product showing that it has the right geometry of a ketenimine addition... 133
Figure 4.3. When base is added right after FSI NHCs seem to form as seen by the
TLC. ............................................................................................................................ 138
Figure 4.4. Synthetic routes for the complexation of NHCs to iridium to form a complex
along with the MALDI showing varies products formed............................................... 146
xii
List of Schemes
Scheme 1.1. A) Example of a general SN2 reaction. B) Example of a general SN1
reaction. C) Example of a general metal catalyzed cross coupling. D) Example of a
strain promoted nucleophilic addition E) Example of a general alkene
functionalization. ............................................................................................................. 2
Scheme 1.2. A) Synthesis of silphinene through a radical cyclization. B) Synthesis of
a silphinene like structure with a cascade radical cyclization of from simple starting
material. .......................................................................................................................... 5
Scheme 1.3. The equilibrium C-centered radicals are in showing stereo
interconversion................................................................................................................ 6
Scheme 1.4 An example of a reaction that can have its regioselectivity switched by
going through a radical process instead of ionic process................................................ 7
Scheme 1.5. A) An example of an organic peroxide acting as a radical initiator. B) An
example of an azo compound acting as a radical initiator. .............................................. 8
Scheme 1.6 Initiation of tin hydrides using AIBN leading stabilized tin radicals. ............. 8
Scheme 1.7 C-centered radical formation of carboxylic acids with the formation of
CO2. ................................................................................................................................ 9
Scheme 1.8. A) Example of a carbanion attacking a carbonyl forming a new Csp3
-
Csp3 bond. B) A general scheme for a heck reaction showing the formation of a new
Csp2
-Csp2 bond. C) A general shceme for a Suzuki froming a new Csp2
-Csp2 bond
between aromatic rings. ................................................................................................ 10
Scheme 1.9. A) General reaction scheme for a Giese reaction adding to an electron
deficient alkene forming a Csp3
-Csp3 bond. B) An example of a Giese addition in the
synthesis of alkyl SO2F derivatives. .............................................................................. 11
Scheme 1.10. A) Synthesis of 1.9 using a novel radical reaction forming a C-C bond
between indol and a carbonyl compound. B) Examples of this reaction being used in
other complex molecule synthesis. ............................................................................... 12
Scheme 1.11. Example of a general free radical polymerization................................... 12
Scheme 1.12. A) Synthesis of barbiturates in a cascade reaction forming 2 rings in
one step. B) Synthesis of polyaromatic ribbons forming 5 new rings in a cascade
radical ring formation..................................................................................................... 13
Scheme 1.13. A) Reactions between radicals and triplet oxygen. B) Synthesis of
carboxylic acids through a SET oxygenation mechanism. C) Synthesis of oxygenated
species through an activated C-H group. D) Oxygenation of polymers leading to a bio
feedstock that can be used in valorization of plastic waste. .......................................... 15
xiii
Scheme 1.14. A) Addition to an alkyl halide exemplified by the amine addition. B)
Heteroatom addition to a carbonyl exemplified by an amine addition. C) Heteroatom
functionalization of a strained molecule exemplified by amine addition to
bicyclobutane. D) Heteroatom functionalization of a ketenimine exemplified by the
amine addition of a ketenimine formed through CuAAC conditions. ............................. 16
Scheme 1.15. A) Wittig reaction forming a ketenimine through the formation of a C=C
bond. B) Wittig reaction using an aza-Wittig reagent forming the C=N bond of the
ketenimine..................................................................................................................... 19
Scheme 1.16. A) Isocyanide addition to a free carbene to form a stable ketenimine.
B) Isocyanide addition to a metal carbene forming a ketenimine which then forms a
naphthalene group. ....................................................................................................... 20
Scheme 1.17. A) General synthesis of ketenes from acyl chlorides that have an alpha
hydrogen. B) Formation of a ketenimine using the same general mechanism for as
the ketenes. C) Synthesis of a ketenimine with a leaving group that is not a halide. .... 21
Scheme 1.18. A) Formation of ketenimines through an aza-Claisen rearrangement.
B) Formation of a ketenimine through a tosyl group migration into an alkyne. ............ 222
Scheme 1.19. A) An example of a ketenimine formation through a isocyanide-NifPerkow sequence. B) An example of a multicomponent coupling using an alkyne,
isocyanide, nucleophile leading to a ketenimine. .......................................................... 23
Scheme 1.20. A method of using CuAAC conditions to form sulfonylated ketenimines.
...................................................................................................................................... 23
Scheme 1.21. Reaction of ketenimines with nucleophiles exemplified in CuAAC
conditions...................................................................................................................... 24
Scheme 1.22. A) synthesis of 2-iminodolines through an intramolecular cyclization.
B) Synthesis of benzothiadiazine dioxides through a metal catalyzed intramolecular
cyclization...................................................................................................................... 25
Scheme 1.23. A) Synthesis of heterocycles to ketenimines using copper as a way to
achieve C-H activation. B) Method of forming 3-functionalized indoles using
ketenimine intermediates. ............................................................................................. 26
Scheme 1.24. Carbene insertion to a ketenimine that can lead to multiple ring
formations. .................................................................................................................... 27
Scheme 1.25. Synthesis of (S)-verapamil with the key step to form the chiral center
was a ketenimine........................................................................................................... 28
Scheme 1.26. Examples of the cycloadditions possible with ketenimine
intermediates................................................................................................................. 29
Scheme 1.27. A) example of a ketenimine undergoing a [1,5]-heteroatom shift
allowing for an electrocyclic reaction forming the final product. B) An example of a
ketenimine undergoing a [1,5]-H shift very similar to the previous example. C) An
xiv
example of a [1,3]-NR2 shift leading to ketenes which can then further react forming
quinolines...................................................................................................................... 31
Scheme 1.28. A) An example of a C-centered radical adding to a ketenimine
intramolecularly. B) An example of a ketenimine rearrangement to nitriles through a
radical process. ............................................................................................................. 32
Scheme 1.29. A) Example of a single electron transfer mechanism going through a
Cu(I)/Cu(II) system. B) Example of a two electron system between Cu(I) and Cu(III).
C) A general catalytic cycle for a system that has Cu(I), Cu(II), and Cu(III) species
going through both single and two electron processes. ................................................ 34
Scheme 1.30. Example of a Glaser coupling reaction between alkynes forming a CspCsp bond....................................................................................................................... 35
Scheme 1.31. A) An example of Csp2
-Csp3
through coupling between a C-H next to
a nitrogen and boronic acid. B) An example of an Csp3
-Csp3 bond formation through
a similar mechanism as the previous example.............................................................. 35
Scheme 1.32. Example of a Csp2
-Csp3
formation without the need of an alpha
nitrogen in one of the reactants..................................................................................... 36
Scheme 1.33. An example of an Csp2
-Csp2
formed in which a new 5 membered ring
is formed. ...................................................................................................................... 36
Scheme 1.34. A) C-N bond formation through copper catalyst with fluorinated aryl
rings with anilines. B) Similar mechanism with anilines but also heterocycles with
activated C-H bonds. C) A reaction between a substituted toluene and sulfonyl amide
forming a C-N................................................................................................................ 37
Scheme 1.35. Example of a C-O bond formation using copper catalyst to assist the
formation of a radical species and an organic catalyst to control stereochemistry. ....... 38
Scheme 1.36. Example of a 3-component coupling with copper activating an amine
to perform a cycloaddition. ............................................................................................ 38
Scheme 1.37. A) Example of copper activating an amidine in order to form imidazoles
intramolecularly. B) Example of copper being able to activate a hydrozine group to
form indazoles. C) Example of copper being to activate amidines intermolecularly. ..... 39
Scheme 1.38. Example of a sulfonamide being converted to radical species with
copper. .......................................................................................................................... 40
Scheme 1.39. A) C-O bond formation from starting amidine. B) C-O bond formation
from starting alcohol. C) C-O bond formation from starting phenol. D) C-O bond
formation from starting carboxylic acids. ....................................................................... 41
Scheme 1.40. An example of an aerobic oxygenation forming oxygenated amides...... 42
Scheme 2.1. Radical reaction with molecular oxygen in the triplet ground state........... 52
xv
Scheme 2.2. Synthesis of non-functionalized amidines using CuAAC conditions
resulting in ketenimines................................................................................................. 54
Scheme 2.3. Silylation of alcohols using HMDS and iodine catalyst ............................. 57
Scheme 2.4. Optimizing the iodine source to maximize reaction yield.......................... 58
Scheme 2.5. Base screening showing how LDA had a reactive conjugate acid while
potassium didn’t allow for similar yields......................................................................... 60
Scheme 2.6. Water is required in this reaction to protonate the peroxy radical (top) or
a 1:1 ratio of hydroxy and oxo products are observed (bottom) .................................... 61
Scheme 2.7. Competitive reaction between oxygenation and protonation upon the
addition of acid explains the increased ratio of desired product and non-functionalized
amidine resulting in lower yields.................................................................................... 62
Scheme 2.8. Formation of the desired hydroxy product along with the two other minor
products still present in the reaction.............................................................................. 63
Scheme 2.9. After oxygenation the peroxy group can either be reduced or oxydized
resulting in either the desired product or oxo byproduct................................................ 64
Scheme 2.10. A) How EDTA is able to quench copper in a solution by coordinating to
copper very strongly. B) Reaction of sodium thiosulfate with iodine producing sodium
iodide............................................................................................................................. 66
Scheme 2.11. Nucleophilic substitution of benzylic iodine with water in various
conditions ...................................................................................................................... 68
Scheme 2.12. Controlled reaction without O2 to test if the source of oxygen is from
water or oxygen from the atmosphere........................................................................... 69
Scheme 2.13. A) An example of a reaction relying on a low energy triplet state. B)
Control reaction with TEMPO to capture a low energy triplet state ............................... 70
Scheme 2.14. Example of a carbanion formation leading to SET mediated aerobic
oxidation........................................................................................................................ 70
Scheme 2.15. A) SET pathway experiment with sulfonyl triazole starting material
using LiHMDS and LDA. B) Expected outcome of the system. ..................................... 71
Scheme 2.16. A) SET pathway experiment with NaH and nonfunctionalized amidine.
B) Expected outcome of the NaH system...................................................................... 72
Scheme 2.17. Control reaction testing for photooxygenation by running reaction in
the absence of light. ...................................................................................................... 73
Scheme 2.18. A) Example of autoxidation with the formation of peroxy-intermediates
through radical formation followed by reduction reaction to alcohols. B) TEMPO
reacts with C-centered radicals and BHT reacts with O-centered radicals.................... 74
xvi
Scheme 2.19. Adding TEMPO to the reaction in step for leads to TEMPO
incorporation into final product 2.25 showing evidence for the presence of C-centered
radicals.......................................................................................................................... 75
Scheme 2.20. BHT reacting with peroxy radicals showing the presence of O-centered
radicals and intermediates indicative of autoxidation. ................................................... 76
Scheme 2.21. Proposed mechanism for the formation of the hydroxyamidine through
a radical process with intermediates either being seen or trapped................................ 80
Scheme 2.22. Formation of both α-bromoamidines and α-fluoroamidines which can
be isolated and do not undergo oxygenation................................................................. 81
Scheme 2.23. Deprotecting the sulfonyl group as well as oxidizing the OH to carbonyl
both are successful further showing utility of this reaction............................................. 83
Scheme 2.24. A) Rhodium carbene formation results in oxygen atom transfer when
sulfonyl amidines are present. B) Solvent effects demonstrate how S-O bonds can
interact with C-I bonds leading to bond polarization. C) Electron rich iodides reacts
with oxygen. .................................................................................................................. 86
Scheme 3.1. Solution of MeOH and sultam mixed with copper mesh resulting in high
conversion to oxygenated products............................................................................... 99
Scheme 3.2. A) Oxygen-free conditions showing the role of O2. B) Na2O2 being too
strong of a nucleophilic source of O2. C) H2O2 is a weaker oxidizing source of O2. C)
water effect in the reaction. ......................................................................................... 108
Scheme 3.3. A) Copper-free condition showing the need for copper. B) CuCl catalysis
showing Cu(I) can be utilized. B) Copper oxides can exist in the catalytic the cycle
without hindering the reaction outcome. D) Radical traps slows down, but not killing
the reaction. ................................................................................................................ 110
Scheme 3.4. A) Carbonyl replacing SO2 group leads to no reaction. B) Alkylating the
N-H of the sultam leads to no oxygenation in optimized conditions. C) The reactive
carbon cannot be aromatic...........................................................................................111
Scheme 3.5. Proposed mechanism for the copper catalyzed oxygenation of sultams.
.................................................................................................................................... 122
Scheme 4.1. SuFEx reaction scheme. ........................................................................ 126
Scheme 4.2. Common methods of producing SO2F groups from sulfonyl chloride..... 127
Scheme 4.3. Sulfonyl Fluoride installation without the use of sulfonyl chloride. .......... 128
Scheme 4.4. Many reactions possible using rhodium carbene chemistry showing the
utility of this chemistry in forming many molecular scaffoldings starting from just
sulfonyl triazoles.......................................................................................................... 129
xvii
Scheme 4.5. A) Our synthetic strategy for SO2F triazole. B) Common
Fluorosulfonylating reagents. C) CuAAC conditions that would require explosive
azides if attempted. ..................................................................................................... 130
Scheme 4.6. Two vial method in which the desired product was not observed........... 131
Scheme 4.7. Formation of the methylimidazole addition by-product from ketenimine
intermediates............................................................................................................... 132
Scheme 4.8. Reaction conditions for the solvent screen............................................. 133
Scheme 4.9. Reaction conditions for the base screen. ............................................... 134
Scheme 4.10. Reaction conditions for the base equivalence screen. ......................... 135
Scheme 4.11. Reaction conditions for the temperature screen. .................................. 136
Scheme 4.12. Reaction conditions for the concentration screen................................. 136
Scheme 4.13. Alternate idea for the use of rhodium carbene chemistry with nitriles as
an example without the need of SO2F triazole. ........................................................... 139
Scheme 4.14. Trying to activate the sulfonyl imidazole triazole by methylating it........ 142
Scheme 4.15. Using the ketenimine formation as a way to form SO2F amidines........ 143
Scheme 4.16. Conditions for the SO2F amidine products. .......................................... 144
Scheme 4.17. Conditions for the optimization of the NHC formation from the FSI...... 145
xviii
Abstract
This dissertation contributes to the development of heteroatom functionalization of
carbon-carbon bonds utilizing aerobic oxidation. The main focus is the development of
novel methodologies leading to oxygenated species of biologic relevance. Aerobic
oxidation could be a very valuable method for introducing oxygen atoms into the carboncarbon backbone of organic molecules, but its adoption has been limited. This is largely
due to the inert nature of molecular oxygen and the difficulty of controlling competing
oxidative processes, which often leads to poor product selectivity.
Chapter 1 is an overview of relevant methods to achieve heteroatom
functionalization including radical, ketenimine, formation, and copper catalyzed methods.
These topics give good background and insight into how projects in the remaining
chapters work.
Chapter 2 goes over the synthesis of α-hydroxyamidines through aerobic
oxidation. The key step in this process is the homolytic cleavage of a C-I bond of an
iodinated intermediate. When exposed to atmospheric oxygen, this intermediate
spontaneously forms C-centered radicals. These radicals efficiently transform into
oxygenated compounds leading to higher molecular complexity. This process uniquely
utilizes molecular oxygen without requiring photocatalysts or pressurized oxygen, and it
occurs under mild conditions. Our mechanistic studies provide insights into the intricate
sequence involved in the formation and selective capture of captodative radicals.
xix
Chapter 3 involves the oxygenation of sultam starting materials forming
compounds very similar to that of the oxicam class of drug. In this study, we present a
mild and easily accessible approach for producing oxygenated sultams through coppercatalyzed aerobic oxidation. By adjusting the copper source and solvent, this process can
selectively generate oxo and hydroxy products with high efficiency.
Chapter 4 involves interesting transformations of SO2F triazoles. These end up
forming ketenimines spontaneously and the main focus of the study was to study the
nature of these reactive intermediate. Through this, it was also found that carbenes can
be formed from the sulfonating reagent used. Chapter 5 contains the supplementary
information including, procedures, optimization, and spectra.
1
Chapter 1. Heteroatom Functionalization of Small Organic
1.1 Introduction
Heteroatom functionalization of organic molecules is a particularly useful tool for
synthetic chemists. Specifically, C(sp3
)–heteroatom functionalization has become
cornerstone of medicinal chemistry, materials, and agrochemical development in the
recent years.1 Currently, this methodology is limited to various SN1/SN2 reactions2
(Scheme 1.1 A and 1.1 B), specialized metal catalyzed cross-coupling reactions3
(Scheme 1.1 C), strain promoted reactions4
(Scheme 1.1 D), and alkenes/alkynes
reactions5
(Scheme 1.1 E). These examples can mainly be split up into two categories.
First, substitution reactions with a heteroatom nucleophile that can replace an often
heteroatom leaving group of lesser biologic activity or synthetic utility. These, however,
can be limited in scope and often require preparation of starting material since a leaving
group that is reactive enough to perform the desired transformation must be installed.
This leads to the second method of C–H activation for C(sp3
)–heteroatom
functionalization. This also has its challenges – the main hurdle has to do with the inherent
stability of C–H bonds and resistance to chemical reactions.
2
Scheme 1.1. A) Example of a general SN2 reaction. B) Example of a general SN1 reaction. C) Example of a general
metal catalyzed cross coupling. D) Example of a strain promoted nucleophilic addition E) Example of a general
alkene functionalization.
Some of the best ways that people have gotten around these challenges is through
the use of radical chemistry, ketenimine chemistry, and metal catalyzed C–H activation.
Radicals can be utilized to increase the reactivity of the system. Once a radical is formed,
a natural reaction pair is O2 (which exists as a diradical in its ground state).6
In its triplet
state, oxygen in the atmosphere is generally inert (spin-forbidden) with most organic
molecules because these organic molecules exist in singlet state with no unpaired
electrons. Ketenimine chemistry with sulfonyl triazoles is capable of taking readily
available starting materials to form more complex products to incorporate heteroatom
functionalization more feasibly.7 Lastly, copper catalyzed C-H activation uses copper to
activate a usually inert bond turning it into a useful substrate.8
In this chapter, I will discuss
the background, chemical reactions, and strategies of these three topic areas.
1.2 Radical Chemistry
Radical chemistry has always seemed to be taken less seriously than ionic
chemistry. Even in undergraduate teaching radicals are skimmed over or skipped entirely
3
to focus more on other common reactions, such as Grignard, aldol, and diels-alder
reactions.9 This is largely due to the perception that radicals are largely high-energy
species and highly unstable to be controlled under reaction conditions with a lack of
selectivity.10, 11 This is generally true in radicals pathways when these unstable species
are too unstable to reach desirable reaction lifetime and often, resulting in radical
degradation. However, the more understanding chemists have for these intermediates’
chemical behaviors, the more power they have in the ability to rationally design reactions
that could utilize them in very interesting ways. Radicals, when controlled, can undergo
many complex transformations and facilitate a large variety of reactions. Some of the
more useful examples of radicals are utilized in polymerization, carbon-carbon bond
formation12, complex molecule transformation and synthesis, and heteroatom
functionalization.
1.2.1 Radical Structure and Reactivity
The main attraction of radical utility is drawn from the fact that they are reactive
intermediates because radical species do not have a full valence shell, with one of their
electrons being unpaired (Figure 1.1). This unpaired electron is unstable in an
unconjugated system and will generally form a new bond in order to complete the octet
rules, despite its neutral state. However, this interesting electronic configuration also gives
radicals some advantages over a normal ionic condition.13 First, radicals can undergo
reactions under mild conditions (low temperature, low pressure, non-catalytic , etc.). They
can form sterically hindered bonds and remain inert towards OH and NH groups. They
also do not undergo β-elimination and alkyl radicals have small barriers for inversion
4
making precursor synthesis easier. Notably, radical mechanisms can have different
stereochemistry from their ionic counterpart.14
Figure 1.1. Comparison of the reactive forms of carbon showing reactive radicals with an unpaired electron as a
neutral species.
Mild reaction conditions allow radicals to tolerate many different functionalities as
well as various regiochemical and stereochemical environments. This makes radicals
excellent intermediates for a late-stage modification or as a method to crosslink molecules
in a convergent synthetic route. The practice of utilizing mild conditions is also desirable
in manufacturing industry because of no toxic additives or elevated temperatures making
the reactions more atom economical and less resource intensive at a large-scale practice.
This also circumvents usage of protection and deprotection reaction that utilizes harsher
conditions, for example, protecting and deprotecting alcohols in basic media or protecting
and deprotecting carbonyls when strong nucleophiles are present.
The ability to form sterically hindered centers, e.g. quaternary and neopentyl
centers, is a significant advantage in radical chemistry. This stems from the fact that
radicals do not involve any counterion and aggregation spheres along with being highly
reactive with early transition states. The ability to readily form crowded bond is particularly
useful in the synthesis of natural products that contain fully substituted bonds that need
to be formed during the synthetic route.15 For example, silphinene 1.1 (Scheme 1.2 A)
and its derivatives 1.2 (Scheme 1.2 B) have multiple quaternary carbons that need to
form in order to start from simple building blocks.16, 17
5
Scheme 1.2. A) Synthesis of silphinene through a radical cyclization. B) Synthesis of a silphinene like structure with a
cascade radical cyclization of from simple starting material.
Inertness character of radicals towards alcohols and amines is another major
advantage to radical based synthetic methods. Many pharmaceutically and agriculturally
relevant molecules contain OH and NH groups to varying degrees. Most conventional
synthetic methods, such as Grignard or aldol reactions, would require these groups to be
either protected or incorporated at a later stage. This greatly increases complexity
simultaneously decreases overall yield of the synthetic route in the final product with these
functionalities. This inertness towards OH and NH groups further shows that radicals can
be used in late-stage transformations because radicals can be formed in the presence of
these groups and still perform designed reactivity.
The final major advantage radicals have is their ability to undergo stereo inversion
(Scheme 1.3).18 Usually, the inability to retain stereochemistry is a major flaw as
stereochemistry is very important in the biologic activity of potential drug candidates.
Some enantiomers are beneficial, meanwhile others can be toxic making stereoselective
design significantly pivotal in drug molecules. However, in radical chemistry, this ability to
6
undergo stereo inversion is beneficial because reactive radical species can be designed
and guided into a preferable stereochemistry. With proper transition states, stereocontrol
can take place at the end of a reaction making stereocontrol not as important right from
the beginning of the synthesis. This allows the radical precursors to have a much simpler
synthetic route as the initial stereochemistry of a radical is not the deciding factor in the
stereo conformation of the final products.
Scheme 1.3. The equilibrium C-centered radicals are in showing stereo interconversion.
Since radicals and ionic species have very different chemical properties, they
undergo chemical transformation processes in different ways. This can lead to differences
in their corresponding product regioselectivity. An example that illustrates their
uniqueness is in the reaction of HBr with isobutene 1.3 (Scheme 1.4).18 In an ionic
reaction, the product is t-butyl bromide 1.4 resulting from the formation of carbocation 1.5
by the Markovnikov rule. The alkene 1.3 accepts a H+
from the HBr to form more stable
tertiary carbocation 1.5. Next, the resulting bromide anion adds to cation 1.5 to obtain
final product 1.4. This process differs when a radical initiator is present to form bromoradical species. This radical reacts with the alkene and form a β-bromo t-Butyl radical 1.6,
which can then be quenched with HBr forming iso-butyl bromide 1.7. Both of these
reactions produce a more stable intermediate, but due to the nature of each process, the
regioselectivity is flipped. Regioselectivity and activities relationship of potential drug
7
molecules is a deciding factor in a synthetic route design whereas radical pathways could
be the only way to produce products with specific regiochemistry.
Scheme 1.4 An example of a reaction that can have its regioselectivity switched by going through a radical process
instead of ionic process.
1.2.2 Radical Formation
In order to use the established utility and unique reactivity of radicals, the main
question would be how to initiate a radical process. There are two main radical initiators:
organic peroxides (Scheme 1.5 A) and aliphatic azo (Scheme 1.5 B) compounds.19 Both
of these radical initiators facilitate through thermolysis by heating the solution. Organic
peroxide homolytically cleave at the O-O bond forming two alkoxyl radicals, while alkyl
azo compounds homolytically cleave at the two C-N bonds forming two alkyl radicals and
a molecule of N2. Both have similar reactivities to be able to abstract protons from
activated C-H bonds forming C-centered radicals. However, organic peroxides pose
significant explosive risks and need to be stored safely in an aqueous solution. Alkyl azo
species, on the other hand, are benchtop stable solids that can be stored and handled
without extreme precautions.20 Because of the different precaution level, azo species are
more desirable and organic peroxides are the last resort, in case reaction with azo species
do not achieve desirable chemical transformation to radical species.
8
Scheme 1.5. A) An example of an organic peroxide acting as a radical initiator. B) An example of an azo compound
acting as a radical initiator.
One of the early methods to produce a controlled radical process is the usage of
tin hydrides.21 For example, tributyltin hydride is capable of forming a stable radical in the
presence of an initiator, such as azobisisobutyronitrile (AIBN) (Scheme 1.6). This tincentered radical can react with alkyl halides to form C-centered radicals that go on and
facilitate radical reactions in a very controlled manner. This method also is very mild and
does not require the protection of alcohol and carbonyl groups to maintain the starting
stereoselectivity. The main drawback of this methodology is the hazard of organotin
reagents. Organotin is known to be toxic and is hard to remove during purification.22
Therefore, this is not favorable in the food and drug industry. Tin hydride also has a
tendency to prematurely quench a C-centered radical before a full radical transformation
could be completed. One substitution of organotin reagents is silanes and germanes
since they do not share the same level of toxicity.
Scheme 1.6 Initiation of tin hydrides using AIBN leading stabilized tin radicals.
Another example of radical formation is through the use of carboxylic acids
(Scheme 1.7). In the Hunsdiecker reaction23, the carboxylic acid can undergo
decarboxylation forming CO2 and C-centered radicals. This can also be achieved through
thermolysis similar to the reaction with azo compounds and organic peroxides, but it is
9
somewhat limited by the required carboxylic starting material. Starting material scarcity is
not a big issue, since carboxylic acids are common and are readily synthesized, yet it can
limit the reaction scope in some complex multi-step synthetic routes.
Scheme 1.7 C-centered radical formation of carboxylic acids with the formation of CO2.
Another way to form radicals is through the usage of metals that can act as singleelectron oxidants.24 Examples of these metals include Cu(II), Mn(III), and Fe(III) – these
metal complexes can accept an electron and oxidize a substrate to produce radicals. This
can be done to C-H and heteroatom-H bonds forming both C-centered radicals and
heteroatom-centered radicals, which is a great advantage over the previously described
radical initiators that can only really form C-centered radicals. For example, Cu(II) is able
to form N-centered radicals with activated N-H bonds, while Fe(II) can form O-centered
OH radicals in hydrogen peroxide. The main downside for this method is the need for
metal additives, which is not always desirable in all synthetic routes especially when trace
metal needs to be removed.
1.2.3 Examples of Radicals in Synthesis
1.2.3.1 Carbon-Carbon Bond Formation
One of the most powerful aspects of radical reactions is their ability to quickly and
efficiently form carbon-carbon bonds, which is a mainstay of organic chemistry. This,
however, is not always the easiest task as carbon-carbon bonds are not polar and to get
carbon to react with another carbon is not energetically favorable. This previously only
happened when a very reactive species was involved like a carbanion (Scheme 1.8 A),
10
consequently required a much more inert reaction condition. The success of
organometallic reagents development in the 1970s became a solution to this issue to
some degree. The Heck25 (Scheme 1.8 B) and Suzuki26 (Scheme 1.8C) reactions came
to the spotlight of carbon-carbon bond formation as the result of organometallic research
and development. The main drawbacks of these reactions are the usage of complex and
expensive metal catalysts and inability to incorporate sp3 carbons.
Scheme 1.8. A) Example of a carbanion attacking a carbonyl forming a new Csp3
-Csp3 bond. B) A general scheme for
a heck reaction showing the formation of a new Csp2
-Csp2 bond. C) A general shceme for a Suzuki froming a new
Csp2
-Csp2 bond between aromatic rings.
Radicals can get around this through the production of C-centered radicals that
can then readily react with alkenes. An early example of this process is the Giese
reaction27, which illustrated the potential of radical mediated carbon-carbon bond
formation in organic synthesis. The Giese reaction takes a nucleophilic alkyl radical and
reacts it with an electron-deficient alkene (Scheme 1.9 A).28 The radical source is alkyl
halides which were originally initiated using a radical initiator with tin hydrides. Later, more
methods were developed excluding organotin as a reagent and expanded to other starting
material with carboxylic acids and esters functional groups. This allowed them to support
11
challenging functionalities, such as SO2F to molecules through ethenylsulfonylfluoride
(ESF) without any side reactions with SO2F (Scheme 1.9 B).29
Scheme 1.9. A) General reaction scheme for a Giese reaction adding to an electron deficient alkene forming a Csp3
-
Csp3 bond. B) An example of a Giese addition in the synthesis of alkyl SO2F derivatives.
A more recent example of the utility of carbon-carbon bond formation through
radical processes was reported by the Baran group.30 A direct coupling of indole with
carbonyl compounds was developed to form 1.8. This reaction could be implemented to
synthesize hapalindole Q 1.9 with 1.8 being converted to 1.9 in 4 steps (Scheme 10 A).
This was a great method, since normally the only way to couple these two compounds is
the ionic method, which required many functional group interconversions to gain the right
electronics to form the bond. The radicals process circumvents all aforementioned
limitations leading to a chemoselective synthesis without any protecting groups or prefunctionalization. This methodology was further developed in the synthesis of (-)-
communesin31 1.10, (-)-vincorine32 1.11, and methyl Ndecarbomethoxychanofruticosinate33 1.12 (Scheme 10 B).
12
Scheme 1.10. A) Synthesis of 1.9 using a novel radical reaction forming a C-C bond between indol and a carbonyl
compound. B) Examples of this reaction being used in other complex molecule synthesis.
Radical reactions are also capable of cascade reactions which can help add
molecular complexity very quickly in one step.34 The main application of radical reaction
is through the production of polymers (Scheme 1.11).12 The ability to synthesize
macromolecules quickly is very important for these reactions. Some examples of radicalmediated polymerization use (meth)acrylates, (meth)acrylamides, acrylonitrile, styrenes,
and dienes as the monomers. This is also able to execute in the presence of unprotected
functional groups within the monomer structure, such as alcohols, amines, carboxylic
acid, amides, and sulfones.35
Scheme 1.11. Example of a general free radical polymerization.
This cascade reaction also provides a straightforward synthetic strategy with ring
formations. Radicals can add to alkenes or alkyens intramolecular to add a high-level
complexity to a natural product synthesis quickly. In a demonstration example in Scheme
13
1.12 A, the used radical cascade reaction forms a tricyclic barbiturate 1.13.
36 This reaction
is readily initiated using a single-electron reductant, samarium(II) iodide (SmI2), to set off
a reaction forming 2 new rings from strategically placed the alkene group to react with the
in-situ radical species. Another example of a cascade reaction can form many rings at
once shown in the synthesis of polyaromatic ribbons 1.14 (Scheme 1.12 B).37 In this
method, a series of alkynes are placed between aromatic rings, which can then undergo
a radical cascade that results in the formation of a conjugated aromatic ring system. This
greatly simplifies synthetic routes for this class of molecule and shows a well-controlled
radical condition that efficiently forms multiple aromaticity all in a single step.
Scheme 1.12. A) Synthesis of barbiturates in a cascade reaction forming 2 rings in one step. B) Synthesis of
polyaromatic ribbons forming 5 new rings in a cascade radical ring formation.
1.2.3.2 Heteroatom Functionalization
The ability to construct a bond between carbon and heteroatoms is a cornerstone
of synthetic chemistry in order to increase functionality and enhance structural diversity
14
to molecules.38 For example, many pharmaceutical products contain OH and NH
functionalities, that provide drug molecules with more enhanced medicinal properties. In
conventional synthetic chemistry, N-alkylation can only be achievable with substitution
reactions with strong electrophiles (e.g. alkyl halides39, carbonyls40, and stained
systems41). Further developments in the introduction of organometallic reaction (e.g.
Buchwald-Hartwig42) and H-borrowing amination to facilitate C-N bond formation43. These
methods suffered various disadvantages resulting in low selectivity, including but not
limited to overalkylation, toxic waste stream, and expensive reagents.
A major aspect of heteroatom functionalization is the oxygenation of organic
molecules. One of the most transformative contribution aspects of radical reactions is its
ability to selectively react with ambient oxygen molecule in the air (Scheme 1.13 A),
despite the inertness of triplet O2 to most organic molecules. However, once a radical is
formed, it will allow a spontaneous formation of a C-O bond as a result of oxygenation.
Due to this reactivity, radicals and oxygen are a natural bonding pair that have been taken
advantage of throughout the years to form new oxygenated species with good
chemoselectivity and functional groups tolerance. For example, this process can be
observed in the formation of new carboxylic acids44 (Scheme 1.13 B) through a single
electron transfer (SET) mechanism and the autoxidation of privileged C-H bonds, e.g.
synthesis of diketopiperazines45 1.15 (Scheme 1.13 C). This process is highly desirable
due to the fact that oxygen is cheap and readily available obtained directly from ambient
air. The formation of radicals also does not involve toxic additives in some oxidation
reactions. This kind of chemistry has already been used in industry in processes, such as
in the cumene process, where phenol and acetone are produced following i-Pr benzene
15
oxygenation, and the Amoco process where carboxylic acid is the final product. There are
even applications of aerobic oxidation in autoxidation of polymers allowing for the quick
and efficient formation of bio feedstock in post-consumer plastic valorization (Scheme
1.13 D).46
Scheme 1.13. A) Reactions between radicals and triplet oxygen. B) Synthesis of carboxylic acids through a SET
oxygenation mechanism. C) Synthesis of oxygenated species through an activated C-H group. D) Oxygenation of
polymers leading to a bio feedstock that can be used in valorization of plastic waste.
1.3 Ketenimine Chemistry
Most heteroatoms are nucleophiles, e.g. alcohols, amines, and thiols. Because of
that, advances in the field of heteroatom functionalization came by way of developing new
electrophiles. The classical electrophiles are alkyl halides (Scheme 1.14 A) and carbonyls
(Scheme 1.14 B), but are limited by the need of stronger nucleophiles and limited by the
16
lack of molecular scaffolds that can be formed. This also limited the number of products
due to a combination of starting material scarcity and limited reactivity of the moieties.
More advancements in the development of more reactive electrophiles that can form more
structures and react with a wider range of nucleophiles are necessary. Some of these
advances were made in the field of strain-promoted reactions with the development of
highly strained structures giving them unprecedented reactivity.41 Some examples of this
are bicyclobutanes47 (Scheme 1.14 C) and strained alkynes48. These can be limited by
synthetic routes that require the use of harsh conditions to achieve the strained system
in the first place. Another advancement was the development of ketenimines that are
readily available through sulfonyl triazole chemistry (Scheme 1.14 D).49 This ensures the
starting material scarcity is not a problem and the ketenimines formed are reactive
enough to react with most alcohols, amines, thiols, and even water. They are also capable
of undergoing radical addition, cycloadditions, ring closures, and rearrangements to
nitriles, but the nucleophilic addition potential is what really makes ketenimines stand
out.50
Scheme 1.14. A) Addition to an alkyl halide exemplified by the amine addition. B) Heteroatom addition to a carbonyl
exemplified by an amine addition. C) Heteroatom functionalization of a strained molecule exemplified by amine
addition to bicyclobutane. D) Heteroatom functionalization of a ketenimine exemplified by the amine addition of a
ketenimine formed through CuAAC conditions.
17
1.3.1 Ketenimine Structure and Reactivity
Ketenimines are a type of heterocumulene that are nitrogenated. They have similar
electronic characteristics of both arenes and ketenes sharing a similar structure (Figure
1.2 A). They are often more thermodynamically stable when compared to ketenes.7
Ketenimines have a basic structure of C=C=N and a 90° angle between the C and N
substituents consistent with having the sp hybridized central carbon (Figure 1.2 B). This
central carbon is very important for the overall reactivity of ketenimines being a very
powerful electrophilic center. Ketenimines are also dipolar in nature having high electron
density in other regions. The double bonds also allow for cyclization, especially when the
π-system is extended. This interesting electronic environment allows ketenimines to
participate in a large scope of reactions ranging from nucleophilic and electrophilic
addition to cycloaddition.51, 52 There is also a isomerization barrier of about 30 to 65
KJ/mol resulting in two different bent isomers (Figure 1.2 C).53 Surprisingly, some
ketenimine derivatives can actually be stabilized enough to be isolated by having
heteroatoms or conjugated groups on the N and C terminals.54, 55
18
Figure 1.2. A) Examples of structures that have similar structures to ketenimines. B) The 90° angle between the
substituent on the C and N terminus of the ketenimines. C) The equilibrium the ketenimine isomers are in.
1.3.2 Synthesis of Ketenimines
1.3.2.1 Wittig Reaction Methods
Ketenimines were first synthesized by Staudinger as early as 1919.56 In this
synthesis, isocyanate 1.15 reacts with phosphorane 1.16 similarly to a Wittig reaction
(Scheme 1.15 A). This forms a four-membered ring oxaphosphetane intermediate 1.21
through a [2+2] cycloaddition. This intermediate undergoes a retro [2+2] cycloaddition
forming a phosphoryl species and ketenimine product 1.17. This general methodology
continues to be one of the most widely used processes to synthesize ketenimines. A
slightly modified method was also developed with aza-Wittig reagents 1.19 and ketenes
(Scheme 1.15 B).57 This undergoes a similar mechanism with a four-membered ring
intermediate 1.22. The main difference is that being that the C=N bond is formed, instead
of the C=C bond in the core C=C=N structure of the ketenimine 1.20.
19
Scheme 1.15. A) Wittig reaction forming a ketenimine through the formation of a C=C bond. B) Wittig reaction using
an aza-Wittig reagent forming the C=N bond of the ketenimine.
1.3.2.2 Nitrile Insertions to Carbenes
Another ketenimines synthetic method is through the addition of isonitriles 1.24 to
carbenes. One example of this was the formation of a N,N’-diamidocarbene 1.23 forming
N,N’-diamidoketenimines 1.25 (Scheme 1.16 A).58 These ketenimine are actually stable
and can be isolated up to 96% yield. Another example is the reaction of isonitriles 1.24
reaction with chromium carbenes 1.26 leading to the facile synthesis of naphthalenes
1.28 (Scheme 1.16 B).59 Ketenimine 1.27 spontaneously reacts with the neighboring
phenyl ring to form another aromatic ring. The overall mechanism involves the addition of
C to the empty p orbital of the Fischer carbene. Following this, either the lone pair or metal
would be able to attack the triple bond leading to a ketenimine structure.60
20
Scheme 1.16. A) Isocyanide addition to a free carbene to form a stable ketenimine. B) Isocyanide addition to a metal
carbene forming a ketenimine which then forms a naphthalene group.
1.3.2.3 Elimination Reactions
Another reaction type that can be used in ketenimine synthesis is elimination
reactions. This is very similar to the standard way of ketenes synthesis in which a
acylchloride that has a α-hydrogen is prepared (Scheme 1.17 A). Following this, a base
is introduced to deprotonate the α-hydrogen forming a C=C bond with the loss of chloride.
This can directly be applied to ketenimine synthesis with the preparation of imidoyl
chlorides, which can also be deprotonated at the α-hydrogen and form a C=C bond on
the resulting ketenimine with the loss of chloride. An example of this is observed when
imidoyl chloride 1.29 is used to form ketenimine 1.30 just with the addition of triethyl amine
(TEA) (Scheme 1.17 B).61
These methods are not only limited to imidoyl halides, but can
also work with other leaving groups. For example, when using strong bases,
imidothioesters can be employed with a thiol leaving group that allows for the formation
of the ketenimine structure. When imidothioester 1.31 is deprotonated with n-BuLi, the
resulting transformation is the desired ketenimine 1.32 (Scheme 1.17 C).62
21
Scheme 1.17. A) General synthesis of ketenes from acyl chlorides that have an alpha hydrogen. B) Formation of a
ketenimine using the same general mechanism for as the ketenes. C) Synthesis of a ketenimine with a leaving group
that is not a halide.
1.3.2.4 Rearrangement Reactions
Intramolecular rearrangements are another source for ketenimine synthesis.
However, these are often limited by the required specialized starting materials as specific
functionalities to perform rearrangement. One example of a rearrangement leading to a
ketenimine is the aza-Claisen rearrangement of N-sulfonyl-N-allyl-ynamides 1.33.
63 This
takes a N-sulfonyl-N-allyl-ynamides 1.33 to undergoes a thermal aza-Claisen
rearrangement at 110 °C resulting in ketenimine product 1.34 (Scheme 1.18 A). Another
example of a rearrangement is the 1,3-Ts sift of sulfonylamides.64 Once again, elevated
temperatures are used in this case at 120 °C leading to a tosyl group shift into alkyne
1.35 leading to ketenimine 1.36 (Scheme 1.18 B).
22
Scheme 1.18. A) Formation of ketenimines through an aza-Claisen rearrangement. B) Formation of a ketenimine
through a tosyl group migration into an alkyne.
1.3.2.5 Multicomponent Coupling Reactions
Some of the most common multicomponent reactions for the synthesis of
ketenimines is the use of isonitriles. Isonitriles can react with acylchlorides (Scheme 1.19
A) and alkynes (Scheme 1.19 B) forming ketenimine intermediates. For example, an
isocyanide can react with aryl acylchloride forming ketenimine 1.37, when imidoyl chloride
intermediate 1.38 reacts with phosphites.65 These reactions have very high yield and can
get around having an acetyl chloride that does not have a α-hydrogen for deprotonation.
An example of isonitrile reacting with alkynes is when an isonitrile reacts with alkynes
between ester groups.66 In this reaction, isonitrile can attack alkyne at one of the sp
hybridized carbons leading to zwitterionic intermediate 1.40 that can deprotonate a
nucleophile. The resulting protonated form of the intermediate can be attacked by the
nucleophile leading to ketenimine 1.39.
23
Scheme 1.19. A) An example of a ketenimine formation through a isocyanide-Nif-Perkow sequence. B) An example of
a multicomponent coupling using an alkyne, isocyanide, nucleophile leading to a ketenimine.
One of the best ways of forming ketenimines is through the usage of coppercatalyzed azide-alkyne cycloaddition (CuAAC) (Scheme 1.20). Normally, this reaction
forms stable triazoles that do not degrade or react further.67 However, when sulfonyl
azides were used, the corresponding metalated sulfonyl triazole intermediates 1.42 were
found to be unstable as nitrogen gas effervesced and ketenimines 1.40 was formed.49
This synthesis is very desirable, since the staring materials, e.g. alkynes and sulfonyl
azides, are commercially available or readily synthesized material. The conversion to
ketenimine 1.40 is also high with good yields of the desired products. Another advantage
in this procedure is that it can tolerate various functional groups with copper reaction
selectively catalyzes azide and alkyne without interfering with other groups, such as alkyl
halides and carbonyls.
Scheme 1.20. A method of using CuAAC conditions to form sulfonylated ketenimines.
24
1.3.3 Ketenimines in Organic Synthesis
1.3.3.1 Nucleophilic Addition to Ketenimines
One of the main advantages of ketenimines is the ability to facilitate heteroatom
functionalization. This heteroatom functionalization can be achieved mainly though
nucleophilic addition to the central sp hybridized carbon which is highly electron deficient.
This reactivity allows for the synthesis of amidines, imidates, and amides with the use of
N- and O-nucleophiles (Scheme 1.21).52 This methodology can also be extended to thiols
for sulfur-containing products.68 The best example of this methodology is shown through
the use of the sulfonylated ketenimines in CuI. In these reactions, the desired nucleophile
couples with azide and alkyne leading to a 3-component coupling in one step. To date,
this still is one of the best ways to achieve heteroatom functionalization to form amidines,
amides, and imidates.
Scheme 1.21. Reaction of ketenimines with nucleophiles exemplified in CuAAC conditions.
The electrophilic nature of ketenimines can also be utilized to form heterocycles.
In order to achieve this, alkyne with an adjacent functional group that can react with a
newly formed ketenimine intramolecularly. For example, this mechanism was observed
in the synthesis of 2-iminoindolines 1.47 from 2-alkynyl alkylated anilines 1.43 reacting
with tosyl azide 1.45 with CuI (Scheme 1.22 A).69 Here, alkyne 1.43 is converted to
ketenimine 1.46 to react with the amine group intramolecularly forming 2-iminoindolines
25
1.47. This methodology can also be extended to include having reactive functional groups
on the group attached to sulfonyl azide. For example, a reaction between bromosubstituted aryl sulfonyl azides 1.48, a terminal alkyne, and NH4Cl, results in ketenimine
addition product 1.49 with a nearby NH2 adjecent to an aryl bromide (Scheme 1.22 B),
then 1.49 proceeds to undergo copper-catalyzed N-arylation to form benzothiadiazine
dioxides 1.50.
70
Scheme 1.22. A) synthesis of 2-iminodolines through an intramolecular cyclization. B) Synthesis of benzothiadiazine
dioxides through a metal catalyzed intramolecular cyclization.
Ketenimines can also react with carbon nucleophiles to form imines. This is
particularly useful for other heterocycles to bind to the copper center in CuAAC method
to produce ketenimines. When reacting a sulfonyl azide with a alkyne in the presence of
pyrroles, a C-C bond is formed (Scheme 1.23 A).71 This happens because the nitrogen of
the pyrrole ligates to copper to put ortho-carbons closer to the central carbon of the
ketenimine 1.52. This close proximity makes the ortho-carbon to the nitrogen more
reactive towards the central carbon of the ketenimine resulting in carbon-carbon bond
formation similar to that of a Friedel-Crafts reaction. Interestingly, N-H functionality is very
important because the reaction is very slow and poor yielding when the N of the pyrrole
26
is alkylated. Unsubstituted indoles cannot undergo this reaction. To get around this, 4,7-
dihydroindole could be utilized and aromatized to form the desired 2-funtionalized
indoles.71 This methodology could also be expanded to alkylated indoles 1.54 by having
a more nucleophilic carbon forming 3-functionalized indoles 1.55 (Scheme 1.23 B).72
Scheme 1.23. A) Synthesis of heterocycles to ketenimines using copper as a way to achieve C-H activation. B)
Method of forming 3-functionalized indoles using ketenimine intermediates.
Ketenimines could also act as electrophiles for carbenes. One of the most common
carbenes that can be formed is a N-heterocyclic carbene (NHC). Thiazolecarbene is a
class of NHC able to undergo this reaction can be readily be formed by having a
thiazolium salts precursor (Scheme 1.24).73 The salts 1.56 are deprotonated to a
thiazolecarbene 1.57. Following deprotonation, NHC 1.57 can attack ketenimine 1.58 to
form a product that can undergo a [3+2] cycloaddition with one equivalent of ketenimine
1.58 to produce 1.60. This methodology has also been applied to other NHCs, for
example the ones that would form with imidazolium salts.74
27
Scheme 1.24. Carbene insertion to a ketenimine that can lead to multiple ring formations.
1.3.3.2 Ketenimines as Nucleophiles
Ketenimines can also act a nucleophile when there is a leaving group on the N
terminal. Most examples of this have a t-butyldimethylsilyl (TBS) protecting group on the
N terminal of the ketenimine. When this group is removed, the added electron density to
the nitrogen allows for the formation of a nitrile to get a nucleophilic carbon. This carbon
can react with a myriad of electrophiles to fully substituted quaternary centers. This has
a very good potential for chiral-controlled quaternary centers, which is not all that easy to
achieve as it is a very sterically hindered center. A very good example of this is in the
synthesis of (S)-verapamil 1.64 (Scheme 1.25).75 The key intermediate, N-silyl ketenimine
1.61, can be acylated to 1.63 with good stereo control to form a quaternary stereocenter.
After further steps, this product can be transformed into (S)-verapamil 1.64.
28
Scheme 1.25. Synthesis of (S)-verapamil with the key step to form the chiral center was a ketenimine.
1.3.3.3 Cycloaddition Reactions of Ketenimines
Ketenimines can be a key part in [3+1], [2+2], [3+2], and [4+2] cycloaddition
reaction, due to the dipole nature of the C=C=N structure. Ketenimines can undergo [3+1]
cycloaddition with isonitriles (Scheme 1.26 A).76 In this reaction, a phosphorous atom from
diphosphinoketenimines 1.65 can take part in a [3+1] cycloaddition to form intermediate
1.66. This can then react with water to form azaphospholene derivatives 1.67. An example
of a [2+2] cycloaddition is best exemplified when ketenimine intermediate 1.68 is able to
react with imines intramolecularly forming 1,2-dihydroazeto[2,1-b]quinazolines 1.70
(Scheme 1.26 B).77 This happens in a step-wise process – the lone pairs of the imine
interact with the sp center of the ketenimine forming 1.69 prior to the full formation of the
four-membered ring. [3+2] cycloaddition can also be exemplified through the synthesis
of 2-amino-H-pyrazolo[5,1-a]isoquinolines 1.74 (Scheme 1.26 C).78 In this reaction, there
are two cyclizations. The first one forms 1,3-dipolar synthon 1.72 through a 6-endocyclization of N′-(2-alkynylbenzylidene)-hydrazides 1.71. The 1,3-dipolar synthon 1.72
can then react in a [3+2] cycloaddition with ketenimine formed with the CuAAC
methodology. The result of this cycloaddition is 2-amino-H-pyrazolo[5,1-a]isoquinolines
29
1.74 after aromatization of intermediate 1.73. The final type of cycloaddition ketenimines
can perform is a [4+2] (Scheme 1.26 D). This type of cycloaddition can be shown by the
ability for ketenimines formed through the CuAAC method to react with azadienes 1.75
forming tetrahydropyrimidines 1.76.
79 This wide-range substrate performance of
cycloadditions ketenimines is a testament to their utility in synthetic chemistry as ring
forming reactions are some of the best ways to enhance molecular complexity in
medicinal chemistry applications when many complex heterocycles are required with high
levels of functionalization.
Scheme 1.26. Examples of the cycloadditions possible with ketenimine intermediates.
30
1.3.3.3 Sigmatropic Rearrangement of Ketenimines
Sigmatropic rearrangements can also be utilized in ketenimine chemistry, such as
[1,5] and [1,3] shifts. [1,5] shifts can occur with both heteroatoms and hydrogen. An
example of a heteroatom shift is when N-(2-X-carbonyl)phenyl ketenimines 1.77 form 2-
X-quinolin-4(3H)-ones 1.79 (Scheme 1.27 A).80 In that reaction, the first step is a [1,5]-X
shift forming 1.78 which then undergoes a 6π-electrocyclic cyclization (6π-ERC) to form
the final product 1.79. This is very similar to a hydrogen shift that forms similar products
leveraging the heightened acidity by being next to two aromatic rings (Scheme 1.27 B).81
[1,3] shifts can occur when a heteroatom group at the α position to the central carbon of
the ketenimine (Scheme 1.27 C).82 This usually requires extreme conditions such as
vacuum pyrolysis. In these reactions, the heteroatom is usually transferred from a
carbonyl group resulting in formation of a ketene. For instance, ketenimine 1.83
undergoes a [1,3]-NR2 shift forming ketene 1.84 under flash vacuum thermolysis (FVT)
conditions. Ketene 1.84 then spontaneously forms quinoline 1.85 in FVT condition.
31
Scheme 1.27. A) example of a ketenimine undergoing a [1,5]-heteroatom shift allowing for an electrocyclic reaction
forming the final product. B) An example of a ketenimine undergoing a [1,5]-H shift very similar to the previous example.
C) An example of a [1,3]-NR2 shift leading to ketenes which can then further react forming quinolines.
1.3.3.4 Radical Reactions of Ketenimines
Radicals can add to the central carbon of the ketenimine similar to nucleophiles.
Most examples are intramolecular forming new rings in the process. An example of this
happening is the synthesis of 3-(1H-indol-2-yl)propionitriles 1.90 in which benzyl radical
1.87 is able to add to ketenimine intramolecularly (Scheme 1.28 A).83 This forms Ccentered radical 1.88 that binds to radical 1.89 from radical initiator reagent AIBN. This
mechanism follows pretty much all radical additions into ketenimines. Ketenimines can
also undergo radical based rearrangements often leading to nitriles. An example of this
is the formation of nitrile 1.95 from the thermally-driven homolytic cleavage of the N-C
32
bond N-benzyl-ketenimines 1.91 (Scheme 1.28 B).84 This forms a nitrile group and a Ccentered radical 1.93, which can form a new C-C bond from benzyl radical 1.94 from the
first step.
Scheme 1.28. A) An example of a C-centered radical adding to a ketenimine intramolecularly. B) An example of a
ketenimine rearrangement to nitriles through a radical process.
1.4 Copper Catalyzed C–H Functionalization
1.4.1 Advantages of Copper Catalyst
Copper, an abundant metal in the earth’s crust and low toxicity, is a very desirable
catalyst to use in organic synthesis. Thus, it a relatively cheap and safe catalyst source
in comparison to other precious platinum-group metal (PGM) catalysts (e.g. iridium,
rhodium, and palladium). Copper salts are benchtop air-stable with an exception of a few
Cu(I) salts (e.g. Cu(I)OTf). This allows for easy storage and handling without the need of
gloveboxes or Schlenk technique. This is a significant advantage that copper has over
other catalyst in practice as the use of a glovebox can be very restricting and Schlenk
technique can be limiting in manufacture.
33
1.4.2 Reactivity of Copper
Most of the PGM catalysts, such as iridium and rhodium, undergo 2-electron
transfer making the catalytic cycles easier to track.85 Copper, however, exists in a myriad
of oxidation states being Cu(0), Cu(I), Cu(II), and Cu(III).86 This allows for single-electron
transfers (SET) to take place with more electron-rich substrates. SET in copper catalysis
can complicate the mechanism study; however, this complexity can also make copper
reactivity very versatile.86 The most common method to achieve copper-catalyzed C–H
functionalization is exploited extensively in Cu(II)/Cu(I) system (Scheme 1.29 A). This
involves a one-electron process that has Cu(II) as an oxidant to accept an electron from
a substrate. This forms a radical species, which can then undergo radical processes
before the Cu(I) is oxidized back to Cu(II) to start the catalytic cycle again. Copper can
also perform two-electron processes in a Cu(I)/Cu(III) system (Scheme 1.29 B). This
mainly is utilized in the synthesis of heterocycles as the first step is considered to be
similar to an oxidative addition in some palladium cross-coupling reactions with a Cu(III)
intermediate. This Cu(III) species can facilitate a reductive elimination type step forming
the heterocycle reforming Cu(I). There are also Cu(I)/Cu(II)/Cu(III) systems that involve
both one- and two-electron transfers (Scheme 1.29 C). This results in structurally similar
products like a Cu(I)/Cu(III) system, but it can be expanded to other substrates that were
previously unachievable. This versatility of copper allows it to perform many different C–
H functionalizations (e.g. Csp–H, Csp2–H, and Csp3–H). These functionalizations can also
form C–C, C–N, and C–O bonds either forming heterocycles or open-chain species.
34
Scheme 1.29. A) Example of a single electron transfer mechanism going through a Cu(I)/Cu(II) system. B) Example of
a two electron system between Cu(I) and Cu(III). C) A general catalytic cycle for a system that has Cu(I), Cu(II), and
Cu(III) species going through both single and two electron processes.
1.4.3 Reactions with Copper
1.4.3.1 C–C Bond Formation
Copper catalyzed reactions can in fact form C–C bonds like in more traditional
palladium catalyzed cross-coupling reactions. These, however, are not limited to just sp2–
sp2 hybridized carbon coupling like in most cross-coupling reactions, but they can also be
expanded to work with sp3
, sp2
, and sp-hybridized carbons.87
An early example of C–C bond formation was the Glaser–Hay reaction (Scheme
1.30).88 This reaction was a homocoupling reaction between two alkynes to form a new
35
Csp–Csp. This reaction takes terminal alkynes and couples them together in the presence
of oxygen to oxidize Cu(I) back to C(II). However, this reaction was highly limited by the
fact that it was not that selective in which alkynes are coupled. This led to a large excess
of one alkyne to force a reaction between the two different ones.
Scheme 1.30. Example of a Glaser coupling reaction between alkynes forming a Csp-Csp bond.
Better examples of C–C bond formation is the synthesis of tetrahydroisoquinoline
1.98 derivatives involving a Csp2–Csp3 bond formation (Scheme 1.31 A).89 In this,
arylation of a Csp3–H α to a nitrogen in 1.96 with an aryl boronic acid 1.97. This same
methodology can be expanded to Csp3–Csp3 bond formation in the alkylation of
tetrahydroisoquinoline 1.100 (Scheme 1.31 B).90 This reaction involves a similar
activation of a Csp3–H bond next to a nitrogen in 1.99, which then contains a nuleophilic
Csp3 atom. The electrophiles in this example involve Csp3–H adjacent to a NO2 group but
can probably be expanded to other Csp3–H carbons adjacent to activating groups.
Scheme 1.31. A) An example of Csp2
-Csp3
through coupling between a C-H next to a nitrogen and boronic acid. B)
An example of an Csp3
-Csp3 bond formation through a similar mechanism as the previous example.
Csp3–Csp3 bonds are not just limited to reaction with Csp3–H adjacent to a
nitrogen or oxygen, but can also work with a Csp3–H that is between electron
36
withdrawing groups like in 1.103 (Scheme 1.32). For instance, benzylic Csp3–H like in
1.101 can react with 1,3-dicarbonyl 1.102 compounds.91 In this case, copper catalyst
forms radicals with an organic peroxide, then react with a benzylic hydrogen to form Ccentered radicals.
Scheme 1.32. Example of a Csp2
-Csp3
formation without the need of an alpha nitrogen in one of the reactants.
Interestingly, Csp2–Csp2 can be formed in the presence of Csp3 and Csp2 by
oxidating the Csp3 (Scheme c1.33). In the synthesis of pyrrolo[2,1-a]isoquinolines
1.108,
92 a [3+2] cycloaddition takes place after the oxidation of the starting material 1.106
to form a zwitter ionic species 1.105. Species 1.105 acts as a dipole for 1.106 to facilitate
the cycloadditions forming 1.107.
Scheme 1.33. An example of an Csp2
-Csp2
formed in which a new 5 membered ring is formed.
1.4.3.2 C–Heteroatom Bond Formation
C–N bond formation can be achieved in a copper-catalyzing reaction through a
SET mechanism. It removes the need to functionalize the hydrocarbon before the
construction of a C–N bond. In a reaction between anilines and aryl C–H bonds (Scheme
37
1.34 A),93 fluorinated aryl 1.109 reacts with aniline 1.110 resulting in the synthesis of
diphenylamines 1.111. This methodology can also be applied to Csp3 carbons in
heterocycles (Scheme 1.34 B), whereas electron-poor anilines 1.113 can react with
heterocycle 1.112 to form 1.114. These methodologies utilize oxygen as an oxidant
capable of changing the oxidation state of copper necessitate for the reaction operation.
C–N bond formation can also proceed with a Csp3 center compound. For example, in a
reaction of a benzylic Csp3–H on a substituted toluene 1.115 with sulfonamides 1.116
(Scheme 1.34 C),94 an oxidant (e.g. peroxide) is required in order to form a catalytic cycle
between the oxidative states of copper in this cycle.
Scheme 1.34. A) C-N bond formation through copper catalyst with fluorinated aryl rings with anilines. B) Similar
mechanism with anilines but also heterocycles with activated C-H bonds. C) A reaction between a substituted toluene
and sulfonyl amide forming a C-N.
C–O bond formation can also be achieved through copper-catalyzing reactions.
This is important because oxygenated species are important both as a synthetic building
block as well as a biologically active product. An example of C–O bond formation leading
to useful synthetic building blocks is demonstrated in a reaction when TEMPO 1.119 was
38
installed on a C–H bond adjacent to a carbonyl like in 1.118 through a resulting Ccentered radical species catalyzed by copper catalyst (Scheme 1.35).95 This OTMP group
is able to maintain the stereochemistry after further modifications with the TMP group
being able to be removed. The organic catalyst is able to react with the carbonyl to control
the stereochemistry. This results to hydroxy groups with mild conditions that don’t affect
the structural integrity of carbonyl group.
Scheme 1.35. Example of a C-O bond formation using copper catalyst to assist the formation of a radical species and
an organic catalyst to control stereochemistry.
1.4.3.3 C–Heteroatom Bond Formation for the Synthesis of Heterocycles
C–heteroatom functionalization is also utilized in the synthesis of heterocycles.86
The synthesis of heterocycles is important for pharmaceuticals and are often involved in
biologically active species. The synthesis of H-pyrazolo[5,1-a]isoquinolines 1.124
(Scheme 1.36 A)96, a three-component coupling reaction takes place that involves oxygen
as an oxidant for the copper to abstract electrons from amine 1.123. This gives amine
1.123 the right activity to attack intermediate 1.125 in a [3+2] cycloadditions. Intermediate
1.125 formed through tosyl hydrazine 1.122 adding to the aldehyde 1.121, which then
perform an intramolecular cyclization with the activated alkyne.
Scheme 1.36. Example of a 3-component coupling with copper activating an amine to perform a cycloaddition.
39
Another example of heterocycle formation is the formation of benzoimidazoles97
1.127 (Scheme 1.37 A) and indazoles98 1.129 (Scheme 1.37 B). Both 1.126 and 1.128
have a reactive N–H bond that can ligate to copper to activate C–H bond and form a new
C–N bond intramolecularly. Similar products can also be formed through Csp–H bond
functionalization, in which imidazole derivatives 1.131 are synthesized (Scheme 1.36
D).99 This happens with the formation of copper acetylide to facilitate the imidazole
formation by binding to the amidine 1.130 with the assistance of O2 in order to oxidize
copper at key parts of the mechanism.
Scheme 1.37. A) Example of copper activating an amidine in order to form imidazoles intramolecularly. B) Example of
copper being able to activate a hydrozine group to form indazoles. C) Example of copper being to activate amidines
intermolecularly.
Another application of C–N bond formation is when sulfonamides is adjacent to
alkenes is introduced to a copper catalyst (Scheme 1.38 ).100 In this reaction, the copper
can ligate to the nitrogen of 1.132 leading to a cyclization with the adjacent alkene forming
intermediate 1.134. The resulting radical species 1.134 then reacts with the nearby aryl
group forming a second ring producing product 1.133. This cascade reaction is able to
40
perform a carboamination cyclization followed by a radical cyclization resulting in a facile
synthesis of pyrrolidine and piperidine derivatives.
Scheme 1.38. Example of a sulfonamide being converted to radical species with copper.
C–O bonds can also be formed to synthesize oxygen-containing heterocycles. An
example is when oxazoles 1.136 are synthesized from amide starting material 1.135
(Scheme 1.39 A).101 This reaction involves a Cu(II)/Cu(I) system where the copper
initiates an SET process facilitating the cyclization. Other examples involve the
carboetherification, followed by C–H functionalization similar to in the synthesis of
tetrahydrofuran 1.38 (Scheme 1.39 B).102 This undergoes a very similar mechanism with
sulfonyl amides adjacent to alkenes, except with a hydroxyl (OH) instead of amine (NH).
A similar mechanism occurs in the synthesis of dibenzofurans 1.140 (Scheme 1.39 C).103
The nitrogen attacks an aromatic ring instead of an alkene. The example could also be
expanded to benzolactones 1.42 when carboxylic acid substitutes biphenyl 1.141 to
undergo a C–H functionalization cyclization (Scheme 1.39 D).104
41
Scheme 1.39. A) C-O bond formation from starting amidine. B) C-O bond formation from starting alcohol. C) C-O
bond formation from starting phenol. D) C-O bond formation from starting carboxylic acids.
1.4.3.4 Copper-Catalyzed Oxygenase Type Reactivity
Previously discussed, oxygenated species are useful in synthetic applications.
Copper is also known for its oxygenase type reactivity – an aerobic oxidation with oxygen.
Reported significant work has been demonstrated in this field to oxygenate a wide range
of substrates.87 In most cases, copper catalyzes the formation of a radical species via
SET mechanism, e.g. synthesis α-ketoamidines 1.145 (Scheme 1.40).105 In this reaction,
an N-alkylation reaction between an aniline 1.143 and terminal alkyne 1.144 to form a
radical species to react with ambient O2 producing the oxygenated species.
42
Scheme 1.40. An example of an aerobic oxygenation forming oxygenated amides.
1.5 Conclusion
Heteroatom functionalization of the carbon-carbon back bone is a mainstay of
organic chemistry. This allows chemists to add molecular complexity to organic molecules
often resulting in better biological activity for pharmaceuticals or more useful physical
properties in materials chemistry. However, traditional methods of forming heteroatomcarbon bonds through substitution or addition reactions are limited by starting material
scarcity or harsh conditions. Some of the best methods of getting around these limitations
is to employ radical, ketenimine, and organocopper intermediates.
1.6 References
1. Ge, L.; Zhang, C.; Pan, C.; Wang, D.-X.; Liu, D.-Y.; Li, Z.-Q.; Shen, P.; Tian,
L.; Feng, C., Photoredox-catalyzed C–C bond cleavage of cyclopropanes for the
formation of C(sp3)–heteroatom bonds. Nature Communications 2022, 13 (1), 5938.
2. Katritzky, A. R.; Brycki, B. E., The mechanisms of nucleophilic substitution in
aliphatic compounds. Chemical Society Reviews 1990, 19 (2), 83-105.
3. Korch, K. M.; Watson, D. A., Cross-Coupling of Heteroatomic Electrophiles.
Chemical Reviews 2019, 119 (13), 8192-8228.
4. Wiberg, K. B., The Concept of Strain in Organic Chemistry. Angewandte Chemie
International Edition in English 1986, 25 (4), 312-322.
5. Beletskaya, I. P.; Nenajdenko, V. G., Towards the 150th Anniversary of the
Markovnikov Rule. Angewandte Chemie International Edition 2019, 58 (15), 4778-4789.
6. Borden, W. T.; Hoffmann, R.; Stuyver, T.; Chen, B., Dioxygen: What Makes This
Triplet Diradical Kinetically Persistent? Journal of the American Chemical Society 2017,
139 (26), 9010-9018.
43
7. Lu, P.; Wang, Y., The thriving chemistry of ketenimines. Chemical Society Reviews
2012, 41 (17), 5687-5705.
8. Saranya, S.; Anilkumar, G., Copper Catalysis. In Copper Catalysis in Organic
Synthesis, 2020; pp 1-5.
9. Zard, S. Z., Radicals in Action: A Festival of Radical Transformations. Organic
Letters 2017, 19 (6), 1257-1269.
10. Ingold, K. U., Kinetic and mechanistic studies of free radical reactions in the 21st
century. 1997, 69 (2), 241-244.
11. Rowlands, G. J., Radicals in organic synthesis. Part 1. Tetrahedron 2009, 65 (42),
8603-8655.
12. Carbon–Carbon Bond Formation by Free-Radical Reactions. In Organic
Chemistry, 2004; pp 272-291.
13. Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S., Radicals: Reactive Intermediates
with Translational Potential. Journal of the American Chemical Society 2016, 138 (39),
12692-12714.
14. Jasperse, C. P.; Curran, D. P.; Fevig, T. L., Radical reactions in natural product
synthesis. Chemical Reviews 1991, 91 (6), 1237-1286.
15. Silva, T. S.; Coelho, F., Methodologies for the synthesis of quaternary carbon
centers via hydroalkylation of unactivated olefins: twenty years of advances. Beilstein
Journal of Organic Chemistry 2021, 17, 1565-1590.
16. Rao, Y. K.; Nagarajan, M., Formal total synthesis of (.+-.)-silphinene via radical
cyclization. The Journal of Organic Chemistry 1989, 54 (24), 5678-5683.
17. Curran, D. P.; Kuo, S. C., Tandem radical cyclization approach to angular
triquinanes. A short synthesis of (.+-.)-silphiperfol-6-ene and (.+-.)-9-episilphiperfol-6-ene.
Journal of the American Chemical Society 1986, 108 (5), 1106-1107.
18. Togo, H., Advanced free radical reactions for organic synthesis. Elsevier
Amsterdam: 2004; Vol. 2.
19. Sheppard, C. S.; Kamath, V. R., The selection and use of free radical initiators.
Polymer Engineering & Science 1979, 19 (9), 597-606.
20. Walling, C., Some properties of radical reactions important in synthesis.
Tetrahedron 1985, 41 (19), 3887-3900.
21. Curran, D. P., 4.2 - Radical Cyclizations and Sequential Radical Reactions. In
Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds. Pergamon: Oxford,
1991; pp 779-831.
44
22. Studer, A.; Amrein, S., Tin hydride substitutes in reductive radical chain reactions.
Synthesis 2002, 2002 (07), 835-849.
23. Johnson, R. G.; Ingham, R. K., The Degradation Of Carboxylic Acid Salts By
Means Of Halogen - The Hunsdiecker Reaction. Chemical Reviews 1956, 56 (2), 219-
269.
24. Fu, G. C., Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A
Radical Alternative to SN1 and SN2 Processes. ACS Central Science 2017, 3 (7), 692-
700.
25. Beletskaya, I. P.; Cheprakov, A. V., The Heck Reaction as a Sharpening Stone of
Palladium Catalysis. Chemical Reviews 2000, 100 (8), 3009-3066.
26. Farhang, M.; Akbarzadeh, A. R.; Rabbani, M.; Ghadiri, A. M., A retrospectiveprospective review of Suzuki–Miyaura reaction: From cross-coupling reaction to
pharmaceutical industry applications. Polyhedron 2022, 227, 116124.
27. Giese, B., Formation of CC Bonds by Addition of Free Radicals to Alkenes.
Angewandte Chemie International Edition in English 1983, 22 (10), 753-764.
28. Kitcatt, D. M.; Nicolle, S.; Lee, A.-L., Direct decarboxylative Giese reactions.
Chemical Society Reviews 2022, 51 (4), 1415-1453.
29. Krutak, J. J.; Burpitt, R. D.; Moore, W. H.; Hyatt, J. A., Chemistry of ethenesulfonyl
fluoride. Fluorosulfonylethylation of organic compounds. The Journal of Organic
Chemistry 1979, 44 (22), 3847-3858.
30. Baran, P. S.; Richter, J. M., Direct Coupling of Indoles with Carbonyl Compounds:
Short, Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and
Fischerindole Alkaloid Families. Journal of the American Chemical Society 2004, 126
(24), 7450-7451.
31. Zuo, Z.; Xie, W.; Ma, D., Total Synthesis and Absolute Stereochemical Assignment
of (−)-Communesin F. Journal of the American Chemical Society 2010, 132 (38), 13226-
13228.
32. Zhang, M.; Huang, X.; Shen, L.; Qin, Y., Total Synthesis of the Akuammiline
Alkaloid (±)-Vincorine. Journal of the American Chemical Society 2009, 131 (16), 6013-
6020.
33. Wei, Y.; Zhao, D.; Ma, D., Total Synthesis of the Indole Alkaloid (±)- and (+)-Methyl
N-Decarbomethoxychanofruticosinate. Angewandte Chemie International Edition 2013,
52 (49), 12988-12991.
34. Plesniak, M. P.; Huang, H.-M.; Procter, D. J., Radical cascade reactions triggered
by single electron transfer. Nature Reviews Chemistry 2017, 1 (10), 0077.
45
35. Moad, G.; Rizzardo, E.; Thang, S. H., Toward Living Radical Polymerization.
Accounts of Chemical Research 2008, 41 (9), 1133-1142.
36. Huang, H.-M.; Procter, D. J., Radical–Radical Cyclization Cascades of
Barbiturates Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls. Journal
of the American Chemical Society 2016, 138 (24), 7770-7775.
37. Byers, P. M.; Alabugin, I. V., Polyaromatic Ribbons from Oligo-Alkynes via
Selective Radical Cascade: Stitching Aromatic Rings with Polyacetylene Bridges. Journal
of the American Chemical Society 2012, 134 (23), 9609-9614.
38. Lovering, F.; Bikker, J.; Humblet, C., Escape from Flatland: Increasing Saturation
as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry 2009, 52
(21), 6752-6756.
39. Cheung, C. W.; Hu, X., Amine synthesis via iron-catalysed reductive coupling of
nitroarenes with alkyl halides. Nature Communications 2016, 7 (1), 12494.
40. Afanasyev, O. I.; Kuchuk, E.; Usanov, D. L.; Chusov, D., Reductive Amination in
the Synthesis of Pharmaceuticals. Chemical Reviews 2019, 119 (23), 11857-11911.
41. Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan, C.-M.;
Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas,
J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.;
Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S., Strain-Release
Heteroatom Functionalization: Development, Scope, and Stereospecificity. Journal of the
American Chemical Society 2017, 139 (8), 3209-3226.
42. Heravi, M. M.; Kheilkordi, Z.; Zadsirjan, V.; Heydari, M.; Malmir, M., BuchwaldHartwig reaction: An overview. Journal of Organometallic Chemistry 2018, 861, 17-104.
43. Alfonso, N.; Do, V. K.; Chavez, A. J.; Chen, Y.; Williams, T. J., Catalyst
carbonylation: a hidden, but essential, step in reaction initiation. Catalysis Science &
Technology 2021, 11 (7), 2361-2368.
44. Bonaparte, A. C.; Betush, M. P.; Panseri, B. M.; Mastarone, D. J.; Murphy, R. K.;
Murphree, S. S., Novel Aerobic Oxidation of Primary Sulfones to Carboxylic Acids.
Organic Letters 2011, 13 (6), 1447-1449.
45. Tian, H.; Ermolenko, L.; Gabant, M.; Vergne, C.; Moriou, C.; Retailleau, P.; AlMourabit, A., Pyrrole-Assisted and Easy Oxidation of Cyclic α-Amino Acid- Derived
Diketopiperazines under Mild Conditions. Advanced Synthesis & Catalysis 2011, 353 (9),
1525-1533.
46. Li, T.; Vijeta, A.; Casadevall, C.; Gentleman, A. S.; Euser, T.; Reisner, E., Bridging
Plastic Recycling and Organic Catalysis: Photocatalytic Deconstruction of Polystyrene via
a C–H Oxidation Pathway. ACS Catalysis 2022, 12 (14), 8155-8163.
46
47. Walczak, M. A. A.; Krainz, T.; Wipf, P., Ring-Strain-Enabled Reaction Discovery:
New Heterocycles from Bicyclo[1.1.0]butanes. Accounts of Chemical Research 2015, 48
(4), 1149-1158.
48. Baskin, J. M.; Prescher, J. A.; Laughlin, S. T.; Agard, N. J.; Chang, P. V.; Miller,
I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R., Copper-free click chemistry for dynamic in
vivo imaging. Proceedings of the National Academy of Sciences 2007, 104 (43), 16793-
16797.
49. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S., A Facile Access to NSulfonylimidates and Their Synthetic Utility for the Transformation to Amidines and
Amides. Organic Letters 2006, 8 (7), 1347-1350.
50. Alajarin, M.; Marin-Luna, M.; Vidal, A., Recent Highlights in Ketenimine Chemistry.
European Journal of Organic Chemistry 2012, 2012 (29), 5637-5653.
51. Lu, P.; Wang, Y., Strategies for Heterocyclic Synthesis via Cascade Reactions
Based on Ketenimines. Synlett 2010, 2010 (02), 165-173.
52. Yoo, J. E.; Chang, S., Copper-Catalyzed Multicomponent Reactions: Securing a
Catalytic Route to Ketenimine Intermediates and their Reactivities. Current Organic
Chemistry 2009, 13 (18), 1766-1776.
53. Perst, H., Science of Synthesis. Thieme Chemistry: 2006; Vol. 23, p 781.
54. Sung, K., N-Substituent effects on the stability of ketenimines. Journal of the
Chemical Society, Perkin Transactions 2 2000, (4), 847-852.
55. Sung, K., Substituent effects on stability of ketenimines. Journal of the Chemical
Society, Perkin Transactions 2 1999, (6), 1169-1174.
56. Staudinger, H.; Meyer, J., Über neue organische phosphorverbindungen III.
Phosphinmethylenderivate und phosphinimine. Helvetica Chimica Acta 1919, 2 (1), 635-
646.
57. Yang, Y.-Y.; Shou, W.-G.; Hong, D.; Wang, Y.-G., Selective Synthesis of 4-
Alkylidene-β-lactams and N,N′-Diarylamidines from Azides and Aryloxyacetyl Chlorides
via a Ketenimine-Participating One-Pot Cascade Process. The Journal of Organic
Chemistry 2008, 73 (9), 3574-3577.
58. Hudnall, T. W.; Moorhead, E. J.; Gusev, D. G.; Bielawski, C. W., N,N′-
Diamidoketenimines via Coupling of Isocyanides to an N-Heterocyclic Carbene. The
Journal of Organic Chemistry 2010, 75 (8), 2763-2766.
59. Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, S. Y., Aminobenzannulation via
metathesis of isonitriles using chromium carbene complexes. Journal of the American
Chemical Society 1992, 114 (22), 8722-8724.
47
60. Qiu, G.; Ding, Q.; Wu, J., Recent advances in isocyanide insertion chemistry.
Chemical Society Reviews 2013, 42 (12), 5257-5269.
61. Katagiri, T.; Handa, M.; Asano, H.; Asanuma, T.; Mori, T.; Jukurogi, T.; Uneyama,
K., Preparations and reactions of 2-trifluoromethylketenimines. Journal of Fluorine
Chemistry 2009, 130 (8), 714-717.
62. Fromont, C.; Masson, S., Reactivity of N-phenyl silylated ketenimines with
electrophilic reagents. Tetrahedron 1999, 55 (17), 5405-5418.
63. DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H.; Deng, J.;
Lohse, A. G.; Zhang, Y.-S., N-Allyl-N-sulfonyl Ynamides as Synthetic Precursors to
Amidines and Vinylogous Amidines. An Unexpected N-to-C 1,3-Sulfonyl Shift in Nitrile
Synthesis. The Journal of Organic Chemistry 2011, 76 (12), 5092-5103.
64. Bendikov, M.; Duong, H. M.; Bolanos, E.; Wudl, F., An Unexpected Two-Group
Migration Involving a Sulfonynamide to Nitrile Rearrangement. Mechanistic Studies of a
Thermal N → C Tosyl Rearrangement. Organic Letters 2005, 7 (5), 783-786.
65. Coffinier, D.; El Kaim, L.; Grimaud, L., Isocyanide-Based Two-Step ThreeComponent Keteneimine Formation. Organic Letters 2009, 11 (8), 1825-1827.
66. Oakes, T. R.; Donovan, D. J., Reactions of isocyanides with activated acetylenes
in protic solvents. The Journal of Organic Chemistry 1973, 38 (7), 1319-1325.
67. Worrell, B. T.; Malik, J. A.; Fokin, V. V., Direct Evidence of a Dinuclear Copper
Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions. Science 2013, 340 (6131),
457-460.
68. Kubíčková, A.; Markos, A.; Voltrová, S.; Marková, A.; Filgas, J.; Klepetářová, B.;
Slavíček, P.; Beier, P., Aza-Wolff rearrangement of N-fluoroalkyl triazoles to ketenimines.
Organic Chemistry Frontiers 2023, 10 (13), 3201-3206.
69. She, J.; Jiang, Z.; Wang, Y., One-Pot Synthesis of Functionalized Benzimidazoles
and 1H-Pyrimidines via Cascade Reactions of o-Aminoanilines or Naphthalene-1,8-
diamine with Alkynes and p-Tolylsulfonyl Azide. Synlett 2009, 2009 (12), 2023-2027.
70. Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S., Synthetic Utility of Ammonium Salts
in a Cu-Catalyzed Three-Component Reaction as a Facile Coupling Partner. The Journal
of Organic Chemistry 2008, 73 (23), 9454-9457.
71. Cho, S. H.; Chang, S., Room temperature copper-catalyzed 2-functionalization of
pyrrole rings by a three-component coupling reaction. Angewandte Chemie 2008, 120
(15), 2878.
72. Wang, J.; Wang, J.; Zhu, Y.; Lu, P.; Wang, Y., Copper-cascade catalysis:
synthesis of 3-functionalized indoles. Chemical Communications 2011, 47 (11), 3275-
3277.
48
73. Cheng, Y.; Ma, Y.-G.; Wang, X.-R.; Mo, J.-M., An Unprecedented Chemospecific
and Stereoselective Tandem Nucleophilic Addition/Cycloaddition Reaction of Nucleophilic
Carbenes with Ketenimines. The Journal of Organic Chemistry 2009, 74 (2), 850-855.
74. Mo, J.-M.; Ma, Y.-G.; Cheng, Y., Synthesis of novel synthetic intermediates from
the reaction of benzimidazole and triazole carbenes with ketenimines and their application
in the construction of spiro-pyrroles. Organic & Biomolecular Chemistry 2009, 7 (23),
5010-5019.
75. Mermerian, A. H.; Fu, G. C., Nucleophile-Catalyzed Asymmetric Acylations of Silyl
Ketene Imines: Application to the Enantioselective Synthesis of Verapamil. Angewandte
Chemie International Edition 2005, 44 (6), 949-952.
76. Ruiz, J.; Gonzalo, M. P.; Vivanco, M.; Rosario Díaz, M.; García-Granda, S., A
three-component reaction involving isocyanide, phosphine and ketenimine functionalities.
Chemical Communications 2011, 47 (14), 4270-4272.
77. Alajarín, M.; Vidal, A.; Tovar, F.; Ramírez de Arellano, M. C.; Cossío, F. P.;
Arrieta, A.; Lecea, B., New Stereoselective Intramolecular [2 + 2] Cycloadditions between
Ketenimines and Imines on an ortho-Benzylic Scaffold: 1,4-Asymmetric Induction. The
Journal of Organic Chemistry 2000, 65 (22), 7512-7515.
78. Li, S.; Luo, Y.; Wu, J., Three-Component Reaction of N′-(2-
Alkynylbenzylidene)hydrazide, Alkyne, with Sulfonyl Azide via a Multicatalytic Process: A
Novel and Concise Approach to 2-Amino-H-pyrazolo[5,1-a]isoquinolines. Organic Letters
2011, 13 (16), 4312-4315.
79. Lu, W.; Song, W.; Hong, D.; Lu, P.; Wang, Y., Copper-Catalyzed One-Pot
Synthesis of 2-Alkylidene-1,2,3,4- tetrahydropyrimidines. Advanced Synthesis &
Catalysis 2009, 351 (11-12), 1768-1772.
80. Alajarín, M.; Ortín, M.-M.; Sánchez-Andrada, P.; Vidal, Á., Tandem
Pseudopericyclic Reactions: [1,5]-X Sigmatropic Shift/6π-Electrocyclic Ring Closure
Converting N-(2-X-Carbonyl)phenyl Ketenimines into 2-X-Quinolin-4(3H)-ones. The
Journal of Organic Chemistry 2006, 71 (21), 8126-8139.
81. Alajarin, M.; Bonillo, B.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Orenes,
R.-A., Domino reactions initiated by intramolecular hydride transfers from
tri(di)arylmethane fragments to ketenimine and carbodiimide functions. Organic &
Biomolecular Chemistry 2010, 8 (20), 4690-4700.
82. Wentrup, C.; Rao, V. V. R.; Frank, W.; Fulloon, B. E.; Moloney, D. W. J.; Mosandl,
T., Aryliminopropadienone−C-Amidoketenimine− Amidinoketene−2-Aminoquinolone
Cascades and the Ynamine−Isocyanate Reaction. The Journal of Organic Chemistry
1999, 64 (10), 3608-3619.
83. Alajarín, M.; Vidal, A.; Ortín, M.-M.; Bautista, D., Persistent radical effect in the
intramolecular addition of benzylic radicals onto ketenimines: selective cross-coupling of
49
α-(indol-2-yl)benzyl radicals with the 1-cyano-1-methylethyl radical. New Journal of
Chemistry 2004, 28 (5), 570-577.
84. Kim, S. S.; Zhu, Y.; Lee, K. H., Thermal Isomerizations of Ketenimines to Nitriles:
Evaluations of Sigma-Dot (σ•) Constants for Spin-Delocalizations. The Journal of Organic
Chemistry 2000, 65 (10), 2919-2923.
85. Arevalo, R.; Chirik, P. J., Enabling Two-Electron Pathways with Iron and Cobalt:
From Ligand Design to Catalytic Applications. Journal of the American Chemical Society
2019, 141 (23), 9106-9123.
86. Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W., Copper-Catalyzed C–H
Functionalization Reactions: Efficient Synthesis of Heterocycles. Chemical Reviews
2015, 115 (3), 1622-1651.
87. Zhang, C.; Tang, C.; Jiao, N., Recent advances in copper-catalyzed
dehydrogenative functionalization via a single electron transfer (SET) process. Chemical
Society Reviews 2012, 41 (9), 3464-3484.
88. Sindhu, K. S.; Anilkumar, G., Recent advances and applications of Glaser coupling
employing greener protocols. RSC Advances 2014, 4 (53), 27867-27887.
89. Baslé, O.; Li, C.-J., Copper-Catalyzed Oxidative sp3 C−H Bond Arylation with Aryl
Boronic Acids. Organic Letters 2008, 10 (17), 3661-3663.
90. Li, Z.; Li, C.-J., Highly Efficient Copper-Catalyzed Nitro-Mannich Type Reaction:
Cross-Dehydrogenative-Coupling between sp3 C−H Bond and sp3 C−H Bond. Journal of
the American Chemical Society 2005, 127 (11), 3672-3673.
91. Borduas, N.; Powell, D. A., Copper-Catalyzed Oxidative Coupling of Benzylic C−H
Bonds with 1,3-Dicarbonyl Compounds. The Journal of Organic Chemistry 2008, 73 (19),
7822-7825.
92. Yu, C.; Zhang, Y.; Zhang, S.; Li, H.; Wang, W., Cu(ii) catalyzed oxidation-[3+2]
cycloaddition-aromatization cascade: Efficient synthesis of pyrrolo [2, 1-a] isoquinolines.
Chemical Communications 2011, 47 (3), 1036-1038.
93. Zhao, H.; Wang, M.; Su, W.; Hong, M., Copper-Catalyzed Intermolecular
Amination of Acidic Aryl C H Bonds with Primary Aromatic Amines. Advanced Synthesis
& Catalysis 2010, 352 (8), 1301-1306.
94. Powell, D. A.; Fan, H., Copper-Catalyzed Amination of Primary Benzylic C−H
Bonds with Primary and Secondary Sulfonamides. The Journal of Organic Chemistry
2010, 75 (8), 2726-2729.
95. Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C., A general approach
to the enantioselective α-oxidation of aldehydesvia synergistic catalysis. Chemical
Science 2012, 3 (1), 58-61.
50
96. Li, S.; Wu, J., Synthesis of H-Pyrazolo[5,1-a]isoquinolines via Copper(II)-
Catalyzed Oxidation of an Aliphatic C−H Bond of Tertiary Amine in Air. Organic Letters
2011, 13 (4), 712-715.
97. Brasche, G.; Buchwald, S. L., C H Functionalization/C N Bond Formation:
Copper-Catalyzed Synthesis of Benzimidazoles from Amidines. Angewandte Chemie
International Edition 2008, 47 (10), 1932-1934.
98. Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H., Copper-Catalyzed Aerobic C(sp2)–H
Functionalization for C–N Bond Formation: Synthesis of Pyrazoles and Indazoles. The
Journal of Organic Chemistry 2013, 78 (8), 3636-3646.
99. Li, J.; Neuville, L., Copper-Catalyzed Oxidative Diamination of Terminal Alkynes by
Amidines: Synthesis of 1,2,4-Trisubstituted Imidazoles. Organic Letters 2013, 15 (7),
1752-1755.
100. Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R., Pyrrolidine and Piperidine
Formation via Copper(II) Carboxylate-Promoted Intramolecular Carboamination of
Unactivated Olefins: Diastereoselectivity and Mechanism. The Journal of Organic
Chemistry 2007, 72 (10), 3896-3905.
101. Cheung, C. W.; Buchwald, S. L., Room Temperature Copper(II)-Catalyzed
Oxidative Cyclization of Enamides to 2,5-Disubstituted Oxazoles via Vinylic C–H
Functionalization. The Journal of Organic Chemistry 2012, 77 (17), 7526-7537.
102. Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R., Copper-Catalyzed
Intramolecular Alkene Carboetherification: Synthesis of Fused-Ring and Bridged-Ring
Tetrahydrofurans. Journal of the American Chemical Society 2012, 134 (29), 12149-
12156.
103. Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu, Q., Cu-Catalyzed Oxidative C(sp2)–H
Cycloetherification of o-Arylphenols for the Preparation of Dibenzofurans. Organic Letters
2012, 14 (4), 1078-1081.
104. Gallardo-Donaire, J.; Martin, R., Cu-Catalyzed Mild C(sp2)–H Functionalization
Assisted by Carboxylic Acids en Route to Hydroxylated Arenes. Journal of the American
Chemical Society 2013, 135 (25), 9350-9353.
105. Zhang, C.; Jiao, N., Dioxygen Activation under Ambient Conditions: Cu-Catalyzed
Oxidative Amidation−Diketonization of Terminal Alkynes Leading to α-Ketoamides.
Journal of the American Chemical Society 2010, 132 (1), 28-29.
51
Chapter 2. C-I Bond Activation of Synthesized α-Iodoamidines leading
to α-Hydroxyamidines Through Aerobic Oxidation
2.1 Introduction
Radicals are reactive intermediates that have become very useful in chemical
synthesis1, 2. Carbon-centered radicals have the ability to functionalize the carbon-carbon
framework of molecules, such as rapid polymerization3
, heteroatom functionalization4
,
complex molecule transformation5, 6, and the ability to form carbon-carbon bonds7 can all
be done utilizing radical chemistry. In fact, this utility derives from unstable radicals having
an unpaired electron in their valence shell that lead to high reactivity as it tries to get an
electron to form an electron pair8
. Although this instability is a source for high chemical
reactivity, it also makes radicals exceedingly hard to work with – they are too short-lived
to be useful and they often dimerize or participate in other side reactions in the presence
of nearby molecules. Due to the instability of radicals, there have been many efforts to
design an ideal system with controlled radical reactions9
. This can often be achieved by
using additives10, e.g. NHPI11, 12 or thiocarbonylthio compounds13, sterics14, 15 (Figure 2.1),
or electronic stabilization (Push-Pull)16-22 (Figure 2.1). These additives control radical
formation by shuttling the radical through the additive in a much more controlled manner.
Sterics prevent the reactive radical from reacting with anything other than the substrates,
and electronically stabilizes the radical itself to slow the reaction resulting in less side
reactions.
52
Figure 2.1. Examples of sterically stabilized and push-pull stabilized radicals.
A major advantage of radical chemistry is its ability to achieve C(sp3
)–
functionalization11, 23. Carbons that are sp3 generally have limited reactivity and often rely
on substitution reactions such as SN1
24/SN2
25, strain promoted reactions, specialized
metal catalyzed cross-coupling, C-H activation26-29, metal carbenoid formation30-32
,
reduction/oxidation of alkenes, and alkynes33. These methods often suffer from limited
starting material availability and or lack of reactivity resulting in low yields. To avoid this
limitation, radical chemistry can be utilized to increase the reactivity of the system.
Scheme 2.1. Radical reaction with molecular oxygen in the triplet ground state.
A natural reaction substrate pair with radicals is O2, which exists as a diradical in
its ground state allowing for direct oxidation34 (Scheme 2.1). In its triplet state,
atmospheric O2 is generally inert while most organic molecules are in the singlet state (no
unpaired electrons). Although radicals are present, triplet oxygen (3O2) loses its inertness
and rapidly reacts to form oxygenated species with sp3 carbons. Oxygenated species are
a cornerstone of pharmaceuticals with many examples of their incorporation into drugliked molecules. Because of that, a direct and desirable way to obtain oxygenated species
is by utilizing the cheapest and most readily available oxidant35-37. The main challenge
53
with this method stems from the aforementioned limitations of radical chemistry such as
limited radical formation methods and hard to control side reactions.
2.2 Reaction Inspiration, Design and Background
Figure 2.2. Sulfonyl amide general structure along and some examples of their presence in biological active drug
molecules
Amidines are very biologically relevant moieties with very limited synthetic routes.
A specific derivative of these amidines are sulfonylamidines which have been shown to
have relevant biological activity38-40 (Figure 2.2). Chang developed a reaction
methodology to easily synthesize sulfonyl amidines utilizing ketenimines 2.3 that result
from the instability of metalated sulfonyl triazoles41, 42 (Scheme 2.2 A). These ketenimines
are strong electrophiles that allow amines to be added to form an amidine group. This is
a very modular synthetic strategy that can tolerate a broad substrate scope. Starting
material scarcity was not a problem since these starting materials are products of copper
catalyzed azide-alkyne cycloaddition (CuAAC)43 needing only alkynes 2.1 and sulfonyl
azides 2.2. However, the main drawback of this chemistry is the azavinyl benzyl
methylene group that could not be modified in compound 2.4.
54
Electrophilic Center Electrophilic Center
Nucleophilic Center
Scheme 2.2. Synthesis of non-functionalized amidines using CuAAC conditions resulting in ketenimines
Using the ability to form lithiated ketenimines 2.6 reported by Fokin44 (Scheme 2.2
B), we envisioned the ability to modify that position further broadening the scope of these
amidine compounds. This would produce a ketenimine that had the same electrophilic
center but also an additional nucleophilic center that could be used to modify the adjacent
methylene position (Scheme 2.2 B). Iodine was the first choice of reagent to form
iodoamidines 2.7, as it is a versatile functional group45 that is capable of undergoing many
useful transformations46 (Figure 2.3 A). However, upon exposing 2.7 to air, the
oxygenated species 2.11 was formed through the aerobic oxidation pathway. Taking
inspirations from reported chemistry in the formation of rhodium carbenes 2.9 starting
from sulfonyl triazoles 2.8
47, this transformation could be able to take advantage of the
3O2-C centered radical reaction pair by forming an aza-vinyl radical 2.10 (Figure 2.3 B).
Because carbenes and radicals have similar stability patterns48, this is believed to be a
unique methodology that relies on a radical pathway to form α-oxygenated amidines 2.11
from a simple sulfonyl triazole starting material 2.8 through aerobic oxidation.
55
Figure 2.3. A) Formation of the iodoamidine from the lithiated ketenimine B) Synthesis of oxygenated amidines from
similar rhodium carbene systems.
2.3 Reaction Optimizations
Initially, the reaction yields were low hovering at around 36% after scaleup and
purification. This requires reaction optimization study to develop reaction conditions with
a high yield to obtain a new practical at-scale methodology. In order to achieve this, a
series of studies was conducted by alternating a single reaction condition variable to
obtain the best conditions combination that yield the highest isolated product. These
reaction variables include an iodine source, a base, a solvent, additives, temperature,
and amount of oxygen. The reaction yield was determined by the analysis of liquid
chromatography-mass spectrometry (LC-MS) equipped with a diode array detector (DAD)
function. This allowed us to observe and trace all reaction species, such as by-products,
starting materials, and products over various reaction times (Figure 2.4). Quantitative
reaction yield analysis was calculated against a LC-MS calibration curve. This allows
56
accurate quantification of product at a given intensity for high throughput screening
without purification and isolation of product for isolated yields.
Figure 2.4. An example of a LC-MS DAD chromatogram showing many reaction species.
Entry Base
(1.1 equiv.) I
+ Source I
+
(equiv.) Piperidine
(equiv.)
Conc.
(mM)
H+
source
O2
Source additive %
Yield
1 LiHMDS I2 1.2 1.2 32 brine air none 75%
2 KHMDS I2 1.2 1.2 32 brine air none 64%
3 n-BuLi I2 1.2 1.2 32 brine air none 30%
4 LDA I2 1.2 1.2 32 brine air none 0%
5 NaH I2 1.2 1.2 32 brine air none >5%
6 LiHMDS I2 1.2 1.2 32 none air none 44%
7 LiHMDS I2 1.2 1.2 32 NH4Cl air none 68%
8 LiHMDS I2 1.2 1.2 32 water air none 76%
9 LiHMDS I2 1.2 1.2 32 brine air EDTA 56%
10 LiHMDS I2 1.2 1.2 32 brine air Na2EDTA 75%
11 LiHMDS I2 1.2 1.2 32 brine air NaI 76%
12 LiHMDS I2 1.2 1.2 32 brine air Na2S2O2 57%
13 LiHMDS ICl 1.2 1.2 32 brine air none 70%
14 LiHMDS PyICl 1.2 1.2 32 brine air none 83%
2.16 2.15 2.14 2.13 2.12
57
15 LiHMDS PyICl 1.2 1.2 32 brine O2
balloon none 84%
16 LiHMDS PyICl 1.5 1.2 32 brine air none 62%
17 LiHMDS PyICl 1.2 1.5 32 brine air none 79%
Table 1.1. Optimization for the α-hydroxyamidine synthesis.
2.3.1 Iodine Source Screening
Scheme 2.3. Silylation of alcohols using HMDS and iodine catalyst
Initially, I2 was used as the iodine source in the reaction as a convenience since it
can easily be purified and does not really decompose. This resulted in the formation of
iodinated intermediate 2.12 to make α-hydroxyamidine 2.14. However, the yields for this
reaction were very lower, around 50%, with many different side reactions upon scaleup
(Scheme 2.4). The side products were determined to be silylation byproducts 2.17. This
can be explained by the fact that I2 is known to catalyze silylation of alcohols in the
presence of hexamethyldisilazane (HMDS) (Scheme 2.3).49 Since HMDS is a product of
LiHMDS protonation, it is reasonable that I2 would react with the oxygenated product 2.14
to form silylated species 2.17. In order to get around this, different iodinating sources
without a secondary iodine atom were screened. First, N-iodosuccinimide (NIS) was used
as it is commercially available and very easy to obtain. This reaction with NIS resulted in
the desired α-hydroxyamidine 2.14, however, α-oxoamidine 2.18 also was formed in a
significant amount lowering the yield of desired product 2.14. Similar results were also
observed when DIH and N-Iodophthalimide were used in replacement of NIS, this implied
that succinimide and other leaving groups could react with ketenimine leading to side
reactions to result in the formation of α-oxoamidine 2.18. To avoid the formation of 2.18,
58
iodine sources without a nucleophilic leaving group such as ICl and PyICl. ICl were used,
which performed as efficiently as I2 to convert of up to 70% (Table 1.1 Entery 13) and 75%
(Table 1.1 Entery 1) respectively, followed by degradation to silylated products 2.17 during
the isolation process. PyICl, on the other hand, lead to both a higher LC-MS yield (83%)
(Table 1.1 Entry 14) and isolated yield (77%) showing that by limiting the amount of iodine
in the reaction solution, the amount of side reactions can be subsequently reduced and
thereby reaction yields can be increased (Scheme 2.4). From this iodine source screening
study, PyICl was chosen to be the best iodine source for this reaction and was used for
the remaining of the reaction optimization.
Scheme 2.4. Optimizing the iodine source to maximize reaction yield
2.3.2 Base Screening
Considering that the first step of the reaction was the deprotonation of the C-H
bond on the starting material triazole, a relatively strong base has to be used. This choice
of a base also requires to have a non-nucleophilic conjugate acid as lithiated ketenimine
2.6 still has an electrophilic center. Bases, such as lithium diisopropylamine (LDA), were
59
avoided as the resulting amine would interfere with the electrophilic center of ketenimine.
This notion was proven when using LDA led to diisopropylamine substituted amidines
2.19 (Scheme 2.5), which greatly limits the modular ability of the reaction. More bases
needed to be screened to avoid the formation of this nucleophilic by-product. Our initial
studies focused on sodium hydride (NaH) and n-butyllithium (n-BuLi) as they do not have
nucleophilic conjugate bases. Reaction with NaH did not proceed with degradation
occurring (Table 1.1 Entry 5). Upon addition of NaH to sulfonyl triazole 2.20 solution,
instantaneous gas effervescence was observed suggesting that a deprotonation reaction
occurred as hydrogen gas was released. However, the desired product 2.14 was not
detected, instead degradation product was observed by TLC. Therefore, sodium is not a
suitable counter ion for the reaction and that lithium might play an important role for the
stability of one or more reaction intermediates as it can form a more covalent bond.50 The
reaction with n-BuLi also did not yield ideal results with low conversions (~20-30%) (Table
1.1 Entry 3). Because reagents such as n-BuLi are a very strong nucleophile allowing it
to react rapidly with SO2 groups in the triazole. This led us to the reaction with lithium
bis(trimethylsilyl)amide (LiHMDS). LiHMDS is similar to LDA being a strong lithium base,
except it does not have a nucleophilic conjugate acid. HMDS is not nucleophilic being
very sterically hindered. This property allows it to deprotonate triazole 2.20 to form
lithiated ketenimine species 2.6 without outcompeting the added amine to form the
amidine group at a good yields (75%) (Scheme 2.5) (Table 1.1 Entry 1). With this success,
KHMDS was also utilized to test whether cation effects play a crucial role in this reaction.
The result showed that potassium cation lowers the reaction yield to 64% (Scheme 2.5)
(Table 1.1 Entry 2), which implied the necessity of lithium. This conclusion is also
60
supported when reaction yield was lower in the presence of NaH. Considering the
improved reaction yield with LiHMDS and the benign effect of HMDS in the LiHMDS/PyICl
system (Table 1.1 Entry 14), further base optimization study with other common lithium
bases (such as phenyl lithium or LiH) was not necessary. Therefore, the future reaction
optimizations proceeded with LiHMDS as a base.
Scheme 2.5. Base screening showing how LDA had a reactive conjugate acid while potassium didn’t allow for similar
yields.
2.3.3 Solvent Selection
Tetrahydrofuran (THF) was used as a dry aprotic solvent in the presence of lithium
reagents. Without extremely water-free conditions, water readily reacts with lithium bases
which results in poor yields as the consequences. THF was an ideal candidate as it is
fairly cheap and is known to work well with Grignard reagents and other highly reactive
metalated intermediates. Purification and drying of THF is a widely adopted and common
established procedure using a benzophenone/sodium metal in a refluxing solvent still can
maintain the water concentration to be under 10 ppm.51 Upon using THF, the resulting
reaction yielded desirable conversion at 70-80% (varies based on the conditions). With
61
that success, THF was chosen to be the system solvent, especially since it has a straightforward protocol for drying.
2.3.4 Proton Source Screening
Scheme 2.6. Water is required in this reaction to protonate the peroxy radical (top) or a 1:1 ratio of hydroxy and oxo
products are observed (bottom)
Additional observation during reaction optimization showed the addition of brine is
very important for the reaction yield improvement. In the LiHMDS/PyICl system, after the
formation of iodinated intermediate 2.12, brine was added through a septum to quench
the remaining metalated species and to protonate the final products (due to the anionic
nature of the system). Without added brine, the obtained yields were ~44% (Table 1.1
Entry 6) with a near 1:1 ratio of α-hydroxyamidine 2.14 and α-oxoamidine 2.15 (Scheme
2.6). This is likely the result of Russel fragmentation52 of the dimerization of peroxy
radicals 2.22 to the Russel fragmentation intermediate, further showing the importance of
62
a proton source to quench any unreacted radical or in-situ anionic intermediates
formation. Different proton sources, such as ammonium hydroxide (NH4OH), dilute HCl,
and ammonium chloride (NH4Cl) were used to test the hypothesis. The slightly acidic
nature of these source could quicken the quenching process, subsequently result in less
side reactions by lowering the reactivity of the system. These proton sources exhibited
lower yields, although the acidic protons were too reactive not only reacting with the Ocentered radical 2.22, but they also reacted with the C-centered radical 2.21 leading to
substantial unfunctionalized amidine 2.13 along with the desired α-hydroxyamidine 2.14
(Scheme 2.7). For example, when NH4Cl is used to replace brine, the reaction yields
dropped from 83% (Table 1.1 Entry 14) to 68% (Table 1.1 Entry 7). Therefore, brine was
used as the proton source to the obtain highest yield for its capability to effectively quench
reactive intermediates, while it is not strong enough to compete with oxygen in the
oxygenation step.
Scheme 2.7. Competitive reaction between oxygenation and protonation upon the addition of acid explains the
increased ratio of desired product and non-functionalized amidine resulting in lower yields
2.3.5 Additives Screening
Additives were added in order to attempt to further optimize the reaction. The
reaction has three byproducts that compete with the α-hydroxyamidine 2.14, including 1/
63
α-oxoamidine 2.15, 2/ non-functionalized amidine 2.13, and 3/ silylated products 2.17.
Silylated product was removed by changing the iodine source to PyICl, while both αoxoamidine 2.15 and non-functionalized amidine 2.13 still remain in the reaction mixture
that require additional optimization study (Scheme 2.8).
Scheme 2.8. Formation of the desired hydroxy product along with the two other minor products still present in the
reaction.
The α-hydroxyamidine 2.14 and α-oxoamidine 2.15 were believed to come from
the same oxygenation mechanism before veering off into different pathways. While
peroxy intermediate 2.22 can be oxidized or reduced53 (Scheme 2.9), oxo product 2.15
can be favored using copper catalysts. Although copper was not directly added to the
reaction, there is likely chance that small quantity of copper was present in our glassware.
The starting sulfonyl triazole 2.20 was synthesized using CuAAC methods and despite
the efforts to remove copper during the purification process via cuprisorb54, it is uncertain
that copper was removed completely, which resulted in the observed side reactions.
Ethylenediaminetetraacetic acid (EDTA) has been known to ligate to copper irreversibly
and deactivate copper to avoid copper from engaging in further oxidation reaction to form
oxo products (Scheme 2.10 A).55 Incorporation of disodium ethylenediaminetetraacetate
dihydrate (Na2EDTA) and EDTA with the protonation source as additives demonstrated
further reaction optimization improvement. When Na2EDTA and EDTA were added to the
solution the reaction did not have any positive affect when compared to the
LiHMDS/PyICl/brine system. This was also seen when using both brine and NH4Cl with
64
either Na2EDTA and EDTA. Reactions with NH4Cl-Na2EDTA mixture yielded 80%, while
reactions with NH4Cl-EDTA mixture yielded 75%. Reactions with brine-Na2EDTA mixture
yielded 75% conversion (Table 1.1 Entry 10), while brine-EDTA mixture yielded 56%
(Table 1.1 Entry 9). It is clear that the addition of EDTA and Na2EDTA lowered the overall
efficiency of the reaction in combination with brine. In addition, NH4Cl also did not improve
reaction efficiency. Cuprisorb and alumina plugs filtered the remaining copper from the
reaction mixture effectively. Inductively Coupled Plasma spectroscopy (ICP) analysis was
conducted to trace copper in the final solution. Two ICP samples were prepared – one
contains the reaction solution with some starting sulfonyl triazole 2.20 and the second
sample is a controlled metal-free solution. The two samples were found to be analytically
identical. The success to remove copper from the reaction mixture remove the copper
neutralization in solution step, instead copper can be effectively removed in the work up
of the starting material 2.20. Efforts to promote the reduction reaction were successfully
optimized through copper removal procedure.
Scheme 2.9. After oxygenation the peroxy group can either be reduced or oxydized resulting in either the desired
product or oxo byproduct.
One way to selectively favor the formation of hydroxy product 2.14 in this reaction
was the utilization of iodide. The presence of iodine species in the solution as it is leaving
65
and reacting with water could be likely the reason that the hydroxy product 2.14 is formed,
instead of remaining in hydroperoxyl form 2.16. To test this hypothesis, an excess of
iodide source (NaI) was introduced with brine to push for the selective formation hydroxy
product 2.14, this resulted in a yield 76% (Table 1.1 Entry 11). When NH4Cl was used
instead of brine, the reaction resulted in a slightly lower yields of ~70%. In addition, iodine
was excluded from the reaction to seek whether a more controlled reaction could be
achieved when in-situ species were reduces/oxidized by sodium thiosulfate (Na2S2O3)
(Scheme 2.10 B). However, this reaction led to significantly lower yields (57%) (Table 1.1
Entry 12) to similar yields (75%). The lower yields were observed when Na2S2O3 was
added in brine mixture and progressively getting higher when Na2S2O3 was added after
1 hour and 2 hours respectively following the addition of brine. Even though Na2S2O3 was
successful at removing iodine observed by the distinct color change from dark
black/purple to transparent solution, the resulting salt was still a strong enough reducing
agent to form hydroxy product 2.14 and didn’t allow for any further control over the
reduction of the hydroperoxide 2.16 to the hydroxide 2.14. The attempts to control the
oxidation/reduction of the hydroperoxide intermediate 2.16 proved unfeasible because
the additives were unable to limit the side oxidations or promote the desired reduction
leading to lower yields (< 80%).
66
Scheme 2.10. A) How EDTA is able to quench copper in a solution by coordinating to copper very strongly. B)
Reaction of sodium thiosulfate with iodine producing sodium iodide.
Next, control of formation of the non-functionalized amidine 2.13 was studied.
While varying the proton source in section 2.3.4 led to more non-functionalized amidine
2.13, addition of bases could also potentially limit the formation of this byproduct further.
In fact, lowering the pH makes the protons less likely to quench carbon radical 2.21.
However, the reaction yields were often dramatically decreased in the presence of a base
(EDTA or sodium thiosulfate) in a brine solution, as observed in copper deactivation study
with a base. Therefore, the attempts to lower the reaction pH to limit non-functionalized
amidine 2.13 were not heavily pursued and the only action taken was to use brine, not
acidic aqueous solutions (e.g. NH4Cl).
2.3.6 Temperature Screening
Temperature is a common and crucial variable to screen aerobic oxidation
reactions. Many reactions are operated at elevated temperatures56 ranging from 40 °C to
120 °C, depending on the substrates. A higher temperatures can help offset the inert
nature of triplet oxygen and increase the reactivity of the system. In this case, an elevated
temperature beyond room temperature was used after the addition of brine and the
67
exposure to oxygen. At 40 °C and 50 °C, the selectivity towards the hydroxyamidine 2.14
and its conversion improved efficiency were not observed. In conclusion, temperature did
not affect the reaction at the screened temperatures. The reaction selectivity and
conversion at elevated temperature and at room temperature resulted in the same
selectivity and conversion.
2.3.7 Atmosphere Screening
The final screening condition was the source of oxygen being used. Only 21% of
the earth’s atmosphere is composed of oxygen. Because of that, it makes sense to run
the reaction under pure oxygen to increase reaction rate and possibly prevent the
formation of non-functionalized amidine byproduct 2.13. To test this hypothesis, instead
of opening the septum when brine is added, brine was added via a syringe, followed by
purging reaction vial with medical-grade oxygen. An O2 balloon was then used to maintain
a vial with positive pressure of oxygen to maintain the pure oxygen environment. The LC
yields of these experiments were identical to that of ambient air (Table 1.1 Entry 15).
2.4 Understanding the Role of Oxygen
At this point, it was not entirely clear how the reaction proceeded and how the
oxygen was incorporated into the final product 2.14. It could have either been from water
through an SN1 or Sn2 type reaction with benzylic iodine, such as an iodine displacement
in Scheme 2.1157, 58. However, it could also originally come from oxygen from the
atmosphere as oxygenation reaction are well-known to incorporate oxygen into molecules
in many different pathways. It is possible that atmospheric oxygen could apply to this
system with the assistance of all of the different reagents in this reaction solution. A set
68
of control experiments were performed in order to shed light on this reaction mechanism,
which would provide us a deeper molecular-level understanding.
Scheme 2.11. Nucleophilic substitution of benzylic iodine with water in various conditions
2.4.1 Water under N2 atmosphere
Initially, the source of oxygen atom was expected to come from water. This is
because of the fact that the proposed α-iodoamidine intermediate 2.12 has a benzylic
iodine, which is susceptible to nucleophilic attack leading to formation of observed αhydroxyamidine 2.14. To test this hypothesis, an experiment was conducted with the
exclusion of O2 from the reaction condition (Scheme 2.12). Under an N2 atmosphere, the
reaction was set up when LiHMDS was added, followed by PyICl and piperidine. Then
water was introduced to the reaction through the septum using a needle and syringe while
maintaining the nitrogen atmosphere. The reaction ran overnight with a positive pressure
of N2 via the Schlenk line and the reaction is monitored by analyzing aliquots in LC-MS.
After 24h, no conversion of the α-iodoamidine intermediate 2.12 was detected by LC-MS
analysis. This result suggested that O2 could be the source of the O atom in 2.14.
Subsequently, the reaction septum was removed to introduce ambient air into the reaction
vial to validate whether the O source came from ambient air. As expected, conversion of
the α-iodoamidine 2.12 to α-hydroxyamidine 2.14 was observed within 18h by LC-MS.
69
The experiment strongly suggested that an oxygen gas source was required for the
reaction to proceed and the incorporated oxygen atom in the products comes from O2,
not water. However, more experiments are required to definitively prove the pathway that
O2 takes place in the reaction to form the final products.
Scheme 2.12. Controlled reaction without O2 to test if the source of oxygen is from water or oxygen from the
atmosphere.
2.4.2 Testing for low energy triplet state
A common pathway for O2 to react with organic molecules is when an organic
molecule is at a low energy triplet state in equilibrium with O2. This triplet state will readily
react with atmospheric oxygen leading to oxygenation. An example of this is when
quinodimethane undergoes aerobic oxidation due to its equilibrium with a low energy
triplet state59 (Scheme 2.13 A). To test this hypothesis, a controlled experiment was
performed. LiHMDS, PyICl, and piperidine were added under a nitrogen atmosphere, then
that atmosphere was maintained when TEMPO was added to the reaction solution
(Scheme 2.13 B). If a low energy triplet state was present in equilibrium, TEMPO would
be able to trap it without the presence of O2 demonstrating its existence. When attempting
this reaction though, like when O2 was not exposed in the water test, the α-iodoamidine
2.12 persisted for 24h before the septum was opened exposing the reaction mixture to
70
oxygen. After which, the reaction proceeded with the disappearance of the α-iodoamidine
2.12.
Scheme 2.13. A) An example of a reaction relying on a low energy triplet state. B) Control reaction with TEMPO to
capture a low energy triplet state
2.4.3 Testing for SET mechanism
Scheme 2.14. Example of a carbanion formation leading to SET mediated aerobic oxidation.
Another method of aerobic oxidation is to form a carbanion, which can undergo
single electron transfer (SET) with oxygen forming superoxides to react with organic
molecules. An example of this transformation is demonstrated in the deprotonation of
benzylic methylene groups also attached to sulfonyl groups60 (Scheme 2.14). The
resulting carbanion undergoes an SET mechanism that transfers an electron to oxygen
forming a superoxide and C-centered radical species. The superoxide and C-centered
radical react together to form a peroxy intermediate that later transforms into a carboxylic
acid. This SET mechanism transformation suggested the order of addition could be
71
modified to control the species that react with ambient O2 (Scheme 2.15 A). In the first
experiment, LiHMDS was added to the starting triazole before O2 exposure and LDA
addition. The point of LDA was to be able to add an amine without protonating the
intermediates maintaining an anionic environment. This would allow oxygen to perform
an SET reaction with either the lithiated ketenimine 2.6 or deprotonated amidine 2.24
(Scheme 2.15 B). Either process would still result in oxygenation at the α position to form
the α-oxoamidine product 2.25. This resulted in non-functionalized amidine 2.23 though
showing that SET does not occur in the system and that the anions are just protonated
when water is added to quench the reaction. This reaction had a lot of variables with the
formation of the amidine from the ketenimine 2.6 in presence of HMDS.
Scheme 2.15. A) SET pathway experiment with sulfonyl triazole starting material using LiHMDS and LDA. B)
Expected outcome of the system.
To simplify this conclusion, a reaction was performed, whereas the starting material
was a non-functionalized amidine 2.23 being deprotonated at the α position with NaH
(Scheme 2.16 A). The resulting carbanion 2.24 could react in an SET process with oxygen
once air was exposed resulting in the alpha oxygenation (Scheme 2.16 B). This reaction
72
produced small quantity of α-oxoamidine 2.25, but the reaction conversion was >5% with
the majority of starting material in the mixture remained non-functionalized amidine 2.23.
These experiments evidently demonstrated that SET reactions are likely not occurring
because both experiments with NaH led to either no conversion to product 2.25 or very
limited conversion (5%).
Scheme 2.16. A) SET pathway experiment with NaH and nonfunctionalized amidine. B) Expected outcome of the
NaH system.
2.4.4 Testing for singlet oxygen (1O2)
One of the main pathways that allows ambient oxygen to oxygenate organic
molecules is to excite 3O2 to its singlet state (1O2)
61. This process puts it into the same
spin state as a typical organic molecule removing the inert nature of oxygen in ambient
conditions. This can be achieved in a photochemical pathway using a photosensitizer or
a photocatalyst that can excite 3O2 to 1O2, thereby allowing it to react with a wide variety
of organic molecules. The most common way to test this is by running the reaction in the
dark, as without light this excitation cannot happen (Scheme 2.17). To do this, we ran the
optimized reaction conditions for the synthesis of α-hydroxyamidine 2.14. However, after
the reaction was brought to room temperature, the reaction vial was wrapped in aluminum
foil to block light from potentially forming 1O2. The septum was then removed and a cover
73
made of aluminum foil was put over the reaction vial to block light, but allow airflow to
come in. The lights in the lab were turned off and the reaction was left to stir overnight in
the dark. The absence of light did not inhibit the reaction. After around 12h, the reaction
resulted in full conversion, despite being devoid of light. This demonstrated that 1O2 is
likely not present as the active species, but instead triplet oxygen (3O2) is the active
species in this reaction.
Scheme 2.17. Control reaction testing for photooxygenation by running reaction in the absence of light.
2.4.5 Testing for autoxidation with triplet oxygen (3O2)
Another pathway of oxygenating organic molecules aerobically is autoxidation.
Autoxidation usually happens when there is a reactive C-H group in which case a Ccentered radical is generated through homolytic cleavage of the C-H. The resulting Ccentered radical species readily react with 3O2 in the atmosphere to oxygenate substrates.
For examples, peroxide formers (such as ethers) with a C-H bonds adjacent to an oxygen
atom can form C-centered radicals slowly, which generates hydroperoxides in the
presence of ambient oxygen. The spoiling of food and oil also happen in a similar
pathway. Other examples when a privileged C-H is present can form radicals more easily
through stabilization62 (Scheme 2.41 A). However, this is not common because it usually
74
requires additives. In order to test this, it is required to confirm that there is a presence of
radical species as a radical pathway is a mainstay of autoxidation. The use of TEMPO
and BHT as radical traps can help identify the type of radical species present in the
reaction. While 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) is known to target Ccentered radicals63, butylhydroxytoluene (BHT) targets O-centered radicals64 (Scheme
2.18 B). The resulting molecular weight of radical fragment attached to TEMPO or BHT
can be identified via LC-MS analysis.
Scheme 2.18. A) Example of autoxidation with the formation of peroxy-intermediates through radical formation
followed by reduction reaction to alcohols. B) TEMPO reacts with C-centered radicals and BHT reacts with Ocentered radicals.
2.4.5.1 C-radical test using TEMPO
TEMPO was employed to test for the presence of in-situ C-centered radical
formation in the reaction. To do this, the optimized procedure was employed with a slight
modification in step 4 when brine and TEMPO were introduced to the reaction in the same
step (Scheme 2.19). Following this, monitoring by LC-MS, a new species with a mass of
75
511.29 g/mol was detected, which did not corelate to either starting material 2.20 or
product 2.14 and known by-products 2.15 or 2.13. This corresponded to a product mass
when TEMPO was added to the alpha position of 2.20. This product was isolated at a
50% yield and provided a solid evidence that a C-centered radical does form to produce
2.25, which hypothetically forms after a homolytic cleavage process of the C-I bond.
Scheme 2.19. Adding TEMPO to the reaction in step for leads to TEMPO incorporation into final product 2.25
showing evidence for the presence of C-centered radicals.
2.4.5.2 O-radical testing using BHT
BHT was employed to test for the presence of in-situ O-centered radical formation
in the reaction. In this test, the optimized procedure was employed with a slight
modification in step 4 when brine and BHT were introduced and the reaction was
monitored by HPLC-MS analysis (Scheme 2.20). LC-MS analysis detected a new
product, whereas a reaction between BHT and the peroxy radical intermediate 2.22
occurred resulting in the addition of BHT fragment to the final product 2.26. This reaction
is also reported in a recent publication,64 however, upon isolation product 2.26 degraded
into the α-oxoamidine 2.15 product and carbonylated BHT byproduct was observed as a
result of the O-O bond breaking in the peroxy structure 2.26.
76
Scheme 2.20. BHT reacting with peroxy radicals showing the presence of O-centered radicals and intermediates
indicative of autoxidation.
2.5 Substrate Scope
Figure 2.5. Substrate scope for the oxygenated amidine with various amines, sulfones, and aryl groups.
In order to understand this transformation further, a reaction scope was done to
study the effect of different electronic structures and steric (Figure 2.5). First, sterics effect
was investigated around the position being oxygenated by changing amine substrates
being added to the ketenimine. The experiments were performed using n-butyl amine
2.28, benzylamine 2.29, t-Butyl amine 2.30, piperidine 2.32, and diisopropylamine 2.34
77
to add varying levels of steric strain to the intermediates. The use of primary amines
worked with decent yields ranging from 77% with benzyl amine 2.29 all the way up to
87% using n-butyl amine 2.28. Secondary amine substrates had lower yields ranging from
drastically lower yield (55%) with substrates diisopropylamine 2.34 and slightly lower yield
(75%) with piperidine 2.32. This indicates that steric bulkiness of amine substrates could
influence the reaction outcome, whereas it could prevent the oxygen from approaching or
even block the SO2 group from interacting with C-I bond for activation. The fact that the
yields lowered when more sterically hindered amines were added is likely not coming
from the formation of the amidine itself though. Synthesis of the non-functionalized
amidines reported by Chang et. al. went through similar ketenimine intermediates that
tolerated bulky amines being added.
A diamine was also used in order to test whether an intramolecular reaction could
occur between the other terminal of the amine and the iodine. Usually, benzylic iodine is
susceptible to nucleophilic attack, which could subsequently lead to a cyclic structure
formation. However, that product formation was not observed and instead the diamine
reacted with two different ketenimines leading to 2.48.
Anilines were then tested to see how weak nucleophiles behave in this reaction
and there was a clear trend between the electron-rich nitrogen substrates and their yield.
The yield of reaction increases, respectively, 47%, 62%, 82%, when 4-nitroaniline 2.47,
aniline 2.46, and 4-methoxyaniline 2.45 were used. Interestingly, in the reaction with 4-
nitroaniline, there was a significant amount of oxo-NH2 product 2.18, but there was only
small amounts of that product when aniline was used and no product was observed with
4-methoxyaniline. This result implies that the strength of the nucleophile matters with
78
weaker C-N bonds leading the oxo-NH2 product 2.18 as they can act as a leaving group.
This hypothesis was tested with succinimide, imidazole, and indazole as they are all
weaker nucleophiles, thus they are better leaving groups than the aliphatic amines.
Following the observations from the aniline experiments, these reactions produced oxoNH2 product 2.18 as the major product. Therefore, this result supports the hypothesis that
electron-deficient nitrogen substrates undergo this transformation because they are good
leaving groups better stabilizing the resulting negative charge they would gain. The
source of NH2 in these conditions is likely from HMDS in solution from the LiHMDS
reagent in the first step of the reaction. In the presence of water, HMDS decomposes into
NH2 and HO-SiMe3 with NH2 being a potential source of the NH2 observed in the final
product. This was partially tested by running a reaction without an amine and the major
product structure still contains an amine fragment in oxo-NH2 product 2.18. This result
shows that the nitrogen could come from HMDS to replace the amine when the amine is
a better leaving groups as observed in the cases of 4-nitroaniline, succinimide, and so
on.
Some heteroatom effect was studied using morpholine, 2-picolylamine, and 4-
picolylamine. Morpholine 2.33 provided a very similar yield to reaction with piperidine 2.32
yielding 77% and 75%, respectively. This suggests that oxygen does not affect the overall
reaction and the oxidation process can tolerate oxygen of the substrate molecule, even
at the position close to where the oxidation event takes place. This same conclusion is
not true for other reactions with pyridine substrates. In a reaction with 2-picolylamine, a
product contains 4-membered ring was formed. In a reaction with 4-picolylamine, the
79
reaction did not proceed to product conversion. The nitrogen atom is playing some role
in side reactivity, however, the true nature of this hypothesis still needs to be elucidated.
Finally, the electronics of this system was tested by varying the substituents on the
phenyl rings of either side of the substrate. When modifying the sulfonylazide side, the
reaction result was not affected. It can tolerate R groups such as the electron rich pmethoxy 2.40 (73%) to the electron poor NO2 2.43 (63%). It can also tolerate naphthalene
2.44 (70%) as well as halogens with p-Br 2.41 (91%) with minimal effects on reaction
time. Modifications of alkyne side were pretty similar with t-Butyl 2.36 and p-CF3 2.39
yielded 60% and 75% conversion, respectively. The reaction can also tolerate halogens
with p-Br 2.37 yielded 76%. In the reaction with p-CN 2.38, the reaction yield drops to
56%, confirming again the extra nitrogens can cause problems similarly to when pyridine
was used. Methoxy 2.35 also had lower yields around 56% and the reaction kinetics was
slowed down with a significantly longer reaction time. Iodo intermediate 2.12 persisted a
lot longer, likely due to the higher electron density around iodine atom, which could make
it a bad leaving group. Another possible reason was that the resulting radical 2.21 is
stabilized, thus making it not as reactive when molecular oxygen is present. This sluggish
reaction could cause more side reactions that explained the lowered yield in of 2.35.
80
2.6 Mechanism Proposal
Scheme 2.21. Proposed mechanism for the formation of the hydroxyamidine through a radical process with
intermediates either being seen or trapped.
Given the results from the controlled experiments to understand the role of oxygen
and the substrate scope study, a possible mechanism was proposed (Scheme 2.21). In
the first step, LiHMDS reacts with a sulfonyl triazole 2.20 to form a lithiated triazolide 2.3.
These metalated triazoles are unstable, subsequently decomposes into ketenimine 2.6.
Although this lithiated ketenimine 2.6 was not detected through NMR or LC-MS analysis,
there is evidence of its presence experimentally. The main one being that when nothing
further is added to the reaction, two ketenimine species can react with each other forming
4-membered ring product 2.49 that can only happen with an amphoteric species. The
resulting lithiated ketenimine 2.6 then had PyICl incorporated to the system in order to
iodinate the ketenimine. Then, it was exposed to an amine forming iodinated amidine
intermediate 2.12. This intermediate is remarkably stable under nitrogen atmosphere – it
81
is resistant to nucleophilic attack and radical formation until being exposed to ambient 3O2
in the presence of brine. Subsequently, the C-I bond homolytically cleaves resulting in
iodine radical (forming I2 in solution) and a C-centered azavinyl radical species 2.21 that
can be trapped by TEMPO forming product 2.25. The radical species 2.21 can react with
ambient O2 leading to peroxy radical intermediate 2.22 that can be trapped by BHT
forming product 2.26. This radical product 2.22 can be protonated in the presence of brine
leading to hydroperoxyl intermediate 2.16 observed by LC-MS analysis. Normally,
autoxidation would end there in the absence of an oxidant or reductant. In this case, the
I2 present can turn into Iin the presence of water which then reduces hydroperoxide 2.16
to an alcohol to reform I2 and water. This phenomenon explains the major product being
the hydroxyamidine product 2.14.
2.7 Further Reactivity of Lithiated Ketenimine and Hydroxy Product
Scheme 2.22. Formation of both α-bromoamidines and α-fluoroamidines which can be isolated and do not undergo
oxygenation.
To further diversify this methodology, modifications and product post
functionalization were performed. One reaction modifications include changing the
electrophile that reacts with lithiated ketenimine 2.6. Other electrophiles in this study were
82
bromine (Br2) and N-fluorobenzenesulfonimide (NFSI). Br2 was able to brominate
ketenimine 2.6 leading to α-bromoamidines 2.51 (62% isolated yield) while NFSI was able
to fluorinate the ketenimine leading to α-fluoroamidines 2.50 (64% isolated yield)
(Scheme 2.22). Interestingly, both products were stable under ambient atmosphere
indicating the unique characteristics of iodine in this system. More electrophiles are
currently studied, however, Michael acceptors, such as ethenesulfonyl fluoride (ESF) and
1-bromoethene-1-sulfonyl fluoride (BESF), did not react with lithiated ketenimine 2.6 in
the desired manner. Also, other nucleophiles, such as thiols, thiolates, alcohols, and
alkoxides, did not work in the present conditions. Thiols and thiolates resulted in very low
conversion >5%, while alcohols and alkoxides proceeded to no product conversion. This
indicates the importance of amine to this system, however the full explanation requires
more thorough experimentation.
Post functionalization could be achieved through oxidation of the alcohol to ketone
or deprotection of sulfonyl group. The conversion of α-hydoxyamidines to α-oxoamidines
2.52 was achieved through the addition of pyridinium chlorochromate (PCC) in
dichloromethane (DCM) to isolated product (Scheme 2.23). Overnight, a quantitative
conversion of α-hydoxyamidines to α-oxoamidines 2.52 was observed. The deprotection
of the sulfonyl group was achieved through the addition of thiophenol (PhSH) resulting in
product 2.53 with 65% NMR yield (Scheme 2.23). Interestingly, other reported conditions
for the desulfonylization of sulfonamides were unsuccessful, suggesting that this system
could have unique electronical characteristics.
83
Scheme 2.23. Deprotecting the sulfonyl group as well as oxidizing the OH to carbonyl both are successful further
showing utility of this reaction.
2.8 C-H Activation Through Radical Initiation
Figure 2.6. Varies conditions that tried to initiate the radical oxidation with none working.
At this point, the key step for this process is the formation of an azavinyl radical
2.21. The radical species 2.21 has interesting properties similarly to rhodium carbenes
found in the same molecules. The push-pull nature of this position leads to stability drives
84
the reaction forward as radical species 2.21 could easily form once α-iodoamidine 2.12
forms. With that in mind, by leveraging that stability, non-functionalized amidine 2.13
could form the same radical species 2.21 with a radical initiator. This would remove the
need to pre-make sulfonyl triazole starting material 2.20 and the need to use a lithiated
reagent, which require extra handling precautions, to streamlining the process. A variety
of conditions were found in the reported literature to form radicals at a reactive C-H bond
(Figure 2.6). The first conditions attempt utilized azobisisobutyronitrile (AIBN) as a radical
initiator, however, no reaction was observed and starting material 2.13 was recovered.
Following, an AIBN-NHPI system was tested whereas AIBN can initiate NHPI to form a
stable, yet, still reaction O-centered radical to facilitate a radical process. This system
resulted in a minimal conversion to oxygenated product 2.25 (< 5%). A metal-catalyzed
radical initiator, Co(acac)2, was tested at varies mol% with NHPI to start the aerobic
oxidation process, however, this initiator also gave minimal conversions to product 2.25
(< 5%). Different copper-catalyzed initiators were tested, CuCl2 and Cu(OAc)2●H2O, led
to no conversion to product 2.25 analyzed by TLC or LC-MS. The inability to form any
oxygenated products 2.25 with these radical initiation conditions implied that the stability
of the radical was not as important as initially predicted. Although the push-pull
stabilization benefits reaction selectivity and a wide substrates scope, the actual initiation
did not provide deeper details into the significant role of iodine.
2.9 C-I Bond Study with Different Lewis Bases
Considering that C-H activation was not achievable using radical initiation, the C-I
bond was looked into with more scrutiny. Previous studies done by Fokin et. al.65 showed
that when specific sulfonyl triazoles were used in rhodium chemistry, interesting products
85
were formed in the process of oxygen atom transfer from a sulfonyl group to a carbene
(Scheme 2.24 A). Normally, this was not observed with the resulting carbenes remains
stable enough in solution to facilitate reactions, such as transannulation, insertion, and
substitution, without the loss of a sulfonyl group. The only difference in this case was the
presence of a sulfonyl amidine group, which suggested that amidine could activate the
sulfonyl group to interact with a carbene. It is hypothesized that the sulfonyl group of a
sulfonyl amidine can be activated to interact with iodine, because C-I bonds have already
been shown to be polarizable through the introduction of S-O bonds. A good example of
this was done by Goroff with iodoalkynes66 (Scheme 2.24 B). Iodoalkynes previously were
reported to have a 13C NMR shift at around 0 ppm corresponding to the C-I bond. This is
due to the heavy atom effect of iodine partially overlapping its electron cloud over the
adjacent carbon. When DMSO was used as the solvent, 13C NMR shift of C-I bond shifted
up by 15 ppm, despite having an electron density overlap with the oxygen in the S-O
bond. This shows that the C-I bond is being polarized as the density could go towards
iodine with the electronic influence of an oxygen. The electron-rich characteristic of
iodides, for example KI, are known to react with oxygen it is a possibility that the iodine is
being activated enough to interact with O2 (Scheme 2.24 C). This would explain why αiodoamidine 2.12 is very stable until oxygen is introduced to the system and it could lead
to an interaction that further polarizes the C-I bond enough to cleave and form azavinyl
radical species 2.21 and I2.
86
~0ppm ~15ppm
Scheme 2.24 A) Rhodium carbene formation results in oxygen atom transfer when sulfonyl amidines are present. B)
Solvent effects demonstrate how S-O bonds can interact with C-I bonds leading to bond polarization. C) Electron rich
iodides reacts with oxygen.
In order to test this, 13C NMRs were done on benzyl iodide using solvents and
additives that had different levels of Lewis basicity to see the shifts of the benzyl carbon.
First a 13C NMR of benzyl iodide was done in CDCl3 to get a baseline ppm shift of the
benzyl carbon shift. After this, solvents with more donating ability were used including
THF-d8, acetone-d6, and DMSO-d6. All three of these solvents showed a down-field shift
in the carbon peak of the benzyl position with acetone-d6 and DMSO-d6 being more
significant (0.6 ppm and 1.7 ppm respectively) (Figure 2.7). Then, diphenyl sulfone was
added to the benzyl iodide-CDCl3 solutions to see how sulfones affect the C-I bond. This
did not lead to a large shift (<0.1 ppm), however, the down-field shift does show that
sulfones can polarize the C-I bond. This result supports the notion that the sulfonyl
group in 2.12 can polarize the C-I bond. This polarization could allow the iodine to then
be electron rich enouph to interact with molecular oxygen causing the homolytic
cleavage forming the aza-vinyl radical 2.21. This would also explain why this radical
87
formation does not occure without oxygen present and why alkyl iodides without the
internal sulfonyl group does not undergo aerobic oxidations spontaneously.
∆ 1.6647 ppm
Figure 2.7. 13CNMRs showing the ppm shift of the benzylic carbon for benzyl iodide.
2.10 Conclusion
The newly discovered cascade transformation described here offers a practical
access to α-oxygenatedamidines, a difficult-to-synthesize class of αoxygenatedcarboxylic acid derivatives. The cheapest oxidant, atmospheric oxygen,
88
serves as the source of the O atom in the final products without producing any metal or
toxic waste. This transformation is an example of a controlled and selective free-radical
autoxidation reaction, which is a valuable addition to the repertoire of oxidations in organic
synthesis. Mechanistic insights into this process help our understanding on the
captodative nature of the previously unreported azavinylbenzyl radicals as well as the
stability of C-I bond and the methodology to activate them which could create a useful
radical transformation.
2.11 References
1. Zard, S. Z., Radicals in Action: A Festival of Radical Transformations. Organic
Letters 2017, 19 (6), 1257-1269.
2. Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S., Radicals: Reactive Intermediates
with Translational Potential. Journal of the American Chemical Society 2016, 138 (39),
12692-12714.
3. Moad, G.; Rizzardo, E.; Thang, S. H., Toward Living Radical Polymerization.
Accounts of Chemical Research 2008, 41 (9), 1133-1142.
4. Budnikov, A. S.; Krylov, I. B.; Mulina, O. M.; Lapshin, D. A.; Terent'ev, A. O., CHFunctionalization of Heterocycles with the Formation of C−O, C−N, C−S/Se, and C−P
Bonds by Intermolecular Addition of Heteroatom-Centered Radicals. Advanced Synthesis
& Catalysis 2023, 365 (11), 1714-1755.
5. Hu, X.; Chen, X.; Li, B.; He, G.; Chen, G., Construction of Peptide Macrocycles
via Radical-Mediated Intramolecular C–H Alkylations. Organic Letters 2021, 23 (3), 716-
721.
6. Hashimoto, S.; Katoh, S.-i.; Kato, T.; Urabe, D.; Inoue, M., Total Synthesis of
Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo
Cyclization. Journal of the American Chemical Society 2017, 139 (45), 16420-16429.
7. Friese, F. W.; Mück-Lichtenfeld, C.; Studer, A., Remote C−H functionalization
using radical translocating arylating groups. Nature Communications 2018, 9 (1), 2808.
8. Dewar, M. J. S., A Molecular Orbital Theory of Organic Chemistry. IV.1 Free
Radicals. Journal of the American Chemical Society 1952, 74 (13), 3353-3354.
89
9. Tang, B.; Zhao, J.; Xu, J.-F.; Zhang, X., Tuning the stability of organic radicals:
from covalent approaches to non-covalent approaches. Chemical Science 2020, 11 (5),
1192-1204.
10. Studer, A.; Curran, D. P., Catalysis of Radical Reactions: A Radical Chemistry
Perspective. Angewandte Chemie International Edition 2016, 55 (1), 58-102.
11. Amaoka, Y.; Kamijo, S.; Hoshikawa, T.; Inoue, M., Radical Amination of C(sp3)–
H Bonds Using N-Hydroxyphthalimide and Dialkyl Azodicarboxylate. The Journal of
Organic Chemistry 2012, 77 (22), 9959-9969.
12. Caruso, M.; Navalón, S.; Cametti, M.; Dhakshinamoorthy, A.; Punta, C.; García,
H., Challenges and opportunities for N-hydroxyphthalimide supported over
heterogeneous solids for aerobic oxidations. Coordination Chemistry Reviews 2023, 486,
215141.
13. Chiefari, J.; Mayadunne, R. T. A.; Moad, C. L.; Moad, G.; Rizzardo, E.; Postma,
A.; Thang, S. H., Thiocarbonylthio Compounds (SC(Z)S−R) in Free Radical
Polymerization with Reversible Addition-Fragmentation Chain Transfer (RAFT
Polymerization). Effect of the Activating Group Z. Macromolecules 2003, 36 (7), 2273-
2283.
14. Veciana, J.; Carilla, J.; Miravitlles, C.; Molins, E., Free radicals as clathrate hosts:
crystal and molecular structure of 1: 1 perchlorotriphenylmethyl radical–benzene. Journal
of the Chemical Society, Chemical Communications 1987, (11), 812-814.
15. Sowndarya S. V, S.; St. John, P. C.; Paton, R. S., A quantitative metric for organic
radical stability and persistence using thermodynamic and kinetic features. Chemical
Science 2021, 12 (39), 13158-13166.
16. Viehe, H. G.; Merényi, R.; Stella, L.; Janousek, Z., Capto-dative Substituent
Effects in Syntheses with Radicals and Radicophiles [New synthetic methods (32)].
Angewandte Chemie International Edition in English 1979, 18 (12), 917-932.
17. Viehe, H. G.; Janousek, Z.; Merenyi, R.; Stella, L., The captodative effect.
Accounts of Chemical Research 1985, 18 (5), 148-154.
18. Tanaka, H., Captodative modification in polymer science. Progress in Polymer
Science 2003, 28 (7), 1171-1203.
19. Baldock, R. W.; Hudson, P.; Katritzky, A. R.; Soti, F., Stable free radicals. Part I.
A new principle governing the stability of organic free radicals. Journal of the Chemical
Society, Perkin Transactions 1 1974, (0), 1422-1427.
20. De Vries, L., The evidence for generation of dimethylaminocyanocarbene in the
thermolysis of dimethylaminomalononitrile. The dimethylamino(dicyano- and
cyano)methyl radicals, carbon analogs of the nitroxides. Journal of the American
Chemical Society 1978, 100 (3), 926-933.
90
21. Peterson, J. P.; Winter, A. H., Solvent Effects on the Stability and Delocalization of
Aryl Dicyanomethyl Radicals: The Captodative Effect Revisited. Journal of the American
Chemical Society 2019, 141 (32), 12901-12906.
22. Stella, L.; Harvey, J. N., Synthetic Utility of the Captodative Effect. In Radicals in
Organic Synthesis, 2001; pp 360-380.
23. Golden, D. L.; Suh, S.-E.; Stahl, S. S., Radical C(sp3)–H functionalization and
cross-coupling reactions. Nature Reviews Chemistry 2022, 6 (6), 405-427.
24. Peters, K. S., Nature of Dynamic Processes Associated with the SN1 Reaction
Mechanism. Chemical Reviews 2007, 107 (3), 859-873.
25. Patil, P.; Zheng, Q.; Kurpiewska, K.; Dömling, A., The isocyanide SN2 reaction.
Nature Communications 2023, 14 (1), 5807.
26. He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q., Palladium-Catalyzed
Transformations of Alkyl C–H Bonds. Chemical Reviews 2017, 117 (13), 8754-8786.
27. Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.,
Functionalization of Organic Molecules by Transition-Metal-Catalyzed C(sp3) H
Activation. Chemistry – A European Journal 2010, 16 (9), 2654-2672.
28. Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q., Enantioselective
C(sp3)‒H bond activation by chiral transition metal catalysts.
Science 2018, 359 (6377), eaao4798.
29. Gupta, A.; Kumar, J.; Rahaman, A.; Singh, A. K.; Bhadra, S., Functionalization of
C(sp3)-H bonds adjacent to heterocycles catalyzed by earth abundant transition metals.
Tetrahedron 2021, 98, 132415.
30. Davies, H. M. L.; Manning, J. R., Catalytic C–H functionalization by metal
carbenoid and nitrenoid insertion. Nature 2008, 451 (7177), 417-424.
31. Davies, H. M. L.; Alford, J. S., Reactions of metallocarbenes derived from Nsulfonyl-1,2,3-triazoles. Chemical Society Reviews 2014, 43 (15), 5151-5162.
32. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L., Catalytic Carbene Insertion into
C−H Bonds. Chemical Reviews 2010, 110 (2), 704-724.
33. Beller, M.; Seayad, J.; Tillack, A.; Jiao, H., Catalytic Markovnikov and antiMarkovnikov Functionalization of Alkenes and Alkynes: Recent Developments and
Trends. Angewandte Chemie International Edition 2004, 43 (26), 3368-3398.
34. Stuhr, R.; Bayer, P.; von Wangelin, A. J., The Diverse Modes of Oxygen Reactivity
in Life & Chemistry. ChemSusChem 2022, 15 (24), e202201323.
91
35. Sterckx, H.; Morel, B.; Maes, B. U. W., Catalytic Aerobic Oxidation of C(sp3)−H
Bonds. Angewandte Chemie International Edition 2019, 58 (24), 7946-7970.
36. Liu, X.; Ryabenkova, Y.; Conte, M., Catalytic oxygen activation versus
autoxidation for industrial applications: a physicochemical approach. Physical Chemistry
Chemical Physics 2015, 17 (2), 715-731.
37. Zhang, C.; Zhang, L.; Jiao, N., Multiple Oxidative Dehydrogenative
Functionalization of Arylacetaldehydes Using Molecular Oxygen as Oxidant Leading to 2-
Oxo-acetamidines. Advanced Synthesis & Catalysis 2012, 354 (7), 1293-1300.
38. Chang, S.-Y.; Bae, S. J.; Lee, M. Y.; Baek, S.-h.; Chang, S.; Kim, S. H., Chemical
affinity matrix-based identification of prohibitin as a binding protein to anti-resorptive
sulfonyl amidine compounds. Bioorganic & Medicinal Chemistry Letters 2011, 21 (2), 727-
729.
39. Gobis, K.; Foks, H.; Sławiński, J.; Sikorski, A.; Trzybiński, D.; AugustynowiczKopeć, E.; Napiórkowska, A.; Bojanowski, K., Synthesis, structure, and biological activity
of novel heterocyclic sulfonyl-carboximidamides. Monatshefte für Chemie - Chemical
Monthly 2013, 144 (5), 647-658.
40. Zhao, Y. Z. Z. C. M. Y. W. C.-C. O.-P. S. o. N. S. A. f. S. H. T. A.; Sulfonyl, A. CopperCatalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal
Alkynes and Sulfonyl Azides Molecules [Online], 2021.
41. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S., A Facile Access to NSulfonylimidates and Their Synthetic Utility for the Transformation to Amidines and
Amides. Organic Letters 2006, 8 (7), 1347-1350.
42. Bugden, F. E.; Clarkson, G. J.; Greenhalgh, M. D., Lithiation-Functionalisation of
Triazoles Bearing Electron-Withdrawing N-Substituents: Challenges and Solutions**.
European Journal of Organic Chemistry 2023, 26 (5), e202201459.
43. Raushel, J.; Fokin, V. V., Efficient Synthesis of 1-Sulfonyl-1,2,3-triazoles. Organic
Letters 2010, 12 (21), 4952-4955.
44. Whiting, M.; Fokin, V. V., Copper-Catalyzed Reaction Cascade: Direct Conversion
of Alkynes into N-Sulfonylazetidin-2-imines. Angewandte Chemie International Edition
2006, 45 (19), 3157-3161.
45. Ajvazi, N.; Stavber, S. Electrophilic Iodination of Organic Compounds Using
Elemental Iodine or Iodides: Recent Advances 2008–2021: Part I Compounds [Online],
2022, p. 3-24.
46. Togo, H.; Iida, S., Synthetic Use of Molecular Iodine for Organic Synthesis. Synlett
2006, 2006 (14), 2159-2175.
92
47. Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V., RhodiumCatalyzed Transannulation of 1,2,3-Triazoles with Nitriles. Journal of the American
Chemical Society 2008, 130 (45), 14972-14974.
48. Breitwieser, K.; Bahmann, H.; Weiss, R.; Munz, D., Gauging Radical Stabilization
with Carbenes. Angewandte Chemie International Edition 2022, 61 (37), e202206390.
49. Karimi, B.; Golshani, B., Mild and Highly Efficient Method for the Silylation of
Alcohols Using Hexamethyldisilazane Catalyzed by Iodine under Nearly Neutral Reaction
Conditions. The Journal of Organic Chemistry 2000, 65 (21), 7228-7230.
50. Weiss, E., Structures of Organo Alkali Metal Complexes and Related Compounds.
Angewandte Chemie International Edition in English 1993, 32 (11), 1501-1523.
51. Inoue, R.; Yamaguchi, M.; Murakami, Y.; Okano, K.; Mori, A., Revisiting of
Benzophenone Ketyl Still: Use of a Sodium Dispersion for the Preparation of Anhydrous
Solvents. ACS Omega 2018, 3 (10), 12703-12706.
52. Howard, J. A.; Ingold, K. U., Self-reaction of sec-butylperoxy radicals. Confirmation
of the Russell mechanism. Journal of the American Chemical Society 1968, 90 (4), 1056-
1058.
53. Su, Y.; Sun, X.; Wu, G.; Jiao, N., Catalyst-Controlled Highly Selective Coupling
and Oxygenation of Olefins: A Direct Approach to Alcohols, Ketones, and Diketones.
Angewandte Chemie International Edition 2013, 52 (37), 9808-9812.
54. Presolski, S. I.; Hong, V. P.; Finn, M. G., Copper-Catalyzed Azide–Alkyne Click
Chemistry for Bioconjugation. Current Protocols in Chemical Biology 2011, 3 (4), 153-
162.
55. Maketon, W.; Zenner, C. Z.; Ogden, K. L., Removal Efficiency and Binding
Mechanisms of Copper and Copper−EDTA Complexes Using Polyethyleneimine.
Environmental Science & Technology 2008, 42 (6), 2124-2129.
56. Melone, L.; Punta, C., Metal-free aerobic oxidations mediated by Nhydroxyphthalimide. A concise review. Beilstein Journal of Organic Chemistry 2013, 9,
1296-1310.
57. Engl, S.; Reiser, O., Catalyst-Free Visible-Light-Mediated Iodoamination of Olefins
and Synthetic Applications. Organic Letters 2021, 23 (14), 5581-5586.
58. Song, T.; Ma, Z.; Ren, P.; Yuan, Y.; Xiao, J.; Yang, Y., A Bifunctional Iron
Nanocomposite Catalyst for Efficient Oxidation of Alkenes to Ketones and 1,2-Diketones.
ACS Catalysis 2020, 10 (8), 4617-4629.
59. Bowes, C. M.; Montecalvo, D. F.; Sondheimer, F., o-Dipropadienylbenzene and
2,3-dipropadienylnaphthalene. The oxidation of diallenes to cyclic peroxides with triplet
oxygen. Tetrahedron Letters 1973, 14 (34), 3181-3184.
93
60. Bonaparte, A. C.; Betush, M. P.; Panseri, B. M.; Mastarone, D. J.; Murphy, R. K.;
Murphree, S. S., Novel Aerobic Oxidation of Primary Sulfones to Carboxylic Acids.
Organic Letters 2011, 13 (6), 1447-1449.
61. Ghogare, A. A.; Greer, A., Using Singlet Oxygen to Synthesize Natural Products
and Drugs. Chemical Reviews 2016, 116 (17), 9994-10034.
62. Tian, H.; Ermolenko, L.; Gabant, M.; Vergne, C.; Moriou, C.; Retailleau, P.; AlMourabit, A., Pyrrole-Assisted and Easy Oxidation of Cyclic α-Amino Acid- Derived
Diketopiperazines under Mild Conditions. Advanced Synthesis & Catalysis 2011, 353 (9),
1525-1533.
63. Chateauneuf, J.; Lusztyk, J.; Ingold, K. U., Absolute rate constants for the
reactions of some carbon-centered radicals with 2,2,6,6-tetramethyl-1-piperidinoxyl. The
Journal of Organic Chemistry 1988, 53 (8), 1629-1632.
64. Ochiai, M.; Sueda, T., Tetrahydrofuranylation of alcohols catalyzed by alkylperoxyλ3-iodane and carbon tetrachloride. Tetrahedron Letters 2004, 45 (18), 3557-3559.
65. Selander, N.; Fokin, V. V., Rhodium(II)-Catalyzed Asymmetric Sulfur(VI) Reduction
of Diazo Sulfonylamidines. Journal of the American Chemical Society 2012, 134 (5),
2477-2480.
66. Rege, P. D.; Malkina, O. L.; Goroff, N. S., The Effect of Lewis Bases on the 13C
NMR of Iodoalkynes. Journal of the American Chemical Society 2002, 124 (3), 370-371.
94
Chapter 3. Copper-Catalyzed C-H Oxidation using ambient Air: A
Selective Oxygenase Type Reactivity
3.1 Introduction
Copper (Cu)1, 2 and oxygen (3O2)
3 are very abundant reagents, however both pose
significant challenges to utilize in practice. Copper, though highly versatile, can undergo
and catalyze complex redox processes easily going from oxidations states of 0 to +34
making the metal very challenging to using conventional methods5
. Oxygen on the other
hand is naturally benign due to its triplet ground state making it spin forbidden to react
with standard organic molecules in the singlet state6
. Despite these challenges, both
copper and oxygen have found their way into organic synthesis due to their great
availability and cheapness. While oxygen has been used in aerobic oxidation processes
utilizing metal catalysts and photocatalysts, copper has been used in a myriad of
applications, such as the Wacker process7
, phenol polymerization8
, CO reduction9
,
oxidation of methane to methanol10, azide-alkyne cycloaddition11, and many more others.
Nature can efficiently activate O2 with the help of metal cofactors (Fe, Mn, Cu, Ni
and Mo) in the active center. Biochemical systems are great inspiration to understand the
fundamental aspects of interaction between Cu complexes and molecular oxygen. Among
these, the following enzymes are relevant to this work as these demonstrate hydroxylation
reaction: Dopamine 𝛽-hydroxylase (D𝛽H) and peptidylglycine α-hydroxylating
monooxygenase (PHM) are mononuclear Cu monooxygenases. These enzymes carry
out hydroxylation of weaker C-H bonds (ca. 88 kcal/mol) using a second reducing
equivalent from a distant Cu center (Cu…Cu ≈ 10 Å).
95
The fusion of copper catalysis with molecular oxygen has emerged as a field of
research12, 13 as copper can bypass the inertness of O2 (S = 1 in triplet state) toward
organic molecules (S = 0) usually by forming superoxides, thereby, getting rid of the need
for toxic oxidants.14 Oxygen can act as a sink for electrons (oxidase type reactivity) or as
a source of oxygen atoms that can be incorporated into the product (oxidase type
reactivity) (Figure 1A). As such, the field has grown exponentially in the last three decades
symbiotically with the emergence of green chemistry as O2 is the greenest oxidant
available.
96
Figure 3.1. A) General oxygenase type reaction. B) Examples of oxygenase type reactions. C) Oxygenase type
reaction with sulfonyl amides.
The resulting ability to modify the carbon-carbon backbone of organic molecules
is great. Examples of copper catalyzed aerobic oxidation usually result in the carbonyl
product forming (Figure 3.1B)15-17. These, however, are limited by not being able to form
the hydroxy product in any amounts. There is also some precedent for sulfonyl groups
being used to activate N-H bonds in order to allow for oxidase reactivity on the same
molecule (Figure 3.1C)18, 19
.
97
3.2 Reaction Discovery
3.2.1 Initial Mass Spectrometry Observations
Figure 3.2. A) General reaction scheme for the oxygenation of the sultam products. B) The chromatograms of both
APCI and ESI runs for the sultams showing the oxygenated species. C) The same observations also shown with
different electronic conditions.
While taking high-resolution mass spectrometry (HRMS) of sultam product 3.1, it
was observed that a new peak was forming at about M+14 amu in which M is the mass
of sultam product 3.1. It was determined to be an oxygenated species 3.2, whereas a
C(sp2
)-H bond was turned into a C=O bond. The new mass corresponds to the fact that
98
sultam 3.1 gains an oxygen atom but loses two hydrogen atoms. The main observation
was found using atmospheric pressure chemical ionization (APCI) with electrospray
ionization (ESI) showing significantly less signal. This could be explained by the fact that
APCI adds current directly to the nebulized solution with air flowing through it. ESI on the
other hand, does not add current relying on electrostatic effects of the droplets happening
in the solution. Due to that, ESI will have a harder time activating the oxygenation and
also getting oxygen to the reactive site. The oxygenated species 3.2 did not, however,
show up in GC or NMR analysis of 3.1 showing that it is a product of ionization and still
occurring even with different substituents on the sultam (Figure 3.2 C). There are
examples of functionalization using ionization, but usually while using ESI20-22 making this
an interesting transformation worth thorough studying.
3.2.2 Initial electrochemistry experiments
Electrochemistry was initially utilized to convert the mass spectrometry
observations into a practical laboratory synthetic method. This is because when more
current and air was added to the ionization with APCI, the amount of oxygenated product
3.2 was increased in both cases (Figure 3.3). However, when experimenting
electrochemical reaction with different electrodes, no reaction was observed, except
Figure 3.3. Air and current showing a positive correlation to oxygenated species forming in APCI experiments.
99
when a copper electrode was used and quantitative conversion was achieved. A negative
control was then performed by adding the copper electrode to a solution of starting sultam
3.1 and letting it sit without applying any current. Surprisingly, the same reactivity was
observed with quantitative conversion to oxygenated species 3.2 and 3.3. This implied
that the copper metal itself was able to catalyze the reaction and was not an
electrochemical process. This conclusion was validated with a separate experiment using
copper mesh and the same quantitative conversion to products was observed in every
run which further proved that it was a copper catalyzed reaction.This promising result led
us to pursue the reaction catalytic conditions with copper catalyst.
Scheme 3.1. Solution of MeOH and sultam mixed with copper mesh resulting in high conversion to oxygenated
products.
3.3 Reaction Optimization
When performing this copper catalyzed reaction in Scheme 3.1, the resulting
peaks of starting sultam 3.1, oxo product 3.2, and hydroxy product 3.3 could all be
visualized distinctly at different retention time in GC through the flame ionization detecter
(FID) chromatogram (Figure 3.4). This made the task of optimization significantly easier
as the conversion and ratios can be found easily with the FID. This allowed us to
qualitatively screen various reaction conditions without a calibration curve for DAD studies
in LC-MS or isolated yields which is more time-consuming. The main factors studied for
100
optimization was catalysts, solvents, and additives in order to get the optimal conversion
and selectivity.
.
2h
24h
Figure 3.4. GC-FID chromatogram shows starting sultam, hydroxy product, and oxo product peaks can be visualized at
distinct retention time and magnitude.
3.3.1 Catalyst Screen to Develop Oxo Conditions
Figure 3.5. Catalyst screen bar graph showing CuCl2 was the best catalyst and copper metal was required.
First, a catalyst screen was performed in in the optimization process to find a
catalytic amount of catalyst necessary for the reaction (Figure 3.5). At this point, the
conversion was good (>90%), however, it was operated with a significant amount of
copper metal (more than 100 mol %), not a catalytic amount. Because of this, different
0
20
40
60
80
100
Catalyst Screening
oxo
hydroxy
101
metal salts were utilized to enhance the results under catalytic conditions. Therefore, a
solution of sultam 3.1 in methanol was prepared with 10 mol% of catalyst as the starting
point of catalyst screening process. The reaction was monitored in GC-FID until starting
material was fully consumed to produce compound 3.2 and 3.3. In this study, copper was
required while other metal catalysts, such as iron, nickel, manganese, and cobalt salts,
showed no catalytic activities with 0% conversion to either of the two products 3.2 and
3.3. Further, CuCl2 was the best catalyst with more selectivity towards the oxo product
3.2 formation. While Cu(OAc)2 demonstrated a superior conversion and selectivity
towards 3.2, it needed a significant longer reaction time (4 hours) than CuCl2 (2 hours) at
a 10 mg scale. Experiments with Cu(2-ethylhexanoate)2, Cu(formate)2, and Cu(OH)2 all
were active, but had lower conversion at 90% instead of 98% with similar selectivity.
Electron-poor copper sources had the hardest time performing reaction with Cu(BF4)2,
Cu(triflate)2, Cu(NO3)2, Cu(acac)2, and Cu(hexafluoroacac)2 with less than 10%
conversion and selectivity favored hydroxy product 3.3. This implies that copper catalyst
source requires a sufficient electron density to perform oxygenation to fully oxidize to final
product 3.2.
102
3.3.2 Solvent Screening to Develop a High Selectivity Condition Towards Oxo
Product
Figure 3.6. Solvent screening showed the strong correlation between high yielding product and selectivity towards
hydroxy in smaller aprotic alcohols.
A solvent screening was studied to further improve the reaction selectivity (Figure
3.6). Solutions of sultam 3.1 in different solvents, 10 mol% of CuCl2 were prepared and
monitored via GC-FID analysis upon completion. Interestingly, smaller alkyl group
containing alcohols exhibit strong selectivity towards the formation of oxo product 3.2,
while more polar aprotic solvents are highly selective towards hydroxy product 3.3.
Therefore, methanol (MeOH) was selected to be the solvent in the oxo reaction. MeOH
when mixed with water, leads to the same selectivity in comparison to reaction in ethanolwater mixture, yet the MeOH-H2O system converted starting material within 1 hour
instead of 2 hours at 10 mg scale for optimization. Due to the ability to shuttle proton
transfer of the protic solvents, it allowed them to favor oxo product 3.2. In order to form a
carbonyl (C=O) bond, a proton needs to be removed from the sultam 3.1 to form the
double bond, which would be harder to accomplish in an aprotic solvent. This would also
0
20
40
60
80
100
Solvent Screening
oxo
hydroxy
103
explain why aprotic solvents such as acetonitrile, dimethyl sulfoxide (DMSO), and
acetone all favor the hydroxy product 3.3 significantly. Dimethylformamide (DMF) was the
only solvent able to selectively make the oxo product 3.2, however this could be due to
the fact that DMF is hygroscopic in benchtop storage. Nonpolar aprotic solvents, such as
chloroform, led to very poor conversions due to the poor solubility of the starting materials
resulting in a nonhomogeneous solution.
3.3.3 Additives Screening to Develop High Selectivity Condition Towards Oxo
Product
Figure 3.7. Additive screening shows that ligands can inhibit the reaction to some extent and bases can promote the
formation of oxo product 3.2, while acids can promote the hydroxy product 3.3.
With the selected catalyst and solvent in the previous studies, different additives
were modified to further optimize the reaction selectivity towards the oxo product 3.2
(Figure 3.7). In order to do this, solutions of sultam 3.1 and 10 mol% of CuCl2 in a 5:95
mixture MeOH-H2O with different additives (e.g. ligands, bases, and acids) were
prepared. The reactions were monitored via GC-FID analysis upon completion. Many
copper catalyzed oxygenase type reactions reported in the literature require the addition
0
20
40
60
80
100
Additives Screening
oxo
hydroxy
104
of ligands or use of exotic copper complexes.23 However, in this case, the addition of
ligands, such as ethylenediaminetetraacetic acid (EDTA) and 2,2'-bipyridine (bipy),
seemed to hinder the reaction selectivity leading to substantially lower conversions (≤
10%). Other ligands, such as tetramethylethylenediamine (TMEDA), ammonium
hydroxide (NH4OH), and triphenylphosphine (PPh3), converted 50% of starting material.
More notably, PPh3 reversed the selectivity towards the hydroxy product 3.3. The fact that
added ligands hinder the reaction implies that sultam 3.1 can act as a ligand leading to
the reactivity observed. This is because the added ligands will start to compete with
sultam 3.1 in ligating to the copper thereby hindering the ligation between copper and 3.1.
Since hindering the 3.1-Cu ligation leads to a hindered reaction, this 3.1-Cu interaction is
vital for the oxygenation observed.
Base additives were then tested to improve the selectivity towards oxo 3.2. Solvent
screening study indicated that proton transfer could be an important step in the formation
of the oxo product, which could be further promoted in a basic solution. Inorganic bases,
such as Li2CO3, Na2CO3, K2CO3, and KHCO3, all showed better selectivity towards the
oxo product 3.2. This demonstrated that deprotonation is important for the formation of
the oxo product facilitating in a protic solvent and a base. Notably, acid additives, such as
HCl and NH4Cl, lead to more hydroxy product 3.3, because acidic condition impede
deprotonation and kinetically more challenging. Interestingly, the addition of LiCl and
tetrabutylammonium chloride (TBAC) also lead to more hydroxy product 3.3 selectivity,
however, this observation have yet to be elucidated.
105
3.3.4 Optimizing Hydroxy Selectivity Condition
Figure 3.8. Optimization of the hydroxy product from oxo product optimization study based off of observations from the
oxo optimization.
Originally, finding conditions for the hydroxy product 3.3 was not a consideration
as selectively forming hydroxy products is very rare within copper catalyzed oxygenation
usually only forming carbonyl (oxo) products (Figure 3.8). However, through the efforts to
optimize the oxo reaction, the hydroxy conditions sort of fell out showing the possibility.
Using CuBr2 as the reaction catalyst, there was slight improvement in selectivity towards
the hydroxy product 3.3. In addition, a polar aprotic solvent further improved significant
selectivity towards the hydroxy product 3.3. Therefore, acetonitrile (MeCN) was found to
be the optimal solvent with highest conversion and selectivity towards hydroxy product
3.3. Solvents, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF),
and acetone, all showed relatively high selectivity towards hydroxy product 3.3, but they
did not fully convert with CuBr2 with conversion at 88%, 91%, and 96% respectively.
Interestingly, the required amount of copper catalyst in the hydroxy conditions was lower
(2.0 mol%) than in oxo conditions (10 mol%). Next, the optimized condition was scaleup
to a practical amount (50 mg) for product isolation. In a 50 mg scale, the reaction became
0
20
40
60
80
100
CuCl2 CuBr2 CH3CN THF 2-Methyl-THF Acetone
Hydroxy Conditions
oxo hydroxy
106
very non-reproducible though with the reaction times varying greatly ranging from 18
hours to 4 days. The irreproducibility could be caused by the varying water content in
different MeCN bottles used. This is because water was shown to quicken the oxo
reactions meaning that water could be important in the hydroxy reaction as wel. In an
experiment with 5% water to the MeCN, the reaction became faster with a lower selectivity
because the water promoted the formation of oxo product. To still have the benefits of
water but still limit the amount of oxo product 3.2, a reaction was done with a catalytic
amount of water. This succeeded in quickening the reaction completing within 18 hours
while still maintaining good selectivity for hydroxy product 3.3. Water could act as a weak
ligand to help free up the copper for the sultam to ligate to and promote proton transfers,
yet not fully oxidize to oxo product 3.2.
3.4 Reactions Control
To understand the mechanism to a higher degree, the conditions required for this
reaction was further explored. The two major factors in this oxygenation mechanism is
oxygen and copper.
3.4.1 Oxygen Effect
To corroborate the source oxygen being from air (3O2) (Scheme 3.2 A), the reaction
was set up in a N2-filled glovebox with stock solution of CuCl2 in MeOH/H2O (95:5). The
reaction was stirred for 24 hours inside the N2-filled glovebox. The reaction yieled no
conversion under inert atmosphere (N2), and GC analysis revealed a single peak
corresponding to the starting material 3.1. This experiment unequivocally describes that
the oxygen atom in the products 3.2 and 3.3 originates from molecular O2 in the
107
atmosphere. Next, different forms of activated O2 were introduced to the reaction. Sodium
peroxide (Na2O2) (Scheme 3.2 B) and hydrogen peroxide (H2O2) (Scheme 3.2 C) were
added to solutions of sultam 3.1 and CuCl2 in MeOH/H2O (95:5 by volume) under a
nitrogen atmosphere. Sodium peroxide formed dimer 3.4, while H2O2 formed hydroxy
product 3.3 at a low conversion (18%). This demonstrated that copper selectively forms
a suitable oxygen species to react with the sultam 3.1, unlike Na2O2 (too reactive) or H2O2
(not strong oxidizing species). Hence, the superoxides that copper normally forms in the
presence of O2 has the ideal reactivity strength in between Na2O2 and H2O2.
To explore the role of water in the reaction, an experiment was designed with dry
CuCl2 and pure O2 was utilized, instead of ambient air (Scheme 3.2 D) in a N2-filled
glovebox. The reaction vial was covered with a screw cap with a PTFE septum and was
sealed with an electric tape before moving out of the glove box. Upon removal from the
glovebox, dry O2 balloon was used to supply pure O2 to the reaction and stirred for 24
hours. Notably, the reaction produced hydroxy product 3.3 as the major species in both
MeOH and MeCN. In the previous solvent screening process, protic solvents favor the
formation of oxo product 3.2. Therefore, the result in this study further elucidated that
conversion of hydroxy product 3.3 to oxo product 3.2 is water mediated.
108
Scheme 3.2. A) Oxygen-free conditions showing the role of O2. B) Na2O2 being too strong of a nucleophilic source of
O2. C) H2O2 is a weaker oxidizing source of O2. C) water effect in the reaction.
3.4.2 Copper Effect
In order to validate the role of copper catalyst in the optimized conditions, a
negative controlled experiment was performed in the absence of copper (Scheme 3.3 A).
Substrate 3.1, Li2CO3, were added to a 5:95 H2O:MeOH solution and stirred for 24 hours.
In the absence of a copper catalyst, starting material 3.1 was not activated and did not
further react, therefore no conversion was observed and substrate 3.1 was recovered.
While copper(II) salts are easier to handle a fresh bottle of Cu(I)Cl was obtained (to avoid
109
Cu(II) impurities) (Scheme 3.3 B). The commercial bottle was freshly opened inside a N2-
filled glovebox and a reaction was set up in dry MeCN. Upon removal from the glovebox,
the reaction was stirred with a dry O2 balloon for 24 hours. The reaction behaved
effectively similar to previous CuCl2 reactions. This suggests that Cu(I) converts to Cu(II)
in-situ under the provided reaction conditions. This suggests that a Cu(I)/Cu(II) system is
being employed. Copper oxides were used as a catalyst in order to test if the reaction can
tolerate copper oxides in the catalytic cycle (Scheme 3.3 C). This was because some
oxygenation reactions often involve catalytic transformation to copper oxides in their
catalytic cycle24. In both reactions catalyzed by Cu2O and CuO, the conversions to
product 3.2 and 3.3 were quantified to be 80-90% with minimal affects to the selectivity
between products 3.2 and 3.3. This showed that copper oxides were tolerated in the
reaction and the mechanisms that form copper oxides could possible.
Following this, the reaction was performed under optimized conditions in the
presence of a radical trap to capture and identify any in-situ radical species under coppercatalyzed C–H functionalization25, 26 (Scheme 3.3 D). In the presence of TEMPO and
gamma-terpinene, the reaction slowed down but were not entirely inhibited. There was
no observed radical trapped species in these reactions. The introduction of BHT to the
reaction, however, led to degradation of starting material without any obvious major
product. This suggests that radicals play a role, because these radical inhibitors cause
an effect to the reaction in a negative manner with lower conversions, however, cannot
definitively prove the presence of them in the reaction.
110
Scheme 3.3. A) Copper-free condition showing the need for copper. B) CuCl catalysis showing Cu(I) can be utilized. B)
Copper oxides can exist in the catalytic the cycle without hindering the reaction outcome. D) Radical traps slows down,
but not killing the reaction.
111
3.5 Structural Limitations of Starting Material
Scheme 3.4. A) Carbonyl replacing SO2 group leads to no reaction. B) Alkylating the N-H of the sultam leads to no
oxygenation in optimized conditions. C) The reactive carbon cannot be aromatic.
To further understand the importance of different components in the starting sultam
structure and explore the limitation of various derivatives, different substrates were
prepared (Scheme 3.4). First, starting material 3.5 was synthesized using reported
literatures27 to replace the sulfonyl group of 3.1 with a carbonyl group (Scheme 3.4 A).
Two derivatives, 3.5 (Ph) and 3.6 (H) modified at the α-carbon with respect to the nitrogen,
were investigated. In both cases, no oxygenation was observed and both starting
materials 3.5 or 3.6 were recovered in GC-MS analysis after 24 h. This suggests that
sulfonyl group plays a unique role in the starting substrate due to its open-book like
112
geometry of the sultam 3.1 ability to coordinate to copper metal. The other possibility is
that the sulfonyl group can act as a withdrawing group without engaging the nitrogen’s
lone electron pair. This shifts more electron density to the nitrogen atom making it more
likely to ligate to copper. Since the ligand studies showed that the sultam 3.1 likely acts
as a ligand in the reaction, therefore a more electron-dense substrate would benefit the
reaction outcome.
To prevent the starting sultam conversion to imino tautomers, experiments with
starting substrate in an enamine form was investigated. To lock starting substrate in its
enamine form, the nitrogen atom was methylated with methyl triflate (CH3OTf) (Scheme
3.4 B). Interestingly, the methylated sultam 3.7 also did not show any conversion under
optimized conditions, thus highlighting the importance of exchangeable protons occurring
at the nitrogen atom and the ability of sultam to switch between the two tautomers. It also
supports the hypothesis that nitrogen acts as a coordinating ligand to the copper center.
This experiment demonstrated the inhibition of alkylated sultam to bind to copper catalyst
and facilitate the copper-catalyzing reaction.
A tosylated aniline 3.8 was also synthesized in order to investigate the reaction
limitation with an aromatic carbon, in place of a vinylic carbon (Scheme 3.4 C). Under
the studied standard condition, this reaction did not proceed. This could also be due to
the fact that aromaticity is hard to break, however, similar reactivity was encountered
when dealing with phenols28 implying that there is something more significant. However,
ongoing studies need to be performed to understand this phenomenon in more details.
113
3.5 Kinetic Profiles for the Oxygenation of the Sultam
The data for the reaction profiles was obtained using GC-FID similar to that of the
optimization. After the reaction was set up, an aliquot was taken for analysis with the
ratios of the starting sultam 3.1, oxo product 3.2, and hydroxy product 3.3 to be plotted.
The aliquots were taken about every hour and 2 blanks of just DCM was ran in between
each run. The purpose of the blanks was to make sure the column was clean so that the
runs would not have inaccurate ratios from starting material or product still being in the
column.
114
3.5.1 Kinetic Profile of the Oxo Reaction
0
25
50
75
100
0 4 8 12 16 20 24 28 32 36 40 44 48 Percent Composition
Reaction Time (h)
Reaction Profile Oxo Conditions With Water
Sarting Material
Hydroxy Product
Oxo Product
0
25
50
75
100
0 4 8 12 16 20 24 28 32 36 40 44 48 Percent Composition
Reaction Time (h)
Reaction Profile Oxo Conditions With Water
Sarting Material
Hydroxy Product
Oxo Product
0
25
50
75
100
0 4 8 12 16 20 24 28 32 36 40 44 48 Percent Composition
Reaction Time (h)
Reaction Profile Oxo Conditions Without Water
Starting Material
Hydroxy Product
Oxo Product
Figure 3.9. A) Reaction performed with only catalyst, MeOH, and starting material. B) Reaction performed with added
water. B) Reaction performed with both water and lithium carbonate.
To further understand the reaction components and reaction mechanism, some
reactions were tracked to observe intermediates and products were seen. Using the
model compound 3.1, different reactions were set up with CuCl2 catalyst to investigate
the role of water and base. An experiment used only methanol as solvent and CuCl2
catalyst (Figure 3.9 A). Another experiment used 5 vol% water in methanol as solvent
115
and CuCl2 catalyst to observe the water effect (Figure 3.9 B). Finally, an experiment used
0.2 equiv. lithium carbonate with 5 vol% methanol in water and CuCl2 catalyst to observe
the base effect (Figure 3.9 C). Many interesting results were observed in these
experiments based on their kinetic profiles. Notably, the conversion of hydroxy 3.3 to oxo
3.2 product is a stepwise reaction. Hydroxy product 3.3 formed first, followed by the
gradual formation of oxo product 3.2 as the hydroxy product 3.3 converted to 3.2. The
presence of water caused the starting material 3.1 converts to hydroxy product 3.3 much
faster. Hydroxy product 3.3 also converting to oxo product 3.2 such that the composition
of hydroxy product 3.3 does not exceed 50% in the reaction. In the presence of lithium
carbonate, this same effect is further enhanced and the reaction yielded more than 95%
conversion from starting material 3.1 within 5 hours. This potentially suggests that that
conversion of hydroxy 3.3 to oxo 3.2 product involves proton transfer mechanism.
3.5.2 Kinetic Profile Done with Optimized Hydroxy Conditions
A similar study utilizing hydroxy conditions showed equally interesting results
showing a gestation over period of 7 hours, while the reaction completes in 9 hours
(Figure 3.11). The same phenomena was observed in this study where hydroxy product
3.3 formed before any oxo product 3.2 (byproduct in this case). This can be explained by
the fact that MeCN is a good ligand for copper catalyst and competing with the sultam
starting material 3.1 to coordinate with the copper center to facilitate the reaction.
116
0
25
50
75
100
0 4 8 12 16 20 24 28 Percent Composition
Reaction Time (h)
Reaction Profile Hydroxy Conditions
Starting Material
Hydroxy Product
Oxo Product
Figure 3.10. Reaction profile for the hydroxy optimized conditions.
3.6 Competition Reaction with added Product in the Oxo Condition
Following the observations in the kinetic profiles, some competition reactions were
designed to observe the formation of products 3.2 and 3.3 effect in the general reaction
path (Figure 3.11). Because products 3.2 and 3.3 could be better ligands for the copper
for the desired reactivity. This hypothesis was investigated, due to the fact that the
reaction is inhibited by the addition of extra ligands implying a competitive process had
occurred. It also concluded that sultam 3.1 is a ligand for copper catalyst in the first step
of the reaction leading to the oxygenation of the sultams 3.2 and 3.3. Another explanation
for this was that only hydroxy product 3.3 was formed at first. After the hydroxy product
3.3 and starting sultam 3.1 formed a 1:1 ratio, the production of the oxo product 3.2 started
to pick up. This implies that the sultam 3.1, when being ligated to the copper, forms an
active species responsible for the oxygenation to hydroxy product 3.3, but not capable of
oxidizing 3.1 to oxo product 3.2. The hydroxy product 3.3, however, could have the right
electronics to form a copper species to perform that oxidation being able to outcompete
117
the sultam starting material 3.1 to the metal center as 3.1 concentration in the solution
diminished to 1:1 ratio.
To test this hypothesis, a series of experiments were set up. A base line for the
experiment was the oxo optimized condition. A set of reactions with an additional 0.25
equiv., 0.5 equiv., and 0.75 equiv. of either hydroxy 3.3 or oxo 3.2 product at the beginning
of the reaction for a total of 7 runs (including the first baseline experiment). These
reactions were monitored and analyzed in GC-FID every hour for 8 hours and the raw
FID data were extracted to calculate the ratios of all of the products and starting material.
The obtained data was extrapolated and plotted in excel. The results of these experiments
were inconclusive because most of the differences in consumption rate and conversion
was insignificant. However, it shows that adding hydroxy product 3.3 to the beginning of
the reaction can speed up the reaction with slightly faster conversion in comparison to the
reactions with spiked oxo 3.2. The ratios between oxo 3.2 and hydroxy 3.3 as well as the
percentages of each did not have a clear and conclusive trend.
118
Figure 3.11. Competition experiments in order to observe product formation effect on the reaction.
3.7 Substrates Scope
A substrate scope was performed to further investigate the limitations of this
reaction (Figure 3.13). The optimized conditions for both oxo and hydroxy reactions were
1
2
3
4
5
6
7
8
1 2 4 6 8 Ratio
Time (h)
oxo:hydroxy Ratio
0.25 oxo
0.5 oxo
0.75 oxo
0.25 hydroxy
0.5 hydroxy
0.75 hydroxy
standard
55
60
65
70
75
80
85
90
1 2 4 6 8 Percent
Time (h)
Oxo Percent
0.25 oxo
0.5 oxo
0.75 oxo
0.25 hydroxy
0.5 hydroxy
0.75 hydroxy
standard
0
2
4
6
8
10
12
14
1 2 4 6 8 Percent
Time (h)
Starting Material Percent
0.25 oxo
0.5 oxo
0.75 oxo
0.25 hydroxy
0.5 hydroxy
0.75 hydroxy
standard
10
15
20
25
30
35
40
1 2 4 6 8 Percent
Time (h)
hydroxy Percent
0.25 oxo
0.5 oxo
0.75 oxo
0.25 hydroxy
0.5 hydroxy
0.75 hydroxy
standard
119
used with various functional groups on the sultam group. Due to the modular ability of the
starting material synthesis developed previously by Aggarwal et. al.29, a wide range of
starting materials were able to be synthesized for the substrate scope study.
First, The reaction was tested to see if alkyl groups at the alpha position to the
nitrogen could be tolerated. Compounds with t-butyl, n-pentyl, and benzyl derivatives
were synthesized. The t-butyl derivative performed with a conversion of 87% hydroxy 3.14
and 95% oxo 3.15. The n-pentyl and benzyl derivatives, on the other hand, did not convert
to desire products. The n-pentyl derivative degraded under the given condition and benzyl
derivative yielded 0% conversion to either hydroxy 3.36 or oxo 3.37 products. This
indicated that the aromatic groups are highly important. It could be explained by the fact
that when radicals are in play for the mechanism, the aryl groups at that position can
stabilize the intermediates. Due to sterically bulkiness of t-butyl group, it was able to
prevent side reactions, hence this could have been the reason n-pentyl derivative
degraded. Interestingly, even in the mass spectrometry experiments, alkyl derivatives did
not produce any oxygenation product, while the t-Bu derivative did albeit to a low amount
(Figure 3.12).
Figure 3.12. Comparison of the APCI studies done with t-Bu and benzyl derivatives showing no conversion with a
benzyl group and limited conversion with a t-Bu group.
Next, electronic affects on the reaction was investigated by modifying the aryl
group alpha to the nitrogen atom of the sultam scaffold. In order to test this, a withdrawing
120
groups, CF3, group was installed onto the sultam. The experiment resulted in a high
conversion to both hydroxy 3.8 (93%) and oxo 3.9 (99%) conditions. Under the same
circumstances, methoxy groups resulted in 90% and 91% conversion for hydroxy 3.16
and oxo 3.17 conditions indicating that the reaction can tolerate electron-rich functional
groups without suffering conversion loss. Derivative with methoxy groups at the ortho
position of the aryl ring led to 100% conversion in both hydroxy 3.22 and oxo 3.23
conditions. The ortho methoxy group also seemed to be active with faster reaction times
of 3-5 hours, instead of 18 hours like most of the other substrates. The starting material
for this reaction also slowly was oxidized in ambient air with a significant conversion after
3 months. Other derivatives were synthesized, including para fluoro and t-Bu. Halogens
can also be tolerated in the reaction – fluoro derivative converted to hydroxy 3.10 (99%)
and oxo 3.11 (94%). The t-Bu derivative also had high conversions of 96% and 100% to
hydroxy 3.20 and oxo 3.21, respectively. This position could also have other aryl
structures such as naphthalene and thiophene with high conversions for both hydroxy
(3.26 and 3.30) and oxo (3.27 and 3.31) conditions. Another sulfur-containing derivative
was used with full conversion to oxo 3.29 conditions but 0% conversion to hydroxy 3.28.
Due to the fact that sulfur can bind to copper and bring it further from the active site, which
would be more significant when lower catalyst loading was used in hydroxy conditions as
2 mol% of catalyst, instead of the 10 mol%.
A few derivatives were also synthesized with modifications to the aryl ring on the
sulfonyl azide. Methoxy and bromo derivatized substrates were synthesized and both of
them can tolerate the applied conditions. The methoxy derivative converted up to 90%
and 91% to hydroxy 3.18 and oxo 3.19, respectively, while the bromo derivative had
121
conversion of 99% and 93% to hydroxy 3.24 and oxo 3.25, respectively, showing that
halogens can also be tolerated at this position.
Interestingly, the hydroxy conditions led to higher selectivity for hydroxy product
than the oxo conditions did for oxo product. Due to the fact that the reaction is stepwise,
it needs a second oxidation to an alcohol to carbonyl and this step could be easily inhibited
by the lower copper catalyst loading required for the reaction.
Figure 3.13. Substrates scope for this reaction showing both hydroxy and oxo conditions.
122
3.8 Mechanism Proposal
The first step of the mechanism is likely the ligation of copper to sultam 3.38
forming complex 3.39. This is supported by the fact that added ligands hurt the reaction
demonstrating that the formation of 3.39 is critical and interfering with that step is
detrimental to the reaction. There are also known examples of substrates acting as
ligands in oxygenation reactions.23 This complex can then lead to radical species 3.40 as
copper is known to form N-centered radicals with N-H groups.25, 26 3.40 would be in
resonance with C-centered radical species 3.41 which could then be oxygenated forming
hydroperoxyl 3.42. This radical process would also explain why radical traps reduced the
conversion of this reaction interfering with the formed radicals 3.40 and 3.41. Following
this, 3.42 can be turned into 3.44 or 3.45 following copper catalyzed processes. The more
oxidizing the environment, the more the reaction will favor product 3.45.
Scheme 3.5. Proposed mechanism for the copper catalyzed oxygenation of sultams.
123
3.9 Conclusion
While new transformations catalyzed by copper are reported on a daily basis,
research aims towards the development of selective, cheap, environmentally friendly, and
benign oxygenation protocols. Most research articles report functionalization of reactions
that employ expensive ligands that also require multi-step synthetic route, adding to the
overall cost effectiveness and the practicality of the method. This work demonstrates an
ease to set up protocol utilizing molecular oxygen, directly from ambient air, while water
as the only byproduct. This protocol is efficient under room temperature conditions, with
cheap copper salts as catalyst and does not require additional stabilizing ligands. The
reaction is a rare example of oxygenase type reactivity facilitated by organic molecules.
Moreover, the resulting novel products offer fundamental structural insights and show
similarity with oxicam class of NSAIDs.
3.10 References
1. Saranya, S.; Anilkumar, G., Copper Catalysis. In Copper Catalysis in Organic
Synthesis, 2020; pp 1-5.
2. Trammell, R.; Rajabimoghadam, K.; Garcia-Bosch, I., Copper-Promoted
Functionalization of Organic Molecules: from Biologically Relevant Cu/O2 Model Systems
to Organometallic Transformations. Chemical Reviews 2019, 119 (4), 2954-3031.
3. Sterckx, H.; Morel, B.; Maes, B. U. W., Catalytic Aerobic Oxidation of C(sp3)−H
Bonds. Angewandte Chemie International Edition 2019, 58 (24), 7946-7970.
4. Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C., Aerobic
Copper-Catalyzed Organic Reactions. Chemical Reviews 2013, 113 (8), 6234-6458.
5. McCann, S. D.; Stahl, S. S., Copper-Catalyzed Aerobic Oxidations of Organic
Molecules: Pathways for Two-Electron Oxidation with a Four-Electron Oxidant and a OneElectron Redox-Active Catalyst. Accounts of Chemical Research 2015, 48 (6), 1756-
1766.
124
6. Walling, C., Autoxidation. In Active Oxygen in Chemistry, Foote, C. S.; Valentine,
J. S.; Greenberg, A.; Liebman, J. F., Eds. Springer Netherlands: Dordrecht, 1995; pp 24-
65.
7. Jira, R., Acetaldehyde from Ethylene—A Retrospective on the Discovery of the
Wacker Process. Angewandte Chemie International Edition 2009, 48 (48), 9034-9037.
8. Gnanou, Y.; Hizal, G., Effect of phenol and derivatives on atom transfer radical
polymerization in the presence of air. Journal of Polymer Science Part A: Polymer
Chemistry 2004, 42 (2), 351-359.
9. Feng, X.; Jiang, K.; Fan, S.; Kanan, M. W., A Direct Grain-Boundary-Activity
Correlation for CO Electroreduction on Cu Nanoparticles. ACS Central Science 2016, 2
(3), 169-174.
10. Snyder, B. E. R.; Bols, M. L.; Schoonheydt, R. A.; Sels, B. F.; Solomon, E. I., Iron
and Copper Active Sites in Zeolites and Their Correlation to Metalloenzymes. Chemical
Reviews 2018, 118 (5), 2718-2768.
11. Worrell, B. T.; Malik, J. A.; Fokin, V. V., Direct Evidence of a Dinuclear Copper
Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions. Science 2013, 340 (6131),
457-460.
12. Jiang, Y.-Y.; Li, G.; Yang, D.; Zhang, Z.; Zhu, L.; Fan, X.; Bi, S., Mechanism of
Cu-Catalyzed Aerobic C(CO)–CH3 Bond Cleavage: A Combined Computational and
Experimental Study. ACS Catalysis 2019, 9 (2), 1066-1080.
13. Shi, Z.; Zhang, C.; Tang, C.; Jiao, N., Recent advances in transition-metal
catalyzed reactions using molecular oxygen as the oxidant. Chemical Society Reviews
2012, 41 (8), 3381-3430.
14. Gupta, A.; Kumar, J.; Rahaman, A.; Singh, A. K.; Bhadra, S., Functionalization of
C(sp3)-H bonds adjacent to heterocycles catalyzed by earth abundant transition metals.
Tetrahedron 2021, 98, 132415.
15. Wdowik, T.; Chemler, S. R., Direct Synthesis of 2-Formylpyrrolidines, 2-
Pyrrolidinones and 2-Dihydrofuranones via Aerobic Copper-Catalyzed Aminooxygenation
and Dioxygenation of 4-Pentenylsulfonamides and 4-Pentenylalcohols. Journal of the
American Chemical Society 2017, 139 (28), 9515-9518.
16. Donthiri, R. R.; Samanta, S.; Adimurthy, S., Copper-catalyzed C(sp3)–H
functionalization of ketones with vinyl azides: synthesis of substituted-1H-pyrroles.
Organic & Biomolecular Chemistry 2015, 13 (40), 10113-10116.
17. Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei, A., Room-Temperature
Copper-Catalyzed Oxidation of Electron-Deficient Arenes and Heteroarenes Using Air.
Angewandte Chemie International Edition 2012, 51 (19), 4666-4670.
125
18. Carmo, R. L. L.; Galster, S. L.; Wdowik, T.; Song, C.; Chemler, S. R., CopperCatalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation:
Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives. Journal of
the American Chemical Society 2023.
19. Chen, S.; Chen, W.; Chen, X.; Chen, G.; Ackermann, L.; Tian, X., Copper(I)-
Catalyzed Oxyamination of β,γ-Unsaturated Hydrazones: Synthesis of Dihydropyrazoles.
Organic Letters 2019, 21 (19), 7787-7790.
20. Rao, Z.; Li, X.; Fang, Y.-G.; Francisco, J. S.; Zhu, C.; Chu, C., Spontaneous
Oxidation of Thiols and Thioether at the Air–Water Interface of a Sea Spray Microdroplet.
Journal of the American Chemical Society 2023, 145 (19), 10839-10846.
21. Qiu, L.; Psimos, M. D.; Cooks, R. G., Spontaneous Oxidation of Aromatic Sulfones
to Sulfonic Acids in Microdroplets. Journal of the American Society for Mass Spectrometry
2022, 33 (8), 1362-1367.
22. Qiu, L.; Cooks, R. G., Simultaneous and Spontaneous Oxidation and Reduction in
Microdroplets by the Water Radical Cation/Anion Pair. Angewandte Chemie International
Edition 2022, 61 (41), e202210765.
23. McNichol, C. P.; DeCicco, E. M.; Canfield, A. M.; Carstairs, D. P.; Paradine, S.
M., Copper-Catalyzed Aerobic Aminooxygenation of Cinnamyl N-Alkoxycarbamates via
Substrate-Promoted Catalyst Activation. ACS Catalysis 2023, 13 (10), 6568-6573.
24. Li, Y.; Ji, G.-C.; Chao, C.; Bi, S.; Jiang, Y.-Y., Computation Study on CopperCatalyzed Aerobic Intramolecular Aminooxygenative C═C Bond Cleavage to Imides:
Different Roles of Mononuclear and Dinuclear Copper Complexes. ACS Catalysis 2023,
13 (6), 3815-3829.
25. Liu, X.-D.; Wang, Q.-A.; Zhu, Y.-P.; Peng, Z.-H.; Li, J.-H., Copper-catalyzed
aerobic hydroxyamination of alkenes of unsaturated keto oximes in EtOH toward cyclic
nitrones. Green Chemistry 2022, 24 (6), 2476-2482.
26. Tang, C.; Qiu, X.; Cheng, Z.; Jiao, N., Molecular oxygen-mediated oxygenation
reactions involving radicals. Chemical Society Reviews 2021, 50 (14), 8067-8101.
27. Mayo, M. S.; Yu, X.; Feng, X.; Yamamoto, Y.; Bao, M., Isoquinolone Synthesis
through SNAr Reaction of 2-Halobenzonitriles with Ketones Followed by Cyclization. The
Journal of Organic Chemistry 2015, 80 (8), 3998-4002.
28. Schneider, R.; Engesser, T. A.; Näther, C.; Krossing, I.; Tuczek, F., CopperCatalyzed Monooxygenation of Phenols: Evidence for a Mononuclear Reaction
Mechanism. Angewandte Chemie International Edition 2022, 61 (25), e202202562.
29. Aggarwal, S.; Vu, A.; Eremin, D. B.; Persaud, R.; Fokin, V. V., Arenes participate
in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes. Nature Chemistry 2023,
15 (6), 764-772.
126
Chapter 4. Reactivities of SO2F Triazoles
4.1 Introduction
In the recent years, one of the most useful functional groups in chemical synthesis
and pharmaceuticals is sulfonyl fluoride (SO2F)1
. SO2F is a functional handle in the sulfur
fluoride exchange (SuFEx) click reaction. SuFEx are reactions of SO2F groups with
nucleophiles, e.g. phenols, amines, or silyl ethers, to form a new O-S or N-S bonds with
HF or F-SiR3 as byproducts (Scheme 4.1). This reaction is proving to be a valuable
reaction as it allows biologically active SO2 groups to be installed in molecules with greater
ease than previously possible. The significant utilities of sulfonyl fluoride in synthetic
chemistry, methodologies to install SO2F to new molecular scaffolds is an area of strong
interest. It is special because sulfonyl fluoride is a good group for late-stage modification
as it can be used in SuFEx click chemistry. SuFEx chemistry has become a growing field
being used in bioconjugation and well as synthesis2
. Click reactions are very desirable as
it is selective, high yielding, and products are easy to isolate and purify3
. It has contributed
to many impactful chemical applications, such as protein labeling4
, materials chemistry5
,
pharmaceutical6
, and chemical synthesis7
.
Scheme 4.1. SuFEx reaction scheme.
Traditionally, sulfonyl fluoride (SO2F) groups are made from sulfonyl chlorides
(SO2Cl)1
(Scheme 4.2). This method utilizes chloride/fluoride exchange with fluoride salts,
normally KHF2
1
. Many SO2Cl-containing compounds, however, are not always readily
available8 and need to be synthesized from their corresponding thiols, halides, and
127
alcohols using oxidizing and toxic chlorinating agents9 and often create toxic waste
stream. In order to get around this drawback, other methods have been developed
including hydrazides10 and sodium sulfonates11
. Aryl halides can also undergo palladium
mediated cross-coupling with 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide)
(DABSO)12
. However, these methods still require the availability of their corresponding
thiols or sulfonyl chlorides, which is not always feasible to obtain.
Scheme 4.2. Common methods of producing SO2F groups from sulfonyl chloride.
Other more direct methods involve a nucleophile reacting with a SO2F source, such
as using SO2F2 or SO2FCl13
. While SO2F2 is a gas at ambient condition and is not reactive
with many nucleophiles, SO2FCl is a low boiling liquid that is difficult to synthesize and
handle. Thus, other reagents were developed, such as ESF14, FSI15 and AISF16
, which
are all not gases at ambient condition and more reactive towards nucleophiles (Scheme
4.3). These new reagents greatly simplified the reaction development process. Despite
their ease of use, these reagents are still currently limited structurally and synthetically.
Products from ESF contain two carbons between the SO2F group and added nucleophile.
Although FSI and AISF react with heteronucleophiles, such as amines and alcohols, to
form a heteroatom-sulfur bond, they are not known to react with carbon-centered
nucleophiles to form a C-S bond.
128
Scheme 4.3. Sulfonyl Fluoride installation without the use of sulfonyl chloride.
Despite the aforementioned limitations, SO2F can be installed onto some
interesting structures (Figure 4.1), e.g. cyclobutane14, 17-20
, bicyclopentanes21, etc. These
approaches are limited in their substrates scope, they either require specific functional
groups or have lengthy inefficient synthetic routes. There are not many examples of SO2F
amidines that have great applications in pharmaceutical industry with easy postfunctionalization of amidines sulfones. Utilizing ketenimine chemistry to form the SO2F
amidine group could overcome most of the challenges of amidine synthesis and advance
these reactions to manufacturing streamline.
Figure 4.1. Examples of structures possible with SO2F groups.
4.2 Reaction Discovery
Initially, the goal of this project was to find applications of SO2F triazoles in rhodium
chemistry. It was found that when sulfonyl triazoles are mixed with rhodium catalysts
rhodium carbenes22 are formed which can then undergo many useful tranformations
129
(Scheme 4.4), such as transanulation23-28 and insertions29-33. Currently, the sulfonyl
groups used, like tosyl, are not further functionalizable and the only modification that can
be done are deprotection of the sulfonyl group. This entirely removes SO2 functionality
that has biological activity and removes the interesting characteristic of the synthetic
route. To get around this, the idea was to use the electron-withdrawing effect of SO2F
allowable for rhodium chemisry, but with a post functionalization capablities with SuFEx
reaction.
Scheme 4.4. Many reactions possible using rhodium carbene chemistry showing the utility of this chemistry in forming
many molecular scaffoldings starting from just sulfonyl triazoles.
However, during the formation of SO2F triazole 4.2, effervescence was observed,
and a small quantity of desired product was obtained along with unexpected byproducts.
The fact that this transformation was happening at room temperature without the need of
any metal catalyst was pretty intriguing and subjected to further study.
130
4.3 Reaction Exploration
4.3.1 Fluorosulfonylating Reagent Screen
The initial attempts to synthesize SO2F triazole 4.2 was performed by reacting NH triazole 4.1 with various fluorosulfonylating reagents (Scheme 4.5A). In a normal
CuAAc condition, it would require an unstable and highly explosive reagent, SO2FN3
(Scheme 4.5C). To tackle this challenge, N-H triazole 4.1 replaces SO2FN3 as the starting
material in the reaction with a known fluorosulfonylating reagents (e.g. SO2F2, SO2FCl,
AISF, and FSI) (Scheme 4.5B). N-H triazole 4.1 was readily synthesized using reported
procedures34 to proceed in the reaction of acetophenone and 4-nitrophenylazide in a
scalable and high yielding manner.
Scheme 4.5. A) Our synthetic strategy for SO2F triazole. B) Common Fluorosulfonylating reagents. C) CuAAC
conditions that would require explosive azides if attempted.
Sulfuryl fluoride (SO2F2) was first attempted as it is the most widespread
fluorosulfonylating reagent. Usually, commercially available SO2F2 is transferred into a
balloon and the reaction via a syringe needle. However, SO2F2 gas could be challenging
131
to obtain because of high cost, a synthesis of SO2F2 was performed and transferred to
the reaction vial through a two-chambered glass reactor.35 SO2F2 was synthesized from
potassium bifluoride (KF2) and methylated sulfonyldiimidazole (MSDI) in one chamber.
SO2F2 can then travel to the other chamber containing N-H triazole 4.1, THF, and sodium
carbonate (Scheme 4.6). Interestingly, after 24 hours no reaction occurs, even though the
same method works with imidazoles15, which implies that N-H triazoles 4.1 are weaker
nucleophiles than imidazole and a stronger fluorosulfonylating reagent is required.
Scheme 4.6. Two vial method in which the desired product was not observed.
In the following experiment, SO2FCl was used. The reaction set up was the same
as the reaction with SO2F2, but with fluorosulfonylating reagent being added directly to
the mixture of N-H triazole 4.1, sodium bicarbonate, and THF. The reaction outcome did
not produce expected product. There was no product detected by thin layer
chromatography (TLC) or LC-MS analysis. Due to the fact that its boiling point is at around
132
6 °C, the loss of reagents during transferring through a pipet was significant. Moreover,
once in solution at room temperature, the reagent vapor could escape the reaction
resulting in more loss. This reagent loss has the same problems that SO2F2 had when
adding to N-H triazole 4.1. Due to the impractical synthesis and use of SO2FCl, other
fluorosulfonylating reagent were pursued.
Scheme 4.7. Formation of the methylimidazole addition by-product from ketenimine intermediates.
The same reaction was set up with AISF and N-H triazole 4.1 in THF. This resulted
in some reactivity with slow bubble release and full consumption of N-H triazole 4.1.
Although this seemed promising, the reaction was far too slow to be useful (8 hours).
Following this, an FSI derivative 4.3 was used in the same condition, which resulted in a
significantly faster reaction with vigorous effervescence and full consumption of N-H
triazole 4.1 within 30 minutes. Despite the full conversion, only about 5% isolated yield of
SO2F triazole 4.2 was obtained after column chromatography. This implied that something
else was happening and the fact that the reaction bubbled vigorously was a sign for
ketenimine 4.5 formation (Scheme 4.7). This was supported by the isolation of an
imidazole addition product 4.4 that would only be able to form with the formation of in-situ
ketenimine 4.5. The nuclear Overhauser effect spectroscopy (NOESY) analysis of this
product support the regioselectivity required for product 4.4 from imidazole addition to a
ketenimine (Figure 4.2).
133
Figure 4.2. NOESY experiments to show the relative stereochemistry of the imidazole addition by-product showing
that it has the right geometry of a ketenimine addition.
4.4.2 Solvent Screening
Scheme 4.8. Reaction conditions for the solvent screen.
From the initial discovery that ketenimines were produced during this reaction, the
working hypothesis was to change the reaction solvent and stabilize the triazole to further
proceed to the desirable product (Scheme 4.8). The screened solvents in this study were
methanol (MeOH), chloroform (CHCl3), acetonitrile (MeCN), benzonitrile (PhCN), and
dichloromethane (DCM). Reaction in MeOH resulted in no conversion of N-H triazole 4.1,
likely due to the fact that FSI derivative 4.3 can react with alcohols and make reagent 4.3
134
react with the solvent before N-H triazole 4.1. The reaction temperature rose quickly upon
addition of FSI derivative 4.3 to MeOH solution. The use of CHCl3 led to similar results in
THF, however, the conversion of N-H triazole 4.1 happened slightly faster as visualized
by TLC. Interestingly, reactions in MeCN and PhCN produced transanulation products 4.5
and 4.6, which would only happen in carbene chemistry. Efforts still need to be made to
fully understand that transformation as NMR analysis structurally suggested the formation
of a five-membered ring. Reaction in DCM gave a very messy reaction outcome implying
that it does not do a good job at stabilizing the intermediates or reacts with the
intermediates. From this study, further investigation proceeded with CHCl3 as a solvent –
CHCl3 resulted in the fastest conversion of N-H triazole 4.1, even though the selectivity
towards SO2F triazole 4.2 didn’t really change with the ketenimine methylimidazole
addition product 4.4 as the major product.
4.4.3 Base Screening
Scheme 4.9. Reaction conditions for the base screen.
A base screening study was investigated further into the selectivity towards SO2F
triazole 4.2 could be improved by moving away from sodium carbonate (Scheme 4.9). To
do this, N-H triazole 4.1 and FSI derivative 4.3 were mixed in CHCl3 before the base was
added. The screened bases include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,
and diisopropylethylamine (DIPEA). Reaction with DBU led to no conversion of N-H
triazole 4.1, likely reacting with FSI derivative 4.3 prior to N-H triazole 4.1. Reaction with
pyridine led to a very slow reaction – full conversion of N-H triazole 4.1 was not achieved
135
after multiple days. This indicates that pyridine could potentially react with the FSI
derivative 4.3 like DBU or it is not strong enough. DIPEA yielded the best results in this
study. Full conversion of N-H triazole 4.1 was achieved after 30 minutes, however, the
reaction still favored ketenimine methylimidazole addition product 4.4. Due to the
increased conversion of N-H triazole 4.1 and lower reaction time, DIPEA was used in
future reaction optimization to increase SO2F triazole 4.2 selectivity.
4.4.4 Base Equivalents Screening
Scheme 4.10. Reaction conditions for the base equivalence screen.
In order to quantify the optimized amount of DIPEA for the reaction, two
experiments were set up with N-H triazole 4.1, FSI derivative 4.3, CHCl3, and DIPEA (1.2
or 0.015 equiv.). Notably, both reactions led to the same results – reactions bubbled for
12 minutes and full consumption of N-H triazole 4.1 was observed within 30 minutes by
TLC analysis. However, the selectivity towards SO2F triazole 4.2 was not improved, but
the same imidazole addition product 4.4. In 0.015 equiv. of DIPEA, a new product was
formed – this methyimidazole addition product 4.4 (35% isolated yield) was found to be
the same product in the reaction between N-H triazole 4.1 and ketenimine 4.5. The unique
product 4.7 was formed because there was not enough base to immediately react with NH triazole 4.1, as a result that allowed it to stay in solution longer and reacted with the
ketenimine 4.5, instead of 4.1. This study shows that base concentration does not have
136
an effect on the selectivity for SO2F triazole 4.2, however at a low base concentration byproduct 4.7 can be formed.
4.4.5 Temperature Screening
Scheme 4.11. Reaction conditions for the temperature screen.
In order to further design a selective reaction condition to acquire the desired SO2F
triazole 4.2, a reaction temperature optimization study was performed (Scheme 4.11).
While lower temperatures can help control reactive intermediates in not participating in
many side reactions, so far the studied reactions were done at ambient temperatures and
many by-products were observed and only ~5% desired product was obtained 4.2. Lower
temperatures (0 °C and -78 °C) were examined to further improve product 4.2 yield.
Overall, there was no significant difference at 0 °C – N-H triazole 4.1 was fully consumed
without any improved selectivity within 30 minutes (TLC analysis). At -78 °C, there was
no formation of SO2F triazole 4.2 because chloroform solvent was frozen and the reaction
did not proceed further.
4.4.6 Concentration Screen
Scheme 4.12. Reaction conditions for the concentration screen.
Another method of controlling reactive intermediates is to lower the overall reaction
concentration to slow down the reaction kinetics. The reaction’s concentration was
137
reduced from 1.0 M solution to 0.5 M and 0.2 M solutions (Scheme 4.12). At 0.5 M
concentration, the reaction result did not change yielding the same amount of desired
SO2F triazole 4.2 (5% conversion) and fully consumed starting material within 30 minutes.
However, the 0.2 M reaction showed some different results – the amount of desired SO2F
triazole 4.2 was 5%, N-H triazole 4.1 was consumed in 30 minutes by TLC analysis, and
a white precipitation (34% yield) co-produced after 3 minutes. This white precipitation was
identified to be methylimidazole addition product 4.4. The lower concentration allowed
formation of ketenimine 4.5 and avoid side reactions. Imidazole addition product 4.4 was
detected and visualized by TLC (longwave UV light) in 5:95 vol% MeOH:DCM.
4.4.7 Order of Addition
Changing the order of addition can sometimes direct the reaction pathway to the
major product with different in-situ intermediates. At this point, N-H triazole 4.1 and FSI
derivative 4.3 were added together before CHCl3 was added followed by DIPEA which
leads to the 5% yield of desired SO2F triazole 4.2 with the formation of by-products such
as methylimidazole addition product 4.4. Next, triazole 4.1 was added to CHCl3, followed
by DIPEA and FSI derivative 4.3. This has the same outcome as the original order. The
N-H triazole 4.1 was consumed in 30 minutes with only 5% yield to desired SO2F triazole
4.2 and methylimidazole product 4.4 as the major product. In the last experiment, FSI
derivative 4.3 was added to CHCl3, follwed by DIPEA and N-H triazole 4.1 (Figure 4.3).
The reaction turned red as soon as DIPEA was added with a new product 4.7 detected
by TLC analysis. Upon addition of N-H triazole 4.1, the reaction effervesced as previously
observed, however triazole 4.1 was never fully consumed confirming that the FSI
derivative 4.3 reacted with base in the first step. This new product was determined to be
138
an N-heterocyclic carbene (NHC) 4.7 that formed when a base deprotonated FSI
derivative 4.3. This showed that the addition of a base is not beneficial to FSI derivative
4.3, especially prior to the presence of N-H triazole 4.1 to the reaction. Moving forward
the reaction order of addtion is following: 1. FSI derivative 4.3, 2. N-H triazole 4.1, 3.
Chloroform, and 4. DIPEA.
Figure 4.3. When base is added right after FSI NHCs seem to form as seen by the TLC.
4.5 Alternate Route for SO2F-Containing Carbene Product
So far, the efforts to selectively form the desired SO2F triazole 4.2 for rhodium
carbene chemistry with sulfonyl triazoles proved to not be feasible. SO2F triazole 4.2 was
not stable and instantanuasly converted into ketenimine 4.5. In order to avoid the
formation of 4.5, SO2-imidazole triazole 4.8 could be synthesized using the pathway
(Table 4.1) to replace SO2F triazole 4.2. This would be, in theory, able to perform the
normal rhodium carbene chemitry, where sulfonyl triazole can be converted the desired
SO2F group (Scheme 4.13). A sulfonyl imidazole group can be methylated using
139
methyltriflate (MeOTf) to act as a good leaving group, then it reacted with KHF2 replacing
the imidazolium with a fluorine.36
Scheme 4.13. Alternate idea for the use of rhodium carbene chemistry with nitriles as an example without the need of
SO2F triazole.
4.5.1 Synthesis of Sulfonyl Imidazole Triazole
In the synthesis of the sulfonyl imidazole triazole 4.8 (Table 4.1), N-H triazole 4.1
and sulfonylating reagent was added to solvent followed by base. Normally, CuAAC
chemistry is utilized to form triazoles using the CuTC catalytic system to get to sulfonyl
triazoels37. In this study, the CuTC system was not employed because it would require
the synthesis of sulfonyl imidazole azide, which is reported to be unstable and explosive
at ambient temperature. A N-H triazole 4.1 was activated by a sulfonylating reagent in a
basic solution to avoid handling extreme and hazardous procedure. First, several bases
were screened – reaction with DBU provided the best yield of sulfonyl imidazole 4.8.
Following, bases such as TEA, DIPEA, Na2CO3, and pyridine all had very low yields of
sulfonyl imidzole triazole 4.8 and persisted to run for a longer time. Solvents, such as
MeCN, THF, and CHCl3, were screened to further optimize the reaction. MeCN led to
some transanulation product 4.9 and a very low yield of the desired sulfonyl imidazole
product 4.8. Reaction in THF led to higher sulfonyl imidazole triazole 4.8 yield (32%
isolated yield) and reaction in chloroform resulted in the best yield (40%). In the reaction
with CHCl3 and DBU, N-H triazole 4.1 was mostly consumed after 2 hours and the desired
product was succesfully isolated via column chromatograhy. Sulfonyl diimidazole (SDI)
was also tried as a sulfonylating agent to streamline the synthesis without having to
140
prepare MDSI. SDI was inactive in these condtions – with no formation of sulfonyl
imidazole product 4.8 detected. The optimized condition of this reaction was determined
to have MSDI (sulfonylating reagent), DBU (base), and CHCl3 (solvent).
Table 4.1. Optimization of sulfonyl imidazole triazole synthesis.
4.5.2 Synthesis of the Sulfonyl Imidazole Triazole through Rhodium Carbenes
Previously, the rhodium-catalyzing transanulation reaction was investigated using
nitriles (MeCN 4.9 or PhCN 4.10) to form imidazoles, according to reported literature
(Table 4.2).22, 25 In a 24-hour reaction, a reaction with Rh2(OAc)4 catalyst, dichloroethane
(DCE) at 80 °C, and PhCN was set up. Upon completion, no conversion to the desired
product 4.10 was observed by either TLC or LC-MS. However, N-H triazole 4.1 was
detected as a result of hydrolysis of starting material 4.8. In the next reaction, the same
reactions were set up in chloroform at 60 °C and 80 °C. Both reactions yielded no
141
conversion to desired product 4.10 and a small amount of N-H triazole 4.1. The same
condition, Rh2(OAc)4, sulfonyl imidazole triazole 4.8, CHCl3, and PhCN, was set up in a
microwave reactor to subject the reaction to a higher temperature (140 °C) at a faster
heating rate. After several hours, product 4.10 was not detected, but only a minimal
amount of N-H triazole 4.1.
Table 4.2. Conditions tried for the rhodium reactions.
A more active catalyst for transanulation reaction, Rh2(Oct)4, was used for this
reaction in both microwave heating and conventional heating. This catalyst also did not
produce the desired product 4.10 and yielded minimal conversion to N-H triazole 4.1 byproduct even after hours of heating (140 °C) and several days (80 °C). Even though the
desired rhodium conditions were not successful and seemingly unfeasible, it was
interesting to observe that the new sulfonyl imidazole triazole 4.8 is very resistant to
hydrolysis – it did not degrade at high temperatures even under microwave heating and
142
remain structurally stable for 6 months in the freezer without being hydrolyzed. This is
unique, considering its derivative tosyl triazoles are more easily hydrolyzed.
4.5.3 Methylated Sulfonyl Imidazole Triazole and Rhodium Chemistry
Scheme 4.14. Trying to activate the sulfonyl imidazole triazole by methylating it.
Since S-N bonds are present that would be more donating than the S-C bonds in
tosy groups, sulfonyl imidazole triazole 4.8 could not be activated to form the diazo
species required for carbene formation to further participate in the rhodium carbene
formation. Compound 4.8 could be activated by methylation to 4.11, then form a cationic
nitrogen making imidazole more electron-withdrawing (Scheme 4.14). This activation
method would allow the diazo and subsequently rhodium carbene to form. In order to
synthesis methylated sulfonyl imidazole triazole 4.11, a reaction with sulfonyl imidazole
triazole 4.8 and MeOTf in DCM at 0 °C was set up and ran at room temperature. After 2
hours, the reaction reached completion with an isolated methylated imidazole triazole
4.11 yield of 84%. Following, methylated sulfonyl imidazole triazole 4.11 was subjected
to rhodium transanulation condition in a microwave reactor. This reaction resulted in
degradation of starting material and no desired product was observed. This experiment
concluded that even with a more activated sulfonyl imidazole triazole 4.11, the reaction
cannot undergo a desired transanulation process 4.12 with PhCN.
143
4.6 The Utilization of Ketenimine from SO2F Triazole
The synthesis of SO2F triazoles was found to not be selective forming ketenimine
4.5 instead. Ketenimine 4.5, however, does have synthetic applications being one of the
most useful precursors for amidines which are biologically relevant moieties in
pharmaceuticals. Due to that, the goal of this study shifted from forming SO2F triazoles to
utilizing ketenimine 4.5 in amidine synthesis.
4.6.1 Amine Screen for Amidine Formation
Scheme 4.15. Using the ketenimine formation as a way to form SO2F amidines.
Due to the success the Chang group in ketenimines synthesis38, those reaction
conditions were employed in our system without using a metal catalyst (Scheme 4.15). In
a reaction with N-H triazole 4.1, FSI, DIPEA, and diisopropylamine in THF.
Diisopropylamine was designed to attach on ketenimine 4.5 and produce amidines,
however, this did not occur and the yielded product was methylimidazole addition 4.4.
The diisopropyl group could be too sterically hindered to react, therefore, an n-butylamine
was used as a less sterically hindered amine. This did not lead to the desired result and
the methylimidazole addition 4.4 remained the major product. A competitive reaction was
performed with the addition of imidazole to the reaction after FSI to compete with
methylimidazole leaving group from FSI. However, this did not lead change the outcome
of this reaction and the reaction still favored methylimidazole, which should not happen
the mechanism was a simple nucleophilic attack. Thus, a different mechanism is at play
with FSI and it could possibly be intramolecular process. However, more experimental
144
studies would need to prove the hypothesis as this would not support the triazole addition
product.
4.6.2 Fluorosulfonylating Reagent Screening
Scheme 4.16. Conditions for the SO2F amidine products.
Since methylimidazole leaving group on FSI may uncontrollably interfere with the
reaction mechanism, other SO2F sources were studied instead of FSI (Scheme 4.16). In
the previous studies, SO2F2 did not react with N-H triazole 4.1 even in conditions where
it would react with imidazole. Similarly, SO2FCl was also not desirable for its synthesis
difficulty and handling along with its poor reactivity towards N-H triazoles 4.1. Hence, AISF
was subjected in this study as it has a deactivated leaving group, which is not likely to
participate in these reactions. Reaction with AISF in the amidine-forming condition
observed no desire product, even with the full consumption of the N-H triazole 4.1. It was
determined that utilizing the ketenimines as building blocks for amidine synthesis will not
work under the standard condition, however, it is impossible. In the future, further
optimization could be done to fully conclude the feasibility of this reaction by changing the
SO2F source (underdeveloped or newly discovered reagent). This entire SO2F triazole
route could also be scrapped in favor of a sulfonyl imidazole derivative using 2-
methylimidazole that would be able to react with LiHMDS or n-BuLi to force ketenimine
formation and converted to SO2F groups using the procedure to turn sulfonyl imidazole
groups to SO2F groups as a later stage modification.
145
4.7 N-heterocyclic Carbene Formation
During the order of addition study to form SO2F triazole 4.2, the presence of Nheterocyclic carbenes (NHC) 4.7 was observed and isolated at 6% yield via column
chromatography and structurally identified via NMR and mass spectrometry data. The
isolation and identification of this NHC 4.7 was one of the first stable carbene without a
sterically hindered group39 and could serve as a versatile ligand with a functionalizable
group.
4.7.1 NHC Species Synthesis Optimization
Scheme 4.17. Conditions for the optimization of the NHC formation from the FSI.
Unfortunately, this reaction yield was not improved beyond 6% isolated yield.
Various bases were utilized, including DBU, DIPEA and t-BuOK, all resulted in 6% isolated
yield of NHC 4.7 (Scheme 4.17). DIPEA produced less impurities in comparison with
reactions of DBU and t-BuOK. Solvents, such as THF, MeCN and CHCl3, all resulted in
similar results – reaction in MeCN produced more impurities by TLC analysis. No
improvement in yield at various reaction concentrations (0.2 M and 0.5 M). The overall
optimization was not successful but this optimization could be improved with the use of
strong bases, such as NaH or lithium-containing bases.
4.7.2 NHC on Iridium Complex
Despite not being able to optimize the reaction for the free carbene 4.7, due to its
stability, it was thought to be able to bind it to a metal fairly successfully. To do this, FSI
146
derivative 4.3 was added to a solution of Ir2(COD)4Cl4 and t-BuOK in MeCN (Figure 4.4).
A new complex was formed, however, was not easily controlled and isolated. Matrixassisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis of reaction
mixture, various of complexes was identified by mass. This was a promising result and
could be a viable method of reacting NHCs 4.7 with the metals. The biggest challenge
would be to cleanly synthesize and recrystallize the resulting complex in a controlled
manner.
Figure 4.4. Synthetic routes for the complexation of NHCs to iridium to form a complex along with the MALDI showing
varies products formed.
147
4.8 Conclusion
SO2F group in SuFEx chemistry coupled with their benign nature outside of those
conditions makes it a vary versatile group in pharmaceuticals, protein tagging, synthetic
chemistry, and meterials. However, incorperating them into new structures and molecular
scaffolds poses a significant challenge. This has gotten easier with the discovery of new
reagents, such as FSI and AISF, but more new methodologies need to be studied.
Potentially, using them in ketenimine chemistry would be very helpful as it would add
amidines to the list of compatiple group to expand the library of potential drug targets.
Some challenges discussed in this chapter will hopefully be persued in the future.
4.9 References
1. Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B., Sulfur(VI) Fluoride
Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angewandte Chemie
International Edition 2014, 53 (36), 9430-9448.
2. Kolb, H. C.; Sharpless, K. B., The growing impact of click chemistry on drug
discovery. Drug Discovery Today 2003, 8 (24), 1128-1137.
3. Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Click Chemistry: Diverse Chemical
Function from a Few Good Reactions. Angewandte Chemie International Edition 2001,
40 (11), 2004-2021.
4. Jones, L. H.; Kelly, J. W., Structure-based design and analysis of SuFEx chemical
probes. RSC Medicinal Chemistry 2020, 11 (1), 10-17.
5. Xiao, X.; Zhou, F.; Jiang, J.; Chen, H.; Wang, L.; Chen, D.; Xu, Q.; Lu, J., Highly
efficient polymerization via sulfur(vi)-fluoride exchange (SuFEx): novel polysulfates
bearing a pyrazoline–naphthylamide conjugated moiety and their electrical memory
performance. Polymer Chemistry 2018, 9 (8), 1040-1044.
6. Narayanan, A.; Jones, L. H., Sulfonyl fluorides as privileged warheads in chemical
biology. Chemical Science 2015, 6 (5), 2650-2659.
7. Barrow, A. S.; Smedley, C. J.; Zheng, Q.; Li, S.; Dong, J.; Moses, J. E., The
growing applications of SuFEx click chemistry. Chemical Society Reviews 2019, 48 (17),
4731-4758.
148
8. Xu, R.; Xu, T.; Yang, M.; Cao, T.; Liao, S., A rapid access to aliphatic sulfonyl
fluorides. Nature Communications 2019, 10 (1), 3752.
9. Laudadio, G.; Bartolomeu, A. d. A.; Verwijlen, L. M. H. M.; Cao, Y.; de Oliveira,
K. T.; Noël, T., Sulfonyl Fluoride Synthesis through Electrochemical Oxidative Coupling of
Thiols and Potassium Fluoride. Journal of the American Chemical Society 2019, 141 (30),
11832-11836.
10. Tang, L.; Yang, Y.; Wen, L.; Yang, X.; Wang, Z., Catalyst-free radical fluorination
of sulfonyl hydrazides in water. Green Chemistry 2016, 18 (5), 1224-1228.
11. Brouwer, A. J.; Ceylan, T.; Linden, T. v. d.; Liskamp, R. M. J., Synthesis of βaminoethanesulfonyl fluorides or 2-substituted taurine sulfonyl fluorides as potential
protease inhibitors. Tetrahedron Letters 2009, 50 (26), 3391-3393.
12. Tribby, A. L.; Rodríguez, I.; Shariffudin, S.; Ball, N. D., Pd-Catalyzed Conversion
of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and Selectfluor. The
Journal of Organic Chemistry 2017, 82 (4), 2294-2299.
13. Prakash Reddy, V.; Bellew, D. R.; Prakash, G. K. S., A convenient preparation of
sulfuryl chloride fluoride. Journal of Fluorine Chemistry 1992, 56 (2), 195-197.
14. Krutak, J. J.; Burpitt, R. D.; Moore, W. H.; Hyatt, J. A., Chemistry of ethenesulfonyl
fluoride. Fluorosulfonylethylation of organic compounds. The Journal of Organic
Chemistry 1979, 44 (22), 3847-3858.
15. Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.; Sharpless, K. B.; Dong,
J., A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt
Emerging as an “F−SO2+” Donor of Unprecedented Reactivity, Selectivity, and Scope.
Angewandte Chemie International Edition 2018, 57 (10), 2605-2610.
16. Zhou, H.; Mukherjee, P.; Liu, R.; Evrard, E.; Wang, D.; Humphrey, J. M.; Butler,
T. W.; Hoth, L. R.; Sperry, J. B.; Sakata, S. K.; Helal, C. J.; am Ende, C. W., Introduction
of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides. Organic
Letters 2018, 20 (3), 812-815.
17. Stepannikova, K. O.; Vashchenko, B. V.; Grygorenko, O. O.; Gorichko, M. V.;
Cherepakha, A. Y.; Moroz, Y. S.; Volovenko, Y. M.; Zhersh, S., Synthesis of Spirocyclic
β- and γ-Sultams by One-Pot Reductive Cyclization of Cyanoalkylsulfonyl Fluorides.
European Journal of Organic Chemistry 2021, 2021 (47), 6530-6540.
18. Liu, J.; Wang, S.-M.; Qin, H.-L., Light-induced [2 + 2] cycloadditions for the
construction of cyclobutane-fused pyridinyl sulfonyl fluorides. Organic & Biomolecular
Chemistry 2020, 18 (21), 4019-4023.
19. Skalenko, Y. A.; Druzhenko, T. V.; Denisenko, A. V.; Samoilenko, M. V.; Dacenko,
O. P.; Trofymchuk, S. A.; Grygorenko, O. O.; Tolmachev, A. A.; Mykhailiuk, P. K., [2+2]-
149
Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-
Azabicyclo[3.2.0]heptanes. The Journal of Organic Chemistry 2018, 83 (12), 6275-6289.
20. Oderinde, M. S.; Ramirez, A.; Dhar, T. G. M.; Cornelius, L. A. M.; Jorge, C.;
Aulakh, D.; Sandhu, B.; Pawluczyk, J.; Sarjeant, A. A.; Meanwell, N. A.; Mathur, A.;
Kempson, J., Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of
Heterocycles for Building Molecular Complexity. The Journal of Organic Chemistry 2021,
86 (2), 1730-1747.
21. Kokhan, S. O.; Valter, Y. B.; Tymtsunik, A. V.; Komarov, I. V.; Grygorenko, O. O.,
3-Carboxy-/3-Aminobicyclo[1.1.1]pentane-Derived Sulfonamides and Sulfonyl Fluorides
– Advanced Bifunctional Reagents for Organic Synthesis and Drug Discovery. European
Journal of Organic Chemistry 2020, 2020 (15), 2210-2216.
22. Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V., RhodiumCatalyzed Transannulation of 1,2,3-Triazoles with Nitriles. Journal of the American
Chemical Society 2008, 130 (45), 14972-14974.
23. Jones, K. D.; Nutt, M. J.; Comninos, E.; Sobolev, A. N.; Moggach, S. A.; Miura,
T.; Murakami, M.; Stewart, S. G., A One-Pot Reaction of α-Imino Rhodium Carbenoids
and Halohydrins: Access to 2,6-Substituted Dihydro-2H-1,4-oxazines. Organic Letters
2020, 22 (9), 3490-3494.
24. Yadagiri, D.; Chaitanya, M.; Reddy, A. C. S.; Anbarasan, P., Rhodium Catalyzed
Synthesis of Benzopyrans via Transannulation of N-Sulfonyl-1,2,3-triazoles with 2-
Hydroxybenzyl Alcohols. Organic Letters 2018, 20 (13), 3762-3765.
25. Zibinsky, M.; Fokin, V. V., Sulfonyl-1,2,3-Triazoles: Convenient Synthones for
Heterocyclic Compounds. Angewandte Chemie International Edition 2013, 52 (5), 1507-
1510.
26. Chattopadhyay, B.; Gevorgyan, V., Rh-Catalyzed Transannulation of N-Tosyl1,2,3-Triazoles with Terminal Alkynes. Organic Letters 2011, 13 (14), 3746-3749.
27. Chuprakov, S.; Kwok, S. W.; Fokin, V. V., Transannulation of 1-Sulfonyl-1,2,3-
triazoles with Heterocumulenes. Journal of the American Chemical Society 2013, 135
(12), 4652-4655.
28. Grimster, N.; Zhang, L.; Fokin, V. V., Synthesis and Reactivity of Rhodium(II) NTriflyl Azavinyl Carbenes. Journal of the American Chemical Society 2010, 132 (8), 2510-
2511.
29. Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.; Fokin, V. V., Stereoselective
1,3-Insertions of Rhodium(II) Azavinyl Carbenes. Journal of the American Chemical
Society 2014, 136 (1), 195-202.
150
30. Miura, T.; Tanaka, T.; Yada, A.; Murakami, M., Doyle–Kirmse Reaction Using
Triazoles Leading to One-pot Multifunctionalization of Terminal Alkynes. Chemistry
Letters 2013, 42 (10), 1308-1310.
31. Chuprakov, S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V., Catalytic Asymmetric C–H
Insertions of Rhodium(II) Azavinyl Carbenes. Journal of the American Chemical Society
2011, 133 (27), 10352-10355.
32. Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M., Synthesis of α-Amino Ketones from
Terminal Alkynes via Rhodium-Catalyzed Denitrogenative Hydration of N-Sulfonyl-1,2,3-
triazoles. Journal of the American Chemical Society 2012, 134 (1), 194-196.
33. Selander, N.; Fokin, V. V., Rhodium(II)-Catalyzed Asymmetric Sulfur(VI) Reduction
of Diazo Sulfonylamidines. Journal of the American Chemical Society 2012, 134 (5),
2477-2480.
34. Thomas, J.; Jana, S.; Liekens, S.; Dehaen, W., A single-step acid catalyzed
reaction for rapid assembly of NH-1,2,3-triazoles. Chemical Communications 2016, 52
(59), 9236-9239.
35. Veryser, C.; Demaerel, J.; Bieliu̅nas, V.; Gilles, P.; De Borggraeve, W. M., Ex Situ
Generation of Sulfuryl Fluoride for the Synthesis of Aryl Fluorosulfates. Organic Letters
2017, 19 (19), 5244-5247.
36. Passia, M. T.; Demaerel, J.; Amer, M. M.; Drichel, A.; Zimmer, S.; Bolm, C., AcidMediated Imidazole-to-Fluorine Exchange for the Synthesis of Sulfonyl and Sulfonimidoyl
Fluorides. Organic Letters 2022, 24 (48), 8802-8805.
37. Raushel, J.; Fokin, V. V., Efficient Synthesis of 1-Sulfonyl-1,2,3-triazoles. Organic
Letters 2010, 12 (21), 4952-4955.
38. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S., A Facile Access to NSulfonylimidates and Their Synthetic Utility for the Transformation to Amidines and
Amides. Organic Letters 2006, 8 (7), 1347-1350.
39. Arduengo, A. J.; Harlow, R. L.; Kline, M., A stable crystalline carbene. Journal of
the American Chemical Society 1991, 113 (1), 361-363.
151
Chapter 5. Procedures and Characterization
5.1 Iodine Project (Chapter 2)
5.1.1 Synthesis of Starting Materials
5.1.1.1 Procedure for 1-Iodopyridin-1-uim chloride (PyICl)
The compound was synthesized using the reported procedure.1 A 500
mL round bottom flask equipped with a stir bar was charged with
pyridine (100 mmol, 8.08 mL). This was followed by the addition of
DCM (50 mL) to make a pyridine DCM solution. A dropping funnel was
then placed on top of the round bottom flask and a solution of ICl (95.5
mmol, 15.5 g) in DCM (250 mL) was added. The ICl solution was
added slowly over the course of 2 h into the pyridine solution.
Following the addition of the ICl solution, the resulting reaction mixture was stirred for 1
h then concentrated under reduced pressure. The resulting brownish red solid was
washed with ethanol and then filtered under vacuum. The desired product was obtained
as a light-yellow solid (23 mg, 95%). The solid was transferred to glass vials, sealed, and
stored in freezer for months.
1H NMR (400 MHz, CDCl3) δ = 8.67 (d, J = 4.8 Hz, 2H), 8.03 (t, J = 8.0 Hz, 1H), 7.48 (t,
J = 6.4 Hz, 2H)
The obtained NMR data is in accordance with the reported values.1
152
5.1.1.2 General procedure for the synthesis of N-sulfonyl-1,2,3-triazoles
The compounds were synthesized using the reported procedure2
. A round bottom flask
was charged with copper(I) thiophene-2-carboxylate (CuTc, 0.1 equiv.), toluene (0.2 M),
and alkyne (1.0 equiv.). Following this, sulfonyl azide (1.0 equiv.) was added slowly. The
reaction was monitored by TLC until consumption of the starting materials was observed.
The reaction was then quenched with NH4Cl (same amount as toluene). This mixture
was twice extracted with EtOAc (same amount as toluene), and the combined organic
layers were dried using Na2SO4 and filtered through celite®. The filtrate was concentrated
under reduced pressure after which the greenish solid was redissolved in chloroform and
charged with cuprisorb resin. The resulting mixture was stirred for a few hours (maximum
overnight) before being filtered through celite® and concentrated under reduced pressure
generating a viscous solid. This solid was pulverized in cyclohexanes and then filtered to
obtain the desired product. The product was transferred to a glass vial and further dried
on high vacuum to avoid any moisture (detrimental for the amidine synthesis). The
synthesized triazole was sealed and stored in the freezer.
Note: Storing the starting triazole for more than a month was avoided as N-sulfonyl
triazole can hydrolyze over long periods of storing (see SI in reference2
for details on
handling the starting triazole).
4-phenyl-1-tosyl-1H-1,2,3-triazole
153
The product (2.8 g, 96%) was prepared using the general procedure from the
corresponding alkyne (1.1 mL, 10 mmol) and azide (1.55 mL, 10 mmol) with toluene (0.2
M, 50 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance with
the reported values.2
Appearance: White solid
1H NMR (600 MHz, CDCl3) δ 8.31 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 7.1 Hz,
2H), 7.43 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.7 Hz, 3H), 2.45 (s, 3H).
4-(4-methoxyphenyl)-1-tosyl-1H-1,2,3-triazole
The product (617.8 mg, 53.4%) was prepared using the general procedure from the
corresponding alkyne (463.7 mg, 3.5 mmol) and azide (540 μL, 3.5 mmol) with toluene
(0.2 M, 17.5 mL) and CuTc (66.7 mg, 0.35 mmol). The obtained NMR data is in
accordance with the reported values.3
Appearance: Yellow solid
1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.05 – 7.99 (m, 2H), 7.79 – 7.71 (m, 2H), 7.39
(d, J = 8.2 Hz, 2H), 6.99 – 6.91 (m, 2H), 3.84 (s, 3H), 2.45 (s, 3H).
4-(4-(tert-butyl)phenyl)-1-tosyl-1H-1,2,3-triazole
N
N N
S
O
O
N
N N
S
O
O
O
154
The product (972.2 mg, 78%) was prepared using the general procedure from the
corresponding alkyne (630 μL, 3.5 mmol) and azide (540 μL, 3.5 mmol) with toluene (0.2
M, 17.5 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance
with the reported values.3
Appearance: White solid
1H NMR (600 MHz, CDCl3) δ 8.27 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz,
2H), 7.45 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 2.45 (s, 3H), 1.33 (s, 9H).
4-(1-tosyl-1H-1,2,3-triazol-4-yl)benzonitrile
The product (829.8 mg, 78%) was prepared using the general procedure from the
corresponding alkyne (405 μL, 3.5 mmol) and azide (540 μL, 3.5 mmol) with toluene (0.2
M, 17.5 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance with
the reported values.4
Appearance: Yellow solid
1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 1.2 Hz, 1H), 8.08 – 8.01 (m, 2H), 7.99 – 7.92
(m, 2H), 7.77 – 7.70 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 2.46 (s, 3H).
1-tosyl-4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole
N
N N
S
O
O
N
N N
S
O
O
NC
155
The product (1072.7 mg, 83.4%) was prepared using the general procedure from the
corresponding alkyne (660 μL, 3.5 mmol) and azide (540 μL, 3.5 mmol) with toluene (0.2
M, 17.5 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance with
the reported values.5
Appearance: White solid
1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.08 – 8.01 (m, 2H), 7.95 (d, J = 8.1 Hz, 2H),
7.70 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 2.46 (s, 3H).
4-(4-bromophenyl)-1-tosyl-1H-1,2,3-triazole
The product (346.2 mg, 26.6%) was prepared using the general procedure from the
corresponding alkyne (630 mg, 3.5 mmol) and azide (540 μL, 3.5 mmol) with toluene (0.2
M, 17.5 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance
with the reported values.5
Appearance: White solid
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.07 – 8.00 (m, 2H), 7.74 – 7.66 (m, 2H), 7.60
– 7.53 (m, 2H), 7.40 (d, J = 8.2 Hz, 2H), 2.46 (s, 3H).
1-((4-methoxyphenyl)sulfonyl)-4-phenyl-1H-1,2,3-triazole
N
N N
S
O
O
F3C
N
N N
S
O
O
Br
156
The product (794.4mg, 72.2%) was prepared using the general procedure from the
corresponding alkyne (380 μL, 3.5 mmol) and azide (750 mg, 3.5 mmol) with toluene (0.2
M, 17.5 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance with
the reported values.3
Appearance: White solid
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.13 – 8.04 (m, 2H), 7.86 – 7.78 (m, 2H), 7.48
– 7.40 (m, 2H), 7.40 – 7.32 (m, 1H), 7.08 – 7.00 (m, 2H), 3.89 (s, 3H).
1-((4-bromophenyl)sulfonyl)-4-phenyl-1H-1,2,3-triazole
The product (1.14 mg, 89 %) was prepared using the general procedure from the
corresponding alkyne (500 μL, 4.55 mmol) and azide (917 mg, 3.5 mmol) with toluene
(0.2 M, 22.75 mL) and CuTc (67 mg, 0.35 mmol). The obtained NMR data is in
accordance with the reported values.6
Appearance: White solid
1H NMR (600 MHz, CDCl3) δ 8.30 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 7.3 Hz,
2H), 7.75 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H).
1-([1,1'-biphenyl]-4-ylsulfonyl)-4-phenyl-1H-1,2,3-triazole
N
N N
S
O
O
O
N
N N
S
O
O
Br
157
The product (273 mg, 46%) was prepared using the general procedure from the
corresponding alkyne (237 μL, 2.16 mmol) and azide (430 mg, 1.66 mmol) with toluene
(0.2 M, 10.8 mL) and CuTc (41.1 mg, 0.216 mmol).
Appearance: White solid
1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 8.21 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.9 Hz,
2H), 7.79 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.44 (t, J
= 7.9 Hz, 3H), 7.38 (t, J = 7.4 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 148.97, 147.61, 138.64, 134.55, 129.36 (2 C), 129.34,
129.31, 129.17, 128.96, 128.55, 127.61, 126.26, 119.10.
HRMS: (ESI-TOF) calcd for C20H13N3O2S+
[M+H]+ 362.0958, found 362.0963 (Δ = 1.3
ppm).
1-(naphthalen-2-ylsulfonyl)-4-phenyl-1H-1,2,3-triazole
The product (331 mg, 59%) was prepared using the general procedure from the
corresponding alkyne (237 μL, 2.16 mmol) and azide (387 mg, 1.66 mmol) with toluene
(0.2 M, 10.8 mL) and CuTc (41.1 mg, 0.216 mmol). The obtained NMR data is in
accordance with the reported values.6
N
N N
S
O
O
N
N N
S
O
O
158
Appearance: White solid
1H NMR (600 MHz, CDCl3) δ 8.78 (s, 1H), 8.37 (s, 1H), 8.07 – 8.00 (m, 3H), 7.93 (d, J =
8.1 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H),
7.43 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H).
1-((4-nitrophenyl)sulfonyl)-4-phenyl-1H-1,2,3-triazole
The product (453 mg, 69 %) was prepared using the general procedure from the
corresponding alkyne (385.5 μL, 2 mmol) and azide (456.4 mg, 2.6 mmol) with toluene
(0.29 M, 7 mL) and CuTc (19 mg, 0.05 mmol). The obtained NMR data is in accordance
with the reported values.7
Appearance: Off-white solid
1H NMR (600 MHz, CDCl3) δ 8.44 (d, J = 9.0 Hz, 2H), 8.37 (d, J = 9.0 Hz, 2H), 8.34 (s,
1H), 7.82 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H).
4-(tert-butyl)-1-tosyl-1H-1,2,3-triazole
The product (586.8 mg, 60%) was prepared using the general procedure from the
corresponding alkyne (430 μL, 3.5 mmol) and azide (540 μL, 3.5 mmol) with toluene (0.2
M, 17.5 mL) and CuTc (191 mg, 0.1 mmol). The obtained NMR data is in accordance with
the reported values.3
N
N N
S
O
O
NO2
N
N N
S
O
O
159
Appearance: White solid
1H NMR (400 MHz, CDCl3) δ 8.03–7.96 (m, 2H), 7.80 (s, 1H), 7.38 (d, J = 8.2 Hz, 2H),
2.45 (s, 3H), 1.33 (s, 9H).
5.1.2 Optimization Studies
5.1.2.1 Calibration for the Optimization
A 30 mL glass reaction vial equipped with a stir bar and sealed with a septum, was flame
dried and purged with nitrogen gas. In a separate flame dried glass vial, iodine-reagent
was added then purged with nitrogen gas, followed by 2.5 mL of THF. To the reaction
vial, 50 mg (0.167 mmol) of starting triazole was added, it was purged with nitrogen gas
and 2.5 mL dry THF was added to it. The vial was placed in a dry ice bath at –78 °C and
the mixture was stirred to dissolve the compound. Base was added to the vial using
Hamilton syringe through the septum. After 5 min, iodine-reagent solution was taken up
in a syringe and was slowly added to the reaction mixture. The reaction was allowed to
stir in the dry ice bath for 45 minutes. To this, amine (piperidine) was added through the
septum with a Hamilton syringe and the reaction mixture was allowed to stir at –78 °C for
15 min. At this point, the vial was removed from the dry ice bath and stirred for 45 minutes.
Brine or ammonium chloride was then added to the reaction mixture and solution was
diluted with additional 1.4 mL ethyl acetate. The septum was immediately removed, and
the system was allowed to stir under air. After 2 h, internal standard (trimethoxybenzene
0.1 M, 594.5 μL) was added to the reaction vial using micropipette. Finally, reaction
aliquot (5 mL) was taken, diluted with methanol (1 mL), and was analyzed by HPLC. The
area under the peak of product was compared to that of the internal standard (IS) using
the DAD chromatogram (recorded at 210 nm). Percentage yield was determined by
160
comparison of these ratios to the calibration curve (HPLC–DAD method). The calibration
curve showed good linearity (R2=0.9978).
5.1.2.2 Optimization Data for hydroxyamidine synthesis
Entry Base
(1.1 equiv.) I
+ Source I
+
(equiv.) Piperidine
(equiv.)
Conc.
(mM)
H+
source
O2
Source additive %
Yield
1 LiHMDS I2 1.2 1.2 32 brine air none 75%
2 KHMDS I2 1.2 1.2 32 brine air none 64%
3 n-BuLi I2 1.2 1.2 32 brine air none 30%
4 LDA I2 1.2 1.2 32 brine air none 0%
5 NaH I2 1.2 1.2 32 brine air none >5%
6 LiHMDS I2 1.2 1.2 32 none air none 44%
7 LiHMDS I2 1.2 1.2 32 NH4Cl air none 68%
8 LiHMDS I2 1.2 1.2 32 water air none 76%
9 LiHMDS I2 1.2 1.2 32 brine air EDTA 56%
10 LiHMDS I2 1.2 1.2 32 brine air Na2EDTA 75%
11 LiHMDS I2 1.2 1.2 32 brine air NaI 76%
12 LiHMDS I2 1.2 1.2 32 brine air Na2S2O2 57%
13 LiHMDS ICl 1.2 1.2 32 brine air none 70%
14 LiHMDS PyICl 1.2 1.2 32 brine air none 83%
15 LiHMDS PyICl 1.2 1.2 32 brine O2
balloon none 84%
y = 0.4009x
R² = 0.9978
0
1
2
3
4
5
6
0 2 4 6 8 10 12 14
Ratio of area under the peak
(Prroduct/Internal Standard)
Ratio of concentration
(Product/Internal Standard)
Calibration curve (HPLC-DAD)
161
16 LiHMDS PyICl 1.5 1.2 32 brine air none 62%
17 LiHMDS PyICl 1.2 1.5 32 brine air none 79%
5.1.3 Procedures for Controls
5.1.3.1 Reaction with water and no O2
A 30 mL amber glass reaction vial equipped with a stir bar and sealed with a septum, was
flame dried and purged with nitrogen gas. In a separate flame dried glass vial, PyICl (0.2
mmol, 48.29 mg) was added then purged with nitrogen gas, followed by 2.5 mL of dry
THF. To the reaction vial, 50 mg (0.167 mmol) of starting triazole 2.20 was added, it was
purged with nitrogen gas and 2.5 mL dry THF was added to it. The vial was placed in a
dry ice bath at –78 °C and the mixture was stirred to dissolve the compound. LiHMDS
(0.184 mmol, 0.184 mL, 1 M solution in THF) was added to the vial using Hamilton syringe
through the septum. After 5 min, PyICl solution was taken up in a syringe and was slowly
added to the reaction mixture. The reaction was allowed to stir in the dry ice bath for 45
minutes. To this, piperidine (0.183 mmol, 18.1 μL) was added through the septum with a
Hamilton syringe and the reaction mixture was allowed to stir at –78 °C for 15 min. At this
point, the vial was removed from the dry ice bath and stirred for 45 minutes. Brine (1 mL)
was then added via a syringe through the septa. An aliquot was taken from the vial and
analyzed by LC-MS after overnight stirring, it was found that iodo intermediate 2.12 was
still present.
162
5.1.3.2 Test for low energy triplet state
A 30 mL amber glass reaction vial equipped with a stir bar and sealed with a septum, was
flame dried and purged with nitrogen gas. In a separate flame dried glass vial, PyICl (0.2
mmol, 48.29 mg) was added then purged with nitrogen gas, followed by 2.5 mL of dry
THF. To the reaction vial, 50 mg (0.167 mmol) of starting triazole 2.20 was added, it was
purged with nitrogen gas and 2.5 mL dry THF was added to it. The vial was placed in a
dry ice bath at –78 °C and the mixture was stirred to dissolve the compound. LiHMDS
(0.184 mmol, 0.184 mL, 1 M solution in THF) was added to the vial using Hamilton syringe
through the septum. After 5 min, PyICl solution was taken up in a syringe and was slowly
added to the reaction mixture. The reaction was allowed to stir in the dry ice bath for 45
minutes. To this, piperidine (0.183 mmol, 18.1 μL) was added through the septum with a
Hamilton syringe and the reaction mixture was allowed to stir at –78 °C for 15 min. At this
point, the vial was removed from the dry ice bath and stirred for 45 minutes. Brine (1 mL)
was then added via a syringe through the septa and TEMPO was added by quickly
removing the septa and putting it back on. An aliquot was taken from the vial and analyzed
by LC-MS after overnight stirring, it was found that iodo intermediate 2.12 was still
present.
163
5.1.3.3 Test for SET mechanism starting from triazole
A 30 mL glass reaction vial equipped with a stir bar and sealed with a septum, was flame
dried and purged with nitrogen gas. Following this, triazole (0.167 mmol, 50 mg) was
added followed by 2.5 mL of dry THF. The flask was then placed into a dry ice and
acetone bath to get –78 °C before LiHMDS (0.184 mmol, 0.184 mL, 1 M solution in THF)
was added using a Hamilton syringe. After 5 min, a balloon of dry air (passed through
drierite®) was then used to purge the vial and the mixture was allowed to stir at –78 °C
for 5 minutes after which LDA (0.167 mmol, 0.167 mL, 1 M solution in THF) was added.
The reactions mixture was stirred for 45 at –78 °C and for 45 minutes at r.t. After which
brine (0.5 mL) and EtOAc (2 mL) was added, and the septum was removed allowing the
reaction mixture to stir until completion before monitored with LC-MS and TLC. The
reaction was concentrated and purified using flash chromatography with silica gel and
ethyl acetate/hexanes solvent system. The product was isolated as a white powdery solid
(44 mg, 70%).
N,N-diisopropyl-2-phenyl-N'-tosylacetimidamide
Appearance: White solid
164
1H NMR (600 MHz, Acetone-d6) δ 7.78 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 5.9 Hz, 5H), 7.24
(tt, J = 5.5, 2.4 Hz, 1H), 4.48 (s, 2H), 4.16 (hept, J = 6.6 Hz, 1H), 3.58 (hept, J = 7.1 Hz,
1H), 2.39 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H), 0.89 (d, J = 6.6 Hz, 6H).
The obtained NMR data is in accordance with the reported values.8
5.1.3.4 Test for SET mechanism starting from non-functionalized amidine
A 30 mL glass reaction vial equipped with a stir bar and sealed with a septum, was flame
dried and purged with nitrogen gas. Following this, amidine (0.134 mmol, 50 mg) was
added followed by NaH (0.268 mmol, 12.88 mg) to the 30 mL glass reaction vial. THF
(2.5 mL) was then added, and the reaction was allowed to stir for 5 min following which a
balloon of dry O2 was used to purge the vial. The reaction mixture was allowed to stir
under O2 atmosphere for an additional 18 h while being monitored with LC-MS and TLC.
Only trace amount of oxygenated product was observed under these conditions.
5.1.3.5 Test for singlet oxygen
165
A 30 mL amber glass reaction vial equipped with a stir bar and sealed with a septum, was
flame dried and purged with nitrogen gas. In a separate flame dried glass vial, PyICl (0.2
mmol, 48.29 mg) was added then purged with nitrogen gas, followed by 2.5 mL of dry
THF. To the reaction vial, 50 mg (0.167 mmol) of starting triazole 2.20 was added, it was
purged with nitrogen gas and 2.5 mL dry THF was added to it. The vial was placed in a
dry ice bath at –78 °C and the mixture was stirred to dissolve the compound. LiHMDS
(0.184 mmol, 0.184 mL, 1 M solution in THF) was added to the vial using Hamilton syringe
through the septum. After 5 min, PyICl solution was taken up in a syringe and was slowly
added to the reaction mixture. The reaction was allowed to stir in the dry ice bath for 45
minutes. To this, piperidine (0.183 mmol, 18.1 μL) was added through the septum with a
Hamilton syringe and the reaction mixture was allowed to stir at –78 °C for 15 min. At this
point, the vial was removed from the dry ice bath and stirred for 45 minutes. The vial was
then covered in aluminum foil before Brine (1 mL) was added and air was introduced
through a balloon to limit the exposure to light. An aliquot was taken from the vial and
analyzed by LC-MS after overnight stirring, we found that the HPLC trace looked same
as in the presence of light.
5.1.3.6 Test for autoxidation using triplet oxygen (3O2) with TEMPO
A 30 mL glass reaction vial equipped with stir bar and sealed with septum, was flame dried and
purged with nitrogen gas. In a separate flame dried glass vial, PyICl (0.4 mmol, 96.78 mg) was
added then purged with nitrogen gas, followed by 5 mL of dry THF. To the reaction vial, 100 mg
166
(0.334 mmol) of starting triazole was added, it was purged with nitrogen gas and 5 mL dry THF
was added to it. The vial was placed in a dry ice bath at –78 °C and the mixture was stirred to
dissolve the compound. LiHMDS (0.368 mmol, 0.368 mL, 1M solution in THF) was added to the
vial using Hamilton syringe through the septum. After 5 min, PyICl solution was taken up in a
syringe and was slowly added to the reaction mixture. The reaction was allowed to stir in the dry
ice bath for 45 minutes. To this, piperidine (0.4 mmol, 39.52 μL) was added through the septum
with a Hamilton syringe and the reaction mixture was allowed to stir at –78 °C for 15 min. At this
point, the vial was removed from the dry ice bath and stirred for 45 minutes. TEMPO (0.5 mmol,
62.5 mg) was then added with brine (2 mL) and EtOAc (4 mL). The reaction was stirred for 60 h
after which the reaction was concentrated and purified using flash chromatography with silca gel
and ethyl acetate/hexanes solvent system. The product was isolated as an off white solid (87 mg,
51%) and characterized.
Note: We observed that the intermediate did not convert to product until the reaction was exposed
to O2.
4-methyl-N-(2-phenyl-1-(piperidin-1-yl)-2-((2,2,6,6-tetramethylpiperidin1yl)oxy)ethylidene) Benzenesulfonamide (2.25)
Appearance: White solid
Polarity of solvent: Gradient column with 0% to 30% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 7.89 (d, J = 8.2 Hz, 2H), 7.76 – 7.71 (m, 2H), 7.44 (t, J
= 7.7 Hz, 2H), 7.37 (d, J = 8.5 Hz, 3H), 7.32 (t, J = 7.4 Hz, 1H), 4.36 (d, J = 12.8 Hz, 1H),
4.00 (d, J = 13.7 Hz, 1H), 3.21 (ddd, J = 14.0, 11.2, 3.0 Hz, 1H), 2.90 – 2.85 (m, 1H), 2.42
167
(s, 3H), 1.67 – 1.59 (m, 1H), 1.59 – 1.46 (m, 4H), 1.45 – 1.36 (m, 3H), 1.35 (s, 3H), 1.33
– 1.22 (m, 3H), 1.17 (d, J = 4.8 Hz, 6H), 0.88 (s, 3H), 0.37 – 0.30 (m, 1H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 165.23, 143.50, 142.49, 139.07, 129.90, 129.19,
128.06, 127.52, 126.63, 83.83, 61.79, 60.15, 48.88, 46.81, 41.16, 40.90, 32.80, 32.38,
25.73, 25.68, 24.52, 21.36, 20.98, 17.63.
HRMS (ESI-TOF) calcd for C29H42N3O3S+
[M+H]+ 512.2941, found 512.2962 (Δ = 4.1
ppm).
5.1.3.7 Test for autoxidation using triplet oxygen (3O2) with BHT
A 30 mL glass reaction vial equipped with stir bar and sealed with septum, was flame
dried and purged with nitrogen gas. In a separate flame dried glass vial, PyICl (0.4
mmol, 96.78 mg) was added then purged with nitrogen gas, followed by 5 mL of dry
THF. To the reaction vial, 100 mg (0.334 mmol) of starting triazole was added, it was
purged with nitrogen gas and 5 mL dry THF was added to it. The vial was placed in a
dry ice bath at –78 °C and the mixture was stirred to dissolve the compound. LiHMDS
(0.368 mmol, 0.368 mL, 1 M solution in THF) was added to the vial using Hamilton
syringe through the septum. After 5 min, PyICl solution was taken up in a syringe and
was slowly added to the reaction mixture. The reaction was allowed to stir in the dry ice
bath for 45 minutes. To this, piperidine (0.4 mmol, 39.52 μL) was added through the
septum with a Hamilton syringe and the reaction mixture was allowed to stir at –78 °C
168
for 15 min. At this point, the vial was removed from the dry ice bath and stirred for 45
minutes. BHT (0.5 mmol, 110.2 mg) was then added, and the reaction was exposed to air
and allowed to stir for 18 h. The product was detected by high-resolution mass
spectrometry, and we attempted to isolate the product using flash chromatography with
silica gel. We noted that the isolated product started to degrade into shown side
products.
N-(2-((2,6-di-tert-butyl-4-methylphenyl)trioxidaneyl)-2-phenyl-1-(piperidin-1-
yl)ethylidene)-4-methylbenzenesulfonamide (2.26)
Appearance: White Solid
1H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.23 (dd, J = 5.1,
3.2 Hz, 5H), 7.15 – 7.10 (m, 2H), 6.94 (d, J = 2.9 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), 3.79
– 3.69 (m, 2H), 3.36 – 3.31 (m, 1H), 3.14 – 3.09 (m, 1H), 2.39 (s, 3H), 1.46 – 1.37 (m,
N
N
S
O O
O
O
O
169
2H), 1.32 (s, 3H), 1.28 (s, 9H), 1.25 (s, 2H), 1.16 (s, 9H), 1.05 (d, J = 4.6 Hz, 1H), 0.90 –
0.85 (m, 1H).
HRMS (ESI-TOF) calcd for C35H47N2O5S+ [M+H]+ 607.3200, found 607.3231 (Δ = 5.1
ppm).
5.1.3.8 Four-membered ring compound 2.49 formation
A 30 mL glass reaction vial equipped with a stir bar and sealed with a septum, was
flame dried and purged with nitrogen gas. Following this, triazole (0.334 mmol, 100 mg)
was added followed by 5 mL of dry THF. LiHMDS (0.401 mmol, 0.401 mL, 1 M in THF)
was then slowly added using a Hamilton syringe. The reaction was stirred for 1 h before
being quenched with aq. NH4Cl (0.5 mL). The reaction was concentrated and purified
using flash chromatography with silica gel and ethyl acetate/hexanes solvent system.
The product was isolated a white solid (59 mg, 65%). The obtained NMR data is in
accordance with the reported values.9
N-(2,4-diphenyl-3-(tosylimino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide 2.49
Appearance: White solid
N
N
H
S
O O
S
O O
170
Polarity of solvent: Gradient column with 70% to 100% ethyl acetate in hexanes.
1H NMR (600 MHz, DMSO-d6) δ 7.83 (d, J = 7.6 Hz, 2H), 7.23 (dt, J = 14.2, 7.5 Hz,
3H), 7.12 (t, J = 7.6 Hz, 2H), 7.08 – 7.01 (m, 3H), 6.94 (d, J = 8.0 Hz, 4H), 6.89 (d, J =
8.3 Hz, 4H), 5.23 (s, 1H), 2.21 (s, 6H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 170.83, 141.31, 141.16, 132.82, 129.57, 128.98,
128.30, 127.83, 126.63, 126.19, 125.91, 125.22, 117.71, 63.49, 21.24.
HRMS (ESI-TOF) calcd for C30H27N2O4S2
+
[M+H]+ 543.1407, found 543.1424 (Δ = 3.1
ppm)
5.1.3.9 Formation of oxoamidine 2.18
A 30 mL glass reaction vial equipped with a stir bar and sealed with a septum, was flame
dried and purged with nitrogen gas. In a separate flame dried glass vial, PyICl (0.2 mmol,
48.29 mg) was added then purged with nitrogen gas, followed by 2.5 mL of dry THF. To
the reaction vial, 50 mg (0.167 mmol) of starting triazole 2.20 was added, it was purged
with nitrogen gas and 2.5 mL dry THF was added to it. The vial was placed in a dry ice
bath at –78 °C and the mixture was stirred to dissolve the compound. LiHMDS (0.184
mmol, 0.184 mL, 1 M solution in THF) was added to the vial using a Hamilton syringe
through the septum. After 5 min, PyICl solution was taken up in a syringe and was slowly
added to the reaction mixture. The reaction was allowed to stir in the dry ice bath for 45
minutes. To this, H2O (1.11 mmol, 20 μL) was added through the septum with a Hamilton
syringe and the reaction mixture was allowed to stir at –78 °C for 15 min. At this point,
171
the vial was removed from the dry ice bath and stirred for 45 minutes. Brine (1 mL) and
EtOAc (2 mL) was then added. The reaction was stirred overnight after which the reaction
was concentrated and purified using flash chromatography with silica gel and ethyl
acetate/hexanes solvent system. Product 2.18 was isolated as a viscous white solid (20
mg, 39%).
2-oxo-2-phenyl-N'-tosylacetimidamide (2.18)
Appearance: White solid
Polarity of solvent: Gradient column with 10% to 40% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.33 (br, 1H), 7.95 (d, J = 7.7 Hz, 2H), 7.83 (s, 2H),
7.69 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 2.43 (s, 3H).
1H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 7.9 Hz, 2H), 8.12 (br, 1H), 7.86 (d, J = 8.0 Hz,
2H), 7.60 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.99 (br,
1H), 2.43 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 186.90, 154.97, 144.01, 138.36, 134.68, 133.13, 131.67,
129.72, 128.49, 126.86, 21.74.
HRMS (ESI-TOF) calcd for C15H15N2O3S+
[M+H]+ 303.0798, found 303.0800 (Δ = 0.7
ppm).
O
N
S
NH O O 2
172
5.1.4 Substrate Scope
5.1.4.1 General Procedure
A 50 mL Schlenk flask was equipped with a stir bar and sealed with a septum before being flame
dried and purged with nitrogen gas. In a separate flame dried glass vial PyICl (1.2 equiv., 1 mmol)
was added then purged with nitrogen gas before 12.5 mL of dry THF was added. To the Schlenk
flask, triazole (1.0 equiv., 0.835 mmol) was added and the flask was purged with nitrogen gas
followed by the addition of 12.5 mL of dry THF. The vial was placed in a dry ice and acetone bath
at –78 °C and the mixture was stirred to dissolve the triazole. LiHMDS (1.1 equiv., 0.919 mmol, 1
M in THF) was added to the vial using a Hamilton syringe through the septum. After 5 min, the
PyICl solution was taken up in a syringe and was slowly added to the reaction mixture. The
reaction was allowed to stir in the dry ice bath for 45 minutes. To this, amine (1.2 equiv., 1 mmol)
was added through the septum with a Hamilton syringe and the reaction mixture was allowed to
stir at –78 °C for 15 min. At this point, the vial was removed from the dry ice bath and stirred for
45 minutes. Brine (2.5 mL) and EtOAc (12 mL) was then added to the reaction mixture and the
septum was immediately removed and the system was allowed to stir under air. The reaction was
monitored by TLC and LC-MS until completion (complete conversion of intermediate to product).
At this point, the reaction mixture was concentrated under reduced pressure with toluene to
remove water. The crude mixture was purified using flash chromatography with silica gel and
gradient ethyl acetate/hexanes or ethyl acetate/DCM solvent system.
Note: In most cases the intermediate to product conversion was complete overnight unless
otherwise noted.
173
5.1.4.2 Characterization for substrate scope
N-(2-hydroxy-2-phenyl-1-(piperidin-1-yl)ethylidene)-4-methylbenzenesulfonamide
(2.32)
The product (234 mg, 75%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (99 μL, 1.00 mmol) with LiHMDS
(0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: White solid
Polarity of solvent: Gradient column with 10% to 65% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 7.80 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H), 7.38
(t, J = 7.6 Hz, 2H), 7.31 (dd, J = 18.0, 7.6 Hz, 3H), 6.96 (d, J = 5.4 Hz, 1H), 6.17 (d, J =
5.3 Hz, 1H), 3.73 (d, J = 11.7 Hz, 1H), 3.58 – 3.42 (m, 3H), 2.40 (s, 10H), 1.58 – 1.44 (m,
4H), 1.34 (s, 1H), 0.90 (s, 1H)
13C{1H} NMR (151 MHz, Acetone-d6) δ 166.41, 143.48, 142.48, 140.46, 129.91, 129.14,
128.07, 126.92, 125.85, 71.24, 49.23, 47.32, 26.26, 26.13, 24.63, 21.33.
HRMS (ESI-TOF) calcd for C20H24N2NaO3S+
[M+Na]+ 395.1400, found 395.1413 (Δ = 3.3
ppm)
N-(2-hydroxy-1-morpholino-2-phenylethylidene)-4-methylbenzenesulfonamide
(2.33)
N
S
N O O
OH
174
The product (239 mg, 77%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (86.4 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: White solid
Polarity of solvent: Gradient column with 10% to 70% ethyl acetate in hexanes.
1H NMR (400 MHz, Acetone-d6) δ 7.81 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.47
– 7.26 (m, 5H), 6.98 (d, J = 5.0 Hz, 1H), 6.32 (d, J = 5.3 Hz, 1H), 3.77 – 3.51 (m, 5H),
3.51 – 3.40 (m, 1H), 3.40 – 3.25 (m, 1H), 3.11 (d, J = 9.2 Hz, 1H), 2.40 (s, 3H)
13C{1H} NMR (126 MHz, Acetone-d6) δ 167.01, 143.00, 142.75, 140.07, 129.97, 129.26,
128.27, 126.98, 125.86, 71.05, 70.95, 66.70, 49.11, 46.52, 21.33.
HRMS (ESI-TOF) calcd for C19H22N2NaO4S+
[M+Na]+ 397.1192, found 395.1204 (Δ = 4.3
ppm)
2-hydroxy-N,N-diisopropyl-2-phenyl-N'-tosylacetimidamide (2.34)
The product (188 mg, 58%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (141 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: White solid
Polarity of solvent: Gradient column with 10% to 50% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 7.80 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.38
(t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 5.4 Hz,
N
S
N O O
OH
175
1H), 6.21 (d, J = 5.2 Hz, 1H), 4.45 (p, J = 6.6 Hz, 1H), 3.51 (p, J = 6.7 Hz, 1H), 2.40 (s,
3H), 1.30 (dd, J = 6.7, 3.6 Hz, 6H), 1.14 (d, J = 6.5 Hz, 3H), 0.45 (d, J = 6.7 Hz, 3H)
13C{1H} NMR (126 MHz, Acetone-d6) δ 165.76, 142.41, 140.65, 129.91, 129.08, 127.97,
126.88, 125.61, 72.15, 51.06, 48.68, 21.34, 20.22, 19.80, 19.68, 18.57
HRMS (ESI-TOF) calcd for C21H29N2O3S+
[M+H]+ 389.1893, found 389.1900 (Δ = 1.8
ppm)
N-butyl-2-hydroxy-2-phenyl-N'-tosylacetimidamide (2.28)
The product (267 mg, 88%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (99.05 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: Tan crystalline solid
Polarity of solvent: Gradient column with 10% to 55% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.08 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 5.8
Hz, 2H), 7.28 (d, J = 5.9 Hz, 3H), 7.19 (d, J = 7.8 Hz, 2H), 6.47 (d, J = 4.5 Hz, 1H), 5.61
(d, J = 4.1 Hz, 1H), 3.36 (q, J = 6.8 Hz, 2H), 2.34 (s, 3H), 1.54 (ddd, J = 13.7, 7.9, 4.5 Hz,
2H), 1.29 (h, J = 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H).
13C{1H} NMR(151 MHz, Acetone-d6) δ 168.46, 143.25, 142.11, 140.79, 129.62, 128.96,
128.79, 128.57, 126.72, 71.52, 41.69, 31.34, 21.27, 20.63, 13.98.
HRMS (ESI-TOF) calcd for C19H25N2O3S+
[M+H]+ 361.1580, found 361.1597 (Δ = 4.7
ppm)
N
S
HN O O
OH
176
N-benzyl-2-hydroxy-2-phenyl-N'-tosylacetimidamide (2.29)
The product (212 mg, 54%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (109.4 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: White solid
Polarity of solvent: Gradient column with 10% to 60% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.53 (s, 1H), 7.57 – 7.46 (m, 4H), 7.34 – 7.22 (m, 8H),
7.17 (d, J = 7.9 Hz, 2H), 6.54 (s, 1H), 5.67 (s, 1H), 4.61 (dd, J = 14.4, 5.6 Hz, 1H), 4.53
(dd, J = 14.5, 5.0 Hz, 1H), 2.35 (s, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 168.58, 142.97, 142.20, 140.69, 138.90, 129.62,
129.17, 128.98, 128.84, 128.81, 128.57, 128.02, 126.77, 71.47, 45.45, 21.28.
HRMS (ESI-TOF) calcd for C22H22N2NaO3S+
[M+Na]+ 417.1243, found 417.1257 (Δ = 3.4
ppm)
N-(tert-butyl)-2-hydroxy-2-phenyl-N'-tosylacetimidamide (2.30)
The product (240 mg, 80%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (99.05 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
N
S
HN O O
OH
N
S
NH O O
OH
177
Appearance: Tan crystalline solid
Polarity of solvent: Gradient column with 10% to 50% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 7.53 (d, J = 8.2 Hz, 2H), 7.49 – 7.44 (m, 2H), 7.33 (br,
1H), 7.30 (dd, J = 5.1, 1.9 Hz, 3H), 7.21 (d, J = 8.0 Hz, 2H), 6.41 (d, J = 4.5 Hz, 1H), 5.71
(d, J = 4.4 Hz, 1H), 2.35 (s, 3H), 1.39 (s, 9H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 166.61, 142.97, 142.19, 140.73, 129.67, 129.04,
128.85, 128.75, 126.65, 71.63, 53.42, 28.34, 21.28
HRMS (ESI-TOF) calcd for C19H24N2NaO3S+
[M+Na]+ 383.1400, found 383.1407 (Δ = 3.4
ppm)
2-hydroxy-2-phenyl-N'-tosylacetimidamide (2.27)
The product (140 mg, 55%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (7M solution in methanol, 143.2
μL, 1.00 mmol) with LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: Off-white fluffy solid
Polarity of solvent: Gradient column with 10% to 75% ethyl acetate in hexanes.
1H NMR (600 MHz, DMSO-d6) δ 8.48 (br, 1H), 8.03 (br, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.34
(dd, J = 6.5, 3.0 Hz, 2H), 7.29 (dd, J = 5.0, 1.9 Hz, 3H), 7.25 (d, J = 8.0 Hz, 2H), 6.46 (br,
1H), 5.03 (s, 1H), 2.34 (s, 3H)
13C{1H} NMR (151 MHz, DMSO-d6) δ 169.70, 142.05, 140.19, 139.50, 129.03, 127.96,
127.77, 126.56, 125.72, 73.31, 20.84
N
S
NH O O 2
OH
178
HRMS (ESI-TOF) calcd for C15H17N2O3S+
[M+H]+ 305.0954, found 305.0968 (Δ = 1.3
ppm)
2-hydroxy-2-phenyl-N-((R)-1-phenylethyl)-N'-tosylacetimidamide (2.31)
The product (274 mg, 87%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (128 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Diasteromer-1 (polar spot on TLC)
Appearance: Pale Orange solid
Polarity of solvent: Gradient column with 0% to 10% ethyl acetate in DCM.
1H NMR (600 MHz, Acetone-d6) δ 8.15 (br, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.34 (dd, J =
7.7, 2.2 Hz, 4H), 7.28 (t, J = 7.3 Hz, 2H), 7.26 – 7.16 (m, 4H), 7.13 (d, J = 8.0 Hz, 2H),
6.47 (s, 1H), 5.68 (br, 1H), 5.16 (p, J = 7.1 Hz, 1H), 2.33 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 206.29, 206.01, 167.48, 143.94, 142.85, 142.08,
140.33, 129.53, 129.21, 129.03, 128.82, 128.78, 128.72, 128.60, 128.04, 127.39, 126.66,
71.43, 51.72, 21.54, 21.27.
HRMS (ESI-TOF) calcd for C23H25N2O3S+
[M+H]+ 409.1580, found 409.1596 (Δ = 3.9
ppm)
Diasteromer-2 (non-polar spot on TLC)
Appearance: Candy-like white viscous solid
Polarity of solvent: Gradient column with 0% to 10% ethyl acetate in DCM.
179
1H NMR (600 MHz, Acetone-d6) δ 8.19 (br, 1H), 7.58 (d, J = 7.1 Hz, 2H), 7.45 – 7.39 (m,
2H), 7.37 – 7.30 (m, 5H), 7.30 – 7.24 (m, 3H), 7.14 (d, J = 7.8 Hz, 2H), 6.47 (s, 1H), 5.71
(br, 1H), 5.17 (t, J = 7.3 Hz, 1H), 2.35 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 167.55, 143.90, 143.01, 142.07, 140.76, 129.57,
129.29, 129.04, 128.89, 128.64, 128.01, 127.27, 126.65, 71.42, 51.53, 21.54, 21.28.
2-hydroxy-N,2-diphenyl-N'-tosylacetimidamide (2.46)
The product (197 mg, 62%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (91.5 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: White solid
Polarity of solvent: Gradient column with 0% to 10% ethyl acetate in DCM.
1H NMR 1H NMR (600 MHz, Acetone-d6) δ 9.49 (br, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.63 (t,
J = 6.0 Hz, 4H), 7.34 (dt, J = 14.4, 7.5 Hz, 5H), 7.26 (d, J = 7.9 Hz, 2H), 7.17 (t, J = 7.5
Hz, 1H), 6.68 (s, 1H), 5.98 (br, 1H), 2.37 (s, 3H).
13C{1H} NMR (126 MHz, Acetone-d6) δ 165.79, 142.84, 142.33, 140.44, 138.32, 129.90,
129.50, 129.16, 129.06, 128.63, 126.94, 126.25, 123.10, 71.66, 21.32.
HRMS (ESI-TOF) calcd for C21H21N2O3S+
[M+H]+ 381.1267, found 381.1277 (Δ = 2.6
ppm)
2-hydroxy-N-(4-nitrophenyl)-2-phenyl-N'-tosylacetimidamide (2.47)
N
S
NH O O
OH
180
The product (170 mg, 48%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (138.4 mg, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: Orange solid
Polarity of solvent: Gradient column with 0% to 10% ethyl acetate in DCM.
1H NMR (500 MHz, Acetone-d6) δ 9.89 (s, 1H), 8.21 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 9.1
Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.67 – 7.61 (m, 2H), 7.40 – 7.29 (m, 5H), 6.71 (d, J =
4.1 Hz, 1H), 6.09 (d, J = 3.8 Hz, 1H), 2.39 (s, 3H).
13C{1H} NMR (126 MHz, Acetone-d6) δ 166.19, 145.13, 144.25, 143.49, 141.57, 140.01,
130.17, 129.28, 129.26, 128.58, 127.12, 125.18, 122.98, 71.67, 21.37.
HRMS (ESI-TOF) calcd for C21H20N3O5S+
[M+H]+ 426.1118, found 426.1126 (Δ = 1.9
ppm)
2-hydroxy-N-(4-methoxyphenyl)-2-phenyl-N'-tosylacetimidamide (2.45)
The product (281 mg, 82%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (123.4 mg, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
181
Appearance: Pale yellow solid
Polarity of solvent: Gradient column with 0% to 12% ethyl acetate in DCM.
1H NMR (600 MHz, Acetone-d6) δ 9.44 (br, 1H), 7.60 (t, J = 9.5 Hz, 6H), 7.33 (q, J = 7.4
Hz, 3H), 7.24 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.65 (s, 1H), 5.92 (br, 1H), 3.78
(s, 3H), 2.36 (s, 3H).
13C{1H} NMR (126 MHz, Acetone-d6) δ 165.53, 158.28, 142.65, 142.56, 140.56, 131.25,
129.84, 129.13, 129.00, 128.65, 126.88, 124.65, 114.57, 71.63, 55.72, 21.32.
HRMS (ESI-TOF) calcd for C22H23N2O4S+
[M+H]+ 411.1373, found 411.1388 (Δ = 3.6
ppm)
2-hydroxy-N-(4-((Z)-2-hydroxy-2-phenyl-N'-tosylacetimidamido)butyl)-2-phenyl-N'-
tosylacetimidamide (2.48)
The product (140 mg, 51%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (101 μL, 1.00 mmol) with
LiHMDS (0.919 mL, 0.919 mmol) and PyICl (241.94 mg, 1.00 mmol).
Appearance: Off-white solid
Polarity of solvent: Gradient column with 30% to 100% ethyl acetate in hexanes.
1H NMR (600 MHz, DMSO-d6) δ 8.82 (br, J = 5.1 Hz, 2H), 7.49 (d, J = 6.9 Hz, 4H), 7.41
(d, J = 6.7 Hz, 4H), 7.29 (q, J = 7.7, 7.0 Hz, 6H), 7.19 (d, J = 7.5 Hz, 4H), 6.56 (d, J = 2.8
N
S
HN O O
OH
N
S
O O NH
OH
182
Hz, 2H), 6.23 (d, J = 4.1 Hz, 2H), 3.19 – 3.08 (m, 4H), 2.30 (s, 6H), 1.38 (q, J = 6.3, 5.9
Hz, 4H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 167.92, 141.66, 141.10, 140.00, 128.93, 128.03,
127.77, 127.45, 125.32, 69.87, 40.23, 25.18, 20.82.
HRMS (ESI-TOF) calcd for C23H25N2O3S+
[M+H]+663.2306, found 663.2312 (Δ = 0.9
ppm)
N-butyl-2-hydroxy-2-(4-methoxyphenyl)-N'-tosylacetimidamide (2.35)
The product (185 mg, 58%) was prepared using the general procedure from the
corresponding triazole (270 mg, 0.820 mmol) and amine (97.2 μL, 984 mmol) with
LiHMDS (0.902 mL, 0.902 mmol) and PyICl (237 mg, 980 mmol).
Appearance: Pale yellow solid
Polarity of solvent: Gradient column with 10% to 65% ethyl acetate in hexanes.
1H NMR (600 MHz, DMSO-d6) δ 8.83 (t, J = 5.6 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.30 (d,
J = 8.6 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.42 (d, J = 4.1 Hz, 1H),
6.16 (d, J = 4.0 Hz, 1H), 3.73 (s, 3H), 3.20 (q, J = 6.7 Hz, 2H), 2.32 (s, 3H), 1.42 (dt, J =
12.9, 5.4 Hz, 2H), 1.20 (h, J = 7.3 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 168.66, 159.32, 142.24, 141.40, 132.46, 129.30,
129.26, 125.74, 113.81, 69.87, 55.51, 40.82, 30.46, 21.27, 19.85, 14.00.
HRMS (ESI-TOF) calcd for C20H27N2O4S+
[M+H]+ 391.1686, found 391.1684 (Δ = 0.5
ppm)
183
N-butyl-2-(4-(tert-butyl)phenyl)-2-hydroxy-N'-tosylacetimidamide (2.36)
The product (204 mg, 60%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.771 mmol) and amine (96.8 μL, 0.979 mmol) with
LiHMDS (0.897 mL, 0.897 mmol) and PyICl (236 mg, 0.979 mmol).
Appearance: Pale Orange Crystals
Polarity of solvent: Gradient column with 10% to 40% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.10 (br, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4
Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.46 (d, J = 4.5 Hz, 1H), 5.50
(d, J = 4.1 Hz, 1H), 3.39 (q, J = 6.8 Hz, 2H), 2.34 (s, 3H), 1.56 (ddd, J = 14.4, 7.2, 2.0 Hz,
2H), 1.35 – 1.28 (m, 11H), 0.87 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 168.66, 151.63, 143.27, 141.95, 137.70, 129.56,
128.41, 126.72, 125.82, 71.25, 41.70, 35.06, 31.65, 31.41, 21.30, 20.67, 14.00.
HRMS (ESI-TOF) calcd for C23H33N2O3S+
[M+H]+ 417.2206, found 417.2214 (Δ = 1.0
ppm)
N-butyl-2-(4-cyanophenyl)-2-hydroxy-N'-tosylacetimidamide (2.38)
N
S
HN O O
OH
184
The product (167 mg, 56%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.771 mmol) and amine (91.4 μL, 925 mmol) with
LiHMDS (0.848 mL, 0.848 mmol) and PyICl (223 mg, 925 mmol).
Appearance: Yellow Solid
Polarity of solvent: Gradient column with 10% to 70% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.25 (s, 1H), 7.71 (s, 4H), 7.59 (d, J = 7.9 Hz, 2H), 7.24
(d, J = 7.8 Hz, 2H), 6.54 (s, 1H), 6.02 (s, 1H), 3.45 – 3.32 (m, J = 6.6 Hz, 2H), 2.37 (s,
3H), 1.55 (td, J = 7.3, 3.0 Hz, 2H), 1.29 (h, J = 7.3 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (126 MHz, Acetone-d6) δ 167.48, 145.78, 142.95, 142.42, 132.89, 129.73,
129.55, 126.70, 119.19, 112.61, 70.98, 41.83, 31.27, 21.30, 20.63, 13.97.
HRMS (ESI-TOF) calcd for C20H24N3O3S+
[M+H]+ 386.1533, found 386.1529 (Δ = 1.0
ppm)
N-butyl-2-hydroxy-N'-tosyl-2-(4-(trifluoromethyl)phenyl)acetimidamide (2.39)
The product (264 mg, 75%) was prepared using the general procedure from the
corresponding triazole (300 mg, 0.817 mmol) and amine (96.9 μL, 980 mmol) with
LiHMDS (0.898 mL, 0.898 mmol) and PyICl (237 mg, 980 mmol).
Appearance: Colorless crystals
Polarity of solvent: Gradient column with 10% to 40% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.23 (br, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2
Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.55 (s, 1H), 5.92 (d, J = 4.1
185
Hz, 1H), 3.40 (qt, J = 8.9, 4.9 Hz, 2H), 2.35 (s, 3H), 1.57 (pd, J = 7.1, 2.5 Hz, 2H), 1.31
(h, J = 7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H).
19F NMR (564 MHz, Acetone-d6) δ -63.03.
13C{1H} NMR (151 MHz, Acetone-d6) δ 167.76, 144.98, 142.95, 142.29, 130.37 (q, J =
32.1 Hz), 129.66, 129.37, 126.66, 128.47 – 122.45 (m), 125.90 (q, J = 3.8 Hz), 71.01,
41.81, 31.30, 21.24, 20.64, 13.97.
HRMS (ESI-TOF) calcd for C20H24F3N2O3S+
[M+H]+ 429.1454, found 429.1449 (Δ = 1.2
ppm)
2-(4-bromophenyl)-N-butyl-2-hydroxy-N'-tosylacetimidamide (2.37)
The product (274 mg, 76%) was prepared using the general procedure from the
corresponding triazole (310 mg, 0.820 mmol) and amine (97.2 μL, 984 mmol) with
LiHMDS (0.902 mL, 0.902 mmol) and PyICl (237 mg, 980 mmol).
Appearance: Pale yellow transparent crystals
Polarity of solvent: Gradient column with 10% to 45% ethyl acetate in hexanes.
1H NMR (600 MHz, DMSO-d6) δ 8.90 (t, J = 5.5 Hz, 1H), 7.49 (dd, J = 8.4, 2.9 Hz, 4H),
7.33 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 4.0 Hz, 1H), 6.18 (d, J = 3.7
Hz, 1H), 3.21 (dt, J = 12.2, 6.7 Hz, 2H), 2.34 (s, 3H), 1.42 (pd, J = 6.8, 2.6 Hz, 2H), 1.19
(h, J = 7.4 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 167.43, 141.53, 141.16, 139.25, 130.95, 129.68,
128.91, 125.28, 121.13, 69.31, 40.45, 29.93, 20.86, 19.38, 13.53.
186
HRMS (ESI-TOF) calcd for C19H24BrN2O3S+
[M+H]+ 439.0686, found 439.0694 (Δ = 1.8
ppm)
N-butyl-2-hydroxy-N'-((4-methoxyphenyl)sulfonyl)-2-phenylacetimidamide (2.40)
The product (227 mg, 73%) was prepared using the general procedure from the
corresponding triazole (260 mg, 0.824 mmol) and amine (97.8 μL, 989 mmol) with
LiHMDS (907 μL, 907 mmol) and PyICl (239 mg, 989 mmol).
Appearance: Transparent Crystals
Polarity of solvent: Gradient column with 10% to 65% ethyl acetate in hexanes.
1H NMR (600 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 7.3
Hz, 2H), 7.34 – 7.26 (m, 3H), 6.94 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 4.2 Hz, 1H), 6.24 (d, J
= 4.2 Hz, 1H), 3.78 (s, 3H), 3.20 (q, J = 6.7 Hz, 2H), 1.45 – 1.38 (m, 2H), 1.19 (h, J = 7.4
Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 167.72, 161.14, 140.08, 136.60, 128.05, 127.82,
127.48, 127.34, 113.63, 69.81, 55.50, 40.39, 30.03, 19.43, 13.60.
HRMS (ESI-TOF) calcd for C19H25N2O4S+
[M+H]+ 377.1530, found 377.1537 (Δ = 1.9
ppm)
N'-((4-bromophenyl)sulfonyl)-N-butyl-2-hydroxy-2-phenylacetimidamide (2.41)
187
The product (319 mg, 91%) was prepared using the general procedure from the
corresponding triazole (300 mg, 0.824 mmol) and amine (97.7 μL, 0.988 mmol) with
LiHMDS (906 μL, 906 mmol) and PyICl (239 mg, 0.988 mmol).
Appearance: Yellow Crystals
Polarity of solvent: Gradient column with 10% to 50% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.30 (s, 1H), 7.56 (s, 4H), 7.46 (dd, J = 6.5, 3.0 Hz,
2H), 7.29 (q, J = 3.6 Hz, 3H), 6.43 (d, J = 4.2 Hz, 1H), 5.66 (d, J = 4.2 Hz, 1H), 3.41 (q, J
= 6.9 Hz, 2H), 1.57 (pd, J = 7.1, 2.5 Hz, 2H), 1.32 (h, J = 7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz,
3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 168.87, 145.17, 140.43, 132.27, 129.06, 128.94,
128.73, 128.62, 125.64, 71.64, 41.82, 31.34, 20.64, 13.98.
HRMS (ESI-TOF) calcd for C18H22BrN2O3S+
[M+H]+ 425.0529, found 425.0528 (Δ = 0.2
ppm)
N'-([1,1'-biphenyl]-4-ylsulfonyl)-N-butyl-2-hydroxy-2-phenylacetimidamide (2.42)
The product (205.7 mg, 60%) was prepared using the general procedure from the
corresponding triazole (295 mg, 0.816 mmol) and amine (96.8 μL, 0.979 mmol) with
LiHMDS (0.898 mL, 0.898 mmol) and PyICl (237 mg, 0.979 mmol).
Appearance: Pale yellow solid
Polarity of solvent: Gradient column with 10% to 45% ethyl acetate in hexanes.
N
S
HN O O
OH
188
1H NMR (600 MHz, Acetone-d6) δ 8.23 (br, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.71 – 7.63 (m,
4H), 7.49 (t, J = 7.3 Hz, 4H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 – 7.24 (m, 3H), 6.51 (s, 1H),
5.68 (br, 1H), 3.42 (q, J = 6.2 Hz, 2H), 1.58 (pd, J = 7.2, 2.0 Hz, 2H), 1.32 (h, J = 7.4 Hz,
2H), 0.86 (t, J = 7.4 Hz, 3H).
13C NMR (126 MHz, Acetone-d6) δ 168.69, 144.75, 144.34, 140.64, 140.63, 129.87,
129.02, 128.93, 128.87, 128.68, 127.99, 127.62, 127.29, 71.55, 41.78, 20.66, 14.01.
HRMS (ESI-TOF) calcd for C24H27N2O3S+
[M+H]+ 423.1737, found 423.1747 (Δ = 2.4
ppm)
N-butyl-2-hydroxy-N'-(naphthalen-2-ylsulfonyl)-2-phenylacetimidamide (2.44)
The product (228 mg, 70%) was prepared using the general procedure from the
corresponding triazole (275 mg, 0.820 mmol) and amine (97.3 μL, 0.984 mmol) with
LiHMDS (0.902 mL, 0.902 mmol) and PyICl (238 mg, 0.984 mmol).
Appearance: Pale Yellow Crystals
Polarity of solvent: Gradient column with 10% to 45% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.21 (br, 1H), 7.94 (dd, J = 14.5, 9.3 Hz, 3H), 7.76 (dd,
J = 8.6, 1.8 Hz, 1H), 7.65 – 7.57 (m, 2H), 7.54 – 7.49 (m, 2H), 7.23 (dt, J = 25.7, 7.2 Hz,
3H), 6.54 (d, J = 3.6 Hz, 1H), 5.64 (d, J = 3.9 Hz, 1H), 3.41 (q, J = 6.6 Hz, 2H), 1.56 (pd,
J = 7.1, 2.3 Hz, 2H), 1.30 (h, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H).
N
S
HN O O
OH
189
13C{1H} NMR (126 MHz, Acetone-d6) δ 168.64, 142.91, 140.60, 135.04, 133.03, 129.92,
129.20, 128.96, 128.89, 128.74, 128.67, 128.56, 127.82, 126.49, 123.63, 71.63, 41.76,
31.34, 20.63, 13.96.
HRMS (ESI-TOF) calcd for C22H25N2O3S+
[M+H]+ 397.1580, found 397.1594 (Δ = 3.5
ppm)
N-butyl-2-hydroxy-N'-((4-nitrophenyl)sulfonyl)-2-phenylacetimidamide (2.43)
The product (200 mg, 63%) was prepared using the general procedure from the
corresponding triazole (270 mg, 0.817 mmol) and amine (96.9 μL, 981 mmol) with
LiHMDS (899 μL, 0.899 mmol) and PyICl (237 mg, 0.981 mmol).
Appearance: Yellow Solid
Polarity of solvent: Gradient column with 10% to 70% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 8.52 (s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8
Hz, 2H), 7.45 – 7.37 (m, 2H), 7.29 – 7.23 (m, 3H), 6.42 (s, 1H), 5.71 (s, 1H), 3.47 (td, J =
7.1, 5.9 Hz, 2H), 1.60 (pd, J = 7.0, 3.2 Hz, 2H), 1.34 (h, J = 7.4 Hz, 2H), 0.87 (t, J = 7.4
Hz, 3H).
13C{1H} NMR (126 MHz, Acetone-d6) δ 169.39, 151.17, 149.87, 140.06, 129.14, 129.11,
128.90, 127.97, 124.45, 71.79, 41.99, 31.32, 20.64, 13.97.
HRMS (ESI-TOF) calcd for C18H22N3O5S+
[M+H]+ 392.1275, found 392.1274 (Δ = 0.3
ppm)
4-methyl-N-(3-phenyl-4-(pyridin-2-yl)azet-2(1H)-ylidene)benzenesulfonamide
190
The product (60 mg, 19%) was prepared using the general procedure from the
corresponding triazole (250 mg, 0.835 mmol) and amine (85.8 μL, 0.877 mmol) with
LiHMDS (0.848 mL, 0.848 mmol) and PyICl (223 mg, 925 mmol).
Appearance: Green Solid
1H NMR (600 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 6.8
Hz, 1H), 7.65 (t, J = 7.6 Hz, 6H), 7.59 (t, J = 7.3 Hz, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.17
(d, J = 7.8 Hz, 2H), 2.30 (s, 3H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 154.85, 149.65, 143.05, 139.52, 130.49, 130.39,
129.73, 129.63, 128.39, 128.23, 127.42, 127.31, 127.04, 126.71, 126.58, 121.49, 20.82.
HRMS (ESI-TOF) calcd for C21H18N3O2S+
[M+H]+ 376.1114, found 376.1129 (Δ = 4.0
ppm)
5.1.5 Post Functionalization
5.1.5.1 Synthesis of fluoroamidine 2.50
Similar conditions and procedure were followed as in section 5.1.5.1, instead of PyICl, a
stock of Br2 was prepared in a separate flask. The product (72 mg, 62%) was prepared
using the general procedure from the corresponding triazole (100 mg, 334.1 mmol) and
amine (39.62 μL, 0.4 mmol) with LiHMDS (0.367 mmol, 1M solution in THF) and Br2 (20.5
μL, 0.4 mmol).
191
N-(2-bromo-2-phenyl-1-(piperidin-1-yl)ethylidene)-4-methylbenzenesulfonamide (2.50)
Appearance: White solid
Polarity of solvent: Gradient column with 10% to 40% ethyl acetate in hexanes.
1H NMR (600 MHz, Acetone-d6) δ 7.80 (d, J = 7.8 Hz, 2H), 7.53 – 7.47 (m, 3H), 7.45 (t, J
= 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 3.76 (d, J = 73.8 Hz, 2H),
3.31 (d, J = 75.7 Hz, 2H), 2.41 (s, 3H), 1.56 (s, 4H), 1.46 (s, 1H), 1.05 (s, 1H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 161.84, 143.11, 142.36, 135.19, 130.11, 129.85,
129.24, 127.59, 127.09, 44.69, 24.21, 21.36.
HRMS (ESI-TOF) calcd for C20H24BrN2O2S+
[M+H]+ 435.0736, found 435.0744 (Δ = 1.8
ppm).
5.1.5.2 Synthesis of bromoamidine 2.51
Similar conditions and procedure were followed as in section 5.1.5.1, instead of PyICl, a
stock of NFSI was prepared in a separate flask. The product (78 mg, 64%) was prepared
using the general procedure from the corresponding triazole (100 mg, 334.1 mmol) and
amine (39.62 μL, 0.4 mmol) with LiHMDS (0.367 mmol, 1M solution in THF) and NFSI
(116 mg, 0.367 mmol).
N-butyl-2-fluoro-2-phenyl-N'-tosylacetimidamide (2.51)
N
S
N O O
Br
N
S
HN O O
F
192
Appearance: Colorless viscous solid
Polarity of solvent: Gradient column with 0% to 2% ethyl acetate in DCM.
1H NMR (600 MHz, Acetone-d6) δ 8.30 (s, 1H), 7.59 – 7.48 (m, 4H), 7.46 – 7.38 (m, 3H),
7.22 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 48.8 Hz, 1H), 3.44 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H),
1.60 (pd, J = 7.0, 2.3 Hz, 2H), 1.33 (q, J = 7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).
19F NMR (564 MHz, Acetone-d6) δ -168.02 (d, J = 48.9 Hz).
13C{1H} NMR (151 MHz, CDCl3) δ 163.28 (d, J = 19.0 Hz), 142.62, 142.44, 135.65 (d, J =
19.3 Hz), 130.65 (d, J = 3.6 Hz), 129.77, 129.47, 129.26 (d, J = 5.1 Hz), 126.81, 90.49
(d, J = 180.8 Hz), 42.07, 31.18, 21.29, 20.67, 13.95.
HRMS: (ESI-TOF) calcd for C19H24FN2O2S+
[M+H]+ 363.1537, found 363.1541 (Δ = 1.1
ppm).
5.1.5.3 Synthesis of oxoamidine 2.52
4-methyl-N-(1-morpholino-2-oxo-2-phenylethylidene)benzenesulfonamide (2.52)
In a screw cap vial equipped with a stir bar, DCM (6 mL) was added. To this, Pyridinium
chlorochromate (PCC) (45.8 mg, 0.214 mmol, 1.6 equiv.) was added and was stirred to
substantially dissolve the reagent. At this point, starting amidine 2.33 (50 mg, 134 mmol)
was added to the vial and an orange color solution was obtained that turns dark as
reaction proceeds. The mixture was allowed to stir overnight after which a heterogenous
solution with black suspension was obtained. The solution was passed through a pad of
193
silica with and washed with ethyl acetate. The resulting solution was concentrated to
obtain the desired product 2.52.
Appearance: Viscous white solid
Polarity of solvent: Gradient column with 30% to 60% ethyl acetate in hexanes.
1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.6 Hz, 2H), 7.69 (dd, J = 20.0, 7.7 Hz, 3H),
7.55 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 3.86 (s, 2H), 3.75 (t, J = 4.8 Hz, 2H),
3.54 (s, 2H), 3.22 (s, 2H), 2.40 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 192.76, 161.05, 142.90, 139.27, 135.16, 134.39,
129.53, 129.40, 129.00, 127.00, 66.39, 66.37, 47.83, 45.15, 21.67.
HRMS: (ESI-TOF) calcd for C19H21N2O4S +
[M+H]+ 273.1219, found 207.1488 (Δ = 0.5
ppm).
5.1.5.4 Synthesis of deprotected amidine 2.53
N-butyl-2-hydroxy-2-phenylacetimidamide (2.53)
In a dry flask equipped with a stir bar, starting amidine (80 mg, 0.204 mmol) was added.
To this, DMF (1 mL, 0.2 M) was added followed by K2CO3 (141mg, 5.0 equiv., 1.02 mmol).
In this mixture, benzenethiol (50 μL, 2.4 equiv., 0.490 mmol) was added and the reaction
turned brown in color. The mixture was allowed to stir for 3 h at r.t. after which it was dried
under vacuum and silica gel was added to prepare slurry for column chromatography.
The desired product was isolated using flash chromatography with 2% MeOH in DCM
NH
HN
OH
194
solvent system. NMR yield: 65% (determined with respect to 1,3,5 trimethoxy benzene
as internal standard).
HRMS: (ESI-TOF) calcd for C12H19N2O+
[M+H]+ 207.1492, found 207.1488 (Δ = 1.9 ppm).
5.1.6 Scaled up synthesis for α-hydroxyamidine 2.28
A 250 mL Schlenk flask was equipped with a stir bar and sealed with a septum before
being flame dried and purged with nitrogen gas. In a separate flame dried glass vial PyICl
(1.2 equiv., 5 mmol, 1.21 g) was added then purged with nitrogen gas before 62.5 mL of
dry THF was added. To the Schlenk flask, triazole (1.0 equiv., 4.175 mmol, 1.25 g) was
added and the flask was purged with nitrogen gas followed by the addition of 62.5 mL of
dry THF. The vial was placed in a dry ice and acetone bath at –78 °C and the mixture
was stirred to dissolve triazole 2.20. LiHMDS (1.1 equiv.), –78 °C, THF, 5 min 2. PyICl
(1.2 equiv.), –78 °C, THF, 45 min 3. n-BuNH2 (1.2 equiv.), –78 °C, 15 min then –78 °C to
r.t. 4. Brine, EtOAc, O2 (air), r.t. 45 addition of 62.5 mL of dry THF. The vial was placed
in a dry ice and acetone bath at –78 °C and the mixture was stirred to dissolve the triazole.
LiHMDS (1.1 equiv., 4.59 mmol, 1 M in THF, 4.59 mL) was added to the vial using a
syringe through the septum. After 8 min, the PyICl solution was taken up in a syringe and
was slowly added to the reaction mixture. The reaction was allowed to stir in the dry ice
bath for 45 minutes. To this, n-butylamine (1.2 equiv., 5 mmol, 494 μL) was added through
the septum with a Hamilton syringe and the reaction mixture was allowed to stir at –78 °C
for 15 min. At this point, the vial was removed from the dry ice bath and stirred for 45
195
minutes. Brine (12.5 mL) and EtOAc (50 mL) was then added to the reaction mixture and
the septum was immediately removed and the system was allowed to stir under air. The
reaction was monitored by TLC and LC-MS until completion (complete conversion of
intermediate to product). At this point, the reaction mixture was concentrated under
reduced pressure with toluene to remove water. The resulting black sticky solid was then
adsorbed to silica and a silica plug was run with a 30% ethyl acetate in hexanes eluent.
The resulting solid was then dissolved in a minimal amount of DCM before having
hexanes layered over it in order to recrystallize the product. A tan crystalline solid 2.28
(1.23 g, 82% isolated yield) was isolated following filtration.
196
5.1.7 NMRs for chapter 2
1H NMR (600 MHz, DMSO-d6) of N-(2,4-diphenyl-3-(tosylimino)cyclobut-1-en-1-yl)-4-
methylbenzenesulfonamide
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
6.19
1.02
4.20
4.10
3.18
2.13
3.13
2.00
2.24
2.50 dmso
3.37 H2O
5.26
6.90
6.92
6.96
6.98
7.05
7.07
7.08
7.10
7.13
7.15
7.17
7.23
7.25
7.27
7.29
7.85
7.87
197
13C{
1H} NMR (151 MHz, DMSO-d6) of of N-(2,4-diphenyl-3-(tosylimino)cyclobut-1-en-1-yl)-4-
methylbenzenesulfonamide
198
1H NMR (600 MHz, CDCl3) of 1-([1,1'-biphenyl]-4-ylsulfonyl)-4-phenyl-1H-1,2,3-triazole
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
1.00
3.06
2.11
2.00
2.06
1.99
1.88
0.94
1.56 H2O
7.26 cdcl3
7.37
7.38
7.39
7.43
7.44
7.45
7.47
7.49
7.50
7.57
7.58
7.78
7.80
7.83
7.85
8.20
8.22
8.35
199
13C{
1H} NMR (151 MHz, CDCl3) of 1-([1,1'-biphenyl]-4-ylsulfonyl)-4-phenyl-1H-1,2,3-triazole
200
1H NMR (600 MHz, Acetone-d6) of compound 2.32
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
1.03
1.05
4.18
3.14
3.11
1.00
0.84
1.00
3.03
2.10
2.00
1.96
0.90
1.34
1.49
1.52
2.05 acetone
2.40
2.79 HDO
2.82 H2O
3.44
3.46
3.53
3.57
3.71
3.72
3.74
6.17
6.18
6.96
6.96
7.28
7.29
7.30
7.32
7.33
7.37
7.38
7.39
7.53
7.54
7.79
7.81
201
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.32
202
1H NMR (400 MHz, Acetone-d6) of compound 2.33
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
0.97
1.05
1.16
5.13
0.65
1.00
5.07
2.00
1.97
2.05 acetone
2.40
2.83 HDO
2.86 H2O
3.07
3.12
3.33
3.36
3.42
3.45
3.57
3.58
3.60
3.68
6.31
6.32
6.97
6.99
7.29
7.31
7.33
7.35
7.37
7.39
7.41
7.53
7.55
7.79
7.82
203
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 3.33
204
1H NMR (400 MHz, Acetone-d6) of compound 2.34
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.02
3.04
6.09
3.00
0.95
1.02
0.59
0.93
1.02
1.99
1.95
1.95
1.89
0.45
0.46
1.15
1.16
1.30
1.31
1.31
1.32
2.05 acetone
2.41
2.78 HDO
2.81 H2O
3.50
3.51
3.52
3.53
3.54
4.44
4.45
4.45
4.46
4.46
4.47
4.48
6.21
6.22
6.92
6.92
7.28
7.29
7.31
7.34
7.36
7.38
7.39
7.41
7.55
7.56
7.80
7.82
205
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.34
206
1H NMR (400 MHz, Acetone-d6) of compound 2.28
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.01
2.16
1.99
2.95
2.08
0.66
0.94
1.98
3.12
1.92
1.88
0.77
0.83
0.84
0.86
1.26
1.27
1.29
1.30
1.31
1.32
1.51
1.53
1.53
1.54
1.54
1.55
1.55
1.56
1.57
2.04 acetone
2.34
2.81 HDO
2.85 H2O
3.35
3.36
3.37
3.38
5.60
5.61
6.47
6.48
7.19
7.20
7.27
7.28
7.49
7.50
7.55
7.57
8.08
8.08
207
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.28
208
1H NMR (600 MHz, Acetone-d6) of compound 2.29
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.10
1.06
1.04
1.01
2.05
8.16
2.04
1.94
2.05 acetone
2.35
2.79 HDO
2.82 H2O
4.51
4.53
4.59
4.62
6.54
7.17
7.18
7.24
7.25
7.25
7.26
7.28
7.28
7.29
7.49
7.50
7.51
7.52
7.52
7.53
209
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.28
210
1H NMR (600 MHz, Acetone-d6) of compound 2.30
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
8.98
3.00
0.83
0.99
2.00
3.00
0.84
2.00
1.92
1.39
2.05 acetone
2.35
2.81 HDO
2.84 H2O
5.71
5.72
6.41
6.41
7.20
7.21
7.29
7.29
7.30
7.30
7.33
7.46
7.46
7.47
7.47
7.48
7.53
7.54
211
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.30
212
1H NMR (600 MHz, DMSO-d6) of compound 2.27
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
1.03
0.86
2.02
3.01
2.09
2.00
0.95
0.74
2.50 dmso
3.30 H2O
5.03
6.46
7.24
7.25
7.28
7.29
7.29
7.29
7.30
7.33
7.34
7.34
7.35
7.53
7.54
8.03
8.48
213
13C{
1H} NMR (151 MHz, DMSO-d6) of compound 2.27
214
1H NMR (600 MHz, Acetone-d6) of compound 2.31 (diastereomer 1)
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.11
3.00
1.02
0.77
0.99
1.98
4.14
2.03
4.05
1.96
0.84
1.57
1.58
2.05 acetone
2.33
2.80 HDO
2.84 H2O
5.14
5.14
5.15
5.16
5.17
5.18
5.68
6.47
7.12
7.13
7.16
7.18
7.19
7.20
7.22
7.23
7.24
7.25
7.27
7.28
7.30
7.34
7.34
7.35
7.35
7.40
7.41
8.15
7.45 7.40 7.35 7.30 7.25 7.20 7.15 7.10
Chemicalshift(pm)
7.12
7.13
7.18
7.19
7.22
7.24
7.27
7.28
7.30
7.34
7.34
7.35
7.35
7.40
7.41
215
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.31 (diastereomer 1)
216
1H NMR (600 MHz, Acetone-d6) of compound 2.31 (diastereomer 2)
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.12
3.00
1.03
0.81
1.03
2.03
3.07
5.01
1.93
1.97
0.81
1.57
1.58
2.05 acetone
2.35
2.81 HDO
2.84 H2O
5.16
5.17
5.18
5.71
6.47
7.13
7.15
7.25
7.26
7.27
7.28
7.28
7.30
7.31
7.32
7.32
7.33
7.34
7.34
7.35
7.41
7.42
7.43
7.58
7.59
8.19
217
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.31 (diastereomer 2)
218
1H NMR (600 MHz, Acetone-d6) of compound 2.46
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
0.42
0.95
0.92
1.94
5.01
3.82
2.01
0.45
2.05 acetone
2.37
2.79 HDO
2.82 H2O
5.98
6.68
7.15
7.17
7.18
7.25
7.26
7.32
7.33
7.34
7.35
7.36
7.62
7.63
7.64
7.71
7.72
9.49
219
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.46
220
1H NMR (500 MHz, Acetone-d6) of compound 2.47
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
0.66
0.99
4.84
1.90
1.70
1.93
1.95
0.62
2.05 acetone
2.39
2.79 HDO
2.82 H2O
6.09
6.09
6.71
6.72
7.31
7.33
7.35
7.37
7.63
7.63
7.64
7.65
7.69
7.70
8.04
8.06
8.20
8.22
9.89
221
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.47
222
1H NMR (600 MHz, Acetone-d6) of compound 2.45
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
3.12
0.38
0.98
2.11
1.99
3.01
5.93
0.37
2.05 acetone
2.36
2.77 HDO
2.81 H2O
3.78
5.92
6.65
6.88
6.89
7.23
7.24
7.31
7.33
7.34
7.35
7.59
7.61
7.62
9.44
223
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.45
224
1H NMR (600 MHz, DMSO-d6) of compound 2.48
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.88
6.09
4.15
2.01
2.01
4.28
6.27
4.15
3.99
2.00
1.36
1.37
1.38
1.39
1.40
1.41
2.30
2.50 dmso
3.12
3.13
3.14
3.15
3.32 H2O
6.23
6.24
6.56
6.56
7.19
7.20
7.26
7.27
7.28
7.29
7.31
7.41
7.42
7.48
7.50
8.81
8.82
8.83
225
13C{
1H} NMR (151 MHz, DMSO-d6) of compound 2.48
226
1H NMR (600 MHz, Acetone-d6) of compound 2.27
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
1.94
1.97
1.00
1.75
1.94
1.09
2.05 acetone
2.43
2.77 HDO
2.80 H2O
7.39
7.41
7.51
7.53
7.54
7.68
7.69
7.71
7.83
7.95
7.96
8.33
227
1H NMR (600 MHz, CDCl3) of compound 2.27
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
0.82
1.96
1.95
0.93
1.82
0.43
2.10
1.56 H2O
2.43
6.99
7.26 cdcl3
7.30
7.32
7.41
7.42
7.43
7.59
7.60
7.61
7.85
7.86
8.12
8.14
8.15
8.25 8.20 8.15 8.10 8.05
Chemicalshift(pm)
0.43
2.10
8.12
8.14
8.15
228
13C{
1H} NMR (151 MHz, CDCl3) of compound 2.27
229
1H NMR (600 MHz, DMSO-d6) of compound 2.35
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.19
2.27
2.06
3.13
2.11
3.17
1.02
1.00
2.08
2.09
2.10
2.05
1.00
0.79
0.80
0.81
1.18
1.19
1.21
1.22
1.41
1.42
1.44
2.32
2.50 dmso
3.19
3.20
3.21
3.22
3.32 H2O
3.73
6.16
6.16
6.42
6.42
6.82
6.84
7.20
7.21
7.29
7.31
7.47
7.48
8.82
8.83
8.84
230
13C{
1H} NMR (151 MHz, DMSO-d6) of compound 2.35
231
1H NMR (600 MHz, Acetone-d6) of compound 2.36
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Chemicalshift(pm)
2.98
11.23
1.93
2.90
1.98
0.33
0.96
1.90
1.99
1.97
1.84
0.83
0.86
0.87
0.88
1.29
1.30
1.31
1.33
1.34
1.54
1.54
1.55
1.56
1.57
1.57
1.58
1.58
1.59
2.05 acetone
2.34
2.77 HDO
2.81 H2O
3.37
3.38
3.39
3.41
5.49
5.50
6.46
6.46
7.17
7.18
7.31
7.32
7.38
7.40
7.51
7.52
8.10
232
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.36
233
1H NMR (600 MHz, Acetone-d6) of compound 2.38
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.31
2.34
2.07
3.07
2.12
0.54
1.00
1.94
1.96
4.03
0.55
0.84
0.85
0.86
1.26
1.28
1.29
1.30
1.31
1.33
1.54
1.54
1.55
1.55
1.56
1.57
2.05 acetone
2.37
2.81 HDO
2.85 H2O
3.34
3.35
3.36
3.37
3.39
3.40
3.41
3.42
6.02
6.54
7.23
7.24
7.58
7.60
7.71
8.25
234
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.38
235
1H NMR (600 MHz, Acetone-d6) of compound 2.39
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.13
2.12
2.09
3.08
2.11
0.66
0.99
1.98
2.00
2.05
2.01
0.77
0.85
0.86
0.87
1.28
1.29
1.31
1.32
1.33
1.34
1.54
1.55
1.55
1.56
1.57
1.57
1.58
1.58
1.59
1.60
2.05 acetone
2.35
2.82 HDO
2.86 H2O
3.37
3.38
3.39
3.40
3.40
3.41
3.41
3.42
3.42
3.43
5.91
5.92
6.55
7.19
7.20
7.56
7.57
7.62
7.63
7.69
7.71
8.23
236
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.39
237
19F NMR (564 MHz, Acetone-d6) of compound 2.39
238
1H NMR (600 MHz, DMSO-d6) of compound 2.37
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.02
2.12
2.01
2.99
2.05
1.01
0.99
2.02
2.03
4.02
0.95
0.79
0.80
0.81
1.16
1.17
1.19
1.20
1.21
1.22
1.40
1.40
1.41
1.41
1.42
1.42
1.43
1.44
1.44
1.45
2.34
2.50 dmso
3.19
3.20
3.21
3.22
3.23
3.31 H2O
6.18
6.19
6.66
6.67
7.22
7.23
7.32
7.33
7.48
7.48
7.49
7.50
8.89
8.90
8.91
239
13C{
1H} NMR (151 MHz, DMSO-d6) of compound 2.37
240
1H NMR (600 MHz, DMSO-d6) of compound 2.40
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.05
2.05
2.00
2.00
3.05
1.04
0.99
1.99
3.05
2.02
2.00
0.96
0.78
0.79
0.80
1.16
1.17
1.18
1.19
1.20
1.22
1.39
1.40
1.41
1.41
1.42
1.43
1.43
1.44
2.50 dmso
3.18
3.19
3.20
3.21
3.34 H2O
3.78
6.24
6.24
6.55
6.56
6.93
6.94
7.27
7.28
7.29
7.30
7.32
7.41
7.42
7.53
7.55
8.84
241
13C{
1H} NMR (151 MHz, DMSO-d6) of compound 2.40
242
1H NMR (600 MHz, Acetone-d6) of compound 2.41
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5
Chemicalshift(pm)
3.04
2.07
1.99
2.06
0.91
1.01
2.99
1.99
3.99
0.82
0.85
0.86
0.88
1.28
1.30
1.31
1.32
1.33
1.35
1.54
1.55
1.55
1.56
1.57
1.57
1.58
1.58
1.59
1.60
2.05 acetone
2.82 HDO
2.85 H2O
3.40
3.41
3.42
3.43
5.66
5.67
6.43
6.44
7.28
7.28
7.29
7.29
7.45
7.45
7.46
7.46
7.56
8.30
243
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.41
244
1H NMR (600 MHz, Acetone-d6) of compound 2.42
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
2.07
1.95
2.00
0.55
0.95
2.94
0.98
3.98
3.90
2.04
0.64
0.85
0.86
0.87
1.29
1.30
1.32
1.33
1.34
1.35
1.55
1.56
1.57
1.57
1.58
1.58
1.59
1.59
1.60
1.61
2.05 acetone
2.86 H2O
3.41
3.42
3.43
3.44
3.44
5.68
6.51
7.28
7.28
7.29
7.40
7.41
7.43
7.48
7.49
7.51
7.65
7.67
7.68
7.69
7.69
7.73
7.74
8.23
245
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.42
246
1H NMR (600 MHz, Acetone-d6) of compound 2.44
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.11
2.17
2.11
2.13
0.87
1.03
3.15
2.01
2.05
0.99
3.12
1.00
0.71
0.81
0.82
0.84
1.28
1.29
1.31
1.32
1.54
1.55
1.56
1.56
1.57
2.05 acetone
2.84 H2O
3.41
3.42
5.64
5.65
6.53
6.54
7.21
7.22
7.24
7.25
7.27
7.50
7.51
7.51
7.52
7.52
7.59
7.60
7.61
7.61
7.62
7.62
7.75
7.75
7.76
7.77
7.92
7.94
7.95
7.96
8.15
247
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.44
248
1H NMR (600 MHz, Acetone-d6) of compound 2.47
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.16
2.13
2.08
2.08
0.90
1.02
2.99
2.06
1.96
1.99
0.84
0.86
0.87
0.89
1.32
1.33
1.34
1.34
1.36
1.37
1.57
1.58
1.59
1.59
1.60
1.60
1.61
1.62
1.62
1.63
2.05 acetone
2.87 H2O
3.45
3.46
3.46
3.47
3.48
3.49
5.71
6.42
7.25
7.26
7.26
7.27
7.41
7.42
7.43
7.83
7.85
8.19
8.21
8.52
249
13C{
1H} NMR (126 MHz, Acetone-d6) of compound 2.47
250
1H NMR (600 MHz, Acetone-d6) of compound 2.25
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
1.19
3.00
5.78
3.04
3.18
3.18
4.17
1.22
2.94
1.05
1.09
1.11
1.08
1.08
2.88
1.98
1.99
2.07
0.88
1.16
1.17
1.24
1.26
1.32
1.35
1.37
1.39
1.39
1.40
1.41
1.41
1.43
1.47
1.48
1.49
1.52
1.52
1.54
1.55
1.56
1.57
2.05 acetone
2.42
2.77 HDO
2.80 H2O
2.87
2.88
3.21
7.32
7.33
7.36
7.37
7.43
7.44
7.45
7.73
7.73
7.73
7.74
7.75
7.75
7.88
7.90
251
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.25
252
1H NMR (600 MHz, Acetone-d6) of compound 2.51
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
1.00
1.10
4.18
3.06
2.06
2.06
1.86
0.90
1.94
2.72
1.72
1.05
1.46
1.56
2.05 acetone
2.41
2.80 HDO
2.84 H2O
3.25
3.37
3.69
3.82
7.34
7.36
7.37
7.39
7.40
7.43
7.45
7.46
7.49
7.50
7.51
7.79
7.81
253
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.51
254
1H NMR (600 MHz, Acetone-d6) of compound 2.50
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.00
2.23
2.03
3.01
2.05
1.02
1.90
3.03
3.87
0.68
0.86
0.87
0.88
1.31
1.33
1.34
1.35
1.57
1.58
1.58
1.59
1.60
1.60
1.61
1.61
1.62
1.63
2.05 acetone
2.36
2.78 HDO
2.81 H2O
3.43
3.44
3.45
7.10
7.18
7.21
7.22
7.39
7.40
7.41
7.42
7.43
7.43
7.44
7.45
7.52
7.53
7.53
7.54
7.54
7.55
8.30
255
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 2.50
256
19F NMR (564 MHz, Acetone-d6) of compound 2.50
257
1H NMR (500 MHz, CDCl3) of compound 2.52
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Chemicalshift(pm)
3.02
1.97
1.98
2.08
1.88
1.94
1.96
2.95
1.92
1.59 H2O
2.40
3.22
3.54
3.74
3.75
3.76
3.86
7.23
7.25
7.26 cdcl3
7.54
7.55
7.57
7.66
7.67
7.69
7.70
7.71
7.94
7.95
258
13C{
1H} NMR (126 MHz, CDCl3) of compound 2.52
259
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5
Chemicalshift(pm)
3.09
2.07
2.08
1.07
6.07
1.02
1.01
1.00
2.30
2.50 dmso
3.32 H2O
7.17
7.18
7.49
7.51
7.58
7.59
7.60
7.63
7.64
7.65
7.67
8.01
8.02
8.26
8.27
9.28
260
261
262
5.2 Copper Project (Chapter 3)
5.2.1 Optimization
A 4 mL glass vial was charged with stir bar and starting material 3.1 (10 mg, 42 μmol).
This was followed by addition of additives if applicable. Solvent and catalyst (solid or stock
in MeOH) was added last. The vial was closed with a screw cap fitted with a PTFE septum
and air balloon was installed on the top through a syringe attached to a needle (22G).
The reaction was allowed to stir and 5 μL aliquot was taken out at 2h and 24 h. The aliquot
was dissolved in 500 μL DCM and analyzed by GC-MS. Conversion and ratio between
the products was calculated by integrating FID chromatogram.
5.2.1.1 Effect of different metal chlorides
24h
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 FeCl2(H2O)4 MeOH 0 n.d. n.d.
2 NiCl2(H2O)6 MeOH 0 n.d. n.d.
3 MnCl2 MeOH 0 n.d. n.d.
4 CoCl2(H2O)6 MeOH 0 n.d. n.d.
5 CuCl2 MeOH 98.1 55.6 42.5
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL) MeOH; time: 24 h. Yield was
calculated by GC-MS analysis (FID integration). Catalyst loading: 10 mol%
Outcome: Copper was the only reactive metal that could undergo the catalytic process
5.2.1.2 Effect of different copper catalysts
2h
263
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 CuCl2 MeOH 52.8 0.0 52.8
2 CuBr2 MeOH 50.0 0.8 50.8
3 Cu(OAc)2 MeOH 44.0 4.3 39.7
4 Cu(BF4)2 MeOH 0.6 0.0 0.6
5 Cu(2-ethylhexanoate)2 MeOH 38.6 3.6 35.0
6 Cu(triflate)2 MeOH 0.5 0.0 0.5
7 Cu(formate)2 MeOH 26.0 2.0 24.0
8 Cu(NO3)2 MeOH 0.9 0.0 0.9
9 Cu(OH)2 MeOH 5.0 0.4 4.6
10 Cu(acac)2 MeOH 1.4 0.0 1.4
11 Cu(hexafluoroacac)2 MeOH 0.4 0.0 0.4
12 Cu(OAc)2 EtOH 26.9 13.7 13.2
13 CuF2 MeOH 45.4 6.1 39.3
14 CuO MeOH 31.9 22.9 9
15 Cu2O MeOH 70 50.5 19.5
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL); time: 2 h. Yield was calculated
by GC-MS analysis (FID integration). Catalyst loading: 10 mol%
24h
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 CuCl2 MeOH 98.1 55.6 42.5
2 CuBr2 MeOH 100 49.6 50.4
3 Cu(OAc)2 MeOH 100 69.4 30.6
4 Cu(BF4)2 MeOH 0.0 0.0 0.0
5 Cu(2-ethylhexanoate)2 MeOH 95.4 61.2 34.2
6 Cu(triflate)2 MeOH 6.3 0.0 6.3
7 Cu(formate)2 MeOH 94.3 61.5 32.8
8 Cu(NO3)2 MeOH 10.8 4.7 6.1
9 Cu(OH)2 MeOH 94.9 57.9 37.0
10 Cu(acac)2 MeOH 5.3 0.0 5.3
264
11 Cu(hexafluoroacac)2 MeOH 5.5 0.0 5.5
12 Cu(OAc)2 EtOH 86.6 67.3 19.3
13 CuF2 MeOH 100 69.9 30.1
14 CuO MeOH 85.2 73 12.1
15 Cu2O MeOH 83.6 69 14.6
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL); time: 24 h. Yield was calculated
by GC-MS analysis (FID integration). Catalyst loading: 10 mol%
Outcome: CuCl2 and Cu(OAc)2 gave the best selectivity and conversion
5.2.1.3 Effect of different solvents
2h
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 CuCl2 MeOH 52.8 0.0 52.8
2 CuCl2 EtOH 51.7 4.8 46.9
3 Cu(OAc)2 EtOH 26.9 13.7 13.2
4 CuCl2 2-Methoxyethanol 19.6 1.0 18.6
5 CuCl2 2,2,2-Trifluoroethanol 1.9 0.0 1.9
6 CuCl2 tert-Butanol 24.9 2.1 22.9
7 CuCl2 1-Propanol 12.7 0.0 12.7
8 CuCl2 1-Octanol 63.3 5.4 57.9
9 CuCl2 2-Methyl-2-propanol 34.2 2.2 32.0
10 CuCl2 THF 79.3 3.1 76.3
11 CuCl2 CH3CN 36.3 0.0 36.3
12 CuCl2 CHCl3 0.0 0.0 0.0
13 CuCl2 2-Methyl-THF 77.0 2.5 74.5
14 CuCl2 DMSO 66.0 12.2 53.9
15 CuCl2 DMF 100 5.4 94.6
16 CuCl2 Acetone 93.5 1.3 92.2
17 CuBr2 CH3CN 41.7 0.7 41.0
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL); time: 2 h. Yield was calculated
by GC-MS analysis (FID integration). Catalyst loading: 10 mol%.
265
24h
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 CuCl2 MeOH 98.1 55.6 42.5
2 CuCl2 EtOH 98.9 79.1 19.8
3 Cu(OAc)2 EtOH 86.6 67.3 19.3
4 CuCl2 2-Methoxyethanol 98.0 10.6 87.4
5 CuCl2 2,2,2-Trifluoroethanol 1.8 0.0 1.8
6 CuCl2 tert-Butanol 87.0 52.0 34.9
7 CuCl2 1-Propanol 93.8 46.9 46.9
8 CuCl2 1-Octanol 72.1 20.8 51.3
9 CuCl2 2-Methyl-2-propanol 91.1 35.9 55.2
10 CuCl2 THF 88.2 16.4 71.9
11 CuCl2 CH3CN 100 9.5 90.5
12 CuCl2 CHCl3 2.1 0.0 2.1
13 CuCl2 2-Methyl-THF 92.9 34.5 58.4
14 CuCl2 DMSO 100 18.1 81.9
15 CuCl2 DMF 100 80.0 20.0
16 CuCl2 Acetone 96.5 4.3 92.2
17 CuBr2 CH3CN 100 0.0 100.0
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL); time: 24 h. Yield was calculated
by GC-MS analysis (FID integration). Catalyst loading: 10 mol%.
Outcome: Polar protic solvents favor oxo products while polar aprotic solvents favor hydroxy
5.2.1.4 Effect of different ligands
24h
Entry a Catalyst Ligand Conversion % Oxo % Hydroxy
1 CuCl2 Bipyridine 9.0 0 9.0
2 CuCl2 Triphenylphosphine 97.1 1.6 95.4
3 CuCl2 Neocuproine 55.7 4.1 51.5
4 CuCl2 TMEDA 54.4 37.8 16.6
266
5 CuCl2 EDA 0.0 0.0 0.0
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL) MeOH; time: 24 h. Yield was
calculated by GC-MS analysis (FID integration). Catalyst loading: 10 mol%; ligand loading: 20 mol%.
Outcome: Ligands primarily hinder reaction progress
5.2.1.5 Effect of different additives
2h
Entry a Catalyst Additive Conversion % Oxo % Hydroxy
1 CuCl2 none 52.8 0.0 52.8
2 CuCl2 1.0 equiv. LiCl 94.7 1.8 93.0
3 CuCl2 Cu metal 100 40.4 59.6
4 CuCl2 1.0 equiv. 18-crown-6 96.7 2.1 94.5
5 CuCl2 1.0 equiv. TBAC 36.7 0.7 36.0
7 CuCl2 0.2 equiv. HCl b 0.0 - -
8 CuCl2 0.2 equiv. NH4OAc b 25.8 7.1 18.7
9 CuCl2 0.2 equiv. NH4Cl b 18.6 0.0 18.6
10 CuCl2 12 equiv. NH4OH b 10.6 3.3 7.3
11 CuCl2 0.2 equiv. NaOH 88.6 42.3 46.3
12 CuCl2 0.2 equiv Li2CO3 86.4 5.7 80.7
13 CuCl2 0.5 equiv. Pyridine 100 60.5 39.5
14 CuCl2 1.1 equiv. NEt3 83.8 34 49.8
15 CuCl2 5μL H2O2 30 wt% 86.3 14.6 71.6
16 none 5μL H2O2 30 wt% - - -
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL) MeOH; time: 2 h. Yield was
calculated by GC-MS analysis (FID integration). Catalyst loading: 10 mol%. Additive: 1.0 equiv. b Solvent:
36 mM (1mL) 5% H2O in MeOH.
24h
Entry a Catalyst Additive Conversion % Oxo % Hydroxy
1 CuCl2 none 98.1 55.6 42.5
2 CuCl2 1.0 equiv. LiCl 97.4 8.6 88.8
3 CuCl2 Cu metal complex
mixture - -
4 CuCl2 1.0 equiv. 18-crown-6 100 49.6 50.4
267
5 CuCl2 1.0 equiv. TBAC 92.5 5.0 87.5
7 CuCl2 0.2 equiv. HCl b 86.4 5.7 80.7
8 CuCl2 0.2 equiv. NH4OAc b 45.5 27.6 17.9
9 CuCl2 0.2 equiv. NH4Cl b 58.5 9.2 49.3
10 CuCl2 12 equiv. NH4OH b 44.7 3.9 40.8
11 CuCl2 0.2 equiv. NaOH 100 87.8 12.2
12 CuCl2 0.2 equiv Li2CO3 100 88.7 11.3
13 CuCl2 0.5 equiv. Pyridine 100 79.5 20.5
14 CuCl2 1.1 equiv. NEt3 100 77.3 22.3
15 CuCl2 5μL H2O2 30 wt% 96.7 73.7 22.9
16 none 5μL H2O2 30 wt% 24 6.9 17.1
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL) MeOH; time: 24 h. Yield was
calculated by GC-MS analysis (FID integration). Catalyst loading: 10 mol%. Additive: 1.0 equiv. b Solvent:
36 mM (1mL) 5% H2O in MeOH.
Outcome: Adding inorganic bases can quicken the reaction to oxo product
5.2.1.6 Effect of water in the reaction
2h
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 CuCl2 MeOH 52.8 0.0 52.8
2 CuCl2 5% H2O in MeOH 80.5 33.6 46.9
3 CuCl2 10% H2O in MeOH 62.6 37.4 25.3
4 CuCl2 15% H2O in MeOH 46.1 31.3 14.8
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL); time: 2 h. Yield was calculated
by GC-MS analysis (FID integration). Catalyst loading: 10 mol%.
24h
Entry a Catalyst Solvent Conversion % Oxo % Hydroxy
1 CuCl2 MeOH 98.1 55.6 42.5
2 CuCl2 5% H2O in MeOH 98.0 76.1 21.9
3 CuCl2 10% H2O in MeOH 98.2 76.3 21.9
4 CuCl2 15% H2O in MeOH 98.2 76.3 21.9
268
a Reaction scale: 0.036 mmol; temperature: 22 °C; solvent: 36 mM (1mL); time: 24 h. Yield was calculated
by GC-MS analysis (FID integration). Catalyst loading: 10 mol%.
Outcome: Adding water to the system sped up the reaction and increased selectivity
5.2.1.7 Effect of different carbonate bases
2h
Entry a Base Solvent Conversion % Oxo % Hydroxy
1 none MeOH, 5 % H2O 80.5 33.6 46.9
2 2.0 equiv. Li2CO3 MeOH, 5 % H2O 100 87.5 12.5
3 1.0 equiv. Li2CO3 MeOH, 5 % H2O 100 13.5 13.7
4 1.0 equiv. Na2CO3 MeOH, 5 % H2O 100 90.2 9.8
5 1.0 equiv. K2CO3 MeOH, 5 % H2O 100 89.2 10.8
6 1.0 equiv. Cs2CO3 MeOH, 5 % H2O
complex
mixture - -
7 1.0 equiv. KHCO3 MeOH, 5 % H2O 100 89.4 10.6
8 1.0 equiv. Li2CO3 MeOH, 5 % H2O, 40 °C 100 86.5 13.5
9 1.0 equiv. Li2CO3 MeOH 100 81.4 18.6
10 0.2 equiv. Li2CO3 MeOH, 5 % H2O 100 76.0 24.0
a Reaction scale: 0.036 mmol; catalyst: CuCl2; temperature: 22 °C; solvent: 36 mM (1mL); time: 2 h. Yield
was calculated by GC-MS analysis (FID integration). Catalyst loading: 10 mol%.
24h
Entry a Base Solvent Conversion % Oxo % Hydroxy
1 none MeOH, 5 % H2O 98.0 76.1 21.9
2 2.0 equiv. Li2CO3 MeOH, 5 % H2O 100 90.1 9.9
3 1.0 equiv. Li2CO3 MeOH, 5 % H2O 100 88.7 11.3
4 1.0 equiv. Na2CO3 MeOH, 5 % H2O 100 89.1 3.0
5 1.0 equiv. K2CO3 MeOH, 5 % H2O 100 87.6 1.9
6 1.0 equiv. Cs2CO3 MeOH, 5 % H2O
complex
mixture - -
7 1.0 equiv. KHCO3 MeOH, 5 % H2O 100 88.8 0.4
8 1.0 equiv. Li2CO3 MeOH, 5 % H2O, 40 °C 100 88.7 11.3
9 1.0 equiv. Li2CO3 MeOH 100 86.4 13.6
269
10 0.2 equiv. Li2CO3 MeOH, 5 % H2O 100 88.5 11.5
a Reaction scale: 0.036 mmol; catalyst: CuCl2; temperature: 22 °C; solvent: 36 mM (1mL);
time: 24 h. Yield was calculated by GC-MS analysis (FID integration). Catalyst loading:
10 mol%.
Outcome: Adding carbonate bases increased the reaction rate and improved selectivity
5.2.2 Synthesis of Starting Materials for Controlled Experiments
5.2.2.1 Methylation of Sultam 3.1
A 4 mL glass reaction vial was charged with a stir bar and starting sultam (100 mg, 0.369
mmol). DCM (1.47 mL) was then added to the vial followed by the addition of TEA (102.8
μL, 0.737 mmol) using a micropipette. The resulting reaction mixture was placed into an
ice bath before MeOTf (48.4 μL, 0.442 mmol) was added slowly via micropipette. The
reaction was stirred for 1 h at 0 °C before warming to room temperature. The reaction
progress was monitored by GC-MS. The reaction mixture was concentrated down before
being purified using flash chromatography with silica gel and ethyl acetate/DCM solvent
system. The product was isolated as a white solid (46 mg, 44%) and 30 mg of starting
material was recovered.
2-methyl-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.7
270
Appearance: White Solid
Polarity of solvent: Gradient column with 0% to 2% ethyl acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 7.78 – 7.73 (m, 3H), 7.54 (t, J = 7.3 Hz, 2H), 7.50 (d,
J = 7.2 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 2.95 (s, 3H), 2.47 (s,
3H).
13C{1H} NMR: 13C NMR (101 MHz, Acetone-d6) δ 145.67, 143.77, 135.73, 133.96,
130.63, 130.31, 130.12, 129.89, 129.09, 128.30, 123.02, 113.40, 36.18, 21.55.
HRMS (ES-TOF) calcd for C16H15NO2S•+ [M]•+ 285.0818, found 285.0823 (Δ = 1.75
ppm).
5.2.2.2 Synthesis of Carbonyl Derivative of Sultam 3.1
This product was synthesized using a reported protocol10. A glass 20 mL reaction vial was
charged with Cu(OAc)2 (9.1 mg, 0.1 mmol), t-BuOK (168 mg, 1.5 mmol), 2-
bromobenzonitrile (90.5 mg, 0.5 mmol), and acetophenone (117 μL, 1.0 mmol). Toluene
(4 mL) was then added along with a stir bar, the reaction was heated to 100 °C and stirred
for 10 h. The reaction mixture was concentrated down before being purified using flash
chromatography with silica gel and ethyl acetate/hexanes solvent system. The product
was isolated as a white solid (84.5 mg, 38.2%) and characterized. The obtained NMR
data is in accordance with the reported values.
6-methyl-3-phenylisoquinolin-1(2H)-one
271
Appearance: White solid
Polarity of solvent: Column with 30% ethyl acetate in hexanes.
5.2.2.3 Synthesis of Tosylated Anilines
This product was synthesized using a reported protocol11. A 20 mL glass reaction vial was
charged with a stir bar, tosyl chloride (1.91 g, 10 mmol,) and pyridine (808.8 μL, 10 mmol).
A solution of aniline (456.5 μL, 5 mmol) and DCM (6 mL) was then added to the reaction
vial slowly at room temperature. The reaction mixture was stirred for 2 h before being
purified via flash chromatography with silica gel and ethyl acetate/hexane as solvent. The
obtained NMR data is in accordance with the reported values.
4-methyl-N-phenylbenzenesulfonamide
Appearance: White solid
Polarity of solvent: Column with 15% ethyl acetate in hexanes.
272
5.2.3 Condition Controlled Experiments
5.2.3.1 Oxygen Free conditions
In a nitrogen filled glove box, a 4 mL glass reaction vial was charged with a stir bar and
starting sultam 3.1 (20 mg, 74 μmol). Dry methanol (2 mL) was added after which CuCl2
(14.8 μL, 0.5 M in water, 7.4 μmol) was added via micropipette. Following this, the vial
was sealed with a screw cap fitted with a PTFE septum. The reaction was left stirring for
24 h in the glove box before being removed and an aliquot was taken for GC-MS. The
reaction was purged with air and allowed to stir for 18 h before an aliquot was taken for
GC-MS again.
Results: No reaction occurred after 24 hours in the glove box but did go to completion
after 18 h stirring in air. This implies that O2 is the source of oxygen.
5.2.3.2 Na2O2 Conditions
A 4 mL glass reaction vial was charged with a stir bar, Na2O2 (15.8 mg, 203 μmol), and
starting sultam 3.1 (50 mg, 184 μmol). Methanol (4.75 mL) was then added followed by
water (0.25 mL) using a micropipette. Following this, the vial was sealed with a screw cap
fitted with a PTFE septum. A balloon fitted to a syringe with a needle was filled with
273
nitrogen was then inserted into the septum and the reaction was left to stir. The reaction
was monitored using GC-MS over time.
Results: Sultams are reactive with superoxides which might be relevant for a copper
catalyzed aerobic oxidation.
5.2.3.3 Hydrogen Peroxide Conditions
A 4 mL glass reaction vial was charged with a stir bar, H2O2 (5 μmol), and starting sultam
3.1 (50 mg, 184 μmol). Methanol (4.75 mL) was then added followed by water (0.20 mL)
using a micropipette. Following this, the vial was sealed with a screw cap fitted with a
PTFE septum. A balloon fitted to a syringe with a needle was filled with nitrogen was then
inserted into the septum and the reaction was left to stir. The reaction was monitored
using GC-MS over time.
Results: Sultams have limited reactivity with hydrogen peroxide which might be relevant
for a copper catalyzed aerobic oxidation.
5.2.3.4 Water Free Conditions
In a nitrogen filled glove box, a 4 mL glass reaction vial was charged with a stir bar, starting
sultam 3.1 (20 mg, 74 μmol) and dry CuCl2* (0.993 mg, 7.4 μmol). Dry methanol (2 mL)
274
was added after which the vial was sealed with a screw cap fitted with a PTFE septum.
The vial was removed from the glove box and purged with dry O2 via balloon for 5 minutes
after which the reaction was allowed to stir under dry O2 for 24 h. The reaction was
monitored using GC-MS over time.
Results: After 24 h full conversion of starting sultam was observed. Both oxo- 3.2 and
hydroxy- 3.3 products were formed with hydroxy being the major. This implies that
hydroxy-product 3.3 forms first and water has a role in how quickly hydroxy-product is
converted to oxo-product 3.2.
5.2.3.5 Copper Free Conditions
A 4 mL glass reaction vial was charged with a stir bar, Li2CO3 (0.5 mg, 7.4 μmol), and
starting sultam (10 mg, 42 μmol). Methanol (995 μL) was then added followed by water
(5 μL). Following this, the vial was sealed with a screw cap fitted with a PTFE septum. A
balloon fitted to a syringe with a needle was filled with air was then inserted into the
septum and the reaction was left to stir. The reaction was monitored using GC-MS over
time.
Result: The absence of copper catalyst leads to no reactivity showing that copper is a key
part of the reactivity of the starting material and is not induced with the base or water
added.
275
5.2.3.6 Cu(I) Conditions
In a nitrogen filled glove box, a 20 mL glass reaction vial was charged with a stir bar,
starting sultam (50 mg, 184 μmol) and CuCl (1.82 mg, 18.4 μmol). The vial was then
purged with nitrogen and placed into a glove box with nitrogen atmosphere. Dry
acetonitrile (5 mL) was added after which the vial was sealed with a screw cap fitted with
a PTFE septum. The vial was removed from the glove box and purged with dry O2 via
balloon for 5 minutes after which the reaction was ran under dry O2 balloon for 24 h. The
reaction was monitored using GC-MS.
Results: The reaction proceeded like usual indicating that the Cu(I) can also catalyze the
reaction as Cu(II).
5.2.3.7 Copper Oxide Conditions
A 4 mL glass reaction vial was charged with a stir bar, Li2CO3 (0.5 mg, 7.4 μmol), copper
oxide (4.2 μmol), and starting sultam 3.1 (10 mg, 42 μmol). Methanol (995 μL) was then
added followed by water (5 μL). Following this, the vial was sealed with a screw cap fitted
with a PTFE septum. A balloon fitted to a syringe with a needle was filled with air was
276
then inserted into the septum and the reaction was left to stir. The reaction was monitored
using GC-MS over time.
Results: Copper oxide is an active catalyst in this reaction which shows that copper oxides
can be used and formed in the catalytic cycle.
5.2.3.8 Radical Trap Conditions
A 4 mL glass reaction vial was charged with a stir bar, radical trap (44.3 μmol), Li2CO3
(0.5 mg, 7.4 μmol), and starting sultam 3.1 (10 mg, 42 μmol). Methanol (1 mL) and CuCl2
(7.38 μL of 0.5 M CuCl2 solution in MeOH, 3.7 μmol) using a micropipette. Following this,
the vial was sealed with a screw cap fitted with a PTFE septum. A balloon fitted to a
syringe with a needle was filled with air was then inserted into the septum and the reaction
was left to stir. The reaction was monitored using GC-MS over time.
Result: Radical traps did not inhibit the reaction but did slow it considerably indicating
that radicals could be at play but cannot be proven.
277
5.2.4 Structural Controlled Experiments
5.2.4.1 Carbonyl Instead of Sulfonyl Group
A 4 mL glass reaction vial was charged with a stir bar, CuCl2 (1.21 mg, 9 μmol), Li2CO3
(1.34 mg, 18 μmol), and starting sultam (20 mg, 90 μmol). Methanol (1.9 mL) was then
added followed by water (0.1 mL) using a micropipette. Following this, the vial was sealed
with a screw cap fitted with a PTFE septum. A balloon fitted to a syringe with a needle
was filled with air was then inserted into the septa and the reaction was left to stir. The
reaction was monitored using GC-MS over time.
Results: Sultam starting material 3.1 never formed the product or degraded in theses
reaction conditions implying that the sulfonyl group plays an important role in the reaction
mechanism.
5.2.4.2 Methylated Sultam Reaction
A 4 mL glass reaction vial was charged with a stir bar, CuCl2 (0.6 mg, 4.2 μmol), Li2CO3
(0.6 mg, 8.4 μmol), and starting sultam 3.1 (12 mg, 42 μmol). Methanol (1.9 mL) was then
added followed by water (0.1 mL) using a micropipette. Following this, the vial was sealed
with a screw cap fitted with a PTFE septum. A balloon fitted to a syringe with a needle
278
was filled with air was then inserted into the septum and the reaction was left to stir. The
reaction was monitored using GC-MS over time.
Results: The sultam starting material never formed the product or degraded in theses
reaction conditions implying that the N-H bond plays an important role in the reaction
mechanism.
5.2.4.3 Sulfonylated Aniline Reaction
A 20 mL glass reaction vial was charged with a stir bar, CuCl2 (2.175 mg, 16.2 μmol),
Li2CO3 (2.387 mg, 32.3 μmol), and sulfonyl aniline (40 mg, 162 μmol). Methanol (3.8 mL)
was then added followed by water (0.2 mL) using a micropipette. Following this, the vial
was sealed with a screw cap fitted with a PTFE septum. A balloon fitted to a syringe with
a needle was filled with air was then inserted into the septa and the reaction was left to
stir. The reaction was monitored using GC-MS over time.
Results: The sulfonyl aniline starting material never formed the product or degraded in
theses reaction conditions implying that the vinyl group is important for the reaction
mechanism to occur.
5.2.5 Kinetic Profile for the Oxygenation of the Sultam
5.2.5.1 Reaction done without added water or lithium carbonate
A 20 mL glass reaction vial was charged with a stir bar, CuCl2 (5.38 mg, 40 μmol), and
sultam 3.1 (400 μmol). Methanol (10 mL) using a syringe. Following this, the vial was
279
sealed with a screw cap fitted with a PTFE septum. A balloon fitted to a syringe with a
needle was filled with air was then inserted into the septa and the reaction was left to stir
at 800 rpm. The reaction was monitored using GC-FID every hour by talking 5 μL
aliquotes into 2 mL of DCM in a GC vial.
5.2.5.2 Reaction done without lithium carbonate
A 20 mL glass reaction vial was charged with a stir bar, CuCl2 (5.38 mg, 40 μmol), and
sultam 3.1 (400 μmol). Methanol (9.5 mL) followed by water (5 mL) using a syringe.
Following this, the vial was sealed with a screw cap fitted with a PTFE septum. A balloon
fitted to a syringe with a needle was filled with air was then inserted into the septa and
the reaction was left to stir at 800 rpm. The reaction was monitored using GC-FID every
hour by talking 5 μL aliquotes into 2 mL of DCM in a GC vial.
5.2.5.3 Reaction done with optimized oxo conditions
A 20 mL glass reaction vial was charged with a stir bar, CuCl2 (5.38 mg, 40 μmol), Li2CO3
(4.91 mg, 80 μmol, and sultam 3.1 (400 μmol). Methanol (9.5 mL) followed by water (5
mL) using a syringe. Following this, the vial was sealed with a screw cap fitted with a
PTFE septum. A balloon fitted to a syringe with a needle was filled with air was then
inserted into the septa and the reaction was left to stir at 800 rpm. The reaction was
monitored using GC-FID every hour by talking 5 μL aliquotes into 2 mL of DCM in a GC
vial.
5.2.5.4 Reaction done with optimized hydroxy conditions
A 20 mL glass reaction vial was charged with a stir bar, CuBr2 (1.79 mg, 8 μmol) and
sultam (400 μmol). Acetonitrile (10 mL) was then added followed by water (2 μL) using a
micropipette. Following this, the vial was sealed with a screw cap fitted with a PTFE
280
septum. A balloon fitted to a syringe with a needle was filled with air was then inserted
into the septa and the reaction was left to stir at 800 rpm. The reaction was monitored
using GC-FID every hour by talking 5 μL aliquotes into 2 mL of DCM in a GC vial.
5.2.6 Competition Reaction with added Products with Oxo Conditions
A 20 mL glass reaction vial was charged with a stir bar, CuCl2 (5.38 mg, 40 μmol), Li2CO3
(4.91 mg, 80 μmol, and sultam 3.1 (400 μmol). Then either 0.25 equiv., 0.5 equiv., or 0.75
equiv. of 3.2 or 3.3 was added to the vial. Methanol (9.5 mL) followed by water (5 mL)
using a syringe. Following this, the vial was sealed with a screw cap fitted with a PTFE
septum. A balloon fitted to a syringe with a needle was filled with air was then inserted
into the septa and the reaction was left to stir at 800 rpm. The reaction was monitored
using GC-FID every hour by talking 5 μL aliquotes into 2 mL of DCM in a GC vial.
5.2.7 Synthesis of Sultams
The starting sultams were synthesized using reported protocol.12 A 50 mL Schlenk flask
was equipped with stir bar and sealed with septum, was flame dried and purged with
nitrogen gas. 25 mL dry THF was added to this flask, and it was cooled to –48 °C. Dry
HMPA (2.0 equiv, 1.6 mmol) was added using a syringe followed by the alkyne (1.0 equiv.,
281
0.8 mmol). To a stirred solution at –48 °C, n-BuLi in hexanes (1.0 equiv., 0.8 mmol) was
added slowly, and it was allowed to stir for 15 min to generate the lithium acetylide. Nsulfonyl azide (1.0 equiv., 0.8 mmol) was added to the lithium acetylide solution. Liquid
azides were added using Hamilton Syringe and solid azides were added under flow of
nitrogen by removing the septum. The reaction mixture was stirred for the specified time
(depending on the substrate). The dry ice/acetonitrile bath was removed, and the reaction
mixture was stirred for the specified time (depending on the substrate), while warming up
to the room temperature. Saturated aq. NH4Cl (2 mL) was added to the reaction mixture
using a syringe. The reaction mixture was left overnight at room temperature to achieve
full conversion to the product. It was then passed through a short plug of Celite® to
remove any precipitate, ethyl acetate was used for washing out any remaining product.
The solution was concentrated under reduced pressure and was purified by column
chromatography on silica gel using the determined solvent system to obtain the desired
product. When the eluted fraction was allowed to slowly evaporate at room temperature,
crystalline product was obtained.
6-methyl-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (89 mg, 86%) was prepared using the general procedure from the
corresponding alkyne (42 L, 0.38 mmol) and azide (58 L, 0.38 mmol) with HMPA (132
L, 0.76 mmol). Reaction was stirred for 15 min at –48 °C and then for another 30 min at
282
rt. The color of reaction mixture was dark orange red which turned to pale tangerine color
after addition of aq. NH4Cl. Polarity of solvent: 30% ethyl acetate in hexanes.
1H NMR (400 MHz, acetone-d6) δ 9.47 (br, 1H), 7.83 (d, J = 5.9 Hz, 2H), 7.76 (d, J = 8.0
Hz, 1H), 7.49 (t, J = 8.0 Hz, 4H), 7.39 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 2.47 (s, 3H).
13C{1H} NMR (126 MHz, acetone-d6) δ 143.29, 130.70, 129.71, 129.19, 128.63, 127.59,
121.71, 107.09, 21.54.
HRMS (APCI-TOF) calcd for C15H14NO2S+
[M+H]+ 272.0740, found 272.0744 (Δ = 1.5
ppm).
3-(4-(tert-butyl)phenyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (243.7 mg, 95%) was prepared using the general procedure from the
corresponding alkyne (141 L, 0.78 mmol) and azide (120 L, 0.78 mmol) with HMPA
(272 L, 1.56 mmol). Reaction was stirred for 15 min at –48 °C and then for another 30
min at rt. The color of reaction mixture was bright red which turned to bright orange color
after addition of aq. NH4Cl. Polarity of solvent: 25% ethyl acetate in hexanes.
1H NMR (400 MHz, acetone-d6) δ 9.39 (br, 1H), 7.75 (t, J = 7.6 Hz, 3H), 7.56 (d, J = 8.6
Hz, 2H), 7.45 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.83 (s, 1H), 2.46 (s, 3H), 1.35 (s, 9H).
13C{1H} NMR (101 MHz, acetone-d6) δ 153.95, 143.23, 140.50, 135.06, 132.86, 131.00,
128.98, 128.51, 127.37, 126.62, 121.69, 106.41, 35.35, 31.48, 21.54.
283
HRMS (APCI-TOF) calcd for C19H22NO2S+
[M+H]+ 328.1366, found 328.1363 (Δ = 0.9
ppm).
3-(4-methoxyphenyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (227 mg, 96%) was prepared using the general procedure from the
corresponding alkyne (101.5 L, 0.78 mmol) and azide (120 L, 0.78 mmol) with HMPA
(340 L, 1.95 mmol). Reaction was stirred for 30 min at –48 °C and then for another 35
min at rt. The color of reaction mixture was deep orange which turned to orange color
after addition of aq. NH4Cl. Polarity of solvent: 35% ethyl acetate in hexanes.
1H NMR (600 MHz, acetone-d6) δ 9.40 (br, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.0
Hz, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.74 (s, 1H), 3.85
(s, 3H), 2.44 (s, 3H).
13C{1H} NMR (126 MHz, acetone-d6) δ 162.12, 143.15, 140.36, 135.18, 130.73, 129.04,
128.70, 128.33, 127.96, 121.62, 115.05, 105.50, 55.79, 21.54.
HRMS (APCI-TOF) calcd for C16H16NO3S+
[M+H]+ 302.0845, found 302.0844 (Δ = 0.3
ppm).
284
6-methyl-3-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (112 mg, 42%) was prepared using the general procedure from the
corresponding alkyne (127.6 L, 0.78 mmol), azide (120 L, 0.78 mmol) with HMPA (272
L, 1.56 mmol). Reaction was stirred for 30 min at –48 °C and then for another 1 h 30
min at rt. The color of reaction mixture was dark brown which turned to light brown color
after addition of aq. NH4Cl. Polarity of solvent: 3% ethyl acetate in DCM.
1H NMR (600 MHz, acetone-d6) δ 9.57 (br, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.1
Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 2.47
(s, 3H).
13C{1H} NMR (151 MHz, acetone-d6) δ 143.52, 139.51, 138.87, 134.42, 131.61 (q, J =
32.1 Hz), 131.47, 129.90, 129.06, 128.23, 126.63 (q, J = 3.8 Hz), 125.16 (q, J = 271.3
Hz), 121.80, 109.41, 21.53.
19F NMR (564 MHz, acetone-d6) δ –63.22.
HRMS (APCI-TOF) calcd for C16H13F3NO2S+
[M+H]+ 340.0614, found 340.0619 (Δ = 1.5
ppm).
3-(4-fluorophenyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
285
The product (190.2 mg, 84%) was prepared using the general procedure from the
corresponding alkyne (89.7 L, 0.78 mmol), azide (120 L, 0.78 mmol) with HMPA (272
L, 1.56 mmol). Reaction was stirred for 25 min at –48 °C and then for another 45 min at
rt. The color of reaction mixture was bright fluorescent orange which turned to orange
color after addition of aq. NH4Cl. Polarity of solvent: 25% ethyl acetate in hexanes.
1H NMR (600 MHz, acetone-d6) δ 9.51 (br, 1H), 7.88 (dd, J = 8.8, 5.4 Hz, 2H), 7.75 (d, J
= 8.0 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.28 (t, J = 8.8 Hz, 2H), 6.84 (s, 1H),
2.46 (s, 3H).
13C{1H} NMR (126 MHz, acetone-d6) δ 164.55 (d, J = 248.0 Hz), 143.32, 139.48, 134.81,
132.15 (d, J = 3.0 Hz), 131.01, 129.85 (d, J = 8.5 Hz), 129.25, 128.63, 121.70, 116.56 (d,
J = 22.0 Hz), 107.23, 21.53.
19F NMR (564 MHz, acetone-d6) δ –113.05 (tt, J = 8.9, 5.4 Hz).
HRMS (APCI-TOF) calcd for C15H13FNO2S+
[M+H]+ 290.0646, found 290.0635 (Δ = 3.8
ppm).
6-methyl-3-pentyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (185.4 mg, 89%) was prepared using the general procedure from the
corresponding alkyne (103 L, 0.78 mmol), azide (120 L, 0.78 mmol) with HMPA (272
286
L, 1.56 mmol). Reaction was stirred for 25 min at –48 °C and then for another 45 min at
rt. The color of reaction mixture was yellow orange which turned to pale yellow color after
addition of aq. NH4Cl. Polarity of solvent: 20% ethyl acetate in hexanes. Appearance:
Pale yellow viscous solid.
1H NMR (400 MHz, acetone-d6) δ 9.31 (br, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.28 (dd, J =
8.1, 1.7 Hz, 1H), 7.24 (s, 1H), 6.11 (s, 1H), 2.42 (d, J = 10.8 Hz, 5H), 1.69 (pd, J = 7.3,
3.9 Hz, 2H), 1.41 – 1.32 (m, 4H), 0.90 (td, J = 5.8, 3.2 Hz, 3H).
13C{1H} NMR (101 MHz, acetone-d6) δ 143.17, 143.10, 135.12, 129.86, 128.07, 127.39,
121.62, 104.61, 35.02, 27.94, 23.03, 21.50, 14.25.
HRMS (APCI-TOF) calcd for C14H20NO2S+
[M+H]+ 266.1209, found 266.1203 (Δ = 2.3
ppm).
3-(tert-butyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (171.3 mg, 87%) was prepared using the general procedure from the
corresponding alkyne (96.4 L, 0.78 mmol), azide (120 L, 0.78 mmol) with HMPA (272
L, 1.56 mmol). Reaction was stirred for 25 min at –48 °C and then for another 40 min at
rt. The color of reaction mixture was yellow orange which turned to pale yellow color after
addition of aq. NH4Cl. Polarity of solvent: 20% ethyl acetate in hexanes.
1H NMR (400 MHz, acetone-d6) δ 8.83 (br, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.4
Hz, 2H), 6.23 (s, 1H), 2.41 (s, 3H), 1.32 (s, 9H).
287
13C{1H} NMR (101 MHz, acetone-d6) δ 150.10, 143.01, 134.97, 130.36, 128.40, 128.21,
121.40, 103.07, 36.13, 28.28, 21.49.
HRMS (APCI-TOF) calcd for C13H18NO2S+
[M+H]+ 252.1053, found 252.1049 (Δ = 1.6
ppm).
3-benzyl-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (115.4 mg, 52%) was prepared using the general procedure from the
corresponding alkyne (97.3 L, 0.78 mmol), azide (120 L, 0.78 mmol) with no HMPA.
Reaction was stirred for 25 min at –48 °C and then for another 55 min at rt. The color of
reaction mixture was brownish red which turned to yellow orange color after addition of
aq. NH4Cl. Polarity of solvent: 25% ethyl acetate in hexanes.
1H NMR (600 MHz, acetone-d6) δ 9.46 (br, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.40 – 7.19 (m,
7H), 6.11 (s, 1H), 3.79 (s, 2H), 2.41 (s, 3H).
13C{1H} NMR (151 MHz, acetone-d6) δ 143.24, 141.74, 141.65, 137.88, 134.85, 129.90,
129.36, 128.42, 127.64, 127.61, 121.64, 106.09, 40.89, 21.48.
HRMS (APCI-TOF) calcd for C16H16NO2S+
[M+H]+ 286.0896, found 286.0903 (Δ = 2.4
ppm).
288
6-methoxy-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (175 mg, 78%) was prepared using the general procedure from the
corresponding alkyne (86 L, 0.78 mmol), azide (166 mg, 0.78 mmol) with HMPA (340
L, 1.95 mmol). Reaction was stirred for 15 min at –48 °C and then for another 45 min at
rt. The color of reaction mixture was reddish orange which turned to bright orange color
after addition of aq. NH4Cl. Polarity of solvent: 35% ethyl acetate in hexanes.
1H NMR (600 MHz, acetone-d6) δ 9.47 (br, 1H), 7.83 (dd, J = 8.1, 1.6 Hz, 2H), 7.79 (d, J
= 8.7 Hz, 1H), 7.54 – 7.45 (m, 3H), 7.19 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H),
6.87 (s, 1H), 3.93 (s, 3H).
13C{1H} NMR (151 MHz, acetone-d6) δ 163.19, 140.97, 136.94, 135.65, 130.75, 129.71,
127.61, 126.35, 123.67, 115.29, 111.77, 106.98, 56.10.
HRMS (APCI-TOF) calcd for C15H14NO3S+
[M+H]+ 288.0689, found 288.0696 (Δ = 2.4
ppm).
6-bromo-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
289
The product (171 mg, 65%) was prepared using the general procedure from the
corresponding alkyne (86 L, 0.78 mmol), azide (205 mg, 0.78 mmol) with HMPA (272
L, 1.56 mmol). Reaction was stirred for 15 min at –48 °C and then for another 40 min at
rt. The color of reaction mixture was reddish brown which turned to deep red color after
addition of aq. NH4Cl. Polarity of solvent: Gradient column with 15% to 30% ethyl acetate
in hexanes.
1H NMR (600 MHz, acetone-d6) δ 9.87 (br, 1H), 7.91 (s, 1H), 7.85 (d, J = 7.1 Hz, 2H),
7.81 (dd, J = 8.3, 2.5 Hz, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.56 – 7.49 (m, 3H), 6.94 (s, 1H).
13C{1H} NMR (126 MHz, acetone-d6) δ 142.01, 136.92, 135.21, 132.09, 131.14, 130.92,
129.79, 127.83, 126.53, 123.79, 105.95.
HRMS (APCI-TOF) calcd for C14H11BrNO2S+ 335.9688, found 335.9687 (Δ = 0.3 ppm).
6-methyl-3-(thiophen-2-yl)-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (171 mg, 65%) was prepared using the general procedure from the
corresponding alkyne (150 L, 1.58 mmol), azide (242.2 L, 1.58 mmol) with HMPA (550
L, 1.56 mmol). Reaction was stirred for 25 min at –48 °C and then for another 45 min at
rt. The color of reaction mixture was dark brown which turned to deep red color after
addition of aq. NH4Cl. Polarity of solvent: Gradient column with 0% to 4% ethyl acetate in
DCM.
290
1H NMR (600 MHz, acetone-d6) δ 9.46 (br, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.1
Hz, 1H), 7.62 (tt, J = 4.9, 3.1 Hz, 2H), 7.41 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H),
2.45 (s, 3H).
13C NMR (151 MHz, acetone-d6) δ 143.30, 137.75, 134.98, 131.08, 128.99, 128.48,
128.09, 126.32, 124.86, 121.74, 106.35, 21.53.
HRMS (ES-TOF) calcd for C13H11NO2S2
•+ [M]•+ 277.0226, found 277.0226 (Δ = 0 ppm).
6-methyl-3-(morpholinomethyl)-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (137 mg, 33%) was prepared using the general procedure from the
corresponding alkyne (175 L, 1.41 mmol), azide (217 L, 1.41 mmol) with HMPA (491
L, 2.82 mmol). Reaction was stirred for 25 min at –48 °C and then for another 60 min at
rt. The color of reaction mixture was orange which turned to pale orange color after
addition of aq. NH4Cl. Polarity of solvent: Gradient column with 15% to 30% ethyl acetate
in hexanes.
Appearance: Candy like orange solid
Polarity of solvent: Column
1H NMR (600 MHz, acetone-d6) δ 7.71 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.27
(s, 1H), 6.24 (s, 1H), 3.63 (d, J = 4.9 Hz, 4H), 3.30 (s, 2H), 2.47 (s, 4H), 2.42 (s, 3H).
13C {
1H} NMR (151 MHz, acetone-d6) δ 143.29, 139.46, 134.54, 130.49, 128.58, 127.61,
121.82, 105.67, 67.26, 61.34, 53.87, 21.48.
291
HRMS (ES-TOF) calcd for C14H18N2O3S•+ [M]•+ 294.1033, found 294.1037 (Δ = 1.36
ppm).
6-methyl-3-(naphthalen-1-yl)-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product was prepared using the general procedure from the corresponding alkyne
(279 mg, 1.82 mmol), azide (279 L, 1.82 mmol) with HMPA (634 L, 3.64 mmol).
Reaction was stirred for 30 min at –48 °C and then for another 60 min at rt. The color of
reaction mixture was dark orange which turned to pale orange color after addition of aq.
NH4Cl. Polarity of solvent: Gradient column with 30% ethyl acetate in hexanes.
Appearance: tan solid
Polarity of solvent: Column with 30% ethyl acetate in hexanes
1H NMR (600 MHz, Acetone-d6) δ 8.36 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.00
(d, J = 7.3 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.60 (s, 3H), 7.46
(s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 2.49 (s, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 143.47, 140.77, 134.91, 134.75, 133.95, 132.90,
131.03, 130.50, 129.25, 129.17, 128.49, 128.34, 127.74, 127.21, 126.28, 126.10,
121.77, 109.28, 21.57.
HRMS (ES-TOF) calcd for C19H15NO2S•+ [M]•+ 321.0818, found 321.0821 (Δ = 0.93
ppm).
3-(2-methoxyphenyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
292
The product (248 mg, 45%) was prepared using the general procedure from the
corresponding alkyne (235.4 L, 1.82 mmol), azide (279 L, 1.82 mmol) with HMPA (634
L, 3.64 mmol). Reaction was stirred for 30 min at –48 °C and then for another 45 min at
rt. The color of reaction mixture was dark brown which turned to dark orange color after
addition of aq. NH4Cl. Polarity of solvent: Gradient column with 0% to 2% ethyl acetate in
DCM.
Appearance: dark brown
Polarity of solvent: Gradient column with 0% to 2% ethyl acetate in DCM
HRMS (ES-TOF) calcd for C19H15NO2S•+ [M]•+ 301.0767, found 301.0769 (Δ = 0.66
ppm).
3-(4,4-dimethylthiochroman-6-yl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide
The product (540.3 mg, 80 %) was prepared using the general procedure from the
corresponding alkyne (368.22 L, 1.82 mmol), azide (279 L, 1.82 mmol) with HMPA
(634 L, 3.64 mmol). Reaction was stirred for 30 min at –48 °C and then for another 40
min at rt. The color of reaction mixture was dark orange which turned to orange color after
293
addition of aq. NH4Cl. Polarity of solvent: Gradient column with 0% to 2% ethyl acetate in
DCM.
Appearance: dark orange solid
Polarity of solvent: Gradient column with 0% to 2% ethyl acetate in DCM
HRMS (ES-TOF) calcd for C20H21NO2S•+ [M]•+ 371.1008, found 371.1008 (Δ = 0 ppm).
5.2.8 Substrate Scope
5.2.8.1 Oxo conditions
A 20 mL glass reaction vial was charged with a stir bar, CuCl2 (5.38 mg, 40 μmol), Li2CO3
(5.91 mg, 80 μmol), and sultam (400 μmol). Methanol (9.5 mL) was then added followed
by water (0.5 mL) using a syringe. Following this, the vial was sealed with a screw cap
fitted with a PTFE septum. A balloon fitted to a syringe with a needle was filled with air
was then inserted into the septa and the reaction was left to stir at 800 rpm. The reaction
was monitored using GC-MS until completion.
6-methyl-3-(4-(trifluoromethyl)phenyl)-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide
3.9
294
The product (130 mg, 88 %, 3.3:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (135.7 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0% to
2% ethyl acetate in DCM.
Appearance: off-white solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.44 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 7.6 Hz, 1H), 8.03
(d, J = 8.3 Hz, 2H), 7.97 (s, 1H), 7.84 – 7.80 (m, 1H), 2.56 (s, 3H).
HRMS (ES-TOF) calcd for C16H10F3NO3S•+ [M]•+ 353.0333, found 353.0330 (Δ = 0.85
ppm).
3-(4-fluorophenyl)-6-methyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.11
The product (105 mg, 82 %, 7.2:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (115.7 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: light yellow solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.36 – 8.31 (m, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.86 (s,
1H), 7.82 (d, J = 7.8 Hz, 1H), 7.48 – 7.42 (m, 2H), 2.55 (s, 3H).
295
6-methyl-3-phenyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.13
The product (113 mg, 99%, 7.1:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (108.5 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: brown-white solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.21 (d, J = 7.3 Hz, 2H), 8.08 (d, J = 7.7 Hz, 1H), 7.83
(s, 3H), 7.68 (t, J = 7.9 Hz, 2H), 2.55 (s, 3H).
6-bromo-3-phenyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.25
The product (102 mg, 73%, 5.4:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (134.5 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: brown solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
296
1H NMR (600 MHz, Acetone-d6) δ 8.36 (s, 1H), 8.26 (s, 1H), 8.09 (s, 3H), 7.72 (s, 1H),
7.60 (s, 2H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 172.77, 166.78, 140.17, 139.05, 134.40, 133.07,
132.17, 132.02, 131.58, 129.31, 128.24, 127.85.
3-(4-methoxyphenyl)-6-methyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.17
The product (126 mg, 99%, 10.3:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (120.5 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: light yellow solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.19 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 7.8 Hz, 1H), 7.81
(d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H), 3.97 (s, 3H), 2.54 (s, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 186.89, 166.81, 146.98, 137.84, 136.02, 134.72,
133.87, 130.50, 128.33, 127.53, 123.42, 115.47, 56.39, 21.49.
HRMS (ES-TOF) calcd for C16H13NO4S•+ [M]•+ 315.0565, found 315.0558 (Δ = 2.22
ppm).
6-methoxy-3-phenyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.19
297
The product (99 mg, 76%, 3.6:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (114.9 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: light yellow solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
HRMS (ES-TOF) calcd for C15H11NO4S•+ [M]•+ 301.0409, found 301.0403 (Δ = 1.99
ppm).
3-(4,4-dimethylthiochroman-6-yl)-6-methyl-4H-benzo[e][1,2]thiazin-4-one 1,1-
dioxide 3.29
The product (151 mg, 98%, 7.2:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (148.6 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: orange solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
298
1H NMR(600 MHz, Acetone-d6) δ 8.27 (s, 1H), 8.08 (s, 1H), 7.82 (s, 2H), 7.77 (s, 1H),
7.34 (s, 1H), 3.18 (s, 2H), 2.54 (s, 3H), 2.01 (s, 2H), 1.37 (s, 6H).
3-(tert-butyl)-6-methyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.15
The product (108 mg, 97%, 3.2:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (100.5 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: off white solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.04 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.68
(s, 1H), 2.54 (s, 3H), 1.40 (s, 9H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 166.52, 147.17, 137.37, 136.11, 132.00, 130.19,
128.19, 123.49, 45.53, 26.06, 21.49.
6-methyl-3-(naphthalen-1-yl)-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.27
The product (128 mg, 94%) was prepared using the general procedure from the
corresponding Sultam (128.6 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04 mmol) with Li2CO3
(5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0% to 2% ethyl acetate
in DCM.
299
Appearance: dark orange solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 9.05 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.13 (d, J =
24.1 Hz, 2H), 7.91 (s, 1H), 7.85 (s, 2H), 7.74 (s, 2H), 2.55 (s, 3H).
13C NMR (151 MHz, Acetone-d6) δ 190.91, 167.75, 147.10, 138.17, 137.39, 136.16,
136.09, 135.04, 131.66, 130.63, 130.62, 130.38, 130.04, 128.40, 128.18, 126.22,
125.65, 123.53, 21.52.
3-(2-methoxyphenyl)-6-methyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.23
The product (126 mg, 99%, 34:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (120.5 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: light yellow solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.06 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.79
(dd, J = 11.4, 7.5 Hz, 2H), 7.58 (s, 1H), 7.29 – 7.22 (m, 2H), 3.66 (s, 3H), 2.52 (s, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 189.38, 169.79, 161.78, 146.93, 138.37, 137.98,
135.81, 130.84, 130.26, 126.85, 125.23, 123.32, 122.50, 114.19, 56.86, 21.44.
HRMS (ES-TOF) calcd for C16H13NO4S•+ [M]•+ 315.0565, found 315.0560 (Δ = 1.59
ppm).
300
3-phenyl-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.33
The product (96 mg, 86%, 8.9:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (98.9 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: light yellow solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.25 – 8.20 (m, 3H), 8.07 (d, J = 7.7 Hz, 1H), 8.02 (t,
J = 7.5 Hz, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.84 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.7 Hz, 2H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 188.85, 165.98, 140.48, 136.40, 135.64, 134.77,
132.12, 131.35, 129.95, 128.42, 125.76, 123.72.
HRMS (ES-TOF) calcd for C14H9NO3S•+ [M]•+ 271.0303, found 271.029 (Δ = 4.8 ppm).
3-(thiophen-2-yl)-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.31
The product (115 mg, 99%, 5:1 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (110.9 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04 mmol) with
Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0% to 2% ethyl
acetate in DCM.
Appearance: off yellow crystal
301
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.81 (dd, J = 2.9, 1.3 Hz, 1H), 8.06 (d, J = 7.8 Hz,
1H), 7.94 (s, 1H), 7.81 – 7.79 (m, 2H), 7.73 (dd, J = 5.2, 2.8 Hz, 1H), 2.56 (s, 3H).
13C NMR (151 MHz, Acetone-d6) δ 181.87, 165.59, 146.90, 140.21, 139.27, 137.88,
135.91, 130.21, 128.85, 128.78, 128.19, 123.41, 21.56.
3-(4-(tert-butyl)phenyl)-4H-benzo[e][1,2]thiazin-4-one 1,1-dioxide 3.21
The product (133 mg, 97%, 36:1 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (131.9 mg, 0.4 mmol), CuCl2 (5.38 mg, 0.04
mmol) with Li2CO3 (5.91 mg, 0.08 mmol). Polarity of solvent: Gradient column with 0%
to 2% ethyl acetate in DCM.
Appearance: off-white solid
Polarity of solvent: Gradient column with 0% to 2% MeOH acetate in DCM
1H NMR (600 MHz, Acetone-d6) δ 8.13 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.85
– 7.77 (m, 2H), 7.73 (d, J = 8.1 Hz, 2H), 2.55 (s, 3H), 1.39 (s, 9H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 188.40, 166.55, 160.63, 147.02, 137.88, 136.08,
132.25, 131.29, 130.40, 128.41, 127.08, 123.48, 36.11, 31.18, 21.51.
HRMS (ES-TOF) calcd for C19H19NO3S•+ [M]•+ 341.1086, found 341.1079 (Δ = 2.05
ppm).
302
5.2.8.2 Hydroxy conditions
A 20 mL glass reaction vial was charged with a stir bar, CuBr2 (1.79 mg, 8 μmol) and
sultam (400 μmol). Acetonitrile (10 mL) was then added followed by water (2 μL) using a
micropipette. Following this, the vial was sealed with a screw cap fitted with a PTFE
septum. A balloon fitted to a syringe with a needle was filled with air was then inserted
into the septa and the reaction was left to stir at 800 rpm. The reaction was monitored
using GC-MS until complete.
4-hydroxy-6-methyl-3-(4-(trifluoromethyl)phenyl)-2H-benzo[e][1,2]thiazine 1,1-
dioxide 3.8
The product (130 mg, 91%, 1:35.2 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (135.7 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8
μmol).
Appearance: dark orange cube shaped crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.26 (d, J = 8.0 Hz, 2H), 8.08 (s, 1H), 8.03 (d, J = 8.0
Hz, 1H), 7.97 – 7.90 (m, 3H), 2.58 (s, 3H).
303
3-(4-fluorophenyl)-4-hydroxy-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.10
The product (115 mg, 94%, 1:49 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (115.7 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: Dark orange-brown cube-shaped crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.18 (t, J = 6.6 Hz, 2H), 8.05 (s, 1H), 8.00 (d, J = 8.0
Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 8.6 Hz, 2H), 2.58 (s, 3H).
13C NMR (151 MHz, Acetone-d6) δ 174.03, 167.62, 165.89 (d, J = 13.3 Hz), 145.52,
138.63, 136.92, 135.05 (d, J = 9.4 Hz), 129.94, 129.71, 129.55, 125.82, 116.39 (d, J =
22.3 Hz), 21.51.
19F NMR (564 MHz, Acetone-d6) δ -106.63.
4-hydroxy-6-methyl-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.12
The product (108 mg, 94%, 1:5.8 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (114.93 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: tan crystals
Crystallization: hexanes layered over DCM
304
1H NMR (600 MHz, Acetone-d6) δ 8.07 (d, J = 7.3 Hz, 2H), 8.05 (s, 1H), 8.00 (d, J = 7.8
Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.59 (t, J = 7.1 Hz, 2H), 2.58
(s, 3H).
13C NMR (151 MHz, Acetone-d6) δ 174.14, 167.22, 145.52, 138.69, 136.88, 134.18,
133.31, 132.08, 130.08, 129.54, 129.24, 125.83, 21.52.
6-bromo-4-hydroxy-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.24
The product (107 mg, 81%, 1:15.3 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (140.88 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8
μmol).
Appearance: brown crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.36 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 7.8
Hz, 4H), 7.72 (t, J = 7.3 Hz, 2H), 7.60 (t, J = 7.6 Hz, 3H).
13C NMR (151 MHz, Acetone-d6) δ 172.77, 166.78, 140.17, 139.05, 134.40, 133.06,
132.17, 132.02, 131.58, 129.31, 128.24, 127.85.
4-hydroxy-3-(4-methoxyphenyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.16
305
The product (123 mg, 97%, 1:30 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (126.94 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: light yellow crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.15 (d, J = 8.5 Hz, 1H), 8.01 (s, 0H), 7.98 (d, J = 8.0
Hz, 0H), 7.88 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 3.96 (s, 1H), 2.57 (s, 1H).
13C NMR (151 MHz, Acetone-d6) δ 175.45, 166.19, 165.60, 145.37, 138.86, 136.73,
134.72, 130.66, 129.52, 125.72, 125.26, 115.00, 56.20, 21.50.
4-hydroxy-6-methoxy-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.18
The product (108 mg, 89%, 1:16 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (121.33 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: off-white crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.10 – 8.02 (m, 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.66 (s,
1H), 7.60 (t, 3H), 4.04 (s, 3H).
13C NMR (151 MHz, Acetone-d6) δ 174.05, 167.05, 164.00, 134.17, 133.59, 133.30,
132.05, 131.96, 129.25, 128.08, 122.70, 112.82, 56.76.
3-(tert-butyl)-4-hydroxy-6-methyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide
3.14
306
The product (101 mg, 89%, 1:120 oxo:hydroxy) was prepared using the general
procedure from the corresponding Sultam (106.9 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8
μmol).
Appearance: white crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 7.96 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.9
Hz, 1H), 2.54 (s, 4H), 1.45 (s, 10H).
13C NMR (151 MHz, Acetone-d6) δ 179.48, 173.23, 145.49, 138.45, 136.73, 130.01,
129.53, 125.77, 41.95, 28.35, 21.47.
4-hydroxy-6-methyl-3-(naphthalen-1-yl)-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.26
The product (131 mg, 97%, 1:11 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (128.6 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: amber crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.35 – 8.27 (m, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.11 –
8.03 (m, 3H), 7.94 (d, J = 7.7 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.64 – 7.58 (m, 2H), 2.59
(s, 3H).
307
13C NMR (151 MHz, Acetone-d6) δ 173.27, 169.15, 145.61, 138.87, 137.09, 134.62,
133.13, 131.96, 131.12, 130.72, 129.64, 129.53, 129.43, 128.26, 127.38, 126.01,
125.99, 125.45, 21.53.
4-hydroxy-3-(2-methoxyphenyl)-6-methyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.22
The product (126 mg, 99%, quant. conversion to hydroxy) was prepared using the general
procedure from the corresponding Sultam (126.9 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8
μmol).
Appearance: yellowish needle-shaped crystals
Crystallization: hexanes layered over DCM
4-hydroxy-3-phenyl-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.32
The product (108 mg, 94%, 1:5.8 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (109.3 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: tan cube shaped crystals
Crystallization: hexanes layered over DCM
1H NMR (500 MHz, Acetone-d6) δ 8.26 (d, J = 7.9 Hz, 1H), 8.11 (dd, J = 18.3, 8.1 Hz,
4H), 7.99 (t, J = 7.6 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 2H).
308
13C NMR (126 MHz, Acetone-d6) δ 173.89, 167.25, 141.36, 136.29, 134.38, 134.23,
133.29, 132.13, 130.28, 129.55, 129.25, 125.76.
4-hydroxy-6-methyl-3-(thiophen-2-yl)-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.30
The product (88 mg, 75%, no oxo observed) was prepared using the general procedure
from the corresponding Sultam (117.34 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: tan crystals
Crystallization: hexanes layered over DCM
1H NMR (600 MHz, Acetone-d6) δ 8.89 (s, 1H), 8.05 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H),
7.89 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 4.8 Hz, 1H), 7.69 – 7.66 (m, 1H), 2.57 (s, 3H).
13C NMR (151 MHz, Acetone-d6) δ 174.54, 160.11, 145.41, 139.61, 138.75, 136.98,
135.27, 129.90, 129.56, 129.20, 127.56, 125.78, 21.50.
3-(4-(tert-butyl)phenyl)-4-hydroxy-2H-benzo[e][1,2]thiazine 1,1-dioxide 3.20
The product (109 mg, 79%, 1:4.9 oxo:hydroxy) was prepared using the general procedure
from the corresponding Sultam (137.37 mg, 0.4 mmol) and CuBr2 (1.79 mg, 8 μmol).
Appearance: tan needle-like crystals
Crystallization: hexanes layered over DCM
309
1H NMR (600 MHz, Acetone-d6) δ 8.05 (d, J = 8.8 Hz, 3H), 8.00 (d, J = 8.0 Hz, 1H), 7.89
(d, J = 7.1 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 2.58 (s, 3H), 1.38 (s, 9H).
13C NMR (151 MHz, Acetone-d6) δ 174.59, 166.96, 158.29, 145.48, 138.76, 136.83,
132.17, 130.50, 130.28, 129.53, 126.35, 125.81, 35.82, 31.28, 21.51.
5.2.9 NMRs for Chapter 3
1H NMR (600 MHz, Acetone-d6) Naphthalene Sultam
310
13C{
1H} NMR (151 MHz, Acetone-d6) Naphthalene Sultam
311
1H NMR (600 MHz, Acetone-d6) of compound 3.7
312
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.9
313
1H NMR (600 MHz, Acetone-d6) of compound 3.9
314
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.9
315
19F NMR (564 MHz, Acetone-d6) of compound 3.9
316
1H NMR (600 MHz, Acetone-d6) of compound 3.11
317
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.11
318
19F NMR (564 MHz, Acetone-d6) of compound 3.11
319
1H NMR (600 MHz, Acetone-d6) of compound 3.13
320
1H NMR (600 MHz, Acetone-d6) of compound 3.15
321
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.15
322
1H NMR (600 MHz, Acetone-d6) of compound 3.17
323
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.17
324
1H NMR (600 MHz, Acetone-d6) of compound 3.21
325
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.21
326
1H NMR (600 MHz, Acetone-d6) of compound 3.23
327
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.23
328
1H NMR (600 MHz, Acetone-d6) of compound 3.25
329
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.25
330
1H NMR (600 MHz, Acetone-d6) of compound 3.27
331
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.27
332
1H NMR (600 MHz, Acetone-d6) of compound 3.29
333
1H NMR (600 MHz, Acetone-d6) of compound 3.31
334
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.31
335
1H NMR (600 MHz, Acetone-d6) of compound 3.33
336
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.33
337
1H NMR (600 MHz, Acetone-d6) of compound 3.8
338
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.8
339
19F NMR (564 MHz, Acetone-d6) of compound 3.8
340
1H NMR (600 MHz, Acetone-d6) of compound 3.10
341
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.10
342
19F NMR (564 MHz, Acetone-d6) of compound 3.10
343
1H NMR (600 MHz, Acetone-d6) of compound 3.12
344
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.12
345
1H NMR (600 MHz, Acetone-d6) of compound 3.14
346
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.14
347
1H NMR (600 MHz, Acetone-d6) of compound 3.16
348
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.16
349
1H NMR (600 MHz, Acetone-d6) of compound 3.18
350
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.18
351
1H NMR (600 MHz, Acetone-d6) of compound 3.20
352
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.20
353
1H NMR (600 MHz, Acetone-d6) of compound 3.24
354
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.24
355
1H NMR (600 MHz, Acetone-d6) of compound 3.26
356
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.26
357
1H NMR (600 MHz, Acetone-d6) of compound 3.30
358
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.30
359
1H NMR (600 MHz, Acetone-d6) of compound 3.33
360
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 3.32
361
5.3 Fluorosulfonyl Triazole (Chapter 4)
5.3.1 Synthesis of Starting Material
5.3.1.1 Synthesis of N-H triazole 4.1
This is a known protocol for N-H triazole synthesis.13 4-nitrophenyl azide (32.41
mmol, 5.32 g) and ammonium acetate (124.84 mmol, 9.62 g) was added to a 50 mL round
bottom flask charged with a magnetic stir bar. DMF (20 mL) was then added followed by
acetophenone (24.97 mmol, 2,91 mL). The 50 mL round bottom flask was then added to
an oil bath and heated to 80 °C for 18 h. The reaction was then checked by TLC using a
30% EtOAc in hexanes as a eluent. The product was purified through flash
chromatography. The column was ran with DCM until the 4-nitrophenylaniline by-product
eluted out. Following this, the column was ran with 30% EtOAc in hexanes yielding the
desired N-H triazole as a tan solid.
5.3.1.2 Synthesis of fluorosulfonylating reagents
5.3.1.2.1 Synthesis of FSI derivatives
This protocol is from a reported procedure.14 Imidazole (41.09 mmol, 2.8 g) and
sodium carbonate (102.74 mmol, 10.89 g) was placed into Vial I along with a magnetic
362
stir bar. MDSI (50 mmol, 18.11 g) and KHF2 (125 mmol, 9.76 g) was then added to vial II
along with a magnetic stir bar. MeCN (41 mL) was then added to vial I and septa was
then added to the openings of the two vials. A vacuum was then pulled on the system by
using a needle through one of the septas until bubbling was seen in the MeCN. After that,
the needle was removed, and water (50 mL) was added into vial II via syringe and a
balloon was added to the reaction vessel to avoid over pressurizing. The reaction was left
to stir for 18 h before the crude reaction mixture in vial I was filtered through a plug of
silica. DCM was then put through the silica plug and the resulting filtrate was washed with
water 3x. The combined washings were then back extracted with DCM and the combined
organic layer was washed with brine. Sodium sulfate was used to dry the organic layer
and filtered out using a celite plug into a round bottom flask. Reduced pressure was used
to evaporate the organic layer affording sulfonylated imidazole.
DCM (41.11 mL) was added to the round bottom flask containing the sulfonylated
imidazole followed by a magnetic stir bar. The reaction was then cooled to 0 °C before
MeOTf (45.22 mmol, 5.12 mL) was added dropwise over the course of 20 minutes using
a dropfunnel. The solution was taken out of the cold bath and let stir left to stir for 1 h
before being concentrated down using reduced pressure affording 4.3 as a viscus solid
1-(fluorosulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (4.3)
1H NMR (600 MHz, Acetonitrile-d3) δ 9.40 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 3.98 (s, 4H).
13C NMR (151 MHz, Acetonitrile-d3) δ 141.04, 127.66, 122.53, 38.61.
19F NMR (564 MHz, Acetonitrile-d3) δ 59.92, -79.37.
363
5.3.1.2.2 Synthesis of AISF
This is from a reported protocol.15 Li bis(fluorosulfonyl)imide (10 mmol, 1.87 g) and
(diacetoxyiodo)benzene was added to a 10 mL round bottom flask. DCE (5.70 mL) was
then added to the falsk and the solution was then refluxed using an oil bath. To this
refluxing solution, acetanilide was added dropwise in DCE (2.214 mL) over the course of
25 mins. The solution was then refluxed for 15 mins before being cooled concentrated
down under reduced pressure. A column was done with 45 % EtOAc in hexanes to afford
AISF as a crystalline solid.
5.3.2 Synthesis of Fluorosulfonyl Triazole
5.3.2.1 Fluorosulfonylating reaction screen
N-H triazole 4.1 (1 mmol, 145.17 mg) and sulfonylating reagent (1.22 mmol) was
added to a vial along with a magnetic stir bar. THF (1 mL) was added to the vial followed
by NaCO3 (2.5 mmol, 264.97 mg). The reaction was tracked using TLC and HPLC over
the course of 2 hours. A column was done with an appropriate EtOAc/hexanes solvent
system to afford 4.2 or 4.4 as a white solid.
364
4-phenyl-1H-1,2,3-triazole-1-sulfonyl fluoride (4.2)
1H NMR (600 MHz, Acetone-d6) δ 8.97 (s, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.65 – 7.53 (m,
3H).
19F NMR (564 MHz, Acetone-d6) δ 51.99.
(Z)-(fluorosulfonyl)(1-(3-methyl-1H-imidazol-3-ium-1-yl)-2-phenylvinyl)amide (4.4)
1H NMR (600 MHz, Acetonitrile-d3) δ 8.80 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.71 (t, J =
1.8 Hz, 1H), 7.39 – 7.32 (m, 4H), 7.24 (t, J = 7.4 Hz, 1H), 6.10 (s, 1H), 3.86 (s, 4H).
13C{1H} NMR (151 MHz, Acetonitrile-d3) δ 136.07, 135.94, 135.27, 129.53, 129.19,
128.06, 124.10, 121.69, 110.88, 37.05.
19F NMR (564 MHz, Acetonitrile-d3) δ 57.15, -79.35.
5.3.2.2 Solvent screen
N-H triazole 4.1 (1 mmol, 145.17 mg) and FSI derivative 4.3 (1.22 mmol, 383.36
mg) was added to a vial along with a magnetic stir bar. Solvent (1 mL) was added to the
vial followed by NaCO3 (2.5 mmol, 264.97 mg). The reaction was tracked using TLC and
365
HPLC over the course of 2 hours. A column was done with an appropriate EtOAc/hexanes
solvent system to afford 4.5 or 4.6 as a white solid.
2-methyl-4-phenyl-1H-imidazole-1-sulfonyl fluoride (4.5)
1H NMR (600 MHz, Acetone-d6) δ 8.05 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.43 (t, J = 7.7
Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 2.69 (s, 3H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 146.97, 141.38, 131.55, 128.65, 128.33, 125.41,
114.79, 14.34.
19F NMR (564 MHz, Acetone-d6) δ 56.94.
2,4-diphenyl-1H-imidazole-1-sulfonyl fluoride (4.6)
1H NMR (600 MHz, Acetone-d6) δ 8.25 (s, 1H), 8.00 (d, J = 7.1 Hz, 2H), 7.78 (d, J = 7.0
Hz, 2H), 7.64 – 7.59 (m, 1H), 7.59 – 7.55 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (t, J =
7.4 Hz, 1H).
13C{1H} NMR (151 MHz, Acetone-d6) δ 149.70, 142.90,132.37, 131.57, 130.60,129.65,
129.64, 129.45, 129.16, 126.49, 117.3.
19F NMR (564 MHz, Acetone-d6) δ 56.97.
366
5.3.2.3 Base screen
N-H triazole 4.1 (1 mmol, 145.17 mg) and FSI derivative 4.3 (1.22 mmol, 383.36
mg) was added to a vial along with a magnetic stir bar. CHCl3 (1 mL) was added to the
vial followed by NaCO3 (2.5 mmol, 264.97 mg). The reaction was tracked using TLC and
HPLC over the course of 2 hours.
5.3.2.4 Base equivalents screen
N-H triazole 4.1 (1 mmol, 145.17 mg) and FSI derivative 4.3 (1.22 mmol, 383.36
mg) was added to a vial along with a magnetic stir bar. CHCl3 (1 mL) was added to the
vial followed by DIPEA. The reaction was tracked using TLC and HPLC over the course
of 2 hours. A column was done with an appropriate EtOAc/hexanes solvent system to
afford 4.7 as a white solid.
(fluorosulfonyl)(2-phenyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)vinyl)sulfamoyl fluoride
(4.7)
367
1H NMR (600 MHz, Acetonitrile-d3) δ 8.67 (s, 1H), 7.94 (d, J = 7.1 Hz, 2H), 7.70 (s, 1H),
7.65 – 7.57 (m, 5H), 7.52 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H).
19F NMR (564 MHz, Acetonitrile-d3) δ 56.14.
5.3.2.5 Temperature screen
N-H triazole 4.1 (1 mmol, 145.17 mg) and FSI derivative 4.3 (1.22 mmol, 383.36
mg) was added to a vial along with a magnetic stir bar. CHCl3 (1 mL) was added to the
vial. The reaction vessel was placed into a cold bath (dry ice and acetone for -78 °C or
water and ice for 0 °C) before DIPEA (1.22 mmol, 210 μL) was added. The reaction was
tracked using TLC and HPLC over the course of 2 hours.
5.3.2.6 Concentration screen
N-H triazole 4.1 (1 mmol, 145.17 mg) and FSI derivative 4.3 (1.22 mmol, 383.36
mg) was added to a vial along with a magnetic stir bar. CHCl3 was added to the vial before
DIPEA (1.22 mmol, 210 μL) was added. The reaction was tracked using TLC and HPLC
over the course of 2 hours.
368
5.3.2.7 Screening the order of additions
5.3.2.7.1 N-H triazole + base then FSI derivative
N-H triazole 4.1 (1 mmol, 145.17 mg) and CHCl3 (1 mL) was added to the vial
along with a magnetic stir bar. DIPEA (1.22 mmol, 210 μL) was then added and allowed
to stir for 5 mins. Following this, FSI derivative 4.3 (1.22 mmol, 383.36 mg) was added
and the reaction was monitored using TLC and HPLC over the course of 2 hours.
5.3.2.7.2 FSI derivative + base then N-H triazole
FSI derivative 4.3 (1.22 mmol, 383.36 mg) and CHCl3 (1 mL) was added to the vial
along with a magnetic stir bar. DIPEA (1.22 mmol, 210 μL) was then added and allowed
to stir for 5 mins. Following this, N-H triazole 4.1 (1 mmol, 145.17 mg) was added and the
reaction was monitored using TLC and HPLC over the course of 2 hours.
3-(fluorosulfonyl)-1-methyl-1H-imidazol-3-ium-2-ide (4.8)
1H NMR (600 MHz, Acetonitrile-d3) δ 7.43 (s, 1H), 7.26 (s, 1H), 3.95 (s, 3H).
13C{1H} NMR (151 MHz, Acetonitrile-d3) δ 135.68, 131.48, 130.39, 36.34.
19F NMR (564 MHz, Acetonitrile-d3) δ 65.19.
5.3.2.8 Rhodium reaction with SO2F triazole 4.2
5.3.2.8.1 room temperature reaction
369
This procedure is based off of reported protocols.16 A vial was flame dried and
purged with N2. To this vial, N-H triazole 4.1 (1 mmol, 145.17 mg) and Rh2(Oct)4 (1 mol
%, 2.21 mg) was added followed by CHCl3 (2 mL) benzonitrile (1.5 mmol, 155 μL). A
magnetic stir bar was added to the reaction vial followed by DIPEA (0.6 mmol,105 μL).
Following this, FSI derivative 4.3 (1.22 mmol, 383.36 mg) was added slowly in portions
and the reaction was monitored using TLC and HPLC.
5.3.2.8.2 microwave reactor reaction
A microwave tube was flame dried and purged with N2. To this tube, N-H
triazole 4.1 (1 mmol, 145.17 mg) and Rh2(Oct)4 (1 mol %, 2.21 mg) was added followed
by CHCl3 (2 mL) benzonitrile (1.5 mmol, 155 μL). A magnetic stir bar was added to the
reaction vial followed by DIPEA (0.6 mmol,105 μL). Following this, FSI derivative 4.3 (1.22
mmol, 383.36 mg) was added slowly in portions and the tube was immediately placed
into a microwave reactor. The reaction was monitored using TLC and HPLC.
5.3.3 Synthesis of Sulfonyl Imidazole Triazole
5.3.3.1 Sulfonylating reagent screen
N-H triazole (1 mmol, 145.17 mg) and sulfonylating reagent (1.1 mmol) were added
to a vial charged with a magnetic stir bar. MeCN (2.8 mL) was added to the vial followed
370
by DBU (1.1 mmol, 164.2 μL). The reaction was left to stir for 2 h while being monitored
by TLC. Apon completion, the reaction was purified using column chromatography
affording the desired product as a tan solid.
1-((1H-imidazol-1-yl)sulfonyl)-4-phenyl-1H-1,2,3-triazole (4.9)
1H NMR 1H NMR (600 MHz, Acetonitrile-d3) δ 8.45 (s, 1H), 8.19 (s, 1H), 7.90 (d, J = 9.7
Hz, 2H), 7.53 (s, 4H), 7.11 (s, 1H).
1-((1H-imidazol-1-yl)sulfonyl)-2-methyl-4-phenyl-1H-imidazole (4.10)
1H NMR (600 MHz, Acetonitrile-d3) δ 8.21 (s, 1H), 7.88 (s, 1H), 7.79 (d, J = 7.0 Hz, 2H),
7.57 (s, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 1.7 Hz, 1H),
2.61 (s, 3H).
5.3.3.2 Solvent screen
N-H triazole (1 mmol, 145.17 mg) and MSDI (1.1 mmol, 398.5 mg) were added to
a vial charged with a magnetic stir bar. CDCl3 (2.8 mL) was added to the vial followed by
DBU (1.1 mmol, 164.2 μL). The reaction was left to stir for 2 h while being monitored by
371
TLC. Apon completion, the reaction was purified using column chromatography affording
the desired product 4.9 (40 % yield) as a tan solid.
5.3.4 Sulfonyl Imidazole used in Rhodium Chemistry
Conventional Heating:
Triazole 4.9 (0.5 mmol, 137.64 mg) and rhodium catalyst (1 mol %) was added to
a vial. Following this, DCE (2 mL) and PhCN (1.5 mmol, 155 μL) was added to the via
with a reflux condenser being placed over it. The reaction vessel was placed into an oil
bath and heated to 80 °C after which, the reaction was monitored by both TLC and HPLCMS.
Microwave Heating:
Triazole 4.9 (0.5 mmol, 137.64 mg) and rhodium catalyst (1 mol %) was added to
a microwave tube. Following this, DCE (2 mL) and PhCN (1.5 mmol, 155 μL) was added
to the tube and the cap was placed over it. The reaction vessel was placed into the
microwave reactor and heated to 140 °C after which, the reaction was monitored by both
TLC and HPLC-MS.
372
5.3.5 Synthesis of Methylated Sulfonyl Imidazole Triazole
Sulfonyl imidazole triazole 4.9 (0.5 mmol, 137.64 mg) was added to a vial along
with a magnetic stir bar. DCM (2 mL) was then added to the vial and the solution was
cooled to 0 °C using a water/ice bath. After letting the reaction cool to 0 °C (~5 min),
MeOTf (0.55 mmol, 62 μL) was added dropwise after which a cap was placed on the vial.
Following this, the reaction was left to stir at 0°C for 30 minutes. After which, the reaction
vessel was removed from the cold bath and let stir for an addition 1.5 hours. The reaction
mixture was concentrated down using a roto evaporator and purified through high vacuum
affording product 4.12 (84 %).
3-methyl-1-((4-phenyl-1H-1,2,3-triazol-1-yl)sulfonyl)-1H-imidazol-3-ium
trifluoromethanesulfonate (4.12)
1H NMR (600 MHz, Acetonitrile-d3) δ 9.28 (s, 1H), 8.66 (s, 1H), 7.97 (d, J = 9.7 Hz, 2H),
7.89 (t, J = 2.1 Hz, 1H), 7.58 (d, J = 6.9 Hz, 4H), 7.53 – 7.51 (m, 1H), 3.88 (s, 3H).
13C{1H} NMR (151 MHz, Acetonitrile-d3) δ 156.38, 142.25, 139.62,132.52, 130.48,
128.35, 127.78, 127.17, 122.14, 38.31.
19F NMR (564 MHz, Acetonitrile-d3) δ -82.06.
373
5.3.6 Methylated Sulfonyl Imidazole in Rhodium Chemistry
Triazole 4.9 (0.416 mmol, 183 mg) and rhodiumRh2(oct)4 (1 mol %, 2.98 mg) was
added to a microwave tube. Following this, o-dichlorobenzene (2 mL) and PhCN (1.5
mmol, 129 μL) was added to the tube and the cap was placed over it. The reaction vessel
was placed into the microwave reactor and heated to 140 °C after which, the reaction was
monitored by both TLC and HPLC-MS.
5.3.7 Synthesis of Amidines from SO2F Triazoles
A vial charged with a magnetic stir bar was flame dried and purged with N2. To this
vial, N-H triazole 4.1 (0.5 mmol, 72.59 mg) followed by the SO2F source (0.61 mmol) was
added. To this vial, THF (0.5 mL) was added followed by DIPEA (0.6 mmol,105 μL). The
resulting solution was stirred for 5 minutes after which amine (0.6 mmol) was added. The
reaction was monitored using TLC and HPLC.
5.3.8 Synthesis of Carbene 4.8
374
FSI derivative 4.3 (1 mmol, 314.23 mg) was added to a vial charged with a magnetic stir
bar. Solvent (2 mL) was then added after which, base (1 mmol) was added dropwise. The
reaction was monitored using HPCL-MS and TLC over the course of 2 h.
5.3.9 Synthesis of Carbene 4.7 Complexes
Ir2(CODCl)4 (0.166 mmol, 112 mg) and t-BuOK (0.733 mmol, 82.3 mg) was added
to a vial in an nitrogen filled glove box. MeCN (2 mL) was then added and the reaction
was left to stir for 45 minutes. After that, FSI derivative 4.3 was added to the reaction
mixture and left to stir for an additional 1 hour and 45 minutes. The resulting reaction
mixture was filtered through celite and Teflon filter. The residue was then washed with
pentane before the filtrate was concentrated down via reduced pressure. This solid was
then subjected to analysis via MALDI.
375
5.3.10 NMRs for Chapter 4
1H NMR (600 MHz, Acetonitrile-d3) of compound 4.3
376
13C{
1H} NMR (151 MHz, Acetonitrile-d3) of compound 4.3
377
19F NMR (564 MHz, Acetonitrile-d3) of compound 4.3
378
1H NMR (600 MHz, Acetone-d6) of 4.2
379
19F NMR (564 MHz, Acetonitrile-d3) of compound 4.2
380
1H NMR (600 MHz, Acetonitrile-d3) of 4.4
381
13C{
1H} NMR (151 MHz, Acetonitrile-d3) of compound 4.4
382
19F NMR (564 MHz, Acetonitrile-d3) of compound 4.4
383
1H NMR (600 MHz, Acetone-d6) of 4.5
384
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 4.5
385
19F NMR (564 MHz, Acetone-d6) of compound 4.5
386
1H NMR (600 MHz, Acetone-d6) of 4.6
387
13C{
1H} NMR (151 MHz, Acetone-d6) of compound 4.6
388
19F NMR (564 MHz, Acetone-d6) of compound 4.5
389
1H NMR (600 MHz, Acetonitrile-d3) of 4.7
390
19F NMR (564 MHz, Acetonitrile-d3) of compound 4.7
391
1H NMR (600 MHz, Acetonitrile-d3) of 4.8
392
13C{
1H} NMR (151 MHz, Acetonitrile-d3) of compound 4.8
393
19F NMR (564 MHz, Acetonitrile-d3) of compound 4.8
394
1H NMR (600 MHz, Acetonitrile-d3) of 4.9
395
1H NMR (600 MHz, Acetonitrile-d3) of 4.10
396
1H NMR (600 MHz, Acetonitrile-d3) of 4.12
397
13C{
1H} NMR (151 MHz, Acetonitrile-d3) of compound 4.12
398
19F NMR (564 MHz, Acetonitrile-d3) of compound 4.12
399
5.3.11 References
1. Yang, S.; Chu, M.; Miao, Q., Connecting two phenazines with a four-membered
ring: the synthesis, properties and applications of cyclobuta[1,2-b:3,4-b′]diphenazines.
Journal of Materials Chemistry C 2018, 6 (14), 3651-3657.
2. Raushel, J.; Fokin, V. V., Efficient synthesis of 1-sulfonyl-1,2,3-triazoles. Org Lett
2010, 12 (21), 4952-5.
3. Lazreg, F.; Cazin, C. S. J., Copper(I)–N-Heterocyclic Carbene Complexes as
Efficient Catalysts for the Synthesis of 1,4-Disubstituted 1,2,3-Sulfonyltriazoles in Air.
Organometallics 2018, 37 (5), 679-683.
4. He, J.; Man, Z.; Shi, Y.; Li, C. Y., Synthesis of beta-Amino-alpha,beta-unsaturated
Ketone Derivatives via Sequential Rhodium-Catalyzed Sulfur Ylide
Formation/Rearrangement. J Org Chem 2015, 80 (9), 4816-23.
5. Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang,
S., Copper-catalyzed synthesis of N-sulfonyl-1,2,3-triazoles: controlling selectivity.
Angew Chem Int Ed Engl 2007, 46 (10), 1730-3.
6. Raushel, J.; Fokin, V. V., Efficient Synthesis of 1-Sulfonyl-1,2,3-triazoles. Organic
Letters 2010, 12 (21), 4952-4955.
7. Medina, F.; Besnard, C.; Lacour, J., One-step synthesis of nitrogen-containing
medium-sized rings via alpha-imino diazo intermediates. Org Lett 2014, 16 (12), 3232-5.
8. Kim, J.; Stahl, S. S., Cu-catalyzed aerobic oxidative three-component coupling
route to N-sulfonyl amidines via an ynamine intermediate. J Org Chem 2015, 80 (4), 2448-
54.
9. Whiting, M.; Fokin, V. V., Copper-Catalyzed Reaction Cascade: Direct Conversion
of Alkynes into N-Sulfonylazetidin-2-imines. Angewandte Chemie International Edition
2006, 45 (19), 3157-3161.
10. Mayo, M. S.; Yu, X.; Feng, X.; Yamamoto, Y.; Bao, M., Isoquinolone Synthesis
through SNAr Reaction of 2-Halobenzonitriles with Ketones Followed by Cyclization. The
Journal of Organic Chemistry 2015, 80 (8), 3998-4002.
11. Zhang, N.; Zhang, C.; Hu, X.; Xie, X.; Liu, Y., Nickel-Catalyzed C(sp3)–H
Functionalization of Benzyl Nitriles: Direct Michael Addition to Terminal Vinyl Ketones.
Organic Letters 2021, 23 (15), 6004-6009.
12. Aggarwal, S.; Vu, A.; Eremin, D. B.; Persaud, R.; Fokin, V. V., Arenes participate
in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes. Nature Chemistry 2023,
15 (6), 764-772.
400
13. Thomas, J.; Jana, S.; Liekens, S.; Dehaen, W., A single-step acid catalyzed
reaction for rapid assembly of NH-1,2,3-triazoles. Chemical Communications 2016, 52
(59), 9236-9239.
14. Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.; Sharpless, K. B.; Dong,
J., A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt
Emerging as an “F−SO2+” Donor of Unprecedented Reactivity, Selectivity, and Scope.
Angewandte Chemie International Edition 2018, 57 (10), 2605-2610.
15. Zhou, H.; Mukherjee, P.; Liu, R.; Evrard, E.; Wang, D.; Humphrey, J. M.; Butler,
T. W.; Hoth, L. R.; Sperry, J. B.; Sakata, S. K.; Helal, C. J.; am Ende, C. W., Introduction
of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides. Organic
Letters 2018, 20 (3), 812-815.
16. Grimster, N.; Zhang, L.; Fokin, V. V., Synthesis and Reactivity of Rhodium(II) NTriflyl Azavinyl Carbenes. Journal of the American Chemical Society 2010, 132 (8), 2510-
2511.
401
Bibliography
1.1. Ge, L.; Zhang, C.; Pan, C.; Wang, D.-X.; Liu, D.-Y.; Li, Z.-Q.; Shen, P.; Tian,
L.; Feng, C., Photoredox-catalyzed C–C bond cleavage of cyclopropanes for the
formation of C(sp3)–heteroatom bonds. Nature Communications 2022, 13 (1), 5938.
1.2. Katritzky, A. R.; Brycki, B. E., The mechanisms of nucleophilic substitution in
aliphatic compounds. Chemical Society Reviews 1990, 19 (2), 83-105.
1.3. Korch, K. M.; Watson, D. A., Cross-Coupling of Heteroatomic Electrophiles.
Chemical Reviews 2019, 119 (13), 8192-8228.
1.4. Wiberg, K. B., The Concept of Strain in Organic Chemistry. Angewandte Chemie
International Edition in English 1986, 25 (4), 312-322.
1.5. Beletskaya, I. P.; Nenajdenko, V. G., Towards the 150th Anniversary of the
Markovnikov Rule. Angewandte Chemie International Edition 2019, 58 (15), 4778-4789.
1.6. Borden, W. T.; Hoffmann, R.; Stuyver, T.; Chen, B., Dioxygen: What Makes This
Triplet Diradical Kinetically Persistent? Journal of the American Chemical Society 2017,
139 (26), 9010-9018.
1.7. Lu, P.; Wang, Y., The thriving chemistry of ketenimines. Chemical Society Reviews
2012, 41 (17), 5687-5705.
1.8. Saranya, S.; Anilkumar, G., Copper Catalysis. In Copper Catalysis in Organic
Synthesis, 2020; pp 1-5.
1.9. Zard, S. Z., Radicals in Action: A Festival of Radical Transformations. Organic
Letters 2017, 19 (6), 1257-1269.
1.10. Ingold, K. U., Kinetic and mechanistic studies of free radical reactions in the 21st
century. 1997, 69 (2), 241-244.
1.11. Rowlands, G. J., Radicals in organic synthesis. Part 1. Tetrahedron 2009, 65 (42),
8603-8655.
1.12. Carbon–Carbon Bond Formation by Free-Radical Reactions. In Organic
Chemistry, 2004; pp 272-291.
1.13. Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S., Radicals: Reactive Intermediates
with Translational Potential. Journal of the American Chemical Society 2016, 138 (39),
12692-12714.
1.14. Jasperse, C. P.; Curran, D. P.; Fevig, T. L., Radical reactions in natural product
synthesis. Chemical Reviews 1991, 91 (6), 1237-1286.
402
1.15. Silva, T. S.; Coelho, F., Methodologies for the synthesis of quaternary carbon
centers via hydroalkylation of unactivated olefins: twenty years of advances. Beilstein
Journal of Organic Chemistry 2021, 17, 1565-1590.
1.16. Rao, Y. K.; Nagarajan, M., Formal total synthesis of (.+-.)-silphinene via radical
cyclization. The Journal of Organic Chemistry 1989, 54 (24), 5678-5683.
1.17. Curran, D. P.; Kuo, S. C., Tandem radical cyclization approach to angular
triquinanes. A short synthesis of (.+-.)-silphiperfol-6-ene and (.+-.)-9-episilphiperfol-6-ene.
Journal of the American Chemical Society 1986, 108 (5), 1106-1107.
1.18. Togo, H., Advanced free radical reactions for organic synthesis. Elsevier
Amsterdam: 2004; Vol. 2.
1.19. Sheppard, C. S.; Kamath, V. R., The selection and use of free radical initiators.
Polymer Engineering & Science 1979, 19 (9), 597-606.
1.20. Walling, C., Some properties of radical reactions important in synthesis.
Tetrahedron 1985, 41 (19), 3887-3900.
1.21. Curran, D. P., 4.2 - Radical Cyclizations and Sequential Radical Reactions. In
Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds. Pergamon: Oxford,
1991; pp 779-831.
1.22. Studer, A.; Amrein, S., Tin hydride substitutes in reductive radical chain reactions.
Synthesis 2002, 2002 (07), 835-849.
1.23. Johnson, R. G.; Ingham, R. K., The Degradation Of Carboxylic Acid Salts By
Means Of Halogen - The Hunsdiecker Reaction. Chemical Reviews 1956, 56 (2), 219-
269.
1.24. Fu, G. C., Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A
Radical Alternative to SN1 and SN2 Processes. ACS Central Science 2017, 3 (7), 692-
700.
1.25. Beletskaya, I. P.; Cheprakov, A. V., The Heck Reaction as a Sharpening Stone of
Palladium Catalysis. Chemical Reviews 2000, 100 (8), 3009-3066.
1.26. Farhang, M.; Akbarzadeh, A. R.; Rabbani, M.; Ghadiri, A. M., A retrospectiveprospective review of Suzuki–Miyaura reaction: From cross-coupling reaction to
pharmaceutical industry applications. Polyhedron 2022, 227, 116124.
1.27. Giese, B., Formation of CC Bonds by Addition of Free Radicals to Alkenes.
Angewandte Chemie International Edition in English 1983, 22 (10), 753-764.
1.28. Kitcatt, D. M.; Nicolle, S.; Lee, A.-L., Direct decarboxylative Giese reactions.
Chemical Society Reviews 2022, 51 (4), 1415-1453.
403
1.29. Krutak, J. J.; Burpitt, R. D.; Moore, W. H.; Hyatt, J. A., Chemistry of ethenesulfonyl
fluoride. Fluorosulfonylethylation of organic compounds. The Journal of Organic
Chemistry 1979, 44 (22), 3847-3858.
1.30. Baran, P. S.; Richter, J. M., Direct Coupling of Indoles with Carbonyl Compounds:
Short, Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and
Fischerindole Alkaloid Families. Journal of the American Chemical Society 2004, 126
(24), 7450-7451.
1.31. Zuo, Z.; Xie, W.; Ma, D., Total Synthesis and Absolute Stereochemical Assignment
of (−)-Communesin F. Journal of the American Chemical Society 2010, 132 (38), 13226-
13228.
1.32. Zhang, M.; Huang, X.; Shen, L.; Qin, Y., Total Synthesis of the Akuammiline
Alkaloid (±)-Vincorine. Journal of the American Chemical Society 2009, 131 (16), 6013-
6020.
1.33. Wei, Y.; Zhao, D.; Ma, D., Total Synthesis of the Indole Alkaloid (±)- and (+)-Methyl
N-Decarbomethoxychanofruticosinate. Angewandte Chemie International Edition 2013,
52 (49), 12988-12991.
1.34. Plesniak, M. P.; Huang, H.-M.; Procter, D. J., Radical cascade reactions triggered
by single electron transfer. Nature Reviews Chemistry 2017, 1 (10), 0077.
1.35. Moad, G.; Rizzardo, E.; Thang, S. H., Toward Living Radical Polymerization.
Accounts of Chemical Research 2008, 41 (9), 1133-1142.
1.36. Huang, H.-M.; Procter, D. J., Radical–Radical Cyclization Cascades of
Barbiturates Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls. Journal
of the American Chemical Society 2016, 138 (24), 7770-7775.
1.37. Byers, P. M.; Alabugin, I. V., Polyaromatic Ribbons from Oligo-Alkynes via
Selective Radical Cascade: Stitching Aromatic Rings with Polyacetylene Bridges. Journal
of the American Chemical Society 2012, 134 (23), 9609-9614.
1.38. Lovering, F.; Bikker, J.; Humblet, C., Escape from Flatland: Increasing Saturation
as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry 2009, 52
(21), 6752-6756.
1.39. Cheung, C. W.; Hu, X., Amine synthesis via iron-catalysed reductive coupling of
nitroarenes with alkyl halides. Nature Communications 2016, 7 (1), 12494.
1.40. Afanasyev, O. I.; Kuchuk, E.; Usanov, D. L.; Chusov, D., Reductive Amination in
the Synthesis of Pharmaceuticals. Chemical Reviews 2019, 119 (23), 11857-11911.
1.41. Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan, C.-M.;
Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas,
J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.;
404
Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S., Strain-Release
Heteroatom Functionalization: Development, Scope, and Stereospecificity. Journal of the
American Chemical Society 2017, 139 (8), 3209-3226.
1.42. Heravi, M. M.; Kheilkordi, Z.; Zadsirjan, V.; Heydari, M.; Malmir, M., BuchwaldHartwig reaction: An overview. Journal of Organometallic Chemistry 2018, 861, 17-104.
1.43. Alfonso, N.; Do, V. K.; Chavez, A. J.; Chen, Y.; Williams, T. J., Catalyst
carbonylation: a hidden, but essential, step in reaction initiation. Catalysis Science &
Technology 2021, 11 (7), 2361-2368.
1.44. Bonaparte, A. C.; Betush, M. P.; Panseri, B. M.; Mastarone, D. J.; Murphy, R. K.;
Murphree, S. S., Novel Aerobic Oxidation of Primary Sulfones to Carboxylic Acids.
Organic Letters 2011, 13 (6), 1447-1449.
1.45. Tian, H.; Ermolenko, L.; Gabant, M.; Vergne, C.; Moriou, C.; Retailleau, P.; AlMourabit, A., Pyrrole-Assisted and Easy Oxidation of Cyclic α-Amino Acid- Derived
Diketopiperazines under Mild Conditions. Advanced Synthesis & Catalysis 2011, 353 (9),
1525-1533.
1.46. Li, T.; Vijeta, A.; Casadevall, C.; Gentleman, A. S.; Euser, T.; Reisner, E., Bridging
Plastic Recycling and Organic Catalysis: Photocatalytic Deconstruction of Polystyrene via
a C–H Oxidation Pathway. ACS Catalysis 2022, 12 (14), 8155-8163.
1.47. Walczak, M. A. A.; Krainz, T.; Wipf, P., Ring-Strain-Enabled Reaction Discovery:
New Heterocycles from Bicyclo[1.1.0]butanes. Accounts of Chemical Research 2015, 48
(4), 1149-1158.
1.48. Baskin, J. M.; Prescher, J. A.; Laughlin, S. T.; Agard, N. J.; Chang, P. V.; Miller,
I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R., Copper-free click chemistry for dynamic in
vivo imaging. Proceedings of the National Academy of Sciences 2007, 104 (43), 16793-
16797.
1.49. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S., A Facile Access to NSulfonylimidates and Their Synthetic Utility for the Transformation to Amidines and
Amides. Organic Letters 2006, 8 (7), 1347-1350.
1.50. Alajarin, M.; Marin-Luna, M.; Vidal, A., Recent Highlights in Ketenimine Chemistry.
European Journal of Organic Chemistry 2012, 2012 (29), 5637-5653.
1.51. Lu, P.; Wang, Y., Strategies for Heterocyclic Synthesis via Cascade Reactions
Based on Ketenimines. Synlett 2010, 2010 (02), 165-173.
1.52. Yoo, J. E.; Chang, S., Copper-Catalyzed Multicomponent Reactions: Securing a
Catalytic Route to Ketenimine Intermediates and their Reactivities. Current Organic
Chemistry 2009, 13 (18), 1766-1776.
1.53. Perst, H., Science of Synthesis. Thieme Chemistry: 2006; Vol. 23, p 781.
405
1.54. Sung, K., N-Substituent effects on the stability of ketenimines. Journal of the
Chemical Society, Perkin Transactions 2 2000, (4), 847-852.
1.55. Sung, K., Substituent effects on stability of ketenimines. Journal of the Chemical
Society, Perkin Transactions 2 1999, (6), 1169-1174.
1.56. Staudinger, H.; Meyer, J., Über neue organische phosphorverbindungen III.
Phosphinmethylenderivate und phosphinimine. Helvetica Chimica Acta 1919, 2 (1), 635-
646.
1.57. Yang, Y.-Y.; Shou, W.-G.; Hong, D.; Wang, Y.-G., Selective Synthesis of 4-
Alkylidene-β-lactams and N,N′-Diarylamidines from Azides and Aryloxyacetyl Chlorides
via a Ketenimine-Participating One-Pot Cascade Process. The Journal of Organic
Chemistry 2008, 73 (9), 3574-3577.
1.58. Hudnall, T. W.; Moorhead, E. J.; Gusev, D. G.; Bielawski, C. W., N,N′-
Diamidoketenimines via Coupling of Isocyanides to an N-Heterocyclic Carbene. The
Journal of Organic Chemistry 2010, 75 (8), 2763-2766.
1.59. Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, S. Y., Aminobenzannulation via
metathesis of isonitriles using chromium carbene complexes. Journal of the American
Chemical Society 1992, 114 (22), 8722-8724.
1.60. Qiu, G.; Ding, Q.; Wu, J., Recent advances in isocyanide insertion chemistry.
Chemical Society Reviews 2013, 42 (12), 5257-5269.
1.61. Katagiri, T.; Handa, M.; Asano, H.; Asanuma, T.; Mori, T.; Jukurogi, T.; Uneyama,
K., Preparations and reactions of 2-trifluoromethylketenimines. Journal of Fluorine
Chemistry 2009, 130 (8), 714-717.
1.62. Fromont, C.; Masson, S., Reactivity of N-phenyl silylated ketenimines with
electrophilic reagents. Tetrahedron 1999, 55 (17), 5405-5418.
1.63. DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H.; Deng, J.;
Lohse, A. G.; Zhang, Y.-S., N-Allyl-N-sulfonyl Ynamides as Synthetic Precursors to
Amidines and Vinylogous Amidines. An Unexpected N-to-C 1,3-Sulfonyl Shift in Nitrile
Synthesis. The Journal of Organic Chemistry 2011, 76 (12), 5092-5103.
1.64. Bendikov, M.; Duong, H. M.; Bolanos, E.; Wudl, F., An Unexpected Two-Group
Migration Involving a Sulfonynamide to Nitrile Rearrangement. Mechanistic Studies of a
Thermal N → C Tosyl Rearrangement. Organic Letters 2005, 7 (5), 783-786.
1.65. Coffinier, D.; El Kaim, L.; Grimaud, L., Isocyanide-Based Two-Step ThreeComponent Keteneimine Formation. Organic Letters 2009, 11 (8), 1825-1827.
1.66. Oakes, T. R.; Donovan, D. J., Reactions of isocyanides with activated acetylenes
in protic solvents. The Journal of Organic Chemistry 1973, 38 (7), 1319-1325.
406
1.67. Worrell, B. T.; Malik, J. A.; Fokin, V. V., Direct Evidence of a Dinuclear Copper
Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions. Science 2013, 340 (6131),
457-460.
1.68. Kubíčková, A.; Markos, A.; Voltrová, S.; Marková, A.; Filgas, J.; Klepetářová, B.;
Slavíček, P.; Beier, P., Aza-Wolff rearrangement of N-fluoroalkyl triazoles to ketenimines.
Organic Chemistry Frontiers 2023, 10 (13), 3201-3206.
1.69. She, J.; Jiang, Z.; Wang, Y., One-Pot Synthesis of Functionalized Benzimidazoles
and 1H-Pyrimidines via Cascade Reactions of o-Aminoanilines or Naphthalene-1,8-
diamine with Alkynes and p-Tolylsulfonyl Azide. Synlett 2009, 2009 (12), 2023-2027.
1.70. Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S., Synthetic Utility of Ammonium Salts
in a Cu-Catalyzed Three-Component Reaction as a Facile Coupling Partner. The Journal
of Organic Chemistry 2008, 73 (23), 9454-9457.
1.71. Cho, S. H.; Chang, S., Room temperature copper-catalyzed 2-functionalization of
pyrrole rings by a three-component coupling reaction. Angewandte Chemie 2008, 120
(15), 2878.
1.72. Wang, J.; Wang, J.; Zhu, Y.; Lu, P.; Wang, Y., Copper-cascade catalysis:
synthesis of 3-functionalized indoles. Chemical Communications 2011, 47 (11), 3275-
3277.
1.73. Cheng, Y.; Ma, Y.-G.; Wang, X.-R.; Mo, J.-M., An Unprecedented Chemospecific
and Stereoselective Tandem Nucleophilic Addition/Cycloaddition Reaction of Nucleophilic
Carbenes with Ketenimines. The Journal of Organic Chemistry 2009, 74 (2), 850-855.
1.74. Mo, J.-M.; Ma, Y.-G.; Cheng, Y., Synthesis of novel synthetic intermediates from
the reaction of benzimidazole and triazole carbenes with ketenimines and their application
in the construction of spiro-pyrroles. Organic & Biomolecular Chemistry 2009, 7 (23),
5010-5019.
1.75. Mermerian, A. H.; Fu, G. C., Nucleophile-Catalyzed Asymmetric Acylations of Silyl
Ketene Imines: Application to the Enantioselective Synthesis of Verapamil. Angewandte
Chemie International Edition 2005, 44 (6), 949-952.
1.76. Ruiz, J.; Gonzalo, M. P.; Vivanco, M.; Rosario Díaz, M.; García-Granda, S., A
three-component reaction involving isocyanide, phosphine and ketenimine functionalities.
Chemical Communications 2011, 47 (14), 4270-4272.
1.77. Alajarín, M.; Vidal, A.; Tovar, F.; Ramírez de Arellano, M. C.; Cossío, F. P.;
Arrieta, A.; Lecea, B., New Stereoselective Intramolecular [2 + 2] Cycloadditions between
Ketenimines and Imines on an ortho-Benzylic Scaffold: 1,4-Asymmetric Induction. The
Journal of Organic Chemistry 2000, 65 (22), 7512-7515.
1.78. Li, S.; Luo, Y.; Wu, J., Three-Component Reaction of N′-(2-
Alkynylbenzylidene)hydrazide, Alkyne, with Sulfonyl Azide via a Multicatalytic Process: A
407
Novel and Concise Approach to 2-Amino-H-pyrazolo[5,1-a]isoquinolines. Organic Letters
2011, 13 (16), 4312-4315.
1.79. Lu, W.; Song, W.; Hong, D.; Lu, P.; Wang, Y., Copper-Catalyzed One-Pot
Synthesis of 2-Alkylidene-1,2,3,4- tetrahydropyrimidines. Advanced Synthesis &
Catalysis 2009, 351 (11-12), 1768-1772.
1.80. Alajarín, M.; Ortín, M.-M.; Sánchez-Andrada, P.; Vidal, Á., Tandem
Pseudopericyclic Reactions: [1,5]-X Sigmatropic Shift/6π-Electrocyclic Ring Closure
Converting N-(2-X-Carbonyl)phenyl Ketenimines into 2-X-Quinolin-4(3H)-ones. The
Journal of Organic Chemistry 2006, 71 (21), 8126-8139.
1.81. Alajarin, M.; Bonillo, B.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Orenes,
R.-A., Domino reactions initiated by intramolecular hydride transfers from
tri(di)arylmethane fragments to ketenimine and carbodiimide functions. Organic &
Biomolecular Chemistry 2010, 8 (20), 4690-4700.
1.82. Wentrup, C.; Rao, V. V. R.; Frank, W.; Fulloon, B. E.; Moloney, D. W. J.; Mosandl,
T., Aryliminopropadienone−C-Amidoketenimine− Amidinoketene−2-Aminoquinolone
Cascades and the Ynamine−Isocyanate Reaction. The Journal of Organic Chemistry
1999, 64 (10), 3608-3619.
1.83. Alajarín, M.; Vidal, A.; Ortín, M.-M.; Bautista, D., Persistent radical effect in the
intramolecular addition of benzylic radicals onto ketenimines: selective cross-coupling of
α-(indol-2-yl)benzyl radicals with the 1-cyano-1-methylethyl radical. New Journal of
Chemistry 2004, 28 (5), 570-577.
1.84. Kim, S. S.; Zhu, Y.; Lee, K. H., Thermal Isomerizations of Ketenimines to Nitriles:
Evaluations of Sigma-Dot (σ•) Constants for Spin-Delocalizations. The Journal of Organic
Chemistry 2000, 65 (10), 2919-2923.
1.85. Arevalo, R.; Chirik, P. J., Enabling Two-Electron Pathways with Iron and Cobalt:
From Ligand Design to Catalytic Applications. Journal of the American Chemical Society
2019, 141 (23), 9106-9123.
1.86. Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W., Copper-Catalyzed C–H
Functionalization Reactions: Efficient Synthesis of Heterocycles. Chemical Reviews
2015, 115 (3), 1622-1651.
1.87. Zhang, C.; Tang, C.; Jiao, N., Recent advances in copper-catalyzed
dehydrogenative functionalization via a single electron transfer (SET) process. Chemical
Society Reviews 2012, 41 (9), 3464-3484.
1.88. Sindhu, K. S.; Anilkumar, G., Recent advances and applications of Glaser coupling
employing greener protocols. RSC Advances 2014, 4 (53), 27867-27887.
1.89. Baslé, O.; Li, C.-J., Copper-Catalyzed Oxidative sp3 C−H Bond Arylation with Aryl
Boronic Acids. Organic Letters 2008, 10 (17), 3661-3663.
408
1.90. Li, Z.; Li, C.-J., Highly Efficient Copper-Catalyzed Nitro-Mannich Type Reaction:
Cross-Dehydrogenative-Coupling between sp3 C−H Bond and sp3 C−H Bond. Journal of
the American Chemical Society 2005, 127 (11), 3672-3673.
1.91. Borduas, N.; Powell, D. A., Copper-Catalyzed Oxidative Coupling of Benzylic C−H
Bonds with 1,3-Dicarbonyl Compounds. The Journal of Organic Chemistry 2008, 73 (19),
7822-7825.
1.92. Yu, C.; Zhang, Y.; Zhang, S.; Li, H.; Wang, W., Cu(ii) catalyzed oxidation-[3+2]
cycloaddition-aromatization cascade: Efficient synthesis of pyrrolo [2, 1-a] isoquinolines.
Chemical Communications 2011, 47 (3), 1036-1038.
1.93. Zhao, H.; Wang, M.; Su, W.; Hong, M., Copper-Catalyzed Intermolecular
Amination of Acidic Aryl C H Bonds with Primary Aromatic Amines. Advanced Synthesis
& Catalysis 2010, 352 (8), 1301-1306.
1.94. Powell, D. A.; Fan, H., Copper-Catalyzed Amination of Primary Benzylic C−H
Bonds with Primary and Secondary Sulfonamides. The Journal of Organic Chemistry
2010, 75 (8), 2726-2729.
1.95. Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C., A general approach
to the enantioselective α-oxidation of aldehydesvia synergistic catalysis. Chemical
Science 2012, 3 (1), 58-61.
1.96. Li, S.; Wu, J., Synthesis of H-Pyrazolo[5,1-a]isoquinolines via Copper(II)-
Catalyzed Oxidation of an Aliphatic C−H Bond of Tertiary Amine in Air. Organic Letters
2011, 13 (4), 712-715.
1.97. Brasche, G.; Buchwald, S. L., C H Functionalization/C N Bond Formation:
Copper-Catalyzed Synthesis of Benzimidazoles from Amidines. Angewandte Chemie
International Edition 2008, 47 (10), 1932-1934.
1.98. Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H., Copper-Catalyzed Aerobic C(sp2)–H
Functionalization for C–N Bond Formation: Synthesis of Pyrazoles and Indazoles. The
Journal of Organic Chemistry 2013, 78 (8), 3636-3646.
1.99. Li, J.; Neuville, L., Copper-Catalyzed Oxidative Diamination of Terminal Alkynes by
Amidines: Synthesis of 1,2,4-Trisubstituted Imidazoles. Organic Letters 2013, 15 (7),
1752-1755.
1.100. Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R., Pyrrolidine and Piperidine
Formation via Copper(II) Carboxylate-Promoted Intramolecular Carboamination of
Unactivated Olefins: Diastereoselectivity and Mechanism. The Journal of Organic
Chemistry 2007, 72 (10), 3896-3905.
1.101. Cheung, C. W.; Buchwald, S. L., Room Temperature Copper(II)-Catalyzed
Oxidative Cyclization of Enamides to 2,5-Disubstituted Oxazoles via Vinylic C–H
Functionalization. The Journal of Organic Chemistry 2012, 77 (17), 7526-7537.
409
1.102. Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R., Copper-Catalyzed
Intramolecular Alkene Carboetherification: Synthesis of Fused-Ring and Bridged-Ring
Tetrahydrofurans. Journal of the American Chemical Society 2012, 134 (29), 12149-
12156.
1.103. Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu, Q., Cu-Catalyzed Oxidative C(sp2)–H
Cycloetherification of o-Arylphenols for the Preparation of Dibenzofurans. Organic Letters
2012, 14 (4), 1078-1081.
1.104. Gallardo-Donaire, J.; Martin, R., Cu-Catalyzed Mild C(sp2)–H Functionalization
Assisted by Carboxylic Acids en Route to Hydroxylated Arenes. Journal of the American
Chemical Society 2013, 135 (25), 9350-9353.
1.105. Zhang, C.; Jiao, N., Dioxygen Activation under Ambient Conditions: Cu-Catalyzed
Oxidative Amidation−Diketonization of Terminal Alkynes Leading to α-Ketoamides.
Journal of the American Chemical Society 2010, 132 (1), 28-29.
2.1. Zard, S. Z., Radicals in Action: A Festival of Radical Transformations. Organic
Letters 2017, 19 (6), 1257-1269.
2.2. Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S., Radicals: Reactive Intermediates
with Translational Potential. Journal of the American Chemical Society 2016, 138 (39),
12692-12714.
2.3. Moad, G.; Rizzardo, E.; Thang, S. H., Toward Living Radical Polymerization.
Accounts of Chemical Research 2008, 41 (9), 1133-1142.
2.4. Budnikov, A. S.; Krylov, I. B.; Mulina, O. M.; Lapshin, D. A.; Terent'ev, A. O., CHFunctionalization of Heterocycles with the Formation of C−O, C−N, C−S/Se, and C−P
Bonds by Intermolecular Addition of Heteroatom-Centered Radicals. Advanced Synthesis
& Catalysis 2023, 365 (11), 1714-1755.
2.5. Hu, X.; Chen, X.; Li, B.; He, G.; Chen, G., Construction of Peptide Macrocycles
via Radical-Mediated Intramolecular C–H Alkylations. Organic Letters 2021, 23 (3), 716-
721.
2.6. Hashimoto, S.; Katoh, S.-i.; Kato, T.; Urabe, D.; Inoue, M., Total Synthesis of
Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo
Cyclization. Journal of the American Chemical Society 2017, 139 (45), 16420-16429.
2.7. Friese, F. W.; Mück-Lichtenfeld, C.; Studer, A., Remote C−H functionalization
using radical translocating arylating groups. Nature Communications 2018, 9 (1), 2808.
2.8. Dewar, M. J. S., A Molecular Orbital Theory of Organic Chemistry. IV.1 Free
Radicals. Journal of the American Chemical Society 1952, 74 (13), 3353-3354.
410
2.9. Tang, B.; Zhao, J.; Xu, J.-F.; Zhang, X., Tuning the stability of organic radicals:
from covalent approaches to non-covalent approaches. Chemical Science 2020, 11 (5),
1192-1204.
2.10. Studer, A.; Curran, D. P., Catalysis of Radical Reactions: A Radical Chemistry
Perspective. Angewandte Chemie International Edition 2016, 55 (1), 58-102.
2.11. Amaoka, Y.; Kamijo, S.; Hoshikawa, T.; Inoue, M., Radical Amination of C(sp3)–
H Bonds Using N-Hydroxyphthalimide and Dialkyl Azodicarboxylate. The Journal of
Organic Chemistry 2012, 77 (22), 9959-9969.
2.12. Caruso, M.; Navalón, S.; Cametti, M.; Dhakshinamoorthy, A.; Punta, C.; García,
H., Challenges and opportunities for N-hydroxyphthalimide supported over
heterogeneous solids for aerobic oxidations. Coordination Chemistry Reviews 2023, 486,
215141.
2.13. Chiefari, J.; Mayadunne, R. T. A.; Moad, C. L.; Moad, G.; Rizzardo, E.; Postma,
A.; Thang, S. H., Thiocarbonylthio Compounds (SC(Z)S−R) in Free Radical
Polymerization with Reversible Addition-Fragmentation Chain Transfer (RAFT
Polymerization). Effect of the Activating Group Z. Macromolecules 2003, 36 (7), 2273-
2283.
2.14. Veciana, J.; Carilla, J.; Miravitlles, C.; Molins, E., Free radicals as clathrate hosts:
crystal and molecular structure of 1: 1 perchlorotriphenylmethyl radical–benzene. Journal
of the Chemical Society, Chemical Communications 1987, (11), 812-814.
2.15. Sowndarya S. V, S.; St. John, P. C.; Paton, R. S., A quantitative metric for organic
radical stability and persistence using thermodynamic and kinetic features. Chemical
Science 2021, 12 (39), 13158-13166.
2.16. Viehe, H. G.; Merényi, R.; Stella, L.; Janousek, Z., Capto-dative Substituent
Effects in Syntheses with Radicals and Radicophiles [New synthetic methods (32)].
Angewandte Chemie International Edition in English 1979, 18 (12), 917-932.
2.17. Viehe, H. G.; Janousek, Z.; Merenyi, R.; Stella, L., The captodative effect.
Accounts of Chemical Research 1985, 18 (5), 148-154.
2.18. Tanaka, H., Captodative modification in polymer science. Progress in Polymer
Science 2003, 28 (7), 1171-1203.
2.19. Baldock, R. W.; Hudson, P.; Katritzky, A. R.; Soti, F., Stable free radicals. Part I.
A new principle governing the stability of organic free radicals. Journal of the Chemical
Society, Perkin Transactions 1 1974, (0), 1422-1427.
2.20. De Vries, L., The evidence for generation of dimethylaminocyanocarbene in the
thermolysis of dimethylaminomalononitrile. The dimethylamino(dicyano- and
cyano)methyl radicals, carbon analogs of the nitroxides. Journal of the American
Chemical Society 1978, 100 (3), 926-933.
411
2.21. Peterson, J. P.; Winter, A. H., Solvent Effects on the Stability and Delocalization of
Aryl Dicyanomethyl Radicals: The Captodative Effect Revisited. Journal of the American
Chemical Society 2019, 141 (32), 12901-12906.
2.22. Stella, L.; Harvey, J. N., Synthetic Utility of the Captodative Effect. In Radicals in
Organic Synthesis, 2001; pp 360-380.
2.23. Golden, D. L.; Suh, S.-E.; Stahl, S. S., Radical C(sp3)–H functionalization and
cross-coupling reactions. Nature Reviews Chemistry 2022, 6 (6), 405-427.
2.24. Peters, K. S., Nature of Dynamic Processes Associated with the SN1 Reaction
Mechanism. Chemical Reviews 2007, 107 (3), 859-873.
2.25. Patil, P.; Zheng, Q.; Kurpiewska, K.; Dömling, A., The isocyanide SN2 reaction.
Nature Communications 2023, 14 (1), 5807.
2.26. He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q., Palladium-Catalyzed
Transformations of Alkyl C–H Bonds. Chemical Reviews 2017, 117 (13), 8754-8786.
2.27. Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.,
Functionalization of Organic Molecules by Transition-Metal-Catalyzed C(sp3) H
Activation. Chemistry – A European Journal 2010, 16 (9), 2654-2672.
2.28. Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q., Enantioselective
C(sp3)‒H bond activation by chiral transition metal catalysts.
Science 2018, 359 (6377), eaao4798.
2.29. Gupta, A.; Kumar, J.; Rahaman, A.; Singh, A. K.; Bhadra, S., Functionalization of
C(sp3)-H bonds adjacent to heterocycles catalyzed by earth abundant transition metals.
Tetrahedron 2021, 98, 132415.
2.30. Davies, H. M. L.; Manning, J. R., Catalytic C–H functionalization by metal
carbenoid and nitrenoid insertion. Nature 2008, 451 (7177), 417-424.
2.31. Davies, H. M. L.; Alford, J. S., Reactions of metallocarbenes derived from Nsulfonyl-1,2,3-triazoles. Chemical Society Reviews 2014, 43 (15), 5151-5162.
2.32. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L., Catalytic Carbene Insertion into
C−H Bonds. Chemical Reviews 2010, 110 (2), 704-724.
2.33. Beller, M.; Seayad, J.; Tillack, A.; Jiao, H., Catalytic Markovnikov and antiMarkovnikov Functionalization of Alkenes and Alkynes: Recent Developments and
Trends. Angewandte Chemie International Edition 2004, 43 (26), 3368-3398.
2.34. Stuhr, R.; Bayer, P.; von Wangelin, A. J., The Diverse Modes of Oxygen Reactivity
in Life & Chemistry. ChemSusChem 2022, 15 (24), e202201323.
412
2.35. Sterckx, H.; Morel, B.; Maes, B. U. W., Catalytic Aerobic Oxidation of C(sp3)−H
Bonds. Angewandte Chemie International Edition 2019, 58 (24), 7946-7970.
2.36. Liu, X.; Ryabenkova, Y.; Conte, M., Catalytic oxygen activation versus
autoxidation for industrial applications: a physicochemical approach. Physical Chemistry
Chemical Physics 2015, 17 (2), 715-731.
2.37. Zhang, C.; Zhang, L.; Jiao, N., Multiple Oxidative Dehydrogenative
Functionalization of Arylacetaldehydes Using Molecular Oxygen as Oxidant Leading to 2-
Oxo-acetamidines. Advanced Synthesis & Catalysis 2012, 354 (7), 1293-1300.
2.38. Chang, S.-Y.; Bae, S. J.; Lee, M. Y.; Baek, S.-h.; Chang, S.; Kim, S. H., Chemical
affinity matrix-based identification of prohibitin as a binding protein to anti-resorptive
sulfonyl amidine compounds. Bioorganic & Medicinal Chemistry Letters 2011, 21 (2), 727-
729.
2.39. Gobis, K.; Foks, H.; Sławiński, J.; Sikorski, A.; Trzybiński, D.; AugustynowiczKopeć, E.; Napiórkowska, A.; Bojanowski, K., Synthesis, structure, and biological activity
of novel heterocyclic sulfonyl-carboximidamides. Monatshefte für Chemie - Chemical
Monthly 2013, 144 (5), 647-658.
2.40. Zhao, Y. Z. Z. C. M. Y. W. C.-C. O.-P. S. o. N. S. A. f. S. H. T. A.; Sulfonyl, A. CopperCatalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal
Alkynes and Sulfonyl Azides Molecules [Online], 2021.
2.41. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S., A Facile Access to NSulfonylimidates and Their Synthetic Utility for the Transformation to Amidines and
Amides. Organic Letters 2006, 8 (7), 1347-1350.
2.42. Bugden, F. E.; Clarkson, G. J.; Greenhalgh, M. D., Lithiation-Functionalisation of
Triazoles Bearing Electron-Withdrawing N-Substituents: Challenges and Solutions**.
European Journal of Organic Chemistry 2023, 26 (5), e202201459.
2.43. Raushel, J.; Fokin, V. V., Efficient Synthesis of 1-Sulfonyl-1,2,3-triazoles. Organic
Letters 2010, 12 (21), 4952-4955.
2.44. Whiting, M.; Fokin, V. V., Copper-Catalyzed Reaction Cascade: Direct Conversion
of Alkynes into N-Sulfonylazetidin-2-imines. Angewandte Chemie International Edition
2006, 45 (19), 3157-3161.
2.45. Ajvazi, N.; Stavber, S. Electrophilic Iodination of Organic Compounds Using
Elemental Iodine or Iodides: Recent Advances 2008–2021: Part I Compounds [Online],
2022, p. 3-24.
2.46. Togo, H.; Iida, S., Synthetic Use of Molecular Iodine for Organic Synthesis. Synlett
2006, 2006 (14), 2159-2175.
413
2.47. Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V., RhodiumCatalyzed Transannulation of 1,2,3-Triazoles with Nitriles. Journal of the American
Chemical Society 2008, 130 (45), 14972-14974.
2.48. Breitwieser, K.; Bahmann, H.; Weiss, R.; Munz, D., Gauging Radical Stabilization
with Carbenes. Angewandte Chemie International Edition 2022, 61 (37), e202206390.
2.49. Karimi, B.; Golshani, B., Mild and Highly Efficient Method for the Silylation of
Alcohols Using Hexamethyldisilazane Catalyzed by Iodine under Nearly Neutral Reaction
Conditions. The Journal of Organic Chemistry 2000, 65 (21), 7228-7230.
2.50. Weiss, E., Structures of Organo Alkali Metal Complexes and Related Compounds.
Angewandte Chemie International Edition in English 1993, 32 (11), 1501-1523.
2.51. Inoue, R.; Yamaguchi, M.; Murakami, Y.; Okano, K.; Mori, A., Revisiting of
Benzophenone Ketyl Still: Use of a Sodium Dispersion for the Preparation of Anhydrous
Solvents. ACS Omega 2018, 3 (10), 12703-12706.
2.52. Howard, J. A.; Ingold, K. U., Self-reaction of sec-butylperoxy radicals. Confirmation
of the Russell mechanism. Journal of the American Chemical Society 1968, 90 (4), 1056-
1058.
2.53. Su, Y.; Sun, X.; Wu, G.; Jiao, N., Catalyst-Controlled Highly Selective Coupling
and Oxygenation of Olefins: A Direct Approach to Alcohols, Ketones, and Diketones.
Angewandte Chemie International Edition 2013, 52 (37), 9808-9812.
2.54. Presolski, S. I.; Hong, V. P.; Finn, M. G., Copper-Catalyzed Azide–Alkyne Click
Chemistry for Bioconjugation. Current Protocols in Chemical Biology 2011, 3 (4), 153-
162.
2.55. Maketon, W.; Zenner, C. Z.; Ogden, K. L., Removal Efficiency and Binding
Mechanisms of Copper and Copper−EDTA Complexes Using Polyethyleneimine.
Environmental Science & Technology 2008, 42 (6), 2124-2129.
2.56. Melone, L.; Punta, C., Metal-free aerobic oxidations mediated by Nhydroxyphthalimide. A concise review. Beilstein Journal of Organic Chemistry 2013, 9,
1296-1310.
2.57. Engl, S.; Reiser, O., Catalyst-Free Visible-Light-Mediated Iodoamination of Olefins
and Synthetic Applications. Organic Letters 2021, 23 (14), 5581-5586.
2.58. Song, T.; Ma, Z.; Ren, P.; Yuan, Y.; Xiao, J.; Yang, Y., A Bifunctional Iron
Nanocomposite Catalyst for Efficient Oxidation of Alkenes to Ketones and 1,2-Diketones.
ACS Catalysis 2020, 10 (8), 4617-4629.
2.59. Bowes, C. M.; Montecalvo, D. F.; Sondheimer, F., o-Dipropadienylbenzene and
2,3-dipropadienylnaphthalene. The oxidation of diallenes to cyclic peroxides with triplet
oxygen. Tetrahedron Letters 1973, 14 (34), 3181-3184.
414
2.60. Bonaparte, A. C.; Betush, M. P.; Panseri, B. M.; Mastarone, D. J.; Murphy, R. K.;
Murphree, S. S., Novel Aerobic Oxidation of Primary Sulfones to Carboxylic Acids.
Organic Letters 2011, 13 (6), 1447-1449.
2.61. Ghogare, A. A.; Greer, A., Using Singlet Oxygen to Synthesize Natural Products
and Drugs. Chemical Reviews 2016, 116 (17), 9994-10034.
2.62. Tian, H.; Ermolenko, L.; Gabant, M.; Vergne, C.; Moriou, C.; Retailleau, P.; AlMourabit, A., Pyrrole-Assisted and Easy Oxidation of Cyclic α-Amino Acid- Derived
Diketopiperazines under Mild Conditions. Advanced Synthesis & Catalysis 2011, 353 (9),
1525-1533.
2.63. Chateauneuf, J.; Lusztyk, J.; Ingold, K. U., Absolute rate constants for the
reactions of some carbon-centered radicals with 2,2,6,6-tetramethyl-1-piperidinoxyl. The
Journal of Organic Chemistry 1988, 53 (8), 1629-1632.
2.64. Ochiai, M.; Sueda, T., Tetrahydrofuranylation of alcohols catalyzed by alkylperoxyλ3-iodane and carbon tetrachloride. Tetrahedron Letters 2004, 45 (18), 3557-3559.
2.65. Selander, N.; Fokin, V. V., Rhodium(II)-Catalyzed Asymmetric Sulfur(VI) Reduction
of Diazo Sulfonylamidines. Journal of the American Chemical Society 2012, 134 (5),
2477-2480.
2.66. Rege, P. D.; Malkina, O. L.; Goroff, N. S., The Effect of Lewis Bases on the 13C
NMR of Iodoalkynes. Journal of the American Chemical Society 2002, 124 (3), 370-371.
3.1. Saranya, S.; Anilkumar, G., Copper Catalysis. In Copper Catalysis in Organic
Synthesis, 2020; pp 1-5.
3.2. Trammell, R.; Rajabimoghadam, K.; Garcia-Bosch, I., Copper-Promoted
Functionalization of Organic Molecules: from Biologically Relevant Cu/O2 Model Systems
to Organometallic Transformations. Chemical Reviews 2019, 119 (4), 2954-3031.
3.3. Sterckx, H.; Morel, B.; Maes, B. U. W., Catalytic Aerobic Oxidation of C(sp3)−H
Bonds. Angewandte Chemie International Edition 2019, 58 (24), 7946-7970.
3.4. Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C., Aerobic
Copper-Catalyzed Organic Reactions. Chemical Reviews 2013, 113 (8), 6234-6458.
3.5. McCann, S. D.; Stahl, S. S., Copper-Catalyzed Aerobic Oxidations of Organic
Molecules: Pathways for Two-Electron Oxidation with a Four-Electron Oxidant and a OneElectron Redox-Active Catalyst. Accounts of Chemical Research 2015, 48 (6), 1756-
1766.
3.6. Walling, C., Autoxidation. In Active Oxygen in Chemistry, Foote, C. S.; Valentine,
J. S.; Greenberg, A.; Liebman, J. F., Eds. Springer Netherlands: Dordrecht, 1995; pp 24-
65.
415
3.7. Jira, R., Acetaldehyde from Ethylene—A Retrospective on the Discovery of the
Wacker Process. Angewandte Chemie International Edition 2009, 48 (48), 9034-9037.
3.8. Gnanou, Y.; Hizal, G., Effect of phenol and derivatives on atom transfer radical
polymerization in the presence of air. Journal of Polymer Science Part A: Polymer
Chemistry 2004, 42 (2), 351-359.
3.9. Feng, X.; Jiang, K.; Fan, S.; Kanan, M. W., A Direct Grain-Boundary-Activity
Correlation for CO Electroreduction on Cu Nanoparticles. ACS Central Science 2016, 2
(3), 169-174.
3.10. Snyder, B. E. R.; Bols, M. L.; Schoonheydt, R. A.; Sels, B. F.; Solomon, E. I., Iron
and Copper Active Sites in Zeolites and Their Correlation to Metalloenzymes. Chemical
Reviews 2018, 118 (5), 2718-2768.
3.11. Worrell, B. T.; Malik, J. A.; Fokin, V. V., Direct Evidence of a Dinuclear Copper
Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions. Science 2013, 340 (6131),
457-460.
3.12. Jiang, Y.-Y.; Li, G.; Yang, D.; Zhang, Z.; Zhu, L.; Fan, X.; Bi, S., Mechanism of
Cu-Catalyzed Aerobic C(CO)–CH3 Bond Cleavage: A Combined Computational and
Experimental Study. ACS Catalysis 2019, 9 (2), 1066-1080.
3.13. Shi, Z.; Zhang, C.; Tang, C.; Jiao, N., Recent advances in transition-metal
catalyzed reactions using molecular oxygen as the oxidant. Chemical Society Reviews
2012, 41 (8), 3381-3430.
3.14. Gupta, A.; Kumar, J.; Rahaman, A.; Singh, A. K.; Bhadra, S., Functionalization of
C(sp3)-H bonds adjacent to heterocycles catalyzed by earth abundant transition metals.
Tetrahedron 2021, 98, 132415.
3.15. Wdowik, T.; Chemler, S. R., Direct Synthesis of 2-Formylpyrrolidines, 2-
Pyrrolidinones and 2-Dihydrofuranones via Aerobic Copper-Catalyzed Aminooxygenation
and Dioxygenation of 4-Pentenylsulfonamides and 4-Pentenylalcohols. Journal of the
American Chemical Society 2017, 139 (28), 9515-9518.
3.16. Donthiri, R. R.; Samanta, S.; Adimurthy, S., Copper-catalyzed C(sp3)–H
functionalization of ketones with vinyl azides: synthesis of substituted-1H-pyrroles.
Organic & Biomolecular Chemistry 2015, 13 (40), 10113-10116.
3.17. Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei, A., Room-Temperature
Copper-Catalyzed Oxidation of Electron-Deficient Arenes and Heteroarenes Using Air.
Angewandte Chemie International Edition 2012, 51 (19), 4666-4670.
3.18. Carmo, R. L. L.; Galster, S. L.; Wdowik, T.; Song, C.; Chemler, S. R., CopperCatalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation:
Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives. Journal of
the American Chemical Society 2023.
416
3.19. Chen, S.; Chen, W.; Chen, X.; Chen, G.; Ackermann, L.; Tian, X., Copper(I)-
Catalyzed Oxyamination of β,γ-Unsaturated Hydrazones: Synthesis of Dihydropyrazoles.
Organic Letters 2019, 21 (19), 7787-7790.
3.20. Rao, Z.; Li, X.; Fang, Y.-G.; Francisco, J. S.; Zhu, C.; Chu, C., Spontaneous
Oxidation of Thiols and Thioether at the Air–Water Interface of a Sea Spray Microdroplet.
Journal of the American Chemical Society 2023, 145 (19), 10839-10846.
3.21. Qiu, L.; Psimos, M. D.; Cooks, R. G., Spontaneous Oxidation of Aromatic Sulfones
to Sulfonic Acids in Microdroplets. Journal of the American Society for Mass Spectrometry
2022, 33 (8), 1362-1367.
3.22. Qiu, L.; Cooks, R. G., Simultaneous and Spontaneous Oxidation and Reduction in
Microdroplets by the Water Radical Cation/Anion Pair. Angewandte Chemie International
Edition 2022, 61 (41), e202210765.
3.23. McNichol, C. P.; DeCicco, E. M.; Canfield, A. M.; Carstairs, D. P.; Paradine, S.
M., Copper-Catalyzed Aerobic Aminooxygenation of Cinnamyl N-Alkoxycarbamates via
Substrate-Promoted Catalyst Activation. ACS Catalysis 2023, 13 (10), 6568-6573.
3.24. Li, Y.; Ji, G.-C.; Chao, C.; Bi, S.; Jiang, Y.-Y., Computation Study on CopperCatalyzed Aerobic Intramolecular Aminooxygenative C═C Bond Cleavage to Imides:
Different Roles of Mononuclear and Dinuclear Copper Complexes. ACS Catalysis 2023,
13 (6), 3815-3829.
3.25. Liu, X.-D.; Wang, Q.-A.; Zhu, Y.-P.; Peng, Z.-H.; Li, J.-H., Copper-catalyzed
aerobic hydroxyamination of alkenes of unsaturated keto oximes in EtOH toward cyclic
nitrones. Green Chemistry 2022, 24 (6), 2476-2482.
3.26. Tang, C.; Qiu, X.; Cheng, Z.; Jiao, N., Molecular oxygen-mediated oxygenation
reactions involving radicals. Chemical Society Reviews 2021, 50 (14), 8067-8101.
3.27. Mayo, M. S.; Yu, X.; Feng, X.; Yamamoto, Y.; Bao, M., Isoquinolone Synthesis
through SNAr Reaction of 2-Halobenzonitriles with Ketones Followed by Cyclization. The
Journal of Organic Chemistry 2015, 80 (8), 3998-4002.
3.28. Schneider, R.; Engesser, T. A.; Näther, C.; Krossing, I.; Tuczek, F., CopperCatalyzed Monooxygenation of Phenols: Evidence for a Mononuclear Reaction
Mechanism. Angewandte Chemie International Edition 2022, 61 (25), e202202562.
3.29. Aggarwal, S.; Vu, A.; Eremin, D. B.; Persaud, R.; Fokin, V. V., Arenes participate
in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes. Nature Chemistry 2023,
15 (6), 764-772.
4.1. Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B., Sulfur(VI) Fluoride
Exchange (SuFEx): Another Good Reaction for Click Chemistry. Angewandte Chemie
International Edition 2014, 53 (36), 9430-9448.
417
4.2. Kolb, H. C.; Sharpless, K. B., The growing impact of click chemistry on drug
discovery. Drug Discovery Today 2003, 8 (24), 1128-1137.
4.3. Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Click Chemistry: Diverse Chemical
Function from a Few Good Reactions. Angewandte Chemie International Edition 2001,
40 (11), 2004-2021.
4.4. Jones, L. H.; Kelly, J. W., Structure-based design and analysis of SuFEx chemical
probes. RSC Medicinal Chemistry 2020, 11 (1), 10-17.
4.5. Xiao, X.; Zhou, F.; Jiang, J.; Chen, H.; Wang, L.; Chen, D.; Xu, Q.; Lu, J., Highly
efficient polymerization via sulfur(vi)-fluoride exchange (SuFEx): novel polysulfates
bearing a pyrazoline–naphthylamide conjugated moiety and their electrical memory
performance. Polymer Chemistry 2018, 9 (8), 1040-1044.
4.6. Narayanan, A.; Jones, L. H., Sulfonyl fluorides as privileged warheads in chemical
biology. Chemical Science 2015, 6 (5), 2650-2659.
4.7. Barrow, A. S.; Smedley, C. J.; Zheng, Q.; Li, S.; Dong, J.; Moses, J. E., The
growing applications of SuFEx click chemistry. Chemical Society Reviews 2019, 48 (17),
4731-4758.
4.8. Xu, R.; Xu, T.; Yang, M.; Cao, T.; Liao, S., A rapid access to aliphatic sulfonyl
fluorides. Nature Communications 2019, 10 (1), 3752.
4.9. Laudadio, G.; Bartolomeu, A. d. A.; Verwijlen, L. M. H. M.; Cao, Y.; de Oliveira,
K. T.; Noël, T., Sulfonyl Fluoride Synthesis through Electrochemical Oxidative Coupling of
Thiols and Potassium Fluoride. Journal of the American Chemical Society 2019, 141 (30),
11832-11836.
4.10. Tang, L.; Yang, Y.; Wen, L.; Yang, X.; Wang, Z., Catalyst-free radical fluorination
of sulfonyl hydrazides in water. Green Chemistry 2016, 18 (5), 1224-1228.
4.11. Brouwer, A. J.; Ceylan, T.; Linden, T. v. d.; Liskamp, R. M. J., Synthesis of βaminoethanesulfonyl fluorides or 2-substituted taurine sulfonyl fluorides as potential
protease inhibitors. Tetrahedron Letters 2009, 50 (26), 3391-3393.
4.12. Tribby, A. L.; Rodríguez, I.; Shariffudin, S.; Ball, N. D., Pd-Catalyzed Conversion
of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and Selectfluor. The
Journal of Organic Chemistry 2017, 82 (4), 2294-2299.
4.13. Prakash Reddy, V.; Bellew, D. R.; Prakash, G. K. S., A convenient preparation of
sulfuryl chloride fluoride. Journal of Fluorine Chemistry 1992, 56 (2), 195-197.
4.14. Krutak, J. J.; Burpitt, R. D.; Moore, W. H.; Hyatt, J. A., Chemistry of ethenesulfonyl
fluoride. Fluorosulfonylethylation of organic compounds. The Journal of Organic
Chemistry 1979, 44 (22), 3847-3858.
418
4.15. Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.; Sharpless, K. B.; Dong,
J., A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt
Emerging as an “F−SO2+” Donor of Unprecedented Reactivity, Selectivity, and Scope.
Angewandte Chemie International Edition 2018, 57 (10), 2605-2610.
4.16. Zhou, H.; Mukherjee, P.; Liu, R.; Evrard, E.; Wang, D.; Humphrey, J. M.; Butler,
T. W.; Hoth, L. R.; Sperry, J. B.; Sakata, S. K.; Helal, C. J.; am Ende, C. W., Introduction
of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides. Organic
Letters 2018, 20 (3), 812-815.
4.17. Stepannikova, K. O.; Vashchenko, B. V.; Grygorenko, O. O.; Gorichko, M. V.;
Cherepakha, A. Y.; Moroz, Y. S.; Volovenko, Y. M.; Zhersh, S., Synthesis of Spirocyclic
β- and γ-Sultams by One-Pot Reductive Cyclization of Cyanoalkylsulfonyl Fluorides.
European Journal of Organic Chemistry 2021, 2021 (47), 6530-6540.
4.18. Liu, J.; Wang, S.-M.; Qin, H.-L., Light-induced [2 + 2] cycloadditions for the
construction of cyclobutane-fused pyridinyl sulfonyl fluorides. Organic & Biomolecular
Chemistry 2020, 18 (21), 4019-4023.
4.19. Skalenko, Y. A.; Druzhenko, T. V.; Denisenko, A. V.; Samoilenko, M. V.; Dacenko,
O. P.; Trofymchuk, S. A.; Grygorenko, O. O.; Tolmachev, A. A.; Mykhailiuk, P. K., [2+2]-
Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-
Azabicyclo[3.2.0]heptanes. The Journal of Organic Chemistry 2018, 83 (12), 6275-6289.
4.20. Oderinde, M. S.; Ramirez, A.; Dhar, T. G. M.; Cornelius, L. A. M.; Jorge, C.;
Aulakh, D.; Sandhu, B.; Pawluczyk, J.; Sarjeant, A. A.; Meanwell, N. A.; Mathur, A.;
Kempson, J., Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of
Heterocycles for Building Molecular Complexity. The Journal of Organic Chemistry 2021,
86 (2), 1730-1747.
4.21. Kokhan, S. O.; Valter, Y. B.; Tymtsunik, A. V.; Komarov, I. V.; Grygorenko, O. O.,
3-Carboxy-/3-Aminobicyclo[1.1.1]pentane-Derived Sulfonamides and Sulfonyl Fluorides
– Advanced Bifunctional Reagents for Organic Synthesis and Drug Discovery. European
Journal of Organic Chemistry 2020, 2020 (15), 2210-2216.
4.22. Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V., RhodiumCatalyzed Transannulation of 1,2,3-Triazoles with Nitriles. Journal of the American
Chemical Society 2008, 130 (45), 14972-14974.
4.23. Jones, K. D.; Nutt, M. J.; Comninos, E.; Sobolev, A. N.; Moggach, S. A.; Miura,
T.; Murakami, M.; Stewart, S. G., A One-Pot Reaction of α-Imino Rhodium Carbenoids
and Halohydrins: Access to 2,6-Substituted Dihydro-2H-1,4-oxazines. Organic Letters
2020, 22 (9), 3490-3494.
4.24. Yadagiri, D.; Chaitanya, M.; Reddy, A. C. S.; Anbarasan, P., Rhodium Catalyzed
Synthesis of Benzopyrans via Transannulation of N-Sulfonyl-1,2,3-triazoles with 2-
Hydroxybenzyl Alcohols. Organic Letters 2018, 20 (13), 3762-3765.
419
4.25. Zibinsky, M.; Fokin, V. V., Sulfonyl-1,2,3-Triazoles: Convenient Synthones for
Heterocyclic Compounds. Angewandte Chemie International Edition 2013, 52 (5), 1507-
1510.
4.26. Chattopadhyay, B.; Gevorgyan, V., Rh-Catalyzed Transannulation of N-Tosyl1,2,3-Triazoles with Terminal Alkynes. Organic Letters 2011, 13 (14), 3746-3749.
4.27. Chuprakov, S.; Kwok, S. W.; Fokin, V. V., Transannulation of 1-Sulfonyl-1,2,3-
triazoles with Heterocumulenes. Journal of the American Chemical Society 2013, 135
(12), 4652-4655.
4.28. Grimster, N.; Zhang, L.; Fokin, V. V., Synthesis and Reactivity of Rhodium(II) NTriflyl Azavinyl Carbenes. Journal of the American Chemical Society 2010, 132 (8), 2510-
2511.
4.29. Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.; Fokin, V. V., Stereoselective
1,3-Insertions of Rhodium(II) Azavinyl Carbenes. Journal of the American Chemical
Society 2014, 136 (1), 195-202.
4.30. Miura, T.; Tanaka, T.; Yada, A.; Murakami, M., Doyle–Kirmse Reaction Using
Triazoles Leading to One-pot Multifunctionalization of Terminal Alkynes. Chemistry
Letters 2013, 42 (10), 1308-1310.
4.31. Chuprakov, S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V., Catalytic Asymmetric C–H
Insertions of Rhodium(II) Azavinyl Carbenes. Journal of the American Chemical Society
2011, 133 (27), 10352-10355.
4.32. Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M., Synthesis of α-Amino Ketones from
Terminal Alkynes via Rhodium-Catalyzed Denitrogenative Hydration of N-Sulfonyl-1,2,3-
triazoles. Journal of the American Chemical Society 2012, 134 (1), 194-196.
4.33. Selander, N.; Fokin, V. V., Rhodium(II)-Catalyzed Asymmetric Sulfur(VI) Reduction
of Diazo Sulfonylamidines. Journal of the American Chemical Society 2012, 134 (5),
2477-2480.
4.34. Thomas, J.; Jana, S.; Liekens, S.; Dehaen, W., A single-step acid catalyzed
reaction for rapid assembly of NH-1,2,3-triazoles. Chemical Communications 2016, 52
(59), 9236-9239.
4.35. Veryser, C.; Demaerel, J.; Bieliu̅nas, V.; Gilles, P.; De Borggraeve, W. M., Ex Situ
Generation of Sulfuryl Fluoride for the Synthesis of Aryl Fluorosulfates. Organic Letters
2017, 19 (19), 5244-5247.
4.36. Passia, M. T.; Demaerel, J.; Amer, M. M.; Drichel, A.; Zimmer, S.; Bolm, C., AcidMediated Imidazole-to-Fluorine Exchange for the Synthesis of Sulfonyl and Sulfonimidoyl
Fluorides. Organic Letters 2022, 24 (48), 8802-8805.
420
4.37. Raushel, J.; Fokin, V. V., Efficient Synthesis of 1-Sulfonyl-1,2,3-triazoles. Organic
Letters 2010, 12 (21), 4952-4955.
4.38. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S., A Facile Access to NSulfonylimidates and Their Synthetic Utility for the Transformation to Amidines and
Amides. Organic Letters 2006, 8 (7), 1347-1350.
4.39. Arduengo, A. J.; Harlow, R. L.; Kline, M., A stable crystalline carbene. Journal of
the American Chemical Society 1991, 113 (1), 361-363.
5.1. Yang, S.; Chu, M.; Miao, Q., Connecting two phenazines with a four-membered
ring: the synthesis, properties and applications of cyclobuta[1,2-b:3,4-b′]diphenazines.
Journal of Materials Chemistry C 2018, 6 (14), 3651-3657.
5.2. Raushel, J.; Fokin, V. V., Efficient synthesis of 1-sulfonyl-1,2,3-triazoles. Org Lett
2010, 12 (21), 4952-5.
5.3. Lazreg, F.; Cazin, C. S. J., Copper(I)–N-Heterocyclic Carbene Complexes as
Efficient Catalysts for the Synthesis of 1,4-Disubstituted 1,2,3-Sulfonyltriazoles in Air.
Organometallics 2018, 37 (5), 679-683.
5.4. He, J.; Man, Z.; Shi, Y.; Li, C. Y., Synthesis of beta-Amino-alpha,beta-unsaturated
Ketone Derivatives via Sequential Rhodium-Catalyzed Sulfur Ylide
Formation/Rearrangement. J Org Chem 2015, 80 (9), 4816-23.
5.5. Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang,
S., Copper-catalyzed synthesis of N-sulfonyl-1,2,3-triazoles: controlling selectivity.
Angew Chem Int Ed Engl 2007, 46 (10), 1730-3.
5.6. Raushel, J.; Fokin, V. V., Efficient Synthesis of 1-Sulfonyl-1,2,3-triazoles. Organic
Letters 2010, 12 (21), 4952-4955.
5.7. Medina, F.; Besnard, C.; Lacour, J., One-step synthesis of nitrogen-containing
medium-sized rings via alpha-imino diazo intermediates. Org Lett 2014, 16 (12), 3232-5.
5.8. Kim, J.; Stahl, S. S., Cu-catalyzed aerobic oxidative three-component coupling
route to N-sulfonyl amidines via an ynamine intermediate. J Org Chem 2015, 80 (4), 2448-
54.
5.9. Whiting, M.; Fokin, V. V., Copper-Catalyzed Reaction Cascade: Direct Conversion
of Alkynes into N-Sulfonylazetidin-2-imines. Angewandte Chemie International Edition
2006, 45 (19), 3157-3161.
5.10. Mayo, M. S.; Yu, X.; Feng, X.; Yamamoto, Y.; Bao, M., Isoquinolone Synthesis
through SNAr Reaction of 2-Halobenzonitriles with Ketones Followed by Cyclization. The
Journal of Organic Chemistry 2015, 80 (8), 3998-4002.
421
5.11. Zhang, N.; Zhang, C.; Hu, X.; Xie, X.; Liu, Y., Nickel-Catalyzed C(sp3)–H
Functionalization of Benzyl Nitriles: Direct Michael Addition to Terminal Vinyl Ketones.
Organic Letters 2021, 23 (15), 6004-6009.
5.12. Aggarwal, S.; Vu, A.; Eremin, D. B.; Persaud, R.; Fokin, V. V., Arenes participate
in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes. Nature Chemistry 2023,
15 (6), 764-772.
5.13. Thomas, J.; Jana, S.; Liekens, S.; Dehaen, W., A single-step acid catalyzed
reaction for rapid assembly of NH-1,2,3-triazoles. Chemical Communications 2016, 52
(59), 9236-9239.
5.14. Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.; Sharpless, K. B.; Dong,
J., A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt
Emerging as an “F−SO2+” Donor of Unprecedented Reactivity, Selectivity, and Scope.
Angewandte Chemie International Edition 2018, 57 (10), 2605-2610.
5.15. Zhou, H.; Mukherjee, P.; Liu, R.; Evrard, E.; Wang, D.; Humphrey, J. M.; Butler,
T. W.; Hoth, L. R.; Sperry, J. B.; Sakata, S. K.; Helal, C. J.; am Ende, C. W., Introduction
of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides. Organic
Letters 2018, 20 (3), 812-815.
5.16. Grimster, N.; Zhang, L.; Fokin, V. V., Synthesis and Reactivity of Rhodium(II) NTriflyl Azavinyl Carbenes. Journal of the American Chemical Society 2010, 132 (8), 2510-
2511.
Abstract (if available)
Abstract
This dissertation contributes to the development of heteroatom functionalization of carbon-carbon bonds utilizing aerobic oxidation. The main focus is the development of novel methodologies leading to oxygenated species of biologic relevance. Aerobic oxidation could be a very valuable method for introducing oxygen atoms into the carbon-carbon backbone of organic molecules, but its adoption has been limited. This is largely due to the inert nature of molecular oxygen and the difficulty of controlling competing oxidative processes, which often leads to poor product selectivity. Chapter 1 is an overview of relevant methods to achieve heteroatom functionalization including radical, ketenimine, formation, and copper catalyzed methods. These topics give good background and insight into how projects in the remaining chapters work. Chapter 2 goes over the synthesis of α-hydroxyamidines through aerobic oxidation. The key step in this process is the homolytic cleavage of a C-I bond of an iodinated intermediate. When exposed to atmospheric oxygen, this intermediate spontaneously forms C-centered radicals. These radicals efficiently transform into oxygenated compounds leading to higher molecular complexity. This process uniquely utilizes molecular oxygen without requiring photocatalysts or pressurized oxygen, and it occurs under mild conditions. Our mechanistic studies provide insights into the intricate sequence involved in the formation and selective capture of captodative radicals. Chapter 3 involves the oxygenation of sultam starting materials forming compounds very similar to that of the oxicam class of drug. In this study, we present a mild and easily accessible approach for producing oxygenated sultams through copper-catalyzed aerobic oxidation. By adjusting the copper source and solvent, this process can selectively generate oxo and hydroxy products with high efficiency. Chapter 4 involves interesting transformations of SO2F triazoles. These end up forming ketenimines spontaneously and the main focus of the study was to study the nature of these reactive intermediate. Through this, it was also found that carbenes can be formed from the sulfonating reagent used. Chapter 5 contains the supplementary information including, procedures, optimization, and spectra.
Linked assets
University of Southern California Dissertations and Theses
Conceptually similar
PDF
Studies on methane functionalization: efficient carbon-hydrogen bond activation via palladium and free radical catalyses
PDF
Peering into the cell: click chemistry and novel dyes towards enhanced biomedical imaging
PDF
Understanding the mechanism of oxygen reduction and oxygen evolution on transition metal oxide electrocatalysts and applications in iron-air rechargeable battery
PDF
Expanding the chemical space by utilizing the efficiency and versatility of click reactions to unveil potent molecular scaffolds
PDF
Chemical depolymerization of amine-epoxy cured carbon fiber reinforced polymer composites and their re-use
PDF
Carbon-hydrogen bond activation: radical methane functionalization; unactivated alkene coupling; saccharide degradation; and carbon dioxide hydrogenation
PDF
Simulations across scales: insights into biomolecular, mechanisms, magnetic materials, and optical processes
PDF
Mechanism and synthesis of molecular building blocks in medicinal chemistry: aerobic azoline oxidation and ultrasound activated MRI contrast agents
PDF
Singlet halofluorocarbenes: Modes of generation and their reactions with alkenes and various heteroatom nucleophiles
PDF
Moleular modelling of organic photoredox catalysts for CO₂ reduction
PDF
Unlocking tools in chemistry to facilitate progress in drug discovery
PDF
Electronic structure analysis of challenging open-shell systems: from excited states of copper oxide anions to exchange-coupling in binuclear copper complexes
PDF
Harnessing fluorinated C1 nucleophilic reagents for the direct fluoroalkylation of ubiquitous C(sp2)-X and C(sp)-H centers
PDF
Adiabatic and non-adiabatic molecular dynamics in nanoscale systems: theory and applications
PDF
Hydrogen energy system production and storage via iridium-based catalysts
PDF
Design and modification of electrocatalysts for use in fuel cells and CO₂ reduction
PDF
Anaerobic iron cycling in an oxygen deficient zone
PDF
Hydrogen transfer reactions catalyzed by iridium and ruthenium complexes
PDF
Controlled synthesis, characterization and applications of carbon nanotubes
PDF
New bifunctional catalysts for ammonia-borane dehydrogenation, nitrile reduction, formic acid dehydrogenation, lactic acid synthesis, and carbon dioxide reduction
Asset Metadata
Creator
Richards, William
(author)
Core Title
Controlled heteroatom functionalization of carbon-carbon bonds by aerobic oxidation
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Degree Conferral Date
2024-08
Publication Date
08/29/2024
Defense Date
06/28/2024
Publisher
Los Angeles, California
(original),
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
aerobic oxidation,copper catalysis,heteroatom functionalization,ketenimine,OAI-PMH Harvest,oxygenation,radical chemistry,sulfonyl fluoride,sultam,triazole
Format
theses
(aat)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Fokin, Valery (
committee chair
), Dawlaty, Jahan (
committee member
), Zavaleta, Cristina (
committee member
)
Creator Email
wjrichar@usc.edu,wjrichar12@gmail.com
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-oUC113999ZIA
Unique identifier
UC113999ZIA
Identifier
etd-RichardsWi-13446.pdf (filename)
Legacy Identifier
etd-RichardsWi-13446
Document Type
Dissertation
Format
theses (aat)
Rights
Richards, William
Internet Media Type
application/pdf
Type
texts
Source
20240830-usctheses-batch-1204
(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
aerobic oxidation
copper catalysis
heteroatom functionalization
ketenimine
oxygenation
radical chemistry
sulfonyl fluoride
sultam
triazole