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Expanding the chemical space by utilizing the efficiency and versatility of click reactions to unveil potent molecular scaffolds

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Expanding the Chemical Space by Utilizing the Efficiency and
Versatility of Click Reactions to Unveil Potent Molecular Scaffolds

By

Sydney Rose Hiller

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 2023

Copyright 2023 Sydney Rose Hiller

ii
Acknowledgments
First off thank you to my mom, whose support and love have been a constant in my
life. You have been there to celebrate my success and there for the midnight calls when no
reactions are working. I love you and would not have been able to do it without you. Thank
you to my dad, Kim, and Andrew for your endless support and letting me turn the basement
into my office during the pandemic. You guys were the best crew to make staying at home
for months not just tolerable but fun.
A big thank you to Silje, Siri, Sonja, Preben, Davey, Bailey, Fredrik, Ellen, and all my
friends up North who helped restore my faith in humanity. Also, for being good sports when
it came to eating unique delicacies during what was the longest, oddest, but one of the most
fun meals I’ve had. Your love, kindness, and support came when I truly needed it most.
Valery, thank you for your unwavering support and mentorship. It has truly been an
honor to work in your lab and learn from you. Thank you for allowing me to explore my
intellectual curiosities no matter whether it was in the lab or the business school. You have
always been there for me, and your mentorship and guidance has taught me so much
Thank you to my committee members; Prof. Seva Katritch, Prof. Elias Picazo, Prof.
Megan Fieser, Prof. Nicos Petasis, and Prof. Barry Thomas for all of your help and guidance
along the way. It has been a pleasure to collaborate with you Seva and Elias and have the
opportunity to learn from you, thank you for your support over the course of my PhD. A
special thank you to my previous mentors; Prof. Raphi Mechoulam, Prof. Ned Seeman, and
Prof. Yoel Ohayon would not be here without your help. A special thank you to Paulina, Claire,
Mitya, Olya, Jessi, Max, and Kathy. I can’t imagine going through the last five years without
having friends like you. You have been there through thick and thin and have been such an
incredible support system. I also want to thank my lab family and everyone who worked
tirelessly to contribute to these projects. Specifically, the colleagues I collaborated with; Dr.
Dmitry Eremin, Dr. Katharina Grotsch, Dr. Joice Thomas, Kevin Vargas, and Alexander Vu
were amazing to collaborate with and in many cases share fume hoods with. And thank you
to the rest of my lab family both past and present; Shubhangi, Shelby, Dr. Jose Ricardo
Moreno, Dr. Jitendra Gurjar, Will, Rudra, Diego, and Josh.
In loving memory of Polo, who was truly the best friend a girl could ask for.
iii
Table of Contents
Acknowledgments ........................................................................................................ ii
List of Tables .................................................................................................................. ix
List Of Figures ................................................................................................................ x
List of Schemes ........................................................................................................... xxi
List of Abbreviations ............................................................................................... xxii
Abstract ...................................................................................................................... xxiii
Chapter 1. Selective Synthesis of Functionalized Isoxazoles ......................... 1
1.1a Problem Inspiring the Studies .............................................................................................................................. 1
1.1b Introduction .................................................................................................................................................................. 4
1.2 Previous Synthetic Strategies .................................................................................................................................. 7
1.3 Optimization of Sulfonyl Fluoride Conditions .................................................................................................. 8
1.4 Optimization of Brominated Conditions .......................................................................................................... 10
1.5 Compounds Synthesized ......................................................................................................................................... 13
1.6 Synthesis of Sulfonyl Fluoride Functionalized Isoxazoles ....................................................................... 15
General Procedure ....................................................................................................................................................... 15
6a: 3-phenylisoxazole-5-sulfonyl fluoride ........................................................................................................ 16
6b: 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride .................................................................................. 16
6c: 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride ...................................................................................... 17
6d: 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride .............................................................................. 17
6e: 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride .................................................................................... 18
6f: 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride .................................................................... 19
6g: 3-(4-chloro-3-nitrophenyl)isoxazole-5-sulfonyl fluoride ................................................................... 19
6h: 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride ................................................................ 20
6i: 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride ............................................................................. 20
6j: 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride ............................................................................ 21
6k: 3-(2,4-dimethoxyphenyl)isoxazole-5-sulfonyl fluoride ...................................................................... 21
6l: 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride ....................................................................................... 22
6m: 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride ......................................................... 22
6n: 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride ........................................................... 23
6o: 3-dodecylisoxazole-5-sulfonyl fluoride ...................................................................................................... 24
Appendix A: Characterization of Sulfonyl Fluoride Isoxazoles ..................................................................... 25
6a: 3-phenylisoxazole-5-sulfonyl fluoride ........................................................................................................ 25
6b: 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride .................................................................................. 26
6c: 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride ...................................................................................... 28
6d: 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride .............................................................................. 29
6e: 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride .................................................................................... 31
6f: 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride .................................................................... 32
6h: 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride ................................................................ 34
iv
6i: 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride ............................................................................. 35
6j: 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride ............................................................................ 37
6l: 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride ....................................................................................... 38
6m: 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride ......................................................... 40
6n: 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride ........................................................... 41
6o: 3-dodecylisoxazole-5-sulfonyl fluoride ...................................................................................................... 42
1.7 Synthesis of Brominated Isoxazoles .................................................................................................................. 44
General Procedure ....................................................................................................................................................... 44
5a: 5-bromo-3-phenylisoxazole ............................................................................................................................. 44
5b: 5-bromo-3-(4-chlorophenyl)isoxazole ....................................................................................................... 44
5c: 5-bromo-3-(4-nitrophenyl)isoxazole ........................................................................................................... 45
5d: 5-bromo-3-(2-methoxyphenyl)isoxazole .................................................................................................. 45
5e: 5-bromo-3-(2-fluorophenyl)isoxazole ........................................................................................................ 46
5f: 5-bromo-3-(2-chloro-5-nitrophenyl)isoxazole ........................................................................................ 46
5g: 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole ....................................................................................... 47
5h: 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole .................................................................................... 47
5i: 5-bromo-3-(2,6-difluorophenyl)isoxazole ................................................................................................. 48
5j: 5-bromo-3-(2,4-dichlorophenyl)isoxazole ................................................................................................. 49
5k: 5-bromo-3-(2,4-dimethoxyphenyl)isoxazole ........................................................................................... 49
5l: 5-bromo-3-(2-nitrophenyl)isoxazole ........................................................................................................... 49
3m: 5-bromo-3-(2-methoxynaphthalen-1-yl)isoxazole .............................................................................. 50
5n: 5-bromo-3-(1-methoxynaphthalen-2-yl)isoxazole ............................................................................... 50
5o: 5-bromo-3-dodecylisoxazole ........................................................................................................................... 50
Appendix B: Characterization of Brominated Isoxazoles ................................................................................ 51
5a: 5-bromo-3-phenylisoxazole ............................................................................................................................. 51
5b: 5-bromo-3-(4-chlorophenyl)isoxazole ....................................................................................................... 52
5c: 5-bromo-3-(4-nitrophenyl)isoxazole ........................................................................................................... 53
5d: 5-bromo-3-(2-methoxyphenyl)isoxazole .................................................................................................. 54
5e: 5-bromo-3-(2-fluorophenyl)isoxazole ........................................................................................................ 55
5g: 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole ....................................................................................... 57
5h: 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole .................................................................................... 58
5i: 5-bromo-3-(2,6-difluorophenyl)isoxazole ................................................................................................. 59
5j: 5-bromo-3-(2,4-dichlorophenyl)isoxazole ................................................................................................. 61
5o: 5-bromo-3-dodecylisoxazole ........................................................................................................................... 62
1.8 Synthesis of Oximes .................................................................................................................................................. 63
Synthesis of Oximes General Procedure ............................................................................................................ 63
Benzaldehyde oxime ................................................................................................................................................... 63
4-chlorobenzaldehyde oxime ................................................................................................................................. 63
4-nitrobenzaldehyde oxime .................................................................................................................................... 64
2-methoxy benzaldehyde oxime ............................................................................................................................ 64
2-fluorobenzaldehyde oxime .................................................................................................................................. 65
2-chloro-5-nitrobenzaldehyde oxime ................................................................................................................. 65
4-chloro-3-nitrobenzaldehyde oxime ................................................................................................................. 66
2-chloro-6-fluorobenzaldehyde oxime ............................................................................................................... 66
2,6-difluorobenzaldehyde oxime .......................................................................................................................... 67
2,4-dichlorobenzaldehyde oxime .......................................................................................................................... 68
2,4-dimethoxybenzaldehyde oxime ..................................................................................................................... 68
4-(dimethylamino)benzaldehyde oxime ........................................................................................................... 69
4-(benzyloxy)benzaldehyde oxime ...................................................................................................................... 69
tridecanal oxime ........................................................................................................................................................... 70
v
2-nitrobenzaldehyde oxime .................................................................................................................................... 70
2-naphthaldehyde oxime .......................................................................................................................................... 71
2-methoxy-1-naphthaldehyde oxime .................................................................................................................. 71
1-methoxy-2-naphthaldehyde oxime .................................................................................................................. 72
Indole-3-carbaldehyde oxime ................................................................................................................................. 73
Appendix C: Characterization of Oximes ................................................................................................................. 74
Benzaldehyde oxime ................................................................................................................................................... 74
4-chlorobenzaldehyde oxime ................................................................................................................................. 75
4-nitrobenzaldehyde oxime .................................................................................................................................... 76
2-methoxy benzaldehyde oxime ............................................................................................................................ 77
2-fluorobenzaldehyde oxime .................................................................................................................................. 78
2-chloro-5-nitrobenzaldehyde oxime ................................................................................................................. 78
4-chloro-3-nitrobenzaldehyde oxime ................................................................................................................. 79
2-chloro-6-fluorobenzaldehyde oxime ............................................................................................................... 80
2,6-difluorobenzaldehyde oxime .......................................................................................................................... 82
2,4-dichlorobenzaldehyde oxime .......................................................................................................................... 83
2,4-dimethoxybenzaldehyde oxime ..................................................................................................................... 84
4-(dimethylamino)benzaldehyde oxime ........................................................................................................... 85
4-(benzyloxy)benzaldehyde oxime ...................................................................................................................... 86
tridecanal oxime ........................................................................................................................................................... 87
2-nitrobenzaldehyde oxime .................................................................................................................................... 88
2-naphthaldehyde oxime .......................................................................................................................................... 89
2-methoxy-1-naphthaldehyde oxime .................................................................................................................. 90
1-methoxy-2-naphthaldehyde oxime .................................................................................................................. 91
Indole-3-carbaldehyde oxime ................................................................................................................................. 92
1.9 Synthesis of Chloro-Oximes ................................................................................................................................... 93
Synthesis of Chloro-oximes: General Procedure ............................................................................................ 93
Compound 3a: N-hydroxybenzimidoyl chloride ............................................................................................ 94
Compound 3b: 4-chloro-N-hydroxybenzimidoyl chloride ......................................................................... 94
Compound 3c: N-hydroxy-4-nitrobenzimidoyl chloride ............................................................................ 94
Compound 3d: N-hydroxy-2-methoxybenzimidoyl chloride .................................................................... 95
Compound 3e: 2-fluoro-N-hydroxybenzimidoyl chloride .......................................................................... 95
Compound 3f: 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride .......................................................... 96
Compound 3g: 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride ......................................................... 96
Compound 3h: 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride ...................................................... 97
Compound 3i: 2,6-difluoro-N-hydroxybenzimidoyl chloride ................................................................... 97
Compound 3j: 2,4-dichloro-N-hydroxybenzimidoyl chloride .................................................................. 98
Compound 3l: N-hydroxy-2-nitrobenzimidoyl chloride ............................................................................. 98
Compound 3m: N-hydroxy-2-methoxy-1-naphthimidoyl chloride ........................................................ 98
Compound 3n: N-hydroxy-1-methoxy-2-naphthimidoyl chloride ......................................................... 99
Compound 3o: N-hydroxytridecanimidoyl chloride ..................................................................................... 99
Compound: N-hydroxy-indole-3-carbimidoyl chloride ............................................................................. 100
Appendix D: Characterization of Chloro-Oximes ............................................................................................... 101
Compound 3a: N-hydroxybenzimidoyl chloride .......................................................................................... 101
Compound 3b: 4-chloro-N-hydroxybenzimidoyl chloride ....................................................................... 102
Compound 3c: N-hydroxy-4-nitrobenzimidoyl chloride .......................................................................... 103
Compound 3d: N-hydroxy-2-methoxybenzimidoyl chloride .................................................................. 104
Compound 3e: 2-fluoro-N-hydroxybenzimidoyl chloride ........................................................................ 104
Compound 3f: 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride ........................................................ 106
Compound 3g: 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride ....................................................... 107
vi
Compound 3h: 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride .................................................... 108
Compound 3i: 2,6-difluoro-N-hydroxybenzimidoyl chloride ................................................................. 109
Compound 3j: 2,4-dichloro-N-hydroxybenzimidoyl chloride ................................................................ 110
Compound 3l: N-hydroxy-2-nitrobenzimidoyl chloride ........................................................................... 111
Compound 3m: N-hydroxy-2-methoxy-1-naphthimidoyl chloride ...................................................... 112
Compound 3n: N-hydroxy-1-methoxy-2-naphthimidoyl chloride ....................................................... 113
Compound 3o: N-hydroxytridecanimidoyl chloride ................................................................................... 114
Compound: N-hydroxy-indole-3-carbimidoyl chloride ............................................................................. 115
Distribution of Credit ..................................................................................................................................................... 116
Chapter 2. Investigation Into Improved SuFEx Conditions ........................ 117
2.1 Introduction ............................................................................................................................................................... 117
2.2 Synthetic Approaches ............................................................................................................................................ 118
2.3 Optimized Conditions ............................................................................................................................................. 119
Chapter 3. Synthesis of Sulfonyl Fluoride Functionalized Triazoles ...... 121
3.1 Introduction ............................................................................................................................................................... 121
3.2 Previous Synthetic Strategies ............................................................................................................................. 122
3.3 Optimized conditions ............................................................................................................................................. 123
3.4 Compounds Synthesized ....................................................................................................................................... 125
3.5 Synthesis of Sulfonyl Fluoride Functionalized Triazoles ........................................................................ 125
Compound 5a: 1-Phenethyl-1,2,3-triazole-4-sulfonyl fluoride .............................................................. 125
Compound 5b: 1-(4-Methoxyphenethyl)-1,2,3-triazole-4- sulfonyl fluoride .................................. 126
Compound 5c: 1-(4-Fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ........................................ 126
Compound 5d: 1-(4-Nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ........................................... 127
Compound 5e: 1-(4-Cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ......................................... 128
Compound 5f: 1-(4-Acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ................................ 128
Compound 5g: 1-(4-Hydroxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride (5E) .......................... 129
Compound 5h: 1-Phenyl-1,2,3-triazole-4-sulfonyl fluoride (5G) .......................................................... 130
Compound 5i: 1-(4-Methoxylphenyl-1,2,3-triazole-4-sulfonyl fluoride (5H) ................................. 130
Compound 5j: 1-(4-Nitrophenyl)-1,2,3-triazole-4-sulfonyl fluoride ................................................... 131
Compound 5k: 1-(3-(Methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl fluoride (5Q) ............. 131
Compound 5l: 1-Benzyl-1,2,3-triazole-4-sulfonyl fluoride (5K) ........................................................... 132
Compound 5m: 1-(4-Cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride .............................................. 132
Compound 5n: Methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate ..................... 133
Compound 5o: 1-([1,1'-Biphenyl]-4-ylmethyl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5Q) ..... 134
Compound 5r: 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride .................................... 134
Compound 5s: 1-((3s,5s,7s)-Adamantan-1-yl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5M) ..... 135
Compound 5t: 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride ............................................................... 135
Compound 5u: 1-(3-Phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride (5J) ..................................... 136
Compound 5v: 1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl fluoride .......... 137
Compound 5w: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-sulfonyl fluoride . 137
Appendix E: Characterization of Sulfonyl Fluoride Triazoles ...................................................................... 139
Compound 5a: 1-Phenethyl-1,2,3-triazole-4-sulfonyl fluoride .............................................................. 139
Compound 5b: 1-(4-Methoxyphenethyl)-1,2,3-triazole-4- sulfonyl fluoride .................................. 140
Compound 5c: 1-(4-Fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ........................................ 142
Compound 5d: 1-(4-Nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ........................................... 143
Compound 5e: 1-(4-Cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ......................................... 145
Compound 5f: 1-(4-Acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride ................................ 146
vii
Compound 5g: 1-(4-Hydroxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride (5E) .......................... 148
Compound 5h: 1-Phenyl-1,2,3-triazole-4-sulfonyl fluoride (5G) .......................................................... 149
Compound 5i: 1-(4-Methoxylphenyl-1,2,3-triazole-4-sulfonyl fluoride ............................................ 151
Compound 5k: 1-(3-(Methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl fluoride (5Q) ............. 152
Compound 5l: 1-Benzyl-1,2,3-triazole-4-sulfonyl fluoride (5K) ........................................................... 154
Compound 5m: 1-(4-Cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride .............................................. 155
Compound 5n: Methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate ..................... 157
Compound 5o: 1-([1,1'-Biphenyl]-4-ylmethyl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5Q) ..... 158
Compound 5r: 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride .................................... 160
Compound 5s: 1-((3s,5s,7s)-Adamantan-1-yl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5M) ..... 161
Compound 5t: 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride ............................................................... 163
Compound 5u: 1-(3-Phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride (5J) ..................................... 164
Compound 5v: 1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl fluoride .......... 166
Compound 5w: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-sulfonyl fluoride . 167
Distribution of Credit ..................................................................................................................................................... 169
Chapter 4. Cannabinoid Type II Receptor ........................................................ 170
4.1a Introduction to Endocannabinoid System .................................................................................................. 170
4.1b Introduction to the Cannabinoid Type II Receptor ................................................................................ 171
4.2 Creation of Virtual Library ................................................................................................................................... 173
4.3 Virtual Ligand Screening ....................................................................................................................................... 180
4.4 Selection and Synthesis of Drug Candidates ................................................................................................ 182
4.5 Synthesis of Selected Compounds .................................................................................................................... 182
Synthesis of BRI-13900 ........................................................................................................................................... 182
Synthesis of BRI-13901 ........................................................................................................................................... 185
Synthesis of BRI-13902 ........................................................................................................................................... 188
Synthesis of BRI-13903 ........................................................................................................................................... 188
Synthesis of BRI-13904 ........................................................................................................................................... 191
Synthesis of BRI-13905 ........................................................................................................................................... 194
Synthesis of BRI-13906 ........................................................................................................................................... 196
Synthesis of BRI-13907 ........................................................................................................................................... 199
Synthesis of BRI-13910 ........................................................................................................................................... 202
Synthesis of BRI-13911 ........................................................................................................................................... 206
Synthesis of BRI-13912 ........................................................................................................................................... 210
4.6 Stereochemical Analysis of Compounds ........................................................................................................ 213
BRI-13900 ..................................................................................................................................................................... 213
BRI-13901 ..................................................................................................................................................................... 214
BRI-13903 ..................................................................................................................................................................... 214
BRI-13911 ..................................................................................................................................................................... 215
BRI-13912 ..................................................................................................................................................................... 216
4.7 Biological Studies Validating Binding ............................................................................................................. 226
Appendix F: Characterization Data of Six Hit Final Compounds ................................................................. 230
BRI-13900 ..................................................................................................................................................................... 230
BRI-13901 ..................................................................................................................................................................... 231
BRI-13902 ..................................................................................................................................................................... 232
BRI-13903 ..................................................................................................................................................................... 233
BRI-13904 ..................................................................................................................................................................... 234
BRI-13905 ..................................................................................................................................................................... 235
BRI-13906 ..................................................................................................................................................................... 236
viii
BRI-13907 ..................................................................................................................................................................... 237
BRI-13910 ..................................................................................................................................................................... 238
BRI-13911 ..................................................................................................................................................................... 239
BRI-13912 ..................................................................................................................................................................... 240
Distribution of Credit ..................................................................................................................................................... 241
References .................................................................................................................. 242

ix
List of Tables
Table 1.1 Selected Optimization Conditions for SO2F-isoxazole Synthesis ..................................................... 9
Table 1.2 Optimization of Sulfonyl Fluoride Conditions ......................................................................................... 9
Table 1.3 Selected Optimization Conditions for Br-isoxazole Synthesis ...................................................... 11
Table 1.4 Optimization of Brominated Conditions ................................................................................................. 12
Table 2.1 Optimization of SuFEx Conditions ........................................................................................................... 120
Table 4.1 Reactions Table ................................................................................................................................................ 175
Table 4.2 Moieties Excluded from Azide Search from the Building Block Library ................................. 176
Table 4.3 Moieties Excluded from Azide Intermediate Generated After Halide Search from the
Building Block Library ........................................................................................................................................................ 177
Table 4.4 Moieties Excluded from Azide Intermediate Generated After Alcohol Search from the
Building Block Library ........................................................................................................................................................ 177
Table 4.5 Moieties Excluded from Carbonyl Search from the Building Block Library .......................... 178
Table 4.6 Moieties Excluded from Primary Amines Search from the Building Block Library for
Fluorotriazole Library ........................................................................................................................................................ 178
Table 4.7 Moieties Excluded from Secondary Amines Search from the Building Block Library for
Fluorotriazole Library ........................................................................................................................................................ 178
Table 4.8 Moieties Excluded from Primary Amines Search from the Building Block Library for
Fluorotriazole Library ........................................................................................................................................................ 178
Table 4.9 Moieties Excluded from Secondary Amines Search from the Building Block Library for
Fluorotriazole Library ........................................................................................................................................................ 179
Table 4.10 Binding Data of Stereoisomers ............................................................................................................... 216

x
List Of Figures
Figure 1.1 Selected Compounds from Combinatorial Library for Synthesis .................................................. 1
Figure 1.2 MS Trace of Reaction Mix Using Initial Isoxazole Conditions ......................................................... 2
Figure 1.3 MS Trace Showing Major Product of Reaction Using Initial Isoxazole Conditions ................ 3
Figure 1.4 MS Trace Showing Mix of Products of BRI-13911 Using Initial Conditions ............................. 3
Figure 1.5 Common Isoxazole Containing Pharmaceuticals ................................................................................. 6
Figure 1.6 Scope and Yields of Synthesized Chloro-Oximes (3a – 3o) ........................................................... 14
Figure 1.7 Scope of Functionalized Isoxazoles Synthesized ............................................................................... 15
Figure 1.8
1
H NMR spectrum of 3-phenylisoxazole-5-sulfonyl fluoride in CDCl3. .................................... 25
Figure 1.9
13
C NMR spectrum of 3-phenylisoxazole-5-sulfonyl fluoride in CDCl3. ................................... 25
Figure 1.10
19
F NMR spectrum of 3-phenylisoxazole-5-sulfonyl fluoride in CDCl3. ................................. 26
Figure 1.11
1
H NMR spectrum of 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride in CDCl3. ........... 26
Figure 1.12
13
C NMR spectrum of 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride in CDCl3. .......... 27
Figure 1.13
1
H NMR spectrum of 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride in CDCl3. ........... 27
Figure 1.14
1
H NMR spectrum of 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ............... 28
Figure 1.15
13
C NMR spectrum of 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .............. 28
Figure 1.16
19
F NMR spectrum of 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .............. 29
Figure 1.17
1
H NMR spectrum of 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ....... 29
Figure 1.18
13
C NMR spectrum of 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ...... 30
Figure 1.19
19
F NMR spectrum of 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ...... 30
Figure 1.20
1
H NMR spectrum of 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ............. 31
Figure 1.21
13
C NMR spectrum of 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ............ 31
Figure 1.22
19
F NMR spectrum of 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ............ 32
Figure 1.23
1
H NMR spectrum of 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
......................................................................................................................................................................................................... 32
xi
Figure 1.24
13
C NMR spectrum of 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
......................................................................................................................................................................................................... 33
Figure 1.25
19
F NMR spectrum of 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
......................................................................................................................................................................................................... 33
Figure 1.26
1
H NMR spectrum of 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
......................................................................................................................................................................................................... 34
Figure 1.27
13
C NMR spectrum of 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 34
Figure 1.28
19
F NMR spectrum of 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 35
Figure 1.29
1
H NMR spectrum of 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ..... 35
Figure 1.30
13
C NMR spectrum of 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .... 36
Figure 1.31
19
F NMR spectrum of 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .... 36
Figure 1.32
1
H NMR spectrum of 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .... 37
Figure 1.33
13
C NMR spectrum of 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ... 37
Figure 1.34
19
F NMR spectrum of 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .. 38
Figure 1.35
1
H NMR spectrum of 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. ............... 38
Figure 1.36
13
C NMR spectrum of 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .............. 39
Figure 1.37
19
F NMR spectrum of 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3. .............. 39
Figure 1.38
1
H NMR spectrum of 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 40
Figure 1.39
13
C NMR spectrum of 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 40
Figure 1.40
19
F NMR spectrum of 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 41
Figure 1.41
1
H NMR spectrum of 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 41
xii
Figure 1.42
13
C NMR spectrum of 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride in
CDCl3. ............................................................................................................................................................................................ 42
Figure 1.43
1
H NMR spectrum of 3-dodecylisoxazole-5-sulfonyl fluoride in CDCl3. ............................... 42
Figure 1.44
13
C NMR spectrum of 3-dodecylisoxazole-5-sulfonyl fluoride in CDCl3. .............................. 43
Figure 1.45
19
F NMR spectrum of 3-dodecylisoxazole-5-sulfonyl fluoride in CDCl3. ............................... 43
Figure 1.46
1
H NMR spectrum of 5-bromo-3-phenylisoxazole in CDCl3. ...................................................... 51
Figure 1.47
13
C NMR spectrum of 5-bromo-3-phenylisoxazole in CDCl3. ..................................................... 52
Figure 1.48
1
H NMR spectrum of 5-bromo-3-(4-chlorophenyl)isoxazole in CDCl3. ................................ 52
Figure 1.49
13
C NMR spectrum of 5-bromo-3-(4-chlorophenyl)isoxazole in CDCl3. ............................... 53
Figure 1.50
1
H NMR spectrum of 5-bromo-3-(4-nitrophenyl)isoxazole in CDCl3. .................................... 53
Figure 1.51
1
H NMR spectrum of 5-bromo-3-(2-methoxyphenyl)isoxazole in CDCl3. ............................ 54
Figure 1.52
13
C NMR spectrum of 5-bromo-3-(2-methoxyphenyl)isoxazole in CDCl3. ........................... 54
Figure 1.53
1
H NMR spectrum of 5-bromo-3-(2-fluorophenyl)isoxazole in CDCl3. ................................. 55
Figure 1.54
13
C NMR spectrum of 5-bromo-3-(2-fluorophenyl)isoxazole in CDCl3. ................................ 55
Figure 1.55
19
F NMR spectrum of 5-bromo-3-(2-fluorophenyl)isoxazole in CDCl3. ................................ 56
Figure 1.56
1
H NMR spectrum of 5-bromo-3-(2-chloro-5-nitrophenyl)isoxazole in CDCl3. ................ 56
Figure 1.57
13
C NMR spectrum of 5-bromo-3-(2-chloro-5-nitrophenyl)isoxazole in CDCl3. ............... 57
Figure 1.58
1
H NMR spectrum of 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole in CDCl3. ................ 57
Figure 1.59
13
C NMR spectrum of 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole in CDCl3. ............... 58
Figure 1.60
1
H NMR spectrum of 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole in CDCl3. .............. 58
Figure 1.61
13
C NMR spectrum of 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole in CDCl3. ............. 59
Figure 1.62
1
H NMR spectrum of 5-bromo-3-(2,6-difluorophenyl)isoxazole in CDCl3. ......................... 59
Figure 1.63
13
C NMR spectrum of 5-bromo-3-(2,6-difluorophenyl)isoxazole in CDCl3. ........................ 60
Figure 1.64
19
F NMR spectrum of 5-bromo-3-(2,6-difluorophenyl)isoxazole in CDCl3. ........................ 60
Figure 1.65
1
H NMR spectrum of 5-bromo-3-(2,4-dichlorophenyl)isoxazole in CDCl3. ......................... 61
Figure 1.66
13
C NMR spectrum of 5-bromo-3-(2,4-dichlorophenyl)isoxazole in CDCl3. ........................ 61
xiii
Figure 1.67
1
H NMR spectrum of 5-bromo-3-dodecylisoxazole in CDCl3. .................................................... 62
Figure 1.68
13
C NMR spectrum of 5-bromo-3-dodecylisoxazole in CDCl3. ................................................... 62
Figure 1.69
1
H NMR spectrum of benzaldehyde oxime in CDCl3. ..................................................................... 74
Figure 1.70
13
C NMR spectrum of benzaldehyde oxime in CDCl3. .................................................................... 74
Figure 1.71
1
H NMR spectrum of 4-chlorobenzaldehyde oxime in CDCl3. ................................................... 75
Figure 1.72
13
C NMR spectrum of 4-chlorobenzaldehyde oxime in CDCl3. .................................................. 75
Figure 1.73
1
H NMR spectrum of 4-nitrobenzaldehyde oxime in CDCl3. ...................................................... 76
Figure 1.74
13
C NMR spectrum of 4-nitrobenzaldehyde oxime in CDCl3. ..................................................... 76
Figure 1.75
1
H NMR spectrum of 2-methoxy benzaldehyde oxime in CDCl3. ............................................. 77
Figure 1.76
13
C NMR spectrum of 2-methoxy benzaldehyde oxime in CDCl3. ............................................ 77
Figure 1.77
1
H NMR spectrum of 2-fluorobenzaldehyde oxime in CDCl3. .................................................... 78
Figure 1.78
1
H NMR spectrum of 2-chloro-5-nitrobenzaldehyde oxime in CDCl3. ................................... 78
Figure 1.79
13
C NMR spectrum of 2-chloro-5-nitrobenzaldehyde oxime in CDCl3. .................................. 79
Figure 1.80
1
H NMR spectrum of 4-chloro-3-nitrobenzaldehyde oxime in CDCl3. ................................... 79
Figure 1.81
13
C NMR spectrum of 4-chloro-3-nitrobenzaldehyde oxime in CDCl3. .................................. 80
Figure 1.82
1
H NMR spectrum of 2-chloro-6-fluorobenzaldehyde oxime in CDCl3. ................................. 80
Figure 1.83
13
C NMR spectrum of 2-chloro-6-fluorobenzaldehyde oxime in CDCl3. ............................... 81
Figure 1.84
19
F NMR spectrum of 2-chloro-6-fluorobenzaldehyde oxime in CDCl3. ................................ 81
Figure 1.85
1
H NMR spectrum of 2,6-difluorobenzaldehyde oxime in CDCl3. ............................................ 82
Figure 1.86
13
C NMR spectrum of 2,6-difluorobenzaldehyde oxime in CDCl3. ........................................... 82
Figure 1.87
19
F NMR spectrum of 2,6-difluorobenzaldehyde oxime in CDCl3. ........................................... 83
Figure 1.88
1
H NMR spectrum of 2,4-dichlorobenzaldehyde oxime in CDCl3. ........................................... 83
Figure 1.89
13
C NMR spectrum of 2,4-dichlorobenzaldehyde oxime in CDCl3. .......................................... 84
Figure 1.90
1
H NMR spectrum of 2,4-dimethoxybenzaldehyde oxime in CDCl3. ....................................... 84
Figure 1.91
13
C NMR spectrum of 2,4-dimethoxybenzaldehyde oxime in CDCl3. ..................................... 85
Figure 1.92
1
H NMR spectrum of 4-(dimethylamino)benzaldehyde oxime in CDCl3. ............................. 85
xiv
Figure 1.93
13
C NMR spectrum of 4-(dimethylamino)benzaldehyde oxime in CDCl3. ............................ 86
Figure 1.94
1
H NMR spectrum of 4-(benzyloxy)benzaldehyde oxime in CDCl3. ........................................ 86
Figure 1.95
13
C NMR spectrum of 4-(benzyloxy)benzaldehyde oxime in CDCl3. ...................................... 87
Figure 1.96
1
H NMR spectrum of tridecanal oxime in CDCl3. ............................................................................. 87
Figure 1.97
13
C NMR spectrum of tridecanal oxime in CDCl3. ............................................................................ 88
Figure 1.98
1
H NMR spectrum of 2-nitrobenzaldehyde oxime in CDCl3. ...................................................... 88
Figure 1.99
13
C NMR spectrum of 2-nitrobenzaldehyde oxime in CDCl3. ..................................................... 89
Figure 1.100
1
H NMR spectrum of 2-naphthaldehyde oxime in CDCl3. ......................................................... 89
Figure 1.101
13
C NMR spectrum of 2-naphthaldehyde oxime in CDCl3. ........................................................ 90
Figure 1.102
1
H NMR spectrum of 2-methoxy-1-naphthaldehyde oxime in CDCl3. ................................. 90
Figure 1.103
13
C NMR spectrum of 2-methoxy-1-naphthaldehyde oxime in CDCl3. ................................ 91
Figure 1.104
1
H NMR spectrum of 1-methoxy-2-naphthaldehyde oxime in CDCl3. ................................. 91
Figure 1.105
13
C NMR spectrum of 1-methoxy-2-naphthaldehyde oxime in CDCl3. ................................ 92
Figure 1.106
1
H NMR spectrum of Indole-3-carbaldehyde oxime in CDCl3. ............................................... 92
Figure 1.107
13
C NMR spectrum of Indole-3-carbaldehyde oxime in CDCl3. .............................................. 93
Figure 1.108
1
H NMR spectrum of N-hydroxybenzimidoyl chloride in CDCl3. ........................................ 101
Figure 1.109
13
C NMR spectrum of N-hydroxybenzimidoyl chloride in CDCl3. ....................................... 101
Figure 1.110
1
H NMR spectrum of 4-chloro-N-hydroxybenzimidoyl chloride in CDCl3. ..................... 102
Figure 1.111
13
C NMR spectrum of 4-chloro-N-hydroxybenzimidoyl chloride in CDCl3. .................... 102
Figure 1.112
1
H NMR spectrum of N-hydroxy-4-nitrobenzimidoyl chloride in CDCl3. ........................ 103
Figure 1.113
13
C NMR spectrum of N-hydroxy-4-nitrobenzimidoyl chloride in CDCl3. ....................... 103
Figure 1.114
1
H NMR spectrum of N-hydroxy-2-methoxybenzimidoyl chloride in CDCl3. ................ 104
Figure 1.115
1
H NMR spectrum of 2-fluoro-N-hydroxybenzimidoyl chloride in CDCl3. ...................... 104
Figure 1.116
13
C NMR spectrum of 2-fluoro-N-hydroxybenzimidoyl chloride in CDCl3. ..................... 105
Figure 1.117
19
F NMR spectrum of 2-fluoro-N-hydroxybenzimidoyl chloride in CDCl3. ..................... 105
Figure 1.118
1
H NMR spectrum of 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride in CDCl3. ..... 106
xv
Figure 1.119
13
C NMR spectrum of 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride in CDCl3. .... 106
Figure 1.120
1
H NMR spectrum of 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride in CDCl3. ..... 107
Figure 1.121
13
C NMR spectrum of 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride in CDCl3. .... 107
Figure 1.122
1
H NMR spectrum of 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride in CDCl3. ... 108
Figure 1.123
13
C NMR spectrum of 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride in CDCl3. . 108
Figure 1.124
1
H NMR spectrum of 2,6-difluoro-N-hydroxybenzimidoyl chloride in CDCl3. .............. 109
Figure 1.125
13
C NMR spectrum of 2,6-difluoro-N-hydroxybenzimidoyl chloride in CDCl3. ............. 109
Figure 1.126
19
F NMR spectrum of 2,6-difluoro-N-hydroxybenzimidoyl chloride in CDCl3. ............. 110
Figure 1.127
1
H NMR spectrum of 2,4-dichloro-N-hydroxybenzimidoyl chloride in CDCl3. ............. 110
Figure 1.128
13
C NMR spectrum of 2,4-dichloro-N-hydroxybenzimidoyl chloride in CDCl3. ............ 111
Figure 1.129
1
H NMR spectrum of N-hydroxy-2-nitrobenzimidoyl chloride in CDCl3. ........................ 111
Figure 1.130
1
H NMR spectrum of N-hydroxy-2-methoxy-1-naphthimidoyl chloride in CDCl3. ...... 112
Figure 1.131
13
C NMR spectrum of N-hydroxy-2-methoxy-1-naphthimidoyl chloride in CDCl3. .... 112
Figure 1.132
1
H NMR spectrum of N-hydroxy-1-methoxy-2-naphthimidoyl chloride in CDCl3. ...... 113
Figure 1.133
13
C NMR spectrum of N-hydroxy-1-methoxy-2-naphthimidoyl chloride in CDCl3. .... 113
Figure 1.134
1
H NMR spectrum of N-hydroxytridecanimidoyl chloride in CDCl3. ................................. 114
Figure 1.135
13
C NMR spectrum of N-hydroxytridecanimidoyl chloride in CDCl3. ................................ 114
Figure 1.136
1
H NMR spectrum of N-hydroxy-indole-3-carbimidoyl chloride in CDCl3. ..................... 115
Figure 1.137
13
C NMR spectrum of N-hydroxy-indole-3-carbimidoyl chloride in CDCl3. ................... 115
Figure 2.1 Examples of Pharmaceuticals Containing the Sulfonamide Moiety ........................................ 118
Figure 3.1 Pharmaceuticals Containing a Triazole Moiety ................................................................................ 122
Figure 3.2 Substrate Scope of Sulfonyl Fluoride Functionalized Triazoles ................................................ 125
Figure 3.3
1
H NMR spectrum of 1-phenethyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. .................. 139
Figure 3.4
13
C NMR spectrum of 1-phenethyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ................. 139
Figure 3.5
19
F NMR spectrum of 1-phenethyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ................. 140
xvi
Figure 3.6
1
H NMR spectrum of 1-(4-methoxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 140
Figure 3.7
13
C NMR spectrum of 1-(4-methoxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 141
Figure 3.8
19
F NMR spectrum of 1-(4-methoxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 141
Figure 3.9
1
H NMR spectrum of 1-(4-fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 142
Figure 3.10
13
C NMR spectrum of 1-(4-fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 142
Figure 3.11
19
F NMR spectrum of 1-(4-fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 143
Figure 3.12
1
H NMR spectrum of 1-(4-nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in DMSO-
d6. ................................................................................................................................................................................................. 143
Figure 3.13
13
C NMR spectrum of 1-(4-nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in DMSO-
d6. ................................................................................................................................................................................................. 144
Figure 3.14
19
F NMR spectrum of 1-(4-nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in DMSO-
d6. ................................................................................................................................................................................................. 144
Figure 3.15
1
H NMR spectrum of 1-(4-cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 145
Figure 3.16
13
C NMR spectrum of 1-(4-cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 145
Figure 3.17
19
F NMR spectrum of 1-(4-cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 146
Figure 3.18
1
H NMR spectrum of 1-(4-acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6. ................................................................................................................................................................................... 146
Figure 3.19
13
C NMR spectrum of 1-(4-acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6. ................................................................................................................................................................................... 147
xvii
Figure 3.20
19
F NMR spectrum of 1-(4-acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6. ................................................................................................................................................................................... 147
Figure 3.21
1
H NMR spectrum of 1-(4-hydroxylphenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 148
Figure 3.22
13
C NMR spectrum of 1-(4-hydroxylphenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 148
Figure 3.23
19
F NMR spectrum of 1-(4-hydroxylphenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 149
Figure 3.24
1
H NMR spectrum of 1-phenyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ...................... 149
Figure 3.25
13
C NMR spectrum of 1-phenyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. .................... 150
Figure 3.26
19
F NMR spectrum of 1-phenyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ..................... 150
Figure 3.27
1
H NMR spectrum of 1-(4-methoxylphenyl)-1,2,3-triazole-4-sulfonyl fluoride inCDCl3.
....................................................................................................................................................................................................... 151
Figure 3.28
13
C NMR spectrum of 1-(4-methoxylphenyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 151
Figure 3.29
19
F NMR spectrum of 1-(4-methoxylphenyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 152
Figure 3.30
1
H NMR spectrum of 1-(3-(methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 152
Figure 3.31
13
C NMR spectrum of 1-(3-(methoxymethyl)phenyl)-1H-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3. ................................................................................................................................................................... 153
Figure 3.32
19
F NMR spectrum of 1-(3-(methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 153
Figure 3.33
1
H NMR spectrum of 1-benzyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ...................... 154
Figure 3.34
13
C NMR spectrum of 1-benzyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ..................... 154
Figure 3.35
19
F NMR spectrum of 1-benzyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ..................... 155
Figure 3.36
1
H NMR spectrum of 1-(4-cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride in DMSO-d6.
....................................................................................................................................................................................................... 155
xviii
Figure 3.37
13
C NMR spectrum of 1-(4-cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride in DMSO-d6.
....................................................................................................................................................................................................... 156
Figure 3.38
19
F NMR spectrum of 1-(4-cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride in DMSO-d6.
....................................................................................................................................................................................................... 156
Figure 3.39
1
H NMR spectrum of methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate
in DMSO-d6. .............................................................................................................................................................................. 157
Figure 3.40
13
C NMR spectrum of methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate
in DMSO-d6. .............................................................................................................................................................................. 157
Figure 3.41
19
F NMR spectrum of methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate
in DMSO-d6. .............................................................................................................................................................................. 158
Figure 3.42
1
H NMR spectrum of 1-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 158
Figure 3.43
13
C NMR spectrum of 1-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 159
Figure 3.44
19
F NMR spectrum of 1-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 159
Figure 3.45
1
H NMR spectrum of 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 160
Figure 3.46
13
C NMR spectrum of 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 160
Figure 3.47
19
F NMR spectrum of 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 161
Figure 3.48
1
H NMR spectrum of 1-((3s,5s,7s)-adamantan-1-yl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3. .......................................................................................................................................................................................... 161
Figure 3.49
13
C NMR spectrum of 1-((3s,5s,7s)-adamantan-1-yl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 162
Figure 3.50
19
F NMR spectrum of 1-((3s,5s,7s)-adamantan-1-yl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3. ..................................................................................................................................................................................... 162
Figure 3.51
1
H NMR spectrum of 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. ............... 163
xix
Figure 3.52
13
C NMR spectrum of 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. .............. 163
Figure 3.53
19
F NMR spectrum of 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. .............. 164
Figure 3.54
1
H NMR spectrum of 1-(3-phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3. 164
Figure 3.55
13
C NMR spectrum of 1-(3-phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 165
Figure 3.56
19
F NMR spectrum of 1-(3-phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
....................................................................................................................................................................................................... 165
Figure 3.57
1
H NMR spectrum of 1-(4-(1,3-dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl
fluoride in DMSO-d6. ............................................................................................................................................................ 166
Figure 3.58
13
C NMR spectrum of 1-(4-(1,3-dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl
fluoride in DMSO-d6. ............................................................................................................................................................ 166
Figure 3.59
19
F NMR spectrum of 1-(4-(1,3-dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl
fluoride in DMSO-d6. ............................................................................................................................................................ 167
Figure 3.60
1
H NMR spectrum of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3. ................................................................................................................................................................... 167
Figure 3.61
13
C NMR spectrum of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-
sulfonyl fluoride in CDCl3. ................................................................................................................................................. 168
Figure 3.62
19
F NMR spectrum of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-
sulfonyl fluoride in CDCl3. ................................................................................................................................................. 168
Figure 4.1 Schematic representation of library design procedure employed to develop the two
compound libraries using click reactions.* ............................................................................................................... 175
Figure 4.2 Chemical Structure of Six Hit Compounds ......................................................................................... 227
Figure 4.3 Dose-response curves of cannabinoid receptors with the hits.* .............................................. 228
Figure 4.4 Primary screening of the V-SYNTHES predicted compounds with β-arrestin recruitment
tango assay.** ......................................................................................................................................................................... 228
Figure 4.5
1
H NMR spectrum of BRI-13900 in DMSO. ......................................................................................... 230
Figures 4.6
13
C NMR spectrum of BRI-13900 in DMSO. ..................................................................................... 230
Figure 4.7
1
H NMR spectrum of BRI-13901 in DMSO. ......................................................................................... 231
xx
Figures 4.8
13
C NMR spectrum of BRI-13901 in DMSO. ..................................................................................... 231
Figure 4.9
1
H NMR spectrum of BRI-13902 in DMSO. ......................................................................................... 232
Figure 4.10
13
C NMR spectrum of BRI-13902 in DMSO. ..................................................................................... 232
Figure 4.11
1
H NMR spectrum of BRI-13903 in DMSO. ...................................................................................... 233
Figure 4.12
13
C NMR spectrum of BRI-13903 in DMSO. ..................................................................................... 233
Figure 4.13
1
H NMR spectrum of BRI-13904 in DMSO. ...................................................................................... 234
Figure 4.14
13
C NMR spectrum of BRI-13904 in DMSO. ..................................................................................... 234
Figure 4.15
1
H NMR spectrum of BRI-13905 in DMSO. ...................................................................................... 235
Figure 4.16
13
C NMR spectrum of BRI-13905 in DMSO. ..................................................................................... 235
Figure 4.17
1
H NMR spectrum of BRI-13906 in DMSO. ...................................................................................... 236
Figure 4.18
13
C NMR spectrum of BRI-13906 in DMSO. ..................................................................................... 236
Figure 4.19
1
H NMR spectrum of BRI-13907 in DMSO. ...................................................................................... 237
Figure 4.20
13
C NMR spectrum of BRI-13907 in DMSO. ..................................................................................... 237
Figure 4.21
1
H NMR spectrum of BRI-13910 in DMSO. ...................................................................................... 238
Figure 4.22
13
C NMR spectrum of BRI-13910 in DMSO. ..................................................................................... 238
Figure 4.23
1
H NMR spectrum of BRI-13911 in CDCl3. ....................................................................................... 239
Figure 4.24
13
C NMR spectrum of BRI-13911 in CD2Cl2. .................................................................................... 239
Figure 4.25
1
H NMR spectrum of BRI-13912 in CD2Cl2. ..................................................................................... 240
Figure 4.26
13
C NMR spectrum of BRI-13912 in CD2Cl2. .................................................................................... 240
xxi
List of Schemes
Scheme 1.1 Synthetic Pathway to Chloro-Oximes ....................................................................................................... 7
Scheme 1.2 Optimized Sulfonyl Fluoride Conditions .............................................................................................. 10
Scheme 1.3 Optimized Brominated Conditions ......................................................................................................... 12
Scheme 2.1 SuFEx Mechanism ........................................................................................................................................ 117
Scheme 3.1 General procedure for the synthesis of sulfonyl fluoride substituted triazoles. .............. 123
Scheme 4.1 Building Blocks for Triazole Library .................................................................................................... 173
Scheme 4.2 Building Blocks for Isoxazole Library ................................................................................................. 173
Scheme 4.3 Steps for Fluorotriazole Reaction ......................................................................................................... 179
Scheme 4.4 Steps for Isoxazole reaction: ................................................................................................................... 179
xxii
List of Abbreviations
GC-MS = gas chromatography-mass spectrometry
LC-MS = liquid chromatography-mass spectrometry
HPLC = high performance liquid chromatography
NMR = nuclear magnetic resonance
s = singlet
d = doublet
t = triplet
m = multiplet
TLC = thin layer chromatography
DCM = dichloromethane
DCE = 1,2-dichloroethane
EtOAc = ethyl acetate
EtOH = ethanol
MeOH = methanol
MeCN = acetonitrile
NaOH – sodium hydroxide
DMF = N,N’-dimethylformamide
DMSO = dimethylsulfoxide
eq. = equivalents
LiHDMS = lithium hexamethyldisilazide
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
DIPEA = N,N-Diisopropylethylamine
ET3N = triethylamine
LiCl = lithium chloride
KCN = potassium cyanide
KF = potassium fluoride
NH4HCOO = ammonium formate
NH4OH = ammonium hydroxide
NaHCO3 = sodium bicarbonate
TBAC = tetrabutylammonium chloride

xxiii
Abstract
Chemistry lies at the heart of everything from biological processes critical to
understanding the human body to the understanding of our planet and its many awe-
inspiring wonders. Whether it is the pan searing a steak, in the bottle we pick to pair with
the steak, or the lifesaving medications that have touched all our personal lives, chemistry,
and its applications are really surrounding us every day. I have always loved to cook and
think that my first reactions were done in the kitchen, where it was nice to have my mom do
the dishes and clean up after me. Some of these reactions led to edible cookies, while others
were complete kitchen disasters reminiscent of the kitchen nightmares show. Similarly, in
the lab, it takes many failed reactions to get one that works. However exciting this moment
is, it is merely the beginning as there is a great deal of optimization that can usually be done.
Although I will always enjoy the triumphs of chemistry in the kitchen, it was extremely
gratifying to transition reactions to the laboratory. Seeing how advances in chemistry unveil
new potent molecular scaffolds to expand the chemical space and exploring the versatility
and efficiency of known (and new) reactions has made me truly appreciate the power of
chemistry. It has been a privilege to have the opportunity to learn, to fail, and to learn many
life lessons along with chemical ones from those many failed reactions to ultimately succeed
with the help of the support of colleagues and mentors.
In Chapter One a new synthetic methodology to create selectively functionalized
isoxazoles with the potential to create molecular scaffolds able to undergo various chemical
transformations is explored. Methodologies and detailed protocols along with optimization
studies that led to the final conditions for both sulfonyl fluoride (SO2F) and Brominated
isoxazoles are discussed. This project stemmed from synthetic issues that arose surrounding
xxiv
the isoxazole molecular scaffold for the cannabinoid receptor discussed in chapter four. In
Chapter Two reaction conditions for complex substrates using SuFEx chemistry are
investigated, to enable the creation of complex molecules. These optimized conditions
allowed for SuFEx reactions to succeed for both complex triazoles and isoxazoles to form the
corresponding sulfonamides. In Chapter Three, sulfonyl fluoride functionalized triazoles are
created using a new methodology that allows for selective functionalization using Br-ESF.
Although the use of Br-ESF to prepare triazoles has been well documented, this new
procedure has greatly enhanced selectivity leading to higher yields of SO2F functionalized
triazoles. These functionalized triazoles are then able to undergo further synthetic
modifications using SuFEx chemistry. Finally, in Chapter Four, we create a diverse library of
heterocyclic compounds with potent molecular scaffolds using a simple set of starting
materials and efficient click reactions. By using the structure of the cannabinoid type (II)
receptor along with the library of compounds found in chemical databases, this chapter
presents an alternative pathway to discover lead compounds with potential therapeutic
applications.

Chapter 1. Selective Synthesis of Functionalized Isoxazoles
1.1a Problem Inspiring the Studies

The combinatorial library for the cannabinoid (II) receptor project that is discussed in
chapter four was based on click reactions to form complex compounds using a potent
heterocyclic scaffold. Both isoxazoles and triazoles were used as backbones to the
compounds that would be formed to have a sulfonyl fluoride (SO2F) handle installed as a site
for further modifications through SuFEx chemistry. Using bromothenesulfonyl fluoride (Br-
ESF) to form triazoles functionalized with SO2F groups from the corresponding azides has
been well-documented and studied in our lab.
1
While probing the tolerance of the reaction
an isoxazole was also created and used to demonstrate the scope of the reaction. As both
triazoles and one isoxazole had been successfully created using the procedure, they were
both used to create the combinatorial library used for the virtual ligand screening (Figure
1.1).

Figure 1.1 Selected Compounds from Combinatorial Library for Synthesis
N
N
N
S
O
O
N
N
N
31769
N
OH
N
N
N
S
O
O
Cl
37912
N
N
N
S
O
O
Cl
HN
OH
39536
H
N
N
N
N
S
O
O
HO
N
126383
N
N
N
S
O
O
NH
OH
S
19786
N
N
N
S
O
O
N
N
N
48
N
N
N
S
O
O
N
H
N
NH
N
38865
N
N
N
S
O
O
NH
N
NH
7414
2339
N
N
N
S
O
O
N
N
N N
Cl
O
11396
O
O
N
S
O
O
N
OH
56933
F
O
O
O
N
S
O
O
HN
HO
857
O
Cl
Cl
O
N
S
O
O
N
HN
N
O
N
S
O
O
N
S
N
N
10532
2
After successfully converting aldehydes to oximes which were then chlorinated, the
cyclization reaction was attempted using Br-ESF. Unfortunately, with the complex
compounds being used the attempts to synthesize the isoxazoles in order for them to then
undergo SuFEx reactions with amines were not successful. Although traces of the desired
product could be detected, the yield of the reactions was not sufficient to isolate the product
and continue to the next step of the synthesis (Figure 1.2).

Figure 1.2 MS Trace of Reaction Mix Using Initial Isoxazole Conditions

This led to the investigation into the major product that was being formed by the
reaction, which was determined to be the dimerization of the nitrile oxides formed in situ
from the chloro-oximes upon the addition of the base (Figure 1.3). In order to synthesize
the desired isoxazoles a new procedure that prevented this dimerization was necessary, as
once the dimers formed the reaction was unable to proceed since the majority of starting
chloro-oxime would be consumed by the process.
O
N
SO
2
F
MW:
222.0791
3

Figure 1.3 MS Trace Showing Major Product of Reaction Using Initial Isoxazole Conditions

Although for the CB2 project only the SO2F functionalized isoxazoles needed to be
accessed, there were also trace amounts of the brominated product visible (Figure 1.4),
which inspired our studies into the selective formation of both functionalized isoxazoles.

Figure 1.4 MS Trace Showing Mix of Products of BRI-13911 Using Initial Conditions

N
O
N
4
1.1b Introduction

Heterocyclic compounds are a vast, heterogenous, and intriguing chemical class that has
often been described as a privileged scaffold in medicinal chemistry. More than 85% of all
biologically active compounds contain a heterocycle.
2
Naturally occurring N-heterocyclic
compounds from vitamins such as ascorbic acid and riboflavin to the base pairs of DNA and
RNA (guanine, cytosine, adenine, and thymine) have crucial physiological roles. Due to the
abundance and importance of heterocycles found in physiology, they are natural target cores
for pharmacological applications.
Approximately 75% of FDA-approved small molecule drugs in the U.S. contain a nitrogen
heterocycle making them a very common structure found in pharmaceuticals and a useful
building block for novel drug candidates.
3, 4
As of 2017 there were over 300 FDA-approved
pharmaceuticals containing oxygen heterocycles.
5
Out of these compounds approximately
95% contain a five-membered oxygen heterocycle, 17 of which are isoxazoles.
5
Due to
intermolecular forces such as dipole-dipole interactions heterocycles with nitrogen and
oxygen atoms present at the same time offer the ability to readily form hydrogen bonds with
biological targets. Isoxazoles represent an appealing fragment for novel pharmaceuticals due
to their broad range of biological activity. This is exemplified by the pharmaceutical
compounds containing isoxazoles on the market with various uses including anti-bacterial
agents, anti-fungal drugs, antidepressants, and anti-inflammatories (Figure 1.5).
6-10
There
is also a significant amount of current research into isoxazole compounds as anticancer
agents, anticonvulsants, antidepressants, and immunosuppressants.
6, 9, 11-16
This explains
the demand to access isoxazoles as building blocks with various functionalities.
17

5
Despite the recent advances in the synthesis of nitrogen-containing heterocycles, with
approximately 100,000 publications between 2009 and 2020, the selective synthesis of
isoxazoles with various functional groups remains elusive. Out of the 17 approved
pharmaceuticals, the majority are disubstituted with all 17 substituted at C5 and 15 out of
the 17 substituted at C3, making these ideal positions to install functional handles.
5

Sulfonamide linkages using 1,3-dipolar cycloadditions to create isoxazole scaffolds were
reported but included the thiophene moiety linked to the isoxazole rather than the creation
of a sulfonyl fluoride handle which can then undergo SuFEx to create a variety of sulfonamide
functionalized isoxazoles.
18
Recent efforts towards the synthesis of sulfonyl fluoride
isoxazoles using 1- bromoethene-1-sulfonyl fluoride (Br-ESF) have been successful using
reported procedures that require a more robust protocol to avoid tedious purification from
brominated derivatives and expand the substrate scope.
1, 19
Noteworthy, some procedures
could lead to the dimerization of the nitrile oxide formed in situ based on the order of
addition of the reactants, lowering the desired product yield. As opposed to the sulfonyl
fluoride functionalized isoxazoles, to the best of our knowledge, the selective synthesis of
brominated isoxazoles has not been reported.
6

Figure 1.5 Common Isoxazole Containing Pharmaceuticals

Herein, we propose a synthetic strategy to selectively control the functionality of
isoxazoles using Br-ESF and install only the desired bromine handle. This selective approach
allows for the chemo selective formation of the brominated product without the need for
column chromatography to separate the products for the studied substrates. This bromine
handle can selectively be introduced so that the isoxazole undergoes further transformations
to increase the diversity of molecular skeleton via well-developed chemistry. Furthermore,
a simple shift from an aqueous to an organic environment enables access to sulfonyl fluoride
substituted isoxazoles maintaining high selectivity. The syntheses reported in this work can
be used to further diversify molecular complexity with isoxazole motive using simple
reactions under mild conditions.
Since nitrile oxides are extremely reactive one prefers to form them in situ from the
respective chloro-oximes, which can be obtained from aldehydes (1) in two steps: (i)
aldehyde oximation (2) with hydroxylamine hydrochloride and (ii) subsequent chlorination
with NCS (Scheme 1.1). Both steps do not require column chromatography and could be
7
achieved in good yields. Obtained chloro-oximes (3) have been directly used for isoxazole
synthesis.
Scheme 1.1 Synthetic Pathway to Chloro-Oximes

1.2 Previous Synthetic Strategies

Isoxazoles have been synthesized using a variety of chemical reactions. In 1903 Claisen
et al. successfully synthesized an isoxazole moiety through the oximation of propargyl acetal.
20
Since then a variety of methods to prepare substituted isoxazoles have been discovered
many of which require harsh reagents such as LiHDMS and inert atmospheric conditions.
21

Nitrile oxides have been used to synthesize isoxazoles through combination with alkenes
and alkynes in a 1,3-dipolar cycloaddition reaction using DBU in a metal-free reaction.
22

These previously reported syntheses have had poor regioselectivity due to the high
activation energy of the reaction and have thus required high temperatures.
23
These nitrile
oxides are normally formed under basic conditions from the corresponding oxime halides
and have successfully been formed under aqueous conditions.
24
Although numerous
methods using nitrile oxides to form isoxazoles in a cycloaddition reaction have been
developed the various methods lead to a limited scope with minimal synthetic diversity
within the method. A convenient one-pot regioselective protocol for the synthesis of 3,5-
8
disubstituted isoxazoles was developed using nitrile oxides and terminal acetylenes in a
copper(I)catalyzed synthesis.
24

After the initial discovery of ethenesulfonyl fluoride’s (ESF) ability to install a sulfonyl
fluoride handle a variety of derivatives were synthesized.
25
An updated and improved
synthesis of Br-ESF was detailed in the 2018 publication by Fokin et al. where its ability to
combine with an azide to create a sulfonyl fluoride functionalized triazole was displayed
with an impressive scope of compounds.
19, 26, 27
The scope included one isoxazole compound,
and when the same synthetic strategy was employed to make complex isoxazoles, both the
brominated and sulfonyl fluoride functionalized triazoles were observed.
26

1.3 Optimization of Sulfonyl Fluoride Conditions

In an aqueous environment Et3N results in poor selectivity (Table 1.1, entry 2),
however, stronger bases like DBU and DIPEA lead to multiple side products only (Table 1.1,
entries 1-2). Compared to NaOH (Table 1.1, entry 3), milder NaHCO3 (Table 1.1, entry 3)
resulted in improved 6a selectivity. Ionic additives such as TBAC and Aliquot 336 only led to
the formation of various side products, thus we attempted to move to an organic
environment. Solvents like MeCN, MeOH, DCE, Toluene, and Anisole resulted in the
formation of multiple side products and lower selectivity, while DCM appeared to be a
solvent of choice in the presence of Et3N (Table 1.1, entry 4). Seeing that dilution generally
assists the reaction 5x dilution improved the yield of 6a from 67% to 86% (Table 1.1, entry
5). Upon completion, the product was washed with water and after solvent evaporation
purified by filtration through a small pad of silica without the need for column
9
chromatography. The desired sulfonyl fluoride functionalized isoxazole 6a was obtained
selectively and in high yield by the reaction.
Table 1.1 Selected Optimization Conditions for SO2F-isoxazole Synthesis
Entry Solvent Base Outcome
1 H2O DIPEA Side products
2 H2O DBU Side products
3 H2O NaHCO3 30% 6, 60% 5
4 DCM NEt3 67% 6
5 DCM (5x dil.) NEt3 86% 6

Table 1.2 Optimization of Sulfonyl Fluoride Conditions

Alternative conditions for direct selective synthesis of sulfonyl fluoride functionalized
isoxazoles 6 were found upon optimizations. The installation of a sulfonyl fluoride handle
can then be used for further synthesis using sulfur (VI) fluoride exchange “SuFEx” chemistry
10
to create complex substrates.
12
Since the sulfonyl fluoride functional handle is fairly stable
to hydrolysis under basic and acidic conditions and has selective reactivity it is a highly
desirable group to have installed on the isoxazole. While there have been successful
syntheses of sulfonyl fluoride isoxazoles reported, the conditions presented herein lead to
the selective synthesis of the desired isoxazole without the formation of the brominated
product and therefore do not require column chromatography.
Scheme 1.2 Optimized Sulfonyl Fluoride Conditions

1.4 Optimization of Brominated Conditions

Initial investigation of the reaction between 3 and Br-ESF (4) revealed the presence of
the brominated product (5a) in significant quantities when water was used as the solvent
rather than using an organic solvent such as DCM or EtOAc where predominantly the SO2F
product was formed. Although no reaction occurs in pure water (Table 1.3, entry 1). Poor
selectivity was observed with strong organic bases like Et3N or DBU, and inorganic bases
(NaOH) although they facilitated the transformation of the chloro-oxime (Table 1.3, entries
2 – 3). Interestingly, simple salt additives such as LiCl, KCN, KF, and NH4HCOO (Table 1.3,
entries 4 – 6) swiftly enabled the desired transformation in substantial yields of the
brominated product 5a. The NH4HCOO in water provided the highest yield of 5a, thus pH
was varied to determine its effect on the yield. Less 5a formed under acidic conditions and
the best pH was found to be 8.3 adjusted using NH4OH (Table 1.3, entry 7).

DCM
Ph Cl
N
+
SO
2
F
Br
Ph
O
N
SO
2
F
OH
6a 3 4
NEt
3
11
Table 1.3 Selected Optimization Conditions for Br-isoxazole Synthesis
Entry Additive Base Outcome
1 none none No reaction
2 none NEt3 78% 6, 22% 5
3 none NaOH 67% 6, 30% 5
4 LiCl (20 equiv.) none 69% 5
5 MeOH (1 equiv.), KF (2 equiv.) none 68% 5
6 NH4HCOO (1M) none 75% 5
7 NH4HCOO buffer pH 8.3 none 83% 5
Upon completion of the reaction, the product was extracted, and after removal of solvents
5a was isolated by simple filtration through a small pad of silica to assist removal of 4 excess.
The desired brominated isoxazole 5a was obtained selectively and in high yield at room
temperature and these conditions were selected to explore the applicability of the method.
Initially, the reactivity of 4 with 3a was examined based on the order of addition of the
reactants. The addition of base before the 4 causes the almost immediate dimerization of the
intermediate nitrile oxide due to its high reactivity. This led to negligible quantities of
isoxazole being formed with the respective furoxan being the major product. For target 6a
to be formed in desirable yields it is critical that both 3a and 4 are present in the reaction
vessel before the addition of any base, limiting the dimerization of the nitrile oxides.
12
Table 1.4 Optimization of Brominated Conditions

The conditions presented herein lead to the selective synthesis of the desired brominated
isoxazole without the formation of the sulfonyl fluoride product and therefore do not require
column chromatography. The reaction proceeds directly from the chloro-oxime with the in-
situ formation of the corresponding nitrile oxide which is preferable due to the difficulty of
isolating the nitrile oxides. The brominated compound is then able to undergo further
chemical modifications at the brominated position to create complex molecules using the
potent isoxazole scaffold.
Scheme 1.3 Optimized Brominated Conditions

pH = 8.28
5eq NH
4
HCOO
in 10mL H
2
O
Ph Cl
N
+
SO
2
F
Br
Ph
O
N
Br
OH
5a 3a 4
13
1.5 Compounds Synthesized

To explore the applicability of the selected reaction conditions different chloro-oximes
were used (Figure 1.6). Ortho, meta, and para-substituted benzenes were all well-behaved
in the reaction as were disubstituted benzenes. The strong electron withdrawing group
effect of the nitro-substituent in the aromatic ring for compounds 3c, 3f, 3g, and 3l
significantly decreased the yields of the brominated isoxazoles 5. This trend was found for
all four nitro-containing substrates with the largest effect being found in the meta position.
While this effect was also seen regarding the sulfonyl fluoride isoxazoles (compounds 6c, 6f,
6g, and 6l) the yields were not impacted to the same extent as the brominated isoxazoles 5
aside from 6g where the reaction did not proceed. Ortho-disubstituted benzenes with
halogens (compounds h and i) were well tolerated for both reactions with yields being
potentially lowered due to steric hindrance. Single methoxy substitution at the ortho
position and di-substitution at the ortho and para positions (compounds d and k) reduced
yields significantly more than substitutions with halogens at the same position (compounds
e and j) except for the ortho-methoxy and ortho-fluoro substituents for the sulfonyl fluoride
isoxazoles 5d and 6d. Furthermore, aliphatic chloro-oximes 3 resulted in excellent yields of
both desired products.

14

Figure 1.6 Scope and Yields of Synthesized Chloro-Oximes (3a – 3o)
96% 92% 71% 97%
82% 80% 54% 71%
98%
scope
Cl
OH
N
Cl
OH
N
Cl
Cl
OH
N
O
2
N
Cl
OH
N O
Cl
OH
N F
Cl
OH
N
NO
2
Cl
Cl
OH N
O
2
N
Cl
Cl
OH N
Cl
F
Cl
OH
N F
F
N Cl
Cl
OH
Cl
OH
N NO
2
98%
Cl
92%
R Cl
N
OH
R
N
OH
N
Cl
O O
(DMF)
O
N
OH
Cl
O
N
OH
Cl
76%
68%
N
H
N
OH
Cl
45%
N
H
Cl
HO
96%
15

Figure 1.7 Scope of Functionalized Isoxazoles Synthesized

1.6 Synthesis of Sulfonyl Fluoride Functionalized Isoxazoles

General Procedure
1 mmol of chloro-oxime was dissolved in 10 mL of DCM in a 20 mL scintillation vial. 2 mmol
of Br-ESF was added and the mixture was stirred at RT for 5 minutes. While the mixture was
stirring, 2 mmol of triethylamine was slowly added dropwise over 1 minute. After 2 hours
of stirring, the reaction was quenched with 10 mL of water. The product was extracted to
DCM (x3), washed with water (x3) and brine (x1), dried over sodium sulfate, and solvents
were evaporated under vacuum. The product was redissolved in 3:1 hexanes: chloroform
5b, 42%
6b, 61%
5c, 4%
6c, 56%
5d, 13%
6d, 68%
5e, 57%
6e, 61%
5f, 23%
6f, 43%
5g, 11%
6g, no reaction
5h, 50%
6h, 66%
5i, 59%
6i, 92%
5j, 35%
6j, 44%
Br
SO
2
F
pH 8.28
(H
2
O)
3 4
5
+
NEt
3
DCM, RT
6
5a, 83%
6a, 86%
scope
R Cl
N
OH
R
O
N
SO
2
F
R
O
N
Br
O
N
X
O
N
X
Cl
O
N
X
O
2
N
O
N
X
O
O
N
X
F
O
N
X
Cl
O
2
N
O N
X
O
2
N
Cl
O N
X
Cl
F
O
N
X
F
F
Cl
Cl
5l, 71%
6l, 37%
O
N
X
NO
2
O
N
O
X
O
N
O
X
5m, no reaction
6m, 58%
5n, 49%
6n, 60%
O
N
X
O
N
X
5o, 72%
6o, 99%
5k, 11%
6k, no reaction
O
N
X
O
O
16
and filtered through a short pad of silica. The flask was rinsed with 3:1 hexanes: chloroform
with a few drops of DCM and filtered through the silica pad. Solvents were evaporated under
vacuum and the product was allowed to crystalize.

6a: 3-phenylisoxazole-5-sulfonyl fluoride

N-hydroxybenzimidoyl chloride (1 mmol, 155.6 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 196.4 mg; 86%
1
H NMR (400 MHz, CDCl3) δ 7.87 – 7.79 (m, 2H), 7.59 – 7.49 (m, 3H), 7.47 (dd, J = 1.4, 0.4 Hz,
1H).
13
C NMR (101 MHz, CDCl3) δ 163.33, 158.81 (d, J = 38.9 Hz), 131.75, 129.57, 127.17, 126.41,
110.39 (d, J = 3.5 Hz).
19
F NMR (376 MHz, CDCl3) δ 64.43 (d, J = 2.0 Hz).
LC-APCI-MS: [M+H]
+
exact for C9H6FNO3S m/z 228.0125, accurate m/z 228.0120 (Δ = 2.2
ppm)

6b: 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride

O
N
SO
2
F
O
N
SO
2
F
Cl
17
4-chloro-N-hydroxybenzimidoyl chloride (1 mmol, 190.0 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mmol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 158.8 mg; 61%
1
H NMR (600 MHz, cdcl3) δ 7.80 – 7.75 (m, 2H), 7.53 – 7.50 (m, 2H), 7.45 (d, J = 1.3 Hz, 1H).
13
C NMR (151 MHz, cdcl3) δ 162.40, 159.15 (d, J = 39.3 Hz), 138.10, 129.95, 128.43, 124.89,
110.17 (d, J = 3.9 Hz).
19
F NMR (564 MHz, cdcl3) δ 64.55 (d, J = 1.6 Hz), 64.51 (d, J = 1.3 Hz)

6c: 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride

N-hydroxy-4-nitrobenzimidoyl chloride (1 mmol, 200.6 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 152.4 mg; 56%
1
H NMR (600 MHz, cdcl3) δ 8.41 (dd, J = 8.9, 0.8 Hz, 2H), 8.05 (dd, J = 9.0, 0.8 Hz, 2H), 7.55 (t,
J = 1.4 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 161.61, 132.24, 128.47, 128.26, 124.82, 123.94, 110.28 (d, J = 3.5
Hz).
19
F NMR (564 MHz, cdcl3) δ 64.90 (d, J = 1.3 Hz).

6d: 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride
O
N
SO
2
F
O
2
N
18

N-hydroxy-2-methoxybenzimidoyl chloride (1 mmol, 185.6 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 174.6 mg; 68%
1
H NMR (600 MHz, cdcl3) δ 7.95 (dd, J = 7.6, 1.7 Hz, 1H), 7.70 (dd, J = 7.4, 1.4 Hz, 1H), 7.54 –
7.44 (m, 1H), 7.13 – 6.96 (m, 2H), 3.95 (s, 3H).
13
C NMR (151 MHz, cdcl3) δ 161.10, 157.61, 133.28, 129.77, 121.66, 115.45, 114.23, 113.32,
111.95, 56.05.
19
F NMR (564 MHz, cdcl3) δ 64.55, 64.37 (d, J = 1.3 Hz).

6e: 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride

2-fluoro-N-hydroxybenzimidoyl chloride (1 mmol, 173.7 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 149.7 mg; 61%
1
H NMR (600 MHz, cdcl3) δ 8.04 (td, J = 7.6, 1.8 Hz, 1H), 7.62 (dd, J = 3.1, 1.4 Hz, 1H), 7.55
(dddd, J = 8.3, 7.3, 5.3, 1.8 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.29 – 7.23 (m, 1H).
13
C NMR (151 MHz, cdcl3) δ 161.30, 159.62, 158.76, 133.66, 129.15 (d, J = 2.3 Hz), 125.31 (d,
J = 3.5 Hz), 116.94, 116.80, 114.71, 114.63, 112.72 (dd, J = 10.7, 3.6 Hz).
O
N
SO
2
F
O
O
N
SO
2
F
F
19
19
F NMR (564 MHz, cdcl3) δ 64.67, -114.20.

6f: 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride

2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride (1 mmol, 235.0 mg), Br-ESF (2 mmol,
378.0 mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 131.2 mg; 43%
1
H NMR (400 MHz, cdcl3) δ 8.70 (dd, J = 2.7, 0.4 Hz, 1H), 8.36 (dd, J = 8.9, 2.7 Hz, 1H), 7.78
(dd, J = 8.8, 0.4 Hz, 1H), 7.71 (d, J = 1.3 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 159.98, 139.38, 131.82, 126.81, 126.55, 126.03, 126.01, 112.56,
112.49.
19
F NMR (376 MHz, cdcl3) δ 65.13 (d, J = 1.6 Hz).

6g: 3-(4-chloro-3-nitrophenyl)isoxazole-5-sulfonyl fluoride

4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride (1 mmol, 235.0 mg), Br-ESF (2 mmol,
378.0 mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield - No Reaction
O
N
SO
2
F
Cl
O
2
N
O
N
SO
2
F
NO
2
Cl
20

6h: 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride

2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride (1 mmol, 208.0 mg), Br-ESF (2 mmol,
378.0 mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 186.3 mg; 66%
1
H NMR (400 MHz, cdcl3) δ 7.49 (td, J = 8.3, 5.8 Hz, 1H), 7.39 (dt, J = 8.0, 1.1 Hz, 2H), 7.20
(ddd, J = 9.1, 8.3, 1.1 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 162.69, 160.13, 144.58, 144.54, 131.36, 131.25, 126.46 (d, J = 3.5
Hz), 115.70, 115.47.
19
F NMR (376 MHz, cdcl3) δ 64.95, -107.07 – -111.16 (m).

6i: 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride

2,6-difluoro-N-hydroxybenzimidoyl chloride (1 mmol, 191.6 mg), Br-ESF (2 mmol, 378.0
mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white powder) 241.1 mg; 92%
1
H NMR (400 MHz, cdcl3) δ 7.58 – 7.49 (m, 2H), 7.16 – 7.09 (m, 2H).
O
N
SO
2
F
Cl
F
O
N
SO
2
F
F
F
21
13
C NMR (100 MHz, cdcl3) δ 161.84, 159.29, 133.38, 113.57 (d, J = 4.0 Hz), 112.82, 112.56,
29.86.
19
F NMR (376 MHz, cdcl3) δ 64.92, -108.98.

6j: 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride

2,4-dichloro-N-hydroxybenzimidoyl chloride (1.0 mmol, 227 mg), Br-ESF (2 mmol, 378.0
mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white solid product) 131 mg; 44 %.
1
H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 2.1 Hz,
1H), 7.43 (dd, J = 8.4, 2.1 Hz, 1H).

13
C NMR (100 MHz, CDCl3) δ 161.10, 158.47 (d, JCF = 39 Hz ) 138.35, 133.86, 131.94, 130.86,
128.30, 124.16, 113.14 (d, JCF = 2 Hz).

19
F NMR (376 MHz, CDCl3) δ 64.85.

6k: 3-(2,4-dimethoxyphenyl)isoxazole-5-sulfonyl fluoride

N-hydroxy-2,4-dimethoxybenzimidoyl chloride (1 mmol, 215.6 mg), Br-ESF (2 mmol, 378.0
mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
O
N
SO
2
F
Cl Cl
O
O
O
N
SO
2
F
22
Yield – No Reaction

6l: 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride

N-hydroxy-2-nitrobenzimidoyl chloride (1 mmol, 200.6 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white powder) 101.0 mg; 37%
1
H NMR (600 MHz, cdcl3) δ 8.22 (dd, J = 8.1, 1.4 Hz, 1H), 7.80 (dtd, J = 25.8, 7.6, 1.5 Hz, 2H),
7.71 (dd, J = 7.5, 1.5 Hz, 1H), 7.30 (d, J = 1.3 Hz, 1H).
13
C NMR (151 MHz, cdcl3) δ 161.43, 158.55, 158.29, 147.95, 134.10, 132.35, 125.58, 122.11,
113.08 (d, J = 3.5 Hz).
19
F NMR (564 MHz, cdcl3) δ 65.01 (d, J = 1.3 Hz).

6m: 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride

N-hydroxy-2-methoxy-1-naphthimidoyl chloride (0.9 mmol, 216 mg), Br-ESF (1.8 mmol, 355
mg), triethylamine (1.8 mol, 186 mg), and DCM (10 mL)
Yield (white crystalline solid) 161.4 mg; 58%
O
N
SO
2
F
NO
2
O
N
O
FO
2
S
23
1
H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 9.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.1 Hz,
1H), 7.53 (ddd, J = 8.2, 6.8, 1.1 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.38 (d, J = 9.1 Hz, 1H), 3.98 (s,
3H).
13
C NMR (101 MHz, CDCl3) δ 160.0, 155.9, 133.4, 132.4, 129.0, 128.5 (d, J = 5.8 Hz), 124.6,
124.1, 115.8 (d, J = 4.2 Hz), 112.6, 109.0, 108.4, 108.4, 56.6.
19
F NMR (376 MHz, CDCl3) δ 64.47 (d, J = 1.1 Hz).
Direct injection APCI-MS: [M + H]
+
exact for C14H11NO4SF m/z 308.0387, accurate m/z
308.0394 (Δ = 2.3 ppm)

6n: 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride

N-hydroxy-1-methoxy-2-naphthimidoyl chloride (1 mmol, 228.6 mg), Br-ESF (2 mmol, 378.0
mg), triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 179.7 mg; 60%
1
H NMR (400 MHz, CDCl3) δ 8.26 – 8.17 (m, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.95 – 7.86 (m, 2H),
7.75 (d, J = 8.7 Hz, 1H), 7.62 (ddd, J = 6.3, 3.3, 0.7 Hz, 2H), 3.92 (s, 3H).
13
C NMR (101 MHz, CDCl3) δ 161.0, 158.7, 158.3, 156.0, 136.6, 128.4 (d, J = 16.0 Hz), 128.1,
127.2, 125.4, 124.8, 122.9, 115.5, 113.3 (d, J = 3.7 Hz), 63.0.
19
F NMR (376 MHz, CDCl3) δ 64.53 (d, J = 1.5 Hz).
GC-ES(TOF): [M]
+•
exact for C14H10NO4SF m/z 307.0309, accurate m/z 307.0316
(Δ = 2.3 ppm)

O
N
O
SO
2
F
24
6o: 3-dodecylisoxazole-5-sulfonyl fluoride

N-hydroxytridecanimidoyl chloride (1.0 mmol, 233.1 mg), Br-ESF (2 mmol, 378.0 mg),
triethylamine (2 mol, 202.4 mg), and DCM (10 mL)
Yield (white crystalline solid) 302.3mg, 99%
1
H NMR (400 MHz, cdcl3) δ 7.02 (d, J = 1.4 Hz, 1H), 2.83 – 2.74 (m, 2H), 1.70 (p, J = 7.4 Hz,
2H), 1.26 (s, 18H), 0.91 – 0.84 (m, 3H).
13
C NMR (100 MHz, cdcl3) δ 165.16, 158.03 (d, J = 38.2 Hz), 111.98 (d, J = 3.6 Hz), 32.04,
29.71, 29.54, 29.46, 29.28, 29.12, 28.03, 26.13, 22.82, 14.26.
19
F NMR (376 MHz, cdcl3) δ 64.18 (d, J = 1.6 Hz).

O
N
SO
2
F
25
Appendix A: Characterization of Sulfonyl Fluoride Isoxazoles

6a: 3-phenylisoxazole-5-sulfonyl fluoride

Figure 1.8
1
H NMR spectrum of 3-phenylisoxazole-5-sulfonyl fluoride in CDCl3.

Figure 1.9
13
C NMR spectrum of 3-phenylisoxazole-5-sulfonyl fluoride in CDCl3.
26

Figure 1.10
19
F NMR spectrum of 3-phenylisoxazole-5-sulfonyl fluoride in CDCl3.

6b: 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride

Figure 1.11
1
H NMR spectrum of 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride in CDCl3.
27

Figure 1.12
13
C NMR spectrum of 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride in
CDCl3.

Figure 1.13
1
H NMR spectrum of 3-(4-chlorophenyl) isoxazole-5-sulfonyl fluoride in CDCl3.

28
6c: 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride

Figure 1.14
1
H NMR spectrum of 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.

Figure 1.15
13
C NMR spectrum of 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
29

Figure 1.16
19
F NMR spectrum of 3-(4-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.

6d: 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride

Figure 1.17
1
H NMR spectrum of 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.
30

Figure 1.18
13
C NMR spectrum of 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.

Figure 1.19
19
F NMR spectrum of 3-(2-methoxyphenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.
31

6e: 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride

Figure 1.20
1
H NMR spectrum of 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.

Figure 1.21
13
C NMR spectrum of 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
32

Figure 1.22
19
F NMR spectrum of 3-(2-fluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.

6f: 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride

Figure 1.23
1
H NMR spectrum of 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride
in CDCl3.
33

Figure 1.24
13
C NMR spectrum of 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride
in CDCl3.

Figure 1.25
19
F NMR spectrum of 3-(2-chloro-5-nitrophenyl)isoxazole-5-sulfonyl fluoride
in CDCl3.
34
6h: 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride

Figure 1.26
1
H NMR spectrum of 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride
in CDCl3.

Figure 1.27
13
C NMR spectrum of 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride
in CDCl3.
35

Figure 1.28
19
F NMR spectrum of 3-(2-chloro-6-fluorophenyl)isoxazole-5-sulfonyl fluoride
in CDCl3.

6i: 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride
Figure 1.29
1
H NMR spectrum of 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
36

Figure 1.30
13
C NMR spectrum of 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.

Figure 1.31
19
F NMR spectrum of 3-(2,6-difluorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.
37
6j: 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride

Figure 1.32
1
H NMR spectrum of 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.

Figure 1.33
13
C NMR spectrum of 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.
38

Figure 1.34
19
F NMR spectrum of 3-(2,4-dichlorophenyl)isoxazole-5-sulfonyl fluoride in
CDCl3.

6l: 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride

Figure 1.35
1
H NMR spectrum of 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.
39

Figure 1.36
13
C NMR spectrum of 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.

Figure 1.37
19
F NMR spectrum of 3-(2-nitrophenyl)isoxazole-5-sulfonyl fluoride in CDCl3.

40
6m: 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl fluoride

Figure 1.38
1
H NMR spectrum of 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl
fluoride in CDCl3.

Figure 1.39
13
C NMR spectrum of 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl
fluoride in CDCl3.
- 1 .0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0
δ ( ppm )
3.27
1.06
2.12
1.11
1.00
1.02
1.00
3.98
7.26 CDCl3
7.36
7.39
7.41
7.41
7.42
7.43
7.43
7.44
7.45
7.46
7.46
7.51
7.52
7.53
7.53
7.54
7.55
7.55
7.85
7.87
7.98
8.00
8.03
8.05
7 . 4 7 . 5 7 . 6 7 . 7 7 . 8 7 . 9 8 . 0 8 . 1
δ ( ppm )
7.36
7.39
7.41
7.41
7.42
7.43
7.43
7.44
7.45
7.46
7.46
7.51
7.52
7.53
7.53
7.54
7.55
7.55
7.85
7.87
7.98
8.00
8.03
8.05
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
56.64
76.84 cdcl3
77.16 CDCl3
77.16 cdcl3
77.48 cdcl3
108.38
108.39
108.94
112.58
115.81
115.85
124.14
124.63
128.47
128.53
129.04
132.38
133.36
155.93
160.04
41

Figure 1.40
19
F NMR spectrum of 3-(2-methoxynaphthalen-1-yl)isoxazole-5-sulfonyl
fluoride in CDCl3.

6n: 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride
Figure 1.41
1
H NMR spectrum of 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl fluoride in
CDCl3.
- 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0
δ ( pp m )
6 4 . 4 7
6 4 . 4 7
- 1 .0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0
δ ( ppm )
2.95
1.87
1.01
1.91
0.91
1.00
3.92
7.26 CDCl3
7.60
7.60
7.61
7.61
7.62
7.62
7.62
7.63
7.63
7.63
7.64
7.64
7.73
7.76
7.89
7.89
7.90
7.90
7.90
7.90
7.91
7.91
7.91
7.92
7.92
7.92
7.93
7.93
7.93
7.98
8.00
8.20
8.20
8.21
8.21
8.21
8.21
8.22
8.22
8.22
8.22
7 .6 7 . 7 7 . 8 7 . 9 8 . 0 8 . 1 8 . 2
δ ( ppm )
7.60
7.61
7.61
7.62
7.62
7.62
7.63
7.63
7.63
7.64
7.73
7.76
7.89
7.89
7.90
7.90
7.90
7.90
7.91
7.91
7.91
7.92
7.92
7.92
7.93
7.93
7.93
7.98
8.00
8.20
8.20
8.21
8.21
8.21
8.21
8.22
8.22
8.22
8.22
42

Figure 1.42
13
C NMR spectrum of 3-(1-methoxynaphthalen-2-yl)isoxazole-5-sulfonyl
fluoride in CDCl3.

6o: 3-dodecylisoxazole-5-sulfonyl fluoride

Figure 1.43
1
H NMR spectrum of 3-dodecylisoxazole-5-sulfonyl fluoride in CDCl3.
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
62.99
77.16 CDCl3
113.34
113.37
115.50
122.93
124.84
125.43
125.50
127.20
128.08
128.34
128.50
136.59
156.02
158.28
158.66
160.96
43

Figure 1.44
13
C NMR spectrum of 3-dodecylisoxazole-5-sulfonyl fluoride in CDCl3.

Figure 1.45
19
F NMR spectrum of 3-dodecylisoxazole-5-sulfonyl fluoride in CDCl3.

44
1.7 Synthesis of Brominated Isoxazoles

General Procedure

1 mmol of chloro-oxime was dissolved in 5mmol ammonium formate in 10 mL of H2O in a 20
mL scintillation vial. pH was adjusted to 8.28 with ammonium hydroxide. 2 mmol of Br-ESF
was added and the mixture was stirred at RT for 5 minutes. After 1 hour of stirring, the
reaction was quenched with 10 mL of water. The product was extracted to DCM (x3), washed
with water (x3) and brine (x1), dried over sodium sulfate, and solvents were evaporated
under vacuum. The product was redissolved in 3:1 hexanes: chloroform and filtered through
a short pad of silica. The flask was rinsed with 3:1 hexanes: chloroform with a few drops of
DCM and filtered through the silica pad. Solvents were evaporated under vacuum and the
product was allowed to crystalize.

5a: 5-bromo-3-phenylisoxazole

N-hydroxybenzimidoyl chloride (1 mmol, 155.6 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white crystalline solid) 186 mg; 83%
1
H NMR (400 MHz, cdcl3) δ 7.79 – 7.74 (m, 2H), 7.50 – 7.45 (m, 3H), 6.60 (d, J = 0.6 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 164.37, 141.88, 130.72, 129.20, 128.17, 126.85, 104.58.

5b: 5-bromo-3-(4-chlorophenyl)isoxazole
O
N
Br
45

4-chloro-N-hydroxybenzimidoyl chloride (1 mmol, 190.0 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white crystalline solid) 107.9 mg; 42%
1
H NMR (400 MHz, cdcl3) δ 7.74 – 7.65 (m, 2H), 7.51 – 7.41 (m, 2H), 6.57 (s, 1H).
13
C NMR (100 MHz, cdcl3) δ 163.39, 142.27, 136.85, 129.52, 128.11, 126.63, 104.47.

5c: 5-bromo-3-(4-nitrophenyl)isoxazole

(Z)-N-hydroxy-4-nitrobenzimidoyl chloride (1 mmol, 200.6 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white crystalline solid) 11.1 mg; 4%
1
H NMR (600 MHz, cdcl3) δ 8.34 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 6.68 (s, 1H).

5d: 5-bromo-3-(2-methoxyphenyl)isoxazole

N-hydroxy-2-methoxybenzimidoyl chloride (1 mmol, 185.6 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white crystalline solid) 34.1 mg; 13%
O
N
Br
Cl
O
N
Br
O
2
N
O
N
Br
O
46
1
H NMR (400 MHz, cdcl3) δ 7.85 (ddd, J = 7.8, 1.8, 0.6 Hz, 1H), 7.44 (dddd, J = 8.2, 7.3, 1.8, 0.8
Hz, 1H), 7.04 (tt, J = 7.6, 1.0 Hz, 1H), 7.00 (dd, J = 8.5, 1.0 Hz, 1H), 6.80 (d, J = 0.9 Hz, 1H), 3.90
(d, J = 0.7 Hz, 3H).
13
C NMR (100 MHz, cdcl3) δ 161.66, 157.07, 140.18, 131.60, 128.97, 120.82, 116.80, 111.27,
107.61, 55.38.

5e: 5-bromo-3-(2-fluorophenyl)isoxazole

2-fluoro-N-hydroxybenzimidoyl chloride (1 mmol, 173.7 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white crystalline solid) 138.9 mg; 57%
1
H NMR (400 MHz, cdcl3) δ 7.95 (tdd, J = 7.6, 1.5, 1.0 Hz, 1H), 7.51 – 7.40 (m, 1H), 7.28 – 7.16
(m, 2H), 6.79 – 6.71 (m, 1H).
13
C NMR (100 MHz, cdcl3) δ 161.70, 159.73 (d, J = 1.4 Hz), 159.18, 141.84 (d, J = 2.2 Hz),
132.45, 128.93 (d, J = 2.6 Hz), 124.89 (d, J = 3.8 Hz), 116.59 (d, J = 21.7 Hz), 107.10.
19
F NMR (376 MHz, cdcl3) δ 64.70, -114.20 – -114.45 (m).

5f: 5-bromo-3-(2-chloro-5-nitrophenyl)isoxazole

O
N
Br
F
O
N
Br
Cl
O
2
N
47
2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride (1 mmol, 235.0 mg), Br-ESF (2 mmol,
378.0 mg)
Yield (white crystalline solid) 69.2 mg; 23%
1
H NMR (400 MHz, cdcl3) δ 8.63 (dd, J = 2.7, 0.4 Hz, 1H), 8.28 (dd, J = 8.8, 2.7 Hz, 1H), 7.70
(dd, J = 8.8, 0.4 Hz, 1H), 6.82 (s, 1H).
13
C NMR (100 MHz, cdcl3) δ 161.14, 142.27, 139.62, 131.63, 125.92, 125.73, 107.32.

5g: 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole

4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride (1 mmol, 235.0 mg), Br-ESF (2 mmol,
378.0 mg)
Yield (white crystalline solid) 34.7 mg; 11%
1
H NMR (400 MHz, cdcl3) δ 8.26 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 8.5, 2.1 Hz, 1H), 7.68 (d, J =
8.4 Hz, 1H), 6.66 (s, 1H).
13
C NMR (100 MHz, cdcl3) δ 161.42, 143.27, 132.80, 130.74, 129.16, 128.07, 123.72, 104.28,
29.69.

5h: 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole
O
N
Br
NO
2
Cl
48

2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride (1 mmol, 208.0 mg), Br-ESF (2 mmol,
378.0 mg)
Yield (white crystalline solid) 139.0 mg; 50%
1
H NMR (400 MHz, cdcl3) δ 7.44 – 7.35 (m, 1H), 7.32 (dt, J = 8.2, 1.1 Hz, 1H), 7.13 (ddd, J = 9.0,
8.3, 1.2 Hz, 1H).
13
C NMR (100 MHz, cdcl3) δ 162.40 (d, J = 3.9 Hz), 159.89, 158.05, 141.93, 132.34 (d, J = 9.6
Hz), 126.38 (d, J = 3.7 Hz), 115.22, 115.00, 108.59 (d, J = 1.8 Hz).

5i: 5-bromo-3-(2,6-difluorophenyl)isoxazole

2,6-difluoro-N-hydroxybenzimidoyl chloride (1 mmol, 191.6 mg), Br-ESF (2 mmol, 378.0
mg)
Yield (white crystalline solid) 153.1 mg; 59%
1
H NMR (400 MHz, cdcl3) δ 7.43 (ttd, J = 8.2, 6.2, 0.5 Hz, 1H), 7.10 – 6.99 (m, 2H), 6.64 (td, J =
1.8, 0.5 Hz, 1H).
13
C NMR (100 MHz, cdcl3) δ 161.95 (d, J = 6.3 Hz), 159.41 (d, J = 6.2 Hz), 155.69, 141.79,
132.15 (t, J = 10.6 Hz), 112.62 – 112.39 (m), 112.34 – 112.16 (m), 107.88 (t, J = 4.0 Hz).
19
F NMR (376 MHz, cdcl3) δ 64.89 (d, J = 10.1 Hz), -109.40 – -109.47 (m).
O
N
Br
Cl
F
O
N
Br
F
F
49

5j: 5-bromo-3-(2,4-dichlorophenyl)isoxazole

2,4-dichloro-N-hydroxybenzimidoyl chloride (1.0 mmol, 228 mg), Br-
ESF (2 mmol, 378.0 mg)
Yield (white solid product) 104 mg; 35%
SO2F: Br selectivity 1:35.
1
H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.4,
2.1 Hz, 1H), 6.77 (s, 1H).
13
C NMR (100 MHz, CDCl3) δ 162.14, 141.57, 137.11, 133.83, 131.68, 130.55, 127.87,
126.04, 107.60.

5k: 5-bromo-3-(2,4-dimethoxyphenyl)isoxazole

N-hydroxy-2,4-dimethoxybenzimidoyl chloride (1 mmol, 215.7 mg), Br-ESF (2 mmol, 378.0
mg)
Yield (white solid) 31.0 mg; 11%

5l: 5-bromo-3-(2-nitrophenyl)isoxazole

O
N
Br
O
O
O
N
Br
NO
2
Cl
Cl
O
N
Br
50

(Z)-N-hydroxy-2-nitrobenzimidoyl chloride (1 mmol, 200.1 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white solid) 190.6 mg; 71%

3m: 5-bromo-3-(2-methoxynaphthalen-1-yl)isoxazole

N-hydroxy-2-methoxy-1-naphthimidoyl chloride (1 mmol, 235 mg), Br-ESF (2 mmol, 378.0
mg)
Yield – No Reaction

5n: 5-bromo-3-(1-methoxynaphthalen-2-yl)isoxazole

(Z)-N-hydroxy-1-methoxy-2-naphthimidoyl chloride (1 mmol, 235.7 mg), Br-ESF (2 mmol,
378.0 mg)
Yield -149 mg; 49%

5o: 5-bromo-3-dodecylisoxazole

O
N
O
Br
O
N
O
Br
O
N
Br
51

N-hydroxytridecanimidoyl chloride (1 mmol, 233.1 mg), Br-ESF (2 mmol, 378.0 mg)
Yield (white solid) 218.5 mg; 72%
1
H NMR (400 MHz, cdcl3) δ 6.13 (s, 01), 2.68 – 2.61 (m, 2H), 1.71 – 1.54 (m, 4H), 1.25 (s, 16H),
0.90 – 0.85 (m, 3H).
13
C NMR (100 MHz, cdcl3) δ 166.43, 141.01, 105.99, 32.05, 29.74, 29.60, 29.47, 29.37, 29.22,
28.12, 26.32, 22.83, 14.27.
Appendix B: Characterization of Brominated Isoxazoles

5a: 5-bromo-3-phenylisoxazole

Figure 1.46
1
H NMR spectrum of 5-bromo-3-phenylisoxazole in CDCl3.
52

Figure 1.47
13
C NMR spectrum of 5-bromo-3-phenylisoxazole in CDCl3.
5b: 5-bromo-3-(4-chlorophenyl)isoxazole

Figure 1.48
1
H NMR spectrum of 5-bromo-3-(4-chlorophenyl)isoxazole in CDCl3.
53

Figure 1.49
13
C NMR spectrum of 5-bromo-3-(4-chlorophenyl)isoxazole in CDCl3.

5c: 5-bromo-3-(4-nitrophenyl)isoxazole

Figure 1.50
1
H NMR spectrum of 5-bromo-3-(4-nitrophenyl)isoxazole in CDCl3.
54

5d: 5-bromo-3-(2-methoxyphenyl)isoxazole

Figure 1.51
1
H NMR spectrum of 5-bromo-3-(2-methoxyphenyl)isoxazole in CDCl3.

Figure 1.52
13
C NMR spectrum of 5-bromo-3-(2-methoxyphenyl)isoxazole in CDCl3.
55
5e: 5-bromo-3-(2-fluorophenyl)isoxazole

Figure 1.53
1
H NMR spectrum of 5-bromo-3-(2-fluorophenyl)isoxazole in CDCl3.

Figure 1.54
13
C NMR spectrum of 5-bromo-3-(2-fluorophenyl)isoxazole in CDCl3.
56

Figure 1.55
19
F NMR spectrum of 5-bromo-3-(2-fluorophenyl)isoxazole in CDCl3.5f: 5-
bromo-3-(2-chloro-5-nitrophenyl)isoxazole

Figure 1.56
1
H NMR spectrum of 5-bromo-3-(2-chloro-5-nitrophenyl)isoxazole in CDCl3.

57

Figure 1.57
13
C NMR spectrum of 5-bromo-3-(2-chloro-5-nitrophenyl)isoxazole in CDCl3.
5g: 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole

Figure 1.58
1
H NMR spectrum of 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole in CDCl3.

58

Figure 1.59
13
C NMR spectrum of 5-bromo-3-(4-chloro-3-nitrophenyl)isoxazole in CDCl3.
5h: 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole

Figure 1.60
1
H NMR spectrum of 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole in CDCl3.

59

Figure 1.61
13
C NMR spectrum of 5-bromo-3-(2-chloro-6-fluorophenyl)isoxazole in CDCl3.
5i: 5-bromo-3-(2,6-difluorophenyl)isoxazole

Figure 1.62
1
H NMR spectrum of 5-bromo-3-(2,6-difluorophenyl)isoxazole in CDCl3.

60

Figure 1.63
13
C NMR spectrum of 5-bromo-3-(2,6-difluorophenyl)isoxazole in CDCl3.

Figure 1.64
19
F NMR spectrum of 5-bromo-3-(2,6-difluorophenyl)isoxazole in CDCl3.

61
5j: 5-bromo-3-(2,4-dichlorophenyl)isoxazole

Figure 1.65
1
H NMR spectrum of 5-bromo-3-(2,4-dichlorophenyl)isoxazole in CDCl3.

Figure 1.66
13
C NMR spectrum of 5-bromo-3-(2,4-dichlorophenyl)isoxazole in CDCl3.

62
5o: 5-bromo-3-dodecylisoxazole

Figure 1.67
1
H NMR spectrum of 5-bromo-3-dodecylisoxazole in CDCl3.

Figure 1.68
13
C NMR spectrum of 5-bromo-3-dodecylisoxazole in CDCl3.

63
1.8 Synthesis of Oximes

Synthesis of Oximes General Procedure

60 mmol of hydroxylamine hydrochloride and 60 mmol of sodium carbonate were dissolved
in 66 mL of a 5:1 water: ethanol mixture and the solution was mixed for 15 minutes. 50
mmol of aldehyde was added portion-wise over 5 minutes, and the reaction was stirred for
45 minutes. Product was extracted in EtOAc (x3), washed with water (x3) and brine (x1),
and dried over sodium sulfate. Reaction progress was monitored via TLC in 3:1 hexanes:
EtOAc. Solvents were evaporated under vacuum and the product, initially a dense, viscous,
pale-yellow liquid, was cooled at -78°C overnight, where it formed a white solid.

Benzaldehyde oxime

Benzaldehyde (50 mmol, 5.30 g), hydroxylamine hydrochloride (60 mmol, 4.17 g), sodium
carbonate (60 mmol, 6.36 g), water (55 mL), and ethanol (11 mL)
Yield (white solid) 5.09 g; 84%
1
H NMR (400 MHz, DMSO-d6) δ 11.22 (d, J = 0.5 Hz, 1H), 8.14 (s, 1H), 7.65 – 7.53 (m, 2H),
7.48 – 7.31 (m, 3H).
13
C NMR (101 MHz, DMSO-d6) δ 148.08, 133.07, 129.24, 128.69, 126.38.

4-chlorobenzaldehyde oxime

N
OH
N
OH
Cl
64

4-chlorobenzaldehyde (3.6 mmol, 0.5 g), hydroxylamine hydrochloride (4.3 mmol, 0.297 g),
sodium carbonate (4.3 mmol, 0.452 g), water (15 mL), and ethanol (3 mL); stirred for 20
hours.
Yield (white solid) 0.519 g; 94%
1
H NMR (400 MHz, cdcl3) δ 9.99 (s, 1H), 8.11 (s, 1H), 7.56 – 7.46 (m, 2H), 7.39 – 7.34 (m, 2H).
13
C NMR (101 MHz, cdcl3) δ 149.47, 136.17, 130.54, 129.23, 128.40.

4-nitrobenzaldehyde oxime

4-nitrobenzaldehyde (3.3 mmol, 0.5 g), hydroxylamine hydrochloride (4.0 mmol, 0.276 g),
sodium carbonate (4 mmol, 0.421 g), water (15 mL), and ethanol (3 mL); stirred for 21 hours.
Yield (white solid) 0.540 g; 98%
1
H NMR (400 MHz, cdcl3) δ 10.16 (d, J = 0.5 Hz, 1H), 8.27 – 8.23 (m, 2H), 8.20 (s, 1H), 7.77 –
7.73 (m, 2H).
13
C NMR (151 MHz, cdcl3) δ 147.13, 132.25, 130.78, 127.97, 123.57.

2-methoxy benzaldehyde oxime

N
OH
O
2
N
N
OH
O
65
2-methoxybenzaldehyde (7.34 mmol, 1.0 g), hydroxylamine hydrochloride (8.8 mmol, 0.612
g), sodium carbonate (8.8 mmol, 0.934 g), water (15 mL), and ethanol (3 mL); stirred for 20
hours.
Yield (off-white solid) 1.07 g; 96%
1
H NMR (400 MHz, cdcl3) δ 8.49 (s, 1H), 7.69 (dt, J = 7.7, 1.6 Hz, 1H), 7.38 (ddt, J = 8.3, 7.4, 1.7
Hz, 1H), 7.02 – 6.89 (m, 2H), 3.89 (d, J = 1.0 Hz, 3H).
13
C NMR (101 MHz, cdcl3) δ 157.93, 146.96, 131.76, 127.57, 121.00, 120.25, 111.33, 55.78
(d, J = 2.4 Hz).

2-fluorobenzaldehyde oxime

2-fluoro benzaldehyde (8.2 mmol, 1.00 g), hydroxylamine hydrochloride (9.8 mmol, 0.680
g), sodium carbonate (9.8 mmol, 1.04 g), water (25 mL), and ethanol (5 mL); stirred for 4
hours.
Yield (white solid) 0.955 g; 84%
1
H NMR (400 MHz, cdcl3) δ 10.38 (s, 1H), 8.38 (s, 1H), 7.82 – 7.71 (m, 1H), 7.43 – 7.32 (m,
1H), 7.20 – 7.05 (m, 2H).

2-chloro-5-nitrobenzaldehyde oxime
N
OH
F
66

2-chloro-5-nitrobenzaldehyde (5.4 mmol, 1.00 g), hydroxylamine hydrochloride (6.5 mmol,
0.449 g), sodium carbonate (6.5 mmol, .685 g), water (25 mL), and ethanol (5 mL); stirred
for 4 hours.
Yield (white solid) 1.08 g; >99%
1
H NMR (400 MHz, cdcl3) δ 8.72 (d, J = 2.8 Hz, 1H), 8.55 (s, 1H), 8.16 (dd, J = 8.8, 2.8 Hz, 1H),
7.57 (dd, J = 8.8, 0.4 Hz, 1H).
13
C NMR (100 MHz, cdcl3) δ 146.89, 145.86, 140.02, 131.61, 131.11, 125.06, 122.41.

4-chloro-3-nitrobenzaldehyde oxime

4-chloro-3-nitrobenzaldehyde (5.4 mmol, 1.00 g), hydroxylamine hydrochloride (6.5 mmol,
0.449 g), sodium carbonate (6.5 mmol, .685 g), water (25 mL), and ethanol (5 mL); stirred
for 4 hours.
Yield (white solid) 1.08 g; >99%
1
H NMR (600 MHz, cdcl3) δ 10.05 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.72 (dd, J =
8.4, 2.1 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H).
13
C NMR (151 MHz, cdcl3) δ 147.55,147.55, 132.70, 132.67, 131.20, 128.40, 124.00.

2-chloro-6-fluorobenzaldehyde oxime
N
OH
Cl
NO
2
N
OH O
2
N
Cl
67

2-chloro-6-fluorobenzaldehyde (6.3 mmol, 1.00 g), hydroxylamine hydrochloride (7.6 mmol,
0.526 g), sodium carbonate (7.6 mmol, 0.802 g), water (15 mL), and ethanol (3 mL); stirred
for 22 hours.
Yield (white solid) 1.02 g; 94%
1
H NMR (400 MHz, cdcl3) δ 8.49 – 8.44 (m, 1H), 7.31 – 7.23 (m, 3H), 7.08 (dddd, J = 10.1, 7.6,
1.7, 0.5 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 162.69, 160.13, 144.56 (d, J = 4.1 Hz), 131.31 (d, J = 10.2 Hz),
126.46 (d, J = 3.5 Hz), 115.70, 115.47.
19
F NMR (376 MHz, cdcl3) δ -105.88 (dd, J = 8.8, 5.7 Hz), -108.73 (dd, J = 10.3, 5.2 Hz).

2,6-difluorobenzaldehyde oxime

2,6-difluorobenzaldehyde (3.5 mmol, 0.5 g), hydroxylamine hydrochloride (4.2 mmol, 0.293
g), sodium carbonate (4.2 mmol, 0.448 g), water (15 mL), and ethanol (3 mL); stirred for 20
hours.
Yield (white solid) 0.489 g; 89%
1
H NMR (400 MHz, cdcl3) δ 8.34 (s, 1H), 7.37 – 7.29 (m, 1H), 7.00 – 6.92 (m, 2H).
13
C NMR (101 MHz, cdcl3) δ 162.32 (d, J = 6.5 Hz), 159.81, 141.20, 131.22 (t, J = 10.8 Hz),
112.33 – 112.20 (m), 112.10 – 112.00 (m).
N
OH
Cl
F
N
OH
F
F
68
19
F NMR (376 MHz, cdcl3) δ -106.82 – -108.42 (m), -111.36 (dd, J = 8.6, 6.4 Hz).

2,4-dichlorobenzaldehyde oxime

2,4-dichlorobenzaldehyde ground using mortar and pestle into powder (5.7 mmol, 1.00 g),
hydroxylamine hydrochloride (6.9 mmol, 0.476 g), sodium carbonate (6.9 mmol, 0.727 g),
water (15 mL), and ethanol (3 mL); stirred for 19 hours.
Yield (white powder) 1.02 g; 93%
1
H NMR (400 MHz, cdcl3) δ 8.50 (d, J = 0.6 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.1 Hz,
1H), 7.25 (dd, J = 8.5, 2.1 Hz, 1H).
13
C NMR (100 MHz, cdcl3) δ 146.85, 136.50, 134.61, 129.89, 128.54, 128.05, 127.71.

2,4-dimethoxybenzaldehyde oxime

2,4-dimethoxybenzaldehyde (6.0 mmol, 1.00 g), hydroxylamine hydrochloride (7.2 mmol,
0.502 g), sodium carbonate (7.2 mmol, 0.765 g), water (15 mL), and ethanol (3 mL); stirred
for 6 hours.
Yield (white powder) 0.93 g; 85%
1
H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 6.51 (dd, J = 8.5, 2.3 Hz, 1H),
6.46 (d, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H).
N
OH
Cl
Cl
N
OH
O
O
69
13
C NMR (100 MHz, CDCl3) δ 162.58, 159.12, 146.74, 128.44, 113.73, 105.46, 98.57, 55.70,
55.59.

4-(dimethylamino)benzaldehyde oxime

4-(dimethylamino)benzaldehyde (6.7 mmol, 1.00 g), hydroxylamine hydrochloride (8.0
mmol, 0.558 g), sodium carbonate (8.0 mmol, 0.852 g), water (15 mL), and ethanol (3 mL);
stirred for 6 hours.
Yield (off-white powder) 0.999 g; 91%
1
H NMR (400 MHz, D2O) δ 9.73 (s, 1H), 7.77 – 7.70 (m, 2H), 7.48 – 7.40 (m, 1H), 6.73 – 6.66
(m, 2H), 3.08 (s, 6H).
13
C NMR (101 MHz, D2O) δ 190.50, 132.13, 128.38, 125.27, 112.10, 111.12.

4-(benzyloxy)benzaldehyde oxime

4-(benzyloxy)benzaldehyde (4.7 mmol, 1.00 g), hydroxylamine hydrochloride (5.7 mmol,
0.393 g), sodium carbonate (5.7 mmol, 0.599 g), water (45 mL), and ethanol (9 mL); stirred
for 8 days
Yield (white powder) 0.976 g; 91%
N
OH
N
N
OH
O
70
1
H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.54-7.50 (m, 2H), 7.45 – 7.32 (m, 5H), 7.02 – 6.95
(m, 2H), 5.10 (s, 2H).
13
C NMR (100 MHz, CDCl3) δ 160.39, 150.08, 136.68, 133.47, 128.80, 128.68, 128.26, 127.61,
124.99, 115.30, 77.16, 70.21.

tridecanal oxime

Tridecanal (5.4 mmol, 0.25 g), hydroxylamine hydrochloride (6.5 mmol, 0.452 g), sodium
carbonate (6.5 mmol, 0.690 g), water (15 mL), and ethanol (3 mL); stirred for 48 hours.
Yield (white crystalline powder) 1.07 g; 99%
1
H NMR (400 MHz, cdcl3) δ 2.45 (td, J = 7.7, 5.6 Hz, 1H), 2.25 – 2.17 (m, 1H), 1.51 (dp, J =
14.8, 7.4 Hz, 2H), 1.27 – 1.24 (m, 18H), 0.91 – 0.86 (m, 3H).
13
C NMR (100 MHz, cdcl3) δ 32.05, 29.75, 29.63, 29.60, 29.48, 29.45, 29.38, 29.24, 26.67,
25.88, 25.35, 22.83, 14.26.

2-nitrobenzaldehyde oxime

2-nitrobenzaldehyde (1.7 mmol, 0.25 g), hydroxylamine hydrochloride (2.0 mmol, 0.138 g),
sodium carbonate (2.0 mmol, 0.210 g), water (10 mL), and ethanol (2 mL); stirred for 21
hours.
Yield (white solid) 0.272 g; 99%
OH
N
N
OH
NO
2
71
1
H NMR (400 MHz, cdcl3) δ 10.44 (d, J = 0.7 Hz, 1H), 8.69 (s, 1H), 8.07 (ddd, J = 8.1, 1.3, 0.4
Hz, 1H), 7.93 (ddt, J = 7.8, 1.5, 0.5 Hz, 1H), 7.65 (tdd, J = 7.9, 1.4, 0.6 Hz, 1H), 7.56 (ddd, J = 8.2,
7.4, 1.5 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 147.20, 133.67, 130.55, 128.95, 127.31, 125.00.

2-naphthaldehyde oxime

2-naphthaldehyde (6.4 mmol, 1.00 g), hydroxylamine hydrochloride (7.7 mmol, 0.534 g),
sodium carbonate (7.7 mmol, 0.814 g), water (15 mL), and ethanol (3 mL); stirred for 24
hours
Yield (white powder) 0.766 g; 70%
1
H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.88 – 7.82 (m, 4H), 7.55
– 7.49 (m, 2H).
13
C NMR (100 MHz, CDCl3) δ 150.76, 134.31, 133.29, 129.75, 128.84, 128.77, 128.48, 128.01,
127.18, 126.79, 122.87.

2-methoxy-1-naphthaldehyde oxime

2-methoxy-1-naphthaldehyde (5.4 mmol, 1.00 g), hydroxylamine hydrochloride (6.4 mmol,
0.448 g), sodium carbonate (6.4 mmol, 0.683 g), water (11 mL), and ethanol (1 mL); stirred
for 6 days.
N
OH
O
N
OH
72
Yield (white solid) 1.02 g; 95%
1
H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.82 (d, J = 8.7 Hz, 1H), 8.67 (s, 1H), 8.00 (d, J =
8.0 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.39 (t, J =
6.5 Hz, 1H), 3.96 (s, 3H).
13
C NMR (101 MHz, DMSO-d6) δ 156.3, 145.2, 131.6, 130.8, 128.7, 128.4, 127.5, 125.5, 123.8,
113.5, 113.4, 56.6.
GC-EI-MS(TOF): [M]
+•
exact for C12H11NO2 m/z 201.0784, accurate m/z 201.0786 (Δ = 1.6
ppm)

1-methoxy-2-naphthaldehyde oxime

1-methoxy-2-naphthaldehyde (5.4 mmol, 1.00 g), hydroxylamine hydrochloride (6.4 mmol,
0.448 g), sodium carbonate (6.4 mmol, 0.683 g), water (11 mL), and ethanol (1 mL); stirred
for 5 days.
Yield (white solid) 0.97 g; 90%
1
H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.94 (dd, J
= 8.1, 1.4 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.62 – 7.54 (m, 2H), 3.91 (s,
3H).
13
C NMR (101 MHz, DMSO-d6) δ 154.3, 143.4, 134.9, 128.2, 127.5, 127.1, 126.8, 124.4, 122.5,
122.0, 121.5, 63.4.
GC-EI-MS(TOF): [M]
+•
exact for C12H11NO2 m/z 201.0784, accurate m/z 201.0786 (Δ = 1.6
ppm)
O
N
OH
73

Indole-3-carbaldehyde oxime

Indole-3-carbaldehyde (10 mmol, 1.46 g), hydroxylamine hydrochloride (10 mmol, 0.69 g),
pyridine (5 mL), and ethanol (100 mL).
In a 250 mL round bottom flask equipped with a stirring bar hydroxylamine hydrochloride
(0.69 g, 10 mmol) was dissolved in 100 mL of EtOH and 5 mL of pyridine were added
dropwise. The mixture was stirred for 15 min and aldehyde (1.46 g, 10 mmol) was added at
once. The mixture was left stirring for 3 h at r.t. After set time 100 mL of brine was added
and the product was extracted with 3 × 30 mL of EtOAc. The combined organic phase washed
with 3 × 30 mL of water and 1 × 30 mL of brine. The solution was passed through a pad of
silica (1 cm), activated carbon (1 cm), and Na2SO4 (4 cm). Volatiles were removed under
reduced pressure to afford pure product.
Yield (off-white solid) 0.91 g; 57%
Consists of two isomers in 1:1 ratio
1
H NMR (400 MHz, CDCl3) δ 11.56 (s, 1H), 11.38 (s, 1H), 11.17 (s, 1H), 10.49 (s, 1H), 8.26 (s,
1H), 8.22 (d, J = 2.7 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.78 (s, 1H), 7.62
(d, J = 2.7 Hz, 1H), 7.43 (ddt, J = 11.8, 8.1, 1.0 Hz, 2H), 7.19 – 7.05 (m, 4H).
13
C NMR (101 MHz, CDCl3) δ 144.6, 138.4, 136.9, 134.9, 130.4, 128.4, 126.2, 124.2, 122.2,
121.9, 121.4, 120.0, 119.9, 118.2, 111.7, 109.6, 106.3.
GC-EI-MS(TOF): [M]
+•
exact for C9H8N2O m/z 160.0631, accurate m/z 160.0635 (Δ = 2.5 ppm)

N
H
N
OH
74
Appendix C: Characterization of Oximes

Benzaldehyde oxime

Figure 1.69
1
H NMR spectrum of benzaldehyde oxime in CDCl3.

Figure 1.70
13
C NMR spectrum of benzaldehyde oxime in CDCl3.
75
4-chlorobenzaldehyde oxime

Figure 1.71
1
H NMR spectrum of 4-chlorobenzaldehyde oxime in CDCl3.

Figure 1.72
13
C NMR spectrum of 4-chlorobenzaldehyde oxime in CDCl3.
76
4-nitrobenzaldehyde oxime

Figure 1.73
1
H NMR spectrum of 4-nitrobenzaldehyde oxime in CDCl3.

Figure 1.74
13
C NMR spectrum of 4-nitrobenzaldehyde oxime in CDCl3.
77
2-methoxy benzaldehyde oxime

Figure 1.75
1
H NMR spectrum of 2-methoxy benzaldehyde oxime in CDCl3.

Figure 1.76
13
C NMR spectrum of 2-methoxy benzaldehyde oxime in CDCl3.
78
2-fluorobenzaldehyde oxime

Figure 1.77
1
H NMR spectrum of 2-fluorobenzaldehyde oxime in CDCl3.

2-chloro-5-nitrobenzaldehyde oxime

Figure 1.78
1
H NMR spectrum of 2-chloro-5-nitrobenzaldehyde oxime in CDCl3.
79

Figure 1.79
13
C NMR spectrum of 2-chloro-5-nitrobenzaldehyde oxime in CDCl3.

4-chloro-3-nitrobenzaldehyde oxime

Figure 1.80
1
H NMR spectrum of 4-chloro-3-nitrobenzaldehyde oxime in CDCl3.
80

Figure 1.81
13
C NMR spectrum of 4-chloro-3-nitrobenzaldehyde oxime in CDCl3.

2-chloro-6-fluorobenzaldehyde oxime

Figure 1.82
1
H NMR spectrum of 2-chloro-6-fluorobenzaldehyde oxime in CDCl3.
81

Figure 1.83
13
C NMR spectrum of 2-chloro-6-fluorobenzaldehyde oxime in CDCl3.

Figure 1.84
19
F NMR spectrum of 2-chloro-6-fluorobenzaldehyde oxime in CDCl3.

82
2,6-difluorobenzaldehyde oxime

Figure 1.85
1
H NMR spectrum of 2,6-difluorobenzaldehyde oxime in CDCl3.

Figure 1.86
13
C NMR spectrum of 2,6-difluorobenzaldehyde oxime in CDCl3.
83

Figure 1.87
19
F NMR spectrum of 2,6-difluorobenzaldehyde oxime in CDCl3.

2,4-dichlorobenzaldehyde oxime

Figure 1.88
1
H NMR spectrum of 2,4-dichlorobenzaldehyde oxime in CDCl3.
84

Figure 1.89
13
C NMR spectrum of 2,4-dichlorobenzaldehyde oxime in CDCl3.

2,4-dimethoxybenzaldehyde oxime

Figure 1.90
1
H NMR spectrum of 2,4-dimethoxybenzaldehyde oxime in CDCl3.
85

Figure 1.91
13
C NMR spectrum of 2,4-dimethoxybenzaldehyde oxime in CDCl3.

4-(dimethylamino)benzaldehyde oxime

Figure 1.92
1
H NMR spectrum of 4-(dimethylamino)benzaldehyde oxime in CDCl3.
86

Figure 1.93
13
C NMR spectrum of 4-(dimethylamino)benzaldehyde oxime in CDCl3.

4-(benzyloxy)benzaldehyde oxime

Figure 1.94
1
H NMR spectrum of 4-(benzyloxy)benzaldehyde oxime in CDCl3.
87

Figure 1.95
13
C NMR spectrum of 4-(benzyloxy)benzaldehyde oxime in CDCl3.

tridecanal oxime

Figure 1.96
1
H NMR spectrum of tridecanal oxime in CDCl3.
88

Figure 1.97
13
C NMR spectrum of tridecanal oxime in CDCl3.

2-nitrobenzaldehyde oxime

Figure 1.98
1
H NMR spectrum of 2-nitrobenzaldehyde oxime in CDCl3.
89

Figure 1.99
13
C NMR spectrum of 2-nitrobenzaldehyde oxime in CDCl3.

2-naphthaldehyde oxime

Figure 1.100
1
H NMR spectrum of 2-naphthaldehyde oxime in CDCl3.
90

Figure 1.101
13
C NMR spectrum of 2-naphthaldehyde oxime in CDCl3.

2-methoxy-1-naphthaldehyde oxime

Figure 1.102
1
H NMR spectrum of 2-methoxy-1-naphthaldehyde oxime in CDCl3.
- 1 . 0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0 1 1 . 5 1 2 . 0
δ ( pp m )
2.88
0.98
1.01
1.01
1.02
0.98
0.98
0.99
0.98
2.50 DMSO-d6
3.96
7.38
7.39
7.40
7.48
7.49
7.51
7.53
7.54
7.88
7.89
7.99
8.00
8.67
8.81
8.83
11.31
91

Figure 1.103
13
C NMR spectrum of 2-methoxy-1-naphthaldehyde oxime in CDCl3.

1-methoxy-2-naphthaldehyde oxime

Figure 1.104
1
H NMR spectrum of 1-methoxy-2-naphthaldehyde oxime in CDCl3.
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
39.52 DMSO-d6
56.57
113.38
113.48
123.81
125.46
127.50
128.37
128.67
130.82
131.55
145.21
156.31
- 1 . 0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0 1 1 . 5 1 2 . 0
δ ( pp m )
3.06
2.05
1.03
0.99
1.00
0.99
0.99
1.00
2.50 DMSO-d6
3.91
7.56
7.56
7.57
7.57
7.57
7.58
7.58
7.59
7.59
7.60
7.60
7.61
7.69
7.71
7.83
7.85
7.93
7.94
7.95
7.95
8.08
8.09
8.44
11.48
92

Figure 1.105
13
C NMR spectrum of 1-methoxy-2-naphthaldehyde oxime in CDCl3.

Indole-3-carbaldehyde oxime

Figure 1.106
1
H NMR spectrum of Indole-3-carbaldehyde oxime in CDCl3.
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
39.52 DMSO-d6
63.36
121.48
121.99
122.45
124.38
126.75
127.11
127.47
128.19
134.87
143.40
154.28
- 1 .0 - 0 .5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0 1 1 . 5 1 2 . 0
δ ( ppm )
4.16
2.07
1.08
1.02
0.99
1.08
0.99
1.07
1.08
1.00
1.06
0.99
2.50 DMSO-d6
7.06
7.07
7.08
7.08
7.09
7.10
7.10
7.11
7.12
7.12
7.14
7.14
7.15
7.16
7.16
7.17
7.18
7.40
7.40
7.40
7.42
7.42
7.42
7.43
7.43
7.43
7.45
7.45
7.45
7.61
7.62
7.78
7.84
7.86
7.96
7.98
8.22
8.22
8.26
10.49
11.17
11.38
11.56
7 . 1 7 . 2 7 . 3 7 . 4 7 . 5 7 . 6 7 . 7 7 . 8 7 . 9 8 . 0
δ ( ppm )
7.06
7.07
7.08
7.08
7.09
7.10
7.10
7.11
7.12
7.12
7.14
7.14
7.15
7.16
7.16
7.17
7.18
7.40
7.40
7.40
7.42
7.42
7.42
7.43
7.43
7.43
7.45
7.45
7.45
7.61
7.62
7.78
7.84
7.86
7.96
7.98
93

Figure 1.107
13
C NMR spectrum of Indole-3-carbaldehyde oxime in CDCl3.

1.9 Synthesis of Chloro-Oximes

Synthesis of Chloro-oximes: General Procedure

10 mmol of oxime was dissolved in 10 mL DMF in a 100 mL RBF and placed in a 15°C water
bath which was then covered with aluminum foil to minimize light exposure. 10.5 mmol of
NCS was added portion-wise over 30 minutes to the stirring reaction. After each addition,
yellowing of the solution was observed, and subsequent additions were made as the color
began to disappear and the solution became clear. The mixture was stirred for 24 hours in
the dark and the water bath was allowed to warm to RT. Reaction progress was monitored
via TLC in 3:1 hexanes: EtOAc. The reaction was quenched with 10 mL of water and the
product was extracted to ether (x3, 30 mL). The ether layer was washed with a 5:1 brine:
water mixture (x3, 50 mL), and brine (x1, 50 mL), and dried over sodium sulfate. Solvents
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
39.52 DMSO-d6
106.31
109.59
111.74
118.17
119.87
120.00
121.44
121.85
122.24
124.22
126.20
128.38
130.44
134.90
136.86
138.36
144.57
94
were evaporated under vacuum and the product was allowed to crystalize. Trace DMF was
removed by placing the crushed crystals under high vacuum overnight.

Compound 3a: N-hydroxybenzimidoyl chloride

Benzaldehyde oxime (23.7 mmol, 2.88 g), NCS (24.9 mmol, 3.34 g), and DMF (25 mL)
Yield (pale yellow solid) 3.40 g; 92%
1
H NMR (400 MHz, cdcl3) δ 7.88 – 7.82 (m, 2H), 7.48 – 7.39 (m, 3H).
13
C NMR (100 MHz, cdcl3) δ 140.43, 132.53, 130.92, 128.67, 127.35.
LC-APCI-MS: [M+H]
+
exact for C7H6ClNO m/z 156.0211, accurate m/z 156.0208 (Δ = 1.9 ppm)

Compound 3b: 4-chloro-N-hydroxybenzimidoyl chloride

4-chlorobenzaldehyde oxime (9.6 mmol, 1.5 g), NCS (10.1 mmol, 1.35 g), and DMF (40 mL)
Yield (pale yellow solid) 1.78 g; 97%
1
H NMR (400 MHz, cdcl3) δ 7.81 – 7.77 (m, 2H), 7.75 (s, 1H), 7.41 – 7.36 (m, 2H).
13
C NMR (101 MHz, cdcl3) δ 139.23, 137.08, 131.05, 128.92, 128.56.

Compound 3c: N-hydroxy-4-nitrobenzimidoyl chloride
N
OH
Cl
N
OH
Cl
Cl
95

4-nitrobenzaldehyde oxime (6.5 mmol, 1.08 g), NCS (6.8 mmol, 0.911 g), and DMF (10 mL)
Yield (pale yellow solid) 1.12 g; 92%
1
H NMR (400 MHz, cdcl3) δ 8.29 – 8.25 (m, 2H), 8.19 (d, J = 1.5 Hz, 1H), 8.07 – 8.02 (m, 2H).
13
C NMR (100 MHz, cdcl3) δ 149.04, 138.55, 137.67, 128.12, 123.79.

Compound 3d: N-hydroxy-2-methoxybenzimidoyl chloride

1
H NMR (600 MHz, cdcl3) δ 7.51 (d, J = 10.9 Hz, 1H), 7.42 (dddd, J = 8.3, 7.4, 1.9, 0.7 Hz, 1H),
7.05 – 6.95 (m, 1H), 3.90 (s, 1H).

Compound 3e: 2-fluoro-N-hydroxybenzimidoyl chloride

2-fluobenzaldehyde oxime (6.8 mmol, 0.950 g), NCS (7.2 mmol, 0.957 g), and DMF (10 mL)
Yield (pale yellow solid) 1.16 g; 97%
1
H NMR (400 MHz, cdcl3) δ 8.91 (s, 1H), 7.72 – 7.64 (m, 1H), 7.44 (dddd, J = 8.3, 7.5, 5.0, 1.8
Hz, 1H), 7.25 – 7.12 (m, 2H).
13
C NMR (101 MHz, cdcl3) δ 161.24, 158.70, 132.33 (d, J = 8.5 Hz), 130.93 (d, J = 1.4 Hz),
124.42 (d, J = 3.9 Hz), 116.86, 116.64.
N
OH
O
2
N
Cl
N
OH
O Cl
N
OH
F Cl
96
19
F NMR (376 MHz, cdcl3) δ -111.92 – -112.00 (m).

Compound 3f: 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride

2-chloro- 5-nitrobenzaldehyde oxime (5 mmol, 1.00 g), NCS (5.2 mmol, 0.699 g), and DMF
(50 mL)
Yield (off-white solid) 0.964 g; 82%
1
H NMR (400 MHz, cdcl3) δ 8.37 (dd, J = 2.6, 0.4 Hz, 1H), 8.25 (dd, J = 8.8, 2.7 Hz, 1H), 8.20 (s,
1H), 7.66 (dd, J = 8.8, 0.4 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 146.45, 140.45, 135.08, 134.02, 131.68, 126.53, 125.97.

Compound 3g: 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride

4-chloro- 3-nitrobenzaldehyde oxime (5 mmol, 1.01 g), NCS (5.3 mmol, 0.705 g), and DMF
(40 mL)
Yield (off-white solid) 0.939 g; 80%
1
H NMR (400 MHz, cdcl3) δ 8.36 (dd, J = 2.2, 0.3 Hz, 1H), 8.00 (dd, J = 8.6, 2.2 Hz, 1H), 7.60
(dd, J = 8.6, 0.4 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 136.93, 132.66, 132.22, 131.04, 129.26, 124.18.
N
OH
Cl
NO
2
Cl
N
OH O
2
N
Cl
Cl
97
Compound 3h: 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride

2-chloro-6-fluoro-benzaldehyde oxime (6.3 mmol, 1.09 g), NCS (6.6 mmol, 0.880 g), and DMF
(40 mL)
Yield (off-white solid) 0.764 g; 54%
1
H NMR (400 MHz, dmso) δ 12.79 (s, 1H), 7.61 (td, J = 8.3, 6.2 Hz, 1H), 7.50 (dt, J = 8.2, 1.0 Hz,
1H), 7.41 (ddd, J = 9.3, 8.4, 1.1 Hz, 1H).
13
C NMR (100 MHz, dmso) δ 161.40, 158.90, 133.28 (d, J = 9.8 Hz), 125.96 (d, J = 3.4 Hz),
121.85, 115.31, 115.10.

Compound 3i: 2,6-difluoro-N-hydroxybenzimidoyl chloride

2,6-difluoro-benzaldehyde oxime (5.9 mmol, 0.930 g), NCS (6.2 mmol, 0.830 g), and DMF (40
mL)
Yield (off-white solid) 0.798g; 71%
1
H NMR (400 MHz, cdcl3) δ 7.48 – 7.36 (m, 1H), 7.01 – 6.94 (m, 2H).
13
C NMR (100 MHz, cdcl3) δ 161.86 (d, J = 5.3 Hz), 159.32 (d, J = 5.6 Hz), 132.48 (t, J = 10.3
Hz), 129.22, 112.20 – 111.82 (m).
19
F NMR (376 MHz, cdcl3) δ -111.14 – -111.21 (m).

N
OH
Cl
F
Cl
N
OH
F
F
Cl
98
Compound 3j: 2,4-dichloro-N-hydroxybenzimidoyl chloride

2,4-dichlorobenzaldehyde oxime (3.7 mmol, 707 mg), NCS (3.9 mmol, 521 mg), and DMF (10
mL)
Yield (pale yellow solid) 816 mg; 98%
1
H NMR (400 MHz, cdcl3) δ 8.37 (s, 1H), 7.48 (dd, J = 2.0, 0.4 Hz, 1H), 7.42 (dd, J = 8.3, 0.4 Hz,
1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H).
13
C NMR (101 MHz, cdcl3) δ 137.09, 134.76, 134.30, 132.07, 131.38, 130.43, 127.44.

Compound 3l: N-hydroxy-2-nitrobenzimidoyl chloride

2-nitrobenzaldehyde oxime (6.3 mmol, 1.05 g), NCS (6.7 mmol, 0.890g), and DMF (10 mL)
Yield (off-white solid) 1.25 g; 98%
1
H NMR (400 MHz, cdcl3) δ 8.16 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.72 – 7.60 (m, 3H).

Compound 3m: N-hydroxy-2-methoxy-1-naphthimidoyl chloride

2-methoxy-1-naphthaldehyde oxime (2.48 mmol, 500 mg), NCS (2.61 mmol, 348.4 g), and
DMF (3 mL)
N
OH
Cl
Cl
Cl
N
OH
NO
2
Cl
O
N
OH
Cl
99
Yield (pale yellow solid) 445.9 mg; 76%
1
H NMR (400 MHz, CDCl3) δ 8.15 (br s, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.81 (t, J = 9.7 Hz, 2H),
7.53 (dt, J = 6.7, 1.0 Hz, 1H), 7.40 (dt, J = 7.2, 0.8 Hz, 1H), 7.31 (d, J = 9.1 Hz, 1H), 4.00 (s, 3H).
13
C NMR (101 MHz, CDCl3) δ 155.8, 135.7, 132.6, 132.5, 128.7, 128.3, 128.0, 124.4, 123.5,
116.4, 113.1, 56.8.
Direct injection APCI-MS: [M – Cl]
+
exact for C12H10NO2 m/z 200.0706, accurate m/z
200.0713 (Δ = 3.5 ppm)

Compound 3n: N-hydroxy-1-methoxy-2-naphthimidoyl chloride

1-methoxy-2-naphthaldehyde oxime (2.56 mmol, 515 mg), NCS (2.68 mmol, 359 g), and DMF
(5 mL)
Yield (pale yellow solid) 478.7 mg; 79%
1
H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.29 – 8.20 (m, 1H), 7.90 – 7.82 (m, 1H), 7.65 (dd, J
= 8.8, 0.7 Hz, 1H), 7.60 – 7.55 (m, 3H), 4.01 (s, 3H).
13
C NMR (101 MHz, CDCl3) δ 155.24, 136.86, 135.74, 128.16, 128.09, 127.97, 126.85, 126.49,
124.19, 123.30, 121.86, 63.05.
GC-EI-MS(TOF): [M-HCl]
+•
exact for C12H9lNO2 m/z 199.0628, accurate m/z 199.0631 (Δ =
1.5 ppm)

Compound 3o: N-hydroxytridecanimidoyl chloride
O
N
OH
Cl
100
v

tridecanal oxime (4.2 mmol, 845 mg), NCS (4.45 mmol, 594 mg), and DMF (3 mL)
Yield (pale yellow solid) 951 mg; 96%
1
H NMR (400 MHz, cdcl3) δ 2.52 – 2.48 (m, 2H), 1.64 (p, J = 7.5 Hz, 2H), 1.26 (s, 18H), 0.88
(td, J = 6.9, 1.0 Hz, 3H).
13
C NMR (100 MHz, cdcl3) δ 37.17, 36.71, 32.65, 32.04, 29.73, 29.59, 29.47, 29.32, 28.65,
26.36, 24.89, 22.82, 14.25.

Compound: N-hydroxy-indole-3-carbimidoyl chloride

Indole-3-carbaldehyde oxime (3.1 mmol, 500 mg), NCS (3.3 mmol, 438 g), and DMF (5 mL)
Yield (dark orange solid) 180.2 mg; 30%
Consists of two isomers in 1:2 ratio, thus integral of 21 H and 18 C are considered in NMR
1
H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 11.66 (m, 4H), 10.93 (br s, 1H), 8.18 (s, 1H),
7.99 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 2.9 Hz, 2H), 7.45 (dt, J = 8.1, 1.0 Hz,
2H), 7.35 (dt, J = 8.1, 1.0 Hz, 1H), 7.23 – 7.11 (m, 6H).
13
C NMR (101 MHz, DMSO-d6) δ 141.9, 136.9, 134.9, 131.7, 128.7, 124.9, 124.1, 123.8, 122.9,
122.6, 121.1, 120.9, 120.7, 120.6, 112.1, 111.2, 109.8.
GC-EI-MS(TOF): [M]
+•
exact for C9H7ClN2O m/z 194.0741, accurate m/z 194.0743 (Δ = 1.0
ppm).

Cl
OH
N
N
H
N
OH
Cl
101
Appendix D: Characterization of Chloro-Oximes

Compound 3a: N-hydroxybenzimidoyl chloride

Figure 1.108
1
H NMR spectrum of N-hydroxybenzimidoyl chloride in CDCl3.

Figure 1.109
13
C NMR spectrum of N-hydroxybenzimidoyl chloride in CDCl3.
102

Compound 3b: 4-chloro-N-hydroxybenzimidoyl chloride

Figure 1.110
1
H NMR spectrum of 4-chloro-N-hydroxybenzimidoyl chloride in CDCl3.

Figure 1.111
13
C NMR spectrum of 4-chloro-N-hydroxybenzimidoyl chloride in CDCl3.
103
Compound 3c: N-hydroxy-4-nitrobenzimidoyl chloride

Figure 1.112
1
H NMR spectrum of N-hydroxy-4-nitrobenzimidoyl chloride in CDCl3.

Figure 1.113
13
C NMR spectrum of N-hydroxy-4-nitrobenzimidoyl chloride in CDCl3.
104
Compound 3d: N-hydroxy-2-methoxybenzimidoyl chloride

Figure 1.114
1
H NMR spectrum of N-hydroxy-2-methoxybenzimidoyl chloride in CDCl3.

Compound 3e: 2-fluoro-N-hydroxybenzimidoyl chloride

Figure 1.115
1
H NMR spectrum of 2-fluoro-N-hydroxybenzimidoyl chloride in CDCl3.
105

Figure 1.116
13
C NMR spectrum of 2-fluoro-N-hydroxybenzimidoyl chloride in CDCl3.

Figure 1.117
19
F NMR spectrum of 2-fluoro-N-hydroxybenzimidoyl chloride in CDCl3.

106
Compound 3f: 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride

Figure 1.118
1
H NMR spectrum of 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride in
CDCl3.

Figure 1.119
13
C NMR spectrum of 2-chloro-N-hydroxy-5-nitrobenzimidoyl chloride in
CDCl3.
107
Compound 3g: 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride

Figure 1.120
1
H NMR spectrum of 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride in
CDCl3.

Figure 1.121
13
C NMR spectrum of 4-chloro-N-hydroxy-3-nitrobenzimidoyl chloride in
CDCl3.
108
Compound 3h: 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride

Figure 1.122
1
H NMR spectrum of 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride in
CDCl3.

Figure 1.123
13
C NMR spectrum of 2-chloro-6-fluoro-N-hydroxybenzimidoyl chloride in
CDCl3.
109
Compound 3i: 2,6-difluoro-N-hydroxybenzimidoyl chloride

Figure 1.124
1
H NMR spectrum of 2,6-difluoro-N-hydroxybenzimidoyl chloride in CDCl3.

Figure 1.125
13
C NMR spectrum of 2,6-difluoro-N-hydroxybenzimidoyl chloride in CDCl3.
110

Figure 1.126
19
F NMR spectrum of 2,6-difluoro-N-hydroxybenzimidoyl chloride in CDCl3.

Compound 3j: 2,4-dichloro-N-hydroxybenzimidoyl chloride

Figure 1.127
1
H NMR spectrum of 2,4-dichloro-N-hydroxybenzimidoyl chloride in CDCl3.
111

Figure 1.128
13
C NMR spectrum of 2,4-dichloro-N-hydroxybenzimidoyl chloride in CDCl3.

Compound 3l: N-hydroxy-2-nitrobenzimidoyl chloride

Figure 1.129
1
H NMR spectrum of N-hydroxy-2-nitrobenzimidoyl chloride in CDCl3.
112
Compound 3m: N-hydroxy-2-methoxy-1-naphthimidoyl chloride

Figure 1.130
1
H NMR spectrum of N-hydroxy-2-methoxy-1-naphthimidoyl chloride in
CDCl3.

Figure 1.131
13
C NMR spectrum of N-hydroxy-2-methoxy-1-naphthimidoyl chloride in
CDCl3.
- 1 .0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0
δ ( ppm )
2.98
1.00
1.05
1.02
2.00
1.04
0.91
4.00
7.26 CDCl3
7.30
7.32
7.38
7.38
7.39
7.40
7.40
7.41
7.42
7.51
7.51
7.53
7.53
7.53
7.55
7.55
7.78
7.79
7.80
7.81
7.83
7.95
7.97
8.15
7 .2 7 . 3 7 . 4 7 . 5 7 . 6 7 . 7 7 . 8 7 . 9 8 . 0 8 . 1 8 . 2
δ ( ppm )
7.26 CDCl3
7.30
7.32
7.38
7.38
7.39
7.40
7.40
7.41
7.42
7.51
7.51
7.53
7.53
7.53
7.55
7.55
7.78
7.79
7.80
7.81
7.83
7.95
7.97
8.15
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
56.83
77.16 CDCl3
113.06
116.45
123.53
124.37
128.03
128.29
128.70
132.47
132.58
135.66
155.75
113
Compound 3n: N-hydroxy-1-methoxy-2-naphthimidoyl chloride

Figure 1.132
1
H NMR spectrum of N-hydroxy-1-methoxy-2-naphthimidoyl chloride in
CDCl3.

Figure 1.133
13
C NMR spectrum of N-hydroxy-1-methoxy-2-naphthimidoyl chloride in
CDCl3.
- 1 . 0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5
δ ( ppm )
3.11
3.23
1.21
1.14
1.32
1.00
4.01
7.26 CDCl3
7.56
7.56
7.57
7.58
7.58
7.64
7.64
7.64
7.66
7.66
7.85
7.86
7.86
7.87
8.23
8.24
8.24
8.25
8.55
7 . 5 7 . 6 7 . 7 7 . 8 7 . 9 8 . 0 8 . 1 8 . 2 8 . 3
δ ( ppm )
7.56
7.56
7.57
7.58
7.58
7.64
7.64
7.64
7.66
7.66
7.85
7.86
7.86
7.87
8.23
8.24
8.24
8.25
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
63.05
77.16 CDCl3
121.86
123.30
124.19
126.49
126.85
127.97
128.09
128.16
135.74
136.86
155.24
114
Compound 3o: N-hydroxytridecanimidoyl chloride

Figure 1.134
1
H NMR spectrum of N-hydroxytridecanimidoyl chloride in CDCl3.

Figure 1.135
13
C NMR spectrum of N-hydroxytridecanimidoyl chloride in CDCl3.

115
Compound: N-hydroxy-indole-3-carbimidoyl chloride

Figure 1.136
1
H NMR spectrum of N-hydroxy-indole-3-carbimidoyl chloride in CDCl3.

Figure 1.137
13
C NMR spectrum of N-hydroxy-indole-3-carbimidoyl chloride in CDCl3.
- 1 . 0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0 1 1 . 5 1 2 . 0 1 2 . 5 1 3 . 0
δ ( pp m )
7.77
1.41
2.28
1.99
1.09
2.22
0.91
0.88
4.23
1.00
2.50 DMSO-d6
7.11
7.11
7.13
7.13
7.13
7.15
7.15
7.18
7.18
7.18
7.19
7.20
7.20
7.20
7.22
7.22
7.22
7.33
7.34
7.34
7.35
7.36
7.36
7.43
7.44
7.44
7.46
7.46
7.46
7.79
7.80
7.92
7.94
7.98
8.00
8.18
10.93
11.65
11.65
11.67
12.28
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0
δ ( pp m )
39.52 DMSO-d6
105.29
109.75
111.17
112.14
120.59
120.71
120.92
121.06
122.62
122.87
123.76
124.08
124.93
128.73
131.66
134.89
136.89
141.94
116
Distribution of Credit

Chapter One was done and conceptualized in collaboration with Dr. Dmitry Eremin.
Alexander Vu helped explore conditions for the optimization of brominated isoxazoles. Some
compounds from the substrate scope were synthesized with the help of Kevin Vargas and
Tamar Koren.

117
Chapter 2. Investigation Into Improved SuFEx Conditions

2.1 Introduction

Sulfur VI Fluoride Exchange (SuFEx) is a selective and efficient method to create
functionalized molecular scaffolds using click methodology. Although the reactivity of sulfur
(VI) fluorides has been known since the 1800s, its reactivity to create functionalized
molecules linking together simple building blocks has recently been explored with the
emergence and surge in popularity of click chemistry reactions.
28, 29
Due to the unique
nature of the sulfonyl fluoride moiety it is a highly desirable functional group in both drug
discovery and materials science.
30, 31

The SO2F functional group has been rediscovered as a clickable scaffold allowing for
SuFEx reactions with selective reactivity due to its high stability.
28, 32
The thermodynamic
stability of the Sulfur(VI) center is higher than that of Sulfur(IV) which makes it able to
withstand harsh reaction conditions far better than its counterpart.
25
The sulfur also
ensures the nucleophilic substitution reaction selectively occurs at the sulfur center. In
contrast to the Sulfur-Chlorine bond, the Sulfur-Fluorine bond is very stable allowing it to
tolerate harsh reaction conditions.
32
The Sulfur-Fluorine bond itself is resistant to reduction
and due to the electronegativity of Fluorine causes solely heterolytic bond cleavage, unlike
the Sulfur Chlorine bond which often undergoes homolytic cleavage. These unique
properties of Sulfur (VI) have led to it being a common moiety in therapeutic compounds,
with over 150 FDA-approved pharmaceuticals to treat several conditions containing the
moiety.
33

Scheme 2.1 SuFEx Mechanism
118

2.2 Synthetic Approaches

The popularity of SuFEx chemistry has in part been driven by the proven therapeutic
applications of sulfonamides. Beginning with the discovery of Prontosil in 1932 numerous
pharmaceuticals including the sulfonamide moiety have been developed (Figure 2.1).
34

With applications ranging from antibiotics and antivirals to NSAIDs and diuretics, there is
always interest in developing new synthetic methods to create complex molecules
containing sulfonamide groups.
35
SuFEx allows for the creation of such compounds taking
advantage of the unique S-F bond to allow for nucleophilic attack by amines, making the
facile installation of a SO2F handle an advantageous functionalization.

Figure 2.1 Examples of Pharmaceuticals Containing the Sulfonamide Moiety

Aryl sulfonyl fluorides have been synthesized from the corresponding aryl chloride
in a halogen exchange reaction with a fluoride source. Early synthetic methods required the
addition of crown ethers to enhance the solubility of inorganic fluorine sources and dry
S
O
O
F
+ Nu
S
O
O
Nu
S
O
O
NH
2
N
N
F
F
F
Celecoxib
N
N
O
HN
S
O
O
NH
NH
O
Glipizide
O
OH
N
N
S
O
O
H
N
N
OH
Sulfasalazine
119
conditions.
36
The reaction was further optimized by using a biphasic mixture and then
improved by the addition of a phase transfer catalyst.
32, 37
Aryl sulfonyl fluorides have also
been successfully synthesized using palladium catalysts and DABSO for the source of sulfur.
38, 39

Phenols have been successfully converted to sulfonyl fluorides using Sulfuryl
Fluoride (SO2F2) gas.
29
This method yielded better results under milder conditions than
previous methods using diazonium salts and chlorine fluoride.
40, 41
Fluorosulfuryl
imidazolium salts have also been used as an alternative to sulfuryl fluoride gas to install the
sulfonyl fluoride handle to phenols which, in addition to being stable and making for a more
facile synthesis, can shorten reaction times because of their ability to act as better leaving
groups.
42, 43

Almost 50 years after its initial discovery in 1953, ethenesulfonyl fluoride (ESF) has
been used to add a sulfonyl fluoride group.
44
ESF can take advantage of its dual reactive sites
to undergo Michael addition at the vinyl position and SuFEx at its sulfonyl fluoride position.
ESF derivates such as Br-ESF can also be used to install a SO2F functional group which can
then undergo SuFEx modifications.

2.3 Optimized Conditions

Using the previously reported synthetic protocol for SuFEx to substitute the fluorine in a
nucleophilic attack by an amine, many of the complex heterocyclic final compounds for the
cannabinoid type II receptor project were not able to be synthesized. Various bases in
addition to the triethylamine that was initially used were compared, and analyzed by LC-MS.
Although the initial results using DBU appeared to yield no product, after the addition of a
120
catalytic amount of DMAP the reaction proceeded. It was also found that when the reaction
vessel contained any significant amount of water the product would be hydrolyzed.
The optimized conditions (Table 2.1) were found to be 1eq of the sulfonyl fluoride
functionalized heterocyclic compound, 2eq of the corresponding amine, 0.20eq DMAP, and
1eq of DBU in ACN at room temperature for approximately 24h (dependent on the
substrate). This updated protocol allowed for the synthesis of many final compounds that
had previously been synthesized successfully through the cyclization and installation of the
SO2F handle and had not proceeded through the final SuFEx step.

Table 2.1 Optimization of SuFEx Conditions

Entry Solvent Base DMAP Outcome
1 - triazole ACN NEt3 No No Product
2 - isoxazole ACN NEt3 No No Product
3 - triazole ACN NEt3 Yes Low Yield, SM Persisted
4 - triazole ACN DBU No No Product
5 - triazole ACN BEMP No No Product
6 - triazole ACN DBU Yes Product Formed
7 - triazole H2O DBU Yes No Product
8 - isoxazole ACN DBU Yes Product Formed

121
Chapter 3. Synthesis of Sulfonyl Fluoride Functionalized Triazoles
3.1 Introduction

Triazoles are a class of heterocyclic compounds containing three nitrogen atoms in a
five-membered ring. Due to their abundance of applications throughout various fields, they
have garnered significant attention as a potent molecular scaffold.
45-49
Their applications
span from drug discovery to polymer chemistry, to pesticides and insecticides, and they have
been used in biological imaging.
50-54

Triazoles have been demonstrated to be biologically active compounds that have
been used as; antifungals, antibacterials, antivirals, analgesics, anticonvulsants, and
antitumor medications.
55-61
1,2,4 – triazoles have been incorporated into pharmaceutical
candidates which are CNS stimulants, sedatives, antianxiety, antimicrobials, and
antimycotics.
62-64
Presently there are many drugs commercially available that contain a
triazole moiety such as Trodelvy which was recently shown to treat triple-negative breast
cancer and acquired by Gilead in a multi-billion-dollar deal.
3, 65, 66

122

Figure 3.1 Pharmaceuticals Containing a Triazole Moiety

3.2 Previous Synthetic Strategies

1,3-dipolar cycloadditions were first described at the beginning of the 20
th
century by
Huisgen et al.
67
Early syntheses of triazoles had poor selectivity, low yields, and required
harsh conditions.
68
Due to the elevated temperature requires, along with severe reaction
conditions that led to low yields of poorly selective products these cycloadditions were not
facile reactions. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) was developed in the
early 2000s and has become a key synthetic reaction throughout industry and academia.
69-
77
Its high yields and selective formation of 1,2,3- triazoles lead to it becoming a powerful
tool in organic synthesis and won it the 2022 Nobel Prize in chemistry.
78, 79

One-pot synthetic pathways to form triazoles using sodium azide t to turn terminal
alkynes into triazoles had previously been reported, however, these uncatalyzed reactions
required high temperatures and provided a mix of 1,4-triazole and 1,5-triazole regioisomers.
OH
N
N
N
N
N
N
F
F
Fluconazole
N
N
N
O
NH
2
OH
HO
O
HO
Ribavirin
mAb
S
N
O
O
N
O
N
N
N
O
O
O
O
O
O
O
O
H
N
O
O
O
NH
O
NH
O O
O
N
N
O
O
O
HO
NH
2
Trodelvy
123
80
Due to the pharmacological activity of the triazole moiety new synthetic methods to create
functionalized triazoles lie at the forefront of chemical research. Notably, sulfonamide
functionalized triazoles were missing from the vast number of functionalized synthesized
apart from multi-step procedures leading to low yields of unselective products. In 2018,
Bromoethane sulfonyl fluoride (Br-ESF) was found to be a unique compound that
transformed azides into sulfonyl fluoride functionalized triazoles.
27, 81
Br-ESF has been
known since 1985, and is a derivative of ESF which has been described as “the most perfect
Michael Accepter ever found”. It has been used as a reagent to introduce sulfonyl fluoride
groups and has been synthesized on a large scale, with recent developments improving the
efficiency of the reaction and purity of the final compound.
1, 82, 83
Due to its ability to tolerate
many functional groups, combining Br-ESF with azides has been used to create a diverse
compound library of sulfonyl fluoride functionalized triazoles that had previously been
inaccessible by using mild conditions and a reaction that is regiospecific and free of metal.
1

This reaction was optimized in organic solvents and good yields were found in DMF at 50°C.
Although highly selective, the reaction also led to the formation of the brominated triazole
decreasing product yields and complicating the isolation of the desired compounds.
To improve yields, and selectively form both the sulfonyl fluoride and brominated
triazoles the conditions were explored and optimized. The SO2F functionalized triazoles can
undergo further modifications using SuFEx chemistry to create complex compounds using
the potent triazole scaffold.

3.3 Optimized conditions

Scheme 3.1 General procedure for the synthesis of sulfonyl fluoride substituted triazoles.

124

A 20 mL scintillation vial (FisherBrand
TM
03-337-15) was charged with azide 1 (1 mmol),
Br-ESF 2 (2 mmol, 378 mg), TBAC 25 mM solution in water (2 mL; 5 mol % of TBAC), and a
stir bar (FisherBrand
TM
14-512-125; 20 mm). The vial was sealed with a cap and placed onto
a stir plate. The mixture was stirred for 8 h at 1400 RPM at room temperature. Unless
otherwise noted: the mixture was transferred into a separating funnel and diluted with 10
mL of water. The product was extracted with 3×10 mL of DCM. The combined organic layer
was washed with 3×15 mL of water, followed by 2×15 mL of brine, dried over Na2SO4, and
filtered. Solvents were removed in vacuo to afford a pure product. Purity was analyzed by
qNMR.

TBAC (5 mol %)
N
3
R
Br
SO
2
F
+
N
N
N
R
SO
2
F
H
2
O, r.t.
125
3.4 Compounds Synthesized

Figure 3.2 Substrate Scope of Sulfonyl Fluoride Functionalized Triazoles

3.5 Synthesis of Sulfonyl Fluoride Functionalized Triazoles

Compound 5a: 1-Phenethyl-1,2,3-triazole-4-sulfonyl fluoride

Phenethyl azide (1 mmol, 147 mg).
Yield (off-white solid) 230mg; 90%.
SO2F : Br selectivity– 36 : 1.
1
H NMR (400 MHz, CDCl3) δ ppm: 7.83 (s, 1H), 7.36 – 7.28 (m, 3H), 7.09 – 7.04 (m, 2H), 4.73
(t, J = 7.0 Hz, 2H), 3.27 (t, J = 7.0 Hz, 2H).
N
N
N
X
N
N
N
X
N
N
N
X
N
N
N
X
N
N
N
X
O F O
2
N NC
N
N
N
X
N
N
N
X
N
H
O
N
N
N
X
N
N
N
X
N
N
N
X
O O
2
N
N
N
N
X
N
N
N
X
N
N N
X
4b, 94%, 28:1
5b, 95%, 1:34
4c, 89%, 38:1
5c, 91%, 1:39
4d, 80%, 28:1
5d, 80%, 1:14
4e, 90%, 26:1
5e, 99%, 1:45
4f, 91%, 13:1
5f, 82%, 1:9
4h, 45%, 64:1
(45%, >100:1)
d
5h, 14%, 1:20
4i, 58%, 8:1
(61%, 7:1)
d
5i, 44%, 1:13
4j, 10%
(11%)
d
5j, not observed
4p, 94%, 29:1
5p, 98%, 1:29
4l, 80%, 53:1
5l, 89%, 1:27
4q, 99%, >100:1
5q, 85%, 1:13
4s, 94%, 23:1
5s, 99%, 1:>100
N
3
Br
SO
2
F
(i) H
2
O, PhOMe, 80 °C
emulsion w/ organic co-solvent
N
N
N
Br
SO
2
F
N
N
N
Br
1 2
4
+
via 3
N
N
N
X
N
N
N
X
N
N
N
X
N
N
N
X
O
(ii) H
2
O, TBAC (5 mol %), RT
emulsion w/ cationic surfactant
N
N
N
SO
2
F
5
4n, 82%,
5n, 97%, 1:8
4r, 78%
4o, 93% 4k, 49%
5k, 59%, 1:4
4a, 92%, 30:1
(87%, 29:1)
c
5a, 90%, 1:36
scope
N
N
N
X
HO
N
N
N
X
4m, 85%, 52:1
5m, 83%, 1:20
NC
4g, 82%, 13:1
5g, 37%, 1:3
N
N
N
SO
2
F
Ph
126
13
C{
1
H} NMR (101 MHz, CDCl3) δ ppm: 135.8, 129.3, 128.7, 128.6 (d, J = 3.0 Hz), 127.9, 53.0,
36.4.
19
F NMR (376 MHz, CDCl3) δ ppm: 66.45.
APCI-MS (TOF): [M + H]
+
exact for C10H11N3SO2F m/z 256.0551, accurate m/z 256.0547
(Δ = 1.6 ppm).

Compound 5b: 1-(4-Methoxyphenethyl)-1,2,3-triazole-4- sulfonyl fluoride

1-(2-azidoethyl)-4-methoxybenzene (1 mmol, 165 mg).
Yield (off-white crystalline solid) 272 mg; 95%.
SO2F : Br selectivity – 34 : 1.
1
H NMR (500 MHz, CDCl3) δ ppm: 7.83 (d, J = 1.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.84 (d, J =
8.7 Hz, 2H), 4.68 (t, J = 7.0 Hz, 2H), 3.79 (s, 2H), 3.20 (t, J = 6.8 Hz, 2H).
13
C NMR (100 MHz, CDCl3) δ ppm: 159.2, 139.7 (d, J = 36.6 Hz), 129.7, 128.6 (d, J = 3.0 Hz),
127.6, 114.7, 55.4, 53.3, 35.6.
19
F NMR (470 MHz, CDCl3) δ ppm: 66.53.
APCI-MS (TOF): [M + H]
+
exact for C11H13FN3O3S m/z 286.0656, accurate m/z 286.0660
(Δ = 1.4 ppm).

Compound 5c: 1-(4-Fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
N
N
N
SO
2
F
MeO
127

1-(2-azidoethyl)-4-fluorobenzene (1 mmol, 165 mg).
Yield (white solid) 250 mg; 91%.
SO2F : Br selectivity – 39 : 1.
1
H NMR (600 MHz, CDCl3) δ ppm: 7.91 (d, J = 1.2 Hz, 1H), 7.07 – 6.98 (m, 3H), 4.70 (t, J = 7.1
Hz, 2H), 3.27 (t, J = 7.0 Hz, 2H).
13
C{
1
H} NMR (151 MHz, CDCl3) δ ppm: 163.2, 131.4 (d, J = 4.0 Hz), 130.3 (d, J = 8.1 Hz), 128.5,
116.4, 116.3, 53.0, 35.7.
19
F NMR (564 MHz, CDCl3) δ ppm: 66.49 (d, J = 1.3 Hz).
APCI-MS (TOF): [M + H]
+
exact for C10H10F2N3O2S m/z 274.0456, accurate m/z 274.0456
(Δ < 0.1 ppm).

Compound 5d: 1-(4-Nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride

1-(2-azidoethyl)-4-nitrobenzene (1 mmol, 192 mg).
Yield (off-white solid) 239.9 mg; 80%.
SO2F : Br selectivity – 14 : 1.
1
H NMR (400 MHz, DMSO-d6) δ ppm: 9.46 (d, J = 1.2 Hz, 1H), 8.20 – 8.14 (m, 2H), 7.55 – 7.48
(m, 2H), 4.87 (td, J = 7.2, 1.0 Hz, 2H), 3.42 (t, J = 7.2 Hz, 2H).
N
N
N
SO
2
F
F
N
N
N
SO
2
F
O
2
N
128
13
C NMR (100 MHz, DMSO-d6) δ ppm: 146.5, 145.2, 137.7 (d, J = 34.8 Hz), 131.5 (d, J = 3.0
Hz), 130.1, 123.6, 51.1, 34.6.
19
F NMR (376 MHz, DMSO-d6) δ ppm: 67.17 (d, J = 1.1 Hz).
APCI-MS (TOF): [M + H]
+
exact for C10H10FN4O4S m/z 301.0401, accurate m/z 301.0405
(Δ = 1.3 ppm).

Compound 5e: 1-(4-Cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride

4-(2-azidoethyl)benzonitrile (1 mmol, 172.3 mg).
Yield (off-white solid) 266.4 mg; 96%.
SO2F : Br selectivity – 1 : 45.
1
H NMR (600 MHz, CDCl3) δ ppm: 8.08 (d, J = 0.8 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.26 – 7.23 (m,
2H), 4.75 (t, J = 7.2 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H).
13
C{
1
H} NMR (151 MHz, CDCl3) δ ppm: 141.2, 140.2 (d, J = 36.9 Hz), 133.0, 129.6, 128.58 (d,
J = 2.7 Hz), 118.4, 112.0, 52.1, 36.3.
19
F NMR (564 MHz, CDCl3) δ ppm: 66.55 (d, J = 1.1 Hz).
APCI-MS (TOF): exact for C11H10SO2FN4 [M + H]
+
m/z 281.0503, accurate m/z 281.0490
(Δ = 4.6 ppm).

Compound 5f: 1-(4-Acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
N
N
N
N
SO
2
F
129

N-(4-(2-azidoethyl)phenyl)acetamide (1 mmol, 204 mg).
Yield (light brown solid) 253 mg; 82%.
SO2F : Br selectivity – 9 : 1.
1
H NMR (600 MHz, DMSO-d6) δ ppm: 9.87 (s, 1H), 9.39 (d, J = 0.9 Hz, 1H), 7.47 (d, J = 8.5 Hz,
2H), 7.09 (d, J = 8.5 Hz, 2H), 4.75 (t, J = 7.3 Hz, 2H), 3.18 (t, J = 7.3 Hz, 2H), 2.01 (s, 3H).
13
C {
1
H} NMR (151 MHz, DMSO-d6) δ ppm: 168.1, 138.1, 131.3, 131.3, 131.2, 128.9,119.0,
51.9, 34.5, 23.9.
19
F NMR (564 MHz, DMSO-d6) δ ppm: 67.16.
APCI-MS (TOF): [M + H]
+
exact for C12H14FN4O3S m/z 313.0765, accurate m/z 313.0778
(Δ = 3.8 ppm).

Compound 5g: 1-(4-Hydroxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride (5E)

4-(2-azidoethyl)phenol (1 mmol, 163 mg).
Yield (pale yellow liquid) 99.8 mg; 37%.
SO2F : Br selectivity – 20 : 1.
1
H NMR (600 MHz, CDCl3) δ ppm: 8.89 – 8.84 (m, 2H), 8.76 – 8.71 (m, 2H), 6.66 – 6.57 (m,
1H), 5.12 (t, J = 7.0 Hz, 2H), 2.95 (td, J = 7.3, 1.2 Hz, 2H).
13
C NMR (151 MHz, CDCl3) δ ppm: 153.8, 153.6, 152.5, 139.6, 59.1, 47.7, 43.5, 37.1.
N
N
N
SO
2
F
AcHN
N
N
N
SO
2
F
HO
130
19
F NMR (564 MHz, CDCl3) δ ppm: 67.91 (d, J = 1.3 Hz).
APCI-MS (TOF): [M + H]
+
exact for C10H11FN3O3S m/z 272.0500, accurate m/z 272.0498
(Δ = 0.7 ppm).

Compound 5h: 1-Phenyl-1,2,3-triazole-4-sulfonyl fluoride (5G)

azidobenzene (1 mmol, 119 mg).
Yield (brown crystalline solid) 33.1 mg; 15%.
SO2F : Br selectivity – 20 : 1.
1
H NMR (400 MHz, CDCl3) δ ppm: 8.65 (d, J = 1.2 Hz, 1H), 7.78 – 7.74 (m, 2H), 7.66 – 7.58 (m,
3H).
13
C NMR (126 MHz, CDCl3) δ ppm: 130.8, 130.5, 129.9, 125.0, 121.3, 119.2.
19
F NMR (376 MHz, CDCl3) δ ppm: 66.59.
APCI-MS (TOF): [M + H]
+
exact for C8H7FN3O2S m/z 228.0238, accurate m/z 228.0234
(Δ = 1.8 ppm)

Compound 5i: 1-(4-Methoxylphenyl-1,2,3-triazole-4-sulfonyl fluoride (5H)

1-azido-4-methoxybenzene (1 mmol, 149 mg).
Yield (brown crystalline solid) 113.8 mg; 44%.
N
N
N
SO
2
F
N
N
N
SO
2
F
MeO
131
SO2F : Br selectivity – 13 : 1.
1
H NMR (400 MHz, CDCl3) δ ppm: 8.57 (dt, J = 1.1, 0.5 Hz, 1H), 7.67 – 7.64 (m, 2H), 7.08 (dt, J
= 9.2, 0.5 Hz, 2H), 3.90 (t, J = 0.6 Hz, 3H).
13
C NMR (151 MHz, CDCl3) δ ppm: 141.3, 133.4, 130.9, 130.5, 126.5 (d, J = 3.0 Hz), 121.1, 21.4.
19
F NMR (376 MHz, CDCl3) δ ppm: 66.57 (d, J = 1.6 Hz).
APCI-MS (TOF): [M + H]
+
exact for C9H9FN3O3S m/z 258.0343, accurate m/z 258.0346
(Δ = 1.2 ppm).

Compound 5j: 1-(4-Nitrophenyl)-1,2,3-triazole-4-sulfonyl fluoride

Not observed

Compound 5k: 1-(3-(Methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl fluoride (5Q)

1-azido-3-(methoxymethyl)benzene (1 mmol, 163 mg).
Yield (brown liquid) 161 mg; 59%.
SO2F : Br selectivity – 4 : 1.
1
H NMR (600 MHz, CDCl3) δ ppm: 8.67 (d, J = 1.1 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.10 (d, J =
7.6 Hz, 1H), 7.03 (d, J = 0.7 Hz, 1H), 6.94 (dd, J = 8.1, 1.6 Hz, 1H), 4.44 (d, J = 0.7 Hz, 2H), 3.40
(s, 3H).
N
N
N
SO
2
F
O
2
N
N
O
N
N
SO
2
F
132
13
C NMR (151 MHz, CDCl3) δ ppm: 140.2 (d, J = 21.2 Hz), 130.2, 129.7, 129.1, 124.0, 119.9 (d,
J = 64.3 Hz), 118.2, 117.9, 74.0, 58.2.
19
F NMR (564 MHz, CDCl3) δ ppm: 66.62 (d, J = 1.2 Hz).
APCI-MS (TOF): [M + H]
+
exact for C10H11FN3O3S m/z 272.0500, accurate m/z 272.0498
(Δ = 0.7 ppm).

Compound 5l: 1-Benzyl-1,2,3-triazole-4-sulfonyl fluoride (5K)

(azidomethyl)benzene (1 mmol, 133 mg).
Yield (off-white crystalline solid) 227.9 mg; 95%.
SO2F : Br selectivity – 27 : 1.
1
H NMR (400 MHz, CDCl3) δ ppm: 8.08 (d, J = 1.2 Hz, 1H), 7.47 – 7.44 (m, 3H), 7.36 – 7.33 (m,
2H), 5.64 (s, 2H).
13
C NMR (151 MHz, CDCl3) δ ppm: 102.9 (d, J = 36.9 Hz), 94.8, 92.4, 92.2, 91.1, 90.5 (d, J = 3.3
Hz), 17.9.
19
F NMR (376 MHz, CDCl3) δ ppm: 66.30 (d, J = 1.2 Hz).
APCI-MS (TOF): [M + H]
+
exact for C9H9FN3O2S m/z 242.0394, accurate m/z 242.0393
(Δ = 0.4 ppm).

Compound 5m: 1-(4-Cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride

4-(azidomethyl)benzonitrile (1.0 mmol, 158.7 mg).
N
N
N
SO
2
F
Ph
N
N
N
N
SO
2
F
133
Yield (light-yellow solid) 221.8 mg; 83%.
SO2F : Br selectivity – 20 : 1.
1
H NMR (399.7 MHz, DMSO-d6) δ ppm: 9.60 (d, J = 1.1 Hz, 1H), 7.91 – 7.87 (m, 2H), 7.62 –
7.53 (m, 2H), 5.89 (s, 2H).
13
C{
1
H} NMR (100.5 MHz, DMSO-d6) δ ppm: 139.7, 138.1 (d, J = 35.1 Hz), 132.9, 132.0 (d, J =
3.1 Hz), 129.3, 118.4, 111.5, 53.4.
19
F NMR (376.0 MHz, DMSO-d6) δ ppm: 67.21 (d, J = 1.2 Hz).
APCI-MS (TOF): exact for C10H8SO2FN4 [M + H]
+
m/z 267.0347, accurate m/z 267.0340
(Δ = 2.6 ppm).

Compound 5n: Methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate

methyl 3-(azidomethyl)benzoate (1.0 mmol, 191.2 mg).
Yield (light yellow solid) 250.9 mg; 84%.
SO2F : Br selectivity – 18 : 1.
1
H NMR (399.7 MHz, DMSO-d6) δ ppm: 9.62 (d, J = 1.1 Hz, 1H), 8.07 (t, J = 1.5 Hz, 1H), 7.96
(dt, J = 7.8, 1.4 Hz, 1H), 7.75 – 7.68 (m, 1H), 7.57 (t, J = 7.7 Hz, 1H), 5.86 (s, 2H), 3.86 (s, 3H).
13
C{
1
H} NMR (100.5 MHz, DMSO-d6) δ ppm: 165.8, 138.0 (d, J = 35.0 Hz), 135.1, 133.5, 131.7
(d, J = 3.0 Hz), 130.2, 129.6, 129.4, 129.4, 53.6, 52.3.
19
F NMR (376.0 MHz, DMSO-d6) δ ppm: 67.22 (d, J = 1.2 Hz).
APCI-MS (TOF): exact for C11H11SFN3O4 [M + H]
+
m/z 300.0449, accurate m/z 300.0436
(Δ = 2.3 ppm).
N
N
N
MeO
2
C
SO
2
F
134

Compound 5o: 1-([1,1'-Biphenyl]-4-ylmethyl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5Q)

4-(2-azidoethyl)phenol (1 mmol, 209 mg).
Yield (off white solid) 307 mg; 97%.
SO2F : Br selectivity – 8 : 1.
1
H NMR (600 MHz, CDCl3) δ ppm: 8.14 (d, J = 1.1 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.61 – 7.56 (m,
2H), 7.50 – 7.44 (m, 2H), 7.41 (dd, J = 8.5, 2.0 Hz, 2H), 5.68 (s, 2H).
13
C NMR (151 MHz, CDCl3) δ ppm: 142.9, 139.7, 131.0, 129.0, 128.9, 128.3, 128.0, 127.9
(J = 2.8 Hz), 127.1, 127.0, 55.02.
19
F NMR (564 MHz, CDCl3) δ ppm: 66.34 (d, J = 1.3 Hz).
APCI-MS (TOF): [M + H]
+
exact for C15H13FN3O2S m/z 318.0707, accurate m/z 318.0714
(Δ = 2.2 ppm).

Compound 5r: 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride

(2-azidopropyl)benzene (1 mmol, 161 mg).
Yield (crystalline white solid) 227.5 mg; 85%.
SO2F : Br selectivity– 13 : 1.
N
N
N
SO
2
F
N
N
N
SO
2
F
135
1
H NMR (599.8 MHz, CDCl3) δ ppm: 7.61-7.60 (m, 1H), 7.57-7.56 (m, 3H), 7.47-7.44 (m, 2H),
7.38-7.35 (m, 1H), 5.85 (q, J = 7.2 Hz, 2H), 2.02 (d, J = 7.2 Hz, 3H)
13
C{
1
H} NMR (150.9 MHz, CDCl3) δ ppm: 135.5, 129.1, 129.0, 127.8, 127.5, 127.4, 60.9, 43.5,
20.3.
19
F NMR (376 MHz, CDCl3) δ ppm: 66.48 (d, J = 1.2 Hz).
APCI-MS (TOF): [M + H]
+
exact for C11H13N3SO2F m/z 270.0707, accurate m/z 270.0712
(Δ = 1.9 ppm).

Compound 5s: 1-((3s,5s,7s)-Adamantan-1-yl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5M)

(3s,5s,7s)-1-azidoadamantane (1 mmol, 177 mg).
Yield (off white crystalline solid) 281.6 mg; 99%.
SO2F : Br selectivity – 100 : 1.
1
H NMR (600 MHz, CDCl3) δ ppm: 8.27 (d, J = 1.2 Hz, 1H), 2.33 (s, 3H), 2.28 (d, J = 3.0 Hz, 6H),
1.87 – 1.77 (m, 7H).
13
C {
1
H} NMR (151 MHz, CDCl3) δ ppm: 139.3, 125.1 (d, J = 3.0 Hz), 62.3, 42.8, 35.5, 29.4.
19
F NMR (564 MHz, CDCl3) δ ppm: 66.30.
APCI-MS (TOF): [M + H]
+
exact for C12H17FN3O2S m/z 286.1020, accurate m/z 286.1022
(Δ = 0.7 ppm).

Compound 5t: 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride
N
N
N
SO
2
F
136

1-azidohexadecane (1.0 mmol, 267.5 mg).
Yield (light yellow solid) 344.4 mg; 92%.
SO2F : Br selectivity – 38 : 1.
1
H NMR (399.7 MHz, CDCl3) δ ppm: 8.24 (d, J = 1.1 Hz, 1H), 4.48 (t, J = 7.3 Hz, 2H), 1.98 (p, J
= 7.3 Hz, 2H), 1.25 (s, 26H), 0.87 (t, J = 6.9 Hz, 3H).
13
C{
1
H} NMR (100.5 MHz, CDCl3) δ ppm: 140.2 (d, J = 36.4 Hz), 128.1 (d, J = 3.0 Hz), 51.8, 32.1,
30.1, 29.83, 29.81, 29.80, 29.76, 29.70, 29.60, 29.50, 29.42, 29.0, 26.4, 22.8, 14.3.
19
F NMR (376.0 MHz, CDCl3) δ ppm: 66.39 (d, J = 1.1 Hz).
APCI-MS (TOF): exact for C18H34SO2FN3 [M + H]
+
m/z 376.2429, accurate m/z 376.2426
(Δ = 0.8 ppm).

Compound 5u: 1-(3-Phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride (5J)

(3-azidopropyll)benzene (1 mmol, 161 mg).
Yield (pale yellow crystalline solid) 263.4 mg; 98%.
SO2F : Br selectivity – 29 : 1.
1
H NMR (400 MHz, CDCl3) δ ppm: 8.10 (d, J = 1.2 Hz, 1H), 7.31 – 7.17 (m, 3H), 7.15 – 7.10 (m,
2H), 4.44 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.32 (p, J = 7.2 Hz, 2H).
13
C {
1
H} NMR (101 MHz, CDCl3) δ ppm: 139.3, 129.0, 128.5, 128.3, 128.3, 126.9, 50.9, 32.5,
31.2.
N
N
N
SO
2
F
14
N
N
N
SO
2
F
Ph
137
19
F NMR (376 MHz, CDCl3) δ ppm: 66.38.
APCI-MS (TOF): [M + H]
+
exact for C11H13FN3O2S m/z 270.0707, accurate m/z 270.0711
(Δ = 1.5 ppm).

Compound 5v: 1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl fluoride

2-(4-azidobutyl)isoindoline-1,3-dione (1 mmol, 244 mg).
Yield (off-white solid) 244 mg; 69%.
SO2F : Br selectivity – 56 : 1.
1
H NMR (399.7 MHz, DMSO-d6) δ ppm: 9.47 (d, J = 1.0 Hz, 1H), 7.90 – 7.78 (m, 4H), 4.55 (t, J
= 7.1 Hz, 2H), 3.61 (t, J = 6.8 Hz, 2H), 2.00 – 1.87 (m, 2H), 1.67 – 1.52 (m, 2H).
13
C{
1
H} NMR (100.5 MHz, DMSO-d6) δ ppm: 168.0, 137.7 (d, J = 34.8 Hz), 134.4, 131.4 (d, J =
2.9 Hz), 131.4, 123.0, 50.4, 36.7, 26.5, 24.8.
19
F NMR (376.0 MHz, DMSO-d6) δ ppm: 67.17 (d, J = 1.1 Hz).
APCI-MS (TOF): exact for C14H14SFN4O4 [M + H]
+
m/z 353.0714, accurate m/z 353.0714
(Δ < 0.1 ppm).

Compound 5w: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-sulfonyl fluoride

(2-azidoethoxy)(tert-butyl)dimethylsilane (1 mmol, 201 mg).
Yield (white solid) 180 mg; 59%.
N
N
N
SO
2
F
N
O
O
N
N
N
SO
2
F
O
Si
138
SO2F : Br selectivity – 91 : 1.
1
H NMR (399.7 MHz, CDCl3) δ ppm: 8.36 (d, J = 1.1 Hz, 1H), 4.64 – 4.58 (m, 2H), 4.03 – 3.98
(m, 2H), 0.84 (d, J = 0.7 Hz, 9H), –0.01 (d, J = 0.8 Hz, 6H).
13
C{
1
H} NMR (100.5 MHz, CDCl3) δ ppm: 139.9 (d, J = 36.7 Hz), 129.8 (d, J = 2.9 Hz), 61.3, 53.8,
25.8, 18.2, –5.6.
19
F NMR (376.0 MHz, CDCl3) δ ppm: 66.48 (d, J = 1.1 Hz).
APCI-MS (TOF): exact for C10H21FN3O3SSi [M + H]
+
m/z 310.1051, accurate m/z 310.1060
(Δ = 2.9 ppm).

139
Appendix E: Characterization of Sulfonyl Fluoride Triazoles

Compound 5a: 1-Phenethyl-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.3
1
H NMR spectrum of 1-phenethyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Figure 3.4
13
C NMR spectrum of 1-phenethyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
N
N
N
SO
2
F
140

Figure 3.5
19
F NMR spectrum of 1-phenethyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Compound 5b: 1-(4-Methoxyphenethyl)-1,2,3-triazole-4- sulfonyl fluoride

Figure 3.6
1
H NMR spectrum of 1-(4-methoxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.
N
N
N
SO
2
F
O
141

Figure 3.7
13
C NMR spectrum of 1-(4-methoxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.

Figure 3.8
19
F NMR spectrum of 1-(4-methoxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.
142
Compound 5c: 1-(4-Fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.9
1
H NMR spectrum of 1-(4-fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3.

Figure 3.10
13
C NMR spectrum of 1-(4-fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.
N
N
N
SO
2
F
F
143

Figure 3.11
19
F NMR spectrum of 1-(4-fluorophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.

Compound 5d: 1-(4-Nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.12
1
H NMR spectrum of 1-(4-nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6.
N
N
N
SO
2
F
O
2
N
144

Figure 3.13
13
C NMR spectrum of 1-(4-nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6.

Figure 3.14
19
F NMR spectrum of 1-(4-nitrophenethyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6.
145
Compound 5e: 1-(4-Cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.15
1
H NMR spectrum of 1-(4-cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.

Figure 3.16
13
C NMR spectrum of 1-(4-cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.
- 1 .0 - 0 .5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0
δ ( ppm )
2.00
2.00
1.98
2.05
1.00
3.38
3.39
3.41
4.74
4.75
4.77
7.24
7.25
7.25
7.26
7.26 CHCl3
7.62
7.62
7.63
7.63
8.08
8.08
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0 2 0 0 2 1 0
δ ( ppm )
36.27
52.10
77.16 CDCl3
112.02
118.39
128.57
128.59
129.58
133.04
140.09
140.33
141.16
N
N
N
N
SO
2
F
146

Figure 3.17
19
F NMR spectrum of 1-(4-cyanophenethyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.

Compound 5f: 1-(4-Acetamidophenethyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.18
1
H NMR spectrum of 1-(4-acetamidophenethyl)-1,2,3-triazole-4-sulfonyl
fluoride in DMSO-d6.
- 1 0 0 - 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
δ ( ppm )
6 6 . 5 5
6 6 . 5 5
N
N
N
SO
2
F
N
H
O
147

Figure 3.19
13
C NMR spectrum of 1-(4-acetamidophenethyl)-1,2,3-triazole-4-sulfonyl
fluoride in DMSO-d6.

Figure 3.20
19
F NMR spectrum of 1-(4-acetamidophenethyl)-1,2,3-triazole-4-sulfonyl
fluoride in DMSO-d6.

148
Compound 5g: 1-(4-Hydroxyphenethyl)-1,2,3-triazole-4-sulfonyl fluoride (5E)

Figure 3.21
1
H NMR spectrum of 1-(4-hydroxylphenethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

Figure 3.22
13
C NMR spectrum of 1-(4-hydroxylphenethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.
N
N
N
SO
2
F
HO
149

Figure 3.23
19
F NMR spectrum of 1-(4-hydroxylphenethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

Compound 5h: 1-Phenyl-1,2,3-triazole-4-sulfonyl fluoride (5G)

Figure 3.24
1
H NMR spectrum of 1-phenyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.
N
N
N
SO
2
F
150

Figure 3.25
13
C NMR spectrum of 1-phenyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Figure 3.26
19
F NMR spectrum of 1-phenyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

151
Compound 5i: 1-(4-Methoxylphenyl-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.27
1
H NMR spectrum of 1-(4-methoxylphenyl)-1,2,3-triazole-4-sulfonyl fluoride
inCDCl3.

Figure 3.28
13
C NMR spectrum of 1-(4-methoxylphenyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.
N
N
N
SO
2
F
O
152

Figure 3.29
19
F NMR spectrum of 1-(4-methoxylphenyl)-1,2,3-triazole-4-sulfonyl fluoride
in CDCl3.

Compound 5k: 1-(3-(Methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl fluoride (5Q)

Figure 3.30
1
H NMR spectrum of 1-(3-(methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.
N
N
N
SO
2
F
O
153

Figure 3.31
13
C NMR spectrum of 1-(3-(methoxymethyl)phenyl)-1H-1,2,3-triazole-4-
sulfonyl fluoride in CDCl3.

Figure 3.32
19
F NMR spectrum of 1-(3-(methoxymethyl)phenyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

154
Compound 5l: 1-Benzyl-1,2,3-triazole-4-sulfonyl fluoride (5K)

Figure 3.33
1
H NMR spectrum of 1-benzyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Figure 3.34
13
C NMR spectrum of 1-benzyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

N
N
N
SO
2
F
155

Figure 3.35
19
F NMR spectrum of 1-benzyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Compound 5m: 1-(4-Cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.36
1
H NMR spectrum of 1-(4-cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6.
- 0 .5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0
δ ( ppm )
1.99
2.36
2.18
1.00
2.50 DMSO-d5
5.89
7.57
7.58
7.58
7.59
7.59
7.88
7.88
7.89
7.90
7.90
7.91
9.60
9.60
N
N
N
N
SO
2
F
156

Figure 3.37
13
C NMR spectrum of 1-(4-cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6.

Figure 3.38
19
F NMR spectrum of 1-(4-cyanobenzyl)-1,2,3-triazole-4-sulfonyl fluoride in
DMSO-d6.
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0 2 0 0 2 1 0
δ ( ppm )
39.52 DMSO-d6
53.42
111.46
118.44
129.26
132.00
132.04
132.87
137.91
138.26
139.68
- 1 0 0 - 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
δ ( ppm )
6 7 . 2 0
6 7 . 2 1
157
Compound 5n: Methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-yl)methyl)benzoate

Figure 3.39
1
H NMR spectrum of methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-
yl)methyl)benzoate in DMSO-d6.

Figure 3.40
13
C NMR spectrum of methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-
yl)methyl)benzoate in DMSO-d6.
- 0 .5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0
δ ( ppm )
3.27
1.98
1.10
1.00
1.15
1.00
1.00
2.50 DMSO-d5
3.86
5.86
7.55
7.57
7.59
7.70
7.70
7.70
7.72
7.95
7.95
7.96
7.97
7.97
7.98
8.06
8.07
8.07
9.62
9.62
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0 2 0 0
δ ( ppm )
39.52 DMSO-d6
52.31
53.58
129.36
129.44
129.55
130.24
131.67
131.70
133.46
135.06
137.86
138.21
165.78
N
N
N
SO
2
F
MeO
2
C
158

Figure 3.41
19
F NMR spectrum of methyl 3-((4-(fluorosulfonyl)-1,2,3-triazol-1-
yl)methyl)benzoate in DMSO-d6.

Compound 5o: 1-([1,1'-Biphenyl]-4-ylmethyl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5Q)

Figure 3.42
1
H NMR spectrum of 1-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.
- 1 0 0 - 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
δ ( ppm )
6 7 . 2 2
6 7 . 2 2
N
N
N
SO
2
F
159

Figure 3.43
13
C NMR spectrum of 1-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

Figure 3.44
19
F NMR spectrum of 1-([1,1'-biphenyl]-4-ylmethyl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

160
Compound 5r: 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.45
1
H NMR spectrum of 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

Figure 3.46
13
C NMR spectrum of 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.
N
N
N
SO
2
F
161

Figure 3.47
19
F NMR spectrum of 1-(1-phenylpropan-2-yl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

Compound 5s: 1-((3s,5s,7s)-Adamantan-1-yl)-1H-1,2,3-triazole-4-sulfonyl fluoride (5M)

Figure 3.48
1
H NMR spectrum of 1-((3s,5s,7s)-adamantan-1-yl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.
N
N N
SO
2
F
162

Figure 3.49
13
C NMR spectrum of 1-((3s,5s,7s)-adamantan-1-yl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

Figure 3.50
19
F NMR spectrum of 1-((3s,5s,7s)-adamantan-1-yl)-1,2,3-triazole-4-sulfonyl
fluoride in CDCl3.

163
Compound 5t: 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.51
1
H NMR spectrum of 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Figure 3.52
13
C NMR spectrum of 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

- 2 - 1 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4
δ ( ppm )
3.17
26.50
2.01
1.99
1.00
0.86
0.87
0.89
1.25
1.29
1.31
1.35
1.94
1.96
1.98
2.00
2.01
4.46
4.48
4.50
7.26 CHCl3
8.24
8.24
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0 2 0 0 2 1 0
δ ( ppm )
14.27
22.83
26.44
28.98
29.42
29.50
29.60
29.70
29.76
29.80
29.81
29.83
30.13
32.06
51.76
77.16 CDCl3
128.08
128.11
139.97
140.34
N
N
N
SO
2
F
14
164

Figure 3.53
19
F NMR spectrum of 1-hexadecyl-1,2,3-triazole-4-sulfonyl fluoride in CDCl3.

Compound 5u: 1-(3-Phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride (5J)

Figure 3.54
1
H NMR spectrum of 1-(3-phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3.
- 1 0 0 - 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
δ ( ppm )
6 6 . 3 9
6 6 . 4 0
N
N
N
SO
2
F
165

Figure 3.55
13
C NMR spectrum of 1-(3-phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3.

Figure 3.56
19
F NMR spectrum of 1-(3-phenylpropyl)-1,2,3-triazole-4-sulfonyl fluoride in
CDCl3.
166
Compound 5v: 1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.57
1
H NMR spectrum of 1-(4-(1,3-dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-
sulfonyl fluoride in DMSO-d6.

Figure 3.58
13
C NMR spectrum of 1-(4-(1,3-dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-
sulfonyl fluoride in DMSO-d6.
- 0 .5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0
δ ( ppm )
2.21
2.01
2.16
2.00
4.37
1.00
1.56
1.57
1.59
1.60
1.61
1.63
1.89
1.91
1.92
1.93
1.95
1.97
2.50 DMSO-d5
3.59
3.61
3.62
4.53
4.55
4.56
7.82
7.82
7.82
7.83
7.83
7.84
7.84
7.85
7.85
7.86
7.86
7.86
7.86
7.87
7.87
9.47
9.47
- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0 2 0 0 2 1 0
δ ( ppm )
24.81
26.50
36.70
39.52 DMSO-d6
50.42
123.02
131.36
131.39
131.67
134.37
137.56
137.91
168.02
N
N
N
SO
2
F
N
O
O
167

Figure 3.59
19
F NMR spectrum of 1-(4-(1,3-dioxoisoindolin-2-yl)butyl)-1,2,3-triazole-4-
sulfonyl fluoride in DMSO-d6.

Compound 5w: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-4-sulfonyl fluoride

Figure 3.60
1
H NMR spectrum of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-
4-sulfonyl fluoride in CDCl3.
- 1 0 0 - 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
δ ( ppm )
6 7 . 1 7
6 7 . 1 7
- 1 .0 - 0 .5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5 3 . 0 3 . 5 4 . 0 4 . 5 5 . 0 5 . 5 6 . 0 6 . 5 7 . 0 7 . 5 8 . 0 8 . 5 9 . 0 9 . 5 1 0 . 0 1 0 . 5 1 1 . 0
δ ( ppm )
6.03
9.19
1.96
1.97
1.00
-0.02
-0.01
0.84
0.84
3.99
4.00
4.01
4.01
4.02
4.60
4.61
4.62
7.26 CHCl3
8.35
8.36
N
N
N
SO
2
F
O
Si
168

Figure 3.61
13
C NMR spectrum of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-
4-sulfonyl fluoride in CDCl3.

Figure 3.62
19
F NMR spectrum of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-triazole-
4-sulfonyl fluoride in CDCl3.

- 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 1 8 0 1 9 0 2 0 0 2 1 0
δ ( ppm )
-5.55
18.19
25.77
53.83
61.29
77.16 CDCl3
129.74
129.77
139.71
140.07
- 1 0 0 - 9 0 - 8 0 - 7 0 - 6 0 - 5 0 - 4 0 - 3 0 - 2 0 - 1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
δ ( ppm )
6 6 . 4 8
6 6 . 4 8
169
Distribution of Credit

Chapter Three was done in collaboration with Dr. Dmitry Eremin, and Kevin Vargas based
on work previously done in our lab by Dr. Joice Thomas. Optimization of both sulfonyl
fluoride and brominated conditions was done by Kevin Vargas. Although I was the lead in
synthesizing the scope for the sulfonyl fluoride functionalized triazoles, starting azides in
addition to some products were also synthesized by Kevin Vargas and Dr. Dmitry Eremin.

170
Chapter 4. Cannabinoid Type II Receptor
4.1a Introduction to Endocannabinoid System

The endocannabinoid system (ECS) is a complex biological system that plays a key
role in the regulation of numerous physiological processes and is present in many types of
tissue found throughout the body.
84-89
The naturally occurring ligands that bind to the
cannabinoid receptors are similar in structure to compounds found in the cannabis sativa
plant and are known as endocannabinoids.
90
These compounds, anandamide, and 2-
arachidonoylglycerol (2-AG) are both synthesized and degraded by the human body.
91-96

The identification and characterization of anandamide by Dr. Raphael Mechoulam sparked
the discovery and investigation into the ECS. Since its discovery, there has been growing
interest in the therapeutic potential of cannabinoids and new drugs targeting the ECS.
There are two main types of cannabinoid receptors; cannabinoid type I (CB1) which
is primarily found in the brain and central nervous system and cannabinoid type II (CB2)
which is primarily found in peripheral tissues including immune cells.
97-99
The CB1 receptor
was first cloned in 1990 with the CB2 receptor shortly following in 1993 and shares a 44%
sequence identity.
89, 97, 100
This similarity in sequence identity is likely why it is difficult to
selectively target one of the receptors. The binding of endocannabinoids to these receptors
triggers a wide range of physiological responses. Compounds that enhance the action of
endocannabinoids through methods such as inhibiting the degradation of the
endocannabinoid have shown promise in the clinical treatment of depression, anxiety, and
pain.
101
Cannabidiol (CBD), a cannabinoid found in the cannabis sativa plant whose structure
and stereochemistry were elucidated by Mechoulam thirty years after its discovery in 1940,
has been shown to have anti-epileptic, analgesic, and anti-inflammatory properties.
97, 102-106

171
Whereas tetrahydrocannabinol (THC), the first structurally elucidated compound found in
the cannabis sativa plant and primary psychoactive constituent, has been demonstrated to
have anti-emetic properties and is a partial agonist of both cannabinoid receptors.
107-111

Synthetic compounds targeting both receptors have been developed with those binding to
the CB1 receptor being used to treat obesity and those binding to CB2 being used to treat
inflammation and diseases impacting the immune system.
112, 113

It has been suggested that the ECS is involved in the pathogenesis of diseases in
addition to the regulation of physiological processes. Research details the potential role of
the ECS in the development and progression of neurodegenerative diseases, mood disorders,
and cancer.
114-118
It has also been shown that the immune response and inflammation can
be modulated by the ECS. Effectively and selectively targeting the ECS is a promising avenue
for the treatment of numerous diseases and inflammation.
Despite the great number of advances made over the past few decades since the
discovery of the ECS, there remain many unsolved mysteries about the system and its role in
physiological processes. The precise mechanisms through which endocannabinoids
modulate specific physiological processes are still largely not understood. Additionally, the
current drugs available targeting the ECS often have limited efficacy and significant side
effects likely due to selectivity issues.

4.1b Introduction to the Cannabinoid Type II Receptor

The cannabinoid type II (CB2) receptor is a G protein-coupled receptor (GPCR) that
shares the common feature of seven transmembrane domains with many other GPCRs in
addition to its extracellular N-terminus and intracellular C-terminus.
84, 98, 99, 119
The CB2
172
receptor has been found to be activated by both endocannabinoids such as 2-AG which is a
full agonist for both receptors as well as exogenous cannabinoids such as delta-9-
tetrahydrocannabinol (THC) which is the main psychoactive constituent of marijuana where
it is a weak antagonist despite being a known CB1 agonist.
84, 89, 120
Notably, CB2 agonists have
been shown to be neuroprotective and do not have the psychotropic effects that are seen
with THC and CB1 agonists.
121
It has also been demonstrated that the receptor can alter the
distribution of other GPCRs in addition to modulating its own signaling which suggests it
may play a role in the general modulation of GPCR signaling.
122

Similarly, to the CB1 receptor which is found predominantly in the central nervous
system (CNS), the CB2 receptor can also be found throughout the CNS to a lesser extent. It is
primarily expressed in immune cells but has also been found in other peripheral tissues
primarily when there is active inflammation suggesting that it plays a role in the regulation
of a wide variety of physiological processes.
100, 123
The distribution of the receptor has been
shown to be impacted by numerous factors such as age and sex. Its ability to modulate
immune responses and inflammation has been demonstrated making it an appealing target
for the treatment of various inflammatory diseases such as osteoarthritis and rheumatoid
arthritis.
124
There have been recent studies suggesting that the CB2 receptor may also play
a role in bone metabolism, neurological processes, and the regulation of cardiovascular
function.
125-127

As evidenced by the unusual distribution of CB2 receptors throughout the human
body and its potential role in various physiological processes it is a fascinating target for
drug discovery. The increased expression of the receptor in inflammation and diseases
impacting the immune system suggests it may play a key role in the progression of the
173
conditions.
128
Although its role in human health and disease pathogenesis is not fully
understood, it is a promising target for new pharmaceuticals aimed at the treatment of a
variety of medical conditions.
129

4.2 Creation of Virtual Library

The virtual libraries for both the isoxazole and triazole libraries were built using the
Zbb “building block library” from ZINC15 database, Enamine, ChemDiv, and Life Chemicals.
Azide-containing compounds as well as their alcohol and halide precursors were used to
generate the triazole library. Whereas aldehydes were used as oxime precursors to create
the isoxazole library. These compounds were enumerated and then enumerated together
with Br-ESF to generate a library of sulfonyl fluoride functionalized heterocycles. Primary
and secondary amines were then selected from the building block libraries and enumerated
with the previously generated heterocyclic compounds to form a library of sulfonamides
created with SuFEx combining the results of the sulfonyl fluoride heterocycles with available
amines (Schemes 4.1 – 4.2).
Scheme 4.1 Building Blocks for Triazole Library

Scheme 4.2 Building Blocks for Isoxazole Library

R
1
N
N
N
S
O
O
H
N
R
2
H
2
N-R
2
+
SO
2
F
Br
+
R
1
OH
R
1 R
1
O
N
S
O
O
H
N
R
2
H
2
N-R
2
+
SO
2
F
Br
+
H
O
174
The resulting compounds were filtered using Lipinski’s rule considering molecular
weight, log P, number of hydrogen bond donors (HBDs), and number of hydrogen bond
acceptors (HBAs). Compounds with a molecular weight >500 Da, log P >5, having more than
five HBDs, or more than ten HBAs were eliminated to create a library of approximately 140
million compounds.
130
All chemical fingerprint searches and enumeration of the final
compounds were performed in ICM Molsoft Pro v3.8.
131

To create a 4D structural model, the known crystal structure of the CB2 receptor was
used with antagonist AM10257 and a ligand-guided receptor optimization algorithm was
used to account for the flexibility of the binding site during the binding of ligands.
119, 132
Two
chemically diverse sets of known CB2 receptor ligands with high binding affinities were used
to generate both a known high-affinity agonist and a known high-affinity antagonist model.
These were then used along with a CB2-specific decoy compound library to evaluate >100
structural conformers to discriminate between the ligands and the decoys.
133

In order to select the best models, the receiver operating characteristic curve (ROC)
and area under the curve (AUC) were used, and the optimized models showed higher affinity
for the CB2 ligands than the crystal structure of the receptor. The two best structural models
were used alongside the crystal structure of the receptor to generate a 4D structural model
that allowed for multiple conformations to be screened in one run.
134

175

Figure 4.1 Schematic representation of library design procedure employed to develop the
two compound libraries using click reactions.*

*Procedures with chemical fingerprinting searches are shown in orange arrows, and the
steps involving chemical enumeration are depicted with purple arrows. Refer to the tables
shown below (Tables 4.1-4.9) for reactions and exclusions included in the procedure.
Table 4.1 Reactions Table
176

Table 4.2 Moieties Excluded from Azide Search from the Building Block Library

1

2

3

4

5

6

7

177

Table 4.3 Moieties Excluded from Azide Intermediate Generated After Halide Search from
the Building Block Library

Table 4.4 Moieties Excluded from Azide Intermediate Generated After Alcohol Search from
the Building Block Library

178

Table 4.5 Moieties Excluded from Carbonyl Search from the Building Block Library

Table 4.6 Moieties Excluded from Primary Amines Search from the Building Block Library
for Fluorotriazole Library

Table 4.7 Moieties Excluded from Secondary Amines Search from the Building Block
Library for Fluorotriazole Library

Table 4.8 Moieties Excluded from Primary Amines Search from the Building Block Library
for Fluorotriazole Library
179

Table 4.9 Moieties Excluded from Secondary Amines Search from the Building Block
Library for Fluorotriazole Library

(Legend: * : any atom; a : any aromatic atom; X : any halogen atom; ! : not; Q: any but not carbon or
hydrogen)

Scheme 4.3 Steps for Fluorotriazole Reaction

Scheme 4.4 Steps for Isoxazole reaction:
1. Download the building block library
2. Search for precursors to azides in the building block library:
a) halides
b) alcohol
3. Make reaction (enumeration/generation of compounds based on reaction):
a) Halide-azide (1
st
row in Rxn1Reaction table)
b) Alcohol-azide (2
nd
row in Rxn1Reaction table)
4. Exclusion of compounds containing certain moieties from:
a) Halide-azide
b) Alcohol-azides
5. Search for azides in the building block library with certain exclusions
6. Append azides from all three sources, and delete all azides with Mol weight > 350
and atom count < 5
7. Make reaction/enumeration/generation of intermediate compounds (3
rd
row in
Rxn1Reaction table)
8. Search for primary and secondary amines with respective exclusions in the
building block library
9. Append primary and secondary amines and delete amines with Mol weight > 350
10. Final make reaction/enumeration/generation of final compounds and filter all
molecules >500 Mol weight (4th row in Rxn1Reaction table)
180

4.3 Virtual Ligand Screening

The traditional drug discovery pathway has remained largely unchanged for years
and is known to be lengthy and costly often taking years and costing millions of dollars to
bring pharmaceuticals from bench to bedside.
135-137
Traditionally the biological
pathogenesis of the disease and its mechanism are required after which potential drug
targets are identified. This traditional methodology has left limited treatment options for
several common diseases such as Alzheimer’s where the cause and progression and
biological targets are not yet fully understood. Only in the case where pathogenesis is
determined and potential biological targets are identified can rationally designed
compounds proceed with the investigation and synthesis of lead compounds
138, 139
After the
initial discovery of a lead compound showing promising binding activity, the compound is
then tweaked at numerous positions indicating which bonds are critical to the binding of the
compound. The lead compound then often goes through many iterations of synthesizing new
compounds that are variations of the lead compound, then collecting and comparing binding
data to the original compound to determine which modifications are advantageous. Despite
this traditional approach to drug discovery being expensive and time intensive it has
1. Download the building block library
2. Search for precursor aldehydes and filter out aldehydes with Mol weight > 350
3. Make reaction/enumeration/generation of intermediate compounds (1
st
row in
Rxn2Reaction table)
4. Make reaction/enumeration/generation of intermediate compounds (2
nd
row in
Rxn2Reaction table)
5. Search for primary and secondary amines with respective exclusions in the
building block library
6. Append primary and secondary amines and delete amines with Mol weight > 350
7. Final make reaction/enumeration/generation of final compounds and filter all
molecules >500 Mol weight (3
rd
row in Rxn2Reaction table)
181
produced many effective medications throughout the years. Modern developments,
however, have made significant advances that make the drug discovery process timelier and
more cost-effective.
Virtual ligand screening (VLS) is a computational method that can be used to predict
the interactions between drug candidates and their biological targets. It is an effective way
to rapidly screen large compound libraries in silico which reduces the time and cost
traditionally associated with drug discovery.
140, 141
After the discovery of the three-
dimensional structure of a protein, a computational model of it can be created and used to
predict the binding of compounds.
Databases such as the Protein Data Bank (PDB) provide information on the protein
structure as well as their known interactions improving the accuracy of the screening for
new potential ligands. The accuracy of the in-silico modeling is dependent on the quality of
the structural data and the software used for the docking of compounds. Once the model of
the target protein and compound library is created, the compounds can be screened and the
binding of the compounds can then be predicted, allowing for compounds that are likely to
be effective to be synthesized. By eliminating compounds unlikely to bind in addition to
visualizing key structural elements within the hits VLS can lower the cost of materials to
synthesize lead compounds and speed up the process of finding these compounds. Structure-
based screening as described has been validated for several classes of targets and has
generated viable hits and lead compounds.
142-145

Approximately 140 million heterocyclic compounds were docked in the 4D CB2
receptor model using the criteria for in-house synthesis based on the selected reactions to
create a diverse library with synthetic feasibility (Tables 4.1-4.9 and Schemes 4.3-4.4 ).
182
Using energy-based docking, binding scores were generated for each ligand and -30 was
used as the score threshold. Based on the initial binding score, the top 170,000 compounds
from each reaction library were re-docked with a higher effort and then the top 5,000
compounds from each library (with the lowest docking scores) were selected for further
evaluation. Based on docking scores, ability to form hydrogen bonds with key residues,
chemical novelty, and library diversity, 500 compounds were selected as potential synthetic
candidates.

4.4 Selection and Synthesis of Drug Candidates

The top 500 compounds from the VLS were then scored based on synthetic feasibility.
Due to synthetic ease halide precursors for azides were preferred over alcohols for the
formation of triazoles. Primary amines were preferred over secondary for the final SuFEx
reaction, and steric concerns were considered as well as the purchase price and availability
of starting materials. 14 compounds were then selected based on these criteria for in-house
synthesis and 11 of which were successfully fully synthesized with >95% purity. *

*BRI-13107 was isolated as the chlorinated isoxazole although numerous synthetic procedures were
attempted to form the non-chlorinated version.

4.5 Synthesis of Selected Compounds

Synthesis of BRI-13900

183

A 50 mL round-bottom flask was charged with 1-([1,1'-biphenyl]-4-yl) ethan-1-ol (1.0 eq.,
350 mg, 1.77 mmol) and dissolved in 5mL toluene. DPPA (1.2 eq., 583 mg, 2.12 mmol) and
DBU (1.5 eq., 403 mg, 2.65 mmol) were added at room temperature. The reaction mixture
was stirred for 24 h and then additional DPPA (1.2 eq., 583 mg, 2.12 mmol) and DBU (1.5 eq.,
403 mg, 2.65 mmol) were added. The reaction mixture was stirred for an additional 24 h
then extracted to DCM (3x10 mL) and the combined organic layers were washed with H2O
(3x10 mL) and brine (1x10 mL) then dried over sodium sulfate. After rotary evaporation of
the solvent, the azide (1) was obtained as a clear oil in 96% (272 mg) yield.
1
H

NMR (400 MHz, Chloroform-d; δ, ppm): 7.65 – 7.56 (m, 4H), 7.54 – 7.31 (m, 5H), 4.67 (d, J
= 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 141.18, 140.67, 139.95, 128.93, 127.61, 127.57,
127.22, 126.94, 60.94, 21.69.
APCI -MS (TOF): measured m/z 223.1107, calcd for C14H13N3 [M]
•+
m/z 223.1104
(Δ = 1.3 ppm).

OH N
3
+ +
N
N
O
P
O
N
3
O
Toluene
1
2
184
In a 10 mL reaction tube, 1 (1.0 eq., 250 mg, 1.12 mmol) and Br-ESF (3.0 eq., 635 mg, 3.36
mmol) were suspended in 1 mL dimethyl formamide and stirred at 80˚C for 24 h.
Subsequently, the reaction mixture was extracted with DCM (3x10 mL) and washed with
brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent
yielded the crude mixture. Subsequent purification by column chromatography (SiO2, 40%
→ 60% DCM in hexanes) yielded the triazole (2) as an off-white solid (80%, 296 mg).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 8.09 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H),
7.60 – 7.56 (m, 2H), 7.50 – 7.36 (m, 5H), 5.96 (q, J = 7.1 Hz, 1H), 2.11 (d, J = 7.1 Hz, 3H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 142.69, 139.94, 136.48, 129.98 (d, J = 1.0 Hz),
129.05, 128.29, 128.02, 127.39, 127.23, 125.74 (d, J = 1.4 Hz), 61.88, 21.19.
19
F NMR (376 MHz, Chloroform-d; δ, ppm): 66.29.
APCI -MS (TOF): measured m/z 331.0794, calcd for C16H14FN3O2S [M]
•+
m/z 331.0785
(Δ = 2.7 ppm).

A 10 mL reaction tube was charged with 2 (1.0 eq., 100 mg, 0.30 mmol), 4-(pyrrolidin-2-yl)
pyrimidine (2.0 eq., 90 mg, 0.60 mmol), and triethylamine (2.0 eq., 0.9 mL, 0.60 mmol). After
addition of 1 mL acetonitrile, the reaction mixture was stirred for 24 h at 80˚C. The crude
mixture was obtained by rotary evaporation of the solvent and subjected to purification by
column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (3, BRI-13900) as
3 2
185
a mixture of two diastereomers with two enantiomers each, as an off-white solid (32%, 44
mg).
1
H NMR (400 MHz, DMSO-d6; δ, ppm): 9.15 (s, 1H), 9.11 (d, J = 1.3 Hz, 1H), 8.81 (d, J = 5.3, 0.8
Hz, 1H), 7.71 – 7.62 (m, 5H), 7.49 – 7.43 (m, 4H), 7.40 – 7.33 (m, 1H), 6.12 (q, J = 7.1 Hz, 1H),
4.87 (apparent ddd, 1H), 3.68 – 3.59 (m, 1H), 3.51 – 3.39 (m, 1H), 2.09 – 1.97 (m, 4H), 1.95 –
1.86 (m, 1H), 1.85 – 1.76 (m, 1H), 1.69 – 1.58 (m, 1H).
13
C NMR (101 MHz, DMSO-d6; δ, ppm): 170.08, 158.08, 157.67, 143.91, 140.23, 139.47,
139.27, 128.95, 127.66, 127.17, 127.02, 126.90, 126.74, 118.53, 63.68, 60.11, 49.77, 33.13,
23.87, 20.66.
APCI -MS (TOF): measured m/z 461.1773, calcd for C24H25N6O2S [M+H]
+
m/z 461.1754
(Δ = 4.1 ppm).

Synthesis of BRI-13901

A 50 mL round bottomed flask was charged with 1-chloro-4-(chloro(phenyl)methyl)
benzene (1.0 eq., 1.00 g, 4.22 mmol) in 10 mL dimethyl formamide. Sodium azide (2.0 eq.,
548 mg, 8.43 mmol) was added to the solution at room temperature and stirred for 10 h.
Upon completion, the reaction mixture was extracted to Et2O (3x20 mL), and the combined
organic layers were washed with water (3x10mL) and brine (1x10mL) then dried over
sodium sulfate. The crude mixture was obtained by rotary evaporation of the solvent and
4
186
subjected to purification by column chromatography (SiO2, 30% DCM in hexanes) to obtain
the product (4) as a yellow oil (75%, 770 mg).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 7.55 – 7.06 (m, 9H), 5.68 (s, 1H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 138.90, 137.95, 133.68, 128.65, 128.63, 128.49,
128.11, 127.15, 67.59.
APCI -MS (TOF): measured m/z 243.0558, calcd for C13H10N3Cl [M]
•+
m/z 243.0558 (Δ = 0
ppm).

In a 10 mL reaction tube, 4 (1.0 eq., 770 mg, 3.16 mmol) and Br-ESF (3.0 eq., 1.79 g, 9.48
mmol) were suspended in 4 mL dimethyl formamide and stirred at 80˚C for 24 h.
Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with
brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent
yielded the crude mixture. Subsequent purification by column chromatography (SiO2, 40%
DCM in Hexanes) yielded the triazole (5) as a yellow oil (81%, 1.17 g).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 8.13 (s, 1H), 7.44 – 7.39 (m, 3H), 7.39 – 7.35 (m,
2H), 7.18 – 7.12 (m, 3H), 7.11 – 7.03 (m, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 135.87, 135.70, 134.96, 129.88, 129.76, 129.74,
129.37, 128.82, 128.12, 127.48, 68.96.
19
F NMR (376 MHz, Chloroform-d; δ, ppm): 66.58.
5
4
187
APCI -MS (TOF): measured m/z 351.0243, calcd for C15H11ClFN3O2S [M]
•+
m/z 351.0239
(Δ = 1.1 ppm).

A 10 mL reaction tube was charged with 5 (1.0 eq., 100 mg, 0.28 mmol), (octahydro-1H-
indol-2-yl) methanol (2.0 eq., 88 mg, 0.57 mmol), and triethylamine (2.0 eq., 0.8 mL,
0.57 mmol). After addition of 1 mL acetonitrile, the reaction mixture was stirred for 20 h at
80˚C. The crude mixture was obtained by rotary evaporation of the solvent and subjected to
purification by column chromatography (SiO2, 5% → 10% MeOH in DCM) to obtain the
product (6, BRI 13901) as two diastereomers as an off-white solid (23%, 32 mg).
1
H NMR (400 MHz, DMSO-d6; δ, ppm): 8.91 (s, 1H), 7.52 – 7.47 (m, 2H), 7.46 – 7.38 (m, 4H),
7.33 – 7.26 (m, 2H), 7.26 – 7.19 (m, 2H), 3.73 – 3.60 (m, 4H), 3.49 (dd, J = 10.4, 6.5 Hz, 1H),
2.03 – 1.85 (m, 1H), 1.78 – 1.65 (m, 2H), 1.63 – 1.52 (m, 2H), 1.51 – 1.30 (m, 4H), 1.27 – 1.05
(m, 2H).
13
C NMR (101 MHz, DMSO-d6; δ, ppm): 144.66, 137.54, 136.14, 133.35, 130.10, 128.95,
128.87, 128.65, 127.85, 127.68, 66.64, 64.49, 61.74, 60.35, 35.88, 30.51, 29.76, 25.26, 23.82,
19.67.
APCI -MS (TOF): measured m/z 487.1578, calcd for C24H28ClN4O3S [M+H]
+
m/z 487.1565
(Δ = 2.7 ppm).

Cl
N
N
N
S
O
F
O
+
N
H
OH
NEt
3
ACN, 80℃, 20h
Cl
N
N
N
S
O
N
O
*
O
H
6
5
188
Synthesis of BRI-13902

In a 10 mL reaction tube, 5 (1.0 eq., 100 mg, 0.28 mmol) was dissolved in 1 mL acetonitrile
and 2-amino-2-phenylethan-1-ol (2.0 eq., 78 mg, 0.57 mmol) was added. DBU (2.0 eq., 87 mg,
0.57 mmol) was added and the reaction mixture was stirred at rt for 24 hours. After
evaporation of the solvent, the crude mixture was purified by column chromatography (SiO2,
5% → 10% MeOH in DCM) to obtain the product (7, BRI 13902) as an off-white solid (15%,
19 mg).
1
H NMR (600 MHz, DMSO-d6, 20 of 21
1
H signals observed; δ, ppm): 7.96 (s, 1H), 7.50 – 7.18
(m, 14H), 3.56 – 3.52 (m, 1H), 3.47 (t, J = 5.9 Hz, 1H), 3.33 (s, 1H), 3.24 (dd, J = 6.6, 5.0 Hz,
1H), 2.66 – 2.60 (m, 1H).
13
C NMR (101 MHz, DMSO-d6; δ, ppm): 165.41, 153.50, 138.28, 137.62, 132.96, 129.95,
128.84, 128.75, 128.52, 128.39, 128.25, 127.99, 127.31, 123.06, 65.77, 53.40, 47.89.
MS (TOF): measured m/z 201.0467, calcd for C13H10Cl [M]
•+
m/z 201.0466 (Δ = 0.5 ppm).

Synthesis of BRI-13903

7
9
5
189

A 50 mL round bottomed flask was charged with 4-(bromomethyl)-1,1'-biphenyl (1.0 eq.,
250 mg, 1.01 mmol) in 2.5 mL dimethyl formamide. Sodium azide (2.0 eq., 132 mg,
2.02 mmol) was added to the solution at room temperature and stirred for 24 h. Upon
completion, the reaction mixture was extracted to Et2O (3x10 mL), and the combined organic
layers were washed with water (3x10mL) and brine (1x10mL) then dried over sodium
sulfate. The crude mixture was obtained by rotary evaporation of the solvent and purified by
column chromatography (SiO2, 20% DCM in Hexanes) to obtain the product (9) as a white
solid (96%, 203 mg).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 7.67 – 7.60 (m, 4H), 7.53 – 7.45 (m, 2H), 7.43 –
7.37 (m, 3H), 4.38 (s, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 141.74, 140.98, 134.80, 129.30, 129.14, 128.04,
127.98, 127.58, 55.01.
APCI -MS (TOF): measured m/z 209.0947, calcd for C13H11N3 [M]
•+
m/z 209.0947(Δ = 0.0
ppm).

In a 10 mL reaction tube, 9 (1.0 eq., 300 mg, 1.34 mmol) and Br-ESF (3.0 eq., 762 mg, 4.03
mmol) were suspended in 2 mL dimethyl formamide and stirred at 80˚C for 24 h.
Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with
brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent
yielded the crude mixture. Purification by column chromatography (SiO2, 50% DCM in
Hexanes) yielded the triazole (10) as a yellow oil (87%, 387 mg).

10 9
190
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 8.13 (s, 1H), 7.74 – 7.64 (m, 2H), 7.64 – 7.55 (m,
2H), 7.54 – 7.36 (m, 5H), 5.68 (s, 2H).
13
C NMR (151 MHz, Chloroform-d; δ, ppm): 142.91, 139.73, 130.95, 129.04, 128.92, 128.32,
127.96, 127.89, 127.10, 127.06, 55.02.
19
F NMR (376 MHz, Chloroform-d; δ, ppm): 66.33.
APCI -MS (TOF): measured m/z 317.0634, calcd for C15H12N3O2SF [M]
•+
m/z 317.0629
(Δ = 1.6 ppm).

In a 10 mL reaction tube, 10 (1.0 eq., 100 mg, 0.32 mmol) was dissolved in 1 mL acetonitrile
and 4-(pyrrolidin-2-yl) pyrimidine (2.0 eq., 94 mg, 0.63 mmol) was added. Triethylamine
(2.0 eq., 64 mg, 0.63 mmol) was added and the reaction mixture was stirred at 80˚C for 24
hours. After evaporation of the solvent, the crude mixture was purified by column
chromatography (SiO2, 5% MeOH in DCM) to obtain the product (11, BRI 13903) as a
mixture of two enantiomers as an off-white solid (49%, 68 mg).
1
H NMR (600 MHz, DMSO-d6; δ, ppm): 9.12 (d, J = 1.4 Hz, 1H), 9.06 (s, 1H), 8.81 (d, J = 5.2 Hz,
1H), 7.73 – 7.69 (m, 2H), 7.68 – 7.64 (m, 3H), 7.49 – 7.44 (m, 4H), 7.39 – 7.35 (m, 1H), 5.76
(s, 2H), 4.86 (dd, J = 8.5, 4.3 Hz, 1H), 3.65 (ddd, J = 10.0, 7.1, 5.0 Hz, 1H), 3.51 – 3.41 (m, 1H),
2.13 – 2.02 (m, 1H), 1.95 – 1.88 (m, 1H), 1.85 – 1.76 (m, 1H), 1.69 – 1.61 (m, 1H).
11
10
191
13
C NMR (151 MHz, DMSO-d6; δ, ppm): 170.10, 158.09, 157.68, 143.93, 140.33, 139.47,
134.25, 129.07, 128.86, 128.65, 128.33, 127.20, 126.73, 118.53, 63.73, 53.27, 49.85, 33.18,
23.88.
APCI -MS (TOF): measured m/z 447.1610, calcd for C23H23N6O2S [M+H]
+
m/z 447.1598
(Δ = 2.7 ppm).

Synthesis of BRI-13904

Sodium borohydride (0.35 eq., 26 mg, 691.13 µmol) was added to a solution of 4-
(diethylamino) benzaldehyde (1.0 eq., 350 mg, 1.97 mmol) in 3 mL ethanol and stirred at
room temperature for 1.5 h. The reaction mixture was extracted with Et2O (3x10 mL) and
the combined organic layers were washed with water (3x10mL) and brine (1x10mL) and
then dried over sodium sulfate. After rotary evaporation of the solvent, the product (12) was
obtained as a white solid (96%, 339 mg).
1
H NMR (400 MHz, Chloroform-d, 16 of 17
1
H signals observed; δ, ppm): 7.24 – 7.19 (m, 2H),
6.69 – 6.65 (m, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.36 (q, J = 7.1 Hz, 4H), 1.16 (d, J = 7.1 Hz, 6H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 147.16, 128.67, 127.49, 111.56, 64.96, 44.14,
12.24.
APCI -MS (TOF): measured m/z 179.1306, calcd for C11H17NO [M]
•+
m/z 179.1305
(Δ = 0.56 ppm).

12
192

In a 50 mL round bottom flask, 12 (1.0 eq., 189 mg, 1.05 mmol) was dissolved in 10mL
toluene. DPPA (1.2 eq., 348 mg, 1.27 mmol) and DBU (1.5 eq., 241 mg, 1.58 mmol) were
added and stirred at room temperature for 4 h. The reaction mixture was extracted with
EtOAc (3x10 mL), and the combined organic layers were washed with water (3x10mL) and
brine (1x10mL) and then dried over sodium sulfate. After rotary evaporation of the solvent
the product (13) was obtained as a yellow oil (81%, 174 mg).
1
H NMR (400 MHz, Acetonitrile-d3; δ, ppm): 7.17 – 7.05 (m, 2H), 6.70 – 6.62 (m, 2H), 4.16 (s,
2H), 3.32 (q, J = 7.0 Hz, 4H), 1.09 (t, J = 7.0 Hz, 6H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 129.99, 125.74 (d, J = 1.2 Hz), 120.25 (d, J = 5.1
Hz), 111.73, 54.93, 44.47, 12.65.
APCI -MS (TOF): measured m/z 204.1368, calcd for C11H16N4 [M]
•+
m/z 205.1453(Δ = -
0.49 ppm).

In a 10 mL reaction tube, 13 (1.0 eq., 150 mg, 0.73 mmol) and Br-ESF (3.0 eq., 416 mg, 2.20
mmol) were suspended in 1 mL dimethyl formamide and stirred at 80˚C for 24 h.
Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with
brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent
+ +
N
N
O
P
O
N
3
O
Toluene
OH
N
N
3
N
12
13
13
14
193
yielded the crude mixture. Purification by column chromatography (SiO2, 50% DCM in
Hexanes → 60% DCM in Hexanes) yielded the triazole (14) as a yellow oil (63%, 146 mg).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 7.97 (s, 1H), 7.14 – 7.05 (m, 2H), 6.67 – 6.48 (m,
2H), 5.39 (s, 2H), 3.28 (q, J = 7.3, 6.7 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H).
13
C NMR (101 MHz, Chloroform-d; δ, ppm): 171.25, 148.60, 130.50, 127.99, 117.65, 111.93,
55.37, 44.46, 12.51.
19
F NMR (376 MHz, Chloroform-d; δ, ppm): 66.28.
APCI -MS (TOF): measured m/z 312.1061, calcd for C13H17N4O2SF [M]
•+
m/z 312.1051
(Δ = 3.2 ppm).

In a 10 mL reaction tube, 14 (1.0 eq., 100 mg, 0.32 mmol) was dissolved in 1 mL acetonitrile,
and (1H-pyrazol-5-yl) methanamine (2.0 eq., 62 mg, 0.64 mmol) and DBU (2.0 eq., 97 mg,
0.64 mmol) were added. DMAP (0.2 eq., 7.82 mg, 0.064 mmol) was added and the reaction
mixture was stirred at rt for 3 h. After evaporation of the solvent, the crude mixture was
purified by column chromatography (SiO2, 2% MeOH in DCM) to obtain the product (15, BRI
13904) as an off-white solid (49%, 68 mg).
1
H NMR (400 MHz, DMSO-d6, 22 of 23
1
H signals observed; δ, ppm): 9.23 (s, 1H), 8.39 (d, J =
2.8 Hz, 1H), 7.31 – 7.16 (m, 2H), 6.71 – 6.47 (m, 3H), 5.49 (s, 2H), 3.67 (s, 2H), 3.29 (q, J = 7.0
Hz, 5H), 1.05 (t, J = 7.0 Hz, 6H).
14
15
194
13
C NMR (101 MHz, DMSO-d6; δ, ppm): 161.40, 147.56, 143.00, 133.56, 129.97, 129.05,
120.33, 111.27, 108.95, 53.84, 43.58, 39.44, 12.31.
APCI -MS (TOF): measured m/z 390.1703, calcd for C17H24N7O2S [M+H]
+
m/z 390.1707
(Δ = 1.0 ppm).

Synthesis of BRI-13905

Sodium borohydride (0.35 eq., 27 mg, 713 µmol) was added to a solution of 4-
benzylbenzaldehyde (1.0 eq., 400 mg, 2.04 mmol) in 3 mL ethanol and stirred at room
temperature for 2 h. The reaction mixture was extracted with Et2O (3x10 mL) and the
combined organic layers were washed with H2O (3x10 mL) and brine (1x10 mL) and then
dried over sodium sulfate. After rotary evaporation of the solvent, the product was obtained
(8) as a white solid (98%, 397 mg).
1
H NMR (400 MHz, Chloroform-d, 13 of 14
1
H signals observed; δ, ppm): 7.33 – 7.27 (m, 4H),
7.24 – 7.17 (m, 5H), 4.66 (s, 2H), 3.99 (s, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 141.47, 141.12, 139.09, 129.59, 129.34, 128.94,
127.73, 126.56, 65.65, 42.08.
APCI -MS (TOF): measured m/z 198.1041, calcd for C14H14O [M]
•+
m/z 198.1039
(Δ = 1.0 ppm).

O
HO
NaBH
4
EtOH
HO N
3
+ +
N
N
O
P
O
N
3
O
Toluene
16
8
8
195

In a 50 mL round bottom flask, (4-benzylphenyl) methanol (1.0 eq., 325 mg, 1.64 mmol) was
dissolved in 12 mL toluene. DPPA (1.2 eq., 541 mg, 1.97 mmol) and DBU (1.5 eq., 374 mg,
2.46 mmol) were added and the reaction was stirred at room temperature for 23 h. The
reaction mixture was extracted to EtAOc (3x 10 mL) the combined organic layers were
washed with H2O (3x10 mL) and brine (1x10 mL) and then dried over sodium sulfate. After
rotary evaporation of the solvent, the azide (16) was obtained as an off-white solid (82%,
302 mg).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 7.39 – 6.85 (m, 9H), 4.29 (s, 2H), 3.99 (s, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 141.46, 140.85, 133.23, 129.48, 129.02, 128.63,
128.52, 126.30, 54.65, 41.70.
APCI -MS (TOF): measured m/z 223.1106, calcd for C14H13N3 [M]
•+
m/z 223.1104
(Δ = 0.9 ppm).

In a 10 mL reaction tube, 16 (1.0 eq., 200 mg, 0.89 mmol) and Br-ESF (3.0 eq., 508 mg, 2.69
mmol) were suspended in 2 mL dimethyl formamide and stirred at 80˚C for 4 h.
Subsequently, the reaction mixture was extracted with DCM (3x 20 mL) and washed with
brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent
yielded the crude mixture. Purification by column chromatography (SiO2, 50% DCM in
Hexanes) yielded the triazole (17) as a yellow oil (96%, 284 mg).
1
H NMR (400 MHz, Methanol-d4; δ, ppm): 8.99 (s, 1H), 7.34 – 7.29 (m, 2H), 7.28 – 7.21 (m,
4H), 7.19 – 7.13 (m, 3H), 5.67 (s, 2H), 3.96 (s, 2H).
16 17
196
13
C NMR (100 MHz, Methanol-d4; δ, ppm): 142.69, 139.94, 136.48, 129.98 (d, J = 1.0 Hz),
129.05, 128.29, 128.02, 127.39, 127.23, 125.74 (d, J = 1.4 Hz), 61.88, 21.19.
19
F NMR (376 MHz, Methanol-d4; δ, ppm): 64.49.
APCI -MS (TOF): measured m/z 331.0791, calcd for C16H14N3O2SF [M]
•+
m/z 331.0785
(Δ = 1.8 ppm).

In a 10 mL reaction tube, 17 (1.0 eq., 50 mg, 0.15 mmol) was dissolved in 1 mL acetonitrile,
and (1H-pyrazol-5-yl) methanamine (2.0 eq., 29 mg, 0.30 mmol) and DBU (2.0 eq., 45 mg,
0.30 mmol) were added. DMAP (0.2 eq., 3.69 mg, 0.030 mmol) was added and the reaction
mixture was stirred at rt for 4 h. After evaporation of the solvent, the crude mixture was
purified by column chromatography (SiO2, 10% MeOH in DCM) to obtain the product (18,
BRI 13905) as an off-white solid (38%, 47 mg).
1
H NMR (400 MHz, DMSO-d6; δ, ppm): 9.26 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.41 – 7.11 (m,
10H), 6.60 (d, J = 2.8 Hz, 1H), 5.60 (s, 2H), 3.89 (s, 2H), 3.60 (s, 2H).
13
C NMR (101 MHz, DMSO-d6; δ, ppm): 162.05, 143.10, 141.89, 140.90, 133.54, 132.35,
129.64, 129.20, 128.69, 128.52, 128.45, 126.04, 108.96, 53.58, 40.69, 39.22.
APCI -MS (TOF): measured m/z 409.1459, calcd for C20H21N6O2S [M+H]
+
m/z 409.1441
(Δ = 4.4 ppm).

Synthesis of BRI-13906

17 18
197

In a 50 mL round bottom flask, 3-(methoxymethyl) aniline (1.0 eq., 1.11 g, 8.12 mmol) was
dissolved in 5 mL 5 M HCl. A solution of sodium nitrite (1.5 eq., 840 mg, 12.18 mmol) in 20
mL H2O was added dropwise at 0˚C and stirred at room temperature for 20 h. Upon
completion, the reaction mixture was quenched with NaHCO3 and extracted with EtOAC (3x
100 mL). After evaporation of the solvent, the azide (19) was obtained as a yellow oil (99%,
1.32 g).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 7.39 – 7.30 (m, 1H), 7.14 – 7.08 (m, 1H), 7.08 –
7.02 (m, 1H), 6.99 – 6.93 (m, 1H), 4.45 (s, 2H), 3.40 (s, 3H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 140.16, 139.99, 129.54, 123.80, 118.05, 117.77,
73.85, 58.07.
APCI -MS (TOF): measured m/z 135.0677, calcd for C8H9NO [M-N2]
•+
m/z 135.0679 (Δ = -
1.5 ppm).

In a 10 mL reaction tube, 19 (1.0 eq., 500 mg, 3.06 mmol) and Br-ESF (3.0 eq., 1.74 g, 9.19
mmol) were suspended in 5 mL dimethyl formamide and stirred at 80˚C for 24 h.
Subsequently, the reaction mixture was extracted with DCM (3x 50 mL) and washed with
brine. The organic layer was dried over sodium sulfate, and rotary evaporation of the solvent
yielded the crude mixture. Purification by column chromatography (SiO2, 10% EtOAc in
Hexanes → 50% EtOAc in Hexanes) yielded the triazole (20) as a yellow oil (59%, 520 mg).
19
19
20
198
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 8.72 (s, 1H), 7.77 – 7.74 (m, 1H), 7.71 – 7.67 (m,
1H), 7.60 – 7.55 (m, 1H), 7.52 – 7.49 (m, 1H), 4.56 (s, 2H), 3.46 (s, 3H).
13
C NMR (151 MHz, Chloroform-d; δ, ppm): 140.21 (d, J = 21.2 Hz), 130.18, 129.68, 129.10,
123.95, 120.06, 119.63, 118.20, 117.92, 58.21.
19
F NMR (376 MHz, Chloroform-d; δ, ppm): 66.64.
APCI -MS (TOF): measured m/z 271.0427, calcd for C10H10FN3O3S [M]
•+
m/z 271.0421
(Δ = 2.2 ppm).

In a 10 mL reaction tube, 20 (1.0 eq., 100 mg, 0.35 mmol) was dissolved in 1 mL acetonitrile,
and (4-chloro-6-(piperazin-1-yl) pyrimidine (2.0 eq., 139 mg, 0.70 mmol) and DBU (2.0 eq.,
106 mg, 0.70 mmol) were added. DMAP (0.2 eq., 8.56 mg, 0.07 mmol) was added and the
reaction mixture was stirred at rt for 4 h. After evaporation of the solvent, the crude mixture
was purified by column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (21,
BRI 13906) as an off-white solid (56%, 90 mg).
1
H NMR (600 MHz, DMSO-d6; δ, ppm): 9.55 (s, 1H), 8.31 (s, 1H), 7.93 – 7.91 (m, 1H), 7.90 –
7.86 (m, 1H), 7.61 – 7.56 (m, 1H), 7.50 – 7.46 (m, 1H), 6.96 (s, 1H), 4.51 (s, 2H), 3.83 – 3.77
(m, 4H), 3.33 (s, 3H), 3.24 – 3.19 (m, 4H).
13
C NMR (151 MHz, DMSO-d6; δ, ppm): 161.95, 159.24, 157.92, 143.54, 140.61, 135.96,
129.83, 128.35, 126.46, 119.86, 119.68, 119.54, 102.09, 72.78, 57.78, 45.22.
20 21
199
APCI -MS (TOF): measured m/z 450.1129, calcd for C18H21ClN7O3S [M+H]
+
m/z 450.1110
(Δ = 4.2 ppm).

Synthesis of BRI-13907

A 50 mL dry round bottom flask was charged with 3-methoxy-2-napthaldehyde (1.0 equiv.,
500 mg, 2.68 mmol) and was dissolved in 5 mL ethanol. Triethylamine (2.0 equiv., 750 µL,
5.37 mmol) and hydroxylamine.HCl (2.0 equiv., 373 mg, 5.37 mmol) were dissolved in 5 mL
water and added dropwise to aldehyde solution. The reaction was stirred at r.t. for 5 h and
extracted with EtOAc (3x10) to obtain 22 as an off-white solid (85%, 425 mg).
1
H NMR (400 MHz, Chloroform-d, 10 of 11
1
H signals observed; δ, ppm): 8.60 (s, 1H), 8.17 (d,
J = 2.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.47 (ddt, J = 8.3, 6.8, 1.6 Hz,
1H), 7.35 (ddt, J = 8.1, 6.9, 1.1 Hz, 1H), 7.16 (s, 1H), 3.99 (s, 3H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 155.49, 135.40, 128.54, 128.49, 127.79, 127.59,
126.65, 124.71, 124.44, 121.84, 105.95, 55.75.
APCI -MS (TOF): measured m/z 201.0787, calcd for C12H11NO2 [M]
•+
m/z 201.0787
(Δ = 1.5 ppm).

A 100 mL dry round bottom flask was charged with 22 (1.0 equiv., 337 mg, 1.67 mmol) and
was dissolved in 22 mL DMF. The flask was covered with aluminuum foil and N-
22
22 23
200
Chlorosuccinimide (1.05 equiv., 235 mg, 1.75 mmol) was added portionwise over 30 min.
The reaction mixture was stirred at r.t. for 48 h and then extracted with diethyl ether (20
mL). The organic layer was extracted with water (10 mL x 3) and brine (10mL). The organic
layer was concentrated in vacuo to obtain the desired product (23) as a pale yellow solid
(99%, 390 mg).
1
H NMR (400 MHz, DMSO-d6; δ, ppm): 11.65 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.14 (dq, J =
8.5, 0.9 Hz, 1H), 8.09 – 8.05 (m, 1H), 7.71 – 7.66 (m, 1H), 7.58 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H),
3.88 (s, 3H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 155.49, 135.40, 128.54, 128.49, 127.79, 127.59,
126.65, 124.71, 124.44, 121.84, 105.95, 55.75.
APCI -MS (TOF): measured m/z 235.0399, calcd for C12H10ClNO2 [M]
•+
m/z 235.0395
(Δ = 1.7 ppm).

A 25 mL dry round bottom flask was charged with 23 (1.0 equiv., 150 mg, 1.67 mmol) and
was dissolved in 3 mL tert-butanol, and DIPEA (2.5 equiv., 277 µL, 1.59 mmol) was added.
The reaction mixture was vigorously stirred. Alongside, 1-bromoethene-1-sulfonyl fluoride
(4 equiv., 481mg, 2.55 mmol) was dissolved in 3 mL tert-butanol and was added dropwise
to the reaction mixture over a period of 20 min. The solution was stirred for 2 h. The reaction
mixture was washed with water (10 mL). The aqueous layer was washed with DCM (3 x
10mL) and finally, the organic layer was washed with brine (10 mL). The organic layer was
23
24
201
dried The residue was purified through silica gel chromatography with 0% to 3% ethyl
acetate in hexanes to obtain the desired product (24) as an off white solid (18%, 27 mg)
1
H NMR (600 MHz, Chloroform-d; δ, ppm): 8.36 (d, J = 3.0 Hz, 1H), 8.29 (dd, J = 8.5, 1.0 Hz,
1H), 7.95 – 7.92 (m, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.58 (ddd,
J = 8.1, 6.9, 1.1 Hz, 1H), 3.90 (s, 3H).
13
C NMR (151 MHz, Chloroform-d; δ, ppm): 162.78, 140.66, 138.18, 137.88, 128.01, 127.13,
125.32, 125.07, 124.82, 123.20, 122.12, 121.25, 110.88, 30.22.
19
F NMR (376 MHz, CDCl3; δ, ppm): 64.70.

In a 10 mL reaction tube, 24 (1.0 eq., 20 mg, 0.06 mmol) was dissolved in 0.5 mL acetonitrile
and piperazin-1-yl(1H-pyrrol-2-yl) methanone (3.0 eq., 31 mg, 0.18 mmol) was added.
Triethylamine (2.0 eq., 12 mg, 0.12 mmol) was added and the reaction mixture was stirred
at 80˚C for 6 hours. After evaporation of the solvent, the crude mixture was purified by
column chromatography (SiO2, 5% MeOH in DCM) to obtain the product (25, BRI 13907) as
an off-white solid (49%, 68 mg).
1
H NMR (400 MHz, DMSO-d6; δ, ppm): 11.47 (s, 1H), 8.52 (s, 1H), 8.39 – 8.18 (m, 1H), 8.18 –
8.07 (m, 1H), 7.83 – 7.77 (m, 1H), 7.72 (s, 1H), 7.71 – 7.64 (m, 1H), 7.06 – 6.78 (m, 1H), 6.73
– 6.52 (m, 1H), 6.26 – 5.92 (m, 1H), 3.94 – 3.73 (m, 7H), 3.40 – 3.35 (m, 4H).
24 25
202
13
C NMR (101 MHz, DMSO-d6; δ, ppm): 163.33, 161.67, 160.14, 151.01, 131.80, 130.32,
129.72, 129.48, 129.16, 126.93, 123.73, 123.63, 123.33, 121.59, 121.45, 112.31, 109.49,
108.49, 61.44, 45.74, 27.10.
APCI-MS (TOF): measured m/z 501.1005, calcd for C23H22ClN4O5S [M-H]
+
m/z 501.0994
(Δ = 1.8 ppm).

Synthesis of BRI-13910

A 50 mL round bottom flask was charged with hydroxylamine hydrochloride (1.2 eq.,
148 mg, 2.1 mmol) and sodium carbonate (1.2 eq., 226 mg, 2.1 mmol) and dissolved in
2.5 mL of a 5:1 water: ethanol mixture and the solution was mixed for 15 min. The aldehyde
(1.0 eq., 500 mg, 1.8 mmol) was added portion-wise over 5 minutes, 10 mL more of EtOH
was added and the reaction was stirred for 45 min. Reaction progress was monitored via LC-
DAD. After 72 h the reaction was complete. The product was extracted in EtOAc (3 × 10 mL),
washed with water (3 × 10 mL) and brine (2 × 10 mL), and dried over sodium sulfate.
Solvents were evaporated under vacuum and the product, initially an oil, was cooled and
crashed out with hexanes to afford a white solid. The solvent was removed under vacuum,
yielding the product (26) as a white solid in 94% (504 mg). Purity was confirmed by LC-UV-
APCI-MS.
+
O
O
Cl
Cl
O
N
Cl
Cl
OH
Na
2
CO
3
NH
3
OHCl
EtOH/H
2
O
26
203
1
H NMR (499.8 MHz, DMSO-d6; δ, ppm): 11.25 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.66 (d,
J = 8.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J = 7.6 Hz,
1H), 7.03 (d, J = 8.3 Hz, 1H), 5.14 (s, 2H).
13
C NMR (125.7 MHz, DMSO-d6; δ, ppm): 158.1, 147.9, 138.2, 134.5, 131.1, 130.7, 130.4,
129.9, 129.4, 127.8, 119.5, 115.9, 112.2, 67.6.
APCI-MS (TOF): exact for C14H12Cl2NO2 [M + H]
+
m/z 296.0240, accurate m/z 296.0242
(Δ = 0.7 ppm).

In a 20 mL scintillation vial, the oxime 26 (1.0 eq., 496 mg, 1.7 mmol) was dissolved in 2 mL
DMF and placed in a 15 °C water bath with continuous stirring. NCS (1.05 eq, 235 mg,
1.8 mmol) was added portion-wise over 30 minutes to the stirring reaction. The mixture was
stirred in the dark at 15 °C. Reaction progress was monitored via LC-DAD. After 2 h the
reaction was complete. The reaction was quenched with 2 mL of water and the product was
extracted to DCM (3 × 10 mL). The combined organic layer was washed with a 5:1 brine:
water mixture (3 × 10 mL), and brine (1 × 10 mL), and dried over sodium sulfate. Solvents
were evaporated under vacuum to yield the product (27) as a light-yellow solid in 98% (545
mg). Purity was confirmed by LC-UV-APCI-MS.
1
H NMR (499.8 MHz, DMSO-d6; δ, ppm): 12.42 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H),
7.59 – 7.34 (m, 4H), 7.25 – 7.12 (m, 1H), 5.18 (s, 2H).
+
O
N
Cl
Cl
OH
DMF
N
O
O
Cl
O
N
Cl
Cl
OH
Cl
26 27
204
13
C NMR (125.7 MHz, DMSO-d6; δ, ppm): 158.0, 138.0, 135.1, 134.0, 131.1, 130.7, 130.4,
130.0, 129.5, 127.8, 119.5, 116.9, 112.8, 67.8.
APCI-MS (TOF): measured for C14H11Cl3NO2 [M + H]
+
m/z 329.9850, calcd m/z 329.9844
(Δ = 1.8 ppm).

In a 20 mL scintillation vial, the chloro-oxime 27 (1.0 eq., 331 mg, 1 mmol) were dissolved
in 10 mL of DCM. Br-ESF (2.0 eq., 378 mg, 2 mmol) was added and the mixture was stirred
at r.t. for 5 min. While the mixture was stirring, triethylamine (2.0 eq., 202 mg, 2.0 mmol)
was slowly added dropwise over 1 min (white fume formed immediately above the solution
and the solution gradually changed color to dark orange). After 2 h of stirring, the reaction
was quenched with 10 mL of water. The product was extracted to DCM (3 x 10 mL), washed
with water (3 × 10 mL) and brine (2 × 10 mL), and dried over sodium sulfate. The solution
was passed through a short pad of silica and solvents were evaporated under vacuum, until
the product (28) crystalized as beige crystals in a yield of 78% (316 mg). Purity was
confirmed by LC-UV-APCI-MS.
1
H NMR (499.8 MHz, DMSO-d6; δ, ppm): 8.71 (s, 1H), 7.76 (s, 1H), 7.69 – 7.65 (m, 2H), 7.64 –
7.60 (m, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.22 (s,
2H)
13
C NMR (125.7 MHz, DMSO-d6; δ, ppm): 163.3, 158.6, 137.9, 131.7, 131.2, 130.8, 130.7,
130.5, 129.6, 127.9, 127.3, 119.8, 118.3, 113.4, 112.8 (d, J = 3.5 Hz), 67.9.
+
O
Cl
Cl
CH
2
Cl
2
O
N
Cl
Cl
OH
SO
2
F
Br
Cl N
O
SO
2
F
Et
3
N
27 28
205
19
F NMR (470.3 MHz, DMSO-d6; δ, ppm): 65.5.
APCI-MS (TOF): measured for C16H11Cl2FNO4S [M + H]
+
m/z 401.9764, calcd m/z 401.9771
(Δ = 1.7 ppm).

In a 20 mL scintillation vial, 28 (1.0 eq., 201 mg, 0.5 mmol) was dissolved in 5 mL MeCN, and
methyl(1H-pyrazol-3-yl) methylamine (2.0 eq., 111 mg, 1 mmol) and DBU (2.0 eq., 152 mg,
1 mmol) were added. DMAP (0.2 eq., 12 mg, 0.1 mmol) was added and the reaction mixture
was stirred at RT for 3 h. Solvent was evaporated until 3 mL total volume and product was
purified by MS-guided HPLC in MeCN/H2O/formic acid system. Removal of solvent resulted
in formate salt of the product (29, BRI 13910) as an off-white solid in a yield of 8% (22 mg).
Purity was confirmed by LC-UV-APCI-MS.
1
H NMR (499.8 MHz, DMSO-d6; δ, ppm): 8.61 (s, 1H), 8.39 (s, 1H), 8.22 (br s, 3H), 7.75 (s, 1H),
7.67 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.23 (d, J =
8.2 Hz, 1H), 6.81 (s, 1H), 5.21 (s, 2H), 3.87 (s, 2H), 2.33 (s, 3H).
13
C NMR (125.7 MHz, DMSO-d6; δ, ppm): 163.9, 163.0, 161.9, 158.5, 157.7, 138.0, 134.8,
131.2, 130.8, 130.7, 130.5, 129.5, 127.9, 127.5, 119.7, 118.2, 113.3, 111.2, 110.2, 67.9, 46.4,
34.1.
APCI-MS (TOF): measured for C21H19Cl2N4O4S [M + H]
+
m/z 493.0499, calcd m/z 493.0501
(Δ = 0.4 ppm).
+
O
Cl
Cl
MeCN
O
N
Cl
Cl
N
O
S
N
O
O
N
N
H
+
H
2
N
N
N
H
O
SO
2
F
Cl
DBU
DMAP
28
29
206

Synthesis of BRI-13911

A round bottom flask (50 mL) was charged with hydroxylamine hydrochloride (1.2 eq., 80
mg 1.15 mmol) and sodium carbonate (1.2 eq., 122 mg, 1.15 mmol) and dissolved in 6 mL of
a 5:1 water: ethanol mixture and the solution was mixed for 15 min. The aldehyde (1.0 eq.,
250 mg, 961 mmol) was added portion wise over 5 minutes. Reaction progress was
monitored via TLC in 3:1 hexanes: EtOAc. After 120 h the reaction was complete. Product
was extracted in EtOAc (3 × 10 mL), washed with water (3 × 10 mL) and brine (2 × 10 mL),
and dried over sodium sulfate. Solvents were evaporated under vacuum and the remaining
solvent was removed under vacuum and product dried overnight to yield the product (30)
as an off-white solid in 98% (259 mg).

1
H NMR (600 MHz, Chloroform-d; δ, ppm): 9.83 (s, 1H), 8.04 (s, 1H), 7.44 – 7.40 (m, 2H), 7.10
– 7.02 (m, 4H), 6.88 (d, J = 8.3 Hz, 1H), 5.11 (s, 2H), 3.90 (s, 3H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 164.22, 161.77, 151.99, 148.75, 129.90 (d, J = 3.8
Hz), 125.01, 122.77, 115.96 (d, J = 21.6 Hz), 111.74, 111.15, 70.75, 56.45, 30.17.
19
F NMR (564 MHz, Chloroform-d; δ, ppm): -113.74 (ddd, J = 13.8, 8.9, 5.3 Hz), -114.27 (ddd,
J = 14.0, 8.9, 5.4 Hz).
APCI -MS (TOF): measured m/z 275.0956, calcd for C15H14NO3F [M]
•+
m/z 275.0952
(Δ = 1.5 ppm).

O
O
O
F
Na
2
CO
3
NH
4
ClOH
EtOH/H
2
O
N
O
O
F
HO
30
207

In a 50 mL round bottom flask oxime 30 (1.0 eq., 254 mg, 923 mmol) was dissolved in 10 mL
DMF and placed in a 15 °C water bath covered in foil with continuous stirring. NCS (1.05 eq.,
129 mg, 969 mmol) was added portion wise over 30 minutes to the stirring reaction. The
mixture was stirred in the dark at 15 °C. Reaction progress was monitored via TLC in 3:1
hexanes: EtOAc. After 24h, 13 mg of NCS was added to push the reaction to completion. After
an additional 5 h the reaction was complete. The reaction was quenched with 5 mL of water
and the product was extracted to ether (3 × 10 mL). The combined organic layer was washed
with a 5:1 brine: water mixture (3 × 10 mL), and brine (1 × 10 mL), and dried over sodium
sulfate. Solvents were evaporated under vacuum and the product was left on a vacuum line
overnight to yield the product (31) as an off-white solid in 99% (282 mg).

1
H NMR (600 MHz, Chloroform-d; δ, ppm): 7.47 – 7.40 (m, 4H), 7.08 – 7.04 (m, 3H), 6.93 –
6.89 (m, 1H), 5.12 (s, 2H), 3.91 (s, 3H).
13
C NMR (151 MHz, Chloroform-d; δ, ppm): 163.31, 161.75, 151.49, 148.25, 130.85, 129.42
(d, J = 8.3 Hz), 126.54, 120.86, 115.43 (d, J = 21.4 Hz), 111.96, 102.15, 70.38, 55.94.
19
F NMR (564 MHz, Chloroform-d; δ, ppm): -113.79 (td, J = 8.7, 4.3 Hz), -114.16 (ddd, J = 14.1,
8.8, 5.4 Hz).
APCI -MS (TOF): measured m/z 309.0562, calcd for C15H13NO3ClF [M]
•+
m/z 309.0563 (Δ = -
0.32 ppm).

N
O
O
F
HO
N
O
O
F
HO
Cl
NCS
DMF
30
31
208

In a 20 mL scintillation vial chloro-oxime 31 (1.0 eq., 310 mg, 1 mmol) was dissolved in 20
mL of DCM. Br-ESF (2.0 eq., 378 mg, 2 mmol) was added and the mixture was stirred at r.t.
for 5 min. While the mixture was stirring, triethylamine (2.0 eq., 202 mg, 2 mmol) was slowly
added dropwise over 1 min (white fumes formed immediately above the solution and the
solution gradually changed color). After 4 h of stirring, the reaction was complete and
quenched with 10 mL of water. The product was extracted to DCM 3×10 mL, washed with
water (3 × 10 mL) and brine (2 × 10 mL), dried over sodium sulfate. Solution was passed
through a short pad of silica and solvents were evaporated under vacuum to yield the
product (32) as an off-white solid in 62% (236 mg).

1
H NMR (400 MHz, Chloroform-d; δ, ppm): 7.48 – 7.42 (m, 3H), 7.38 – 7.36 (m, 1H), 7.33 (dd,
J = 8.3, 2.0 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 5.16 (s, 2H), 3.94 (s, 3H).
19
F NMR (376 MHz, Chloroform-d; δ, ppm): 64.31, -113.85 (ddd, J = 14.0, 8.8, 5.3 Hz).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 163.99, 162.85, 161.53, 152.69, 148.73, 132.19
(d, J = 3.1 Hz), 129.57 (d, J = 8.3 Hz), 121.29, 118.77, 115.86, 115.65, 111.87 (d, J = 2.3 Hz),
110.24 (d, J = 3.6 Hz), 70.66, 56.20.
APCI -MS (TOF): measured m/z 382.1, calcd for C17H14NO5SF2 [M+H]
+
m/z 382.1
(Δ = 0.0 ppm).

N
O
O
F
HO
Cl
NEt
3
DCM
Br
SO
2
F
N
O
O
F
O
FO
2
S
+
31 32
209

In a 10 mL reaction tube, the isoxazole 32 (1.0 eq., 130 mg, 341 mmol) was dissolved in 0.5
mL DMSO. Subsequently, the amine (2.0 eq., 29 mg 284 mmol), HOBt (1 mol%), 1,1,3,3-
tetramethyldisiloxane (2.0 eq., 76 mg, 568 mmol), and DIPEA (2.0 eq., 73 mg, 568 mmol)
were added and the reaction was stirred at rt and the reaction was monitored by LCMS. After
24 h the reaction was complete and diluted with 10 mL of EtOAc. The product was washed
with water (2 x 10 mL) and 1M HCl (1 x 1 mL) then brine (1 x 10 mL) After rotary evaporation
of the solvent, the crude mixture was purified by Semi-prep to obtain the final product (33,
BRI 13911) as one diastereomer with two enantiomers as an off-white solid in 10% (13 mg).

1
H NMR (600 MHz, Methylene Chloride-d2, 22 of 23
1
H signals observed; δ, ppm): 7.61 – 7.57
(m, 3H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.25 – 7.20 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 5.45 – 5.44
(m, 1H), 5.39 (d, J = 6.7 Hz, 1H), 5.23 (s, 2H), 4.20 – 4.15 (m, 1H), 4.03 (s, 3H), 3.67 (tt, J = 7.9,
6.3 Hz, 1H), 2.22 (dtd, J = 13.1, 8.2, 4.8 Hz, 1H), 2.16 – 2.11 (m, 1H), 1.88 – 1.77 (m, 2H), 1.69
(ddt, J = 13.1, 9.5, 6.5 Hz, 1H), 1.60 (ddt, J = 13.4, 9.2, 7.9 Hz, 1H).
13
C NMR (151 MHz, Methylene Chloride-d2; δ, ppm): 166.59, 163.90, 162.80, 152.67, 149.04,
133.06 (d, J = 2.9 Hz), 130.22 (d, J = 8.1 Hz), 121.41, 120.23, 115.93, 115.79, 112.30, 106.50,
78.48, 70.93, 62.96, 56.39, 32.08, 30.80, 20.40.
19
F NMR (564 MHz, Methylene Chloride-d2; δ, ppm): -114.70 (tt, J = 8.9, 5.4 Hz).
APCI-MS (TOF): exact for C22H24FN2O6S [M + H]+ m/z 463.1334, accurate m/z 463.1347
(Δ = 2.8 ppm).
N
O
O
F
O
FO
2
S
NH
2
HO
DMSO
DIPEA
TMDS
HOBTt (1 mol%)
N
O
O
F
O
S
O
O
NH
OH
+
32
33
210

Synthesis of BRI-13912

In a 50 mL round bottom flask, dibenzo[b,d]thiophene-4-carbaldehyde (1.0 eq., 500 mg, 2.36
mmol) was dissolved in 8 mL ethanol. Potassium carbonate (1.2 eq., 390 mg, 2.83 mmol) and
hydroxylamine (2.0 eq., 327 mg, 4.71 mmol) were dissolved in 2 mL water and added
dropwise to the aldehyde solution. After stirring at room temperature for 24 h, the reaction
was quenched with cold water and dilute hydrochloric acid was added until the solution was
brought down to a pH of 6-7. After extraction to dichloromethane (3x 10), the combined
organic layers were washed with brine and dried with sodium sulfate to obtain the product
(34) as an off-white solid (92%, 490 mg) that was used for chlorination without further
purification.
1
H NMR (400 MHz, Chloroform-d, 8 of 9
1
H signals observed; δ, ppm): 8.48 (s, 1H), 8.27 –
8.18 (m, 2H), 7.94 – 7.89 (m, 1H), 7.56 – 7.52 (m, 2H), 7.51 – 7.47 (m, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 150.39, 141.21, 136.84, 135.98, 134.80, 128.98,
127.14, 126.78, 124.69, 124.46, 122.99, 122.87, 121.65.
APCI -MS (TOF): measured m/z 227.0401, calcd for C13H9NOS [M]
•+
m/z 227.0399
(Δ = 0.88 ppm).

S
O
S
N
OH
NH
3
OHCl
EtOH/H
2
O
K
2
CO
3
+
DMF, 0˚C to rt
S
N
OH
S
N
OH Cl
NCS
34
34 35
211

In a 50 mL round bottom flask, 34 (1.0 eq., 200 mg, 0.49 mmol) was dissolved in 6 mL DMF.
NCS (1.1 eq., 109 mg, 1.07 mmol) was added at 0˚C and the reaction was warmed up to room
temperature and stirred at room temperature for 5 h. The resulting mixture was extracted
with DCM (3x 10) and washed with water to obtain the product (35) as a yellow solid (86%,
101 mg).
1
H NMR (400 MHz, Chloroform-d, 7 of 8
1
H signals observed; δ, ppm): 8.28 (dd, J = 7.9, 1.1
Hz, 1H), 8.22 – 8.17 (m, 1H), 8.12 (dd, J = 7.7, 1.1 Hz, 1H), 7.91 – 7.87 (m, 1H), 7.59 (t, J = 7.8
Hz, 1H), 7.52 – 7.47 (m, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 141.06, 139.20, 136.89, 136.70, 134.82, 127.90,
127.27, 126.83, 124.75, 124.44, 123.70, 122.64, 121.68.
APCI -MS (TOF): measured m/z 225.0245, calcd for C13H7NOS [M-HCl]
•+
m/z 225.0243
(Δ = 0.89 ppm).

In a 20 mL scintillation vial, 35 (1.0 eq., 70 mg, 0.27 mmol) was dissolved in 7 mL DCM and
cooled to 0˚C. NEt3 (1.0 eq., 19 mg, 0.19 mmol) was added and the solution was stirred for
20 minutes. Br-ESF (2.0 eq., 72 mg, 0.38 mmol) was added dropwise at 0˚C and the solution
was warmed to rt and stirred. After 1 hour, another equivalent of NEt3 was added (1.0 eq.,
19 mg, 0.19 mmol), and the reaction was stirred for 20 hours. After rotary evaporation of the
S
N
OH
Cl
FO
2
S Br
NEt
3
DCM, rt, 20h
S
N
O
FO
2
S
+
35 36
212
solvent, the crude mixture was purified by column chromatography (SiO2, 25% DCM in
Hexanes) to obtain the product (36) as a white crystalline solid (12%, 7.3 mg).
1
H NMR (400 MHz, Chloroform-d; δ, ppm): 8.37 (dd, J = 7.9, 0.9 Hz, 1H), 8.26 – 8.21 (m, 1H),
7.99 – 7.93 (m, 1H), 7.84 (dq, J = 7.6, 1.0 Hz, 1H), 7.72 (dd, J = 1.4, 0.8 Hz, 1H), 7.68 – 7.61 (m,
1H), 7.58 – 7.50 (m, 2H).
13
C NMR (100 MHz, Chloroform-d; δ, ppm): 140.39, 137.88, 137.59, 134.61, 127.75, 127.54,
126.86, 125.05, 124.80, 124.56, 123.18, 122.94, 121.86, 120.95, 110.62 (d, J = 3.6 Hz).
19
F NMR (564 MHz, Chloroform-d; δ, ppm): 64.74.
APCI -MS (TOF): measured m/z 332.9931, calcd for C15H8FNO3S2 [M]
•+
m/z 332.9924
(Δ = 2.1 ppm).

In a 10 mL reaction tube, 36 (1.2 eq., 7.3 mg, 0.02 mmol) was dissolved in 0.5 mL DMSO.
Subsequently, 4-(pyrrolidin-2-yl)pyrimidine (1.0 eq., 2.7 mg, 0.018 mmol), HOBt (1 mol%),
1,1,3,3-tetramethyldisiloxane (2.0 eq., 4.9 mg, 0.036 mmol), and DIPEA (2.0 eq., 4.7 mg, 0.036
mmol) were added and the reaction was stirred at rt for 24 hours. After rotary evaporation
of the solvent, the crude mixture was purified by column chromatography (SiO2, DCM → 5%
MeOH in DCM) to obtain the product (37, BRI 13912) as a mixture of two enantiomers as
an off-white solid (12%, 7.3 mg).
1
H NMR (600 MHz, Methylene Chloride-d2; δ, ppm): 9.11 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 5.1
Hz, 1H), 8.39 (dd, J = 7.9, 1.1 Hz, 1H), 8.33 – 8.25 (m, 1H), 8.08 – 7.93 (m, 1H), 7.87 (dd, J =
N
H
N
N
N
O
S
O O
N
N
N
+
DMSO, rt, 24h
S
N
O
S
O O
S
F
DIPEA
TMDS
HOBt (1 mol%)
36
37
213
7.5, 1.1 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.62 – 7.51 (m, 3H), 7.38 (s, 1H), 5.03 (dd, J = 8.5, 3.8
Hz, 1H), 3.94 – 3.79 (m, 1H), 3.79 – 3.62 (m, 1H), 2.41 – 2.24 (m, 1H), 2.24 – 2.09 (m, 1H),
2.09 – 1.98 (m, 1H), 1.98 – 1.87 (m, 1H).
13
C NMR (151 MHz, Methylene Chloride-d2; δ, ppm): 169.82, 165.66, 162.34, 159.11, 158.16,
141.02, 138.01, 137.82, 135.23, 128.04, 127.46, 125.41, 125.30, 124.56, 123.29, 122.45,
122.30, 119.02, 107.76, 64.94, 50.74, 34.17, 24.85.
APCI -MS (TOF): measured m/z 463.0901 calcd for C23H19N4O3S2 [M+H]
+
m/z 463.0893
(Δ = 1.7 ppm).

4.6 Stereochemical Analysis of Compounds

All potential stereoisomers for the six hit compounds were individually docked (see
Table 4.10) to see the impact of stereochemistry on the binding score. The binding scores
slightly vary from the initial calculations likely due to software upgrades and time since the
initial docking was done, however, there were no major changes in predicted binding score.
After the binding scores of all individual stereoisomers were determined chiral HPLC was
used to examine the compounds that were synthesized and determine the number of
stereoisomers.

BRI-13900 was isolated as a mixture of two diastereomers with two enantiomers each.
Chiral SFC: 250 mm ChiralPak IG–3, 15% MeOH, 3.0 mL/min, λ = 270 nm, 35 °C, nozzle
pressure = 140 bar CO2, tR1 (major) = 6.021 min, tR2 (major) = 6.578 min, tR3 (minor) = 8.547
min, tR4 (minor) = 11.424 min.

214

Peak
#
Retention
Time
Type Width Quantity Height Area Area
[Min] [Min] [% Area] [mAU] [mAU*s] [%]
1 6.021 MF 0.1713 26 36.31330 373.32098 26.1242
2 6.578 FM 0.1859 24 30.53725 340.60007 23.8345
3 8.547 MM 0.2413 24 23.51103 340.45648 23.8244
4 11.424 MM 0.3230 26 19.32999 374.64429 26.2168

Total 100 109.69157 1429.02182 100

BRI-13901 was isolated as a mixture of two diastereomers.
Chiral SFC: 250 mm ChiralPak IC–3, 20% MeOH, 3.0 mL/min, λ = 210 nm, 35 °C, nozzle
pressure = 140 bar CO2, tR1 = 13.170 min, tR2 = 14.037 min.

Peak
#
Retention
Time
Type Width Quantity Height Area Area
[Min] [Min] [% Area] [mAU] [mAU*s] [%]
1 13.170 MM 0.4226 49 51.83939 1314.47766 48.8586
2 14.037 MM 0.4739 51 48.38411 1375.89343 51.1414

Total 100 100.22350 2690.37109 100

BRI-13903 was isolated as a mixture of two isomers.
215
Chiral SFC: 250 mm ChiralPak IJ–3, 40% MeOH, 3.0 mL/min, λ = 270 nm, 35 °C, nozzle
pressure = 140 bar CO2, tR1 = 4.773 min, tR2 = 6.211 min.

Peak
#
Retention
Time
Type Width Quantity Height Area Area
[Min] [Min] [% Area] [mAU] [mAU*s] [%]
1 4.773 MM 0.1616 50 27.17681 263.51401 50.2453
2 6.211 MM 0.2059 50 21.12261 260.94098 49.7547

Total 100 48.29942 524.45499 100

BRI-13911 as one diastereomer with two enantiomers.
Chiral SFC: 250 mm ChiralPak IJ–3, 20% MeOH, 3.0 mL/min, λ = 270 nm, 35 °C, nozzle
pressure = 140 bar CO2, tR1 = 6.854 min, tR2 = 8.219 min.

Peak
#
Retention
Time
Type Width Quantity Height Area Area
[Min] [Min] [% Area] [mAU] [mAU*s] [%]
1 6.854 MM 0.2128 50 55.60233 709.85291 50.4697
2 8.219 MM 0.2471 50 46.98981 696.64111 49.5303

Total 100 102.59858 1406.49402 100

216
BRI-13912 was isolated as a mixture of two enantiomers.
Chiral SFC: 250 mm ChiralPak IJ–3, 40% MeOH, 3.0 mL/min, λ = 270 nm, 35 °C, nozzle
pressure = 140 bar CO2, tR1 = 10.568 min, tR2 = 11.156 min.

Peak
#
Retention
Time
Width Quantity Height Area Area
[Min] [Min] [%
Area]
[mAU] [mAU*s] [%]
1 10.568 0.2628 51 4.55702 71.85730 51.0634
2 11.156 0.2927 49 3.92095 68.86440 48.9366

Total 100 8.47797 140.7217 100

Table 4.10 Binding Data of Stereoisomers
mol
L
IX
Name
Score
Natom
Nflex
Hbond
Hphob
VwInt
Eintl
Dsolv
SolEl
mfScore
RTCNNsc
ore
dTSsc
217

0
1
BRI-13900_s1
-25.806923
57
6
0
-9.753899
-39.148998
11.076478
8.675733
4.734095
-230.126877
-32.00317
1.608574

0
2
BRI-13900_s2
-29.918043
57
6
0
-9.995556
-41.38612
9.452932
8.447218
3.875644
-227.284286
-31.5588
1.602925

0
3
BRI-13900_s3
-34.355919
57
6
-4.025951
-9.511232
-36.127266
6.476428
7.32171
8.109684
-174.282562
-29.427212
1.447101
218

0
4
BRI-13900_s4
-41.028988
57
6
-3.717223
-9.586307
-41.687447
6.759962
8.199816
4.06064
-222.74527
-27.166588
1.458481

0
5
BRI-13901_s1
-42.531013
60
7
-3.186673
-9.993904
-44.941086
7.689745
7.437324
4.206711
-222.466782
-35.989174
1.528997

0
6
BRI-13901_s2
-36.416542
60
7
-3.329788
-9.488514
-41.677975
11.670076
7.956765
4.353763
-214.458298
-33.704315
1.517779
219

0
7
BRI-13901_s3
-33.843506
60
7
-2.588446
-10.077561
-40.509922
8.043902
8.537982
6.874729
-234.017548
-36.063187
1.651332

0
8
BRI-13901_s4
-32.53764
60
7
-1.051212
-10.093682
-43.763428
5.914472
9.205955
9.083293
-229.408752
-39.922859
1.67612

0
9
BRI-13901_s5
-33.675266
60
7
-1.090096
-10.458963
-44.557758
5.699984
8.697262
9.856068
-247.278748
-34.749115
1.667702
220

0
10
BRI-13901_s6
-30.790386
60
7
-0.968187
-9.86281
-42.681976
7.721872
8.713428
8.456051
-236.20105
-37.687992
1.694973

0
11
BRI-13901_s7
-41.213333
60
7
-3.157236
-10.195314
-42.767498
3.972411
8.778972
4.856295
-224.006714
-32.496891
1.612996

0
12
BRI-13901_s8
-42.522823
60
7
-2.982063
-10.104442
-43.318184
4.876936
7.665326
3.386058
-212.93399
-32.0979
1.566351
221

0
13
BRI-13901_s9
-32.469185
60
7
-1.078339
-10.425954
-37.695377
5.511527
9.205239
0.801414
-240.41748
-31.028143
1.795034

0
14
BRI-13901_s10
-24.861099
60
7
-0.974484
-10.717857
-38.587559
8.382482
9.483444
10.652726
-255.017059
-31.005913
1.841191

0
15
BRI-13901_s11
-34.294132
60
7
-2.749314
-10.119147
-38.210281
6.395712
9.350062
3.942071
-238.26825
-35.915287
1.718388
222

0
16
BRI-13901_s12
-32.775932
60
7
-2.989838
-10.135789
-35.855331
7.206405
9.280016
2.955776
-223.643784
-28.260321
1.718659

0
17
BRI-13901_s13
-32.726929
60
7
-3.276649
-9.911426
-34.375713
3.955555
9.616322
4.233012
-230.60791
-32.230659
1.62361

0
18
BRI-13901_s14
-27.938765
60
7
-1.10524
-10.429428
-38.583313
8.981125
8.783731
6.442498
-249.420242
-32.99424
1.729414
223

0
19
BRI-13901_s15
-31.676514
60
7
-0.972819
-9.983348
-41.268581
7.702927
8.650461
5.200817
-232.826935
-41.04546
1.705218

0
20
BRI-13901_s16
-34.319508
60
7
-3.264097
-10.197858
-36.786343
7.914679
7.623071
4.380991
-208.641327
-32.601089
1.574501

0
21
BRI-13903_s1
-28.365345
54
6
0
-9.404168
-40.840916
6.891068
8.626509
6.92703
-218.39006
-23.406178
1.585635
224

0
22
BRI-13903_s2
-40.62458
54
6
-3.266137
-9.340856
-41.307617
4.719787
8.35903
3.793319
-219.051682
-22.734283
1.441533

0
23
BRI-13907
-35.230923
55
3
-2.944052
-10.110346
-39.803528
6.807808
11.293488
6.727555
-211.367538
-31.093004
1.716083

0
24
BRI-13911_s1
-27.066429
55
6
-2.471601
-10.252729
-37.452686
6.294534
13.819608
8.738349
-242.517502
-28.019571
1.741192
225

0
25
BRI-13911_s2
-31.484486
55
6
-1.15396
-9.521308
-41.12291
5.733779
8.446819
8.427025
-238.293777
-28.811842
1.411572

0
26
BRI-13911_s3
-28.748611
55
6
-2.34921
-9.983671
-38.659729
3.951519
14.139726
9.042384
-233.003738
-31.225903
1.7157

0
27
BRI-13911_s4
-34.461239
55
6
-3.542769
-9.857198
-39.622662
9.454711
8.816618
7.338885
-212.135468
-27.823681
1.484442
226

0
28
BRI-13912_s1
-34.639214
50
3
0
-9.856065
-41.648106
4.023137
9.215116
3.768539
-218.068253
-33.943161
1.52787

0
29
BRI-13912_s2
-42.695763
50
3
-3.888982
-9.858897
-40.806828
2.575232
9.132936
6.607281
-225.599701
-32.140602
1.550751

4.7 Biological Studies Validating Binding

The eleven compounds that were successfully synthesized were then tested in CB2
functional assays. Tango arrestin recruitment assays were performed to determine the
functional potency in CB1/Cb2 as previously described.
146
In order to determine the affinities
(Ki) for the compounds radioligand binding assays were done using CB1 and CB2 receptors,
as previously described.
147, 148
There were six compounds that showed binding affinities to
227
the CB2 receptor below 10µM, two of which showed sub-micromolar binding affinities
(Figure 4.2).

Figure 4.2 Chemical Structure of Six Hit Compounds

The hits included compounds from both the triazole and isoxazole libraries and
achieved chemical diversity despite their common heterocyclic scaffold. The predicted
binding poses of the experimentally confirmed hits show that all compounds aside from BRI-
13911 have an aromatic moiety in the hydrophobic pocket formed by residues F183, I186,
Y190, L191, and W194. Hydrogen bonds appear to be crucial for the docking poses of BRI-
13907 and 13911 as the hydroxy and pyrrole groups can form H-bonds with residues F87
and Y25, respectively.
Binding Data

N
OH
N
N
N
S
O
O
Cl
N
N
N
S
O
O
N
N
N
N
N
N
S
O
O
N
N
N
F
O
O
O
N
S
O
O
HN
HO
O
N
S
O
O
N
S
N
N
N
O
S
O
O
O
N
N
O
HN
Cl
BRI-13900 BRI-13901
BRI-13903
BRI-13907
BRI-13911 BRI-13912
228

Figure 4.3 Dose-response curves of cannabinoid receptors with the hits.*

*The relative antagonist activity of hits to CB1 (A) and CB2 (B) receptors were determined by
β-arrestin recruitment tango assay. The compounds rimonabant (A) and SR144528 (B) were
used as positive controls. The assays were carried out in the presence of 100 nM (EC80) of
the dual CB1/CB2 agonist CP55,940. The data were presented as mean ± SEM with three
technical replicates and n=3 biological replicates

Figure 4.4 Primary screening of the V-SYNTHES predicted compounds with β-arrestin
recruitment tango assay.**
229
**All the predicted compounds were tested at 10 µM concentrations. (A-B) Relative agonist
activity of CB1 (A) and CB2 (B) receptors. The dual CB1/CB2 agonist CP55,940 at 1 µM was
used as a positive control, and DMSO was used as a negative control. (C-D) Relative
antagonist activity of CB1 (C) and CB2 (D) receptors. 10 µM of Rimonabant (C) or SR144528
(D) was used as a positive control, and DMSO was used as a negative control. The assays were
carried out in the presence of 100 nM (EC80) of CP55,940. All the data were presented as
mean ± SEM (n=4) and normalized the relative positive controls, respectively.

230
Appendix F: Characterization Data of Six Hit Final Compounds

BRI-13900
Figure 4.5
1
H NMR spectrum of BRI-13900 in DMSO.

Figures 4.6
13
C NMR spectrum of BRI-13900 in DMSO.
N
N
N
S
O
O
N
N
N
BRI-13900
231
BRI-13901

Figure 4.7
1
H NMR spectrum of BRI-13901 in DMSO.

Figures 4.8
13
C NMR spectrum of BRI-13901 in DMSO.
N
OH
N
N
N
S
O
O
Cl
BRI-13901
232
BRI-13902

Figure 4.9
1
H NMR spectrum of BRI-13902 in DMSO.

Figure 4.10
13
C NMR spectrum of BRI-13902 in DMSO.
N
N
N
S
O
O
Cl
HN
OH
BRI-13902
233
BRI-13903

Figure 4.11
1
H NMR spectrum of BRI-13903 in DMSO.

Figure 4.12
13
C NMR spectrum of BRI-13903 in DMSO.
N
N
N
S
O
O
N
N
N
BRI-13903
234
BRI-13904

Figure 4.13
1
H NMR spectrum of BRI-13904 in DMSO.

Figure 4.14
13
C NMR spectrum of BRI-13904 in DMSO.
N
N
N
S
O
O
N
H
N
NH
N
BRI-13904
235
BRI-13905

Figure 4.15
1
H NMR spectrum of BRI-13905 in DMSO.

Figure 4.16
13
C NMR spectrum of BRI-13905 in DMSO.
N
N
N
S
O
O
NH
N
NH
BRI-13905
236
BRI-13906

Figure 4.17
1
H NMR spectrum of BRI-13906 in DMSO.

Figure 4.18
13
C NMR spectrum of BRI-13906 in DMSO.
BRI-13906
N
N
N
S
O
O
N
N
N N
Cl
O
237
BRI-13907

Figure 4.19
1
H NMR spectrum of BRI-13907 in DMSO.

Figure 4.20
13
C NMR spectrum of BRI-13907 in DMSO.
N
O
S
O
O
O
N
N
O
HN
Cl
BRI-13907
238
BRI-13910

Figure 4.21
1
H NMR spectrum of BRI-13910 in DMSO.

Figure 4.22
13
C NMR spectrum of BRI-13910 in DMSO.

O
Cl
Cl
O
N
S
O
O
N
HN N
BRI-13910
239
BRI-13911

Figure 4.23
1
H NMR spectrum of BRI-13911 in CDCl3.

Figure 4.24
13
C NMR spectrum of BRI-13911 in CD2Cl2.

F
O
O
O
N
S
O
O
HN
HO
BRI-13911
240
BRI-13912

Figure 4.25
1
H NMR spectrum of BRI-13912 in CD2Cl2.

Figure 4.26
13
C NMR spectrum of BRI-13912 in CD2Cl2.
O
N
S
O
O
N
S
N
N
BRI-13912
241
Distribution of Credit

This project was started by Dr.Katharina Grotsch, Dr.Joice Thomas in collaboration with
Dr.Vsevolod Katrich and members of his lab; Dr.Anastasiia Sadybekov and Dr. Saheem Zaidi.
All computational aspects and studies including the VLS were performed by them while our
group focused on synthetic components. I worked with both Dr.Katharina Grotsch and
Dr.Dmitry Eremin on the synthesis of the final compounds and their analysis. Biological
studies were performed by our collaborators at Northeastern University and the University
of North Carolina. Analysis of stereoisomers was performed by Cesar Reyes and Dr.Elias
Picazo using chiral HPLC. Thank you to all our wonderful collaborators on this project, it
would not have been possible without you.

242
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Creator Hiller, Sydney Rose (author)

Core Title Expanding the chemical space by utilizing the efficiency and versatility of click reactions to unveil potent molecular scaffolds

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Degree Conferral Date 2023-08

Publication Date 06/06/2024

Defense Date 05/08/2023

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemical space,chemistry,click chemistry,click reactions,isoxazoles,molecular scaffolds,OAI-PMH Harvest,organic chemistry,triazoles,virtual ligand screening

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Language English

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Advisor Fokin, Valery V. (committee chair), Katritch, Vsevolod (committee member), Picazo, Elias (committee member)

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