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Probing fluorinated carbenes: a pathway to fluoroalkylation

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Probing fluorinated carbenes: a pathway to fluoroalkylation

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Content Probing Fluorinated Carbenes: A Pathway to
Fluoroalkylation
By
Ziyue Zhu
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)
DECEMBER 2024
Copyright 2024 Ziyue Zhu

ii
Dedication
This dissertation is dedicated to my wife, Fangyi Zhou, my parents, Dr. Zhencai Zhu
and Lili Zhu, my daughter, Ellie Zhu, my parents in-law, Lihong Zhang and Yinghui
Zhou for their unconditional love and support.
In the magnificent world of chemistry, I soar.

iii
Acknowledgements
First, I want to express my gratitude and respect to my mentor, Prof. Dr. G. K.
Surya Prakash. He took me in as a graduate student without hesitation and provided me
with unconditional trust. This means a lot to me because I was questioning myself if I
could be a qualified graduate student at that time. I am very lucky and proud to
accomplish my graduate education in his group where I had complete freedom to work
on any interesting projects. Moreover, Dr. Prakash created a collaborative and friendly
environment where I felt welcomed, respected, and trusted to perform high quality
research. His influence on me is not limited to science but also on how to be a good
colleague and a good person. I would also like to thank my mentor at Shanghai
Institution of Organic Chemistry, Prof. Dr. Jinbo Hu who offered an opportunity to get
on the right track and be prepared for graduate school with high quality training. I still
remember before I left SIOC, you told me that I would do very well if I was a graduate
student in your group. In addition, I would like to thank Dr. Qiqiang Xie who was a
senior PhD student in SIOC at that time. He is a sharp and knowledgeable chemist, and
trained me with extensive patience from the beginning even till now. In addition to the
fundamental skills and techniques of organic chemistry, he also taught me how to think
like a fluorine chemist. I learnt a lot from him not just as a chemist but also as a helpful
senior student in the lab. I also want to thank Prof. Dr. Mark Maroncelli and Prof. Dr.
Forrest Landis from Penn State University. Mark kindly took me in as an undergraduate
student despite my ignorance in chemistry. He and his group members treated me with
kindness and patience which let me have a taste of graduate school. Dr. Landis taught

iv
my general chemistry and organic chemistry classes in the freshman year and
sophomore year. I have to say his classes are very very very difficult, but I was able to
learn some real chemistry instead of just getting a good score from his class. And he is
actually the first professor who encouraged me to pursue a PhD degree. I still remember
that you revised my Chem 111 lab reports word by word and encouraged me when my
English improved after the first half semester.
I would like to thank my parents Dr. Zhencai Zhu and Lili Zhu for their unconditional
support and love throughout my life. No matter what I wanted to try, you always
encourage me and try to provide the best resource for me so that I can focus on the
important matters. I also want to thank my wife, best friend and soulmate, Fangyi Zhou
for the constant support, trust and love. Only when I am with you, I feel relief from the
pressure of graduate school. You make me become a better, responsible and mature
person and I look forward to continuing our journey together for the rest of my life. I
also want to thank my parents-in-law, Lihong Zhang and Yinghui Zhou, for supporting
me and accepting me as your own son. I am very grateful that you took very nice care
of Ellie and me which helped me focus on my research. I want to thank my little
daughter Ellie Zhu who is the cutest baby in this world. You motivated me to improve
into a good father.
In the last section, I would like to thank my senior PhD students in lab. Vinayak,
Xanath and Colby, you are good mentors not just in lab, but also in life. Thank you for
guiding me to do high-quality research independently and also bringing me to all kinds
of activities off-work. You taught me a lot of things about America and made me start

v
to think of staying in the United States after graduation. I also would like to thank Dr.
Bo Yang, for taking care of me like a big brother during my PhD. I will always
remember your kindness. I would also like to thank Yijie Xu, the first student I
mentored. Mentoring you is also a unique learning experience for me. You are a good
chemist with great potential. Be confident. Other current and previous lab members, CJ,
Matt, Alex, Daniel, Sam, Thomas, Raktim, Fang, Sahar, Anushan, Zohaib, Eric, Prince,
Shiladitya, Hamid, Ryuichi, Yeshvi, Antonio for creating a collaborative, respectful and
friendly environment. I really enjoyed discussing chemistry and chit chatting with all
of you. I know sometimes I can be talkative, and I am grateful that all of you are patient
to me. I wish all of you the best of luck in your career. I also want to thank Prof. Dr.
Chao Zhang, Jiaqi Thang and Yida Zhang for being a very helpful collaborator and
friends who are always ready to help. Especially Jiaqi, it is a great pleasure to work
with you. I also want to acknowledge senior lab members, Dr. Robert Aniszfeld, Dr.
Alain Goeppert and Dr. Patrice Batamack for always providing wise advice when I have
problems and questions. Thank you to all the LHI staff, Jessy May, Carole Philips,
David, Hunter, Michele Dea, and Gloria Canada for your dedication to make sure this
institution runs smoothly. For my mentor at Pfizer during my internship, Dr. Chase
Salazer. Thank you for being a great mentor and giving me this opportunity to
experience the workflow in big pharma. I also want to thank my friends in China,
Chengjun Zhang, Haoliang Wang, Yanxin Shen, Xiaotian Zhu, Guangwei Meng, Yang
Li, Yuming Huang, Yue Xia, Tai Ma, Jiajun Yue, Jiachen Xu, Naiyi Hu, Haixing Wang,
Guangzhi Tang, Yuanye Yang and Zhichu Sun. Thank you all for being supportive and

vi
bring me happiness and sense of accompany.
Finally, I would like to thank again for everyone I mentioned above and everyone
who helped me, but I forgot to mention. Without any of you, I cannot achieve anything.
Therefore, this dissertation is dedicated to all of you!

vii
List of Publications
1. Zhu, Z.; Krishnamurti, V.; Isupizua-Rodriguez, X.; Barrett, C.; Prakash, G.K.S.
Chemoselective N- and O-difluromethylation of 2-pyridones, isoquinolinones, and
Quinolineones with TMSCF2Br. Org. Lett. 2021, 23, 6494-6498
2. Zhu, Z.; Krishnamurti, V.; Koch, C.J.; Isupizua-Rodriguez, X.; Barrett, C.; Prakash,
G.K.S. Synthesis of difluoromethylated formimidamides from primary aryl amines
using TMSCF2Br as a dual C1 synthon. J. Fluor. Chem. 2022, 261−262, 110023
3. Zhu, Z.; Tang, J.; Kyriazakos, S.; Knieb, A.; Xu, Y.; Zhang, C.; Prakash, G.K.S.
Mono- and difluoromethylation of 3(2H)-pyidazinones. Org. Lett. 2024, 26, 8106-
8109
4. Zhu, Z.; Tang, J.; Coe, M.; Knieb, A.; Xu, Y.; Lin, D.; Zhang, C.; Prakash, G.K.S.
Access to 2,2-halofluorobicyclo[1.1.1]pentanes via non-ozone-depleting ethyl
dihalofluoroacetate. Submitted to Angew. Chem. Int. Ed.
5. Barrett, C.; Krishnamurti, V.; Isupizua-Rodriguez, X.; Zhu, Z.; Koch, C.J.; Prakash,
G.K.S. gem-Halofluorocyclopropanes via [2 + 1]cycloadditions of in situ generated
CFX carbene with alkenes. Org. Lett. 2022, 24, 5417-5421
6. Knieb, A.; Krishnamurti, V.; Zhu, Z.; Prakash, G.K.S. Monofluoromethylarenes:
direct monofluoromethylation of diaryliodonium bromides using
fluorobis(phenylsulfonyl)methane (FBSM). J. Fluor. Chem. 2023, 267, 110095
7. Zhu, Z.; Carbonyldiimidazole (CDI) as an efficient replacement of triphosgene for
trifluoromethoxylation (Work in progress)
8. Zhu, Z.; Investigation on TMSCF2Br as a potential difluorocarbene source for 18F-

viii
labeled trifluoromethylation. (Work in progress)

ix
Table of Contents
Dedication........................................................................................................................................ii
Acknowledgements........................................................................................................................ iii
List of Publications........................................................................................................................vii
List of Tables................................................................................................................................xvii
List of Schemes and Figures..................................................................................................... xviii
Abbreviation..................................................................................................................................xx
Abstract........................................................................................................................................xxii
Chapter 1: Introduction .................................................................................................................1
1.1 The fluorine atom. Introduction of organofluorine and relevant advances.........................1
1.2 Monofluoromethylation ......................................................................................................3
1.2.1 Nucleophilic monofluoromethylation ......................................................................4
1.2.2 Electrophilic monofluoromethylation ......................................................................6
1.2.3 Radical monofluoromethylation.............................................................................11
1.3 Difluoromethylation..........................................................................................................14
1.3.1 Electrophilic difluoroemthylation via TMSCF2Br.................................................17
1.3 Trifluoromethylation .........................................................................................................29
1.3.1 Nucleophilic trifluoromethylation..........................................................................30
1.3.2 Electrophilic trifluoromethylation..........................................................................33
1.3.3 Transition metal-catalyzed trifluoromethylation....................................................36
1.3.4 Radical trifluoromethylation ..................................................................................38
18F labeled trifluoromethylation......................................................................................40
1.4 Trifluoromethoxylation .....................................................................................................51
Nucleophilic trifluoromethoxylation...............................................................................53
Radical trifluoromethoxylation .......................................................................................65
Chapter 2 .......................................................................................................................................68
2.1 Introduction.......................................................................................................................68
2.2 Results and discussion ......................................................................................................72
2.3 Conclusion ........................................................................................................................78
2.4 Experimental data. General procedures and characterization data....................................78
Procedure for synthesis of S2 .......................................................................................78
General Procedure for the synthesis of S3t, S3v – S3x...............................................79
Procedure for the synthesis of S3u...............................................................................80
General Procedure for the synthesis of S4t – S4x.......................................................81
General procedure for the synthesis of 2a – 2x...........................................................81
General procedure for the synthesis of 3a – 3e, 3h, 3i, 3k – 3m, 3t –3x....................82
Procedure for the large scale (gram-scale) synthesis of 2b........................................83
Procedure for the large scale (gram-scale) synthesis of 3b........................................84
5-bromopyridin-2-yl 4-methylbenzenesulfonate (S2).................................................84
5-(4-Vinylphenyl)pyridine-2-yl 4-methylbenzenesulfonate (S3t)..............................85
tert-Butyl 4-(6-(tosyloxy)pyridin-3-yl)benzoate (S3v) ................................................85
5-(4-(Methylthio)phenyl)pyridin-2-yl 4-methylbenzenesulfonate (S3w)..................86
5-(4-Fluorophenyl)pyridin-2-yl-4-methylbenzenesulfonate (S3x).............................86

x
5-(Thiophen-3-yl)pyridin-2-yl 4-methylbenzenesulfonate (S3u)...............................86
5-(4-Vinylphenyl)pyridine-2(1H)-one (S4t).................................................................87
5-(Thiophen-3-yl)pyridin-2(1H)-one (S4u) .................................................................87
tert-Butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoate (S4v)......................................88
5-(4-Methylthio)phenyl)pyridin-2(1H)-one (S4w)......................................................88
5-(4-Fluorophenyl)pyridin-2(1H)-one (S4x)................................................................89
2-(Difluoromethoxy)-5-methylpyridine (2a) ...............................................................89
4-(Benzyloxy)-2-(difluoromethoxy)pyridine (2b) .......................................................90
2-(Difluoromethoxy)-3-methoxypyridine (2c).............................................................90
2-(Difluoromethoxy)-4-methylpyridine (2d)...............................................................91
2-(Difluoromethoxy)-3-methylpyridine (2e)................................................................91
2-(Difluoromethoxy)-6-methylpyridine (2f)................................................................92
4-Bromo-2-(difluoromethoxy)pyridine (2g)................................................................92
5-Bromo-2-(difluoromethoxy)pyridine (2h)................................................................93
2-(Difluoromethoxy)-3(trifluoromethyl)pyridine (2i) ................................................93
2-(Difluoromethoxy)-6-methyl-3-nitropyridine (2j)...................................................94
1-(Difluoromethoxy)isoquinoline (2k) .........................................................................94
6-Bromo-1-(difluoromethoxy)isoquinoline (2l)...........................................................94
7-Bromo-1-(difluoromethoxy)isoquinoline (2m).........................................................95
2-(Difluoromethoxy)quinoline (2n)..............................................................................96
2-(Difluoromethoxy)-4-(trifluoromethyl)quinoline (2o).............................................96
1-((Difluoromethyl)thio)isoquinoline (2p)...................................................................97
Methyl 2-(difluoromethoxy)nicotinate (2q).................................................................97
2-(Difluoromethoxy)-6-(trifluoromethyl)nicotinamide (2r).......................................98
2-(Difluoromethoxy)benzofuro[3,2-b]pyridine (2s)....................................................98
2-(Difluoromethoxy)-5-(4-vinylphenyl)pyridine (2t)..................................................99
2-(Difluoromethoxy)-5-(thiophen-3-yl)pyridine (2u) ...............................................100
tert-Butyl 4-(6-(difluoromethoxy)pyridine-3-yl-benzoate (2v) ................................100
2-(Difluoromethoxy)-5-(4-(methylthio)phenyl)pyridine (2w)..................................101
2-(Difluoromethoxy)-5-(4-fluorophenyl)pyridine (2x) .............................................101
1-(Difluoromethyl)-5-methylpyridin-2(1H)-one (3a)................................................102
4-(Benzyloxy)-1-(difluoromethyl)pyridin-2(1H)-one (3b)........................................102
1-(Difluoromethyl)-3-methoxypyridin-2(1H)-one (3c).............................................103
1-(Difluoromethyl)-4-methylpyridine-2(1H)-one (3d)..............................................104
1-(Difluoromethyl)-3-methylpyridin-2(1H)-one (3e)................................................104
5-Bromo-1-(difluoromethyl)pyridin-2(1H)-one (3h)................................................105
1-(Difluoromethyl)-3-(trifluoromethyl)pyridine-2(1H)-one (3i)..............................105
2-(Difluoromethyl)isoquinoline-1(2H)-one (3k)........................................................106
6-Bromo-2-(difluoromethyl)isoquinolin-1(2H)-one (3l)...........................................106
7-Bromo-2-(difluoromethyl)isoquinoline-1(2H)-one (3m).......................................107
1-(Difluoromethyl)-5-(4-vinylphenyl)pyridine-2(1H)-one (3t) ................................107
1-(Difluoromethyl)-5-(thiophen-3-yl)pyridin-2(1H)-one (3u)..................................108
tert-Butyl 4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-yl-benzoate (3v)....108
1-(Difluoromethyl)-5-(4-(methylthio)phenylpyridin-2(1H)-one (3w) .....................109

xi
1-(Difluoromethyl)-5-(4-fluorophenyl)pyridin-2(1H)-one (3x)................................110
Chapter 3 ..................................................................................................................................... 111
3.1 Introduction..................................................................................................................... 111
3.2 Results and discussion ....................................................................................................112
3.3 Conclusion ......................................................................................................................117
3.4 Experimental data. General procedures and characterization data..................................118
Optimization on Reaction Conditions for Monofluoromethylation of 2a ..............118
Preparation of 1b.........................................................................................................127
Preparation of 1a.........................................................................................................129
General Procedure C – Monofluoromethylation of 2-Pyridaziones.......................129
General Procedure D for Difluoromethylation of 3(2H)-Pyridazinones ................130
((fluoromethyl)sulfinyl)-benzene................................................................................130
S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonioum
tetrafluoroborate (1a) .................................................................................................131
S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonioum triflate (1b)
triflate (1b)...................................................................................................................132
2-(fluoromethyl)phthalazin-1(2H)-one (3a) ..............................................................132
6-fluoro-2-(fluoromethyl)phthalazin-1(2H)-one (3b) ...............................................133
6-chloro-2-(fluoromethyl)phthalazin-1(2H)-one (3c) ...............................................133
6-bromo-2-(fluoromethyl)phthalazin-1(2H)-one (3d) ..............................................134
7-bromo-2-(fluoromethyl)phthalazin-1(2H)-one (3e)...............................................134
4-bromo-2-(fluoromethyl)phthalazin-1(2H)-one (3f) ...............................................135
4-chloro-2-(fluoromethyl)phthalazin-1(2H)-one (3g)...............................................136
2-(fluoromethyl)pyridazin-3(2H)-one (3h)................................................................136
2-(fluoromethyl)-6-methylpyridazin-3(2H)-one (3i).................................................137
6-chloro-2-(fluoromethyl)pyridazin-3(2H)-one (3j) .................................................137
2-(fluoromethyl)-6-phenylpyridazin-3(2H)-one (3k)................................................138
4-chloro-2-(fluoromethyl)-5-methoxypyridazin-3(2H)-one (3l) ..............................138
4,5-dichloro-2-(fluoromethyl)pyridazin-3(2H)-one (3m).........................................139
2-fluoro-5-((3-(fluoromethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzonitrile
methyl)benzonitrile (3n) .............................................................................................140
tert-butyl 4-(2-fluoro-5-((3-(fluoromethyl)-4-oxo-3,4-dihydrophthalazin-1-
dihydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carboxylate (3o) ................140
2-(difluoromethyl)phthalazin-1(2H)-one (5a)...........................................................141
4-bromo-2-(difluoromethyl)phthalazin-1(2H)-one (5f)............................................142
4-chloro-2-(difluoromethyl)phthalazin-1(2H)-one (5g)............................................142
2-(difluoromethyl)-6-methylpyridazin-3(2H)-one (5i) .............................................143
6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one (5j)..............................................143
2-(difluoromethyl)-6-phenylpyridazin-3(2H)-one (5k).............................................144
tert-butyl 4-(5-((3-(difluoromethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-
methyl)-2-fluorobenzoyl)piperazine-1-carboxylate (5o)..........................................144
1-bromo-4-(difluoromethoxy)phthalazine (6f)..........................................................145
1-chloro-4-(difluoromethoxy)phthalazine (6g) .........................................................146
2-(difluoromethyl)-6-methylpyridazin-3(2H)-one (6i) .............................................146

xii
6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one (6j)..............................................147
2-(difluoromethyl)-6-phenylpyridazin-3(2H)-one (6k).............................................147
6o...................................................................................................................................148
Investigating bis-difluoromethylated byproduct ...................................................................149
16p ................................................................................................................................149
Proposed Mechanism of the formation of 16p..........................................................150
Chapter 4 .....................................................................................................................................151
4.1 Introduction.....................................................................................................................151
4.2 Results and discussion ....................................................................................................153
4.3 Conclusion ......................................................................................................................160
4.4 Experimental data. General procedures and characterization data..................................160
(E)-N-(difluoromethyl)-N,N'-di-p-tolylformimidamide (2a)....................................161
(E)-N-(difluoromethyl)-N,N'-di-m-tolylformimidamide (2b)..................................162
(E)-N,N'-bis(4-(4-chlorophenoxy)phenyl)-N-(difluoromethyl)formimidamide (2c)
formimidamide (2c).....................................................................................................163
(E)-N-(difluoromethyl)-N,N'-bis(4-methoxyphenyl)formimidamide (2d)..............163
(E)-N,N'-bis(4-(tert-butyl)phenyl)-N-(difluoromethyl)formimidamide (2e)...........164
(E)-N-(difluoromethyl)-N,N'-bis(4-fluorophenyl)formimidamide (2f)...................165
(E)-N,N'-bis(4-chlorophenyl)-N-(difluoromethyl)formimidamide (2g)..................166
(E)-N,N'-bis(3-bromophenyl)-N-(difluoromethyl)formimidamide (2h) .........................166
(E)-N,N'-bis(4-(difluoromethoxy)phenyl)-N-(difluoromethyl)formimidamide (2i)
formimidamide (2i) .....................................................................................................167
(E)-N-(difluoromethyl)-N,N'-bis(4-ethynylphenyl)formimidamide (2j).................168
2k ..................................................................................................................................169
5,6-dichloro-1-(difluoromethyl)-1H-benzo[d]imidazole (2l)....................................170
5(6)-bromo-1-(difluoromethyl)-1H-benzo[d]imidazole (2m)...................................170
Chapter 5 .....................................................................................................................................172
5.1 Introduction.....................................................................................................................172
5.2 Results and discussion ....................................................................................................174
5.3 Conclusion ......................................................................................................................181
5.4 Experimental Data. General procedures and characterization data.................................182
General procedures to prepare bicylco[1.1.0]butanes (S5)......................................182
General procedure 5: preparation of 2a-2i (2a was used as an example)...............187
General procedure 6: preparation of 3a-3g, and 3i (3a was used as example) ......188
General Procedure 7: one-pot deprotection of 1h to 4h...........................................189
General procedure 8: Deprotection of esters (5a was used as example).................190
Procedures of post-functionalization reactions.........................................................190
Procedure to prepare BCP-, and analogues..............................................................197
3-Hydroxy-3-phenylcyclobutane-1-carboxylic acid (S2a)........................................198
tert-Butyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (1a)....................................199
tert-Butyl 3-(o-tolyl)bicyclo[1.1.0]butane-1-carboxylate (1b)..................................199
tert-Butyl 3-(p-tolyl)bicyclo[1.1.0]butane-1-carboxylate (1c) ..................................200
tert-Butyl 3-(4-bromophenyl)bicyclo[1.1.0]butane-1-carboxylate (1d)...................200
tert-Butyl 3-(4-chlorophenyl)bicyclo[1.1.0]butane-1-carboxylate (1e)....................201

xiii
tert-Butyl 3-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxylate (1f).....................201
tert-Butyl 3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butane-1-carboxylate (1g) .202
Methyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (1h)........................................202
Benzyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (1i)..........................................203
2a...................................................................................................................................203
2b ..................................................................................................................................204
2c...................................................................................................................................204
2d ..................................................................................................................................205
2e...................................................................................................................................205
2f ...................................................................................................................................206
2g...................................................................................................................................207
2h ..................................................................................................................................207
2i ...................................................................................................................................208
3a...................................................................................................................................209
3b ..................................................................................................................................209
3c...................................................................................................................................210
3d ..................................................................................................................................211
3e...................................................................................................................................211
3g...................................................................................................................................212
Benzyl (S)-2-Chloro-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (3i) ..213
(S)-2-Chloro-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (4h)........213
(S)-2-Bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (5a) ........214
6.....................................................................................................................................215
7.....................................................................................................................................215
8.....................................................................................................................................216
9.....................................................................................................................................217
9’ ...................................................................................................................................217
12...................................................................................................................................218
13...................................................................................................................................218
14...................................................................................................................................219
Tert-Butyl 4-bromo-3-chloro-2-fluorobenzoate.........................................................220
tert-Butyl 2-chloro-3-fluoro-[1,1'-biphenyl]-4-carboxylate (15)..............................220
tert-Butyl 2-fluoro-[1,1'-biphenyl]-4-carboxylate (16) .............................................221
tert-Butyl 3-fluoro-[1,1'-biphenyl]-4-carboxylate (17) .............................................222
Chapter 6 .....................................................................................................................................223
6.1 Introduction.....................................................................................................................223
6.2 Results and discussion ....................................................................................................225
6.3 Conclusion ......................................................................................................................233
6.4 Experimental data. General procedures and characterization data..................................234
General procedure for the preparation of 2..............................................................234
Detailed optimization data .........................................................................................235
1-((Trifluoromethoxy)methyl)-4-(trifluoromethyl)benzene (2b).............................239
4-((Trifluoromethoxy)methyl)benzonitrile (2c) ........................................................239
1-Nitro-4-((trifluoromethoxy)methyl)benzene (2d)..................................................240

xiv
1-Iodo-4-((trifluoromethoxy)methyl)benzene (2e)....................................................240
1-Iodo-2-((trifluoromethoxy)methyl)benzene (2f)....................................................240
1-Bromo-4-((trifluoromethoxy)methyl)benzene (2g)................................................241
1-Bromo-3-((trifluoromethoxy)methyl)benzene (2h) ...............................................241
1-(Methylsulfonyl)-4-((trifluoromethoxy)methyl)benzene (2i)................................242
4-((Trifluoromethoxy)methyl)benzenesulfonyl fluoride (2j) ...................................242
1-((Phenylsulfonyl)methyl)-2-((trifluoromethoxy)methyl)benzene (2k).................242
1-(tert-Butyl)-4-((trifluoromethoxy)methyl)benzene (2l) .........................................243
1-Phenoxy-3-((trifluoromethoxy)methyl)benzene (2m)...........................................243
Methyl 4-nitro-2-((trifluoromethoxy)methyl)benzoate (2n)....................................244
Methyl 4'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-carboxylate (2o).............245
4-((Trifluoromethoxy)methyl)-1,1'-biphenyl (2p).....................................................245
2-((Trifluoromethoxy)methyl)anthracene-9,10-dione (2q) ......................................246
Chapter 7 .....................................................................................................................................247
7.1 Introduction.....................................................................................................................247
7.2 Results and discussion ....................................................................................................248
7.3 Conclusion ......................................................................................................................260
7.4 Experimental Data. General procedures and characterization data........................260
General procedure for the preparation of 2..............................................................260
General procedure for the preparation of 5 from 3 .................................................261
General procedure for the preparation of 5 from 4 .................................................262
Trimethyl(2,2,2-trifluoro-1-(4-nitrophenyl)ethoxy)silane (2a)................................263
Trimethyl(2,2,2-trifluoro-1-(2-nitrophenyl)ethoxy)silane (2b)................................263
Trimethyl(2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethoxy)silane (2c).............264
(1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethoxy)trimethylsilane (2d)....264
(1-(4-Bromophenyl)-2,2,2-trifluoroethoxy)trimethylsilane (2e)..............................265
(1-(2-Bromophenyl)-2,2,2-trifluoroethoxy)trimethylsilane (2f) ..............................265
Trimethyl(2,2,2-trifluoro-1-(3-fluorophenyl)ethoxy)silane (2g)..............................266
Trimethyl(2,2,2-trifluoro-1-phenylethoxy)silane (2h)..............................................266
Trimethyl(2,2,2-trifluoro-1-(4-methoxyphenyl)ethoxy)silane (2i)...........................267
(1-(1-Bromonaphthalen-2-yl)-2,2,2-trifluoroethoxy)trimethylsilane (2j)...............267
(1-(Benzo[b]thiophen-2-yl)-2,2,2-trifluoroethoxy)trimethylsilane (2k)..................268
Trimethyl((1,1,1-trifluoro-3-phenylpropan-2-yl)oxy)silane (2l)..............................268
(E)-Trimethyl((1,1,1-trifluoro-4-(4-fluorophenyl)but-3-en-2-yl)oxy)silane (2m)...269
Trimethyl(2,2,2-trifluoro-1-phenyl-1-(3,4,5-trifluorophenyl)ethoxy)silane (2q)....269
4-(1,1,1-Trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)benzonitrile (2r) .................270
3-(1,1,1-Trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)benzonitrile (2s)..................271
Trimethyl((1,1,1-trifluoro-2-(perfluorophenyl)propan-2-yl)oxy)silane (2t)...........271
Trimethyl((1,1,1-trifluoro-2-(4-(trifluoromethyl)phenyl)propan-2-yl)oxy)silane..272
4-(Trifluoromethyl)benzonitrile (5a) .........................................................................273
1-Nitro-4-(trifluoromethyl)benzene (5b)...................................................................273
1-(Trifluoromethyl)-4-vinylbenzene (5c)...................................................................273
1-(4-(Trifluoromethyl)phenyl)ethan-1-one (5d)........................................................274
tert-Butyl 4-(trifluoromethyl)benzoate (5e)...............................................................274

xv
4-(Trifluoromethyl)benzaldehyde (5f).......................................................................275
1-(Benzyloxy)-4-(trifluoromethyl)benzene (5g)........................................................275
Methyl(4-(trifluoromethyl)phenyl)sulfane (5h)........................................................275
2-(Trifluoromethyl)naphthalene (5i)..........................................................................276
5j ...................................................................................................................................276
Phenyl(trifluoromethyl)sulfane (7)............................................................................277
References....................................................................................................................................278

xvi
List of Tables
Table 2.1 Optimization experiments for 2a.....................................................................................72
Table 2.2 Optimization experiments on 3a .....................................................................................74
Table 3.1 Optimization Experiments for 3a and 4a ......................................................................112
Table 3.2 Optimization Experiments for 5a and 6a ......................................................................115
Table 3.3: Counter anion screening (X)........................................................................................118
Table 3.4: Reaction temperature screening (T).............................................................................118
Table 3.5: Bases screening ............................................................................................................119
Table 3.6: Solvent screening .........................................................................................................119
Table 3.7: Stoichiometry screening...............................................................................................120
Table 3.8: Reaction temperature screening ...................................................................................121
Table 3.9: Solvent screening .........................................................................................................121
Table 3.10: Base screening............................................................................................................121
Table 3.11: Screening of additives................................................................................................122
Table 3.12: Screening of reaction concentrations .........................................................................122
Table 3.13: Screening of difluoromethylating reagents (Ethyl bromodifluoroacetate).................123
Table 3.14: Screening of difluoromethylating reagents (Sodium chlorodifluoroacetate) .............123
Table 3.15: Screening of difluoromethylating reagents - Diethyl
(bromodifluoromethyl)phosphonate .............................................................................................124
Table 3.16: Screening of difluoromethylating reagents – FSO2CF2CO2TMS...............................124
Table 3.17: Screening of difluoromethylating reagents – HCF2Cl................................................125
Table 3.18：Screening of difluoromethylating reagents – TMSCF3 ............................................125
Table 3.19：Screening of difluoromethylating reagents – PhSO2CF2Cl......................................126
Table 3.20：Screening of difluoromethylating reagents – S-difluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonium tetrafluoroborate..............................................................................126
Table 3.21：Screening of difluoromethylating reagents – Difluoromethyl
trifluoromethanesulfonate .............................................................................................................127
Table 4.1 Optimization Experiments for 2a..................................................................................154
Table 5.1 Optimization of the reaction conditions........................................................................175
Table 6.1 Optimization of trifluoromethoxylation ........................................................................226
Table 6.2 Solvent screening ..........................................................................................................235
Table 6.3 Reaction temperature screening ....................................................................................236
Table 6.4 Rection time screening ..................................................................................................237
Table 6.5 Sociometry screening ....................................................................................................237
Table 6.6 Additive screening.........................................................................................................238
Table 7.1. Optimization of 2a .......................................................................................................248
Table 7.2 Optimization for the preparation of [CuCF3] with TMSCF2Br.....................................253
Table 7.3 Optimization of trifluoromethylation of diaryliodonium salts (4).................................255
Table 7.4 Optimization of trifluoromethylation of 4a...................................................................256

xvii
List of Schemes and Figures
Scheme 1.1 Representative reagents for nucleophilic, electrophilic and radical monofluoromethylation
radical monofluoromethylation ................................................................................................................4
Scheme 1.2 Preparation of FBSM............................................................................................................5
Scheme 1.3 Indirect monofluoromethylations with FBSM......................................................................6
Scheme 1.4 First electrophilic monofluoromethylation ...........................................................................6
Scheme 1.5 Electrophilic monofluoromethylation with H2CFX (X = I, Br, Cl) ......................................7
Scheme 1.6 Pd and Cu catalyzed monofluoromethylation.......................................................................8
Scheme 1.7 Cu-catalyzed regio-selective borylfluoromethylation...........................................................9
Scheme 1.8 Preparation of S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenyl sulfonium
tetrafluoroborate .......................................................................................................................................9
Schehem 1.9 Electrophilic monofluoromethylation with S-monofluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenyl sulfonium salts.......................................................................................................... 11
Scheme 1.10 Radical monofluoromethylation with FBSM-I.................................................................12
Scheme 1.12 Radical monofluoromethylation with N-Tosyl-S-fluoromethyl-S-phenylsulfoximine......13
Scheme 1.13 Ir-catalyzed monofluoromethylation with EBFA under light irradiation..........................14
Scheme 1.14 Silicon-based difluorocarbene precursors.........................................................................16
Scheme 1.15 KOH-promoted difluoromethylation reaction of TMSCF2Br with (thio)alcohols............17
Scheme 1.16 Difluoromethylation of alkyl alcohols with TMSCF2Br and different activators.............18
Scheme 1.17 S- and O-selective difluoromethylation of (4-mercatophenyl)methanol via TMSCF2Br .19
Scheme 1.18 Synthesis of S-difluoromethyl dithiocarbamate with TMSCF2Br ....................................20
Scheme 1.19 Difluoromethylation of carboxylic acids with TMSCF2Br...............................................20
Scheme 1.20 Ring-opening difluoromethylation of cyclic (thio)ethers with TMSCF2Br......................21
Scheme 1.21 Difluoromethylation of N- and P-nucleophilies with TMSCF2Br ....................................22
Scheme 1.22 N-difluoromethylation of ketone hydrazones with TMSCF2Br........................................23
Scheme 1.23 Ring-opening difluoromethylation of cyclic amines with TMSCF2Br.............................23
Scheme 1.24 Chemoselective N- and O-difluoromethylation of 2-pyridones with TMSCF2Br ............24
Scheme 1.25 N- and O-Difluoromethylation of 3(2H)-pyridazinones...................................................25
Scheme 1.26 Synthesis of difluoromethylated formimidamides from primary amine and TMSCF2Br.26
Scheme 1.27 Synthesis of pentacoordinate phosphoranes from tertiary phosphines and TMSCF2Br ...27
Scheme 1.28 Difluoromethylation of organozinc reagents with TMSCF2Br.........................................27
Scheme 1.29 C-selective difluoromethylation of β-ketoesters or β-ketoamides with TMSCF2Br.........28
Scheme 1.30 Comprehensive difluoromethylation of sp3
- or sp-hybrided C-nucleophiles with
TMSCF2Br..............................................................................................................................................29
Figure 1.1 Representative CF3-containing pharmaceutical molecules...................................................30
Scheme 1.31 Representative nucleophilic trifluoromethylation with TMSCF3 .....................................31
Scheme 1.32 Representative nucleophilic trifluoromethylation with HCF3 ..........................................32
Figure 1.2 Representative electrophilic trifluoromethylating reagents..................................................33
Scheme 1.33 Representative electrophilic trifluoromethylation via Umemoto reagent II .....................34
Scheme 1.34 Recycling of fluoro S-(trifluoromethyl)dibenzothiophenium salts...................................35

xviii
Scheme 1.35 Electrophilic trifluoromethylation with Togni’s reagents I and II ....................................36
Scheme 1.36 Cu-mediated trifluoromethylation ....................................................................................38
Scheme 1.37 Radical trifluoromethylation.............................................................................................39
Figure 1.3 Representative 18F-labeled and [18F]trifluoromethylated tracers..........................................41
Scheme 1.38 Representative 19F18F isotopic exchange trifluoromethylation........................................42
Scheme 1.39 18F-labeled trifluoromethylation via nucleophilic substitution .........................................43
Scheme 1.40 DBU- and TBD-facilitated [18F]trifluoromethylation via nucleophilic substitution.........44
Scheme 1.41 Ag-mediated [18F]trifluoromethylation via nucleophilic substitution...............................45
Scheme 1.42 Preparation of [18F]fluoroform via nucleophilic substitution ...........................................46
Scheme 1.43 Difluorocarbene-mediated [18F]trifluoromethylation .......................................................47
Scheme 1.44 Difluorocarbene-mediated [18F]trifluoromethylthiolation ................................................48
Scheme 1.45 Preparation of [18F]fluoroform via electrophilic difluoromethylated sulfonium salts ......49
Scheme 1.46 Preparation of 18F-labeled Umemoto reagent ...................................................................50
Scheme 1.47 Preparation of [18F]-SelectfluorR
......................................................................................50
Scheme 1.48 Eletctrophilic trifluoromethylation of 2,3,3-trifluoroallyl with [18F]F2 and [18F]KF ........51
Figure 1.4 Representative OCF3-containing pharmaceutical and agrochemical molecules...................52
Scheme 1.49 Rapid decomposition of trifluoromethoxide anion (-OCF3) .............................................52
Scheme 1.50 Nucleophilic and radical trifluoromethylation reagents ...................................................53
Scheme 1.51 Nucleophilic trifluoromethoxylation with TFMT.............................................................54
Scheme 1.52 Nucleophilic trifluoromethoxylation with DNTFB ..........................................................55
Scheme 1.53 Ag-mediated nucleophilic trifluoromethoxylation with TAS-OCF3 .................................55
Scheme 1.54 Nucleophilic trifluoromethoxylation with TFMS.............................................................56
Scheme 1.55 Preparation of TFBz .........................................................................................................57
Figure 1.5 Reaction set up for the preparation of TFBz ........................................................................58
Scheme 1.56 Nucleophilic trifluoromethylation with TFBz ..................................................................59
Scheme 1.57 Nucleophilic trifluoromethoxylation with TFBO .............................................................59
Scheme 1.58 Preparation of NR4OCF3 salts ..........................................................................................60
Scheme 1.59 Nucleophilic trifluoromethoxylation with NR4OCF3 salts ...............................................61
Scheme 1.60 Preparation of TFNf and nucleophilic trifluoromethoxylation with TFNf .......................62
Scheme 1.61 Nucleophilic trifluoromethoxylation with Phth-OCF3......................................................63
Scheme 1.62 Nucleophilic trifluoromethoxylation with DNTFB ..........................................................63
Scheme 1.63 Radical trifluoromethoxylation with N-OCF3 ..................................................................65
Scheme 1.64 Radical trifluoromethoxylation with N-trifluoromthoxy-4-cyano-pyridinium .................66
Scheme 1.65 Radical trifluoromethoxylation with OCF3-benzotriazole................................................67
Scheme 1.66 Radical trifluoromethoxylation with BTMP.....................................................................67
Scheme 2.1 Prior Arts ............................................................................................................................70
Scheme 2.2 Proposed mechanism..........................................................................................................71
Scheme 2.3 O- and N-difluoromethylation of 2-pyridaones, Isoquinolinones, and Quinolinones.........75
Scheme 2.4 19F NMR yield of 6-substituted 2-pyridones under Method B ...........................................77
Scheme 3.1 Substrates Scope Mono- and Difluoromethylation of 3(2H)-Pyridazinones and
Phthalazine-1(2H)ones......................................................................................................................... 113
Figure 3.1 Failed attempts with conventional difluoromethylation reagents....................................... 116
Scheme 4.1 Reaction pathways of difluorocarbene as C1 source.........................................................152
Scheme 4.2 Prior art on the synthesis of difluoromethylated formimidamides with difluorocarbene .153

xix
Figure 4.1 19F NMR signal of 2a at various temperatures (0.05M in toluene). ...................................155
Figure 4.2. Proposed intramolecular hydrogen-bonding of 2a under different temperatures..............156
Scheme 4.3 Substrate Scope ................................................................................................................157
Scheme 4.4 Substrate Scope ................................................................................................................159
Scheme 4.5 Proposed Mechanism (L.A. = BF3/TMS).........................................................................159
Scheme 5.1 Synthetic methods to 2-fluorinated BCPs.........................................................................173
Scheme 5.2. Substrate scope of 2,2-bromofluorinated BCPs and 2,2-chlorofluorinated BCPs...........176
Scheme 5.3 One-pot reaction and deprotection reaction to yield 2,2-halofluoro-BCP ........................177
Scheme 5.4 Post-functionlizations with 2,2-chlorofluoro-, and 2,2-bromofluoro-BCPs.....................179
Scheme 5.5 Kinetic solubility of 2a, 3a, and their analogues..............................................................181
Scheme 6.1 Representative trifluoromethoxylating reagent ................................................................224
Scheme 6.2 Substrate scope .................................................................................................................228
Figure 6.1. Control experiment 1.........................................................................................................229
Figure 6.2 Control experiment 2..........................................................................................................230
Figure 6.3 Control experiment 3..........................................................................................................231
Figure 6.4 AgF + 4F-BnBr vs. CDI + AgF + 4F-BnBr........................................................................231
Scheme 6.3 Reaction with other electrophilies....................................................................................232
Scheme 6.4 Proposed mechanism of CDI-mediated trifluoromethoxylation.......................................233
Scheme 7.1 Substrate scope of trifluoromethylation of 2 ....................................................................252
Scheme 7.2 Substrate scope of trifluoromethylation of 3 and 4...........................................................258
Scheme 7.3. Substrate scope of trifluoromethylation of diphenyldisulfide and terminal alkyne. ........259

xx
Abbreviation
Abbreviation Definition
ACN Acetonitrile
BSM Bis(phenylsulfonyl)methane
DAST Diethylaminosulfur trifluoride
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM Dichloromethane
DMAP 4-Dimethylaminopyridine
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
DNTFB 1,4-Dinitro-trifluoromethoxybenzene
EBFA Ethyl bromofluoroacetate
EtOAc Ethyl acetate
FBSM Fluorobis(phenylsulfonyl)methane
KHMDS Potassium bis(trimethylsilyl)amide
M.P. Melting point
NaHMDS Sodium bis(trimethylsilyl)amide
NBS N-Bromosuccinimide
NFSI N-fluorobenzenesulfonimide
Phth-OCF3 N-Trifluoromethoxyphthalimide
PVDF polyvinylidene fluoride
r.t. Room temperature
TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
TFBO (E)-O-Trifluoromethyl-benzaldoximes
TFBz Trifluoromethyl Benzoate (TFBz)
TFMS Trifluoromethyl arylsulfonate
TFMT Trifluoromethyl
trifluoromethanesulfonate
TFNf Trifluoromethyl
nonafluorobutanesulfonate
THF Tetrahydrofuran
TMS Trimethylsilane

xxi
Abstract
Fluoroalkylated molecules have emerged as important moieties in pharmaceuticals,
agrochemicals, and functional materials. However, naturally occurred organofluoro
compounds are rare. Therefore, synthetic protocols for fluoroalkylation including
monofluoromethylation, difluoromethylation, trifluoromethylation and
trifluoromethoxylation are of great interest. Among all the strategies, fluorinated
carbenes are potent intermediate to achieve fluoroalkylation. This thesis summarized
difluoromethylation and trifluoromethylation with difluorocarbene generated from
TMSCF2Br. Investigation of monofluoromethylation and trifluoromethoxylation was
also discussed.

1
Chapter 1: Introduction
The objective of this chapter is to introduce organofluorine chemistry and to highlight
the important roles of fluorine in pharmaceutical, agrochemical and functional material
industry. This section will highlight the key achievements in the numerous efforts to
access fluorine-contained moieties including mono-, di- and trifluoromethylation, as
well as difluorocarbene-mediated 18F-labeled trifluoromethylation and
trifluoromethoxylation.
1.1 The fluorine atom. Introduction of organofluorine and relevant advances
Being the most electronegative element and the second smallest atom in the periodic
table. These properties enabled an extremely polarized yet strong carbon-fluorine bond
(C-F). Moreover, fluorine has emerged as the third most used element in life science
industry after carbon and nitrogen.1
In fact, about 25% of the pharmaceuticals and 50%
of agrochemicals marketed after 21st century contained at least one fluorine atom.2–7
Florine atoms can be introduced via direct fluorination or fluoroalkylation including
monofluoro-, difluoro- and trifluoromethylation. Incorporating these fluorinecontained moieties can fine-tune multiple important physicochemical properties such
as metabolic stability, bioactivity, bioavailability, lipophilicity and hydrogen bonding
ability. In addition, radioactive 18F-isotope with a 110-minute half-life time has played
a crucial role in positron emission tomography applications. Fluorinated functional
materials are also of great interest due to their ubiquitous properties.

2
In contrast to the very abundant inorganic fluorides such as CaF2, naturally occurred
organofluorine compounds are scarce.
8,9 Only 12 fluorine-contained natural products
were found on earth.10 Therefore, most of the organofluorine compounds are
synthesized and the methods to access those compounds are highly desired. Despite the
abundance of CaF2 (in mineral form), direct fluorination with CaF2 was not feasible
owing to its almost inert reactivity and extremely low solubility in all kinds of organic
and inorganic solvent.11 Although Gouverneur’s group recently reported a breakthrough
protocol to achieve the direct fluorination via CaF2, this approach remains
underexplored.12 The current source of the fluorine for all the organofluorine reagents
and reactions is HF (firstly reported in 1764), which is prepared by reacting fluorite
(CaF2 mineral) with sulfuric acid. After about 70 years, in 1835, the first organofluorine
compounds HCF3 was synthesized from KF and dimethyl sulfate.13 Since then, a vast
number of fluorination and fluoroalkylation methods have been disclosed to access
various types of fluorine-contained molecules.14–16 Prior to 1960s, some convention
procedures such as the Swarts reaction, the halex reaction, the Balz-Schiemann reaction
and electrochemical fluorination have been developed to attach fluorine atoms on
different molecules. However, the industrial applications of these reactions were
dramatically deterred by the utilization of toxic, explosive, corrosive reagents including
HF, F2, SbF3 and CoF3. Moreover, the function groups tolerance and chemoselectivity
was low for these fluorination methods due to the harsh reaction conditions.17 Since
1960s, research in fluorination and fluoroalkylation methods boomed with the
development of various modern fluorination regents such as diethylaminosulfur

3
trifluoride (DAST),18,19 SelectfluorR
,
20,21 and N-fluorobenzenesulfonimide (NFSI).
22,23
TMSCF3 (Ruppert-Prakash reagent),24 FSO2CF2CO2Me (Chen’s reagent),25 CF3SO2Na
(Langlois reagent),26 Umemoto reagent27 and Togni’s reagent28 were developed to
achieve nucleophilic, electrophilic and radical trifluoromethylation under much milder
conditions with an improved function group tolerance and chemoselectivity. In the past
30 years, other fluoroalkylation approaches such as difluoromethylation,29–36 18Flabeled trifluoromethylation,37–42 monofluoromethylation36,43–47 and
trifluoromethoxylation48–52 have emerged as important paradigm in organofluorine
chemistry. The prevalent strategies of these fluoroalkylation will be discussed in detail
in the next sections of this chapter.
1.2 Monofluoromethylation
As fluorine has been an increasingly critical role in fine-tuning the physical, chemical,
and biological properties of organic molecules including novel pharmaceutical,
agrochemicals, and function materials.36,45,53 In this context, the monofluoromethyl
groups (-CFH2) are of special interest because of its ability to serve as bioisosteres of -
CH3, -CH2OH, -CH2NH2, -CH2CH3, -CH2NO2, -CH2SH groups in bioactive
molecules.53,54 Moreover, incorporating monofluoromethyl groups has been proved to
be a successful strategy to modulate potency and metabolic stability of the drug
candidates.55,56 Despite the importance of this fluoroalkyl group, the synthetic methods
to install CFH2-contained building blocks into organic compounds is underexplored
compared to its di- and trifluoromethylation counterparts. Currently, three major

4
approaches including nucleophilic,47,53 electrophilic,43,44,57 and radical
monofluoromethylation58,59 have been reported.
1.2.1 Nucleophilic monofluoromethylation
Scheme 1.1 Representative reagents for nucleophilic, electrophilic and radical
monofluoromethylation
For nucleophilic monofluoromethylation, four different sulfone-based reagents were
developed as a pronucleophile to achieve the indirect monofluoromethylation by
assembling the sulfone-protected -CFH2 moieties on various electrophiles (Schem
1.1).
60–66 The resulting sulfone-contained products could be easily deprotected to afford
the desired monofluoromethylated products upon treated with reducing reagents such
as Mg powder in methanol at 0 oC.36 Among these reagents,
fluorobis(phenylsulfonyl)methane (FBSM) has been the most prevalent nucleophilic
monofluoromethylating regent owing to the strong electron-withdrawing property of
the two phenylsulfonyl groups which allows a facile deprotonation of the acidic proton

5
of FBSM under mild conditions.67
Scheme 1.2 Preparation of FBSM
FBSM was first prepared by Shibata and coworkers via bis(phenylsulfonyl)methane
(BMS) and SelectfluorR
(Scheme 1.2 A).
60 However, the utilization of NaH, and the
inseparable bisfluorinated byproduct limited the application of these reagents. Later,
our group invented a promising large-scale (76 mmol) protocol to synthesize FBSM
(Scheme 1.2 B).
62 Since then, vast number of reactions have been carried out with
FBSM including, Michael reactions,68–70 Mitsunobu reactions,71 nucleophilic
substitutions,69,72 monofluoro-olefinations,
73,74 epoxide ring-opening reactions,61 and
nucleophilic additions to unsaturated systems (Scheme 1.3).
60,75–77

6
Scheme 1.3 Indirect monofluoromethylations with FBSM
1.2.2 Electrophilic monofluoromethylation
In contrast to FBMS and its analogues, electrophilic monofluoromethylating reagents
are of great interest due to their ability to directly transfer -CFH2 groups to C-, O-, S-,
N-, P-, and Se-nucleophilies. In 1952, our group disclosed fluoromethanol as the first
electrophilic monofluoromethylating reagent to synthesize benzyl fluoride directly
from benzene and ZnCl2 as a Lewis acid (Scheme 1.4).
78
Scheme 1.4 First electrophilic monofluoromethylation
Later, various halons such as H2CFCl (Scheme 1.4 A) and H2CFBr (Scheme 1.4 B)

7
were employed as monofluoromethylating reagents, which readily interacted with
phenol, imidazoles, and thiols to provide the corresponding monofluoromethylated
products. Inorganic Bases was utilized to deprotonate the acidic protons of the
substrates, and the resulting anions further performed nucleophilic attacks towards the
C-center of the halons.43,79–81 Moreover, 18F-labeled H2CFI was prepared and applied
to 18F-labeled fluoromethyl-contained tracers for positron emission tomography (PET)
(Schem 1.4 C).
82
Scheme 1.5 Electrophilic monofluoromethylation with H2CFX (X = I, Br, Cl)
Even though these protocols enabled access to O-, S-, and N-CFH2 compounds, the

8
reactivities between these reagents to C-nucleophilies were not observed despite
extensive optimizations. Since the C-X (X = Br and I) bond can be a good handle for
transition metal mediated cross-coupling reaction.
Scheme 1.6 Pd and Cu catalyzed monofluoromethylation
In 2009, Suzuki and coworkers reported the first Pd-catalyzed Suzuki reaction between
aryl boronic esters and H2CFI (Scheme 1.6 A). However, only 1 example with
[
18F]H2CFI was reported (40 equiv of boronic esters and stoichiometric of Pd catalysts
were used).
82 As such, other indirect monofluoromethylating reagents were adapted into
Ni-catalyzed cross-coupling reactions with aryl boronic acids (Scheme 1.6 B).
83 In
2015, Hu and coworkers reported a general protocol of Pd-catalyzed Suziki coupling
via CH2FI under mild reaction conditions with a good functional group tolerance
(Scheme 1.6 C).
84 Zhang’s group also developed the first Ni-catalyzed direct Ar-CFH2

9
method with H2CFBr (Scheme 1.6 D).
85 Similarly, H2CFI was employed in Cucatalyzed regio-selective borylfluoromethylation of alkenes (Scheme 1.7).
86
Scheme 1.7 Cu-catalyzed regio-selective borylfluoromethylation
In addition, the utilization of ozone-depleting greenhouse gases (especially considering
excess amount of the reagents were employed) left considerable space for improvement.
As such, a bench-stable, solid, and non-ozone-depleting monofluoromethylating
Scheme 1.8 Preparation of S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenyl
sulfonium tetrafluoroborate
reagent, S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenyl sulfonium salts
were invented by our group to circumvent these drawbacks.57

10
Notably, the sulfonium salts were initially prepared from H2CFCl and PhSNa
(Scheme 1.8 A). Later, Veliks’s group developed an alternative way to avoid using
ozone-depleting reagents (Scheme 1.8 B).
87 However, the overall yield of this method
was not high (38% isolated yield for the first two steps). After deep-diving into the
reaction process, it was found that the yields for the formation of PhSCFH2 and
((fluoromethyl)sulfinyl)-benzene were strongly depended on the quality of the reagents.
For example, when using old SelectfluorR which has been exposed in atmosphere for a
long time (at least more than 1 year), the yields for PhSCFH2 was only 65%. Whereas
a new SelectfluorR which was packed under inert condition and stored in Ar glovebox
yielded 88% of PhSCFH2. Similarly, when freshly recrystallized and dried NBS (white
solid) was employed, the yield of step 2 was dramatically improved compared to that
of using NBS without further purification (Schem 1.8 C).
88

11
Schehem 1.9 Electrophilic monofluoromethylation with S-monofluoromethyl-Sphenyl-2,3,4,5-tetramethylphenyl sulfonium salts
In 2007, our group reported the reaction of sulfonium salts with a series of nucleophiles
including C-nucleophiles which were evidenced to be challenging previously.
Moreover, the monofluoromethylation of some other nucleophiles such as benzoic
acids, sulfonic acids, and triphenylphosphine was firstly revealed in this work.57
Recently, our group further developed the first chemo-selective Nmonofluoromethylation of 3(2H)-pyridazinones. Interestingly, compared to the prior
art which BF4
- was employed as a counteranion, OTf- was found to be a more suitable
counteranion to provide an improved N- vs. O-selectivity.88
1.2.3 Radical monofluoromethylation
In contrast to the other two established monofluoromethylating approaches, radical

12
monofluoromethylation methods were rarely reported. FBSM-I were reported to
perform double addition reaction of terminal alkenes when Et3B/air was used as the
radical initiating system (Scheme 1.10).
89
Scheme 1.10 Radical monofluoromethylation with FBSM-I
Due to the steric hindrance provided by the two bulky phenylsulfonyl groups, the
protected -CFH2 group was always added to the terminal carbons of alkenes. In 2011,
Shibata and coworkers developed monofluoromethylsulfoxinium salts to achieve
Scheme 1.11 Radical monofluoromethylation with monofluoromethylsulfoxinium salts
chemo-selective O-monofluoromethylation. Even though this type of reagents appeared
to go through an electrophilic pathway owing to the structural similarity to the

13
sulfonium salts, further studies indicated that a radical mechanism was involved in this
reaction system (Scheme 1.11).90
For example, the energy calculation showed that if a monofluoromethyl cation is
generated, it tends to react with C-nucleophiles, while a monofluoromethyl radical
shows preference oxygen centers. Investigation on the reactivities to ketoesters
exhibited the selectivity towards O-nucleophiles demonstrated a radical-like SET
process is a more plausible mechanism. Later, a similar reagent N-Tosyl-Sfluoromethyl-S-phenylsulfoximine was reported to produce CH2F radicals via similar
SET pathway from nucleophiles and reacted smoothly with O-, N-, P-, S- nucleophiles
to furnish the corresponding monofluoromethylated products (Scheme 1.12).
91
Scheme 1.12 Radical monofluoromethylation with N-Tosyl-S-fluoromethyl-Sphenylsulfoximine
Another important monofluoromethyl radical precursor is ethyl bromofluoroacetate

14
(EBFA) which is bench stable, inexpensive and commercially available.
83,92 Visible
light-induced indirect monofluoromethylation was conducted between EBFA and
different heteroaromatic molecules with the help of fac-Ir(ppy)3 (Scheme 1.13).
93
Scheme 1.13 Ir-catalyzed monofluoromethylation with EBFA under light irradiation
Similarly, monofluoromethylated phenanthridine derivatives could be obtained from
isocyanides under these conditions through fluoroalkylation-cyclization mechanism.94
1.3 Difluoromethylation
During the past decades, incorporating difluoromethyl group (-CF2H) and
difluoromethylene (-CF2-) have been a fruitful approach to leverage the physiochemical
properties of bioactive and pharmaceutical molecules such as lipophilicity, hydrogen
bonding ability, and metabolic stability.15,95 Moreover, CF2H moiety has been found to
be bioisosteric to thiol (-SH) and alcohol (-OH) groups.96–99 In that case, three major
approaches including nucleophilic,100–106 electrophilic,107–112 and radical
difluoromethylation113,114 have been developed to assemble -CF2H group on various
organic scaffolds. Among all the strategies reported to achieve difluoromethylation,
electrophilic difluoromethylation via difluorocarbene (:CF2) is the one of the most

15
prevalent ways.
36,115,116 Difluorocarbene is a singlet carbene with an empty p-orbital,
which was stabilized by the π-back-donation of the 2p lone pair electrons of fluorine
atoms. In addition, difluorocarbene is stabilized by resonance effect provided by the
fluorine atoms while destabilized by the strong electron-withdrawing fluorine atoms.
The stabilizing and destabilizing effects add up to provide difluorocarbene an
intrinsically electrophilic property.117–119 Since difluorocarbene is a highly reactive
intermediate with a short half-life (0.5 ms in solution), it cannot be employed into the
reactions directly. As a result, numerous difluorocarbene precursors have been
developed to generate difluorocarbene in situ upon activations in different reaction
systems. In 1945, Benning reported the first generation of :CF2 with HCF2Cl via
thermal decomposition to prepare tetrafluoroethylene (TFE).
120–122 Since then, vast
amount of difluorocarbene precursors have been invented to achieve
difluoromethylation of different types of substrates. However, the difluorocarbene
reagents developed before 2006 suffer from utilizing ozone-depleting starting materials,
instability under bench conditions, high toxicity, and requiring harsh activation
conditions. In addition, most of these reagents showed reactivities only to a narrow
range of compounds, and the yields were low for some of the reactions.117,118,123–131 In
2006, Hu and coworkers reported 2-chloro-2,2-difluoroacetophenone (PhCOCF2Cl) as
the first non-ozone depleting reagent and readily performed difluoromethylation on
phenols at elevated temperature (80 oC).
132 In 2007, Hu and coworkers further
developed a more reactive difluorocarbene reagent PhSO2CF2Cl.133 In 2011, our group
and Hu’s group revealed together that the Ruppert-Prakash reagent TMSCF3 could also

16
release difluorocarbene which reacted smoothly with alkenes and alkynes to give the
corresponding cycloaddition products. Notably, for electron-rich alkenes,
tetrabutylammonium triphenyldifluorosilicate (TBAT) was employed as the activator
at low temperature (-50 oC) to room temperature. For electron-poor alkenes, NaI was
used to activate TMSCF3 at elevated temperature to obtain the gemdifluorocyclopropanes in good yields.134 Later, our group used TMSCF3 to perform the
difluoromethylation of N-nucleophiles such as imidazoles at similar conditions (NaI
and 90 oC).135 Owing to the stability of C-F bonds, TMSCF3 is the least reactive
difluorocarbene reagent compared to its halogenated analogues with the general
formula TMSCF2X (X = Br, Cl, and I).
136 Even though these silicon-based reagents
showed higher reactivities under milder activation conditions than TMSCF3, the
convenience of preparation, price, and availability differs.
Scheme 1.14 Silicon-based difluorocarbene precursors
For example, TMSCF2Cl has to be synthesized via an ozone-depleting starting material
BrCF2Cl, and TMSCF2I can only be prepared from the i-PrZnI-promoted halogen
exchange between TMSCF2Br and I2. In contrast, TMSCF2Br can be prepared via a
non-ozone depleting process from commercially available TMSCF3.
136–139 Further

17
investigations on the reactivities of TMSCF2Br with a wide range of substrates
demonstrate that it is in fact one of the most versatile difluorocarbene precursors. Given
the vast number of reactions reported with TMSCF2Br, this sub section will mainly
focus on the electrophilic difluoromethylation reactions (-CF2H) between TMSCF2Br
and different nucleophiles (Scheme 1.14).
1.3.1 Electrophilic difluoroemthylation via TMSCF2Br
O, S-nucleophiles
In 2013, Hu and coworkers employed TMSCF2Br to obtain difluoromethylated
phenols in moderate to excellent yields. KOH not only served as a base to deprotonate
the acidic proton of phenol, but also an activator of TMSCF2Br (Scheme 1.15 A).
Scheme 1.15 KOH-promoted difluoromethylation reaction of TMSCF2Br with
(thio)alcohols.
Similarly, thiols and thiophenolates also underwent difluoromethylation at the same
conditions to afford the corresponding difluoromethylated thioethers in good yields
(from 66 to 91% isolated yields) (Scheme 1.15 B).
137 Further studies revealed that

18
TMSCF2Br could be efficiently activated under weak basic conditions (KOAc) and
weak acidic conditions (KHF2) and performed difluoromethylation to a series of
primary, secondary and tertiary alkyl alcohol. In contrast, strong basic activator NaOH
was only suitable for the electron-rich and less sterically hindered substrates (Scheme
1.16 A) According to the control experiments, two possible reaction pathways were
proposed.
Scheme 1.16 Difluoromethylation of alkyl alcohols with TMSCF2Br and different
activators.
For thiols, thiophenols, and electron-poor alkyl alcohols, they tend to be deprotonated
first to generate alcoholate anions, and reacted with :CF2 to give ROCF2
-
intermediates
followed by protonation to afford the target products (Scheme 1.16 B-path a). On the
other hand, electron-rich alkyl alcohols will react with difluorocarbene first and go
through intermediate A to provide the ROCF2H products (Scheme 1.16 B-path b).

19
Scheme 1.17 S- and O-selective difluoromethylation of (4-mercatophenyl)methanol via
TMSCF2Br
Moreover, the reactions of (4-mercaptophenyl)methanol under weak basic and
weak acidic conditions furnished OCF2H as the predominate product, while SCF2H was
observed as the major product under strong basic conditions (Scheme 1.17). These
results not only further proved the proposed mechanisms, but also demonstrated the
superiority of TMSCF2Br as a difluorocarbene reagent with a great potential for postfunctionalization in medicinal chemistry.
140 Later, the authors also found the
difluoromethylation of liquid alkyl alcohols could be performed in water without the
presence of any organic solvent via KHF2 and TMSCF2Br. For solid alcohols with
moderate melting points (less than 65 oC), elevated temperature was essential to melt
the alcohols into liquid form, which allowed the alcohols to interact with
difluorocarbene in water.141

20
Scheme 1.18 Synthesis of S-difluoromethyl dithiocarbamate with TMSCF2Br
Dilman and coworkers synthesized S-difluorrmethyl dithiocarbamates via a threecomponent reaction (Scheme 1.18). The reaction initiated by the nucleophilic addition
of secondary amine to CS2. The resulting anion A served as another nucleophile which
attack difluorocarbene to give intermediate B followed by protonation to afford the
desired product.
142
Scheme 1.19 Difluoromethylation of carboxylic acids with TMSCF2Br
In 2019, our group developed an operationally simple protocol to access
difluoromethylation of carboxylic acids with TMSCF2Br (Scheme 1.19). Similar to the
difluoromethylation of alcohols, alkyl carboxylic acids afforded lower yields compared
to benzoic acids.143

21
Scheme 1.20 Ring-opening difluoromethylation of cyclic (thio)ethers with TMSCF2Br
In 2021, Hu and coworkers reported an interesting TMSCF2Br-mediated ring-opening
procedure of cyclic ethers and thioethers. As shown in Scheme 1.20 A, the reaction
started with nucleophilic attack of the oxygen or sulfur atoms and generated
difluoromethylated onium intermediates. After the protonation step, bromides produced
from the activation of difluorocarbene served as nucleophiles to afford the ring-opening
difluoromethylated products. TMSCF2Br is the key reagent in this system which serves
as a difluorocarbene source as well as a bromide source.144 About one year later,
Sheng’s group reported a TMSCF2Br-mediated three-component ring-opening system
of tertrahydrogen furan (THF) to give difluoromethylated aryl-hydroxyamine in

22
moderate to excellent yields (Schem 1.20 B).
145 Almost at the same time, Song and
coworkers also reported a similar ring-opening system and carboxylic acids were
introduced as the nucleophiles for the ring-opening process (Schem 1.20 C).
146
N, P-nucleophiles
In 2013, Hu and coworkers also applied the conditions for difluoromethylation of
alcohols under strong basic conditions (scheme X) to heterocyclic amines. Even though
all the substrates showed some reactivities under the reaction conditions, some
imidazoles only provided the desired N-CF2H product in low yields.
Scheme 1.21 Difluoromethylation of N- and P-nucleophilies with TMSCF2Br
This was tentatively attributing to a second difluoromethylation to the target N-CF2H
products, which formed unstable difluoromethyl ammonium salts. Moreover, for
substrates with tautomers such as pyrazolones, both N- and O-difluoromethylated
products were obtained as a mixture in low yields with low selectivity. On the other
hand, P-nucleophilessuch as hydrophosphine oxides reacted smoothly with TMSCF2Br
to furnish the corresponding P-CF2H products.137
In 2019, Wu’s group disclosed a difluoromethylation reaction of ketone hydrazones

23
with TMSCF2Br with a broad scope and high stereoselectivity (Scheme 1.22).
Scheme 1.22 N-difluoromethylation of ketone hydrazones with TMSCF2Br
Interestingly, 5 mol% of TEBAC is determined to be essential to the success of this
reaction because it behaves as a phase transfer catalyst to aid the solubility of Cs2CO3
in non-polar solvent, toluene. Similar to the reaction with cyclic ethers, Seo and
Scheme 1.23 Ring-opening difluoromethylation of cyclic amines with TMSCF2Br
coworkers reported the TMSCF2Br-promoted ring-opening of non-tensile cyclic
tertiary amines via similar mechanism (Scheme 1.23).147
However, the resulting N-CF2H product further hydrolyze to formaldehydes.147 In 2021,
our group reported a convenient chemoselective N- and O-difluoromethylation of 2-

24
pyridones with TMSCF2Br (Scheme 1.24 A). Previous attempts with other
difluorocarbene precursors including BrCF2COOEt and ClCF2COONa at elevated
temperature yielded only O-CF2H product as the predominant species. The major
reason of this challenging direct N-difluoromethylation is owing to the tautomerization
between 2-pyridone form and 2-hydroxypyridine form.
Scheme 1.24 Chemoselective N- and O-difluoromethylation of 2-pyridones with
TMSCF2Br
At high temperature, 2-hydroxypyridine form is the major tautomer which can be
deprotonated by the base and provide O-difluoromethylated product, whereas at low
temperature, 2-pyridone form is the major tautomer and generates Ndifluoromethylated products (Scheme 1.24 B). However, the activation of
BrCF2COOEt and ClCF2COONa requires relatively harsh conditions such as high

25
temperature, which means O-CF2H products will always be the predominant products
under these conditions. In that case, TMSCF2Br was chosen as a suitable
difluorocarbene source due to its versatile activation modes including low temperatures.
As a result, when NaOt-Bu was utilized as the base and activator, 2-pyridones reacted
with TMSCF2Br in triglyme at -15 oC to furnish N-CF2H product selectively in
moderate to excellent yields. On the other hand, when Na2CO3 was employed as the
base and activator, 2-pyridones could yield O-difluoromethylated products selectively
in ACN at 60 oC.112 Furthermore, 2-pyridaziones were adapted into the similar manner
with TMSCF2Br to achieve the N- and O-difluoromethylation of these important
bioactive moieties with increasing interest (Scheme 1.25). However, the corresponding
O-CF2H and N-CF2H products were observed as a mixture with low selectivity and
moderate yields despite extensive optimizations.
Scheme 1.25 N- and O-Difluoromethylation of 3(2H)-pyridazinones
Although the yields and selectivity were not ideal, the O-CF2H and N-CF2H products
could be easily separated via flash column chromatography. Moreover, TMSCF2Br was
proved to the only effective difluorocarbene reagent for this transform after some
comparison experiments using other conventional difluorocarbene sources.88 In 2022,
our group synthesized difluoromethylated formimidamides and imidazoles from
primary amines and TMSCF2Br (Scheme 1.26 A).

26
Scheme 1.26 Synthesis of difluoromethylated formimidamides from primary amine
and TMSCF2Br
In this reaction, the primary amines firstly react with difluorocarbene followed by a 1,2-
proton transfer under basic conditions to afford intermediate a under basic conditions.
Then A undergoes a defluorination in the presence of BF3 and produces N-formimidoyl
fluoride (b) which undergoes addition-elimination with another portion of the aniline
to give c. Intermediate c proceeds with another nucleophilic attack to CF2 followed by
1,2 proton transfer to furnish the final product (Scheme 1.26 B). Notably, this reaction
provided E-isomer selectively, but the E-isomer was not stable over silica gel during
isolation: it isomerized into Z-isomer and further degraded into formaldehyde. 3% Et3N
in hexanes solution was used as the mobile phase to circumvent the interconversion or
decomposition of the target E-isomer.148 In 2023, Hu and coworkers reported a bisdifluoromethylation reaction between phosphines and TMSCF2Br (Scheme 1.27).

27
Interestingly, the protons of the two difluoromethyl groups came from two different
protons sources, NaBH4 and H2O.
Scheme 1.27 Synthesis of pentacoordinate phosphoranes from tertiary phosphines and
TMSCF2Br
In addition, the resulting pentacoordinate phosphoranes have been proved to be highly
efficient difluorocarbene and difluoromethyl radical precursors.149
C-nucleophiles
Scheme 1.28 Difluoromethylation of organozinc reagents with TMSCF2Br
In 2013, Dilman achieved C-difluoromethylation with TMSCF2Br and organozinc
reagents (Scheme 1.28). The resulting difluoromethylated organozinc intermediates a
could further react with electrophiles including I2, Br2, and HOAc and afforded

28
corresponding difluoromethylated products.150 Further studies proved that a could also
react with other electrophiles including SOCl2,
151 allyl bromides and chlorides,152
nitroso,
153 β -nitrostyrenes,
154 1-bromoalkynes,155 propargyl halides,156 and Selectrophiles.157
In 2018, Shibata’s group reported a selective C-difluoromethylation of β-ketoesters
with TMSCF2Br (Scheme 1.29 A). Notably, LiOH is crucial as the base and activator
to control the C- and O-regioselectivity.158
Scheme 1.29 C-selective difluoromethylation of β-ketoesters or β-ketoamides with
TMSCF2Br
Three years later, Wang and coworkers utilized the same conditions to realize the Cselective difluoromethylation of β-ketoamides with TMSCF2Br (Scheme 1.29 B).
159
Additionally, the authors further obtained the asymmetric difluoromethylated βketoesters with high ee value by adding chiral catalysts (Scheme 1.29 C).
160 In 2019,

29
Hu and coworkers disclosed a comprehensive protocol of difluoromethylation of sp3
-
or sp-hybrided C-nucleophiles via TMSCF2Br (Scheme 1.30). With 2 equivalences of
KO-tBu, TMSCF2Br reacted efficiently with various activated carbon nucleophiles
including esters, amides, fluorene derivatives, terminal alkynes, β-ketoesters, and
malonates under mild conditions (30 minutes at room temperature).
Scheme 1.30 Comprehensive difluoromethylation of sp3
- or sp-hybrided Cnucleophiles with TMSCF2Br
Notably, comparison with other conventional difluorocarbene precursors highlighted
the unique reactivity and advantage of TMSCF2Br as a privileged difluorocarbene
precursor.111
1.3 Trifluoromethylation
Trifluoromethylation is the most well-studied and well-recognized fluoroalkylation
reactions which has been employed to modulate the physicochemical properties of
bioactive molecules such as metabolic stability, lipophilicity, bioactivity and binding
affinity, depending on the biological target being examined (Figure 1.1).
161

30
Figure 1.1 Representative CF3-containing pharmaceutical molecules
In addition, trifluoromethyl group is also found to be bioisosteric to ethyl and isopropyl
groups with enhanced hydrogen-bonding effect.162 Therefore, numerous
trifluoromethylating reagents including TMSCF3, NaSO2CF3, Togni reagent, Umemoto
reagent and Yagupolskii-Umemoto reagent. These powerful reagents have facilitated
various trifluoromethylation strategies such as nucleophilic,163–169 electrophilic,17,170,171
photoinduced,58,172,173 radical and transition-metal catalyzed or mediated reactions.174–
176
1.3.1 Nucleophilic trifluoromethylation
The direct nucleophilic attack to different electrophiles by the CF3
-
anion is
arguably the most straightforward and efficient approach to install trifluoromethyl
moieties. TMSCF3, also known as Ruppert-Prakash reagent, is the most prevalent

31
reagent for nucleophilic trifluoromethylation.177,178
Scheme 1.31 Representative nucleophilic trifluoromethylation with TMSCF3
Extensive works have been done with TMSCF3 to achieve trifluoromethylation on
a big scope of electrophiles such as aldehydes,179–184 ketones,184,185 esters,171,178,184,186
imines,187–189 acyl chlorides,190 disulfides,166 deselenides,191 aryl nitriles,192 and so on
(Scheme 1.31). Moreover, a vast number of initiators have been employed to activate
TMSCF3 under mild conditions. In addition, TMSCF3 is a non-toxic, inexpensive, nonozone-depleting, commercially available and safe reagent. Another representative
nucleophilic trifluoroemthylating reagent is HCF3 which is a large-volume by-product
in the manufacture of important function materials such as TeflonR
, polyvinylidene

32
fluoride (PVDF), fire-extinguishing agents and foams.193 It is a persistent greenhouse
gas (about 250 years lifetime in atmosphere) with a much higher global warming
potential than CO2 (11700 times greater). Current available storage of HCF3 in industry
and the free-flowing HCF3 in atmosphere is massive in quantity.
194 In that case, efficient
mitigation methods to convert HCF3 into various useful trifluoromethyl-contained
compounds are of great interest in recent decades.195,196
Scheme 1.32 Representative nucleophilic trifluoromethylation with HCF3
In 2013, our group reported a general protocol to activate HCF3 under mild
conditions (KO-tBu/KHMDS and THF) and the resulting -CF3 anion readily reacted
with different types of substrates to afford the corresponding trifluoromethylated
products including aldehydes, non-enolizable ketones, chalcones, formates, benzyl
bromide, methyl benzoate in low to moderate yields. Notably, other
trifluoromethylation reagents such as TMSCF3 and K[CF3B(OMe)3] could be prepared

33
from fluoroform in high yields.197
1.3.2 Electrophilic trifluoromethylation
Figure 1.2 Representative electrophilic trifluoromethylating reagents
Electrophilic trifluoromethylation strategies can be utilized to achieve
trifluoromethylation on various heteroatom-centered nucleophiles, as well as electronrich carbon-centered nucleophiles such as enloates (Figure 1.2).
In 1984, Yagupolskii developed trifluoromethylated sulfonium salts to achieve
electrophilic trifluoromethylation. Since then, various analogues were synthesized to
improve the reactivity, stability, availability of this reagent system.27 In 2006, Togni’s

34
group firstly invented trifluoromethylated hypervalent iodide compounds as +CF3
Scheme 1.33 Representative electrophilic trifluoromethylation via Umemoto reagent II
sources.198 Within the reported precursors, Umemoto reagents II and Tongni’s reagents
I&II are the most prevalent electrophilic trifluoromethylating reagents.90,199–212
In 2017, 2,8-difluoro-S-(trifluoromethyl)dibenzothiophenium triflate salt has been
recognized as the most potent one compared to other Umemoto reagents. Thermal
stability tests showed that the fluorine atoms at the 2- and 8-position exert a strong
stabilizing effect which led to a much higher decomposition temperature (203 oC）than

35
that of the first-generation Umemoto reagent reported in 1990 (153 oC). Despite its
higher thermal stability, the fluorinated salts exhibited a higher reactivity towards
various nucleophiles compared to the non-fluorination analogues owing to the strong
electron-withdrawing effect of the two fluorine atoms. As shown in Scheme 1.33, the
most recent Umemoto reagents could easily react with different substrates under basic
conditions with good to excellent yields. Notably, the dibenzothiophene byproduct after
the trifluoromethylation could be recovered and the CF3 reagent could be recycled via
a desulfurization followed by a one-pot preparation (Scheme 1.34).
Scheme 1.34 Recycling of fluoro S-(trifluoromethyl)dibenzothiophenium salts
This operationally simple recycling process dramatically reduce the atomic
economic and environment cost of this protocol.27
Similarly, trifluoromethyl-3,3-dimethyl-1,2-benziodoxol (Togni’s reagent I&II) is
well-documented to trifluoromethylate nucleophiles including keto derivatives,213,214
hydroxylamines,
215 phosphines,216 phosphates,217 alcohols,218 thios,
214 amines,219,220
sulfonic acids,221 and enol silyl ethers (Scheme 1.35).
222

36
Scheme 1.35 Electrophilic trifluoromethylation with Togni’s reagents I and II
Zinc(II) salts are commonly introduced as Lewis acids to enhance the
electrophilicity of Togni’s reagents. The Zinc2+ cation chelated with the oxygens from
Togni’s reagents, the resulting carboxylate iodonium complex underwent a ligand
exchange upon treated with nucleophiles followed by a reductive elimination to furnish
the target CF3 products.28
It is worth mentioning, both Togni’s regent (I) and (II) have been reported to have
an extremely exothermic or even explosive decomposition upon heating, impact and
friction in some reaction systems. This disadvantage limited the large-scale application
of these useful reagents in pharmaceutical industry.223
1.3.3 Transition metal-catalyzed trifluoromethylation
Multiple transition metals have been employed to achieve some types of

37
trifluoromethylations which were proved to be challenging with either nucleophilic or
electrophilic approaches. Even though nickel,224,225 palladium,226 copper227 and silver228
all demonstrated their abilities to catalyze trifluoromethylation reactions, Coppermediated or -catalyzed trifluoromethylation is the most prevalent approach owing to
the high efficiency and low cost of copper. Different forms of CuCF3 species are
determined to be the key intermediates in the copper-promoted coupling reactions.
These complexes could be prepared from Cu(I) salts and TMSCF3 with fluorides as
activators.229–231 FSO2CF2CO2Me (Chen reagent),25,232,233 K[CF3B(OMe)3],234 Togni’s
reagents,235–239 Umemoto reagents
240 and HCF3 have also been reported to generate
CuCF3 species in similar manner.
241,242

38
Scheme 1.36 Cu-mediated trifluoromethylation
Ligands are commonly introduced into the reaction system to modulate the
stabilities and reactivities of the ligand-coordinated CuCF3 intermediates. Some of the
intermediates such as (phen)CuCF3 and (Ph3P)3CuCF3 are bench-stable solids which
can be isolated and used as precatalysts. In some case, these precatalysts exhibited
unique reactivities to the substrates, whereas generating the same complexes in situ
could not afford the target products efficiently.
243–245 As depicted in scheme, coppermediated coupling reactions could be employed to a wide scope of compounds such as,
aryl/alkyl halides, aryldiazonium salts, diaryl iodinium salts, alkyl bronic acids and
esters via a reductive elimination process from the R-Cu(III)CF3 intermediates.246–248
1.3.4 Radical trifluoromethylation
CF3 Radical-involved trifluoromethylation has been attracted more and more

39
attention in recent decades due to its versatile reactivity to both unsaturated systems
and alkyl radicals. All the previously mentioned trifluoromethylation reagents could
generate CF3 radicals.
28,249,250 Other reagents such as (bpy)Zn(CF3)2,
251–253
CF3SO2Na254 and CF3I
255 have also been reported to afford the CF3 radicals.
Scheme 1.37 Radical trifluoromethylation

40
As shown in Scheme 1.37, The CF3 radicals could react smoothly with alkenes and
alkynes directly to provide the corresponding double-addition products without the
presence of transition metals.
256,257 On the other hand, alkyl radicals can be generated
from carboxylic acids, alkyl halides and C-H bonds which could readily react with
CuCF3 complex to furnish the desired CF3-products.258 However, the direct homolysis
between CF3 radicals and alkyl radicals generated from C-H bonds remains challenging
due to the high bond energy of the C-H bonds.
18F labeled trifluoromethylation
Positron emission tomography (PET) imaging has emerged as a promising function
imaging technique due to its unique diagnostic applications for precise investigation of
biological processes in vivo via radio-labeled organic small-molecule tracers. It is also
utilized to mechanistic assessment of drug candidates.
259–262 A general PET experiment
is carried out in nanomolar scale owing to the extremely high sensitivity of this
technique. In addition, the half-life time of radioisotopes are usually very short. For
instance, the half-life time of 18F isotope is about 110 minutes. These two factors
together make PET studies a safe and efficient diagnostic protocol.
Fluorine-18 (18F) is the most prevalent radioisotopes utilized for PET due to the
vast number of fluorine-contained drug molecules commercially available in the market
and the well-documented studies on the pharmacology and toxicology of these FDAapproved pharmaceutical molecules (Figure 1.3).
263,264

41
Figure 1.3 Representative 18F-labeled and [18F]trifluoromethylated tracers
Among all the 18F-labeled tracers, [18F]-FDG (2-[
18F]fluoro-2-deoxy-D-glucose) is
arguably the most important radiotracers since it can quantitatively measure the
elevated glucose metabolism caused by various types of cancers.265 Later, [18F]FMISO
(1H-1-(3-[
18F]Fluoro-2-hydroxyporpyl-2-nitroimidazole) was invented to diagnose
cancers and other diseases via monitoring the abnormal hypoxia of the target organs or
tissues.
266 Recently, another FDA approved 18F labeled radiotracers 6-[
18F]fluoro-LDOPA was prepared to diagnose Parkinson’s disease.267
In contrast to the popularity of CF3-contained molecules among organofluorine
compounds, [18F]trifluoromethylations are underexplored despite some primitive
procedures reported in the literature.268,269 Nowadays, four major strategies were
developed to achieve 18F-labeled trifluoromethylation including isotopic exchange,
nucleophilic [18F]trifluoromethylation, electrophilic [18F]trifluoromethylation and
difluorocarbene-mediated [18F]trifluoromethylation.

42
19F to 18F isotopic exchange trifluoromethylation
Scheme 1.38 Representative 19F18F isotopic exchange trifluoromethylation
19F/18F isotopic exchange with CF3-preinstalled tracers is the earliest and most
straightforward method due to the direct utilization of commercially available bioactive
molecules (Scheme 1.38).
269–271 However, harsh condition such as high temperature
dramatically lower the applicability of this methods. Moreover, the uncontrollable overlabeling also affects the accuracy of the resulting tracers for PET assessment. The
unexchanged starting materials are basically the same as the radiolabeled products in
chemical and biological reactivities, which raises a high risk of molar activity
dilution.272
Nucleophilic substitution or addition
To circumvent the molar activity dilution, numerous electrophilic precursors were
synthesized to achieve the 18F-labeled trifluoromethylation. One of the most prevalent
types of substrates are R-CF2X (X = I, Br, Cl, and OMs).

43
Scheme 1.39 18F-labeled trifluoromethylation via nucleophilic substitution
The R-CF2X underwent nucleophilic attack by different 18F-labeled fluorides such
as [18F]KF (Scheme 1.39 A), [
18F]TBAF (Scheme 1.39 B) and [18F]CsF (Scheme 1.39
C) smoothly to furnish the radiolabeled products with high radiochemical yields. In
contrast to alkyl- and aryl-CF2X which no other additive was required, enolizable

44
substrates generally utilized organic bases such as DBU and TBD to facilitate the
transformation (Scheme 1.40).
268,270,273–282
Scheme 1.40 DBU- and TBD-facilitated [18F]trifluoromethylation via nucleophilic
substitution
Further studies on the role of these additives indicated that these organic bases
served as nucleophiles which attacked the target carbon center prior to fluorides and
generated more active intermediates. These intermediates reacted with fluorides more
efficiently compared to the starting materials to afford the desired products with higher
yields in shorter reaction time.273

45
Scheme 1.41 Ag-mediated [18F]trifluoromethylation via nucleophilic substitution
For ArSCF2Br and ArOCF2Br, AgOTf was determined to be a critical additive to
facilitate the nucleophilic attack (Scheme 1.41). Similarly, HCF2X compounds were
used to produce [18F]HCF3 which could be converted into [18F]TMSCF3 and
[
18F]CuCF3 under basic conditions. The 18F-labeled TMSCF3 was further reacted with
benzaldehydes and diphenyl-disulfides to afford the 18F-labeled 2,2,2-trifluoroethanols
and ArSCF3 products, respectively (Scheme 1.42 A).
40,283,284

46
Scheme 1.42 Preparation of [18F]fluoroform via nucleophilic substitution
On the other hand, [18F]CuCF3 could be adapted into the Cu-mediated aryltrifluoromethylation with aryl halides, boronic acids, diaryl iodinium salts, and aryl
diazonium salts to furnish the corresponding [
18F]Ar-CF3 products (Scheme 1.42
B).
285–287

47
Difluorocarbene-Mediated Chemistry
18F-Labeled trifluoromethylation benefited from the availability of difluorocarbene
precursors. Multiple difluorocarbene reagents have been employed to achieve in this
transformation.
Scheme 1.43 Difluorocarbene-mediated [18F]trifluoromethylation
In 2013, Gouverneur and coworkers reported the pioneering difluorocarbene-

48
mediated 18F-labeled trifluoromethylation of heteroaryl iodides with the [18F]CuCF3
generated by [
18F]KF, CuI and ClCF2COMe (Scheme 1.43 A).
39 Since then, multiple
difluorocarbene reagents have been employed to achieve in this transformation
(Scheme 1.43 B-F).38,41,286,288–290
Scheme 1.44 Difluorocarbene-mediated [18F]trifluoromethylthiolation
Liang and Xiao and coworkers utilized another difluorocarbene precursor
diflurormethylene phosphobetaine (PDFA) to achieve 18F-labeled
trifluoromethylthiolation. Notbaly, the generated difluorocarbene reacted with element
sulfur and formed carbonothioyl difluoride intermediate which readily captured by
[
18F]fluorides (Scheme 1.44).
291

49
Electrophilic substitution or addition
Scheme 1.45 Preparation of [18F]fluoroform via electrophilic difluoromethylated
sulfonium salts
There are three major reagents that have been reported for electrophilic
trifluoromethylation. Difluoromethylated sulfonium salts, firstly synthesis and reported
by our group as potent electrophilic difluoromethylating reagents, were attacked [
18F]Fto produce [18F]HCF3 in situ. Jubault and coworkers developed a procedure to produce
[
18F]ArSCF3, and [18F]ArSeCF3 in good yields via [18F]HCF3 generated from the same
sulfonium salts (Schem 1.45 A). Similarly, the 18F-labeled fluoroform was readily
converted into [18F]CuCF3 with Cu(I) salts under basic conditions. The resulting
[
18F]CuCF3was then reacted with aryl iodides and aryl boronic acids to provide [18F]ArCF3 (Scheme 1.45 B).292,293

50
Scheme 1.46 Preparation of 18F-labeled Umemoto reagent
18F-Labeled Umemoto reagent was synthesized to facilitate the electrophilic
[
18F]trifluoromethyltion of unmodified cysteines. The preparation of this regent started
with a silver-mediated nucleophilic attack of [1,1’-biphenyl]-2-
yl(bromodifluoromethyl)sulfane. The labeled product underwent a cyclization reaction
via Tf2O to afford the radio-labeled Umemoto reagent (Scheme 1.46).
40
Scheme 1.47 Preparation of [18F]-SelectfluorR
In 2013, Gouverneur, Solin, and Passchier’s groups disclosed an Ag-catalyzed
radio-fluorination with [18F]SelectfluorR
. In this reaction, the starting materials, 2,2-
difluoro-2-phenylacetic acids, underwent a decarboxylative pathway to afford the target
products. Compared to other methods, this pathway was not sensitive to moisture due
to the stability of SelectfluorR
in water (Scheme 1.47). However, the utilization of

51
[
18F]F2 to prepare [18F]SelectfluorR
left a considerable space for improvement.294
Another approach is to use 2,3,3-trifluoroallyl compounds or perfluorinated enols as
electrophiles which could be labeled by highly toxic [18F]F2 (Scheme 1.48 A & B) or
[
18F]KF (Scheme 1.48 C).
295–299
Scheme 1.48 Eletctrophilic trifluoromethylation of 2,3,3-trifluoroallyl compounds with
[
18F]F2 and [18F]KF
1.4 Trifluoromethoxylation
Trifluoromethoxylation is also an important approach to modulate the
physicochemical properties such as chemical and metabolic stabilities, bioavailability,
and lipophilicity.
300–302 Compared to trifluoromethyl groups (-CF3), the conjugation
between lone pair electrons of the oxygen atoms and benzene rings is reduced by the

52
hyperconjugation of C-F bond with the lone pair electrons of oxygen atoms and the
steric repulsion between -CF3 and the nearby protons of the aromatic rings.303,304
Figure 1.4 Representative OCF3-containing pharmaceutical and agrochemical
molecules
This leads to the free rotation of OCF3 group which results in a 90 o
-dihedral bond angle
(Ar-O-CF3). Owing to this distinct structural conformation, incorporating
trifluoromethoxy groups into organic compounds including pharmaceuticals, pesticides,
and functional materials could provide enhanced binding affinity (Figure 1.4).
305
Despite the broad applications of -OCF3 group, the direct and convenient
trifluoromethoxylation methods remains challenging due to the unstable
trifluoromethoxide anion which readily decomposes into highly toxic difluorophosgene
and fluorides upon generation (Scheme 1.49).
Scheme 1.49 Rapid decomposition of trifluoromethoxide anion (-OCF3)

53
In that case, numerous reagents have been synthesized to achieve
trifluoromethoxylation.50 In this sub-section, two major types of trifluoromethoxylation
approaches including nucleophilic and radical trifluoromethoxylation will be
discussed.306,307
Scheme 1.50 Nucleophilic and radical trifluoromethylation reagents
Nucleophilic trifluoromethoxylation
TFMT
In 1965, Noftle and coworkers synthesized the first nucleophilic OCF3-precursor,
trifluoromethyl trifluoromethansulfonate (TFMT).308,309 In 2008, Langois group

54
reported a general protocol to activate TFMT with fluorides and generate the
corresponding trifluoromethoxide salts such as AgOCF3, CsOCF3, TBAOCF3, etc
which lead to a series trifluoromethylations (Schem 1.51).
310
Scheme 1.51 Nucleophilic trifluoromethoxylation with TFMT
However, TMFT has a very low boiling point (19 oC) which makes its preparation,
storage and utilization difficult.311
DNTFB
In 2010, Langlois’s group disclosed a trifluoromethoxylation via a commercially
available reagent, 2,4-dinitro(trifluoromethoxy)benzene (DNTFB) (Scheme 1.52).

55
Scheme 1.52 Nucleophilic trifluoromethoxylation with DNTFB
Under batch reaction conditions, the transformation required 4 days to afford
moderate yields with DNTFB and benzyl bromide. Even though DNTFB exhibited
enhanced reactivity under microwave conditions, the limited substrate scope hindered
the application of this method.312
TSA-OCF3
In 2011, Ritter’s group firstly utilized TSA-OCF3 to achieve a transition-metalmediated coupling reaction with aryl stannanes and arylboronic acids (Scheme 1.53).
Scheme 1.53 Ag-mediated nucleophilic trifluoromethoxylation with TAS-OCF3
Despite the broad substrate scope, N-heterocyclic arenes and anilines were not

56
tolerated under the reaction conditions. Moreover, both the toxic Sn-containing starting
materials and the utilization of excessive amount of silver salts left considerable space
for improvement.313
TFMS
Scheme 1.54 Nucleophilic trifluoromethoxylation with TFMS
In 2017, Tang’s group developed a sulfone-based -OCF3 precursor with high
boiling point, TFMS, which was prepared by non-toxic Togni’s reagent. This regent
smoothly reacted with various electrophiles including alkenes to afford the asymmetric
bromo- and iodofluoromethoxylation products (Scheme 1.54).
314,315 Later in 2018, the
same group realized the first direct dehydroxytrifluoromethoxylation of alcohols with
TFMS. The proposed mechanism indicated that the activated -OCF3 anion decomposed
into difluorophosgene (COF2) which readily reacted with alcohols to generate

57
fluoroformates followed by nucleophilic attack with fluorides to furnish the desired
products.49 In the same year, TFMS was utilized in silver-mediated C-H
trifluoromethoxylation. For this method, substrates with acidic protons including
hydroxy, amine, carboxylic acid groups were not tolerated under the optimal
conditions.316,317 The reactivities of TFMS with primary alkylsilane and alkylborate
compounds under SelectfluorR
/AgI
conditions system were also demonstrated by Tang
and coworkers. Owing to its higher reactivity, alkylborate required fewer silver salts
and TFMS loading in contrast to alkylsilanes. In addition, secondary alkylsilanes and
alkylborates showed almost no reactivity under the reported conditions.
318,319 In 2021,
ring-opening hydroxyltrifluoromethoxylation of epoxides and aziridines were carried
out with TMFS.320,321 After extensive success in trifluoromethoxylation of saturated
carbon centers (C-sp3
), reactions of C-sp2 with TFMS were also investigated by Tang
and coworkers. Various starting materials including aryldiazonium salts,322
(hetero)arenes,48 terminal alkynes323 and propargyl sulfonates324 were reported to afford
the corresponding O-CF3 products in high efficiency.
Scheme 1.55 Preparation of TFBz
TFBz
Despite the numerous achievements in trifluoromethoxylation with TFMS,
stoichiometric amount of silver salt was constantly employed to stabilize the

58
trifluoromethoxide anion. Considering the high prices of Ag-contained reagents, silverfree protocol is of great interest.
Figure 1.5 Reaction set up for the preparation of TFBz
In 2018, Hu and coworkers developed a novel bench-stable trifluoromethoxylating
reagent, trifluoromethyl benzoate (TFBz), to achieve the first silver-free
trifluoromethoxylation of arenes with benzyne and indolynes precursors (Scheme 1.55).
It is worth mentioning that KF and cis-dicyclohexane-18-crown-6 was used as the
counteraction system to stabilize the OCF3-
, which formed an isolatable and thermal
stable key intermediate [K(cis-dicyclohexane-18-crown-6)]+CF3O-
. To demonstrate the
versatility of TFBz as a trifluoromethoxylating reagent, different nucleophilic
substitutions including alkylhalides, asymmetric difunctionlization of alkenes, etc
(Scheme 1.56).
325

59
Scheme 1.56 Nucleophilic trifluoromethylation with TFBz
However, the applicability of this method is limited by using toxic reagent
triphosgene, generating toxic gaseous intermediate difluorophosgene ex situ, and
sensitivity to moisture (spray dried KF is essential to have a high yield of TFBz) (Figure
1.5).
TFBO
Scheme 1.57 Nucleophilic trifluoromethoxylation with TFBO
In 2020, Tang and coworkers developed another reagent, (E)-O-trifluoromethyl-

60
benzaldoximes (TFBO), which can be deprotonated under basic conditions to release
OCF3
-
and reacted with alkyl halides including inactivated alkyl chlorides without
silver salts (Scheme 1.57). The major disadvantage of this method is that the yields of
the preparation of TFBO is not very high.326
NR4OCF3
At the same year, a various of quaternary ammonium trifluoromethoxide salts were
prepared by Friesen’s group via tertiary amines and trifluoromethyl ethers.
Scheme 1.58 Preparation of NR4OCF3 salts
The resulting NR4OCF3 salts were stable in solid forms and in solution. The
reactivity of these salts as trifluoromethylating reagents were investigated, and Nmethylmorpholine trifluoromethoxide salt was found to the most reactive with good
stability and availability. (Scheme 1.58)

61
Scheme 1.59 Nucleophilic trifluoromethoxylation with NR4OCF3 salts
However, only limited types of compounds including benzyl bromides, alkyl
iodides, diazo esters and glycosyl bromides were converted into the target products
(Scheme 1.59).
327,328

62
TFNf
Scheme 1.60 Preparation of TFNf and nucleophilic trifluoromethoxylation with TFNf
Inspired by the success of Umemoto reagents, Umemoto and Hammonda and
coworkers introduced a derivative of Umemoto reagents, trifluoromethyl nonaflate
(TFNf) as a new sulfone-based trifluoromethoxylating reagent (Scheme 1.60 A). In
addition to the trifluoromethoxylation of alkenes, a novel type of reaction, hydro-
(halo)trifluoromethoxylation of alkynes, was described with TFNf. Moreover, serval
classical nucleophilic substitutions were also carried out with TFNf including gramscale reactions, which demonstrated the potential of this reagent in pharmaceutical and
agrochemical applications (Scheme 1.60 B). Similar to the other reagents discussed
above, this reagent is also not commercially available, and its preparation requires a 4-
step procedure including a thermolysis step and a distillation process for purification.329

63
Phth-OCF3
Scheme 1.61 Nucleophilic trifluoromethoxylation with Phth-OCF3
In 2023, Qing and co-workers discovered a new application for Ntrifluoromethoxyphthalimide (Phth-OCF3) as a nucleophilic trifluoromethylating
reagent. This bench-stable reagent could be easily obtained by reacting N-hydroxyphthalimide and CF3SO2Na under mild conditions (Scheme 1.61).
330
Py-OCF3
Despite the fruitful achievements obtained by these trifluoromethoxylating
reagents, one common drawback is that almost all the reagents mentioned above are
not commercially available. Moreover, tedious or multiple-step preparation are usually
required to provide the target reagents.
Scheme 1.62 Nucleophilic trifluoromethoxylation with DNTFB
Recently, Sanford and Billard’s group revisited the only commercially
trifluoromethoxylating reagent, DNTFB, which was not favored due to its low reactivity.

64
Further studies showed that DNTFB can be activated by DMAP and generate a benchstable and isolatable solid compound, Py-OCF3. The resulting intermediate reacted
smoothly with benzyl bromides and iodides to afford the benzyl trifluoromethyl ethers
in moderate to excellent yields (Scheme 1.62). In addition, a one-pot procedure of
DNTFB and DMAP to achieve the trifluoromethoxylation of benzyl bromide via PyOCF3 was also introduced. Considering the ease of availability of inexpensive reagents
DNTFB and DMAP, it is obvious to envision that this method will attract more and
more attention in the near future.331,332

65
Radical trifluoromethoxylation
In 2018, Ngai and coworkers reported the first radical trifluoromethoxylation with
N-OCF3 (Scheme 1.63 A).
Scheme 1.63 Radical trifluoromethoxylation with N-OCF3
This reagent could easily achieve C-H trifluoromethylation of (hetero)arenes under
LED. The control experiments and DFT calculations indicated that a nitrogen radical
and a OCF3 radical were generated under light. Subsequently, the OCF3 radical is added
to substrates to form an aryl radical. The resulting aryl radical was oxidized by the
Ru(III) catalyst to provide the final products (Scheme 1.63 B). Notably, only 0.03 mol%
of the photocatalyst was used in the optimal conditions.333,334
Almost at the same time, Togni’s group invented N-trifluoromethoxy-4-cyanopyridinium to achieve the aryl C-H trifluoromethoxylation and a trifluoromethoxylation
of enolizable-ketones.

66
Scheme 1.64 Radical trifluoromethoxylation with N-trifluoromthoxy-4-cyanopyridinium
For the aryl C-H trifluoromethoxylation, a mixture of o-, m-, ptrifluoromethoxylated arenes with bad regioselectivities were obtained as the final
products. For a-trifluoromethylation of ketones, even though most of the products were
obtained in modest yields to low yields, the reaction could be subjected to continuous
flow system to improve the reaction time. Notably, the 4-CN substituent on the reagent
is crucial to tune the electron density, which allows controllably generation of OCF3
radicals.
335
Later Ngai’s group synthesized a trifluoromethoxylated benzotriazole to
selectively generate OCF3 radicals.

67
Scheme 1.65 Radical trifluoromethoxylation with OCF3-benzotriazole
This reagent was successfully employed on a wide range of (hetero)aryl rings with
higher efficiency. However, the regioselectivity remained not ideal with only ortho-
/para-trifluoromethoxylated product obtained with this system (Scheme 1.65).
336,337
In 2021, Hopkinson and coworkers employed F3CO-OCF3 (BTMP) as a new CF3
radical precursor. This reagent can be adapted into both Ru-catalyzed photo-redox
reaction and TEMPO-catalyzed reaction with good efficiency under mild conditions
(Scheme 1.66).
338
Scheme 1.66 Radical trifluoromethoxylation with BTMP

68
Chapter 2
Chemoselective N- and O-Difluoroemthylation of 2-Pyridones, Isoquinolineones,
and Quinolinones with TMSCF2Br
This chapter will cover the discussion and analysis of the direct chemoselective Nand O-difluoromethylation of 2-pyridones using commercially available TMSCF2Br.
The two tautomers, 2-pyridone and 2-hydroxypridine forms are determined to be the
predominant species under different temperatures. The versatile activation modes of
TMSCF2Br allow the smooth generation of difluorocarbene at low temperature to form
N-difluoromethylated pyridones as the major products without protection/deprotection
steps. Diverse, synthetically relevant functional groups are tolerated, including
functional groups that have reported reactivity with TMSCF2Br. Gram-scale reactions
to prepare both N- and O-difluoromethyl compounds are included.
2.1 Introduction
Fluorofunctionalizaion to enhance the physical and chemical properties of organic
molecules is a successful strategy in pharmaceutical,7,54,339 biochemical,340 and material
science applications.341,342 Particularly, difluoromethylation has emerged as an
important paradigm due to the lipophilicity and hydrogen bond donor ability of

69
−CF2H,
99,343,344 enabling bioisosteric replacement of commonly encountered functional
groups including −OH and −SH.99 Consequently, nucleophilic,345–347
electrophilic,135,348,349 and radical difluoromethylations350–352 have been developed.
Electrophilic difluoromethylation using difluorocarbene is a popular method for
insertion of −CF2− into alkenes/alkynes,134,137 as well as C−H,111,353 O−H,140 S−H,354
N−H,355 and P−H356 bonds. Numerous reagents have been developed to generate
difluorocarbene. ClCF2COONa and its derivatives, despite widespread utility, 357–359 are
limited by high activation temperatures. Freons and halons like HCF2Cl and CF3Br are
used as difluorocarbene precursors despite their inherent toxicity, commercial
inaccessibility, and environmental impact (ozone-depleting green-house gases).360
Difluorocarbene can also be efficiently generated from (per)fluoroalkylsilanes like
TMSCF3
134 or TMSCF2Br.361 The latter compound, first synthesized by our group,362 is
defining a new trend in difluoromethylation methodology due in part to its versatility
and ease of activation.111,137,143
2-Pyridones are important structures prevalent in pharmaceuticals and
biomolecules.363–365 For example, leporin A is known to possess antifungal
properties.366 In 2021, Forrestall and co-workers reported leporin A and 12 other
analogues as potential treatments for the novel coronavirus, SARS-CoV-2.367 2-
Pyridone moieties are also studied as selective inhibitors of HIV-1 RT.364 Additionally,
2-pyridones have found increasing value in anticancer research in the past decade.365

70
Scheme 2.1 Prior Arts
In 2009, Ando and co-workers found that N-difluoromethyl-2-pyridones are
important substructures which improve binding affinity with target receptors.363 Despite
the relevance of 2-pyridones, methods for their selective N- and O-difluoromethylation
are scarce (Figure 1).368,369 A two-step synthesis of N-difluoromethyl-2-pyridones using
ClCF2COONa is reported. Initial attempts at selective N-difluoromethylation of 2-
pyridones were unsuccessful, resulting in mixtures of compounds favoring the O−CF2H
products. The pyridone substrates were prefunctionalized into (2-pyridyl)acetamides,
thereby negating the possibility of forming O-difluoromethyl products and selectively
furnishing the N−CF2H compounds. The products could then be deprotected to yield N-
(difluoromethyl)pyridones. The requisite protection and deprotection steps and long
reaction times leave room for improvement. Furthermore, only 4- and 5-substituted
substrates could be converted into the desired N-difluoromethyl-2-pyridone products.368
In 2018, Ma and co-workers performed an O-difluoromethylation of 2-pyridones using
BrCF2COOEt, which suffers from long reaction times (12 h). Also, Ndifluoromethylation was not explored.369 Herein, we describe a fast, effective, and

71
tunable approach to selectively obtain N-and O-difluoromethylated 2-pyridones in one
pot.
Scheme 2.2 Proposed mechanism
The facile tautomerism of 2-pyridones, wherein the pyridine form is in equilibrium
with the hydroxypyridine form, has been well-described in the literature.370–372
Evidence has shown that temperature plays a role in the relative populations of the
tautomers.371 As shown by Forlani and co-workers, at 45 °C in a polar solvent system,
the hydroxypyridine form is favored, and at 20 °C the pyridone form is favored.373 On
the basis of these considerations, we reasoned that elevated temperatures would favor
the hydroxypyridine form, allowing for selective O-difluoromethylation. Likewise,
lower temperatures would favor the pyridone form, allowing for selective Ndifluoromethylation. Thus, our optimization was based on the following mechanistic
hypothesis (Scheme 1). The deprotonation of these structures produces form A (aryloxy
form) and form B (amide form), respectively. It can be expected that the −OH form
(hydroxypyridine) would have a lower pKa than the −NH form (pyridone). This may
warrant the need of a stronger base for the formation of form B, and a milder base for
form A. Given that forms A and B are in equilibrium, strict temperature control would

72
be necessary to limit the interconversion. Subsequent reaction with difluorocarbene
affords the corresponding O−CF2H and N−CF2H products. Initial trials with TMSCF3
were unsuccessful, so TMSCF2Br was employed as the :CF2 source.
2.2 Results and discussion
Table 2.1 Optimization experiments for 2a
Traila Base (equiv) T (oC) Time (h) 2a/3a (%)b
1 KOH (2.2) 60 1 68/6
2 K2CO3 (1.1) 60 1 44/54
3 LiOH (2.2) 60 1 57/13
4 Cs2CO3 (1.1) 60 1 93/5
5 Na2CO3 (1.1) 60 1 99/1
6 Na2CO3 (1.1) 0 1 68/2
7 Na2CO3 (1.1) rt 1 92/3
8 Na2CO3 (1.1) 60 2 76/2
9 Na2CO3 (1.1) 60 0.5 82/2
aReaction performed at 0.5 mmol scale. bYields determined by 19F NMR using fluorobenzene as internal standard.
5-methyl-2-pyridone (1a) was chosen as the model substrate to explore the Odifluoromethylation reaction. At 60°C in ACN (acetonitrile), employing KOH (Table
2.1, trial 1) as the base afforded 68% and 6% yield of the O−CF2H (2a) and N−CF2H
(3a) products, respectively, in one hour. Performing the reaction at room temperature
did not increase the yield or selectivity. Further increasing the reaction temperature to

73
60 °C resulted in a higher yield of 2a. K2CO3 and LiOH provided mixtures of 3a and
2a with low selectivity. Further optimization revealed that Cs2CO3 and Na2CO3 were
suitable bases to selectively obtain the O-difluoromethyl product in near-quantitative
yield. We also observed that longer reaction times led to decreased yield. This suggests
there is some decomposition of the product under the basic reaction conditions.
Next, the optimization focused on selectively obtaining N−CF2H products (Table
2.2). According to our hypothesis, the N−CF2H products are favored at lower
temperatures. When the reaction temperature was switched to 0 °C with Na2CO3 as the
base, 2a was still the predominant product. Of the bases screened, NaOt-Bu produced
the best result with 57% of 3a and trace (< 1%) 2a. However, the solubility of NaOtBu in ACN was low even with stoichiometric loading of 18-crown-6 (18-C-6). To
circumvent any reproducibility issues that may arise from this low solubility, alternative
solvents were tested. DCM was found to give a comparable yield of 3a (55%) with 1
equivalent of 18-C-6. However, the DCM system was ineffective on substrates with
electron withdrawing substituents. For example, the chemoselectivity of the reaction
with 1h was flipped, furnishing the corresponding O−CF2H product in DCM instead of
the N−CF2H product. Triglyme, a cheaper surrogate of 18-C-6,374 when used as the
solvent

74
Table 2.2 Optimization experiments on 3a
Traila Base (equiv) Solventb T (oC) 3a/2a (%)c
1 Na2CO3 (1.1) ACN 0 2/68
2 NaH (2.2) ACN 0 0/55
3 KOH (2.2) ACN 0 9/68
4 KO-tBu (2.2) ACN 0 13/46
5 LiHMDS (2.2) ACN 0 0/0
6 NaO-tBu (2.2) ACN 0 57/2
7 NaO-tBu (2.2) ACN -15 63/2
8 NaO-tBu (2.2) DCM -15 55/6
9 NaO-tBu (2.2) DMF -15 50/1
10 NaO-tBu (2.2) THF -15 43/3
11 NaO-tBu (2.2) DMSO -15 0/0
12 NaO-tBu (2.2) Triglyme -15 72/3
13 NaO-tBu (2.2) Triglyme -45 59/2
14d NaO-tBu (2.2) Triglyme -15 84/5
aReaction performed with 0.5 mmol scale. b0.25M concentration of 1a in solvent. cYields determined by 19F NMR using
fluorobenzene as internal standard. dTMSCF2Br added dropwise over 2.5 minutes.
provided 72% of 3a by 19F NMR. Lower reaction temperatures favored the formation
of 3a. The optimal temperature was found to be -15°C. Further reducing the reaction
temperature did not increase the yield of 3a (Table 2.2, trial 12 and 13). Changing the

75
reaction time did not effect a better yield. Adding more than 1.2 equivalents of
TMSCF2Br in the reaction was detrimental to the yields. When the substrate was
replaced with 5-bromo-2-pyridone, the N−CF2H product was obtained in 45% yield.
During the optimization of the N−CF2H products, 30 mol% to 40 mol% of CF2BrH was
consistently observed as a notable byproduct. This is likely due to the protonation of
CF2Br‾ intermediate by the tert-butanol formed in the deprotonation of the substrate.
We found that the dropwise addition of TMSCF2Br suppressed the formation of
CF2BrH and led to a higher yield of 3a (84%) (Table 2.2, Trial 14).
Scheme 2.3 Condition-Dependent O- and N-difluoromethylation of 2-pyridaones,
Isoquinolinones, and Quinolinonesa
aReactions were performed at 0.5 mmol scale for isolated yield with standard conditions. Yields within parentheses were determined
by 19F NMR using fluorobenzene as internal standard. bReactions were performed at 5 mmol scale.
The model substrate 1a gave 88% of 2a and 71% of 3a under methods A and B,
respectively (Scheme 2.3). Alkoxy-substituted substrates 1b and 1c afforded 2b and 2c
in excellent yields. Methyl-2-pyridones 2d and 2e were isolated in 55% and 46% yields,

76
respectively. Compounds 3d and 3e were also synthesized by method B in 42% and 39%
yields, respectively. The volatility of these compounds is likely responsible for the
reduced isolated yields. 6-Methyl-2-pyridone (1f) only generated target products under
method A and was unable to produce 3f (see Scheme 3). The brominated 2-pyridones
1g and 1h furnished 2g and 2h in good yields. Compound 1h afforded 3h in 38%
isolated yield under method B. The strongly electron-withdrawing −CF3 group was also
compatible with both methods (2i and 3i). Pyridones with electron-donating
substituents (1a−1f) gave higher yields than those with electron-withdrawing groups
(1g−1i) with both methods. Large-scale reactions (gram scale, 5 mmol) were performed
on substrate 1b with methods A and B (87% and 47% isolated yields, respectively). A
disubstituted pyridone 1j was also explored. Related isoquinolinones 1k, 1l, and 1m
were converted to 2k, 2l, and 2m in good to excellent yields, while 3k, 3l, and 3m were
afforded in moderate yields. Similarly, difluoromethylated quinolinones 2n and 2o were
obtained in good yields. However, both 1n and 1o gave very low yields of the N−CF2H
products likely due to the sterics of the benzo-fused system, which may deter
nucleophilic attack. Similarly, 1s furnished 2s in 75% yield (method A), whereas only
a trace amount of N−CF2H product was formed under method B. Quinoline-2-thiol 1p
produced 2p as the major product under both methods due to the enhanced
nucleophilicity of S−
. Method A tolerated important functional groups, providing ester
(2q) and amide (2r) (albeit in modest yield). Neither 3q nor 3r was obtained from
method B. Heteroaryl-2-pyridones 1t−1x afforded 2t−2x in good to excellent yields,
and 3t−3x in moderate to good yields. Notably, the vinyl group on substrate 1t was

77
unreactive toward the difluorocarbene generated under our conditions, despite their
known [2 + 1] cycloaddition.134,137
Scheme 2.4 19F NMR yield of 6-substituted 2-pyridones under Method B
6-Subsituted 2-pyridones, 1f, 1j, and 1r, were unreactive under method B. To
further probe this interesting result, more 6-substituted 2-pyridones were tested. For the
electron-withdrawing groups −Br and −CF3, the major products were Odifluoromethylated pyridones even under method B (Scheme 2.4). Considering the
small size of the F atom and its strong withdrawing effect, 1z was subjected to method
B to isolate the steric effects on the 6-position from the electronic effects. The reaction
furnished 45% O−CF2H product.
Accordingly, we propose that the electronics of the substituents influence the
interconversion between form A and form B (Scheme 2.2) by inductive effects. The
reversed selectivity when difluoromethylating 1z, 1aa, and 1ab was due to the strong
inductive effects of substituents ortho to the nitrogen. In contrast, the methyl group in
1f did not completely inhibit the reaction and yielded 12% of N−CF2H, which is lower
than the analogous 3-, 4-, 5-methylated 2-pyridones (1e, 1d, 1a). These data suggest
that steric effects can significantly inhibit the reaction despite favorable electronics
rendering the N atom more nucleophilic. Finally, 1y afforded 53% of the N−CF2H
product. These results demonstrate dependence of reaction outcomes on electronic and

78
steric parameters.
2.3 Conclusion
In summary, this paper presents direct O- and N-difluoromethylations of 2-
pyridones, isoquinolinones, and quinolinones. The chemo-selective protocol employs
commercially available reagents and mild conditions. Tolerance to important functional
groups including esters, amides, and alkenes demonstrates potential for late-stage
functionalization.
2.4 Experimental data. General procedures and characterization data
Procedure for synthesis of 5-bromopyridine-2-yl-4-methylbenzenesulfonate (S2).
The procedure was adapted from a previous report.375 5-bromo-2-hydroxypyridine
(1.0 eq, 28.75 mmol, 5g), TsCl (1.2 eq, 34.5 mmol, 6.6g) and 4-dimethylaminopyridine
(0.05 eq, 1.44 mmol, 175mg) were added into an oven-dried vial under air. Then, 87
mL of DCM and 8 mL of Et3N were added into the vial, and the reaction mixture was
stirred under air for 1 h at room temperature. After the reaction was complete, the
product mixture was quenched with saturated NH4Cl (100 mL) and diluted with Et2O
(100 mL). The organic phase was collected, and the aqueous phase was extracted again
with Et2O (2 x 100 mL). The combined organic layer was washed with brine (3 x 100
mL) and dried with MgSO4. Then, the drying agent was filtered, and the organic solvent
was removed under reduced pressure. The residue was purified by flash column
chromatography, eluted with 20% ethyl acetate in hexane to give the product 5-

79
bromopyridin-2-yl-4-methylbenzenesulfonate S2 (7.44g, 79% yield). White solid.
General Procedure for the synthesis of aryl-2-sulfonyloxypyridines S3t, S3v – S3x.
The procedure was adapted from a previous report.375 Bromo-2-
sulfonyloxypyridine S2 (1.0 eq), boronic acids (1.8 eq), K2CO3 (2.2 eq), Ad2BnP (0.024
eq) and Pd(OAc)2 (0.02 eq) were added into an oven-dried flask under argon protection.
Then, degassed dry toluene and degassed water (0.1 M, toluene/water = 30:1) were
added under N2, and the mixture was stirring at room temperature under N2 until the
reaction was complete (reaction time specifies for individual substrate). After the
reaction was complete, the product mixture was diluted with DCM (50 mL), and brine
(50 mL) was added. The organic phase was collected, and the aqueous phase was
extracted again with DCM (2 x 50 mL). The combined organic layer was washed with
brine (3 x 50 mL) and dried with MgSO4. Then, the drying agent was filtered, and the
organic solvent was removed under reduced pressure. The residue was purified by flash
column chromatography to give products S3.
Note: Toluene and water should be degassed separately.

80
Procedure for the synthesis of 5-(Thiophen-3-yl)pyridin-2-yl 4-
methylbenzenesulfonate (S3u)
The procedure was adapted from a previous report.375 Bromo-2-
sulfonyloxypyridine S2 (1.0 eq, 10 mmol, 3.28 g), boronic acids (1.8 eq, 18 mmol, 2.3
g), K2CO3 (2.2 eq, 22 mmol, 3.04 g), P(Cy)3 (0.024 eq, 0.24 mmol, 67.3 mg) and
Pd(OAc)2 (0.02 eq, 0.2 mmol, 45 mg) were added into an oven-dried flask under argon
and the vessel was sealed. Then, degassed dry toluene and degassed water (0.1 M, 100
mL, toluene/water = 30:1) were added under N2, and the mixture were stirred in a 100˚C
oil bath for 1.5 h. After the reaction was complete, the resulting mixture was diluted
with DCM (50 mL), and brine (50 mL) was added. The organic phase was collected,
and the aqueous phase was extracted again with DCM (2 x 50 mL). The combined
organic layer was washed with brine (3 x 50 mL), dried with MgSO4, filtered,
concentrated under reduced pressure. The residue was purified by flash column
chromatography (eluted with 10% ethyl acetate in hexane) to give product 5-(Thiophen3-yl)pyridin-2-yl 4- methylbenzenesulfonate S3u (3.31 g, 99% yield). Pale-yellow solid.
Note: Toluene and water should be degassed separately.

81
General Procedure for the synthesis of aryl-2-pyridones (S4t – S4x)
The procedure was adapted from a previous report.375 Compound S3 (1.0 eq) was
added into an oven-dried flask under air. Then, methanol, THF and 1N NaOH aqueous
solution (0.02 M, MeOH/THF/1N NaOH = 2:2:1) were added into the flask at room
temperature under air. The solution was then stirred in a 50 oC oil bath for 1 h. Then,
the reaction was diluted with EtOAc (50 mL) and brine (50 mL). The organic phase
was collected, and the aqueous phase was extracted again with EtOAc (2 x 50 mL). The
combined organic layer was washed with brine (3 x 50 mL), dried with Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by flash column
chromatography to give products S4.
Notes: When the reactions were performed with only methanol as the solvent, the major
products were 2-methoxy-pyridines.
The volumes of the solvents will be specified individually for each compound.
General procedure for the synthesis of O-difluoromethylated pyridones (2a – 2x)
Substrate 1 (1.0 eq, 0.5 mmol) and Na2CO3 (1.1 eq, 0.55 mmol, 58.3mg) were
added into an oven-dried vial under air. Then, 1.25 mL of acetonitrile was added at
room temperature, and the suspension was stirred for 10 min in an oil bath preheated to

82
60˚C. After that, TMSCF2Br (1.2 eq, 0.6 mmol, 100 µL) was added to the vial, and the
resulting solution was stirred for 1 h at 60 oC. Subsequently, the reaction mixture was
cooled to room temperature, and diluted with DCM (15 mL) and brine (15 mL). The
organic phase was collected, and the aqueous phase was extracted again with DCM (2
x 15 mL). The combined organic layer was washed with brine (3 x 15 mL) and dried
with Na2SO4. Then the drying agent was filtered, and the organic solvent was removed
under reduced pressure. The residue was purified by flash column chromatography to
give products 2.
General procedure for the synthesis of N-difluoromethylated pyridones (3a – 3e,
3h, 3i, 3k – 3m, 3t –3x)
Substrate 1 (1.0 eq, 0.5 mmol) and NaOt-Bu (2.2 eq, 1.1 mmol, 105.6 mg) were
added into an oven-dried vial under argon. Then, 2 mL triglyme was added under N2 at
room temperature, and the solution was stirred for 10 mins at -15 oC (NH4Cl/ice water
bath). Next, TMSCF2Br (1.2 eq, 0.6 mmol, 100 µL) was added into the solution
dropwise (the addition was complete in 2.5 min), and the solution was stirred for 1 h at
-15 oC. Subsequently, the reaction mixture was warmed to room temperature, and
diluted with EtOAc (15 mL) and brine (15 mL). The organic phase was collected, and
the aqueous phase was extracted again with EtOAc (2 x 15 mL). The combined organic
layer was washed with brine (6 x 20 mL) and dried with Na2SO4. Then the drying agent

83
was filtered, and the organic solvent was removed under reduced pressure. The residue
was purified by flash column chromatography to give products 3.
Note: Washing the organic layer for more than three times was necessary to fully
remove the triglyme from the final product.
Procedure for the large scale (gram-scale) synthesis of O-difluoromethylated
pyridones 2b.
Substrates 1b (1.0 eq, 5.0 mmol, 1.006 g) and Na2CO3 (1.1 eq, 5.5 mmol, 583 mg)
were added into an oven-dried 30 mL vial under air. Then, 12.5 mL of acetonitrile was
added at room temperature, and the suspension was stirred for 10 min in an oil bath
preheated to 60 oC. After that, TMSCF2Br (1.2 eq, 6.0 mmol, 1.0 mL) was added into
the vial, and the resulting solution was stirred for 1 h at 60 oC. Subsequently, the
reaction mixture was cooled to room temperature, and diluted with DCM (100 mL) and
brine (100 mL). The organic phase was collected, and the aqueous phase was extracted
again with DCM (2 x 100 mL). The combined organic layer was washed with brine (3
x 100 mL) and dried with Na2SO4. Then the drying agent was filtered, and the organic
solvent was removed under reduced pressure. The residue was purified by flash column
chromatography, and eluted with 10% ethyl acetate in hexane to afford 2b (1.091 g,
4.34 mmol, 87% yield). Colorless oil.

84
Procedure for the large scale (gram-scale) synthesis of N-difluoromethylated
pyridones 3b.
Substrate 1b (1.0 eq, 5.0 mmol, 1.006 g), NaOt-Bu (2.2 eq, 11.0 mmol, 1.056 g)
were added into an oven-dried 30 mL vial under Argon protection. Then, 20 mL
triglyme was added under N2 protection at room temperature, and the solution was
stirred for 10 mins at -15 oC. After that, TMSCF2Br (1.2 eq, 6 mmol, 1 mL) was added
into the solution dropwise (the addition was complete in 15 min), and the solution was
stirred for 1 h at -15 oC (NH4Cl/ice water bath). Subsequently, the reaction mixture was
warmed to room temperature, and diluted with EtOAc (100 mL) and brine (100 mL).
The organic phase was collected, and the aqueous phase was extracted again with
EtOAc (2 x 100 mL). The combined organic layer was washed with brine (6 x 100 mL)
and dried with Na2SO4. Then the drying agent was filtered, and the organic solvent was
removed under reduced pressure. The residue was purified by flash column
chromatography, and eluted with 40% ethyl acetate in hexane to afford 3b (593 mg,
2.36 mmol, 47% yield). White solid. Note: Washing the organic layer for more than
three times was necessary to fully remove the triglyme from the final product.
5-bromopyridin-2-yl 4-methylbenzenesulfonate (S2)
Known compound. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 2.4 Hz, 1H), 7.88 – 7.85
(m, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 1H), 2.46 (s, 3H). The 1H NMR
data obtained agreed with literature report.
375

85
5-(4-Vinylphenyl)pyridine-2-yl 4-methylbenzenesulfonate (S3t)
Reaction was complete in 50 min. Performed on 10.0 mmol scale, eluted with 10%
ethyl acetate in hexane to afford 3t (2.28 g, 65% yield). White solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 2.4 Hz, 1H), 7.96 – 7.91 (m, 3H), 7.52 –
7.48 (m, 4H), 7.36 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.78 – 6.72 (m, 1H),
5.82 (d, J = 17.6 Hz, 1H), 5.32 (d, J = 10.9 Hz, 1H), 2.46 (s, 3H). The 1H NMR data
obtained agreed with literature report.
375
tert-Butyl 4-(6-(tosyloxy)pyridin-3-yl)benzoate (S3v)
Reaction was complete in 1.5 h. Performed on 8.0 mmol scale, eluted with 15% ethyl
acetate in hexane to afford 3v (1.32g, 39% yield). White solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.48 (dd, J = 2.6, 0.7 Hz, 1H), 8.08 (d, J = 8.7 Hz, 2H),
7.97 (dd, J = 8.4, 2.6 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.37
(d, J = 8.0 Hz, 2H), 7.22 (dd, J = 8.5, 0.8 Hz, 1H), 2.46 (s, 3H), 1.61 (s, 9H). The 1H
NMR data obtained agreed with literature report.
375

86
5-(4-(Methylthio)phenyl)pyridin-2-yl 4-methylbenzenesulfonate (S3w)
Reaction was complete in 4.5 h. Performed on 13.45 mmol scale, eluted with 10% ethyl
acetate in hexane to afford 3w (1.54 g, 31% yield). Yellow solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.43 (dd, J = 2.6, 0.8 Hz, 1H), 7.93 – 7.90 (m, 3H), 7.44
(d, J = 8.4 Hz, 2H), 7.37 – 7.32 (m, 4H), 7.17 (dd, J = 8.4, 0.7 Hz, 1H), 2.52 (s, 3H),
2.46 (s, 3H). The 1H NMR data obtained agreed with literature report.
375
5-(4-Fluorophenyl)pyridin-2-yl-4-methylbenzenesulfonate (S3x)
Reaction was complete in 40 min. Performed on 8.0 mmol scale, eluted with 10% ethyl
acetate in hexane to afford 3x (2.47 g, 90% yield). White solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 2.6 Hz, 1H), 7.94 – 7.90 (m, 3H), 7.51 –
7.48 (m, 2H), 7.38 – 7.36 (m, 2H), 7.21 – 7.15 (m, 3H), 2.47 (s, 3H). The 1H NMR data
obtained agreed with literature report.
375
5-(Thiophen-3-yl)pyridin-2-yl 4-methylbenzenesulfonate (S3u)
1H NMR (500 MHz, CDCl3) δ 8.48 (dd, J = 2.6, 0.7 Hz, 1H), 7.95 – 7.91 (m, 3H), 7.49
– 7.44 (m, 2H), 7.37 – 7.36 (m, 2H), 7.33 (dd, J = 5.0, 1.4 Hz, 1H), 7.16 (dd, J = 8.4,

87
0.7 Hz, 1H), 2.47 (s, 3H). The 1H NMR data matches the previous report.375
5-(4-Vinylphenyl)pyridine-2(1H)-one (S4t)
Performed on 2.5 mmol scale, eluted with 20% methanol in ethyl acetate to afford 4t
(310 mg, 63% yield). White solid. Mp: 177 – 182 oC.
1H NMR (500 MHz, CDCl3) δ 13.85 (br s, 1H), 7.78 (dd, J = 9.4, 1.9 Hz, 1H), 7.66 –
7.65 (m, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.75 – 6.68 (m, 2H),
5.77 (d, J = 17.6 Hz, 1H), 5.27 (d, J = 10.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
164.5, 141.4, 137.0, 136.2, 135.7, 131.8, 127.1, 126.0, 121.0, 120.6, 114.4. FT-IR (
-1
cm-1
) 2962, 2838, 2248, 2148, 1658, 1612, 1511, 1469, 1423, 1257, 1214, 1083, 998,
906, 829, 736. HRMS (ESI) m/z calculated for C13H12NO [M + H]+
: 198.0913; found
198.0912 (0.5048 ppm).
5-(Thiophen-3-yl)pyridin-2(1H)-one (S4u)
Performed on 3.0 mmol scale, eluted with 20% methanol in ethyl acetate to afford 4u
(252.4 mg, 70% yield). Yellow solid. Mp: 171 – 176 oC.
1H NMR (500 MHz, CDCl3) δ 13.57 (br s, 1H), 7.78 (d, J = 9.4, 1H), 7.66 (s, 1H), 7.41
– 7.39 (m, 1H), 7.27 – 7.26 (m, 1H), 7.19 (d, J = 5.0 Hz, 1H), 6.70 (d, J = 9.4 Hz, 1H);

88
13C NMR (126 MHz, CDCl3) δ 164.8, 141.2, 137.4, 131.4, 127.2, 125.2, 120.5, 119.3,
116.9. FT-IR (
-1 cm-1
) 3768, 3691, 3070, 2958, 2375, 2306, 2260, 2152, 2028, 1967,
1909, 1658, 1438, 1257, 1025, 863, 782. HRMS (ESI) m/z calculated for C9H8NOS
[M + H]+
: 178.0321; found 178.0322 (0.5616 ppm).
tert-Butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoate (S4v)
Performed on 3.0 mmol scale, eluted with 20% methanol in ethyl acetate to afford 4v
(540.6 mg, 66% yield). White solid. Mp: 190 – 193 oC.
1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.83 (dd, J = 9.5, 2.6 Hz, 1H),
7.71 (d, J = 2.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 9.5 Hz, 1H), 1.62 (s, 9H);
The N-H peak was not observed. 13C NMR (126 MHz, CDCl3) δ 165.3, 164.4, 141.2,
140.0, 132.4, 131.0, 130.3, 125.4, 120.6, 120.4, 81.2, 28.2. FT-IR (
-1 cm-1
) 2958, 2857,
2159, 2001, 1928, 1708, 1658, 1577, 1469, 1407, 1353, 1257, 1076, 1022, 863, 798,
709. HRMS (ESI) m/z calculated for C16H18NO3 [M + H]+
: 272.1281; found 272.1281
(1.4699 ppm).
5-(4-Methylthio)phenyl)pyridin-2(1H)-one (S4w)
Performed on 3 mmol scale, eluted with 20% methanol in ethyl acetate to afford 4w

89
(412.4 mg, 63% yield). Pale-yellow solid. Mp: 201 – 203 oC.
1H NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 9.4, 2.6 Hz, 1H), 7.62 (d, J = 2.6 Hz, 1H),
7.35 – 7.30 (m, 4H), 6.70 (d, J = 9.4 Hz, 1H), 2.51 (s, 3H); The N-H peak was not
observed. 13C NMR (126 MHz, CDCl3) δ 164.7, 141.4, 138.1, 133.2, 131.7, 127.3,
126.3, 120.8, 120.6, 16.0. HRMS (ESI) m/z calculated for C12H12NOS [M + H]+
:
218.0634; found 212.0633 (0.4586 ppm).
5-(4-Fluorophenyl)pyridin-2(1H)-one (S4x)
Performed on 4.0 mmol scale, eluted with 20% methanol in ethyl acetate to afford 4x
(560 mg, 74% yield). White solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 7.75 (dd, J = 9.4, 2.7 Hz, 1H), 7.61 (d, J = 2.6 Hz, 1H),
7.39 – 7.36 (m, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.72 (d, J = 9.4 Hz, 1H). The N-H peak
was not observed, otherwise agreed with the literature report.
376
2-(Difluoromethoxy)-5-methylpyridine (2a)
Performed on 0.5 mmol scale, eluted with 10% dichloromethane in pentane afford 5a
(70 mg, 88% yield). Colorless liquid. Known compound.
1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.6, 2.2 Hz, 1H),
7.40 (t, J = 73.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 2.27 (s, 3H). The 1H NMR data

90
obtained agreed with literature report.
369
4-(Benzyloxy)-2-(difluoromethoxy)pyridine (2b)
Performed on 0.5 mmol scale, eluted with 5% to 10% ethyl acetate in hexane to afford
5b (102.9 mg, 82% yield). Colorless oil.
1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 5.6 Hz, 1H), 7.67 – 7.31 (m, 5H), 6.74 –
6.73 (m, 1H), 6.44 (s, 1H), 5.10 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 167.8, 160.9
(t, J = 3.7 Hz), 147.7, 135.3, 128.8, 128.6, 127.6, 114.1 (t, J = 254.8 Hz), 109.1, 96.3,
70.3; 19F NMR (470 MHz, CDCl3) δ -89.1 (d, J = 73.2 Hz, 2F). FT-IR (
-1 cm-1
) 3043,
2942, 2881, 1573, 1481, 1430, 1334, 1257, 1172, 914, 833. HRMS (ESI) m/z
calculated for C13H12F2NO2 [M + H]+
: 252.0831; found 252.0832 (0.3966 ppm).
2-(Difluoromethoxy)-3-methoxypyridine (2c)
Performed on 0.5 mmol scale, eluted with 30% dichloromethane in pentane to afford
5c (72.6 mg, 83% yield). Colorless liquid.
1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 4.8 Hz, 1H), 7.47 (t, J = 73.0 Hz, 1H), 7.20
(d, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.8, 5.0 Hz, 1H), 3.87 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 149.2 (t, J = 3.6 Hz), 143.9, 137.0, 120.6, 119.8, 114.4 (t, J = 255.5 Hz), 56.0;
19F NMR (470 MHz, CDCl3) δ -89.0 (d, J = 73.0 Hz, 2F). FT-IR (
-1 cm-1
) 3019, 2942,

91
2846, 1585, 1457, 1353, 1280, 1207, 1110, 1068, 1018, 887. HRMS (ESI) m/z
calculated for C7H8F2NO2 [M + H]+
: 176.0518; found 176.0520 (1.1360 ppm).
2-(Difluoromethoxy)-4-methylpyridine (2d)
Performed on 0.5 mmol scale, eluted with 20% ethyl acetate in dichloromethane to
afford 5d (36.6 mg, 46% yield). Colorless liquid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 4.9 Hz, 1H), 7.45 (t, J = 73.3 Hz, 1H), 6.91
(d, J = 4.7 Hz, 1H), 6.71 (s, 1H), 2.35 (s, 3H). The 1H NMR data obtained agreed with
literature report.
369
2-(Difluoromethoxy)-3-methylpyridine (2e)
Performed on 0.5 mmol scale, eluted with pure pentane to afford 5e (58.6 mg, 55%
yield). Colorless liquid.
1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 4.3 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.49
(t, J = 73.4 Hz, 1H), 7.01 – 6.99 (m, 1H), 2.27 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
157.6, 144.1, 140.3, 121.2, 120.0, 114.3 (t, J = 254.2 Hz), 15.3; 19F NMR (470 MHz,
CDCl3) δ -89.2 (d, J = 73.5 Hz, 2F). FT-IR (
-1 cm-1
) 3860, 3741, 3679, 3617, 3027,
2962, 2310, 1581, 1481, 1357, 1257, 1103, 1072, 910, 821, 732. HRMS (ESI) m/z
calculated for C7H8F2NO [M + H]+
: 160.0568; found 160.0569 (0.6248 ppm).

92
2-(Difluoromethoxy)-6-methylpyridine (2f)
Performed on 0.5 mmol scale, eluted with 10% dichloromethane in pentane to afford
5f (49.3 mg, 62% yield). White solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 7.59 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 73.4 Hz, 1H), 6.93
(d, J = 7.4 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 2.46 (s, 3H). The 1H NMR data obtained
agreed with literature report.
369
4-Bromo-2-(difluoromethoxy)pyridine (2g)
Performed on 0.5 mmol scale, eluted with pure hexane to afford 5g (43.5 mg, 39%
yield). Colorless liquid.
1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 5.4 Hz, 1H), 7.44 (t, J = 72.6 Hz, 1H), 7.30
– 7.26 (m, 2H), 7.12 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 159.6 (t, J = 3.8 Hz),
147.7, 135.4, 123.8, 115.0, 114.0 (t, J = 256.5 Hz); 19F NMR (470 MHz, CDCl3) δ -
89.6 (d, J = 72.5 Hz, 2F). FT-IR (
-1 cm-1
) 3062, 2306, 1670, 1569, 1461, 1403, 1349,
1295, 1265, 1218, 1068, 910, 860, 813, 771, 709. HRMS (ESI) m/z calculated for
C6H5BrF2NO [M + H]+
: 223.9517; found 212.9523 (2.6791 ppm).

93
5-Bromo-2-(difluoromethoxy)pyridine (2h)
Performed on 0.5 mmol scale, eluted with 10% dichloromethane in pentane to afford
5h (83.6 mg, 75% yield). Colorless liquid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 2.6 Hz, 1H), 7.82 (dd, J = 8.7, 2.5 Hz, 1H),
7.40 (t, J = 72.7 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H). The 1H NMR data obtained agreed
with literature report.
368
2-(Difluoromethoxy)-3(trifluoromethyl)pyridine (2i)
Performed on 0.5 mmol scale, eluted with 15% dichloromethane in pentane to afford 5i
(60.7 mg, 57% yield). Colorless liquid.
1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 4.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.54
(t, J = 71.9 Hz, 1H), 7.24 – 7.22 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 156.0, 150.5,
137.7, 121.1, 119.7, 113.7 (t, J = 257.9 Hz), 14.2; 19F NMR (470 MHz, CDCl3) δ -63.8
(s, 3F), -90.1 (d, J = 72.0 Hz, 2F). FT-IR (
-1 cm-1
) 3860, 3741, 3679, 3617, 3081, 2958,
2314, 1747, 1681, 1573, 1454, 1322, 1261, 1218, 1083, 906, 852, 809, 771, 732.
HRMS (ESI) m/z calculated for C7H5F5NO [M + H]+
: 214.0286; found 214.0298
(5.6067 ppm).

94
2-(Difluoromethoxy)-6-methyl-3-nitropyridine (2j)
Performed on 0.5 mmol scale, eluted with 10% dichloromethane in pentane to afford
5j (30 mg, 25% yield). White solid. Mp: 44 – 45 oC.
1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 71.5 Hz, 1H), 7.11
(d, J = 8.2 Hz, 1H), 2.58 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 163.0, 150.7 (t, J =
4.3 Hz), 136.4, 119.7, 113.8 (t, J = 259.0 Hz), 29.8, 24.5; 19F NMR (470 MHz, CDCl3)
δ -90.3 (d, J = 71.5 Hz, 2F). FT-IR (
-1 cm-1
) 3019, 2923, 2854, 2167, 1592, 1527,
1461, 1349, 1284, 1214, 1137, 1091, 840, 756. HRMS (ESI) m/z calculated for
C7H7F2N2O3 [M + H]+
: 205.0419; found 205.0414 (2.4385 ppm).
1-(Difluoromethoxy)isoquinoline (2k)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 5k (83
mg, 85% yield). Colorless liquid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.26 (dd, J = 8.3, 1.1 Hz, 1H), 8.01 (d, J = 5.8 Hz, 1H),
7.86 – 7.57 (m, 4H), 7.43 (d, J = 5.8 Hz ,1H). The 1H NMR data obtained agreed with
literature report.
369
6-Bromo-1-(difluoromethoxy)isoquinoline (2l)

95
Performed on 0.5 mmol scale, eluted with 10% ethyl acetate in hexane to afford 5l
(110.5 mg, 81% yield). Pale-yellow solid. Mp: 50 – 52 oC.
1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 5.8 Hz, 1H), 7.99
(d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.9, 1.9 Hz, 1H), 7.69 (t, J = 72.5 Hz, 1H), 7.35 (d, J
= 5.6 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 156.1 (t, J = 3.6 Hz), 140.3, 139.7, 131.4,
128.8, 126.5, 125.5, 117.1, 114.2 (t, J = 256.3 Hz); 19F NMR (470 MHz, CDCl3) δ -
90.0 (d, J = 72.5 Hz, 2F). FT-IR (
-1
cm-1
) 3073, 2923, 2850, 1673, 1623, 1565, 1481,
1396, 1330, 1265, 1128, 910, 821. HRMS (ESI) m/z calculated for C10H7BrF2NO [M
+ H]+
: 273.9674; found 273.9675 (0.3650 ppm).
7-Bromo-1-(difluoromethoxy)isoquinoline (2m)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 5m (89.6
mg, 66% yield). White solid. Mp: 84 – 85 oC.
1H NMR (500 MHz, CDCl3) δ 8.43 – 8.42 (m, 1H), 8.04 (d, J = 5.8 Hz, 1H), 7.87 –
7.52 (m, 3H), 7.41 (dd, J = 5.8, 1.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 155.1 (t,
J = 3.6 Hz), 139.5, 137.1, 135.1, 128.2, 126.3, 121.6, 119.7, 117.9, 114.2 (t, J = 256.5
Hz); 19F NMR (470 MHz, CDCl3) δ -90.0 (d, J = 72.2 Hz, 2F). FT-IR (
-1 cm-1
) 3860,
3741, 3679, 3617, 3073, 2314, 1747, 1685, 1573, 1484, 1407, 1349, 1303, 1265, 1106,
1076, 829, 779. HRMS (ESI) m/z calculated for C10H7BrF2NO [M + H]+
: 273.9674;
found 273.9671 (1.0950 ppm).

96
2-(Difluoromethoxy)quinoline (2n)
Performed on 0.5 mmol scale, eluted with pure hexane to afford 5n (71.2 mg, 73%
yield). Colorless liquid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.7 Hz, 1H), 7.84 (dd, J = 41.3, 8.3 Hz, 2H),
7.76 (t, J = 72.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.02 (d, J =
8.7 Hz, 1H). The 1H NMR data obtained agreed with literature report.
369
2-(Difluoromethoxy)-4-(trifluoromethyl)quinoline (2o)
Performed on 0.5 mmol scale, eluted with pure hexane to 5% ethyl acetate in hexane to
afford 5o (59.2 mg, 45% yield). Colorless oil.
1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 1H), 7.99 – 7.97 (m, 1H), 7.80 (ddd,
J = 8.4, 7.1, 1.2 Hz, 1H), 7.72 (t, J = 72.1 Hz, 1H), 7.62 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H),
7.36 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 156.4 (t, J = 3.9 Hz), 146.7, 139.0 (q, J =
32.4 Hz), 131.4, 128.8, 127.3, 124.3 (q, J = 2.3 Hz), 123.9, 121.7, 113.8 (t, J = 257.0
Hz), 110.4 (q, J = 5.7 Hz); 19F NMR (470 MHz, CDCl3) δ -62.6 (s, 3F), -90.5 (d, J =
72.1 Hz, 2F). FT-IR (
-1 cm-1
) 3097, 2310, 1616, 1581, 1519, 1473, 1400, 1338, 1288,
1253, 1226, 1126, 1076, 964, 879, 767. HRMS (ESI) m/z calculated for C11H7F5NO
[M + H]+
: 264.0442; found 264.0440 (0.7574 ppm).

97
1-((Difluoromethyl)thio)isoquinoline (2p)
Performed on 0.5 mmol scale, eluted with 10% ethyl acetate in hexane to afford 5p (96
mg, 91% yield). Yellow liquid.
1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 5.5 Hz, 1H), 8.14 – 7.92 (m, 2H), 7.81 (d,
J = 8.1 Hz, 1H), 7.74 – 7.71 (m, 1H), 7.63 – 7.60 (m, 1H), 7.48 (d, J = 5.2 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 154.8 (t, J = 3.6 Hz), 142.0, 136.2, 131.1, 127.9, 127.5,
127.1 (t, J = 2.0 Hz), 124.4, 121.8 (t, J = 270.0 Hz), 119.3; 19F NMR (470 MHz, CDCl3)
δ -98.1 (d, J = 56.2 Hz). FT-IR (
-1
cm-1
) 3856, 3741, 3054, 2923, 2854, 2314, 1693,
1619, 1550, 1496, 1373, 1311, 1268, 1056, 983, 790, 736. HRMS (ESI) m/z calculated
for C10H18F2NS [M + H]+
: 212.0340; found 212.0348 (3.7730 ppm).
Methyl 2-(difluoromethoxy)nicotinate (2q)
Performed on 0.5 mmol scale, eluted with 80% ethyl acetate in hexane to afford 5q
(46.7 mg, 46% yield). Colorless oil.
1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 4.9, 1.9 Hz, 1H), 8.28 (dd, J = 7.6, 2.0 Hz,
1H), 7.54 (t, J = 72.4 Hz, 1H), 7.19 (dd, J = 7.6, 4.9 Hz, 1H), 3.94 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 164.5, 157.2 (t, J = 4.0 Hz), 150.5, 142.4, 119.9, 115.0, 114.1 (t,
J = 256.4 Hz), 52.8; 19F NMR (470 MHz, CDCl3) δ -89.9 (d, J = 72.1 Hz, 2F). FT-IR
(
-1 cm-1
) 3054, 2954, 2850, 1727, 1589, 1438, 1346, 1307, 1265, 1184, 1072, 890, 817.

98
HRMS (ESI) m/z calculated for C8H8F2NO3 [M + H]+
: 204.0467; found 204.0467
(0.0000 ppm).
2-(Difluoromethoxy)-6-(trifluoromethyl)nicotinamide (2r)
Performed on 0.5 mmol scale, eluted with 60% ethyl acetate in hexane to afford 5r
(47.4 mg, 37% yield). Yellow solid. Mp: 95 – 97 oC.
1H NMR (500 MHz, CDCl3) δ 8.80 (d, J = 7.8 Hz, 1H), 7.81 – 7.53 (m, 2H), 6.26 (s,
1H); 13C NMR (126 MHz, CDCl3) δ 162.6, 155.6 (t, J = 3.7 Hz), 147.9, 145.5, 121.5,
119.2, 117.6 (q, J = 2.8 Hz), 113.8 (t, J = 261.0 Hz); 19F NMR (470 MHz, CDCl3) δ -
68.7 (s, 3F), -90.0 (d, J = 70.8 Hz, 2F). FT-IR (
-1 cm-1
) 3486, 3359, 3293, 3154, 2931,
2857, 1681, 1600, 1473, 1419, 1338, 1245, 1145, 1049, 948, 856. HRMS (ESI) m/z
calculated for C8H6F5N2O2 [M + H]+
: 257.0344; found 257.0343 (0.3890 ppm).
2-(Difluoromethoxy)benzofuro[3,2-b]pyridine (2s)
Performed on 0.5 mmol scale, eluted with 20% ethyl acetate in hexane to afford 5s (88.1
mg, 75% yield). Light-yellow solid. Mp: 76 – 78 oC.
1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 5.8 Hz, 1H), 8.13 – 8.12 (m, 1H), 7.75 (t, J
= 72.6 Hz, 1H), 7.63 - 7.61 (m, 1H), 7.55 – 7.52 (m, 1H), 7.47 – 7.44 (m, 1H), 7.35 (d,

99
J = 5.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 163.8, 155.8, 154.6 (t, J = 3.9 Hz),
144.3, 128.2, 124.5, 123.2, 120.5, 114.2 (t, J = 256.4 Hz), 111.8, 109.0, 105.4; 19F NMR
(470 MHz, CDCl3) δ -89.2 (d, J = 72.6 Hz). FT-IR (
-1 cm-1
) 3016, 2919, 2850, 2383,
2156, 2036, 1982, 1662, 1604, 1407, 1214, 937. HRMS (ESI) m/z calculated for
C12H8F2NO2 [M + H]+
: 236.0518; found 236.0526 (3.3890 ppm).
2-(Difluoromethoxy)-5-(4-vinylphenyl)pyridine (2t)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 5t (102.5
mg, 83% yield). White solid. Mp: 83 – 86 oC.
1H NMR (500 MHz, CDCl3) δ 8.41 (dd, J = 2.6, 0.8 Hz, 1H), 7.93 (dd, J = 8.5, 2.6 Hz,
1H), 7.65 – 7.36 (m, 5H), 6.98 (dd, J = 8.5, 0.8 Hz, 1H), 6.82 – 6.71 (m, 1H), 5.82 (dd,
J = 17.6, 0.7 Hz, 1H), 5.31 (dd, J = 10.9, 0.6 Hz,1H); 13C NMR (126 MHz, CDCl3) δ
158.6 (t, J = 3.7 Hz), 145.1, 138.7, 137.6, 136.4, 136.2, 133.3, 127.1 (d, J = 3.9 Hz),
116.1, 114.8, 114.3 (t, J = 255.4 Hz), 111.5; 19F NMR (470 MHz, CDCl3) δ -89.2 (d, J
= 73.0 Hz). FT-IR (
-1 cm-1
) 3016, 2911, 2850, 2368, 1990, 1666, 1546, 1438, 1311,
1214, 1022, 944, 867. HRMS (ESI) m/z calculated for C14H12F2NO [M + H]+
:
248.0881; found 248.0887 (2.4184 ppm).

100
2-(Difluoromethoxy)-5-(thiophen-3-yl)pyridine (2u)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 5u (90.8
mg, 80% yield). Pale-yellow solid. Mp: 54 – 55 oC.
1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 8.5, 2.5 Hz, 1H),
7.49 (t, J = 73.1 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.34 – 7.33 (m, 1H), 6.94 (dd, J = 8.5,
0.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 158.2 (t, J = 3.7 Hz), 144.6, 138.2, 138.0,
128.8, 127.3, 125.9, 121.2, 114.3 (t, J = 255.3 Hz), 111.6; 19F NMR (470 MHz, CDCl3)
δ -89.2 (d, J = 73.0 Hz, 2F). FT-IR (
-1 cm-1
) 3741, 3104, 3058, 2923, 1654, 1592,
1531, 1481, 1330, 1257, 1214, 1064, 763. HRMS (ESI) m/z calculated for
C10H8F2NOS [M + H]
+
: 228.0289; found 228.0290 (3.7730 ppm).
tert-Butyl 4-(6-(difluoromethoxy)pyridine-3-yl-benzoate (2v)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 5v (123.6
mg, 77% yield). White solid. Mp: 97 – 98 oC.
1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.95
(dd, J = 8.5, 2.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 72.9 Hz, 1H), 7.00 (d, J
= 8.5 Hz, 1H), 1.62 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 165.3, 158.9 (t, J = 3.7 Hz),
145.4, 140.8, 138.79, 132.6, 131.6, 130.3, 126.6, 114.0 (t, J = 255.7 Hz), 111.5, 81.3,

101
28.2; 19F NMR (470 MHz, CDCl3) δ -89.4 (d, J = 72.7 Hz). FT-IR (
-1 cm-1
) 3016,
2969, 2923, 2857, 1693, 1608, 1519, 1473, 1361, 1265, 1214, 1099, 836, 755. HRMS
(ESI) m/z calculated for C17H18F2NO3 [M + H]+
: 322.1249; found 322.1256 (2.1730
ppm).
2-(Difluoromethoxy)-5-(4-(methylthio)phenyl)pyridine (2w)
Performed on 0.5 mmol scale, eluted with 10% ethyl acetate in hexane to afford 5w
(114.5 mg, 86% yield). White solid. Mp: 79 – 80 oC.
1H NMR (500 MHz, CDCl3) δ 8.38 – 8.37 (m, 1H), 7.90 (dd, J = 8.5, 2.5 Hz, 1H), 7.64
– 7.34 (m, 5H), 6.97 (dd, J = 8.5, 0.7 Hz, 1H), 2.53 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 158.3 (t, J = 3.6 Hz), 144.9, 138.9, 138.4, 133.6, 133.0, 127.2, 127.0, 114.1
(t, J = 255.5 Hz), 111.4, 15.7; 19F NMR (470 MHz, CDCl3) δ -89.2 (d, J = 73.0 Hz).
FT-IR (
-1 cm-1
) 3841, 3741, 3617, 3343, 2931, 2857, 2159, 2044, 1990, 1658, 1542,
1392, 1307, 1184, 775. HRMS (ESI) m/z calculated for C13H12F2NOS [M + H]+
:
268.0602; found 268.0601 (0.3731 ppm).
2-(Difluoromethoxy)-5-(4-fluorophenyl)pyridine (2x)
Performed on 0.5 mmol scale, eluted with 10% ethyl acetate in hexane to afford 5x

102
(96.5 mg, 81% yield). White solid. Mp: 116 – 117 oC.
1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.5, 2.6 Hz, 1H),
7.65 – 7.36 (m, 3H), 7.16 (t, J = 8.6 Hz, 2H), 6.98 (dd, J = 8.5, 0.8 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ 163.0 (d, J = 247.9 Hz), 158.6 (t, J = 3.7 Hz), 145.2, 138.8, 133.2
(d, J = 3.3 Hz), 132.8, 128.8 (d, J = 8.2 Hz), 116.3 (d, J = 21.7 Hz), 114.2 (t, J = 255.4
Hz), 111.6; 19F NMR (470 MHz, CDCl3) δ -89.3 (d, J = 73.5 Hz, 2F), -114.7 – -114.8
(m, 1F). FT-IR (
-1 cm-1
) 3833, 3745, 3444, 2927, 2854, 2163, 1982, 1712, 1654, 1558,
1407, 1284, 1199, 1141, 956, 860, 771. HRMS (ESI) m/z calculated for C12H9F3NO
[M + H]+
: 240.0631; found 240.0633 (0.8331 ppm).
1-(Difluoromethyl)-5-methylpyridin-2(1H)-one (3a)
Performed on 0.5 mmol scale, eluted with 60% dichloromethane in pentane to afford
6a (56.6mg, 71% yield). Colorless liquid. Known compound.
1H NMR (500 MHz, CDCl3) δ 7.66 (t, J = 60.4 Hz, 1H), 7.23 (dd, J = 9.5, 2.2 Hz, 1H),
7.19 (s, 1H), 6.48 (d, J = 9.5 Hz, 1H), 2.09 (s, 3H). The 1H NMR data obtained agreed
with the literature report.
368
4-(Benzyloxy)-1-(difluoromethyl)pyridin-2(1H)-one (3b)

103
Performed on 0.5 mmol scale, eluted with 80% dichloromethane in pentane to afford
6b (90.4 mg, 72% yield). Colorless prisms. Mp: 100 – 105 oC.
1H NMR (500 MHz, CDCl3) δ 7.63 (t, J = 60.4 Hz, 1H), 7.44 – 7.36 (m, 5H), 7.34 (d,
J = 7.9 Hz, 1H), 6.09 (dd, J = 7.9, 2.3 Hz, 1H), 5.89 (s, 1H), 5.01 (s, 2H); 13C NMR
(126 MHz, CDCl3) δ 168.1, 162.8, 134.7, 129.8 (t, J = 3.2 Hz), 128.9, 128.9, 127.9,
107.6 (t, J = 250.2 Hz), 103.7, 97.8, 70.8; 19F NMR (470 MHz, CDCl3) δ -103.5 (d, J
= 60.4 Hz). FT-IR (
-1 cm-1
) 3097, 3066, 2453, 2194, 1835, 1735, 1670, 1612, 1546,
1481, 1338, 1238, 1184, 1133, 1060, 998. HRMS (ESI) m/z calculated for
C13H12F2NO2 [M + H]+
: 252.0831; found 252.0839 (3.1735 ppm).
1-(Difluoromethyl)-3-methoxypyridin-2(1H)-one (3c)
Performed on 0.5 mmol scale, eluted with 80% dichloromethane in pentane to pure
dichloromethane to afford 6c (73 mg, 83% yield). Colorless liquid.
1H NMR (500 MHz, CDCl3) δ 7.75 (t, J = 60.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.59
(d, J = 7.3 Hz, 1H), 6.22 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 157.3, 150.0, 120.2 (t, J = 3.6 Hz), 112.7, 107.7 (t, J = 251.1 Hz), 106.3, 56.1; 19F
NMR (470 MHz, CDCl3) δ -103.6 (d, J = 60.2 Hz). FT-IR (
-1 cm-1
) 3058, 3008, 2927,
2842, 1670, 1626, 1558, 1457, 1392, 1253, 1222, 1133, 1049, 925, 852. HRMS (ESI)
m/z calculated for C7H8F2NO2 [M + H]+
: 176.0518; found 176.0519 (0.5680 ppm).

104
1-(Difluoromethyl)-4-methylpyridine-2(1H)-one (3d)
Performed on 0.5 mmol scale, eluted pure dichloromethane to afford 6d (31 mg, 39%
yield). Yellow solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 7.66 (t, J = 60.1 Hz, 1H), 7.33 (d, J = 6.4 Hz, 1H), 6.33
(s, 1H), 6.12 (d, J = 6.2 Hz, 1H), 2.20 (s, 3H). The 1H NMR data obtained agreed with
the literature report.
368
1-(Difluoromethyl)-3-methylpyridin-2(1H)-one (3e)
Performed on 0.5 mmol scale, eluted with 10% ethyl acetate in dichloromethane to
afford 6e (33.4 mg, 66% yield). Colorless liquid.
1H NMR (500 MHz, CDCl3) δ 7.67 (t, J = 60.4 Hz, 1H), 7.24 (dd, J = 9.5, 2.4 Hz, 1H),
7.19 (s, 1H), 6.49 (d, J = 9.5 Hz, 1H), 2.10 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
160.7, 144.3, 126.2 (t, J = 3.4 Hz), 121.4, 116.3, 107.6 (t, J = 250.6 Hz), 17.4; 19F NMR
(470 MHz, CDCl3) δ -104.1 (d, J = 60.3 Hz). FT-IR (
-1 cm-1
) 3378, 3297, 2923, 2857,
2152, 1963, 1689, 1604, 1473, 1376, 1218, 1133, 1068. HRMS (ESI) m/z calculated
for C7H8F2NO [M + H]+
: 160.0568; found 160.0566 (1.2495 ppm).

105
5-Bromo-1-(difluoromethyl)pyridin-2(1H)-one (3h)
Performed on 0.5 mmol scale, eluted with 10% ethyl acetate in hexane to afford 6h
(42.3 mg, 38% yield). White solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 7.61 (t, J = 60.0 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.40
(dd, J = 9.9, 2.7 Hz, 1H), 6.48 (d, J = 9.9 Hz, 1H). The 1H NMR data obtained agreed
with the literature report.
368
1-(Difluoromethyl)-3-(trifluoromethyl)pyridine-2(1H)-one (3i)
Performed on 0.5 mmol scale, eluted with 75% dichloromethane in pentane to afford 6i
(46.4 mg, 44% yield). Yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.83 – 7.81 (m, 1H),
7.71 (t, J = 59.8 Hz, 1H), 7.66 (dd, J = 7.2, 1.5 Hz, 1H), 6.40 (t, J = 7.1 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 140.6 (q, J = 5.0 Hz), 133.7 (t, J = 3.4 Hz), 125.2, 123.0,
120.9, 107.2 (t, J = 253.8 Hz), 105.5; 19F NMR (470 MHz, CDCl3) δ -66.8 (s, 3F), -
104.1 (d, J = 59.8 Hz, 2F). FT-IR (
-1 cm-1
) 3023, 2923, 2854, 1689, 1623, 1565, 1457,
1400, 1365, 1315, 1261, 1214, 1141, 1083, 863. HRMS (ESI) m/z calculated for
C7H5F5NO [M + H]+
: 214.0286; found 214.0285 (0.4672 ppm).

106
2-(Difluoromethyl)isoquinoline-1(2H)-one (3k)
Performed on 0.5 mmol scale, eluted with 5% to 10% ethyl acetate in hexane to afford
6k (51.6 mg, 53% yield). Orange solid. Known compound.
1H NMR (500 MHz, CDCl3) δ 8.42 (dd, J = 8.1, 0.8 Hz, 1H), 7.96 – 7.71 (m, 2H), 7.57
– 7.53 (m, 2H), 7.27 (s, 1H), 6.62 (d, J = 7.7 Hz, 1H). The 1H NMR data obtained
agreed with literature report.
377
6-Bromo-2-(difluoromethyl)isoquinolin-1(2H)-one (3l)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 6l (50.5
mg, 37% yield). Red-brown solid. Mp: 173 - 176 oC.
1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 60.2 Hz, 1H), 7.69
(d, J = 1.8 Hz, 1H), 7.63 (dd, J = 8.6, 1.9 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 6.51 (d, J
= 7.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 160.9, 138.1, 131.3, 130.2, 129.3, 129.2,
124.4 (t, J = 3.4 Hz), 124.4, 107.9 (t, J = 249.9 Hz), 106.9; 19F NMR (470 MHz, CDCl3)
δ -103.3 (d, J = 60.4 Hz). FT-IR (
-1 cm-1
) 3104, 3062, 2927, 2857, 1662, 1631, 1592,
1465, 1376, 1322, 1261, 1211, 1124, 1025, 952, 890, 809. HRMS (ESI) m/z calculated
for C10H7BrF2NO [M + H]+
: 273.9674; found 273.9675 (0.3650 ppm).

107
7-Bromo-2-(difluoromethyl)isoquinoline-1(2H)-one (3m)
Performed on 0.5 mmol scale, eluted with 5% ethyl acetate in hexane to afford 6m (54.5
mg, 40% yield). White solid. Mp: 109 – 110 oC.
1H NMR (500 MHz, CDCl3) δ 8.54 (d, J = 2.1 Hz, 1H), 7.91 – 7.67 (m, 2H), 7.41 (d,
J = 8.4 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 160.2, 137.1, 135.4, 131.1, 128.2, 127.0, 123.5 (t, J = 3.4 Hz), 121.9, 107.9
(t, J = 250.0 Hz), 107.5; 19F NMR (470 MHz, CDCl3) δ -103.3 (d, J = 60.1 Hz). FT-IR
(
-1 cm-1
) 3741, 3089, 2923, 2857, 1770, 1670, 1627, 1546, 1481, 1384, 1326, 1268,
1211, 1153, 1126, 1091, 1045, 879, 825, 771 HRMS (ESI) m/z calculated for
C10H7BrF2NO [M + H]+
:273.9674; found 273.9661 (4.7451 ppm).
1-(Difluoromethyl)-5-(4-vinylphenyl)pyridine-2(1H)-one (3t)
Performed on 0.5 mmol scale, eluted with 20% to 35% ethyl acetate in hexane to afford
6t (54 mg, 44% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.88 – 7.63 (m, 3H), 7.48 (d, J = 8.3 Hz, 2H), 7.40 (d,
J = 8.4 Hz, 2H), 6.77 – 6.71 (m, 1H), 6.66 (d, J = 9.7 Hz, 1H), 5.80 (dd, J = 17.6, 0.8
Hz, 1H), 5.31 (dd, J = 10.9, 0.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 160.6, 141.5,
137.6, 136.1, 135.0, 127.2, 126.2, 122.0, 121.2, 116.1, 114.8, 107.77 (t, J = 252.0 Hz);
19F NMR (470 MHz, CDCl3) δ -103.99 (d, J = 60.4 Hz). FT-IR (
-1 cm-1
) 3066, 2981,

108
1681, 1616, 1515, 1400, 1361, 1268, 1149, 1064, 914, 829. HRMS (ESI) m/z
calculated for C14H12F2NO [M + H]+
: 248.0881; found 248.0883 (0.8061 ppm).
1-(Difluoromethyl)-5-(thiophen-3-yl)pyridin-2(1H)-one (3u)
Performed on 0.5 mmol scale, eluted with 20% ethyl acetate in hexane to afford 6u
(70.3 mg, 62% yield). Yellow solid. Mp: 95 – 98 oC.
1H NMR (500 MHz, CDCl3) δ 7.74 (t, J = 60.3 Hz, 1H), 7.67 (dd, J = 9.6, 2.6 Hz, 1H),
7.64 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 5.1, 2.9 Hz, 1H), 7.33 – 7.32 (m, 1H), 7.22 (dd,
J = 5.0, 1.5 Hz, 1H), 6.64 (dd, J = 9.7, 0.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
160.5, 141.3, 136.6, 127.5, 125.5 (t, J = 3.4 Hz), 125.2, 122.0, 120.5, 116.9, 107.7 (t, J
= 251.8 Hz); 19F NMR (470 MHz, CDCl3) δ -104.0 (d, J = 60.2 Hz, 2F). FT-IR (
-1
cm1
) 3089, 2915, 2854, 1677, 1616, 1527, 1384, 1265, 1203, 1141, 1064, 948, 836, 786,
736. HRMS (ESI) m/z calculated for C10H8F2NOS [M + H]+
: 228.0289; found 228.0289
(0.0000 ppm).
tert-Butyl 4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-yl-benzoate (3v)
Performed on 0.5 mmol scale, eluted with 20% to 30% ethyl acetate in hexane to afford

109
6v (51.3 mg, 32% yield). Pale-yellow solid. Mp: 91 – 93 oC.
1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.7 Hz, 2H), 7.75 (t, J = 60.2 Hz, 1H), 7.72
– 7.68 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 9.6 Hz, 1H), 1.62 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 165.3, 160.5, 141.2, 139.5, 131.8, 130.5, 127.0 (t, J = 3.4
Hz), 125.7, 122.2, 120.6, 107.7 (t, J = 252.3 Hz), 81.6, 28.4; 19F NMR (470 MHz,
CDCl3) δ -104.0 (d, J = 60.0 Hz). HRMS (ESI) m/z calculated for C17H18F2NO3 [M +
H]+
: 322.1249; found 322.1251 (0.6209 ppm).
1-(Difluoromethyl)-5-(4-(methylthio)phenylpyridin-2(1H)-one (3w)
Performed on 0.5 mmol scale, eluted with 35% ethyl acetate in hexane to afford 6w
(80.5 mg, 60% yield). Yellow solid. Mp: 68 – 72 oC.
1H NMR (500 MHz, CDCl3) δ 7.75 (t, J = 60.3 Hz, 1H), 7.66 (dd, J = 9.7, 2.6 Hz, 1H),
7.59 (d, J = 2.5 Hz, 1H), 7.36 – 7.31 (m, 4H), 6.65 (d, J = 9.6 Hz, 1H), 2.52 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 160.5, 141.5, 139.1, 132.4, 127.2, 126.4, 126.0 (t, J =
3.4 Hz), 122.0, 121.0, 107.8 (t, J = 251.9 Hz), 15.8; 19F NMR (470 MHz, CDCl3) δ -
104.0 (d, J = 60.4 Hz). FT-IR (
-1 cm-1
) 3783, 3698, 3058, 2919, 2854, 2109, 1882,
1681, 1616, 1535, 1496, 1396, 1268, 1149, 1064, 917, 813, 744. HRMS (ESI) m/z
calculated for C13H12F2NOS [M + H]+
: 268.0602; found 268.0600 (0.7461 ppm).

110
1-(Difluoromethyl)-5-(4-fluorophenyl)pyridin-2(1H)-one (3x)
Performed on 0.5 mmol scale, eluted with 25% to 35% ethyl acetate in hexane to afford
6x (35.5 mg, 30% yield). Yellow Solid. Mp: 97 – 99 oC.
1H NMR (500 MHz, CDCl3) δ 7.87 – 7.62 (m, 2H), 7.57 (d, J = 2.4 Hz, 1H), 7.41 –
7.38 (m, 2H), 7.16 – 7.12 (m, 2H), 6.66 (d, J = 9.7 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 163.8, 161.2 (d, J = 178.1 Hz), 141.5, 131.9, 127.9 (d, J = 8.2 Hz), 126.3 (t,
J = 3.1 Hz), 122.1, 120.7, 116.4 (d, J = 21.7 Hz), 107.8 (t, J = 251.9 Hz); 19F NMR
(470 MHz, CDCl3) δ -104.0 (d, J = 60.3 Hz), -114.0 – -114.9 (m, 1F).
FT-IR (
-1 cm-1
) 3016, 2954, 2923, 2857, 2248, 1681, 1511, 1400, 1361, 1261, 1226,
1145, 1072, 1025, 910, 813, 752. HRMS (ESI) m/z calculated for C12H9F3NO [M +
H]+
: 240.0631; found 240.0627 (1.6662 ppm).

111
Chapter 3
Mono- and Difluoromethylation of 3(2H)-Pyridazinones
3.1 Introduction
Pyridazinone and its derivatives are key nitrogen-rich heterocyclic moieties that
have garnered increasing interest due to their bioactivities in anticancer,378–380
antiviral,381 anti-inflammatory,382–386 analgesic, and antimicrobial fields.387,388 As a
result, substantial efforts have been made on the modification of pyridazinones in order
to improve the biochemical properties of the target pharmaceutical compounds.389–391
N-Alkylation of 3(2H)-pyridazinones has been proved to be one of the most promising
modifications, leading to improved anti-inflammatory and analgesic activities of the
drug molecules.382,385,392 Incorporating fluoroalkyl groups such as monofluoromethyl,
difluoromethyl, and trifluoromethyl groups has been a fruitful approach to leverage the
physiochemical properties such as lipophilicity, hydrogen-bonding ability, and
metabolic stability.7,99,339,343,393,394 It can be envisioned that fluoroalkylated
pyridazinones can serve important roles in fine-tuning the bioactivities of related
pharmaceutical candidates. However, no general synthetic protocols for fluoroalkylated
pyridazinones have been reported. Herein we describe the monofluoromethylation and

112
first difluoromethylation of 3(2H)-pyridazinones using S-monofluoromethyl-S-phenyl2,3,4,5-tetramethylphenylsulfonium salts (1) and TMSCF2Br, respectively. Even
though a synthetic method to prepare one example of N-monofluoromethylated 3-
pyridazinone (51% yield) has been reported in the patent literature, the utilization of
ozone-depleting BrCH2F and harsh reaction conditions (150 °C) leaves considerable
space for improvement.395 Therefore, a bench-stable, solid, and non-ozone-depleting
monofluoromethylating reagent 1 was employed. Sulfonium salt 1, first prepared by
our group as a potent electrophilic monofluoromethylating reagent, readily reacts with
tertiary amines, imidazoles, and carboxylic acids to provide the corresponding
monofluoromethylated products.57
3.2 Results and discussion
We directly adapted the reported conditions with 2a as the model substrate to
explore the monofluoromethylation (Table 3.1, entry 1).
Table 3.1 Optimization Experiments for 3a and 4aa
entry reagent X T (oC) 3a/4a (%)b
1 1a BF4 23 60/25
2 1b OTf 23 72/11
3 1b OTf 0 84/1
aReaction were performed at 0.15 mmol scale. bYields were determined by 19F NMR using fluorobenzene

113
as an internal standard.
To our delight, an initial attempt with Cs2CO3 in ACN afforded 60% and 25%
yields of the N-CFH2 (3a) and O-CFH2 (4a) products by 19F NMR, respectively.
Replacing the BF4
−
(1a) counteranion with OTf−
(1b) increased the selectivity toward
the N-CFH2 product (72% N-CFH2 and 11% O-CFH2 by 19F NMR; Table 3.1, entry 2).
Performing the reaction at 0 °C provided improved selectivity, which gave an 84% yield
of the N-CFH2 product with trace amounts of the O-CFH2 product (Table 3.1, entry 3).
Increasing the reaction temperature resulted in a lower selectivity. Performing the
reaction with other inorganic bases and aprotic solvents did not improve the yield or
the selectivity. With the optimized conditions in hand, the scope of Nmonofluoromethylation was investigated (Scheme 3.1).
Scheme 3.1 Substrates Scope Mono- and Difluoromethylation of 3(2H)-Pyridazinones
and Phthalazine-1(2H)onesa
aReactions were performed at 0.5 mmol scale with standard conditions. Isolated yields are reported. Yields within parentheses were

114
determined by 19F NMR using fluorobenzene as an internal standard.
bThe reaction was performed at 5 mmol scale. cThe reaction
was performed at 1 mmol scale.
The model substrate 2a gave the desired product 3a in 77% isolated yield.
Surprisingly, 6-fluorophthalazine-1(2H)-one (2b) afforded a 23% yield of the N-CFH2
product 3b. In contrast, 6-chloro- and 6-bromophthalazin-1(2H)-one (2c and 2d,
respectively) both resulted in the formation of products 3c and 3d in good yields. Also,
7- and 4-bromophthalazine-1(2H)one (3e and 3f, respectively) provided the Nmonofluoromethylated products in good yields. 4-Chlorinated substrate 2g furnished
3g in 85% isolated yield. The reaction was scaled up to 5 mmol with substrate 2g, and
a 75% yield of 3g was obtained. 3(2H)-Pyridazinone (2h) afforded 3h in 66% isolated
yield. Similarly, 6-substituted-3(2H)-pyridazinones 2i, 2j, and 2k all gave good yields
of up to 72%. Substrate 2l containing an electron-donating methoxy group afforded the
N-CFH2 product in 57% yield, while 3m was obtained in 88% yield. These results
indicate that electronics of the substituent at the 6-position of the starting material (2i,
2j, or 2k) shows no significant effect on the reaction outcome, whereas an electronwithdrawing group at the 5-position (3m) leads to a higher yield compared to an
electron-donating group (3l). Lynparza analogues 2n and 2o furnished 3n and 3o in
synthetically useful yields (55% and 29%, respectively), which showcases the
applicability of this novel method to late-stage functionalization of 3(2H)-
pyridazinone-containing drug candidates.
In 2021, our group reported an efficient chemoselective N- and Odifluoromethylation of 2-pyridones and their derivates with TMSCF2Br, first efficiently
synthesized by our group,362 as the difluorocarbene precursor under various

115
conditions.112 Model substrate 2a was adapted to similar conditions with TMSCF2Br
and Na2CO3 in ACN at 60 °C. Initial trials afforded trace amounts of N- and Odifluoromethylated pyridazinones along with a large amount of bisdifluoromethylated
byproduct 16p, which was isolated and fully characterized
Table 3.2 Optimization Experiments for 5a and 6aa
entry additive base solvent (M) T (oC) x:y 5a/6a (%)
1 N/A Na2CO3 ACN (0.11) 60 1:1.2 1/1
2 N/A Na2CO3 ACN (0.11) 60 1.5:1 4/6
3 N/A Na2CO3 ACN (0.11) 90 1.5:1 7/8
4 N/A Na2CO3 ACN (0.11) 100 1.5:1 2/5
5 N/A Na2CO3 toluene (0.11) 90 1.5:1 9/7
6 N/A Cs2CO3 toluene (0.11) 90 1.5:1 12/5
7 TMAF Cs2CO3 toluene (0.11) 90 1.5:1 18/2
8 TMAF Cs2CO3 toluene (0.11) 90 1.5:1 34/1
aReactions were performed at 0.5 mmol scale. bYields were determined by 19F NMR using fluorobenzene
as an internal standard.
(Table 3.2, entry 1). To circumvent the formation of the bisdifluoromethylated
byproduct, TMSCF2Br was employed as the limiting reagent, which afforded a 6%
yield of O-CF2H product and 4% yield of N-CF2H product with no observable amount
of the byproduct (Table 3.2, entry 2). Increasing the reaction temperature to 90 °C

116
provided an 8% yield of O-CF2H product and 7% yield of N-CF2H product (Table 3.2,
entry 3). Further increasing the reaction temperature to 100 °C led to a decreased yield
of both target products (Table 3.2, entry 4). To avoid accumulating pressure during the
reaction, various solvents with high boiling points were investigated, and toluene
afforded comparable yields at 90 °C (Table 3.2, entry 5). Utilizing Cs2CO3 improved
the selectivity while providing slightly increased yields (Table 3.2, entry 6). The
addition of TMAF as a phase transfer catalyst increased the yield and selectivity (Table
3.2, entry 7). Increasing the concentration from 0.11 to 0.33 M furnished N-CF2H
product 5a in 34% yield and a trace amount of O-CF2H product 6a.
Figure 3.1 Failed attempts with conventional difluoromethylation reagents.
Employing other difluorocarbene precursors or electrophilic difluoromethylating
reagents (7−15), which were reported to achieve N- and O-difluoromethylation

117
reactions, failed to improve the yields or selectivity (Figure 3.1).107,131
Interestingly, when 6-substituted-3(2H)-pyridazinones and 4-substitutedphthalazine-1(2H)ones were adapted into the optimized conditions, Odifluoromethylated products were found to be the predominant products (Scheme 3.1).
4- Bromophthalazin-1(2H)-one (2f) afforded 5f and 6f in 12% and 13% isolated yield,
respectively. 4-Chlorophthalazin-1(2H)-one (2g) furnished 5g and 6g in moderate
yields. Methylated 3(2H)-pyridazinone 2i gave a 16% yield of 5i and 30% yield of 6i.
Notably, a significant loss of yield (more than 15%) was observed for 6i during isolation
due to its high volatility. Similarly, a 51% yield of 6j (69% by 19F NMR) was obtained
along with a 23% yield of 5j. 6-Phenyl-3(2H)- pyridazinone (2k) provided the N-CF2H
and O-CF2H products in 22% and 57% yield, respectively. Lynparza analogue 2o
afforded 4% and 22% yields of the corresponding difluoromethylated products 5o and
6o, respectively.
3.3 Conclusion
In conclusion, this work presents the first efficient selective Nmonofluoromethylation of 3(2H)-pyridazinone and its derivatives from inexpensive
commodity chemicals under mild reaction conditions with short reaction times. We also
investigated the first difluoromethylation of 3(2H)-pyridazinones using TMSCF2Br,
which can lead to a mixture of O- and N-difluoromethylated pyridazinones in
synthetically useful yields. Late-stage functionalization was demonstrated on a
molecule of pharmaceutical interest, namely, an analogue of Lynparza.

118
3.4 Experimental data. General procedures and characterization data.
Optimization on Reaction Conditions for Monofluoromethylation of 1(2H)-
phthalazinone (2a)
General Procedure A (Taking Table 3.3, trail 1 as an example)
To an oven-dried 7-mL microwave vial, substrate (1.0 eq, 0.5 mmol, 73.1 mg),
Cs2CO3 (1.1 eq, 0.55 mmol, 179.2 mg), and sulfonium salts (1.1 eq, 0.55 mmol) were
added under Ar protection. Then, 3.3 mL of ACN was added to the vial at 23 °C, and
the mixture was stirred at the same temperature for one hour. PhF (1.0 equiv, 0.5 mmol,
48.1 mg, 47 uL) was added into the reaction mixture and stirred for 1 minute. The yield
was then determined by 19F NMR.
Table 3.3: Counter anion screening (X)a
X 3a/4a (%)
1 BF4 60/25
2 OTf 72/11
3 PF6 66/16
aThe reaction was performed at 0.15 mmol scale. Yield was determined by 19F NMR with PhF as an
internal standard.
Table 3.4: Reaction temperature screening (T)a
Temp (oC) 3a/4a (%)

119
1 0 84/1
2
b
-10 67/4
3 45 71/4
4 60 68/5
aThe reaction was performed at 0.15 mmol scale. Yield was determined by 19F NMR with PhF as an
internal standard. bThe reaction was performed in a sat.NH4Cl/ice water bath.
Table 3.5: Bases screeninga
Base (1.1 equiv) 3a/4a (%)
1 Na2CO3 76/5
2 K2CO3 50/14
3 Li2CO3 43/20
4 NaOtBu 20/2
5 NaOH 46/13
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.6: Solvent screeninga
Solvent (0.15 M) 3a/4a (%)
1 THF 66/4
2 DMF 32/1
3 Toluene 48/1
4
b 1,4-dioxane 57/9
5 PhCN 53/2
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard. bThe reaction was performed at room temperature.

120
General Procedure B (Taking Table S4, trail 1 as an example)
To a 7 mL oven-dried microwave vial, 2a (1.0 equiv, 1.0 mmol, 146.1 mg), and
Cs2CO3 (2.25 equiv, 2.25 mmol, 733.3 mg) were added under Ar protection. ACN (9.0
mL) was added under Ar protection, and the resulting suspension was placed in a 60 °C
oil bath and stirred for 2 minutes. Then TMSCF2Br (1.2 equiv, 1.2 mmol, 243.7 mg,
186 uL) was added in one portion to the mixture under N2 protection, and the resulting
mixture was allowed to stir for 1 hour at 60 °C. After the reaction is complete, the vial
was allowed to warm to room temperature. PhF (2.0 equiv, 2.0 mmol, 192.2 mg, 188
uL) was added into the reaction mixture and stirred for 1 minute. The yield was then
determined by 19F NMR.
Table 3.7: Stoichiometry screeninga
x:y 5a/6a (%)
1 1:1.2 1/1
2 1.5:1 4/6
3 2:1 5/5
4 1:1 1/4
5 1:2 0/7
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.

121
Table 3.8: Reaction temperature screeninga
T (oC) 5a/6a (%)
1 90 7/8
2 100 2/5
3 80 1/1
4 23 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.9: Solvent screeninga
Solvents (0.11 M) 5a/6a (%)
1 PhCN 2/3
2 DMF 0/0
3 DCE 0/0
4 1,4-dioxane 3/5
5 Toluene 9/7
6 Triglyme 2/4
7 DMPU 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.10: Base screeninga
Bases (2.25 equiv) 5a/6a (%)
1 K2CO3 0/3

122
2 Cs2CO3 12/5
3 Li2CO3 0/0
4 NaOtBu 0/0
5 NaOH 2/2
6 KOH 3/5
7 DBU 0/0
8 Et3N 0/0
9 NaOAc 0/0
10 NaHCO3 0/3
11 NaOMe 2/1
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.11: Screening of additivesa
Additive 5a/6a (%)
1 TEBAC 5/0
2 TBAF 6/3
3 TBAB 5/6
4 TBAC 6/6
5 TMAF 18/2
6 TMBAB 7/4
7 TEBAB 15/5
8
b TMAF 10/3
9
c TMAF 3/7
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard. 10 mol% of additive was added. b20 mol% of TMAF was added. c50 mol% of TMAF was
added.
Table 3.12: Screening of reaction concentrationsa
Concentration (M) 5a/6a (%)
1 0.33 34/1

123
2 0.67 35/2
3 0.2 24/4
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.13: Screening of difluoromethylating reagents (Ethyl
bromodifluoroacetate)a
Solvent (M) T (oC) t (h) Activator (2.2 equiv) 5a/6a (%)
1 ACN (0.25 M) 80 1 Na2CO3 0/0
2 ACN (0.25 M) 100 1 Na2CO3 0/3
3 ACN (0.25 M) 100 24 Na2CO3 0/1
4 DMF (0.25 M) 100 1 Na2CO3 0/0
5 THF (0.25M) 100 1 Na2CO3 0/0
6 ACN (0.25 M) 100 1 K2CO3 1/1
7 ACN (0.25 M) 100 1 Cs2CO3 0/0
8 ACN (0.25 M) 100 1 NaOH 0/0
9 ACN (0.25 M) 100 1 NaOtBu 0/0
10 ACN (0.25 M) 90 1 Na2CO3 0/3
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.14: Screening of difluoromethylating reagents (Sodium
chlorodifluoroacetate)a
T (oC) t (h) Activator (3.0 equiv) 5a/6a (%)
1 23 5 K2CO3 0/0
2 120 5 K2CO3 0/0
3 120 24 K2CO3 0/0
4 120 24 KOH 0/0
5 120 24 KOtBu 0/0
6 120 24 NaOtBu 0/0
7 120 24 K3PO4 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.

124
Table 3.15: Screening of difluoromethylating reagents - Diethyl
(bromodifluoromethyl)phosphonatea
Solvent (0.2 M) T (oC) t (h) Activator (0.5 equiv) 5a/6a (%)
1 DCM 23 12 CsF 0/0
2 DCM 45 12 CsF 0/0
3 DCM 45 24 CsF 0/0
4 ACN 45 24 CsF 0/0
5 ACN 60 24 CsF 0/0
6 ACN 60 24 NaF 0/0
7 ACN 60 24 KF 0/0
8 ACN 60 24 TBAT 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.16: Screening of difluoromethylating reagents – FSO2CF2CO2TMSa
Solvent (0.2 M) T (oC) t (h) Activator (0.5 equiv) 5a/6a (%)
1 1,4-dioxane 120 24 K2CO3 0/0
2 1,4-dioxane 65 24 K2CO3 0/0
3 THF 65 24 K2CO3 0/0
4 DMF 65 24 K2CO3 0/0
5 ACN 65 24 K2CO3 0/0
6 ACN 80 24 K2CO3 0/0
7 ACN 80 24 Na2CO3 0/0
8 ACN 80 24 Cs2CO3 0/0
9 ACN 80 72 K2CO3 0/0
10 ACN 80 2 K2CO3 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.

125
Table 3.17: Screening of difluoromethylating reagents – HCF2Cla
Solvent (0.25 M) T (oC) Activator (2.0
equiv)
5a/6a (%)
1 THF 90 NaI 1/1
2 Toluene 90 Cs2CO3 0/0
3 THF 100 NaI 1/1
4 THF rt NaI 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.18：Screening of difluoromethylating reagents – TMSCF3
a
Solvent (0.25 M) T (oC) Activator (2.0
equiv)
5a/6a (%)
1 THF 90 NaI 1/1
2 Toluene 90 Cs2CO3 0/0
3 THF 100 NaI 1/1
4 THF rt NaI 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.

126
Table 3.19：Screening of difluoromethylating reagents – PhSO2CF2Cla
Solvent (0.33 M) T (oC) Activator (2.0 equiv) 5a/6a (%)
1 THF 23 50% aq. KOH 0/0
2 ACN 23 50% aq. KOH 0/0
3 DMF 23 50% aq. KOH 0/0
4 ACN 60 50% aq. KOH 0/0
5 ACN 60 K2CO3 0/0
6 ACN 60 KOH 0/0
7 ACN 60 KOtBu 0/0
8 ACN rt KOH 0/0
9 ACN rt NaOH 0/0
10 ACN rt Cs2CO3 0/0
11 ACN rt Na2CO3 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Table 3.20：Screening of difluoromethylating reagents – S-difluoromethyl-Sphenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroboratea
Solvent (0.33 M) T (oC) 5a/6a (%)
1 ACN 23 0/0
2 ACN 0 0/0
3 ACN 60 0/0
4 Toluene 23 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.

127
Table 3.21 ： Screening of difluoromethylating reagents – Difluoromethyl
trifluoromethanesulfonatea
Solvent (0.1
M)
Bases T (oC) 5a/6a (%)
1 ACN 50% aq. NaOH 23 0/0
2 THF 50% aq. NaOH 23 0/0
3 ACN 50% aq. NaOH 0 0/0
4 ACN NaOH 23 0/0
5 ACN KOH 23 0/0
6 ACN Cs2CO3 23 0/0
7 ACN Na2CO3 23 0/0
aThe reaction was performed at 1 mmol scale. Yield was determined by 19F NMR with PhF as an internal
standard.
Preparation of S-monofluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonioum triflate (1b)
To an oven-dried 250-mL round-bottom flask, SelectfluoR
(20.0 g, 56.45 mmol,
1.25 equiv) was added under Ar protection. Then, 100 mL of ACN was added to the
flask and the suspension was cooled to 0 oC in an ice bath. Thioanisole (5.61 g, 45.2
mmol, 5.3 mL, 1.0 equiv) was added dropwise over 30 min at 0 oC under Ar protection.
The resulting mixture was stirred for 1 h at the same temperature, and Et3N (5.73 g,
56.6 mmol, 7.9 mL, 1.25 equiv) was added dropwise (addition complete in about 30
min) into the reaction mixture at 0 oC under Ar protection. The reaction mixture was
allowed to stir for another 30 min at the same temperature, and water (200 mL) was
added into the mixture. The aqueous layer was extracted with hexane (150 mL x 3). The

128
combined organic layers were washed with water (100 mL) and brine (100 mL), and
dried over drying agent. Then the combined organic layer was filtered, and the solvent
was removed under reduced pressure to afford crude PhSCH2F.
The crude PhSCH2F was dissolved in MeOH (80 mL) and H2O (7 mL), and the
solution was cooled to 0 oC under N2 protection. Freshly recrystallized and dried NBS
(16.1 g, 90.33 mol, 2.0 equiv) was added in one portion into the solution under N2
protection at 0 oC, and the resulting mixture was allowed to stir at the same temperature
for 2.5 h. Then, the reaction was quenched with 10% Na2SO3 solution (50 mL), and the
solution was neutralized with saturated NaHCO3 until pH = 8. After MeOH was
removed under reduced pressure, and the aqueous phase was extracted with DCM (100
mL x 3). The combined organic layers were washed with water (100 mL) and brine
(100 mL), and dried over drying agent. Then the combined organic layer was filtered,
and the solvent was removed under reduced pressure. The residue was purified by flash
column chromatography (eluted with 35% EtOAc in hexane) to afford product
((fluoromethyl)sulfinyl)-benzene as a yellow oil (5.52 g, 78% isolated yield).
To an oven-dried 250-mL round-bottom flask, ((Fluoromethyl)sulfinyl)-benzene
(2.21 g, 14 mmol, 1.0 equiv), and 1,2,3,4-tetramethylbenzene (1.88 g, 14 mmol, 2.1 mL,
1.0 equiv) were added under N2 protection. Then, 65 mL of Et2O was added to the flask
and the solution was cooled to 0 oC in an ice bath. Tf2O (3.95 g, 14 mmol, 2.36 mL, 1.0
equiv) was added dropwise over 30 min into the solution at the same temperature under
N2 protection. The resulting mixture was allowed to stir at 0 oC for 1 h. After the
reaction was complete, the suspension was filtered, and the residue solid was washed

129
with cold Et2O (150 mL x 3). The resulting solid was collected and dried under reduced
pressure to afford product S-monofluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonium triflate as a grey solid (3.59 g, 60% isolated yield).
Preparation of S-monofluoromethyl-S-phenyl-2,3,4,5-
tetramethylphenylsulfonium Tetrafluoroborate (1a)
2.00g of 1b was dissolved in 50 mL of DCM, then the solution was washed with
1.0 M NaBF4 aqueous solution (5 x 50 mL). The solution was dried over drying agent,
Na2SO4. The organic solvents were removed under reduced pressure to afford 1a as a
pale-yellow solid (1.49 g, 87% isolated yield).
General Procedure C – Monofluoromethylation of 2-Pyridaziones
To an oven-dried 7-mL microwave vial, 2 (1.0 eq, 0.5 mmol), Cs2CO3 (1.1 eq, 0.55
mmol, 179.2 mg), and sulfonium salts 1 (1.1 eq, 0.55 mmol, 233.5 mg) were added
under Ar protection. Then, 3.3 mL of ACN was added to the vial at 0 °C, and the mixture
was stirred at the same temperature for one hour. Then the reaction was allowed to
warm to room temperature, and diluted with DCM (15 mL) and water (15 mL). The
aqueous layer was separated, and extracted with DCM (15 mL x 2). The combined
organic layer was washed with water (10 mL) and brine (10 mL), and dried with Na2SO4.
The drying agent was filtered, and the organic solvent was removed under reduced
pressure. The residue was purified by flash column chromatography to afford product
3.
Note: Compounds were wet loaded with 50% DCM in hexane for flash column

130
chromatography.
General Procedure D for Difluoromethylation of 3(2H)-Pyridazinones
To a 7 mL oven-dried microwave vial, 2 (1.5 equiv, 1.5 mmol), Cs2CO3 (2.25 equiv,
2.25 mmol, 733.3 mg), and TMAF (0.1 equiv, 0.1 mmol, 9.3 mg) were added under Ar
protection. Toluene (3 mL) was added under Ar protection, and the resulting suspension
was put in a 90 °C oil bath and stirred for 2 minutes. Then TMSCF2Br (1.0 equiv, 1.0
mmol, 203.1 mg, 155 uL) was added in one portion to the mixture under N2 protection,
and the resulting mixture was allowed to stir for 1 hour at 90 °C. After the reaction is
complete, the vial was allowed to warm to room temperature. Toluene was removed
under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL) and
water (50 mL). The aqueous layer was separated, and extracted with EtOAc (50 mL x
2), The combined organic layer was washed with water (50 mL x 1) and brine (50 mL
x 1), and dried with Na2SO4. The drying agent was filtered, and the organic solvent was
removed under reduced pressure. The residue was purified by flash column
chromatography to afford products 5 and 6.
Note: Compounds were dry loaded with silica for flash column chromatography.
((fluoromethyl)sulfinyl)-benzene
1H NMR (400 MHz, CDCl3) δ 7.70 – 7.57 (m, 5H), 5.09 (dd, J = 47.82, 2.55 Hz, 2H);
19F NMR (376 MHz, CDCl3) δ -212.25 (t, J = 47.80 Hz). 13C NMR (126 MHz, CDCl3)
δ 138.9 (d, J = 6.29 Hz), 132.2, 129.7, 124.8, 98.3 (d, J = 221.25 Hz); FT-IR (v-1 cm-1
)

131
2978, 1444, 1090, 1037, 750, 690; HRMS (ESI) m/z calculated for C7H8OFS [M + H]+
:
159.0280; found 159.0277 (1.8865 ppm). Characterization data match the literature
report.
57
Note: This method was modified based on report procedure87 which provided 38%
isolated yield of target ((fluoromethyl)sulfinyl)-benzene. In our protocol, dry
SelectfluorR
and freshly recrystallized NBS were utilized, and the sulfoxide product
was obtained in improved yield (78% isolated yield).
S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonioum
tetrafluoroborate (1a)
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.80 Hz, 2H), 7.71 (t, J = 7.43 Hz, 1H), 7.64
(t, J = 7.74 Hz, 2H), 7.42 (s, 1H), 6.55 – 6.41 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.27
(s, 3H), 2.25 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -151.80 (m, 4F), -207.54 (t, J =
46.05 Hz, 1F). 13C NMR (126 MHz, CDCl3) δ 144.0, 139.4, 138.4, 137.4, 134.5, 131.5,
130.9, 128.9, 128.3 (d, J = 3.93 Hz), 127.5, 121.2, 116.1, 89.4 (d, J = 240.86 Hz), 21.0,
17.6, 16.9, 16.8; FT-IR (v-1 cm-1
) 3039, 2971, 1583, 1476, 1447, 1385, 1339, 1287,
1219, 1023, 750, 680; HRMS (ESI) m/z calculated for C17H20FS [M – BF4]
+
: 275.1264;
found 275.1263 (0.3635 ppm). Since the product is a salt, only the mass of
corresponding cation was observed. Characterization data match the reference.57

132
S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonioum triflate (1b)
1H NMR (400 MHz, ACN-d3) δ 7.85 – 7.79 (m, 3H), 7.75 – 7.71 (m, 2H), 7.38 (s, 1H),
6.45 (d, J = 45.31 Hz, 2H), 2.48 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H); 19F
NMR (376 MHz, ACN-d3) δ -78.87 (s, 3F), -206.75 (t, J = 46.96 Hz, 1F). 13C NMR
(126 MHz, ACN-d3) δ 145.0, 140.5, 139.2, 138.4, 135.6, 132.3, 132.0, 129.3 (d, J =
3.12 Hz), 122.3, 122.1 (q, J = 321.34 Hz), 117.2, 90.4 (d, J = 238.59 Hz), 20.9, 18.0,
17.0, 17.0; FT-IR (v-1 cm-1
) 3034, 1449, 1273, 1250, 1222, 1153, 1062, 1028, 1000;
HRMS (ESI) m/z calculated for C17H20FS [M – CF3SO3]
+
: 275.1264; found 275.1269
(1.8173 ppm). Since the product is a salt, only the mass of corresponding cation was
observed. Characterization data match the literature report.
57
2-(fluoromethyl)phthalazin-1(2H)-one (3a)
Performed on 0.5 mmol scale. Eluted with pure DCM to afford 3a (68.9 mg, 77%
isolated yield). White solid. M.P. 140 °C - 144 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.31 (d, J = 7.90 Hz, 1H), 8.04 – 7.99
(m, 2H), 7.95 – 7.91 (m, 1H), 6.11 (d, J = 52.40 Hz, 2H); 19F NMR (376 MHz, DMSOd6) δ -175.33 (t, J = 51.92 Hz). 13C NMR (126 MHz, DMSO-d6) δ 160.0 (d, J = 2.02
Hz), 139.4 (d, J = 1.04 Hz), 134.3, 132.4, 130.0, 127.9, 127.4, 126.6, 87.6 (d, J = 201.59
Hz). FT-IR (v-1 cm-1
) 3050, 2992, 2853, 1667, 1595, 1452, 1337, 1271, 1193, 1017;

133
HRMS (ESI) m/z calculated for C9H8N2OF [M + H]+
: 179.0621; found 179.0623
(1.1169 ppm).
6-fluoro-2-(fluoromethyl)phthalazin-1(2H)-one (3b)
Performed on 0.5 mmol scale. Eluted with 15% EtOAc in hexane to afford 3b (44.8 mg,
23% isolated yield). White solid. M.P. 124 °C - 126 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.38 (dd, J = 8.85, 5.37 Hz, 1H), 7.86
(dd, J = 8.80, 2.58 Hz, 1H), 7.78 (td, J = 8.84, 2.58 Hz, 1H), 6.10 (d, J = 52.36 Hz, 2H);
19F NMR (376 MHz, DMSO-d6) δ -175.66 (t, J = 51.64 Hz). 13C NMR (126 MHz,
DMSO-d6) δ 166.3 (d, J = 253. 58 Hz), 158.4, 138.8, 132.0 (d, J = 10.41 Hz), 130.2 (d,
J = 10.07 Hz), 123.9, 121.1 (d, J = 23.63 Hz), 112.9 (d, J = 22.82 Hz), 87.7 (d, J =
197.39 Hz); FT-IR (v-1 cm-1
) 3116, 2922, 2852, 1669, 1616, 1563, 1486, 1450, 1358,
1294, 1197, 1024; HRMS (ESI) m/z calculated for C9H7N2OF2 [M + H]
+
: 197.0526;
found 197.0524 (1.0150 ppm).
6-chloro-2-(fluoromethyl)phthalazin-1(2H)-one (3c)
Performed on 0.5 mmol scale. Eluted with 15% EtOAc in hexane to afford 3c (57.6 mg,
54% isolated yield). White solid. M.P. 185 °C - 188 °C.

134
1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 7.74 (dd, J =
8.51, 1.95 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 51.69 Hz, 2H); 19F NMR (376
MHz, CDCl3) δ -175.55 (t, J = 51.68 Hz); 13C NMR (126 MHz, CDCl3) δ 159.3 (d, J
= 2.18 Hz), 141.1, 138.1, 132.9, 131.2, 129.3, 126.3, 126.0, 87.5 (d, J = 202.52 Hz);
FT-IR (v-1 cm-1
) 3065, 1653, 1593, 1557, 1460, 1322, 1292, 1222, 1188, 1085; HRMS
(ESI) m/z calculated for C9H7N2OFCl [M + H]+
: 213.0231; found 213.0234 (1.4083
ppm).
6-bromo-2-(fluoromethyl)phthalazin-1(2H)-one (3d)
Performed on 0.5 mmol scale. Eluted with 10% EtOAc in hexane to afford 3d (84.7 mg,
66% isolated yield). White solid. M.P. 202 °C - 205 °C.
1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.43 Hz, 1H), 8.11 (s, 1H), 7.92 – 7.87 (m,
2H), 6.14 (d, J = 51.65 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -175.56 (t, J = 51.70
Hz). 13C NMR (126 MHz, CDCl3) δ 159.5 (d, J = 2.15 Hz), 137.9 (d, J = 1.29 Hz),
135.7, 131.2, 129.5, 129.3, 129.2, 126.6, 87.5 (d, J = 202.52 Hz); FT-IR (v-1 cm-1
) 3089,
2922, 1652, 1604, 1460, 1339, 1318, 1291, 1220, 1187, 1027; HRMS (ESI) m/z
calculated for C9H7N2OFBr [M + H]+
: 256.9726; found 256.9724 (0.7783 ppm).
7-bromo-2-(fluoromethyl)phthalazin-1(2H)-one (3e)

135
Performed on 0.5 mmol scale. Eluted with 15% EtOAc in hexane to afford 3e (83.3 mg,
65% isolated yield). White solid. M.P. 129 °C - 131 °C.
1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.02 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J =
8.34, 2.01 Hz, 1H), 7.59 (d, J = 8.36 Hz, 1H), 6.15 (d, J = 51.59 Hz, 2H); 19F NMR
(376 MHz, CDCl3) δ -175.66 (t, J = 51.64 Hz). 13C NMR (126 MHz, CDCl3) δ 157.9
(d, J = 2.07 Hz), 139.2, 137.7, 129.7, 128.5, 128.4, 128.4, 126.2, 87.8 (d, J = 197.66
Hz); FT-IR (v-1 cm-1
) 3351, 3089, 2996, 2925, 2851, 1675, 1589, 1443, 1400, 1318,
1286, 1234; HRMS (ESI) m/z calculated for C9H7N2OFBr [M + H]+
: 256.9726; found
256.9723 (1.1674 ppm).
4-bromo-2-(fluoromethyl)phthalazin-1(2H)-one (3f)
Performed on 0.5 mmol scale. Eluted with 10% EtOAc in hexane to afford 3f (77.3 mg,
60% isolated yield). White solid. M.P. 195 °C - 200 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 7.93 Hz, 1H), 8.11 (td, J = 7.85, 1.29
Hz, 1H), 8.02 – 7.99 (m, 2H), 6.09 (d, J = 52.18 Hz, 2H); 19F NMR (376 MHz, DMSOd6) δ -174.80 (t, J = 51.58 Hz); 13C NMR (126 MHz, DMSO-d6) δ 158.5 (d, J = 1.71
Hz), 135.6, 133.9, 130.9, 129.7, 128.2, 127.4, 127.3, 87.4 (d, J = 199.10 Hz);
FT-IR (v-1 cm-1
) 2920, 2852, 1671, 1576, 1452, 1343, 1301, 1256, 1203, 1021, 966;
HRMS (ESI) m/z calculated for C9H7N2OFBr [M + H]+
: 256.9726; found 256.9727
(0.3891 ppm).

136
4-chloro-2-(fluoromethyl)phthalazin-1(2H)-one (3g)
Performed on 0.5 mmol scale. Eluted with 35% EtOAc in hexane to afford 3g (90.0 mg,
85% isolated yield). White solid. M.P. 178 °C - 180 °C
1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 7.85, 1.38 Hz, 1H), 8.14 – 8.01 (m,
3H), 6.08 (d, J = 52.18 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ -174.99 (t, J = 51.61
Hz). 13C NMR (126 MHz, DMSO-d6) δ 158.5 (d, J = 1.73 Hz), 138.3 (d, J = 1.57 Hz),
135.4, 133.9, 128.2, 127.6, 127.4, 126.1, 87.3 (d, J = 199.13 Hz). FT-IR (v-1 cm-1
) 3105,
3055, 1668, 1580, 1552, 1455, 1344, 1300, 1264, 1165, 1044, 993, 967; HRMS (ESI)
m/z calculated for C9H7N2OFCl [M + H]+
: 213.0231; found 213.0229 (0.9389 ppm).
2-(fluoromethyl)pyridazin-3(2H)-one (3h)
Performed on 0.5 mmol scale. Eluted with 50% EtOAc in hexane to afford 3h (42.5 mg,
66% isolated yield). White waxy solid. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 3.83
Hz, 1H), 7.49 (dd, J = 9.61, 3.80 Hz, 1H), 7.05 (dd, J = 9.56, 1.56 Hz, 1H), 6.00 (d, J
= 51.57 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -177.49 (t, J = 50.75 Hz). 13C NMR
(126 MHz, CDCl3) δ 159.7 (d, J = 2.25 Hz), 138.3, 133.8, 130.4, 87.8 (d, J = 197.67
Hz); FT-IR (v-1 cm-1
) 3071, 3047, 2919, 1667, 1595, 1534, 1414, 1404, 1362, 1288,

137
1205, 1136; HRMS (ESI) m/z calculated for C5H6N2OF [M + H]+
: 129.0464; found
129.0462 (1.5498 ppm).
2-(fluoromethyl)-6-methylpyridazin-3(2H)-one (3i)
Performed on 0.5 mmol scale. Eluted with 55% EtOAc in hexane to afford 3i (44.9 mg,
63% isolated yield). White solid. M.P. 85 °C - 86 °C.
1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 9.65 Hz, 1H), 6.89 (d, J = 9.59 Hz, 1H),
6.01 (d, J = 51.19 Hz, 2H), 2.34 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -176.95 (t, J
= 51.09 Hz). 13C NMR (126 MHz, CDCl3) δ 159.9 (d, J = 2.20 Hz), 145.7, 134.9, 130.8,
87.5 (d, J = 202.32 Hz), 20.9. FT-IR (v-1 cm-1
) 3047, 2987, 2921, 2851, 1672, 1606,
1484, 1390, 1332, 1214, 1144, 1039; HRMS (ESI) m/z calculated for C6H8N2OF [M
+ H]+
: 143.0621; found 143.0623 (1.3980 ppm).
6-chloro-2-(fluoromethyl)pyridazin-3(2H)-one (3j)
Performed on 0.5 mmol scale. Eluted with 20% EtOAc in hexane to afford 3j (58.7 mg,
72% isolated yield). White solid. M.P. 65 °C - 68 °C.
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 9.79 Hz, 1H), 6.96 (d, J = 9.74 Hz, 1H),
5.97 (d, J = 50.71 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -176.40 (t, J = 50.74 Hz);

138
13C NMR (126 MHz, CDCl3) δ 158.8 (d, J = 2.22 Hz), 139.0 (d, J = 1.60 Hz), 135.4,
133.0, 87.2 (d, J = 205.64 Hz); FTIR (v-1 cm-1
) 3343, 3074, 1682, 1586, 1455, 1404,
1325, 1178, 1138; HRMS (ESI) m/z calculated for C5H5N2OFCl [M + H]+
: 163.0074;
found 163.0079 (3.06732 ppm).
2-(fluoromethyl)-6-phenylpyridazin-3(2H)-one (3k)
Performed on 0.5 mmol scale. Eluted with 35% EtOAc in hexane to afford 3k (69.9 mg,
67% isolated yield). White solid. M.P. 85 °C - 86 °C.
1H NMR (400 MHz, CDCl3) δ 7.81 – 7.79 (m, 2H), 7.73 (d, J = 9.82 Hz, 1H), 7.50 –
7.47 (m, 3H), 7.06 (d, J = 9.81 Hz, 1H), 6.14 (d, J = 50.95 Hz, 2H); 19F NMR (376
MHz, CDCl3) δ -177.17 (t, J = 51.03 Hz); 13C NMR (126 MHz, CDCl3) δ 159.9 (d, J
= 2.07 Hz), 145.7 (d, J = 1.08 Hz), 134.1, 132.0, 131.3, 130.2, 129.2, 126.3, 88.0 (d, J
= 203.39 Hz); FT-IR (v-1 cm-1
) 3051, 2994, 1677, 1600, 1517, 1441, 1327, 1282, 1213,
1166, 984; HRMS (ESI) m/z calculated for C11H10N2OF [M + H]+
: 205.0777; found
205.0775 (0.9752 ppm).
4-chloro-2-(fluoromethyl)-5-methoxypyridazin-3(2H)-one (3l)
Performed on 0.5 mmol scale. Eluted with 35% EtOAc in hexane to afford 3l (57.4 mg,

139
57% isolated yield). White solid. M.P. 120 °C - 121 °C
1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 1.34 Hz, 1H), 6.05 (d, J = 51.49 Hz, 2H),
4.13 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -176.51 (t, J = 50.76 Hz). 13C NMR
(126 MHz, DMSO-d6) δ 157.8 (d, J = 2.15 Hz), 130.2, 114.0, 109.0, 88.1 (d, J = 199.43
Hz), 58.5. FT-IR (v-1 cm-1
) 3064, 2963, 2920, 1644, 1604, 1471, 1412, 1390, 1310,
1207, 1178, 1096, 1024; HRMS (ESI) m/z calculated for C6H7N2O2FCl [M + H]+
:
193.0180; found 193.0180 (0.0000 ppm).
4,5-dichloro-2-(fluoromethyl)pyridazin-3(2H)-one (3m)
Performed on 0.5 mmol scale. Eluted with 20% EtOAc in hexane to afford 3m (87.0
mg, 88% isolated yield). Yellow solid. M.P. 108 °C - 110 °C.
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 6.06 (d, J = 50.41 Hz, 2H); 19F NMR (376
MHz, CDCl3) δ -177.56 (d, J = 50.18 Hz); 13C NMR (400 MHz, CDCl3) δ 156.5 (d, J
= 2.18 Hz), 137.7, 137.1 (d, J = 1.17 Hz), 135.4, 88.1 (d, J = 206.52 Hz); FT-IR (v-1
cm-1
) 3307, 3092, 3049, 3001, 1677, 1582, 1514, 1449, 1372, 1330, 1294, 1227;
HRMS (ESI) m/z calculated for C5H4N2OFCl2 [M + H]+
: 196.9685; found 196.9690
(2.5385 ppm).

140
2-fluoro-5-((3-(fluoromethyl)-4-oxo-3,4-dihydrophthalazin-1-
yl)methyl)benzonitrile (3n)
Performed on 0.5 mmol scale. Eluted with 50% EtOAc in hexane to afford 3n (92.1 mg,
55% isolated yield). White solid. M.P. 165 °C - 166 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 7.79 Hz, 1H), 8.01 – 7.88 (m, 4H), 7.78
– 7.74 (m, 1H), 7.48 (t, J = 9.07 Hz, 1H), 6.09 (d, J = 52.48 Hz, 2H), 4.41 (s, 2H); 19F
NMR (376 MHz, CDCl3) δ -109.26 – -109.28 (m, 1H), -175.29 (t, J = 51.79 Hz, 1H).
13C NMR (126 MHz, CDCl3) δ 161.3 (d, J = 254.74 Hz), 159.0 (d, J = 2.17 Hz), 145.8,
136.4 (d, J = 8.64 Hz), 135.2 (d, J = 3.56 Hz), 134.6, 133.7, 132.5, 128.8, 127.8, 127.3,
126.9, 126.0, 116.7 (d, J = 19.49 Hz), 114.0, 100.1 (d, J = 15.22 Hz), 87.2 (d, J = 197.18
Hz), 36.0; FT-IR (v-1 cm-1
) 3049, 2233, 1661, 1593, 1501, 1431, 1349, 1305, 1259,
1206, 1115, 1067; HRMS (ESI) m/z calculated for C17H12N3OF2 [M + H]+
: 312.0948;
found 312.0954 (1.9225 ppm).
tert-butyl 4-(2-fluoro-5-((3-(fluoromethyl)-4-oxo-3,4-dihydrophthalazin-1-
yl)methyl)benzoyl)piperazine-1-carboxylate (3o)
Performed on 0.5 mmol scale. Eluted with pure EtOAc in hexane to afford 3o (64.8 mg,
29% isolated yield). White solid. M.P. 70 °C - 72 °C.

141
1H NMR (400 MHz, CDCl3) δ 8.51 – 8.48 (m, 1H), 7.80 – 7.74 (m, 2H), 7.69 – 7.67
(m, 1H), 7.34 – 7.30 (m, 2H), 7.04 (t, J = 8.76 Hz, 1H), 6.17 (d, J = 51.90 Hz, 2H), 4.29
(s, 2H), 3.75 (s, 2H), 3.51 (s, 2H), 3.38 (t, J = 4.93 Hz, 2H), 3.26 (s, 2H), 1.46 (s, 9H);
19F NMR (376 MHz, CDCl3) δ -117.96 (m, 1F), -175.25 (t, J = 51.89 Hz, 1F); 13C
NMR (126 MHz, CDCl3) δ 165.2, 159.9, 157.2 (d, J = 247.82 Hz), 154.6, 145.9, 134.2,
134.1, 132.1, 131.6 (d, J = 8.00 Hz), 129.4, 129.3, 128.2, 128.2, 125.4, 124.2 (d, J =
18.32 Hz), 116.4 (d, J = 21.91 Hz), 87.6 (d, J = 201.86 Hz), 80.6, 47.1, 42.1, 38.0, 28.5;
FT-IR (v-1 cm-1
) 2981, 2928, 1674, 1594, 1495, 1456, 1364, 1285, 1236, 1163, 1123,
1014, 993; HRMS (ESI) m/z calculated for C26H28N4O4F2Na [M + Na]+
: 521.1976;
found 521.1972 (0.7675 ppm).
2-(difluoromethyl)phthalazin-1(2H)-one (5a)
Performed on 1.0 mmol scale. Eluted with 75% DCM in hexane to afford 5a (49.0 mg,
25% isolated yield). White solid. M.P. 91 °C - 92 °C.
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 7.84 Hz, 1H), 8.30 (s, 1H), 8.00 – 7.70 (m,
4H); 19F NMR (376 MHz, CDCl3) δ -106.16 (d, J = 58.79 Hz); 13C NMR (126 MHz,
CDCl3) δ 159.1, 140.3, 134.9, 132.8, 129.5, 127.5, 127.4, 127.0, 107.0 (t, J = 249.69
Hz); FT-IR (v-1 cm-1
) 2925, 1548, 1351, 1285, 1213, 1075, 1036; HRMS (ESI) m/z
calculated for C9H7N2OF2 [M + H]+
: 197.0526; found 197.0528 (1.0150 ppm).

142
4-bromo-2-(difluoromethyl)phthalazin-1(2H)-one (5f)
Performed on 1.0 mmol scale. Eluted with 50% DCM in hexane to afford 5f (33.8 mg,
12% isolated yield). White solid. M.P. 125 °C - 127 °C.
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 7.83 Hz, 1H), 8.03 (d, J = 8.05 Hz, 1H),
7.97 (td, J = 8.13, 7.68, 1.34 Hz, 1H), 7.89 (t, J = 7.58 Hz, 1H), 7.77 (t, J = 58.52 Hz,
1H); 19F NMR (376 MHz, CDCl3) δ -105.81 (d, J = 58.40 Hz); 13C NMR (126 MHz,
CDCl3) δ 158.4, 135.5, 133.7, 133.0, 130.2, 128.9, 128.1, 127.7, 106.7 (t, J = 251.71
Hz); FT-IR (v-1 cm-1
) 2925, 1548, 1351, 1285, 1213, 1075, 1036; HRMS (ESI) m/z
calculated for C9H6BrN2OF2 [M + H]+
: 274.9632; found 274.9629 (1.0911 ppm).
4-chloro-2-(difluoromethyl)phthalazin-1(2H)-one (5g)
Performed on 1.0 mmol scale. Eluted with 50% DCM in hexane to afford 5g (77.5 mg,
34% isolated yield). White solid. M.P. 130 °C - 131 °C. 1H NMR (400 MHz, DMSOd6) δ 8.35 (d, J = 7.79 Hz, 1H), 8.18 – 7.89 (m, 4H); 19F NMR (376 MHz, DMSO-d6)
δ -104.63 (d, J = 57.68 Hz); 13C NMR (126 MHz, DMSO-d6) δ 157.8, 140.0, 135.8,
134.1, 127.9, 127.4, 127.3, 126.4, 107.2 (t, J = 249.45 Hz); FT-IR (v -1 cm-1 ) 3358,
3085, 2922, 1678, 1586, 1459, 1387, 1288, 1267, 1195, 1175, 1075; HRMS (ESI) m/z
calculated for C9H6N2OF2Cl [M + H]+ : 231.0137; found 231.0136 (0.4329 ppm).

143
2-(difluoromethyl)-6-methylpyridazin-3(2H)-one (5i)
Performed on 1.0 mmol scale. Eluted with 20% EtOAc in DCM to afford 5i (26.3 mg,
16% isolated yield). White solid. M.P. 48 °C - 57 °C.
1H NMR (400 MHz, CDCl3) δ 7.66 (t, J = 58.90 Hz, 1H), 7.13 (d, J = 9.69 Hz, 1H),
6.86 (d, J = 9.70 Hz, 1H), 2.40 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -107.10 (d, J =
58.84 Hz); 13C NMR (126 MHz, CDCl3) δ 158.6, 146.3, 134.9, 130.5, 106.4 (t, J =
251.03 Hz), 21.0; FT-IR (v-1 cm-1
) 3020, 1687, 1612, 1214, 1156, 1088; HRMS (ESI)
m/z calculated for C6H7N2OF2 [M + H]+
: 161.0526; found 161.0524 (1.2418 ppm).
6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one (5j)
Performed on 1.0 mmol scale. Eluted with 50% DCM in hexane to afford 5j (41.0 mg,
23% isolated yield). White solid. M.P. 65 °C.
1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 57.79 Hz, 1H), 7.66 (d, J = 9.94 Hz, 1H),
7.18 (d, J = 9.90 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ -105.62 (d, J = 57.84 Hz);
13C NMR (126 MHz, DMSO-d6) δ 157.5, 140.0, 136.1, 133.3, 107.1 (t, J = 251.28 Hz);
FT-IR (v-1 cm-1
) 3069, 2921, 1685, 1596, 1370, 1304, 1215, 1166, 1043; HRMS (ESI)
m/z calculated for C5H4N2OF2Cl [M + H]+
: 180.9980; found 180.9976 (2.2100 ppm).

144
2-(difluoromethyl)-6-phenylpyridazin-3(2H)-one (5k)
Performed on 1.0 mmol scale. Eluted with 85% DCM in hexane to afford 5k (127.7 mg,
22% isolated yield). Yellow solid. M.P. 100 °C - 104 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 9.96 Hz, 1H), 7.99 (t, J = 58.23 Hz, 1H),
7.94 – 7.92 (m, 2H), 7.57 – 7.52 (m, 3H), 7.21 (d, J = 9.94 Hz, 1H); 19F NMR (376
MHz, DMSO-d6) δ - 107.05 (d, J = 58.71 Hz); 13C NMR (126 MHz, DMSO-d6) δ 158.2,
145.6, 133.4, 132.9, 131.0, 130.3, 129.1, 126.3, 107.6 (t, J = 249.96 Hz); FT-IR (v-1
cm-1
) 3356, 3072, 1682, 1603, 1523, 1445, 1384, 1320, 1216, 1159, 1059, 1025; HRMS
(ESI) m/z calculated for C11H9N2OF2 [M + H]+
: 223.0683; found 223.0687 (1.7932
ppm).
tert-butyl 4-(5-((3-(difluoromethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-
fluorobenzoyl)piperazine-1-carboxylate (5o)
Performed on 1.0 mmol scale. Eluted with 25% EtOAc in DCM to afford 5o (21.7 mg,
4% isolated yield). White solid. M.P. 119 °C - 120 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.52 Hz, 1H), 8.18 – 7.89 (m, 4H), 7.47
– 7.43 (m, 1H), 7.40 – 7.38 (m, 1H), 7.25 (t, J = 8.99 Hz, 1H), 4.42 (s, 2H), 3.59 (s,
2H), 3.37 (s, 2H), 3.21 (s, 2H), 3.13 (s, 2H), 1.40 (s, 9H); 19F NMR (376 MHz, DMSO-

145
d6) δ -104.81 (d, J = 58.22 Hz, 2F), -119.5 (m, 1F); 13C NMR (126 MHz, DMSO-d6) δ
163.9, 158.3, 156.5 (d, J = 245.03 Hz), 153.7, 147.5, 135.0, 133.9 (d, J = 3.20 Hz),
132.8, 131.6 (d, J = 8.13 Hz), 128.8 (d, J = 3.57 Hz), 128.4, 127.0, 126.9, 126.4, 123.7
(d, J = 18.31 Hz), 116.1 (d, J = 21.61 Hz), 107.6 (t, J = 248.00 Hz), 79.3, 46.3, 41.2,
36.6, 28.0; FT-IR (v-1 cm-1
) 2978, 2864, 1687, 1636, 1458, 1414, 1328, 1285, 1237,
1125, 1056; HRMS (ESI) m/z calculated for C26H26N4O4F3 [M – H]–
: 515.1906; found
515.1906 (0.0000 ppm).
1-bromo-4-(difluoromethoxy)phthalazine (6f)
Performed on 1.0 mmol scale. Eluted with 25% EtOAc in DCM to afford 6f (36.7 mg,
13% isolated yield). White solid. M.P. 114 °C - 116 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.28 – 8.23 (m, 3H), 8.22 – 8.18 (m, 1H), 8.01 (t, J
= 71.14 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ -86.66 (d, J = 71.20 Hz); 13C NMR
(126 MHz, DMSO-d6) δ 157.2 (t, J = 3.54 Hz), 146.0, 135.5, 135.0, 129.2, 127.4, 123.0,
119.5, 114.6 (t, J = 258.58 Hz); FT-IR (v-1 cm-1
) 2925, 1548, 1351, 1285, 1075, 1036;
HRMS (ESI) m/z calculated for C9H6N2OF2Br [M + H]+
: 274.9632; found 274.9631
(0.3637 ppm).

146
1-chloro-4-(difluoromethoxy)phthalazine (6g)
Performed on 1.0 mmol scale. Eluted with 75% EtOAc in hexane to afford 6g (115.8
mg, 50% isolated yield).White solid. M.P. 110 °C - 111 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.34 – 8.32 (m, 1H), 8.29 – 8.19 (m, 3H), 8.03 (t, J
= 71.16 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ -86.69 (d, J = 71.28 Hz); 13C NMR
(126 MHz, DMSO-d6) δ 156.9 (t, J = 3.56 Hz), 152.1, 135.3, 134.9, 127.5, 125.2, 123.0,
119.8, 114.6 (t, J = 258.61 Hz); FT-IR (v-1 cm-1
) 3226, 2851, 1578, 1488, 1348, 1289,
1167, 1053; HRMS (ESI) m/z calculated for C9H6N2OF2Cl [M + H]+
: 231.0137; found
231.0137 (0.0000 ppm).
2-(difluoromethyl)-6-methylpyridazin-3(2H)-one (6i)
Performed on 1.0 mmol scale. Eluted with 20% EtOAc in DCM to afford 6i (48.2 mg,
30% isolated yield).Yellow solid. M.P. 41 – 42 °C.
1H NMR (400 MHz, DMSO-d6) δ 7.86 (t, J = 72.08 Hz, 1H), 7.73 (d, J = 9.02 Hz, 1H),
7.43 (d, J = 9.02 Hz, 1H), 2.59 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -86.90 (d, J
= 72.29 Hz); 13C NMR (126 MHz, DMSO-d6) δ 160.3 (t, J = 3.67 Hz), 158.5, 132.2,
117.5, 114.6 (t, J = 256.46 Hz), 21.0; FT-IR (v-1 cm-1
) 3064, 1685, 1592, 1446, 1364,
1281, 1247, 1171, 1090, 1061; HRMS (ESI) m/z calculated for C6H7N2OF2 [M + H]+
:
161.0526; found 161.0529 (1.8627 ppm).

147
6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one (6j)
Performed on 1.0 mmol scale. Eluted with 50% DCM in hexane to afford 6j (92.7 mg,
51% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.60 (t, J = 71.47 Hz, 1H), 7.57 (d, J = 9.11 Hz, 1H),
7.15 (d, J = 9.14 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -89.43 (d, J = 71.43 Hz); 13C
NMR (126 MHz, CDCl3) δ 161.1 (t, J = 3.73 Hz), 154.1, 132.5, 120.0, 113.5;
FT-IR (v-1 cm-1
) 3078, 1582, 1557, 1420, 1373, 1321, 1279, 1185, 1132, 1059, 873,
838; HRMS (ESI) m/z calculated for C5H4N2OF2Cl [M + H]+
: 180.9980; found
180.9985 (2.7625 ppm).
2-(difluoromethyl)-6-phenylpyridazin-3(2H)-one (6k)
Performed on 1.0 mmol scale. Eluted with pure DCM to afford 6k (49.4 mg, 57%
isolated yield). White solid. M.P. 123 °C
1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 9.24 Hz, 1H), 8.11 (dd, J = 7.80, 1.88
Hz, 2H), 7.96 (t, J = 71.88 Hz, 1H), 7.65 (d, J = 9.22 Hz, 1H), 7.59 – 7.52 (m, 3H); 19F
NMR (376 MHz, DMSO-d6) δ -89.17 (d, J = 71.85 Hz); 13C NMR (126 MHz, DMSOd6) δ 160.8 (t, J = 3.43 Hz), 157.3, 135.2, 130.1, 129.4, 129.0, 126.7, 118.2, 114.6 (t, J

148
= 257.03 Hz); FT-IR (v-1 cm-1
) 3073, 2922, 1453, 1363, 1286, 1127, 1059, 1011;
HRMS (ESI) m/z calculated for C11H9N2OF2 [M + H]+
: 223.0683; found 223.0687
(1.7932 ppm).
tert-butyl 4-(5-((4-(difluoromethoxy)phthalazin-1-yl)methyl)-2-
fluorobenzoyl)piperazine-1-carboxylate (6o)
Performed on 1.0 mmol scale. Eluted with 75% EtOAc in DCM to afford 6o (115.6 mg,
22% isolated yield). White solid. M.P. 80 – 81 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.36 – 8.34 (m, 1H), 8.23 – 7.86 (m, 4H), 7.49 –
7.45 (m, 1H), 7.39 – 7.37 (m, 1H), 7.23 (t, J = 9.01 Hz, 1H), 4.69 (s, 2H), 3.58 (s, 2H),
3.37 (s, 2H), 3.22 (s, 2H), 3.13 (s, 2H), 1.40 (s, 9H); 19F NMR (376 MHz, DMSO-d6)
δ -87.06 (d, J = 71.61 Hz, 2F), -119.59 (m, 1F); 13C NMR (126 MHz, DMSO-d6) δ
163.9, 157.9, 156.3 (d, J = 244.58 Hz), 156.3 (t, J = 3.37 Hz), 153.8, 135.0 (d, J = 3.11
Hz), 134.0, 133.5, 131.8 (d, J = 7.63 Hz), 128.9 (d, J = 3.70 Hz), 127.7, 125.2, 123.6
(d, J = 18.26 Hz), 122.5, 118.1, 116.0 (d, J = 21.36 Hz), 114.7 (t, J = 257.29 Hz), 79.3,
46.3, 41.2, 37.0, 28.0; FT-IR (v-1 cm-1
) 2976, 1692, 1634, 1558, 1496, 1414, 1352,
1249, 1165, 1125, 1012; HRMS (ESI) m/z calculated for C26H28N4O4F3 [M + H]+
:
517.2063; found 517.2065 (0.3867 ppm).

149
Investigating bis-difluoromethylated byproduct
During the optimization of difluoromethylation conditions for model substrate 2a,
the bisdifluoromethylated byproduct was observed by 19F NMR. However, attempts to
isolate this byproduct were not successful. To ascertain the dimerization feasibility,
various other substrates were investigated. 3-Bromopyrido[2,3-d]pyridazin-8(7H)-one
2p provided isolable bisdifluoromethylated product 16p. Based on 1H, 13C NMR, and
HRMS data, the structure of 16p was assigned. A plausible mechanism for the
formation of this byproduct could start with the formation of N-CF2H product 5p (Step
1). Then, the deprotonated substrate A attacks the carbon center of the carbonyl of 5p
(Step 2). The resulting intermediate B attacks on difluorocarbene followed by a
protonation to afford the bis-difluoromethylated product 16p (Step 3).
16p
Performed on 5.0 mmol scale. Eluted with 75% EtOAc in hexanes to afford 16p (15.4
mg, 0.5% isolated yield). Yellow oil.
1H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 2.13 Hz, 1H), 8.86 (d, J = 1.99 Hz, 1H),
8.18 (d, J = 2.07 Hz, 1H), 8.09 (d, J = 1.94 Hz, 1H), 8.07 (d, J = 2.65 Hz, 1H), 7.99 (s,
1H), 7.26 (t, J = 71.76 Hz, 1H), 6.67 (t, J = 60.34 Hz, 1H); 19F NMR (376 MHz, CDCl3)
δ -87.00 (dd, J = 172.67, 72.40 Hz, 1F), -89.15 (dd, J = 172.64, 71.13, 1F), -96.63 (dd,

150
J = 217.13, 61.19 Hz, 1F), -101.13 (dd, J = 216.99, 59.56 Hz, 1F); 13C NMR (126 MHz,
CDCl3) δ 158.2, 157.2, 156.1, 153.1, 141.6, 137.4, 137.2, 136.8, 135.8, 136.5, 127.8,
126.8, 126.3, 124.3, 115.0 (d, J = 249.99 Hz), 113.9 (d, J = 259.68 Hz); FT-IR (v
-1
cm1
) 3093, 2851, 2262, 1683, 1457, 1339, 1200, 1101, 1029; HRMS (ESI) m/z calculated
for C16H8Br2F4N6O2Na [M + Na]
+
: 579.8909; found 579.8930 (3.6214 ppm).
Proposed Mechanism of the formation of 16p

151
Chapter 4
Synthesis of difluoromethylated formimidamides from primary aryl amines using
TMSCF2Br as a dual C1 synthon
4.1 Introduction
The addition of groups containing one carbon atom is a prevalent strategy in the
production of liquid fuels, pharmaceutical molecules, and chemical building blocks.
396–
398 These transformations are generally performed using CO,399 CO2,
400,401 CH3OH,402
and CH4
398,403 as C1 (one carbon atom-containing) synthons.404 Prevalent examples
include the industrial production of formaldehyde from methanol405 and the FischerTropsch process to produce diesel from syngas (CO and H2).399 Despite the increasing
relevance of this chemistry, the scope of inexpensive and abundant C1 sources that can
lead selectively to target products is limited. As such, the development of novel C1
synthons and related methods constitutes an urgent need. Singlet difluorocarbene is one
such synthon, which can be conveniently generated in-situ from a host of different
reagents.131,406 Electrophilic difluoromethylation of nucleophilic substrates using
difluorocarbene has become increasingly popular over the past 10 years.
407–411
Although less explored, difluorocarbene has also been used to generate vinyl fluoridetype intermediates via an alpha-fluoride elimination (Scheme 1, Pathway B), which
are subsequently employed as electrophiles. This overall process allows the coupling
of two nucleophiles, linked via a single carbon.
408,412

152
Scheme 4.1 Reaction pathways of difluorocarbene as C1 source
TMSCF2Br, first efficiently synthesized by our group,362 and further developed by
Hu and coworkers,111,137,410,413 is an inexpensive, and versatile singlet difluorocarbene
precursor. It has been implemented in various types of difluoromethylenation reactions
such as [2+1] cycloaddition with alkenes/alkynes and electrophilic difluoromethylation
of nucleophiles.
112,137,143,414 Even though TMSCF2Br has been utilized through pathway
A (Scheme 4.1), interestingly, a reaction involving TMSCF2Br via pathway B is not
reported in the literature. Herein, we propose a method that utilizes primary aryl amines
in combination with TMSCF2Br as a dual C1 source to prepare N-difluoromethylated
formimidamides. Formimidamides are important chelating ligands in organometallic
chemistry and are useful building blocks in drug design.415 Previous work (Scheme 4.2)
employed ClCF2H, an ozone-depleting greenhouse gas, which produced a mixture of
E- and Z-isomers. The long reaction times (36 hours) and the use of excess ClCF2H
(especially considering its industrial production is restricted) reduce the method’s
applicability.408 In contrast, our method is Freon-free, faster (1 hour reaction time), and
stereoselective for the formation of E isomer.

153
Scheme 4.2 Prior art on the synthesis of difluoromethylated formimidamides with
difluorocarbene
4.2 Results and discussion
Previous literature has shown that anilines can react with difluorocarbene under
basic conditions to generate an N-CF2H species which can undergo defluorination in
the presence of catalytic S8.
409 We envisioned that introducing other Lewis acids could
also facilitate the desired defluorination. Thus, we chose p-toluidine as the model
substrate, and BF3-etherate as the initial Lewis acid due to its strong affinity toward
fluoride.416 At 60oC in ACN, using LiOH as the base (Table 4.1, trial 1) provided 12%
of the target product 2a in five hours. The addition of TMSCF2Br in one portion led to
an uncontrolled exothermic reaction with marked effervescence. To circumvent this,
TMSCF2Br was added dropwise via syringe pump. Further screening of bases revealed
that Na2CO3 was the optimal base which afforded 48% conversion by NMR (Table 4.1,
trial 2, and 3). Varying the reaction temperature did not improve the yields. Reducing
the reaction time led to a higher yield, which indicates that under the reaction conditions,
the product may decompose over time (Table 4.1, trial 5). Further optimization of the
stoichiometry showed that 0.5 equivalents of Na2CO3, 0.15 equivalents of BF3-etherate
and 1.75 equivalents of TMSCF2Br in ACN at 60oC produced the highest yield of 2a

154
(77%) in one hour (Table 4.1, trial 4, 6, and 7). Replacing BF3-etherate with the other
Lewis acids such as Ga(OTf)3 or B(OiPr)3 dramatically lowered the yields (Table 4.1,
trial 8, and 9). Interestingly, even when BF3-etherate was excluded from the reaction
(Table 4.1, trial 10), 2a was obtained in similar yields to trial 7. We hypothesize that
the TMS group of TMSCF2Br could also serve as a Lewis acid. Extension of this
method to other substrates showed a substrate-specific dependance of the reaction’s
success on the presence of BF3, which will be discussed further below.
Interestingly, the corresponding 19F signal of the difluoromethylated
formimidamide 2a appeared as a broad singlet instead of the expected doublet. The
Table 4.1 Optimization Experiments for 2aa
trial Base (equiv) Time (h) Lewis Acid (equiv) TMSCF2Br (equiv) Yield (%)b
1 LiOH (4.0) 5 BF3-ether (1.1) 2.0 12
2 Na2CO3 (4.0) 5 BF3-ether (1.1) 2.0 48
3 K2CO3 (4.0) 5 BF3-ether (1.1) 2.0 30
4 Na2CO3 (1.1) 5 BF3-ether (1.1) 2.0 45
5 Na2CO3 (1.1) 1 BF3 ether (1.1) 2.0 60
6 Na2CO3 (0.5) 1 BF3-ether (0.5) 2.0 62
7 Na2CO3 (0.5) 1 BF3-ether (0.15) 1.75 77

155
8 Na2CO3 (0.5) 1 B(Oipr)3 (0.15) 1.75 15
9 Na2CO3 (0.5) 1 Ga(OTf)3 (0.15) 1.75 21
10 Na2CO3 (0.5) 1 - 1.75 75
aReaction performed at 0.5 mmol scale. bYields were determined by 19F NMR using PhCF3 as an internal standard.
previously reported 19F NMR of the isolated difluoromethylated formimidamide
showed a similar broad peak for this isomer. However, the literature did not distinguish
the isomers. To further investigate this unexpected peak shape, a VT-NMR study was
conducted on model substrate 2a.
Figure 4.1 19F NMR signal of 2a at various temperatures (0.05M in toluene). All spectra
are referenced to PhCF3 as an internal standard
At -60 ◦C, we observe a well-defined doublet at -101.3 ppm (61.3 Hz) by 19F NMR
(Figure 4.1). On increasing the temperature past -45 ◦C, this signal broadens to a broad
singlet at around -11 ◦C. On further increasing the temperature, this broad signal slowly

156
sharpens and is observed to resolve into a clear doublet (-98.6 ppm, 61.1 Hz).
Figure 4.2. Proposed intramolecular hydrogen-bonding of 2a under different
temperatures
We tentatively attribute this phenomenon to a weak five-membered intramolecular
hydrogen-bonding interaction between the N-CF2H moiety and the other N atom at low
temperature (Figure 4.2). We propose that at lower temperatures (-60 ◦C to -45 ◦C), the
molecule is in a “locked” state (Figure 4.2, State 1), in which free rotation of the
highlighted N-CF2H bond and iminyl C-N bond is restricted due to the weak fivemembered intramolecular hydrogen-bonding. Increasing temperature (-35 ◦C to 35 ◦C)
overcomes this weak interaction. Thus, the N-CF2H bond can rotate freely, while the
rotation of the iminyl C-N bond is still restricted, which means the molecule is in a
“mixed” state of restricted and free rotation (Figure 4.2, State 2). The broadness of the
peak is due to slow exchange between the two states on NMR time scale. Further
elevating temperature (45 ◦C to 60 ◦C), however, the rotational barrier of the iminyl CN bond is also overcome, enabling free rotation of both N-CF2H and iminyl C-N bond
(Figure 4.2, State 3). In addition, the chemical shift difference (2.70 ppm) of the target

157
Scheme 4.3 Substrate Scopea
aReactions performed at 0.5 mmol scale for isolated yield with standard conditions. Yields within
parentheses were determined by 19F NMR using PhCF3 as an internal standard. bReaction performed at
5 mmol scale. cBF3-etherate was not added. See Experimental section.
peak in 19F NMR while varying the temperature also indicates exchange between the
States 1 and 3. A small amount of Z-isomer can also be seen between -25 ◦C and 25 ◦C
in the spectrum (Figure 4.2).
Notably, the E-isomer was not stable over conventional silica gel used for
chromatographic isolation: it isomerized into the Z-isomer, which further degraded into
formaldehyde (observed by GC-MS and 19F NMR). We propose that this degradation

158
is effected by the interaction of silica gel with the basic N atoms. To circumvent this,
3% Et3N in hexanes solution was used as the mobile phase in order to quench the Lewis
acidic centers of the silica gel during isolation. As a result, the target E-isomers were
obtained without decomposition or interconversion.
The model substrate 1a provided 70% and 81% of 2a at 0.5 mmol scale and 5 mmol
scale, respectively (Scheme 4.3). Similarly, m-toluidine 1b, afforded the target
compound 2b in good yield. Aryloxy- and alkoxysubstituted products 2c and 2d,
respectively, were isolated in modest and excellent yields. t-Butyl-substituted substrate
1e yielded 86% of 2e. Halogenated anilines 1f, 1g, and 1h furnished the corresponding
products 2f, 2g, and 2h in good yields. Surprisingly, 4-bromoaniline did not react under
the standard conditions. Difluoromethoxylated substrate 1i was transformed into
derivative 2i in 33% isolated yield. Notably, the ethynyl moiety of 1j was left unreacted,
despite the well documented reactivity of alkynes with difluorocarbene. Interestingly,
carbonyl-containing ester substrate 1k only afforded target product 2k when BF3-
etherate was excluded from the reaction system. The presence of BF3-etherate lead to a
side reaction between the carbonyl groups and BF3 followed by nucleophilic attack
from the primary amino groups of the anilines. Even though sulfone-containing
substrate 1l gave 56% of 2l (detected by 19F NMR), the product decomposed during
isolation. Benzyl amine 1m also yielded 33% of 2m by 19F NMR, but it similarly
decomposed during isolation.

159
Scheme 4.4 Substrate Scopea
aReactions performed at 0.5 mmol scale for isolated yield with standard conditions. Yields within
parentheses were determined by 19F NMR using PhCF3 as an internal standard.
Difluoromethylated-benzimidazoles 2n and 2o (Scheme 4.4) were also furnished
in modest yields from 1,2-diaminobenezenes via an intramolecular nucleophilic attack
on the N-fluoroiminium intermediate discussed previously (Scheme 4.1, pathway B).
Scheme 4.5 Proposed Mechanism (L.A. = BF3/TMS)
Our proposed mechanism for the reaction is depicted in Scheme 4.5 First,

160
TMSCF2Br is activated by a nucleophile such as carbonate or bicarbonate to form the
singlet difluorocarbene. The primary amine R-NH2 performs a nucleophilic attack on
difluorocarbene followed by a 1,2-proton transfer to afford intermediate A under basic
conditions. Then, A undergoes a defluorination in the presence of BF3-etherate and
generates N-formimidoyl fluoride intermediate B which undergoes additionelimination with another R-NH2 to give C. Intermediate C proceeds with another
nucleophilic attack to difluorocarbene followed by 1,2-proton transfer to furnish the
final product D.
4.3 Conclusion
In conclusion, the developed method presents the potential of TMSCF2Br as a C1
synthon via alpha-fluoride elimination to generate N-difluoromethylated
formimidamides under mild conditions. In contrast to the previous method, the Eisomer can be selectively obtained simply by adding Et3N to the mobile phase during
column chromatography to prevent isomerization and decomposition. Additionally, our
work circumvents the use of Freons, which makes this approach much more attractive
for wider applications.
4.4 Experimental data. General procedures and characterization data
Substrate 1 (1.0 equiv, 0.5 mmol) and Na2CO3 (0.5 equiv, 0. 25 mmol, 26.5 mg)
were added into an oven-dried vial under argon. Then, ACN (2 mL) and BF3-etherate
(0.15 equiv, 0.075 mmol, 10 µL) were added successively under N2 at room temperature,
and the solution was stirred at 60oC (oil bath) for 10 min. Next, TMSCF2Br (1.75 equiv,

161
0.875 mmol, 135 µL) was added into the solution dropwise (the addition was complete
in 7 min), and the solution was stirred at 60oC for 1 h. Subsequently, the reaction
mixture was cooled to room temperature, and diluted with DCM (20 mL) and water (20
mL). The organic phase was collected, and the aqueous phase was extracted again with
DCM (2 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL) and
dried with Na2SO4. Then the drying agent was filtered, and the organic solvent was
removed under reduced pressure. The residue was purified by flash column
chromatography to give products 2.
(E)-N-(difluoromethyl)-N,N'-di-p-tolylformimidamide (2a)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2a (47.8 mg,
70% yield). Reddish brown oil.
1H NMR (500 MHz, CDCl3) δ 7.79 (t, J = 2.78 Hz, 1H), 7.52 (t, J = 61.21 Hz, 1H),
7.25 (s, 4H), 7.11 (d, J = 8.06 Hz, 2H), 6.92 (d, J = 8.21 Hz, 2H), 2.39 (s, 3H), 2.32 (s,
3H). 19F NMR (470 MHz, CDCl3) δ -98.34 (br s). 13C NMR (126 MHz, CDCl3) δ 149.1,
147.1, 138.4, 134.2, 133.9, 130.2, 129.9, 127.6, 121.0, 110.4 (t, J = 243.7 Hz), 21.2,
21.0. FT-IR (ν
-1
cm-1
) 3034, 2922, 1644, 1606, 1507, 1424, 1370, 1341, 1316, 1285,
1203, 1170, 1098, 1074, 1069, 1045, 1040, 1023, 1011, 815, 788, 732. Elemental
Analysis Anal. calcd for C16H16F2N2: C, 70.06; H, 5.88; N, 10.21; found: C, 70.19; H,

162
6.22; N, 9.87.
(E)-N-(difluoromethyl)-N,N'-di-m-tolylformimidamide (2b)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2b (34.7 mg,
51% yield). Reddish brown oil.
1H NMR (500 MHz, CDCl3) δ 7.82 (t, J = 2.87 Hz, 1H), 7.55 (t, J = 61.11 Hz, 1H),
7.43 – 7.31 (m, 1H), 7.21 – 7.17 (m, 4H), 6.95 (d, J = 7.54 Hz, 1H), 6.85 – 6.82 (m,
2H), 2.40 (s, 3H), 2.34 (s, 3H). 19F NMR (470 MHz, CDCl3) δ -98.48 (br s). 13C NMR
(126 MHz, CDCl3) δ 149.6, 149.2, 139.7, 139.1, 136.5, 129.4, 129.1, 129.1, 128.1,
125.5, 124.5, 122.0, 118.3, 110.3 (t, J = 244.21 Hz), 21.49, 21.47. FT-IR (v
-1
cm-1
)
3278, 3271, 3037, 2921, 2859, 1645, 1600, 1585, 1489, 1457, 1402, 1370, 1289, 1237,
1199, 1152, 1127, 1111, 1100, 1094, 1079, 1071, 1063, 1053, 1043, 1033, 1021, 935,
893, 833, 775, 720, 697, 639, 622, 608, 583, 548, 532, 509, 503, 495, 476, 464, 458.
Elemental Analysis Anal. calcd for C16H16F2N2: C, 70.06; H, 5.88; N, 10.21; found: C,
69.86; H, 6.03; N, 9.85.

163
(E)-N,N'-bis(4-(4-chlorophenoxy)phenyl)-N-(difluoromethyl)formimidamide (2c)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2c (41.6 mg,
33% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.82 (t, J = 2.43 Hz, 1H), 7.59 – 7.33 (m, 5H), 7.29 –
7.26 (m, 2H), 7.07 – 6.90 (m, 10H). 19F NMR (470 MHz, CDCl3) δ -98.04 (br s). 13C
NMR (126 MHz, CDCl3) δ 157.4, 156.7, 155.2, 153.9, 149.0, 145.6, 131.3, 130.1,
129.8, 129.7, 129.3, 128.0, 122.5, 120.9, 120.2, 119.6, 119.2, 110.5 (t, J = 243.93 Hz).
FT-IR (
-1
cm-1
) 3041, 2848, 2125, 1664, 1604, 1588, 1499, 1481, 1427, 1235, 1199,
1165, 1127, 1085, 1066, 1056, 1045, 1037, 1025, 1010, 826, 735, 631, 596, 568, 523,
513, 501. Elemental Analysis Anal. calcd for C26H18Cl2F2N2O2: C, 62.54; H, 3.63; N,
5.61; found: C, 62.69; H, 3.68; N, 5.98.
(E)-N-(difluoromethyl)-N,N'-bis(4-methoxyphenyl)formimidamide (2d)
Performed on 0.5 mmol scale, eluted with 3% Et3N in 1% EtOAc in Hexane to afford

164
2d (65.6 mg, 86% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.76 (t, J = 2.76 Hz, 1H), 7.47 (t, J = 61.57 Hz, 1H),
7.29 (d, J = 8.82 Hz, 2H), 6.96 (dd, J = 8.80 Hz, 4.78 Hz, 4H), 6.85 (d, J = 8.84 Hz,
2H), 3.83 (s, 3H), 3.79 (s, 3H). 19F NMR (470 MHz, CDCl3) δ -98.22 (br s). 13C NMR
(126 MHz, CDCl3) δ 159.6, 157.0, 148.9, 142.9, 129.7, 128.9, 122.0, 114.7, 114.5,
110.4 (t, J = 243.12 Hz), 55.6, 55.6. FT-IR (v
-1
cm-1
) 3004, 2914, 2836, 1641, 1505,
1464, 1442, 1401, 1372, 1346, 1241, 1203, 1179, 1129, 1098, 1074, 1062, 1052, 1014,
883, 829, 795, 743, 715, 689, 569, 537. Elemental Analysis Anal. calcd for
C16H16F2N2O2: C, 62.74; H, 5.27; N, 9.15; found: C, 63.13; H, 5.44; N, 9.45.
(E)-N,N'-bis(4-(tert-butyl)phenyl)-N-(difluoromethyl)formimidamide (2e)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2e (77.1 mg,
86% yield). Reddish brown oil.
1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.70 – 7.45 (m, 3H), 7.34 – 7.29 (m, 4H),
6.97 (d, J = 8.37 Hz, 2H), 1.35 (s, 9H), 1.32 (s, 9H). 19F NMR (470 MHz, CDCl3) δ -
98.63 (br s). 13C NMR (126 MHz, CDCl3) δ 151.3, 149.2, 147.6, 147.0, 133.9, 127.1,
126.5, 126.1, 120.8, 110.3 (t, J = 243.75), 34.8, 34.5, 31.6, 31.4.
The NMR data obtained agreed with literature report.
408

165
(E)-N-(difluoromethyl)-N,N'-bis(4-fluorophenyl)formimidamide (2f)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2f (47.4 mg,
67% yield). Reddish brown solid. Mp: 84 oC – 86 oC.
1H NMR (500 MHz, CDCl3) δ 7.77 (t, J = 2.52 Hz, 1H), 7.42 (t, J = 60.95 Hz, 1H),
7.37 – 7.34 (m, 2H), 7.16 – 7.13 (m, 2H), 7.01 – 6.94 (m, 4H). 19F NMR (470 MHz,
CDCl3) δ -97.93 (br s, 2F), -113.11 (m, 1F), -119.73 (m, 1F). 13C NMR (126 MHz,
CDCl3) δ 162.5 (d, J = 257.33 Hz), 159.5 (d, J = 251.0 Hz), 149.0, 145.5, 132.0 (d, J =
3.23 Hz), 130.1 (d, J = 8.73 Hz), 122.4 (d, J =8.12 Hz), 116.6 (d, J = 22.84 Hz), 116.0
(d, J = 22.49 Hz), 110.4 (t, J = 244.38 Hz). FT-IR (ν
-1
cm-1
) 3058, 2946, 1653, 1599,
1501, 1426, 1386, 1344, 1294, 1253, 1213, 1173, 1152, 1126, 1092, 1074, 1062, 1055,
1043, 1037, 1028, 1010, 991, 954, 944, 884, 838, 827, 802, 742, 715, 701, 689, 590,
554, 543, 522, 505, 475. Elemental Analysis Anal. calcd for C14H10F4N2: C, 59.58; H,
3.57; N, 9.93; found: C, 59.56; H, 3.68; N, 9.69.

166
(E)-N,N'-bis(4-chlorophenyl)-N-(difluoromethyl)formimidamide (2g)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2g (54.4 mg,
69% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.77 (t, J = 2.53 Hz, 1H), 7.57 – 7.24 (m, 7H), 6.92 (d,
J = 8.68 Hz, 2H). 19F NMR (470 MHz, CDCl3) δ -97.86 (br s). 13C NMR (126 MHz,
CDCl3) δ 148.8, 147.9, 134.6, 134.5, 130.3, 129.9, 129.4, 129.0, 122.5, 110.4 (t, J =
245.32 Hz). FT-IR (ν
-1
cm-1
) 3272, 2850, 2157 1989, 1643, 1589 1486, 1418, 1372
1341, 1308 1283, 1256, 1205, 1180, 1168, 1127, 1106, 1091, 1083, 1071, 1062, 1056,
1052, 1043, 1011 883, 828 790, 771 746, 673, 639, 519, 500. Elemental Analysis Anal.
calcd for C14H10Cl2F2N2: C, 53.36; H, 3.20; N, 8.89; found: C, 53.08; H, 3.55; N, 8.95.
(E)-N,N'-bis(3-bromophenyl)-N-(difluoromethyl)formimidamide (2h)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2h (58.1 mg,
57% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.59 – 7.28 (m, 3H),7.52 (s, 2H), 7.24 –
7.14 (m, 3H), 6.93 (d, J = 6.98 Hz, 1H). 19F NMR (470 MHz, CDCl3) δ -98.18 (br s).

167
13C NMR (126 MHz, CDCl3) δ 150.6, 149.0, 137.4, 131.7, 130.9, 130.6, 130.6, 127.9,
126.1, 124.2, 123.0, 122.9, 120.3, 110.2 (t, J = 245.87 Hz). FT-IR (ν
-1
cm-1
) 2916, 2849,
1703, 1644, 1582, 1476, 1420, 1340, 1289, 1244, 1201, 1180, 1131, 1097, 1090, 1080,
1072, 1064, 1052, 1047, 1037, 1023, 995, 869, 822, 777, 741, 696. Elemental Analysis
Anal. calcd for C14H10Br2F2N2: C, 41.62; H, 2.49; N, 6.93; found: C, 41.92; H, 2.13; N,
6.88.
(E)-N,N'-bis(4-(difluoromethoxy)phenyl)-N-(difluoromethyl)formimidamide (2i)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2i (30.8 mg,
33% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.79 (t, J = 2.18 Hz, 1H), 7.43 (t, J = 60.84 Hz, 1H),
7.38 (d, J = 8.85 Hz, 2H), 7.21 (d, J = 8.85 Hz, 2H), 7.07 (d, J = 8.79 Hz, 2H), 6.99 (d,
J = 8.81, 2H), 6.69 – 6.32 (m, 2H).
19F NMR (470 MHz, CDCl3) δ -81.12 (d, J = 73.94
Hz, 2F), -81.82 (d, J = 73.13 Hz, 2F), -97.87 (br s, 2F). 13C NMR (126 MHz, CDCl3)
δ 150.9 (t, J = 2.88 Hz), 149.0, 148.3 (t, J = 2.87 Hz), 146.9, 133.2, 129.5, 122.3, 120.8,
120.7, 116.2 (t, J = 259.84 Hz), 115.7 (t, J = 261.31 Hz), 110.5 (t, J = 245.16 Hz). FTIR (ν
-1
cm-1
) 3296, 3281, 3268, 2922, 1646, 15j04, 1430, 1379, 1291, 1258, 1198, 1109,
1102, 1094, 1085, 1079, 1071, 1064, 1059, 1050, 1043, 1036, 1021, 888, 834, 769, 750.

168
Elemental Analysis Anal. calcd for C16H12F6N2O2: C, 50.8; H, 3.20; N, 7.41; found: C,
50.95; H, 3.00; N, 7.12.
(E)-N-(difluoromethyl)-N,N'-bis(4-ethynylphenyl)formimidamide (2j)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2j (45.2 mg,
61% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.83 (t, J = 2.59 Hz, 1H), 7.63 – 7.44 (m, 3H), 7.43 –
7.38 (m, 2H), 7.29 – 7.26 (m, 2H), 7.16 – 7.15 (m, 1H), 7.04 – 7.02 (m, 1H),
3.16 (s, 1H), 3.08 (s, 1H). 19F NMR (470 MHz, CDCl3) δ -98.22 (br s). 13C NMR (126
MHz, CDCl3) δ 149.4, 149.1, 136.4, 132.1, 130.9, 129.7, 129.3, 128.6, 128.0, 124.5,
123.9, 123.1, 122.4, 110.3 (t, J = 245.47 Hz), 83.5, 82.4, 78.8, 77.4. FT-IR (ν
-1
cm-1
)
3285, 3238, 2917, 2369, 2165, 2155, 2139, 2022, 2007, 1949, 1644, 1593, 1574, 1482,
1439, 1372, 1340, 1289, 1229, 1188, 1142, 1113, 1103, 1095, 1079, 1067, 1057, 1046,
1037, 1030, 1022, 939, 889, 782, 718, 631. Elemental Analysis Anal. calcd for
C18H12F2N2: C, 73.46; H, 4.11; N, 9.52; found: C, 73.08; H, 4.35; N, 9.62.

169
Ethyl (E)-4((((difluoromethyl)(4-
(ethoxycarbonylphenyl)amino)methylene)amino)benzoate (2k)
Performed on 0.5 mmol scale, eluted with 3% Et3N in Hexane to afford 2k (21.3 mg,
22% yield). colorless oil.
1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 8.62 Hz, 2H), 8.01 (d, J = 8.55 Hz, 2H),
7.92 (t, J = 2.51 Hz, 1H), 7.55 (t, J = 60.43 Hz, 1H), 7.45 (d, J = 8.62 Hz, 2H), 7.05 (d,
J = 8.5 Hz, 2H), 4.42 – 4.34 (m, 4H), 1.42 – 1.38, (m, 6H). 19F NMR (470 MHz, CDCl3)
δ -98.43 (br s). 13C NMR (126 MHz, CDCl3) δ 166.5, 165.7, 153.3, 148.8, 140.2, 131.1,
130.2, 127.1, 126.6, 126.2, 121.2, 110.4 (t, J = 246.44 Hz), 61.5, 61.0, 14.5, 14.5. FTIR (ν
-1
cm-1
) 2979, 2931, 2910, 2871, 2123, 1709, 1645, 1594, 1509, 1464, 1431, 1413,
1367, 1306, 1268, 1206, 1166, 1108, 1096, 1086, 1073, 1065, 1056, 1046, 1037, 1030,
1021, 889, 855, 770, 745, 729, 701, 666. Elemental Analysis Anal. calcd for
C20H20F2N2O2: C, 61.53; H, 5.16; N, 7.18; found: C, 61.39; H, 5.48; N, 7.52.

170
5,6-dichloro-1-(difluoromethyl)-1H-benzo[d]imidazole (2l)
Performed on 0.5 mmol scale, eluted with 20% EtOAc in hexane to afford 2l (30.2 mg,
25% yield). Yellow solid. Mp: 92 – 93 oC.
1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 7.28 (t, J = 60.09
Hz, 1H). 19F NMR (470 MHz, CDCl3) δ –94.37 (d, J = 59.87 Hz). 13C NMR (126 MHz,
CDCl3) δ 143.3, 140.7, 129.5, 129.3, 128.8, 122.3, 112.8 (t, J = 1.65 Hz), 108.7 (t, J =
251.55 Hz). FT-IR (ν
-1
cm-1
) 3103, 1508, 1438, 1402, 1364, 1311, 1295, 1234, 1225,
1202, 1123, 1098, 1060, 1052, 1046, 1032, 1022, 876, 866, 845, 810, 729, 659, 628,
535. Elemental Analysis Anal. calcd for C8H4Cl2F2N2: C, 40.54; H, 1.70; N, 11.82;
found: C, 40.93; H, 1.68; N, 11.47.
5(6)-bromo-1-(difluoromethyl)-1H-benzo[d]imidazole (2m)
Performed on 0.5 mmol scale, eluted with 20% EtOAc in Hexane to afford 2m (42.6
mg, 32% yield). Yellow oil.
1H NMR (500 MHz, CDCl3) δ [8.09 (d, J = 7.76 Hz), 7.99 (d, J = 1.59 Hz), 7.78 (d, J
= 1.86 Hz), 7.70 (d, J = 8.64 Hz), 7.52 – 7.48 (m), 4H], [7.30 (td, J = 60.25 Hz, 7.19
Hz, 1H]. 19F NMR (470 MHz, CDCl3) δ -94.30 (d, J = 60.38 Hz). 13C NMR (126
MHz, CDCl3) δ 145.4, 143.1, 140.2, 139.7, 131.6, 129.6, 128.1, 127.9, 124.1, 122.4,
118.4, 117.4, 114.6 (t, J = 1.62 Hz), 112.5 (t, J = 1.50 Hz), 109.0 (t, J = 250.8 Hz),

171
108.9 (t, J = 251.0 Hz). FT-IR (ν
-1
cm-1
) 3086, 2117, 1736, 1612, 1504, 1412, 1358,
1284, 1203, 1142, 1030, 899, 864, 806, 683, 629. Elemental Analysis Anal. calcd for
C8H5BrF2N2: C, 38.9; H, 2.04; N, 11.34; found: C, 39.15; H, 2.27; N, 11.04.

172
Chapter 5
Access to 2-Halofluorobicyclo[1.1.1] pentanes via Non Ozone-depleting Ethyl
Dihalofluoroacetate
5.1 Introduction
Incorporating [1.1.1]bicylcopentane (BCP) moieties into pharmaceutical
molecules as bioisosteres for phenyl,417–419 t-butyl,420,421 and alkynyl422 groups has
emerged as an important reaction paradigm in the past decade. It has been shown that
BCP-modification in drug candidates can significantly enhance the physicochemical
properties such as aqueous solubility, metabolic stability, passive permeability, threedimensional character (Fsp3
), and reduce non-specific binding.
417,423–426 Therefore,
synthetic methods to functionalized BCPs have attracted an increasing attention and
interest.427–430
Furthermore, introducing fluorine-containing moieties, such as -CF3, -CF2H, and -
CFH2, have been demonstrated to be a successful and ubiquitous strategy to modify
biopharmaceutical properties such as metabolic stability and lipophilicity.7,99,339,393,394
For example, the difluoromethyl group (-CF2H) is employed as a bioisostere for -SH
and -OH functional groups.343 It can be easily envisioned that fluorinated BCPs possess
important roles in fine-tuning and expanding the biopharmaceutical profiles of drug
molecules.
Compared to the well adopted 1,3-fluoroalkylated BCPs commonly prepared from
[1.1.1]propellane, approaches to 2-fluorinated BCPs are scarce in literature. In 2001,
Michl and coworkers reported a fluorination of bicylco[1.1.1]pentane-1,3-dicarboxylic

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acid under fluorine gas with a low yield (7%) (Scheme 5.1 a).
431 In 2019, Mykhailiuk’s
and Ma’s group have independently reported efficient methods for the preparation of
2,2-difluorobicyclo[1.1.1]pentane via cycloaddition of bicyclo[1.1.0]butanes (BCBs)
with difluorocarbene (:CF2) generated from TMSCF3 and FSO2CF2CO2TMS,
respectively (Scheme 5.1 b & c).
432,433 In addition, Mykhailiuk and coworkers have
further developed a synthetic route to 2,2-bromofluoro-bicyclo[1.1.1]pentanes from
BCBs and halon CHFBr2 as the bromofluorocarbene source (Scheme 5.1 d).
434
Scheme 5.1 Synthetic methods to 2-fluorinated BCPs

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However, this method is limited by the use of ozone-depleting halofluoromethanes
(Halons), which have been banned for industrial usage by the Montreal Protocol. It also
suffers from long reaction times (~ 3 days), and low yields to 2,2-chlorofluoro-BCPs
(< 20%), which leave a considerable space for improving this method for drug
screening purposes.
Unlike with difluorocarbene, there are very few halofluorocarbene precursors,
making it difficult to avoid halons in their generation. Recently, in 2021, Hu and
coworkers disclosed TMSCFBr2 and TMSCFCl2 as :CFBr and :CFCl sources for
cycloaddition reactions.435 However, these reagents are not commercially available, and
the synthesis of the reagents requires very low temperature (-70 oC), and employs
ozone-depleting CFBr3 and CFCl3. In 2022, our group documented a non-ozone
depleting and bench-stable method using ethyl dibromofluoroacetate (EDBFA) and
ethyl dichlorofluoroacetate (EDCFA) as halofluorocarbene precursors.436,437 To extend
the scope of this reaction system, we explored the cycloaddition reaction of EDBFA
and EDCFA with BCBs, and herein report a fast (30 minutes), non-ozone depleting,
inexpensive, and commercially available method to 2,2-chlorofluoro- and
bromofluorinated BCPs (Scheme 5.1 e).
5.2 Results and discussion
The initial trial with EDBFA, model substrate 1a, and NaOEt as an activator in
DCM provided 54% of target 2,2-bromofluorinated BCP product 2a at room
temperature in 2.5 hours (Table 5.1, trial 1). Further optimization on solvents
demonstrated that THF was the optimal solvent, in which 6a was afforded in 72% yield

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(Table 5.1, trail 2 – 7). Extending reaction time did not increase the yield (Table 5.1,
trial 8), while shortening the reaction time to 30 minutes (Table 5.1, trial 9) led to a
similar yield (69%). Interestingly, the reaction was found to be sensitive to activator
Table 5.1 Optimization of the reaction conditionsa
Trial Solvent Time (h) activator Yield (%)b
1 DCM 2.5 NaOEt 54
2 Toluene 2.5 NaOEt 30
3 Benzene 2.5 NaOEt 45
4 THF 2.5 NaOEt 72 (65)
5 ACN 2.5 NaOEt 56
6 2Me-THF 2.5 NaOEt 64
7 1,4-dioxane 2.5 NaOEt 50
8 THF 16 NaOEt 70
9 THF 0.5 NaOEt 69
10 THF 0.5 KOEt 12
11 THF 0.5 NaO-tBu 0
12 THF 0.5 NaF 0
13c THF 0.5 NaOEt 71
14d THF 0.5 NaOEt 88 (53)
aReactions were performed on 0.3 mmol scale (1a) in 0.45 mL of the solvents (0.67 M) with EDBFA (2.0

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equiv) and activators (2.3 equiv). Yields were determined by 19F NMR spectroscopy using PhF as an
internal standard. b
Isolated yield is given in parentheses.
cThe reaction is performed under air with NaOEt
freshly taken from Ar glovebox. dEDCFA was used (2.0 equiv).
identity. Switching to other basic and neutral activators such as KOEt (Table 5.1, trial
10), NaO-tBu (Table 5.1, trial 11), and NaF (Table 5.1, trial 12) significantly deterred
the yields. Despite the hygroscopic nature of NaOEt, the reaction surprisingly produced
similar yields when being performed under air with NaOEt, which was freshly taken
out of the glovebox (Table 5.1, trial 13). Notably, NaOEt exposed to air for a week led
to no yield of the desired product. This means that NaOEt was stable during the reaction
time period, and the reaction itself was not sensitive to oxygen and moisture. However,
if NaOEt degraded into NaOH with moisture or other sodium salts with CO2, impurities
could be introduced as co-activators and could dramatically affect this activatorsensitive reaction. To our delight, the same conditions with EDCFA (Table 5.1, trial
14) afforded 3a in excellent yield (88%).
Scheme 5.2. Substrate scope of 2,2-bromofluorinated BCPs and 2,2-chlorofluorinated
BCPsa
aReactions were performed at 0.5 mmol scale for isolated yield with EDBFA (2 equiv) or EDCFA (2
equiv) and NaOEt (2.3 equiv) in THF (0.67 M) at room temperature in 30 minutes. Yields within
parentheses were determined by 19F NMR using fluorobenzene as an internal standard. bReaction was
performed at 4 mmol scale. c3f was not isolated due to high volatility. d3h was hydrolyzed and isolated
as 4h.
With the optimized conditions in hand, we further explored the method with EDBFA

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and EDCFA on a series of BCBs (Scheme 5.2). Model substrate 1a gave 65% of 2a and
53% of 3a with EDBFA and EDCFA, respectively. Other substituents on the aryl rings
were tested. For example, 2- and 4-methylphenyl substrates 1b and 1c afforded 2b and
2c in moderate yields. Product 3b and 3c were also synthesized in 55% and 49% yields,
respectively. The bromophenyl BCB 1d furnished 41% 2,2-bromofluorinated-BCP and
42% 2,2-chlorofluorinated-BCP. Chlorophenyl substrate 1e also afforded 2e and 3e in
good and moderate yields. Compound 1f yielded 46% of 2f and 36% of 3f by 19F NMR,
which were much lower than the other halogenated substrates. This could be attributed
to an unexpected de-fluorination reaction under strong basic conditions. In addition to
that, 3f was not isolated due to its high volatility (fully evaporated under 325 torr at
room temperature). Strongly electron-withdrawing -CF3 group 1g was also compatible
with EDBFA and EDCFA. Other protection groups such as methyl and benzyl groups
(1h and 1i) were also tolerated under the standard conditions to give synthetic useful
yields. However, 3h was not isolated because it co-eluted with inseparable byproducts
during flash column chromatography. In that case, 3h was hydrolyzed with LiOH•H2O
and isolated as the free carboxylic acid 4h with LiOH•H2O in 66% isolated yield
(Scheme 5.3).
Scheme 5.3 One-pot reaction and deprotection reaction to yield 2,2-halofluoro-BCP

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acids.
Notably, significant loss of products during isolation was observed due to partial
co-elution of target products, inseparable byproducts, and unreacted EDBFA or EDCFA
via flash chromatography. Some fractions were sacrificed to separate the byproducts.
At the same time, EDBFA and EDCFA were removed by exposing the mixture to high
vacuum conditions (20 minutes – 5 hours), but loss of desired products was also
observed. Due to the fact that most of the post-functionalization reactions would
employ the hydrolysed form of the products, an efficient hydrolyses of both 2,2-
bromofluoro and chlorofluoro-BCPs was investigated. Pure 2a was mixed with
LiOH•H2O in THF and H2O for 24 hours at room temperature to furnish the
corresponding carboxylic acid 5a (80% conversion by 19F NMR), which was isolated
without flash chromatography in 76% isolated yield. Moreover, one-pot
halofluorination and deprotection reaction were tolerated and led to carboxylic acids
without purification of ester intermediates, successfully converted substrate 5h to 9h in
66% isolated yield (Scheme 5.3).
To further understand the stability and the potential of the bromofluorinated and
chlorofluorinated BCPs as potent pharmaceutical building blocks with three different

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active sites, a series of post-functionalization reactions were performed on our products.
The resulting carboxylic acid 5a was subjected to common reactions such as CDIcatalysed amide formation with piperidine (6) or morpholine (7), and DMAP-catalysed
N-hydroxyphthalimide ester formation (8) in excellent yields (Scheme 5.4 A-C).
Difluoromethylation of carboxylic acids with TMSCF2Br was also performed on 5a
Scheme 5.4 Post-functionlizations with 2,2-chlorofluoro-, and 2,2-bromofluoro-BCPs
and 4h to provide the difluoromethylated esters 9 and 9’ in synthetically useful yields
(Scheme 5.4 D). The protected product 2h could also go through the Prakash reaction

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via TMSCF3 to afford corresponding trifluoromethylated ketone 10 with 47% yields
based on 19F NMR, which could serve as a reversible covalent warhead for targeting
proteins kinases, such as FGFR and JAK3 (Scheme 5.4 E).
438 However, isolation of the
target trifluoromethylated ketone 10 was not successful due to the rapid hydration of
the product. On the other hand, -Br on the bridge-head position of BCPs was also
proved to be a useful handle for follow-up reactions. The C-Br bond could be activated
by different initiators including blue LED and Et3B-O2, and the generated radical was
trapped by radical acceptors such as 1-benzyl-1H-pyrrole-2,5-dione, and hydrogen
atom (11 and 12) (Scheme 5.4 F & G). The bromophenyl-substituted BCP 3d was
compatible with commonly encountered transformations in drug discovery. For
instance, 3d can react with phenylboronic acid and form the related biphenyl product
13 via Suzuki coupling under microwave conditions in 73% isolated yield (31%
isolated yield over two steps) and Pd-catalyzed C-N bond formation with
difluoromethylated azetidine 14 to afford target product in 61% isolated yield (Scheme
5.4 H & I).

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Scheme 5.5 Kinetic solubility of 2a, 3a, and their analogues. Round up concentrations
and just show two significant figures.
Rigid structure and aromaticity of the benzene ring leads to strong hydrophobicity
and low solubility in aqueous phase. BCP, in contrast, improves physicochemical
profiles when used as a surrogate for benzene rings. Kinetic solubilites of 2-halogensubstituted BCPs, such as 2a, 3a and 2-monofluorinated BCP 12, were measured, and
compared to their bi-aryl counterparts (Scheme 5.5). Indeed, at pH 7.4, all three BCPs
exhibit increased aqueous solubilities compared to bi-aryl analogs (15-17). Notably, dihalogenation at the bridge-head position introduces additional lipophilicity and tunes
to moderate solubility. These data demonstrate a great potential of incorporating 2,2-
bromofluoro-, and 2,2-chlorofluoro-BCPs to fine-tune the balance between solubility
and lipophilicity for screening and developing drug candidates.
5.3 Conclusion
In conclusion, we have developed convenient methods to access both 2,2-
bromofluoro-BCPs and 2,2-chlorofluoro-BCPs without using halons. Both methods
utilize the non-ozone depleting, commercially available, inexpensive, and bench stable

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carbene sources based on EDBFA, and EDCFA. The resulting 2,2-bromofluoro-, and
2,2-chlorofluoro-BCPs proved to be versatile building blocks, which contain three
potential reaction sites for post-functionalizations. Aqueous solubility tests
demonstrated that 2,2-bromofluoro, and 2,2-chlorofluoro-BCPs can be used to modify
physicochemical properties of drug candidates.
5.4 Experimental Data. General procedures and characterization data
General procedures to prepare bicylco[1.1.0]butanes (S5)
General procedure 1A. Step 1-Method A (S2a was used as an example)
Carboxylic acid S1 (1.0 eq, 100.0 mmol, 11.41 g) was added into an oven-dried
flask under argon protection. Then, 140 mL of THF was added at room temperature,
and the mixture was stirred for 2 minutes in a water bath at room temperature. After
that, PhMgCl (2.0 eq, 2.0 M, 100 mL) was slowly added into the solution dropwise (the
addition was complete in 2 hours), and the resulting solution was stirred for 30 minutes
at room temperature. Subsequently, saturated NH4Cl aqueous solution (100 mL) was
slowly added at room temperature, and the mixture was further acidified with
concentrated HCl (pH < 2). The solution was extracted with Et2O (100 mL x 3), and the
combined organic layer was washed with brine (100 mL x 1) and dried with Na2SO4.
Then the drying agent was filtered, and the organic solvent was removed under reduced
pressure. The residue was purified by flash column chromatography, and eluted with

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50% ethyl acetate in hexane to 75% ethyl acetate in hexane to afford S2a (15.1 g, 78.6
mmol, 79%). White solid.
Notes: The major byproduct was about 10% of the corresponding biphenyls, which
could be purified in step 4. S2a was not soluble in conventional organic solvents
including EtOAc, hexanes, DCM, and MeOH (hot MeOH could dissolve S2a, but S2a
crushed out immediately while cooling down. In that case, dry loading was used for
isolation in flash column chromatography.
General procedure 1B. Step 1-Method B (S2d was used as an example)
n-BuLi (2.0 eq, 40.0 mmol, 2.5 M, 16 mL) was added into a solution of 1,4-
dibromobenzene (2.0 eq, 40.0 mmol, 9.44 g) in THF (80 mL) dropwise at -78 oC under
Ar protection (addition was complete in 30 minutes). The mixture was stirred at -78 oC
for 2 hours, and a solution of S1 (1.0 eq, 20.0 mmol, 2.28 g) in THF (20 mL) was added
in one portion at the same temperature. The resulting solution was allowed to warm to
room temperature, and stirred for another 1 hour. Subsequently, saturated NH4Cl
aqueous solution (50 mL) was added at 0 oC in an ice bath to quench the reaction. Water
(50 mL) and Et2O (50 mL) were added into the mixture, and the aqueous layer was
separated, and extracted with Et2O (50 mL x 2). The combined organic layer was dried
with Na2SO4. Then, the drying agent was filtered, and the organic solvent was removed

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under reduced pressure to afford crude S2d (5.23 g, 19.3 mmol, 97% yield) which was
used in the next step without further purification. White solid.
General procedure 2. Step 2 (S3a was used as an example)
S2a (1.0 eq, 78.0 mmol, 15.0 g) was added into an oven-dried flask under air.
Then, 200 mL of concentrated HCl and 200 mL of Toluene were added into flask under
air at room temperature. The solution was stirred vigorously (1200 RPM) at room
temperature for 4 hours. The aqueous layer was separated and extracted with toluene
(50 mL x 2). The combined organic layer was washed with water (100 mL x 1), brine
(100 mL x 1), and dried with Na2SO4. Then the drying agent was filtered, and the
organic solvent was removed under reduced pressure to afford crude product S3a (14.6
g, 69.1 mmol, 89%) which was used in the next step without further purification. White
solid.
General procedure 3A. Step 3-Method A (S4a was used as an example)
DMAP (5 mol%, 2.1 mmol, 257 mg) and crude S3a (1.0 eq, 42 mmol, 8.85 g) was
added into an oven-dried flask under air. Then, 126 mL of THF was added into the flask,

185
and the mixture was stirred for 2 minutes in a water bath at room temperature. Boc2O
(1.2 eq, 50.4 mmol, 11.0 g, 12 mL) was added into the flask, and the resulting solution
was stirred overnight at room temperature. Subsequently, saturated NH4Cl aqueous
solution (50 mL) and Et2O (100 mL) were added, and the aqueous layer was separated
and extracted with Et2O (100 x 2 mL). The combined organic layer was washed with
saturated NaHCO3 aqueous solution (50 mL), brine (50 mL) and dried with Na2SO4.
Then the drying agent was filtered, and the organic solvent was removed under reduced
pressure to afford crude S4a (10.3 g, 39 mmol, 93%) which was used in the next step
without further purification. Colorless liquid.
General procedure 3B. Step 3-Method B (S4h)
S3a (1.0 eq, 12.0 mmol, 2.53 g) and K2CO3 (2.0 eq, 24.0 mmol, 3.32 g) was added into
an oven-dried flask under air. Then, 25 mL of DMF and MeI (1.5 eq, 18.0 mmol, 2.55g,
1.12 mL) was added into the flask, and the resulting mixture was stirred for overnight
at room temperature. Subsequently, the mixture was diluted with EtOAc and water, and
the aqueous layer was separated and extracted with EtOAc (50 mL x 2). The combined
organic layer was washed with brine (50 mL x 5), and dried with Na2SO4. The drying
agent was filtered, and the organic solvent was removed under reduced pressure to
afford S4h (1.91 g, 8.5 mmol, 71% yield) which was used in the next step without
further purification. White solid.

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General procedure 3C. Step 3-Method C (S4i)
S3a (1.0 eq, 12.0 mmol, 2.53 g) and K2CO3 (2.0 eq, 24.0 mmol, 3.32 g) was added
into an oven-dried flask under air. Then, 25 mL of DMF and benzyl bromide (1.1 eq,
13.2 mmol, 2.26 g, 1.6 mL) was added into the flask, and the resulting mixture was
stirred for overnight at room temperature. Subsequently, the mixture was diluted with
EtOAc and water, and the aqueous layer was separated and extracted with EtOAc (50
mL x 2). The combined organic layer was washed with brine (50 mL x 5), and dried
with Na2SO4. The drying agent was filtered, and the organic solvent was removed under
reduced pressure to afford S4i (1.49 g, 4.95 mmol, 41% yield) which was used in the
next step without further purification. Colorless liquid.
General procedure 4. Step 4 (1a was used as an example)
Crude S4a (1.0 eq, 11.0 mmol, 2.93 g) was added into an oven-dried flask under
Ar protection. Then, 44.0 mL of THF was added into the flask, and the resulting mixture
was stirred at 0 oC in an ice bath for 10 minutes. NaHMDS in THF solution (1.2 eq,
13.2 mmol, 1.0 M, 13.2 mL) was slowly added into the solution dropwise at 0 oC (the
addition was complete in 30 minutes), and the resulting solution was stirred for 30

187
minutes at the same temperature. Subsequently, saturated NH4Cl aqueous solution (5
mL), water (50 mL), and DCM (50 mL) was added into the mixture. The aqueous layer
was separated, and extracted with DCM (50 mL x 2). The combined organic layer was
washed with water (50 mL x 1), brine (50 mL x 1), and dried with Na2SO4. Then the
drying agent was filtered, and the organic solvent was removed under reduced pressure.
The residue was purified by flash column chromatography, and eluted with 50% DCM
in hexane afford 1a (2.02 g, 8.76 mmol, 80% yield). White solid.
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 7.36 – 7.22 (m, 5H), 2.90 (s, 2H),
1.57 (s, 2H), 1.05 (s, 1H); The 1H NMR data obtained agreed with literature report.434
Note: The products 1 are not stable in CDCl3. In that case, DMSO-d6 was used as
solvent for NMR data. All of the products 1 were not stable under any HRMS conditions
attempted.
General procedure 5: preparation of 2a-2i (2a was used as an example)
Substrate 1a (1.0 eq, 0.5 mmol, 115.2 mg) and NaOEt (2.3 eq, 1.15 mmol, 78.3 mg)
were added into an oven-dried microwave vial under Ar protection. Then, 0.75 mL of
THF was added at room temperature, and the mixture was stirred for 1 minute. After
that, EDBFA (2.0 eq, 1.0 mmol, 263.9 mg, 140 µL) was added into the solution in one
portion, and the resulting solution was stirred for 30 minutes at room temperature.

188
Subsequently, the reaction mixture was diluted with DCM (10 mL) and saturated NH4Cl
aqueous solution (10 mL). The aqueous layer was separated and extracted with DCM
(20 mL x 2). The combined organic layer was washed with brine (20 mL x 1), and dried
with Na2SO4. Then the drying agent was removed, and the organic solvent was removed
under reduced pressure. The residue was purified by flash column chromatography, and
eluted with 35% DCM in pentane to afford 2a (110.4 mg, 65% isolated yield). Yellow
oil.
General procedure 6: preparation of 3a-3g, and 3i (3a was used as example)
Substrate 1a (1.0 eq, 0.5 mmol, 115.2 mg) and NaOEt (2.3 eq, 1.15 mmol, 78.3 mg)
were added into an oven-dried microwave vial under Ar protection. Then, 0.75 mL of
THF was added at room temperature, and the mixture was stirred for 1 minute. After
that, EDCFA (2.0 eq, 1.0 mmol, 175.0 mg, 135 µL) was added into the solution in one
portion, and the resulting solution was stirred for 30 minutes at room temperature.
Subsequently, the reaction mixture was diluted with DCM (10 mL) and saturated NH4Cl
aqueous solution (10 mL). The aqueous layer was separated and extracted with DCM
(20 mL x 2). The combined organic layer was washed with brine (20 mL x 1), and dried
with Na2SO4. Then the drying agent was removed, and the organic solvent was removed
under reduced pressure. The residue was purified by flash column chromatography, and
eluted with 10% DCM in pentane to afford 3a (79.8 mg, 53% isolated yield). Colorless

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oil.
General Procedure 7: one-pot deprotection of 1h to 4h
Substrate 1h (1.0 eq, 0.25 mmol, 47.1 mg) and NaOEt (2.3 eq, 0.575 mmol, 39.1
mg) were added into an oven-dried microwave vial under Ar protection. Then, 0.4 mL
of THF was added at room temperature, and the mixture was stirred for 1 minute. After
that, EDCFA (2.0 eq, 0.5 mmol, 87.5 mg, 68 µL) was added into the solution in one
portion, and the resulting solution was stirred for 30 minutes at room temperature. After
that, the vial cap was opened, and LiOH·H2O (5.0 eq, 1.25 mmol, 53 mg) was added
into the solution under air in one portion. THF (1.6 mL) and water (2.0 mL) were added,
and the resulting suspension was allowed to stir for 24 hours at room temperature under
air. Subsequently, the reaction mixture was diluted with Et2O (20 mL) and saturated
NaHCO3 aqueous solution (20 mL). The organic layer was separated and washed with
saturated NaHCO3 aqueous solution (20 mL x 2). The combined aqueous layer was
acidified with concentrated HCl (pH < 2), and extracted with DCM (20 mL x 3). The
combined organic layer was dried with Na2SO4. Then the drying agent was removed,
and the organic solvent was removed under reduced pressure to afford 4h (40.0 mg, 66%
isolated yield). Yellow solid. M.P. 73 - 78 oC.

190
General procedure 8: Deprotection of esters (5a was used as example)
2a (0.3 mmol, 1.0 equiv, 102.4 mg), and LiOH·H2O (2.0 eq, 0.6 mmol, 25.2 mg)
were added into an oven-dried microwave vial under air. Then THF (1.2 mL) and water
(1.2 mL) were added into vial at room temperature, and the solution was allowed to stir
at the same temperature for 24 hours. Subsequently, the reaction mixture was diluted
with Et2O (20 mL) and saturated NaHCO3 aqueous solution (20 mL). The organic layer
was separated and washed with saturated NaHCO3 aqueous solution (20 mL x 2). The
combined aqueous layer was acidified with concentrated HCl (pH < 2), and extracted
with DCM (20 mL x 3). The combined organic layer was dried with Na2SO4. Then the
drying agent was removed, and the organic solvent was removed under reduced
pressure to afford 5a (64.6 mg, 76% isolated yield). Yellow solid. M.P. 167 - 168 oC.
Procedures of post-functionalization reactions.
General procedure 9: Preparation of 6
5a (1.0 eq, 0.228 mmol, 65.0 mg) and CDI (1.25 eq, 0.285 mmol, 46.2 mg) were
added into an oven-dried microwave vial under air. Then, DCM (1.0 mL) was added,

191
and the mixture was stirred at room temperature for 2 hours. After that, piperidine (1.1
eq, 0.25 mmol, 21.4 mg, 25 µL) was added into the mixture, and the resulting solution
was stirred overnight at room temperature. Subsequently, water and DCM was added
into the mixture. The aqueous layer was separated, and extracted with DCM (20 mL x
2). The combined organic layer was washed with water and brine, and dried with
Na2SO4. The drying agent was filtered, and the organic solvent was removed under
reduced pressure to afford 6 (79.5 mg, 99% isolated yield). Yellow solid. M.P. 73 - 75
oC.
Procedure to prepare 7
General procedure 9. 5a (1.0 eq, 0.5 mmol, 142.5 mg) and CDI (1.25 eq, 0.625
mmol, 101.3 mg) were added into an oven-dried microwave vial under air. Then, DCM
(2.2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After
that, morpholine (1.1 eq, 0.55 mmol, 47.9 mg, 48 µL) was added into the mixture, and
the resulting solution was stirred overnight at room temperature. Subsequently, water
and DCM was added into the mixture. The aqueous layer was separated, and extracted
with DCM (20 mL x 2). The combined organic layer was washed with water and brine,
and dried with Na2SO4. The drying agent was filtered, and the organic solvent was
removed under reduced pressure to afford 7 (168.5 mg, 96% isolated yield). Yellow
solid. M.P. 84 - 99 oC.

192
Procedure to prepare 8
5a (0.25 mmol, 1.0 equiv, 71.3 mg), DMAP (0.05 mmol, 0.2 equiv, 6.1 mg), and
NHPI (0.3 mmol, 1.2 equiv, 48.9 mg) were added to an oven-dried microwave vial
under air. Then DCM (1.25 mL) was added followed by the addition of DIC (0.3 mmol,
1.2 equiv, 37.9 mg, 47 µL). The resulting solution was allowed to stir at room
temperature for overnight. Subsequently, water and DCM was added into the mixture.
The aqueous layer was separated, and extracted with DCM (20 mL x 2). The combined
organic layer was washed with water and brine, and dried with Na2SO4. The drying
agent was filtered, and the organic solvent was removed under reduced pressure. The
residue was purified by flash column chromatography, and eluted with 20% EtOAc in
hexane to afford 8 (90.4 mg, 84% isolated yield). White solid. M.P. 89 - 92 oC.
General procedure 10: preparation of 9.
5a (1.0 eq, 1 mmol, 67.9 mg) and KOH (2.2 eq, 0.621 mmol, 25.0 mg) (ground just

193
prior to addition) were added into an oven-dried microwave vial under Ar protection.
Then, ACN (2.5 mL) and water (0.4 mL) were added into the vial, and the mixture was
stirred for 30 minutes at room temperature. TMSCF2Br (2.0 eq, 2.0 mmol, 406.2 mg,
310 µL) was then added, and the resulting solution was stirred for 2 hours at room
temperature. Subsequently, the mixture was diluted with water (20 mL) and DCM (20
mL). The aqueous layer was separated, and extracted with DCM (20 mL x 2). The
combined organic layer was washed with water (15 mL) and brine (15 mL), and dried
with Na2SO4. The drying agent was filtered, and the organic solvent was removed under
reduced pressure. The residue was purified by flash column chromatography, and eluted
with 20% pentane in DCM to afford 9 (114.0 mg, 32% isolated yield). Colorless liquid.
Procedure for the preparation of 9’
General procedure 10. Performed on 0.5 mmol scale, eluted with 20% DCM in
pentane to afford 9’ (61.2 mg, 42% isolated yield). Colorless liquid.
Procedure to prepare 10
2h (1.0 eq, 0.4 mmol, 119.7 mg) was added into an oven-dried microwave under

194
Ar protection. Then, Toluene (2.1 mL) and TMSCF3 (1.25 eq, 0.5 mmol, 71.1 mg, 74
µL) were added into the vial, and the mixture was stirred at 0 oC in an ice bath for 2
minutes. TBAF in THF solution (0.1 eq, 0.04 mmol, 1M, 40 µL) was added into the
mixture, and the resulting solution was stirred at 0 oC for another 30 minutes. The
reaction was allowed to warm to room temperature, and stirred overnight at room
temperature. After that, 1M HCl (1 mL) was added into reaction at room temperature,
and the mixture was stirred at the same temperature for 1 hour. The reaction yield was
determined by 19F NMR.
Procedure to prepare 11
2a (0.5 mmol, 2.0 equiv, 170.0 mg), and 1-benzyl-1H-pyrrole-2,5-dione (0.25
mmol, 1.0 equiv, 46.8 mg) were added to an oven-dried microwave under Ar protection.
Then ACN (1.1 mL) was added to the vial, and the solution was degassed by bubbling
N2 for 5 minutes. TTMSS (0.5 mmol, 2.0 equiv, 124 mg, 154 µL) was added, and the
resulting mixture was allowed to stir under Blue LED irradiation at room temperature
(cooling by a fan) for overnight. The reaction yield was determined by 19F NMR.

195
Procedure to prepare 12
2a (1.0 eq, 0.327 mmol, 112 mg) was added into an oven-dried microwave vial
under air. Then, dried Et2O (3.3 mL) and TTMSS (1.3 eq, 0.426 mmol, 106 mg, 130
µL) were added into the vial, and the mixture was stirred under air at room temperature
for 2 minutes. Et3B in hexane solution (0.1 eq, 0.0327 mmol, 1M, 33 µL) was added
into the vial (needle head in solution). The resulting solution was stirred at room
temperature under air for 1 hour. Subsequently, the mixture was diluted with water (20
mL) and Et2O (20 mL). The aqueous layer was separated, and extracted with Et2O (20
mL x 2). The combined organic layer was washed with water (15 mL) and brine (15
mL), and dried with Na2SO4. The drying agent was filtered, and the organic solvent was
removed under reduced pressure. The residue was purified by flash column
chromatography, and eluted with 80% DCM in hexane to afford 12 (51.4 mg, 60%
isolated yield). Colorless liquid.
General procedure 11. 13 was used as an example
3d (1.0 eq, 0.3 mmol, 113 mg), Pd(dppf)Cl2·CH2Cl2 (2 mol%, 0.006 mmol, 6 mg),

196
and PhB(OH)2 (1.2 eq, 0.36 mmol, 56 mg) were added into an oven-dried microwave
vial under Ar protection. Then, 2-propanol (0.27 mL), water (60 µL), and
diisopropylethylamine (3.0 eq, 0.9 mmol, 116.3 mg, 156 µL) were added into the vial,
and the mixture was stirred at room temperature for 5 minutes. The resulting solution
was microwaved at 120 oC for 30 minutes. Subsequently, the reaction vial was cooled
to room temperature, and was diluted with EtOAc (15 mL) and water (15 mL). The
aqueous layer was separated, and extracted with EtOAc (15 mL x 2). The combined
organic layer was washed with water (15 mL) and brine (15 mL), and dried with Na2SO4.
The drying agent was filtered, and the organic solvent was removed under reduced
pressure. The residue was purified by flash column chromatography, and eluted with
10% DCM in hexane to afford 13 (82.7 mg, 79% isolated yield). White solid. M.P. 74
- 75 oC.
Procedure to prepare 14
3d (1.0 eq, 0.22 mmol, 83 mg), XantPhos Pd G3 (0.1 eq, 0.022 mmol, 21 mg), 3-
(difluoromethyl)azetidine hydrochloride (3.0 eq, 0.66 mmol, 94.7 mg), and Cs2CO3
(5.0 eq, 1.1 mmol, 358.4 mg) were added into an oven-dried microwave vial under Ar
protection. Then, 1.0 mL of 1,4-dioxane was added, and the resulting suspension was

197
stirred at 120 oC for 4 hours. Subsequently, Et2O and water were added to dilute the
mixture. The aqueous layer was separated, and extracted with Et2O (15 mL x 2). The
combined organic layer was washed with water (15 mL) and brine (15 mL), and dried
with Na2SO4. The drying agent was filtered, and the organic solvent was removed under
reduced pressure. The residue was purified by flash column chromatography, and eluted
with pure DCM to afford 14 (53.1 mg, 61% isolated yield). Yellow solid. M.P. 138 -
140 oC.
Procedure to prepare BCP-, and analogues
Procedure to prepare tert-butyl 4-bromo-3-chloro-2-fluorobenzoate
General procedure 3A. Performed on 10.0 mmol scale, eluted with pure hexane
to afford tert-butyl 4-bromo-3-chloro-2-fluorobenzoate (2596.4 mg, 84% isolated
yield). White solid. M.P. 34 - 36 oC.
Procedure to prepare 15
General Procedure 11. Performed on 1.0 mmol scale, eluted with 5% EtOAc in

198
hexane to afford 15 (342.9 mg, 100% isolated yield). Colorless oil.
Procedure to prepare 16
General Procedure 11. Performed on 1.0 mmol scale, eluted with pure hexane to
afford 16 (274.2 mg, 100% isolated yield). Yellow oil.
Procedure to prepare 17
General Procedure 11. Performed on 1.0 mmol scale, eluted with 10% EtOAc in
hexane to afford 17 (255.4 mg, 94% isolated yield). Yellow oil.
3-Hydroxy-3-phenylcyclobutane-1-carboxylic acid (S2a)
Performed on 100.0 mmol scale, eluted with 50% EtOAc in hexane to 75% EtOAc in
hexane to afford S2a (15.1 g, 78% yield). White solid.

199
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (br s, 1H), 7.50 (d, J =
7.73 Hz, 2H), 7.35 (t, J = 7.56 Hz, 2H), 7.24 (t, J = 7.34 Hz, 1H), 5.67 (br s, 1H), 2.70
– 2.11 (m, 5H); The 1H NMR data obtained agreed with literature report.
434
tert-Butyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (1a)
Performed on 13.0 mmol scale, eluted with 50% DCM in hexane to afford 1a (1246.3
mg, 42% yield). White solid.
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 7.36 – 7.22 (m, 5H), 2.90 (s, 2H),
1.57 (s, 2H), 1.05 (s, 9H); The 1H NMR data obtained agreed with literature report.
434
tert-Butyl 3-(o-tolyl)bicyclo[1.1.0]butane-1-carboxylate (1b)
Performed on 10.0 mmol scale, eluted with 50% DCM in hexane to afford 2b (505.3
mg, 21% yield). White solid.
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 7.21 – 7.08 (m, 4H), 2.54 (s, 2H),
2.41 (s, 3H), 1.58 (s, 2H), 1.30 (s, 9H); The 1H NMR data obtained agreed with
literature report.
434

200
tert-Butyl 3-(p-tolyl)bicyclo[1.1.0]butane-1-carboxylate (1c)
Performed on 10.0 mmol scale, eluted with 50% DCM in hexane to afford 1c (458.7
mg, 19% yield). White solid.
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.12 Hz, 2H), 7.14
(d, J = 8.01 Hz, 2H), 2.85 (s, 2H), 2.27 (s, 3H), 1.53 (s, 2H), 1.07 (s, 9H); The 1H NMR
data obtained agreed with literature report.
434
tert-Butyl 3-(4-bromophenyl)bicyclo[1.1.0]butane-1-carboxylate (1d)
Known compound. Performed on 20 mmol scale, eluted with 50% DCM in hexane to
afford 1d (1584.8 mg, 26% yield). White solid.
1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.57 Hz, 2H), 7.31 (d, J = 8.50 Hz, 2H),
2.90 (s, 2H), 1.59 (s, 2H), 1.08 (s, 9H). The 1H NMR data obtained agreed with
literature report.
432

201
tert-Butyl 3-(4-chlorophenyl)bicyclo[1.1.0]butane-1-carboxylate (1e)
Performed on 12.5 mmol scale, eluted with 50% DCM in hexane to afford 1e (504.5
mg, 15% yield). White solid. M.P. 58 - 61 oC.
1H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.36 (m, 4H), 2.90 (s, 2H), 1.59 (s, 2H), 1.08
(s, 9H); 13C NMR (400 MHz, DMSO-d6) δ 167.9, 133.2, 131.5, 128.4, 127.7, 80.0,
35.9, 31.1, 27.7, 24.0. FT-IR (v
-1
cm-1
) 2932, 2359, 2159, 1687, 1597, 1520, 1480, 1451,
1402, 1369, 1347, 1250, 1207, 1151, 1121, 1113, 1101, 1089, 1062, 1044, 1029, 1010,
933, 883, 846, 836, 827, 775, 763, 738, 722, 631, 586, 538, 518, 501, 472, 466.
tert-Butyl 3-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxylate (1f)
Performed on 10.0 mmol scale, eluted with 50% DCM in hexane to afford 1f (270.6
mg, 11% overall yield). White solid.
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.37 (m, 2H), 7.18 (t, J =
8.94 Hz, 2H), 2.89 (s, 2H), 1.57 (s, 2H), 1.08 (s, 9H); 19F NMR (376 MHz, DMSO-d6)
δ -115.84 (m). The 1H NMR and 19F NMR data obtained agreed with literature report.
434

202
tert-Butyl 3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butane-1-carboxylate (1g)
Performed on 20 mmol scale, eluted with 50% DCM in hexane to afford 1g (1029.9 mg,
23% yield). White solid.
Known compound. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.12 Hz, 2H), 7.18
(d, J = 8.14 Hz, 2H), 2.99 (s, 2H), 1.66 (s, 2H), 1.04 (s, 9H); 19F NMR (376 MHz,
DMSO-d6) δ -60.33 (s). The 1H NMR and 19F NMR data obtained agreed with literature
report.
432
Methyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (1h)
Performed on 12.0 mmol scale, eluted with 50% DCM in hexane to afford 1h (1057.3
mg, 47% yield). White solid. M.P. 67 - 68 oC.
1H NMR (400 MHz, DMSO-d6) δ 7.37 – 7.26 (m, 5H), 3.38 (s, 3H), 2.94 (s, 2H), 1.62
(s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 169.5, 133.7, 128.8, 127.3, 126.2, 51.9,
35.8, 33.0, 23.3; FT-IR (v
-1
cm-1
) 3030, 2998, 1701, 1600, 1523, 1489, 1476, 1439,
1402, 1341, 1194, 1150, 1114, 1099, 1065, 1043, 984, 897, 868, 782, 739, 692, 546;

203
Benzyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (1i)
Performed on 12 mmol scale, eluted with 50% DCM in hexane to afford 1i (668.4 mg,
21% yield). White solid. M.P. 74 - 76 oC.
1H NMR (400 MHz, DMSO-d6) δ 7.38 – 6.92 (m, 10H), 4.90 (s, 2H), 2.99 (s, 2H), 1.66
(s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 168.8, 136.3, 133.4, 128.7, 128.4, 127.7,
127.3, 127.2, 126.1, 65.4, 35.7, 33.4, 23.0. FT-IR (v
-1
cm-1
) 3367, 3065, 2944, 1706,
1694, 1601, 1494, 1448, 1405, 1378, 1339, 1208, 1187, 1146, 1115, 1041, 974, 890,
868, 779, 743, 726, 689, 548.
tert-Butyl (S)-2-bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (2a)
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.31 (m, 5H), 3.09 (dt, J =
10.65, 2.20 Hz, 1H), 2.50 (t, J = 2.62 Hz, 1H), 2.37 (dt, J = 10.39, 3.97 Hz, 1H), 2.08
(dd, J = 18.89, 3.57 Hz, 1H), 1.52 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -103.99 (d,
J = 18.53 Hz). The 1H NMR and 19F NMR data obtained agreed with literature report.
434

204
tert-Butyl (S)-2-bromo-2-fluoro-3-(o-tolyl)bicyclo[1.1.1]pentane-1-carboxylate (2b)
General Procedure 5. Performed on 0.4 mmol scale, eluted with 50% DCM in pentane
to afford 2b (62.8 mg, 44% isolated yield). Colorless oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.14 (m, 4H), 3.20 (d, J =
10.44 Hz, 1H), 2.63 (s, 1H), 2.47 – 2.44 (m, 1H), 2.42 (s, 3H), 2.22 (dd, J = 19.00, 3.33
Hz, 1H), 1.53 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -100.42 (d, J = 18.63 Hz). The
1H NMR and 19F NMR data obtained agreed with literature report.
434
tert-Butyl (S)-2-bromo-2-fluoro-3-(p-tolyl)bicyclo[1.1.1]pentane-1-carboxylate (2c)
General Procedure 5. Performed on 0.4 mmol scale, eluted with 10% DCM in pentane
to afford 2c (48.5, 34%). Colorless oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.25 – 7.17 (m, 3H),
3.10 (d, J = 10.53 Hz, 1H), 2.51 (s, 1H), 2.41 – 2.35 (m, 4H), 2.09 (dd, J = 18.91, 3.47
Hz, 1H), 1.56 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -104.01 (d, J = 18.84 Hz). The
1H NMR and 19F NMR data obtained agreed with literature report.
434

205
tert-Butyl (S)-2-bromo-3-(4-bromophenyl)-2-fluorobicyclo[1.1.1]pentane-1-
carboxylate (2d)
General Procedure 5. Performed on 0.5 mmol scale, eluted with 10% DCM in hexane
to afford 2d (85.7mg, 41% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.45 Hz, 2H), 7.18 (d, J = 8.43 Hz, 2H),
3.07 (d, J = 10.48, 1H), 2.49 (s, 1H), 2.35 (dt, J = 10.16, 3.92 Hz, 1H), 2.07 (dd, J =
18.72, 3.59 Hz, 1H), 1.52 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -104.17 (d, J = 18.60
Hz); 13C NMR (126 MHz, CDCl3) δ164.6, 131.9, 131.7, 128.9, 122.9, 108.2 (d, J =
310.69 Hz), 82.7, 56.1 (d, J = 17.43 Hz), 52.9 (d, J = 17.43 Hz), 46.5 (d, J = 5.43 Hz),
46.4, 28.2; FT-IR (v
-1
cm-1
) 2979, 2934, 2864, 1725, 1487, 1457, 1392, 1366, 1320,
1217, 1157, 1130, 1099, 1066, 1023, 972, 905, 839, 798, 508, 497, 469; HRMS (ESI)
m/z calculated for C16H18Br2FO2 [M + H]+
: 418.9652; found 418.9676 (3.5803 ppm).
tert-Butyl (S)-2-bromo-3-(4-chlorophenyl)-2-fluorobicyclo[1.1.1]pentane-1-
carboxylate (2e)
General Procedure 5. Performed on 0.5 mmol scale, eluted with 20% DCM in pentane
to afford 2e (110.6 mg, 59% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.46 Hz, 2H), 7.24 (d, J = 8.37 Hz, 2H),

206
3.07 (dt, J = 10.51, 2.17 Hz, 1H), 2.49 (s, 1H), 2.35 (d, J = 10.34, 3.94 Hz, 1H), 2.07
(dd, J = 18.74, 3.50 Hz, 1H), 1.52 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -104.17 (d,
J = 18.63 Hz); 13C NMR (126 MHz, CDCl3) δ 164.6, 134.7, 131.2, 128.9, 128.6, 108.3
(d, J = 310.68 Hz), 82.7, 63.9, 56.0 (d, J = 17.46 Hz), 52.9 (d, J = 17.46 Hz), 46.5, 46.5
(d, J = 7.78 Hz), 28.2; FT-IR (v
-1
cm-1
) 2926, 2359, 2188, 2156, 2032, 2026, 1722,
1392, 1370, 1216, 1161, 1092, 761, 502; HRMS (ESI) m/z calculated for C12H9BrClO2
[M – C4H8F]–
: 298.9480; found 298.9478 (0.6690 ppm).
tert-Butyl (S)-2-bromo-2-fluoro-3-(4-fluorophenyl)bicyclo[1.1.1]pentane-1-
carboxylate (2f)
General Procedure 5. Performed on 0.4 mmol scale, eluted with 35% DCM in pentane
to afford 2f (43.1 mg, 30% isolated yield). Yellow oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.22 (m, 2H), 7.02 (t, J =
8.61 Hz, 2H), 3.04 – 3.01 (m, 1H), 2.44 (s, 1H), 2.31 (dt, J = 9.97, 3.71 Hz, 1H), 2.03
(dd, J = 18.85, 3.52 Hz, 1H), 1.48 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -104.23 (d,
J = 18.42 Hz, 1F), -113.50 (m, 1F). The 1H NMR and 19F NMR data obtained agreed
with literature report.
434

207
tert-Butyl (S)-2-bromo-2-fluoro-3-(4-
(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxylate (2g)
General Procedure 5. Performed on 0.5 mmol scale, eluted with 10% DCM in hexane
to afford 2g (78.0mg, 38% isolated yield). White solid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.97 Hz, 2H), 7.43 (d,
J = 7.93 Hz, 2H), 3.12 (d, J = 10.46, 1H), 2.53 (s, 1H), 2.43 – 2.38 (m, 1H), 2.12 (dd, J
= 18.66, 3.51 Hz, 1H), 1.53 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -63.22 (s, 3F), -
104.14 (d, J = 18.43 Hz, 1H); The 1H NMR and 19F NMR data obtained agreed with
literature report.
434
Methyl (S)-2-bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (2h)
General Procedure 5. Performed on 0.5 mmol scale, eluted with 10% DCM in pentane
to afford 2h (56.6 mg, 37% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 5H), 3.82 (s, 3H), 3.15 (d, J = 10.31 Hz,
1H), 2.55 (s, 1H), 2.43 (dt, J = 10.18, 3.84 Hz, 1H), 2.15 (dd, J = 18.75, 3.63 Hz, 1H);
19F NMR (376 MHz, CDCl3) δ -103.91 (d, J = 18.50 Hz); 13C NMR (126 MHz, CDCl3)
δ 165.9, 132.4, 129.8, 128.7, 127.2, 108.2 (d, J = 310.84 Hz), 57.0 (d, J = 17.32 Hz),
52.4, 52.1 (d, J = 17.62 Hz), 46.8 (d, J = 12.8 Hz), 46.5 (d, J = 7.99 Hz); FT-IR (v
-1

208
cm-1
) 3024, 2972, 2921, 2865, 2844, 2164, 2071, 2041, 2033, 2016, 1051, 1033, 902,
741, 722, 671, 622, 484; HRMS (ESI) m/z calculated for C13H12BrO2 [M – F]–
:
279.0026; found 279.0027 (0.3584 ppm).
Benzyl (S)-2-bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (2i)
General Procedure 5. Performed on 0.5 mmol scale, eluted with 40% DCM in pentane
to afford 2i (84.5 mg, 45% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.42 – 7.31 (m, 5H), 5.26 (s, 2H), 3.17 (dt, J = 10.36,
2.15 Hz, 1H), 2.56 (t, J = 2.88 Hz, 1H), 2.45 (dt, J = 10.49, 4.00 Hz, 1H), 2.16 (dd, J =
18.70, 3.56 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -103.78 (d, J = 18.62 Hz); 13C
NMR (126 MHz, CDCl3) δ 165.3, 135.5, 132.4, 128.8, 128.7, 128.7, 128.5, 128.1,
127.2, 108.3 (d, J = 311.00 Hz), 67.0, 57.1 (d, J = 17.27 Hz), 52.1 (d, J = 17.62 Hz),
46.8 (d, J = 12.81 Hz), 46.6 (d, J = 7.97 Hz); FT-IR (v
-1
cm-1
) 3064, 3032, 2949, 2181,
1734, 1606, 1492, 1447, 1394, 1369, 1305, 1260, 1193, 1156, 1134, 1097, 1023, 1006,
971, 903, 791, 754, 743, 735, 695; HRMS (ESI) m/z calculated for C19H20BrFNO2 [M
+ NH4]
+
: 392.0656; found 392.0658 (0.5101 ppm).

209
tert-Butyl (S)-2-chloro-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (3a)
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 5H), 2.99 (dt, J = 10.40, 2.33 Hz, 1H),
2.49 (m, 1H), 2.36 (t, J = 2.51 Hz, 1H), 2.10 (dd, J = 18.31, 3.30 Hz, 1H), 1.52 (s, 9H);
19F NMR (376 MHz, CDCl3) δ -111.38 (d, J = 18.37 Hz). 13C NMR (126 MHz, CDCl3)
δ 164.9, 132.6, 128.7, 128.5, 127.3, 114.6 (d, J = 297.33 Hz), 82.5, 56.6 (d, J = 18.39
Hz), 52.9 (d, J = 18.61 Hz), 46.4 (d, J = 11.2 Hz), 45.1 (d, J = 7.95 Hz), 28.2. FT-IR
(v
-1
cm-1
) 3032, 2979, 2931, 2913, 1726, 14921726, 1492, 1478, 1457, 1448, 1390,
1368, 1320, 1259, 1215, 1161, 1136, 1102, 1029, 1007, 974, 931, 839, 807, 761, 696,
662; HRMS (ESI) m/z calculated for C12H9O2 [M – C4H9FCl]+
: 185.0619; found
185.0615 (2.1614 ppm).
tert-Butyl (S)-2-chloro-2-fluoro-3-(o-tolyl)bicyclo[1.1.1]pentane-1-carboxylate (3b)
General Procedure 6. Performed on 0.5 mmol scale, eluted with 20% DCM in pentane
to afford 3b (85.6 mg, 55% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.24 – 7.13 (m, 4H), 3.09 (d, J = 10.30 Hz, 1H), 2.55
(dt, J = 9.87, 3.43 Hz, 1H), 2.47 (s, 1H), 2.40 (s, 3H), 2.21 (dd, J = 18.38, 2.89 Hz, 1H),
1.51 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -107.90 (d, J = 18.54 Hz); 13C NMR (376

210
MHz, CDCl3) δ 164.8 (d, J = 1.48 Hz), 137.6, 131.2, 130.7, 128.9, 128.6, 126.1, 115.3
(d, J = 298.2 Hz), 82.4, 57.5 (d, J = 18.24 Hz), 53.3 (d, J = 18.69 Hz), 47.3 (d, J = 10.30
Hz), 45.6 (d, J = 8.30 Hz), 28.2, 20.6. FT-IR (v
-1
cm-1
) 3020, 2982, 2935, 1722, 1458,
1384, 1369, 1317, 1216, 1162, 1144, 1103, 1052, 1032, 933, 753; HRMS (ESI) m/z
calculated for C13H12ClO2 [M – C4H8F]+
: 235.0531; found 235.0528 (1.2763 ppm).
tert-Butyl (S)-2-chloro-2-fluoro-3-(p-tolyl)bicyclo[1.1.1]pentane-1-carboxylate (3c)
General Procedure 6. Performed on 0.4 mmol scale, eluted with 10% DCM in pentane
to afford 3c (60.8, 49%). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.21 – 7.16 (m, 4H), 2.96 (d, J = 10.39 Hz, 1H), 2.46
(dt, J = 10.22, 3.91 Hz, 1H), 2.35 (s, 3H), 2.31 (s, 1H), 2.07 (dd, J = 18.33, 3.30 Hz,
1H), 1.51 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -114.45 (d, J = 18.32 Hz); 13C NMR
(376 MHz, CDCl3) δ 165.0, 138.4, 129.6, 129.4, 127.2, 114.7 (d, J = 297.31 Hz), 82.4,
56.4 (d, J = 18.53 Hz), 52.9 (d, J = 18.34 Hz), 46.4 (d, J = 11.20 Hz), 45.1 (d, J = 7.88
Hz), 29.9, 28.2; FT-IR (v
-1
cm-1
) 2887, 2213, 1731, 1666, 1391, 1171, 1105, 1040, 1025,
930, 718, 612, 494; HRMS (ESI) m/z calculated for C17H20FClO2Na [M + Na]+
:
333.1028; found 333.1028 (0 ppm).

211
tert-Butyl (S)-3-(4-bromophenyl)-2-chloro-2-fluorobicyclo[1.1.1]pentane-1-
carboxylate (3d)
General Procedure 6. Performed on 0.5 mmol scale, eluted with 10% DCM in hexane
to afford 3d (78.4 mg, 42% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.32 Hz, 2H), 7.18 (d, J = 8.35 Hz, 2H),
2.97 (d, J = 10.35 Hz, 1H), 2.47 (m, 1H), 2.36 (s, 1H), 2.09 (dd, J = 18.18, 3.34 Hz,
1H), 1.52 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -111.46 (d, J = 18.25 Hz); 13C NMR
(126 MHz, CDCl3) δ 164.6, 131.9, 131.5, 129.0, 128.7, 127.3, 122.8, 114.3 (d, J =
297.31 Hz), 82.6, 56.0 (d, J = 18.47 Hz), 52.9 (d, J = 18.48 Hz), 46.4 (d, J = 11.17 Hz),
45.1 (d, J = 7.63 Hz), 28.2; FT-IR (v
-1
cm-1
) 2981, 2157, 1727, 1487, 1391, 1368, 1320,
1259, 1216, 1162, 1136, 1103, 1070, 1030, 1014, 974, 932, 839, 798; HRMS (ESI) m/z
calculated for C16H18BrClFO2 [M + H]+
: 375.0157; found 375.0152 (1.3333 ppm).
tert-Butyl (S)-2-chloro-3-(4-chlorophenyl)-2-fluorobicyclo[1.1.1]pentane-1-
carboxylate (3e)
General Procedure 6. Performed on 0.5 mmol scale, eluted with 20% DCM in pentane
to afford 3e (69.2 mg, 42% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.03 Hz, 2H), 7.24 (d, J = 8.21 Hz, 2H),

212
2.97 (d, J = 10.38 Hz, 1H), 2.47 (d, J = 10.54 Hz, 1H), 2.35 (s, 1H), 2.09 (dd, J = 18.21,
2.81 Hz, 1H), 1.51 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -111.48 (d, J = 18.11 Hz);
13C NMR (126 MHz, CDCl3) δ 164.6, 134.6, 131.0, 128.9, 128.7, 114.4 (d, J = 297.26
Hz), 82.6, 63.9, 56.0 (d, J = 18.46 Hz), 52.9 (d, J = 18.51 Hz), 46.4 (d, J = 11.18 Hz),
45.12 (d, J = 7.65 Hz), 28.2. FT-IR (v
-1
cm-1
) 3019, 2982, 1722, 1489, 1394, 1323,
1219, 1164, 1106, 1033, 914, 771, 745, 667; HRMS (ESI) m/z calculated for
C12H9Cl2O2 [M–C4H8F]–
: 254.9985; found 254.9980 (1.9608 ppm).
tert-Butyl (S)-2-chloro-2-fluoro-3-(4-
(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxylate (3g)
General Procedure 6. Performed on 0.5 mmol scale, eluted with 20% DCM in hexane
to afford 3g (82.8 mg, 46% isolated yield). White solid. M.P. 76 oC - 77 oC.
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.95 Hz, 2H), 7.43 (d, J = 7.90 Hz, 2H),
3.02 (dt, J = 10.65, 2.17, 1H), 2.53 – 2.51 (m, 1H), 2.40 (s, 1H), 2.14 (dd, J = 18.10,
3.29 Hz, 1H), 1.52 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -63.22 (s, 3F), -111.35 (d, J
= 18.17 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 164.5 (d, J = 1.05 Hz), 130.8 (q, J =
32.64 Hz), 125.68 (q, J = 3.78 Hz), 124.1 (q, J = 272.17 Hz), 114.4 (d, J = 297.47 Hz),
56.0 (d, J = 18.49 Hz), 53.0 (d, J = 18.51 Hz), 46.5 (d, J = 11.15 Hz), 45.2 (d, J = 7.45
Hz), 28.2; FT-IR (v
-1
cm-1
) 2986, 2928, 2852, 1718, 1622, 1497, 1458, 1411, 1394,
1370, 1323, 1261, 1219, 1160, 1119, 1103, 1067, 1035, 1019, 975, 933, 876, 861, 847,

213
806, 762, 691, 661, 603, 510, 488, 482, 475; HRMS (ESI) m/z calculated for
C17H18ClF4O2 [M+H]+
: 365.0926; found 365.0943 (4.6564 ppm).
Benzyl (S)-2-Chloro-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (3i)
General Procedure 6. Performed on 0.5 mmol scale, eluted with 20% DCM in pentane
to afford 3i (53.1 mg, 32% isolated yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.30 (m, 5H), 5.26 (s, 2H), 3.06 (dt, J = 10.39,
2.18 Hz, 1H), 2.57 (dt, J = 10.45, 3.77 Hz, 1H), 2.43 (s, 1H), 2.17 (dd, J = 18.19, 3.37
Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -110.98 (d, J = 18.05 Hz); 13C NMR (126
MHz, CDCl3) δ 165.4 (d, J = 1.46 Hz), 135.5, 132.3, 128.8, 128.7, 128.7, 128.5, 128.1,
127.3, 114.6 (d, J = 297.65 Hz), 67.0, 57.0 (d, J = 18.30 Hz), 52.2 (d, J = 18.62 Hz),
46.7 (d, J = 11.19 Hz), 45.3 (d, J = 7.55 Hz); FT-IR (v
-1
cm-1
) 3063, 3034, 2952, 2920,
2851, 2362, 1734, 1492, 1456, 1448, 1395, 1305, 1260, 1195, 1164, 1135, 1099, 1029,
1007, 975, 929, 907, 753, 695; HRMS (ESI) m/z calculated for C19H20ClFNO2 [M +
NH4]
+
: 348.1161; found 348.1161 (0 ppm).
(S)-2-Chloro-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (4h)

214
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.32 (m, 5H), 3.20 (d, J = 10.76 Hz, 1H), 2.60 (s,
1H), 2.48 (dt, J = 10.44, 3.96 Hz, 1H), 2.19 (dd, J = 18.59, 3.59 Hz, 1H); 19F NMR
(376 MHz, CDCl3) δ -111.17 (d, J = 18.12 Hz); 13C NMR (126 MHz, CDCl3) δ 169.0,
132.0, 128.8, 128.5, 128.4, 127.3, 127.0, 114.4 (d, J = 297.84 Hz), 57.2 (d, J = 18.45
Hz), 51.7 (d, J = 18.52 Hz), 46.8 (d, J = 11.27 Hz), 45.3 (d, J = 7.40 Hz); FT-IR (v
-1
cm-1
) 3032, 2918, 2852, 2594, 1699, 1492, 1447, 1320, 1225, 1162, 1110, 1030, 972,
931, 909, 780, 758, 745, 737, 698, 660, 510, 486; HRMS (ESI) m/z calculated for
C12H9ClFO2 [M – H]–
: 239.0281; found 239.0280 (0.4184 ppm).
(S)-2-Bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (5a)
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.32 (m, 5H), 3.20 (dd, J = 10.64, 2.19 Hz, 1H),
2.60 (s, 1H), 2.48 (dt, J = 10.79, 3.79 Hz, 1H), 2.19 (dd, J = 18.57, 3.55 Hz, 1H); 19F
NMR (376 MHz, CDCl3) δ -104.05 (d, J = 18.66 Hz). 13C NMR (126 MHz, CDCl3) δ
168.4, 132.2, 128.8, 128.8, 127.2, 108.0 (d, J = 311.4 Hz), 57.2 (d, J = 17.09 Hz), 51.6,
(d, J = 17.79 Hz), 46.9 (d, J = 12.83 Hz), 46.6 (d, J = 7.48 Hz); FT-IR (v
-1
cm-1
) 3014,
2858, 2806, 2665, 2588, 1698, 1490, 1447, 1321, 1224, 1158, 1107, 1026, 1019, 967,
948, 910, 864, 825, 753, 735, 698, 676, 656, 505; HRMS (ESI) m/z calculated for
C12H9BrFO2 [M – H]+
: 282.9775; found 282.9775 (0 ppm).

215
(S)-(2-Bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentan-1-yl)(piperidin-1-
yl)methanone (6)
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.32 (m, 5H), 3.73 – 3.64 (m, 2H), 3.57 – 3.47
(m, 2H), 3.19 (d, J = 10.56, 1H), 2.59 (s, 1H), 2.46 (dt, J = 10.37, 4.16 Hz, 1H), 2.16
(dd, J = 19.58, 3.83 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -100.07 (d, J = 19.57 Hz).
13C NMR (126 MHz, CDCl3) δ 163.0, 132.8, 128.7, 128.5, 127.2, 109.6 (d, J = 310.92
Hz), 56.3 (d, J = 17.70 Hz), 54.8, (d, J = 16.38 Hz), 48.4 (d, J = 11.42 Hz), 46.7 (d, J =
8.99 Hz), 43.8, 27.1, 25.7, 24.7; FT-IR (v
-1
cm-1
) 3060, 3025, 2938, 2921, 2855, 1720,
1621, 1491, 1458, 1441, 1393, 1368, 1324, 1290, 1245, 1215, 1159, 1140, 1119, 1093,
1053, 1036, 1023, 999, 988, 966, 951, 918, 897, 881, 851, 802, 769, 748, 698, 659, 617,
600, 565, 542, 502, 482, 473, 457; HRMS (ESI) m/z calculated for C17H20BrFNO [M
+ H]+
: 352.0707; found 352.0712 (1.4202 ppm).
(S)-(2-Bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentan-1-
yl)(morpholino)methanone
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.32 (m, 5H), 3.75 – 3.57 (m, 8H), 3.19 (dt, J =
10.68, 2.19, 1H), 2.61 (s, 1H), 2.46 (dt, J = 10.58, 4.14 Hz, 1H), 2.18 (dd, J = 19.54,
3.81 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -99.60 (d, J = 19.41 Hz); 13C NMR (126

216
MHz, CDCl3) δ 163.5, 132.5, 128.7, 128.7, 127.2, 109.4 (d, J = 310.65 Hz), 67.0, 56.4
(d, J = 17.74 Hz), 54.4, (d, J = 16.43 Hz), 48.3 (d, J = 11.49 Hz), 46.6 (d, J = 8.93 Hz),
42.9; FT-IR (v
-1
cm-1
) 3248, 3127, 3104, 3038, 3019, 2986, 2897, 2850, 2767, 1677,
1632, 1511, 1494, 1460, 1436, 1392, 1362, 1333, 1304, 1289, 1269, 1211, 1171, 1144,
1117, 1103, 1037, 1023, 1006, 966, 941, 917, 904, 880, 845, 816, 759, 693, 680, 619,
583, 566, 517, 499; HRMS (ESI) m/z calculated for C16H18BrFNO2 [M + H]+
:
354.0499; found 354.0505 (1.6947 ppm).
1,3-Dioxoisoindolin-2-yl (S)-2-bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-
carboxylate (8)
1H NMR (400 MHz, CDCl3) δ 7.93 – 7.91 (m, 2H), 7.83 – 7.81 (m, 2H), 7.42 – 7.34
(m, 5H), 3.39 (d, J = 10.67 Hz, 1H), 2.79 (s, 1H), 2.66 (m, 1H), 2.37 (dd, J = 18.23,
3.69 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -103.53 (d, J = 18.39 Hz); 13C NMR (126
MHz, CDCl3) δ 161.5, 161.3 (d, J = 1.33 Hz), 135.1, 131.9, 129.0 (d, J = 2.81 Hz),
128.8, 128.7, 127.2j, 107.6, (d, J = 312.58 Hz), 83.4, 58.1 (d, J = 17.55 Hz), 49.9 (d, J
= 18.24 Hz), 47.7 (d, J = 12.64 Hz), 47.2 (d, J = 7.02 Hz); FT-IR (v
-1
cm-1
) 2928, 2865,
1784, 1736, 1466, 1378, 1177, 1131, 1056, 1022, 1002, 953, 903, 875, 840, 792, 764,
694, 519, 513, 501, 479, 473, 466, 461, 456; HRMS (ESI) m/z calculated for
C20H14BrFNO4 [M + H]+
: 430.0085; found 430.0104 (4.4185 ppm).

217
Difluoromethyl (S)-2-bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-
carboxylate (9)
1H NMR (400 MHz, CDCl3) δ 7.43 – 7.39 (m, 3H), 7.34 – 6.97 (m, 3H), 3.25 (d, J =
10.50 Hz, 1H), 2.65 (s, 1H), 2.53 (dt, J = 10.47, 4.01 Hz, 1H), 2.24 (dd, J = 18.29, 3.65
Hz); 19F NMR (376 MHz, CDCl3) δ -92.10 (d, J = 70.21 Hz, 2F), -104.09 (d, J = 17.91
Hz, 1F); 13C NMR (126 MHz, CDCl3) δ 161.5 (td, J = 3.16, 1.49 Hz), 131.8 (d, J =
1.17 Hz), 129.0, 128.8, 127.2, 112.3 (t, J = 260.75 Hz), 107.5 (d, J = 311.70 Hz), 57.4
(d, J = 17.51 Hz), 51.3 (d, J = 18.31 Hz), 47.1 (d, J = 12.72 Hz), 46.7 (d, J = 7.26 Hz);
FT-IR (v
-1
cm-1
) 3034, 1773, 1492, 1448, 1396, 1370, 1299, 1189, 1063, 1023, 970,
910, 850, 803, 759, 696, 645, 566, 494, 476, 467; HRMS (ESI) m/z calculated for
C13H10O2F3Br [M]: 333.9811; found: 333.9825 (4.1919 ppm).
Difluoromethyl (S)-2-bromo-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-
carboxylate (9’)
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.38 (m, 3H), 7.33 – 6.96 (m, 3H), 3.14 (d, J =
10.41 Hz, 1H), 2.64 (dt, J = 10.54, 3.89 Hz, 1H), 2.51 (s, 1H), 2.25 (d, J = 17.82, 3.45,
1H); 19F NMR (376 MHz, CDCl3) δ -92.13 (d, J = 70.33 Hz, 2F), -110.97 (d, J = 17.73
Hz, 1F); 13C NMR (126 MHz, CDCl3) δ 161.5 (d, J = 3.15, 1.60 Hz), 131.5 (d, J = 1.25
Hz), 129.0, 128.8, 127.2, 114.2 (d, J = 298.67 Hz), 112.3 (t, J = 260.75 Hz), 57.4 (d, J

218
= 18.47 Hz), 51.4 (d, J = 18.97 Hz), 46.9 (d, J = 11.08 Hz), 45.4 (d, J = 6.91 Hz); FTIR (v
-1
cm-1
) 3036, 1773, 1492, 1448, 1397, 1370, 1299, 1191, 1064, 1029, 973, 933,
805, 756, 696, 649, 571, 518, 493, 481, 458; HRMS (ESI) m/z calculated for
C13H10O2F3Cl [M]: 290.0316; found: 290.0317 (0.3448 ppm).
tert-Butyl (S)-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylate (12)
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 3H), 7.24 – 7.22 (m,
2H), 5.00 (dd, J = 72.00, 6.59 Hz, 1H), 3.07 (dd, J = 9.80, 6.59 Hz, 1H), 2.27 (dt, J =
5.88, 2.85 Hz, 1H), 2.20 (dd, J = 28.68, 3.12 Hz, 1H), 1.77 (dt, J = 9.52, 2.78 Hz, 1H),
1.48 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -183.61 (dd, J = 72.09, 28.73 Hz). The 19F
and 1H NMR data obtained agreed with literature report.
434
tert-Butyl (S)-3-([1,1'-biphenyl]-4-yl)-2-chloro-2-fluorobicyclo[1.1.1]pentane-1-
carboxylate (13)
1H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 7.22 Hz, 4H), 7.45 (t, J = 7.64 Hz, 2H), 7.40
– 7.32 (m, 3H), 3.02 (d, J = 11.08 Hz, 1H), 2.52 (dt, J = 10.44, 3.69 Hz, 1H), 2.40 (s,
1H), 2.13 (dd, J = 18.32, 3.11 Hz), 1.53 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -111.28

219
(d, J = 18.38 Hz); 13C NMR (126 MHz, CDCl3) δ 164.7 (d, J = 1.18 Hz), 141.4, 140.6,
131.7, 131.3 (d, J = 1.09 Hz), 128.8, 127.6, 127.5, 127.3, 127.1, 114.5 (d, J = 297.33
Hz), 82.4, 56.2 (d, J = 18.40 Hz), 52.8 (d, J = 18.45 Hz), 46.34 (d, J = 11.15 Hz), 45.02
(d, J = 7.85 Hz), 28.1; FT-IR (
-1
cm-1
) 3033, 3003, 2979, 2931, 1734, 1485, 1459,
1447, 1392, 1370, 1319, 1258, 1214, 1158, 1137, 1099, 1073, 1029, 1007, 976, 930,
846, 831, 800, 763, 750, 729, 697, 662, 646, 576, 545, 511, 488, 467, 458, 452; HRMS
(ESI) m/z calculated for C20H24ClF3NO2 [M + H]+
: 373.1365; found 373.1378 (3.4840
ppm).
tert-Butyl (S)-2-chloro-3-(4-(3-(difluoromethyl)azetidin-1-yl)phenyl)-2-
fluorobicyclo[1.1.1]pentane-1-carboxylate (14)
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.33 Hz, 2H), 6.48 (d, J = 8.48 Hz, 2H),
6.05 (td, J = 56.46, 5.19 Hz, 1H), 4.00 (t, J = 7.94 Hz, 2H), 3.89 – 3.86 (m, 2H), 2.93
(d, J = 10.55 Hz, 1H), 2.43 (dt, J = 10.48 Hz, 3.84 Hz, 1H), 2.30 (s, 1H), 2.03 (dd, J =
18.46, 3.28, 1H), 1.51 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -111.48 (d, J = 18.33 Hz,
1F), -123.06 (dd, J = 56.36, 13.40, 2F); 13C NMR (126 MHz, CDCl3) δ 165.1, 151.1,
128.1, 122.0, 118.4, 116.8, 115.8, 115.2, 114.4, 113.8, 111.5, 82.3, 56.5 (d, J = 18.25
Hz), 52.8 (d, J = 18.35 Hz), 51.5 (t, J = 6.18 Hz), 46.4 (d, J = 11.17 Hz), 45.1 (d, J =
8.01 Hz), 28.2; HRMS (ESI) m/z calculated for C20H24ClF3NO2 [M+H]+
: 402.1442;

220
found 402.1448 (1.4920 ppm).
Tert-Butyl 4-bromo-3-chloro-2-fluorobenzoate
1H NMR (400 MHz, CDCl3) δ 7.67 – 7.63 (m, 1H), 7.47 (dd, J = 8.54, 1.51 Hz, 1H),
1.59 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -104.50 (d, J = 6.88 Hz); 13C NMR (126
MHz, CDCl3) δ 162.4 (d, J = 4.30 Hz), 159.2, 156.5, 130.2 (d, J = 1.63 Hz), 128.3 (d,
J = 4.39 Hz), 128.3, 124.3 (d, J = 20.48 Hz), 121.0 (d, J =10.96 Hz), 83.1, 28.3; FT-IR
(v
-1
cm-1
) 2979, 2928, 2855, 1712, 1591, 1557, 1454, 1410, 1394, 1368, 1303, 1289,
1255, 1236, 1160, 1120, 1037, 907, 866, 848, 769; HRMS (ESI) m/z calculated for
C11H11FClBrO2 [M]+
: 307.9609; found 307.9616 (2.2730 ppm).
tert-Butyl 2-chloro-3-fluoro-[1,1'-biphenyl]-4-carboxylate (15)
1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 7.49 Hz, 1H), 7.48 – 7.43 (m, 5H), 7.19 (d,
J = 8.13 Hz, 1H), 1.63 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -109.27 (d, J = 6.80 Hz);
13C NMR (126 MHz, CDCl3) δ 162.9 (d, J = 4.08 Hz), 158.6, 156.8, 146.3, 137.8 (d, J

221
= 2.13 Hz), 129.4 (d, J = 1.58 Hz), 129.3, 128.6, 128.4, 125.7 (d, J = 4.14 Hz), 121.5
(d, J = 18.64 Hz), 120.7 (d, J = 11.31 Hz), 82.6, 28.3; FT-IR (v
-1
cm-1
) 2978, 2931,
2165, 1710, 1610, 1549, 1471, 1406, 1368, 1292, 1252, 1226, 1176, 1149, 1119, 1095,
1029, 914, 870, 848, 779, 758, 698; HRMS (ESI) m/z calculated for C17H16FClO2Na
[M + Na]+
: 329.0715; found 329.0715 (0 ppm).
tert-Butyl 2-fluoro-[1,1'-biphenyl]-4-carboxylate (16)
1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.00 Hz, 1H), 7.77 (d, J = 12.27 Hz, 1H),
7.58 (d, J = 8.04 Hz, 2H), 7.52 – 7.41 (m, 4H), 1.62 (s, 9H); 19F NMR (376 MHz,
CDCl3) δ -118.10 – -118.15 (m); 13C NMR (126 MHz, CDCl3) δ 164.6 (d, J = 2.61 Hz),
160.7, 158.2, 135.1, 133.3, 133.2, 133.1, 133.0, 130.6 (d, J = 3.47 Hz), 129.1 (d, J =
3.05 Hz), 128.7, 128.4, 125.5 (d, J = 3.46 Hz), 117.3 (d, J = 24.73 Hz), 81.7, 28.3; FTIR (v
-1
cm-1
) 3071, 2977, 2930, 1713, 1583, 1564, 1514, 1480, 1450, 1409, 1393, 1368,
1301, 1257, 1235, 1204, 1160, 1123, 1094, 1011, 944, 893, 849, 820, 756, 696; HRMS
(ESI) m/z calculated for C17H17O2F [M]: 272.1207; found: 272.1214 (2.5724 ppm).

222
tert-Butyl 3-fluoro-[1,1'-biphenyl]-4-carboxylate (17)
1H NMR (400 MHz, CDCl3) δ 7.93 (t, J = 7.90 Hz, 1H), 7.61 – 7.59 (m, 2H), 7.49 –
7.45 (m, 2H), 7.43 – 7.39 (m, 2H), 7.33 (dd, J = 12.03, 1.67 Hz, 1H), 1.62 (s, 9H); 19F
NMR (376 MHz, CDCl3) δ -110.31 (d, J = 12.28, 7.61 Hz); 13C NMR (126 MHz,
CDCl3) δ 163.6 (d, J = 3.82 Hz), 163.2, 147.3 (d, J = 8.69 Hz), 139.0, 132.5, 129.2,
128.7, 127.3, 122.4 (d, J = 3.37 Hz), 119.1 (d, J = 9.94 Hz), 115.4 (d, J = 23.66 Hz),
82.0, 28.4; FT-IR (v
-1
cm-1
) 2977, 2930, 1707, 1619, 1562, 1479, 1453, 1407, 1392,
1367, 1299, 1247, 1192, 1174, 1139, 1091, 1033, 906, 844, 757, 695; HRMS (ESI) m/z
calculated for C17H17FO2Na [M + Na]+
: 295.1105; found 295.1105 (1.6943 ppm).

223
Chapter 6
Carbonyldiimidazole (CDI) as an efficient replacement of triphosgene for
trifluoromethoxylation
6.1 Introduction
In the past decades, incorporating fluorine-contained molecules has been a wellrecognized strategy to modulate the physicochemical and biochemical properties of
organic compounds including pharmaceuticals, agrochemicals, and functional
materials.300–302 In fact, numerous fluorinations and fluoroalkylation methods have
been developed to introduce fluorine-containing groups in pharmaceutical and function
material industries.17,339 Within all the fluoroalkylation methods,
trifluoromethoxylation is of increasing interest in recent decades. Compared to
trifluoromethyl groups (-CF3), the conjugation between lone pair electrons of the
oxygen atoms and benzene rings is reduced by the hyperconjugation of C-F bond with
the lone pair electrons of oxygen atoms and the steric repulsion between -CF3 and the
nearby protons of the aromatic rings. This leads to the free rotation of OCF3 group
which results a 90 o
-dihedral bond angle (Ar-O-CF3).303–305 Owing to this distinct
structural conformation, incorporating trifluoromethoxy groups into organic
compounds including pharmaceuticals,439 pesticides,440,441 and functional materials442
could provide enhanced binding affinity. Despite the broad applications of -OCF3 group,
the direct and convenient trifluoromethoxylation methods remains challenging.
Several reagents have been synthesized to achieve trifluoromethoxylation (Scheme
6.1). In 1965, Noftle and coworkers synthesized the first nucleophilic OCF3-precursor,

224
trifluoromethyl trifluoromethansulfonate (TFMT).308 In 2010, Langois group reported
a general protocol to activate TFMT with fluorides and generate the corresponding
trifluoromethoxide salts such as AgOCF3, CsOCF3, TBAOCF3 which lead to a series
trifluoromethylations.310,311 However, TMFT has a very low boiling point (19 oC) which
makes its preparation, storage and utilization difficult.303–305 In 2017, Tang’s group
developed a sulfone-based -OCF3 precursor with high boiling point, TFMS, which was
prepared by non-toxic Togni’s reagent. This regent smoothly reacted with various
electrophiles.
50 Later, Hu and coworkers developed a novel bench-stable
trifluoromethoxylating reagent, trifluoromethyl benzoate (TFBz), to achieve the first
silver-free trifluoromethoxylation of arenes with benzyne and indolynes precursors.325
Recently, Sanford and Billard’s group introduced the only commercially
trifluoromethoxylating reagent, DNTFB, which was activated by DMAP and generated
Scheme 6.1 Representative trifluoromethoxylating reagent

225
a bench-stable and isolatable solid compound, Py-OCF3. The resulting intermediate
reacted smoothly with benzyl bromides and iodides to afford the benzyl trifluoromethyl
ethers in moderate to excellent yields.331,332
Even though various reagents have achieved trifluoromethoxylation, all these
protocols generate unstable trifluoromethoxide anion as an intermediate which readily
decomposes into highly toxic difluorophosgene and fluorides upon generation. In
addition, most of the reagents (except DNTFB) required toxic (triphosgene) and
explosive (Togni’s reagent) starting materials and tedious preparation processes.
These two disadvantages limit the applicability of these methods. In that case, a
general protocol utilizing a non-toxic commercially available reagent without
generating difluorophosgene is highly desired. Herein, we reported this inexpensive,
commercially available, operational simple and non-toxic method with
carbonyldiimidazole (CDI). Further study indicated that trifluoromethoxide anions and
difluorophosgene were not formed during this reaction process.
6.2 Results and discussion
To our joy, initial attempt with 1 equiv of CDI, 10 equiv of AgF, and 1 equiv of
benzyl bromide (1a) in ACN (0.125 M) at room temperature afforded 22% of
trifluoromethoxylated product 2a by 19F NMR (Table 6.1, trial 1). Surprisingly,
replacing AgF with other fluorides including CsF, KF, NaF, KHF2, FeF3, ZnF2, TBAF,
TMAF and TBAT led to completely no yield of 2a (Table 6.1, trail 2 – 10). Reducing
the loading of AgF to 3.2 equiv gave compatible yields of 2a (21%), whereas further
reducing the amount of AgF dramatically lowered the yield (Table 6.1, trail 11 and

226
12). Increasing the reaction concentration to 0.25 M improved the yields to 53% (Table
6.1, trail 13). Changing the reaction temperature did not improve the yield (Table 6.1,
trail 14 and 15).
Table 6.1 Optimization of trifluoromethoxylationa
Trail -F sources X
equiv
Concentration
(M)
Temperature
(
oC)
Yields of 2a
%
1 AgF 10 0.125 rt 22
2 CsF 10 0.125 rt 0
3 KF 10 0.125 rt 0
4 NaF 10 0.125 rt 0
5 KHF2 10 0.125 rt 0
6 FeF3 10 0.125 rt 0
7 ZnF2 10 0.125 rt 0
8
b TBAF 10 0.125 rt 0
9 TMAF 10 0.125 rt 0
10 TBAT 10 0.125 rt 0
11 AgF 3.2 0.125 rt 21
12 AgF 1.1 0.125 rt 5
13c AgF 3.2 0.25 rt 53 (29)
14 AgF 3.2 0.25 45 20

227
15 AgF 3.2 0.25 0 3
aReactions were performed at 0.5 mmol scale. Yields determined by 19F NMR using trifluorotoluene as internal standard. bTBAF
was added as a 1.0 M stock solution in THF. c
Isolated yield was given in parentheses.
Further optimization of the reaction conditions failed to provide higher yield.
The substrate scope of this method was explored with various substituted benzyl
bromides (Scheme 6.2). Model substrate 1a afforded 53% of 2a by 19F NMR yield.
However, significant loss of yield during isolation was observed owing to the low
boiling point of 2a. Similarly, 4-CF3-substituted benzyl bromide 1b was obtained only
in 31% isolated yield. Other electron-withdraw groups substituted substrates 1c and 1d
furnished product 2c and 2d in 39% and 35% isolated yields, respectively. 4- and 2-
iodo benzyl bromides (1e and 1f) afforded the corresponding trifluoromethoxylated
products in modest yields. Brominated products 2g and 2h were isolated in 42% and
40% yields, respectively. Sulfone-based substrates 1i, 1j and 1k were also tolerated
under optimal conditions. Compared to electron-withdrawing substituents, electronrich groups such as tert-butyl and phenoxy groups (1l and 1m) led to compatible yields
of 2l and 2m. Bis-substituted substrate 1n provided target product 2n in 32% isolated
yield. Biphenyl benzyl bromides 1o and 1p yielded 2o and 2p in moderated yields.

228
Scheme 6.2 Substrate scopea
aReactios were performed at 1.0 mmol scale. Yields in parentheses determined by 19F NMR using trifluorotoluene as an internal
standard.
2-((trifluoromethoxy)methyl)anthracene-9,10-dione (2q) could also be obtained in low
yield from 1q. Even though 2r and 2s were observed in the reaction mixture by 19F
NMR, the desired products were not isolated due to the coelution of inseparable benzyl
fluoride byproducts during flash chromatography. 2t was also not isolated owing to
high volatility of the product (fully evaporated at 325 torr at room temperature).
The reaction mechanism was then investigated via control experiments, and 19F
NMR was used to monitor the progress of the control experiments. Initial mechanism

229
proposed that AgOCF3 intermediate was formed with CDI and AgF, followed by a
nucleophilic substitution of the resulting -OCF3 anion to benzyl bromide.
Figure 6.1. Control experiment 1
However, mixing CDI and AgF without the presence of benzyl bromide did not
generate any AgOCF3 (reported to be observed at -27 ppm by 19F NMR)325,329 or
difluorophosgene (predicted to be observed at -19 ppm by 19F NMR)443 even with
extended reaction time under reaction conditions (Figure 6.1). On the other hand,
reacting AgF and benzyl bromide without CDI led to full conversion of the
corresponding benzyl fluoride in 3 hours (Figure 6.2). Surprisingly, when CDI was
added with AgF and benzyl bromide, no benzyl fluoride was observed by 19F NMR

230
until 6 hours after the reaction initiated, which implied a substrate-inhibition occurred
Figure 6.2 Control experiment 2
in this reaction (Figure 6.3). Moreover, the same unidentified 19F NMR signal reported
in control experiment 1 was also observed during the first 5 hours of reaction. At 6
hours after the reaction was started, the intermediate fully converted into the target
product along with the benzyl fluoride byproduct. These results indicate that this
reaction did not undergo the conventional mechanism, in which -OCF3 was formed as
a nucleophile, and benzyl bromide only served as an electrophile.

231
Figure 6.3 Control experiment 3
Figure 6.4 AgF + 4F-BnBr vs. CDI + AgF + 4F-BnBr
To further investigate our hypothesis, a series of better electrophiles including

232
benzyl iodide (BnI), benzyl tosylate (BnOTs) and benzyl triflate (BnOTf) were
prepared and adapted into the optimal conditions. Previous works which utilized
AgOCF3 to react with BnBr all reported that when these electrophiles was used under
the same reaction conditions, the trifluoromethoxylated products were obtained in
similar or improved yields, since -I, -OTs and -OTf groups are better leaving groups
compared to -Br group. However, when these electrophiles were subjected to our
reaction system, much lower yields of the target products (Scheme 6.3). This
observation also matched with our hypothesis that it was not a conventional
nucleophilic substitution of trifluoromethoxide anion to BnBr.
Scheme 6.3 Reaction with other electrophilies
In that case, a tentative mechanism was proposed for this reaction. In this reaction,
BnBr participated in the intermediate formation step with AgF and CDI. Based on the
results from control experiment 2, BnBr was proposed to react with CDI first to form
the activated CDI intermediate, A. Then, a fluoride attacked intermediate A to give
intermediate B via addition-elimination process, followed by a second nucleophilic

233
attack by fluoride to provide intermediate C. After that, C underwent an intramolecular
nucleophilic attack with oxygen to benzylic carbon and generated D. At last, D was
attacked by the third fluoride to afford the trifluoromethoxylated products (Scheme 6.4).
Scheme 6.4 Proposed mechanism of CDI-mediated trifluoromethoxylation
Attempts to isolate the unreported intermediate by 19F NMR (-6.3 ppm peak) were
not successful owing to the instability of this intermediate (stable in ACN as a stock
solution for hours, but decomposed right away after filtration). However, the mass
corresponding to the cation of intermediate B was found by GC-MS, which further
supported our hypothesis.
6.3 Conclusion
In conclusion, an operationally simple method for trifluoromethoxylation of benzyl
bromides with commercially available and inexpensive reagents CDI was descripted in
this chapter. Deep diving into the reaction mechanism indicated that this reaction did
not underwent conventional AgOCF3 pathway which avoid the production of highly
toxic difluorophosgene intermediate. Therefore, we envision that this approach can
have instant application of drug screening purposes.

234
6.4 Experimental data. General procedures and characterization data
General procedure for the preparation of 2
To a 7-mL oven dried vial, AgF (3.2 equiv, 3.2 mmol, 406.2 mg), CDI (1.0 equiv,
1.0 mmol, 162.1 mg) and 1 (1.0 equiv, 1.0 mmol) were added under Ar protection. Dry
ACN (4.0 mL) was added into the reaction vial under N2 protection at room temperature,
and the resulting mixture was allowed to stir at room temperature for 6 hours. After the
reaction is complete, water (20 mL) was added to the reaction mixture, and extracted
with DCM (20 mL x 3). The organic layer was combined and washed with water (20
mL) and brine (20 mL). Then the resulting organic layer was dried with Na2SO4, and
filtered. The organic solvent was removed under reduced pressure, and the crude
mixture was purified by flash chromatography to afford the final product 2.
Notes: 1. Since many of the products are volatile compounds, the products were wet
loaded with pentane for column.
2. While removing solvents via rotovap, the pressure was set to be at least 300 torr at
room temperature to avoid significant loss of the volatile products.

235
Detailed optimization data
Table 6.2 Solvent screening
Trail Solvents (ml) Yield (%)
1 ACN 53
2 DMF 12
3 THF 5
4 Toluene 6
5 DCM 11
6 0.5 ACN + 1.5 DCM 19
7 1 ACN + 1 DCM 26
8 1.5 ACN + 0.5 DCM 34
9 0.5 ACN + 1.5 Et2O 12
10 1 ACN + 1.5 Et2O 27
11 1.5 ACN + 0.5 Et2O 39
12 1.75 ACN + 0.25 Et2O 39

236
Table 6.3 Reaction temperature screening
Trail Temperature (
oC) Yield (%)
1 60 27
2 60 oC for 1 h then rt for 5 h 20
3 80 4
4 50 30
5 40 31
6 30 44
7 rt for 1 h then 60 oC for 5 h 6
8 -30 0
9 -20 11
10 -10 27
11 0 33
12 -30 for 1 h then rt for 5 h 26
13 rt 53

237
Table 6.4 Rection time screening
Trail Time (h) Yield (%)
1 1 0
2 2 0
3 4 0
4 6 53
5 8 52
6 12 55
7 72 37
Table 6.5 Sociometry screening
Trail x: y: z Yield (%)
1 1:1:3.2 53
2 1:2:3.2 42
3 2:1:3.2 16
4 2:1:6.4 47
5 1:1:10 48

238
6 1:1:1 0
7 1:3:1 0
Table 6.6 Additive screening
Trail Additive (equiv) Yield (%)
1 1,10-phen (1 eq) 16
2 2,2-bipyridine (1 eq) 18
3 DBU (1 eq) 0
4 TMEDA (1 eq) 0
5 PPh3 (1 eq) 7
6 KI (0.5 eq) 0
7 CuI (0.2 eq) 12
8 TMACl (1.0 eq) 0
9 TMABr (1.0 eq) 0
10 TMABr (0.2 eq) 33
11 TBAB (0.5 eq) 27
12 TBAI (0.5 eq) 39
13 TBAC (0.5 eq) 21
14 TEBAC (0.5 eq) 0

239
15 TEBAB (0.5 eq) 0
16 TBAPF6 (0.5 eq) 36
17 TBABF4 (0.5 eq) 24
18 TBAI (0.5 eq) 29
19 TBAI (1.0 eq) 30
20 TBAI (0.2 eq) 46
21 KHF2 (1.0 eq) 35
22 KHF2 (0.3 eq) 38
1-((Trifluoromethoxy)methyl)-4-(trifluoromethyl)benzene (2b)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2b (76.1 mg, 31% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.02 Hz, 2H), 7.49 (d, J = 7.92 Hz, 2H),
5.05 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -61.17 (s, 3F), -63.29 (s, 3F). The 1H NMR
and 19F NMR data obtained agreed with literature report.
49
4-((Trifluoromethoxy)methyl)benzonitrile (2c)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2c
(77.6 mg, 39% isolated yield). Colorless liquid.

240
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.33 Hz, 2H), 7.48 (d, J = 7.69 Hz, 2H),
5.04 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -61.24 (s). The 1H NMR and 19F NMR
data obtained agreed with literature report.
49
1-Nitro-4-((trifluoromethoxy)methyl)benzene (2d)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2d (78.2 mg, 35% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.31 Hz, 2H), 7.55 (d, J = 8.26 Hz, 2H),
5.10 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -61.29 (s). The 1H NMR and 19F NMR
data obtained agreed with literature report.
444
1-Iodo-4-((trifluoromethoxy)methyl)benzene (2e)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2e
(106.0 mg, 35% isolated yield). Colorless liquid. The 1H NMR and 19F NMR data
obtained agreed with literature report.
49
1-Iodo-2-((trifluoromethoxy)methyl)benzene (2f)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2f

241
(75.0 mg, 25% isolated yield). Colorless liquid.445
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.93 Hz, 1H), 7.46 – 7.38 (m, 2H), 7.07 (td,
J = 7.78, 1.68 Hz, 1H), 5.02 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -61.05 (s).
1-Bromo-4-((trifluoromethoxy)methyl)benzene (2g)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2f
(105.9 mg, 42% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.39 Hz, 2H), 7.24 (d, J = 8.36 Hz, 2H),
4.94 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -60.96 (s). The 1H NMR and 19F NMR
data obtained agreed with literature report.
49
1-Bromo-3-((trifluoromethoxy)methyl)benzene (2h)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2h (102.6 mg, 40% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.52 – 7.49 (m, 2H), 7.30 – 7.24 (m, 2H), 4.94 (s, 2H);
19F NMR (376 MHz, CDCl3) δ -61.06 (s). The 1H NMR and 19F NMR data obtained
agreed with literature report.
444

242
1-(Methylsulfonyl)-4-((trifluoromethoxy)methyl)benzene (2i)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2i
(105.2 mg, 41% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.44 Hz, 2H), 7.58 (d, J = 8.27 Hz, 2H),
5.08 (s, 2H), 3.06 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -61.23 (s). The 1H NMR and
19F NMR data obtained agreed with literature report.
330
4-((Trifluoromethoxy)methyl)benzenesulfonyl fluoride (2j)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2j
(105.2 mg, 41% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.05 Hz, 2H), 7.64 (d, J = 8.05 Hz, 2H),
5.12 (s, 2H); 19F NMR (376 MHz, CDCl3) δ 65.59 (s, 1F), -61.37 (s, 3F); 13C NMR
(126 MHz, CDCl3) δ 142.3, 133.5 (d, J = 25.18 Hz), 130.0 (d, J = 60.11 Hz), 128.7 (d,
J = 76.58 Hz), 121.7 (q, J = 256.60 Hz), 67.4; FT-IR (
-1 cm-1
) 3708, 3326, 2981, 1675,
1592, 1456, 1213, 1132, 1053, 1011, 977;
1-((Phenylsulfonyl)methyl)-2-((trifluoromethoxy)methyl)benzene (2k)

243
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2k (94.9 mg, 29% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.73 – 7.64 (m, 3H), 7.53 – 7.49 (m, 2H), 7.39 – 7.36
(m, 2H), 7.31 – 7.27 (m, 1H), 7.07 (d, J = 7.45 Hz, 1H), 5.03 (s, 2H), 4.44 (s, 2H); 19F
NMR (376 MHz, CDCl3) δ -60.90 (s); 13C NMR (126 MHz, CDCl3) δ 138.3, 134.2,
134.1, 133.0, 130.7, 129.6, 129.6, 129.3, 128.6, 127.2, 121.6 (q, J = 256.32 Hz), 67.3
(q, J = 3.23 Hz), 59.5; FT-IR (
-1 cm-1
) 3065, 2926, 1447, 1319, 1256, 1134, 1083, 881,
848, 782; HRMS (ESI) m/z calculated for C15H13F3O3SNa [M + Na]
+
: 353.0435; found
353.0430 (1.4163 ppm).
1-(tert-Butyl)-4-((trifluoromethoxy)methyl)benzene (2l)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2l
(67.7 mg, 29% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.38 Hz, 2H), 7.31 (d, J = 8.34 Hz, 2H),
4.96 (s, 2H), 1.33 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -60.78 (s). The 1H NMR and
19F NMR data obtained agreed with literature report.
49
1-Phenoxy-3-((trifluoromethoxy)methyl)benzene (2m)

244
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2m (99.9 mg, 37% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.33 (m, 3H), 7.16 – 7.09 (m, 2H), 7.03 – 6.99
(m, 4H), 4.95 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -60.94 (s); 13C NMR (126 MHz,
CDCl3) δ 157.9, 156.9, 135.9, 130.3, 130.0, 123.8, 122.6, 121.0, 119.3, 119.2, 118.3,
68.7 (q, J = 3.55 Hz); FT-IR (
-1 cm-1
) 3069, 1695, 1563, 1488, 1257, 1158, 1073, 1014;
HRMS (ESI) m/z calculated for C14H11F3O2 [M]+
: 268.0711; found 268.0703 (2.9843
ppm).
Methyl 4-nitro-2-((trifluoromethoxy)methyl)benzoate (2n)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2n (88.0 mg, 32% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.27 – 8.21 (m, 2H), 5.52 (s, 2H), 3.98 (s,
3H); 19F NMR (376 MHz, CDCl3) δ -61.24 (s); 13C NMR (126 MHz, CDCl3) δ 165.4,
150.4, 139.1, 132.6, 132.3 (m), 122.9 (d, J = 11.16 Hz), 122.2 (d, J = 27.99 Hz), 121.8
(q, J = 256.14 Hz), 66.2 (q, J = 3.61 Hz), 53.2; FT-IR (
-1 cm-1
) 2958, 1724, 1617,
1587, 1438, 1348, 1257, 1139, 1079, 1038, 961; HRMS (ESI) m/z calculated for
C10H8NF3O5 [M]+
: 279.0355; found 279.0359 (1.4335 ppm).

245
Methyl 4'-((trifluoromethoxy)methyl)-[1,1'-biphenyl]-2-carboxylate (2o)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford 2o
(119.2 mg, 38% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.63, 1.10 Hz, 1H), 7.55 (td, J = 7.66, 1.47
Hz, 1H), 7.45 – 7.40 (m, 3H), 7.37 – 7.33 (m, 3H), 5.04 (s, 2H), 3.66 (s, 3H); 19F NMR
(376 MHz, CDCl3) δ -60.79 (s); 13C NMR (126 MHz, CDCl3) δ 168.9, 142.2 (d, J =
27.21 Hz), 132.9, 131.6, 130.9, 130.8, 130.1, 128.9, 127.9, 127.6, 121.9 (q, J = 255.38
Hz), 69.1 (q, J = 3.49 Hz), 52.1; FT-IR (
-1 cm-1
) 2951, 1726, 1652, 1520, 1434, 1245,
1126, 1091, 1033, 884; HRMS (ESI) m/z calculated for C16H14F3O3 [M + H]
+
:
311.0890; found 311.0897 (2.2502 ppm).
4-((Trifluoromethoxy)methyl)-1,1'-biphenyl (2p)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2p (100.3 mg, 40% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.64 – 7.59 (m, 4H), 7.48 – 7.44 (m, 4H), 7.40 – 7.36
(m, 1H), 5.04 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -60.79 (s). The 1H NMR and 19F
NMR data obtained agreed with literature report.
49

246
2-((Trifluoromethoxy)methyl)anthracene-9,10-dione (2q)
Known compound. Performed on 1.0 mmol scale, eluted with pure pentane to afford
2q (29.6 mg, 10% isolated yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 8.36 – 8.29 (m, 4H), 7.82 – 7.79 (m, 3H), 5.14 (s, 2H);
19F NMR (376 MHz, CDCl3) δ -61.19 (s); 13C NMR (126 MHz, CDCl3) δ 182.8, 182.8,
144.4, 140.5, 134.5, 134.5, 133.9, 133.7, 133.6, 132.8, 128.1, 127.5, 127.5, 126.1, 121.8
(q, J = 256.54 Hz), 67.9; FT-IR (
-1 cm-1
) 3326, 2956, 1674, 1591, 1457, 1393, 1269,
1213, 1176, 1052, 976;

247
Chapter 7
Investigation on TMSCF2Br as a potential difluorocarbene source for 18F-labeled
trifluoromethylation.
7.1 Introduction
As mentioned in Chapter 1.,
18F-labeled trifluoromethylation is of increasing interest
in recent decades due to vast numbers of commercially available CF3-contained
pharmaceutical molecules.37,446 The existing literatures on toxicological,
pharmacodynamics and pharmacokinetics profiles of these drug candidates
dramatically facilitate the design and development of the corresponding [18F]CF3
tracers. However, current prevalent methods to achieve [18F]trifluoromethylation (
19F
to 18F isotopic exchange and nucleophilic substitution) are limited by low molar
activities and low radiochemical yields. This is mainly owing to the dilution of
unlabeled products generated from 18F19F isotopic exchange side reactions.272
Therefore, novel synthetic methods to prepare 18F-labeled trifluoromethylated
compounds with high molar activities and radiochemical yields are highly desired.
Difluorocarbene-mediated [18F]trifluoromethylation has been developed to mitigate
undesired 18F19F isotopic exchange. It has benefited from the numerous available
difluorocarbene precursors and trifluoromethylation protocols developed based on
these reagents. Various difluorocarbene sources including HCF2I, Ph3P
+CF2CO2
-
and
EtCO2CF2X (X = Br and Cl) have been reported to achieve 18F-labeled
trifluoromethylation with improved radio activities.
38,39,291
On the other hand, TMSCF2Br is leading a new trend as a difluorocarbene precursors

248
in the past decade.30 This versatile regent was reported to accomplish multiple
previously challenging fluoroalkylation reactions because it can be activated by
different types of activators (strong basic,111 weak basic,140 weak acidic413 and neutral
activators137). It can also release difluorocarbene under various temperatures including
high temperatures,88 room temperature111 and low temperature112
. Moreover,
TMSCF2Br could also be prepared efficiently with non-ozone-depleting reagents
TMSCF3 and BBr3.
137 As such, it is obvious to envision that TMSCF2Br could be an
ideal difluorocarbene reagent to synthesize [18F]trifluoromethylated tracers.
7.2 Results and discussion
Table 7.1. Optimization of 2aa
Trail Solvent (mL) -F (X equiv) Temperature (oC) Yield
(%)
1 ACN (1.3) KF (1.2) rt 61
2 THF (1.3) KF (1.2) rt 0
3 Et2O (1.3) KF (1.2) rt 0
4 DMF (1.3) KF (1.2) rt 0
5 DMSO (1.3) KF (1.2) rt 0
6 Toluene (1.3) KF (1.2) rt 0
7 PhCN (1.3) KF (1.2) rt 35

249
8 Propionitrile (1.3) KF (1.2) rt 45
9 Isobutyronitrile (1.3) KF (1.2) rt 55
10 ACN-d3 (1.3) KF (1.2) rt 60
11b ACN KF (1.2) rt 63
12 ACN KF (1.2) 30 (68) 76
13 ACN KF (1.2) 45 52
14 ACN KF (1.2) 0 5
15 ACN NaF (1.2) 30 52
16 ACN CsF (1.2) 30 36
17 ACN TMAF (1.2) 30 0
18c ACN TBAF (1.2) 30 0
19 ACN TBAT (1.2) 30 0
20d ACN KF (1.2) 30 66
21 ACN KF (1.5) 30 50
22 ACN KF (2.0) 30 34
23 ACN KF (1.0) 30 65
24 ACN KF (0.5) 30 22
24e ACN KF (1.2) 30 70
25f ACN KF (1.2) 30 55
aReactions were performed at 0.25 mmol scale. The yields were determined by 19F NMR using trifluorotoluene as an internal
standard. bFreshly distilled ACN (over P2O5) was used as the solvent. cTBAF was added as a 1M stock solution in THF. dK222 was
used. e2 equiv of 1a was used. f0.5 equiv of 1a was used.
Initial trail with model substrate 1a showed that 61% of 2a could be obtained with
TMSCF2Br (1 equiv), KF (1.2 equiv), 18-C-6 (1.2 equiv) in ACN (1.3 mL) at room

250
temperature for 10 minutes (Table 7.1, trail 1). Replacing the solvent to other
conventional organic solvents including THF, DMF, Et2O, toluene and DMSO led to
completely no yield (Table 7.1, trail 2-6). Changing ACN to nitrile-contained solvents
such as PhCN, propionitrile and isobutyronitrile gave 2a with lower yields (Table 7.1,
trail 7-9). Notably, ACN-d3 and freshly distilled ACN furnished 2a in compatible yields
compared to DrisolvR ACN (Table 7.1, trail 10 and 11). Increasing temperature to 30
oC improved the yield to 76% by 19F NMR (Table 7.1, trail 12). However, further
increasing the reaction temperature did not improve the yield (Table 7.1, trail 13).
Decreasing the temperature to 0 oC dramatically lower the yields owing to low
solubility of 18-C-6 in ACN at that temperature (Table 7.1, trail 14). Utilizing other
inorganic fluorides such as NaF and CsF lowered the yields, while organic fluorides
such as TBAF, TMAF and TBAT dramatically deterred the yields (Table 7.1, trail 15-
19). Employing K2,2,2 as the phase transfer catalyst slightly reduced the yield of 2a
compared to 18-C-6 (Table 7.1, trail 20). Increasing and reducing the loading of KF
did not improve the yields (Table 7.1, trail 21-24). Similarly, changing the equivalence
of substrate 1a also yielded less 2a (Table 7.1, trail 25 and 26).
With the optimal conditions in hand, we further explore the substrate scope
(Scheme 7.1). Model substrate 1a afforded 68% of 2a. 2-Nitro-substituted substrate 1b
furnished 2b in 46% isolated yield. Other electron-deficient substituents 1c and 1d were
also tolerated in moderate to good yields. 4- and 2-bromo-benzaldehydes 1e and 1f
provided 60% and 56% of 2e and 2f, respectively. 3-fluoro-product 2g was also
synthesized in 52% yield. Benzaldehyde 1h produced 51% of the corresponding

251
trifluoromethylated product 2h. Electron-donating group attached substrate 1i could
also be converted into 2i in good yields by 19F NMR. However, significant loss of
yield was observed during the isolation owing to the high volatility of 2i. Surprisingly,
1-bromo-naphthalene substrate 1j only yielded 23% of the target product 2j.
Benzo[b]thiophene-2-carbaldehyde 1k was also tolerated under optimal conditions to
give 2k in 42% isolated yield. Acyclic aliphatic aldehydes 1l and 1m afforded the
corresponding trifluoromethylated products 2l and 2m in modest yields. Even though
2o and 2p were observed by 19F NMR in the reaction mixture, they were not isolated
successfully due to high volatilities (both compounds completely evaporated under 325
torr at room temperature). Benzophenone substrate 1q afforded only trace amount of
2q even under the optimal conditions. Moreover, a large amount of HCF3 was observed
by 19F NMR. Since benzophenone is much less electrophilic than benzaldehyde, -CF3
anion tends to react with acetonitrile to form HCF3 instead of benzophenone. Increasing
the loading of the substrate to 4 equivalences improved the yield of 2q to 18%. Further
optimization of the conditions did not provide higher yields. For the same reason, other
benzophenones with electron-donating substituents only gave trace amount of the target
products. Similarly, acetophenones with electron-withdrawing substituents 1r, 1s, 1t
and 1u furnished the corresponding trifluoromethylated product in modest to good
yields.

252
Scheme 7.1 Substrate scope of trifluoromethylation of benzaldehydes, acetophenones,
benzophenones (2)
aReactions were formed in 0.25 mmol scale with KF (1.2 equiv), TMSCF2Br (1 equiv), 18-C-6 (1.2 equiv) and ACN (1.3 mL).
Yields were determined by 19F NMR using trifluorotoluene as an internal standard. bKF (2 equiv), 18-C-6 (2 equiv) and ACN (2.2
mL) were used. c1.5 mL of ACN was used. dKF (2 equiv), 18-C-6 (2 equiv), ACN (2.2 mL) and 1i (4 equiv) were used. e2.5 mL of
ACN was used. fKF (1.5 equiv), 18-C-6 (1.5 equiv), ACN (2 mL) and 1p (4 equiv) were used. g4 equiv of substrates were used.
Then Cu-mediated trifluoromethylation with TMSCF2Br was also investigated. 3a

253
was chosen as the model substrate. Multiple CuI
salts were used to generate CuCF3
species, and CuCl provided highest yield of [CuCF3] (Table 7.2, trail 1-5). Since CuCl
is extremely air sensitive, the purchased CuCl was purified by washing with
concentrated HCl, ethanol, and ether and dried under reduced pressure prior to being
utilized for the reactions.
Table 7.2 Optimization for the preparation of [CuCF3] with TMSCF2Br
Trail CuI
salts -F solvent Ligand Yields (%)
1 CuI KF DMF L1 28
2 CuBr KF DMF L1 36
3 CuCl KF DMF L1 55
4 CuTc KF DMF L1 20
5 CuOTf KF DMF L1 16
6 CuCl NaF DMF L1 45
7 CuCl CsF DMF L1 39

254
8 CuCl TBAF DMF L1 0
9 CuCl KF THF L1 11
10 CuCl KF ACN L1 3
11 CuCl KF DMA L1 46
12 CuCl KF DMF L2 16
13 CuCl KF DMF L3 72
14 CuCl KF DMF L4 trace
15 CuCl KF DMF L5 17
16 CuCl KF DMF L6 22
17 CuCl KF DMF L7 42
18 CuCl KF DMF L8 10
19
b CuCl KF DMF L3 42
aReactions were performed at 0.25 mmol scale. The yields were determined by 19F NMR using trifluoromethoxybenzene as an
internal standard. TMSCF2Br was added dropwisely in 4 minutes. bTMSCF2Br was added in one portion.
KF was determined to be the most suitable fluoride source which afforded 55% of
the CuCF3 species (Table 7.2, trail 6-8). Changing DMF into other organic solvents
such as THF, ACN and DMA deterred the yields (Table 7.2, trail 9-11). Notably, the
solvents need to be degassed via “freeze pump thaw” to circumvent reproducibility
issues owing to the high air sensitivity of CuI
. Different ligands were also examined
and L3 furnished 72% of [CuCF3] (Table 7.2, trail 12-18). Adding TMSCF2Br in one
portion dramatically lower the yield (Table 7.2, trail 19).

255
Table 7.3 Optimization of trifluoromethylation of diaryliodonium salts (4)a
Trail X (equiv) Solvent (mL) Temperature (oC) Time (min) Yield (%)
1 1 DMF 0 10 20
2 1 ACN 0 10 75
3 1 ACN 0 20 77
4 2 ACN 0 10 65
5 0.5 ACN 0 10 45
6 1 ACN rt 10 (92) 100
aReactions were performed at 0.25 mmol scale. The yields were determined by 19F NMR using trifluoromethoxybenzene as an
internal standard.
After the conditions to prepare [CuCF3] was optimized, the reactivity of the [CuCF3]
with diaryliodinium salts was explored. Initial attempt started with adding a stock
solution of 3a (1 equiv) in DMF (1.3 mL) solution directly into the pre-generated
[CuCF3] mixture at 0 oC and 20% of 5a was detected by 19F NMR (Table 7.3, trail 1).
Replacing DMF with ACN as the solvent to dissolve 3a dramatically improve the yield
(Table 7.3, trail 2). Extending the reaction time failed to increase the yield (Table 7.3,
trail 3). Increasing or decreasing the equivalence of 3a deterred the yield of 5a (Table
7.3 trail, 4 and 5). Finally, when the reaction temperature was increased to room
temperature, quantitative amount of 5a was observed by 19F NMR (Table 7.3, trail 6).
Since diaryliodonium salts 3 are not commercially available and required tedious

256
preparation procedures, the reactivity of [CuCF3] to commercially available and
inexpensive boronic acids 4 was examined. As shown in Table 7.4, various oxidants
were investigated, and air proved to be the optimal oxidant which readily converted all
the CuICF3 into the corresponding CuII
-intermediates in 5 minutes and afforded 56% of
5a (Table 7.4, trail 1-12). Among all the bases that were tested, TMSOK furnished
highest yield of 5a (79% by 19F NMR) (Table 7.4, trail 13-17). Replacing DMF with
other conventional organic solvents such as ACN, THF and DMSO lowered yields
(Table 7.4, trail 18-20). Changing the concentration did not improve the yield (Table
7.4, trail 21 and 22). At last, increasing or decreasing reaction temperature deterred the
yield of 5a (Table 7.4, trail 23 and 24).
Table 7.4 Optimization of trifluoromethylation of 4aa
Trail Oxidant Base (equiv) Solvent (mL) T (oC) Yield (%)
1 Ag2CO3 KO-tBu (1) DMF 45 47
2 AgOTf KO-tBu (1) DMF 45 49
3 DDQ KO-tBu (1) DMF 45 16
4 TEMPO KO-tBu (1) DMF 45 12
5 TCQ KO-tBu (1) DMF 45 37
6 AgOAc KO-tBu (1) DMF 45 21
7 AgNO3 KO-tBu (1) DMF 45 7

257
8
b AgOTf KO-tBu (1) DMF 45 22
9
c AgOTf KO-tBu (1) DMF 45 48
10 AgOTf KO-tBu (2) DMF 45 33
11d Air KO-tBu (1) DMF 45 36
12e Air KO-tBu (1) DMF 45 58
13 Air K3PO4 (1) DMF 45 29
14 Air K2CO3 (1) DMF 45 10
15 Air NaO-tBu (1) DMF 45 51
16 Air NaHCO3 (1) DMF 45 18
17 Air TMSOK (1) DMF 45 79
18 Air TMSOK (1) ACN 45 34
19 Air TMSOK (1) THF 45 0
20 Air TMSOK (1) DMSO 45 6
21 Air TMSOK (1) DMF (2.6 mL) 45 75
22 Air TMSOK (1) DMF (0.65 mL) 45 56
23 Air TMSOK (1) DMF (1.3 mL) 60 46
24 Air TMSOK (1) DMF (1.3 mL) rt 29
aReactions were performed at 0.25 mmol scale. The yields were determined by 19F NMR using trifluoromethoxybenzene as an
internal standard. After AgOTf was added, the resulting mixture was allowed to be stirred for 10 minutes. bAfter AgOTf was
added, the resulting mixture was allowed to be stirred for 5 minutes. c After AgOTf was added, the resulting mixture was allowed
to be stirred for 15 minutes. dThe reaction was exposed to air for 5 minutes. eAir was inject into the mixture with syringe (head into
the solution) for 5 minutes.

258
Scheme 7.2 Substrate scope of trifluoromethylation of diaryliodinium salts (3) and
boronic acids (4)
aReactions were performed at 0.25 mmol scale with CuCl (1 equiv), KF (4 equiv), TMSCF2Br (1 equiv), 18-C-6 (4 equiv), 4,7-
diphenyl-1,10-phenanthroline (1 equiv), diaryliodonium salts 3 (1 equiv) and ACN (1.3 mL) . Yields in parentheses were
determined by 19F NMR using trifluoromethoxybenzene an internal standard. bReactions were performed at 0.25 mmol scale
with CuCl (1 equiv), KF (4 equiv), TMSCF2Br (1 equiv), 18-C-6 (4 equiv), 4,7-diphenyl-1,10-phenanthroline (1 equiv), TMSOK
(1 equiv) and boronic acids 4 (1.0 equiv). Yields in parentheses were determined by 19F NMR using trifluoromethoxybenzene
an internal standard.
Multiple diaryliodonium salts were prepared and adapted to the optimal conditions

259
(Scheme 7.2, Method A). Electron-withdrawing groups 3a and 3b afford 5a and 5b in
100% and 49% isolated yield, respectively. In contrast, 4-methoxy substrate 3i only
yielded 22% of 5i by 19F NMR. However, the product was not isolated owing to the
high volatility of 5i.
Then, the substrate scope of Method B was also investigated with various boronic
acids. 4a, 4b and 4i all furnished compatible yields of 5a, 5b and 5i (Scheme 7.2
Method B). Styrene boronic acid 4c afforded 5c in 19% yield. Carbonyl-contained
substituents such as acetyl (4d), ester (4e), and aldehyde (4f) were all tolerated under
optimal conditions in modest to good yields. Electron-rich substrates 4g and 4h
provided 35% and 36% of 5g and 5h, respectively. 2-(trifluoromethyl)naphthalene, 5j
was obtained from 4j in 43% isolated yield. Heterocyclic substrate 4k also yielded 53%
of 5k. Trifluoromethylated dibenzofuran was synthesized from 4l in good yield.
However, the product was not isolated owing to the inseparable homo-coupling
byproduct.
Scheme 7.3. Substrate scope of trifluoromethylation of diphenyldisulfide and terminal
alkyne.
PhSCF3 (7) could be prepared from diphenyl disulfide (6), TMSCF2Br, KF and 18-

260
C-6. However, for electron-rich diphenyl disulfides or aliphatic disulfides, RS-CF2-SR
were detected as the predominant product with trace amount of the desired
trifluoromethylated compound. Terminal alkyne 8 was also subjected to Method B.
However, only 13% of the target product was generated along with a large amount of
homo-coupling byproduct (> 60%) by GC-MS (Scheme 7.3).
7.3 Conclusion
In conclusion, this work disclosed the reactivity of TMSCF2Br with fluorides to
generate -CF3 anion which readily reacted with benzaldehydes, benzophenones,
acetophenones, diphenyl disulfides, terminal alkynes to afford the corresponding
trifluoromethylated products. It could react with CuI salts to form [CuCF3] in situ and
produce PhCF3 compounds with diaryliodonium salts and boronic acids. With these
[
19F]trifluoromethylation conditions in hand, further investigation of utilizing
TMSCF2Br for 18F-labeled trifluoromethylation is in progress.
7.4 Experimental Data. General procedures and characterization data
General procedure for the preparation of 2
To an oven-dried 7-mL microwave vial, 1 (1.0 equiv, 0.25 mmol), KF (1.2 equiv,
0.3 mmol, 17.4 mg) and 18-C-6 (1.2 equiv, 0.3 mmol, 79.3 mg) were added under Ar
protection in glovebox. Then, 1.3 mL of ACN was added and the resulting mixture was
allowed to stir at 30 oC in a water bath. TMSCF2Br (1.0 equiv, 0.25 mmol, 50.8 mg, 39
uL) was added in one portion into the mixture at 30 oC and the resulting solution was
allowed to stir for 10 minutes at the same temperature. After the reaction finished, the

261
reaction mixture was diluted with DCM (20 mL), and water (20 mL) was added. The
organic layer was collected, and the aqueous layer was extracted with DCM (20 mL x
2). The combined organic layer was washed with water (20 mL) and brine (20 mL),
and dried with Na2SO4. The drying agent was filtered, and the organic solvent was
removed under reduced pressure. The residue was purified by flash column
chromatography to afford products 2.
General procedure for the preparation of 5 from 3
To an oven-dried 7-mL microwave vial, KF (4.0 equiv, 1.0 mmol, 17.4 mg) and
18-C-6 (4 equiv, 1.0 mmol, 264.3 mg), CuCl (1.0 equiv, 0.25 mmol, 24.8 mg) and 4,7-
diphenyl-1,10-phenanthroline (1.0 equiv, 0.25 mmol, 83.1 mg) were added under Ar
protection in glovebox. Then 1.3 mL of DMF was added, and the resulting mixture was
allowed to stir at 0 oC in an ice-water bath. TMSCF2Br (2.0 equiv, 0.5 mmol, 101.6 mg,
78 uL) was added dropwise into the mixture at 0 oC (the addition completed in about 4
minutes) and the resulting solution was allowed to stir for 10 mins at the same
temperature. After that, 3 (0.25 equiv, 0.25 mmol) in ACN (1.3 mL) solution was added
into the reaction mixture under Ar protection, and the resulting solution was allowed to
stir at room temperature for 10 mins. After the reaction finished, the reaction mixture
was diluted with EtOAc (20 mL), and water (20 mL) was added. The organic layer was
collected, and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined
organic layer was washed with water (20 mL x 3) and brine (20 mL x 3), and dried with
Na2SO4. The drying agent was filtered, and the organic solvent was removed under

262
reduced pressure. The residue was purified by flash column chromatography to afford
products 5.
General procedure for the preparation of 5 from 4
To an oven-dried 7-mL microwave vial, KF (4.0 equiv, 1.0 mmol, 17.4 mg) and
18-C-6 (4 equiv, 1.0 mmol, 264.3 mg), CuCl (1.0 equiv, 0.25 mmol, 24.8 mg) and 4,7-
diphenyl-1,10-phenanthroline (1.0 equiv, 0.25 mmol, 83.1 mg) were added under Ar
protection in glovebox. Then 1.3 mL of DMF was added, and the resulting mixture was
allowed to stir at 0 oC in an ice-water bath. TMSCF2Br (2.0 equiv, 0.5 mmol, 101.6 mg,
78 uL) was added dropwise into the mixture at 0 oC (the addition completed in about 4
minutes) and the resulting solution was allowed to stir for 10 mins at the same
temperature. After that, the reaction mixture was exposed to air, and air was injected
into the mixture (needle head into the solution) for 5 minutes. TMSOK (1 equiv, 0.25
mmol, 32.1) was added in solid form into the reaction mixture. Then, 4 (1.0 equiv, 0.25
mmol) in DMF (1.3 mL) solution was added into the reaction mixture, and the solution
was allowed to stir for 20 mins at 45 oC in an oil-bath in air. After the reaction finished,
the reaction mixture was diluted with EtOAc (20 mL), and water (20 mL) was added.
The organic layer was collected, and the aqueous layer was extracted with EtOAc (20
mL x 2). The combined organic layer was washed with water (20 mL x 3) and brine (20
mL x 3), and dried with Na2SO4. The drying agent was filtered, and the organic solvent
was removed under reduced pressure. The residue was purified by flash column
chromatography to afford products 5.

263
Trimethyl(2,2,2-trifluoro-1-(4-nitrophenyl)ethoxy)silane (2a)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 2a (25.0 mg, 68%
yield). Yellow oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.7 Hz, 2H), 7.66 (d, J
= 8.2 Hz, 2H), 5.02 (q, J = 6.2 Hz, 1H), 0.15 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -
78.6 (d, J = 6.5 Hz). The 19F NMR and 1H NMR data obtained agreed with literature
report.
447
Trimethyl(2,2,2-trifluoro-1-(2-nitrophenyl)ethoxy)silane (2b)
Performed on 0.25 mmol scale, 0.5 mmol of KF, 18-C-6 and 2.2 mL of ACN were used,
eluted with pure pentane to afford 2b (17.1 mg, 46% yield). Yellow oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.70 (t, J
= 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 6.12 (q, J = 6.0 Hz, 1H), 0.17 (s, 9H); 19F NMR
(376 MHz, CDCl3) δ -78.6 (d, J = 6.1 Hz). The 19F NMR and 1H NMR data obtained
agreed with literature report.
187

264
Trimethyl(2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl)ethoxy)silane (2c)
Performed on 0.75 mmol scale, at room temperature, eluted with 70% DCM in pentane
to afford 2c (40.9 mg, 33% yield). White solid. Mp: 61 – 64 oC.
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 5.00
(q, J = 6.0 Hz, 1H), 3.08 (s, 3H), 0.15 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -78.6 (d,
J = 6.3 Hz); 13C NMR (101 MHz, CDCl3) δ 141.6, 141.4, 128.7, 127.6, 123.9 (d, J =
282.7 Hz), 72.8 (d, J = 32.5 Hz), -0.2. FT-IR (ν
-1
cm-1
) 2962, 2933, 2360, 2022, 2011,
1603, 1411, 1375, 1303, 1259, 1200, 1166, 1149, 1125, 1102, 1087, 1013, 958, 864,
846, 763, 735, 696, 672, 621, 549, 535, 478, 471. HRMS (ESI) m/z calculated for
C12H17F3O3SSi [M + H]+
: 327.0693; found 327.0692 (0.3057 ppm).
(1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethoxy)trimethylsilane (2d)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 2d (27.3 mg, 68%
yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.92 (m, 3H), 5.05 (q, J = 6.6 Hz, 1H), 0.17 (s, 9H); 19F
NMR (376 MHz, CDCl3) δ -63.4 (s, 2F), -78.8 (d, J = 6.2 Hz, 3F); 13C NMR (101
MHz, CDCl3) δ 138.3, 132.1 (q, J = 33.6 Hz), 127.8, 123.6 (d, J = 282.7 Hz), 123.4
(m), 123.2 (d, J = 272.8 Hz), 72.4 (d, J = 32.8 Hz), -0.2. FT-IR (ν
-1
cm-1
) 2959, 2919,

265
2854, 2362, 1628, 1507, 1465, 1418, 1384, 1364, 1340, 1276, 1171, 1128, 1052, 976,
907, 877, 842, 808, 753, 714, 682, 659, 630, 568, 550, 528, 469. HRMS (ESI) m/z
calculated for C13H13F9OSi [M - TMS]-
: 311.0124; found 311.0122 (0.6431 ppm).
(1-(4-Bromophenyl)-2,2,2-trifluoroethoxy)trimethylsilane (2e)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 2e (24.5mg, 60%
yield). Colorless oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.5 Hz, 2H), 7.32 (d, J
= 8.4 Hz, 2H), 4.86 (q, J = 6.6 Hz, 1H), 0.12 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -
79.1 (d, J = 6.3 Hz). The 19F NMR and 1H NMR data obtained agreed with literature
report.
187
(1-(2-Bromophenyl)-2,2,2-trifluoroethoxy)trimethylsilane (2f)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 2f (22.9 mg, 56%
yield). Colorless oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.8 Hz, 1H), 7.56 (d, J
= 8.0 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.23 (m, 1H), 5.51 (q, J = 6.2 Hz, 1H), 0.11 (s,
9H); 19F NMR (376 MHz, CDCl3) δ -78.5 (d, J = 6.2 Hz). The 19F NMR and 1H NMR

266
data obtained agreed with literature report.
448
Trimethyl(2,2,2-trifluoro-1-(3-fluorophenyl)ethoxy)silane (2g)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 2g (34.6 mg, 52%
yield). Colorless liquid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.32 (m, 1H), 7.22 – 7.18 (m,
2H), 7.09 – 7.05 (m, 1H), 4.90 (q, J = 6.43 Hz), 0.13 (s, 9H); 19F NMR (376 MHz,
CDCl3) δ -78.95 (d, J = 6.30 Hz, 3F), -113.15 – -113.19 (m, 1F). The 19F NMR and 1H
NMR data obtained agreed with literature report.
449
Trimethyl(2,2,2-trifluoro-1-phenylethoxy)silane (2h)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 2h (47.2 mg, 51%
yield). Colorless liquid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 2H), 7.38 (m, 3H), 4.91 (q,
J = 6.6 Hz, 1H), 0.12 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -78.9 (d, J = 6.7 Hz). The
19F NMR and 1H NMR data obtained agreed with the literature report.
449

267
Trimethyl(2,2,2-trifluoro-1-(4-methoxyphenyl)ethoxy)silane (2i)
Performed on 0.25 mmol scale, 0.5 mmol of KF, 18-C-6, 2.2 mL of ACN, and 1.0 mmol
of aldehyde were used, eluted with pure pentane to afford 2i (9.7 mg, 28% yield).
Colorless liquid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 6.90 (d, J
= 8.8 Hz, 2H), 4.85 (q, J = 6.6 Hz, 1H), 3.82 (s, 3H), 0.13 (s, 9H); 19F NMR (376 MHz,
CDCl3) δ -79.2 (d, J = 6.8 Hz). The 19F NMR and 1H NMR data obtained agreed with
literature report.
449
(1-(1-Bromonaphthalen-2-yl)-2,2,2-trifluoroethoxy)trimethylsilane (2j)
Performed on 0.25 mmol scale, 2.5 mL of ACN was used, eluted with pure hexane to
afford 2j (22.6 mg, 23% yield). Colorless oil.
1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.73
(d, J = 8.6 Hz, 1H), 7.59 (m, 2H), 5.86 (q, J = 6.3 Hz, 1H), 0.10 (s, 9H); 19F NMR (376
MHz, CDCl3) δ -78.0 (d, J = 6.5 Hz); 13C NMR (101 MHz, CDCl3) δ 135.0, 133.3,
132.0, 128.4, 128.2, 128.1, 127.8, 127.5, 126.1, 124.6 (d, J = 283.3 Hz), 124.3, 72.8 (d,
J = 32.6 Hz), -0.2. FT-IR (ν
-1
cm-1
) 3073, 3062, 2955, 2925, 2854, 2179, 2163, 1971,
1559, 1504, 1458, 1369, 1328, 1268, 1254, 1220, 1173, 1127, 971, 916, 874, 841, 815,
745, 700, 658, 585, 532. HRMS (ESI) m/z calculated for C15H16BrF3OSi [M - H]-
:

268
375.0033; found 375.0040 (1.8667 ppm).
(1-(Benzo[b]thiophen-2-yl)-2,2,2-trifluoroethoxy)trimethylsilane (2k)
Performed on 0.5 mmol scale, eluted with pure pentane to afford 2k (31.9 mg, 42%
yield). White solid. Mp: 49 – 51 oC.
1H NMR (400 MHz, CDCl3) δ 7.80 (m, 2H), 7.36 (m, 3H), 5.26 (q, J = 6.3 Hz, 1H),
0.19 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -79.0 (d, J = 6.0 Hz); 13C NMR (101 MHz,
CDCl3) δ 140.0, 139.4, 139.2, 124.9, 124.6, 124.0, 123.7 (d, J = 282.5 Hz), 123.4, 122.5,
70.4 (d, J = 34.1 Hz), -0.2. FT-IR (v
-1
cm-1
) 3059, 2958, 2923, 2853, 2361, 2342, 1700,
1684, 1653, 1636, 1593, 1559, 1534, 1507, 1458, 1437, 1358, 1316, 1288, 1254, 1209,
1176, 1146, 1125, 1103, 1065, 1009, 944, 875, 843, 750, 727, 709, 683, 676, 627, 595,
564, 546, 526, 512, 489, 472, 464. HRMS (ESI) m/z calculated for C13H15F3OSSi [M
- TMS]-
: 231.0097; found 231.0088 (3.8959 ppm).
Trimethyl((1,1,1-trifluoro-3-phenylpropan-2-yl)oxy)silane (2l)
Performed on 0.75 mmol scale, eluted with pure pentane to afford 2l (26.7 mg, 27%
yield). Colorless liquid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 3H), 7.21 (m, 2H), 4.03 (m,
1H), 2.88 (m, 2H), -0.17 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -79.5 (d, J = 6.5 Hz).

269
The 19F NMR and 1H NMR data obtained agreed with literature report.
450
(E)-Trimethyl((1,1,1-trifluoro-4-(4-fluorophenyl)but-3-en-2-yl)oxy)silane (2m)
Performed on 0.75 mmol scale, eluted with pure pentane to afford 2m (25.1 mg, 23%
yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 8.3, 5.5 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H),
6.72 (d, J = 16.2 Hz, 1H), 6.09 (d, J = 15.9, 6.4 Hz, 1H), 4.53 (q, J = 6.4 Hz, 1H), 0.20
(s, 9H); 19F NMR (376 MHz, CDCl3) δ -79.2 (d, J = 6.6 Hz, 3F), -113.6 (m, 1F); 13C
NMR (101 MHz, CDCl3) δ 162.94 (d, J = 248.1 Hz), 133.8, 132.0 (d, J = 3.4 Hz), 128.6
(d, J = 8.2 Hz), 124.3 (d, J = 282.2 Hz), 122.3, 115.8 (d, J = 21.7 Hz), 72.2 (q, J = 32.6
Hz), 0.1. FT-IR (ν
-1
cm-1
) 3044, 2961, 2927, 2904, 2859, 2365, 2341, 2194, 2183, 2030,
1658, 1603, 1510, 1415, 1373, 1254, 1231, 1168, 1158, 1131, 1100, 970, 885, 838, 817,
751, 679, 652, 553, 515, 489. HRMS (ESI) m/z calculated for C13H16F4OSi [M - TMS]-
:
231.0439; found 219.0437 (0.8656 ppm).
Trimethyl(2,2,2-trifluoro-1-phenyl-1-(3,4,5-trifluorophenyl)ethoxy)silane (2q)
Performed on 0.5 mmol scale, eluted with pure pentane to afford 6b (30.5 mg, 16%
yield). Colorless liquid.

270
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.34 (m, 5H), 7.06 – 7.02 (m, 2H), -0.04 (s, 9H);
19F NMR (376 MHz, CDCl3) δ -73.17 (s, 3F), -134.52 (m, 2F), -160.7 (m, 1F); 13C
NMR (101 MHz, CDCl3) δ 151.9 (m), 149.4 (m), 140.9 (t, J = 15.4 Hz), 139.4, 138.4
(t, J = 15.3 Hz), 137.7 (td, J = 6.6, 4.5 Hz), 129.1, 128.5, 128.1 (q, J = 2.0 Hz), 121.9
(d, J = 287.8 Hz), 112.7 (m), 81.3 (q, J = 29.3 Hz), 1.3. FT-IR (ν
-1
cm-1
) 2966, 2864,
2844, 1624, 1526, 1438, 1341, 1255, 1202, 1167, 1148, 1116, 1104, 1048, 1033, 1008,
948, 885, 841, 760, 736, 709, 697, 670. Elemental Analysis Anal. Calcd for
C17H16F6OSi: C, 53.96; H, 4.26; found: C, 53.77; H, 4.57.
In 13C NMR, the doublet peak at 121.9 ppm should be a quartet (part of the peaks
overlapped with other peaks, only peaks at 126.2, 123.3, and 120.4 ppm can be
observed).
4-(1,1,1-Trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)benzonitrile (2r)
Performed on 0.5 mmol scale, eluted with 25% DCM in pentane to afford 2o (80.0 mg,
56% yield). Pale-yellow liquid.
1H NMR (400 MHz, CDCl3) δ 7.67 (s, 4H), 1.83 (s, 3H), 0.18 (s, 9H); 19F NMR (376
MHz, CDCl3) δ -81.76 (s); 13C NMR (101 MHz, CDCl3) δ 145.5, 132.0, 127.8, 127.8,
123.0 (d, J = 286.0 Hz), 118.6, 112.7, 22.7, 2.1. FT-IR (v
-1
cm-1
) 2961, 2232, 2165,
1504, 1464, 1407, 1381, 1294, 1267, 1255, 1161, 1118, 1102, 1068, 993, 841, 757, 737,
695, 625, 609. Elemental Analysis Anal. Calcd for C13H16F3NOSi: C, 54.34; H, 5.61;

271
N, 4.87; found: C, 54.27; H, 5.26; N, 4.69.
In 13C NMR, the doublet peak at 123.0 ppm should be a quartet (part of the peaks
overlapped with other peaks, only peaks at 125.9, 124.0, and 122.1 ppm can be
observed).
3-(1,1,1-Trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)benzonitrile (2s)
Performed on 0.5 mmol scale, eluted with 25% DCM in pentane to afford 2p (74.7 mg,
52% yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.66 – 7.64 (m,
1H), 7.52 – 7.48 (m, 1H), 1.83 (s, 3H), 0.18 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -
82.0 (s); 13C NMR (101 MHz, CDCl3) δ 142.0, 132.2, 131.4, 130.8, 129.1, 124.9 (q, J
= 285.9 Hz), 118.8, 112.6, 76.9 (q, J = 29.8 Hz), 22.7, 2.1. FT-IR (ν
-1
cm-1
) 2961, 2359,
2230, 2170, 1977, 1382, 1328, 1297, 1255, 1167, 1106, 993, 891, 846, 756, 691.
Elemental Analysis Anal. Calcd for C13H16F3NOSi: C, 54.34; H, 5.61; N, 4.87; found:
C, 53.98; H, 5.38; N, 4.54.
Trimethyl((1,1,1-trifluoro-2-(perfluorophenyl)propan-2-yl)oxy)silane (2t)
Performed on 0.5 mmol scale, eluted with pure pentane to afford 4b (50.7 mg, 23%

272
yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 1.97 (s, 3H), 0.15 (s, 9H); 19F NMR (376 MHz, CDCl3)
δ -83.5 (t, J = 8.7 Hz, 3F), -135.8 (m, 2F), -152.9 (m, 1F), -162.0 (m, 2F); 13C NMR
(101 MHz, CDCl3) δ 146.3 (dm, J = 255.1 Hz), 141.4 (dm, J = 256.3 Hz), 138.1 (dm,
J = 251.4 Hz), 124.6, (q, J = 286.0 Hz), 113.7 (t, J = 12.6 Hz), 24.1, 1.7. FT-IR (ν
-1
cm1
) 2964, 1650, 1526, 1485, 1467, 1387, 1310, 1298, 1256, 1173, 1152, 1139, 1105, 1086,
1036, 1015, 979, 906, 862, 842, 810, 755, 735, 694, 648, 589, 531. Elemental Analysis
Anal. Calcd for C12H12F8OSi: C, 40.91; H, 3.43; found: C, 40.90; H, 3.08.
The peak for the center carbon overlapped with CDCl3 peak in 13C NMR, thus was not
observed.
Trimethyl((1,1,1-trifluoro-2-(4-(trifluoromethyl)phenyl)propan-2-yl)oxy)silane
(2u)
Performed on 0.5 mmol scale, eluted with pure pentane to afford 4g (94.1 mg, 48%
yield). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.68 – 7.62 (m, 4H), 1.84 (s, 3H), 0.17 (s, 9H); 19F NMR
(376 MHz, CDCl3) δ -63.2 (s, 3F), -81.9 (s, 3F). The 19F NMR and 1H NMR data
obtained agreed with literature report.451

273
4-(Trifluoromethyl)benzonitrile (5a)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5a (23.7 mg, 55%).
Pale-yellow solid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.29 Hz, 2H), 7.76 (d,
J = 8.42 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -64.02 (s). The 19F NMR and 1H NMR
data obtained agreed with literature report.
452
9% of homo-coupling byproducts co-eluted with the target product.
1-Nitro-4-(trifluoromethyl)benzene (5b)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5b (12.2 mg, 25%).
Colorless Solid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.36 Hz, 2H), 7.85 (d,
J = 8.44 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -63.63 (s). The 1H NMR data obtained
agreed with literature report.
452
1-(Trifluoromethyl)-4-vinylbenzene (5c)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5c (6.2 mg, 14%).
Volatile colorless liquid.

274
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.14 Hz, 2H), 7.50 (d,
J = 8.12 Hz, 2H), 6.75 (dd, J = 17.59, 10.86 Hz, 1H), 5.85 (d, J = 17.58 Hz, 1H), 5.39
(d, J = 10.90 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -63.04 (s). The 19F NMR and 1H
NMR data obtained agreed with literature report.453
1-(4-(Trifluoromethyl)phenyl)ethan-1-one (5d)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5d (8.6 mg, 18%).
Yellow oil.
Known compound. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.05 Hz, 2H), 7.74 (d,
J = 8.05 Hz, 2H), 2.65 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -63.62 (s). The 19F NMR
and 1H NMR data obtained agreed with literature report.454
tert-Butyl 4-(trifluoromethyl)benzoate (5e)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5e (17.6 mg, 29%).
Yellow waxy solid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.22 Hz, 2H), 7.66 (d,
J = 8.22 Hz, 2H), 1.62 (s, 9H); 19F NMR (376 MHz, CDCl3) δ -63.53 (s). The 19F NMR
and 1H NMR data obtained agreed with literature report.455

275
4-(Trifluoromethyl)benzaldehyde (5f)
Performed on 0.25 mmol scale, eluted with 15% pentane in DCM to afford 5f (6.5 mg,
15 %). Colorless liquid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.02 (d, J = 7.90 Hz,
2H), 7.82 (d, J = 7.95 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -63.70 (s). The 19F NMR
and 1H NMR data obtained agreed with literature report.456
1-(Benzyloxy)-4-(trifluoromethyl)benzene (5g)
Performed on 0.25 mmol scale, eluted with 3% DCM in pentane to 10% DCM in
pentane to afford 5g (15.8 mg, 25% yield). White solid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.46 Hz, 2H), 7.45 –
7.33 (m, 5H), 7.03 (d, J = 8.57 Hz, 2H), 5.11 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -
62.03 (s). The 19F NMR and 1H NMR data obtained agreed with literature report.242
Methyl(4-(trifluoromethyl)phenyl)sulfane (5h)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5h (12.6 mg, 26 %).
Colorless liquid.
Known compound. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.17 Hz, 2H), 7.30 (d,

276
J = 8.20 Hz, 2H), 2.52 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -62.83 (s). The 19F NMR
and 1H NMR data obtained agreed with literature report.457
2-(Trifluoromethyl)naphthalene (5i)
Performed on 0.25 mmol scale, eluted with pure pentane to afford 5i (15.3 mg, 31%).
White solid.
1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.97 – 7.90 (m, 3H), 7.66 – 7.57 (m, 3H);
19F NMR (376 MHz, CDCl3) δ -62.77 (s). The 19F NMR and 1H NMR data obtained
agreed with literature report.242
5j
Performed on 0.25 mmol scale, eluted with 70% pentane in DCM to afford 5j (21.8 mg,
38%). Yellow solid.
1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.95,
1H), 3.82 – 3.80 (m, 4H), 3.61 – 3.59 (m, 4H); 19F NMR (376 MHz, CDCl3) δ -61.68
(s). The 19F NMR and 1H NMR data obtained agreed with literature report.458

277
Phenyl(trifluoromethyl)sulfane (7)
Performed on 0.25 mmol scale, eluted with 70% pentane in DCM to afford 7 (18.8 mg,
42%). Colorless liquid.
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.17 Hz, 2H), 7.51 – 7.40 (m, 3H); 19F NMR
(376 MHz, CDCl3) δ -43.27 (s). The 19F NMR and 1H NMR data obtained agreed with
literature report.166

278
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Abstract (if available)

Abstract Fluoroalkylated molecules have emerged as important moieties in pharmaceuticals, agrochemicals, and functional materials. However, naturally occurred organofluoro compounds are rare. Therefore, synthetic protocols for fluoroalkylation including monofluoromethylation, difluoromethylation, trifluoromethylation and trifluoromethoxylation are of great interest. Among all the strategies, fluorinated carbenes are potent intermediate to achieve fluoroalkylation. This thesis summarized difluoromethylation and trifluoromethylation with difluorocarbene generated from TMSCF2Br. Investigation of monofluoromethylation and trifluoromethoxylation was also discussed.

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Asset Metadata

Creator Zhu, Ziyue (author)

Core Title Probing fluorinated carbenes: a pathway to fluoroalkylation

Contributor Electronically uploaded by the author (provenance)

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Degree Conferral Date 2024-12

Publication Date 11/26/2024

Defense Date 11/06/2024

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

Tag 18F-labeling,bicyclopentane,difluorocarbene,difluoromethylation,halofluorocarbene,monofluoromethylation,organofluorine chemistry,Radiochemistry,trifluoromethoxylation,trifluoromethylation

Format theses (aat)

Language English

Advisor Prakash, Surya (committee chair), Sharada, Shaama (committee member), Zhang, Chao (committee member)

Creator Email ziyuezhu@usc.edu,zzysdsg@hotmail.com

Unique identifier UC11399E4HC

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Legacy Identifier etd-ZhuZiyue-13657

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Format theses (aat)

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