Copper-Catalyzed Radical N-Demethylation of Amides Using N-Fluorobenzenesulfonimide as an Oxidant

Article abstract of DOI:10.1021/acs.orglett.0c00863

An unprecedented N-demethylation of N-methyl amides has been developed by use of N-fluorobenzenesulfonimide as an oxidant with the aid of a copper catalyst. The conversion of amides to carbinolamines involves successive single-electron transfer, hydrogen-atom transfer, and hydrolysis, and is accompanied by formation of N-(phenylsulfonyl)benzenesulfonamide. Carbinolamines spontaneously decompose to N-demethylated amides and formaldehyde, because of their inherent instability.

Full text of DOI:10.1021/acs.orglett.0c00863

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Letter
Copper-Catalyzed Radical N‑Demethylation of Amides Using
N‑Fluorobenzenesulfonimide as an Oxidant
Xuewen Yi,∥ Siyu Lei,∥ Wangsheng Liu, Fengrui Che, Chunzheng Yu, Xuesong Liu, Zonghua Wang,*
Xin Zhou, and Yuexia Zhang*
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ABSTRACT: An unprecedented N-demethylation of N-methyl
amides has been developed by use of N-fluorobenzenesulfonimide
as an oxidant with the aid of a copper catalyst. The conversion of
amides to carbinolamines involves successive single-electron
transfer, hydrogen-atom transfer, and hydrolysis, and is accom-
panied by formation of N-(phenylsulfonyl)benzenesulfonamide.
Carbinolamines spontaneously decompose to N-demethylated
amides and formaldehyde, because of their inherent instability.
he removal of methyl unit attached to a nitrogen atom in
Tmolecules (N-demethylation) is an important metabolic
process in living systems.1 For example, N-demethylation of
amines belongs to an important pathway of xenobitic
metabolism that is mediated by cytochrome P450 mon-
oxygenases.2 This enzymatic reaction is believed to proceed
through α-carbon oxidation of amines as a key step (Figure
1A). In synthetic chemistry, two major types of approaches
have been extensively examined for the demethylation of
amines (Figure 1B). One is based on reaction of a tertiary
amine with cyanogen bromide, followed by the release of
bromomethane and a hydrolysis step (von Braun reaction).3
The cyanogen bromide may also be replaced by chloroformate
esters to achieve similar demethylation process.4 Another main
approach is based on oxidation of the tertiary amine to the
corresponding N-oxide, followed by activation (e.g., with
anhydrides; Polonovski reaction), iminium ion formation, and
hydrolysis.5 Examples of other common approaches for
demethylation of amines include photochemical,6 biochem-
ical,7 and electrochemical8 processes. In contrast to the
extensive studies with amines, demethylations of the equally
useful amides are rarely examined.9 Compared with amines,
the corresponding amides are much less susceptible to
oxidation or nucleophilic substitution.10 Thus, the methods
developed for demethylation of amines typically do not work
for amides. Novel methods specifically designed for amide
demethylation is of important need, for both fundamental and
practical reasons. Here, we disclose an unprecedented
approach that can effectively remove the methyl group from
amides through a copper-catalyzed radical process11 (Figure
1C). The readily available N-fluorobenzenesulfonimide
(NFSI) is used as a single-electron transfer (SET) oxidant12
that converts amide to the corresponding iminium ion
Figure 1. N-Demethylation reactions: (A) amine N-demethylation
catalyzed by cytochrome P450 monooxygenase in metabolic events,
(B) general approaches for N-demethylation of tertiary amines, and
(C) copper-catalyzed N-demethylation of amides with NFSI as an
oxidant (this work).
Received: March 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00863
© XXXX American Chemical Society
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A

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a
intermediate with the N-methyl group oxidized. Subsequent
hydrolysis with a release of a formaldehyde affords the N-
demethylated amide product. Mild conditions are used, and
our reaction works for a broad range of amide substrates.
We started by using N-methyl amide 1a as a model amide
substrate to search for suitable N-demethylation conditions.
The choice of model amide 1a is for operational reasons as
both this amide and its demethylation product are easy to
monitor during the reaction and workup. A relatively extensive
study led to the optimal conditions (10 mol % Cu(acac)2,
NFSI 1.5 equiv and MeOH 3.0 equiv in CH3CN under a N2
atmosphere at 80 °C (Table 1, entry 1)) with the formation of
Table 2. Substrate Scope for N-Demethylation of Amides
a
Table 1. Optimized Reaction and Control Experiments
entry
variation from the “standard conditions”
isolated yield (%)
1
2
none
without NFSI
73
0
3
H2O2 instead of NFSI
0
4
without Cu(acac)2
6
5
6
7
8
9
10
11
CuBr2 instead of Cu(acac)2
Cu(OAc)2 instead of Cu(acac)2
without MeOH additive
add 50 μL H2O as an additive
CH2Cl2 instead of CH3CN
toluene instead of CH3CN
under air instead of under N2 atmosphere
61
54
46
43
0
0
48
a
The reactions were performed in 15 mL Schlenk tubes; solvents (AR
grade) were used as received without further purification. Legend:
Cu(acac)2, cupric acetylacetonate; NFSI, N-fluorobenzenesulfoni-
mide.
the demethylated product 1b in 73% yield. Removing NFSI
from the reaction mixture or replacing NFSI with H2O2 as the
potential oxidant led to no product formation (Table 1, entries
2 and 3). In the absence of Cu(acac)2, the N-demethylated
product was isolated in very low yield (6% yield; see Table 1,
entry 4). Both CuBr2 and Cu(OAc)2 could be used to replace
Cu(acac)2, albeit with slightly lower yields (Table 1, entries 5
and 6). The use of CH3OH as an additive is beneficial for this
reaction (Table 1, entry 7), and adding water to the reaction
mixture led to a drop in reaction yield (Table 1, entry 8).
Solvents have profound effects on the reaction outcomes, and
replacing CH3CN with CH2Cl2 or toluene failed to give
demethylated product (Table 1, entries 9 and 10). When the
reaction was performed in air (instead of a N2 atmosphere), a
significant decrease in reaction yield was observed (Table 1,
entry 11). This result (Table 1, entry 11) suggests that a well-
controlled SET oxidation process mediated by NFSI is
necessary for this N-demethylation reaction. The presence of
air (O2) causes the interruption of the desired radical reaction
pathways for the transformation.
a
The reactions were performed with amides (0.4 mmol) in 15 mL
Schlenk tubes, Cu(acac)2 (10 mol %), NFSI (1.5 equiv) and MeOH
(3.0 equiv) in CH3CN (1.0 mL) under N2 atmosphere at 80 °C for
24 h. CH3CN (AR grade) and MeOH (AR grade) were used as
received without further purification. Isolated yields. bIsolated yield of
product of the N-demethylation reaction at 2.0 mmol scale is given
within parentheses.
With acceptable conditions on hand, we examined the scope
of this reaction (Table 2). A variety of N-aryl amides derived
from methacryloyl chloride (1a−11a) served as viable
substrates, yielding the corresponding N-demethylated amides
(1b−11b) in moderate yields. Amides bearing electron-
donating groups at phenyl rings (2a−5a) smoothly proceeded
through the N-demethylation reactions to yield N-demethy-
lated products (2b−5b) in moderate yields. Amides (6a−11a)
with halogen functional groups (F, Cl, and Br) and
B
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trifluoromethyl at the para, meta, or ortho position of the
phenyl ring were also tolerated for N-demethylation. A diverse
range of N-methyl amide substrates with different N-aromatic
rings (12a−19a) and aromatic rings at the acyl side (20a−
22a) underwent N-demethylation successfully to give rise to
the desired products (12b−22b). N-methyl-N-phenyl amides
with simple aliphatic functionality (23a−28a) furnished the N-
demethylated products (23b−28b) in moderate to good
yields. The reaction was also compatible with N-methyl-N-
phenylcinnamamide (29a). Moreover, various N-alkyl amides
(30a−37a) participated in the reaction smoothly. Note that
the yield could be maintained when the reaction was scaled up
to 2.0 mmol (26b, 36b).
reductive peak potential (Erped) of −0.996 V vs Ag/AgCl and a
corresponding oxidation peak (Eopx) at −0.657 V vs Ag/AgCl
(Figure 2A). Cu(acac)2 could be reduced in two voltammetric
processes: (1) the first reduction process occurred at a peak
potential (Erped) of −0.939 V vs Ag/AgCl, and (2) the second
reductive peak potential was observed at −1.482 V. The
corresponding oxidation peaks (Eopx) occurred at −0.902 V and
−1.376 V (Figure 2B). NFSI exhibited two reductive peak
potentials at −1.038 V and −1.953 V vs Ag/AgCl (Figure 2C).
Deuterium-labeling experiments (Table 3) and free radical
scavenging experiments (Scheme 1) were also performed to
a
Table 3. Deuterium Experiments
Cyclic voltammetry (CV) experiments (Figure 2) were
performed to gain insights into the mechanism. A voltam-
metric process was detected for N-methyl amide 1a with a
b
entry
change from the “standard conditions”
1b′ (%)
1
2
3
CD3CN instead of CH3CN
CD3OD instead of MeOH
CD3CN, CD3OD instead of CH3CN, MeOH
CH3CN (anhydrous), D2O (20 μL)
none
0
28
26
42
0
c
4
d
5
a
The reactions were performed with 1a on 0.4 mmol scale.
Percentage of N−D bonds in product, determined by crude 1H
b
c
d
NMR (DMSO-d6). Without MeOH. 1a′ was used instead of 1a.
Scheme 1. Free Radical Scavenging Experiments
develop the picture of a mechanism (see the Supporting
Information for more details). The N−D bond formation was
not observed in the product when CD3CN was used as a
solvent instead of CH3CN (Table 3, entry 1). In contrast, 28%
of the N−D bonds were observed when CD3OD was used as
the additive instead of methanol (Table 3, entry 2). These
results suggest that MeOH is a proton donor for N−H bond
formation and the solvent CH3CN does not supply any proton
for product. It is further demonstrated by the use of CD3CN
and CD3OD together (Table 3, entry 3). Adventitious water
(in solvent, reagents, and tube) in the reaction is the biggest
proton donor for N−H bond formation, since 42% of the N−
D bonds in the product were observed by using D2O (20 μL)
Figure 2. Cyclic voltammograms of 10 mM analytes obtained in
CH3CN containing 0.2 M Bu4NPF6 at a 1-mm-diameter planar glassy
carbon (GC) electrode and at a scan rate of 0.1 V s−1 at 10 °C: (A)
amide 1a, (B) Cu(acac)2, and (C) NFSI.
C
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and anhydrous CH3CN in the absence of methanol (Table 3,
entry 4). In addition, no deuterium was detected in N-
demethylated product when N-methyl-d3 amide 1a′ was used
as the substrate (Table 3, entry 5).
methyl amides undergo N-demethylation smoothly and lead to
the N-demethylated product under mild conditions. This
simple protocol for N-demethylation of amides will allow facile
access to the functionalization of amides.
Free radical scavenging experiments (Scheme 1) showed
that the N-demethylation was inhibited by adding 2 equiv of
2,2,6,6-tetramethylpiperidinooxy (TEMPO) into reaction. It
was found that NFSI was consumed as usual, and 38 was
obtained as the side product. It is particularly noteworthy that
the oxidant NFSI is finally converted to amide 38 in N-
demethylation reactions. Surprisingly, the TEMPO was
reduced and isolated in the form of piperidinium 39, which
connected with 38 by hydrogen-bonding to form crystal
ZHQDU-1 (CCDC 1980938). The mechanism for formation
of 39 is not clear at the present stage. In addition, similar
results were obtained when 2 equiv of 4-OMe-TEMPO was
added instead of TEMPO (see the Supporting Information).
A possible mechanism for N-demethylation of amide was
proposed based on the mechanistic studies and literature
reports9 (Scheme 2). Amide a undergoes a SET to Cu(acac)2
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00863.
Full experimental details, characterization data and
1
copies of H, 13C, and 19F NMR spectra and HRMS
spectra relative to mechanism studies (PDF)
Accession Codes
CCDC 1980938 and 1980939 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 2. Proposed Mechanism for N-Demethylation of
Amide
AUTHOR INFORMATION
■
Corresponding Authors
Yuexia Zhang − College of Chemistry and Chemical Engineering,
Shandong Sino-Japanese Center for Collaborative Research of
Carbon Nanomaterials, Qingdao University, Qingdao 266071,
China; orcid.org/0000-0002-2489-1253;
Email: zhangyx@qdu.edu.cn
Zonghua Wang − College of Chemistry and Chemical
Engineering, Shandong Sino-Japanese Center for Collaborative
Research of Carbon Nanomaterials, Qingdao University,
Qingdao 266071, China; orcid.org/0000-0002-9120-
4089; Email: wangzonghua@qdu.edu.cn
Authors
Xuewen Yi − College of Chemistry and Chemical Engineering,
Shandong Sino-Japanese Center for Collaborative Research of
Carbon Nanomaterials, Qingdao University, Qingdao 266071,
China; Division of Chemistry & Biological Chemistry, School of
Physical & Mathematical Sciences, Nanyang Technological
University, Singapore 639798 Singapore
Siyu Lei − College of Chemistry and Chemical Engineering,
Shandong Sino-Japanese Center for Collaborative Research of
Carbon Nanomaterials, Qingdao University, Qingdao 266071,
China
Wangsheng Liu − Division of Chemistry & Biological
Chemistry, School of Physical & Mathematical Sciences,
Nanyang Technological University, Singapore 639798
Singapore
Fengrui Che − College of Chemistry and Chemical Engineering,
Shandong Sino-Japanese Center for Collaborative Research of
Carbon Nanomaterials, Qingdao University, Qingdao 266071,
China
Chunzheng Yu − College of Chemistry and Chemical
Engineering, Shandong Sino-Japanese Center for Collaborative
Research of Carbon Nanomaterials, Qingdao University,
Qingdao 266071, China
Xuesong Liu − College of Chemistry and Chemical Engineering,
Shandong Sino-Japanese Center for Collaborative Research of
Carbon Nanomaterials, Qingdao University, Qingdao 266071,
China
(Erped = −0.939 V vs Ag/AgCl) to generate radical cation I;
meanwhile, Cu2+ is reduced to Cu+. Consequently, NFSI (Erped
= −1.038 V vs Ag/AgCl) is reduced by this in situ Cu+ (Epox
=
−0.902 V vs Ag/AgCl), resulting in cleavage of the C−F bond
to give the N-centered radical II,13 which goes through a HAT
process with radical cation I to furnish amide 38 and iminium
cation III.12,14 The resulting iminium cation III undergoes
nucleophilic attack by adventitious water (in solvent, reagents,
and tube), followed by proton transfer (PT) to form
carbinolamine V (detected by high-resolution mass spectros-
copy (HRMS); see the Supporting Information for details).
The carbinolamine undergoes cleavage of C−N bond and
proton transfer to afford N-demethylated amide b via
liberation of a formaldehyde. The additive MeOH engages in
these PT processes and supplies some of the protons for
product N−H bond formation.
In the present work, we first demonstrate herein the N-
demethylation of amides. NFSI has been shown to be an
efficient oxidant for the N-demethylation of many N-methyl
amides in the presence of a copper catalyst. The SET from N-
methyl amides to NFSI, with the aid of a copper catalyst,
results in the formation of iminium cation intermediates, which
are then converted to carbinolamines upon hydrolysis.
Carbinolamines undergo spontaneous cleavage to afford N-
demethylated amides and formaldehyde. Readily available N-
D
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Ghosh, Y.; Chandrasekaran, S. A mild and selective method for N-
dealkylation of tertiary amines. Tetrahedron Lett. 2004, 45, 7983−
7985.
Xin Zhou − College of Chemistry and Chemical Engineering,
Shandong Sino-Japanese Center for Collaborative Research of
Carbon Nanomaterials, Qingdao University, Qingdao 266071,
China
(5) (a) Polonovski, M., Polonovski, M. Amine oxides of the
alkaloids. III. Action of organic acid chlorides and anhydrides.
Preparation of the nor bases. Bull. Soc. Chim. Fr. 1927, 1190−1208.
(b) (b) Grierson, D. The Polonovski reaction. Org. React. 1990, 39,
85−295. (c) McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P.
J. Efficient N-Demethylation of Opiate Alkaloids Using a Modified
Nonclassical Polonovski Reaction. J. Org. Chem. 2003, 68, 9847−
9850. (d) Kok, G. B.; Scammells, P. J. Polonovski-type N-
demethylation of N-methyl alkaloids using substituted ferrocene
redox catalysts. Synthesis 2012, 44, 2587−2594.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00863
Author Contributions
∥X.Y. and S.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
(6) For selected papers on photochemical N-demethylation, see:
(a) Sako, M.; Shimada, K.; Hirota, K.; Maki, Y. Photochemical
oxygen-atom transfer reaction by heterocycle N-oxides involving a
single-electron transfer process: oxidative demethylation of N, N-
dimethylaniline. J. Am. Chem. Soc. 1986, 108, 6039−6041.
(b) Santamaria, J.; Ouchabane, R.; Rigaudy, J. Electron-transfer
activation. Photochemical N-demethylation of tertiary amines.
Tetrahedron Lett. 1989, 30, 2927−2928. (c) Santamaria, J.;
Ouchabane, R.; Rigaudy, J. Electron-transfer activation. Salt effects
on the photooxidation of tertiary amines: A useful N-demethylation
method. Tetrahedron Lett. 1989, 30, 3977−3980. (d) Wu, G.; Li, Y.;
Yu, X.; Gao, Y.; Chen, H. Acetic Acid Accelerated Visible-Light
Photoredox Catalyzed N-Demethylation of N, N-Dimethylamino-
phenyl Derivatives. Adv. Synth. Catal. 2017, 359, 687−692.
(7) (a) Shannon, P.; Bruice, T. C. A novel P-450 model system for
the N-dealkylation reaction. J. Am. Chem. Soc. 1981, 103, 4580−4582.
(b) Nee, M. W.; Bruice, T. C. Use of the N-oxide of p-cyano-N, N-
dimethylaniline as an ″oxygen″ donor in a cytochrome P-450 model
system. J. Am. Chem. Soc. 1982, 104, 6123−6125. (c) Stenmark, H.
G.; Brazzale, A.; Ma, Z. Biomimetic synthesis of macrolide/ketolide
metabolites through a selective N-demethylation reaction. J. Org.
Chem. 2000, 65, 3875−3876.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Zhong-Quan Liu and Prof. Longmin
Wu (Lanzhou University), and Prof. Yonggui Robin Chi
(Nanyang Technological University) for helpful discussions.
We also thank Prof. Lingbing Kong (Shandong University)
and Dr. Longjiang Huang (Qingdao University of Science &
Technology) for assistance with X-ray and HRMS, respec-
tively. We acknowledge financial support by the National
Natural Science Foundation of China (No. 21801149),
Shandong Province Natural Science Foundation of China
(No. ZR2018BB025), Taishan Scholar Program of Shandong
Province (No. ts201511027), and Qingdao University.
ABBREVIATIONS
NFSI, N-fluorobenzenesulfonimide; SET, single-electron trans-
fer; HAT, hydrogen-atom transfer; PT, proton transfer.
■
REFERENCES
■
(1) (a) Hathway, D. E.; Hutson, D. H. Foreign Compound
Metabolism in Mammals, Vol. 3; Royal Society of Chemistry: London,
1975; pp 449−549. (b) Bu, H.-Z. A literature review of enzyme
kinetic parameters for CYP3A4-mediated metabolic reactions of 113
drugs in human liver microsomes: structure-kinetics relationship
assessment. Curr. Drug Metab. 2006, 7, 231−249. (c) Bolleddula, J.;
DeMent, K.; Driscoll, J. P.; Worboys, P.; Brassil, P. J.; Bourdet, D. L.
Biotransformation and bioactivation reactions of alicyclic amines in
drug molecules. Drug Metab. Rev. 2014, 46, 379−419. (d) Willi, P.;
Bickel, M. H. Liver metabolic reactions. Tertiary amine N-deal-
kylation, tertiary amine N-oxidation, N-oxide reduction, and N-oxide
N-dealkylation. II. N,N-Dimethylaniline. Arch. Biochem. Biophys.
1973, 156, 772−779.
(2) For reviews on Cytochrome P 450-mediated N-demethylation of
amines, see: (a) Rose, J.; Castagnoli, N., Jr. The metabolism of tertiary
amines. Med. Res. Rev. 1983, 3, 73−88. (b) Guengerich, F. P.;
Okazaki, O.; Seto, Y.; MacDonald, T. L. Radical cation intermediates
in N-dealkylation reactions. Xenobiotica 1995, 25, 689−709.
(c) Hlavica, P. N-oxidative transformation of free and N-substituted
amine functions by cytochrome P450 as means of bioactivation and
detoxication. Drug Metab. Rev. 2002, 34, 451−477. (d) Masic, L. P.
Role of cyclic tertiary amine bioactivation to reactive iminium species:
structure toxicity relationship. Curr. Drug Metab. 2011, 12, 35−50.
(3) (a) von Braun, J. Action of cyanogen bromide on tertiary amines.
Ber. Dtsch. Chem. Ges. 1900, 33, 1438−1452. (b) Hageman, H. The
Von Braun cyanogen bromide reaction. Org. React. 2011, 198−262.
(c) Lee, S. S.; Liu, Y. C.; Chang, S. H.; Chen, C. H. N-Demethylation
studies of pavine alkaloids. Heterocycles 1993, 36, 1971−1974.
(4) (a) Montzka, T. A.; Matiskella, J. D.; Partyka, R. A. 2,2,2-
Trichloroethyl chloroformate. General reagent for demethylation of
tertiary methylamines. Tetrahedron Lett. 1974, 15, 1325−1327.
(b) Rice, K. C. An improved procedure for the N-demethylation of
6,7-benzomorphans, morphine and codeine. J. Org. Chem. 1975, 40,
1850−1851. (c) Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081−2082. (d) Bhat, R. G.;
(8) Hall, L. R.; Iwamoto, R. T.; Hanzlik, R. P. Electrochemical
models for cytochrome P-450. N-Demethylation of tertiary amides by
anodic oxidation. J. Org. Chem. 1989, 54, 2446−2451.
(9) Thavaneswaran, S.; McCamley, K.; Scammells, P. J. N-
Demethylation of alkaloids. Nat. Prod. Commun. 2006, 1, 885−897.
(10) (a) Xu, H.-C.; Campbell, J. M.; Moeller, K. D. Cyclization
Reactions of Anode-Generated Amidyl Radicals. J. Org. Chem. 2014,
79, 379−391. (b) Murahashi, S.; Naota, T.; Kuwabara, T.; Saito, T.;
Kumobayashi, H.; Akutagawa, S. Ruthenium-catalyzed oxidation of
amides and lactams with peroxides. J. Am. Chem. Soc. 1990, 112,
7820−7822. (c) Pace, V.; Holzer, W.; Olofsson, B. Increasing the
Reactivity of Amides towards Organometallic Reagents: An Overview.
Adv. Synth. Catal. 2014, 356, 3697−3736.
(11) For a review on radical reactions, see: Studer, A.; Curran, D. P.
Catalysis of Radical Reactions: A Radical Chemistry Perspective.
Angew. Chem., Int. Ed. 2016, 55, 58−102.
(12) Zhang, Y.; Wong, Z. R.; Wu, X.; Lauw, S. J. L.; Huang, X.;
Webster, R. D.; Chi, Y. R. Sulfoxidation of alkenes and alkynes with
NFSI as a radical initiator and selective oxidant. Chem. Commun.
2017, 53, 184−187.
(13) (a) Sun, J.; Zheng, G.; Xiong, T.; Zhang, Q.; Zhao, J.; Li, Y.;
Zhang, Q. Copper-Catalyzed Hydroxyl-Directed Aminoarylation of
Alkynes. ACS Catal. 2016, 6, 3674−3678. (b) Zhang, B.; Studer, A.
Copper-Catalyzed Intermolecular Aminoazidation of Alkenes. Org.
Lett. 2014, 16, 1790−1793.
(14) For papers on N-centered radical promoted HAT, see:
(a) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.;
Stahl, S. S.; Liu, G. Enantioselective cyanation of benzylic C-H bonds
via copper-catalyzed radical relay. Science 2016, 353, 1014−1018.
(b) Li, J.; Zhang, Z.; Wu, L.; Zhang, W.; Chen, P.; Lin, Z.; Liu, G.
Site-specific allylic C-H bond functionalization with a copper-bound
N-centered radical. Nature 2019, 574, 516−521.
E
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