Regioselective N-F and α C(sp3)-H Arylation of Aliphatic N-Fluorosulfonamides with Imidazopyridines

Article abstract of DOI:10.1021/acs.orglett.1c02381

A regioselective arylation of aliphatic N-fluorosulfonamides with imidazopyridines enabled by breaking of N-F and α C(sp3)-H bond to form C-N and C-C bonds was described. With CuCl as the catalyst, a radical mechanism was proposed to produce N-arylated aliphatic sulfonamides via a N radical intermediate. Importantly, under acidic conditions, an in situ generated imine was the possible intermediate, which was trapped by imidazopyridines to form α C(sp3)-H arylated aliphatic sulfonamides. The current protocol featured a broad substrate scope, tunable reaction conditions, operational convenience, and good regioselectivity.

Full text of DOI:10.1021/acs.orglett.1c02381

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Letter
Regioselective N−F and α C(sp3)−H Arylation of Aliphatic
N‑Fluorosulfonamides with Imidazopyridines
Yuting Xue,† Linlin Shi,† Xu Wang, Xiaoni Yu, Xinju Zhu,* Xin-Qi Hao,* and Mao-Ping Song
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ABSTRACT: A regioselective arylation of aliphatic N-fluorosulfonamides with imidazopyridines enabled by breaking of N−F and α
C(sp3)−H bond to form C−N and C−C bonds was described. With CuCl as the catalyst, a radical mechanism was proposed to
produce N-arylated aliphatic sulfonamides via a N radical intermediate. Importantly, under acidic conditions, an in situ generated
imine was the possible intermediate, which was trapped by imidazopyridines to form α C(sp3)−H arylated aliphatic sulfonamides.
The current protocol featured a broad substrate scope, tunable reaction conditions, operational convenience, and good
regioselectivity.
liphatic amines are important structural scaffolds that are
prevalent in pharmaceutically active molecules and
advances mainly confined to δ C(sp3)−H functionalization of
aliphatic N-fluoroamides since 1,5-HAT is kinetically more
favorable. Meanwhile, most of the above transformations
required the addition of transition metals. To the best of our
knowledge, C(sp3)−H functionalization of N-fluoroamides at
the α position to nitrogen atom is still limited,19,20 which in
some reports utilized substrates without the δ C(sp3)−H
bond.19a,b Until now, only C(sp3)−H cyanation of N-
fluoroamides was achieved at the α-carbon position under
basic conditions (Scheme 1b).20 Moreover, the exploration of
N-fluoroamides in other transformations remains to be
developed.
Imidazopyridines are unique N-heterocycles with wide
applications in pharmaceuticals, natural products, catalysis,
and optoelectronics.21 Consequently, considerable efforts have
been made to construct and functionalize imidazopyridines.22
Specially, C−H alkylation and amination have been studied
recently.23 However, regioselective formation C−C and C−N
bonds using the same coupling partners has not been reported.
A
natural products.1 In this context, considerable attention has
been paid to elaborate and diversify aliphatic amines with
increased complexity. Nevertheless, the site-selective function-
alization of C(sp3)−H bonds is challenging due to their inert
and ubiquitous nature.2 To solve this problem, transition-metal
catalysts have demonstrated versatile reactivity in functional-
ization of aliphatic amines via a chelation-assisted strategy,
which enabled selective β, γ, and δ C(sp3)−H functionaliza-
tion.3 Alternatively, radical strategies involving hydrogen atom
transfer (HAT) have also been utilized for regioselective
C(sp3)−H functionalization inspired by the classic Hofmann−
4
̈
Loffler−Frettag (HLF) reaction. The major breakthroughs in
the HLF field were achieved by Knowles et al. and Rovis et al.,
which significantly enhanced distal C(sp3)−H functionaliza-
tion via nitrogen-centered radicals.5
As air-, moisture-, and thermal-stable species,6a N-
fluoroamides were also successfully utilized to realize iron-
catalyzed C(sp3)−H fluorination by Cook et al. in 2016.6b The
N−F reduction followed by HLF-type HAT regioselectively
generates carbon radicals, which allows for further C(sp3)−H
functionalization, including cyclization,7 halogenation,8 cyana-
tion,9 difluomethylation,10 trifluomethylation,11 trifluorome-
thylchalcogenation,12 thiolation,13 thiocyanation,14 azida-
tion,14b amination,15 alkylation,15a arylation,16 alkynlation,17
and other transformations (Scheme 1a).18 Nevertheless, these
Received: July 16, 2021
https://doi.org/10.1021/acs.orglett.1c02381
© XXXX American Chemical Society
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A

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Scheme 1. C(sp3)−H Functionalization of N-Fluoroamides
With the optimized reaction conditions in hand, the
substrate scope of imidazopyridines was investigated for the
C−N coupling reaction (Scheme 2). In general, different
Scheme 2. Substrate Scope of Imidazopyridines for C−N
a
Coupling
As a continuation of our previous work,24 we herein develop α
C(sp3)−H and N−F arylation of aliphatic N-fluorosulfona-
mides with imidazopyridines (Scheme 1c). Notably, the
regioselectivity was successfully achieved according to tunable
reaction conditions. In the presence of Cu salt and base, N-
fluorosulfonamides were utilized as aminating reagents. On the
other hand, N-fluorosulfonamides served as alkylating reagents
under acidic conditions to give α-arylated aliphatic amines.
Our investigation commenced with reaction of N-
fluorosulfonamide 1a (0.15 mmol) and 2-phenylimidazo[1,2-
α]pyridine 2a (0.1 mmol) in the presence 5 mol % of
Cu(OAc)2 in 1,2-dichloroethane (DCE). Unexpectedly, N−F
arylated product 3aa was isolated in 43% yield as run at 100 °C
for 12 h under air (Table S1, entry 1). Next, other Cu salts
were investigated, indicating that CuCl was the best choice to
afford 3aa in 52% yield (Table S1, entry 2). When DCE was
replaced by EA, the reaction efficient was significantly
improved to provide 3aa in 77% yield (Table S1, entry 3).
Moreover, additive NaOAc (0.05 mmol) was found to be
beneficial to give the desired product 3aa in 83% yield (Table
S1, entry 4). To further increased the reaction conversion, the
temperature and reaction time were screened to generate 3aa
in 87% yield (Table S1, entry 5). The structure of N−F
arylated product 3aa was also determined by X-ray diffraction
(see the Supporting Information). During the above
exploration, an interesting phenomenon was discovered that,
without Cu salt and additive, 3aa was isolated in 18% yield
accompanied by formation of α C(sp3)−H arylated product
4aa in 18% yield confirmed by NMR and HRMS analysis
(Table S1, entry 6). Considering the “two birds with one
stone” strategy, it would be highly desirable if 3aa and 4aa
could be selectively produced via tunable reaction conditions.
When the reaction was carried out in DCE, 4aa was obtained
in 47% yield (Table S1, entry 7). In the presence of NaOAc,
the reaction transformation was further increased to give 4aa in
61% yield (Table S1, entry 8). Finally, α C(sp3)−H arylated
product 4aa could be isolated in 75% yield using MesCOOH
as the additive (Table S1, entry 9).
a
Reaction conditions: 1a (0.15 mmol), 2 (0.1 mmol), CuCl (5 mol
%), NaOAc (0.05 mmol), EA (1 mL), 60 °C, 10 h, under air.
b
Cu(OTf)2 (5 mol %), phen (5 mol %), AcOH (0.1 mmol), DCE (1
mL), 100 °C, 12 h. Isolated yield. EA = ethyl acetate.
substituents at various positions of imidazopyridine ring were
well tolerated with electron-donating groups (OMe, Bu, Et,
t
and Me) exhibiting increased reactivity. Initially, para-, meta-,
and ortho-substituted imidazo[1,2-α]pyridines were employed
to provide products 3ab−ai in 60−91% yields. Subsequently,
imidazopyridines bearing substituents on the pyridine rings
were also explored to afford products 3aj−ap in 66−90%
yields. Next, disubstituted imidazopyridines also proceeded
smoothly to give products 3aq−as in 77−90% yields.
Moreover, when thiophene and naphthalene moieties locate
at the C2 position, the corresponding products 3at−av were
obtained in 69−80% yield. Finally, indazole was also tested to
give N-arylated product 3aw in 23% yield under modified
conditions. However, when benzoxazole was employed, only δ
C(sp3)−H arylated product 3ex (R = Me) was isolated in 15%
yield.
Next, we turned our attention to exploring the generality of
N-fluorosulfonamides for C−N coupling reactions (Scheme 3).
Various aliphatic amides were compatible with the reaction
conditions to afford the corresponding products in good yields.
B
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Scheme 3. Substrate Scope of N-Fluorosulfonamides for C−
Scheme 4. Substrate Scope of Imidazopyridines for C−C
a
a
N Coupling
Coupling
a
Reaction conditions: 1 (0.15 mmol), 2a (0.1 mmol), CuCl (5 mol
%), NaOAc (0.05 mmol), EA (1 mL), 60 °C, 10 h, under air. Isolated
yield. EA = ethyl acetate.
a
Reaction conditions: 1a (0.15 mmol), 2 (0.1 mmol), MesCOOH
(0.05 mmol), DCE (1 mL), 100 °C, 12 h, under air. Isolated yield.
Initially, N-fluorosulfonamides bearing different alkyl chain
lengths were investigated, which gave products 3ba−ga in 83−
95% yields. Apparently, substrates bearing shorter alkyl chain
exhibited higher reactivity. Next, β-substituted amide was
employed to generate 3ha and 3ia in 98% yield. The reaction
also worked well with cyclic systems to produce 3ja in 81%
yields, respectively. When (hetero)aryl moieties were intro-
duced onto the aliphatic amides chain, the desired products
3ka−ma was obtained in 74−96% yields. Additionally, the
scope of sulfonamides groups was studied. Thienyl-substituted
sulfonamides reacted with imidazopyridine smoothly to
provide products 3na in 91% yield. Meanwhile, sulfonamides
bearing electron-donating (OMe) and electron-withdrawing
(Cl) groups on the phenyl ring were examined to deliver
products 3oa−qa in 78−88% yields. Finally, ester functionality
could survive under the reaction conditions to furnish product
3ra in 81% yield.
Scheme 5. Substrate Scope of N-Fluorosulfonamides for C−
a
C Coupling
Encouraged by the above results, α C(sp3)−H arylation of
N-fluorosulfonamide 1a was investigated via structural
modification of the imidazopyridine scaffold (Scheme 4).
Notably, imidazopyridines bearing Me, OMe, Et, or Ph groups
at different positions of C2 phenyl or pyridine rings afforded
the excepted products 4ab−ad, 4af, 4ah−ak, and 4am in 57−
80% yields. For Cl and Br substituents, decreased reaction
activity was observed to afford products 4ae, 4ag, and 4al in
30−63% yields. Likewise, disubstituted and C2-thienyl
substituted imidazopyridines proceeded smoothly to give
products 4an−ar in 53−82% yields.
Additionally, a diverse array of N-fluorosulfonamides were
examined for the C−C coupling reaction (Scheme 5). Varying
the length of the aliphatic chains had little effect on the
reaction performance to afford products 4ba−ga in 69−82%
yields. For amide bearing branched alkyl chain, the
corresponding product 4ha was isolated in 66% yield. Also,
a
Reaction conditions: 1 (0.15 mmol), 2a (0.1 mmol), MesCOOH
(0.05 mmol), DCE (1 mL), 100 °C, 12 h, under air. Isolated yield.
aliphatic N-fluorosulfonamides bearing thienyl and phenyl
groups were also employed to provide products 4ia−ka in 62−
82% yields. When sulfonamides were installed with 2-thienyl
and para-substituted phenyl groups, the desired products 4la−
oa were obtained in 72−88% yields. Furthermore, N-
fluorosulfonamides with ester functionality was also examined
to deliver product 4pa in 56% yields. Nevertheless, for α-
C
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substituted steric hindered amides, no desired products could
be obtained (scheme S1).
aliphatic amines via tunable reaction conditions. Notably,
this provided an effective strategy to achieve α C(sp3)−H
arylation of N-fluorosulfonamides, which overrides the classic
HLF-type 1,5-HAT process. Under the optimized conditions, a
broad range of substrate was well tolerated to give the
corresponding products in up to 98% yield with good
regioselectivity.
To explore the reaction mechanism, a set of control
experiments were conducted. Performing the reaction in the
presence of sulfonamide led to no formation of C−N coupling
product 3aa and C−C coupling product 4aa (Scheme S2a),
indicating sulfonamide is not an intermediate for both
transformations. Meanwhile, it suggests that N−F bond is an
important driving force to achieve α C(sp3)−H and N−F
arylation of aliphatic amides. When the reaction was carried
out in the presence of 1.0 equiv of TEMPO, no product of 3aa
(trace, if any) was detected. Nevertheless, the addition of
radical scavenger (1.0 and 2.0 equiv) did not hinder generation
of the C−C coupling product, which gave 4aa in 53% and 46%
yields, respectively (Scheme S2b). The above experiments
demonstrate that a N radical is generated during N−F
arylation while α C(sp3)−H does not undergo a radical
mechanism. Moreover, during the formation of 4pa, an imine
intermediate 5 was detected by HRMS analysis (Scheme S2c).
The imine intermediate mechanism was further verified
through nucleophilic addition between imine 6 and 2a in the
presence of MesCOOH, HF, or a combination of MesCOOH
and HF, which afforded product 7 in the range of 17−27%
yield. Without the addition of acid, product 7 could not be
obtained. (Scheme S2d). Finally, two 1 mmol scale production
experiments were conducted to give 3aa and 4aa in 72% and
67% yields, respectively (Scheme S2e).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02381.
Experimental procedures, crystallographic data, and
NMR spectra for new compounds (PDF)
Accession Codes
CCDC 2096697 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
On the basis of the above mechanistic studies and a previous
report,20 plausible mechanisms were proposed for N−F and α
C(sp3)−H arylation of N-fluorosulfonamides (Scheme 6).
Xinju Zhu − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China; orcid.org/0000-0003-
1966-3480; Email: zhuxinju@zzu.edu.cn
Xin-Qi Hao − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China; orcid.org/0000-0003-
1942-8309; Email: xqhao@zzu.edu.cn
Scheme 6. Proposed Reaction Mechanism
Authors
Yuting Xue − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China
Linlin Shi − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China; orcid.org/0000-0001-
9089-2388
Xu Wang − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China
Xiaoni Yu − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China
Mao-Ping Song − College of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China; orcid.org/0000-0003-
3883-2622
Initially, a single electron transfer (SET) between Cu(I)
species and N-fluorosulfonamide 1a afforded a copper(II)-
coordinated amidyl radical A, which underwent a radical
addition process to provide intermediate B. Next, reductive
elimination of intermediate B would provide cation inter-
mediate C, accompanied by the regeneration of Cu(I) species
for the next catalytic cycle. Finally, the desired product 3aa was
obtained with the assistance of NaOAc. On the other hand,
MesCOOH-assisted HF elimination of N-fluorosulfonamide
1a via a hydrogen bonding effect could generate imine
intermediate D, which was intercepted by the nucleophile 2a
to form the desired product 4aa.
In conclusion, we have developed Cu-catalyzed N−F
arylation and metal-free α C(sp3)−H arylation of N-
fluorosulfonamides with imidazopyridines under air. The
reactions involved the formation of a N radical or imine
intermediate to afford the corresponding functionalized
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02381
Author Contributions
†Y.X. and L.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Nos. 21803059, U1904212, and
U2004191) and the Natural Science Foundation of Henan
Province (202300410477) is gratefully appreciated.
D
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