Visible-light-promoted sulfonylmethylation of imidazopyridines

Article abstract of DOI:10.1016/j.cclet.2019.09.040

The visible light promoted C–H sulfonylmethylation of imidazopyridines with easily accessible bromomethyl sulfones under mild reaction conditions was described. This protocol provides an effective and practical access to sulfonylmethylated imidazopyridines with good functional group tolerance. The desired products were provided in moderate to excellent yields for 50 examples at room temperature. The method could also be an attractive strategy to install a methyl group on imidazopyridines.

Full text of DOI:10.1016/j.cclet.2019.09.040

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CCLET 5246 No. of Pages 4
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Visible-light-promoted sulfonylmethylation of imidazopyridines
b
b,
Xia Mia, Yuanfang Konga, Jingyu Zhanga, , Chao Pi , Xiuling Cui
*
*
a
College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
b
College of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University, Zhengzhou 450052, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The visible light promoted C–H sulfonylmethylation of imidazopyridines with easily accessible
bromomethyl sulfones under mild reaction conditions was described. This protocol provides an
effective and practical access to sulfonylmethylated imidazopyridines with good functional group
tolerance. The desired products were provided in moderate to excellent yields for 50 examples at room
Received 7 September 2019
Received in revised form 16 September 2019
Accepted 19 September 2019
Available online xxx
temperature. The method could also be an attractive strategy to install
imidazopyridines.
a methyl group on
Keywords:
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Visible light promoted
Imidazopyridine
Sulfonylmethylation
Radical process
Desulfonylation
Methylation involved in many fundamental biological process-
es, such as DNA replication, transcription, and epigenetics [1]. Also,
the methyl group is one of the most prevalent functionalities in
biologically active molecules (Fig. 1a). This simplest alkyl fragment
can modulate both the biological and physical properties of a
molecule, such as solubility, selectivity and metabolic half-life [2].
As was the case with anti-inflammatory drug celecoxib, a methyl
group was introduced to decrease the half-life, (Fig. 1b) [3]. In light
of these merits, catalytic methods to attach methyl group are
particularly important to develop.
The most extensive studies on the direct methylation of C–H
bond involve the use of MeI or organometallic reagents [4], such as
Me4Sn, MeB(OH)2, MeMgCl, Me3Al, and Me2Zn. Since the seminal
work of Minisci in 1971 on the addition of the nucleophilic methyl
radical to electron-deficient heterocycles, substantial progress has
been made in radical C–H methylation [5]. Some methyl radical
precursors are known, such as HOAc [5], peroxide [6], DMSO [7],
methanol [8], and others [9]. Unfortunately, these one-step
methylation methodologies are limited in their application owing
to the use of strong stoichiometric oxidants or high temperature to
generate the requisite methyl radical. A great difficulty arises from
the similar polarities of the starting material and the methylated
product, which makes purification difficult. Recently, a two-step
radical methylation becomes one of the effectively alternative
pathways to circumvent the problem [10]. In particular, bromo-
methyl phenyl sulfone, a readily accessible, stable, easily handled
reagent, has been successfully introduced for C–H functionaliza-
tion. The benzenesulfonyl (PhSO2-) group could be easily removed
to reveal a methyl group by reduction reaction, providing easy
access to methylated compounds. In 2014, Baran and co-workers
[11] reported an elegant C–H methylation of heteroarenes. A
masked zinc sulfinate reagent was designed and synthesized from
bromomethyl phenyl sulfone. Afterwards, bromomethyl phenyl
sulfone was reported to directly generate phenylsulfonyl methyl
radical for introducing a methyl group through a two-step
synthetic procedure [12].
In the past few years, much attention has been drawn on
the imidazopyridine and their derivatives due to their unique
bioactivity [13] and chemical properties [14]. There already
are several marketed drugs containing the imidazo[1,2-a]pyridine
unit, including zolpidem (hypnotic) [15], alpidem (anxiolytic) [16]
and olprinone (PDE-3 inhibitor) [17]. As a consequence, represen-
tative synthetic approaches have been developed for the function-
alization of imidazoheterocycles [18]. In comparison, the synthesis
of imidazo[1,2-a]pyridines bearing a sulfonylmethyl substituent at
C-3 has been rarely reported [19]. Recently, visible light-induced
photoredox catalysis has emerged as a powerful technique in
organic synthesis because of its environmental compatibility,
excellent functional group tolerance, high reactivity and versatility
[20]. As a part of our continued studies focusing on clean C–H
functionalization [21], herein we disclose an efficient and mild
protocol for sulfonylmethylation of imidazopyridines using
Ir(ppy)3 as a photo catalyst at room temperature through a
* Corresponding authors.
E-mail addresses: jyzhang2004@hactcm.edu.cn (J. Zhang), cuixl@zzu.edu.cn
(X. Cui).
https://doi.org/10.1016/j.cclet.2019.09.040
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: X. Mi, et al., Visible-light-promoted sulfonylmethylation of imidazopyridines, Chin. Chem. Lett. (2019),
https://doi.org/10.1016/j.cclet.2019.09.040

G Model
CCLET 5246 No. of Pages 4
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X. Mi et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
yield of 72% yield (Table 1, entry 14). Finally, the control
experiments suggested that photo-catalyst and light were essen-
tial for this reaction (Table 1, entries 15 and 16).
With the optimized conditions in hand (Table 1, entry 11), the
generality and scope of the substrates were explored (Scheme 1).
Initially,substrateswithsubstituentsontheC6,C7, andC8positionsof2-
phenylimidazo[1,2-a]pyridines were examined. Various functional
groups, including methoxy, methyl, ethyl, halogen and ester, were
well tolerated under optimized reaction conditions (3ba-3oa).
Moderate to excellent yields were obtained for most cases. While
weak electron-withdrawing group (Cl) at C6 position led to a low
yield (3ea). Furthermore, the effect of the substituent on the C2
phenyl ring was examined. Imidazo[1,2-a]pyridines bearing
electron-donating groups (OMe, Me, Ph) as well as electron-
withdrawing groups (halogen, CF3, SO2CH3) on the 2-phenyl ring
efficiently reacted with 2a to produce the C-3 sulfonylmethylated
imidazo[1,2-a]pyridine derivatives 3pa-3g in 52%–99% yields. The
structure of 3ta was confirmed by single crystal X-ray crystallo-
graphic analysis (CCDD No: 1903608). It is worth mentioning that
steric hindrance could not be observed for congested o-substituted
imidazo[1,2-a]pyridines (3d-3g). In addition, di-substituted imi-
dazo[1,2-a]pyridines, with substitutions on both the pyridine and
C2-phenyl ring also provided the corresponding products 3h-3l in
highyields(71%–93%). 2-Thienyland2-pyridyl-substitutedimidazo
[1,2-a]pyridine gave the products 3 m and 3n in 68% and 70% yields.
Imidazo[2,1-b]thiazole was also subjected to this reaction and
produced the desired product 3o in good yield. Particularly,
Fig. 1. Examples of methylated drugs and a magic methyl effect.
visible-light irradiated radical process, providing an attractive
approach to various sulfonylmethylated imidazopyridines. The
products could be conveniently transformed into methylated
compounds through reduction.
Our initial work started from the reaction of imidazo[1,2-a]
pyridine (1a) with bromomethyl phenyl sulfone (2a) in the
presence of 2 mol% Ir(ppy)3 in MeCN. It was encouraging to see
that the desired product 3aa was obtained in 46% yield after 12 h of
irradiation (26 W CFL) at room temperature (Table 1, entry 1). An
improved yield of 78% was achieved using 2 equiv. of Li2CO3 as base
(Table1, entry 2). Other solvents, such as DMSO (dimethyl
sulfoxide), 1,2-DCE (1,2-dichloroethane), toluene, THF (tetrahydro-
furan) were screened and MeCN proved to be particularly effective
(Table 1, entries 3–6). Subsequent screening base, including Et3N,
K2CO3, NaOAc, NaOH and K2HPO4, revealed that the yield was
further increased to 89% with K2HPO4 (Table 1, entries 7–11).
Moreover, the yield of the desired product decreased using other
photo catalysts, such as Ru(bpy)3Cl2 and eosin Y (Table 1, entries 12
and 13). Shortening the reaction time to 8 h resulted in a lower
Table 1
Optimization of the reaction conditions.a
Entry
Catalyst
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ru(bpy)3Cl2
Eosin Y
Ir(ppy)3
Ir(ppy)3
–
–
MeCN
MeCN
DMSO
1,2-DCE
toluene
THF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
46
78
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Et3N
K2CO3
NaOAc
NaOH
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
42
39 (8e)
17 (13e)
34 (56e)
69
82
75
46
9
10
11
12
13
14c
15d
16
89
6 (90e)
Trace (95e)
72
0
0
a
1a (0.2 mmol), 2a (0.4 mmol), photocatalyst (2 mol%), base (0.4 mmol), solvent
(1.0 mL), under N2 atmosphere at 25 ꢀC for 12 h and at 26 W CFL irradiation.
b
Isolated yield.
8 h.
No irradiation.
Recovery of 1a in parentheses.
c
Scheme 1. Substrate scope. Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol),
d
Ir(ppy)3 (2 mol%), K2HPO4 (0.4 mmol), CH3CN (1 mL) under N2 atmosphere at 25 ꢀ
for 12 h and at 26 W CFL irradiation. Isolated yields. 4.0 equiv. of 2 for 24 h.
C
e
a
Please cite this article in press as: X. Mi, et al., Visible-light-promoted sulfonylmethylation of imidazopyridines, Chin. Chem. Lett. (2019),
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CCLET 5246 No. of Pages 4
X. Mi et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
3
unsubstitutedimidazo[1,2-a]pyridinecouldbesulfonylmethylated,
giving the target product 3p in 57% yield. Other heterocycles
generally gave moderate to good yields of product in the case of
indoles and pyrroles (3q-3t). Notably, this reaction tolerates free
NÀÀH bonds and this method allows for the easy separation of
product from starting material. To further examine the scope of the
sulfonylmethylation reaction, the bromomethyl aryl sulfones were
tested. Substituents, such as CH3, F, Cl, Br, were well tolerated and
gave good to excellent yields (3u-3x).
Scheme 3. Mechanism study.
Desulfonylation of 3aa, 3na, 3wa, 3a, 3q was easily achieved
under reducing conditions (SmI2 in THF/H2O) to unveil the methyl
group and afforded the target products 4aa, 4na, 4wa, 4a, 4q,
respectively (Scheme 2).
To understand the mechanism of this transformation, we
attempted to perform the reaction under standard conditions with
the addition of 2.0 equiv. of TEMPO (2,2,6,6-tetramethylpiper-
idinooxyl) as a radical scavenger (Scheme 3). Trace amount of
product was obtained. However, the coupling product 5 of TEMPO
with PhSO2CH2Br was captured by HRMS. These results indicated
that the radical process might be involved in this sulfonylmethy-
lation reaction.
Based on these observations and literatures [11,12],
a
possible catalytic cycle is proposed, as shown in Scheme 4.
Firstly, the excited state [Ir(ppy)3*] was formed under light
irradiation, which was next oxidized by PhSO2CH2Br 2a to
generate a [Ir(ppy)3]+ complex and a ꢁCH2SO2Ph radical A.
Subsequently, the radical A reacted with imidazo[1,2-a]pyridine
1a to produce the intermediate B. Then, intermediate B was
oxidized by [Ir(ppy)3]+ to form the intermediate C along with the
regeneration of Ir(ppy)3. Finally, the deprotonation of C assisted by
base afforded the desired product 3aa.
In summary, we have successfully developed an efficient
visible-light-induced C3-H sulfonylmethylation of imidazopyri-
dines with bromomethyl aryl sulfones using Ir(ppy)3 as a photo-
catalyst. Various sulfonylmethylated imidazopyridines were
prepared in moderate to excellent yields with a wide range of
functional group tolerance at room temperature. Meanwhile,
desulfonylation of several selected compounds was easily achieved
under reducing conditions to unveil the methyl group. The method
may be an attractive strategy to install a methyl group on
imidazopyridines.
Scheme 4. Proposed mechanism.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (No.21602046), the MOST of
China (No. 2016YFE0132600) and the Doctor’s Scientific
Research Foundation of Henan University of Chinese Medicine
(No. BSJJ2016-12).
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.09.040.
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