Oxidative dual C–H sulfenylation: A strategy for the synthesis of bis(imidazo[1,2-a]pyridin-3-yl)sulfanes under metal-free conditions using sulfur powder

Article abstract of DOI:10.1016/j.cclet.2020.12.046

An efficient approach to sulfur-bridged imidazopyridines has been developed under metal-free conditions using inexpensive sulfur powder as the sulfur source. Most appealingly, the reaction can proceed smoothly without addition of any additives, ultimately decreasing the production of chemical waste. The inexpensive and green method should provide a useful strategy for constructing a library of novel and biological interesting heteroaromatic sulfides.

Full text of DOI:10.1016/j.cclet.2020.12.046

Chinese Chemical Letters 32 (2021) 1705–1708
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Chinese Chemical Letters
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Communication
Oxidative dual C–H sulfenylation: A strategy for the synthesis of bis
(imidazo[1,2-a]pyridin-3-yl)sulfanes under metal-free conditions
using sulfur powder
Ziyu Gana,b, Xiaolong Zhub, Qiuli Yanb, Xiuyan Songb, Daoshan Yangb,
*
a
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China
b
Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, State Key Laboratory Base of Eco-Chemical Engineering, College of
Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 21 October 2020
Received in revised form 20 December 2020
Accepted 23 December 2020
Available online 28 December 2020
An efficient approach to sulfur-bridged imidazopyridines has been developed under metal-free
conditions using inexpensive sulfur powder as the sulfur source. Most appealingly, the reaction can
proceed smoothly without addition of any additives, ultimately decreasing the production of chemical
waste. The inexpensive and green method should provide a useful strategy for constructing a library of
novel and biological interesting heteroaromatic sulfides.
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
C-S bond
Metal-free
Sulfur powder
Disulfides
Heterocycle
Organosulfur compounds have drawn considerable attentions,
because of their remarkably bioactivities in medicinal chemistry
[1], as well as their widespread applications in material science [2].
Therefore, the construction of C–S bonds is a fundamental process
in the synthesis of sulfur-containing molecules [3]. Transition
metal-catalyzed cross-coupling reactions between thiols, arylbor-
onic acids or pseudo-halides with disulfides or organic halides have
been broadly used as a general method for the construction of C–S
bonds [4]. On the other hand, C–H bonds functionalization has
been widely regarded as an alternative approach to traditional
cross-coupling reactions due to its high efficiency and atom
economy [5]. In recent years, tremendous progress has been made
for the construction of C–S bonds through C–H bond functional-
ization [6]. However, these methods inevitably involve using
odorous sulfur sources and usually harsh reaction conditions were
required. Elemental sulfur exists in the form of sulfur powder
which was considered as non-poisonous and tractable reagent
compared to thiols [7]. Over the last several years, elemental sulfur
has emerged as an ideal sulfur surrogate in the organic trans-
formations [8]. However, challenges still remain, and it is highly
desirable to develop more efficient and convenient strategies for
the synthesis of sulfur-containing compounds using sulfur powder
as sulfur source.
Imidazo[1,2-a]pyridines are readily accessible heterocycles
that have found widely applications across organic chemistry,
materials science, medicinal chemistry, and chemical biology [9].
Compounds with an imidazo[1,2-a]pyridine motifs are well known
to possess various pharmacological activities. Most importantly,
some commercially available drugs contain this core structure,
such as minodronic acid (used to treat osteoporosis) [10],
zolmidine (gastroprotective agent) [11] and zolpidem (used to
treat insomnia) [12]. Importantly, some C-3 sulfenylation imidazo-
[1,2-a]pyridines possess medical activities, such as the inhibitor of
human rhinovirus I [13], antitumor agent II [14], and antiosteo-
porotic agent III [15] (Fig. 1). As a consequence, in the past few
decades, significant efforts have been made toward to the
synthesis and modification of imidazo[1,2-a]pyridines [16].
Recently, many methods have been developed for C-3 function-
alization of imidazo[1,2-a]pyridines [17]. On the other hand,
biheteroaryl skeletons have been widely known as prominent
heterocycles possessing various biological, and pharmacological
activities [18]. In consideration of the biological activities of
biheteroaryl scaffolds and imidazopyridine derivatives in medici-
nal chemistry, extensive efforts have been devoted to the
* Corresponding author.
E-mail address: yangdaoshan@tsinghua.org.cn (D. Yang).
https://doi.org/10.1016/j.cclet.2020.12.046
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

Z. Gan, X. Zhu, Q. Yan et al.
Chinese Chemical Letters 32 (2021) 1705–1708
[(Fig._1)TD$FIG]
Table 1
Optimization of reaction conditions.a
[DT$INLE]
Fig. 1. Bioactive molecules containing imidazo[1,2-a]pyridine frameworks.
Entry
Solvent
Sulfur source
Yield (%)b
1
2
3
4
5
6
7
DMF
S8
S8
S8
S8
67
87
0
trace
53
0
DMSO
Toluene
THF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
development of efficient methods for their synthesis and
functionalization. In 2017, Sakhuja et al. disclosed that bis-
(imidazo[1,2-a]pyridin-3-yl)sulfanes could be obtained in high
yields when treatment of imidazo[1,2-a]pyridines with Na2S by
using iodine as a green catalyst (Scheme 1a) [17f]. In 2019, Song
et al. reported an elegant Cu(I)-catalyzed double thiolation of
imidazopyridines for the construction of bis(imidazo[1,2-a]pyr-
idin-3-yl)sulfanes using isothiocyanate as the sulfur source
(Scheme 1b) [17e]. Although these reactions have made some
great advantages, the development of a convenient and green
method that can complement existing synthetic methods remains
an ongoing challenge. To the best of our knowledge, double C–S
bonds forming reactions at C-3 position of imidazo[1,2-a]pyridines
using environmentally benign sulfur powder as sulfur surrogate
under metal-free condition is rarely reported. With our growing
interest in the synthesis of sulfur-containing compounds [19],
herein, we report an efficient, practical and simple method for the
synthesis of bis(imidazo[1,2-a]pyridin-3-yl)sulfanes using S8 as
sulfur source under metal-free conditions (Scheme 1d). Notably,
during the submission process of our manuscript, Song and
co-workers developed a novel approach to bis(imidazo[1,2-a]-
pyridin-3-yl)sulfanes through iodine catalyzed chalcogenation of
imidazopyridines and KSCN (Scheme 1c) [20].
Initially, the reaction was carried out by treatment of
imidazo[1,2-a]pyridines 1a with sulfur powder in 2 mL DMF at
120 ꢀC under air atmosphere (Table 1). To our delight, the desired
product 2a was isolated in 67% yield (entry 1). To enhance the
reaction efficiency, other solvents were then examined. As shown
in Table 1, three solvents including DMSO, toluene, THF (entries
2–4) were investigated, and DMSO was found to be the most
effective solvent, giving desired product 2a in 87% yield (entry 2).
We also tested various sulfur sources, and sulfur powder showed
the best result (compare with entries 2, 5–7). A series control
experiments indicated that the reaction did not take place when
K2S
Na2S
Na2S
S8
S8
S8
Á
9H2O
0
8c
9d
10e
61
76
69
a
Reaction conditions: 2-(2-bromophenyl)imidazo[1,2-a]pyridine 1a (0.2 mmol),
S-source (0.4 mmol), solvent (2 mL), under air atmosphere, at 120 ꢀC for 12 h.
b
Isolated yield.
c
Under N2 atomosphere.
d
At 110 ꢀC.
e
At 100 ꢀC.
K2S was used in the present transformation, the reaction could
proceed and delivered
a 53% yield. Interestingly, the yield
decreased to 61% under N2 atomsphere (entry 8), which showed
that O2 plays an important role in the present transformation.
Finally, decreasing the reaction temperature resulted in a lower
conversion (entries 9 and 10).
With the optimal conditions in hand, we next proceeded to
explore the substrate scope with the corresponding imidazo[1,2-
a]-pyridines (Scheme 2). To our delight, most of the substrates
provided the corresponding products in moderate to good yields.
The structures of the products were unambiguously confirmed by
the single crystal X-ray diffraction of compound (2a). Both
electron-withdrawing and electron-donating groups were found
to show no significant difference in reactivity in the present
transformation. Various functional groups such as fluorine,
chlorine, bromo and methyl group were well tolerated with the
]
optimum conditions, providing more chances for further function-
alization or modification. In addition, ÀCOOMe, -CN and -OMe
were compatible in present transformation. Notably, 2-(2-bromo-
phenyl)benzo[d]imidazo[2,1-b]thiazole also afforded the desired
product 2q in 63% yield. Analyzing substrates from the perspective
of steric hindrance effect, 2-phenylimidazo[1,2-a]pyridine deriv-
atives bearing Br atom at C-2 position on the benzene ring should
have lower reactivity in the transformation. Unexpectedly, these
derivatives showed higher reactivity than other types of imidazo-
[1,2-a]pyridines. It is interesting to note that disulfide products 2o'
and 2p' were obtained when 1o and 1p were tested with sulfur
powder at 100 ꢀC.
Na2S or Na2S 9H2O were used as the sulfur source. However, when
Á
[(Scheme_1)TD$FIG]
In addition, the feasibility of the synthesis method in gram level
was also investigated (Scheme 3). To our delight, the present
reaction could afford 1.29 g of 2a under the standard conditions,
with no significant loss of its efficiency.
To acquire insights into this oxidative dual C–H sulfenylation
reaction, control experiment was carried out (Scheme 4). The
reaction proceed smoothly in the presence of a radical scavenger
TEMPO, which preliminarily indicates that this transformation
might not involve a radical process (Scheme 4a). When 1o reacted
Scheme 1. Recent strategies for the synthesis of bis(imidazo[1,2-a]pyridin-3-yl)
sulfanes.
1706

Z. Gan, X. Zhu, Q. Yan et al.
Chinese Chemical Letters 32 (2021) 1705–1708
[(Scheme_2)TD$FIG]
Scheme 2. Reaction scope of imidazo[1,2-a]pyridines with sulfur powder. Reaction conditions: imidazo[1,2-a]pyridine 1 (0.2 mmol), sulfur powder (0.4 mmol), DMSO (2 mL),
under air atmosphere, at 120 ꢀC for 12 h. Isolated yield.
[(Scheme_3)TD$FIG]
Scheme 5. The initial transformation would be the activation of
elemental sulfur by nucleophilic attack of 1 on the S8 ring
to generate intermediate (A), which could be changed into
2-phenylimidazo[1,2-a]pyridine-3-thiol (B). Subsequently, the
intermediate (B) was oxidized to disulfide (C) by using DMSO as
the oxidant. Finally, the imidazo[1,2-a]pyridines attacked the
disufides (C) resulting the desired product 2.
In summary, we have successfully developed a novel, practical
and easy-handle method for the synthesis of heteroaromatic
sulfides with potentially biological activities using sulfur powder
as a sulfur source. Notably, the developed method could be carried
out using cheap and abundantly chemicals, without the need of a
transition metal catalyst, as well as strong oxidants or bases, thus
facilitating benchtop reactions that could be performed in a simple
fashion. Therefore, the protocol will attract much attention in
organic chemistry and medicinal chemistry. Further investigation
of the bioactivities of these compounds is ongoing in our
laboratory.
Scheme 3. Synthesis of 2a on a gram scale.
with 1o' under the standard conditions, the desired product 2o was
obtained in 95% yield, which suggests that disulfides might be a
key intermediate in this transformation (Scheme 4b).
On the basis of the preliminary results and the previous
literature reports [21], a plausible mechanism was proposed in
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Z. Gan, X. Zhu, Q. Yan et al.
Chinese Chemical Letters 32 (2021) 1705–1708
[(Scheme_4)TD$FIG]
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Appendix A. Supplementary data
Supplementary material related to this article can be
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