Cu-catalyzed sulfenylation of imidazol[1,2-: A] pyridine via C-H functionalization using a combination of Na2S2O3 and halides

Article abstract of DOI:10.1039/c6ra18136h

A novel copper-catalysed sulfenylation method by using the inorganic salt Na₂S₂O₃ and alkyl halides (Cl, Br, I) or iodobenzene homologues is described. The reactions proceeded smoothly, giving regioselective 2-phenylimidazo[1,2-a]pyridine thioether derivatives in good yields via a C-H functionalization process. More importantly, this method has extended the existing methods by offering a better method which can make both alkyl and aryl thioether derivatives under one set of reaction conditions.

Full text of DOI:10.1039/c6ra18136h

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DOI: 10.1039/C6RA18136H
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Cu-catalyzed sulfenylation of imidazol[1,2-α]pyridine via C-H
functionalization using a combination of Na2S2O3 and halides
Yingcai Ding,† Ping Xie,ξ Wenhui Zhu,† Baojun Xu,† Wannian Zhao,† Aihua Zhou*†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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transition metal copper catalyst. In this paper, instead of using
Bunte salt as reactants, Na2S2O3 and halides were directly
used as starting materials for sulfenylation reaction.
A novel copper-catalysed sulfenylation method by using inorganic
salt Na2S2O3 and alkyl halides (Cl, Br, I) or iodobenzene
homologues is described. The reactions proceeded smoothly,
giving regioselective 2-phenylimidazo[1,2-α]pyridine thioether
derivatives in good yields via C-H functionalization process. More
important, this method has extended the existing methods by
offering a better method which can make both alkyl and aryl
thioether derivatives under one reaction condition.
16
Sulfides are widely present in nature, many natural products and
drugs possess sulfide function.1 By the oxidation of sulfide
functions, sulfoxides, sulfones and sulfoximines can be easily
made.2 On the other hand，imidazol[1,2-α]pyridine is also an
privileged structure in drug discovery,3 several drugs possessing this
moiety have important biological activities, such as anticancer,4
sedative-hypnotics,5 gout6 and Alzheimer’s disease,7 therefore,
much time and effort has been addressed to the synthesis of its
derivatives. Among these derivatives, thioether derivatives are very
important one. Until now, several methods related to the synthesis
of imidazol[1,2-α]pyridine thioether derivatives have been
reported.8 These thioether derivatives were mainly made by using
these sulfur agents, such as ArSSAr,9 ArSH,10 ArSO2NHNH2,11
ArSO2Na,12 ArSO2Cl and DMSO13 with or without using transition
metal catalysts. Here, we reported a new sulfenylation method of
Scheme 1. Different routes for the synthesis of 2-
phenylimidazo[1,2-a]pyridine thioether derivatives
To find a suitable reaction condition for this sulfenylation, 2-
imidazol[1,2-α]pyridine by using inorganic Na2S2O3 and different phenylimidazo[1,2-α]pyridine
(
1a), n-butyl chloride and
sodium thiosulfate (Na2S2O3) were chosen as model
substrates. Initially when CuI was used as a catalyst in EtOAc
halides.
，
Actually, Na2S2O3 and alkyl halide were starting materials for
making Bunte salt which was first invented by Hans Bunte in
1874.14 Traditionally, this salt was used to react with
nucleophiles such as thiols, Na2S and cyanide to generate
disulfides, trisulfides and thiocyanates,15 few people used this
salt for sulfenylation reaction of other molecules via C-H
functionalization process, let alone use aromatic halide and
Bunte salt for sulfenylation reaction under the action of
at 120oC, only 20% yield of 2a was obtained after 12hrs (Table
1, entry 1). No product was formed and isolated, when toluene
was used as a solvent under the same reaction condition
(entry 2). Using DMSO as a solvent increased the yield to 30%
(entry 3). Switching solvent from DMSO to CH3CN generated
the expected product 2a in a 45% yield (entry 4). To our
delight, when DMF was employed as a solvent, the reaction
gave a 75% yield in the presence of CuI catalyst (entry 5).
Changing CuI into CuBr decreased the reaction yield to 59%
(entry 6). But when CuCl was used as a catalyst, only 10% yield
of expected product 2a was produced (entry 7). The reaction
catalysed by CuCl2 didn’t afford the desired product (entry 8).
Using Cu(OAc)2 and CuNO3 gave reaction yields of 25% and
†Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu,
China 212013. ξJiangsu University Library, Xuefu Road 301, Jiangsu, China 212013
E-mail: ahz@ujs.edn.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the reaction conditionsa
Table
phenylimidazo[1,2-α]pyridine
2.
Generation
of
alkyl-S-substituted
via
2-
C-H
derivatives
functionalization using alkyl halides and Na2S2O3 as reactantsa
Entry
1
2
3
4
5
6
7
8
Catalyst (equiv.) Solvent
Yield[b] (%)
CuI
CuI
CuI
CuI
EtOAc
Toluene
DMSO
CH3CN
DMF
20
0
30
45
75
59
10
trace
25
23
15
0
Br
N
N
N
N
N
N
CuI
CuBr
CuCl
CuCl2
Cu(OAc)2
Cu(NO3)2
CuO
DMF
DMF
DMF
DMF
DMF
DMF
S
S
S
Et
2b
61%, X=Cl
2a
75%, X=Cl
2c
80%, X=Br
9
10
11
12
FeCl3
DMF
aReaction conditions: 2-phenylimidazo[1,2-α]pyridine (1.0
mmol, 1.0 equiv.), Butyl chloride (2.0 equiv.), Na2S2O3 (1.25
equiv.), CuI (20 mol%.), solvent (0.5 mL). b Isolated yields are
based on 2-phenylimidazo[1,2-α]pyridine, the reaction was run
for 12 hrs.
N
N
N
N
N
N
S
S
S
Et
Me
Me
2f
2d
81%, X=Br
2e
Cl
65%, X=I
67%, X=I
23% respectively (entries 9, 10). When CuO was used as a
catalyst, only 15% yield was obtained (entry 11), the usage of
FeCl3 didn’t give any product (entry 12). In summary, the
suitable condition for the sulfenylation of 2-phenylimidazo[1,2-
α]pyridine: 2-phenylimidazo[1,2-α]pyridine (1.0 equiv.),
Na2S2O3 (1.25 equiv.), butyl chloride (2 equiv.), and CuI (20
Br
N
N
S
N
N
N
N
S
S
mol%), DMF was used as
temperature is 120 oC.
a solvent and the reaction
2i
2g
70%, X=Cl
2h
With a suitable reaction condition in hand, we started to
determine the limitations and generality of this new
sulfenylation method. In addition to 2-phenylimidazo[1,2-
α]pyridine (1a) and n-butyl chloride, several other alkyl halides
and 2-phenylimidazo[1,2-α]pyridine homologues were used
and evaluated. It was found that all tested primary alkyl
halides (Bu-Cl, CH2=C(CH3)CH2Cl, EtBr, BnBr, MeI) were suitable
for the sulfenylation of 2-phenylimidazo[1,2-a]pyridine (1a),
whether they contained Cl, Br or I element in their structures,
they all afforded regioselective desired products in good
yields. To check if secondary alkyl halides were suitable for the
sulfenylation reaction, secondary i-PrBr was tested as a
representative halide under the same reaction condition, it
was found that the reaction gave a 70% yield. To further
explore if tertiary alkyl halide was feasible for this sulfenyaltion
process, t-BuCl was also tried, but it was found that only a
small amount of the expected product was produced.
70%, X=Br
75%, X=Br
Br
N
N
N
N
N
N
HO
S
S
S
2l
63%, X=Br
2k
65%, X=Br
2j
73%, X=Br
aReaction conditions: 2-phenylimidazo[1,2-α]pyridine (1.0
mmol, 1.0 equiv.), alkyl chloride (2.0 equiv.), Na2S2O3 (1.25
equiv.), CuI (20 mol%), solvent (0.5 mL). b Isolated yields are
based on 2-phenylimidazo[1,2-α]pyridine, the reaction was run
for 12 hrs.
carried-out reactions generated the expected products in good
yields via C-H functionalization process, the experimental
results are shown in Table 2. But when bromobenzene and
chlorobenzene were also tried under the same condition, both
reactions failed to provide any the corresponding thioether
derivatives, This fact also explained the reason why bromide
function on the structures of 2q and 2r didn’t have any impact
on the sulfenylation reactions.
In summary, we have demonstrated a copper-catalysed
sulfenylation of 2-phenylimidazo[1,2-α]pyridine by using
inorganic salt Na2S2O3 and alkyl halides (Cl, Br, I) or
iodobenzene homologues via C-H functionalization process. All
To check if aryl halides could be used as reactants for this
sulfenylation method, so we selected different aromatic
iodobenzene as
a model reactant and carried out the
sulfenyaltion reaction under the same condition, it was found
that this sulfenylation reaction still proceeded well, giving the
desired product in a 69% yield. Without further considering for
optimized reaction condition, different iodobenzene
homologues including electron-donating and eletron-
withdrawing substituents were used to react with different 2-
phenylimidazo[1,2-α]pyridines in the presence of Na2S2O3, all
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Graphic abstract
A copper-catalysed sulfenylation of 2-phenylimidazo[1,2-α]pyridine by using inorganic salt Na2S2O3 and alkyl halides (Cl, Br, I) or
iodobenzene homologues via C-H functionalization process was reported here.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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