Metal-Free Mediated C-3 Methylsulfanylation of Imidazo[1,2- a ]-pyridines with Dimethyl Sulfoxide as a Methylsulfanylating Agent

Article abstract of DOI:10.1055/s-0036-1588419

A simple approach is described for the regioselective C-3 methylsulfanylation of imidazo[1,2- a ]pyridines through diiodine-mediated, acetone-promoted, C-S bond construction with dimethyl sulfoxide as both the source of the methylsulfanyl moiety and the s

Full text of DOI:10.1055/s-0036-1588419

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
Z. Chen et al.
Letter
Synlett
Metal-Free Mediated C-3 Methylsulfanylation of Imidazo[1,2-a]-
pyridines with Dimethyl Sulfoxide as a Methylsulfanylating Agent
Zhengkai Chen*
Gangjian Cao
Fengjin Zhang
Hongli Li
0
0
0
0
0-
0
0
2
5-
5
5
6
6-
4
6
1
Metal-free process
I2
R1
R1
DMSO as -SMe source
Mild reaction conditions
Broad substrate scope
34 examples, 26–74% yield
O
N
N
S
N
N
+
Me
Me
MeS
R2
R2
Jianfeng Xu
0
0
0
0
0-
0
0
3
2-
1
1
1
2-
9
4
4
1 = alkyl, (hetero)aryl, halo
Maozhong Miao
Hongjun Ren*
R
R2 = alkyl, (hetero)aryl
Department of Chemistry, Zhejiang Sci-Tech University,
Hangzhou 310018, P. R. of China
zkchen@zstu.edu.cn
renhj@zstu.edu.cn
Received: 01.03.2017
Accepted after revision: 18.04.2017
Published online: 10.05.2017
ment and atom economy, a combination of a C–H function-
alization strategy and the use of green DMSO constitutes a
straightforward and sustainable approach for the efficient
assembly of structurally diverse (hetero)aryl methyl thio-
ethers.
DOI: 10.1055/s-0036-1588419; Art ID: st-2017-w0152-l
Abstract A simple approach is described for the regioselective C-3
methylsulfanylation of imidazo[1,2-a]pyridines through diiodine-
mediated, acetone-promoted, C–S bond construction with dimethyl
sulfoxide as both the source of the methylsulfanyl moiety and the sol-
vent. Preliminary mechanistic investigations indicated that three differ-
ent reaction mechanisms might be involved in the transformation.
Functionalized imidazo[1,2-a]pyridine derivatives are
ubiquitous heterocyclic scaffolds that possess numerous bi-
ological activities and serve as versatile building blocks for
several pharmaceutically significant compounds.6 For in-
stance, some C-3 substituted imidazo[1,2-a]pyridines have
been successfully applied as neuroactive drugs; these in-
clude necopidem, saripidem, zolpidem, alpidem, and olpri-
none.6e,7 In the past few years, substantial steps have been
made toward the regioselective functionalization of imid-
azo[1,2-a]pyridines, especially in C-3 sulfanylation, by the
use of various promoters and sulfanylating reagents.8 Un-
like the C-3 sulfanylation of imidazo[1,2-a]pyridines, the
corresponding methylsulfanylation has been rarely report-
ed.8b,9 The C-3 methylsulfanylation of imidazo[1,2-a]pyri-
dines was explored by Roychowdhury9a and Wu9b and their
respective co-workers; however, the reactions involved tox-
ic POCl3 or NH2CN. Encouraged by our continuing efforts in
iodine-mediated tandem reactions,10 we have developed a
nontoxic, mild, and operationally simple approach to the C-
3 methylsulfanylation of imidazo[1,2-a]pyridines by using
DMSO as both methylsulfanylating agent and solvent in the
presence of inexpensive molecular iodine.
We began our study by using 2-phenylimidazo[1,2-
a]pyridine (1a) as a model substrate. First, we examined the
treatment of 1a with 20 mol% I2 and 2.0 equivalents of ace-
tone in DMSO at 100 °C under air for 12 hours. Unfortunate-
ly, only a trace of the desired product 2a was detected (Ta-
ble 1, entry 1). To our delight, however, the yield of the
methylsulfanylated product 2a was markedly enhanced by
increasing the amounts of I2, and 2.0 equivalents of I2 were
found to give the highest yield (74%) of 2a (entries 2–5). A
Key words methylsulfanylation, C–S bond formation, imidazo-
pyridines, dimethyl sulfoxide, iodine
The introduction of a methylsulfanyl moiety into aro-
matic or heteroaromatic rings represents a fundamental
and attractive area of research because of the remarkable
biological activities of (hetero)aryl methyl thioethers,
which are regarded as versatile and privileged structures in
pharmaceutical chemistry.1 (Hetero)aryl methyl thioethers
are also used in a range of transition-metal-catalyzed cross-
coupling reactions.2 The conventional methods for the con-
struction of (hetero)aryl methyl thioethers include the re-
duction of sulfoxides, the nucleophilic substitution of io-
domethane, the electrophilic substitution of dimethyl di-
sulfide, and the nucleophilic aromatic substitution (SNAr) of
thiolate anions, all of which suffer from a range of draw-
backs.3 In recent years, much progress has been made in the
use of the environmentally benign and readily available sol-
vent dimethyl sulfoxide (DMSO) as a methylsulfanylation
agent to form C–SMe bonds. The methylsulfanylation of
aryl halides by using DMSO as a source of the methylsulfa-
nyl moiety in the presence or absence of a transition metal
has been described by Cheng and others.4 Notably, a direct
methylsulfanylation of C(sp2)–H bonds with DMSO through
C–H activation has been developed by Qing and co-workers
and by other groups.5 From the viewpoints of the environ-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
Z. Chen et al.
Letter
Synlett
further increase in the amount of iodine resulted in an ob-
vious decrease in the reaction efficiency (entry 6). Notably,
no reaction occurred in the absence of iodine (entry 7). The
effect of the volume of the DMSO solvent was also tested,
and 1.0 mL of DMSO was found to the optimal quantity (en-
tries 8–10). The transformation proceeded sluggishly in the
absence of acetone, highlighting the crucial role of acetone
in the reaction (entry 11). Replacement of I2 with NH4I to-
tally inhibited the reaction (entry 12). Further investiga-
tions on the reaction temperature revealed that the reac-
tion did not take place at room temperature, and that a re-
duced or elevated temperature (80 or 120 °C) gave slightly
inferior results (entries 13–15).
Although the exact role of the ketones remains elusive, we
speculate that they facilitate the formation of an active
methylsulfanyl moiety during the reaction.
I2 (2.0 equiv)
ketone (2.0 equiv)
O
N
N
N
S
N
+
100 °C, air, 12 h
MeS
Ph
Ph
1a
2a
O
O
O
O
O
O
Ph
74%
60%
64%
trace
39%
61%
Scheme 1 The effects of various ketones
Table 1 Optimization of the Reaction Conditionsa
With the optimized reaction conditions in hand, we in-
vestigated the scope and limitations of the transforma-
tion.11 A wide variety of substituents attached to the imid-
azole ring were examined. Gratifyingly, various substitu-
ents and functional groups on the aryl ring were smoothly
tolerated under the reaction conditions, and the corre-
sponding methylsulfanylated products 2a–n were obtained
in moderate to good yields (Scheme 2). Ortho- and meta-
substituted substrates showed similar reactivities to para-
substituted ones, suggesting that steric hindrance in the
aryl ring has a marginal influence on the reaction (2b–d).
Impressively, the sensitive hydroxy and dimethylamino
functional groups were compatible with the reaction sys-
tem, albeit with relatively low efficiencies (2f and 2g). Note
that halogenated substituents showed acceptable reactivi-
ties and provide an opportunity for further derivatization
of the products (2h–j). Overall, the electronic nature of the
aryl ring had a negligible effect on the reaction, as illustrat-
ed by the similar reactivities of substrates bearing electron-
donating or electron-withdrawing groups (2b–n). Further-
more, a naphthalene ring and several heterocyclic moieties,
such as furan or thiophene, were each incorporated into the
target methylsulfanylated molecules in satisfactory yields
(2o–r). More significantly, alkyl-substituted imidazo[1,2-
a]pyridines are viable substrates for the methylsulfanyla-
tion process (2s and 2t). The low yield of product 2t might
be attributable to steric hindrance by the vicinal tert-butyl
group.
I2 (x equiv)
O
acetone (2.0 equiv)
N
N
N
S
N
+
100 °C, air, 12 h
MeS
Ph
Ph
1a
2a
Entry
I2 (equiv)
DMSO (mL)
Yieldb (%)
1
2
0.2
0.5
1.0
1.5
2.0
3.0
–
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
2.0
1.0
1.0
1.0
1.0
1.0
trace
25
3
42
4
64
5
74
6
64
7
NRc
51
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
9
63
10
11d
12e
13f
14g
15h
71
22
NR
NR
65
60
a Reaction conditions: 1a (0.3 mmol), I2, acetone (0.6 mmol), DMSO, under
air, 100 °C, 12 h.
b Isolated yield.
c NR = no reaction.
d In the absence of acetone.
e I2 was replaced with NH4I.
f At r.t.
The generality of the present protocol was subsequently
explored by an examination of the scope of imidazo[1,2-
a]pyridines with various substituents on the pyridine ring
(Scheme 3). A series of electron-donating or electron-with-
drawing groups at various positions of the pyridine ring of
the imidazo[1,2-a]pyridine were compatible with the reac-
tion, leading to the corresponding methylsulfanylated prod-
ucts 3a–k in moderate to good yields. Strongly electron-
withdrawing cyano or trifluoromethyl groups (3j–k) were
tolerated under the optimized conditions, indicating that
g At 80 °C.
h At 120 °C.
Because of the dramatically promotive role of acetone,
we examined the effects of a range of ketone analogues
(Scheme 1). Interestingly, butanone, pentan-3-one, or ace-
tophenone produced comparatively efficient reactions,
whereas a relatively lower reactivity was observed with cy-
clohexanone. With 1-cyclopropylethanone, however, only a
trace of the methylsulfanylated product 2a was obtained.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
Z. Chen et al.
Letter
Synlett
R
I2 (2.0 equiv)
acetone (2.0 equiv)
I2 (2.0 equiv)
acetone (2.0 equiv)
R
O
S
O
S
N
N
N
N
R
N
N
R
N
+
N
+
100 °C, air, 12 h
100 °C, air, 12 h
MeS
N
MeS
Ph
Ph
2
3
1
1
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
MeS
MeS
MeS
MeS
MeS
MeS
MeS
Ph
Ph
Ph
MeS
3b, 58%
Ph
3a, 62%
3c. 64%
Br
3d, 44%
2a, 74%
2b, 53%
2c, 63%
2d, 52%
F
Cl
I
2e, R = OMe, 62%
2f, R = OH, 43%
2g, R = NMe2, 26%
2h, R = F, 57%
2i, R = Cl, 52%
2j, R = Br, 57%
2k, R = CN, 55%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
MeS
3e, 48%
MeS
MeS
3g, 53%
MeS
Ph
Ph
Ph
Ph
MeS
MeS
MeS
3f, 53%
3h, 42%
CN
F3C
Cl
R
2l, 65%
2m, 60%
N
N
N
N
N
N
N
N
MeS
3l, 26%
MeS
MeS
3k, 57%
Ph
MeS
Ph
Ph
Ph
N
N
N
N
N
N
3i, 45%
3j, 68%
MeS
MeS
MeS
O
N
N
S
N
N
N
O
2n, 64%
2o, 48%
2p, 62%
MeS
MeS
3n, 51%
Ph
Ph
3m, 31%
N
N
N
N
Scheme 3 The scope of imidazo[1,2-a]pyridines with modifications of
the pyridine core. Reagents and conditions: 1 (0.3 mmol), I2 (0.6 mmol),
acetone (0.6 mmol), DMSO (1.0 mL), under air, 100 °C, 12 h. Isolated
yields are reported.
N
N
N
N
MeS
MeS
S
O
MeS
MeS
t-Bu
2q, 51%
2r, 57%
2s, 51%
2t, 29%
Scheme 2 The scope of imidazo[1,2-a]pyridines. Reagents and condi-
tions: 1 (0.3 mmol), I2 (0.6 mmol), acetone (0.6 mmol), DMSO (1.0 mL),
under air, 100 °C, 12 h. Isolated yields are reported.
tert-butyl-4-methylphenol (BHT) and 2,2,6,6-tetramethyl-
piperidine 1-oxyl (TEMPO) (Scheme 4, eq. 2). These obser-
vations indicated that a radical process might be involved in
the transformation, but other pathways were not entirely
ruled out.
the current method has excellent functional-group compat-
ibility. A methylsulfanyl group was incorporated into the
C-3 position of the imidazo[1,2-a]pyridine derived from
quinolin-2-amine, albeit with relatively lower efficiency
(3l). Note that two structurally complicated imidazohetero-
cycles underwent methylsulfanylation to give the desired
products 3m and 3n, albeit in low to moderate yields. We
speculate that the low yields from some substrates resulted
from the unavoidable formation of 3-iodinated or dimeric
products during the reaction.
To verify the exact source of the methylsulfanyl group,
we used deuterated dimethyl sulfoxide as a solvent for the
reaction and we detected fully deuterated methylsulfanyl
groups in the desired product, confirming that DMSO acts
as the terminal source of the methylsulfanyl group (Scheme
4, eq. 1). Furthermore, when a radical-trapping experiment
was carried out, the yield of the reaction showed a dramatic
decrease in the presence of the radical scavengers 2,4-di-
O
standard conditions
N
S
N
(1)
N
N
+
D3C
CD3
D3C
S
Ph
Ph
(DMSO-d6)
1a
2a', 65%
O
S
standard conditions
N
N
N
N
+
(2)
MeS
Ph
Ph
1a
2a
BHT (2.0 equiv), 38%
TEMPO (2.0 equiv), 33%
TEMPO (4.0 equiv), 18%
Scheme 4 Mechanistic investigations
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
Z. Chen et al.
Letter
Synlett
which subsequently reacts with DMSO to give DMS. Ther-
mal decomposition of DMSO might give CH3SH and
HCHO.5b,13 Then, homolysis of I2 releases an iodine radical14
that undergoes subsequent reaction with CH3SH to release
a methylsulfanyl radical CH3S•.15 In path A, the radical CH3S•
adds to the C-3 atom of imidazo[1,2-a]pyridine to give in-
termediate A, which is converted into intermediate B
through a resonance effect. The desired product 2a is ob-
tained by elimination of H• assisted by I•. In path B, 1a reacts
with DMS and I2 to give the sulfonium intermediate C,
which undergoes loss of CH3I and subsequent deprotona-
tion to afford product 2a.9b In path C, the atypical nucleo-
philic aromatic substitution of compound 4 with DMS de-
livers the complex E,4c which releases CH3I to give the final
product 2a.
In conclusion, we have developed a general and simple
synthetic strategy for the efficient C-3 methylsulfanylation
of imidazo[1,2-a]pyridines under metal-free conditions by
using DMSO as both a source of the methylsulfanyl moiety
and a solvent. The protocol features mild operating condi-
tions, a broad substrate scope, and good functional-group
compatibility. A number of control experiments were per-
formed to shed light on the reaction mechanism. The trans-
formation provides an alternative for the methylsulfanyla-
tion of imidazo[1,2-a]pyridines.
conditions
DMS, 100 °C, 12 h
N
(1)
N
N
N
MeS
Ph
Ph
1a
2a
conditions:
A: I2 (2.0 equiv), acetone (2.0 equiv), 26%
B: I2 (2.0 equiv), 21%
C: acetone (2.0 equiv), NR
D: without I2 and acetone, NR
conditions
N
DMSO, 100 °C, 12 h
N
N
N
(2)
MeS
I
Ph
Ph
2a
4
conditions:
A: I2 (2.0 equiv), acetone (2.0 equiv), 72%
B: I2 (2.0 equiv), trace
C: acetone (2.0 equiv), 34%
D: without I2 and acetone, NR
conditions
N
N
(3)
N
N
Ph
DMS, 100 °C, 12 h
MeS
I
Ph
4
2a
conditions:
A: I2 (2.0 equiv), acetone (2.0 equiv), 30%
(38% of 1a recovery)
B: I2 (2.0 equiv), 27% (47% of 1a recovery)
C: acetone (2.0 equiv), 22% (10% of 1a recovery)
D: without I2 and acetone, 10% (17% of 1a recovery)
Funding Information
Scheme 5 Control experiments
National Nature Science Foundation of China 21602202
Science Foundation of Zhejiang Sci-Tech University 15062092-Y
Science Foundation of Zhejiang Sci-Tech University 1206820-Y
Science Foundation of Zhejiang Sci-Tech University 1206821-Y
To gain further insights into the reaction mechanism,
we conducted a series of control experiments (Scheme 5).
Substrate 1a was treated under various conditions with di-
methyl sulfide (DMS) as solvent. The reaction did not pro-
ceed in the absence of I2, showing that a combination of I2
and DMS was essential for the conversion of substrate 1a
into product 2a (Scheme 5, eq. 1). When the C-3 iodinated
imidazo[1,2-a]pyridine 4 was prepared and subjected to
various reaction conditions, the transformation proceeded
smoothly under the standard conditions, but only a trace of
product 2a was obtained when 4 was treated with DMSO
and I2 in the absence of acetone (Scheme 5, eq. 2). These re-
sults show that compound 4 might be an intermediate in
the reaction, and demonstrated that acetone plays a crucial
role. We also used compound 4 as a substrate in the reac-
tion in DMS as solvent under various conditions (Scheme 5,
eq. 3). We observed that the desired product 2a was ob-
tained in only a relatively low yield, and a certain amount of
1a was recovered. The product 2a was isolated in 10% yield,
even in the absence of I2 and acetone, suggesting that an
atypical SNAr-type reaction between compound 4 and DMS
might have occurred (Scheme 5, eq. 3, conditions D).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588419.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
Z. Chen et al.
Letter
Synlett
O
O
I2
+
+
HI
I
(CH3)2SO
(CH3)2SO
CH3SCH3
CH3SH
I2
+ +
+
2 HI
H2O
HCHO
+
•
I
I
2I
•
•
I
+
CH3SH
CH3S
HI
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•
I
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CH3S
Ph
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H3CS
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Path A
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2a
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I2
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+
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E
I–
Path C
Scheme 6 Plausible reaction mechanism
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
Z. Chen et al.
Letter
Synlett
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J = 9.2 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.39 (m, 1 H), 7.30 (m, 1
H), 6.94 (td, J1 = 6.8, J2 = 0.8 Hz, 1 H), 2.26 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 148.7, 146.3, 133.7, 128.4, 128.3, 128.2, 126.0,
124.2, 117.6, 112.7, 111.4, 18.1. HRMS (ES+–TOF): m/z [M + H]+
calcd for C14H13N2S: 241.0799; found: 241.0799.
(11) 3-(Methylsulfanyl)-2-phenylimidazo[1,2-a]pyridine
(2a);
Typical Procedure
I2 (152 mg, 0.6 mmol) and acetone (35 mg, 0.6 mmol) were
added to a solution of substrate 1a (0.3 mmol) in DMSO (1 mL),
and the mixture was stirred at 100 °C under air for 12 h. When
the reaction was complete (TLC), the mixture was cooled to r.t.,
the reaction was quenched by H2O, and the mixture was
extracted with EtOAc (3 × 15 mL). The extracts were washed
with 10% aq Na2S2O3 (2 × 15 mL), dried (Na2SO4), and concen-
trated in vacuo. The resulting crude product was purified by
column chromatography (silica gel, PE–EtOAc) to give a brown-
yellow solid; yield: 53 mg (74%); mp 65–67 °C. 1H NMR (400
MHz, CDCl3): δ = 8.49 (d, J = 6.8 Hz, 1 H), 8.29 (m, 2 H), 7.68 (d,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F