Iodine-Mediated Multicomponent Synthesis of 3-Sulfenylimidazo[1,2- a ]pyridines from 2-Aminopyridines, Ketones, and Sulfonyl Hydrazides

Article abstract of DOI:10.1055/s-0037-1612082

A one-pot multicomponent reaction for the synthesis of 3-sulfenylimidazo[1,2- a ]pyridines from readily available 2-aminopyridines, ketones, and sulfonyl hydrazides, mediated by molecular iodine, has been developed. The transformations proceed smoothly wi

Full text of DOI:10.1055/s-0037-1612082

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
S. Hu et al.
Letter
Synlett
Iodine-Mediated Multicomponent Synthesis of 3-Sulfenylimid-
azo[1,2-a]pyridines from 2-Aminopyridines, Ketones, and Sulfo-
nyl Hydrazides
Sipei Hu
R1
I2/PPh3
Shiying Du
O
R1
N
N
+
+
R3SO2NHNH2
Yunjie Yao
N
NH2
R2
R3
Zuguang Yang
Hongjun Ren*
Zhengkai Chen*
S
R2
Metal and Oxidant-free
Readily Available Reagents
Broad Substrate Scope
R1 = alkyl, halo, -NO2, -CN
R2, R3 = (het)aryl
0
0
0
0-0
0
0
2-5
5
5
6-6
4
6
1
High Efficiency and Regioselectivity
Insensitive to Air and Moisture
Multicomponent Reaction
Scale Up
27 examples, up to 92% yield
Department of Chemistry, Zhejiang Sci-Tech University,
Hangzhou 310018, P. R. of China
renhj@zstu.edu.cn
zkchen@zstu.edu.cn
Received: 05.11.2018
Accepted after revision: 26.12.2018
Published online: 13.02.2019
olprinone, zolimidine, necopidem, saripidem, and the anti-
HIV drug GSK812397.4 In the past few years, substantial ef-
forts have been expended in the synthesis and regioselec-
tive functionalization of imidazo[1,2-a]pyridines.5 Among
the various functionalized imidazo[1,2-a]pyridine deriva-
tives, imidazol[1,2-a]pyridine thioethers are regarded as an
important entities because of their unique therapeutic val-
ue against a variety of diseases,6 as the introduction of a
sulfenyl group onto an azaheterocycle can markedly affect
its biological properties.
DOI: 10.1055/s-0037-1612082; Art ID: st-2018-w0717-l
Abstract A one-pot multicomponent reaction for the synthesis of 3-
sulfenylimidazo[1,2-a]pyridines from readily available 2-aminopyri-
dines, ketones, and sulfonyl hydrazides, mediated by molecular iodine,
has been developed. The transformations proceed smoothly with high
efficiency and a broad substrate scope, affording the desired heterocy-
clic products in moderate to excellent yields.
Key words metal-free synthesis, multicomponent reaction, C–S bond
The method most commonly used for the preparation of
3-sulfenylimidazopyridines is sulfenylation of previously
synthesized imidazopyridines. A number of sulfenylating
agents have been used, including disulfides, thiols, sodium
sulfinates, sulfonyl chloride, sulfonyl hydrazides, and
DMSO.7 Among the several synthetic approaches, a protocol
involving multicomponent synthesis of 3-sulfenylimidazo-
pyridines is quite competitive and promising. In 2013, Wei
and co-workers reported an aerobic CeCl3·7H2O/NaI-cata-
lyzed multicomponent synthesis of 3-sulfenylimidazopyri-
dines from 2-aminopyridines, ketones, and disulfides
[Scheme 1(a)].8 Later, Basu and co-workers demonstrated a
multicomponent reaction catalyzed by the green carbocat-
alyst graphene oxide for the synthesis of 3-sulfenylimid-
azo[1,2-a]pyridines using a thiol as a sulfenylating agent
[Scheme 1(b)].9 Recently, the groups of Zhou10 and of Ad-
imurthy11 independently developed one-pot three-compo-
nent reactions for the arylsulfenylation of imidazo[1,2-
a]pyridine by using sodium thiosulfate (Na2S2O3) or ele-
mental sulfur as the sulfenylating agent [Scheme 1(c)]. Al-
though significant advances have been made in this field, an
exploration of highly efficient and practical transforma-
tions through a metal-free iodine-mediated approach for
the synthesis of valuable heterocyclic molecules is still at-
tractive. It is noteworthy that when a combination of I2 and
DMSO was applied to the construction of structurally di-
formation, imidazopyridines, N-heterocyclic compounds
Multicomponent reactions (MCRs) have emerged as a
powerful strategy for the construction of diverse heterocy-
cles, because it is possible to integrate various functional
groups in the final product with high structural diversity
and complexity.1 MCRs, especially those involving C–H
functionalizations, exhibit significant advantages over con-
ventional synthetic methods; for example, they do not re-
quired presynthesized reactants, they eliminate time-con-
suming multiple workup processes, and they demonstrate
atom economy and high efficiency. Recently, molecular io-
dine has been extensively employed as a good activator in
various chemical transformations, and considerable prog-
ress in metal-free approaches has been achieved.2 A combi-
nation of an iodine-mediated strategy with MCRs might
provide a more straightforward and robust pathway for the
preparation of structurally complex nitrogen-containing
heterocycles with high efficiency.
Functionalized imidazo[1,2-a]pyridines are privileged
heterocyclic scaffolds that possess numerous pharmaceuti-
cal and biological activities, such as antiviral, cytotoxic, an-
tibacterial, fungicidal, or antiinflammatory activities.3 Sev-
eral imidazo[1,2-a]pyridine motifs are present in commer-
cially available clinical drugs, including alpidem, zolpidem,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
S. Hu et al.
Letter
Synlett
verse N-heterocycles, this catalytic system showed unique
and superior properties.12 Encouraged by a previously re-
ported metal-free C(sp2)–H sulfenylation13 and by our con-
tinuing researches in the field of I2-mediated syntheses of
nitrogen-containing heterocycles and various derivatiza-
tions of imidazo[1,2-a]pyridines,14 we report an efficient
I2/PPh3-mediated multicomponent synthesis of structurally
diverse 3-sulfenylimidazo[1,2-a]pyridines from readily
available 2-aminopyridines, ketones, and sulfonyl hydra-
zides [Scheme 1(d)]. Compared with disulfides and thiols,
sulfonyl hydrazides are stable solid, odorless, easy to han-
dle, and easily accessible.
use of 1.0 equivalent of I2 gave the target product in reduced
yield (entry 18). Furthermore, an inert atmosphere obvi-
ously inhibited the efficiency of the reaction (entry 19).
Table 1 Optimization of the Reaction Conditionsa
O
I2/additive
TsNHNH2
N
+
+
N
Ph
N
NH2
solvent, air, T, 12 h
S
Ph
1a
2a
3a
4a
Entry
Additive
Solvent
Temp (°C)
Yieldb (%)
1
2
K2CO3
Et3N
DABCO
HOAc
PivOH
PPh3
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
H2O
100
100
100
100
100
100
100
100
100
100
100
100
100
rt
NDc
trace
trace
ND
61
CeCl3•7H2O/NaI/O2
O
R1
(a)
(b)
(c)
R3SSR3
+
+
R2
Ref. 8
N
NH2
NH2
3
O
graphene oxide/NaI
Ref. 9
4
R1
+
+
R3 SH
N
N
R2
R1
R3
5
N
N
6
81
R1
Na2S2O3
or
S
CuI/base
R3
X
S
R2
+
+
7
ND
ND
ND
ND
ND
21
N
Ref. 10–11
8d
9
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
R2
O
I2/PPh3
R1
(d)
R3SO2NHNH2
+
+
R2
this work
N
NH2
10
11
12
13
14
15
16
17e
18f
19g
DCE
Scheme 1 Multicomponent syntheses of 3-sulfenylimidazo[1,2-a]pyri-
dines
DMF
toluene
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
27
We chose the readily available 2-aminopyridine (1a),
acetophenone (2a), and 4-methylbenzenesulfonohydrazide
(3a) as model substrates with promotion by 0.5 equivalents
of I2 to start our investigation. The required reaction did not
occur in the presence of a combination of molecular iodine
and an inorganic or organic base (Table 1, entries 1–3). Re-
placement of the base by acidic HOAc also failed to give a
positive result, whereas the use of pivalic acid (PivOH) gave
the desired heterocyclic product 4a in 61% yield (entries 4
and 5). The yield of 4a increased to 81% when PPh3 was
used as an additive (entry 6). We assume that PPh3 can be
regarded as a reducing agent in the reaction.7d Notably, no
reaction was observed in the absence of I2 or PPh3 (entries 7
and 8, respectively). The effects of various solvents on the
reaction was then examined, and DMSO was identified as
the best choice, affording the highest yield (entries 9–13). In
addition to its frequent use as an excellent solvent, DMSO is
also used as an inexpensive, nontoxic, and readily available
oxidant in numerous organic transformations.12 When the
reaction was performed at room temperature or 60 °C, no
reaction was detected (entries 14 and 15). Increasing the
temperature to 120 °C resulted in inferior reactivity (entry
16). We speculate that low temperatures do not permit the
formation of the imidazo[1,2-a]pyridine heterocycle and
that an elevated temperature might reduce the transforma-
tion efficiency of TsNHNH2 (3a). The effects of the amount
of I2 was also screened, and a trace of product was observed
when 0.2 or 2.0 equivalents of I2 were tested (entry 17). The
ND
ND
63
60
120
100
100
100
trace
53
33
a Reaction conditions: 1a (0.3 mmol), 2a (1.4 equiv, 0.42 mmol), 3a (2.0
equiv, 0.6 mmol), I2 (0.5 equiv), additive (2.0 equiv), solvent (1.0 mL), un-
der air, 12 h.
b Isolated yield.
c ND = not detected.
d In the absence of I2.
e I2 (0.2 equiv) or I2 (2.0 equiv) was used.
f I2 (1.0 equiv) was used.
g Under N2.
With the optimal reaction conditions in hand, we next
investigated the scope and limitations of the multicompo-
nent reaction (Scheme 2).15 A variety of 2-aminopyridines
bearing electron-donating or electron-withdrawing groups
were subjected to the standard conditions, and moderate to
excellent yields were attained from most of these sub-
strates. Various methyl-substituted 2-aminopyridines re-
acted smoothly to afford the corresponding products 4b–d
in good yields; however, 6-methylpyridin-2-amine showed
an effect of steric hindrance, and the corresponding product
4e was obtained only in trace amounts. Other electron-
withdrawing substituents, including chloro, iodo, trifluoro-
methyl, nitro, and cyano groups, were compatible with the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
S. Hu et al.
Letter
Synlett
reaction (4f–j). It is worth mentioning that electronic fac-
tors associated with the 2-aminopyridines appeared to ex-
ert a negligible effect on the reaction. When 1,3-benzothi-
azol-2-amine was used as a reactant, the desired product
4k was obtained in 75% yield. More importantly, in the case
of 4g, the transformation could be scaled up to a gram scale
without any difficulty.
withdrawing trifluoromethyl group (5r). These results
clearly demonstrate the broad compatibility of our transfor-
mation.
I2 (0.5 equiv)
PPh3 (2.0 equiv)
O
N
N
+
R3SO2NHNH2
+
R2
N
NH2
DMSO, 100 °C
R3
S
R2
1a
2
3
5
R1
I2 (0.5 equiv)
O
PPh3 (2.0 equiv)
N
R1
N
N
N
+
+
TsNHNH2
N
S
N
N
N
DMSO, 100 °C
Ph
N
NH2
S
Ph
S
S
1
2a
3a
4
5a, 71%
5b, 74%
5c, 58%
N
N
N
N
N
N
N
N
5d, R4 = OCH3, 76%
5e, R4 = F, 56%
N
N
S
S
S
S
N
N
Ph
Ph
Ph
S
Ph
5f, R4 = Cl, 74%
S
4a, 81%
4b, 78%
4c, 65%
4d, 76%
5g, R4 = Br, 69%
5h, R4 = SO2CH3, 88%
Cl
I
F3C
R4
5i, 78%
N
S
N
N
N
N
N
N
N
N
N
S
S
S
N
S
Ph
Ph
Ph
Ph
N
N
N
S
4f, 87%
4g, 92% (80%)a
4h, 86%
4e, trace
S
S
Fe
O2N
CN
S
5l, 0%
5j, 47%
5k, 81%
N
N
N
N
N
N
S
S
5n, R5 = OCH3, 70%
5o, R5 = F, 72%
5p, R5 = Cl, 74%
5q, R5 = Br, 63%
5r, R5 = CF3, 77%
S
Ph
Ph
Ph
N
N
N
N
4i, 73%
4j, 78%
4k, 75%
R5
S
S
Ph
Ph
Scheme 2 The scope of the 2-aminopyridines. Reaction conditions: 1
(0.3 mmol), 2a (1.4 equiv, 0.42 mmol), 3a (2.0 equiv, 0.6 mmol), I2 (0.5
equiv), PPh3 (2.0 equiv), DMSO (1.0 mL), under air, 100 °C, 12 h.
a Yield from the reaction at a 10 mmol scale.
5m, 61%
Scheme 3 The scope of ketones and sulfonyl hydrazides. Reaction con-
ditions: 1a (0.3 mmol), 2 (1.4 equiv, 0.42 mmol), 3 (2.0 equiv, 0.6
mmol), I2 (0.5 equiv), PPh3 (2.0 equiv), DMSO (1.0 mL), under air,
100 °C, 12 h. Isolated yields are reported.
a Yield from the reaction at a 10 mmol scale.
Next, we explored the generality of the present method
for various ketones (Scheme 3). To our delight, the transfor-
mation displayed good tolerance toward a range of elec-
tron-rich or electron-deficient groups, giving the corre-
sponding heterocyclic products 5a–h in moderate to good
yields. The orientation of the substituents on the aromatic
ring system had a slight but obvious effect on the efficiency
of the protocol, as exemplified by the inferior result for the
ortho-methylated product 5c. Reactants with various halo
groups or sulfonyl groups participated in the reaction with
reasonable reactivity (5e–h). 1-(2-Naphthyl)ethanone
worked well in this transformation, providing 5i in 78%
yield. Note that 2-thienyl and ferrocenyl moiety could be
successfully incorporated into the desired 3-sulfenylimid-
azo[1,2-a]pyridine products 5j and 5k, respectively. Unfor-
tunately, an aliphatic ketone was not compatible with the
current reaction system (5l). The applicability of the proto-
col was further extended by subjecting various sulfonyl hy-
drazides to the reaction. Gratifyingly, we found that satis-
factory yields of the relevant products 5m–q were obtained,
even in the case of a substrate with a strongly electron-
Next, a series of radical-trapping experiments were
conducted to elucidate the nature of the reaction (Scheme
4). It was noteworthy that the addition of two equivalents
of the radical scavenger TEMPO shut down the reaction,
whereas comparable yields were obtained when the reac-
tion was performed in the presence of two equivalents of
2,4-di-tert-butyl-4-methylphenol (BHT), 1,4-benzoquinone
(BQ), or 1,1-diphenylethene. It has been reported that TEM-
PO can react with TsNHNH2 to afford a TEMPO–Ts or TEM-
PO–4-tolyl adduct.16 Therefore, our results suggest that our
reaction might not involve a single-electron transfer pro-
cess and that it might proceed by an ionic mechanism.
radical scavenger (2.0 equiv)
I2 (0.5 equiv)
O
PPh3 (2.0 equiv)
N
N
+
+
TsNHNH2
Ph
N
NH2
DMSO, air, 100 °C, 12 h
S
Ph
1a
2a
3a
4a
Ph
Ph
TEMPO: 0%
BHT: 69%
BQ: 71%
: 64%
Scheme 4 Radical-trapping experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
S. Hu et al.
Letter
Synlett
We also synthesized 2-phenylimidazo[1,2-a]pyridine
(6) and reacted this with TsNHNH2 under the standard con-
ditions (Scheme 5). As expected, the target product 4a was
isolated in 89% yield. We speculate that the heterocyclic
molecule 6 is involved as a key intermediate in the reaction
process. This result is in accordance with a previous re-
port.7h When 2-iodo-1-phenylethanone (7) was used as an
alternative substrate for the reaction, product 4a was also
obtained in 68% yield, implying the intermediacy of com-
pound 7.
I2/PPh3
SO2NHNH2
SI
– HI, – HOI, – N2, or – PPh3O
A
3a
OH2
OH
HI
HI
S
I
S
I2
DMS
H2O
DMSO
+
+
H3C
CH3
H3C
CH3
I
I
B
C
O
O
I2
I
+
N
NH2
O
Ph
Ph
N
NH2
I
7
2a
1a
D
Ph
SI
I2 (0.5 equiv)
PPh3 (2.0 equiv)
+
N
N
N
– HI
N
– H2O
N
N
TsNHNH2
+
N
N
A
H
DMSO, air, 100 °C, 12 h
Ph
Ph
I
3a
S
6
Ph
E
Ph
4a, 89%
6
N
N
N
I
N
Ph
O
standard conditions
– HI
N
+
+
TsNHNH2
S
N
I
S
H
Ph
N
NH2
Ph
S
F
4a
Ph
1a
7
3a
4a, 68%
Scheme 6 Plausible mechanism
Scheme 5 Control experiment
Based on the results from the preliminary mechanistic
investigations and previous reports,7h,8,9 a plausible reaction
pathway is proposed as outlined in Scheme 6. First, sulfenyl
iodide A is formed by the reaction of sulfonyl hydrazide 3a
and I2/PPh3 with release of HI, HOI, N2, or PPh3O. DMSO
serves as an oxidant for the catalytic recycling of I2; the ad-
dition of HI to DMSO gives intermediate B, which under-
goes protonation and nucleophilic attack by I– to regenerate
I2 with release of H2O and Me2S.13d Then, α-iodination of ac-
etophenone 2a in the presence of I2 gives iodide 7, which
reacts with 2-aminopyridine (1a) through nucleophilic
substitution to deliver intermediate D. Intramolecular cy-
clization of D through dehydration and elimination of HI
leads to the imidazo[1,2-a]pyridine 6. Electrophilic attack
by the sulfenyl iodide electrophile A at the 3-position of the
imidazopyridine moiety affords the imidazolenium inter-
mediate F, which finally undergoes elimination of HI to pro-
vide the desired product 4a. The reaction of HI and HOI can
also regenerate the catalyst I2 to complete the catalytic cy-
cle.
In conclusion, we have developed a direct and efficient
multicomponent reaction for the construction of 3-
sulfenylimidazo[1,2-a]pyridines from 2-aminopyridines,
ketones, and sulfonyl hydrazides. The transformation fea-
tures readily available starting reagents, mild and conve-
nient operating conditions, good functional-group toler-
ance, and high efficiency. The reaction can also be scaled up
to a gram scale. Further studies toward understanding of
the detailed reaction mechanism and developing synthetic
applications of this methodology are underway.
Funding Information
We thank the financial support from the National Natural Science
Foundation of China (Grant No. 21602202) and the Natural Science
Foundation of Zhejiang Province (Grant No. LY19B020016).
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612082.
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References and Notes
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(15) 2-Phenyl-3-(4-tolylthio)imidazo[1,2-a]pyridine (4a); Typical
Procedure
PPh3 (157.4 mg, 0.6 mmol) and I2 (38.1 mg, 0.15 mmol) were
added to a solution of amine 1a (0.3 mmol), ketone 2a (0.42
mmol), and sulfonyl hydrazide 3a (0.6 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 with 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 to provide a crude product, that was purified by
column chromatography (silica gel, PE–EtOAc) to give a white
solid; yield: 77 mg (81%); mp 136–138 °C.
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 6.8 Hz, 1 H), 8.22 (d,
J = 7.6 Hz, 2 H), 7.72 (d J = 9.2 Hz, 1 H,), 7.44 (t, J = 7.4 Hz, 2 H),
7.38 (d, J = 7.2 Hz, 1 H), 7.32 (t, J = 8 Hz, 1 H), 7.02 (d, J = 8 Hz, 2
H), 6.91 (d, J = 8 Hz, 2 H), 6.86 (t, J = 6.8 Hz, 1 H), 2.26 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 151.2, 147.0, 136.0, 133.4, 131.5,
130.2, 128.5, 128.4, 126.5, 125.9, 124.5, 117.6, 113.0, 106.9,
20.9. HRMS (ES+-TOF): m/z [M + H]+ calcd for C20H17N2S:
317.1107; found: 317.1116.
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Jiang, B. J. Org. Chem. 2018, 83, 9890.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E