N-chlorosuccinimide-promoted regioselective sulfenylation of imidazoheterocycles at room temperature

Article abstract of DOI:10.1021/ol501117z

Regioselective sulfenylation of imidazoheterocycles with thiophenols at room temperature is reported. Sulfenylation is promoted by N-chlorosuccinimide under metal-free conditions with a broad range of substrate scopes.

Full text of DOI:10.1021/ol501117z

Letter
pubs.acs.org/OrgLett
N‑Chlorosuccinimide-Promoted Regioselective Sulfenylation of
Imidazoheterocycles at Room Temperature
Chitrakar Ravi, Darapaneni Chandra Mohan, and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, Scale up & Process Engineering Unit, CSIR−Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar 364 002, Gujarat, India
S
* Supporting Information
ABSTRACT: Regioselective sulfenylation of imidazoheterocycles with
thiophenols at room temperature is reported. Sulfenylation is promoted by
N-chlorosuccinimide under metal-free conditions with a broad range of
substrate scopes.
Scheme 1
midazoheterocyclic compounds are well established as
I
“privileged scaffolds”. Subsequently, a number of these
molecular frameworks have shown interesting biological
activities.1 For example, they exhibit good antiviral,2 anti-
bacterial,3 fungicidal,4 and anti-inflammatory properties5 and
also as bradykinin B2-receptor6 as well as CXC-chemokine
receptor 4 (CXCR4) antagonists.7 Because of their diverse
biological activities, many commercially available drugs (Figure
S1, Supporting Information) including alpidem, olprinone,
minodronic acid (to treat anxiety, heart failure, and
osteoporosis), zolimidine (peptic ulcer), necopidem, and
saripidem are derived from imidazo[1,2-a]pyridine (IP) core
entities.8 They are also potentially used in material science as
charge transporters,9 and hence, remarkable progress has been
made by various groups,10 including our own group,11 on the
synthesis of IP derivatives
For the direct sulfenylation of 2-phenylimidazo[1,2-a]-
pyridine 1a to 2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine
3a, thiophenol 2a and NCS were chosen to determine the
optimum reaction conditions (Table 1). Initially, with 1 equiv
of 2a and NCS, 40% of the desired product 2-phenyl-3-
(phenylthio)imidazo[1,2-a]pyridine 3a was isolated in acetoni-
trile along with 3-chloro-2-phenylimidazo[1,2-a]pyridine as the
chloro-substituted product (Table 1, entry 1). By increasing the
amount of 2a and NCS (1.7 and 1.5 equiv, respectively) with
respect to 1a, the yield of desired product 3a was also increased
(Table-1, entries 2 and 3). In toluene as solvent, the yield was
further increased to 79% (Table 1, entry 4). A marginal
improvement of yield (81%) was observed when 2 equiv of 1a
was employed (Table 1, entry 5). There was no advantage
when chlorobenzene used as solvent (Table 1, entry 6). A clear
improvement in yield (87%) was observed in dichloroethane
(Table 1, entry 7). Shifting the solvent system to dichloro-
methane, 3a was isolated in 94% yield under the same
conditions (Table 1, entry 8). Further, no improvements were
observed when the reactions were carried out in other solvents
(Table 1, entries 9−11). We then tested with other halogen
sources such as N-bromosuccinimide (NBS), N-iodosuccini-
mide (NIS), and without halogen source for this trans-
formation, they were either poorly effective or entirely
ineffective (Table-1, entries 12−14). The reaction with NBS
and NIS resulted diphenyl disulfide as major product compared
to desired 3a, which may be due to the high reactivities of the
corresponding sulfenyl halide (Br, I) intermediates. Hence,
The biological profile is mainly reliant on the nature of the
substituents and introduction of sulfenyl groups on the
azaheterocyclic rings that could impart marked biological
properties.12 As a result, the synthesis of sulfenated
imidazoheterocyclic molecules has gained much attention.
However, few reports are available for the synthesis of these
molecules employing preparative sulfonating agents in the
presence of transition-metal catalysts and others.13 The
separation of metal catalyst from products is of particular
importance for the synthesis of pharmaceuticals because their
residual toxicity in the target compound is a central issue to
consider. Moreover, transition-metal-catalyzed reactions also
generate hazardous waste, which is environmentally problem-
atic and, hence, should be avoided wherever possible.
Furthermore, it is also highly desirable to develop environ-
mentally benign chemical processes to access pharmacologically
potent sulfenated imidazoheterocyclic compounds without
requirement of any metal catalyst. In continuation of our
efforts on the development of green and sustainable methods
for the synthesis of IPs,11 we report herein an efficient N-
chlorosuccinimide (NCS)14 promoted synthesis of sulfenated
azaheterocycles at room temperature under transition-metal-
free conditions15 (Scheme 1).
Received: April 18, 2014
Published: May 16, 2014
© 2014 American Chemical Society
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 3. Substrate Scope of Sulfonation Reactions
b
entry
NXS (equiv)
thiophenol (equiv)
solvent
yield (%)
1
NCS (1)
1
CH3CN
CH3CN
CH3CN
toluene
toluene
PhCl
40
2
NCS (1.4)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NBS (1.5)
NIS (1.5)
1.2
1.7
1.7
2
49
3
66
4
79
5
81
6
2
78
7
2
DCE
87
8
2
DCM
95
9
2
EtOH
DMF
NR
trace
NR
43
10
11
12
13
14
2
2
DMSO
DCM
2
2
DCM
32
2
DCM
NR
a
Reaction conditions: Thiophenol and N-halosuccinimide under a
nitrogen atmosphere in solvent (2−3 mL) at rt for 30 min for the first
step; 2-phenylimidazo[1,2-a]pyridine (1.0 mmol) was added and the
b
mixture reacted at rt for 30 min for the second step. Isolated yield.
NR = no reaction.
NCS was found to be the best selective and efficient halogen
source for the present transformation.
Before extension of the substrate scope for the present
transformation, we performed a reaction with unsubstituted
imidazo[1,2-a]pyridine 4 with thiophenol under optimized
conditions (Table 1, entry 8), the selective C-3 sulfenated
product 4a was isolated in 72% yield (Scheme 2). When C-3-
Scheme 2. Selective Sulfenylation
a
Reaction conditions: thiophenol and N-halosuccinimide under a
nitrogen atmosphere in solvent (2−3 mL) at rt for 30 min for the first
step; 2-phenylimidazo[1,2-a]pyridine (1.0 mmol) was added and the
substituted substrate 3-methylimidazo[1,2-a]pyridine 5 was
subjected to the same reaction conditions, no product 5a
formation was observed. These experiments (Scheme 2)
indicate that if the C-3 position of imidazo[1,2-a]pyridine IP
is substituted by any group, no reaction takes place to yield the
sulfenylation product. The present transformation proceeds
with only unsubstituted IP core units at the C-3 position to
yield sulfenated imidazo[1,2-a]pyridine derivatives. Hence, the
present transformation is highly desirable for selective synthesis
of structural isomers.
Under this set of optimized conditions (Table 1, entry 8), the
sulfenylation of various imidazo[1,2-a]pyridines 1 was exam-
ined (Scheme 3). The results in Scheme 3 demonstrate that the
reaction has a high degree of functional group tolerance with
broad substrate scope. Initially, 2-arylimidazo[1,2-a]pyridines
bearing electron-donating groups (Me, Et, OMe, and SMe) at
the para and ortho positions of the phenyl ring could react
smoothly and afford the selective C-3 sulfenated products 6b−f
in good to excellent yields (75−96%). Similarly, the presence of
b
mixture reacted at rt for 30 min for the second step. Isolated yield.
electron-withdrawing groups (SO2Me, Cl, Br, and CN) at
either o/p position of the phenyl ring 2-phenylimidazo[1,2-
a]pyridines provided the corresponding sulfenated products
(6g−l) in good yields. As evident from the yields of products
6b−l, the electronic effects associated with electron-donating/-
withdrawing substituents on the phenyl ring of 2-
phenylimidazo[1,2-a]pyridines do not affect the efficiency of
the reaction. However, o-dimethoxyphenyl gave 34% isolated
yield of desired product 6m. Interestingly, naphthyl-substituted
imidazo[1,2-a]pyridines 6n and the important heterocycles
such as 3-(phenylthio)-2-(thiophene-2-yl)imidazo[1,2-a]-
pyridine 6o, 3-(phenylthio)-2-(thiophene-3-yl)imidazo[1,2-a]-
pyridine 6p, and (E)-3-(phenylthio)-2-styrylimidazo[1,2-a]-
pyridine 6q were obtained in excellent yields under the present
conditions. The reactions with various substituted imidazo[1,2-
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Letter
a]pyridines [groups such as aliphatic (methyl and 2-tert-butyl),
halogens, and aryl at different positions] and thiophenol also
successfully provided the corresponding C-3 sulfenated
products 6r−aa in good to excellent yields (67−97%), and
one of the products 6x was further confirmed by single-crystal
XRD (Figure 1). To check the feasibility of the present system,
Scheme 5
Based on the literature reports and our observation in the
present work, a plausible reaction mechanism has been
proposed (Scheme 6). Initially, sulfenyl chloride intermediate
Scheme 6. Plausible Mechanism
Figure 1. Crystal structure of 6x.
reactions with other thiophenols (chlorothiophenol and
naphthalene-1-thiol) were subjected to this procedure, and
the desired products 6ab−af were obtained in excellent yields
(83−93%).
Furthermore, the optimal reaction conditions for sulfenyla-
tions were extended to other imidazoheterocyclic compounds
to ascertain the scope of the methodology (Scheme 4). The
A is formed by the reaction of NCS with benzenethiol 2 under
the present conditions. Subsequently, regioselective electro-
philic attack of PhSCl16 on the C-3 position of 1a yields the
imidazolenium intermediate B. Finally, dehydrochlorination of
B provides the final product 2-phenyl-3-(phenylthio)imidazo-
[1,2-a]pyridine 3a.
Scheme 4. Substrate scope for Sulfenylation of
a
Imidazoheterocyclic Compounds
In conclusion, we have developed an efficient strategy for the
regioselective sulfenylation of imidazo[1,2-a]pyridine deriva-
tives without transition-metal catalysts at room temperature
with a high degree of functional group tolerance. The scope of
the methodology has been extended to imidazo[2,1-b]thiazoles
and 2-phenylbenzo[d]imidazo[2,1-b]thiazole derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectroscopic data. This
material is available free of charge via the Internet at http://
pubs.acs.org. Crystallographic data for compound 6x (CCDC-
998765) can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
a
Reaction conditions: Thiophenol and N-halosuccinimide under a
nitrogen atmosphere in solvent (2−3 mL) at rt for 30 min for the first
step; imidazoheterocyclic compounds (1.0 mmol) were added, and the
mixture was reacted at rt for 30 min for the second step. Isolated
yield.
b
AUTHOR INFORMATION
Corresponding Author
■
reaction of various thiophenols with 6-phenylimidazo[2,1-
b]thiazole 7 gave the corresponding 6-phenyl-5-(phenylthio)-
imidazo[2,1-b]thiazoles (8a−c) in excellent yield (84−93%).
Further, 2-phenylbenzo[d]imidazo[2,1-b]thiazole also gave
good yields of sulfenylated products 8d−f in 72−76% yield,
respectively. Interestingly, the reactions of aliphatic secondary
thio-2-propanol with 1a and 7a proceeded smoothly to afford
the corresponding sulfenylated products 10a and 10b in 48%
and 47% yield (Scheme 5).
*E-mail: adimurthy@csmcri.org. Fax: +91-278-2567562.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CSIR-CSMCRI- Communication No. 060/2014. D.C.M. and
C.R. are thankful to AcSIR for Ph.D. enrollment and the
“Analytical Discipline and Centralized Instrumental Facilities”
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Letter
Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013,
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support. We also thank CSIR-CSMCRI(OLP-0076) for partial
assistance and Dr. E. Suresh and Mr. Aruk K. Das of this
institute for their help in Crystal XRD and HRMS, respectively.
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