Solvent-Driven Iodine-Mediated Oxidative Strategies for the Synthesis of Bis(imidazo[1,2-a]pyridin-3-yl)sulfanes and Disulfanes

Article abstract of DOI:10.1002/asia.201701274

Two efficient iodine-mediated strategies, which are economical and one-pot, are described to access bis(imidazo[1,2-a]pyridin-3-yl)sulfanes and bis(imidazo[1,2-a]pyridin-3-yl)disulfanes in chloroform and acetic acid, respectively, by a direct oxidative homocoupling of imidazo-heterocycles using inexpensive sodium sulfide as a sulfur source. These strategies are scalable, and an array of substrates delivered their corresponding stable sulfur-bridged imidazo-heterocycles in excellent yields.

Full text of DOI:10.1002/asia.201701274

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Solvent-Driven Iodine-mediated Oxidative Strategies for
the Synthesis of Bis(imidazo[1,2-a]pyridin-3-yl)sulfanes and
Disulfanes
Authors: S. M Abdul Shakoor, Devesh S Agarwal, Sadhika Khullar,
Sanjay K Mandal, and RAJEEV Sakhuja
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10.1002/asia.201701274
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Solvent-Driven Iodine-mediated Oxidative Strategies for the
Synthesis of Bis(imidazo[1,2-a]pyridin-3-yl)sulfanes and
Disulfanes
S. M. Abdul Shakoor,[a] Devesh S. Agarwal,[a] Sadhika Khullar,[b] Sanjay K. Mandal,[c] and Rajeev
Sakhuja*[a]
Abstract: Two efficient, economic, one-pot, iodine-mediated
profile.[11] The presence of imidazo[1,2-a]pyridine (IP) core in
many currently marketed drugs including Alpidem, Olprinone,
Minodronic acid, Zolimidine, and optically active GSK812397,[11d,
12] have spurred special interest towards regioselective synthesis
of C-3 sulfur decorated imidazo[1,2-a]pyridines using disulfides,
thiols, sulfenyl chlorides, sulfonyl hydrazines, sodium thiosulfate,
sodium sulfonate, DMSO and elemental sulfur as sulfur
sources.[13] In 2014, Murai et al. demonstrated an interesting
protocol for the synthesis of bis imidazo[1,5-a]pyridyl sulfides in
appreciable yields in presence of CuTC (copper(I)
thiophenecarboxylate) using elemental sulfur (Scheme 1).[14a]
Very recently, Yasuike et al. reported the synthesis of one
example of bis[2-(2-iodophenyl)imidazopyridin-3-yl]sulfide in
57% yield under copper-catalyzed conditions using sulfur
powder along with the targeted benzothiophene-fused
imidazopyridine.[14b] Much prior to these strategies, Glover and
coworkers reported the conventional synthesis of bis
strategies are described to access bis(imidazo[1,2-a]pyridin-3-
yl)sulfanes
and
bis(imidazo[1,2-a]pyridin-3-yl)disulfanes
in
chloroform and acetic acid respectively, via direct oxidative
homocoupling of imidazo-heterocycles using in-expensive sodium
sulfide as a sulfur source. These strategies are scalable, and an
array of substrates delivered their corresponding stable sulfur
bridged imidazo-heterocycles in excellent yields.
Introduction
Sulfur heterocycles and sulfur-derived functional groups
constitute an integral part of numerous natural products and
potential pharmaceuticals.[1] Over the years, the accountability of
sulfur in about 362 FDA approved drugs has strongly contributed
in building up its dominating repute, besides carbon and
nitrogen.[2] In particular, sulfide and disulfide linkages are
frequently observed in many drugs and bioactive alkaloids such
as Discorhabdin B, Butoconazole, Axitinib, Disulfram, Epicorazin
imidazo[1,5-a]pyridyl sulphides
&
disulphides, and bis
imidazo[l,2-a]pyridyl disulphides using sulfur dichloride and
sulphur monochloride in comparatively lower yields.[14c]
Recently, noticeable efforts have also been made by various
research group’s and us towards the synthesis of 3,3'-
B, Emerthallicin
E
etc.[1a,1b,2-3] Disulfide linkages are also
responsible for folding and stabilization of tertiary structure of
proteins and enzymes.[4] Thus, development of direct synthetic
strategies for the construction of C-S-C and C-S-S-C linkages
are highly valuable.
biimidazo[1,2-a]pyridine
and
methylene
linked
3,3'-
biimidazo[1,2-a]pyridine derivatives.[15] To complement these
reports, it became highly desirable to develop environmentally
benign protocol for sulfur linked bis-imidazo[1,2-a]pyridines as a
potential pharmacological lead. Within our continuous program
for functionalization of IP,[15f,16] we herein report novel metal-free
iodine-mediated strategies for the synthesis of bis(imidazo[1,2-
a]pyridin-3-yl)sulfanes and disulfanes in different solvent
systems, using sodium sulfide as a sulfur source (Scheme 1).
With the increasing demand of sustainable chemistry, cross-
dehydrogenative coupling strategies leading to the construction
of C–C and C–X (X = N, S, O) bonds[5] have streamlined the
chemical processes by providing shorter, atom-economical and
environmentally benign protocols.[6] The oxidative C−S bond
formation is a highly useful, and challenging approach for the
construction of sulfur-containing frameworks.[7]
A number
transition-metal catalyzed[7a,8] and metal-free[9] C–S bond
forming strategies have been developed in recent years. Within
this realm, molecular iodine has been elegantly employed as an
inexpensive and air-insensitive reagent for the oxidative C−S
bond formation.[9a,10]
On the other hand, imidazo-heterocycles are well recognized as
“privileged scaffolds” due to their eye-catching pharmacological
[a]
Department of Chemistry, Birla Institute of Technology & Science,
Pilani, Rajasthan, 333031, India
Fax: 91-1596-244183, Tel: 91 5196-5155711
E-mail: sakhuja.rajeev@gmail.com
Scheme 1. Previous and the present report on sulfur-bridged dimeric imidazo-
heterocycles
[b]
[c]
Department of Chemistry, D.A.V. University, Jalandhar - Pathankot
National Highway, Jalandhar-144012, Punjab, India
Department of Chemical Sciences, Indian Institute of Science
Education and Research Mohali, Sector 81, S.A.S. Nagar, Manuali
P.O., Punjab 140306, India
Results and Discussion
With an anticipation to synthesize sulfur-bridged dimeric
imidazo-heterocycles, and following a trail from our recent report
on phenyliodine diacetate (PIDA)-mediated homocoupling of 2-
Supporting information for this article is given via a link at the end of
the document.
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arylimidazo[1,2-a]pyridines,[15f] we attempted the reaction of 2-
phenylimidazo[1,2-a]pyridine (1a) with 3 equiv. of sodium sulfide
(Na2S) as a model reaction under PIDA-mediated conditions
(Table 1, entry 1). Sodium sulfide failed to participate in the
reaction, and consequently 3,3'-biimidazo[1,2-a]pyridine[15a, 15c-e]
was obtained in a variety of solvents under reflux conditions over
the targeted 3,3′-bis(imidazo[1,2-a]pyridin-3-yl)sulfane (Table 1,
entry 1). Moreover, PIDA-mediated reaction of 1a and Na2S in
dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide (DMA)
failed to yield any product at all (Table 1, entry 2). Interestingly,
the desired product bis(imidazo[1,2-a]pyridin-3-yl)sulfane (2a)
was first witnessed and isolated in 18% yield by replacing PIDA
with molecular iodine in DCM under ambient conditions (Table 1,
entry 3). Interestingly, unexpected formation of bis disulfane 3a
in 10% yield was observed along with 2a in 48%, when the
model reaction was performed using 2 equiv. of iodine in DCM
under reflux conditions for 20 h (Table 1, entry 4). The structures
of 2a and 3a were unambiguously confirmed by 1H and 13C NMR
spectroscopy, HRMS analysis. A further enhancement in the
yield of 2a up to 69% was observed by screening solvents from
DCM to DCE, and finally to chloroform under reflux conditions
(Table 1, entries 5-6). The reaction was further optimized by
varying the number of equivalents of sodium sulfide and iodine.
The results indicated that increasing the equivalents of sodium
sulfide to five can yield 2a in 75% yield (Table 1, entry 7).
Delightfully, the best result was obtained by using three and five
equiv. of molecular iodine and sodium sulfide respectively,
yielding 80% of 2a with trace formation of 3a (Table 1, entry 8).
comparatively lower yields of 2a were obtained (Table 1, entries
9-10). A marginal decrease in the yield of the 2a was observed
by replacing Na2S with K2S (Table 1, entry 11).
With optimized reaction conditions in hand, the practical
applicability of the methodology was systematically investigated
using various substituted imidazo[1,2-a]pyridines bearing
electron-donating and electron-withdrawing groups (Scheme 2).
Table 1. Selected Optimizationa of Reaction Conditions for synthesis of 2a
and 3a
Entry
Reagent
(equiv.)
Sulfur
Source
(equiv.)
Solvent
Yieldb (%)
2a
3a
DCE/CH3CN/
CHCl3/DCM
1c
PhI(OAc)2 (2) Na2S (3)
PhI(OAc)2 (2) Na2S (3)
-
-
2d
3e
4a
5a
6a
7a
8a
9a
10a
11a
12f
13g
DMSO/DMA
DCM
-
-
-
I2 (2)
I2 (2)
Na2S (3)
Na2S (3)
Na2S (3)
Na2S (3)
Na2S (5)
Na2S (5)
Na2S (5)
Na2S (5)
K2S (5)
18
48
61
69
75
80
41
44
78
<5
<10
DCM
10
<10
<5
<5
<5
<5
<5
<5
47
85
I2 (2)
DCE
I2 (2)
CHCl3
I2 (2)
CHCl3
I2 (3)
KI (3)
NH4I (3)
I2 (3)
CHCl3
CHCl3
CHCl3
CHCl3
I2 (3)
I2 (3)
Na2S (5)
Na2S (5)
CH3COOH
CH3COOH
Scheme 2. Substrate scope of substituted 2-arylimidazo-heterocycles towards
the synthesis of bis sulfane 2
[a]Reaction conditions: 1a (0.25 mmol), Reagent (as indicated), Sulfur Source
(as indicated), Solvent (5 mL), reflux, 20 h; [b]Isolated yield; [c]T = Boiling point
of the solvent for 20 h; [d]T = 110 oC (for 20 h); [e]r.t. for 30 h; fT = 100 oC for 20
h; gT = 100 oC for 48 h
2-Arylimidazo[1,2-a]pyridine possessing Me and OMe group on
the phenyl ring showcased excellent reactivity offering 2b and
2c in 83% and 85% yield, respectively. The presence of Me and
OMe group on the pyridyl and phenyl rings respectively proved
Subsequently, a number of iodine source replacements such as
KI or NH4I were screened for the reaction, however
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1d to be the best substrate, producing the corresponding bis
sulfane 2d in 90% yield. Similarly, 2-arylimidazo[1,2-a]pyridines
bearing Me group on both the pyridyl and phenyl rings yielded
their desired bis sulfanes 2f in 83% yield. Halogen (–F, Cl and
Br) substitued 2-phenylimidazo[1,2-a]pyridines (1h-k) afforded
the corresponding products (2h-k) in 69-80% isolated yields.
The reaction also tolerated bulkier naphthyl group (in place of
phenyl) yielding the expected bis sulfane (2l) in 87% yield. The
m-nitro substituted 2-phenylimidazo[1,2-a]pyridine (1m) showed
slight sluggish behavior in reactivity offering 2m in only 47%
yield, whereas p-nitro substituted 2-phenylimidazo[1,2-a]pyridine
(1n) showed reluctance in reactivity yielding only trace amount
of bis sulfane. This is probably due to the insolubility p-NO2-2-
phenylimidazo[1,2-a]pyridine in chloroform even under reflux
conditions. To our delight, the reaction was also successful with
ORTEP diagrams of 2h (CCDC No. 1559710), 3j (CCDC No.
1559711) and 3o (CCDC No. 1559712), are shown in Figure 1
(Crystallographic data of 2h, 3j and 3o is provded in SI).
2-phenylimidazo[2,1-b]thiazole
(1o)
yielding
bis(6-
phenylimidazo[2,1-b]thiazol-5-yl)sulfane (2o) in 81% yield.
Interestingly, during further solvent optimization, 3,3′-
bis(imidazo[1,2-a]pyridin-3-yl)disulfane (3a) was obtained in
47% yield at 100 0C in acetic acid after 20 h (Table 1, entry 12).
Gratifyingly, increasing the reaction time to 48 h in acetic acid at
0
100 C predominantly, yielded 3a in 85% yield (Table 1, entry
13). Within this realm, the substrate scope of imidazo-
heterocycles bearing different electron-donating and electron-
withdrawing groups on phenyl and pyridyl rings were examined
(Scheme 3). In general, all 2-phenylimidazo[1,2-a]pyridine
derivatives exhibited admirable reactivity yielding their
corresponding disulfanes in excellent yields. Interestingly, the
nitro m/p-substituted 2-phenylimidazo[1,2-a]pyridines (1m-n)
comfortably delivered the desired products (3m-n) in 85% and
87% yields, respectively. The methodology was also extended
towards the synthesis of 1,2-bis(6-phenylimidazo[2,1-b]thiazol-5-
yl)disulfane (3o) from imidazo[2,1-b]thiazole (1o) in appreciable
yield. Unfortunaltely, 2-phenylimidazo[1,2-a]pyrimidine (1p)
failed to yield either bis sulfane (2p) or bis disulfane (3p) under
optimized conditions. In order to further confirm the proposed
structures, as representative examples single crystals of bis
sulfane (2h) and bis disulfane (3j & 3o) were grown by
chloroform for the X-ray diffraction studies.
Scheme 3. Substrate scope of 2-phenylimidazo-heterocycles towards the
synthesis of bis disulfane 3
To access the scalability of the developed synthetic strategies, 1
gram scale reactions of 2-(p-tolyl)imidazo[1,2-a]pyridine (1b)
with 5 equivalents of sodium sulfide under optimized reaction
conditions, yielded bis sulfane (2b) and bis disulfane (3b) in 65%
(0.696 g) and 71% (0.815 g) yields, respectively (Scheme 4).
Figure 1. ORTEP diagrams of 2h, 3j, 3o with 50% thermal probability
ellipsoids
Both 2h & 3j crystallize in the monoclinic C2/c space group,
while 3o crystallizes in the orthorhombic C2221 space group.
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c]
Subsequently, iodine-mediated oxidation[17b,d] of C affords 3f
(Scheme 6, Path b). Alternatively, the reaction in acetic acid
could also proceed by the nucleophilic attack of in-situ
2-
generated S2 species (by I2-mediated oxidation of S2-) on 1f'
resulting in D, which eventual attacks another 1f' to yield 3f
(Scheme 6, Path b').
Scheme 4. Gram scale synthesis of bis sulfane (2b) & bis disulfane (3b)
To probe the reaction mechanism, several preliminary
experiments were performed (Scheme 5). 3-iodo-8-methyl-2-(p-
tolyl)imidazo[1,2-a]pyridine (1f') was observed to be formed (&
isolated) in almost quantitative yields (TLC) after refluxing 1f and
I2 (3 equiv.) in chloroform within 4 h. 1f' upon further reaction
with Na2S/I2 in chloroform under reflux conditions resulted in the
formation
of
bis(8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-
yl)sulfane 2f in major amounts (Scheme 5i). It is noteworthy to
mention that subsequent de-halogenation of 1f' to 1f was also
observed during the progress of the reaction. Similarly, 1f' upon
reaction with Na2S/I2 in acetic acid resulted in the formation of
1,2-bis(8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)disulfane 3f
in major amounts, albeit the formation of 1f' in acetic acid was
observed to be a slow process and in lower yield (Scheme 5ii).
The mass spectral studies (ESI-MS) of the reaction mixture
obtained by reacting 1f under optimized conditions in chloroform
after 7 h affirmed the formation of 1f', B (R-S-I) and 2f, thereby
suggesting the possible involvement of B (R-S- I) intermediate in
the reaction pathway (Scheme 5iii). Similarly, the mass spectral
studies (ESI-MS) of the reaction mixture obtained by reacting 1f
under optimized conditions in acetic acid after 18 h affirmed the
formation of 1f', B, C and 3f, thereby suggesting the possible
involvement of intermediates B (R-S-I) and C (R-S-H) in the
reaction pathway (Scheme 5iv) (details in supporting information
file).
Scheme 5. Preliminary Mechanistic Studies
On the basis of our current studies and available literature,[17]
a
plausible mechanism is proposed (Scheme 6). The initial
reaction (in chloroform or acetic acid) is believed to proceed via
C-3 nucleophilic attack of imidazo[1,2-a]pyridine (1f) on I2,
forming intermediate 1f'. In chloroform, the reaction of 1f’ with
sulfide ion seems to proceed via SNAr mechanism forming
intermediate species A along with the elimination of NaI. At the
same time, the formation of a substantial amount of de-iodinated
compound 1f was also observed (on TLC) during monitoring the
progress of the reaction,[18] probably using HI from the reaction
mixture. Thereafter, species A generates electrophilic species B
which on further reaction[17a] with 1f furnishes 2f (Scheme 6,
Path a). On the other hand, due to possible conversion of S2- to
either SH- or H2S (existing in equilibrium with each other) in
acetic acid, the reaction might proceed via nucleophilic
substitution of I- in 1f' by SH- (or H2S) to generate thiol
intermediate C (which is known to exist in equilibrium with B).[17b-
Scheme 6. Plausible mechanism
Conclusions
In summary, we have successfully described solvent-driven
straightforward, direct oxidative strategies for the synthesis of
bis(imidazo[1,2-a]pyridin-3-yl)sulfanes
and
bis(imidazo[1,2-
a]pyridin-3-yl)disulfanes using Na2S as a sulfur source. This is
the first report for the iodine-mediated direct homocoupling of
imidazo-heterocycles with sulfur atom(s) linker.
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Experimental Section
106.9, 21.5; HRMS (ESI-TOF) (m/z) calculated C28H23N4S+: 447.1643;
found 447.1657 [M+H]+.
General
Bis(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)sulfane
(2c):
Commercially available reagents were used without purification.
Commercially available solvents were dried by standard procedures prior
to use. Nuclear magnetic resonance spectra were recorded on 400 MHz
spectrometer and chemical shifts are reported in δ units, parts per million
(ppm), relative to residual chloroform (7.26 ppm) or DMSO (2.5 ppm) in
the deuterated solvent. The following abbreviations were used to
describe peak splitting patterns when appropriate: s = singlet, d = doublet,
t = triplet, dd = doublet of doublet and m = multiplet. Coupling constants J
were reported in Hz. The 13C NMR spectra were reported in ppm relative
to deuterochloroform (77.0 ppm) or [d6] DMSO (39.5 ppm). Melting points
were determined on a capillary point apparatus equipped with a digital
thermometer and are uncorrected. High resolution mass spectra were
recorded with a TOF analyzer spectrometer by using electrospray mode.
White solid; yield: 95 mg (85%); Rf = 0.38 (silica gel, hexanes/EtOAc, 6:4
1
v/v); mp 220–222 °C; H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.7 Hz,
4H), 7.64 (d, J = 6.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.7 Hz,
4H), 7.14 – 7.06 (m, 2H), 6.41 (t, J = 6.8 Hz, 2H), 3.97 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 160.2, 150.6, 146.5, 130.7, 126.3, 126.2, 125.4,
117.2, 114.0, 112.5, 106.5, 55.4; HRMS (ESI-TOF) (m/z) calculated
C28H23N4O2S+ : 479.1541; found 479.1538 [M+H]+.
Bis(2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)sulfane
(2d): White solid; yield: 117 mg (90%); Rf
= 0.35 (silica gel,
1
hexanes/EtOAc, 6:4 v/v); mp 238–239 °C; H NMR (400 MHz, CDCl3) δ
8.17 – 8.06 (m, 4H), 7.47 (d, J = 7.0 Hz, 2H), 7.24 (s, 2H), 7.19 – 7.11
(m, 4H), 6.24 (dd, J = 7.0, 1.6 Hz, 2H), 3.97 (s, 6H), 2.27 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 160.1, 150.3, 146.8, 137.4, 130.6, 126.46,
124.5, 115.7, 115.0, 113.9, 105.8, 55.4, 21.2; HRMS (ESI-TOF) (m/z)
calculated C30H27N4O2S+ : 507.1854; found 507.1873 [M+H]+.
General procedure for bis sulfane and bis disulfane
A mixture of imidazo-heterocycles (1a-o) (0.5 mmol), molecular iodine
(1.5 mmol), sodium sulfide (2.5 mmol), in chloroform (10 mL) was
refluxed at 65 °C under air atmosphere for 15-20 h. On completion of
reaction as indicated by TLC, water was added to the reaction mixture.
The organic layer was separated, and washed with a 20% sodium
thiosulfate solution (30 mL × 2). The organic layer was concentrated
under reduced pressure and the crude product was purified by silica gel
column chromatography [SiO2 (100–200 mesh), hexanes/EtOAc, 8:2 v/v],
affording the corresponding bis sulfanes (2a-o).
Bis(2-(4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridin-3-yl)sulfane
(2e): White solid; yield: 121 mg (81%); Rf
= 0.36 (silica gel,
hexanes/EtOAc, 6:4 v/v); mp 208-209 °C; 1H NMR (400 MHz, CDCl3) δ
8.15 – 8.03 (m, 4H), 7.56 – 7.45 (m, 2H), 7.21 – 7.10 (m, 4H), 6.94 –
6.86 (m, 2H), 6.33 (t, J = 6.9 Hz, 2H), 3.97 (s, 6H), 2.54 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 160.1, 150.2, 146.7, 130.9, 127.1, 126.7, 124.9,
123.2, 113.9, 112.3, 107.0, 55.4, 16.7; HRMS (ESI-TOF) (m/z) calculated
C30H27N4O2S+ : 507.1854; found 507.1859 [M+H]+.
Similarly, a mixture of imidazo-heterocycles (1a-o) (0.5 mmol), molecular
iodine (1.5 mmol), sodium sulfide (2.5 mmol), in acetic acid (10 mL) was
heated at 100 °C under air atmosphere for 45-48 h. On completion of
reaction as indicated by TLC, 10% sodium bicarbonate solution (20 mL)
was added to the reaction mixture. Thereafter, the reaction mixture was
extracted with ethyl acetate (20 mL × 2) and the organic layer was
washed with a 20% sodium thiosulfate solution (30 mL × 2). Finally The
organic layer was separated, concentrated under reduced pressure and
subjected to silica gel column chromatography [SiO2 (100–200 mesh),
hexanes/EtOAc, 3:7 v/v], affording bis sulfanes (3a-o).
Bis(8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)sulfane (2f): White
solid; yield: 98 mg (83%); Rf = 0.44 (silica gel, hexanes/EtOAc, 6:4 v/v);
mp 239–240 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 4H),
7.47 (d, J = 6.7 Hz, 2H), 7.42 (d, J = 7.9 Hz, 4H), 6.94 – 6.85 (m, 2H),
6.29 (t, J = 6.9 Hz, 2H), 2.53 (s, 12H); 13C NMR (100 MHz, CDCl3) δ
150.5, 146.7, 138.5, 131.2, 129.5, 129.2, 127.2, 124.9 123.3, 112.4,
107.5, 21.5, 16.7; HRMS (ESI-TOF) (m/z) calculated C30H27N4S+:
475.1956; found 475.1977 [M+H]+.
Bis(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane (2g): White
solid; yield: 88 mg (80%); Rf = 0.46 (silica gel, hexanes/EtOAc, 6:4 v/v);
mp 203–204 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.10 – 8.04 (m, 4H),
7.60 – 7.55 (m, 6H), 7.40 (d, J = 7.0 Hz, 2H), 7.32 (s, 2H), 6.36 (dd, J =
7.0, 1.3 Hz, 2H), 2.21 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 150.1,
146.5, 138.1, 133.9, 129.3, 129.3, 129.0, 123.9, 116.1, 115.7, 106.4,
20.9; HRMS (ESI-TOF) (m/z) calculated C28H23N4S+: 447.1643; found
447.1640 [M+H]+.
Bis(2-phenylimidazo[1,2-a]pyridin-3-yl)sulfane (2a): White solid; yield:
83 mg (80%); Rf = 0.41 (silica gel, hexanes/EtOAc, 6:4 v/v); mp > 250
1
°C; H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.08
(m, 4H), 7.68 – 7.62 (m, 4H), 7.61 – 7.55 (m, 4H), 7.53 (dt, J = 9.0, 1.0
Hz, 2H), 7.17 – 7.07 (m, 2H), 6.38 (td, J = 6.9, 1.1 Hz, 2H).13C NMR (100
MHz, CDCl3) δ 150.9, 146.5, 133.8, 129.6, 128.9, 128.6, 126.4, 125.4,
117.4, 112.6, 107.5, 104.9; HRMS (ESI-TOF) (m/z) calculated
C26H19N4S+: 419.1330; found 419.1343 [M+H]+.
Bis(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane (2h): White
solid; yield: 86 mg (76%); Rf = 0.52 (silica gel, hexanes/EtOAc, 6:4 v/v);
mp >250 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.6, 5.5 Hz, 4H),
7.60 (d, J = 6.9 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.33 (t, J = 8.6 Hz, 4H),
7.16 (dd, J = 11.5, 4.3 Hz, 2H), 6.46 (t, J = 6.6 Hz, 2H).; 13C NMR (100
MHz, CDCl3) δ 164.5, 162.0, 149.9, 146.5, 131.3, 131.2, 129.9, 126.5,
125.1, 117.5, 115.8, 115.6, 112.7, 106.9; HRMS (ESI-TOF) (m/z)
calculated C26H17F2N4S+ : 455.1141; found 455.1165 [M+H]+.
Bis(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)sulfane (2b): White solid;
yield: 93 mg (83%); Rf = 0.45 (silica gel, hexanes/EtOAc, 6:4 v/v); mp
244–245 °C; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 4H), 7.63
– 7.58 (m, 2H), 7.54 – 7.48 (m, 2H), 7.44 (d, J = 7.9 Hz, 4H), 7.15 – 7.06
(m, 2H), 6.41 – 6.34 (m, 2H), 2.54 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
150.9, 146.5, 138.8, 130.9, 129.4, 129.3, 126.2, 125.4, 117.2, 112.5,
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Bis(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane (2i): White
solid; yield: 97 mg (80%); Rf = 0.58 (silica gel, hexanes/EtOAc, 6:4 v/v);
(dd, J = 12.5, 7.1 Hz, 6H), 6.78 (td, J = 6.8, 1.1 Hz, 2H); 13C NMR* (100
MHz, CDCl3) δ 147.3, 131.9, 128.1, 127.9, 127.7, 127.0, 124.4, 117.3,
113.0; HRMS (ESI-TOF) (m/z) calculated C26H19N4S2+: 451.1051; found
451.1075 [M+H]+. (*Note: In the 13C NMR of most of the bis disulfanes,
the numbers of the carbon signals observed are less than the expected
number. This is due to the accidental degeneracy of some of the carbons
and is been affirmed by 1H-13C correlation spectra of one of the
representative compound 3f (Supporting Information).
1
mp >250 °C; H NMR (400 MHz, CDCl3) δ 8.18 – 8.05 (m, 4H), 7.69 –
7.58 (m, 6H), 7.54 (d, J = 9.0 Hz, 2H), 7.21 – 7.14 (m, 2H), 6.49 (td, J =
6.9, 0.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 149.7, 146.6, 135.1,
132.2, 130.6, 128.9, 126.7, 125.1, 117.6, 112.9, 107.1; HRMS (ESI-TOF)
(m/z) calculated C26H17Cl2N4S+ : 487.0551; found 487.0569 [M+H]+.
Bis(2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane (2j): White
solid; yield: 99 mg (69%); Rf = 0.61 (silica gel, hexanes/EtOAc, 6:4 v/v);
mp >250°C; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 4H), 7.76
(d, J = 8.4 Hz, 4H), 7.63 (d, J = 6.9 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.23
– 7.12 (m, 2H), 6.49 (t, J = 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
149.7, 146.6, 132.7, 131.8, 130.9, 126.7, 125.1, 123.3, 117.6, 113.0,
107.1; HRMS (ESI-TOF) (m/z) calculated C26H17Br2N4S+: 574.9541;
found 574.9552 [M+H]+.
1,2-bis(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)disulfane (3b): White
solid; yield: 106 mg (89%); Rf = 0.38 (silica gel, hexanes/EtOAc, 2:8 v/v);
mp 203–204 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.5 Hz, 2H),
7.70 – 7.47 (m, 4H), 7.35 (d, J = 8.0 Hz, 2H), 7.23 – 7.13 (m, 2H), 6.90
(d, J = 6.8 Hz, 4H), 6.77 (td, J = 6.8, 0.9 Hz, 2H), 2.29 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 147.3, 138.0, 128.4, 127.7, 126.8, 124.4, 117.5,
112.9, 21.3; HRMS (ESI-TOF) (m/z) calculated C28H23N4S2+: 479.1364;
found 479.1387 [M+H]+.
Bis(2-(4-bromophenyl)-8-methylimidazo[1,2-a]pyridin-3-yl)sulfane
(2k): White solid; yield: 108 mg (72%); Rf
=
0.64 (silica gel,
1,2-Bis(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)disulfane
hexanes/EtOAc, 6:4 v/v); mp 248-250 °C; 1H NMR (400 MHz, CDCl3) δ
8.07 – 7.98 (m, 4H), 7.78 – 7.70 (m, 4H), 7.49 (d, J = 6.6 Hz, 2H), 6.98 –
6.91 (m, 2H), 6.40 (t, J = 6.9 Hz, 2H), 2.54 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 149.2, 146.8, 133.0, 131.7, 131.1, 127.6, 125.3, 123.1, 122.9,
112.9, 107.5, 16.6; HRMS (ESI-TOF) (m/z) calculated C28H21Br2N4S+:
602.9854; found 602.9863 [M+H]+.
(3c): Yellow solid; yield: 111 mg (87%); Rf
= 0.34 (silica gel,
1
hexanes/EtOAc, 2:8 v/v); mp 211–213 °C; H NMR (400 MHz, CDCl3) δ
8.15 (d, J = 6.1 Hz, 2H), 7.78 – 7.46 (s, 4H), 7.36 (d, J = 7.4 Hz, 2H),
7.25 – 7.18 (m, 2H), 6.79 (t, J = 6.7 Hz, 2H), 6.63 (d, J = 6.8 Hz, 4H),
3.81 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.8, 147.3, 129.1, 127.0,
124.5, 117.3, 113.1, 112.9, 55.2; HRMS (ESI-TOF) (m/z) calculated
C28H23N4O2S2+ : 511.1262; found 511.1276 [M+H]+.
Bis(6-methyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)sulfane
(2l): White solid; yield: 123 mg (87%); Rf
=
0.45 (silica gel,
1,2-Bis(2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-
hexanes/EtOAc, 6:4 v/v); mp: >250 °C; 1H NMR (400 MHz, CDCl3) δ 8.67
(s, 2H), 8.33 (dd, J = 8.5, 1.4 Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H), 8.70 –
7.97 (m, 4H), 7.61 (dd, J = 6.2, 3.2 Hz, 4H), 7.46 – 7.33 (m, 4H), 6.89
(dd, J = 9.0, 1.2 Hz, 2H), 1.34 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
150.4, 145.6, 133.4, 131.5, 129.5, 128.6, 128.2, 127.8, 127.0, 126.7,
126.5, 123.6, 122.5, 116.5, 107.3, 17.3; HRMS (ESI-TOF) (m/z)
calculated C36H27N4S+ : 547.1956; found 547.1951 [M+H]+.
yl)disulfane (3d): Yellow solid; yield: 125 mg (93%); Rf = 0.30 (silica gel,
1
hexanes/EtOAc, 2:8 v/v); mp 219–220 °C; H NMR (400 MHz, CDCl3) δ
7.99 (d, J = 6.7 Hz, 2H), 7.78 – 7.39 (m, 4H), 7.17 – 6.92 (m, 2H), 6.75 –
6.45 (m, 6H), 3.81 (s, 6H), 2.39 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
159.7, 147.6, 138.4, 129.1, 123.8, 115.9, 115.2, 112.8, 55.0, 21.2; HRMS
(ESI-TOF) (m/z) calculated C30H27N4O2S2+: 539.1575 ; found 539.1573
[M+H]+.
Bis(2-(3-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)sulfane (2m): Yellow
solid; yield: 59 mg (47%); Rf = 0.60 (silica gel, hexanes/EtOAc, 6:4 v/v);
mp: >250°C; 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 2H), 8.47 (d, J = 7.6
Hz, 2H), 8.27 (d, J = 7.0 Hz, 4H), 7.68 (t, J = 8.1 Hz, 4H), 7.42 – 7.30 (m,
2H), 7.02 (t, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 148.3, 145.4,
135.4, 134.2, 129.4, 126.7, 126.3, 123.2, 122.9, 117.9, 113.8; HRMS
(ESI-TOF) (m/z) calculated C26H17N6O4S+: 509.1032; found 509.1047
[M+H]+.
1,2-Bis(2-(4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridin-3-
yl)disulfane (3e): Yellow solid; yield: 123 mg (92%); Rf = 0.38 (silica gel,
1
hexanes/EtOAc, 2:8 v/v); mp 221–223 °C; H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 3.0 Hz, 2H), 7.75 – 7.70 (m, 4H), 6.97 (d, J = 6.8 Hz, 2H),
6.71 (t, J = 6.8 Hz, 2H), 6.57 (d, J = 5.8 Hz, 4H), 3.78 (s, 6H), 2.48 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 159.3, 147.5, 128.8, 127.2, 125.7,
124.8, 122.4, 112.6, 112.5, 55.0, 16.7; HRMS (ESI-TOF) (m/z) calculated
C30H27N4O2S2+ : 539.1575; found 539.1572 [M+H]+.
Bis(6-phenylimidazo[2,1-b]thiazol-5-yl)sulfane (2o): White solid; yield:
87 mg (81%); Rf = 0.70 (silica gel, hexanes/EtOAc, 6:4 v/v); mp 230–231
°C; δ 8.09 (dd, J = 5.2, 3.3 Hz, 4H), 7.60 – 7.52 (m, 4H), 7.51 – 7.45 (m,
2H), 6.54 (d, J = 4.5 Hz, 2H), 6.51 (d, J = 4.5 Hz, 2H); 13C NMR (100
1,2-Bis(8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)disulfane (3f):
Yellow solid; yield: 110 mg (87%); Rf = 0.51 (silica gel, hexanes/EtOAc,
2:8 v/v); mp 178–180 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.02 (m,
2H), 7.48 (d, J = 7.6 Hz, 4H), 6.99 – 6.92 (m, 2H), 6.84 (d, J = 7.7 Hz,
4H), 6.71 (t, J = 6.8 Hz, 2H), 2.49 (s, 6H), 2.26 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 151.3, 151.2, 133.6, 128.6, 128.5, 118.4, 112.6, 109.4;
+
HRMS (ESI-TOF) (m/z) calculated C22H15N4S3
:
431.0458; found
MHz, CDCl3) δ 147.4, 137.2, 129.2, 127.8, 127.5, 127.2, 125.8, 122.4,
+
431.0475 [M+H]+.
112.7, 21.2, 16.7; HRMS (ESI-TOF) (m/z) calculated C30H27N4S2
:
507.1677; found 507.1683 [M+H]+.
1,2-Bis(2-phenylimidazo[1,2-a]pyridin-3-yl)disulfane (3a): Yellow
solid; yield: 96 mg (85%); Rf = 0.32 (silica gel, hexanes/EtOAc, 2:8 v/v);
1,2-Bis(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)disulfane (3g):
Yellow solid; yield: 102 mg (85%); Rf = 0.46 (silica gel, hexanes/EtOAc,
2:8 v/v); mp 224–225 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 6.9
1
mp 242–243 °C; H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.6 Hz, 2H),
7.78 – 7.50 (m, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.26 – 7.20 (m, 2H), 7.14
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Hz, 2H), 7.86 – 7.45 (m, 4H), 7.25 – 6.96 (m, 8H), 6.56 (dd, J = 6.9, 1.5
Hz, 2H), 2.40 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 147.6, 138.3, 132.2,
127.9, 127.6, 123.6, 116.2, 115.5, 21.3; HRMS (ESI-TOF) (m/z)
calculated C28H23N4S2+: 479.1364; found 479.1371 [M+H]+.
122.8, 117.5, 113.4, 109.8; HRMS (ESI-TOF) (m/z) calculated
C26H17N6O4S2+: 541.0752 ; found 541.0769 [M+H]+.
1,2-Bis(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)disulfane
(3n):
Orange solid; yield: 117 mg (87%); Rf = 0.60 (silica gel, hexanes/EtOAc,
2:8 v/v); mp >250 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 6.9
Hz, 2H), 8.59 – 8.53 (m, 4H), 8.28 – 8.22 (m, 4H), 7.61 (d, J = 9.0 Hz,
2H), 7.43 – 7.35 (m, 2H), 7.04 (td, J = 6.8, 1.0 Hz, 2H); 13C NMR (100
MHz, DMSO-d6 + CDCl3) δ 147.2, 146.8, 140.4, 128.9, 127.5, 125.5,
123.6, 117.6, 113.6, 110.7; HRMS (ESI-TOF) (m/z) calculated
C26H17N6O4S2+: 541.0752 ; found 541.0778 [M+H]+.
1,2-Bis(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)disulfane (3h):
White solid; yield: 121 mg (92%); Rf = 0.56 (silica gel, hexanes/EtOAc,
2:8 v/v); mp 227–229 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J =
6.8 Hz, 2H), 8.31 – 8.23 (m, 4H), 7.54 (d, J = 9.0 Hz, 2H), 7.34 – 7.28 (m,
2H), 7.14 – 7.07 (m, 4H), 6.95 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6 + CDCl3) δ 161.4, 146.4, 130.2, 130.1, 126.9, 125.3, 117.2,
115.4, 115.2, 113.0, 108.5; HRMS (ESI-TOF) (m/z) calculated
C26H17F2N4S2+: 487.0862; found 487.0880 [M+H]+.
2-Phenyl-3-((6-phenylimidazo[2,1-b]thiazol-5-yl)disulfanyl)imidazo
[1,2-b]isothiazole (3o): Pale yellow solid; yield: 96 mg (83%); Rf = 0.54
(silica gel, hexanes/EtOAc, 2:8 v/v); mp 177–179 °C; 1H NMR (400 MHz,
CDCl3) δ 7.80 – 7.77 (m, 4H), 7. 29 – 7.24 (m, 6H), 7.13 (d, J = 4.4 Hz,
2H), 6.70 (d, J = 4.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 154.2, 152.2,
132.4, 128.2, 127.9, 127.3, 117.6, 113.3, 110.1; HRMS (ESI-TOF) (m/z)
calculated C22H15N4S4+ : 463.0179; found 463.0164 [M+H]+.
1,2-Bis(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)disulfane
(3i):
White solid; yield: 103 mg (80%); Rf = 0.53 (silica gel, hexanes/EtOAc,
2:8 v/v); mp 210–212 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (dd, J =
6.9, 1.1 Hz, 2H), 8.34 – 8.22 (m, 4H), 7.56 (dd, J = 9.0, 1.0 Hz, 2H), 7.45
– 7.37 (m, 4H), 7.34 – 7.26 (m, 2H), 6.99 (td, J = 6.8, 1.1 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6 + CDCl3) δ 148.1, 146.5, 133.8, 132.6, 129.6,
128.5, 126.9, 125.3, 117.3, 113.1; HRMS (ESI-TOF) (m/z) calculated
C26H17Cl2N4S2+: 519.0272; found 519.0285 [M+H]+.
Acknowledgements
1,2-Bis(2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)disulfane (3j):
Orange solid; yield: 116 mg (87%); Rf = 0.60 (silica gel, hexanes/EtOAc,
2:8 v/v); mp 235–236 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 6.6
Hz, 2H), 7.49 – 7.29 (m, 8H), 7.10 (d, J = 8.1 Hz, 4H), 6.96 – 6.88 (m,
SMAS and DA thank BITS Pilani for providing SRFs. The use of
X-ray facility at IISER Mohali is gratefully acknowledged. The
authors sincerely acknowledge financial support from DST under
FIST program [Project: SR/FST/CSI-270/2015] for HRMS facility.
2H); 13C NMR (100 MHz, CDCl3) δ 147.4, 130.5, 128.9, 127.8, 124.7,
+
122.5, 117.9, 113.4; HRMS (ESI-TOF) (m/z) calculated C26H17Br2N4S2
:
Keywords: 2-Phenylimdazo[1,2-a]pyridine • Iodine
Sulfenylation • C-H Activation
606.9261; found 606.9274 [M+H]+.
1,2-Bis(2-(4-bromophenyl)-8-methylimidazo[1,2-a]pyridin-3-
yl)disulfane (3k): Yellow solid; yield: 132 mg (83%); Rf = 0.64 (silica gel,
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1
hexanes/EtOAc, 2:8 v/v); mp 184–186 °C; H NMR (400 MHz, CDCl3) δ
8.18 (d, J = 6.2 Hz, 2H), 7.42 (d, J = 7.8 Hz, 4H), 7.14 – 7.03 (m, 6H),
6.86 (t, J = 6.8 Hz, 2H), 2.51 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
147.5, 130.5, 130.0, 128.7, 127.5, 127.0, 122.5, 121.8, 113.4, 16.7;
HRMS (ESI-TOF) (m/z) calculated C28H21Br2N4S2+: 634.9574; found
634.9597 [M+H]+.
1,2-Bis(6-methyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-
yl)disulfane (3l): Yellow solid; yield: 113 mg (78%); Rf = 0.47 (silica gel,
1
[3] S. Pola, in Scope of Selective Heterocycles from Organic and
Pharmaceutical Perspective (Ed.: R. Varala), InTech, Rijeka, 2016, p. Ch.
01.
hexanes/EtOAc, 2:8 v/v); mp 245–247 °C; H NMR (400 MHz, CDCl3) δ
8.05 (s, 2H), 7.81 (d, J = 7.7 Hz, 2H), 7.79 – 7.67 (m, 5H), 7.61 (d, J =
8.2 Hz, 2H), 7.56 – 7.36 (m, 5H), 6.74 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 8.3
Hz, 2H), 2.13 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 146.2, 133.1, 129.8,
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128.6, 127.4, 126.9, 125.9, 125.7, 125.4, 122.8, 122.2, 116.1, 18.2;
+
HRMS (ESI-TOF) (m/z) calculated C36H27N4S2
: 579.1677; found
579.1673 [M+H]+.
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2009, 48, 5094-5115; b) X.-X. Guo, D.-W. Gu, Z. Wu, W. Zhang, Chem.
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1,2-Bis(2-(3-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)disulfane
(3m):
Yellow solid; yield: 115 mg (85%); Rf = 0.59 (silica gel, hexanes/EtOAc,
2:8 v/v); mp >250 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.69
– 8.57 (m, 4H), 8.15 (dd, J = 2.3, 1.0 Hz, 2H), 7.63 – 7.57 (m, 4H), 7.35 –
7.28 (m, 2H), 7.00 – 6.92 (m, 2H); 13C NMR (100 MHz, DMSO-d6
+
[6] a) Y. Yang, J. Lan, J. You, Chem. Rev. 2017,117, 8787-8863; b) S. E.
Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem. Rev.
CDCl3) 148.4, 147.1, 146.7, 135.5, 134.1, 129.4, 127.2, 125.2, 122.9,
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FULL PAPER
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10.1002/asia.201701274
Chemistry - An Asian Journal
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S. M. Abdul Shakoor, Devesh S.
Agarwal, Sadhika Khullar, Sanjay K.
Mandal, Rajeev Sakhuja*
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Solvent-Driven
Iodine-mediated
Strategies for the
of Bis(imidazo[1,2-
Oxidative
Synthesis
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a]pyridin-3-yl)sulfanes and Disulfanes
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