Graphene oxide (GO)-catalyzed multi-component reactions: Green synthesis of library of pharmacophore 3-sulfenylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1039/c5ra04983k

The green carbocatalyst graphene oxide (GO) has been successfully utilized for selective and expedient synthesis of biologically important motifs imidazo[1,2-a]pyridines, and 3-sulfenylimidazo[1,2-a]pyridines via one-pot multi-component reactions (MCR). D

Full text of DOI:10.1039/c5ra04983k

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Graphene Oxide (GO)–catalyzed Multi–component Reactions: Green
Synthesis of Library of Pharmacophore 3–Sulfenylimidazo[1,2–a]pyridines
Samir Kundu and Basudeb Basu*
Department of Chemistry, North Bengal University, Darjeeling 734013, India
E–mail: basu_nbu@hotmail.com, Fax: +91 353 2699001
Abstract:
Green carbocatalyst graphene oxide (GO) has been successfully utilized for selective and
expedient synthesis of biologically important motifs imidazo[1,2–a]pyridines, and 3–
sulfenylimidazo[1,2–a]pyridines via oneꢀpot multi–component reactions (MCR). Diversity in
small heterocyclic molecular synthesis has been demonstrated with tolerance of broad range
of functional groups establishing the generality of the reaction and as well as demonstrating
preparation of libraries of potential pharmacophores. The reactions are believed to proceed
via selective and tandem reactions in the presence of GO and NaI (as the additive), and the
catalyst GO was found to be easily recoverable and recyclable with appreciable conversions.
Introduction:
Imidazo[1,2–a]pyridines represent an important N–bridged and fused bicyclic scaffolds
finding versatile applications in pharmaceuticals and organic functional materials.1 The
heterocyclic motif occurs in various clinical drugs including alpidem, necopidem, zolpidem,
saripidem, olprinone, miroprofen, zolimidine and anti–HIV drugs GSK812397, a few
representative examples are shown in Fig. 1.2 Its anticancer,3a antiviral,3bꢀc antimicrobial,3d
anti–rhinoviral,3eꢀf antiulcer3g activities are responsible for its wide applications in medicinal
chemistry. This moiety has also been used in material sciences.4 Further functionalized N–
bridged fused bicyclic imidazo[1,2–a]pyridines, such as 3–sulfenylimidazo[1,2–a]pyridines,
(Figure 1) are also of considerable therapeutic value against a variety of diseases and do find
broad spectrum uses in pharmaceutical industries.5

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N
N
N
N
CH3
Cl
N
N
H3C
Cl
SO2Me
O
O
N
CH3
N
N CH3
H3C
H3C
Alpidem
Zolpidem
Zolimidine
O
O
N
N
NH2
OH
N
N
N
H
C6H5S
SO2
N
NOH
CH3
S
Miroprofen
Enviroxime analog
Broad spectrum anthelmintic
Fig. 1 Representative examples of imidazo[1,2–a]pyridine–based drugs.
In spite of enormous applications, most of the imidazo[1,2–a]pyridine derivatives are not
commercially available and hence its synthesis from easily available substances has remained
in the focus of synthetic organic and pharmaceutical chemists. Most synthetic procedures
involve the reaction of 2ꢀaminopyridine with a variety of chemicals like acetophenones, αꢀ
haloketones, αꢀdiazoketones, αꢀtosyloxyketones, nitroalkenes, suitably substituted alkyne
derivatives etc.6 The reactions are usually done through condensation, tandem reactions or in
a multiꢀcomponent approach in the presence of Brønsted or Lewis acids or other metal
catalysts. For example, protic acid,7a,b Lewis acids7cꢀe or metal catalysts like Cu(I) salts,7fꢀh
Cu(I)/Cu(II),7i,j Cu(I)/Zn(II),7k Cu(II)/Fe(III)7l systems have been employed for the synthesis
of imidazo[1,2–a]pyridine derivatives.
Among several approaches, CeCl3.7H2O/NaI–catalyzed multicomponent tandem
procedure,7c has emerged possibly as a powerful methodology. However, modern green
practices demand for ecoꢀfriendly procedures without metal toxicity, contamination with the
product and final disposal. As such, the need for metal–free, non–toxic and easily available or
prepared catalysts are attractive targets for green and sustainable synthesis. In this
perspective, carbon materials like GO has emerged as an efficient and promising
carbocatalyst.8 Large surface area, bio–compatibility, inertness, and outstanding electronic,
optical, thermal & mechanical properties make GO as an versatile material, which is obtained
from low–cost and easily available starting materials.9 The presence of multiple
functionalities such as epoxide, hydroxyl and carboxyl groups (Fig. 2) account for its acidic
nature (pH 4.5 at 0.1 mg/mL),10 and strong oxidizing property.11 Harnessing these unique
qualities over the last few years, GO has been finely exploited as a metalꢀfree and robust
carbocatalyst in various synthetic processes like hydration of alkyne,12 selective oxidation of

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thiols and sulphides,11c oxidation of olefins to diones, methyl benzenes to aldehydes,
diarylmethanes to ketones,11d oxidative coupling of amines to imines,11e Friedel–Craft
addition of indole to α, β–unsaturated ketones etc.11f From our laboratory, we successfully
developed controlled use of this carbocatalyst in one–pot sequential dehydration–
hydrothiolation of sec–aryl alcohols,13a as well as chemoselective thioacetalization of aryl
aldehydes.13b
COOHCOOHOH
HOOC
COOH
O
O
O
O
HOOC
HO
HO
O
COOH
COOH
O
O
O
OH
COOH
COOH
Fig.2 Schematic presentation of graphene oxide (GO)
Considering the vast applicability of GO as the carbocatalyst in C–H oxidation, C–C and
C–heteroatom bondꢀforming reactions,13f,14 and our previous findings on oneꢀpot diverse
reactions to prepare complex molecules,13a we wanted to explore further GO–catalyzed
synthesis of complex heterocycles of biological relevance. We describe herein highly
selective metalꢀfree synthetic protocol for imidazo[1,2–a]pyridines from the reaction of 2–
aminopyridine and acetophenone, and an efficient oneꢀpot MCR procedure using aryl/alkyl
thiol as the third component leading to the synthesis of 3–sulfenylimidazo[1,2–a]pyridines in
the presence of a catalytic combination of GO and NaI.
Results and discussion:
Direct reaction of 2–aminopyridine (1) and acetophenone (2) can produce a number of
possible products like 3–(1–phenylethane)–2–phenyl (3), 3–(1–phenylethene)–2–phenyl (4)
and 2–phenyl (5) substituted imidazo[1,2–a] compounds and 4–methyl–2,4–diphenyl–4H–
pyrido[1,2–a]pyrimidine (6), either via ketimine intermediate or via OrtolevaꢀKing type
reaction intermediate (Scheme 1).7a Among metalꢀfree catalytic conditions, Kurteva et al
demonstrated pTSA–catalyzed selective formation of 3 from a mixture of 2–aminopyridine
o
(1) and acetophenone (2) at 210 C.7b Hitherto, there are no metalꢀfree conditions developed
that can furnish selectively a single product other than 3.

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O
N
Ph
Ph
CH3
N
N
N
2
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
NH2
Catalyst, heat
H3C Ph
1
3
4
5
6
Scheme 1. Possibility of formation of different products from 2ꢀaminopyridine and
acetophenone
As GO has been shown to act as an efficient carbocatalyst for both oxidation and acid–
catalyzed reactions,11ꢀ13 we presume that the use of GO in this reaction might play an active
role. We thus conducted experiments taking equimolar quantities of 2–aminopyridine and
acetophenone in the presence of catalytic amounts of GO under varying reaction conditions.
The results are presented in Table 1. Initial attempt of heating a mixture of reactants 1 (1
o
mmol) and 2 (1 mmol), the catalyst GO (100 mg) in acetonitrile (1 mL) at 80 C did not
afford any product (entry 1). However, the same reaction in the presence of an additive (NaI,
10 mol%) did produce a single product 5 in good yield (82%, entry 2). It is interesting to
observe that other possible products 3, 4 & 6 (Scheme 1) were not formed and the compound
5 was obtained as the sole product (HPLC analysis of the reaction mixture before
purification). Being encouraged by this finding, we tried to optimize other facets of the
reaction. For example, varying the quantity of GO, it was found that 50 mg of GO is the
minimal requirement to obtain >80% isolated yield of 5 (entries 3, 4). Reactions performed in
different solvents such ethanol or water were not productive either (entries 6, 7), but the same
reaction carried out in toluene afforded the single product 5 in excellent yield (entries 8, 9).
As seen from the results, the additive NaI does have a significant role in the catalytic process,
and possibly in the selective formation of 5. Decreasing its quantity below 10 mol% afforded
the product 5 either in low yields or not formed at all (entries 5, 10 and 1). In the absence of
GO, lowering of temperature or carrying out the reactions under N2 resulted in rather poor
yields of the desired product (entries 10ꢀ12). Use of other alkali metal salts such as KI or KBr
acted less efficiently as compared to NaI (entries 13, 14). Thus the optimized condition
established at our hand is as in entry 8, with the combination of GO (50 mg mmol−1) and the
additive, especially NaI (10 mol%), in solvent toluene, can produce selectively the product 5
in excellent yield. When we scaled up the reaction up to 3ꢀ5 mmols of the starting
compounds in the presence of GO (50ꢀ100 mg), appreciable conversions (67ꢀ88%) were
achieved (entries 15ꢀ17). This signifies that proportionate increase in the quantity of the

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catalyst (50 mg of GO mmol−1) is not an essential factor. Among the solvents tried for the
reaction, nonꢀpolar toluene performed best, polar aprotic solvent like acetonitrile can also
perform the reaction, but protic and polar solvents like ethanol or water were not suitable for
this conversion. Among other greener solvents,15 the reaction works as well in ethyl acetate
(entry 18).
Table 1: Optimization of the reaction conditionsa
O
N
Graphene oxide (GO), Additive
Solvent, Temp., Open air
CH3
N
N
NH2
1
2
5
Entry
GO
Additive
(Salt/mol%)
Nil
Solvent
Temp. (oC)
Time (h)
5 (Yield %)b
(mg)
100
1
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
80
80
80
80
80
80
80
80
80
60
80
80
80
8
No product
100
50
30
50
50
50
50
50
50
Nil
50
50
NaI/10
NaI/10
NaI/10
NaI/5
8
82
3
14
20
24
24
24
6
81
4
20
5
65
6
NaI/10
NaI/10
NaI/10
NaI/20
NaI/10
NaI/10
NaI/10
KI/10
40
7
H2O
No product
8
toluene
toluene
toluene
toluene
toluene
toluene
92
92
9
6
10
11
12c
13
15
24
24
15
55
No product
trace
57
14
15d
16e
17f
18
50
50
KBr/10
NaI/10
NaI/10
NaI/10
NaI/10
NaI/10
toluene
toluene
80
80
15
8
34
67
88
81
84
48
100
100
50
toluene
80
8
toluene
80
8
ethyl acetate
2ꢀpropanol
reflux
80
12
15
19
50

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a
General reaction conditions: Mixture of 2–aminopyridine (1 mmol), acetophenone (1
mmol), GO and NaI in solvent (1 mL) was stirred with a magnetic spin bar at
c
temperatures/times. b Yield represents pure product isolated after purification. Reaction was
d
e
carried out under N2 blanket. Reaction was carried out with 3 mmol of 1 & 2. Reaction
was performed in 3 mmol scale. f Reaction was performed in 5 mmol scale.
Next, the scope of this selective one–pot condensation–cyclization reaction was examined
employing the optimized condition and the results are summarized in Table 2. It can be seen
that diverse functional groups attached with the aromatic moiety of both reaction partners did
not have significant influence in the course of the reaction and in all cases the desired
imidazo[1,2–a]pyridine derivatives were obtained as the sole product and in good to excellent
yields. We studied with amino pyridines substituted with –CH3 and –Cl, while the
acetophenones bearing –C2H5, –Cl, –Br or –I afforded the corresponding product in a highly
selective manner (Table 2, compounds 5a–i). All reactions were carried out under open air
and at 80 oC.
Table 2: Reaction of different 2–aminopyridines with different acetophenones to
synthesise imidazo[1,2–a]pyridines.a,b
R
R1
GO (50 mg), NaI (10 mol %)
N
R
Toluene, 80oC, open air
(6 ꢀ 9 h)
N
O
N
NH2
R1
1
5
2
N
N
N
Et
Br
N
N
N
5a, 92%, 6 h
5b, 85%, 6 h
5c, 93%, 8 h
Br
Br
N
N
N
I
N
N
N
5d, 90%, 8 h
5e, 84%, 8 h
5f, 81%, 9 h
Br
N
N
N
N
N
Et
Cl
N
Cl
Me
5g, 83%, 8 h
Me
5h, 85%, 8 h
5i, 84%, 8 h
a A mixture of 1 (1 mmol), 2 (1 mmol), GO (50 mg), NaI (10 mol%) in toluene (1 mL) was
b
stirred at 80 oC in open air.
chromatography.
Yield represents pure product isolated by column

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The electrophilic addition to imidazo[1,2–a]pyridine ring system is ought to be facile and
likely to take place at Cꢀ3 position. Since thiol addition would lead to important
pharmacophores,16,7c we performed a three–component reaction involving 2–aminopyridine,
acetophenone and benzenethiol in the presence of GO and NaI. Indeed the thiophenol is
suitably reactive to add to imidazo[1,2–a]pyridine in a selective manner yielding the 2–
phenyl–3–(phenylthio)H–imidazo[1,2–a]pyridine (8a) in 84% isolated yield. Based on this
observation, we performed the GO/NaI–catalyzed MCR of broad range of functionalized
aminopyridines, acetophenones and arylthiols to generate a library of potential heterocyclic
scaffolds, 3–sulfenylimidazo[1,2–a]pyridines (8). In general, the reaction occurred fairly
smoothly producing the corresponding 3–sulfenylimidazo[1,2–a]pyridine derivatives in 70–
89% isolated yields. Critically, a marginal effect of the presence of orthoꢀsubstitutent in
thiophenol has been observed affording slightly lower yields of 8e, 8f, 8l, 8q), possibly due to
steric encumbrance. However, there was no significant electronic effect of the substitutents
present in either benzenethiol or acetophenone observed. Aliphatic thiol also worked
efficiently to afford the corresponding heterocyclic scaffold (8r). In general, the present MCR
procedure using the catalytic combination of GO and NaI was found to be effective with
diverse functional groups, as listed in the Table 3.
Table 3: Preparation of library of 3–sulfenylimidazo[1,2–a]pyridines from multi–
component reaction of 2–aminopyridines, acetophenone and thiol under the optimized
reaction condition.a,b
O
R1
Ar SH
or
R2 SH
R1
N
GO (50 mg), NaI (10 mol %)
Toluene, 80oC, Open air
CH3
N
N
NH2
S
Ar (or R2)
1
2
8
7

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N
N
N
N
N
N
N
N
S
S
S
S
OMe
OMe
Me
Et
Cl
8c, 89%, 10 h
8a, 84%, 12 h
8b, 86%, 10 h
8d, 81%, 12 h
N
N
N
N
N
N
N
Et
Me
N
S
S
S
S
Me
MeO
Me
8h, 79%, 14 h
8e, 80%, 13 h
8f, 81%, 12 h
8g, 83%, 12 h
OMe
OMe
N
N
N
N
N
N
N
N
Me
Me
OMe
S
S
S
S
F
Cl
Cl
Br
8i, 84%, 12 h
8j, 82%, 14 h
8k, 87%, 12 h
8l, 73%, 14 h
N
N
N
N
N
N
N
N
Br
I
Cl
S
S
S
S
Me
Me
Me
Cl
8m, 80%, 14 h
8n, 76%, 14 h
8o, 74%, 14 h
8p, 77%, 12 h
Br
N
N
N
N
Me
S
S
nꢀC5H11
Br
8r, 70%, 15 h
8q, 73%, 14 h
a A mixture of 1 (1 mmol), 2 (1 mmol), GO (50 mg), 7 (1.2 mmol), NaI (10 mol%) in toluene
o
b
(1 mL) was stirred at 80 C in open air. Yield represents isolated product by column
chromatography.
Catalytic performance is often measured by its lifeꢀcycle. After recovering the GO from
the first batch of reaction by simple filtration, it was washed successively with ethyl acetate,
water and acetone and finally dried under vacuum. The recovered freeꢀflowing GO black
powder was reused along with fresh NaI for three consecutive batches under similar reaction
conditions giving nearly same yield in each batch (Table 4, 84–80%). In order to see any
changes of the catalyst, we compared the FT–IR spectra of GO before and after use, and
found no significant changes in characteristic absorption bands (Figure 3). The absorption
bands for various functional groups of graphene oxide remain unchanged during the course of

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the reaction. Isolation of the product in comparable yield in each run suggest the active sites
of the surface of GO remain unaffected.
Table 4: Recyclability of GO in three–component tandem reaction of 2–aminopyridine,
acetophenone and thiophenol.a
Entry
1st run
2nd run
3rd run
4th run
Yield (%) b
84
83
84
80
a
2–aminopyridine (1 mmol), acetophenone (1 mmol), thiophenol (1.2 mmol), GO (50 mg),
NaI (10 mol%) in toluene was stirred at 80oC. b Yield represents isolated pure product.
Fig. 4 Comparative FTꢀIR spectra of GO before use (black), after 1st (blue) and 2nd run (red).
Previous mechanistic considerations suggest for two possible mechanistic pathways, viz.
via ketimine or Ortoleva–King type intermediate.7a,b Since the reaction condition results in
the formation of the bicyclic imidazo[1,2–a]pyridine 5 selectively, the reaction might proceed
via Ortoleva–King type intermediate and possibly not through the formation of ketimine.
Control experiments in the absence of GO (Table 1, entry 11) and under N2 (Table 1, entry
12), afforded no product or trace conversion respectively signifying that the oxidation of
iodide to iodine is likely to be possible in the presence of GO under aerobic condition. Based
on our experimental observations, we propose that initially NaI is oxidized under aerobic
condition to I2 in the presence of GO and then acetophenone is iodinated to phenacyl iodide 9
(Scheme 2). Liberation of I2 vapour is realized on mixing of GO with NaI in a blank test and
without the presence of either of the components, the reaction is unsuccessful. Subsequently,

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phenacyl iodide 9 is attacked by the lone–pair pyridine nitrogen electrons to form the
Ortoleva–King type intermediate 10, which is eventually on dehydration afforded bicyclic
imidazo[1,2–a]pyridine 5. In the presence of thiol, compound 5 presumably undergoes
hydrothiolation entirely in anti–Markovnikov fashion 11, which is then oxidized to the
desired 3–sulfenylimidazo[1,2–a]pyridines (Scheme 2). While GO has been shown to
catalyze oxidation under aerobic condition, the active sites of the GO surface consisting of
carboxylic acids may also help in acid–catalyzed reactions. In the present study, presumably
the primary role of GO is to promote the oxidation of NaI to I2 as well as that of the
hydrothiolated intermediate 11 efficiently, resulting in the formation of 3–
sulfenylimidazo[1,2–a]pyridines 8.
NaI
O2
O
O
I
GO
OrtolevaꢀKing
N
NH2
O
type intermediate
I
N
NH2
H
I2
9
10
Ph
N
N
N
N
GO
O2
ArS
HI
H2O
Ph
Ph
Ph
Ph
N
N
N
N
GO
H
H
H
ArS
SAr
I
8
11
5
Scheme 2 Proposed mechanism for the formation of 3–sulfenylimidazopyridine via
Ortoleva–King type intermediate.
Conclusion:
In summary, we have demonstrated that catalytic amounts of graphene oxide in
combination with NaI can efficiently perform the reaction of 2–aminopyridine and
acetophenone leading to the selective formation of important pharmacophore imidazo[1,2–
a]pyridine. The same catalytic system can further carry out one–pot multiꢀcomponent
reactions, established with the formation of another class of important scaffolds 3–thiophenyl
imidazo[1,2–a]pyridine. Both reactions are highly selective, metalꢀfree, tolerant with diverse
functional groups, and the carbocatalyst can be recovered and reused. The GO–catalyzed
multi–component tandem reactions and application to important pharmaceutically active
scaffolds are hitherto unknown and reported for the first time. Further applications of this
sustainable and easily available carbonaceous material are expected to come out in the
synthesis of diverse complex molecules of importance in pharmaceutical chemistry and
material sciences.

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Experimental section:
All chemicals were purchased from commercial suppliers (Sigma–Aldrich) and used without
further purification. NMR spectra were recorded on Varian AV–300 spectrometer using
1
CDCl3 solvent. Chemical shifts (δ) are reported in ppm and referenced to TMS for H NMR
and residual solvent signals for 13C NMR as internal standard. Coupling constants (J) are
reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s
= singlet, d = doublet, t = triplet, q = quartet, qnt = quintet, m = multiplet. Melting points
were determined by heating in open capillary tube.
Preparation of Graphene Oxide (GO):
GO was prepared according to the modified Hummer’s method,9c,17 and our
previously reported conditions (see ESI, S1).13a
General procedure for the synthesis of imidazo[1,2–a]pyridines (Table 2, 5a–5i):
To a solution of 2–aminopyridine (1 mmol), acetophenone (1 mmol) in toluene (1
mL) was added GO (50 mg) followed by NaI (15 mg, 10 mol%). The reaction mixture was
then stirred using a small spin bar at 80oC under an open air for the time indicated in Table 2.
After completion of the reaction (monitored by tlc), the catalyst was filtered off, washed with
ethyl acetate (3 x 3 mL) and the combined organic layer was washed with H2O, dried (anhy.
Na2SO4) and concentrated under vacuum. The residue was purified by passing through a
short path of silica gel and elution with 9:1 light petroleum/ethyl acetate to afford the desired
1
imidazo[1,2–a]pyridine (5a–5i). All products were characterized by H– & 13C–NMR
spectral data and comparison with their melting points with the literature value, wherever
reported (see ESI, S2).
General procedure for the multi–component synthesis of 3–sulfenylimidazo[1,2–
a]pyridines (Table 3, 8a–8i):
To a solution of 2–aminopyridine (1 mmol), acetophenone (1 mmol) and thiol (1.2
mmol) in toluene (1 mL), were added GO (50 mg), and NaI (15 mg, 10 mol%). The reaction
mixture was stirred with magnetic spin bar at 80oC for the time indicated in Table 3. After
completion of the reaction (monitored by tlc), the catalyst was filtered off and the catalyst
washed with ethyl acetate (3 x 3 mL) and the combined filtrate was washed with H2O and
then dried (anhy. Na2SO4) and concentrated under vacuum. The residue was purified by
column chromatography over silica gel and elution with light petroleum/ethyl acetate (19:1 –
9:1) to obtain the desired 3–sulfenylimidazo[1,2–a]pyridine (Table 3, 8a – 8i) in pure form.

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All products were characterized by 1H–& 13C–NMR spectral data and comparison of melting
points with their literature values, wherever reported (see ESI, S2).
Acknowledgements
We thank the Department of Science and Technology (SR/S1/OC–86), India for generous
financial support. SK thanks the UGC, New Delhi for award of research fellowship.
Notes and references:
1. (a) For a general review on the chemistry of imidazopyridine derivatives, see: F.
Couty, G. Evano in Comprehensive Heterocyclic Chemistry III, Vol. 11 (Eds.: A. R.
Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor), Elsevier, Oxford, 2008,
pp. 409–499, and references therein. (b) E. G. Cecile and G. Alain, Mini reviews in
Med. Chem., 2007, 7, 888–899. (c) S. Husinec, R. Markovic, M. Petkovic, V.
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Table of Content
81x41mm (300 x 300 DPI)