A copper-catalyzed multi-component reaction accessing fused imidazo-heterocycles via C-H functionalization

Article abstract of DOI:10.1039/c5ra09025c

An efficient synthesis of fused imidazo-heterocycles is described using Cu(OTf)₂ in [bmim]BF₄ by the multi-component reaction of pyridin-2(1H)-one or thiazol/benzo[d]thiazol-2(3H)-ones with O-tosylhydroxyl amine and acetophenones under microwave irradiation. The present method is very rapid and the product formation occurs via a C-H functionalization/tandem addition-cyclization process. The ionic liquid containing copper triflate is recovered and reused four times.

Full text of DOI:10.1039/c5ra09025c

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DOI: 10.1039/C5RA09025C
Copperꢀcatalyzed multiꢀcomponent reaction accessing fused imidazoꢀ
heterocycles via C−H functionalization
G. Santosh Kumar, S. Pushpa Ragini, A. Sanjeeva Kumar, H. M. Meshram*
Highlights
N
Ar
ligand-free
N
N
H
O
O
Cu(OTf)2
base-free
H
+ H2N OTs
OR
S
+
OR
Ar
[bmim]BF4
oxidant-free
110 O
C
S
N
H
3 C-N bond formations
in single step
O
MW
N
Ar
N
H
reusable catalytic system
Multi-component reaction

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COMMUNICATION
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RSCPublishing
Copperꢀcatalyzed multiꢀcomponent reaction accessing
fused imidazoꢀheterocycles via C−H functionalization
G. Santosh Kumar, S. Pushpa Ragini, A. Sanjeeva Kumar, H. M. Meshram*
Abstract. An efficient synthesis of fused imidazoꢀheterocycles
is described using Cu(OTf)2 in [bmim]BF4 by the multiꢀ
component reaction of pyridinꢀ2(1H)ꢀone or thiazol/benzo[d]
thiazolꢀ2(3H)ꢀones with Oꢀtosylhydroxyl amine and
acetophenones under microwave irradiation. The present
method is very rapid and the product formation occurs via Cꢀ
H functionalization/tandem additionꢀcyclization process. The
ionic liquid containing copper triflate is recovered and reused
four times.
N
N
N
N
N
Cl
Me
SO2Me
N
N
N
Cl
Me
O
O
Zolimidine (3)
n-Pr
Me
n-Pr
Me
Alpidem (2)
NEt2HCl
Zolpidem (1)
O
NH
11CH3
N
N
H3CO
Transitionꢀmetalꢀcatalyzed direct functionalization of C−H bonds
towards the CꢀN bond formation is of great interest and application
of these strategies to build azaheterocycles has attracted intensive
attention. In particular, the synthesis of fused imidazoꢀheterocycles
(IHs) have received considerable attention because of their diverse
biological and pharmaceutical activities1 such as antiviral, antitumor,
antimicrobial, herbicidal, antiulcer agents and immunosuppressive
agents. It has wide application as selective cyclinꢀdependent kinase
inhibitors,2 calcium channel blockers,3 bꢀamyloid formation
inhibitors,4 benzodiazepine receptor agonists5 and liver X receptor
agonists.6 Some of the drug7 molecule like Zolpidem (1), Alpidem
(2) and Zolimidine (3) also containe Imidazo[1,2ꢀa]pyridine (IP)
moieties. In addition to this 2ꢀarylimidazo [2,1ꢀb] [1,3]benzothiazole
derivative (YMꢀ201627) (4) was found to be a potent and orally
active antitumor agent and useful for treatment of solid tumors,8 In
perticular, 11Cꢀlabeled imidazo[2,1ꢀb]benzothiazole9 (5) has been
shown to be a superb fluoroprobe in PET analysis of Alzheimer’s
disease. Several synthetic protocols exist in the literature for the
construction of IPs and its derivatives (Scheme 1). The condensaꢀ
N
HCl
S
N
S
YM-201627 (4)
(5)
Figure 1. Imidazoꢀheeterocycleꢀcontaining drugs.
N
O
N
N
N
+
X
R1
R2
+
N
NH2
R1
N
X = Br, I, Cl, OTs
E
A
R1
OAc
N
+
B
N
NH2
R2
+
F
R1
N
N
N
O2N
C
R1
R1
R2
R1
+
OR
N
NH2
+
O2N
O
G
N3
D
+
R1
N
O
+
This work
N
NH2
R1
O
H2N OTs
+
+
H
Ar
N
O
Medicinal chemisty and pharmacology division, CSIR-Indian
Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007,
India. E-mail: hmmeshram@yahoo.com; Tel.: +91-40-27191640,
Fax: 91-40-27160512
H
H
Scheme 1. Various methods for accessing imidazo[1,2ꢀa]pyridines.
This journal is © The Royal Society of Chemistry 2015
1 | J. Name., 2015, 00, 1-3

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ꢀation between 2ꢀaminopyridines and perꢀfunctionalized carbonyl
compounds under various conditions was the most convenient
method for the synthesis of IPs (Scheme 1. Route A).10
Subsequently other alternative methods also reported which includes
silverꢀcatalyzed oxidative coupling/cyclization of 2ꢀ aminopyridines
with terminal alkynes (Scheme 1. Route B),11 and Feꢀcatalyzed
method using 2ꢀaminopyridines and nitroolefins to obtain IPs
(Scheme 1. Route C).12 Another method involves Cuꢀcatalyzed
oxidative coupling of 2ꢀaminopyridines and unactivated methyl
ketones in the presence of ligands or additives were reported
(Scheme 1. Route D).13 In addition to this several homogeneous Cuꢀ
catalyzed methods using pyridines with Nꢀ(alkylidene)ꢀ4Hꢀ1,2,4ꢀ
triazolꢀ4ꢀamines (Scheme 1. Route E),14 acetophenone oxime
acetates (Scheme 1. Route F),15 and vinyl azides (Scheme 1. Route
G)16 were accomplished to give IPs. Though the reported methods
are satisfactory for the synthesis of these compounds, it encounter
some drawbacks like high catalyst loading, harsh reaction
conditions, long reaction times and low yield of the products and
limited applications. Therefore, there is a scope to develop a general,
efficient and high yield method by addressing the shortcomings of
reported methods to afford IH derivatives.
Results and discussions:
We have selected pyridinꢀ2(1H)ꢀone 1a, simple acetophenone 2a,
and Oꢀtosylhydroxylamine as starting materials for the
3
optimization of reaction. Intially the reaction of pyridinꢀ2(1H)ꢀone
1a (1 mmol) with simple acetophenone 2a (1 mmol) and Oꢀ
tosylhydroxylamine (2 mmol) in presence of 10 mo1% Cu(OTf)2 at
70 °C under microwave irradiation for
phenylimidazo[1,2ꢀa]pyridine 4a in 10 % yield (Table 1, entry 1).
5 min gave 2ꢀ
1
The structure of obtained product was confirmed by means of H
NMR, 13C NMR, IR and Mass spectrometry analysis. We presumed
that the formation of fused IHs occurred may be via CꢀH
functionalization followed by two CꢀN bond formations. As the
ionic liquids are known to accelerated the rate of reaction, the same
reaction was performed in ionic liquid (1ꢀbutylꢀ3ꢀmethyl
imidazolium tetrafluoroborate [bmim]BF4) under MW in 5 min. We
were pleased to observe the remarkable improvement in the yield of
desired product (45%) (Table 1, entry 2). During experiment it was
noticed that increase in the MW irradiation time 10 min. gave more
yield of the product (52%) (Table 1, entry 3). Later to improve the
yield, the reaction was carried out at different temperatures. It was
noticed that there was a gradual increase in the yield (62 %), when
the temperature raised from 70 oC to 110 oC (Table 1, entry 5).
Further increase in the temperature (120 oC) did not improve the
yield (Table 1, entry 6). Next we examined the effect of the catalyst
by performing the reaction with different ratio (15 mol% and 20
mol%) of catalyst. After screening, 20 mol% of catalyst was found
suitable for maximum conversion (85%) (Table 1, entry 8). The
same reaction in presence of other copper salts CuBr2, CuCl and CuI
gave different degree of conversion (Table 1, entries 9−11). ꢀ
In recent years technology plays major role in synthetic organic
chemistry, one such technology involves microwave heating.
Operational simplicity, high yields, purity of products, and enhanced
reaction rates are the important features of microwave.17 On the
other hand ionic liquids are a peculiar class of reaction media with
the potential to improvement in organic chemistry.18 They are
environmentally benign and are recyclable. In many reactions they
are known to accelerate the rate of reaction. Among the ionic liquids,
the more intensively investigated are 1,3ꢀdialkylimidazolium salts.
They are stable to air water and are compatible with various organic
compounds. In the synthesis of IP derivatives, 2ꢀaminopyridines are
usually employed as starting materials. As 2ꢀaminopyridines are
derived from pyridinꢀ2(1H)ꢀones,19 the direct use of pyridinꢀ2(1H)ꢀ
ones to build desired IP would be of great advantage. To the best of
our knowledge there is no report for the synthesis of IHs using
pyridinꢀ2(1H)ꢀone/benzo[d]thiazolꢀ2(3H)ꢀones.
Table 1. Optimization of the Reaction Conditions for the synthesis
of 2ꢀphenylimidazo[1,2ꢀa]pyridine a
O
N
catalyst
H
+
H2
N OTs
+
N
N
H
O
ionic liquid
temperature
time
H
1a
3
4a
2a
catalyst (mol%)
ionic liquid
temp (oC)
time (min) microwave
yieldb
entry
_
1
2
Cu(OTf)2 (10)
Cu(OTf)2 (10)
5
5
10
45
70
70
In continuation of our research in the area of CꢀH activation under
microwave,20aꢀd and ionic liquid assisted reactions,20eꢀh herein we
wish to disclosed a novel and an efficient protocol for the synthesis
of functionalized fused imidazoꢀheterocycles in presence of
Cu(OTf)2 in [bmim]BF4 by the multiꢀcomponent reaction of pyridinꢀ
2(1H)ꢀone/benzo[d]thiazolꢀ2(3H)ꢀones, acetophenones and Oꢀ
tosylhydroxylamine under microwave conditions in good to high
yields (Scheme 2). In this protocol, we synthesized different fused
imidazoꢀheterocycles via CꢀH functionalization followed by addition
and cyclization process.
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
70
10
10
10
10
52
57
62
60
3
4
100
110
120
5
6
[bmim]BF4
[bmim]BF4
[bmim]BF4
Cu(OTf)2 (15)
110
10
70
7
110
85
Cu(OTf)2 (20)
10
8
110
35
40
9
CuBr2 (20)
10
[bmim]BF4
[bmim]BF4
[bmim]PF6
[Hbim]BF4
110
110
110
10
11
12
13
CuCl (20)
CuI (20)
10
10
10
50
42
Cu(OTf)2 (20)
N
Ar
110
110
40
40
Cu(OTf)2 (20)
Cu(OTf)2 (20)
10
10
N
N
H
O
O
Cu(OTf)2
[emim]BF4
14
H
+ H2N OTs
OR
S
+
Ar
OR
[bmim]BF4
110 O
MW
C
a Reaction conditions pyridin-2(1H)-one 1a (1 mmol), acetophenone 2a (1 mmol), O-tosylhydroxylamine 3
(2 mmol), catalyst, and ionic liquid (2 mL) in microwave vial (10 mL) sealed and placed in MW reactor.
b Isolated yield
H
N
S
O
N
Ar
N
H
Scheme 2. Cu(II) catalyzed CꢀH functionalization.
2 | J. Name., 2015, 00, 1-3
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Later we tested the same reaction in various ionic liquids such as 1ꢀ (3) in same reaction conditions to furnish corresponding products in
nꢀbutylimidazolium tetrafluoroborate [Hbim]BF4, 1ꢀbutylꢀ3ꢀ high yields (Scheme 3, 4e and 4j).
methylimidazolium hexafluorophosphate [bmim]PF6, and 1ꢀethylꢀ3ꢀ
Encouraged by the results obtained from the reactions of
acetophenone derivatives with pyridinꢀ2(1H)ꢀones, we extended our
efforts to study the reaction of acetophenone derivatives with
thiazol/benzo[d]thiazolꢀ2(3H)ꢀones under similar reaction condition.
methylimidazolium tetrafluoroborate [emim]BF4 and found that
there is no improvement as compared to [bmim]BF4 (Table 1, entry
12ꢀ14). From this study, the optimum conditions described for the
present protocol was 20 mol% Cu(OTf)2 as the catalyst in
[bmim]BF4 ionic liquid under MW irradiation at 110 oC temperature
in 10 min. The same reaction requires 3h for completion in preꢀ
heated (110 oC) conventional oil bath. This observation indicated
that the effect is from not thermal but it is because of MW.
Likewise,
the electronic effects of acetophenones studied,
acetophenones bearing electronꢀwithdrawing groups reacted faster
and gave the products in excellent yields (Scheme 4, 6d, 6e, 6g, 6h,
6i and 6j) whereas acetophenones bearing electronꢀdonating groups
reacted slowly gave comparatively less yields of the products
To make the present protocol general, various substituted pyridinꢀ (Scheme 4, 6b, 6c, 6k and 6l). In this method the reactions
2(1H)ꢀones 1 and acetophenones 2 were examined under optimized proceeded smoothly to form three CꢀN bonds and therefore it should
conditions. The results are summarized in Scheme 3. A wide variety provide a novel and efficient strategy for the synthesis of nitrogen
of acetophenones participated well in this conversion to afford containing heterocycles.
corresponding imidazo[1,2ꢀa]pyridines (4) in good to high yields.
Scheme 4. Scope of thiazol/benzo[d]thiazolꢀ2(3H)ꢀones and
The electronic effects of substituted acetophenones studied in detail,
and found that substituents on the acetophenones have influence on
rate of reaction. In general, acetophenones bearing electronꢀ
acetophenonesa
S
S
N
O
2
Cu(OTf)2
O
R
+
H2N OTs
3
N
Scheme 3. Scope of pyridinꢀ2(1H)ꢀones and acetophenonesa
Ar
H
+
Ar
R
[bmim]BF4
N
H
110 O
C
H
6
5
MW
N
N
N
S
S
S
S
OMe
N
N
N
6b 80%
6c 76%
S
6a 86%
N
N
N
N
N
S
N
Cl
Br
MeO
6d 88%
6e 88%
6f 88%
S
N
S
N
S
N
N
N
Br
N
F
Cl
MeO
MeO
MeO
6g 90%
6i 89%
6h 90%
S
N
S
N
S
N
OMe
N
N
N
NO2
MeO
6k 79%
6l 77%
6j 89%
MeO
MeO
a Reaction conditions: Thiazol or benzo[d]thiazol-2(3H)-one (1 mmol), acetophenones (1 mmol),
5
2
O-tosylhydroxylamine (2 mmol), and Cu (OTf)2 (20 mmol%) in 2 mL of [bmim]BF4 under MW at 110 oC.
3
b Isolated yield
OTs
O
N
+
H2N OTs
3
Ar
2a
Ar
A
N
H2O
Ar
N
OTs
Ar
4
HN
OH
N
Ar
N
B
)
f
2
T
F
H
O
1a
O
(
N
u
C
H
ꢀwithdrawing groups reacted faster and furnished high yields of the
products (Scheme 3, 4b, 4c, 4d, 4f, 4g, 4k, 4l, 4m, 4p, and 4s)
whereas acetophenones bearing electronꢀdonating groups reacted
slowly and gave comparatively less yields of the products (Scheme
3, 4h, 4i, 4n, 4o and 4r). It may be presumed that electronꢀdonating
substrates were unfavorable for the nucleophilic addition step
proposed in Scheme 3. It is worthy to mention that 4ꢀmethyl pyridinꢀ
2(1H)ꢀone (1b) and 5ꢀmethyl pyridinꢀ2(1H)ꢀone (1c) underwent
reaction with simple acetophenone (2a) and Oꢀtosylhydroxylamine
H
O
Cu(OTf)2
Cu(OTf)2
N
TsO
Ar
N
N
H
N
O
H
Ar
E
C
D
TsOH
Scheme 5. Plausible mechanistic pathway for the formation of
substituted imidazo[1,2ꢀa]pyridines.
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A putative mechanism for this Cu(OTf)2 catalyzed, microwave mild conditions. Moreover, the recovery and reusability of ionic
promoted synthesis of imidazo[1,2ꢀa]pyridines 4 by the reaction of liquid containing catalyst makes the procedure environmental
pyridinꢀ2(1H)ꢀone, acetopheneone, and Oꢀtosylhydroxylamine is friendly.
outlined in Scheme 5. Initially the reaction of simple acetophenone
2a and Oꢀtosylhydroxylamine 3 gave acetophenone oxime tosylate Acknowledgment
A. Then the isomerization of A provided enamine B, coordination of
The authors G S K and A S K thank CSIR for the award of a
fellowship and S P R thank to Dr. A. Kamal, Outstanding scientist
and Head of the MCP Division, for his support and encouragement.
the copper catalyst (Cu(OTf)2) to B furnished complex D via CꢀH
functionalization, at the same time the in situ generated pyridinꢀ
2(1H)ꢀylidene oxonium ion C from pyridinꢀ2(1H)ꢀone 1a attacked
the inter mediate D to produce the species E with the elimination of
TsOH. And intramolecular cycloaddition of E yields F with the
regeneration of the catalyst Cu(OTf)2. Finally, the isomerization of E
The authors also thank CSIR, New Delhi for financial support as part
of XII Five Year plan programme under title ACT (CSCꢀ0301).
by the elimination of water lead to the formation of the desired
imidazo[1,2ꢀa]pyridines 4.
References
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80
65
50
6g
4e
6c
4o
Fresh First Second Third Fourth
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Figure 2. Reusability data for Cu(OTf)2/[bmim]BF4.
The recovery and recyclability parameter of ionic liquid containing
copper catalyst was applied for four model products, such as 4e, 4o,
6c, and 6g. After completion of the reaction in ionic liquid
[bmim]BF4 containing with copper triflate the reaction mixture was
extracted with ether (3x15ml), activated at 80 oC under reduced
pressure and then subjected to the next run with the same substrates
and the same reaction time. We reused Cu(OTf)2/[bmim]BF4 up to
four cycles and did not notice any substantial loss in the catalytic
activity of Cu(OTf)2/[bmim]BF4. These results are summarized in
figure 2. We believe that the present protocol is favouring the
formation of only one desired product. The ease of recovery and
reuse of this reaction media may contribute to the development of
green strategy for the preparation of fused IHs.
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In summary, we have developed a novel multiꢀcomponent reaction
for the synthesis of IH derivatives using Cu(OTf)2/[bmim]BF4
through C−H functionalization under microwave irradiation. The
reaction is very rapid, simple and convenient. This novel method
involves the formation of three new CꢀN bonds in a cascade
pathway. The present reaction provides an excellent alternative over
earlier methods in terms of high yields, operational simplicity and
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