A facile protocol for the synthesis of 3-aminoimidazo-fused heterocycles via the Groebke-Blackburn-Bienayme reaction under catalyst-free and solvent-free conditions

Article abstract of DOI:10.1039/c3gc42130a

A one-pot catalyst, solvent, work-up and column free synthesis of 3-aminoimidazo-fused heterocycles by a three-component reaction of a 2-aminoheterocycle, aldehyde, and isocyanide is presented. This efficient and green protocol has the advantages of environmental friendliness, high yields and operational simplicity.

Full text of DOI:10.1039/c3gc42130a

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A facile protocol for the synthesis of
3-aminoimidazo-fused heterocycles via the
Groebke–Blackburn–Bienayme reaction under
catalyst-free and solvent-free conditions†
Cite this: DOI: 10.1039/c3gc42130a
Received 14th October 2013,
Accepted 5th December 2013
DOI: 10.1039/c3gc42130a
www.rsc.org/greenchem
Shinde Vidyacharan, Anand H. Shinde, Bishnupada Satpathi and Duddu S. Sharada*
A one-pot catalyst, solvent, work-up and column free synthesis sustainable routes, among which catalyst-free and solvent-free
of 3-aminoimidazo-fused heterocycles by
three-component reactions (CFR & SFR)7 have gained importance recently. These
a
reaction of a 2-aminoheterocycle, aldehyde, and isocyanide is approaches have several advantages over the conventional
presented. This efficient and green protocol has the advantages of organic synthetic methods, like (a) reduced pollutant production,
environmental friendliness, high yields and operational simplicity.
(b) reduced use or elimination of toxic and hazardous chemicals,
(c) operational simplicity, (d) reduced reaction time (under SFR),
(e) formation of pure products which avoids tedious purifi-
cations, (f) high yields, (g) reduced cost and many more.7a,8
Among the nitrogen derivatives, imidazo-fused heterocycles
are becoming more important in medicinal and organic chem-
istry, as they exhibit a broad spectrum of pharmacological and
biological activities, such as antiviral, antibacterial, fungicidal,
and anti-inflammatory properties.9 The significance of
imidazopyridine scaffolds in the drug discovery sector is well
appreciated because of the appealing benefits they offer. Many
commercially available drugs featuring this scaffold have been
developed, for example an anxiolytic drug (alpidem),10 a hyp-
Introduction
Synthetic organic chemistry has a vast scope in various areas
like pharmaceuticals, industry and academia. Sustainability
has become one of the greatest scientific challenges nowadays,
due to environmental, health and societal concerns. Thus,
there is a need for developing facile, efficient, and non-pollut-
ing synthetic procedures that reduce the use of organic sol-
vents and toxic reagents. One such approach, which involves
green and sustainable chemistry,1 drives towards pollution pre-
vention and environmental protection, and is now gaining
importance. It mainly involves designing chemical products
and processes that reduce or eliminate the use of hazardous
substances, volatile organic compounds, generation of waste
materials, by-product formation and unnecessary derivatiza-
tion (like blocking, protecting/deprotecting) etc.2
notic drug (zolapidem),11 an anti-ulcer drug (zolimidine),12
a
PDE 3 inhibitor (olprinone),13 sedative agents (saripidem &
necopidem),14 and an optically active drug (GSK812397) which
is a prospect for the treatment of HIV infection9 (Fig. 1).
Due to the high biological activity of 3-aminoimidazo-fused
heterocyclic derivatives, several isocyanide based three com-
ponent reactions have been reported in past decades, such as
the condensation of 2-aminoazine, aldehydes and isocyanides
in the presence of Bronsted acids like AcOH,15 HClO4,16 cellu-
lose sulfuric acid,17 p-toluene sulfonic acid,18 and Lewis acids
Multicomponent reactions (MCRs)3 provide diverse and
highly functionalized molecules via the formation of multiple
bonds4 in a one-pot operation, without isolating the intermedi-
ates or changing the reaction conditions. It involves the use of
three or more different starting materials to get a complex
product5 which has incorporated in it most, if not all, of the
starting materials. MCRs comply with the principles of green
chemistry and as a consequence of which, they have emerged
as a significant tool in organic synthesis.6 One of the strategies
widely implemented is the development of alternative
23
like Sc(OTf)3,19 MgCl2,20 SnCl2,21 ZrCl4,22 ZnCl2 and recently
reported RuCl3.24 Nevertheless, many of these methods suffer
from drawbacks such as long reaction time, requirement for
an inert atmosphere, low yield, tedious work-up leading to
the generation of large amounts of toxic metal-containing
waste, and the use of stoichiometric or relatively expensive
reagents. In order to overcome some of these drawbacks a
few mild catalytic and solid supported protocols such as the
use of γ-Fe2O3@SiO2-OSO3H nanoparticles,25 montmorillonite
K10 (microwave)26 and resin supported reactions have
been reported. They too have certain disadvantages, and
even though several methods are available for making
Department of Chemistry, Indian Institute of Technology, Ordinance Factory Estate,
Yeddumailaram-502205, Medak District, Hyderabad, Andhra Pradesh, India.
E-mail: sharada@iith.ac.in
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3gc42130a
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Table 1 Optimization of reaction conditions for the synthesis of
N-cyclohexyl-2-phenylimidazo[1,2-a]pyridine-3-amine 4aa
Entry
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
35
60
90
120
140
160
48
30
15
12
6
90
90
91
92
93
95
2
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (1 mmol).
b Isolated yield after recrystallization from EtOH.
Fig. 1 Selected biologically and medicinally active molecules of
imidazo[1,2-a]pyridines.
3-aminoimidazo-fused heterocycles, to date there has been no
report of the synthesis of such skeletons under catalyst-free
and solvent-free conditions.
As a part of our research program on the development of
MCRs in a greener way, we wish to report a green and con-
venient protocol for the synthesis of 3-aminoimidazo-fused
heterocycles via the Groebke–Blackburn–Bienayme reaction
using 2-aminoheterocycle, aldehydes, and isocyanides, under
catalyst-free and solvent-free conditions. So far, to the best of
our knowledge, there are no reports on the synthesis of
3-amino imidazo-fused heterocycles under catalyst and solvent-
free conditions.
Results and discussion
Multicomponent reactions are very powerful tools for the
efficient synthesis of libraries of diverse complex molecules via
Fig. 2 Reaction time vs. temperature for the synthesis of N-cyclohexyl-
2-phenylimidazo[1,2-a]pyridine-3-amine .
Scheme 1 Plausible mechanism for the synthesis of N-cyclohexyl-2-phenylimidazo[1,2-a]pyridine-3-amine 4a.
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Table 2 The synthesis of 3-aminoimidazo[1,2-a]pyridines 4 via the Groebke–Blackburn–Bienayme reactiona
Entry
1
Comp. 1
Comp. 2
Comp. 3
Product 4b
Time (h)
2.00
Yieldc (%)
97
2
3
1a
1a
2a
2.00
2.00
95
98
3a
3a
4
1a
1.25
96
5
6
1a
1a
3a
3a
1.25
1.50
95
90
7
8
1a
1a
3a
3a
1.75
2.00
89
86
9
1a
3a
2.00
84
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Table 2 (Contd.)
Entry
10
Comp. 1
Comp. 2
Comp. 3
Product 4b
Time (h)
1.75
Yieldc (%)
93
2a
3a
11
12
13
2a
2b
2a
3a
3a
3a
3.50
3.00
2.25
80
83
85
1c
a Reaction conditions: 2-aminoheterocycle (1 mmol), aldehyde (1 mmol), isocyanide (1 mmol). b All the compounds were confirmed by 1H NMR,
13C NMR and HR-MS spectral analyses. c Isolated yield after recrystallization from EtOH.
a green approach. One of the strategies to develop a greener Scheme 1. It involves reaction of 2-aminopyridine (1a) and
methodology for the synthesis of 3-aminoimidazo-fused benzaldehyde (2a) to form an imine derivative (I). It is then fol-
heterocyclic scaffolds is to perform the reaction under catalyst- lowed by trapping of the imine carbon by cyclohexyl isocyanide
free and solvent-free conditions.
(3a), giving a nitrilium ion intermediate (II) which then under-
Initially, to optimize the reaction conditions, we performed goes intramolecular cyclization to form imidazopyridine (4a).
the Groebke–Blackburn–Bienayme reaction between 2-amino- To probe the reaction course, GC-MS was recorded for the reac-
pyridine (1a), benzaldehyde (2a) and cyclohexylisocyanide (3a), tion mixture at various time intervals. The GC-MS data clearly
under catalyst and solvent-free conditions at various tempera- indicates the formation of imine and nitrilium ion intermedi-
tures (Table 1).
ates (For data see ESI†).
To start with, the reaction was performed at ambient temp-
Having optimized the reaction conditions, in order to check
erature i.e. 35 °C, which although gave the desired product in the generality of the method we extended it to various alde-
90% yield took around 48 h (entry 1). Further to this, in order hydes and isocyanides, keeping the amine component con-
to reduce the reaction time and also to increase the yields, the stant, to obtain corresponding imidazopyridine derivatives
temperature of the reaction was increased gradually. As (4a–4m) in 80–98% yields. The electronic nature of the alde-
expected, with an increase in temperature the desired product hydes had an influence on the reaction efficiency, and all the
was obtained in >90% yields (entries 2–6) with reduced reac- corresponding products were obtained in good to excellent
tion times. Interestingly, we found that the reaction time was yields. For example, aromatic aldehydes with an electron with-
drastically reduced to 2 h at 160 °C, resulting in a 95% yield of drawing group like nitro and chloro afforded the corres-
the desired product. The product was recrystallized using ponding imidazo-[1,2-a]pyridines (4c & 4d) in excellent yields
EtOH (Table 1 & Fig. 2).
(>90%) and with shorter reaction times. The aminoazines
The proposed mechanism for the formation of N-cyclo- bearing electron withdrawing groups, for example nitro, gave
hexyl-2-phenylimidazo[1,2-a]pyridine-3-amine is outlined in 4k & 4l in moderate yields (80 & 83%) and with prolonged
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Table 3 The synthesis of 3-aminoimidazo-fused N-rich heterocycles 4 via the Groebke–Blackburn–Bienayme reactiona
Entry
1
Comp. 1
Comp. 2
Comp. 3
Product 4b
Time (h)
1.75
Yieldc (%)
86
2a
3a
2
3
1e
1e
1e
2b
2d
3a
3a
1.50
1.50
94
90
4
5
3b
3a
1.50
1.50
85
95
2a
2b
2d
2f
6
7
8
1f
1f
1f
3a
3a
3a
1.50
1.75
1.75
94
91
90
a Reaction conditions: 2-aminoheterocycle (1 mmol), aldehyde (1 mmol), isocyanide (1 mmol). b All the compounds were confirmed by 1H NMR,
13C NMR and HR-MS spectral analyses. c Isolated yield after recrystallization from EtOH.
reaction times, while electron donating groups like methyl
In order to demonstrate the efficiency and applicability of
gave 4j in an excellent yield (93%) with shorter reaction times our protocol, we performed the reaction with a variety of nitro-
(Table 2).
gen rich amines, aldehydes and isocyanides to obtain the
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Table 4 The synthesis of 3-aminoimidazo-fused tricyclic scaffolds 4 via the Groebke–Blackburn–Bienayme reactiona
Entry
1
Comp. 1
Comp. 2
Comp. 3
Product 4b
Time (h)
2.25
Yieldc (%)
91
2a
3a
2
3
1g
1g
2a
2b
3b
3a
1.50
1.25
90
95
4
5
1g
1g
2j
3b
3a
1.75
2.00
90
81
2d
a Reaction conditions: 2-aminoheterocycle (1 mmol), aldehyde (1 mmol), isocyanide (1 mmol). b All the compounds were confirmed by 1H NMR,
13C NMR and HR-MS spectral analyses. c Isolated yield after recrystallization from EtOH.
Table 5 Comparison of reported methods of the synthesis of N-cyclohexyl-2-phenylimidazo[1,2-a]pyridine-3-amine 4a
Isolated
yield (%)
Mass
intensity
Entry
Solvent, catalyst and condition
Time (h)
E-factor
23
1
2
3
4
1,4-Dioxane, microwave, ZnCl2
Montmorillonite K10 clay, 900 W, microwave26
RuCl3·3H2O, 40 °C24
1
78
86
89
95
7.20
0.43
0.32
0.09
8.20
1.43
1.32
1.09
3 (min)
1
2
No solvent, no catalyst, 160 °C
desired N-rich heterocycles in good to excellent yields
(85–95%), as summarized in Table 3.
It is worth mentioning here that this strategy resulted in
some interesting and diverse heterocycles, having a ring junc-
To further expand the scope of the reaction, we turned tion carbon attached to three heteroatoms.
our attention towards the synthesis of sulphur and nitrogen
All the compounds, except a few (4d, 4h, 4l, 4q & 4z) which
containing heterocycles. Accordingly, we treated 2-amino- are viscous in nature, were purified by recrystallization, thus
benzothiazole (1g) with other pairs of components. To our avoiding tedious purification methods and the use of excess
delight, we obtained interesting and attractive tricyclic solvents.
scaffolds (imidazo-fused benzothiazoles), as shown in
To check the applicability of our protocol, we performed
Table 4.
a scaled-up reaction for the synthesis of N-cyclohexyl-2-
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phenylimidazo[1,2-a]pyridine-3-amine 4a, resulting in a 93%
yield.
5 (a) G. V. Der Heijden, E. Ruijter and R. V. A. Orru, Synlett,
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Green concept: to recognize the efficiency of our protocol
with respect to existing protocols for the synthesis of N-cyclo-
hexyl-2-phenylimidazo[1,2-a]pyridine-3-amine 4a, the results
are collected and tabulated (Table 5). These results clearly
indicate that our protocol (Table 5, entry 4) is a more efficient,
clean and green process. Calculations are shown in the ESI.†
Conclusion
In conclusion, a facile methodology has been developed for
the synthesis of imidazo-fused heterocycles under catalyst-free
and solvent-free conditions. The important features of this
procedure are mild conditions, high yield, operational simpli-
city, atom economy and environmental friendliness. Thus, this
CFR & SFR methodology should prove useful for the facile syn-
thesis of such scaffolds on an industrial scale.
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We gratefully acknowledge the Department of Science and
Technology (DST-W.O.S.), New Delhi, and the Indian Institute
of Technology, Hyderabad, for financial support. S.V.C. and
A.H.S. thank UGC, New Delhi, for the award of a research
fellowship.
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