A highly efficient synthesis of imidazo-fused polyheterocycles via Groebke-Blackburn-Bienaymè reaction catalyzed by LaCl3·7H2O

Article abstract of DOI:10.1016/j.tetlet.2014.08.126

A highly efficient and mild protocol for the synthesis of imidazo-fused polyheterocycles via Groebke-Blackburn-Bienaymè reaction under the influence of catalytic amount of lanthanum chloride heptahydrate has been described. A wide range of nitrogen-enriched polyheterocycles are synthesized with high yields under neat conditions.

Full text of DOI:10.1016/j.tetlet.2014.08.126

Accepted Manuscript
A highly efficient synthesis of imidazo-fused polyheterocycles via Groebke-
Blackburn-Bienaymè reaction catalyzed by LaCl3.7H2O
Anand H. Shinde, Malipatel Srilaxmi, Bishnupada Satpathi, Duddu S. Sharada
PII:
S0040-4039(14)01488-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.126
TETL 45093
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 June 2014
28 August 2014
31 August 2014
Please cite this article as: Shinde, A.H., Srilaxmi, M., Satpathi, B., Sharada, D.S., A highly efficient synthesis of
imidazo-fused polyheterocycles via Groebke-Blackburn-Bienaymè reaction catalyzed by LaCl3.7H2O, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.126
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A highly efficient synthesis of imidazo-fused polyheterocycles via
Groebke-Blackburn-Bienaymѐ reaction catalyzed by LaCl3.7H2O
Anand H. Shinde, Malipatel Srilaxmi, Bishnupada Satpathi, and Duddu S. Sharada∗
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate, Yeddumailaram-502205, Medak District, Telangana, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A highly efficient and mild protocol for the synthesis of imidazo-fused polyheterocycles via
Groebke-Blackburn-Bienaymѐ reaction under the influence of catalytic amount of lanthanum
chloride heptahydrate has been described. A wide range of nitrogen-enriched polyheterocycles
are synthesized with high yields under neat conditions.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridine
Lanthanum chloride-catalyzed
Solvent-free
Multicomponent reaction
Multicomponent reactions (MCRs)1 are known for generating
complex, diverse molecules in single step and continuous efforts
are going on by scientific community for the development of
environmental benign solvent-free MCRs. MCRs occupy a
special place in ‘diversity oriented synthesis’ (DOS)2 and
biology-oriented synthesis (BIOS)3 design strategies for
achieving higher degree of scaffold diversification.
N
N
SO2CH3
N
N
Zolmidine
N
N
N
Nicopidem
Cl
N
O
Cl
O
N
Cl
Alpidem
N
N
N
Nowadays, the use of lanthanide (III) compounds as catalysts
or promoters in organic synthesis has attracted great attention
from scientific community. Literatures reveals that, lanthanide
additives or complexes can enhance the reactivity and selectivity
of many types of reactions such as, reduction, carbon-carbon
bond formation, aldol condensation, cycloaddition, ring-opening
and polymerization.4 Lanthanide ions are considered "hard"
Lewis acids and form complexes with substantial ionic character
because of poor overlap of the contracted 4f orbitals.4c
Lanthanides are also able to polarize bonds upon coordination
and thus alter the electrophilicity of compounds. Lanthanide (III)
compounds are soluble in water, making it easy to isolate from
the reaction mixture by aqueous work-up. The lack of orbital
interactions combined with the lanthanide contraction allows for
easy tuning of the nuclearity and steric environments of the
complexes, which have been used to improve the catalytic
activity of the lanthanide (III) complexes.5 Among them,
lanthanum complexes are widely used in organic transformations
such as, azide-nitrile [3+2] cycloaddition,6a benzimidazole
synthesis,6b Friedlander reaction,6c allylation of aldehyde,6d
chlorination of methane,6e guanylation reaction,6f Grignard
addition6g and Biginelli reaction.6h
N
N
O
Saripidem
Zolpidem
O
Figure 1: Representative examples of pharmaceutically important
molecules having imidazo[1,2-a]pyridine as core moiety
Bicyclic pyridines containing ring junction nitrogen are a
common structural motif in a wide range of natural products and
pharmacologically active molecules.
In specific, imidazo-
pyridine derivatives are broadly investigated and utilized in the
pharmaceutical industry; for example, Zolpidem (treatment of
insomnia and some brain disorder),7 Alpidem (a nonsedative
anxiolytic),8 Saripidem (sedative anxiolytic),9 Olprinone (cardio
tonic agent),10 Zolimidine (anti-inflammatory),11 Levamisole
(anticancer),12 and DS-1 (acts as a GABAA receptor agonist).13
They are also used in bio-imaging probes and molecular
recognition because of their structural characters.14
Several methods have been reported for the synthesis of these
compounds by condensation of an aminoazine, aldehyde and an
isocyanide via the Groebke-Blackburn-Bienaymѐ reaction in the
presence of Bronsted acids such as AcOH,15 HClO4,16 cellulose
———
∗ Corresponding author. Tel.: +91-40-23017058; e-mail: sharada@iith.ac.in

2
sulphuric acid,17 p-toluene sulfonic acid18 or Lewis acids such
was examined by introducing metal containing aldehyde, e.g.,
ferrocene-2-carboxaldehyde, which gave 4aja in 96% yield with
short reaction time.
as Sc(OTf)3,19 MgCl2,20 SnCl2,21 ZrCl4,22 ZnCl2,23 RuCl3,24 and
solvent-free protocols like nanoparticle γ-Fe2O3@-SiO2-
OSO3H,25 montmorilonite K10.26 However, most of these
methods possess several disadvantages such as low yields of
products, longer reaction times, harsh reaction conditions, tedious
work-ups, and are inconvenient for industrial scale. Hence,
development of novel methods to construct a variety of
imidazo[1,2-a]pyridines is still desirable.
Table1 Optimization of reaction conditions a
Our interest in the area of developing green and sustainable
methods,27 has provoked us to investigate an alternate milder
method for the synthesis of imidazo[1,2-a]pyridines. Herein, we
wish to report a green protocol for the synthesis of imidazo[1,2-
a]pyridines under solvent-free conditions by using cheap and
readily available hydrated lanthanum chloride as catalyst under
milder reaction conditions. So far to the best of our knowledge,
there are no reports on solvent-free lanthanum chloride catalyzed
synthesis of imidazo[1,2-a]pyridine derivatives via Groebke-
Blackburn-Bienaymѐ reaction.
LaCl3.7H2O
(mol %)
c
-
Time
(min.)
Yield
(%)b
Entry
Solvent
Temperature (oC)
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
RT
RT
35
60
60
RT
60
60
60
60
60
90
90
80
80
60
90
60
20
40
120
120
-
1
2
60
65
79
85
70
95
95
85
70
65
2
3
4
5
6
7
2
2
5
10
10
10
5
d
-
d
-
In our investigation, initially we have selected 2-
aminopyridine (1a, 1.06 mmol), benzaldehyde (2a, 1.06 mmol)
and cyclohexyl isocyanide (3a, 1.06 mmol) in ethanol (2ml) as a
test reaction for optimum reaction conditions and the results are
listed in Table 1. No reaction occured in the absence of catalyst
at room temperature. However, when LaCl3.7H2O (2 mol%) was
added at room temperature, the corresponding imidazo[1,2-
a]pyridine (4aaa) was obtained in 60% yield (Table1, entry 2).
The effect of different mol% of lanthanum chloride at various
temperatures on the reaction was examined. After successfully
obtaining the maximum yield with 10 mol% of lanthanum
8
9
MeOH
H2O
10
10
10
11
a
b
Reaction conditions: 1a (1.06 mmol), 2a (1.06 mmol) and 3a (1.06 mmol)
c
Isolated yield after filtration through short pad of silica column.
d
No
Solvent-free condition.; For compound 4aaa first letter
catalyst used.
refers to 2-aminopyridine part 1a, second letter refers to benzaldehyde part 2a
and third letter refers to part coming from cyclohexylisocyanide 3a.
It is worth to mention here that, the protocol would serve to
make further ferrocene-based heterocycles, which may have
renewed interest due to their well-documented medicinal
properties, attractiveness as redox-active biomolecular probes
and structural models for peptides.28 The protocol was also
successfully extended to various hetero amino azines, thus
resulting in corresponding bicyclic (4dbc-4dfc, Table 3) and
tricyclic imidazo-fused heterocycles (4eaa-4eab, Table 3).
Further, scope of the reaction was extended to aromatic
isocyanides, which provided the products in high yields (4alb
and 4eab). All the products were purified by filtration through
short pad of silica column. The products were confirmed by FT-
IR, NMR spectroscopic techniques and mass spectrometry.
o
chloride at 60 C, we next examined the reaction under solvent-
free conditions, which to our delight gave the desired product
4aaa in excellent yield (95%) in 20 min (Table 1, entry 8). The
solvents like methanol and water did not give satisfactory yields.
Hence, we choose 10 mol% lanthanum chloride under solvent-
o
free conditions at 60 C as the optimized condition for further
study.
With the optimal condition established, we explored the
generality of the reaction by extending the methodology to the
aliphatic, aromatic as well as heteroaromatic aldehydes resulting
in wide range of imidazo[1,2-a]pyridine derivatives in excellent
yields as shown in Table 2. In addition, the scope of aldehydes
Table 2 The synthesis of 3-aminoimidazo[1,2-a]pyridines 4 via Groebke-Blackburn-Bienaymѐ reactiona
Entry
R1
R2
R3
Product b
Time (min)
Yield (%)c
1
20
95
1a
2a
3a
3a
2
60
90
1a
2b

3
Table 2 (Continued)
Entry
R1
R2
R3
Product b
Time (min)
Yield (%)c
1a
3a
3
4
5
40
96
2c
1a
1a
1a
3a
3a
3a
55
90
2d
2e
2f
70
89
6
65
86
1a
1a
1a
3a
3a
3a
7
40
96
2g
2h
2i
8
9
40
93
75
83
10
1a
3a
45
96
2j
11
1a
3a
50
92
2k
1a
3a
12
20
90
2l

4
Table 2 (Continued)
Entry
R1
R2
R3
Product b
Time (min) Yield (%)c
1a
1a
2l
13
25
45
90
85
3b
3a
14
2m
2a
3a
15
60
90
1b
1b
2h
2g
2a
3a
16
50
45
90
92
92
73
1b
17
3c
3a
18
1c
a
b
Reaction conditions: Aminoazines 1 (1.06 mmol), aldehyde 2 (1.06 mmol), isocyanide 3 (1.06 mmol). Product was confirmed by1H NMR, 13C NMR and
c
mass spectral analyses.
letter refers to aldehydes part 2a-2o and third letter refers to part coming from isocyanides 3a-3c.
Isolated yield after filtration through short pad of silica column. For compound 4 first letter refers to aminoazines part 1a-1e, second
Table 3 The synthesis of 3-aminoimidazo-fused hetero substituted tricyclic and bicyclic scaffolds 4 via Groebke-Blackburn-
Bienaymѐ reactiona
Entry
R1
R2
R3
Product b
Time (min)
Yield (%)c
2b
3c
1
45
90
1d
2k
3c
55
85
2
1d

5
Table 3 (Continued)
Entry
R1
R2
R3
Product b
Time (min)
25
Yield (%)c
99
1d
2a
3a
3
1d
2f
3c
4
60
93
2a
3a
5
80
75
1e
1e
3a
6
90
83
2n
2i
1e
3a
7
80
76
1e
3c
8
120
79
2o
2f
1e
3c
9
90
81
1e
2l
3c
10
90
80
2a
1e
3b
11
30
85
a
b
Reaction conditions: Aminoazines 1 (1.06 mmol), aldehyde 2 (1.06 mmol), isocyanide 3 (1.06 mmol). Product was confirmed by1H NMR, 13C NMR and
c
mass spectral analyses.
letter refers to aldehydes part 2a-2o and third letter refers to part coming from isocyanides 3a-3c.
Isolated yield after filtration through short pad of silica column; For compound 4 first letter refers to aminoazines part 1a-1e, second

6
Tetrahedron Letters
R2
R1
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Press: New York, 1994; b) Kobayashi, S. Synlett 1994, 689; (c)
Molander, G. A. Chem. Rev. 1992, 92, 29.
H
O
R2
-
H2O
N
N
5. (a) Kobayashi, S; Manabe, K. Org. Lett. 2001, 3, 165; (b)
Aspinall, H. C.; Dwyer, J. L.; Steiner, A. Organometallics 1999,
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VanmHecke, K.; Van Meervelt, L.; Binnemans, K. Eur. J. Org.
Chem. 2004, 22, 4560.
H
LaCl3
LaCl3
B
A
R1
C
N
N
NH2
R3
6. (a) Meshram, G. A.; Deshpande, S. S.; Wagh, P. A.; Vala, V. A.
Tetrahedron lett. 2014, 55, 3557; (b) Venkateswarlu, Y.; Ramesh
Kumar, S.; Leelavathi, P. Org. Med. Chem. Lett. 2013, 3, 7; (c)
Chen, Y.; Huang, J.; Hwang, T-L.; Li, T. J.; Cui, S.; Chan, J.;
Bio, M. Tetrahedron Lett. 2012, 53, 3237; (d) Reddy, G. S. S.;
Sammaiah B.; Sharada, L. N. Synth. Commun. 2009, 39, 3905; (e)
Podkolzin, S. G.; Stangland, E. E.; Jones, M. E.; Peringer E.;
Lercher, J. A. J. Am. Chem. Soc. 2007, 129, 2569; (f) Li, Q.;
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Chem., Int. Ed. 2006, 45, 497; (h) Lu, J.; Bai, Y.; Wang, Z.;
Yang B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075.
[ 4+1 ]
cycloaddition
-
LaCl3
R2
R1
R2
R1
N
aromatization
N
N
N
N
H
NH
R3
R3
4
C
Figure 2. Plausible reaction mechanism for the synthesis of imidazo[1,2-
a]pyridine 4.
7. Harrison, T. S.; Keating, G. M. CNS Drugs 2005, 19, 65.
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Psychopharmacol. 1990, 46, 61.
A tentative mechanism is proposed (Figure 2). Initially the
aldehyde oxygen gets coordinated with the lanthanum chloride,
9. (a) Bartholini, G. L. E. R. S. Monogr. Ser. 1993, 8, 1; (b)
Bartholini, G. L. E. R. S. Chem. Abstr. 1996, 124, 164079n.
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Cerebrovasc. Dis. 2003, 16, 396.
which increases the carbonyl electrophilicity.
Then the
aminopyridine condenses with the aldehyde leading to imine,
which is further activated by lanthanum chloride to form Schiff
base B29 and subsequent attack of isocyanide on electrophilic
imine carbon followed by [4+1] cycloaddition30 to form cyclic
adduct C. Finally, the intermediate adduct C undergoes
aromatization via 1,3-H shift to furnish the desired product 4.31
11. Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B. M. J.
Med. Chem. 1991, 34, 533.
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Lett. 2006, 16, 1518.
In summary, we have successfully developed a highly
efficient lanthanum chloride heptahydrate promoted protocol via
one-pot three component Groebke-Blackburn-Bienaymѐ reaction
to synthesize medicinally and biologically relevant imidazo-fused
polyheterocycles. There are several advantages associated with
this method (i) high yields (ii) easy accessibility of imidazo[1,2-
a]pyridines (iii) wide substrate scope (iv) minimal energy
requirement and (v) short reaction time. This methodology
might prove as a better alternative to the existing literature
methods.
14. (a) Wiegand, M. H. Drugs 2008, 68, 2411; (b) Gudmundsson, K.
S.; Williams, J. D.; Drach, J. C.; Townsend, L. B. J. Med. Chem.
2003, 46, 1449; (c) Kaminsky, J. J.; Doweyko, A. M. J. Med.
Chem. 1999, 40, 427.
15. Blackburn, C. Tetrahedron Lett. 1998, 39, 5469.
16. Bienayme´, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234.
17. Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
18. (a) Chen, J. J.; Golebiowski, A.; Clenaghan, J.; Klopfenstein, S.
R.; West, L. Tetrahedron Lett. 2001, 42, 2269; (b) Shaabani, A.;
Soleimani, E.; Maleki, A.; Moghimi-Rad, J. Synth. Commun.
2008, 38, 1090.
Acknowledgments:
19. Shaabani, A.; Maleki, A.; Rad, J.; Soleimani, E. Chem. Pharm.
Bull. 2007, 55, 957.
Financial support by the Council of Scientific and Industrial
Research (CSIR), New Delhi is gratefully acknowledged. AHS
and MS thank UGC, New Delhi, for the award of research
fellowship.
20. Odell, L. R.; Nilsson, M.; Gising, J.; Lagerlund, O.; Muthas, D.;
Nordqvist, A.; Karlen, A.; Larhed, M. Bioorg. Med. Chem. Lett.
2009, 19, 4790.
21. Shaabani, A.; Soleimani, E.; Sarvary, A.; Rezayan,H.; Maleki, A.
Chin. J. Chem. 2009, 27, 369.
22. Guchhait, S. K.; Maadan, C. Synlett, 2009, 628.
Supplementary Material
Supplementary material associated with this manuscript can
be found in online version as separate electronic file.
23. Rousseau, A. L.; Matlaba, P.; C. J. Parkinson, C. J. Tetrahedron
Lett. 2007, 48, 4079.
24. Rostamnia, S.; Hassankhanib, A. RSC Adv. 2013, 3, 18626.
25. Rostamnia, S.; Lamei, K.; Mohammadquli, M.; Sheykhan. M.;
Heydari, A. Tetrahedron Lett. 2012, 53, 5257.
References and notes
26. Varma R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665.
27. (a) Vidyacharan, S.; Shinde, A. H.; Satpathi, B.; Sharada, D. S.
Green Chem. 2014, 16, 1168; (b) Shinde, A. H.; Vidyacharan, S.
Sharada, D. S. Tetrahedron Lett. 2014, 55, 3064.
1. (a) Multicomponent Reactions, Zhu, J. P.; Bienaymѐ, ed H.;
Wiley-VCH Weinheim, Germany, 2005; (b) Dömling, A.; Wang,
W.; Wang, K. Chem. Rev. 2012, 112, 3083; (c) Der Heijden, G.
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D.; Bigatti, M.; Banfi, L.; Riva, R; Basso, A. Org. Lett. 2014, 16
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Chakraborti, A. K. Green Chem. 2012, 14, 2038; (f) Ramachary,
B. D.; Sangeeta, J. Org. Biomol. Chem. 2011, 9, 1277; (g) Roy, S.
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Staveren, D. R. V.; Nolte, N-M. Chem. Rev. 2004, 104, 5931.
29. (a) Our attempts to isolate pure imine from the reaction mixture
failed, however, we have confirmed the imine formation by mass
spectral analysis and also by TLC of reaction mixture with
reference imine (separately prepared); (b) When we have
performed the reaction of reference imine (prepared separately)
with isocyanide 3 in presence of lanthanum chloride as catalyst
gave the product 4 in excellent yield (90%), supporting the
proposed plausible mechanism.
Synthesis 2011, 14, 2261; (h) Bhagat, S.; Chakraborti, A. K.
J. Org. Chem. 2008, 73, 6029; (i) Bhagat, S.; Chakraborti, A. K.
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30. For similar kind of cycloaddition see: Umkehrer, M; Ross, G.;
Jager, N.; Burdack, C.; Kolb, J.; Hu, H.; Alvim-Gastonb, M.;
Hulme, C. Tetrahedron Lett. 2007, 48, 2213.
31. The proposed plausible mechanism is well known mechanism
proposed in the isocyanide-based multicomponent reactions,13-24
which also proposes the intermediate imine formation and further
its transformation to product 4 through similar kind of reaction
mechanism.