InBr3-catalyzed three-component, one-pot synthesis of imidazo[1,2-a] pyridines

Article abstract of DOI:10.1016/j.tetlet.2011.08.110

Indium(III) bromide has been used for the first time for the synthesis of imidazo[1,2-a]pyridines in a onepot operation from 2-aminopyridine, aldehydes, and alkynes. InBr₃ was found to be more effective for the activation of both alkyne and imi

Full text of DOI:10.1016/j.tetlet.2011.08.110

Tetrahedron Letters 52 (2011) 5789–5793
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Tetrahedron Letters
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InBr3-catalyzed three-component, one-pot synthesis of imidazo[1,2-a]pyridines
⇑
B.V. Subba Reddy , P. Sivaramakrishna Reddy, Y. Jayasudhan Reddy, J.S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Revised 18 August 2011
Accepted 20 August 2011
Available online 25 August 2011
Indium(III) bromide has been used for the first time for the synthesis of imidazo[1,2-a]pyridines in a one-
pot operation from 2-aminopyridine, aldehydes, and alkynes. InBr3 was found to be more effective for the
activation of both alkyne and imine derived from aryl aldehyde and 2-aminopyridine.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indium(III) reagents
Alkyne activation
Three-component reaction
Imidazo[1,2-a]pyridines
Over the years, multi-component reactions (MCRs) or three
component coupling (3CC) reactions have attracted much attention
in medicinal chemistry to generate structural diversity for drug
discovery programs.1 The imidazopyridine motif is an important
pharmacophore and is known to exhibit promising biological
properties, such as anti-biotic, -bacterial, -ulcer, and -inflammatory
behavior.2–5 They have been identified as selective cyclin-depen-
dent kinase inhibitors,6 calcium channel blockers,7 and b-amyloid
formation inhibitors8 and also constitute a novel class of orally
active non-peptide bradykinin B2 receptor antagonists.9
Furthermore, imidazo[1,2-a]pyridine is a core structure of several
drug molecules10 such as zolpidem for the treatment of insomnia,
alpidem, a anxiolytic agent, olprinone for the treatment of acute
heart failure, and minodronic acid for the treatment of osteoporosis,
and zolimidine, an anti-ulcer agent (Fig. 1).
Consequently, various methods have been developed for the
synthesis of imidazo[1,2-a]pyridine scaffolds.11 Of these, the three
component coupling (3CC) of 2-aminopyridine, aldehyde, and
alkyne is one of the most attractive methods for the synthesis of
imidazo[1,2-a]pyridines. Typically, transition metal salts such as
Ag(I), Au(III), and Cu(II) in combination with either p-TSA or
copper(I) complex have been employed to accomplish this
three-component coupling for the synthesis of imidazo[1,2-a]pyr-
idines.12 The current method has the advantage as it requires
(but also tolerates) the addition of triethylamine which can be
considered a buffer and provides for much milder reaction condi-
tions. To the best of our knowledge there are no reports on
three-component, one-pot syntheses of imidazo[1,2-a]pyridines
using InBr3/triethylamine system.
Recently, indium tribromide has received increasing attention
as a water-tolerant, green Lewis acid catalyst for organic synthesis
demonstrating highly chemo-, regio-, and stereo-selective re-
sults.13 Compared to conventional Lewis acids, it has advantages
of water stability, recyclability, operational simplicity, strong toler-
ance to oxygen and nitrogen-containing substrates and functional
groups, and it can often be used in catalytic amounts. Furthermore,
indium(III) also acts as a pi-Lewis acid catalyst.14
In continuation of our interest in exploring the catalytic applica-
tion of indium salts,15 we herein report a three-component,
N
N
N
N
Cl
N
N
Cl
O
O
Alpidem
Zolpidem
O
S
N
N
N
O
N
HN
Zolimidine
Olprinone
O
N
O
CN
N
OH
OH
P
HO
O
P
Minodronic acid
HO
OH
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Figure 1. Examples of imidazo[1,2-a]pyridine containing drugs.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.110

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B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 5789–5793
one-pot synthesis of imidazopyridines using a catalytic amount of
indium (III) bromide in toluene. Accordingly, we first treated benz-
aldehyde (1 mmol) and 2-aminopyridine (1 mmol) with phenyl-
acetylene (1.5 mmol) in dry toluene in the presence of 10 mol %
indium(III) bromide. The reaction proceeded well in refluxing tolu-
ene and gave the desired imidazo[1,2-a]pyridine 4a in 60% yield
along with uncyclized propargyl amine 5 (25% Scheme 2). By the
addition of 1.2 equiv of triethylamine, the corresponding imi-
dazo[1,2-a]pyridine 4a was obtained in 82% yield (Scheme 1).
This result provided the incentive to investigate the scope of
this reaction with respect to various aldehydes and alkynes. A vari-
ety of aromatic aldehydes such as p-chloro-, o-bromo-, o-methoxy-
, p-bromo-, m-chloro-, o-nitro-, and p-nitro benzaldehyde (entries
b–d and g–k, Table 1) participated well in this 3CC reaction. Nota-
bly, sterically hindered substrates such as 1-naphthaldehyde,
2-naphthaldehyde also participated effectively to afford the
respective imidazo[1,2-a]pyridines (entries e and f, Table 1). Fur-
thermore, acid sensitive furfural also gave the corresponding imi-
dazo[1,2-a]pyridine in 78% yield (entry l, Table 1).
N
3
N
InBr3 (10 mol %)
N
Dry toluene, 4A0 MS
Et3N, 12h, reflux
+
NH2
O
1
2
4a
Scheme 1. 3CC reaction of 2-aminopyridine, benzaldehyde, and phenylacetylene.
NH2
N
InBr3
Ph
+
N
N
OHC
Other alkynes such as p-methyl phenylacetylene and ethyl
propiolate, 1-octyne and O-benzyl propargyl alcohol were also par-
ticipated in the 3CC reaction to give the corresponding imidazo-
pyridines (entries h, and m–o, Table 1). On the other hand,
aliphatic aldehyde, for example 1-hexanaldehyde also gave the de-
sired imidazopyridine in 58% yield under similar reaction condi-
tions (entry p, Table 1). In all cases, no propargylic alcohol (an
adduct between the aldehyde and alkyne) was obtained under sim-
ilar reaction conditions. This is likely due to the rapid formation of
the imine compared to the addition of the alkyne to the aldehyde.
The effects of various indium(III) salts such as InCl3, In(OTf)3,
In(OAc)3, and In(ClO4)3 were screened for this transformation. Of
these catalysts, indium tribromide was found to be superior in
terms of conversion and selectivity. For example, treatment of
benzaldehyde with 2-aminopyridine and phenylacetylene in the
H
N
N
NH
N
InBr3
InBr3
5
Ph
Ph
N
N
N
Ph
Scheme 2. A plausible mechanism of 3CC reaction.
N
Ph
Table 1
InBr3/Et3N-promoted synthesis of imidazole[1,2-a]pyridines via 3CC reaction
Entry
2-Aminopyridine
Aldehyde
CHO
Alkyne
Producta
Time (h)
12
Yield (%)b,c
NH2
N
N
N
a
82
NH2
N
CHO
N
Cl
N
N
N
Cl
b
10
11
79
71
NH2
N
CHO
NO2
O2N
N
N
c
NH2
N
CHO
Br
Br
d
10
80

B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 5789–5793
5791
Table 1 (continued)
Entry 2-Aminopyridine
NH2
Aldehyde
CHO
Alkyne
Producta
Time (h)
Yield (%)b,c
N
N
N
e
12
77
NH2
CHO
N
N
N
N
N
N
N
f
12
12
11
79
81
76
NH2
NH2
CHO
OMe
N
N
g
h
MeO
CHO
NH2
NH2
NH2
CHO
N
N
Br
N
N
N
N
Br
i
j
10
12
83
74
CHO
NO2
O2N
CHO
Cl
N
N
N
N
N
N
N
k
11
10
82
75
Cl
O
NH2
O
CHO
CHO
CHO
l
NH2
NH2
O
N
O
N
N
OEt
m
n
12
12
65
70
OEt
N
O
Ph
N
OBn
(continued on next page)

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B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 5789–5793
Table 1 (continued)
Entry
2-Aminopyridine
Aldehyde
CHO
Alkyne
Producta
Time (h)
12
Yield (%)b,c
NH2
N
N
( )3
N
N
N
o
62
( )5
NH2
CHO
N
p
12
58
a
b
c
All products were characterized by 1H NMR and mass spectroscopy.
Yield refers to pure products after chromatography.
4A MS, Et3N, toluene, reflux.
9. Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Imai, K.; Inamura, N.;
Asano, M.; Hatori, C.; Katayama, A.; Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41,
564.
presence of 10 mol % of InBr3 over 12 h gave the product 4a in 82%
yield compared to 67% when 10 mol % of InCl3 was used. Although,
indium tribromide is water tolerant, the reaction was unsuccessful
either in pure water or in toluene/water (7:3) system. The scope
and generality of this process is illustrated with respect to various
aldehydes and alkynes and the results are presented in Table 1.15,16
Mechanistically, the reaction is expected to proceed via the
in situ formation of an imine from an aldehyde and the 2-amino-
pyridine. This is followed by addition of the alkyne, likely after
activation through In(III) and deprotonation by Et3N in the forma-
tion of the desired imidazo[1,2-a]pyridine (Scheme 2).12
To provide further support for the proposed mechanism, the
alkyne addition to imine was carried out by simply combining
indium(III) bromide/Et3N. However, the product was similar to
that obtained in the three-component coupling which indicates
that the reaction proceeds with the proposed mechanism.
In summary, we have developed the one-pot strategy for the
synthesis of imidazo[1,2-a]pyridines by means of coupling of
2-aminopyridine, aldehyde, and alkyne. The use of indium(III) bro-
mide makes this method simple, convenient and practical. The
present method significantly expands the scope of the 3CC reaction
by studying the reactivity of naphthyl- and o-substituted aryl-
aldehydes. This method works not only with aromatic and but also
with aliphatic substrates.
10. Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7, 888.
11. (a) Ueno, M.; Nabana, T.; Togo, H. J. Org. Chem. 2003, 68, 6424; (b) Adib, M.;
Mahdavi, M.; Noghani, M. A.; Mirxaei, P. Tetrahedron Lett. 2007, 48, 7263; (c)
Adib, M.; Mahdavi, M.; Abbasi, A.; Jahromi, A. H.; Bijanzadeh, H. R. Tetrahedron
Lett. 2007, 48, 3217; (d) Enguehard-Gueiffier, C.; Croix, C.; Hervet, M.; Kazock,
J.-Y.; Gueiffier, A.; Abarbri, M. Helv. Chim. Acta 2007, 90, 2349; (e) Parenty, A. D.
C.; Cronin, L. Synthesis 2008, 1479; (f) Koubachi, J.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271; (g) Adib, M.; Shebani, E.;
Zhu, L.-G.; Mirzaei, P. Tetrahedron Lett. 2008, 49, 5108.
12. (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743; (b) Liu, P.;
Fang, L.; Lei, X.; Lin, G. Tetrahedron Lett. 2010, 51, 4605; (c) Yadav, J. S.; Reddy,
B. V. S.; Rao, Y. G.; Srinivas, M.; Narsaiah, A. V. Tetrahedron Lett. 2007, 48, 7717;
(d) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem. 2006, 118, 7237; (e)
Bakherad, M.; Nasr-Isfahani, H.; Keivanloo, A.; Sang, G. Tetrahedron Lett. 2008,
49, 6188; (f) Bakherad, M.; Nasr-Isfahani, H.; Keivanloo, A.; Doostmohammadi,
N. Tetrahedron Lett. 2008, 49, 3819.
13. (a) Zhang, Z.-H. Synlett 2005, 711; (b) Sakai, N.; Hirasawa, M.; Konakahara, T.
Tetrahedron Lett. 2005, 46, 6407; (c) Agnusdei, M.; Bandini, M.; Melloni, A.;
Umani-Ronchi, A. J. Org. Chem. 2003, 68, 7126; (d) Huang, J.-M.; Wong, C.-M.;
Xu, F.-X.; Loh, T.-P. Tetrahedron Lett. 2007, 48, 3375; (e) Harada, S.; Takita, R.;
Ohshima, T.; Matsunaga, S.; Shibasaki, M. Chem. Commun. 2007, 948.
14. (a) Tsuchimoto, T.; Kanbara, M. Org. Lett. 2011, 13, 912. and reference 21 cited
therein; (b) Tsuchimoto, T. J. Synth. Org. Chem. Jpn. 2006, 64, 752–765.
15. (a) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.; Prasad, A. R.; Kumar, S. K.;
Kunwar, A. C.; Jayaprakash, P. J.; Jagannath, B. Angew. Chem., Int. Ed. 2003, 42,
5198; (b) Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Swamy, T. Tetrahedron Lett.
2003, 44, 6055; (c) Yadav, J. S.; Reddy, B. V. S.; Gakul, B. Green Chem. 2003, 5,
264.
16. General procedure:
A solution of 2-aminopyridine (1 mmol), benzaldehyde
(1 mmol) and phenylacetylene (1.5 mmol) in 2 mL dry toluene was mixed in a
round bottom flask containing 4 Å molecular sieves (oven-dried powder). A
mixture of 10 mol % of InBr3 and triethylamine (1.2 mmol) was added to the
above mixture and the resulting solution was allowed to stir under reflux for
the appropriate time (Table 1). After completion of the reaction as indicated by
TLC, the solvent was evaporated in vacuo and extracted with ethyl acetate (2–
10 mL). The combined organic layers were dried over anhydrous Na2SO4.
Removal of the solvent followed by purification on silica gel (Merck, 60–
120 mesh, ethyl acetate–hexane, 1:9) gave the pure imidazo[1,2-a]pyridine.
The products thus obtained were characterized by NMR and mass
spectroscopy. Spectral data for the selected products: 4a: 3-Benzyl-2-
phenylH-imidazo[1,2-a]pyridine: White solid, mp = 122 °C. 1H NMR (300 MHz,
CDCl3): d 8.16 (d, J = 9.0 Hz, 1H), 7.75–7.82 (m, 3H), 7.36–7.51 (m, 4H), 7.72–
7.34 (m, 3H), 7.08 (d, J = 8.3 Hz, 2H), 6.95 (t, J = 6.7, 1H), 4.47 (s, 2H); 13C NMR
(75 MHz, CDCl3): d 138.8, 129.0, 128.8, 128.2, 127.6, 126.9, 124.2, 123.4, 117.4,
112.2, 29.7; HRMS (ESI)[M+H] calcd for C20H17N2: 285.1391, found: 285.1399.
4b: 3-Benzyl-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridine: 1H NMR (300 MHz,
CDCl3): d 7.60–7.70 (m, 4H), 7.33 (d, J = 8.3 Hz, 2H), 7.10–7.29 (m, 4H), 7.05 (d,
J = 6.0 Hz, 1H), 6.56–6.71(m, 2H), 4.40 (s, 2H); 13C NMR (75 MHz, CDCl3): d
144.8, 136.4, 133.6, 132.9, 129.3, 129.0, 128.8, 127.5, 127.0, 124.4, 123.3, 117.5,
Acknowledgments
P.S.R.K.R. and Y.J.S.R. thank CSIR and UGC, respectively, New
Delhi, for the award of fellowships.
References and notes
1. (a) Zhu, J.; Bienayme, H. Multi-Component Reactions; Wiley-VCH: Weinheim,
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F. Chem. Eur. J. 2009, 15, 1300; (d) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10,
51; (e) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8; (f) Domling, A. Comb. Chem.
High Throughput Screening 1998, 1, 1.
2. Lhassani, M.; Chavignon, O.; Chezal, J.-M.; Teulade, J.-C.; Chapat, J.-P.; Snoeck,
R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J. Med. Chem. 1999, 34,
271.
3. Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170.
4. Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Takasugi, H. Chem. Pharm. Bull.
1992, 40, 371.
112.3, 29.8.; HRMS (ESI) [M+H] calcd for
C20H16 ClN2: 319.1002, found:
319.1017. 4d: 3-Benzyl-2-(2-bromophenyl)H-imidazo[1,2-a]pyridine: 1H NMR
(500 MHz, CDCl3): d 7.66 (t, J = 9.8 Hz, 3H), 7.48 (d, J = 7.8 Hz, 1H), 7.35(t,
J = 6.8 Hz, 1H), 7.17–7.26 (m, 3H), 7.15 (t, J = 6.8 Hz, 2H), 7.03 (d, J = 6.8 Hz, 2H),
6.67 (t, J = 6.8 Hz, 1H), 4.25 (s, 2H); 13C NMR (75 MHz, CDCl3): d 136.1, 133.5,
132.5, 132.2, 129.4, 128.4, 127.6, 126.8, 126.4, 123.8, 117.4, 29.4; HRMS (ESI)
[M+H] calcd for C20H16 BrN2: 363.0496, found: 363.0487. 4e: 3-Benzyl-2-
(naphthalen-1-yl)H-imidazo[1,2-a]pyridine: 1H NMR (500 MHz, CDCl3): d 8.15
(d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.37–7.58 (m,
4H), 7.11–7.27 (m, 4H), 7.03 (d, J = 7.1 Hz, 2H), 6.71 (t, J = 6.6 Hz, 1H), 4.29 (s,
2H); 13C NMR (75 MHz, CDCl3): d 128.8, 128.6, 128.1, 127.7, 126.6, 126.38,
126.33, 125.8125.1, 124.0, 123.7, 117.6, 112.1, 29.6; HRMS (ESI) [M+H] calcd
5. Rupert, K. C.; Henry, J. R.; Dodd, J. H.; Wadsworth, S. A.; Cavender, D. E.; Olini, G.
C.; Fahmy, B.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 2003, 13, 347.
6. Hamdouchi, C.; Zhong, B.; Mendoza, J.; Collins, E.; Jaramillo, C.; De Diego, J. E.;
Robertson, D.; Spencer, C. D.; Anderson, B. D.; Watkins, S. A.; Zhanga, F.; Brooks,
H. B. Bioorg. Med. Chem. Lett. 2005, 15, 1943.
7. Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.; Moore, J. B., Jr. J. Med.
Chem. 1991, 34, 2060.
8. Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth, J. M.; Kelly, S.; Owens, A. P.;
Blackaby, W. P.; Lewis, R. T.; Stanley, J.; Smith, A. J.; Ferris, P.; Sohal, B.; Cook, S.
M.; Pike, A.; Brown, N.; Wafford, K. A.; Marshall, G.; Castro, J. L.; Atack, J. R. J.
Med. Chem. 2006, 49, 35.

B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 5789–5793
5793
for C24H19N2: 335.1548, found: 335.1559. 4n: 3-(2-(Benzyloxy)ethyl)-2-
J = 9.8 Hz, 2H), 1.70–1.78 (m, 2H), 1.34–1.45 (m, 8H), 0.99 (t, J = 9.9 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): d 144.5, 142.4, 135.1, 128.8, 128.1, 127.9, 127.6, 123.8,
123.0, 120.9, 117.6, 112.1, 31.8, 27.4, 23.8, 22.6, 22.2, 21.5, 13.2; HRMS (ESI)
phenylimidazo[1,2-a]pyridine: 1H NMR (300 MHz, CDCl3): d 7.81–7.84 (m, 4H),
7.45 (t, J = 7.6 Hz, 2H), 7.32–7.36 (m, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.15–7.23 (m,
2H), 7.12 (d, J = 8.1 Hz, 2H), 6.71 (t, J = 6.7 Hz, 1H), 4.98 (s, 2H), 4.01 (t,
J = 6.4 Hz, 2H), 3.32 (t, J = 6.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 144.2, 136.9,
134.2, 129.5, 128.8, 128.6, 127.9, 127.7, 127.2, 124.4, 123.6, 117.5, 112.6, 76.9,
71.8, 59.8; HRMS (ESI) [M+H] calcd for C22H20N2O: 328.1576, found: 328.1578.
4o: 3-Heptyl-2-phenylimidazo[1,2-a]pyridine: Viscous liquid; 1H NMR
(300 MHz, CDCl3): d 7.94 (d, J = 6.8 Hz, 1H), 7.76 (s, 2H), 7.64–7.68 (m, 1H),
7.49 (s, 2H), 7.33–7.38 (m, 1H); 7.13–7.19 (m, 1H), 6.78–6.84 (m, 1H), 3.11 (t,
[M+H] calcd for
C20H24N2: 292.1939, found: 292.1935. 4p: 3-Benzyl-2-
pentylimidazo[1,2-a]pyridine: 1H NMR (300 MHz, CDCl3): d 7.64 (t, J = 8.84 Hz,
2H), 7.25–7.29 (m, 2H), 7.11–7.16 (m, 4H), 6.63 (t, J = 7.85 Hz, 1H), 4.29 (s, 2H),
2.82 (t, J = 6.8 Hz, 2H), 1.84–1.86 (m, 2H), 1.60–1.64 (m, 4H), 1.0 (t, J = 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 137.4, 128.9, 127.1, 123.8, 123.5, 123.0,
119.0, 117.1, 111.6, 110.3, 29.9, 29.2, 24.2, 24.0, 23.2, 14.2; HRMS (ESI) [M+H]
calcd for C19H22N2: 278.1783, found: 278.1779.