Hypervalent Iodine in Synthesis. 94. A Facile Synthesis of 2-Substituted-imidazo[1,2-a]pyridines by Cyclocondensation of Alkynyl(phenyl) iodonium Salts and 2-Aminopyridine

Article abstract of DOI:10.1081/SCC-120027273

A facile method for the synthesis of 2-substituted-imidazo[1,2-a]pyridines is achieved by cyclocondensation of alkynyl(phenyl)iodonium salts with 2-aminopyridine.

Full text of DOI:10.1081/SCC-120027273

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Hypervalent Iodine in Synthesis. 94. A Facile
Synthesis of 2-Substituted-imidazo[1,2-a]pyridines
by Cyclocondensation of Alkynyl(phenyl) iodonium
Salts and 2-Aminopyridine
a b
a b
c
Zhi Liu
, Zhen-Chu Chen
& Qin-Guo Zheng
a
Ningbo Institute of Technology , Zhejiang University , Ningbo, P.R. China
b
Department of Chemistry , Zhejiang University , XiXi Campus, 34, Tian Mu Shan Rd.,
XiHu District, Hangzhou, 310028, P.R. China
c
Pharmaceutical Sciences Research Institute , Aston University , Birmingham, UK
Published online: 18 Oct 2011.
To cite this article: Zhi Liu , Zhen-Chu Chen & Qin-Guo Zheng (2004) Hypervalent Iodine in Synthesis. 94. A Facile
Synthesis of 2-Substituted-imidazo[1,2-a]pyridines by Cyclocondensation of Alkynyl(phenyl) iodonium Salts and 2-
Aminopyridine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 34:2, 361-367, DOI: 10.1081/SCC-120027273
To link to this article: http://dx.doi.org/10.1081/SCC-120027273
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SYNTHETIC COMMUNICATIONS
Vol. 34, No. 2, pp. 361–367, 2004
Hypervalent Iodine in Synthesis. 94.
A Facile Synthesis of 2-Substituted-
imidazo[1,2-a]pyridines by
Cyclocondensation of Alkynyl(phenyl)
iodonium Salts and 2-Aminopyridine
1,2
Zhi Liu, Zhen-Chu Chen,1,2,* and Qin-Guo Zheng3
1
Ningbo Institute of Technology, Zhejiang University, Ningbo,
P.R. China
2
Department of Chemistry, Zhejiang University, XiXi Campus,
Hangzhou, P.R. China
3
Pharmaceutical Sciences Research Institute, Aston University,
Birmingham, UK
ABSTRACT
A facile method for the synthesis of 2-substituted-imidazo[1,2-a]pyri-
dines is achieved by cyclocondensation of alkynyl(phenyl)iodonium salts
with 2-aminopyridine.
Key Words: Hypervalent iodine; 2-Substituted-imidazo[1,2-a]pyri-
dines; Cyclocondensation; Alkynyl(phenyl)iodonium salts.
*
Correspondence: Zhen-Chu Chen, Department of Chemistry, Zhejiang University,
XiXi Campus, 34, Tian Mu Shan Rd., XiHu District, Hangzhou 310028, P.R. China;
E-mail: zhenchuc@mail.hz.zj.cn.
3
61
DOI: 10.1081/SCC-120027273
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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62
Liu, Chen, and Zheng
Our recent investigations dealing with hypervalent iodine mediated
synthesis have shown that the phenylethynyl(phenyl)iodonium salt is an
extremely important equivalent reagent of the highly lachrymatory a-
halogenoacetophenone, providing new and useful synthesis of various
[1]
[2]
heterocyclic compounds such as 2-mercaptothiazoles, selenazoles and 3-
substituted-5,6-dihydroimidazo[2,1-b]thiazoles.
[3]
This new approach has
obvious advantages over the literature methods such as simple experimen-
tation and avoiding the use of lachrymatory, toxic and not readily available
a-halogeno-ketones. These encouraging results coupled with the ready
availability and high reactivity of alkynyl(phenyl)iodonium salts prompted us
to examine their reaction with 2-aminopyridine for providing a new and facile
synthesis of bridgehead heterocyclic compounds, namely, 2-substituted-
imidazo[1,2-a]pyridines. Part of our reason for undertaking this study was that
2-substituted-imidazo[1,2-a]pyridines are known to possess important
biological properties such as anti-inflammatory, antifungal, long-acting
[4]
[5]
[
6]
[7]
[8]
local anesthetic, antiulcer and anthelmintic or bacterostatic activities.
[9,10]
Several derivatives have also been described as fluorescent materials.
Herein we would like to report a new facile method for the synthesis of 2-
substituted-imidazo[1,2-a]pyridines by cyclocondensation of alkynyl(pheny-
l)iodonium salts with 2-aminopyridine.
We found that the cyclocondensation of alkynyl(phenyl)iodonium salts
with 2-aminopyridine occurred easily in CHCl under reflux in the presence of
3
K CO . Thus, simple stirring of a mixture of the alkynyl(phenyl)iodonium
2 3
salts 1 with 2-aminopyridine 2 in chloroform under reflux for two hours in the
presence of K CO gave, after workup, the 2-substituted-imidazo[1,2-
2
3
a]pyridines 3 in moderate to good yield (Sch. 1). The results are summarized
in Table 1.
1
The products were characterized by mp, H NMR, IR spectral data and
microanalyses. They are identical to the data reported by the literature.
The reaction was found to be applicable to arylethynyl(phenyl)iodonium
salts possessing various substituents, such as fluoro, chloro, bromo, alkyl and
alkoxy groups.
Scheme 1.

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Hypervalent Iodine in Synthesis. 94
363
Table 1. Synthesis of 2-substituted-imidazo[1,2-a]pyridines by cyclocondensation of
alkynyl(phenyl)iodonium salts and 2-aminopyridine.
a
Entry
Alkynyl(phenyl)iodonium salts
3
Product 3, R ¼
Yield (%)
1
2
3
4
5
3a
3b
3c
3d
3e
3f
65
71
63
67
55
53
6
a
Isolated yield based on alkynyl(phenyl)iodonium salt.
A plausible mechanism for the formation of 2-substituted-imidazo[1,2-
a]pyridines 3 can be reasoned from the synthesis of thiazoles by cyclocon-
[11]
densation of alkynyl(phenyl)iodonium salts and thioamides and is shown in
Sch. 2. It involves the attack of the iodonium ion of alkynyl(phenyl)iodonium
salts 1 on the nitrogen of pyridine to form the primary addition products 4
[
12]
followed by a polyhetero-claisen rearrangement
iodobenzene to generate the carbene 7, and cycloaromatization of 7 to give
and 1,1-elimination of
2-substituted-imidazo[1,2-a]pyridines 3.
Due to the increasing interest in 2-substituted-imidazo[1,2-a]pyridines,
there are several methods for their synthesis involving (a) reaction
of a-halocarbonyl-compounds with 2-aminopyridine (Tschitschibabin
[
13]
method),
elimination of nitrogens,
(b) reaction of 2-chloropyridine with triazole, and subsequent
14]
[
(c) intramolecular photocyclization of styrylimi-
(d) reaction of an a-bromoacyl derivative with sulfonohydrazide
[
15]
dazole,
and subsequently with pyridine,
[16]
and (e) pyridine ring formation starting
[9]
from imidazole compounds. However, these methods often suffer from
lengthy sequences, low overall yields, drastic reaction conditions and the use
of lachrymatory, toxic or relatively inaccessible starting materials. Our present
reaction represents a new facile method for synthesis of 2-substituted-
imidazo[1,2-a]pyridines by cyclocondensation of alkynyl(phenyl)iodonium
salts and 2-aminopyridine which has some advantages over existing ones such
as avoiding the use of lachrymatory and toxic a-halogenoketones, mild
reaction conditions, ready availability of starting materials and short reaction

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64
Liu, Chen, and Zheng
Scheme 2.
time. Furthermore, the range of useful applications of alkynyl(phenyl)iodo-
nium salts in organic chemistry has been extended.
EXPERIMENTAL
Melting points were determined on a X -data microscopic melting point
4
apparatus and were uncorrected. Microanalyses were obtained using Carlo-
1
Erba 1106. H NMR spectra were obtained at 400 MHz in DMSO-d or CDCl
6
3
using TMS as an internal standard. IR spectra were recorded on a Perkin–
Elmer 683 spectrometer at r.t.
General Procedure for the Preparation of 2-Substituted-
imidazo[1,2-a]pyridines
To a solution of 2-aminopyridine (1.2 mmol) in CHCl (15 mL) was
3
added K CO (0.6 mmol). While stirring, the corresponding alkynyl(phenyl)-
3
2
iodonium salts (1 mmol) was added to the mixture. The resulting mixture was
refluxed for 2hrs and water (20 mL) was added. The chloroform phase was
dried (Na SO ), concentrated and chromatographed on a silical gel plate using
2
4
petroleum ether (b.p. 60-908C)/Et O (4 : 1) as eluent to afford the product.
2
2
-Phenyl-imdazo[1,2-a]pyridine, 3a. White powder, m.p.: 1338C
[
10]
1
(
Lit
1348C). IR (KBr): 1634, 830. H NMR (CDCl , 400 MHz) d: 7.03
3
(
1H, t, J ¼ 6.8 Hz), 7.45 (1H, t, J ¼ 8.4 Hz), 7.53 (1H, dd, J ¼ 4.3 Hz,
1
J ¼ 8.4 Hz), 7.60 (4H, d, J ¼ 4.3 Hz), 7.79 (1H, s), 7.99 (1H, d, J ¼ 8.4 Hz),
2
8
.42 (1H, d, J ¼ 6.8 Hz).

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Hypervalent Iodine in Synthesis. 94
365
0
2
-(4 -Fluorophenyl)-imdazo[1,2-a]pyridine, 3b. White powder, m.p.:
1
[
10]
1
64-1658C (Lit
1698C). IR (KBr): 1645, 1217, 838. H NMR (CDCl ,
3
4
00 MHz) d: 7.21–7.24 (2H, m), 7.31 (1H, t, J ¼ 6.8 Hz), 7.72 (1H, t,
J ¼ 8.4 Hz), 7.92 (1H, s), 8.10 (2H, q), 8.36 (1H, d, J ¼ 6.8 Hz), 8.41 (1H, d,
J ¼ 8.4 Hz).
0
2
-(4 -Chlorophenyl)-imdazo[1,2-a]pyridine, 3c. White powder, m.p.:
[
17]
1
205–2068C (Lit
2088C). IR (KBr): 1640, 835, 710. H NMR (CDCl ,
3
4
00 MHz) d: 6.80 (1H, t, J ¼ 6.8 Hz), 7.22 (1H, t, J ¼ 8.0 Hz), 7.40 (2H, d,
J ¼ 8.4 Hz), 7.65 (1H, d, J ¼ 8.0 Hz), 7.83 (1H, s), 7.87 (2H, d, J ¼ 8.4 Hz),
8.11 (1H, d, J ¼ 6.8 Hz).
0
2
-(4 -Bromophenyl)-imdazo[1,2-a]pyridine, 3d White powder, m.p.:
1
1
0
213–2148C (Lit 215–2178C). IR (KBr): 1638, 830, 506. H NMR (CDCl ,
3
4
00 MHz) d: 6.92 (1H, t, J ¼ 6.8 Hz), 7.32 (1H, t, J ¼ 8.0 Hz), 7.54 (2H, d,
J ¼ 8.0 Hz), 7.71 (1H, d, J ¼ 8.0 Hz), 7.82 (2H, d, J ¼ 8.0 Hz), 7.91 (1H, s),
8.18 (1H, d, J ¼ 6.8 Hz).
0
2
-(4 -Butylphenyl)-imdazo[1,2-a]pyridine, 3e. White powder, m.p.:
1
153–1558C. IR (KBr): 2980, 1640, 828. H NMR (CDCl , 400 MHz) d: 0.94
3
(
(
(
3H, t, J ¼ 7.6 Hz), 1.39 (2H, m), 1.64 (2H, m), 2.67 (2H, t, J ¼ 8.0 Hz), 6.80
1H, t, J ¼ 6.8 Hz), 7.20 (1H, t, J ¼ 7.2 Hz), 7.31 (2H, d, J ¼ 8.0 Hz), 7.44
2H, d, J ¼ 8.0 Hz), 7.68 (1H, s), 7.70 (1H, d, J ¼ 6.8 Hz), 8.31 (1H, d,
J ¼ 7.2 Hz). Anal. Calcd. for C H N : C, 81.56; H, 7.25; N, 11.19. Found:
1
7 18 2
C, 81.48; H, 7.24; N, 11.28.
0
2
-(4 -Methoxyphenyl)-imdazo[1,2-a]pyridine, 3f. White powder, m.p.:
1
0
1
1
4
7
8
33–1358C (Lit 1368C). IR (KBr): 1635, 1248, 825. H NMR (DMSO-d ,
6
00 MHz) d: 3.80 (3H, s), 6.87 (1H, t, J ¼ 6.8 Hz), 7.01 (2H, d, J ¼ 8.0 Hz),
.22 (1H, t, J ¼ 6.8 Hz), 7.55 (1H, d, J ¼ 9.6 Hz), 7.90 (2H, d, J ¼ 8.0 Hz),
.29 (1H, s), 8.50 (1H, d, J ¼ 6.4 Hz).
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Received in the UK May 7, 2003

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