An efficient synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2008.05.134

An efficient synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines is described via a novel multicomponent reaction between 2-aminopyridines, benzaldehydes and imidazoline-2,4,5-trione under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2008.05.134

Tetrahedron Letters 49 (2008) 5108–5110
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Tetrahedron Letters
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An efficient synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines
a
b
c
Mehdi Adib a, , Esmail Sheibani , Long-Guan Zhu , Peiman Mirzaei
*
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Chemistry Department, Zhejiang University, Hangzhou 310027, PR China
c Department of Chemistry, Shahid Beheshti University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines is described via a novel multicomponent
reaction between 2-aminopyridines, benzaldehydes and imidazoline-2,4,5-trione under solvent-free
conditions.
Received 1 February 2008
Revised 19 May 2008
Accepted 28 May 2008
Available online 3 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminopyridines
Benzaldehydes
Imidazoline-2,4,5-trione
3-Amino-2-arylimidazo[1,2-a]pyridines
Multicomponent reactions
Solvent-free synthesis
Multi-component reactions (MCRs) have emerged as an effi-
cient and powerful tool in modern synthetic organic chemistry
due to their valued features such as atom economy, straightfor-
ward reaction design and the opportunity to construct target com-
pounds by the introduction of several diversity elements in a single
chemical event. Typically, purification of products resulting from
MCRs is also simple, since all the organic reagents employed are
consumed and are incorporated into the target compound.1 MCRs,
leading to interesting heterocyclic scaffolds, are particularly useful
for the construction of diverse chemical libraries of ‘drug-like’
molecules.
Imidazo[1,2-a]pyridines, fused bicyclic 5–6 heterocycles with
one ring junction nitrogen atom and one nitrogen atom in the
five-membered ring, are of interest because of the occurrence of
their saturated and partially saturated derivatives in biologically
active compounds.2 Derivatives containing the imidazo[1,2-a]pyr-
idine ring system have been shown to possess a broad range of use-
ful pharmacological activities, including antibacterial, antifungal,
anthelmintic, antiviral, antiprotozoal, antiinflammatory, anticon-
vulsant, anxiolytic, hypnotic, gastrointestinal, antiulcer and immu-
nomodulatory.2–4
ularly interesting are those structures that contain an amino group
at C-2 or C-3. There are well-established methods for the prepara-
tion of 3-aminoimidazo[1,2-a]pyridines; these include nitration at
C-3 of the already formed heterocycle and subsequent reduction,5
a multicomponent reaction between 2-aminopyridines, aldehydes
and isonitriles6–8 or preparation from pyridinium fluorides,9 Strec-
ker-type reaction between 2-aminopyridines, cyanide ions and a
limited number of aldehydes,10 or by use of benzotriazole as an
auxiliary group.11 Most of these methods involve three or more
sequential synthetic steps, the use of harsh reaction conditions that
give low yields, and in some cases, use of hazardous or expensive
starting materials.
As part of our continuing efforts on the development of
new routes for the preparation of biologically active heterocyclic
compounds, we recently described an efficient synthesis of
2-aryl-2-(2-oxo-2-arylethyl)imidazo[1,2-a]pyridin-3(2H)-ones 1 via
a condensation reaction between 2-aminopyridines and diaroyl-
acetylenes.3 We have also developed an efficient synthesis of
3-alkylamino-2-arylimidazo[1,2-a]pyridines 2 via a catalyst-free
reaction between 2-aminopyridines, aldehydes and isocyanides
in water.4
So far, several synthetic methods have been reported for the
preparation of 2- or 3-substituted imidazo[1,2-a]pyridines with
the majority relying on the condensation of 2-aminopyridine with
O
N
N
-bromoketones to form the five-membered cyclic system.2 Partic-
N
N
a
Ar
R
O
N
Ar
Ar
H
* Corresponding author. Tel./fax: +98 21 66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
1
2
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.134

M. Adib et al. / Tetrahedron Letters 49 (2008) 5108–5110
5109
Considering the important biological properties of imidazo-
[1,2-a]pyridines, we report herein another novel synthesis of this
nucleus bearing in mind previously reported syntheses. Thus, 2-
aminopyridines 3, benzaldehydes 4 and imidazoline-2,4,5-trione
5 were found to undergo a novel one-pot multicomponent addition
reaction under solvent-free conditions to produce 3-amino-2-ary-
limidazo[1,2-a]pyridines 6a–j (Table 1).
When the reaction was performed using equivalent ratios of 2-
aminopyridine (3, R = H), benzaldehyde (4, Ar = C6H5) and imidaz-
oline-2,4,5-trione 5, 1H NMR analysis of the reaction mixture indi-
cated the formation of imidazo[1,2-a]pyridine 6a in nearly 45%
yield. Almost half the 2-aminopyridine 3 was recovered unreacted
at the end of the reaction. The best results were obtained when the
reactions were carried out using the three components in a ratio of
1:2.5:1.5.12
200 °C and were complete within a few minutes affording 3-ami-
no-2-arylimidazo[1,2-a]pyridines 6 in 92–97% yields.12
The structures of products 6a–j were deduced by 1H and 13C
NMR spectroscopy, mass spectrometry and elemental analysis.
The mass spectrum of 6d displayed the molecular ion (M+) peak
at m/z 357, which was consistent with the adduct structure. The
1H NMR spectrum of 6d exhibited three sharp singlets, arising from
the two CH3O (d 3.81 and 3.82 ppm) and aldimine (d 8.67 ppm)
groups along with characteristic multiplets with appropriate
chemical shifts and coupling constants for the four H atoms of
the electron-rich diene moiety of the six-membered ring and the
eight H atoms of the two aryl substituents. The 1H-decoupled 13C
NMR spectrum of 6d showed 18 distinct resonances, in agreement
with the suggested structure. Partial assignments of these reso-
nances are given.12 Single-crystal X-ray analysis of 6d confirmed
conclusively the structure of the isolated products. An ORTEP
diagram of 6d is shown in Figure 1.13
The reactions were carried out by mixing the 2-aminopyridine,
the aldehyde and imidazoline-2,4,5-trione followed by heating at
Although we have not yet established the mechanism of the
reaction between 2-aminopyridines, benzaldehydes and imidazo-
line-2,4,5-trione in an experimental manner, a mechanistic ratio-
nalization for this reaction is provided in Scheme 1. The first step
may involve condensation of the aldehyde with the 2-aminopyr-
idine and imidazoline-2,4,5-trione with formation of aldimine 7
and imidazolium ion 8, respectively. Then the imidazolium ion 8
is probably attacked by the pyridine-N atom of the aldimine 7 lead-
ing to adduct 9. Intramolecular nucleophilic addition of alkoxide to
the adjacent carbonyl group would yield epoxide intermediate 10,
which may undergo ring opening to form ylide 11. This ylide may
undergo intramolecular cyclization to dihydroimidazo[1,2-a]pyr-
idine intermediate 12 from which a carbon dioxide, an isocyanic
acid and an acetic acid molecule may be removed to afford the
imidazo[1,2-a]pyridine 6.
Table 1
Solvent-free synthesis of imidazo[1,2-a]pyridines
R
R
O
O
solvent-free
+
ArCHO +
N
HN
NH
N
200 ºC, 5 min
N
NH2
O
ArCH
N
Ar
6
3
4
5
6
a
R
Ar
Mpa (°C)
% Yieldb
H
161–163
95
In conclusion, we have developed a novel, efficient, one-pot
multicomponent synthesis of 3-amino-2-arylimidazo[1,2-a]pyri-
dines of potential synthetic and pharmacological interest. Sol-
vent-free conditions, excellent yields of the products and use of
simple starting materials are the main advantages of this method.
Further investigations on the reaction mechanism, scope and lim-
itations are underway.
b
H
154–155
92
CH3
c
d
e
f
H
H
H
165
92
94
96
97
H3C
175
CH3O
158–160
189–190
F
6-CH3
CH3O
g
6-CH3
7-CH3
154–156
176
97
94
F
h
CH3O
i
j
6-CH3
8-CH3
139–140
155–156
92
93
CH3
CH3O
a
Recrystallized from n-hexane–EtOAc (1:2).
Isolated yields.
b
Figure 1. ORTEP diagram of the structure of 6d.

5110
M. Adib et al. / Tetrahedron Letters 49 (2008) 5108–5110
Ar
+
ArCHO
N
Ar
N
7
+
N
_
..
N
_
NH2
O
AcO
Ar
N
O
_
AcO
Ar
O
+
N
H
N
O
+
N
AcOH
+ ArCHO
O
O
N
O
N
O
O
H
N
H
H
9
8
Ar
N
+
N
+
N
_
_
_
_
N
AcO
AcO
AcO
Ar
N
N
H
_
CO2
+
N
+
O
+
N
6
Ar
Ar
_
N
_
Ar
Ar
HNCO
AcOH
O
O
O
_
N
O
O
O
N
N
H
O
O
H
H
10
11
12
Scheme 1.
12. The procedure for the preparation of 2-(4-methoxyphenyl)-N3-[(E)-1-(4-
methoxyphenyl)methylidene]imidazo[1,2-a]pyridin-3-amine 6d is described
Acknowledgement
as an example:
A mixture of 2-aminopyridine (0.188 g, 2 mmol), 4-
This research was supported by the Research Council of the Uni-
versity of Tehran as research project (6102036/1/02).
methoxybenzaldehyde (0.681 g, 5 mmol) and imidazoline-2,4,5-trione
(0.342 g, 3 mmol) was stirred at 200 °C for 5 min. Then the reaction mixture
was cooled to room temperature and the residue was purified by column
chromatography using n-hexane–ethyl acetate (1:3) as eluent. The solvent was
removed and the product was obtained as yellow crystals, mp 175 °C, yield
0.67 g, 94% (relative to 2-aminopyridine). EI-MS, m/z (%): 357 (M+, 100), 342
(8), 239 (9), 211 (88), 196 (9), 178 (5), 78 (72). Anal. Calcd for C22H19N3O2
(357.41): C, 73.93; H, 5.36; N, 11.76. Found: C, 73.8; H, 5.4; N, 11.6. 1H NMR
(300.1 MHz, CDCl3): d 3.81 and 3.82 (6H, 2s, 2 OCH3), 6.79 (1H, dt, J = 6.8 and
1.0 Hz, CH), 6.91 (2H, d, J = 8.7 Hz, 2CH), 6.93 (2H, d, J = 8.8 Hz, 2CH), 7.14 (1H,
ddd, J = 6.7, 6.6 and 1.3 Hz, CH), 7.54 (1H, d, J = 9.0 Hz, CH), 7.74 (2H, d,
J = 8.7 Hz, 2CH), 7.76 (2H, d, J = 8.8 Hz, 2CH), 8.32 (1H, d, J = 6.8 Hz, CH), 8.67
(1H, s, CH). 13C NMR (75.5 MHz, CDCl3): d 55.24 and 55.42 (OCH3), 112.22,
114.19, 114.20, 116.90, 123.09 and 124.83 (CH), 126.91, 128.79 and 129.28 (C),
129.48 and 130.04 (CH), 132.57 and 142.32 (C), 157.27 (CH), 159.27 and 162.31
(C).
References and notes
1. Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim,
2005.
2. Howard, A. S. In Comprehensive Heterocyclic Chemistry II; Katritzky, AR. A. R.,
Rees, C. W., Scriven, E. V. F., Eds.; Pergamon Press: London, 1996; Vol. 8, pp
262–274; Chapter 10 and references cited therein.
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Tetrahedron Lett. 2007, 48, 3217–3220 and references cited therein.
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48, 7263–7265. and references cited therein.
5. Roubaud, C.; Vanelle, P.; Maldonado, J.; Crozet, M. P. Tetrahedron 1995, 51,
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39, 3635–3638.
9. Kiselyov, A. Tetrahedron Lett. 2005, 46, 4487–4490.
10. Bristow, N. W.; Charlton, P. T.; Peak, D. A.; Short, W. F. J. Chem. Soc. 1954, 616–
629.
13. Selected X-ray crystallographic data for compound 6d: C22H19N3O2, monoclinic,
space group = P21/n, a = 10.4920(16) Å, b = 8.7631(13) Å. c = 20.768(3) Å,
b = 91.269(2)°, V = 1908.96(5) Å3, T = 295(2) K, Z = 4, Dcalcd = 1.24 g cmÀ3
,
l
= 0.081 mmÀ1, 1986 observed reflections, final R1 = 0.054, wR2 = 0.124 and
for all data R1 = 0.107, wR2 = 0.124. CCDC 666888 contains the supplementary
crystallographic data for the structure reported in this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
11. Katritzky, A. R.; Xu, Y. J.; Tu, H. B. J. Org. Chem. 2003, 68, 4935–4937.