Microwave-assisted, one-pot reaction of pyridines, -bromoketones and ammonium acetate: An efficient and simple synthesis of Imidazo[1,2- a ]-pyridines

Article abstract of DOI:10.1055/s-0029-1219962

A novel and efficient synthesis of imidazo[1,2-a]pyridines is described. N-Phenacylpyridinium bromides, which were prepared in situ from the addition of pyridines to -bromoketones, undergo nucleophilic addition of ammonium acetate under microwave irradiation and solvent-free conditions to afford the corresponding imidazo[1,2-a]pyridines in excellent yields.

Full text of DOI:10.1055/s-0029-1219962

1606
LETTER
Microwave-Assisted, One-Pot Reaction of Pyridines, a-Bromoketones and
Ammonium Acetate: An Efficient and Simple Synthesis of Imidazo[1,2-a]-
pyridines
S
ynthesisof Imidazo[1
e
,2-
a
]pyridi
h
nes di Adib,*a Ali Mohamadi,a Ehsan Sheikhi,a Samira Ansari,a Hamid Reza Bijanzadeh*b
a
b
Received 23 November 2009
N
Abstract: A novel and efficient synthesis of imidazo[1,2-a]py-
ridines is described. N-Phenacylpyridinium bromides, which were
prepared in situ from the addition of pyridines to a-bromoketones,
undergo nucleophilic addition of ammonium acetate under micro-
wave irradiation and solvent-free conditions to afford the corre-
sponding imidazo[1,2-a]pyridines in excellent yields.
Ar
N
R1
R2
Alpidem R1 = Cl, R2 = CH2CON(CH2CH2Me)2, Ar = 4-ClC6H4.
Zolpidem R1 = Me, R2 = CH2CONMe2; Ar = 4-MeC6H4
Zolmidine R1 = R2 = H; Ar = 4-MeSO2C6H4
Key words: imidazo[1,2-a]pyridines, pyridines, a-bromoketones,
ammonium acetate, microwave irradiation, solvent-free synthesis,
cyclizations, heterocycles
Figure 1 Examples of pharmacologically important imidazo[1,2-
a]pyridines
epoxides, a-epoxyketones or a-epoxyaldehydes, 1,2-di-
ols, a-dicarbonyl compounds, and 1,2-dihaloethanes. Al-
ternative approaches involve construction of the six-
membered ring – although no single procedure of wide
applicability has emerged and the sequences reported are
largely divided into annulation of imidazoles or reaction
of cyclic ketene aminals – and formation of both
rings.1,3,4,9–11
Imidazo[1,2-a]pyridines – fused bicyclic 5,6-heterocycles
with one ring junction nitrogen atom and one extra nitro-
gen atom in the five-membered ring – are of interest be-
cause of the occurrence of their saturated and partially
saturated derivatives in biologically active compounds.1
Derivatives containing the imidazo[1,2-a]pyridine ring
system have been shown to possess a broad range of use-
ful pharmacological activities, including: antibacterial,
antifungal, anthelmintic, antiviral, antiprotozoal, anti-
inflammatory, anticonvulsant, anxiolytic (e.g., Alpidem,
Figure 1), hypnotic (e.g., Zolpidem, Figure 1), gas-
trointestinal, antiulcer (e.g., Zolmidine, Figure 1), and im-
munomodulatory activities.1–4 Furthermore, some
examples have been claimed to be cardiotonics, blood
platelet aggregation inhibitors, acetylcholinesterase inhib-
itors,1 cyclin-dependent kinase inhibitors,5 gastric H+/K+-
ATPase inhibitors,6 potential agents for imaging b-amy-
loids in Alzheimer’s disease,7 antagonists and agonists of
the bradykinin B-2 receptor,8 angiotensin II antagonists,1
5-HT3 antagonists,9 and potential inhibitors of UV-in-
duced keratinocyte apoptosis.10
In 2001, Hu et al. reported that substituted phenacyl bro-
mides react with isoquinoline to form the corresponding
quaternary salts which, when heated in ammonium acetate
and acetic acid in the presence of CuO, undergo cycliza-
tion to give 2-arylimidazo[2,1-a]isoquinolines.12 Another
imidazo[1,2-a]pyridine synthesis has also been reported,
wherein reaction between the O-methyl oxime of phena-
cyl bromide and pyridines led to the pyridinium salts
which, when heated in methanol in the presence of Et3N,
underwent cyclization followed by elimination of MeOH
to produce imidazo[1,2-a]pyridines.13
The application of microwave irradiation in organic syn-
thesis for conducting reactions at highly accelerated rates
is an emerging technique.14 Considering the chemical and
pharmacological importance of the imidazo[1,2-a]py-
ridines, we have focused on introducing new facile and ef-
ficient syntheses of these heterocycles. As part of our
continuing efforts on the development of new routes for
the preparation of biologically active heterocyclic com-
pounds,15 we have recently reported several imidazo[1,2-
a]pyridine syntheses, including the reaction between 2-
aminopyridines, benzaldehydes and imidazoline-2,4,5-
trione under solvent-free conditions,16 catalyst-free reac-
tion between 2-aminopyridines, aldehydes and isocya-
nides in water,17 and condensation of 2-aminopyridines
and diaroylacetylenes.18
So far, several synthetic methods have been reported for
the preparation of imidazo[1,2-a]pyridine ring systems: in
the most common synthetic methods the five-membered
ring is constructed by condensation of 2-aminopyridines
with a-haloketones or a-haloaldehydes, but this system
has also been successful synthesized using other 1,2-di-
electrophilic compounds such as a-ketohydroximoyl or a-
ketohydrazidoyl chlorides, a-haloacyl cyanides, dicyano
SYNLETT 2010, No. 11, pp 1606–1608
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Advanced online publication: 04.06.2010
DOI: 10.1055/s-0029-1219962; Art ID: D34009ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Imidazo[1,2-a]pyridines
1607
Herein, we wish to report another new and simple synthe- acylpyridinium bromide 4. Then the pyridinium ion is
sis of imidazo[1,2-a]pyridines. Thus, pyridines 1, a-bro- presumably attacked by ammonium acetate leading to ad-
moketones 2, and ammonium acetate undergo a 1:1:1 duct 5, which may be cyclized to the dihydroimidazo[1,2-
addition reaction to produce the corresponding imida- a]pyridine intermediate 6. This intermediate could finally
zo[1,2-a]pyridines 3a–j in 88–98% yields (Table 1). The undergo aerial oxidation under the reaction conditions to
reactions were carried out by first reacting pyridine 1 with afford the imidazo[1,2-a]pyridine 3.
the a-bromoketone 2 in anhydrous CH2Cl2 at ambient
R1
temperature for 30 minutes. After conversion into and
precipitation of the corresponding N-phenacylpyridinium
bromide, the organic solvent was removed by suction and
an excess of ammonium acetate was added to the residue
and the mixture was irradiated in a microwave oven19 at
R1
O
NH4OAc
Br
N+
+
Br–
O
Ar
N
R2
Ar
R2
1
180 °C for 4 minutes under solvent-free conditions. H
1
2
NMR analysis of the reaction mixtures clearly indicated
the formation of the corresponding imidazo[1,2-a]py-
ridines 3 in excellent yields.20
All products were characterized by 1H and 13C NMR spec-
troscopy and by comparison of their spectral data and
melting point values with those of the authentic samples
reported in the literature.
4
R1
R1
N
R1
NH2
Ar
N
N
N
N
R2
R2
R2
Ar
Ar
O
5
6
3
Table 1 Synthesis of Imidazo[1,2-a]pyridines 3a–j
Scheme 1
R1
R1
In summary, we have reported a convenient, simple and
efficient approach to the three-component condensation
reaction of pyridines, a-bromoketones and ammonium ac-
etate resulting in the formation of imidazo[1,2-a]-
pyridines, which are of potential synthetic and pharmaco-
logical interest. Solvent-free conditions, short reaction
times, excellent yields of the products and use of simple
starting materials are the key advantages of this method.
O
1. CH2Cl2, r.t., 30 min
Br
+
Ar
N
2. NH4OAc, solvent-free,
MW, 180 °C, 4 min
N
N
R2
R2
1
2
Ar
3
3
a
b
c
d
e
f
R1 Ar
R2 Mp (°C)
Lit mp (°C) Yield (%)a
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
132–133 13421
98
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
133–134 13421
137–138 13722
207
20821
90
95
97
Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
214–216 215–21621 96
163–165 164–16523 98
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g
h
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Me Ph
174
241–242 240–24222 96
216
216–21724 92
88
172–17424 94
Me 4-ClC6H4
Me 4-BrC6H4
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Synlett 2010, No. 11, 1606–1608 © Thieme Stuttgart · New York