International Journal of Organic Chemistry, 2011, 1, 15-19
doi:10.4236/ijoc.2011.12003 Published Online June 2011 (
Copyright © 2011 SciRes. IJOC
One-Pot Three-Component Synthesis of
Abbas Rahmati*, Zahra Khalesi
Department of Chemistry, University of Isfahan, Isfahan, Iran
Received March 3, 2011; revised April 8, 2 011; accepted April 16, 2011
A one-pot three component condensation synthesis of imidazo[1,5-a]pyridines using of various aromatic al-
dehydes and dipyridil ketone with ammonium acetate in the presence of Lithium chloride as catalyst in good
yields under microwave irradiation has been described.
Keywords: Lithium Chloride, Imidazo[1,5-a]pyridine, Microwave Irradiation
1. Introduction
Imidazo[1,5-a]pyridines and their derivatives with a
nodal nitrogen atom, an important class of ring fused
heterocyclic compounds exhibit a wide spectrum of bio-
logical activities [1]. Therefore development of new and
efficient synthetic method for the synthesis of these
compounds is of importance in both synthetic organic
chemistry and medicinal chemistry [2 ]. In addition, oth er
applications of these compound in organic light-emitting
diodes (OLEDs) [3] and organic thin-layer field effect
transistors (FETs) [4] have been reported.
The classical method for synthesis of imidazo[1,5-a]
pyridines mainly involves the use of 2-pyr i dyla l kylamin e s
with acylchlorides [5-15] and/or organic acids deriva-
tives [16,17] in two step addition and cyclization. Be-
sides these reactions, pereparation of imidazo[1,5-a]
pyridines from 2-pyridylalkylamines with α,β-unsuturated
compounds [18], and/or aldehydes [19] have been re-
ported. Other approaches include the use of imine de-
rivatives [20], 2-cyanopyridine [21] and benzotriazoles
[22]. Recently, the generation these compounds by a
three component condensation reaction using pyridilke-
tons, aldehyds and ammonium acetate were reported
[23-25]. Most syntheses require harsh reaction cond itions
because of the use of highly sensitive reagents. In addi-
tion, the syntheses of these heterocycles have been usu-
ally carried out in polar organic solvents such as metha-
nol, ethanol, DMF and DMSO leading to complex isola-
tion and recovery procedures. These processes also gen-
erate waste containing catalyst and solvent, which have
to be recovered, treated and disposed of.
During the course of our studies towards the develop-
ment of new routes to the synthesis of nitrogen contain-
ing heterocyclic compounds [26,27], we wish to intro-
duce an efficient procedure for the synthesis of imi-
dazo[1,5-a]pyridine via one-pot three component con-
densation of dipyridyl ketone 1 with aldehyde 2 and
NH4OAc in the presence of lithium chloride as an inex-
pensive mild Lewis acid using microwave irradiation
(Scheme 1).
2. Results and Discussion
In synthesis of imidazo[1,5-a]pyridines, p-methoxyben-
zaldehyde, dipyridyl ketone and ammonium acetate were
selected as model reactants during the optimization con-
ditions. Initially in order to, in this condensation reaction
different solvents such as DMF, EtOH and HOAc in the
presence and absen ce of LiCl salt were utili zed ( Ta bl e 1).
Studies indicated that among the solvents, HOAc is the
best solvent at 3 min (Table 1). However, the results of
various times of irradiation show that in all solvents the
best yield was obtained in during 3 min by medium
power at 300 W. Then, the reactions were performed in
the presence of different salts such as Li2SO4, Li2CO3,
LiHSO4, Na2SO4, NaBr and NaCl under micr owave irra-
diation in HOAc. Among the various salts, LiCl was
identified to be the best salts for this three-component
reaction in HOAc under the microwave irradiation as
illustrated in Tab le 1 (Entry 10). In all cases molar ratio
of reactant was used based on previous report [21]. After
good consideration we found that these ratios are the
Y=H , CH
3, OCH3, Cl, OH, NO2
LiCl/HOA c
Scheme 1
Table 1. One-pot synthesis of imidazo[1,5-a]pyridines in the presence of various salts in different solvents under
microwave irradiationa.
Experimental number Solvent and Catalystb Yield (%) (Time (m in : sec)) MWc
1 DMF 21(3:00)
2 EtOH 46(3:00)
3 HOAc 53(2:00)
4 HOAc 72(3:00)
5 HOAc 72(4:00)
6 DMF/LiCl 39(3:00)
7 EtOH/LiCl 65(3:00)
8 HOAc/LiCl 81(2:00)
9 HOAc/LiCl 93(3:00)
10 HOAc/LiCl 93(4:00)
11 HOAc/Li2SO4 77(3:00)
12 HOAc/Li2CO3 70(3:00)
13 HOAc/LiHSO4 73(3:00)
14 HOAc/NaCl 69(3:00)
15 HOAc/NaBr 69(3:00)
16 HOAc/Na2SO4 68(3:00)
17 LiCl 61(3:00)
18 - 22(5:00)
aDipyridil ketone (1 mmol), para-methoxybenzaldehyde (2 mmol) and ammonium acetate (6 mmol); bCatalyst (0.1 g, 2 mmol), Solvent (0.5
mL); c360 W.
It is important to note in the presence of only LiCl or
HOAc the reaction yield is considerably decreased (Ta-
ble 1, Entries 4 and 17).
The optimum amount of lithium chloride was 2
equivalents and lithium chloride of more than 2 equiva-
lents was identified to give the similar results (Table 2).
To explore the scope and limitations of this reaction,
we extended the reaction of dipyridyl ketone with vari-
ous aromatic aldehydes carrying either electron-releasing
or electron-withdrawing subs tituen ts in the meta and para
positions. As indicated in Table 3, the reaction pro-
ceeded very efficiently in all cases, however with
4-nitrobenzaldehyde no reaction took place. In addition,
we have repeated the reaction with dipyridyl ketone in-
stead of phenylpyridyl ketone and the desired product
has been efficiently produced (Table 3).
The conceivable mechanism of the reaction is as fol-
lowing: lithium cation is coordinated with phenylpyridyl
ketone to make carbonyl group as an activated group to
nucleophilic attack by the in situ generated imine. The
subsequent intramolecular interaction leads to the cycli-
zation and finally to the formation of the desirable imi-
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Table 2. Optimization of amounts of LiCl in the one-pot synthesis of imidazo[1,5-a]pyridines in
HOAc (0.5 mL) under microwave irradiationa.
Experimental number Catalyst (mmol) LiCl Time (min) Yield (%)
1 - 3 22
2 0.5 mmol 3 39
3 1 mmol 3 65
4 2 mmol 3 93
5 2 mmol 2 62
5 2 mmol 1 34
6 4 mmol 3 93
aPyridilphenyl ketone (1 mmol), para-methylbenzaldehyde (2 mmol) and ammonium acetate (6 mmol).
Table 3. One-pot synthesis of imidazo[1,5-a]pyridines in the presence of lithium chloride as a Lewis acid under solvent-free
conditions using microwave irradiation.a
Entry Aldehyde Product Yield (%) M.P. (˚C)
Found Reportedb
4a 94 119 - 120 120 - 121
4b 88 195 - 196 195 - 196
4c 82 180 - 181 180 - 182
4d 83 94 - 96 92 - 93
4e 81 91 - 92 96 - 97
4f 89 129 - 131 132 - 133
6 71 127 - 130 131 - 132
a Using microwave irradiation HOAc/LiCl at 3 min; bref [25] .
dazo[1,5-a]pyridine. (Scheme 2)
In conclusion, we have introduced an efficient and en-
vironmentally friendly approach for the synthesis of bio-
logically active imidazo[1,5-a]pyridines via condensa-
tion of dipyridyl ketone with various aromatic aldehydes
and ammonium acetate using lithium chloride as a neu-
tral Lewis acid catalyst. Corrosiveness safety, less waste
and ease of separation are all among desirable factors for
the chemical industry which we have considered in our
green chemistry approach.
3. Experimental
Melting points were measured with an Electrothermal
9100 apparatus and are uncorrected. IR spectra were re-
corded with a Shimadzu IR-470 spectrometer. 1H and
13C NMR spectra were recorded with a BRUKER
DRX-300 AVANCE spectrometer at 300.13 and 75.47
Copyright © 2011 SciRes. IJOC
Scheme 2
MHz, respectively. NMR spectra were obtained on solu-
tions in DMSO-d6. All the products are known com-
pounds, which were characterized by IR and 1H NMR
spectral data and their mp’s compared with literature
reports. The microwave apparatus that used for these
experiments is APEX, EU-CHEMICAL apparatus. This
apparatus is a scientific microwave that designed for
chemical experiments.
General procedure for the preparation of imi-
A mixture of pyridyl ketone (1 mmol), aldehyde (2
mmol), ammonium acetate (0.462 g, 6 mmol), lithium
chloride (0.1 g, 2 mmol) and acetic acid (0.5 mL) was
irradiated in a microwave oven for 3 min. The solid ma-
terials residue was then washed with water and to give
the crude product. For further purification it was crystal-
lized from ethanol:acetone mixture or by column chro-
matography t o aff or d p ure p ro duct s.
4. Acknowledgements
Author gratefully acknowledges the financial support
from the Research Council of the University of Isfahan.
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