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D. Suresh et al. / Tetrahedron Letters 54 (2013) 6479–6484
intramolecular cyclization of 5a to 6a catalyzed by Al3+-K10 clay
in toluene, benzene, dimethylformamide, and hexamethylphos-
phoramide showed lower yields of 6a compared to xylene. It was
also observed that catalyst loading, solvent quantity, and reaction
time influenced the percentage yield of 6a (Table 1, entries 13–17).
These interesting results prompted us to expand the scope of
Al3+-K10 clay with various substituted derivatives of 5a. The
observed results are given in Table 2. The synthetic utility of
Al3+-K10 clay catalyzed the intramolecular cyclization was
explored with various aromatic, heteroaromatic, and aliphatic
amides. As shown in Table 2, all the substituted amides were re-
acted smoothly toward completion of the cyclization to give the
corresponding 2-substituted imidazo[4,5-b]pyridine derivatives
in excellent yields. It was observed that the nature of the substitu-
ent directly linked with N-(which formed amide from acid) moiety
influences the yield of the product.
A series of imidazopyridines with the various functional groups
and the heterocyclic rings were synthesized from their correspond-
ing amides using Al3+-K10 clay as a catalyst. The yield of the prod-
uct was influenced by R1 and R2 in the amide. Notably, the
substituents with respect to R2 range from alkyl, aryl, heteroaro-
matic, cyclopropyl, pyridinyl etc., and they afford high yields of
imidazopyridine derivatives. In any case, the present protocol of-
fers a wide range of imidazopyridine heterocycles reported for
the first time using a solid acid catalyst under mild reaction condi-
tions. Although it is believed that the reaction is catalyzed by the
presence of Lewis acid sites (Al3+) in the catalyst, further analytical
evidences are still required to disclose the reaction mechanism.
Recovery and reuse of the catalyst are among the main advan-
tages of heterogeneous catalysts. In this context, the reusability
of the catalyst was checked in the cyclization of 5a to 6a. The reac-
tion was performed under the optimized conditions and catalyst
was recovered by filtration after completion of the reaction,
washed thrice with acetonitrile, dried under vacuum, and heated
at 100 °C for activation. The recovered and activated catalyst was
reused for the next run and it was observed that the catalyst
showed a slightly lower yield than the fresh catalyst after five runs
(Table 3). Although the catalyst maintained its activity over five
runs, further investigations with larger number of reuses or
monitoring the rate of the reaction for each cycle would need to
be performed, to achieve reliable data on catalyst reusability or
long term stability. Further, to support the claim of catalyst stabil-
ity under the present experimental conditions, hot filtration test
was performed. After achieving 20% of yield, the catalyst was
filtered in hot condition and the remaining solution stirred contin-
uously for 24 h. It was noticed that the yield of the product margin-
NO2
NH
NO2
NH
NO2
NH
N
O
N
O
N
O
OMe
COOMe
CN
3a
3c
3b
Figure 1. Structure of nitro intermediates.
The imidazopyridines were synthesized from the corresponding
amides (5) as starting materials. Compound (5) was synthesized
from commercially available raw materials, nitro intermediates
3(a–c) (Fig. 1) as described in Scheme 1. Nucleophilic attack of
ethylamine on 2,6-dichloro-3-nitropyridine (1) under vigorous
stirring at ambient temperature resulted in the formation of 2.
Then, chlorine at 6th carbon was displaced by the corresponding
phenolic groups using cesium carbonate in dimethylformamide
at 80 °C for 4–6 h to obtain 3. The reduction of nitro groups was
performed by treating with iron powder/ammonium chloride in
methanol and water mixture as a solvent to obtain the correspond-
ing amine 4. The subsequent reaction of 4 with the corresponding
acid chloride in the presence of triethylamine in dichloromethane
as a solvent gave 5.
The amide, 5a was selected as a model substrate to optimize the
reaction conditions35 using different catalysts to give imidazo[4,5-
b]pyridine, 6a and the observed results are summarized in Table 1.
Control experiment in the absence of Al3+ K10 clay (Table 1, entry
1) showed the absence of 6a suggesting the need for catalyst to
promote the intramolecular cyclization of 5a to 6a. On the other
hand, Lewis acid, AlCl3, and Lewis base, Al2O3 (Table 1, entries 2
and 3) as catalysts showed 45 and 21% 6a respectively after 24 h
in xylene. Cu2+-K10 and Zn2+-K10 resulted in 56% and 58% 6a in xy-
lene at 24 h, respectively (Table 1, entries 4 and 5), indicating the
active participation of Lewis acid sites in intramolecular cycliza-
tion. Further, Ti4+-K10 clay showed a slightly higher yield (69%)
of 6a in xylene after 24 h. The moderate activity offered by AlCl3
forced us to use Al3+-K10 clay as a catalyst for the intramolecular
cyclization (Table 1, entry 6). To our surprise, this catalyst resulted
in the highest yield 93% of 6a in xylene at 140 °C in 24 h with
100 mg of catalyst as the optimal catalyst loading. However, the
R1
NO2
NH
R1
OH
NO2
Cl
NO2
NH
C2H5NH2
a
N
O
Cl
N
1
Cl
N
2
Cs2CO3
b
3
Fe / NH Cl
c
4
R1
NHCOR2
NH
R1
NH2
NH
2
2
R COOH / R COCl
N
O
N
O
d
4
5
Scheme 1. Synthetic route (a) ethylamine in THF (or) aqueous solution, dichloromethane, room temperature; (b) hydroxy compound, Cs2CO3, DMF, 80 °C; (c) iron powder,
NH4Cl, methanol, water, and at 55 °C; (d) acid (or) acid chloride, triethylamine, dichloromethane, 30 °C.
Suresh, Dhanusu
