substituents around the periphery of the heterocyclic ring
system. Our approach could comprise the relay processes
of the following domino sequences (Scheme 1): (1) two-
component Knoevenagel reaction, (2) two-component
Michael-type reaction followed by elimination, (3) two-
component ring closure, and (4) two-component cycliza-
tionꢀaromatization process.
Scheme 2
brings the active methylene compound to the lone pair of
electrons of amine nitrogen of the catalyst through hydro-
gen-bonding.9 Thus, realizing environmental concerns,10
as well as vast utility and scope of reactions10a,11 carried
out in water, we established water to be the preferred
solvent.
Scheme 1
To find the optimized reaction conditions, we initiated
a catalyst screen employing 40-chloro acetophenone (1b)
(2 mmol), malononitrile (2) (2 mmol), and morpholine (3c)
(1 mmol) in the presence of various base catalysts under
refluxing conditions, and the results are summarized in
Table 1. Screening of the reaction conditions established
that the nature of the catalyst had significant effect on the
yield of naphthyridine (4bc). The yield decreased substan-
tially with stronger base catalysts, since the carbonyl
compounds undergo extensive polymerization reaction
(entries 1 and 2, Table 1) in the presence of a strong base
and at high temperature conditions. Interestingly, in ab-
sence of any base catalyst, this pseudo-five-component
coupling cyclization reaction proceeded smoothly to
afford the desired 5-amino-2,4-bis(4-chlorophenyl)-2-
methyl-7-morpholin-4-yl-1,2-dihydro[1,6]naphthyridine-
8-carbonitrile (4bc) in excellent yield after 3 h of heating at
100 °C in water as solvent (entry 5, Table 1). Therefore, the
amines itself are acting as a bronsted base catalyst in the
formation of intermediate 5ꢀ7 and also as a nucleophile in
the last step. This is why the weaker bases than morpholine
have no effect on reaction yield (entries 10 and 11, Table 1).
Hence, we vary the amount of morpholine to monitor any
effect on the yield of the reaction. With a higher amount of
morpholine no increase in the yield of 4bc is observed
(entries 5ꢀ8, Table 1). However, diminishing the amount
of morpholine resulted in incomplete conversion (entry 9,
Table 1).
With these optimized conditions in hand, this multi-
component reaction can be readily diversified through a
combination of a range of methyl ketones, amines, and
malononitrile. Among the amines, cyclic secondaryamines
afforded excellent yields (Scheme 3). Remarkably, low
nucleophilic diallylamine and low boiling dimethylamine
also gave products 4bf, 4ff, and 4ae, 4be, 4fe in excellent
yields (88% for 4bf, 90% for 4ff, and 90% for all 4ae, 4be,
and 4fe). Similarly, aliphatic primary amines were also
successfully employed to give naphthyridines in excellent
yields (Scheme 3, 4bg). However, the yield was low with
benzylamine (Scheme 3, entry 4fh). It should be noted that
It is proposed that the aromatic ketones undergo a
Knoevenagel condensation reaction first with malono-
nitrile which is a very characteristic reaction of carbonyl
compounds in the presence of a base.8 This is evident
from NMR spectrum of the major product [(5), (R =
40ꢀCl-C6H4-)] isolated after 30 min. This intermediate
(5) undergoes Michael-type reaction with another mo-
lecule of 5, and subsequent elimination of the malono-
nitrile leads to intermediate 6. Again the attack of
malononitrile on intermediate 6 triggers the ring closure
to yield intermediate (7). The structure of 7 is confirmed
from NMR spectrum of the major product (R = 40ꢀCl-
C6H4-) isolated by quenching the reaction after 2 h.
Finally the second ring is produced by attack of amino
group on ꢀCN functionality in intermediate 7. The
driving force may be the aromatization in the target
compound.
The detailed mechanism of the formation of 4 (final
compound) from 6 is shown in Scheme 2.
Here, despite Knoevenagel condensation being a net
dehydration of the water molecule, the reaction is favored
in aqueous medium. A plausible explanation is that water
(8) (a) Guan-Wu Wang, G. W.; Cheng, B. ARKIVOC 2004, ix, 4. (b)
Balalaie, S.; Nemati, N. Synth. Commun. 2000, 30, 869. (c) Barnes,
D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.; Mei, J.;
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Tedrowy, J. S.; Toma, J. D. R. Tetrahedron 2006, 62, 11311. (d) Gora,
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M.; Kozik, B.; Jamrozy, K.; Łuczynski, M. K.; Brzuzanc, P.; Woznyc,
M. Green Chem. 2009, 11, 863. (e) Rodriguez, I.; Iborra, S.; Rey, F.;
Corma, A. Appl. Catal., A 2000, 194, 241.
(9) (a) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999,
1033. (b) Mukhopadhyay, C.; Ray, S. Catal. Commun. 2011, 12, 1496.
(10) (a) Hailes, H. C. Org. Process Res. Dev. 2007, 11, 114. (b)
Andrade, C. K. Z.; Alves, L. M. Curr. Org. Chem. 2005, 9, 195. (c)
Shi, D. Q.; Chen, J.; Zhuang, Q. Y.; Wang, X. S.; Hu, H. W. Chin. Chem.
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Org. Lett., Vol. 13, No. 17, 2011
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