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Published on the web January 30, 2010
A Straightforward and Efficient Catalyst-free One-pot Synthesis of
N-Acyl-1,3-diaryl-2-azaphenalene Derivatives via Multicomponent Reactions
Naser Foroughifar,* Akbar Mobinikhaledi, and Hassan Moghanian
Department of Chemistry, Faculty of Sciences, Arak University, Arak 38156-879, Iran
(Received December 8, 2009; CL-091086; E-mail: N-froughifar@araku.ac.ir)
A novel, one-pot multicomponent reaction of two molecules
of aldehydes with 2,7-naphthalenediol and ammonium carbox-
ylates is described as an efficient and direct procedure for the
preparation of N-acyl-1,3-diaryl-2-azaphenalene derivatives in
EtOH under reflux conditions. N-Acyl-1,3-diaryl-2-azaphena-
lene derivatives were obtained in good to high yields without
any catalyst or activation.
HO
OH
HO
OH
+
EtOH
Ar
N
Ar
O
O
2
Ar
R
O
+
+
H
R
O-NH4
Figure 1. Synthesis of N-acyl-1,3-diaryl-2-azaphenalene de-
rivatives.
Multicomponent reactions (MCRs), with three or more
reactants combining in a one-pot procedure to give a single
product, are a promising and vital field of chemistry because the
synthesis of complicated molecules can be achieved in a very
fast, efficient, and time-saving manner without the isolation of
any intermediate.1-4 As a result, it requires minimum effort,
which minimizes the environmental loading and is acceptable
from a “Green Chemistry” point of view. MCRs are perfectly
suited for combinatorial library synthesis, and thus are finding
increased use in the discovery process for new drugs and
agrochemicals.5,6 Therefore, the design of novel MCRs has
attracted great attention from research groups working in
medicinal chemistry, drug discovery, and materials science.
The Biginelli,7 Ugi,8 Passerini,9 and Mannich10 reactions are
some example of MCRs. Nevertheless, development and
discovery of new MCRs is still in demand.
Table 1. Solvent effect on the reaction of benzaldehyde,
ammonium acetate, and 2,7-naphthalenediol
Entry
Solvent
Time/h
Yield/%a
1
2
3
4
5
6
Ethanol
6
15
15
15
15
15
91
<10
<10
20
Chloroform
Acetonitrile
Tetrahydrofuran
Dimethyl formamide
Toluene
0
0
aIsolated yields.
Encouraged by this result, the reaction of 2,7-naphthalenediol
with various aromatic aldehydes, bearing electron-withdrawing
groups (such as nitro and halide), electron-donating groups (such
as methyl and methoxy), and ammonium acetate was carried out
in ethanol under reflux conditions and afforded the correspond-
ing N-acyl-1,3-diaryl-2-azaphenalene derivatives in good to high
yields (Table 2).14 To extend the preparative utility and general-
ity of this multicomponent reaction, a variety of aromatic
aldehydes were treated with 2,7-naphthalenediol and ammonium
benzoate under the same experimental conditions, and the
corresponding products were obtained in good to high yields
without any difficulties (Table 2).14 On the other hand, aliphatic
aldehydes such as propionaldehyde or butyraldehyde and
heterocyclic aldehydes such as 2-pyridinecarbaldehyde or
furfural were also examined under the same conditions, but
the corresponding products were isolated only in trace amounts.
Next we turned our attention to study the mechanistic aspect
of this multicomponent reaction. Thus, the reaction of benz-
aldehyde with 2,7-naphthalenediol and ammonium acetate was
chosen as a model reaction for this study. First, we attempted to
explain the reaction with formation of acetamide from ammonia
and ethyl acetate that can be formed from ethanol and acetic
acid. Therefore, the reaction of 2,7-naphthalenediol with benz-
aldehyde and acetamide was carried out in ethanol or 1,2-
dichloroethane similar to 2-naphthol in the synthesis of
amidoalkyl naphthols,12 but the reaction was unsuccessful. On
the other hand, the reaction of 2,7-naphthalenediol, benzalde-
hyde, ammonia, and ethyl acetate was also examined and it was
In this context, recently we have reported11 the reaction of 2-
naphthol and aldehydes (2:1) in the presence of p-toluenesul-
fonic acid (p-TSA) to form dibenzoxanthenes. The reaction
proceeds through the in situ formation of ortho-quinone
methides (o-QMs) and 2-naphthol acts as a nucleophile. To
expand this type of tandem process that would permit the
condensation of the in situ generated o-QMs with nucleophiles
other than phenols, we utilized urea, amides, and semicarbazide
hydrochloride (to work as nucleophiles) to produce correspond-
ing amidoalkyl and semicarbazonoalkyl naphthols.12
In the present study, we report our results on a new type of
multicomponent reaction where five molecules react to form a
piperidine ring. Thus, aromatic aldehydes, ammonium carbox-
ylates, and 2,7-naphthalenediol are directly transformed into
N-acyl-1,3-diaryl-4,9-dihydroxy-2,3-dihydro-2-azaphenalenes
(Figure 1).
First, to evaluate the synthetic potential of the proposed
procedure and to optimize the reaction conditions, the reaction
of benzaldehyde, 2,7-naphthalenediol, and ammonium acetate
was examined in different solvents such as ethanol, chloroform,
acetonitrile, tetrahydrofuran, dimethyl formamide, and toluene
under reflux conditions. As shown in Table 1, ethanol gave the
most satisfactory results in comparison with other solvents.
A slight excess of the ammonium acetate was found to be
advantageous and hence the molar ratio of 2,7-naphthalenediol
to benzaldehyde and ammonium acetate was kept at 1:2:1.2.
Chem. Lett. 2010, 39, 180-181
© 2010 The Chemical Society of Japan
Foroughifar, Naser
