Microwave-induced bismuth nitrate-catalyzed synthesis of dihydropyrimidones via Biginelli condensation under solventless conditions

Article abstract of DOI:10.1016/j.tetlet.2007.08.007

Microwave-induced bismuth nitrate-catalyzed efficient and extremely rapid synthesis of 4-aryl-3,4-dihydropyrimidones via Biginelli condensation reaction has been developed in excellent yield.

Full text of DOI:10.1016/j.tetlet.2007.08.007

Tetrahedron Letters 48 (2007) 7392–7394
Microwave-induced bismuth nitrate-catalyzed synthesis of
dihydropyrimidones via Biginelli condensation
under solventless conditions
a,
a
b
b
*
Bimal K. Banik, Anupama T. Reddy, Arup Datta and Chhanda Mukhopadhyay
a
The University of Texas Pan American, Department of Chemistry, 1201 West University Drive, Edinburg, TX 78541, USA
b
Department of Chemistry, University of Calcutta, India
Received 18 June 2007; revised 26 July 2007; accepted 1 August 2007
Available online 6 August 2007
Abstract—Microwave-induced bismuth nitrate-catalyzed efficient and extremely rapid synthesis of 4-aryl-3,4-dihydropyrimidones
via Biginelli condensation reaction has been developed in excellent yield.
Ó 2007 Published by Elsevier Ltd.
8
Dihydropyrimidones have attracted immense interest as
tions. Bismuth nitrate is readily available at a very
low cost. It is a stable and non-toxic crystalline solid.
Our research has established that this reagent can act
as an effective Lewis acid, and it can be used successfully
in the presence of commercially available solvents with-
out any drying or treatment. Several experimental con-
ditions toward the preparation of dihydropyrimidones
have been attempted (Table 1). The reactants (aldehyde
1, urea 2, and dicarbonyl compound 3) and bismuth ni-
trate are mixed in the presence of an organic solvent
(THF or ethanol) and heated under reflux for approxi-
mately 6 h. After the addition of crushed ice the solid
product was filtered to isolate product 4 in excellent
yield. A number of dihydropyrimidones were prepared
following this method in good yield. It is remarkable
to note that this reaction produces product even with
0.1 mol % of bismuth nitrate (Table 1, entries 21 and
22). Microwave-induced reactions using CEM Discover
Lab-Mate and domestic microwave have also been per-
calcium channel blockers, antihypertensive agents, alpha-
1
1
a-antagonists, and neuropeptide Y (NPY) antag-
2
,3
onists. The most important examples are batzelladine
alkaloids, which are potent HIV group-120-CD4 inhib-
itors. As a result of their medicinal properties, synthesis
4
of the dihydropyrimidone nucleus has received much
attention. The initial synthesis of dihydropyrimidone
following Biginelli condensation has proved to be ineffi-
5
cient with 20–50% yield. Recently, methods have been
discovered to synthesize these types of heterocycles,
however, they involve multiple sequences and hazardous
6
conditions. A few attractive methods are known, but
most of them employ anhydrous reaction conditions
and Lewis acids (BF ÆEt O, LiClO , InCl , ZrCl , NiCl Æ
3
2
4
3
4
2
7
6
H O, BiCl , Bi(OTf) , and FeCl ). Many of these
2 3 3 3
methods are also time consuming. Therefore, develop-
ment of an efficient, rapid, and catalytic method is
necessary for the synthesis of this type of multifunction-
alized rings. We report here a remarkably fast and sim-
ple microwave-induced bismuth nitrate-catalyzed
synthesis of dihydropyrimidones through a three-com-
ponent reaction under solventless conditions.
9
formed under solventless conditions. To our surprise,
product 4 has been isolated in excellent yield within 4–
5 min using 2 mol % of bismuth nitrate with four other
substrates (Table 1, entries 14–18). However, the reac-
tion did not proceed through stirring in a mortar and
pestle (Table 1, entry 12), at high temperature in water
(Table 1, entry 13), or room temperature in acetonitrile
In a series of publications, we have demonstrated the
versatility of bismuth nitrate-catalyzed organic reac-
(
Table 1, entry 19). In contrast to other available meth-
ods, this present method for the synthesis of dihydro-
pyrimidione is extremely rapid and highly efficient.
This is a novel, powerful, and economical one-pot pro-
cedure for the preparation of dihydropyrimidones.
Keywords: Biginelli condensation; Microwave; 4-Aryl-3,4-dihydropyr-
imidones; Bismuth nitrate; Solventless reaction.
*
Corresponding author. Tel.: +1 956 380 8741; fax: +1 956 384
006; e-mail: banik@panam.edu
5
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.08.007

B. K. Banik et al. / Tetrahedron Letters 48 (2007) 7392–7394
Table 1. Synthesis of 4-aryl-3,4-dihydropyrimidones
7393
Entry
1
2
3
Catalyst
Method
Percent yield
a
a
a
a
a
a
a
a
a
a
b
c
d
e
e
e
e
f
a
a
a
a
a
a
a
a
a
a
b
c
d
e
e
e
e
f
a
a
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1a
1a
1b
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3a
3a
3a
3a
3b
3a
3b
3a
3a
3a
3a
3a
Bi(NO
3
)
3
Reflux
85
44
87
43
80
84
83
85
81
82
96
13
23
98
97
98
97
88
18
95
91
75
a
a
BiCl
Bi(OTf)
3
Reflux
a
a
3
Reflux
a
a
BiCl
Bi(NO
Bi(OTf)
3
Reflux
a
a
3
)
3
Reflux
a
a
3
Reflux
a
a
Bi(NO
3
)
3
Reflux
a
a
Bi(OTf)
3
Reflux
a
a
Bi(NO
3
)
3
Reflux
a
a
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
Bi(OTf)
3
Reflux
b
c
d
e
e
e
e
f
b
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
Bi(NO
3
3
3
3
3
3
3
3
3
3
3
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
Reflux
c
Mortar and pestle
d
Reflux
e
MWI
e
MWI
e
MWI
e
MWI
f
MWI
g
h
i
g
h
i
g
h
i
g
RT
h
Reflux
i
Reflux
j
j
j
j
Steam bath
The reactions were performed using 1:1.1:1.1 ratios (aldehyde, urea, keto ester, respectively).
a
Substrates and 10 mol % of catalyst were refluxed in 2 mL of anhydrous THF for 6 h.
Substrates and 10 mol % of catalyst were refluxed in 2 mL of anhydrous ethanol for 5 h.
Substrates and 10 mol % of catalyst were mixed in a mortar and pestle for 2 h.
Substrates and 10 mol % of catalyst were refluxed in 2 mL of ice water for 6 h.
b
c
d
e
Substrates and 2 mol % of catalyst were microwaved in the CEM Discover Lab-Mate microwave for 4.5 min.
Substrates and 2 mol % of catalyst were microwaved in a domestic microwave for 5 min.
Substrates and 10 mol % of catalyst were stirred at room temperature in 2 mL of acetonitrile for 1 h.
Substrates and 1 mol % of catalyst were refluxed in 2 mL of anhydrous ethanol for 7 h.
Reaction was carried out on 10 mmol scale with 0.1 mol % of catalyst and 20 mL of anhydrous ethanol under reflux for 7 h.
Reaction was carried out on 10 mmol scale with 0.1 mol % of catalyst under reflux in a steam bath for 2 h.
f
g
h
i
j
Different types of bismuth catalysts have been investi-
times less catalyst with respect to the substrate) rapid
(4–5 min) process performed in the absence of solvent
Scheme 1.
gated. Although bismuth triflate produces product in
comparable yield in the presence of anhydrous ethanol
or tetrahydrofuran, it is an expensive and hygroscopic
solid. Bismuth trichloride produces the product in low
yield (Table 1, entries 2 and 4). However, Kaimal
et al. reported synthesis of dihydropyrimidones using
bismuth trichloride-catalyzed reaction in large excess
of acetonitrile for 5 h (eight times less catalyst with
The mechanism of the dihydropyrimidone formation
1
0,11
has been investigated by Folkers and Johnson.
It
has been hypothesized that the reaction proceeds
through an acylimine intermediate. Following this
explanation, it can be assumed that due to the presence
of vacant d-orbital, bismuth salts may stabilize the acyl-
imine intermediate and this intermediate complex may
then react effectively with a b-ketoester. A cyclization
and dehydration path may then follow to produce the
dihydropyrimidone system as described in earlier
1
0
respect to the substrate). The reaction was highly effi-
cient as indicated by the product yield. Our present bis-
muth nitrate-catalyzed reaction is much superior to the
existing methods because of several reasons. For exam-
ple, our microwave-induced reaction is a catalytic (100
R
O
NH2
O
O
Catalyst
Y
NH
OHC
R
+
O
+
Y
NH2
H C
3
N
O
3
3
a Y=OEt
b Y=OMe
H
1
1
a R=H
b R=OMe
2
4
Scheme 1.

7394
B. K. Banik et al. / Tetrahedron Letters 48 (2007) 7392–7394
papers.10,11 As a result of our long-term involvement in
the use of imine in organic synthesis, we became inter-
ested to identify the formation of the acylimine interme-
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem.
993, 36, 119.
. Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828.
4. Evans, P. A.; Manangan, T. Tetrahedron Lett. 2005, 46,
811, and references cited therein.
1
3
1
2
diate. Reaction of urea 2 with benzaldehyde 1a was
performed in the presence and absence of bismuth ni-
trate for 2–16 h under reflux temperature in benzene
using a Dean Stark. However, formation of acylimine
8
5
. (a) Biginelli, P. Gazz Chim. Ital. 1893, 360; For a review of
the Biginelli reaction see: (b) Kappe, C. O. Tetrahedron
1
993, 34, 6937.
1
0,11
could not be detected.
The staring materials (urea
6
. (a) Singh, K.; Arora, D.; Singh, S. Tetrahedron Lett. 2006,
47, 4205; (b) Kappe, C. O.; Stadler, A. Org. React. 2004,
63, 1.
and benzaldehyde) remain unreacted as evidenced from
1
H NMR study. On this basis, it seems that the mecha-
nism of Biginelli reaction is complex and further work is
necessary to determine the course of the reaction.
7. Ranu, B. C.; Hazra, A.; Jana, U. J. Org. Chem. 2000, 65,
270, and references cited therein.
6
8
. (a) Bose, A.; Sanjoto, P.; Aguilar, H.; Banik, B. K.
Tetrahedron Lett. 2007, 48, 3945; (b) Banik, B. K.; Garcia,
I.; Morales, F. Heterocycles 2007, 71, 919; (c) Banik, B.
K.; Cardona, M. Tetrahedron Lett. 2006, 47, 7385; (d)
Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. Tetra-
hedron Lett. 2005, 46, 2643; (e) Banik, B. K.; Samajdar, S.;
Banik, I. J. Org. Chem. 2004, 69, 213; (f) Banik, B. K.;
Alder, D.; Nguyen, P.; Srivastava, N. Heterocycles 2003,
61, 97, and references cited therein.
In conclusion we have demonstrated a new, mild, cost
effective, catalytic, and highly efficient procedure for
the synthesis of 4-aryl-3,4-dihydropyrimidones.13 In
contrast, most the available procedures require much
longer reaction times, expensive and/or corrosive acids
(
catalytic or stoichiometric), dry reaction conditions,
and dry solvents.
9
. For microwave-induced organic synthesis, see: Banik,
B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M. S.; Bose,
A. K. J. Org. Chem. 1999, 64, 5746.
Acknowledgment
1
0. Ramalinga, K.; Vijayalashmi, P.; Kaimal, T. N. B. Synlett
001, 863.
2
We gratefully acknowledge the financial support for this
research project from National Institutes of Health-
SCORE (2SO6GM008038-36).
11. Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55,
3784.
1
2. For the use of imine, see: (a) Banik, B. K.; Banik, I.;
Becker, F. F. Bioorg. Med. Chem. 2005, 13, 3611; (b)
Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003,
4
6, 12.
References and notes
13. A representative experimental procedure is described
below: Microwave synthesis of 4-aryl-3,4-dihydropyr-
imidones: Aromatic aldehyde (1 mmol), b-ketoester
(1.1 mmol), and urea (1.1 mmol) were mixed with bismuth
nitrate (10 mg) and placed in a microwave reaction vial.
The CEM Discover Lab-Mate microwave was programed
to the following settings: 300 W, 100 °C, and reaction time
of 4.5 min. After the reaction, ice water was added, which
resulted in the precipitation of the solid product. This was
crystallized (ether–hexane) to afford the pure product as
1
. (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashi-
matsu, M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.;
Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara,
T.; Funahashi, K.; Sato, F.; Morita, M.; Noguchi, T. J.
Med. Chem. 1989, 32, 2399; (b) Hu, E. H.; Sidler, D. R.;
Dolling, U. H. J. Org. Chem. 1998, 68, 3454; (c) Kappe, C.
O. Eur. J. Med. Chem. 2000, 35, 1043; (d) Rovnyak, G. C.;
Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254.
. Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.;
1
4
described earlier.
14. Mukhopadhyay, C.; Dutta, A.; Banik, B. K. Heterocycles
2007, 71, 81.
2