Copper dipyridine Dichloride as a mild and efficient catalyst for a one pot condensation Bigenelli reaction

Article abstract of DOI:10.1002/jhet.5570420543

The condensation reaction of aldehydes, β-ketoesters and urea/thiourea in presence of a catalytic amount of CuPy₂Cl₂ complex proceeded under very mild reaction conditions in high yield (80-90%).

Full text of DOI:10.1002/jhet.5570420543

Jul-Aug 2005
1017
Copper Dipyridine Dichloride as a Mild and Efficient Catalyst for a One
Pot Condensation Bigenelli Reaction
V. Naveen Kumar, P. Someshwar, P. Narsimha Reddy, Y. Thirupathi Reddy, B. Rajitha*
Department of Chemistry, National Institute of Technology, Warangal, India
Fax: 0091-9712-2459547; E-mail: rajitabhargavi@yahoo.com
Received January 19, 2005
The condensation reaction of aldehydes, β-ketoesters and urea/thiourea in presence of a catalytic amount
of CuPy Cl complex proceeded under very mild reaction conditions in high yield (80-90%).
2
2
J. Heterocyclic Chem., 42, 1017 (2005).
Introduction.
cold water and recrystallized from ethanol to afford pure
product in 80-90% yield.
There has been considerable interest in the development
of preparative methods for the products of dihydro-
pyrimidines-2(1H)-ones (DHPMS).This seems to be
because of their pharmacologically importance as well as
to understand the mechanism of reaction involved in what
is commonly called the Biginelli condensation [1]. The
DHPMS compounds have shown promising activity as
calcium channel blockers, antihypertensive agents, α-1-a-
antagonists, and neuropeptide Y(NPY) antagonists [2]. In
addition, the dihydropyrimidinone-5-carboxylate core unit
is found in many marine natural products, including the
batazelladine alkaloids, which have been found to be
Scheme I
potent HIVgp-120-cd inhibitors [3]. Many synthetic
4
Table 1
methods for the preparing DHPMS compounds under clas-
sical reflux [4a-h] (or) solvent free conditions [5-11] and
microwave [12-15] (or) ultrasonic irradiation [16-17] have
been reported.
CuPy Cl Catalyzed Efficient Synthesis of Dihydropyrimidin-2(1H)-ones
2
2
1
Product
R
R
X
Time
(h)
Yield
m.p.
(°C)
(%) [a]
Interest in the transition metal complex-catalyzed
Biginelli reaction has been growing during the last few
years. Copper, palladium, nickel and cobalt derivatives
have proved to display good catalytic activity toward this
important type of condensation reaction [18-19]. With
such catalysts, the reaction is completed in a shorter time
and in excellent yield, as compared with previously
reported methods [20]. Now, we found that an analogous
condensation reaction can be conveniently performed
under neutral and mild conditions in the presence of a cat-
4a [4a]
4b [4a]
4c [4a]
4d [4a]
4e [4d]
4f [4a]
4g [4a]
4h [4a]
4i [4b]
4j [4b]
4k [4a]
4l [4a]
C H
4-(Cl)-C H
4-(NO )-C H
3-(NO )-C H
3-(Cl)-C H
4-(OCH )-C H
3-(NO )-C H
4-(OH)-C H
4-(OH)-C H
4-(OCH )-C H
4-(NO )-C H
4-(OCH )-C H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OEt
OMe
OMe
OMe
OMe
O
O
O
O
O
O
S
O
S
S
O
O
O
O
O
O
O
1.0
3.0
1.5
3.0
2.5
2.5
2.0
2.0
3.0
3.0
2.5
3.0
2.5
3.0
2.0
3.0
3.0
90
82
89
85
88
82
85
88
90
89
90
84
89
90
90
89
88
200-202
209-211
205-207
225-227
215-217
198-200
203-205
179-181
195-198
137-139
235-236
191-193
204-206
214-216
207-09
6
5
6
4
2
6
4
4
2
6
6
4
3
6
4
2
6 4
6
4
4
6
3
6
4
2
6 4
3
6
4
4m [4c] 2-furyl
alytic amount of CuPy2Cl [21-22]. Catalytic improve-
2
4n [4a]
4o [4d]
4p [4a]
4q [4a]
C H
6 5
ment is apparently due to the presence of two pyridine
rings, which increases the electron deficiency on the nitro-
gen hence it is efficiently act as a Lewis acid.
3-(Cl)-C H
4-(Cl)-C H
4-(OH)-C H
6
4
205-207
175-177
6
4
6
4
[a] Yields refer to pure solid products, all products were characterized by
comparison of their physical and spectral data with those of authentic
samples.
Results and Discussion.
The Biginelli condensation reaction was carried out at
40-50 °C under a nitrogen atmosphere using an aldehyde,
urea and ethyl acetoacetate to CuPy Cl molar ratio of
2
2
EXPERIMENTAL
General Procedure.
100:1. An aldehyde, β-ketoester and urea/thiourea
(1:1:1.5mmol) were added into the mixture of CuPy Cl
2
2
(0.01 mmol) dissolved in anhydrous acetonitrile (10 mL).
The homogeneous reaction mixture was stirred at 40-50 °C
for 1-3 hour. The solvent was evaporated under reduced
pressure. The solid thus obtained was washed with ice-
A solution of an appropriate β-ketoester (1 mmol), corre-
sponding aldehyde (1 mmol), urea or thiourea (1.5 mmol), and
CuPy Cl (0.01 m mol) in anhydrous acetonitrile (10 mL) was
2
2
stirred at 40-50 °C for a certain period of time as required to com-

1018
V. N. Kumar, P. Someshwar, P. N. Reddy, Y. T. Reddy, B. Rajitha
Vol. 42
1
plete the reaction (TLC). The solvent was removed under
reduced pressure to yield a solid, which was washed thoroughly
with water, filtered and recrystallized from ethanol to afford pure
4m: H NMR (200MHz, DMSO-d ): δ 1.07 (t, 3H, J = 6.8 Hz,
6
CH ), 2.20 (s, 3H, CH ), 3.94 (q, 2H, J=7.2 Hz, OCH ), 5.02 (s,
1H, C -H), 6.64 (m, 3H, Ar-H), 7.57 (bs, 1H, NH), 9.10 (bs, 1H,
3
3
2
4
1
+
product. H NMR and MS data for compounds 4a-q are given
NH); MS: m/z=251.2 (M ).
1
below:
4n: H NMR (200MHz, DMSO-d ): 2.26 (s, 3H, CH ), 3.54
6
3
1
4a: H NMR (200MHz, DMSO-d ): δ 1.10 (t, 3H, J = 6.82 Hz,
(s, 3H, OCH ) 5.15 (d, 1H, J=3.13 Hz, C -H), 7.24-7.36 (m, 5H,
Ar-H), 7.78 (bs, 1H, NH), 9.16 (bs, 1H, NH); MS: m/z=247.09
6
3
4
CH ), 2.22 (s, 3H, CH ), 3.92 (q, 2H, J=6.74, OCH ), 5.11 (d,
3
3
2
+
1H, J=3.05 Hz, C -H), 7.71 (bs, 1H, NH), 7.20-7.35 (m, 5H, Ar-
(M ).
4
+
1
H), 9.16 (bs, 1H, NH); MS: m/z=261.1 (M ).
4b: H NMR (200MHz, DMSO-d ): δ 1.07 (t, 3H, J = 6.8 Hz,
CH ), 2.20 (s, 3H, CH ), 3.94 (q, 2H, J=7.2 Hz, OCH ), 5.02 (s,
4o: H NMR (200MHz, DMSO-d ): δ 2.32 (s, 3H, CH ), 3.55
6
3
1
(s, 3H, OCH ), 5.38 (s, 1H, CH, C -H), 7.66 (s, 1H, Ar-H), 7.91
6
3
4
(bs, 1H, NH), 8.01-8.12 (m, 3H, Ar-H), 9.41 (bs, 1H, NH); MS:
3
3
2
+
1H, C -H), 6.64 (d, 2H, J= 8.2 Hz, Ar-H), 7.02 (d, 2H, J=8.2 Hz,
m/z=281.7 (M ).
4
+
1
Ar-H), 7.57 (bs, 1H, NH), 9.10 (bs, 1H, NH); MS: m/z=295 (M ),
4p: H NMR (200MHz, DMSO-d ): δ 2.34 (s, 3H, CH ), 3.63
6
3
265.
(s, 3H, OCH ), 5.40 (s, 1H, CH, C -H), 7.63-7.72 (m, 2H, Ar-H),
3
4
1
4c: H NMR (200MHz, DMSO-d ): δ 1.07 (t, 3H, J = 6.8 Hz,
7.95 (bs, 1H, NH), 8.11-8.18 (m, 2H, Ar-H), 9.41 (bs, 1H, NH);
6
+
CH ), 2.24 (s, 3H, CH ), 3.96 (q, 2H, J=5.4 Hz, OCH ), 5.25 (s,
MS: m/z=281.7 (M ).
3
3
2
1
1H, C -H), 7.50 (d, 2H, J= 7.3 Hz, Ar-H), 7.85 (bs, 1H, NH),
4q: H NMR (200MHz, DMSO-d ): δ 2.26 (s, 3H, CH ), 3.85
4
6
3
8.20 (d, 2H, J=7.2Hz, Ar-H), 9.31 (bs, 1H, NH); MS:
(s, 3H, OCH ), 5.26 (d, 1H, J=2.78 Hz, C -H), 6.71 (d, 2H, J= 8.38
2
4
+
m/z=306.29 (M ).
Hz, Ar-H), 7.24 (d, 2H, J=8.36 Hz, Ar-H), 7.63 (bs, 1H, NH),
9.11(bs, 1H, NH), 9.32 (bs, 1H, OH); MS: m/z=263.25 (M ).
1
+
4d: H NMR (200MHz, DMSO-d ): δ 1.06 (t, 3H, J = 7. 01
6
Hz, CH ), 2.26 (s, 3H, CH ), 3.98 (q, 2H, J=4.6 Hz, OCH ), 5.30
3
3
2
Acknowledgement.
(d, 1H, J= 2.64 Hz, C -H), 7.60-7.70 (m, 2H, Ar-H), 7.95 (bs, 1H,
4
NH), 8.11-817 (m, 2H, Ar-H), 9.38 (bs, 1H, NH); MS: m/z=306
The authors are thankful to University Grants Commission,
New Delhi for financial assistance and to the Director, IICT
Hyderabad for H NMR and mass spectral analysis.
+
(M ).
1
4e: H NMR (200MHz, DMSO-d ): δ 1.05 (t, 3H, J = 6.83 Hz,
1
6
CH ), 2.22 (s, 3H, CH ), 3.96 (q, 2H, J=7.2 Hz, OCH ), 5.12 (s,
3
3
2
1H, C -H), 6.65-6.92 (m, 3H, Ar-H), 7.05 (s, 1H, Ar-H), 7.61 (bs,
4
+
REFERENCES AND NOTES
1H, NH), 9.13 (bs, 1H, NH); MS: m/z=295 (M ).
1
4f: H NMR (200MHz, DMSO-d ): δ 1.10 (t, 3H, J = 7.05 Hz,
6
CH ), 2.16 (s, 3H, CH ), 3.72 (s, 3H, OCH ), 3.96 (q, 2H, J=7.22
[1a] P. Biginelli, Gazz. Chim. Ital. 23, 360 (1893); [b] C. O. Cappe,
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3
3
3
Hz, OCH ), 5.08 (d, 1H, C -H), 6.86 (d, 2H, J= 8.52 Hz, Ar-H),
2
4
7.14 (d, 2H, J=8.54 Hz, Ar-H), 7.67 (bs, 1H, NH), 9.13 (bs, 1H,
+
NH); MS: m/z=291.3 (M ).
1
4g: H NMR (200MHz, DMSO-d ): δ 1.06 (t, 3H, J = 7. 01
6
Hz, CH ), 2.25 (s, 3H, CH ), 3.97 (q, 2H, J=4.6 Hz, OCH ), 5.29
3
3
2
(d, 1H, J= 2.64 Hz, C -H), 7.59-7.68 (m, 2H, Ar-H), 7.93 (bs, 1H,
4
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NH), 8.10-815 (m, 2H, Ar-H), 9.36 (bs, 1H, NH); MS: m/z=322
+
(M ), 292.
1
4h: H NMR (200MHz, DMSO-d ): δ 1.07 (t, 3H, J =
6
6.9 Hz, CH ), 2.22 (s, 3H, CH ), 3.95 (q, 2H, J=7.12 Hz, OCH ),
3
3
2
5.05 (d, 1H, J=2.78 Hz, C -H), 6.68 (d, 2H, J= 8.42 Hz, Ar-H),
4
7.04 (d, 2H, J=8.49 Hz, Ar-H), 7.65 (bs, 1H, NH), 9.13 (bs, 1H,
+
NH), 9.33 (bs, 1H, OH); MS: m/z=277 (M ), 247, 246.
1
4i: H NMR (200MHz, DMSO-d ): δ 1.07 (t, 3H, J = 6.95 Hz,
6
CH ), 2.24 (s, 3H, CH ), 3.96 (q, 2H, J=7.16Hz, OCH ), 5.13 (d,
3
3
2
1H, J=2.75 Hz, C -H), 6.67 (d, 2H, J= 8.46 Hz, Ar-H), 7.06 (d,
4
2H, J=8.47 Hz, Ar-H), 7.68 (bs, 1H, NH), 9.15 (bs, 1H, NH),
+
9.35 (bs, 1H, OH); MS: m/z=293 (M ), 263, 262.
1
4j: H NMR (200MHz, DMSO-d ): δ 1.05 (t, 3H, J = 7.25 Hz,
6
CH ), 2.08 (s, 3H, CH ), 3.72 (s, 3H, OCH ), 3.94 (q, 2H, J=7.25
3
3
3
Hz, OCH ), 5.02 (d, 1H, C -H), 6.82 (d, 2H, J= 8.55 Hz, Ar-H),
2
4
7.11 (d, 2H, J=8.57 Hz, Ar-H), 7.65(bs, 1H, NH), 9.11 (bs, 1H,
+
NH); MS: m/z=307.39 (M ).
1
4k: H NMR (200MHz, DMSO-d ): δ 2.28 (s, 3H, CH ), 3.53
6
3
(s, 3H, OCH ), 5.25 (d, 1H, J= 3.17 Hz, C -H), 7.50 (d, 2H, J=
3
4
7.3 Hz, Ar-H), 7.85 (bs, 1H, NH), 8.20 (d, 2H, J=7.2Hz, Ar-H),
+
9.31 (bs, 1H, NH); MS: m/z=292.08 (M ), 274, 232, 186.
1
4l: H NMR (200MHz, DMSO-d ): δ 2.18 (s, 3H, CH ), 3.82
6
3
(s, 3H, OCH ), 3.91 (s, 3H, OCH ), 5.13 (d, 1H, C -H), 6.88 (d,
3
3
4
2H, J= 8.46 Hz, Ar-H), 7.17(d, 2H, J=8.49 Hz, Ar-H), 7.67 (bs,
+
[10] A. Shaabani, A. Bazgir, and F. Teimouri, Tetrahedron Lett.,
1H, NH), 9.13 (bs, 1H, NH); MS: m/z=277.2 (M ).

Jul-Aug 2005
Copper Dipyridine Dichloride as a Mild and Efficient Catalyst
1019
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