Zirconium(IV) chloride catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/S0040-4039(02)00280-0

Zirconium tetrachloride catalyzes efficiently the three component condensation reaction of an aromatic aldehyde, a β-ketoester and urea in refluxing ethanol to afford the corresponding dihydropyrimidinone in high yield.

Full text of DOI:10.1016/S0040-4039(02)00280-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2657–2659
Zirconium(IV) chloride catalyzed one-pot synthesis of
3,4-dihydropyrimidin-2(1H)-ones†
Ch. Venkateshwar Reddy, M. Mahesh, P. V. K. Raju, T. Ramesh Babu and
V. V. Narayana Reddy*
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 November 2001; revised 3 January 2002; accepted 6 February 2002
Abstract—Zirconium tetrachloride catalyzes efficiently the three component condensation reaction of an aromatic aldehyde, a
b-ketoester and urea in refluxing ethanol to afford the corresponding dihydropyrimidinone in high yield. © 2002 Elsevier Science
Ltd. All rights reserved.
Many dihydropyrimidinones (DHPMs) and their
derivatives are pharmaceutically important as calcium
channel blockers, antihypertensive agents and a1-1-a-
antagonists.1 The biological activity of some alkaloids
isolated recently has been attributed to the dihydropy-
rimidinone moiety.2 The simple and direct method for
the synthesis of dihydropyrimidinones reported by
Biginelli in1893, involves the one-pot condensation of
an aldehyde, a b-ketoester and urea under strongly
acidic conditions.3 However, this method suffers from
low yields especially in the case of aliphatic and substi-
tuted aromatic aldehydes. This has led to the develop-
ment of multistep synthetic strategies that produce
somewhat better yields but lack the simplicity of the
one-pot, one-step synthesis.1,4,5
thioacetylization of acetals,8 deoxygenation of hetero-
cyclic-N-oxides,9 reduction of nitro compounds,10 con-
version of carbonyl compounds to 1,3-oxathiolanes11
and Friedel–Crafts reactions has been well documented
in the literature.
Herein we wish to report a simple and efficient method
for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
using zirconium tetrachloride as the catalyst. The reac-
tion of benzaldehyde, ethyl acetoacetate and urea in the
presence of 10 mol% zirconium(IV) chloride in reflux-
ing ethanol gave the corresponding dihydropyrimidi-
none in 90% yield.15 This one-pot synthesis is novel in
the sense that it preserves the simplicity of Biginelli’s
one-pot reaction and improves the yields to an extent of
83–96% (Scheme 1).
Thus, Biginelli’s reaction for the synthesis of dihy-
dropyrimidinones has received renewed interest and
several improved procedures have recently been
reported.3b,6 The use of zirconium(IV) chloride as an
efficient Lewis acid for various transformations such as
electrophilic amination of activated arenes,7 trans-
It is interesting to note that when ethyl trifluoroace-
toacetate is used as the b-ketoester in this synthesis, the
hexahydropyrimidine (Scheme 2), considered to be an
intermediate in the Biginelli reaction, was isolated in
very good yields. This confirms the earlier report by
O
R
X
O
O
EtO
H3C
NH
ZrCl4
R-CHO
H3C
OEt
H2N
NH2
+
+
Ethanol
, 4-6 h
N
H
X
1
2
3
4 a-m
Scheme 1.
Keywords: zirconium tetrachloride; b-ketoesters; Biginelli reaction; dihydropyrimidinones.
* Corresponding author. Fax: 91-40-7160757; e-mail: vaddu@iict.ap.nic.in
† IICT Communication No. 011112.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00280-0

2658
Ch. V. Reddy et al. / Tetrahedron Letters 43 (2002) 2657–2659
R
H
X
O
O
EtOOC
HO
NH
ZrCl4
R-CHO
F3C
OEt
H2N
NH2
+
+
Ethanol
, 4-6 h
N
H
X
F3C
1
2
3
6 a-b
Scheme 2.
1
Kappe et al.14 that in the H NMR spectrum of 6b the
doublets at l 2.91 and 4.71 with a coupling constant of
11.0 Hz are assignable to the 4-H and 5-H protons
which are trans to each other. The isolation and charac-
terization of this intermediate (6b) for the first time
assumes significance in terms of confirming the mecha-
nism of the reaction. It may be presumed that the OH
group at C-6 may be cis to 5-H, thereby the elimination
of water requires drastic conditions.
method utilizes readily available reagents at low cost
and also affords high yields of DHPMs in short reac-
tion times.
Thus, this procedure offers easy access to substituted
dihydropyrimidinones with a variety of substitution
patterns. Among the various solvents such as acetoni-
trile, methanol, THF and ethanol used for the transfor-
mation, ethanol and methanol were found to be the
best. The results summarized in Table 1 reveal the
scope and generality of the reaction with respect to
various aldehydes, b-ketoesters and urea or thiourea. It
is presumed that the reaction may proceed through the
imine intermediate formed from the aldehyde and urea,
stabilized by the zirconium ion followed by the addition
of the b-ketoester enolate and cyclodehydration to
afford the dihydropyrimidine (Scheme 3).
The three component condensation reactions proceeded
smoothly in refluxing ethanol and were completed
within 4–6 h. Many pharmacologically important moi-
eties may be substituted on the aromatic ring with high
efficiency under the zirconium tetrachloride catalyzed
conditions. Aromatic aldehydes carrying either elec-
tron-donating or withdrawing substituents afforded
high yields of products in high purity. Acid sensitive
aldehydes such as furfural worked well without the
formation of any side products. Besides its simplicity
and mild reaction conditions, this method is effective
for the preparation of DHPMs. Another important
feature of this procedure is the survival of a variety of
functional groups such as ether, nitro, hydroxy, halides,
etc., under the reaction conditions. The advantage of
the ZrCl4 for this reaction lies in its simplicity. This
In conclusion, we have developed a simple and general
method for the synthesis of dihydropyrimidinones using
the inexpensive and easily available zirconium tetra-
chloride as catalyst. The method offers several advan-
tages including high yields, short reaction times and a
simple experimental workup procedure, which makes it
a
useful process for the synthesis of dihydro-
pyrimidinones.
Table 1. ZrCl4 catalyzed formation of dihydropyrimidinones
Producta (4)
R
X
Time (h)
Yieldb (%)
Melting point (°C)
Observed Reported
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
O
O
O
O
O
O
O
O
O
O
O
4
4
5
5
6
6
6
5
4
6
6
90
88
97
98
95
88
90
95
96
83
84
200–202
169–171
198–200
198–200
210–212
206–208
229–232
173–176
192–194
229–232
203–205
20212
1726
20112
–
4-(Me)-C6H4
4-(OMe)-C6H4
4-(OH)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
4-(NMe2)-C6H4
4-(F)-C6H4
21212
20912
–
17512
19413
23213
20513
3-(OPh)-C6H4
C6H5CHꢀCH
4j
4k
O
4l
C6H5
4-(OH)-C6H4
C6H5
S
S
O
O
5
4
6
5
90
95
80
85
190–192
193–194
160–162
186–188
–
–
–
–
4m
6a
6b
4-(OH)-C6H4
a All products were characterized by 1H NMR, IR and mass spectroscopy.
b Isolated and unoptimized yields and melting points are uncorrected.

Ch. V. Reddy et al. / Tetrahedron Letters 43 (2002) 2657–2659
2659
Zr+4
X
R
H
O
O
H N
NH2
+
N
R-CHO
EtO
+
H3C
OEt
2
NH2
Zr+4
R
X
H
O
R
R
EtOOC
H3C
EtOOC
HO
NH
- H2O
NH
NH
X
N
H
H3C
X
O
N
H
X
H3C
NH2
Scheme 3.
Acknowledgements
Spectroscopic data. 4d: Mp 198–200°C; 1H NMR
(DMSO-d6): l 1.18 (t, J=7.5 Hz, 3H, CH3), 2.28 (s, 3H,
CH3), 4.0 (q, J=7.5 Hz, 2H, -OCH2), 5.18 (s, 1H), 6.7 (d,
J=8.9 Hz, 2H, Ar), 7.09 (d, J=8.9 Hz, 2H, Ar), 7.25 (s,
1H), 8.95 and 9.0 (2s, 2H, brs. NH). EIMS: m/z (%)=276
(10) (M+), 248 (100), 231 (28), 204 (80), 168 (87), 136 (48).
IR (KBr): w=3520, 3230, 3150, 1705, 1690 cm−1. Anal.
calcd for C14H16N2O4: C, 60.86; H, 5.83; N, 10.17.
Found: C, 60.81; H, 5.78; N, 10.11.
Ch.V.R. and M.M. are thankful to the Director, IICT,
for financial support.
References
4g: Mp 229–232°C; 1H NMR (DMSO-d6): l 1.20 (t,
J=7.6 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 2.87 (s, 6H,
N(CH3)2), 4.0 (q, J=7.6 Hz, 2H, -OCH2), 5.18 (s, 1H,
CH), 6.62 (d, J=9.1 Hz, 2H, Ar), 7.19 (d, J=9.1 Hz, 2H,
Ar), 8.90 and 8.95 (2s, 2H, brs. NH). EIMS: m/z (%)=
303 (75) (M+), 274 (100), 257 (15), 230 (78), 155 (20). IR
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(KBr): w=3200, 3100, 1700, 1685 cm−1
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J=7.3 Hz, 3H, CH3), 2.27 (s, 3H, CH3), 4.08 (q, J=7.3
Hz, 2H, -OCH2), 5.22 (s, 1H, CH), 7.23 (m, 5H, Ar), 9.25
and 9.9 (2s, 2H, 2brs. NH). EIMS: m/z (%)=276 (65)
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.
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J=7.5 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 4.0 (q, J=7.5
Hz, 2H, -OCH2), 5.10 (s, 1H, CH), 6.65 (d, J=9.1 Hz,
2H, Ar), 7.00 (d, J=9.1 Hz, 2H, Ar), 9.10 (br. s, 1H,
OH), 9.15 and 9.8 (2br. s, 2H, NH). EIMS: m/z (%)=292
(25) (M+), 264 (28), 220 (20), 200 (15), 142 (25), 50 (100).
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.
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6a: Mp 160–162°C; 1H NMR (DMSO-d6): l 0.85 (t,
J=7.5 Hz, 3H, CH3), 3.10 (d, J=11.5 Hz, 1H, CH), 3.88
(q, J=7.5 Hz, 2H, -OCH2), 4.86 (d, J=11.5 Hz, 1H),
5.70 (br. s, 1H, NH), 5.72 (br. s, 1H, NH) 6.30 (s, 1H,
OH), 7.36 (s, 5H, Ar). EIMS: m/z (%)=332 (80) (M+),
285 (20), 269 (75), 241 (100), 237 (72), 142 (25). IR (KBr):
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pyrimidinones 4: A mixture containing an appropriate
b-ketoester (5 mmol), corresponding aldehyde (5 mmol),
urea or thiourea and ZrCl4 (10 mol%) in ethanol (15 ml)
was refluxed for 4 h. After completion of the reaction, as
indicated by 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 product.
w=3450, 3210, 1700, 1690 cm−1
.
6b: Mp 186–188°C; 1H NMR (DMSO-d6): l 0.92 (t,
J=7.3 Hz, 3H, CH3), 2.92 (d, J=11 Hz, 1H), 3.86 (q,
J=7.3 Hz, 2H, -OCH2), 4.74 (d, J=11 Hz, 1H, CH), 6.65
(s, 1H), 6.70 (d, J=8.25 Hz, 2H, Ar), 6.96 (d, NH), 7.16
(d, J=9.1 Hz, 2H, Ar), 9.10 (s, 1H, NH). EIMS: m/z
(%)=348 (75) (M+), 288 (30), 272 (70), 244 (100), 224
(65). IR (KBr): w=3410, 3250, 3195, 1710, 1695 cm−1
.