A highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc chloride

Article abstract of DOI:10.1055/s-2004-822331

Dihydropyrimidinones are prepared from zinc chloride (20 mol%) catalyzed Biginelli condensation of an aldehyde, 1,3-dicarbonyl compounds and urea or thiourea at 80°C for short time under solvent-free conditions in high yields.

Full text of DOI:10.1055/s-2004-822331

PAPER
1047
A Highly Efficient Solvent-Free Synthesis of Dihydropyrimidinones Catalyzed
by Zinc Chloride
Efficient
S
ynthesis
i
of
D
ihydrop
S
yrimidinonesun, Yi-qiang Wang, Ze-mei Ge, Tie-ming Cheng, Run-tao Li*
School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. China
Fax +86(10)62346154; E-mail: lirt@mail.bjmu.edu.cn
Received 9 January 2004; revised 9 February 2004
recently. Such as, under solvent-free conditions, Qian’s
Abstract: Dihydropyrimidinones are prepared from zinc chloride
(20 mol%) catalyzed Biginelli condensation of an aldehyde, 1,3-di-
carbonyl compounds and urea or thiourea at 80 °C for short time un-
der solvent-free conditions in high yields.
group used ytterbium triflate as catalyst to give Biginelli
condensation products in 81–99% yields within 20–40
minutes;14 Reddy’s group found that the N-butyl-N,N-
dimethyl-a-phenylethylammonium bromide could cata-
lyze Biginelli reaction to afford corresponding products in
86–99% yields within 1 hour.29 Ammonium chloride has
also been used as catalyst under solvent-free conditions,30
the yields are not so satisfactory (42–92%) and longer re-
action time (3 h) is required, though it is cheap and readily
available.
Key words: Biginelli reaction, dihydropyrimidinones, zinc chlo-
ride, solvent-free, catalyst
Many dihydropyrimidinones (DHPMs) are pharmacolog-
ically important as calcium channel blockers,1 antihyper-
tensive agents,2 a-adrenergic antagonists3 and
neuropeptide Y (NPY) antagonists.4 Several recently iso-
lated marine alkaloids with interesting biological activi-
ties also contain the dihydropyrimidinone-5-carboxylate
core.5 Most notably among these are the batzelladine alka-
loids, which have been found to be potent HIV gp-120-
CD4 inhibitors.6
Herein we wish to report a zinc chloride-catalyzed sol-
vent-free synthetic method for the preparation of 3,4-di-
hydropyrimidin-2-(1H)-ones. Zinc chloride, a very
inexpensive and easily available Lewis acid catalyst, has
been widely used in organic reactions, but it hasn’t been
carefully studied as a catalyst in Biginelli condensation
until now, except for a few mention in literature.31 During
the research, we found that zinc chloride could catalyze
Biginelli condensation under solvent-free conditions. To
optimize the reaction conditions, the reaction of benzalde-
hyde, ethyl acetoacetate and urea was selected as model to
examine the effects of catalyst (0–30 mol%) and reagents
at different reaction temperatures (r.t., 50, 80 and 100 °C).
The results were evaluated qualitatively through TLC.
The best result was achieved by carrying out the reaction
with 0.2:1:1:1.5 mole ratios of zinc chloride, benzalde-
hyde, ethyl acetoacetate and urea at 80 °C for 20 min un-
der solvent-free conditions (Scheme 1).
The Biginelli reaction, which was discovered more than a
century ago,7 is one of the most important reactions in the
synthesis of dihydropyrimidinones (DHPMs). The classi-
cal Biginelli reaction of an aldehyde, b-keto ester and urea
or thiourea requires strongly acidic conditions. Usually
only low to moderate yields are obtained, in particular
when substituted aromatic or aliphatic aldehydes are em-
ployed.
In order to improve the efficiency of Biginelli reaction,
many catalysts have been developed, such as zirconi-
um(IV) chloride,8 indium(III) bromide,9 ytterbium(III)-
resin,10 ionic liquids (BMImPF6 and BMImBF4),11 ceric
ammonium nitrate (CAN),12 Mn(OAc)3·2H2O,13 lan-
thanide triflate,14 indium(III) chloride,15 lanthanum chlo-
ride,16 TFA,17 BF3·OEt2-CuCl,18 Boric acid,19
CeCl3·7H2O,20 Cu(OTf)2,21 lithium bromide,22 silica/sul-
furic acid,23 vanadium(III) chloride,24 FeCl3·6H2O,25 TM-
SI,26 montmorillonite/KSF,27 and zinc triflate.28 Some of
them are really very fascinating from a synthetic chem-
ist’s point. Despite their tremendous success, however,
some drawbacks still remain. For example, some of the
catalysts are expensive, complex or unavailable and or-
ganic solvents are always used.
Using the optimized reaction conditions (Method A), the
reactions of various aldehydes, 1,3-dicarbonyl com-
pounds and urea or thiourea were investigated. Compared
with the corresponding results in the absence of catalyst
(Method B), all the reactions proceeded smoothly and fast
to give the corresponding 3,4-dihydropyrimidin-2-(1H)-
ones in high yields (Table 1). Cinnamic aldehyde, which
showed poor yields in the absence catalyst and 81% yield
in the presence of lanthanide triflate,14 gave the corre-
sponding dihydropyrimidinones 4g and 4o in 90% yields.
Both aromatic aldehydes bearing electron-donating such
as 4d (96%), 4e (84%), and 4l (90%) and electron-with-
drawing groups such as 4b (96%), 4f (92%), and 4n (84%)
all gave excellent yields, though former kind of aromatic
aldehydes required longer reaction times (60 min). More
importantly, 2-furaldehyde 4j and 4p, which normally
give low yield of products,16,21 afforded the desired prod-
ucts in 94 and 95% yields, respectively, in 10 minutes.
As the increase of environmental consciousness in chem-
ical research and industry, the solvent-free Biginelli reac-
tion has attracted much attention and got good results
SYNTHESIS 2004, No. 7, pp 1047–1051
x
x
.
x
x
.2
0
0
4
Advanced online publication: 02.04.2004
DOI: 10.1055/s-2004-822331; Art ID: F00704SS
© Georg Thieme Verlag Stuttgart · New York

1048
Q. Sun et al.
PAPER
O
R1
O
O
X
R2
H3C
NH
20 mol% ZnCl2
R1 CHO
+
H3C
R2
+
H2N
NH2
80 °C, 10-60 min
N
H
X
4
1
2
3
Scheme 1
Furthermore, the scope of this methodology was found (4c, 216–217 °C). To consider the effect of the different
not to be limited to aromatic aldehydes, as valeraldehyde crystals from different solvents, 5-aceto-6-methyl-2-oxo-
underwent conversion to the corresponding dihydropyri- 4-phenyl-1,2,3,4-tetrahydropyridimidine (4k) was recrys-
midinone 4h in 70% yield. By using thiourea instead of tallized from acetone–ethanol and methanol,29 respective-
urea in the reaction, the thiopyrimidine 4q was obtained in ly, and their DSC spectra were recorded (Figure 2 and
87% yield. Therefore, the present protocol has the ability Figure 3). The results showed that 4k recrystallized from
to tolerate the variations in all the three components.
two different solvent systems had the same melting point
(242–244 °C) and almost the same DSC spectral data
(243.70 °C and 241.72 °C).
It is noteworthy that most of the melting points of dihy-
dropyrimidinones synthesized by us are 6 to 12 °C higher
than that of the corresponding reported. In an effort to ver- In conclusion, we have developed a solvent-free, zinc
ify these results, we selected the ethyl 4-(4-chlorophenyl)- chloride-catalyzed procedure for the synthesis of dihydro-
6-methyl-2-oxo-1,2,3,4-tetrahydropyridimidine-5-car-
pyrimidinones. Its advantages are, the catalyst is inexpen-
boxylate (4c) as representative for further study. Firstly, sive and easily available, reaction times are short,
1
we confirmed its structure through H NMR, 13C NMR, excellent yields are obtained, and the reaction conditions
MS and elemental analysis; then the DSC (Figure 1, are environmental friendly.
216.13 °C) was performed to accord with its melting point
Table 1 Zinc Chloride-Catalyzed Synthesis of Dihydropyrimidinones under Solvent-Free Conditions
Entrya
R1
R2
X
Time
(min)
Method A Method B
Mp (°C)
Mp (°C)
Reported
Yield (%)b Yield (%)b Found
4a
4b
4c
4d
4e
4f
C6H5
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
20
12
10
50
40
20
60
40
40
10
10
30
13
30
60
10
60
90
96
96
96
84
92
90
70
83
94
91
90
97
84
90
95
87
73
85
71
73
62
72
36
38
41
77
80
85
78
78
48
78
89
209–210
211–213
216–217
236–238
197–198
231–235
245–246
165–166
222–223
208–210
242-244
260 (dec.)
233–235
220 (dec.)
224–226
217–219
230 (dec.)
200–20230
205–20730
210–21214
22829
4-NO2C6H4
4-ClC6H4
4-OHC6H4
3,4-(OCH2O)C6H3
3-NO2C6H4
C6H5CH=CH
CH3CH2CH2CH2
2-ClC6H4
2-furyl
188–18921
225–22730
230–23223
157–15814
216–21830
203–20521
233–23614
23029
4g
4h
4i
4j
4k
4l
C6H5
4-OHC6H4
4-ClC6H4
4-NO2C6H4
C6H5CH=CH
2-furyl
CH3
4m
4n
4o
4p
4q
CH3
-
CH3
230 (dec.)14
-
CH3
CH3
210–21215
183 (dec.)23
C6H5
CH3
a Characterized by 1H NMR spectroscopy by comparison with literature reports.
b Isolated yields.
Synthesis 2004, No. 7, 1047–1051 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Dihydropyrimidinones
1049
1
Melting points were determined on X4 microscope. H NMR and
13C NMR spectra were performed on a VXR 300 (300 MHz) instru-
ment. Elemental analyses were performed on a Vario EL III (Ger-
many). DSC (differential scanning calorimeter) was performed on
disc 2010 (TA, USA), TLC was carried out on GF254 silica gel
plates. All aldehydes, 1,3-dicarbonyl compounds, urea and thiourea
were obtained from freshly opened containers and used without fur-
ther purification, with the exception of benzaldehyde and 2-furalde-
hyde, which were distilled prior to use. Petroleum ether used had bp
of 60–90 °C.
Dihydropyrimidinones 4; General Procedures
Method A: A mixture of 1,3-dicarbonyl compound (10 mmol), alde-
hyde (10 mmol), urea or thiourea (15 mmol) and ZnCl2 (273 mg, 2
mmol) was heated at 80 °C for the appropriate time as mentioned in
Table 1. After completion of the reaction, the reaction mixture was
poured into H2O (30 mL). The precipitate was filtered and succes-
sively washed with H2O (30 mL) and petroleum ether–EtOAc (5:1,
30 mL). The crude product was purified by recrystallization (ace-
tone–EtOH) to give the pure compound 4 (Table 1).
Figure 1 The DSC spectrum of compound 4c
Method B: A mixture of 1,3-dicarbonyl compound (10 mmol), alde-
hyde (10 mmol) and urea or thiourea (15 mmol) was heated at 100
°C for 2 h, and then poured into H2O (30 mL). The precipitate was
filtered and successively washed with H2O (30 mL) and petroleum
ether–EtOAc (5:1, 30 mL). The crude product was purified by re-
crystallization (acetone–EtOH) to give the pure compound 4
(Table 1).
Ethyl 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyridimi-
dine-5-carboxylate (4a)
1H NMR (DMSO-d6): d = 9.19 (s, 1 H, NH), 7.73 (s, 1 H, NH), 7.22
(m, 5 Harom), 5.14 (d, 1 H, J = 3.6 Hz, H-4), 3.40 (q, 2 H, J = 6.9 Hz,
OCH2), 2.24 (s, 3 H, CH3), 1.09 (t, 3 H, J = 6.9 Hz, CH3).
Ethyl 6-Methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropy-
ridimidine-5-carboxylate (4b)
1H NMR (DMSO-d6): d = 9.36 (s, 1 H, NH), 8.23 (dd, 2 Harom
,
J = 6.9, 2.1 Hz), 7.90 (s, 1 H, NH), 7.52 (dd, 2 Harom, J = 6.9, 2.1
Hz), 5.27 (d, 1 H, J = 3.0 Hz, H-4), 4.02 (q, 2 H, J = 7.2 Hz, OCH2),
2.26 (s, 3 H, CH3), 1.12 (t, 3 H, J = 6.9 Hz, CH3).
Figure 2 The DSC spectrum of compound 4k recrystallized from
acetone–ethanol
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
pyridimidine-5-carboxylate (4c)
1H NMR (DMSO-d6): d = 9.25 (s, 1 H, NH), 7.77 (s, 1 H, NH), 7.40
(d, 2 Harom, J = 8.7 Hz), 7.26 (d, 2 Harom, J = 8.4 Hz), 5.14 (d, 1 H,
J = 3.6 Hz, H-4), 4.00 (q, 2 H, J = 7.2 Hz, OCH2), 2.25 (s, 3 H,
CH3), 1.09 (t, 3 H, J = 6.9 Hz, CH3).
13C NMR (DMSO-d6): d = 165.2, 151.9, 148.7, 143.8, 131.7, 128.4,
128.1, 98.8, 59.2, 53.4, 40.3, 17.8, 14.0.
MS (+FAB): m/z (%) = 295.1 (M+, 89), 277.2 (61), 241.1 (81),
184.9 (100), 149.1 (100).
Anal. Calcd for C14H15ClN2O3: C, 57.05; H, 5.13; N, 9.50. Found:
C, 56.67; H, 5.11; N, 9.83.
Ethyl 4-(4-Hydroxyphenyl)-6-methyl--2-oxo-1,2,3,4-tetrahy-
dropyridimidine-5-carboxylate (4d)
1H NMR (DMSO-d6): d = 9.32 (s, 1 H, OH), 9.11 (s, 1 H, NH), 7.61
(s, 1 H, NH), 7.04 (d, 2 Harom, J = 8.4 Hz), 6.70 (d, 2 Harom, J = 8.4
Hz), 5.04 (d, 1 H, J = 3.0 Hz, H-4), 3.98 (q, 2 H, J = 7.2 Hz, OCH2),
2.23 (s, 3 H, CH3), 1.09 (t, 3 H, J = 8.4 Hz, CH3).
Figure 3 The DSC spectrum of compound 4k recrystallized from
methanol
Ethyl 6-Methyl-4-(3,4-methylenedioxophenyl)-2-oxo-1,2,3,4-
tetrahydropyridimidine-5-carboxylate (4e)
1H NMR (DMSO-d6): d = 9.18 (s, 1 H, NH), 7.68 (s, 1 H, NH), 6.86
(d, 1 Harom, J = 7.8 Hz), 6.74 (d, 1 Harom, J = 1.8 Hz), 6.70 (dd, 1
Harom, J = 8.1, 1.5 Hz), 5.98 (s, 2 H, CH2), 5.06 (d, 1 H, J = 3.3 Hz,
Synthesis 2004, No. 7, 1047–1051 © Thieme Stuttgart · New York

1050
Q. Sun et al.
PAPER
H-4), 4.00 (q, 2 H, J = 7.2 Hz, OCH2), 2.09 (s, 3 H, CH3), 1.11 (t, 3
H, J = 6.9 Hz, CH3).
15.9 Hz, CH=), 4.81 (m, 1 H, H-4), 2.24 (s, 3 H, CH3), 2.22 (s, 3 H,
CH3).
Ethyl 6-Methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropy-
ridimidine-5-carboxylate (4f)
5-Aceto-4-(2-furyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyridim-
idine (4p)
1H NMR (DMSO-d6): d = 9.38 (s, 1 H, NH), 8.15 (m, 2 Harom), 7.91
(s, 1 H, NH), 7.71 (m, 2 Harom), 5.30 (d, 1 H, J = 3.3 Hz, H-4), 4.00
(m, 2 H, OCH2), 2.27 (s, 3 H, CH3), 1.09 (t, 3 H, J = 7.2 Hz, CH3).
1H NMR (DMSO-d6): d = 9.25 (s, 1 H, NH), 7.87 (s, 1 H, NH), 7.57
(d, 1 Harom, J = 1.8 Hz), 6.36 (dd, 1 Harom, J = 1.8, 3.3 Hz), 6.13 (d,
1 Harom, J = 3.3 Hz), 5.31 (d, 1 H, J = 3.6 Hz, H-4), 2.24 (s, 3H,
CH3), 2.16 (s, 3H, CH3).
Ethyl 6-Methyl-2-oxo-4-styryl-1,2,3,4-tetrahydropyridimidine-
5-carboxylate (4g)
5-Aceto-6-methyl-4-phenyl-2-thio-1,2,3,4-tetrahydropyridimi-
dine (4q)
1H NMR (DMSO-d6): d = 9.15 (s, 1 H, NH), 7.56 (s, 1 H, NH), 7.39
(d, 2 Harom, J = 7.2 Hz), 7.32 (d, 2 Harom, J = 7.2 Hz), 7.23 (t, 1 Harom
,
1H NMR (DMSO-d6): d = 10.29 (s, 1 H, NH), 9.77 (s, 1 H, NH),
7.22 (m, 5 Harom), 5.29 (d, 1 H, J = 3.9 Hz, H-4), 2.16 (s, 3 H, CH3),
2.09 (s, 3 H, CH3).
J = 7.2 Hz), 6.39 (d, 1 H, J = 15.6 Hz, CH=), 6.20 (dd, 1 H, J = 15.6,
6.0 Hz, CH=), 4.73 (d, 1 H, J = 3.6 Hz, H-4), 4.09 (qt, 2 H, J = 3.6,
7.2 Hz, OCH2), 2.20 (s, 3 H, CH3), 1.20 (t, 3 H, J = 7.2 Hz, CH3).
Acknowledgments
Ethyl 4-Butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyridimidine-
5-carboxylate (4h)
The authors thank the Natural Science Foundation of China for the
financial support (NSFC 29972005 and 20372006).
1H NMR (DMSO-d6): d = 8.92 (s, 1 H, NH), 7.31 (s, 1 H, NH), 4.11
(s, 1 H, H-4), 4.07 (t, 2 H, J = 6.9 Hz, OCH2), 2.15 (s, 3 H, CH3),
1.37 (m, 2 H, CH2), 1.24 (m, 4 H, CH2), 1.76 (dt, 3 H, J = 1.5, 7.2
Hz, CH3), 0.84 (m, 3 H, CH3).
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dine-5-carboxylate (4j)
1H NMR (DMSO-d6): d = 9.25 (s, 1 H, NH), 7.70 (s, 1 H, NH), 7.56
(dd, 1 Harom, J = 1.8, 0.9 Hz), 6.35 (dd, 1 Harom, J = 1.8, 3.0 Hz), 6.09
(d, 1 Harom, J = 3.3 Hz), 5.20 (d, 1 H, J = 3.3 Hz, H-4), 4.03 (q, 2 H,
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CH3).
5-Aceto-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyridimi-
dine (4k)
1H NMR (DMSO-d6): d = 9.18 (s, 1 H, NH), 7.82 (s, 1 H, NH), 7.30
(m, 5 Harom), 5.25 (d, 1 H, J = 3.3 Hz, H-4), 2.77 (s, 3 H, CH3), 2.09
(s, 3 H, CH3).
5-Aceto-4-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahy-
dropyridimidine (4l)
1H NMR (DMSO-d6): d = 9.36 (s, 1 H, OH), 9.11 (s, 1 H, NH), 7.70
(s, 1 H, NH), 7.05 (d, 2 Harom, J = 8.4 Hz), 6.71 (d, 2 Harom, J = 8.4
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(d, 2 Harom, J = 6.3 Hz), 7.26 (d, 2 Harom, J = 6.3 Hz), 5.25 (d, 1 H,
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Hz), 7.98 (s, 1 H, NH), 7.51 (d, 2 Harom, J = 8.7 Hz), 5.39 (d, 1 H,
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5-Aceto-6-methyl-2-oxo-4-styryl-1,2,3,4-tetrahydropyridimi-
dine (4o)
1H NMR (DMSO-d6): d = 9.16 (s, 1 H, NH), 7.62 (s, 1 H, NH), 7.20
(m, 5 Harom), 6.41 (d, 1 H, J = 15.9 Hz, CH=), 6.14 (dd, 1 H, J = 6,
Synthesis 2004, No. 7, 1047–1051 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Dihydropyrimidinones
1051
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Synthesis 2004, No. 7, 1047–1051 © Thieme Stuttgart · New York