Expedient Synthesis of Biginelli-Type Dihydropyrimidinones Using α-(Benzotriazolyl)alkyl Urea Derivatives

Article abstract of DOI:10.1055/s-2003-42398

Reaction of readily available α-(benzotriazolyl)alkyl urea derivatives (derived from aromatic, heteroaromatic, and aliphatic aldehydes) with β-keto esters resulted in 3,4-dihydropyrimidin-2(1H)-ones in good to excellent yields.

Full text of DOI:10.1055/s-2003-42398

2358
PAPER
Expedient Synthesis of Biginelli-Type Dihydropyrimidinones Using
a-(Benzotriazolyl)alkyl Urea Derivatives
Biginelli-Type
D
ih
s
ydropyrim
h
idinones
U
s
r
ing
a
-
(B
a
enzotriazol
fyl)alkyl
Urea
D
A
erivatives . A. Abdel-Fattah*
Chemistry Department, Faculty of Science, Benha University, Benha-Egypt
E-mail: ashraf25894@yahoo.com
Received 16 June 2003; revised 28 July 2003
microwave28 has also been used to assist Biginelli conden-
sation. The yields quoted in the literature17–22,24 of 53–
99% (average 76%) are based on the amount of either al-
dehyde or b-keto ester utilized, whereas recalculation
based on the amount of urea used gives yields 35–66%
(average 51%). However, in the procedure of one
reference23 a 1:1:3 ratio of reagents gave yields of 20–
27% (average 24%) based on the amount of reagent, a
three fold excess was used.
Abstract: Reaction of readily available a-(benzotriazolyl)alkyl
urea derivatives (derived from aromatic, heteroaromatic, and ali-
phatic aldehydes) with b-keto esters resulted in 3,4-dihydropyrimi-
din-2(1H)-ones in good to excellent yields.
Key words: urea, heterocycles, pyrimidines, condensation, esters,
cyclizations
In recent years, there has been increasing interest in the
synthesis of alkyl dihydropyrimidine-5-carboxlates
(DHPMs)1 of type 4. This stems from their close structural
relationship to clinically important 1,4-dihydropyridine
calcium channel modulators of the type nifedipine etc. Al-
so, dihydropyrimidinone derivatives exhibit a similar
pharmacological profile to DHP.1–4 Some dihydropyrimi-
dinone uses are: aa1 adrenoaceptor-selective antagonists,5
anticancer drugs capable of inhibiting kinesin motor pro-
tein,6 calcium channel blockers and antihypertensives,3,7
and also for the treatment of benign prostatic hyperlasia.8
Several marine-derived natural products such as cram-
bine, batzelladine B (potent HIV gp-120CD4 inhibitors)
and ptilomycelin A9–11 alkaloids also contain the dihydro-
pyrimidinone-5-carboxlate core.
Scheme 1
The most simple and straightforward procedure for the
synthesis of dihydropyrimidinones reported by P. Biginel-
li in 1893, involves the acid-catalyzed condensation of a
b-keto ester 3 with an aromatic aldehyde 1 and urea deriv-
ative 2 (Scheme 1).12,13 The major drawback associated
with this protocol is the low yields, particularly in the case
of aliphatic or substituted aromatic aldehydes.13,14 This
has led to the development of multi-step synthetic strate-
gies that produce somewhat better yields but lack the sim-
plicity of the one-pot, one-step synthesis14–16 (Scheme 2).
Recently, Biginelli dihydropyrimidinone synthesis has re-
ceived great interest in order to improve the efficiency of
the procedure. Lewis acids (BF3·Et2O,17 FeCl3·6 H2O,18
LaCl3·7 H2O,19 polyphosphate ester (PPE),20 acidic clay
montmorillonite KSF,21 manganese(III) acetate,22 ytter-
bium (III)-resin,23 1-butyl-3-methylimidazolium tetra-
fluoroborate (BMImBF4) or hexafluorophosphate
(BMImPF6),24 lanthanide triflate,25 zirconium chloride,26
and indium chloride27 were employed as catalysts for the
one-pot syntheses of DHPMs. More recently,
Scheme 2
Benzotriazole has been emphasized as a new synthetic
auxiliary that offers many advantages.29 N-(a-Ami-
doalkyl)benzotriazoles have been used as powerful re-
agents for the N-amidoalkylation of amines,30 O-
amidoalkylation of alcohols,31 S-amidoalkylation of mer-
captans,32 and C-amidoalkylation of CH-acidic,33 elec-
tron-rich aromatic compounds,34 and deactivated
SYNTHESIS 2003, No. 15, pp 2358–2362
x
x.
x
x
.
2
0
0
3
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42398; Art ID: P05003SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Biginelli-Type Dihydropyridiminones Using a-(Benzotriazolyl)alkyl Urea Derivatives
2359
olefins.35 This offered some clues that reaction of a-ben- NMR spectra of the compounds 4a–q showed two charac-
zotriazolated urea with a b-keto ester could be a possible teristic signals in the region d = 5.75–8.62 and 5.46–6.36,
modification of the Biginelli reaction that produces high ppm which were assigned to the proton type attached to
yields of the target dihydropyrimidines. We now report the nitrogen at the 3-position and the methine proton type
the reaction of a-(benzotriazolyl)alkyl urea derivatives attached to the carbon at 4-position, respectively. In the
with a b-keto ester, which provides a convenient route for 13C NMR spectra, the carbonyl groups of both ester and
the synthesis of 3,4-dihydropyrimidin-2(1H)-ones 4a–q imide in compounds 4a–o,q exhibited signals in the re-
in yields of 77–97% (average 87%) based on using the re- gions d = 164.5–166.4, 153.2–156.0 ppm, and the tertiary
agents in a 1:1 ratio.
carbon at 4-position showed a signal in the region d =
51.3–60.4 ppm.
Treatment of a-(benzotriazolyl)alkyl urea derivatives 9a–
j, which were prepared in excellent yields by the conden- The Lewis acid used in this reaction as a catalyst is inex-
sation of benzotriazole, an aldehyde, and urea in perfor- pensive, easily available and highly efficient for this
mance fluids in the presence of Amberlyst® 15 resin with transformation. The reaction may proceed through the
azeotropic removal of water as previously reported36 acylimine intermediate [generated in situ by the displace-
(Scheme 3), with b-keto esters 3a–c in the presence of ment of the benzotriazolyl moiety from a-(benzotriaz-
zinc bromide in refluxing 1,2-dichloroethane afforded the olyl)alkyl urea 9], which is stabilized by the zinc ion, and
corresponding alkyl 3,4-dihydropyrimidine-5-carboxlates the subsequent addition of the b-keto ester enloate to the
4a–q (Scheme 3, Table 1). The TLC and NMR of the acylimine followed by cyclization and dehydration, af-
crude products show that the reactions are very clean; usu- fords the corresponding dihydropyrimidinones.
ally benzotriazole is the only byproduct, and occasionally,
small amounts of unreacted b-keto ester 3 were detected.
This synthetic route provided the previously known com-
This new synthetic procedure for the preparation of dihy-
dropyrimidinones offers advantages. It has demonstrated
good generality: it could be used with a-(benzotriaz-
olyl)alkyl urea derived from aromatic aldehydes contain-
ing either electron-donating or electron-withdrawing
groups (to give 4a–m), heteroaromatic aldehydes (to give
4n–p), and an aliphatic aldehyde (to give 4q). It utilizes
easily prepared a-(benzotriazolyl)alkyl as ureidoalkylat-
ing reagents, and the by product (benzotriazole) can be
easily removed by washing with saturated aqueous
pounds 4a,q in comparable yields with those reported in
the literature.25,28 The yields of previously unreported 4b–
p were 81–97%. Several adducts 9 derived from aromatic
aldehydes containing either electron-donating or electron-
withdrawing groups were examined. Furthermore, the re-
activity of benzotriazole adducts 9 derived from heteroar-
omatic and aliphatic aldehydes with b-keto esters in the
presence of a Lewis acid was also examined. In all cases,
Na2CO3.
the reaction proceeded smoothly to give the correspond-
In summary, the use of a-(benzotriazolyl)alkyl ureas 9 as
a masked acyliminium ion in the reaction with b-keto es-
ing dihydropyrimidinones in high yield. Compared to the
classical Biginelli method, one important feature of the
ters provides a simple and convenient method particularly
present protocol is the ability to tolerate variation in all the
for the preparation of C6-aryl substituted Biginelli com-
reaction components.
pounds. The adopted procedure is effective, involves sim-
NMR spectroscopy and elemental analyses supported the
ple experimental procedures and product isolation; hence,
1
structures of the dihydropyrimidineones 4a–q. The H
it is a useful addition to the existing synthetic methods.
All mps are uncorrected. 1H and 13C NMR spectra were recorded on
a Varian Gemini (300 MHz) spectrometer in CDCl3, DMSO-d6 or
Me2CO-d6 with TMS as the internal standard. Microanalyses were
performed on a Carlo Erba 1106 elemental analyzer.
Benzotriazole Derivatives 9; General Procedure
A mixture of benzotriazole (1.19 g, 10 mmol), aldehyde (10 mmol),
urea (10 mmol) and acidic cationic resin Amberlyst® 15 (0.1 g) was
heated under reflux together with performance fluid (15 mL; avail-
able from the 3M company) in a 50 mL round-bottom flask fitted
with a Dean–Stark trap. After refluxing for 12 h, H2O (0.2 mL) was
removed. Then the mixture was allowed to cool and the crude prod-
uct was removed from the performance fluid by decantation. The
product was dissolved in benzene (100 mL), the resin filtered off
and the solvent removed to give 9 as low melting solids in 80–90%
1
yields with 94–97% purity (as estimated by H and 13C NMR),
which were used as such for further reaction.
Alkyl 3,4-Dihydropyrimidin-2(1H)-one-5-carboxlates 4a–q;
General Procedure
A mixture of a-(benzotriazolyl)alkyl urea 9 (2 mmol), b-keto ester
(2 mmol) and zinc bromide (4 mmol) in anhydrous 1,2-dichloro-
Scheme 3 For designation of R1, R2, R3, R3, and X in 4 see Table 1
Synthesis 2003, No. 15, 2358–2362 © Thieme Stuttgart · New York

2360
A. A. A. Abdel-Fattah
PAPER
Table 1 Synthesis of Alkyl 3,4-Dihydropyrimidine-5-carboxlates 4a–q via Ureidoalkyation of b-Keto Esters 3 with a-(Benzotriazolyl)alkyl
Urea Derivatives 9
Entry
4a
4b
4c
R1
R2
R3
Et
R4
X
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Yield (%)
85
Lit. yield (%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Ph
Ph
8928
–
Et
Ph
91
Ph
Et
4-MeC6H4
1-Naphthyl
1-Naphthyl
2-MeO-5-BrC6H3
2-MeO-5-BrC6H3
4-ClC6H4
4-ClC6H4
4-CNC6H4
4-CNC6H4
4-NO2C6H4
4-NO2C6H4
2-Thienyl
2-Thienyl
2-Thienyl
CHMe2
81
–
4d
4e
Me
Ph
Me
Et
84
–
90
–
4f
Me
Ph
Me
Et
89
–
4g
4h
4i
93
–
Me
Ph
Me
Et
92
–
94
–
4j
Me
Ph
Me
Et
81
–
4k
4l
85
–
Me
Ph
Et
89
–
4m
4n
4o
4p
4q
Et
97
–
Me
Ph
Me
Et
82
–
91
–
Me
Me
Me
Et
85
–
H
O
77
8325
ethane (20 mL) was refluxed for 24 h and poured into ice–H2O (50
mL), then extracted with EtOAc (3 × 20 mL). The combined organ-
ic extract was washed with sat. aq Na2CO3 (40 mL) and H2O (30
mL) and dried (MgSO4, 5 g). The solvent was removed in vacuo and
the resulting oil was purified by column chromatography (silica gel;
CH2Cl2–EtOAc, 4:1) or by recrystallization from EtOH to give
products 4a–q.
Ethyl 1-Methyl-4-(4-methylphenyl)-2-oxo-6-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (4c)
Yield: 0.57 g (81%); colorless microcrystals; mp 223–225 °C.
1H NMR: d = 7.41–7.14 (m, 9 H), 5.95 (br s, 1 H), 5.45 (d, 1 H,
J = 1.8 Hz), 3.78 (q, 2 H, J = 7.1 Hz), 2.80 (s, 3 H), 2.34 (s, 3 H),
0.77 (t, 3 H, J = 7.1 Hz).
13C NMR: d = 165.3, 154.1, 150.2, 140.4, 137.6, 134.9, 129.4,
128.7, 128.2, 127.4, 126.2, 105.5, 59.9, 54.9, 32.4, 21.1, 13.4.
Ethyl 1,6-Dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4a)
Anal. Calcd for C21H22N2O3 (350.42): C, 71.98; H, 6.33; N, 7.99.
Found C, 71.76; H, 6.49; N, 8.12.
Yield: 0.47 g (85%); colorless microcrystals; mp 176–177 °C (lit.28
180 °C).
1H NMR: d = 7.32–7.24 (m, 5 H), 5.75 (br s, 1 H), 5.39 (d, 1 H,
J = 3.2 Hz), 4.11 (q, 2 H, J = 7.1 Hz), 3.2 (s, 3 H), 2.52 (s, 3 H), 1.19
(t, 3 H, J = 7.1 Hz).
Methyl 1,6-Dimethyl-4-(1-naphthyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4d)
Yield: 0.52 g (84%); colorless plates; mp 177–179 °C.
1H NMR: d = 8.17 (d, 1 H, J = 8.2 Hz), 7.87 (d, 1 H, J = 8.2 Hz),
7.76 (d, 1 H, J = 8.0 Hz), 7.58–7.49 (m, 2 H), 7.41–7.30 (m, 2 H),
6.22 (br s, 1 H), 5.89 (br s, 1 H), 3.47 (s, 3 H), 3.47 (s, 3 H), 2.65 (s,
3 H).
13C NMR: d = 166.4, 153.5, 150.7, 137.3, 134.2, 130.2, 129.2,
128.6, 126.6, 125.7, 125.6, 123.6, 122.0, 102.3, 51.3, 49.4, 30.2,
16.5.
13C NMR: d = 166.0, 154.1, 149.3, 143.3, 128.6, 127.6, 126.1,
104.1, 60.1, 53.6, 30.2, 16.4, 14.1.
Ethyl 4,6-Diphenyl-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4b)
Yield: 0.61 g (91%); colorless microcrystals; mp 162–164 °C.
1H NMR: d = 7.41–7.22 (m, 10 H), 6.12 (br s, 1 H), 5.49 (d, 1 H,
J = 3.2 Hz), 3.79 (q, 2 H, J = 7.1 Hz), 2.80 (s, 3 H), 0.78 (t, 3 H,
J = 7.1 Hz).
Anal. Calcd for C18H18N2O3 (310.36): C, 69.66; H, 5.85; N, 9.03.
Found C, 69.45; H, 6.09; N, 8.89.
13C NMR: d = 165.3, 154.2, 150.4, 143.3, 134.8, 128.8, 128.4,
Ethyl 1-Methyl-4-(1-naphthyl)-2-oxo-6-phenyl-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4e)
Yield: 0.67 g (90%); pale yellow plates; mp 193–195 °C.
128.2, 127.9, 127.3, 126.2, 105.3, 59.9, 54.1, 32.4, 13.4.
Anal. Calcd for C20H20N2O3 (336.39): C, 71.41; H, 5.99; N, 8.33.
Found C, 71.70; H, 5.81; N, 8.14.
Synthesis 2003, No. 15, 2358–2362 © Thieme Stuttgart · New York

PAPER
Biginelli-Type Dihydropyridiminones Using a-(Benzotriazolyl)alkyl Urea Derivatives
2361
1H NMR: d = 8.07 (d, 1 H, J = 8.4 Hz), 7.88 (d, 1 H, J = 8.0 Hz),
7.81 (d, 1 H, J = 8.1 Hz), 7.63–7.24 (m, 9 H), 6.33 (br s, 1 H), 6.06
(br s, 1 H), 3.67 (q, 2 H, J = 7.1 Hz), 2.81 (s, 3 H), 0.62 (t, 3 H,
J = 7.1 Hz).
13C NMR: d = 165.1, 153.5, 151.2,137.6, 134.9, 134.2, 130.3,
129.1, 128.8, 128.7, 128.6, 128.3, 126.6, 125.7, 125.6, 123.8, 122.3,
103.9, 59.8, 50.0, 32.2, 13.3.
13C NMR: d = 166.1, 154.0, 150.6, 148.2, 132.4, 126.8, 118.5,
111.4, 102.8, 52.9, 51.4, 30.3, 16.5.
Anal. Calcd for C15H15N3O3 (285.31): C, 63.15; H, 5.30; N, 14.73.
Found C, 62.97; H, 5.19; N, 14.66.
Ethyl 4-(4-Cyanophenyl)-1-methyl-2-oxo-6-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (4k)
Yield: 0.61 g (85%); colorless needles; mp 187–189 °C.
Anal. Calcd for C23H20N2O3 (372.43): C, 74.18; H, 5.41; N, 7.52.
Found C, 73.93; H, 5.63; N, 7.69.
1H NMR: d = 7.67 (d, 2 H, J = 8.2 Hz), 7.56 (d, 2 H, J = 8.1 Hz),
7.46–7.27 (m 3 H), 7.21–7.15 (m, 2 H), 6.63 (d, 1 H, J = 3.2 Hz),
5.56 (d, 1 H, J = 3.6 Hz), 3.79 (q, 2 H, J = 7.1 Hz), 2.80 (s, 3 H),
0.74 (t, 3 H, J = 7.1 Hz).
Methyl 1,6-Dimethyl-4-(5-bromo-2-methoxyphenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f)
Yield: 0.66 g (89%); colorless microcrystals; mp 150–152 °C.
13C NMR: d = 165.2, 154.1, 151.3, 148.3, 134.3, 132.6, 129.0,
1H NMR: d = 7.34 (d, 1 H, J = 8.7 Hz), 7.03 (s, 1 H), 6.76 (d, 1 H,
J = 8.8 Hz), 5.94 (br s, 1 H), 5.60 (s, 1 H), 3.84 (s, 3 H), 3.62 (s, 3
H), 3.19 (s, 3 H), 2.64 (s, 3 H).
13C NMR: d = 166.2, 156.0, 153.9, 152.1, 131.7, 131.4, 128.9,
112.9, 112.3, 100.1, 55.5, 51.4, 48.2, 30.3, 16.5.
128.5, 128.3, 127.3, 127.0, 111.7, 104.5, 60.2, 53.6, 32.5, 13.3.
Anal. Calcd for C21H19N3O3 (361.40): C, 69.79; H, 5.30; N, 11.63.
Found C, 69.93; H, 5.13; N, 11.57.
Ethyl 1,6-Dimethyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4l)
Yield: 0.54 g (89%); yellow plates; mp 112–114 °C.
1H NMR: d = 8.14 (d, 2 H, J = 8.5 Hz), 7.44 (d, 2 H, J = 8.4 Hz),
6.85 (br s, 1 H), 5.51 (d, 1 H, J = 3.0 Hz), 4.14 (q, 2 H, J = 7.1 Hz),
3.22 (s, 3 H), 2.54 (s, 3 H), 1.21 (t, 3 H, J = 7.1 Hz).
Anal. Calcd for C15H17BrN2O4 (369.22): C, 48.80; H, 4.64; N, 7.59.
Found C, 49.07; H, 4.39; N, 7.80.
Ethyl 4-(5-Bromo-2-methoxyphenyl)-1-methyl-2-oxo-6-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4g)
Yield: 0.83 g (93%); colorless plates; mp 179–181 °C.
13C NMR: d = 165.6, 154.0, 151.3, 150.3, 147.3, 127.1, 123.9,
1H NMR: d = 7.47–7.25 (m, 7 H), 6.80 (d, 1 H, J = 8.7 Hz), 5.91 (br
s, 1 H), 5.68 (d, 1 H, J = 3.7 Hz), 3.80 (q, 2 H, J = 7.1 Hz,), 2.78 (s,
3 H), 0.78 (t, 3 H, J = 7.1 Hz).
13C NMR: d = 165.0, 156.2, 154.0, 152.6, 134.9, 131.8, 131.4,
129.4, 128.9, 128.6, 127.3, 113.0, 112.6, 101.5, 59.9, 55.7, 48.9,
32.4, 13.4.
103.1, 60.4, 53.0, 30.4, 16.6, 14.1.
Anal. Calcd for C14H15N3O5 (305.29): C, 55.08; H, 4.95; N, 13.76.
Found C, 54.97; H, 5.11; N, 13.84.
Ethyl 1-Methyl-4-(4-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (4m)
Yield: 0.74 g (97%); colorless plates; mp 190–192 °C.
Anal. Calcd for C21H21BrN2O4 (445.32): C, 56.64; H, 4.75; N, 6.29.
Found C, 56.78; H, 4.69; N, 5.97.
1H NMR: d = 8.22 (d, 2 H, J = 7.4 Hz), 7.62 (d, 2 H, J = 7.6 Hz),
7.44 –7.15 (m, 5 H), 6.86 (br s, 1 H), 5.62 (s, 1 H), 3.80 (q, 2 H,
J = 7.1 Hz), 2.80 (s, 3 H), 0.77 (t, 3 H, J = 7.1 Hz).
13C NMR: d = 165.2, 154.2, 151.4, 150.3, 147.5, 134.3, 129.1,
128.7, 128.4, 127.2, 124.1, 104.4, 60.2, 53.3, 32.5, 13.3.
Methyl 4-(4-Chlorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4h)
Yield: 0.54 g (92%); colorless plates; mp 117–119 °C.
1H NMR: d = 7.26 (d, 2 H, J = 8.2 Hz), 7.17 (d, 2 H, J = 7.8 Hz),
6.30 (br s, 1 H), 5.36 (s, 1 H), 3.66 (s, 3 H), 3.21 (s, 3 H), 2.51 (s, 3
H).
Anal. Calcd for C20H19N3O5 (381.39): C, 62.99; H, 5.02; N, 11.02.
Found C, 63.11; H, 5.07; N, 11.23.
13C NMR: d = 166.3, 154.0, 149.9, 141.7, 133.5, 128.8, 127.5,
103.6, 52.9, 51.4, 30.3, 16.6.
Methyl 1,6-Dimethyl-2-oxo-4-(2-thienyl)-1,2,3,4-tetrahydropy-
rimidine-5-carboxylate (4n)
Yield: 0.44 g (82%); brownish yellow microcrystals; mp 149–
151 °C.
1H NMR (DMSO-d6): d = 8.14 (d, 1 H, J = 3.8 Hz), 7.35 (d, 1 H,
J = 4.9 Hz), 6.93 (dd, 1 H, J = 3.6, 8.4 Hz), 6.88 (br s, 1 H), 5.40 (d,
1 H, J = 3.6 Hz), 3.64 (s, 3 H), 3.10 (s, 3 H), 2.47 (s, 3 H).
Anal. Calcd for C14H15ClN2O3 (294.74): C, 57.05; H, 5.13. Found
C, 56.88; H, 5.06.
Ethyl 4-(4-Chlorophenyl)-1-methyl-6-phenyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (4i)
Yield: 0.70 g (94%); colorless microcrystals; mp 203–205 °C.
3C NMR (DMSO-d6): d = 165.6, 153.2, 151.3, 147.8, 126.8, 124.7,
1H NMR: d = 7.42–7.19 (m, 9 H), 6.18 (br s, 1 H), 5.47 (d, 1 H,
J = 3.3 Hz), 3.79 (q, 2 H, J = 7.1 Hz), 2.80 (s, 3 H), 0.76 (t, 3 H,
J = 7.1 Hz).
123.6, 102.8, 51.2, 48.1, 29.8, 16.0.
Anal. Calcd for C12H14N2O3S (266.32): N, 10.52. Found N, 10.29.
13C NMR: d = 165.3, 154.1, 150.6, 141.8, 134.6, 133.6, 128.9,
128.5, 128.3, 127.7, 127.3, 105.1, 60.0, 53.5, 32.5, 13.4.
Ethyl 1-Methyl-2-oxo-6-phenyl-4-(2-thienyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4o)
Yield: 0.62 g (91%); pale yellow needles; mp 170–172 °C.
Anal. Calcd for C20H19ClN2O3 (370.84): C, 64.78; H, 5.16; N, 7.55.
Found C, 64.69; H, 5.13; N, 7.34.
1H NMR (DMSO-d6): d = 8.29 (d, 1 H, J = 3.9 Hz), 7.45–7.41 (m,
4 H), 7.27–6.99 (m, 4 H), 5.47 (d, 1 H, J = 3.9 Hz), 3.72 (q, 2 H,
J = 7.0 Hz), 2.65 (s, 3 H), 0.71 (t, 3 H, J = 7.1 Hz).
13C NMR (DMSO-d6): d = 164.5, 153.2, 151.0, 147.7, 134.5, 128.7,
128.3, 127.4, 127.0, 125.0, 124.1, 104.4, 59.3, 48.5, 32.0, 13.3.
Methyl 4-(4-Cyanophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (4j)
Yield: 0.46 g (81%); pale yellow needles; mp 162–164 °C.
1H NMR: d = 7.60–7.36 (m, 4 H), 6.95 (br s, 1 H), 5.44 (d, 1 H,
J = 3.7 Hz), 3.67 (s, 3 H), 3.20 (s, 3 H), 2.52 (s, 3 H).
Anal. Calcd for C18H18N2O3S (342.42): C, 63.14; H, 5.30; N, 8.18.
Found C, 63.46; H, 5.19; N, 7.99.
Synthesis 2003, No. 15, 2358–2362 © Thieme Stuttgart · New York

2362
A. A. A. Abdel-Fattah
PAPER
Leppert, P.; Nagarathnam, D.; Forray, C. J. Med. Chem.
Methyl 6-Methyl-4-(2-thienyl)-2-thioxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (4p)
2000, 43, 2703.
Yield: 0.46 g (85%); brown microcrystals; mp 212–214 °C.
1H NMR (acetone-d6): d = 9.47 (br s, 1 H), 8.91 (br s, 1 H), 7.40–
6.99 (m, 3 H), 5.74 (s, 1 H), 3.74 (s, 2 H), 2.48 (s, 3 H).
13C NMR (acetone-d6): d = 177.0,166.3, 148.0, 146.0, 127.7, 127.6,
126.0, 125.3, 103.0, 60.8, 51.6, 17.8.
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Anal. Calcd for C11H12N2O2S2 (268.36): N, 10.44. Found N, 10.61.
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Ethyl 4-Isopropyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4q)
Yield: 0.35 g (77%); colorless microcrystals; mp 192–194 °C (lit.25
mp 194–195 °C).
1H NMR: d = 8.62 (br s, 1 H), 6.36 (br s, 1 H), 4.23–4.13 (m, 3 H),
2.29 (s, 3 H), 1.89–1.83 (m, 1 H), 1.28 (t, 3 H, J = 7.1 Hz), 0.92 (d,
3 H, J = 6.9 Hz), 0.86 (d, 3 H, J = 6.7 Hz).
13C NMR: d = 166.2, 155.3, 147.1, 100.2, 59.8, 56.8, 34.5, 18.4,
15.6, 14.2.
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Acknowledgment
The author gratefully acknowledges Professor Alan R. Katritzky
and Professor A. F. M. Fahmy for their generous help and discussi-
on during this work.
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Synthesis 2003, No. 15, 2358–2362 © Thieme Stuttgart · New York