Synthesis of N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5- carboxamides

Full text of DOI:10.1134/S1070428009100315

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 10, pp. 1581–1582. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.L. Gein, T.M. Zamaraeva, A.A. Zorina, M.I. Vakhrin, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 10,
pp. 1591–1592.
SHORT
COMMUNICATIONS
Synthesis of N,6-Diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydro-
pyrimidine-5-carboxamides
V. L. Gein, T. M. Zamaraeva, A. A. Zorina, and M. I. Vakhrin
Perm State Pharmaceutical Academy, ul. Lenina 48, Perm, 614990 Russia;
e-mail: geinvl48@mail.ru
Received February 17, 2009
DOI: 10.1134/S1070428009100315
Examples of microwave-assisted Biginelli reactions
have been reported. Fedorova et al. [1] developed
a sonochemical method of synthesis of 2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylic acid esters.
2-Aryl-6-hydroxy-N,N,6-trimethyl-4-oxocyclohexane-
1,3-dicarboxamides were synthesized by reaction of
N,N-dimethylacetoacetamide with aromatic aldehydes
in the presence of piperidine [2]. Three-component
condensation of N-arylacetoacetamides with aromatic
aldehydes and thiourea was not studied previously.
the presence of hydrochloric acid [3] or heating under
reflux over a period of 3–4 h [4].
Compounds Ia–If were isolated as colorless crys-
talline substances that are soluble in chloroform, DMF,
DMSO, and hot ethanol and insoluble in water. The IR
spectra of Ia–If contained absorption bands due to
stretching vibrations of the amide carbonyl group
(1660–1680 cm–1), N–H bonds (3150–3200 cm–1), and
double C=C bond (1600–1620 cm–1). Compounds Ia–
1
If displayed in the H NMR spectra signals from
protons in the aromatic rings, a singlet from the
4-methyl group at δ 1.85–2.05 ppm, a doublet from the
6-H proton at δ 5.32–5.36 ppm (J = 2.61–2.63 Hz),
a singlet at δ 9.26–9.70 ppm and a doublet at δ 9.61–
9.89 ppm (J = 1.37–1.40 Hz) from the NH protons in
the pyrimidine ring, and a singlet at δ 8.96–9.44 ppm
from the amide NH group. In addition, a singlet at
δ 2.11 ppm was observed in the spectrum of Ie due to
methyl protons at the aromatic ring, while compound
If gave rise to two singlets at δ 2.09 and 2.18 ppm.
With a view to obtain new heterocyclic compounds
we were the first to study the reaction of acetoacet-
anilides [N-phenyl-3-oxobutanamide, N-(2-methyl-
phenyl)-3-oxobutanamide, and N-(2,4-dimethylphen-
yl)-3-oxobutanamide] with a mixture of thiourea and
aromatic aldehyde. The reactions were carried out by
heating the reactants for 5–7 min at 120–150°C, and
the products were the corresponding N,6-diaryl-4-
methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-car-
boxamides Ia–If. The proposed procedure is charac-
terized by shorter reaction time and higher yields than
in the classical Biginelli reaction which implies pro-
longed (2–3 days) stirring of the reactants in ethanol in
The mass spectrum of If contained the molecular
ion peak, m/z 351 [M]+, together with fragment ion
peaks with m/z 231 [M – (CH3)2C6H3NH]+, 121
R
O
Me
H
N
Me
CHO
N
NH
S
H
+
+
O
O
N
H
S
H2N
NH2
R
R'
R'
Ia–If
I, R = H, R′ = H (a), 3-O2N (b), 4-Cl (c), 2-Cl (d); R = 2-Me, R′ = H (e), R = 2,4-Me2, R′ = H (f).
1581

GEIN et al.
1582
[(CH3)2C6H3NH2]+, and 77 [Ph]+, which were consist-
ent with the assumed structure.
spectrum, δ, ppm: 1.99 s (3H, CH3), 5.56 d (1H, 6-H,
J = 2.63 Hz), 7.27 m (9H, Harom), 9.18 s (1H, NH),
9.70 s (1H, 3-H), 9.89 d (1H, 1-H, J = 1.37 Hz).
Found, %: C 60.20, 60.62; H 4.41, 4.61; N 11.54,
11.92; S 8.74, 9.21. C18H16ClN3OS. Calculated, %:
C 60.41; H 4.51; N 11.74; S 8.96.
4-Methyl-N,6-diphenyl-2-thioxo-1,2,3,6-tetrahy-
dropyrimidine-5-carboxamide (Ia). A mixture of
0.01 mol of acetoacetanilide, 0.01 mol of benzalde-
hyde, and 0.01 mol of thiourea was heated for 5–7 min
at 120–150°C until gaseous products no longer
evolved. The resulting material was cooled and treated
with ethanol, and the precipitate was filtered off and
recrystallized from alcohol. Yield 2.10 g (65%),
mp 216–217°C. IR spectrum, ν, cm–1: 3200 (NH), 1675
(C=O), 1600 (C=C). 1H NMR spectrum, δ, ppm: 2.04 s
(3H, CH3), 5.32 d (1H, 6-H, J = 2.61 Hz), 7.21 m
(10H, C6H5), 9.29 s (1H, NH), 9.59 s (1H, 3-H), 9.84 d
(1H, 1-H, J = 1.37 Hz). Found, %: C 67.15, 66.65;
H 5.40, 5.24; N 13.19, 12.79; S 9.71, 9.87. C18H17N3OS.
Calculated, %: C 66.85; H 5.30; N 12.99; S 9.91.
4-Methyl-N-(2-methylphenyl)-6-phenyl-2-thioxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (Ie).
Yield 2.05 g (61%), mp 229–231°C. IR spectrum, ν,
1
cm–1: 3200 (NH), 1680 (C=O), 1612 (C=C). H NMR
spectrum, δ, ppm: 1.90 s (3H, 4-CH3), 2.11 s (3H,
CH3C6H4), 5.33 d (1H, 6-H, J = 2.62 Hz), 7.16 m (9H,
Harom), 9.05 s (1H, NH), 9.26 s (1H, 3-H), 9.81 d (1H,
1-H, J = 1.37 Hz). Found, %: C 67.93, 67.42; H 5.78,
5.54; N 12.24, 12.65; S 9.65, 9.35. C19H19N3OS. Cal-
culated, %: C 67.63; H 5.68; N 12.45; S 9.50.
N-(2,4-Dimethylphenyl)-4-methyl-6-phenyl-2-
thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
(If). Yield 1.60 g (46%), mp 238–239°C. IR spectrum,
ν, cm–1: 3200 (NH), 1680 (C=O), 1612 (C=C). 1H NMR
spectrum, δ, ppm: 1.85 s (3H, 4-CH3), 2.09 s and
2.18 s (3H each, 2′-CH3, 4′-CH3), 5.33 d (1H, 6-H, J =
2.61 Hz), 7.23 m (8H, Harom), 8.96 s (1H, NH), 9.24 s
(1H, 3-H), 9.77 d (1H, 1-H, J = 1.37 Hz). Found, %:
C 68.05, 68.55; H 6.12, 5.90; N 11.75, 12.16; S 9.24,
8.85. m/z 351 [M]+. C20H21N3OS. Calculated, %:
C 68.35; H 6.02; N 11.96; S 9.12 M 351.47.
Compounds Ib–If were synthesized in a simi-
lar way.
4-Methyl-6-(3-nitrophenyl)-N-phenyl-2-thioxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (Ib).
Yield 1.91 g (53%), mp 234–235°C. IR spectrum, ν,
1
cm–1: 3200 (NH), 1680 (C=O), 1612 (C=C). H NMR
spectrum, δ, ppm: 1.99 s (3H, CH3), 5.36 d (1H, 6-H,
J = 2.63 Hz), 7.23 m (9H, Harom), 9.44 s (1H, NH),
9.70 s (1H, 3-H), 9.89 d (1H, 1-H, J = 1.38 Hz).
Found, %: C 58.98, 58.38; H 4.48, 4.28; N 15.40,
15.01; S 8.90, 8.62. C18H16N4O3S. Calculated, %:
C 58.68; H 4.38; N 15.21; S 8.70.
The IR spectra were recorded in mineral oil on
1
a Specord M-80 spectrophotometer. The H NMR
spectra were measured on a Bruker 500 instrument at
500.13 MHz using DMSO-d6 as solvent and tetra-
methylsilane as internal reference. The mass spectrum
(electron impact, 70 eV) was obtained on a Finnigan
MAT INCOS-50 mass spectrometer.
6-(4-Chlorophenyl)-4-methyl-N-phenyl-2-thioxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (Ic).
Yield 1.8 g (51%), mp 221–223°C. IR spectrum, ν,
1
cm–1: 3200 (NH), 1680 (C=O), 1612 (C=C). H NMR
spectrum, δ, ppm: 2.05 s (3H, CH3), 5.32 d (1H, 6-H,
J = 2.61 Hz), 7.30 m (9H, Harom), 9.40 s (1H, NH),
9.59 s (1H, 3-H), 9.61 d (1H, 1-H, J = 1.40 Hz).
Found, %: C 60.71, 60.21; H 4.41, 4.59; N 11.58,
11.82; S 8.72, 9.19. C18H16ClN3OS. Calculated, %:
C 60.41; H 4.51; N 11.74; S 8.96.
REFERENCES
1. Fedorova, O.V., Zhidovinova, M.S., Rusinov, G.L., and
Ovchinnikova, I.G., Izv. Ross. Akad. Nauk, Ser. Khim.,
2003, p. 2389.
2. Gein, V.L., Levandovskaya, E.B., Nosova, N.V., Vakh-
rin, M.I., Kriven’ko, A.P., and Aliev, Z.G., Russ. J. Org.
Chem., 2007, vol. 43, p. 1096.
6-(2-Chlorophenyl)-4-methyl-N-phenyl-2-thioxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (Id).
Yield 1.4 g (39%), mp 218–219°C. IR spectrum, ν,
3. Kappe, C.O., J. Org. Chem., 1997, vol. 62, p. 7201.
4. Kappe, C.O., Heterocycles, 1997, vol. 45, p. 1976.
1
cm–1: 3200 (NH), 1680 (C=O), 1612 (C=C). H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009