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

Article abstract of DOI:10.1134/S107036321612015X

Three-component reactions of acetoacetic acid N-arylamides, aromatic aldehydes, and thiourea afforded N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides. Structure and antimicrobial activity of the compounds obtained were examined.

Full text of DOI:10.1134/S107036321612015X

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 12, pp. 2666–2670. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.L. Gein, T.M. Zamaraeva, A.V. Balandina, M.V. Dmitriev, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 12,
pp. 2033–2038.
Synthesis and Antimicrobial Activity of N,6-Diaryl-4-methyl-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides
V. L. Geina*, T. M. Zamaraevaa, A. V. Balandinaa, and M. V. Dmitrievb
a Perm State Pharmaceutical Academy, Ministry of Healthcare of the Russian Federation,
ul. Polevaya 2, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
b Perm State National Research University, Perm, Russia
Received April 14, 2016
Abstract—Three-component reactions of acetoacetic acid N-arylamides, aromatic aldehydes, and thiourea
afforded N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides. Structure and antimicro-
bial activity of the compounds obtained were examined.
Keywords: three-component reaction, N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides,
antimicrobial activity
DOI: 10.1134/S107036321612015X
Dihydropyrimidine-2-one(thione) derivatives are of
interest due to wide spectrum of biological activity.
Structure of these pyrimidine derivatives includes ester
group at the position 5 of heterocycle [1–5]. Some of
alkoxycarbonyl derivatives of pyrimidine show cardio-
vascular [6, 7], antihypertensive [8], antiarrhythmic
[9], anticancer [10–12], antioxidant [13, 14], anti-
inflammatory [15], fungicidal [16, 17], and antimicro-
bial [18, 19] activity.
derivatives without using expensive catalysts and toxic
solvents.
In order to obtain new pyrimidine derivatives, study
their spatial structure and antimicrobial activity, we
synthesized new N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-
tetrahydropyrimidine-5-carboxamides 1–12 by react-
ing acetoacetic acid N-arylamides with aromatic
aldehydes and thiourea. The reactions were carried out
without solvent under conditions analogous to those
described in [20] (Scheme 1).
Data on the synthesis of 5-carbamoyl derivatives of
dihydropyrimidine-2-ones and -2-thiones are scarce. It
is known that biological activity is retained when
changing ester moiety at the position 5 of hydro-
genated pyrimidine ring with amide group [1–5].
Compounds 1–12 were colorless crystalline sub-
stances, soluble in DMF, DMSO, as well as in acetic
acid and ethanol on heating, and insoluble in water,
benzene and toluene.
Currently principles of green chemistry are preferred
that make promising the synthesis of pyrimidine
The IR spectra of compounds 1–12 contained the
absorption bands due to stretching vibrations of amide
Scheme 1.
R1
O
R1
120_150oC
N
NH
O
S
O
O
+
+
H
R2
H
R2
N
S
H2N
NH2
N
H
H
R1 = 2-CH3 (1–6), 2,4-(CH3)2 (7–9), 2-Cl (10–12); R2 = 4-FC6Н4 (1), 4-CH3OOCC6Н4 (2, 9), 4-(CH3)2NC6Н4 (3), 2,4-
Cl2C6Н3 (4, 10), 4-BrC6Н4 (5), 2-NO2C6Н4 (6, 11), 3-pyridyl (7), 2-thienyl (8), 2-FC6Н4 (12).
2666

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
2667
Crystal structure of 4-methyl-6-(4-dimethylaminophenyl)-N-2-methylphenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide 3.
groups (1660–1688 cm–1), N–H (3120–3400 cm–1) and
C=C bonds (1600–1630 cm–1).
distorted boat conformation; deviations of the C1 and
N1 atoms from the C4C3C2N2 plane equal 0.395 and
0.559 Å, respectively. The dimethylaminophenyl moiety
occupies pseudo-axial position. The carbonyl group is
turned with respect to the C4C3C2N2 plane: the torsion
angle C2C3C14O1 is –137.1(3)°. The tolylcarbamoyl
substituent is not planar: the torsion angles O1C14N3C15
and C14N3C15C20 are 8.9(8)° and 50(1)°, respectively.
The ortho-tolyl fragment is disordered by two posi-
tions with populations of 0.703(8) and 0.297(8) that
indicates the presence of two conformers of compound
3 in the crystal. Molecules of 3 in the crystal are linked
to each other through intermolecular hydrogen bonds
to form infinite two-dimensional network parallel to
the plane (1 0 0). Hydrogen bonding parameters are
shown in Table 1.
Compounds 1–12 showed characteristically in the 1H
NMR spectra a singlet of С4Н3 group (1.85–2.15 ppm),
doublets of H1 and H6 protons (5.20–6.02 and 9.05–
9.39 ppm, J1,6 = 1.9–3.0 Hz), a singlet of amide NH
proton (8.91–9.37 ppm), and a broad signal of N3H
moiety (9.74–10.07 ppm). Signals from the corres-
ponding aryl substituents were also present. In the
mass spectrum of compound 5 we observed the
molecular ion peak [M]+ of m/z 417 and the fragment
ion peaks of m/z 311 [M – CH3С6H4NH]+, 106
[CH3С6H4NH]+. These data confirmed the structure of
the obtained compounds.
The crystal structure of compound 3 was deter-
mined by X-ray diffraction analysis (see figure) of a
single crystal obtained by slow crystallization from
ethanol. Compound 3 crystallizes in the centro-
symmetric space group belonging to the monoclinic
crystal system. The tetrahydropyrimidine ring adopts a
Antimicrobial activity of compounds 1–12 was
determined in relation to St. aureus, E. coli, C.
albicans strains (Table 2). According to the data
obtained, they posses weak antimicrobial activity.
Table 1. Hydrogen bonds parameters in the molecule of 3
D–H···A
N1–H1···N4 [x, –y + 1/2, z − 1/2]
d(D–H), Å
d(H···A), Å
d(D···A), Å
Angle DHA, deg
160(2)
0.85(2)
2.22(2)
3.031(3)
N2–H2···S1 [–x + 1, –y, –z + 2]
N3–H3···O1 [x, –y + 1/2, z + 1/2]
0.83(3)
0.82(2)
2.56(3)
2.00(2)
3.378(3)
2.819(3)
169(3)
174(3)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

2668
GEIN et al.
disordered components were determined taking into
Table 2. Antimicrobial activity of compounds 1–12
MIC, μg/mL
account SAME soft limits. All calculations were
performed using SHELX-97 [22] and OLEX2 [23]
program packages. The final divergence factors: R1 =
0.0657, wR2 = 0.1243 for 2288 reflections with I > 2σ(I),
R1 = 0.1609, wR2 = 0.1659 for all 4943 independent
reflections, S = 1.002. The crystallographic data for
compound 3 were deposited to the Cambridge
Crystallographic Data Centre (CCDC 1471336).
Compound
St. aureus
E. coli
С. albicans
ATCC 6538 ATCC 25922 ATCC 24433
1
2
3
4
5
6
7
8
500
500
500
500
500
500
1000
500
500
500
1000
1000
1000
500
1000
500
500
н/а
1000
1000
500
–
250
125
250
1000
500
250
1000
–
4-Methyl-N-(2-methylphenyl)-6-(4-fluorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
(1). A mixture of 0.01 mol of 2-methylacetoacet-
anilide, 0.01 mol of 4-fluorobenzaldehyde, and
0.01 moles of thiourea was heated at 120–150°C for 5–
10 min until gas evolution ceased and the reaction
mixture solidified. After cooling, the solid was treated
with ethanol, filtered, and recrystallized from ethanol.
Yield 2.56 g (72%), mp 170–172°С (EtOH). IR
spectrum, ν, cm–1: 1616 (C=C), 1688 (CON), 3216
9
10
11
500
1000
1000
500
1000
1000
500
12
Dioxidine
62.5–1000
3.9–62.5
Chloramine B
Fluconazole
500
–
250
–
–
1
(NH). Н NMR spectrum (DMSO-d6), δ, ppm: 1.89 s
8–32
(3Н, 4-СН3), 2.12 s (3Н, СН3C6H4), 5.34 d (1Н, СН,
J1,6 = 1.9 Hz), 7.02–7.24 m (8H, СН3C6H4, FC6H4),
9.10 s (1Н, NH, amide), 9.30 d (1Н, N1H, J1,6 = 1.9 Hz),
9.88 br.s (1Н, N3H). Found, %: С 64.10, 64.33; Н
5.02, 5.19; N 11.71, 11.95. C19H18FN3OS. Calculated,
%: С 64.21; Н 5.10; N 11.82.
EXPERIMENTAL
IR spectra in mineral oil were recorded on a
Specord M-80 spectrometer. H NMR spectra of the
1
solutions in DMSO-d6 were registered on a Bruker 500
spectrometer (500.13 MHz) relative to internal TMS.
Mass spectrum was obtained on a Finnigan MAT
INCOS-50 instrument (ionization energy 70 eV).
Elemental analysis was performed on a Perkin Elmer
2400 analyzer. Melting points were determined on a
M-565 instrument.
Compounds 2–12 were prepared similarly.
6-(4-Carbomethoxyphenyl)-4-methyl-N-(2-methyl-
phenyl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-
carboxamide (2). Yield 3.08 g (78%), mp 234–236°С
(EtOH). IR spectrum, ν, cm–1: 1630 (C=C), 1680
1
(CON), 1720 (CO), 3150, 3200, 3360 (NH). Н NMR
spectrum (DMSO-d6), δ, ppm: 1.90 s (3Н, 4-СН3),
2.12 s (3Н, СН3C6H4), 3.79 s (3Н, СН3OOCC6H4),
5.42 d (1Н, СН, J1,6 = 2.1 Hz), 7.02–7.93 m (8H,
СН3C6H4, CH3OOCC6H4), 9.14 s (1Н, NH, amide),
9.36 d (1Н, N1H, J1,6 = 2.1 Hz), 9.93 br.s (1Н, N3H).
Found, %: С 63.67, 63.90; Н 5.27, 5.45; N 10.49,
10.75. C21H21N3O3S.. Calculated, %: С 63.78; Н 5.35;
N 10.62.
X-ray diffraction analysis of compound 3 was
performed on a Xcalibur R diffractometer equipped
with a CCD-detector [MoKα-radiation, 295(2) K, ω-
scanning]. A correction for absorption was applied
empirically using SCALE3 ABSPACK algorithm [21].
Crystals of compound 3, C21H24N4O3S, monoclinic,
space group P21/c, unit cell parameters: a = 11.630(5),
b = 19.765(6), c = 9.414(3) Å, β = 101.47(3)°,
V 2120.6(14) Å3, dcalc = 1.192 g/cm3, µ = 0.170 mm–1,
Z = 4. The structure was solved by the direct full-
matrix method and refined by anisotropic approxi-
mation for all non-hydrogen atoms. Hydrogen atoms
were refined according to a rider model in isotropic
approximation with dependent thermal parameters; the
NH hydrogen atoms were localized from difference
electron density synthesis and refined independently in
an isotropic approximation. Atomic coordinates of the
4-Methyl-N-(2-methylphenyl)-6-(4-dimethylamino-
phenyl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-
carboxamide (3). Yield 2.21 g (58%), mp 238–240°С
(EtOH). 1Н NMR spectrum (DMSO-d6), δ, ppm: 1.89 s
(3Н, 4-СН3), 2.10 s (3Н, СН3C6H4), 2.82 s [6Н,
(CH3)2NC6H4], 5.20 d (1Н, СН, J1,6 = 2.1 Hz), 6.57–
7.02 m [8H, СН3C6H4, (CH3)2NC6H4], 8.95 s (1Н, NH,
amide), 9.18 d (1Н, N1H, J1,6 = 2.1 Hz), 9.74 br.s (1Н,
N3H). Found, %: С 66.17, 66.41; Н 6.26, 6.45; N
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
2669
14.59, 14.84. C21H24N4OS. Calculated, %: С 66.29; Н
6.36; N 14.72.
(8). Yield 2.26 g (63%), mp 240–242°С (EtOH). IR
spectrum, ν, cm–1: 1610 (C=C), 1660 (CON), 3120,
3210, 3320 (NH). Н NMR spectrum (DMSO-d6), δ,
ppm: 1.94 s (3Н, 4-СН3), 2.13 s and 2.22 s [6Н,
(СН3)2C6H3], 5.59 d (1Н, СН, J1,6 = 2.8 Hz), 6.79–
7.33 m [6H, (СН3)2C6H3, C4H3S], 8.91 s (1Н, NH,
amide), 9.39 d (1Н, N1H, J1,6 = 2.8 Hz), 9.90 br.s (1Н,
N3H). Found, %: С 60.37, 60.61; Н 5.28, 5.45; N
11.62, 11.87. C18H19N3OS2. Calculated, %: С 60.48; Н
5.36; N 11.75.
1
4-Methyl-N-(2-methylphenyl)-6-(2,4-dichlorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carbox-
amide (4). Yield 2.76 g (68%), mp 262–264°С
(EtOH). IR spectrum, ν, cm–1: 1610 (C=C), 1660
1
(CON), 3180, 3210, 3352 (NH). Н NMR spectrum
(DMSO-d6), δ, ppm: 1.91 s (3Н, 4-СН3), 2.08 s (3Н,
СН3C6H4), 5.67 d (1Н, СН, J1,6 = 2.8 Hz), 6.99–7.34
m (7H, СН3C6H4, 2,4-Cl2C6H3), 9.02 s (1Н, NH,
amide), 9.05 d (1Н, N1H, J1,6 = 2.8 Hz), 9.82 br.s (1Н,
N3H). Found, %: С 56.04, 56.27; Н 4.13, 4.30; N
10.22, 10.47. C19H17Cl2N3OS. Calculated, %: С 56.16;
Н 4.22; N 10.34.
6-(4-Carbomethoxyphenyl)-4-methyl-N-(2,4-di-
methylphenyl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-
5-carboxamide (9). Yield 3.24 g (79%), mp 240–242°С
(EtOH). IR spectrum, ν, cm–1: 1630 (C=C), 1680
1
(CON), 1720 (CO), 3200, 3150, 3380 (NH). Н NMR
4-Methyl-6-(4-bromophenyl)-N-(2-methylphenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carbox-
amide (5). Yield 2.87 g (69%), mp 246–248°С
(EtOH). 1Н NMR spectrum (DMSO-d6), δ, ppm: 1.91 s
(3Н, 4-СН3), 2.11 s (3Н, СН3C6H4), 5.31 d (1Н, СН,
spectrum (DMSO-d6), δ, ppm: 1.86 s (3Н, 4-СН3),
2.11 s and 2.19 s [6Н, (СН3)2C6H3], 3.79 s (3Н,
CH3OOCC6H4), 5.41 d (1Н, СН, J1,6 = 2.1 Hz), 6.86–
7.92 m [7H, (СН3)2C6H3, CH3OOCC6H4], 9.06 s (1Н,
NH, amide), 9.34 d (1Н, N1H, J1,6 = 2.1 Hz), 9.92 br.s
(1Н, N3H). Found, %: С 64.42, 64.65; Н 5.58, 5.75; N
10.14, 10.39. C22H23N3O3S. Calculated, %: С 64.53; Н
5.66; N 10.26.
J
1,6 = 3.0 Hz), 6.85–7.55 m (8H, СН3C6H4, 4-BrC6H4),
9.13 s (1Н, NH, amide), 9.20 d (1Н, N1H, J1,6
=
3.0 Hz), 10.00 br.s (1Н, N3H). Found, %: С 54.68,
54.93; Н 4.28, 4.45; N 9.98, 10.22. C19H18BrN3OS.
Calculated, %: С 54.81; Н 4.36; N 10.09.
4-Methyl-6-(2,4-dichlorophenyl)-N-(2-chlorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carbox-
amide (10). Yield 3.50 g (82%), mp 256–258°С
(EtOH). IR spectrum, ν, cm–1: 1620 (C=C), 1680
4-Methyl-N-(2-methylphenyl)-6-(2-nitrophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
(6). Yield 2.44 g (64%), mp 216–218°С (EtOH). IR
spectrum, ν, cm–1: 1620 (C=C), 1670 (CON), 3180,
1
(CON), 3190, 3220, 3390 (NH). Н NMR spectrum
(DMSO-d6), δ, ppm: 2.10 s (3Н, 4-СН3), 5.66 d
(1Н, СН, J1,6 = 1.9 Hz), 7.06–7.49 m (7H, ClC6H4, 2,4-
Cl2C6H3), 9.23 d (1Н, N1H, J1,6 = 1.9 Hz), 9.37 s (1Н,
NH, amide), 9.99 br.s (1Н, N3H). Found, %: С 50.55,
50.79; Н 3.24, 3.39; N 9.73, 9.98. C18H14Cl3N3OS.
Calculated, %: С 50.66; Н 3.31; N 9.85.
1
3280, 3400 (NH). Н NMR spectrum (DMSO-d6), δ,
ppm: 1.86 s (3Н, 4-СН3), 2.10 s (3Н, СН3C6H4), 6.02 d
(1Н, СН, J1,6 = 2.8 Hz), 7.00–7.89 m (8H, СН3C6H4,
2-NO2C6H4), 9.07 d (1Н, N1H, J1,6 = 2.8 Hz), 9.16 s
(1Н, NH, amide), 10.02 br.s (1Н, N3H). Found, %: С
59.56, 59.80; Н 4.64, 4.83; N 14.52, 14.77.
C19H18N4O3S. Calculated, %: С 59.67; Н 4.74; N 14.65.
4-Methyl-6-(2-nitrophenyl)-N-(2-chlorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carbox-
amide (11). Yield 3.17 g (79%), mp 200–202°С
(EtOH). IR spectrum, ν, cm–1: 1620 (C=C), 1680
4-Methyl-6-(3-pyridyl)-N-(2,4-dimethylphenyl)-2-
thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
(7). Yield 2.64 g (75%), mp 266–268°С (EtOH). IR
spectrum, ν, cm–1: 1600 (C=C), 1660 (CON), 3200
1
(CON), 3190, 3320, 3410 (NH). Н NMR spectrum
(DMSO-d6), δ, ppm: 2.15 s (3Н, 4-СН3), 6.01 d (1Н,
СН, J1,6 = 1.9 Hz), 7.06–7.89 m (8H, ClC6H4, 2-
NO2C6H4), 9.09 d (1Н, N1H, J1,6 = 1.9 Hz), 9.30 s (1Н,
NH, amide), 10.07 br.s (1Н, N3H). Found, %: С 53.55,
53.80; Н 3.65, 3.84; N 13.78, 14.04. C18H15ClN4O3S.
Calculated, %: С 53.67; Н 3.75; N 13.91.
1
(NH). Н NMR spectrum (DMSO-d6), δ, ppm: 1.85 s
(3Н, 4-СН3), 2.12 s and 2.19 s [6Н, (СН3)2C6H3], 5.35
d (1Н, СН, J1,6 = 2.1 Hz), 6.86–7.63 m [7H,
(СН3)2C6H3, C5H4N], 9.08 s (1Н, NH, amide), 9.32 d
(1Н, N1H, J1,6 = 2.1 Hz), 9.90 br.s (1Н, N3H). Found,
%: С 64.64, 64.87; Н 5.62, 5.81; N 15.78, 16.03.
C19H20N4OS. Calculated, %: С 64.75; Н 5.72; N 15.90.
4-Methyl-6-(2-fluorophenyl)-N-(2-chlorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
1
(12). Yield 3.15 g (84%), mp 210–212°С (EtOH). Н
4-Methyl-6-(2-thienyl)-N-(2,4-dimethylphenyl)-2-
NMR spectrum (DMSO-d6), δ, ppm: 2.11 s (3Н, 4-
thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
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GEIN et al.
Manic, V., Mishra, R.K., and Majeed, A.B.A., Eur. J.
Med. Chem., 2012, vol. 48, p. 16. doi 10.1016/
j.ejmech.2011.11.028
СН3), 5.57 d (1Н, СН, J1,6 = 1.9 Hz), 6.99–7.36 m
(8H, ClC6H4, FC6H4), 9.20 d (1Н, N1H, J1,6 = 1.9 Hz),
9.30 s (1Н, NH, amide), 9.91 br.s (1Н, N3H). Found,
%: С 57.41, 57.64; Н 3.93, 4.10; N 11.06, 11.31.
C18H15ClFN3OS. Calculated, %: С 57.52; Н 4.02; N
11.18.
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Antimicrobial activity of the compounds obtained
against strains of St. aureus, E. coli and C. albicans
was determined by serial dilutions of the test
compound solution with meat-peptone broth and
Sabouraud liquid medium and examined activity.
Bacterial load on 1 mL of culture liquid was 250 000
microbial cells. Control and test tubes were incubated
at 36–37°C for 18–20 h. Growth of bacterial cultures
or inhibition due to the bacteriostatic action of the test
compounds was registered. Minimum inhibitory
concentration of the substance (MIC, μg/mL), which
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