Synthesis and antimicrobial activity of 6-Aryl-3,4-dimethyl-N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides

Article abstract of DOI:10.1134/S1070363214100168

Three-component reaction of acetoacetanilide, aromatic aldehydes, and N-methylurea afforded 6-aryl-3,4-dimethyl-N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides. IR, ¹H NMR spectroscopy, mass spectrometry, and X-ray diffraction analys

Full text of DOI:10.1134/S1070363214100168

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 10, pp. 1950–1952. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © T.M. Zamaraeva, T.F. Odegova, A.Yu. Fedotov, M.V. Tomilov, V.L. Gein, P.A. Slepukhin, 2014, published in Zhurnal Obshchei
Khimii, 2014, Vol. 84, No. 10, pp. 1672–1675.
Synthesis and Antimicrobial Activity
of 6-Aryl-3,4-dimethyl-N-phenyl-2-oxo-1,2,3,6-
tetrahydropyrimidine-5-carboxamides
T. M. Zamaraevaa, T. F. Odegovaa, A. Yu. Fedotova,
M. V. Tomilova, V. L. Geina, and P. A. Slepukhinb,c
a Perm State Pharmaceutical Academy, Ministry of Health of the Russian Federation,
ul. Polevaya 2, Perm, 614990 Russia
е-mail: geinvl48@mail.ru
b Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
c B.N. Yeltsin Ural Federal University, Yekaterinburg, Russia
Received May 5, 2014
Abstract—Three-component reaction of acetoacetanilide, aromatic aldehydes, and N-methylurea afforded 6-aryl-
1
3,4-dimethyl-N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides. IR, H NMR spectroscopy, mass
spectrometry, and X-ray diffraction analysis data confirmed the structure of the compounds obtained.
Antimicrobial activity of these compounds was investigated.
Keywords: three-component synthesis, 1,2,3,6-tetrahydropyrimidine-5-carboxamide, antimicrobial activity
DOI: 10.1134/S1070363214100168
Currently the chemistry of the nitrogen-containing
heterocyclic compounds is one of rapidly developing
areas of organic and pharmaceutical chemistry. The
application in medical practice of preparations
containing pyrimidine ring in their structures shows
the usefulness of the search for new biologically active
compounds among pyrimidine derivatives. Com-
pounds having a pyrimidine ring have been known as
antibacterial and antifungal agents; some pyrimidine
derivatives show a pronounced antiviral and antitumor
activity [1–5].
activity, we synthesized 6-aryl-3,4-dimethyl-N-phenyl-
2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides
I–VI by reacting acetoacetanilide, aromatic aldehydes,
and N-methylurea as described in [6] (Scheme 1).
Compounds I–VI are colorless crystalline solids
soluble in DMF, DMSO, in acetic acid and ethanol
upon heating, insoluble in water, toluene, and benzene.
The IR spectra of I–VI contained the absorption
bands of amide groups (1644–1688 cm–1), N–H (3200–
3384 cm–1) and С=С bonds (1608–1640 cm–1).
1
In the H NMR spectra of I–VI there were the
Aiming to obtain the previously unknown
pyrimidine derivatives and to study their antimicrobial
signals of the protons of 4-CH3 and 3-CH3 moieties
Scheme 1.
O
R
O
O
O
O
H
CH3
O
N
H
N
N
H
+
+
H2N
N
H
R
CH3
N
H
I−VI
R = 4-NO2C6Н4 (I) , 4-FC6Н4 (II), 4-EtOC6Н4 (III), 4-ClC6Н4 (IV), 3-NO2C6Н4 (V), 3-MeOC6Н4 (VI).
1950

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
1951
(2.14–2.20 and 3.05–3.23 ppm, respectively), H6 (5.17–
Antimicrobial activity of compounds I–VI
Minimum inhibitory concentration,
mg mL–1
E. coli
5.38 ppm), H1 (7.14–7.91 ppm, J1,6 2.95–3.30 Hz), and
NH of the amide group (9.58–9.84 ppm).
Compound
The spatial structure of V was established by X-ray
diffraction analysis (see Figure). Single crystals were
obtained by slow evaporation of ethanol solution.
General geometric parameters of the molecule
(bond lengths and angles) are close to the standard. In
the crystal packing there are 2 types of hydrogen
bonds: chained intermolecular hydrogen bonds NH···O
between the amide moieties, and dimeric bonds
NH···O between the pyrimidinone moieties.
Antimicrobial activity of these compounds against
strains of St. aureus, E. coli, C. albicans (see table)
was determined by serial dilutions of the test com-
pound solution in meat-peptone broth and Sabouraud
liquid medium. Bacterial load on 1 mL of the culture
liquid reached 250 000 microbial cells. Control and
test samples were incubated at 36–37°C for 18–20 h.
The performed biological tests indicate that the
compounds obtained show weak antimicrobial activity.
St. aureus
Сandida albicans
1000
1000
1000
1000
1000
1000
250
250
500
125
125
250
–
I
II
III
IV
V
VI
1000
1000
1000
500
500
1000
Dioxidine
Chloramine B
Fluconazole
62.5–1000 3.9–62.5
500
–
250
–
–
8–32
mixture of 0.01 mol of acetoacetanilide, 0.01 mol of 4-
nitrobenzaldehyde, and 0.01 mol of N-methylurea was
heated at 120–150°C for 10–15 min until gas evolution
ceased and the reaction mixture solidified. After
cooling, the residue was treated with ethanol, filtered,
and recrystallized from ethanol. Yield 2.85 g (78%),
mp 236–238°C (EtOH). IR spectrum, ν, cm–1: 1610
EXPERIMENTAL
1
(C=C), 1680 (CON), 3200 (NH). Н NMR spectrum
(DMSO-d6), δ, ppm: 2.20 s (3Н, 4-СН3), 3.23 s (3Н, 3-
СН3), 5.38 d (1Н, СН, J1,6 3.30 Hz), 6.87–8.21 m (9H,
C6H5, NO2C6H4), 7.91 d (1Н, 1-NH, J1,6 3.30 Hz), 9.84
s (1Н, NH, amide). Found, %: С 62.42, 62.15; Н 5.02,
4.86; N 15.40, 15.19. C19H18N4O4. Calculated, %: С
62.29; Н 4.95; N 15.29.
IR spectra were recorded on a Specord M-80
1
spectrometer from mulls in mineral oil. H NMR
spectra were registered on a Bruker 500 spectrometer
(500.13 MHz) in DMSO-d6, internal reference TMS.
Mass spectra were obtained on a Finnigan MAT
INCOS-50 spectrometer with ionization energy of
electrons 70 eV. Elemental analysis was performed on
a Perkin Elmer 2400 instrument. Melting points were
determined on a Melting Point M-565 apparatus.
X-Ray diffraction analysis of compound V was
performed on a Xcalibur E automatic diffractometer
(MoKα-radiation, graphite monochromator, ω-scanning,
140 K). Data collection and processing were per-
formed using the CrysAlisPro software package [7];
the structure was solved and refined using the OLEX2
program [8]. The main crystallographic parameters and
results of structure refinement are as follows: crystals
monoclinic, space group P21/c, a 15.0841(6), b 5.0547(2),
c 22.7354(11) Å, β 96.371(4)°, dcalc 1.413 g cm–3,
μ 0.102 mm–1; 9279 reflections collected, 4727 in-
dependent, Rin 0.0208, for reflections with I > 2σ(I)
R1 0.0438, wR2t 0.1192. Crystallographic data were de-
posited in the Cambridge Crystallographic Data Center
(CCDC 996028).
General view of the molecule of 3,4-dimethyl-6-(3-nitro-
phenyl)-N-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidine-5-
carboxamide V.
3,4-Dimethyl-6-(4-nitrophenyl)-N-phenyl-2-oxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (I). A
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 10 2014

1952
Compounds II–VI were prepared similarly.
ZAMARAEVA et al.
1Н NMR spectrum (DMSO-d6), δ, ppm: 2.18 s (3Н,
4-СН3), 3.06 s (3Н, 3-СН3), 5.31 d (1Н, СН, J1,6 2.8 Hz),
6.90–8.05 m (9H, C6H5, NO2C6H4), 7.84 d (1Н, 1-NH,
J1,6 2.8 Hz), 9.70 s (1Н, NH, amide). Found, %: С 62.38,
62.21; Н 5.05, 4.89; N 15.42, 15.16. C19H18N4O4.
Calculated, %: С 62.29; Н 4.95; N 15.29.
3,4-Dimethyl-6-(4-fluorophenyl)-N-phenyl-2-oxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (II).
Yield 2.78 g (82%), mp 251–253°C (EtOH). IR
spectrum, ν, cm–1: 1620 (C=C), 1675 (CON), 3232
1
(NH). Н NMR spectrum (DMSO-d6), δ, ppm: 2.15 s
(3Н, 4-СН3), 3.10 s (3Н, 3-СН3), 5.30 d (1Н, СН, J1,6
3.1 Hz), 6.91–7.57 m (9H, C6H5, FC6H4), 7.75 d (1Н,
1-NH, J1,6 3.1 Hz), 9.80 s (1Н, NH, amide). Mass spec-
trum (70 eV), m/z (Irel, %): 339 [М]+, 247 [M – С6Н5NH]+,
219 [M – С6Н5NHCO]+, 123 [M – С6Н5NHCO –
FС6Н4]+, 77 [Ph]+. Found, %: С 67.36, 67.11; Н 5.43,
5.26; N 12.51, 12.28. C19H18FN3O2. Calculated, %: С
67.25; Н 5.35; N 12.38.
3,4-Dimethyl-6-(3-methoxyphenyl)-N-phenyl-2-
oxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide
(VI). Yield 2.17 g (62%), mp 198–200°C (EtOH). IR
spectrum, ν, cm–1: 1616 (C=C), 1688 (CON), 3384
1
(NH). Н NMR spectrum (DMSO-d6), δ, ppm: 2.15 s
(3Н, 4-СН3), 3.10 s (3Н, 3-СН3), 3.70 s (3Н, СН3O),
5.25 d (1Н, СН, J1,6 3.0 Hz), 6.60–7.60 m (9H, C6H5,
CH3OC6H4), 7.77 d (1Н, 1-NH, J1,6 3.0 Hz), 9.80 s
(1Н, NH, amide). Mass spectrum (70 eV), m/z (Irel, %):
351 [М]+, 336 [М – СН3]+, 259 [М – С6Н5NH]+.
Found, %: С 68.44, 68.26; Н 6.09, 5.93; N 12.08, 11.85.
C20H21N3O3. Calculated, %: С 68.36; Н 6.02; N 11.96.
3,4-Dimethyl-6-(4-ethoxyphenyl)-N-phenyl-2-oxo-
1,2,3,6-tetrahydropyrimidine-5-carboxamide (III).
Yield 2.34 g (64%), mp 244–246°C (EtOH). IR
spectrum, ν, cm–1: 1640 (C=C), 1672 (CON), 3248 (NH).
1Н NMR spectrum (DMSO-d6), δ, ppm: 1.36 t (3Н,
СН3СН2O, J 6.4 Hz), 3.87 q (2Н, СН3СН2O, J 6.4 Hz),
2.14 s (3Н, 4-СН3), 3.05 s (3Н, 3-СН3), 5.17 d (1Н,
СН, J1,6 2.8 Hz), 6.67–7.50 m (9H, C6H5, C2H5OC6H4),
7.14 d (1Н, 1-NH, J1,6 2.8 Hz), 9.58 s (1Н, NH,
amide). Found, %: С 69.12, 68.89; Н 6.42, 6.28; N
11.62, 11.39 C21H23N3O3. Calculated, %: С 69.02; Н
6.34; N 11.50.
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1,2,3,6-tetrahydropyrimidine-5-carboxamide (IV).
Yield 2.52 g (71%), mp 263–265°C (EtOH). IR spec-
trum, ν, cm–1: 1608 (C=C), 1672 (CON), 3288 (NH).
1Н NMR spectrum (DMSO-d6), δ, ppm: 2.15 s (3Н,
4-СН3), 3.05 s (3Н, 3-СН3), 5.28 d (1Н, СН, J1,6 2.9 Hz),
7.61 m (9H, C6H5, ClC6H4), 7.77 d (1Н, 1-NH, J1,6
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