2-acylthioacetamides in the biginelli reaction

Article abstract of DOI:10.1007/s10593-014-1429-z

We have demonstrated for the first time a Biginelli reaction of 2-acylthioacetamides with aromatic aldehydes and ureas or thioureas, leading to N-Ar¹-4-Ar²-6-R¹-1-R²-2-oxo(thioxo)- 1,2,3,4-tetrahydro-pyrimidine-5-carbothioamides. The regioselectivity of this process matched the concept of hard/soft Lewis acids and bases. It was established that nitrous acid or other oxidants converted the synthesized compounds into N-Ar¹-4-Ar²-6-R¹-1-R ²-2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxamides, and not the expected 4-Ar²-6-R¹-1-R²-5-(1,3- benzothiazol-2-yl)-1,2,3,4-tetrahydropyrimidin-2-ones(thiones).

Full text of DOI:10.1007/s10593-014-1429-z

Chemistry of Heterocyclic Compounds, Vol. 49, No. 12, March, 2014 (Russian Original Vol. 49, No. 12, December, 2013)
2-ACYLTHIOACETAMIDES IN THE BIGINELLI REACTION
1
1
1
*
M. N. Kurmach , A. B. Ryabitskiy , and V. N. Britsun
We have demonstrated for the first time a Biginelli reaction of 2-acylthioacetamides with aromatic
aldehydes and ureas or thioureas, leading to N-Ar1-4-Ar2-6-R1-1-R2-2-oxo(thioxo)-1,2,3,4-tetrahydro-
pyrimidine-5-carbothioamides. The regioselectivity of this process matched the concept of hard/soft Lewis
acids and bases. It was established that nitrous acid or other oxidants converted the synthesized compounds
into N-Ar1-4-Ar2-6-R1-1-R2-2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxamides, and not the
expected 4-Ar2-6-R1-1-R2-5-(1,3-benzothiazol-2-yl)-1,2,3,4-tetrahydropyrimidin-2-ones(thiones).
Keywords: 2-acylthioacetamides, aromatic aldehydes, 2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-
5-carbothioamides, thioureas, ureas, three-component heterocyclization.
2-Acylthioacetamides are known as polyfunctional reagents useful as starting materials for the synthesis
of various nitrogen- or sulfur-containing compounds [1]. Nevertheless, multicomponent reactions of
2-acylthioacetamides remain little known. Some examples are known of one-pot condensation between 2-acyl-
thioacetamide and nitriles or aldehydes with activated methylene groups [2, 3], or with Meldrum's acid and
aldehydes [4], leading to 1,4-dihydropyridines or 1,5-dihydro-4Н-thiochromeno[2,3-b]pyridin-5-ones,
respectively. However, the heterocyclization of 2-acylthioacetamides with aldehydes and ureas/thioureas (the
Biginelli reaction) so far has not been investigated.
The Biginelli reaction is a general method for the synthesis of 3,4-dihydropyrimidin-2-ones with
antiviral, antitumor, antihypertensive, antimalarial, and antituberculosis properties [5, 6]. This work is aimed at
introducing 2-acylthioacetamides in the Biginelli reaction and investigating the regioselectivity in such
reactions.
We established that the 2-acylthioacetamides 1a-d reacted with the aldehydes 2a-f and the
ureas/thioureas 3a-c in the presence of boric acid as a catalyst. The synthesis was performed in acetic acid at
100-110°С. The reaction did not proceed in the absence of boric acid. Using propionic acid instead of acetic
acid and increasing the reaction mixture temperature to 130-135°С had essentially no impact on the product
yield.
The reaction was selective and produced N-Ar1-4-Ar2-6-R1-1-R2-2-oxo(thioxo)-1,2,3,4-tetrahydro-
pyrimidine-5-carbothioamides 4a-m in 53-72% yields. The potential reaction products 5a-m were not observed.
Electron-donating substituents in the phenyl rings of the starting materials slightly improved the yields of the
_______
*To whom correspondence should be addressed, e-mail: britsun167@rambler.ru.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1910-1916, December, 2013.
Original article submitted October 9, 2013; revision submitted November 26, 2013.
1770
0009-3122/14/4912-1770©2014 Springer Science+Business Media New York

expected products (70-72%), compareed to electron-withdrawing substituents (51-58%). The reaction with
unsymmetrical N-methylthiourea (3с) was selective and produced 1-methyl-1,2,3,4-tetrahydropyrimidine-
2-thione 4k.
2-Acylthioacetamides played the role of 1,2-reactive bifunctional reagents in this [2+1+3]-
cyclocondensation reaction.
It should be pointed out that the heterocyclization reactions occurred at the carbonyl group, not the
thiocarbonyl group of the starting 2-acylthioacetamides 1a-d. Since the carbonyl group has a lower
polarizability and smaller size than the thiocarbonyl group, and amino group is a hard nucleophile, the
regioselectivity of this reaction was in agreement with the hard-soft acid-base theory.
S
Ar2
Ar1
4
N
H
3NH
2
5
6
1
R1
N
X
R2
NHR2
O
S
H2N
Ar1
H3BO3
AcOH
4a–m
+ Ar2CHO +
R1
Ar2
N
H
O
N
X
100–110°C
4–8 h
R1
Ar1
1a–d
2a–f
3a–c
NH
N
X
R2
5a–m
1a,d, 4a,d–m, 5a,d–m Ar1 = Ph; 1b, 4b, 5b Ar1 = 4-MeOC6H4; 1c, 4c, 5c Ar1 = 4-O2NC6H4;
2a, 4a–c,h,i , 5a–c,h,i Ar2 = Ph; 2b, 4e,k,l, 5e,k,l Ar2 = 4-MeOC6H4;
2c, 4f,m, 5f,m Ar2 = 3-O2NC6H4; 2d, 4d, 5d Ar2 = 4-FC6H4; 2e, 4j, 5j Ar2 = 2-thienyl;
2f, 4g, 5g Ar2 = 2-furyl; 1a–c, 4a–g,i–m, 5a–g,i–m R1 = Me; 1d, 4h, 5h R1 = Ph;
3a,b, 4a–j,l,m, 5a–j,l,m R2 = H; 3c, 4k, 5k R2 = Me
3a, 4, 5 a–h X = O; 3b,c, 4, 5 i–m X = S
According to review articles [5, 6], a Biginelli reaction in acidic medium probably involves azomethine
intermediates, formed from aldehyde and urea/thiourea. It has been proposed [7] that boric acid with azomethine
and the 2-acylthioacetamide 1a-d formed reactive adducts 6 and 7, having highly electrophilic carbon atoms in
the C=N and С=О groups, respectively.
The reaction of the adducts 6 and 7 apparently led to the intermediate 8, which underwent intra-
molecular cyclization accompanied by elimination of water and formation of the tetrahydropyrimidin-
2-ones(thiones) 4a-m.
B(OH)3
O
S
B(OH)3
Ar1
R1
Ar2
C
H
N
H2N
NHR2
N
H
NHR2
7
Ar2CHO
+
– H3BO3
X
– H2O
S
X
3a–c
2a–f
(HO)3B
6
Ar2
Ar1
H
N
N
H
4a–m
X
– H2O
R1
HN
HO
R2
8
1771

We have previously demonstrated that interaction of 2-acylthioacetamides with nitrous acid induced a
cyclization of the N-arylthioamide moiety to a benzothiazole [8]. A further research suggested that the 1,2,3,4-
tetrahydropyrimidin-2-ones 4 could be oxidized to the 5-(benzothiazol-2-yl)-1,2,3,4-tetrahydropyrimidin-2-ones 9.
However, data from the literature indicated that oxidation reactions of N-arylthioamides may proceed as
heterocyclizations to 1,2,4-thiadiazoles [9] and benzothiazoles [10-12], and/or as desulfurization and conversion
to amides [11-15]. The oxidants were nitrous acid [8, 9, 13], palladium chloride with atmospheric oxygen [10],
phenyliodonium bis(trifluoroacetate) [11, 12], N-nitrosopiperidine and N-methyl-N-nitrosoaniline [14], ceric
ammonium nitrate [12], and silver carbonate [15]. Other researchers have previously suggested that such
reactions occur through a nitrosonium cation intermediate [13, 14], and by a radical cation mechanism [11, 12].
We should note that even with the same reagent (nitrous acid [8, 9, 13], phenyliodonium
bis(trifluoroacetate) [11, 12]) the reactions can yield not only the heterocyclization products, but also products
from the thioamide group oxidation to an amide group. The substrate structure is likely a major factor affecting
these reactions.
We used the NaNO2/AcOH and KClO3/AcOH systems as oxidants. However, the attempt to convert the
N-arylthioamide group of compounds 4a,b,d,e,i into a benzothiazole system failed to close the ring and resulted
in oxidation of the thioamide to an amide group. The reaction products in all cases were N-aryl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxamides 10а-е in 40-48% yields.
S
Ar2
Y
Ar2
NaNO2
Ar2
O
Ar1
Ar1
S
or
N
H
N
H
KClO3
NH
NH
NH
N
AcOH
N
H
X
Me
N
H
X
Me
X
N
H
Me
9a–e
10a–e
4a,b,d,e,i
4a,d,e,i, 10a,b,d,e Ar1 = Ph; 4b, 10c Ar1 = 4-MeOC6H4;
4a,b,i, 9a,c,e, 10a,c,e Ar2 = Ph; 4, 9d, 10d Ar2 = 4-FC6H4; 4e, 9b, 10b Ar2 = 4-MeOC6H4;
4a,b,d,e, 9a–d, 10a–d X = O; 4i, 9e, 10e X = S; 9a,b,d,e Y = H; 9c Y = MeO
1
The structures of the synthesized compounds were confirmed by IR, Н NMR, and 13С NMR
spectroscopy, and the composition was determined by elemental analysis.
1
The Н NMR spectra of compounds 4a-m, 10а-е exhibited signals of all the structural fragments that
contained protons. The characteristic signals were those of the 6-methyl group protons (1.89-2.10 ppm), 4-CН
protons (5.35-6.00 ppm), 1-NH (8.58-8.82 ppm for the tetrahydropyrimidin-2-ones 4a-h, 10a-d and 9.88-
10.14 ppm for the tetrahydropyrimidine-2-thiones 4i-m, 10е), 3-NH (7.48-9.46 ppm), NHCS (10.57-11.46 ppm),
and NHCO (9.35-9.67 ppm). The vicinal 3-NH and 4-CH proton signals were typically present as broad
singlets, probably due to the rapid deuterium exchange at the nitrogen atom. The most informative 13С NMR
signals of compounds 4a,d,e,i,h and 10a,е were those of the carbonyl groups (NHCОNH (152.5-163.1 ppm),
NHCO (164.9-165.2 ppm)) and the thiocarbonyl groups (NHCS (194.7-195.4 ppm), NHCSNH (173.4-174.0 ppm)).
The IR spectra of the compounds 4a-m, 10а-е contained absorption bands of NH groups (3350-3200 cm-1),
aromatic СН (3100-2950 cm-1), and carbonyl groups (1660-1690 cm-1).
Compounds 10 were also obtained in 27-82% yields by the condensation of acetoacetanilides with
aldehydes and ureas [16]. We should note that this reaction required forcing conditions when no catalysts were
used: a mixture of the starting materials was fused at the temperature range from 120°С to 150°С. Our reported
method presents an alternative, which may be used depending on the availability of the starting
acetoacetanilides and 2-acylthioacetamides.
Thus, we have demonstrated for the first time a Biginelli reaction with 2-acylthioacetamides. It was
established that the reaction occurred between the hard reaction centers according to the hard-soft acid-base
1772

theory. N-Ar1-4-Ar2-6-R1-1-R2-2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-5-carbothioamides were synthesized
and characterized, and the structure was confirmed by spectroscopy. The attempts at oxidation of these
compounds with NaNO2/AcOH or KClO3/AcOH systems resulted in desulfurization and produced the
respective carboxamides.
EXPERIMENTAL
1
13
IR spectra of compounds were acquired on a Vertex 70 spectrometer in KBr pellets. H and C NMR
spectra were acquired on a Varian GEMINI 2000 instrument (400 and 100 MHz, respectively) in DMSO-d6,
with TMS as internal standard. Elemental analysis was performed on a Carlo Erba elemental analyzer. The
melting points were determined with a PTP-1 apparatus. The 2-acylthioacetamides 1a-d were synthesized by a
literature method [17].
Preparation of N-Ar1-4-Ar2-6-R1-1-R2-2-Oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-5-carbothio-
amides 4а-m (General Method). A solution of 2-thioacetamide 1a-d (1.0 mmol), aldehyde 2a-f (1.0 mmol),
urea or thiourea 3а-с (1.0 mmol), and boric acid (0.2 mmol) in acetic acid (2-3 ml) was heated for 4-8 h at 100-
110°C. A crystalline precipitate of the tetrahydropyrimidine 4а-m formed upon cooling. In cases when there
was no precipitation, the reaction mixture was poured into aqueous NaCl solution. The precipitate was filtered
off, dried, and purified by crystallization.
6-Methyl-2-oxo-N,4-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4a). Yield 65%; mp
235-237°С (PhCN). IR spectrum, , cm-1: 3200-2950, 1675 (C=O), 1495, 1445, 1365, 1305. 1H NMR spectrum,
δ, ppm: 1.91 (3Н, s, CH3); 5.72 (1Н, br. s, 4-CН); 7.17-7.58 (11Н, m, H Ph, 3-NH); 8.62 (1H, s, 1-NH); 11.06
13
(1Н, s, NHCS). C NMR spectrum, δ, ppm: 16.9 (CH3); 57.8 (C-4); 113.4, 123.6, 125.9, 126.2, 127.1, 128.2,
128.3, 131.7 (C Ph); 139.2 (C-5); 143.7 (C-6); 152.5 (C=O); 195.2 (C=S). Found, %: С 66.90; Н 5.27; N 12.69;
S 10.15. С18Н17N3ОS. Calculated, %: С 66.85; Н 5.30; N 12.99; S 9.91.
N-(4-Methoxyphenyl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4b).
Yield 70%; mp 179-182°С (MeNO2). IR spectrum, , cm-1: 3200, 3100, 2950, 1680 (C=O), 1513, 1436, 1372,
1299. 1H NMR spectrum, δ, ppm (J, Hz): 1.90 (3Н, s, CH3); 3.73 (3H, s, 4-CH3O); 5.71 (1Н, br. s, 4-CН); 6.85
(2H, d, J = 8.1, H Ar); 7.23-7.41 (7Н, m, H Ph, 3-NH); 7.47 (2H, d, J = 8.1, H Ar); 8.58 (1H, s, 1-NH); 10.94
(1Н, s, NHCS). Found, %: С 64.61; Н 5.55; N 12.18; S 9.36. С19Н19N3О2S. Calculated, %: С 64.57; Н 5.42;
N 11.89; S 9.07.
6-Methyl-N-(4-nitrophenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4c).
Yield 55%; mp 238-240°С (PhCN). IR spectrum, , cm-1: 3345, 3230, 3090, 2930, 1690 (C=O), 1615, 1600,
1525, 1500, 1462, 1431. 1H NMR spectrum, δ, ppm (J, Hz): 1.97 (3Н, s, CH3); 5.71 (1Н, br. s, 4-CН); 7.25-7.35
(5H, m, H Ph); 7.56 (1Н, s, 3-NH); 7.80 (2H, d, J = 8.4, H Ar); 8.20 (2H, d, J = 8.4, H Ar); 8.81 (1H, s, 1-NH);
11.40 (1Н, s, NHCS). Found, %: С 58.74; Н 4.27; N 14.97; 8.48. С18Н16N4О3S. Calculated, %: С 58.68; Н 4.38;
N 15.21; S 8.70.
4-(4-Fluorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide
(4d).
Yield 64%; mp 162-165°С (EtOH). IR spectrum, , cm-1: 3200, 3100, 2950, 1660 (C=O), 1510, 1446, 1365,
1
1307. H NMR spectrum, δ, ppm: 1.93 (3Н, s, CH3); 5.70 (1Н, br. s, 4-CН); 7.11-7.43 (8Н, m, H Ar, 3-NH);
13
7.54-7.62 (2H, m, H Ar); 8.64 (1H, s, 1-NH); 11.06 (1Н, s, NHCS). C NMR spectrum, δ, ppm: 16.6 (CH3);
57.2 (C-4); 113.3, 115.0, 115.3, 123.6, 126.0, 128.3, 128.5, 132.0 (C Ar); 139.6 (C-5); 152.4 (C-6); 162.4
(C=O); 195.2 (C=S). Found, %: С 63.44; Н 4.87; N 12.04; S 9.25. С18Н16FN3ОS. Calculated, %: С 63.32;
Н 4.72; N 12.31; S 9.39.
4-(4-Methoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4е).
Yield 72%; mp 184-185°С (MeNO2). IR spectrum, , cm-1: 3200, 3100, 2950, 1660 (C=O), 1610, 1555, 1510,
1445. 1H NMR spectrum, δ, ppm (J, Hz): 1.91 (3Н, s, CH3); 5.66 (1Н, br. s, 4-CН); 6.88 (2H, d, J = 8.2, H Ar);
7.23–7.40 (6Н, m, H Ph, 3-NH); 7.59 (2H, d, J = 8.2, H Ar); 8.60 (1H, s, 1-NH); 11.06 (1Н, s, NHCS).
1773

13C NMR spectrum, δ, ppm: 16.7 (CH3); 54.9 (OCH3); 57.3 (C-4); 113.3, 123.5, 123.7, 125.7, 127.5, 128.4,
131.6, 135.8 (C Ar); 139.2 (C-5); 152.4 (C-6); 158.0 (C=O); 195.4 (C=S). Found, %: С 64.63; Н 5.58; N 12.13;
S 8.80. С19Н19N3О2S. Calculated, %: С 64.57; Н 5.42; N 11.89; S 9.07.
6-Methyl-4-(3-nitrophenyl)-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4f).
Yield 51%; mp 170-172°С (EtOH). IR spectrum, , cm-1: 3350, 3200, 3100, 2950, 1670 (C=O), 1600, 1525,
1
1495, 1465. H NMR spectrum, δ, ppm: 1.97 (3Н, s, CH3); 5.77 (1Н, br. s, 4-CН); 7.17-7.22 (1H, m, H Ar);
7.31-7.36 (2Н, m, H Ar); 7.51-7.83 (5Н, m, H Ar, 3-NH); 8.12-8.17 (2H, m, H Ph); 8.82 (1H, s, 1-NH); 11.17
(1Н, s, NHCS). Found, %: С 58.79; Н 4.10; N 14.95; S 8.98. С18Н16N4О3S. Calculated, %: С 58.68; Н 4.38;
N 15.21; S 8.70.
4-(2-Furyl)-6-methyl-2-oxo-N-phenylthiocarbamoyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide
(4g). Yield 53%; mp 145-147°С (EtOH). IR spectrum, , cm-1: 3200, 3100, 2955, 1670 (C=O), 1600, 1510,
1
1445, 1365. H NMR spectrum, δ, ppm (J, Hz): 1.89 (3Н, s, CH3); 5.76 (1Н, br. s, 4-CН); 6.25-6.29 (1H, m,
H Ar); 6.37 (1H, d, J = 4.0, H Ar); 7.17-7.23 (1Н, m, H Ph); 7.32-7.38 (2Н, m, H Ar); 7.55-7.63 (4H, m, H Ar,
3-NH); 8.73 (1H, s, 1-NH); 11.20 (1Н, s, NHCS). Found, %: С 61.57; Н 5.09; N 13.22; S 10.46. С16Н15N3О2S.
Calculated, %: С 61.32; Н 4.82; N 13.41; S 10.23.
2-Oxo-N,4,6-triphenyl-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4h). Yield 60%; mp
232-234°С (EtOH). IR spectrum, , cm-1: 3350, 3300, 3100, 3000, 1680 (C=O), 1595, 1530, 1490, 1460, 1430.
1H NMR spectrum, δ, ppm: 5.68 (1Н, br. s, 4-СН); 7.05-7.63 (16Н, m, Н Ph, 3-NH); 8.78 (1H, s, 1-NH); 10.57
(1Н, s, NHCS). 13C NMR spectrum, δ, ppm: 58.2 (C-4); 123.4, 124.2, 125.6, 126.2, 126.5, 127.1, 127.5, 128.1,
128.6, 129.3, 130.0, 133.9 (С Ph); 143.1 (C-5); 152.8 (C-6); 163.1 (C=O); 195.0 (C=S). Found, %: С 71.73;
Н 5.23; N 11.04; S 8.12. С23Н19N3ОS. Calculated, %: С 71.66; Н 4.97; N 10.90; S 8.32.
6-Methyl-N,4-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4i). Yield 70%;
1
mp 251-253°С (PhCN). IR spectrum, , cm-1: 3350, 3200–3000, 2950, 1560, 1490, 1440, 1345. H NMR
spectrum, δ, ppm: 1.97 (3Н, s, CH3); 5.71 (1Н, br. s, 4-СН); 7.25-7.55 (8Н, m, Н Ph); 7.57-7.63 (2H, m, Н Ph);
13
9.26 (1H, s, 3-NH); 9.91 (1H, s, 1-NH); 11.21 (1Н, s, NHCS). C NMR spectrum, δ, ppm: 16.3 (CH3); 58.1
(C-4); 114.8, 123.4, 124.2, 125.9, 126.4, 126.9, 127.5, 128.9 (С Ph); 138.6 (C-5); 142.4 (C-6); 173.4 (C=S);
194.7 (C=S). Found, %: С 63.89; Н 4.88; N 12.25; S 19.17. С18Н17N3S2. Calculated, %: С 63.68; Н 5.05;
N 12.38; S 18.89.
6-Methyl-N-phenyl-4-(2-thienyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbothioamide
(4j).
Yield 68%; mp 220-222°С (MeNO2). IR spectrum, , cm-1: 3350, 3150, 2955, 1580, 1554, 1480, 1440.
1H NMR spectrum, δ, ppm: 1.99 (3Н, s, CH3); 6.00 (1Н, br. s, 4-СН); 6.95-6.99 (2H, m, Н Ar); 7.18-7.23 (1H,
m, Н Ar); 7.35-7.45 (3Н, m, Н Ar); 7.60-7.64 (2H, m, Н Ph); 9.46 (1H, s, 3-NH); 10.05 (1H, s, 1-NH); 11.32
(1Н, s, NHCS). Found, %: С 55.38; Н 4.55; N 12.26; S 28.12. С16Н15N3S3. Calculated, %: С 55.62; Н 4.38;
N 12.16; S 27.84.
4-(4-Methoxyphenyl)-1,6-dimethyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbothio-
amide (4k). Yield 60%; mp 225-227°С (MeNO2). IR spectrum. , cm-1: 3180, 3030, 2900, 1605, 1535, 1509,
1450, 1370. 1H NMR spectrum, δ, ppm (J, Hz): 2.10 (3Н, s, CH3); 3.47 (3H, s, NCH3); 3.73 (3Н, s, CH3О); 5.56
(1Н, d, J = 3.0, 4-СН); 6.88 (2H, d, J = 8.1, H Ar); 7.18-7.22 (3H, m, H Ph); 7.34-7.40 (2Н, m, H Ph); 7.69
(2H, d, J = 8.1, H Ar); 9.37 (1H, d, J = 3.0, 3-NH); 11.46 (1Н, s, NHCS). Found, %: С 62.90; Н 5.34; N 11.23;
S 16.49. С20Н21N3OS2. Calculated, %: С 62.63; Н 5.52; N 10.96; S 16.72.
4-(4-Methoxyphenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbothioamide
(4l). Yield 73%; mp 170-172°С (MeNO2). IR spectrum, , cm-1: 3300, 3170, 2970, 1595, 1565, 1522, 1472,
1
1440. H NMR spectrum, δ, ppm (J, Hz): 1.97 (3Н, s, CH3); 3.73 (3Н, s, CH3О); 5.64 (1Н, br. s, 4-CН); 6.90
(2H, d, J = 8.3, H Ar); 7.18-7.25 (3H, m, H Ph); 7.30-7.37 (2Н, m, H Ph); 7.60 (2H, d, J = 8.3, H Ar); 9.21
(1H, s, 3-NH); 9.88 (1H, s, 1-NH); 11.21 (1Н, s, NHCS). Found, %: С 62.02; Н 5.35; N 11.55; S 17.08.
С19Н19N3OS2. Calculated, %: С 61.76; Н 5.18; N 11.37; S 17.36.
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6-Methyl-4-(3-nitrophenyl)-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbothioamide (4m).
Yield 58%; mp 185-188°С (MeNO2). IR spectrum, , cm-1: 3300, 3170, 2975, 1563, 1525, 1475, 1440, 1350.
1H NMR spectrum, δ, ppm: 2.02 (3Н, s, CH3); 5.77 (1Н, br. s, 4-CН); 7.18-7.22 (1H, m, H Ar); 7.32-7.37 (2Н,
m, H Ar); 7.57-7.72 (4Н, m, H Ar); 8.10-8.17 (2H, m, H Ph); 9.44 (1H, s, 3-NH); 10.14 (1H, s, 1-NH); 11.33
(1Н, s, NHCS). Found, %: С 56.50; Н 4.38; N 14.73; S 16.94. С18Н16N4О2S2. Calculated, %: С 56.23; Н 4.19;
N 14.57; S 16.68.
Preparation of N-Ar1-4-Ar2-6-R1-1-R2-2-Oxo(thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxamides
10а-е (the method by nitrous acid oxidation). A suspension of tetrahydropyrimidine 4a,b,е,d,i (1.0 mmol) and
NaNO2 (172.5 mg, 2.5 mmol) in acetic acid (3 ml) was stirred for 8 h at 5°С and poured into 50 ml of cold
water. The precipitate of tetrahydropyrimidine 10а-е was filtered off, dried, and purified by crystallization.
Preparation of N-Ar1-4-Ar2-6-R1-1-R2-2-Oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides 10а,с
(the method by potassium chlorate oxidation). A solution of tetrahydropyrimidine 4a,b (3 mmol) and KClO3
(122.5 mg, 1.0 mmol) in acetic acid (5 ml) was stirred for 2 h at 30-40°С, cooled, and poured into 50 ml of cold
water. The precipitate of tetrahydropyrimidine 10а,с was filtered off, dried, and purified by crystallization.
6-Methyl-2-oxo-N,4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10a). Yield 48%; mp
240-243°С (PhCN) (246-248°С (EtOH) [16]). IR spectrum, , cm-1: 3230, 3100, 2980, 1675 (C=O), 1620,
1
1595, 1520, 1440. H NMR spectrum, δ, ppm: 2.04 (3Н, s, CH3); 5.40 (1Н, br. s, 4-СН); 6.95-7.02 (1Н, m,
Н Ph); 7.18-7.29 (7H, m, H Ph, 3-NH); 7.50 (3Н, m, H Ph); 8.63 (1H, s, 1-NH); 9.47 (1H, s, NHCO). 13C NMR
spectrum, δ, ppm: 17.1 (Me); 55.0 (C-4); 105.4, 119.5, 123.0, 126.1, 127.2, 128.4, 128.6, 138.4 (C Ph); 139.1
(C-5); 144.2 (C-6); 152.6 (C-2); 165.2 (NHCО). Found, %: С 70.37; Н 5.29; N 13.90. С18Н17N3О2. Calculated,
%: С 70.34; Н 5.58; N 13.67.
4-(4-Methoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10b).
Yield 45%; mp 222-223°С (PhCN). IR spectrum, , cm-1: 3240, 3100, 2950, 1675 (C=O), 1625, 1600, 1510,
1
1450. H NMR spectrum, δ, ppm (J, Hz): 2.04 (3Н, s, CH3); 3.71 (3Н, s, CH3О); 5.35 (1Н, br. s, 4-CН); 6.86
(2H, d, J = 8.4, H Ar); 6.94-7.00 (2Н, m, H Ph); 7.18-7.24 (3Н, m, H Ph); 7.40 (1Н, s, 3-NH); 7.53 (2H, d,
J = 8.4, H Ar); 8.62 (1H, s, 1-NH); 9.45 (1H, s, NHCO). Found, %: С 67.40; Н 5.39; N 12.72. С19Н19N3О3.
Calculated, %: С 67.64; Н 5.68; N 12.46.
N-(4-Methoxyphenyl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10с).
Yield 42%; mp 229-230°С (PhCN). IR spectrum, , cm-1: 3250, 3100, 2950, 1680 (C=O), 1670 (C=O), 1620,
1
1515, 1465, 1410. H NMR spectrum, δ, ppm (J, Hz): 2.03 (3Н, s, CH3); 3.69 (3Н, s, CH3О); 5.37 (1Н, br. s,
4-CН); 6.78 (2H, d, J = 9.0, H Ar); 7.27-7.33 (5Н, m, H Ph); 7.42 (2H, d, J = 9.0, H Ar); 7.48 (1Н, s, 3-NH);
8.59 (1Н, s, 1-NH); 9.35 (1H, s, NHCO). Found, %: С 67.90; Н 5.95; N 12.45. С19Н19N3О3. Calculated, %:
С 67.64; Н 5.68; N 12.46.
4-(4-Fluorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10d).
Yield 41%; mp 190-193°С (MeNO2). IR spectrum, , cm-1: 3280, 3100, 2950, 1670 (C=O), 1630, 1600, 1505,
1440. 1H NMR spectrum, δ, ppm: 2.05 (3Н, s, CH3); 5.39 (1Н, br. s, 4-CН); 6.96-7.02 (1Н, m, H Ph); 7.08-7.12
(2Н, m, H Ar); 7.20-7.24 (2H, m, H Ar); 7.30-7.35 (2H, m, H Ar); 7.49-7.56 (3H, m, H Ar, 3-NH); 8.68 (1H, s,
1-NH); 9.49 (1Н, s, NHCO). Found, %: С 66.47; Н 5.24; N 13.05. С18Н16FN3О2. Calculated, %: С 66.45;
Н 4.96; N 12.92.
6-Methyl-N,4-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10e). Yield 40%;
mp 160-162°С (MeNO2). IR spectrum, , cm-1: 3270, 3100, 3000, 1675 (C=O), 1630, 1595, 1525, 1490, 1440.
1H NMR spectrum, δ, ppm (J, Hz): 2.07 (3Н, s, CH3); 5.40 (1Н, br. s, 4-CН); 6.93-7.03 (1Н, m, H Ph);
7.25-7.35 (6H, m, H Ph); 7.50-7.54 (3Н, m, H Ph); 9.35 (1H, s, 3-NH); 9.67 (1H, s, NHCO); 9.91 (1H, s,
13
1-NH). C NMR spectrum, δ, ppm: 16.3 (CH3); 55.2 (C-4); 120.2, 123.2, 124.0, 125.5, 126.6, 127.3, 129.0,
134.7 (C Ph); 139.3 (C-5); 142.9 (C-6); 164.9 (C=O); 174.0 (C=S). Found, %: С 66.93; Н 5.40; N 13.90;
S 10.07. С18Н17N3ОS. Calculated, %: С 66.85; Н 5.30; N 12.99; S 9.91.
1775

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
V. N. Britsun, 2-Functionalized methylene active thioacetamides, CP "Komprint", Kiev (2012).
M. Li, Z. Zuo, L. Wen, and S. Wang, J. Comb. Chem., 10, 436 (2008).
L.-R. Wen, I.-H. Sun, M. Li, E.-T. Sun, and S.-S. Zhang, J. Org. Chem., 73, 1852 (2008).
L.-R. Wen, C. Ji, M. Li, and H.-Y. Xie, Tetrahedron, 65, 1287 (2009).
S. V. Vdovina and V. A. Mamedov, Usp. Khim., 77, 1091 (2008). [Russ. Chem. Rev., 77, 1017 (2008).]
Suresh and J. S. Sandhu, ARKIVOC, i, 66 (2012).
S. J. Tu, F. Fang, С. Miao, H. Jiang, Y. Feng, and D. Shi, Tetrahedron Lett., 44, 6153 (2003).
V. N. Britsun, A. N. Borisevich, L. S. Samoilenko, and M. O. Lozinskii, Zh. Org. Khim., 41, 759
(2005). [Russ. J. Org. Chem., 41, 745 (2005).]
9.
10.
11.
12.
13.
14.
15.
M. V. Cronyn and T. W. Nakagawa, J. Am. Chem. Soc., 74, 3693 (1952).
K. Inamoto, K. Nozawa, and Y. Kondo, Synlett, 23, 1678 (2012).
P. Huang, X. Fu, Y. Liang, R. Zhang, and D. Dong, Aust. J. Chem., 65, 121 (2012).
N. K. Downer-Riley and Y. A. Jackson, Tetrahedron, 64, 7741 (2008).
K. A. Jørgensen, A.-B. A. G. Ghattas, and S. O. Lawesson, Tetrahedron, 38, 1163 (1982).
K. A. Jørgensen, M. T. M. El-Wassimy, and S. O. Lawesson, Tetrahedron, 39, 469 (1983).
B. Movassagh, M. M. Lakouraj, and A. Gholami, Phosphorus, Sulfur Silicon Relat. Elem., 178, 1943
(2003).
16.
17.
V. L. Gein, T. M. Zamaraeva, A. A. Kurbatova, and M. I. Vakhrin, Khim. Geterotsikl. Soedin., 7, 1058
(2010). [Chem. Heterocycl. Compd., 46, 856 (2010).]
V. N. Britsun, A. N. Borisevich, L. S. Samoilenko, and M. O. Lozinskii, Ukr. Khim. Zh., 71, 8, 111
(2005).
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