Three-component condensation of 1,3-dimethyl-barbituric acid, arylglyoxals, and substituted thioureas

Article abstract of DOI:10.1007/s10593-013-1214-4

4-Aryl-2-methylaminothiazoles and 5-aryl-2-mercapto-1-methylimidazoles, containing a fragment of 1,3-dimethylbarbituric acid, have been synthesized by the one-pot three-component condensation of 1,3-dimethylbarbituric acid, arylglyoxal hydrates, and N-methylthiourea. The analogous reaction involving N-arylthioureas proceeds regioselectively with the formation of 4-aryl-2-arylaminothiazoles. It was established that in the crystalline state 5-aryl-2-mercaptoimidazoles exist in the imidazoline-2-thione form.

Full text of DOI:10.1007/s10593-013-1214-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
THREE-COMPONENT CONDENSATION OF 1,3-DIMETHYL-
BARBITURIC ACID, ARYLGLYOXALS, AND SUBSTITUTED
THIOUREAS
N. N. Kolos1*, L. L. Zamigailo2, N. V. Chechina1, I. V. Omel'chenko2,
O. V. Shishkin2, and E. V. Vashchenko2
4-Aryl-2-methylaminothiazoles and 5-aryl-2-mercapto-1-methylimidazoles, containing a fragment of
1,3-dimethylbarbituric acid, have been synthesized by the one-pot three-component condensation of
1,3-dimethylbarbituric acid, arylglyoxal hydrates, and N-methylthiourea. The analogous reaction
involving N-arylthioureas proceeds regioselectively with the formation of 4-aryl-2-arylaminothiazoles.
It was established that in the crystalline state 5-aryl-2-mercaptoimidazoles exist in the imidazoline-
2-thione form.
Keywords: arylglyoxals, 5-(4-aryl-2-(methylamino)thiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-
2,4-diones, 5-(5-aryl-1-methyl-2-thioxoimidazolidin-4-ylidene)-1,3-dimethylpyrimidine-2,4,6-triones,
1,3-dimethylbarbituric acid, N-methyl(aryl)thioureas, one-pot synthesis.
The thiazole ring is part of the composition of a series of biologically and pharmacologically important
natural and synthetic products. Thus, the active chemical center of the coenzyme thiamine is the thiazolium
fragment [1]. Derivatives of thiazole display antitumor activity [2], and are also used in medicine as antibiotics
[3-5], anticonvulsants [6], preparations for treating ulcerous diseases [7, 8], and antimicrobial agents [9, 10].
This stimulates enhanced interest in the development of simple and convenient methods of synthesis and
functionalization of the triazole nucleus.
We showed previously that a three-component one-pot condensation of 1,3-dimethylbarbituric acid
(1,3-DMBA), arylglyoxals, and thiourea or N-arylthioureas led to a 2-aminothiazole derivatives [11]. With the
aim of broadening the potential of this method for obtaining functionalized thiazoles, in the present work we
have studied the three-component condensation of 1,3-DMBA 1 with arylglyoxal hydrates 2a-g and
N-methyl(aryl)thioureas 3a-d. The reaction was carried out by refluxing the starting materials in ethanol. In the
case of N-methylthiourea 3a, high-melting products 4b-f were isolated by filtration from the hot reaction
mixture, and compounds 5a-f from the cooled mother liquor, the melting points of which proved to be
approximately 100oC lower, but the yields were somewhat higher than those of compounds 4b-f. On using
phenylglyoxal 2a we successfully isolated only the low-melting compound 5a from the reaction mixture.
_______
*To whom correspondence should be addressed, e-mail: kolos_n@mail.ru.
1 V. N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv 61022, Ukraine.
2Scientific-Technological Complex "Institute of Monocrystals", National Academy of Sciences of Ukraine, 60
Lenina Ave., Kharkiv 61001, Ukraine; e-mail: shishkin@xray.isc.kharkov.com.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1941-1947, December, 2012.
Original article submitted May 19, 2012.
0009-3122/13/4812-1817©2013 Springer Science+Business Media New York
1817

The formation of a thiazole ring in the reactions of arylglyoxals, 1,3-DMBA, and thiourea was
considered previously and may occur through the formation of phenacylidene derivative A [12]. Nucleophilic
addition of a mercapto group at the most electrophilic center of the exocyclic enone fragment, with subsequent
cyclization, leads to thiazoles 4b-i. The formation of imidazoles 5a-f is probably linked to the competing
1,2-nucleophilic additions of the more basic center at the carbonyl group, and by the formation of a five-
membered ring as a result of exotrigonal cyclization. The exclusive formation of thiazoles 4g-i in the reactions
of acid 1, the corresponding arylglyoxal hydrates 2b,e,g, and N-arylthioureas 3b-d point in favor of such a
hypothesis, which may be explained by the decrease of the nucleophilicity of the nitrogen atoms in
N-arylthioureas [13], and as a result the lack of initial attack at the carbonyl group.
O
O
O
Me
O
Me
O
Ar
N
N
EtOH
HO
+
Ar
O
N
O
N
O
OH
2a–g
Me
Me
1
A
H2N
NHR
NH
S
HO
O
3a–d
Ar
NMe
S
NHR
Ar
O
Me
(R = Me)
N
Me
O
N
S
H N
N
O
O
2
O
N
O
Me
Me
Me
Me
N
Ar
Ar
Ar
N
N
O
O
O
NHR
SH
S
Me
Me
O
Me
O
S
N
.
N
.
N
N
N
.
H
.
.
.
.
O
N
OH
N
N
OH
O
Me
Me
Me
4b–i
5a–f
2a, 5a Ar = Ph, 2b, 4b,i, 5b Ar = 4-MeC6H4, 2c, 4c, 5c Ar = 4-MeSC6H4, 2d, 4d, 5d Ar = 4-ClC6H4,
2e, 4e,h, 5e Ar = 4-BrC6H4, 2f, 4f, 5f Ar = 4-O2NC6H4, 2g, 4g Ar = 4-MeOC6H4,
3a, 4b–f R = Me, 3b, 4g R = Ph, 3c, 4h R = 2-MeC6H4, 3d, 4i R = 2-BrC6H4
The structures of the obtained compounds were established using physicochemical methods. The
1H NMR spectra of compounds 4b-f were similar to the spectra of previously described thiazoles [11]. They are
characterized by multiplets for the aromatic protons, by the nine-proton singlet of the superimposed methyl
groups of the thiourea fragment and the methyl groups of the dimethylbarbituric acid fragment, and also by the
broadened singlets of the exchanged NH protons (9.0-9.2 ppm) and of the 6-OH protons of the pyrimidine ring
1
(12.1-12.5 ppm). The special feature of the H NMR spectra of thiazoles 4g-i was absence of the 6-hydroxyl
group signal as a result of the rapid exchange with water present in DMSO-d6. An analogous picture was also
observed for the previously described thiazoles containing a carbamoyl fragment at the ring position 2 [11].
1
In the H NMR spectra of compounds 5a-f, the N-methyl proton of the thiourea fragment was shifted
towards lower field (δ ≈ 3.4 ppm), the six-proton singlet of the pyrimidine ring methyl groups was displayed at
3.1 ppm, and an exchanged broadened signal of the hydroxyl group proton was present at 12.0-12.2 ppm.
We note that the 13C NMR spectra of compounds 5 and the corresponding thiazoles 4 differed
insignificantly. The carbon spectra of compounds 4b,c,e were revised by a DEPT-135 experiment which
1818

enabled the quaternary carbon atoms to be excluded from consideration and the correct assignment of the
remaining signals to be carried out.
The mass spectra of compounds 4, 5b,d have the same values for the molecular ion peaks. A special
feature of the fragmentation of compounds 5a-f was the ejection of ionized methanimine molecule
[M-CH2NH]+, the cleavage of an isothiocyanate radical [M-CNS]+, and also the formation of a fragment ion
[M-C2H4N2S]+. The main direction of fragmentation of thiazoles 4b,d was the destruction of the thiazole ring
with ejection of ionized N-methylcyanamide, molecule [M-MeNHCN]+.
The obtained results enabled us to identify compounds 5a-f as 5-aryl-2-mercapto-1-methylimidazoles
containing a residue of 1,3-DMBA at the position 4. The presence of an aryl residue at position 5 of the ring
was confirmed by NOE (Nuclear Overhauser Effect) experiment, carried out for the imidazole 5d. Saturation of
the N-methyl proton signal of the thiourea fragment led to a response from the ortho protons of the chlorophenyl
radical, which indicated their spatial proximity.
Finally, the structures of compounds 5a-f were confirmed by an X-ray structural investigation of one
such representative 5c (Fig. 1). In the crystalline phase, the compound assumed the thione form, stabilized by an
intramolecular hydrogen bond N(3)–H(3N)···O(1) (H···O was 2.03 Å, N–H···O 124o). Bond C(3)–C(7) 1.385(3)
Å was extended relative to the mean value of 1.340 Å [14]. Bonds C(7)–N(3) 1.340(3) Å and C(3)–C(4) 1.443(3)
Å were shortened (mean values 1.355 and 1.509 Å, respectively) as a result of conjugation between the C(4)–
O(1) carbonyl group and the thioamide group. The five-membered ring was in a "flattened envelope"
conformation. The C(8) atom deviated from the plane of the remaining imidazole ring atoms by 0.14 Å.
Fig. 1. Molecular structure of compound 5c with atoms represented by thermal vibration ellipsoids of 50%
probability.
Imidazoles 5a-f in DMSO-d6 solution existed predominantly in the thiol form. The fraction of the thione
form of compounds 5a-e did not exceed 25%, as indicated by the integral intensity of the imidazole ring H-5
proton signal at 5.04-5.08 ppm (data not given in Experimental), and also by the absence of thioamide group
1
signal at the 170-180 ppm region of the 13C NMR spectra. The thione form was not detected in the H NMR
spectra of compound 5f. It should be emphasized that both tautomeric forms of compound 5 were additionally
stabilized by intramolecular hydrogen bonds.
1819

We note that the synthesized imidazolones 5a-f contain a structural fragment of the medication timazol
(1-methylimidazoline-2-thione), which is a synthetic antithyroid (thyreostatic) agent and is used in medicinal
practice for a specific treatment of thyroid gland hyperactivity [15]. Consequently, a further investigation of the
pharmacological activity of the obtained imidazoles is justified.
In the investigation of three-component condensation, a competition has been discovered between the
different nucleophilic centers of N-methylthiourea. This led to the formation of both thiazole and imidazole
rings. In the case of N-arylthioureas the interaction proceeded regioselectively with the formation of
2-aminofunctionalized thiazoles.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian VX-200 Mercury instrument (200 MHz), and the
13C NMR spectra on a Bruker AM-400 spectrometer (100 MHz) in DMSO-d6, internal standard was TMS. The
mass spectra were recorded on a Hewlett-Packard LC/MSD 1100 instrument, ionization method EI (70 eV).
Elemental analysis was carried out on a LECO CHNS-900 instrument. Melting points were determined on a
Kofler hot stage apparatus. A check on the reaction progress and purity of the obtained compounds was effected
by TLC on Silufol UV-254 plates in the systems: PhMe–EtOAc, 1:1, CH2Cl2–2-PrOH, 10:1, visualization with
iodine vapor.
5-(4-Aryl-2-methylaminothiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-diones
4b-f
and 5-(5-Aryl-1-methyl-2-sulfanyl-1H-imidazol-4-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-diones
5a-f (General Method). A mixture of equimolar quantities (about 1.0 mmol) of 1,3-DMBA 1, arylglyoxal
hydrates 2a-f, and thiourea 3a in EtOH (10 ml) was refluxed for 5-30 min until the start of precipitation of solid
compounds 4b-f (when using arylglyoxal hydrate 2a, compound 4a was not formed). After rapid cooling to
room temperature, compounds 4b-f were filtered off and washed on the filter with EtOH. Compounds 5a-f
precipitated as solids from the filtrate after 1-3 h at room temperature and were purified by recrystallization
from EtOH.
5-(4-Aryl-2-arylaminothiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-diones 4g-i were
synthesized analogously to compounds 4b-f from 1,3-DMBA 1, arylglyoxal hydrates 2b,e,g and thioureas 3b-d.
Since compounds 5 were not formed in this case, the reaction mixture was maintained at room temperature for 1
day, and products 4g-i were filtered off.
6-Hydroxy-1,3-dimethyl-5-[2-methylamino-4-(4-methylphenyl)thiazol-5-yl]pyrimidine-2,4(1H,3H)-dione
1
(4b). Yield 0.11 g (30%). Cream-colored powder. Mp >300oC. H NMR spectrum, δ, ppm (J, Hz): 2.27 (3H, s,
ArCH3); 3.01 (9H, s, 3NCH3); 7.14 (2H, d, J = 8.1, H-3,5 Ar); 7.31 (2H, d, J = 8.1, H-2,6 Ar); 9.02 (1H, s, NH);
12.40 (1H, s, OH). 13C NMR spectrum, δ, ppm: 20.8 (ArCH3); 28.4 (2NCH3); 32.1 (NHCH3); 79.9 (C-5'); 120.4
(C-5); 128.0, 129.5, 130.8, 131.5 (C Ar); 137.7 (C-4); 150.0 (C-2); 161.8 (2C=O); 168.2 (COH). Mass
spectrum, m/z (Irel, %): 358 [M]+ (100), 332 (5), 302 [M-MeNHCN]+ (9), 270 (7), 265 (15), 115 (8), 114 (5), 91
(10), 56 (10). Found, %: C 56.88; H 5.12; N 15.52. C17H18N4O3S. Calculated, %: C 56.97; H 5.06; N 15.63.
6-Hydroxy-1,3-dimethyl-5-[2-methylamino-4-(4-methylsulfanylphenyl)thiazol-5-yl]pyrimidine-
1
2,4(1H,3H)-dione (4c). Yield 0.12 g (30%). Cream-colored powder. Mp >300oC. H NMR spectrum, δ, ppm
(J, Hz): 2.53 (3H, s, SCH3); 3.00 (9H, s, 3NCH3); 7.21 (2H, d, J = 8.0, H-3,5 Ar); 7.39 (2H, d, J = 8.0, H-2,6 Ar);
13
9.10 (1H, s, NH); 12.48 (1H, s, OH). C NMR spectrum, δ, ppm: 14.1 (SCH3); 27.9 (2NCH3); 32.4 (NHCH3);
80.0 (C-5'); 122.0 (C-5); 128.9, 125.2, 129.8, 136.3 (C Ar); 138.7 (C-4); 151.1 (C-2); 160.9 (2C=O); 167.8
(COH). Found, %: C 52.35; H 4.59; N 14.42; S 16.56. C17H18N4O3S2. Calculated, %: C 52.29; H 4.65; N 14.35;
S 16.42.
5-[4-(4-Chlorophenyl)-2-methylaminothiazol-5-yl]-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(4d). Yield 0.13 g (35%). Cream-colored powder. Mp 290-292°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.07 (9H,
s, 3NCH3); 7.39 (2H, d, J = 8.8, H-3,5 Ar); 7.45 (2H, d, J = 8.8, H-2,6 Ar); 9.12 (1H, s, NH); 12.11 (1H, s, OH).
1820

13C NMR spectrum, δ, ppm: 27.8 (2NCH3); 32.1 (NHCH3); 78.2 (C-5'); 120.4 (C-5); 129.2, 130.1, 130.8, 131.1
35
(C Ar); 135.5 (C-4); 153.0 (C-2); 161.8 (2C=O); 168.2 (COH). Mass spectrum (for Cl isotope), m/z (Irel, %):
378 [M]+ (100), 322 [M-MeNHCN]+ (7), 264 (25), 229 (30), 201 (15), 180 (10), 137 (12), 100 (100), 76 (11).
Found, %: C 50.80; H 4.04; N 14.71. C16H15ClN4O3S. Calculated, %: C 50.73; H 3.99; N 14.79.
5-[4-(4-Bromophenyl)-2-methylaminothiazol-5-yl]-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-
1
dione (4e). Yield 0.12 g (29%). Finely crystalline cream-colored powder. Mp >300°C. H NMR spectrum, δ,
ppm (J, Hz): 3.02 (9H, s, 3NCH3); 7.41 (2H, d, J = 8.6, H-3,5 Ar); 7.51 (2H, d, J = 8.6, H-2,6 Ar); 9.07 (1H, s,
NH); 12.15 (1H, s, OH). 13C NMR spectrum, δ, ppm: 27.9 (2NCH3); 32.5 (NHCH3); 78.8 (C-5'); 121.8 (C-5);
127.9, 131.0, 131.6, 132.2 (C Ar); 136.7 (C-4); 151.1 (C-2); 160.9 (2C=O); 168.8 (COH). Found, %: C 45.31;
H 3.64; N 13.33. C16H15BrN4O3S. Calculated, %: C 45.40; H 3.57; N 13.24.
6-Hydroxy-1,3-dimethyl-5-[2-methylamino-4-(4-nitrophenyl)thiazol-5-yl]pyrimidine-2,4(1H,3H)-
dione (4f). Yield 0.12 g (31%). Pale-yellow crystals. Mp >300°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.01 (9H,
s, 3NCH3); 7.62 (2H, d, J = 8.6, H-2,6 Ar); 8.17 (2H, d, J = 8.6, H-3,5 Ar); 9.20 (1H, s, NH); 12.15 (1H, s, OH).
Found, %: C 49.40; H 3.94; N 18.04. C16H15N5O5S. Calculated, %: C 49.35; H 3.88; N 17.99.
6-Hydroxy-1,3-dimethyl-5-[4-(4-methoxyphenyl)-2-phenylaminothiazol-5-yl]pyrimidine-2,4(1H,3H)-
dione (4g). Yield 0.36 g (82%). White powder. Mp 281-282°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.13 (6H, s,
2NCH3); 3.61 (3H, s, OCH3); 6.88 (2H, d, J = 8.0, H-3,5 Ar); 6.98 (1H, t, J = 7.2, H-4 Ph); 7.30-7.37 (2H, m,
H-3,5 Ph); 7.53-7.63 (4H, m, H-2,6 Ph, H-2,6 Ar); 10.29 (1H, s, NH). Mass spectrum, m/z (Irel, %): 436 [M]+
(100), 323 (10), 322 (30), 279 (5), 202 (10), 176 (12), 194 (10), 135 (12), 77 (70), 76 (13). Found, %: C 60.38;
H 4.69; N 12.77. C22H20N4O4S. Calculated, %: C 60.54; H 4.62; N 12.84.
5-[4-(4-Bromophenyl)-2-(2-methylphenyl)aminothiazol-5-yl]-6-hydroxy-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (4h). Yield 0.31 g (62%). White powder. Mp 263-264°C. 1H NMR spectrum, δ, ppm (J, Hz):
2.28 (3H, s, ArCH3); 3.09 (6H, s, 2NCH3); 7.22-7.30 (3H, m, H Ar); 7.45-7.65 (5H, m, H Ar); 9.92 (1H, s, NH).
Mass spectrum (for 79Br isotope), m/z (Irel, %): 498 [M]+ (100), 350 (50), 311 (10), 227 (20), 160 (25), 133 (80),
132 (50), 131 (30), 104 (18), 76 (5). Found, %: C 52.72; H 3.70; N 11.10. C22H19BrN4O3S. Calculated, %:
C 52.91; H 3.83; N 11.22.
5-[2-(2-Bromophenyl)amino-4-(4-methylphenyl)thiazol-5-yl]-6-hydroxy-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (4i). Yield 0.34 g (68%). White powder. Mp 260-262°C. 1H NMR spectrum, δ, ppm (J, Hz):
2.26 (3H, s, ArCH3); 3.09 (6H, s, 2NCH3); 7.08-7.12 (3H, m, H Ar); 7.34-7.44 (3H, m, H Ar); 7.70 (1H, d, J = 7.6,
H Ar); 7.90 (1H, d, J = 7.6, H Ar); 9.95 (1H, s, NH). Mass spectrum (for 79Br isotope), m/z (Irel %): 498 [M]+
(35), 420 (25), 419 (100), 305 (35), 270 (5), 153 (12), 115 (15), 91 (12). Found, %: C 52.80; H 3.69; N 11.27.
C22H19BrN4O3S. Calculated, %: C 52.91; H 3.83; N 11.22.
6-Hydroxy-5-(1-methyl-5-phenyl-2-sulfanyl-1H-imidazol-4-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
1
dione (5a). Yield 0.20 g (58%). Pale-sandy crystals. Mp 228-229°C. H NMR spectrum, δ, ppm (J, Hz): 3.07
(6H, s, 2NCH3); 3.41 (3H, s, 1'-CH3); 7.27-7.33 (5H, m, H Ph); 12.32 (1H, s, OH). Mass spectrum, m/z (Irel, %):
344 [M]+ (100), 315 [M-CH2NH]+ (5), 286 [M-CNS]+ (7), 256 [M-C2H4N2S]+ (8), 215 (5), 118 (5), 91 (6), 58
(5). Found, %: C 55.60; H 4.59; N 16.37. C16H16N4O3S. Calculated, %: C 55.80; H 4.68; N 16.27.
6-Hydroxy-5-[2-mercapto-1-methyl-5-(4-methylphenyl)-2-sulfanyl-1H-imidazol-4-yl]-1,3-dimethyl-
1
pyrimidine-2,4(1H,3H)-dione (5b). Yield 0.19 g (53%). Pale-yellow crystals. Mp 208-210°C. H NMR
spectrum, δ, ppm (J, Hz): 2.28 (3H, s, ArCH3); 3.11 (6H, s, 2NCH3); 3.35 (3H, s, 1'-CH3); 7.20-7.32 (4H, m,
H Ar); 12.05 (1H, s, OH). Mass spectrum, m/z (Irel, %): 358 [M]+ (100), 329 [M-CH2NH]+ (3), 300 [M-CNS]+
(10), 270 [M-C2H4N2S]+ (10), 156 (8), 116 (15), 91 (20), 88 (3), 58 (18). Found, %: C 56.85; H 5.12; N 15.70.
C17H18N4O3S. Calculated, %: C 56.97; H 5.06; N 15.63.
6-Hydroxy-5-[2-mercapto-1-methyl-5-(4-methylsulfanylphenyl)-2-sulfanyl-1H-imidazol-4-yl]-
1,3-dimethylpyrimidine-2,4(1H,3H)-dione (5c). Yield 0.16 g (40%). Pale-yellow crystals. Mp 196-198°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.47 (3H, s, SCH3); 3.12 (6H, s, 2NCH3); 3.37 (3H, s, 1'-CH3); 7.22-7.37
(4H, m, H Ar); 12.04 (1H, s, OH). 13C NMR spectrum, δ, ppm: 14.8 (SCH3); 28.8 (2NCH3); 33.9 (1'-CH3); 80.5
(C-5'); 116.7 (C-5); 126.2, 126.6, 130.1, 139.3 (C Ar); 130.8 (C-4); 151.6 (C-2); 161.6 (2C=O); 168.7 (COH).
1821

Mass spectrum, m/z (Irel, %): 390 [M]+ (100), 361 [M-CH2NH]+ (5), 332 [M-CNS]+ (10), 302 [M-C2H4N2S]+
(15), 149 (20), 110 (5), 88 (5), 58 (20). Found, %: C 52.20; 4.69; N 14.27. C17H18N4O3S2. Calculated, %:
C 52.29; 4.65; N 14.35.
5-[5-(4-Chlorophenyl)-1-methyl-2-sulfanyl-1H-imidazol-4-yl]-6-hydroxy-1,3-dimethylpyrimidine-
1
2,4(1H,3H)-dione (5d). Yield 0.16 g (42%). Pale-yellow crystals. Mp 200-201°C. H NMR spectrum, δ, ppm
(J, Hz): 3.11 (6H, s, 2NCH3); 3.43 (3H, s, 1'-CH3); 7.32 (2H, d, J = 7.8, H-3,5 Ar); 7.43 (2H, d, J = 7.8, H-2,6 Ar);
12.05 (1H, s, OH). 13C NMR spectrum, δ, ppm: 28.8 (2NCH3); 33.4 (1'-CH3); 79.0 (C-5'); 116.0 (C-5); 129.0,
130.9, 131.1, 131.5, 132.5 (C-4, C Ar); 151.0 (C-2); 161.8 (2C=O); 169.0 (COH). Mass spectrum (for 35Cl
isotope), m/z (Irel, %): 378 [M]+ (100), 349 [M-CH2NH]+ (5), 320 [M-CNS]+ (10), 290 [M-C2H4N2S]+ (10), 156
(8), 111 (15), 88 (4), 58 (12). Found, %: C 50.65; H 4.07; N 14.72. C16H15ClN4O3S. Calculated, %: C 50.73;
H 3.99; N 14.79.
5-[5-(4-Bromophenyl)-1-methyl-2-sulfanyl-1H-imidazol-4-yl]-6-hydroxy-1,3-dimethylpyrimidine-
1
2,4(1H,3H)-dione (5e). Yield 0.17 g (40%). Pale-yellow crystals. Mp 192-193°C. H NMR spectrum, δ, ppm
(J, Hz): 3.10 (6H, s, 2NCH3); 3.38 (3H, s, 1'-CH3); 7.29 (2H, d, J = 8.2, H-3,5 Ar); 7.58 (2H, d, J = 8.2, H-2,6 Ar);
12.05 (1H, s, OH). Mass spectrum (for 79Br isotope), m/z (Irel, %): 422 [M]+ (100), 393 [M-CH2NH]+ (6), 364
[M-CNS]+ (11), 334 [M-C2H4N2S]+ (9), 156 (8), 155 (13), 88 (4), 58 (12). Found, %: C 45.30; H 3.45; N 13.16.
C16H15BrN4O3S. Calculated, %: C 45.40; H 3.57; N 13.24.
6-Hydroxy-1,3-dimethyl-5-[1-methyl-5-(4-nitrophenyl)-2-sulfanyl-1H-imidazol-5-yl]pyrimidine-
1
2,4(1H,3H)-dione (5f). Yield 0.14 g (37%). Yellow crystals. Mp 200-202°C. H NMR spectrum, δ, ppm
(J, Hz): 3.01 (6H, s, 2NCH3); 3.43 (3H, s, 1'-CH3); 7.58 (2H, d, J = 8.6, H-2,6 Ar); 8.17 (2H, d, J = 8.6, H-3,5 Ar);
12.20 (1H, s, OH). Mass spectrum, m/z (Irel, %): 389 [M]+ (100), 360 [M-CH2NH]+ (8), 331 [M-CNS]+ (10), 301
[M-C2H4N2S]+ (14), 122 (20), 110 (10), 88 (8), 58 (20). Found, %: C 49.20; H 3.84; N 17.84. C16H15N5O5S.
Calculated, %: C 49.35; H 3.88; N 17.99.
X-Ray Structural Investigation of Compound 5c. Crystals of compound 5c were monoclinic,
C17H18N4O3S2, at 20°C: a 5.9678(5), b 15.4918(11), c 19.5066(14) Å; β 97.080(7)°; V 1789.7(2) Å3; M 390.47;
Z 4; space group P21/c, dcalc 1.449 g/cm3, μ(MoKα) 0.323 mm-1, F(000) 816. The parameters of the unit cell and
the intensities of 10916 reflections (5208 independent, Rint 0.049) were measured on an Xcalibur-3
diffractometer (MoKα radiation, CCD detector, graphite monochromator, ω-scanning, 2θmax 60°). The structure
was solved by the direct method with the SHELXTL software package [16]. The positions of hydrogen atoms
were determined by an electron density difference synthesis and were refined isotropically, with the exception
of the methyl group hydrogen atoms which were refined with a "rider" model with Uiso = 1.5 Ueq. The structure
was refined on F2 with a full-matrix least-squares method in an anisotropic approximation for the non-hydrogen
atoms to wR2 0.105 for 5208 reflections (R1 0.056 on 2556 reflections with F>4σ(F), S 0.89). All the
crystallographic data have been deposited at the Cambridge Crystallographic Data Center (deposit CCDC
874086).
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