Unexpected result in the reaction of 3-amino-3-thioxopropanamides with 2-anilinomethylene derivatives of 1,3-dicarbonyl compounds. synthesis of pyrimidine-5-carboxamide derivatives

Article abstract of DOI:10.1007/s10593-013-1266-5

The interaction of 3-amino-3-thioxopropanamides with 2-anilinomethylene derivatives of dimedone, 1,3-cyclohexanedione and Meldrum's acid led to the formation of 2-(2-amino-2-oxoethyl)-6-thioxo-1,6-dihydropyrimidine-5- carboxamides. The latter were alkylated in alkaline medium with the formation of 4-(alkylthio)pyrimidine-5-carboxamide derivatives.

Full text of DOI:10.1007/s10593-013-1266-5

Chemistry of Heterocyclic Compounds, Vol. 49, No. 3, June, 2013 (Russian Original Vol. 49, No. 3, March, 2013)
UNEXPECTED RESULT IN THE REACTION OF
3-AMINO-3-THIOXOPROPANAMIDES WITH
2-ANILINOMETHYLENE DERIVATIVES OF
1,3-DICARBONYL COMPOUNDS. SYNTHESIS
OF PYRIMIDINE-5-CARBOXAMIDE DERIVATIVES
V. V. Dotsenko1*, K. A. Frolov1, S. G. Krivokolysko1, and V. V. Polovinko2
The interaction of 3-amino-3-thioxopropanamides with 2-anilinomethylene derivatives of dimedone,
1,3-cyclohexanedione and Meldrum's acid led to the formation of 2-(2-amino-2-oxoethyl)-6-thioxo-
1,6-dihydropyrimidine-5-carboxamides. The latter were alkylated in alkaline medium with the
formation of 4-(alkylthio)pyrimidine-5-carboxamide derivatives.
Keywords: 3-amino-3-thioxopropanamides, pyrimidine-5-carboxamides, thiomalonamides, alkylation,
heterocyclization.
Reactions of activated methylene groups belonging to nitriles and amides with β-enamino ketones and
esters are quite widely used in synthetic practice for obtaining pyridine heterocycles (for reviews, see [1-8]).
Among the most available enaminocarbonyl substrates are the 2-anilinomethylene derivatives of 1,3-dicarbonyl
compounds, which are readily obtained by three-component condensation of activated methylene compound,
triethyl orthoformate, and aniline [9-13]. The reaction of 2-anilinomethylene derivatives of 1,3-dicarbonyl
compounds with activated methylene nitriles and amides has been used repeatedly and successfully for the
synthesis of a range of oxygen- and nitrogen-containing heterocyclic systems [12, 14-20].
We have previously shown [13] that the interaction of compounds 1-3 with cyanothioacetamide (4) is a
convenient method of preparing azines 5-7. The practical value of these compounds is explained by the fact that
they are starting materials for obtaining a series of biologically active substances, viz. modulators of
metabotropic glutamate receptors of subtype I (mGluR1) [21], IKKβ enzyme inhibitors [22], ubiquitin
C-terminal hydrolase L1 inhibitors [23], HIV-1 integrase inhibitors [24], phosphodiesterase PDE4B inhibitors
[25], etc.
_______
*To whom correspondence should be addressed, e-mail: victor_dotsenko@bigmir.net.
1"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A Molodyozhnyi Kv, Lugansk
91034, Ukraine.
2Enamine Ltd, 67/45 Krasnotkatskaya St., Kyiv 02094, Ukraine; e-mail: nmr@mail.enamine.net.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 474-485, March, 2013. Original
article submitted December 17, 2012.
0009-3122/13/4903-0440©2013 Springer Science+Business Media New York
440

CN
O
NH
Ph
CN
NH
R
O
N
R1
O
R
R1
[15]
O
[18, 19]
Y
O
R
R
[12, 14, 16]
[17]
O
O
R1
O
NHPh
R
O
R
O
PhNH2
+
O
HC(OEt)3
R1
[12]
R1
X
O
[20]
R1
N
H
CN
O
R1
O
X
R
N
R
R1
N
O
Ph
O
Ph
O
CN
O
R
CN
N
S
1) KOH, EtOH
2) HCl
R
H
X
NHPh
5, 6
NH2
+
R
O
O
X
O
S
R
CN
SH
4
1–3
HO
1 R = H, X = CH2; 2 R = Me, X = CH2;
3 R = Me, X = O; 5 R = H; 6 R = Me
N
H
7
While continuing investigations in this direction we attempted to prepare analogs of compounds 5-7
from enaminodicarbonyl compounds 1-3 and structural analogs of cyanothioacetamide (4), the 3-amino-
3-thioxopropanamides (thiomalonamides) 8a-e. Preliminary results [26] proved to be quite unexpected. Thus,
on interacting thiomalonamide 8a (R = H) with the dimedone 2-anilinomethylene derivative 2 (ratio of 8a:2 =
1:1, excess of KOH, EtOH) we obtained 6-thioxo-1,6-dihydropyrimidine-5-carboxamide 9a. The same product
was also formed on introducing the anilinomethylene derivative of Meldrum's acid 3 into the reaction. We
established that the analogous thioxopyrimidines 9b-e could be readily obtained from N-substituted
3-thioxopropanamides 8b-e and electrophilic substrates 1-3. As expected, the yields and purity of compounds
9a-e increased on introducing a twofold excess of thioamide component 8a-e into the reaction with enamines
1-3. A small library of pyrimidines 10a-v was obtained by alkylating thioxopyrimidines 9a-e at the sulfur atom.
The low yields of compounds 10a-v (15-46%) were presumably linked to the unoptimized reaction conditions
and the occurrence of side processes in the alkaline medium.
1
The structures of compounds 9a-e and 10a-v were confirmed by data of IR, H and 13C NMR
spectroscopy, HPLC-MS, and elemental analysis, as well as by NMR experiments for compounds 10a (1H-13C
HMBC, 13C APT) and 10b (13C APT). In the mass spectra of compounds 9a-e peaks were detected for
molecular ions with m/z [2M(8a-e)-23], in IR spectra absorption bands were observed for amide C=O groups.
1
The H NMR spectra of compounds 9a-e and 10a-v lacked signals for the fragments of dimedone,
441

1,3-cyclohexanedione, or the COOH group. Instead, a singlet was detected for the methylene protons at 3.39-
4.05 ppm, as well as signals for two CONHR fragments, and also a narrow singlet for the pyrimidine ring
proton at 8.71-8.93 ppm. The spectral characteristics of compounds 10a-v are given in Table 1.
O
N
NHR
S
O
N
NHR
S
O
NHR
NH2
R1
1) KOH, EtOH
2) HCl
R1CH2Hal
1–3
+
NH
KOH, H2O
EtOH
N
S
8a–e
NHR
NHR
O
O
9a–e
10a–v
8, 9 a R = H, b R = Bn, c R = Ph, d R = 4-MeC6H4, e R = 4-BrC6H4;
10 a R = H, R1 = CONH2; b R = H, R1 = COPh; с R = H, R1 = CONH-4-ClC6H4;
d R = Ph, R1 = COOPr; e R = 4-MeC6H4, R1 = CONH-4-BrC6H4; f R = 4-MeC6H4, R1 = COOEt;
g R = 4-MeC6H4, R1 = CONH(3-EtOOC-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl;);
h R = 4-MeC6H4, R1 = CONH-4-EtC6H4; i R = 4-MeC6H4, R1 = CONH-2-ClC6H4;
j R = 4-MeC6H4, R1 = CONH-3-MeOC6H4; k R = 4-MeC6H4, R1 = CONH-2-MeOC6H4;
l R = 4-BrC6H4, R1 = CONHPh; m R = 4-BrC6H4, R1 = CONHCH2Ph;
n R = 4-BrC6H4, R1 = CONH-2-MeC6H4; o R = 4-BrC6H4, R1 = CONH-4-MeC6H4;
p R = 4-BrC6H4, R1 = CONH-2-EtC6H4; q R = 4-BrC6H4, R1 = CONH-4-EtC6H4;
r R = 4-BrC6H4, R1 = CONH-2,6-Me2C6H3; s R = 4-BrC6H4, R1 = CONH-2,4-Me2C6H3;
t R = 4-BrC6H4, R1 = CONH-2-Me-3-ClC6H3; u R = 4-BrC6H4, R1 = CO-4-MeC6H4;
v R = 4-BrC6H4, R1 = CO-4-ClC6H4
Proceeding from the data of HPLC-MS, IR, and NMR spectroscopy, thioxopyrimidines 9a-e and their
S-alkyl derivatives 10a-v may be ascribed the structure of either 2-(carbamoylmethyl) isomer A, or 4-(carba-
moylmethyl) isomer B. An unambiguous choice in favor of structure A for the compound 10a was based on 1H
13
and C heteronuclear correlation experiment through 2-3 bonds. The sole proton of the pyrimidine ring in the
HMBC spectrum had four correlation cross peaks (isomer A), while in the spectrum of the alternative structure
1
B only two cross peaks might be expected (Fig. 1). The observed H-13C HMBC correlations for 2-(2-amino-
2-oxoethyl)-4-[(2-amino-2-oxoethyl)thio]pyrimidine-5-carboxamide (10a) are given in Figure 2.
Each of the singlets of the methylene groups 2-CH2CONH2 and SCH2 gave two cross peaks: 3.73/165.8
(CH2/C-2), 3.73/170.4 (CH2/CONH2) and 3.79/169.2 (SCH2/C-4), 3.79/170.3 ppm (SCH2/CONH2), while four
correlations were detected for the proton H-6 at 8.73/123.5 (H-6/C-5), 8.73/165.8 (H-6/C-2), 8.73/166.4 (H 6/5-
CONH2), and 8.73/169.2 ppm (H-6/C-4). In the 13C APT spectrum of 2-(2-amino-2-oxoethyl)-4-[(2-oxo-
8.73
O
H
N
166.4
154.9
165.8
SCH2R1
N
H
N
NHR
NH2
N
O
CONHR
SCH2R1
H
N
O
O
123.5
3.73
33.7
S
H
H
46.7
O
N
H
H
H2N
170.3
170.4
169.2
NH2
O
NHR
NHR
3.79
A
B
Fig. 1. Alternative structures A and B for compounds
10a-v.
Fig. 2. Scheme of the observed correlations in the
1H-13C HMBC spectrum of compound 10a
442

2-phenylethyl)thio]pyrimidine-5-carboxamide (10b) four peaks of opposite phase were observed (154.4 ppm,
C-6, 128.1, 128.6, and 133.1 ppm, phenyl CH) and nine peaks in phase (phenyl C-1, three C=O signals, two
13
methylene group peaks, C-2, C-4, C-5). In the C APT spectrum of pyrimidine 10a a sole peak of opposite
phase (154.9 ppm, C-6) was observed.
The pyrimidine ring formation mechanism of compound 9 was of interest to us. The enaminodicarbonyl
compounds 1-3 had the obvious role of methine C1-synthons, while one of the thiomalonamide 8 molecules
formally reacted as an N-nucleophile, and another as a C-nucleophile. The possible mechanisms of the
interaction are shown below.
O
NHR
O
NHPh
NH2
+
S
O
NHR
O
1–3
8
O
KOH –PhNH2
R
S
O
N
H
NH
Mechanism 1 Mechanism 2
O
N
H
S
O
O
O
O
–
8
O
R
N
O
O
CSNH2
N
O
HN
SH
R
11
CONHR
S
RHN
8
13
O
O
–
O
S
N
H2N
–
NHR
O
CH
O
RHN
RHN
S
N
RHN
S
SH
O
O
NH
NH2
N
NH
–H2S
NHR
S
12
O
9
The mechanism 1 includes vinylic substitution of the aniline fragment with a thioamide fragment and
removal of 1,3-dicarbonyl compound followed by cyclization to the pyrimidine derivative 11. It is suggested
that the latter was attacked at the C-2 atom by the carbanion of compound 8 and underwent recyclization
through the intermediate 12 with elimination of H2S and the formation of pyrimidine 9. The alternative
mechanism 2 assumes a sequential formation of the open-chain intermediates 13 and 12.
The known ability of thioamides to play the role of N-nucleophiles in vinylic substitution reactions
supports the proposed aniline fragment substitution by thioamide as the first stage of the process [27, 28]. It
should also be noted that the competitive C-/N-nucleophilicity of thiomalonamides 8 in SNVin reactions was
noted in a previous work [29]. Presumably the most probable reason for the anomalous reactivity of compounds
8 with enamine substrates 1-3 was the decreased CH-acidity of the methylene fragment of
443

444

445

thioamides 8 (estimated pKa = 14-15, assessed by analogy with structurally related compounds [30]), in
comparison with the CH acidity of cyanothioacetamide 4 (pKa ~ 9.5 [31] and the overall NH acidity of primary
thioamides (pKa 12-13 [32]). Compounds 11 have been described in the work [29] among other products of the
thiomalonamide 8 reaction with ethoxymethylenemalonic ester. The conversion 11 → 12 → 9 is formally a
variant of the Kost–Sagitullin rearrangement. The possibility of nucleophilic attack at C-2 position of the
pyrimidine ring is in agreement with literature data for this type of reactions [33].
Compounds 9a-e were yellow powders, insoluble in EtOH, poorly soluble in acetone and AcOH,
moderately soluble in DMF and DMSO. Pyrimidines 10a-v were colorless crystals or white/beige powders,
insoluble in EtOH, moderately soluble in acetone, and soluble in hot AcOH and DMF.
In conclusion it should be mentioned that the reaction discovered by us opened a principally new
approach to the construction of the pyrimidine ring and enabled the creation of new fuctionally substituted
derivatives of pyrimidine. Currently the work continues on the method optimization for obtaining these
compounds, characterization of their properties and investigating the mechanism of their formation.
EXPERIMENTAL
The IR spectra were recorded on Thermo Nicolet Avatar 370 DTGS (in KBr pellets, compound 9a) and
on IKS-29 spectrophotometers (in nujol, remaining compounds). The 1H NMR spectra were recorded on Bruker
DRX-500 (500 MHz for compounds 9a, 10a-c), Varian Gemini 200 (200 MHz for compounds 8a, 9c-e,
13
10e,f,l,o,p,r),Varian Unity Plus (400 MHz for compounds 9b, 10d,g-k,m,n,q,s-v) instruments. The C NMR,
13C APT, and two-dimensional 1H–13C HMBC spectra were recorded on a Bruker DRX-500 (500 and 125 MHz
1
for H and 13C nuclei, respectively). The solvent for all NMR spectra was DMSO-d6, internal standard was
TMS. The HPLC-MS analysis of compounds 10d,j was carried out on an Agilent 1100 chromatograph with a
diode matrix (215, 254, and 264 nm) and mass selective (Agilent LC/MSD SL) detectors, ionization type APCI.
HPLC-MS analysis of the remaining compounds was performed on a Shimadzu LC-10AD liquid
chromatograph with Shimadzu SP D-10A UV-Vis (254 nm) and Sedex 75 ELSD detectors, linked with a PE
SCIEX API 150EX mass detector, ionization by electrospray at atmospheric pressure. Elemental analysis was
performed on a Carlo-Erba 1106 Elemental Analyzer. Melting points were determined on a Kofler hot stage
apparatus and were not corrected. The purity of the obtained compounds was checked by TLC on Silufol
UV-254 plates, eluent was acetone–hexane, 1:1, visualization with iodine vapor, UV detector.
2-Anilinomethylene-1,3-cyclohexanedione (1), 2-anilinomethylene-5,5-dimethyl-1,3-cyclohexanedione
(2) and 5-anilinomethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (3) were obtained by known procedures [13,
17]. 3-Amino-3-thioxopropanamides 8a-e were obtained by passing H2S through a solution of the
corresponding cyanoacetamide in a pyridine–Et3N mixture [34, 35].
3-Amino-3-thioxopropanamide (8a) was obtained by a modification of published procedure [34] in
the following way. Cyanoacetamide (25 g, 0.297 mol) was placed in an 150-ml Erlenmeyer flask, then pyridine
(25 ml) and Et3N (21 ml, 0.151 mol) were added. H2S was passed through the obtained suspension with heating
(40-50°C) and stirring for 6 h. The reaction mixture was maintained overnight in a freezer (-10°C), the
precipitated solid was filtered off and washed with cold EtOH and Et2O. The filtrate was kept in the freezer for
72 h and a further quantity of pure product was obtained. The overall yield was 23.65 g (67%), beige powder,
mp 105-107°C (EtOH) (mp 103-105°C [35], mp 110-112ºC [36]). The product dissolved readily in water, hot
1
EtOH, and was not soluble in Et2O. H NMR spectrum, δ, ppm: 3.42 (2H, s, CH2); 6.96 (1H, br. s) and 7.41
(1H, br. s, CONH2); 9.29 (1H, br. s) and 9.43 (1H, br. s, CSNH2). Found, %: C 30.66; H 5.18; N 23.59.
C3H6N2OS. Calculated, %: C 30.49; H 5.12; N 23.71.
446

2-(2-Amino-2-oxoethyl)-6-thioxo-1,6-dihydropyrimidine-5-carboxamides 9a-e (General Method).
Thioamide 8a-e with activated methylene group (0.030 mol) and the corresponding enamino-1,3-dicarbonyl
compound 1-3 (0.015 mol) were placed in a 100-ml beaker, and 96% EtOH (40 ml) was added. KOH (3.4 g,
0.061 mol) was added to the obtained suspension with vigorous stirring and mild heating (~40°C). In this way
the starting compounds gradually dissolved (in the case of thioamides 8a,e, the solid potassium salt of the
product precipitated after 10-20 min). The reaction mixture was stirred for 6 h at 25°C, maintained for 48 h at
room temperature, and then an excess (10 ml) of conc. HCl was added dropwise with stirring. The precipitated
yellow product was filtered off, washed with EtOH, water, and acetone. The obtained substances were refluxed
in AcOH or acetone to obtain analytically pure samples. Thioxopyrimidines 9a-e were also formed by reacting
compounds 8a-e and 1-3 at a ratio of 1:1, but in reduced yield and significantly contaminated with the starting
enamines 1-3.
2-(2-Amino-2-oxoethyl)-4-[(2-amino-2-oxoethyl)thio]pyrimidine-5-carboxamide (9a). Yield 2.13 g
(67%) (from thiomalonamide 8a and enamino diketone 2, 2:1), 2.04 g (64%) (from thiomalonamide 8a and
Meldrum's acid derivative 3, 2:1), 0.81 g (51% calculated compound 8a, from thiomalonamide 8a and
compound 3, 1:1). The preparation of compound 9a from compounds 8a and 2 (1:1) was described in the work
[26]. Yellow powder; mp 245-250°C (decomp.). 1H NMR spectrum, δ, ppm: 3.74 (2H, s, 2-CH2); 7.08 (1H, br.
s) and 7.54 (1H, br. s, CH2CONH2); 7.72 (1H, br. s) and 9.28 (1H, br. s, 5-CONH2); 8.71 (1H, s, H-4); 14.03
(1H, br. s, NH). The results of HPLC-MS, elemental analysis, and spectral investigations (IR and 13C NMR
spectra) were in agreement with those given in study [26].
N-Benzyl-2-[2-(benzylamino)-2-oxoethyl]-6-thioxo-1,6-dihydropyrimidine-5-carboxamide
(9b).
Yield 4.36 g (74%) (from thioamide 8b and enaminoketone 2, 2:1). Pale-yellow powder; mp >250°C (decomp.).
1
Rf 0.45. IR spectrum, , cm-1: 3275 (N–H), 1650 (C=O). H NMR spectrum, δ, ppm (J, Hz): 3.83 (2H, s,
3
3
CH2CONH); 4.30 (2H, d, J = 5.9, CH2NH); 4.55 (2H, d, J = 5.7, CH2NH); 7.24-7.37 (10H, m, H Ph); 8.72
3
(1H, s, H-4); 8.33 (1H, t, J = 5.7, CH2NH); 10.36-10.42* (1H, m, CH2NH); 14.57 (1H, br. s, CONH). Mass
spectrum, m/z: 393.6 [M+H]+, 786.0 [2M+H]+. Found, %: C 64.40; H 5.27; N 14.12. C21H20N4O.S. Calculated,
%: C 64.27; H 5.14; N 14.28.
2-(2-Anilino-2-oxoethyl)-N-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxamide (9c). Yield 4.15
g (76%, from thiomalonamide 8c and enamino diketone 1, 2:1), 1.78 g (65% calculated from the
thiomalonamide 8c, from thiomalonamide 8c and enamino diketone 2, 1:1). Lemon-colored powder; mp
1
>250°C (decomp., AcOH). IR spectrum, , cm-1: 3285, 3180 (N–H), 1665, 1650 (C=O). H NMR spectrum, δ,
ppm : 4.00 (2H, s, CH2CONH); 6.95-7.13 (2H, m, H Ar); 7.24-7.37 (4H, m, H Ar); 7.57-7.70 (4H, m, H Ar);
8.83 (1H, s, H-4); 10.37 (1H, s, CH2CONH); 12.27 (1H, s, 5-CONH); 14.37 (1H, br. s, NH). Found, %:
C 62.89; H 4.57; N 15.32. C19H16N4O2S. Calculated, %: C 62.62; H 4.43; N 15.37.
N-(4-Methylphenyl)-2-{2-[(4-methylphenyl)amino]-2-oxoethyl}-6-thioxo-1,6-dihydropyrimidine-
5-carboxamide (9d). Yield 1.59 g (54% calculated on thioamide 8d, from the thioamide 8d and enamino
diketone 2, 1:1), 3.53 g (60%, from thioamide 8d and enamino diketone 2, 2:1). Sandy-colored powder; mp >
1
250°C (decomp., AcOH). Rf 0.64. IR spectrum, , cm-1: 3285, 3180 (N–H), 1672, 1650 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH3); 2.32 (3H, s, CH3); 3.96 (2H, s, CH2CONH); 7.04 (2H, d, 3J = 8.2,
H Ar); 7.09 (2H, d, 3J = 8.4, H Ar); 7.44 (2H, d, 3J = 8.4, H Ar); 7.56 (2H, d, 3J = 8.2, H Ar); 8.93 (1H, s, H-4);
10.09 (1H, s, CH2CONH); 12.36 (1H, s, 5-CONH); 14.60 (1H, br. s, NH). Mass spectrum, m/z: 393.6 [M+H]+,
786.0 [2M+H]+. Found, %; C 64.57; H 5.29; N 14.25. C21H29N4O2S. Calculated, %: C 64.27; H 5.14; N 14.28.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-6-thioxo-1,6-dihydropyrimidine-
5-carboxamide (9e). Yield 2.51 g (64%, calculated on thiomalonamide 8e, from the thiomalonamide 8e and
1
enamino diketone 2, 1:1), Yellow powder; mp >250°C (decomp., DMF). H NMR spectrum, δ, ppm (J, Hz):
_______
*Unresolved triplet
447

3.97 (2H, s, CH2CONH); 7.37-7.43** (4H, m, H Ar); 7.55 (2H, d, 3J = 8.7, H Ar); 7.64 (2H, d, 3J = 8.8, H Ar);
8.92 (1H, s, H-4); 10.36 (1H, s, CH2CONH); 12.53 (1H, s, 5-CONH). Found, %: C 44.01; H 2.79; N 10.63.
C19H14Br2N4O2S. Calculated, %: C 43.70; H 2.70; N 10.73.
4-(Alkylthio)-2-(2-amino-2-oxoethyl)pyrimidine-5-carboxamides 10a-v (General Method).
Aqueous 10% KOH solution (2.1 ml, 4.1 mmol) was added to a suspension of thioxopyrimidine 9a-e
(4.0 mmol) in EtOH (20 ml), and the mixture was stirred until complete dissolution, with heating as necessary.
A solution of alkylating agent (4.0 mmol of phenacyl bromide, chloroacetic ester, or chloroacetanilide
derivative) in EtOH (6-7 ml) was added dropwise to the obtained solution. The reaction mixture was stirred for
3 h at 15-20°C, maintained for 72 h without stirring, then diluted with H2O (10 ml), stirred for 5 h, and the solid
was filtered off. The product was recrystallized as necessary from an appropriate solvent (in those cases the
yields are indicated for the recrystallized product).
2-(2-Amino-2-oxoethyl)-4-[(2-amino-2-oxoethyl)thio]pyrimidine-5-carboxamide (10a). Yield 0.69 g
13
(33%). White powder; mp >250°C (DMF). C APT NMR spectrum, δ, ppm: 33.7 (CH2); 46.7 (SCH2); 123.5
(C-5); 154.9* (C-6); 165.8 (C-2); 166.4 (5-CONH2); 169.2 (C-4); 170.3 (SCH2CONH2); 170.4 (2-CH2CONH2).
Mass spectrum, m/z: 270.6 [M+H]+, 539.8 [2M+H]+. Found, %: C 40.27; H 4.25; N 25.95. C9H11N5O3S.
Calculated, %: C 40.14; H 4.12; N 26.01.
2-(2-Amino-2-oxoethyl)-4-[(2-oxo-2-phenylethyl)thio]pyrimidine-5-carboxamide (10b). Yield 0.48 g
13
(36%). White powder; mp >200°C (acetone–MeOH, 1:2). C APT NMR spectrum, δ, ppm; 36.6 (CH2); 45.6
(SCH2); 122.6 (C-5); 128.1* (CH Ar); 128.6* (CH Ar); 133.1* (CH Ar); 136.5 (C-1 Ar); 154.4* (C-6); 165.1
(C-2); 165.8 (5-CONH2); 168.3 (C-4); 169.3 (2-CH2CONH2); 194.5 (PhCO). Found, %: C 54.44; H 4.30;
N 17.05. C15H14N4O3S. Calculated, %: C 54.53; H 4.27; N 16.96.
2-(2-Amino-2-oxoethyl)-4-({2-[(4-chlorophenyl)amino]-2-oxoethyl}thio)pyrimidine-5-carboxami-
13
de (10c). Yield 0.70 g (46%). White powder; mp 226-228°C (decomp., AcOH). C NMR spectrum, δ, ppm:
34.7 (CH2); 46.0 (SCH2); 120.8 (C Ar); 122.6 (C-5); 126.8 (C Ar); 128.5 (C Ar); 137.9 (C Ar); 154.5 (C-6);
165.2 (C-2); 165.8 (5-CONH2); 166.9 (C-4); 168.7 (2-CH2CONH2); 169.7 (CONHAr). Mass spectrum, m/z:
380.8 [M+H]+, 759.8 [2M+H]+. Found, %: C 47.35; H 3.79; N 18.35. C15H14ClN5O3S. Calculated, %: C 47.43;
H 3.72; N 18.44.
Propyl {[2-(2-Anilino-2-oxyethyl)-5-(N-phenylcarbamoyl)pyrimidin-4-yl]thio}acetate (10d). Yield
0.59 g (32%). White powder, mp 210-212°C (EtOH–acetone, 1:1). Mass spectrum, m/z: 465.0 [M+H]+, 463.0
[M-H]-. Found, %: C 61.92; H 5.36; N 12.00. C24H24N4O4S. Calculated, %: C 62.05; H 5.21; N 12.06.
4-({2-[(4-Bromophenyl)amino]-2-oxoethyl}thio)-N-(4-methylphenyl)-2-{2-[(4-methylphenyl)amino]-
2-oxoethyl}pyrimidine-5-carboxamide (10e). Yield 0.87 g (36%). White powder; mp >250°C (DMF). Found,
%: C 57.85; H 4.46; N 11.49. C29H26BrN5O3S. Calculated, %: C 57.62; H 4.34; N 11.59.
Ethyl [(2-{2-[(4-Methylphenyl)amino]-2-oxoethyl}-5-[N-(4-methylphenyl)carbamoyl]pyrimidin-
4-yl)thio]acetate (10f). Yield 0.52 g (27%). Colorless crystals; mp 218-220°C (AcOH). Found, %: C 62.65;
H 5.46; N 11.89. C25H26N4O4S. Calculated, %: C 62.74; H 5.48; N 11.71.
Ethyl
2-({[(5-{[(4-Methylphenyl)amino]carbonyl}-2-{2-[(4-methylphenyl)amino]-2-oxoethyl}pyri-
midin-4-yl)thio]acetyl}amino)-4,5,6,7-tetrahydro-1-benzo[b]thiophene-3-carboxylate (10g). Yield 1.05 g
(40%). Beige powder; mp >250°C (AcOH). Found, %: C 61.94; H 5.49; N 10.79. C34H35N5O5S2. Calculated, %:
C 62.08; H 5.36; N 10.65.
N-(4-Methylphenyl)-4-({2-[(4-ethylphenyl)amino]-2-oxo-ethyl}thio)2-{2-[(4-methylphenyl)amino]-
2-oxoethyl}pyrimidine-5-carboxamide (10h). Yield 0.82 g (37%). Beige, finely crystalline powder; mp
>250°C (AcOH). Found, %: C 67.19; H 5.73; N 12.73. C31H31N5O3S. Calculated, %: C 67.25; H 5.64; N 12.65.
_______
*Overlap of two doublets. Signal of endocyclic NH proton is not displayed, evidently due to deuterium
exchange.
**Signal in antiphase.
448

4-({2-[(2-Chlorophenyl)amino]-2-oxoethyl}thio)-N-(4-methylphenyl)-2-{2-[(4-methylphenyl)amino]-
2-oxoethyl}pyrimidine-5-carboxamide (10i). Yield 0.43 g (19%). White powder; mp >250°C (AcOH). Found,
%: C 62.05; H 4.80; N 12.71. C29H26ClN5O3S. Calculated, %: C 62.19; H 4.68; N 12.50.
4-({2-[(3-Methoxyphenyl)amino]-2-oxoethyl}thio)-N-(4-methylphenyl)-2-{2-[(4-methylphenyl)amino]-
2-oxoethyl}pyrimidine-5-carboxamide (10j). Yield 0.38 g (17%). White powder, mp >250°C (AcOH). Found,
%: C 64.77; H 5.40; N 12.57. C30H29N5O4S. Calculated, %: C 64.85; H 5.26; N 12.60.
4-({2-[(2-Methoxyphenyl)amino]-2-oxoethyl}thio)-N-(4-methylphenyl)-2-{2-[(4-methylphenyl)-
amino]-2-oxoethyl}pyrimidine-5-carboxamide (10k). Yield 0.42 g (19%). White powder; mp 187-189°C
(AcOH). Mass spectrum, m/z: 556.0 [M+H]+, 554.1 [M-H]-. Found, %: C 64.72; H 5.34; N 12.69. C30H29N5O4S.
Calculated, %: C 64.85; H 5.26; N 12.60.
4-[(2-Anilino-2-oxoethyl)thio]-N-(4-bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}pyrimidi-
ne-5-carboxamide (10l). Yield 0.84 g (32%). White powder; mp >250°C. Found, %: C 49.70; H 3.30; N 10.57.
C27H21Br2N5O3S. Calculated, %: C 49.48; H 3.23; N 10.69.
4-{[2-(Benzylamino)-2-oxoethyl]thio}-N-(4-bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-
pyrimidine-5-carboxamide (10m). Yield 1.04 g (39%). Beige powder; mp 233-235°C. Found, %: C 50.07;
H 3.54; N 10.39. C28H23Br2N5O3S. Calculated, %: C 50.24; H 3.46; N 10.46.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(2-methylphenyl)amino]-2-oxo-
ethyl}thio)pyrimidine-5-carboxamide (10n). Yield 0.83 g (31%). Beige powder; mp >240°C (decomp.).
Found, %: C 50.10; H 3.50; N 10.49. C28H23Br2N5O3S. Calculated, %: C 50.24; H 3.46; N 10.46.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(4-methylphenyl)amino]-2-oxo-
ethyl}thio)pyrimidine-5-carboxamide (10o). Yield 1.10 g (41%). White powder; mp >300°C (acetone–DMF,
4:1). Found, %: C 50.15; H 3.59; N 10.59. C28H23Br2N5O3S. Calculated, %: C 50.24; H 3.46; N 10.46.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(2-ethylphenyl)amino]-2-oxo-
ethyl}thio)pyrimidine-5-carboxamide (10p). Yield 0.71 g (26%). White powder; mp >250°C. Found, %:
C 50.85; H 3.73; N 10.14. C29H25Br2N5O3S. Calculated, %: C 50.97; H 3.69; N 10.25.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(4-ethylphenyl)amino]-2-oxo-
ethyl}thio)pyrimidine-5-carboxamide (10q). Yield 0.63 g (23%). Beige powder; mp >250°C. Found, %:
C 50.89; H 3.78; N 10.28. C29H25Br2N5O3S. Calculated, %: C 50.97; H 3.69; N 10.25.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(2,6-dimethylphenyl)amino]-
2-oxoethyl}thio)pyrimidine-5-carboxamide (10r). Yield 0.41 g (15%). White powder; mp 252-254°C
(AcOH). Found, %: C 51.11; H 3.78; N 10.11. C29H25Br2N5O3S. Calculated, %: C 50.97; H 3.69; N 10.25.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(2,4-dimethylphenyl)amino]-
2-oxoethyl}thio)pyrimidine-5-carboxamide (10s). Yield 0.93 g (34%). Sandy-colored powder; mp >235°C
(decomp., DMF). Found, %: C 50.91; H 3.73; N 10.18. C29H25Br2N5O3S. Calculated, %: C 50.97; H 3.69;
N 10.25.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-({2-[(3-chloro-2-methylphenyl)-
amino]-2-oxoethyl}thio)pyrimidine-5-carboxamide (10t). Yield 0.99 g (35%). White powder; mp >250°C
(DMF). Found, %: C 47.61; H 3.23; N 10.02. C28H22Br2ClN5O3S. Calculated, %: C 47.78; H 3.15; N 9.95.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-{[2-(4-methylphenyl)-2-oxoethyl]-
thio}pyrimidine-5-carboxamide (10u). Yield 0.58 g (22%). Sandy-colored powder; mp 240-242°C (decomp.,
AcOH–DMF, 2:1). Found, %: C 51.27; H 3.37; N 8.70. C28H22Br2N4O3S. Calculated, %: C 51.39; H 3.39;
N 8.56.
N-(4-Bromophenyl)-2-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-{[2-(4-chlorophenyl)-2-oxo-ethyl]-
thio}pyrimidine-5-carboxamide (10v). Yield 1.11 g (41%). Beige powder; mp 239-240°C (decomp., AcOH–
DMF, 2:1). Found, %: C 47.97; H 3.02; N 8.37. C27H19Br2ClN4O3S. Calculated, %: C 48.06; H 2.84; N 8.30.
The work was carried out with the support of grant No. F47/032 from the President of Ukraine.
449

REFERENCES
1.
L. A. Rodinovskaya, V. K. Promonenkov, Yu. A. Sharanin, V. P. Litvinov, and A. M. Shestopalov, in:
M. I. Kabachnik (editor), Results of Science and Technology. Organic Chemistry [in Russian], Vol. 17,
VINITI, Moscow (1989), p. 3.
2.
3.
4.
5.
6.
B. Stanovnik and J. Svete, Chem. Rev., 104, 2433 (2004).
J. V. Greenhill, Chem. Soc. Rev., 6, 277 (1977).
A.-Z. A. Elassar and A. A. El-Khair, Tetrahedron, 59, 8463 (2003).
G. Negri, C. Kascheres, and A. J. Kascheres, J. Heterocycl. Chem., 41, 461 (2004).
S. M. Riyadh, I. A. Abdelhamid, H. M. Al-Matar, N. M. Hilmy, and M. H. Elnagdi, Heterocycles, 75,
1849 (2008).
7.
8.
9.
10.
11.
12.
P. Lue and J. V. Greenhill, Adv. Heterocycl. Chem., 67, 207 (1996).
C. Camoutsis and G. Pairas, Trends Heterocycl. Chem., 9, 237 (2003).
F. A. L'Eplattenier, L. Vuitel, H. Junek, and O. S. Volfbeis, Synthesis, 543 (1976).
G. Bouillon and K. Schank, Chem. Ber., 113, 2630 (1980).
O. S. Wolfbeis, Chem. Ber., 114, 3471 (1981).
O. S. Wolfbeis, E. Ziegler, A. Knierzinger, H. Wipfler, and I. Trummer, Monatsh. Chem., 111, 93
(1980).
13.
V. V. Dotsenko, S. G. Krivokolysko, A, N. Chernega, and V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim.,
1432 (2002). [Russ. Chem. Bull., Int. Ed., 51, 1556 (2002).]
14.
15.
A. Knierzinger and O. S. Wolfbeis, J. Heterocycl. Chem., 17, 225 (1980).
V. K. Ahluwalia, M. K. Sharma, and R. Sharma, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 32B, 1272 (1993).
16.
17.
18.
19.
20.
21.
I. Trummer, E. Ziegler, and O. S. Wolfbeis, Synthesis, 225 (1981).
G. Zacharias, O. S. Wolfbeis, and H. Junek, Monatsh. Chem., 105, 1283 (1974).
H. Junek, O. S. Wolfbeis, H. Sprintschnik, and H. Wolny, Monatsh. Chem., 108, 689 (1977).
O. S. Wolfbeis and E. Ziegler, Z. Naturforsch., 31B, 1519 (1976).
A. D. Yukhnevich and E. Yu. Gudriniece, Izv. Akad. Nauk LatvSSR, Ser. Khim., 694 (1973).
M. Vanejevs, C. Jatzke, S. Renner, S. Müller, M. Hechenberger, T. Bauer, A. Klochkova, I. Pyatkin,
D. Kazyulkin, E. Aksenova, S. Shulepin, O. Timonina, A. Haasis, A. Gutcaits, C. G. Parsons, V. Kauss,
and T. Weil, J. Med. Chem., 51, 634 (2008).
22.
S. Nagarajan, M. R. Doddareddy, H. Choo, Y. S. Cho, K.-S. Oh, B. H. Lee, and A. N. Pae, Bioorg.
Med. Chem., 17, 2759 (2009).
23.
24.
A. H. Mermerian, A. Case, R. L. Stein, and G. D. Cuny, Bioorg. Med. Chem. Lett., 17, 3729 (2007).
R. Dayam, L. Q. Al-Mawsawi, Z. Zawahir, M. Witvrouw, Z. Debyser, and N. Neamati, J. Med. Chem.,
51, 1136 (2008).
25.
26.
P. N. Ibrahim, H. Cho, B. England, S. Gilette, D. R. Artis, R. Zuckerman, and C. Zhang, US Pat. Appl.
2006041006.
V. V. Dotsenko, S. G. Krivokolysko, Khim. Geterotsikl. Soedin., 1680 (2012). [Chem. Heterocycl.
Compd., 48, 1568 (2012)].
27.
28.
29.
A. M. El-Sayed and O. A. A. Allah, Phosphorus, Sulfur Silicon Relat. Elem., 170, 75 (2001).
A. Lorente, J. L. Balcázar, and F. Florencio, J. Chem. Soc., Perkin Trans. 1, 3377 (1992).
R. P. Tkachev, O. S. Bityukova, V. D. Dyachenko, V. P. Tkacheva, and A. D. Dyachenko, Zh. Obshch.
Khim., 77, 125 (2007). [Russ. J. Gen. Chem., 77, 116 (2007)].
30.
31.
V. A. Pechenyuk, P. V. Kuznetsov, and L. B. Dashkevich, Zh. Org. Khim., 11, 1345 (1975).
V. N. Britsyun, V. A. Doroshchuk, N. V. Bogdan, V. N. Zaitsev, and M. O. Lozinskii, Ukr. Khim. Zh.,
73 (5), 40 (2007).
32.
W. Walter and R. F. Becker, Justus Liebigs Ann. Chem., 727, 71 (1969).
450

33.
G. G. Danagulyan, Khim. Geterotsikl. Soedin., 1445 (2005). [Chem. Heterocycl. Compd., 41, 1205
(2005)].
34.
35.
36.
K. Sasse, Justus Liebigs Ann. Chem., 1976, 768 (1976).
W. Schaper, Synthesis, 861 (1985).
M. Ohto and Y. Kato, Yakugaku Zasshi, 67, 136 (1947).
451