Synthesis of azinylthioureas and their heterocyclization using α-chloroacetoacetic ester

Article abstract of DOI:10.1007/s10593-006-0097-z

Treatment of aminopyrimidines with a mixture of PhCOCl and NH ₄SCN and subsequent debenzoylation of the N-benzoyl-N′-(4,6- substituted pyrimidin-2-yl)thioureas obtained gave pyrimidinyl-2-thioureas. The heterocyclization of the azinyl-2-thioure

Full text of DOI:10.1007/s10593-006-0097-z

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
SYNTHESIS OF AZINYLTHIOUREAS
AND THEIR HETEROCYCLIZATION USING
α-CHLOROACETOACETIC ESTER
V. V. Dovlatyan, K. A. Eliazyan, E. A. Ghazaryan, and A. P. Yengoyan
Treatment of aminopyrimidines with a mixture of PhCOCl and NH4SCN and subsequent debenzoylation
of the N-benzoyl-N'-(4,6-substituted pyrimidin-2-yl)thioureas obtained gave pyrimidinyl-2-thioureas.
The heterocyclization of the azinyl-2-thioureas with α-chloroacetoacetic ester gave ethyl
2-(4,6-substituted azin-2-yl)aminothiazole-5-carboxylates.
Keywords: azinylthioureas, thiazole-5-carboxylic acid, heterocyclization.
Treatment of thioureas and related compounds with halo-β-dicarbonyl compounds gives thiazole
derivatives [1-4]. It might be expected that, in similar conditions, azinyl(pyrimidinyl, sym-triazinyl)thioureas
would give azinylaminothiazoles which, having a multinuclear heterocyclic system, would be of interest as
potential pesticides and medicinal compounds.
NH2
NHCSNHCOPh
NHCSNH2
PhCOCl
NH4SCN
N
N
N
N
N
N
NaOH
R
R1
R
R1
R1
R
1a–c
2a–c
3a–c
COOEt
Me
S
COOEt
Me
S
NHCSNH2
N
N
H
HN
N
N
N
N
N
MeCOCHCOOEt
Cl
+
N
N
– H2O
.
HCl
R1
R
X
R
R1
X
R
R1
X
3a–f
4a–f
5a–f
1–5 a R = R1 = Me, b R = Me, R1 = OMe, c R = R1 = OMe; 3–5 d R = R1 = NHEt,
e R = NHEt, R1 = NHPr-i, f R = R1 = NHPr-i; 3–5 a–c X = CH, d–f X = N
With this objective treatment of the 2-aminopyrimidines 1a-c with a mixture of benzoyl chloride and
ammonium thiocyanate gave the N-benzoyl-N'-(pyrimidin-2-yl)thioureas 2a-c, debenzoylation of which in basic
medium gave the pyrimidin-2-yl thioureas 3a-c.
__________________________________________________________________________________________
Armenian Agricultural Academy, Yerevan 375009; e-mail: vdovlat@netsys.am. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 437-440, March, 2006. Original article submitted
December 15, 2003.
0009-3122/06/4203-0389©2006 Springer Science+Business Media, Inc.
389

TABLE 1. Characteristics of Compounds 2, 3 and 5
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp,°С
Yield, %
N
S
2а
2b
2c
3a
3b
3c
5a
5b
5c
5d
5e
5f
C14H14N4OS
C14H14N4O2S
C14H14N4O3S
C7H10N4S
19.76
19.58
18.81
18.54
17.40
17.61
30.49
30.77
28.59
28.28
25.79
26.17
19.40
19.18
17.85
18.18
17.56
17.28
27.54
27.92
27.22
26.85
26.27
25.86
12.11
11.89
10.91
10.60
10.35
10.06
17.16
17.58
15.81
16.16
15.36
14.95
11.31
10.96
10.64
10.39
10.29
9.88
8.87
9.12
8.45
8.77
8.72
8.44
181-183
176-177
171-173
264-265
222-223
275-277
157-158
169-170
152-154
264-266
197-199
182-184
87
63
76
95
60
70
75
70
79
81
79
80
C7H10N4OS
C7H10N4O2S
C13H16N4O2S
C13H16N4O3S
C13H16N4O4S
C14H21N7O2S
C15H23N7O2S
C16H25N7O2S
TABLE 2. 1H NMR Spectra of Compounds 2, 3, and 5
Com-
pound
Chemical shifts, δ, ppm. (SSCC, J, Hz)
2а
2b
2c
2.42 (6H, s, (CH3)2); 6.75 (1H, s, CH); 7.50-8.05 (5H, m, C6H5); 11.50 (1H, br. s, NH);
12.75 (1H, br. s, NH)
2.40 (3H, s, CH3); 3.96 (3H, s, OCH3); 6.42 (1H, s, CH); 7.50-8.08 (5H, m, C6H5);
11.35 (1H, br. s, NH); 13.70 (1H, br. s, NH)
3.95 (6H, s, (OCH3)2); 5.83 (1H, s, CH); 7.42-8.08 (5H, m, C6H5); 11.90 (1H, br. s, NH);
12.50 (1H, br. s, NH)
3a
3b
2.40 (6H, s, (CH3)2); 6.72 (1H, s, CH); 8.20 (2H, v. br. s , NH2); 11.20 (1H, br. s, NH)
2.42 (3H, s, CH3); 3.95 (3H, s, OCH3); 6.45 (1H, s, CH); 8.25 (2H, v. br. s , NH2);
10.90 (1H, br. s, NH)
3c
5a
3.95 (6H, s, (OСН3)2; 5.92 (1H, s, CH); 8.10 (2H, v. br. s , NH2); 10.95 (1H, br. s, NH)
1.35 (3H, t, J = 6.5, CH3–CH2); 2.42 (6H, s, (CH3)2); 2.56 (3H, s, CH3 thiazole);
4.25 (2H, q, J = 6.5, OCH2); 6.72 (1H, s, CH); 11.20 (1H, br. s, NH)
5b
1.35 (3H, t, J = 6.25, CH3–CH2); 2.40 (3H, s, CH3); 2.56 (3H, s, CH3 thiazole);
4.03 (3H, s, OCH3); 4.27 (2H, q, J = 6.25, OCH2); 6.20 (1H, s, CH);
11.40 (1H, br. s, NH)
5c
1.35 (3H, t, J = 6.4, CH3–CH2); 2.56 (3H, s, CH3 thiazole); 4.00 (6H, s, (OCH3)2);
4.25 (2H, q, J = 6.4, OCH2); 5.63 (1H, s, CH); 11.42 (1H, br. s, NH)
5d
1.18 (6H, br. t, CH3–CH2N); 1.33 (3H, t, J = 6.2, CH3–CH2O); 2.53 (3H, s, CH3 thiazole);
3.38 (4H, br. m, NCH2); 4.22 (2H, q, J = 6.2, OCH2); 7.10 (2H, br. s, NH(Et));
11.00 (1H, br. s, NH)
5e
5f
1.15-1.25 (9H, br. m, CH3(Et and Pr-i)); 1.30 (3H, t, J = 6.4, CH3–CH2O); 2.55 (3H, s,
CH3 thiazole); 3.40 (4H, br. m, NCH2); 4.23 (2H, q, J = 6.4, OCH2); 4.10-4.30 (1H,
br. m, CH(Pr-i)); 6.75 and 8.00 (2H, br. s, NH(Alk)); 11.50 (1H, br. s, NH)
1.12-1.28 (12H, br. m, CH3(Pr-i)); 1.35 (3H, t, J = 6.4, CH3–CH2O); 2.57 (3H, s,
CH3 thiazole); 4.22 (2H, q, J = 6.4, OCH2); 4.10-4.25 (2H, br. m, CH(Pr-i));
6.50-6.70 (2H, br. s, NH(Alk)); 11.17 (1H, br. s, NH)
390

Refluxing compounds 3a-f (compounds 3d-f had been prepared earlier [5]) with α-chloroacetoacetic
ester in absolute ethanol gave the ethyl 2-(4,6-substituted azin-2-yl)aminothiazole-5-carboxylate hydrochlorides
4a-f, neutralization of which was carried out to give the bases 5a-f. The structure of the latter was confirmed by
1H NMR spectroscopic data.
EXPERIMENTAL
Monitoring of the reaction course and the purity of the compounds synthesized was performed
chromatographically of Silufol UV-254 plates using acetone–hexane (2:1) as eluent. IR spectra were obtained on
a UR-20 instrument for KBr tablets. 1H NMR spectra were obtained on a Mercury-300 (300 MHz) spectrometer
using DMSO-d6 with TMS as internal standard.
N-Benzoyl-N'-(4-R-6-R1-pyrimidin-2-yl)thioureas 2a-c. PhCOCl (2.4 ml, 20 mmol) was added with
stirring to a solution of NH4SCN (1.7 g, 20 mmol) in acetone (10 ml) and the reaction mixture was refluxed for 5
min. Compound 1a-c (20 mmol) was added in small portions at a rate such that the mixture refluxed gently.
After 30 min the mixture was poured into iced water (150 ml), filtered, and the precipitated compound 2a-c was
filtered off and washed on the filter with EtOH.
N-4,6-Substituted Pyrimidin-2-ylthioureas 3a-c. Compound 2a-c (11 mmol) was added to a solution
of NaOH (1.7 g, 38 mmol) in water (20 ml) and the mixture was refluxed for 30 min. The precipitated compound
3a-c was separated and washed on the filter with water.
Ethyl 2-(4,6-Substituted azin-2-yl)aminothiazole-5-carboxylates 5a-f. A suspension of α-chloro-
acetoacetic ester (1.4 ml, 10 mmol) and azinylthiourea 3a-f (10 mmol) in absolute EtOH (15 ml) was refluxed
for 5 h. The product was filtered, the filtrate evaporated, and the residue was triturated with petroleum ether to
give the ethyl ester hydrochlorides 4a-f. A suspension of the compound 4a-f (10 mmol) in CHCl3 (25 ml) was
then neutralized with Na2CO3 (0.58 g, 5.5 mmol) (finely ground powder). After 2 h the product was filtered, the
filtrate was evaporated, and the residue was recrystallized from a mixture of heptane and toluene (2:1).
The work was carried out with finansial support of MNTTs (project A-370).
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