Thiazolecarboxylic acid derivatives. 1. N-substituted 2-amino-4- methylthiazole-5-carboxylic acid derivatives

Article abstract of DOI:10.1023/B:COHC.0000023773.23834.ba

Acylation of the ethyl ester and anilide of 2-amino-4-methylthiazole-5- carboxylic acid gave 2-acetyl(arylsulfonyl)amino derivatives. Methylation of acetylaminothiazole and subsequent deacetylation gave 2-methylamino-4- methylthiazole-5-carboxylic acid, w

Full text of DOI:10.1023/B:COHC.0000023773.23834.ba

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004
THIAZOLECARBOXYLIC ACID
DERIVATIVES. 1. N-SUBSTITUTED
2-AMINO-4-METHYLTHIAZOLE-
5-CARBOXYLIC ACID DERIVATIVES
V. V. Dovlatyan, K. A. Eliazyan, V. A. Pivazyan, E. A. Kazaryan, and A. P. Engoyan
Acylation of the ethyl ester and anilide of 2-amino-4-methylthiazole-5-carboxylic acid gave
2-acetyl(arylsulfonyl)amino derivatives. Methylation of acetylaminothiazole and subsequent
deacetylation gave 2-methylamino-4-methylthiazole-5-carboxylic acid, which was then converted into
esters. The ethyl ester and anilide of thiazole-2-carboxylic acid were used as starting compounds for the
synthesis of 2-dimethylaminoformimino- and 2-chlorobenzenesulfonylureido derivatives.
Keywords: aminoformiminothiazole, acylaminoformiminothiazole, dimethylaminoformiminothiazole,
thiazole-5-carboxylic acid, thiazole-5-carboxylate esters.
In a continuation of a study of the synthesis and derivatives of thiazoline-5-carboxylic acid [1], we
sought new pesticides and pharmaceuticals among products obtained from the available ethyl ester (1) and
anilide 2 of 2-amino-4-methylthiazole-5-carboxylic acid [2].
In the present work, we describe several transformations of 1 and 2 at the amino group. Acylation of
aromatic and heterocyclic amines may lead to the appearance or enhancement of the biological activity of these
derivatives [3]. This led us to study the acylation of 1 and 2, which can undergo amino–imino tautomerization,
and, thus, may react in either the amine or imine form, as in the case of their closest analog, 2-aminothiazole [4].
Methylthiazoles 1 and 2 react regioselectively in acetic anhydride or by the action of arylsulfonyl
chlorides in pyridine to give exclusively acylaminothiazoles 3a-e, 4a-e, and 5. Ester 5 is an NH-acid readily
methylated to give 6, which may be deacylated to give 2-methylamino-4-methylthiazole-5-carboxylic acid (7)
and, then, some of its esters 8a-c.
The action of thionyl chloride on
1
and
2
was studied in an attempt to obtain
N,N'-thionyldi(aminothiazole), which is a possible fungicide. However, 2-N-dimethylaminoformimino
derivatives 9a and 9b, which are the products of the condensation of 1 and 2 with the DMF solvent, are formed
instead of the expected thionyldi(aminothiazoles).
We also found that aminothiazoles 1 and 2 react with 2-chlorobenzenesulfonyl isocyanate to give 10a
and 10b, which are related to the highly active herbicide, thiamethuronmethyl (harmony) [6] and, thus, may hold
some interest.
__________________________________________________________________________________________
Armenian Agricultural Academy, Yerevan 375009, Armenia; e-mail: artak@dolphin.am. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 90-95, January, 2004. Original article submitted
July 6, 2001.
84
0009-3122/04/4001-0084©2004 Plenum Publishing Corporation

O
O
O
Me
Me
Me
X
OEt
OEt
ArSO2Cl
(MeCO)2O
N
S
N
S
N
S
NH2
1, 2
MeNCOMe
HNCOMe
6
5
O
O
O
Me
Me
Me
X
OH
S
OR
R–Hal
N
S
N
N
S
HNSO2Ar
HNMe
HNMe
3a–e, 4a–e
7
8a–c
1, 3a–e X = OEt, 2, 4a–e X = NHPh; 3, 4 a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 2-ClC6H4,
d Ar = 2,5-Me2C6H3, e Ar = 4-AcNHC6H4; 8 a R = CH2Ph, b R = CH2COOMe,
c R = (CH2)2OPh
O
Me
SOCl2
X
N
S
Me
Me
N
X
N
CH
1, 2
9a,b
O
Me
N
S
Cl
HNCONHSO2
10a,b
9, 10 a X = OEt, b X = NHPh
EXPERIMENTAL
1
The H NMR spectra were taken in DMSO-d6 on a Mercury-300 spectrometer at 300 MHz. Thin-layer
chromatography was carried out on Silufol UV-254 plates using 1:1 or 1:2 acetone–heptane as the eluent and 2%
AgNO3 + 0.4% bromophenol blue + 4% citric acid as the developer.
Ethyl Esters (3a-e) and Anilides (4a-e) of 2-Arylsulfamido-4-methylthiazole-5-carboxylic Acids. A
sample of arylsulfonyl chloride (10 mmol) was added in portions to a solution of ethyl ester of 2-amino-4-
methylthiazole-5-carboxylic acid (1) (1.86 g, 10 mmol) or corresponding anilide 2 (2.33 g, 10 mmol) in pyridine
(5 ml). The mixture was maintained for 48 h at 20°C and, then, ice water (20 ml) was added. The precipitate
formed of 3a-e or 4a-e was filtered off, washed with water, and dried in the air. The products were purified by
dissolution in alkali and reacidification by adding acetic acid.
85

TABLE. 1. Physicochemical and Spectral Characteristics of Compounds 3a-e and 4a-e
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
1H NMR spectrum, δ, ppm
Yield, %
N
S
3а
3b
3c
3d
3e
C13H14N2O4S2
C14H16N2O4S2
C13H13ClN2O4S2
C15H18N2O4S2
C15H17N3O5S2
8.80
8.59
19.27
19.63
157-158
198-200
192-194
174-175
136-137
1.38 (3H, t, J = 6.5, CH3CH2); 2.43 (3H, s, CH3); 4.27 (2H, q, J = 6.5, CH2);
7.43-7.83 (5H, m, Ph); ~12.50 (1H, v. br. s, NH)
77
76
80
86
79
8.41
8.24
19.12
18.82
1.36 (3H, t, J = 6.5, CH3CH2); 2.00 (3H, s, CH3–Ar); 2.42 (3H, s, CH3);
4.17 (2H, q, J = 6.5, CH2); 7.22-7.75 (4H, m, Ar); 12.20 (1H, br. s, NH)
7.93
7.77
17.31
17.75
1.30 (3H, t, J = 6.5, CH3CH2); 2.50 (3H, s, CH3); 4.25 (2H, q, J = 6.5, CH2CH3);
7.60-8.20 (4H, m, Ar); 12.30 (1H, br. s, NH)
1.35 (3H, t, J = 6.5, CH3CH2); 2.08 (3H, s, CH3); 2.20 (3H, s, CH3); 2.45 (3H, s, CH3);
4.22 (2H, q, J = 6.5, CH2); 7.70-8.10 (3H, m, Ar); 12.20 (1H, br. s, NH)
7.76
7.91
18.40
18.08
11.22
10.97
17.09
16.71
1.38 (3H, t, J = 6.5, CH3CH2); 2.08 (3H, s, C(=О)CH3); 2.40 (3H, s, CH3);
4.25 (2H, q, J = 6.5, CH2); 7.70 (4H, s, Ar); 10.02 (1H, s, NHC=O);
12.90 (1H, v. br. s, NHSO2)
4a
4b
C17H15N3O3S2
C18H17N3O3S2
11.45
11.26
17.59
17.16
222-224
230-231
2.45 (3H, s, CH3); 7.10-7.80 (10H, m, 2Ph); 10.10 (1H, s, NH);
12.40 (1H, br. s, NHSO2)
80
94
10.61
10.85
16.07
16.54
2.05 (3H, s, CH3–Ar); 2.45 (3H, s, CH3); 6.90-7.80 (9H, m, Ar); 10.20 (1H, s, NH);
12.30 (1H, br. s, NHSO2)
4c
C17H14ClN3O3S2
C19H19N3O3S2
10.57
10.31
10.70
10.47
16.09
15.71
16.32
15.96
140-141
142-143
2.50 (3H, s, CH3); 7.05-8.20 (9H, m, Ar); 10.15 (1H, s, NH); 12.30 (1H, br. s, NHSO2)
95
96
4d
2.10 (3H, s, CH3); 2.25 (3H, s, CH3); 2.45 (3H, s, CH3); 6.90-8.00 (8H, m, Ar);
10.10 (1H, s, NH); 12.25 (1H, br. s, NHSO2)
4e
C19H18N4O4S2
12.83
13.02
15.21
14.88
213-214
2.07 (3H, s, C(=О)CH3); 2.43 (3H, s, CH3); 6.95-7.80 (9H, m, Ar); 9.70 (1H, s, NHPh);
10.05 (1H, s, NHPh); 12.80 (1H, br. s, NHSO2)
55

TABLE 2. Characteristics of Compounds 8a-c
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С*
1H NMR spectrum, δ, ppm
Yield, %
N
H
8а
8b
8c
C13H14N2O2S
C9H12N2O4S
C14H16N2O3S
11.00
10.69
11.71
11.48
12.52
12.21
13.43
13.11
125-127
160-162
118-120
2.43 (3H, s, CH3); 2.90 (3H, d, J = 5.5, N–CH3); 5.20 (2H, s, CH2); 7.23-7.38 (H, m, Ph);
7.96 (1H, br. s, NH)
2.45 (3H, s, CH3); 2.90 (3H, d, J = 5.5, N–CH3); 3.75 (3H, s, ОCH3); 4.65 (2H, s, CH2);
8.20 (1H, br. s, NH)
61
62
55
9.47
9.59
11.21
10.96
2.45 (3H, s, CH3); 2.90 (3H, d, J = 5.5, N–CH3); 4.25 (2H, t, J = 6.2, ОCH2);
4.56 (2H, t, J = 6.2, CH2ОPh); 6.90-7.30 (5H, m, Ph); 8.00 (1H, br. s, NH)
_______
* 1:1 Heptane–benzene for 8a and 8b, heptane for 8c.

The physicochemical and spectral data are given in Table 1.
Ethyl Ester of 2-Acetylamino-4-methylthiazole-5-carboxylic Acid (5). A suspension of 1 (1.86 g) in
acetic anhydride (5 ml) was heated for 5 h at 105-110°C. Excess acetic anhydride was distilled off and the
residue was treated with water (10-15 ml). The precipitate of 5 was filtered off, washed with water, and dried to
1
give 2.1 g (92%) of compound 5; mp 215-217°C. H NMR spectrum, δ, ppm (J, Hz): 1.47 (3H, t, J = 6.5,
CH3CH2); 2.40 (3H, s, CH3); 3.55 (3H, s, C(=O)CH3); 4.25 (2H, q, J = 6.5, CH2); 8.10 (1H, br. s, NH).
Found, %: N 12.45; S 13.69. C9H12N2O3S. Calculated, %: N 12.28; S 14.04.
Ethyl Ester of 2-N-Acetylamino-N-methyl-4-methylthiazole-5-carboxylic Acid (6). A sample of 5
(2.3 g, 10 mmol) was added with stirring to a solution of 84% KOH (0.7 g, 10 mmol) in DMF (10 ml). After
30 min, freshly distilled dimethyl sulfate (ρ 1.26 g/cm3) (1 ml, 10 mmol) was added dropwise at 0°C. The
mixture was maintained for 24 h at 20°C and DMF was evaporated off. The precipitate was treated with water
1
and filtered off to give 1.86 g (83%) of compound 6; mp 102-104°C (octane). H NMR spectrum, δ, ppm
(J, Hz): 1.38 (3H, t, J = 6.5, CH3CH2); 2.40 (3H, s, CH3); 2.57 (3H, s, C(=O)CH3); 3.67 (3H, s, N–CH3); 4.25
(2H, q, J = 6.5, CH2). Found, %: N 11.39; S 13.56. C10N14N2O3S. Calculated, %: N 11.57; S 13.22.
2-Methylamino-4-methylthiazole-5-carboxylic Acid (7). A sample of 6 (2.42 g, 10 mmol) was added
to a solution of 84% KOH (1.4 g, 20 mmol) in ethanol (20 ml) and the mixture was heated at reflux for 2 h.
Ethanol was distilled off. The residue was dissolved in water (10 ml) and acidified by adding acetic acid. The
1
precipitate was filtered off to give 1.1 g (64%) of compound 7; mp 159-160°C, Rf 0.41. H NMR spectrum,
δ, ppm: 2.40 (3H, s, CH3); 2.85 (3H, s, N–CH3); 7.83 (1H, br. s, NH); ~11.0 (1H, v. br. s, OH). Found, %:
N 16.47; S 18.97. C6H8N2O2S. Calculated, %: N 16.28; S 18.60.
Esters of 2-Methylamino-4-methylthiazole-5-carboxylic Acid (8a-c). Benzyl chloride (1.52 g,
12 mmol) (for 8a), methyl chloroacetate (for 8b) (1.30 g, 12 mmol), or phenoxyethyl bromide (for 8c) (2.00 g,
12 mmol) was added to a solution of potassium salt (2.1 g, 10 mmol) of acid 7 and the mixture was heated for
3 h at 50-60°C. The suspension was poured into a Petri dish and DMF was evaporated off. The residue was
treated with 15 ml water and the precipitates of 8a-c were filtered off (Table 2).
Ethyl Ester (9a) and Anilide (9b) of 2-Dimethylaminoformimino-4-methylthiazole-5-carboxylic
Acid. A sample of DMF (4 ml) and, then, thionyl chloride (0.8 ml, 11 mmol) were added slowly in portions with
stirring to 1 (1.86 g, 10 mmol) or 2 (2.33 g, 10 mmol) cooled to 0°C. The mixture was maintained for 24 h at
20°C and ice water (20 ml) was added. The solution was filtered to remove turbidity and the filtrate was
neutralized by adding NaHCO3. The precipitated product was filtered off.
1
Ethyl Ester 9a was obtained in 87% yield (2.1 g); mp 60-62°C (heptane), Rf 0.51. H NMR spectrum,
δ, ppm: 2.50 (3H, s, CH3); 3.07 (3H, s, N(CH3)2); 3.20 (3H, s, N(CH3)2); 6.95-7.70 (5H, m, Ph); 8.40 (1H, s,
CH=N); 9.35 (1H, s, NH). Found, %: N 17.63; S 13.58. C10H15N3O2S. Calculated, %: N 17.43; S 13.28.
1
Anilide 9b was obtained in 86% yield (2.48 g); mp 93-95°C (1:1 heptane–benzene), Rf 0.45. H NMR
spectrum, δ, ppm: 2.50 (3H, s, CH3); 3.10 (3H, s, N(CH3)2); 3.20 (3H, s, N(CH3)2); 6.95-7.70 (5H, m, Ph); 8.42
(1H, s, N=CH); 9.35 (1H, s, NH). Found, %: N 19.62; S 11.48. C14H16N4OS. Calculated, %: N 19.44; S 11.11.
N-Thiazolyl-N'-(2-chlorobenzenesulfonyl)ureas (10a,b). A sample of 2-chlorobenzenesulfonyl
isocyanate (2.2 g, 10 mmol) and five drops of pyridine were added to a solution of 1 (1.86 g, 10 mmoles) or 2
(2.33 g, 10 mmol) in absolute toluene (10 ml). The mixture was heated at reflux for 2 h and urea 10a or 10b was
filtered off.
Urea 10a was obtained in 93% yield (3.75 g); mp 246-247°C (dec.) (heating at reflux in 50% ethanol),
Rf 0.35. 1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, t, J = 6.5, CH3CH2); 2.50 (3H, s, CH3); 4.0 (2H, q, J = 6.5,
CH2CH3); 7.55-8.15 (4H, m, Ar). Found, %: Cl 8.80; N 10.12; S 16.17. C14H14ClN3O5S2. Calculated, %: Cl 8.80;
N 10.41; S 15.86.
Urea 10b was obtained in 95% yield (4.3 g); mp 292-293°C (dec.), Rf 0.44. 1H NMR spectrum, δ, ppm:
2.45 (3H, s, CH3); 6.09-8.20 (9H, m, Ar); 9.70 (1H, s, NH); 10.20 (1H, s, NH); 12.80 (1H, br. s, NH–SO2Ar).
Found, %: Cl 8.17; N 12.64; S 14.65. C18H15ClN4O4S2. Calculated, %: Cl 7.88; N12.43; S 14.21.
88

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89