Some conversions of thiazoline carboxylic acid esters

Article abstract of DOI:10.1023/B:COHC.0000008273.38554.9a

We have carried out solvolysis of the previously described ethyl esters of 3-methyl(aryl)-4-methyl-2-thioxothiazoline-5-carboxylic acids, leading to the corresponding acids without breaking down the heterocycle. We synthesized a series of novel esters fro

Full text of DOI:10.1023/B:COHC.0000008273.38554.9a

Chemistry of Heterocyclic Compounds, Vol. 39, No. 9, 2003
SOME CONVERSIONS OF THIAZOLINE
CARBOXYLIC ACID ESTERS
V. V. Dovlatyan, K. A. Eliazyan, V. A. Pivazyan, and A. P. Engoyan
We have carried out solvolysis of the previously described ethyl esters of 3-methyl(aryl)-4-methyl-2-
thioxothiazoline-5-carboxylic acids, leading to the corresponding acids without breaking down the
heterocycle. We synthesized a series of novel esters from the latter by treatment with dimethyl sulfate or
reactive halides. Of these, only in the case of the ethyl ester of 3,4-dimethyl-2-thioxothiazoline-5-
carboxylic acid did we obtain the hydrazinolysis product (the hydrazide), from which we synthesized
novel hydrazones by treatment with aldehydes and ketones.
Keywords: 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide, N-(3,4-dimethyl-2-
thioxothiazolinylcarbonyl)hydrazones of aromatic and heteroaromatic aldehydes, acetophenone and
p-benzoquinone, 3-aryl-4-methyl-2-thioxo-1,3-thiazoline-5-carboxylic acid esters, solvolysis.
In continuing our search for new physiologically active substances in a series of thiazole derivatives and
related compounds [1, 2], we carried out solvolysis of the ethyl esters of 3-methyl(aryl)-4-methyl-2-
thioxothiazoline-5-carboxylic acids 1a-c that we obtained earlier [3]. We showed that under solvolysis
conditions, the dithiocarbamate group of these esters is not involved: when treated with an aqueous or alcoholic
base, they react exclusively at the ester functional group, with retention of the heterocycle and formation of
acids 2a-c.
O
O
O
_
Me
R
Me
R
Me
R
C
C
C
R1Hal
KOH
OH
OR1
OEt
OH
N
S
N
S
N
S
S
S
1a–c
S
2a–c
3a–m
R2
R3
O
O
Me
Me
Me
C
C
R2
R3
C=O
NH2NH2
NHNH2
NHN=C
1a
N
S
N
S
Me
S
4
S
5a–e
1
а
1a, 2a, 3 -g R =Me; 1b, 2b, 3h-j R = Ph; 1c, 2c, 3k-m R = C6H4Cl-4; 3a,h,k R = Me;
b,i,l R1 = CH2COOMe; c,j,m R1 = CH2Ph; d R1 = CH2CH2OPh; e R1 = CH2CH2OC6H4Me-4;
f R1 = CH2CH2OC6H3Cl2-2,4; g R1 = CH(Ac)COOEt; 5a–c R2 = H; d R2 = Me, a R3 = Ph,
b R3 = 2-furyl, c R3 = 5-nitro-2-furyl; d R3 = Ph; e R2, R3 =
O
__________________________________________________________________________________________
Armenian Agricultural Academy, Yerevan 375009; e-mail: artak@dolphin.am. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1409-1412, September, 2003. Original article submitted
December 26, 2001; revision submitted October 30, 2002.
1238
0009-3122/03/3909-1238$25.00©2003 Plenum Publishing Corporation

TABLE 1. Characteristics of Synthesized Compounds 1H NMR spectrum, δ, ppm, spin–spin coupling constants (J, Hz)
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С
1Н NMR spectrum, , ppm, SSCC (J, Hz)
Yield, %
δ
N (Cl)
3
S
4
1
2
5
6
7
85
C11H9NO2S2
—
25.11
25.50
230-232 2.25 (3H, s, 4-CH3); 6.85-7.58 (5H, m, Ph); 11.80 (1H, v. br. s, OH)
226-228 2.28 (3H, s, 4-CH3); 7.32-7.60 (4H, m, C6H4); 11.50 (1H, v. br. s, OH)
102-104 2.68 (3H, s, 4-CH3); 3.65 (3H, s, 3-CH3); 3.81 (3H, s, OCH3)
2b
2c
3a
3b
3c
3d
C11H8ClNO2S2 (12.68) 22.09
87
83
60
65
65
(12.43) 22.42
C7H9NO2S2
C9H11NO4S2
C13H13NO2S2
C14H15NO3S2
7.11
6.90
31.14
31.53
5.29
24.70
138-140 2.70 (3H, s, 4-CH3); 3.67 (3H, s, 3-CH3); 3.75 (3H, s, OCH3); 4.77 (2H, s, CH2)
105-107 2.70 (3H, s, 4-CH3); 3.64 (3H, s, 3-CH3); 5.25 (2H, s, CH2); 7.30-7.40 (5H, m, Ph)
5.36
24.52
5.37
5.10
23.51
23.27
4.70
20.98
70-72
2.67 (3H, s, 4-CH3); 3.63 (3H, s, 3-CH3); 4.22 (2H, t, J = 5.8, COOCH2); 4.55 (2H, t, J = 5.8, PhOCH2);
4.53
20.71
6.90-7.25 (5H, m, Ph)
C15H17NO3S2
4.58
4.33
20.13
19.81
136-138 2.27 (3H, s, CH3 in Ar); 2.67 (3H, s, 4-CH3); 3.65 (3H, s, 3-CH3); 4.22 (2H, t, J = 5.9, COOCH2);
74
73
88
83
3e
3f
4.55 (2H, t, J = 5.8, ArOCH2); 6.75-7.07 (4H, m, Ar)
C14H13ClNO3S2 (19.05) 17.31
150-152 2.68 (3H, s, 4-CH3); 3.65 (3H, s, 3-CH3); 4.32 (2H, t, J = 5.9, COOCH2); 4.57 (2H, t, J = 5.9, ArOCH2);
(18.78) 16.93
4.61
4.42
7.10-7.38 (3H, m, Ar)
C12H15NO5S2
C12H11NO2S2
20.58
20.19
64-65
1.33 (3H, t, J = 6.2, CH3 in Et); 2.35 (3H, s, COCH3); 2.73 (3H, s, 4-CH3); 3.68 (3H, s, 3-CH3);
3g
3h
4.28 (2H, q, J = 6.2, CH2 in Et); 5.72 (1H, s, COCH)
5.47
24.49
165-167 2.30 (3H, s, 4-CH3); 3.85 (3H, s, OCH3); 7.25-7.62 (5H, m, Ph)
5.28
24.15

TABLE 1 (continued)
1
2
3
4
5
6
7
C14H13NO4S2
C18H15NO2S2
4.54
4.33
20.22
19.81
95-97
2.32 (3H, s, 4-CH3); 3.78 (3H, s, OCH3); 4.81 (2H, s, CH2); 7.30-7.62 (5H, m, Ph)
93
73
70
83
72
84
91
89
3i
3j
4.41
19.00
107-109 2.30 (3H, s, 4-CH3); 5.28 (2H, s, OCH2); 7.25-7.60 (10H, m , 2Ph)
133-135 2.30 (3H, s, 4-CH3); 3.83 (3H, s, OCH3); 7.30-7.60 (4H, m, Ar)
4.11
18.77
C12H10ClNO2S2 (11.62) 21.63
(11.85) 21.37
C14H12ClNO4S2 (9.67)
3k
3l
18.23
89-91
82-84
2.32 (3H, s, 4-CH3); 3.77 (3H, s, OCH3); 4.82 (2H, s, CH2); 7.30-7.60 (4H, m, Ar)
2.30 (3H, s, 4-CH3); 5.28 (2H, s, CH2); 7.30-7.60 (9H, m, Ph and Ar)
(9.93)
17.90
C18H14ClNO2S2 (9.80)
(9.45)
C6H9N3OS2
17.38
17.04
3m
4
20.45
31.82
202-204 2.58 (3H, s, 4-CH3); 3.63 (3H, s, 3-CH3); 4.50 (2H, v. br. s, NH2); 9.10 (1H, v. br. s, NH)
20.69
31.53
C13H13N3OS2
C11H11N3O2S2
14.25
14.43
21.58
21.99
237-239 2.70 (3H, s, 4-CH3); 3.70 (3H, s, 3-CH3); 7.36-7.83 (5H, m, Ph); 8.00 (1H, s, N=CH); 11.60 (1H, br s, NH)
5a
5b
14.38
23.01
216-218 2.76 (3H, s, 4-CH3); 3.70 (3H, s, 3-CH3); 6.50, 6.80 and 7.70 (1H, d. d, J = 5.4 and 5.0;
14.95
22.78
1H, d, J = 5.4 and 1H, d, J = 5.0, 4-, 3- 5-Н, respectively, in furyl); 7.90 (1H, s, N=CH); 11.63 (1H, br. s, NH)
C11H10N4O4S2
17.41
17.18
20.04
19.63
252-253 2.76 (3H, s, 4-CH3); 3.70 (3H, s, 3-CH3); 7.13 and 7.60 (1H, d, J = 5.2 and 1H, d, J = 5.2,
87
5c
3- and 4-Н, respectively, in nitrofuryl); 8.00 (1H, s, N=CH); 12.16 (1H, br. s, NH)
C14H15N3OS2
C12H11N3O2S2
14.04
21.27
240-242 2.33 (3H, s, =CCH3); 2.76 (3H, s, 4-CH3); 3.70 (3H, s, 3-CH3); 7.30-7.85 (5H, m, Ph); 10.60 (1H, br. s, NH)
92
85
5d
5e
13.77
20.98
13.99
14.33
21.57
21.84
189-190 2.73 (3H, s, 4-CH3); 3.70 (3H, s, 3-CH3); 6.80 and 7.63 [2H, d, J = 9.2 and 2H, d, J = 9.2, (CH2)2C=O
and (CH2)2C=N respectively]; 9.60 (1H, br. s, NH)

The latter, as their potassium salts, were esterified in water or DMF by dimethyl sulfate or various
reactive halides, and in this case a series of novel esters 3a-m was formed.
In studying hydrazinolysis of compounds 1a-c, we observed that only compound 1a is readily converted
to the expected hydrazide 4 when treated with excess hydrazine hydrate at room temperature. When this
reaction is carried out at elevated temperature, as described for the methyl ester of 2-methyl-5-
phenylthiazolecarboxylic acid [4], breakdown of the thiazoline ring occurs.
We synthesized new potentially biologically active hydrazones 5a-e from respectively hydrazide 4 and
benzaldehyde, furfural, 5-nitrofurfural, acetophenone, or p-benzoquinone.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Mercury-300 spectrometer (300 MHz) in DMSO-d6.
The composition and structure of the synthesized compounds were confirmed by the results of elemental
analysis and 1H NMR spectra (see Table 1).
3,4-Dimethyl-2-thioxo-1,3-thiazolinyl-5-carboxylic Acid (2a) was obtained according to the known
procedure in [3].
3-Aryl-4-methyl-2-thioxo-1,3-thiazolinyl-5-carboxylic acid 2b,c. Ester 1b,c (10 mmol) was added to
a solution of 84% KOH (10 mmol) in ethanol (10 ml) and the reaction mixture was refluxed for 3 h. Then the
ethanol was distilled off and the residue was dissolved in H2O (10 ml) and the solution was filtered; the filtrate
was acidified with HCl to pH 4 and the precipitate formed of product 2b,c was filtered out.
Esters of Acids 2a-c (3a-m). Acid 2a-c (10 mmol) was added to a suspension of 84% KOH powder
(10 mmol) in DMF (10 ml); the mixture was stirred for 1 h, and then the halide (10 mmol) was added in
portions. The reaction mass was held for 3 h at 50-60°C and then cooled, and the potassium halide was filtered
out. The filtrate was evaporated down, the residue was treated with H2O (10 ml), the precipitate of product
3a-m was filtered out and dried in air.
3,4-Dimethyl-2-thioxothiazolinyl-5-carboxylic Acid Hydrazide (4). Ester 1a (2.2 g, 10 mmol) was
added with stirring to 55% hydrazine hydrate (10 ml), and the reaction mixture was held for 24 h at 20°C. Then
the product 4 was filtered out and washed with water (10 ml).
N-(3,4-Dimethyl-2-thioxothiazolinylcarbonyl)hydrazones of Benzaldehyde (5a), Furfural (5b),
5-Nitrofurfural (5c), Acetophenone (5d), and p-Benzoquinone (5e). 36% HCl (0.86 ml) was added to
compound 4 (2.03 g, 10 mmol) in H2O (30 ml) and then the carbonyl compound (10 mmol) were added to the
solution obtained at 0°C. The mixture was held for 4 h at 20°C, and the precipitate of product 5a-e was filtered
out, washed on the filter with H2O (10 ml) and dried in air. Compounds 5 were purified by grinding with
acetone and then filtered out.
REFERENCES
1.
N. N. Mel'nikov, K. P. Novozhilov, and T. N. Pylova, Chemicals for Plant Protection [in Russian],
Khimiya, Moscow (1980), p. 263.
2.
3.
M. D. Mashkovskii, Drugs [in Russian], Meditsina, Moscow (1984), Pt. 1, p. 202.
V. V. Dovlatyan, K. A. Eliazyan, V. A. Pivazyan, E. A. Kazaryan, A. P. Engoyan, R. T. Grigoryan, and
R. G. Mirzoyan, Khim. Geterotsikl. Soedin., 677 (2000).
4.
V. A. Mamedov, N. A. Nuretdinov, and F. G. Sigbatulina, Izv. Akad. Nauk SSSR. Ser. Khim., 2835
(1991).
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