Synthesis of N-substituted 3-aminothiazolidin-4-ones containing hetaryl fragments

Article abstract of DOI:10.1023/A:1023772509165

Condensation of the N-(3,5-dichloropyridyl-2)- and N- (benzothiazolyl-2-thioacetyl)hydrazones of carbonyl compounds with thioglycolic acid gave the 3-(3,5-dichloropyridyl-2)amino- and 3-[N-(benzothiazolyl-2-thioacetyl)amino]-2-R¹-2-R²

Full text of DOI:10.1023/A:1023772509165

Chemistry of Heterocyclic Compounds, Vol. 39, No. 2, 2003
SYNTHESIS OF N-SUBSTITUTED
3-AMINOTHIAZOLIDIN-4-ONES
CONTAINING HETARYL FRAGMENTS
V. I. Kelarev1, M. A. Silin1, I. G. Kotova1, K. I. Kobrakov2, I. I. Rybina2, and V. K. Korolev2
Condensation of the N-(3,5-dichloropyridyl-2)- and N-(benzothiazolyl-2-thioacetyl)hydrazones of
carbonyl compounds with thioglycolic acid gave the 3-(3,5-dichloropyridyl-2)amino- and
3-[N-(benzothiazolyl-2-thioacetyl)amino]-2-R1-2-R2-thiazolidin-4-ones. Reaction of 1-(benzothiazolyl-
2-thioacetyl)-4-R-thiosemicarbazides with chloroacetic acid in the presence of sodium acetate gave the
2-[N-(benzothiazolyl-2-thioacetyl)hydrazono]-3-R-thiazolidin-4-ones. It was found that the
N-(benzothiazolyl-2-thioacetyl)hydrazones, both in the solid state and in solution, exist in the form of an
equilibrium mixture of the EZ'- and EE'-isomers as a result of hindered rotation around the amide
N–CO bond.
Keywords: N-acylhydrazones, 1-acylthiosemicarbazides, benzothiazole, hydrazones, dichloropyridines,
thioglycolic acid, thiazolidin-4-one, condensation.
Hetaryl substituted thiazolidin-4-ones, e.g. those containing ∆2-imidazoline [1], thiazole[2, 3],
benzimidazole [4], acridine [5], quinazolin-4(3H)-one [6], and sym-triazine [7] fragments show high
antibacterial, antimicrobial, and antitumor activity and also have an effect on the CNS.
In this work we report the preparation of N-substituted 3-aminothiazolidin-4-ones which contain a
3,5-dichloropyridyl or benzothiazole fragment. Derivatives of thiazolidin-4-one with benzothiazolyl substituents
have been little studied and there are isolated examples in the literature [8]. Evidence for the synthesis of
thiazolidin-4-ones having dichloropyridyl substituents has been absent to the present time.
Compounds with a C=N grouping, e.g. azomethines [1, 3, 4, 6, 7, 9, 10], hydrazones [5, 11],
N-acylhydrazones [12], and thiosemicarbazones [13] are convenient synthons for the preparation of thiazolidine
derivatives. In this work the starting materials used were the products of the condensation of
N-(3,5-dichloropyridyl-2)hydrazine (1) and benzothiazolyl-2-thioacetic acid hydrazide (2) with different
carbonyl compounds giving the N-(3,5-dichloropyridyl-2)hydrazones 3a-g and the N-(benzothiazolyl-2-
thioacetyl)hydrazones 4a-f (Table 1).
The reaction of hydrazones 3a-g and N-acylhydrazones 4a-f with thioglycolic acid gives the
corresponding 2-R1-2-R2-3-[N-(benzothiazolyl-2-thioacetyl)amino]thiazolidin-4-ones 6a-f. The best yields of
compounds 5a-g and 6a-f (Table 2) are achieved by refluxing the reagents in benzene or dioxane for 10-12 h
with a molar ratio of hydrazone 3a-g (or the N-acetylhydrazone 4a-f) to thioglycolic acid of 1:2 to 1:2.5 in the
presence of 3-5 weight % of zinc chloride. It should be noted that when the condensation of the
N-acylhydrazones 4a,b,f with thioglycolic acid is carried out in the absence of the ZnCl2 the yield of the thiazolidin-
__________________________________________________________________________________________
1
I. M. Gubkin Oil and Gas State University, Moscow 117917, Russia; e-mail: himeko@dol.ru.
2 A. N. Kosygin Moscow State Textile University, Moscow 117918, Russia; e-mail: office@msta.ac.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 243-252, February, 2003. Original article
submitted April 28, 2000.
0009-3122/03/3902-0213$25.00©2003 Plenum Publishing Corporation
213

TABLE 1. Parameters for Hydrazine 1, N-(3,5-Dichloropyridyl-2)hydrazones 3a-g and N-(Benzothiazolyl-2-
thioacetyl)hydrazones 4a-f
Found, %
——————
Com-
Empirical
formula
2
Calculated, %
mp, °C*
*
1H NMR spectrum, , ppm, (Hz)***
Yield, %
Rf
δ
J
pound
C
3
H
4
N
5
S
6
1
1
2
7
8
9
10
90
84
С5H5Cl2N3
C12H9Cl2N3
33.81
33.73
2.85
2.83
23.57
23.60
180-182
171-172
0.32 (c)
0.52 (a)
6.38 (1H, br. s, NH); 6.58 (2H, br. s, NH2); 7.38 (1H, d, J46 = 2.3,
4-H pyridine); 7.88 (1H, d, J46 = 2.3, 6-H pyridine)
7.70-7.74 (5H, m, Ph); 7.78 (1H, d, J46 = 2.5, 4-Н pyridine);
8.12 (1H, s, CH=N); 8.20 (1H, d, J46 = 2.5, 6-Н pyridine);
10.37 (1H, br. s, NH)
54.03
3.45
15.84
3a
54.13
3.38
15.79
C12H9Cl2N3O
C13H11Cl2N3O
C14H94Cl2N4
51.05
51.09
3.22
3.19
15.02
14.89
162-164
142-143
160-161
0.44 (a)
0.62 (a)
0.81 (b)
6.80-7.02 (2H, m, H arom.); 7.20-7.28 (2H, m, H arom.);
70
96
66
3b
3c
3d
7.76 (1H, d, J46 = 2.4, 4-Н pyridine);
8.20 (1H, d, J46 = 2.4, 6-Н pyridine); 8.48 (1H, s, CH=N);
10.37 (1H, br. s, NH); 11.76 (1Н, s, НО)
3.82 (3Н, s, MеО); 6.90 (2H, d, J = 8.0, Н arom.);
7.55 (1H, d, J46 = 2.4, 4-Н pyridine); 7.69 (2H, d, J = 8.0, Н arom.);
7.98 (1H, s, CH=N); 8.20 (1H, d, J46 = 2.4, 6-Н pyridine);
8.45 (1H, br. s, NH)
3.00 (6Н, s, Mе2N); 6.75 (2H, d, J = 8.5, Н arom.);
7.58 (2H, d, J = 8.5, Н arom.); 7.73 (1H, d, J46 = 2.4, 4-Н pyridine);
8.12 (1H, d, J46 = 2.4, 6-Н pyridine); 8.21 (1H, s, CH=N);
9.48 (1H, br. s, NH)
52.61
52.72
3.68
3.74
14.10
14.19
54.05
54.37
4.58
4.53
18.10
18.12
C12H8Cl2N4O2
C20H25Cl2N3O
46.17
46.30
2.44
2.57
18.11
18.00
185-186
225-226
0.74 (b)
0.52 (c)
7.86 (1H, d, J46 = 2.4, 4-Н pyridine); 7.98 (2H, d, J = 8.0, Н arom.);
8.23 (1H, d, J46 = 2.4, 6-Н pyridine); 8.28 (2H, d, J = 8.0, H arom.);
8.44 (1H, s, CH=N); 10.23 (1H, br. s, NH)
1.52 (18Н, br. s, 2 t-Bu); 5.25 (1H, s, OH); 6.77 (1H, s, CH=N);
7.12 (2H, s, H arom.); 7.52 (1H, d, J46 = 2.7, 4-Н pyridine);
7.88 (1H, d, J46 = 2.7, 6-Н pyridine); 8.38 (1H, br. s, NH)
75
75
3e
3f
61.08
60.91
6.22
6.34
10.78
10.66

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
83
C16H25Cl2N3
58.03
58.18
7.65
7.57
12.56
12.73
48-49.5
0.42 (a)
1.14 (6H, t, 2Me); 1.28-1.56 (12H, m, CH2); 3.22 (4H, t, 2CH2C=);
7.80 (1H d, J46 = 2.5, 4-Н pyridine);
3g
8.10 (1H, d, J46 = 2.5, 6-Н pyridine); 9.34 (1H, br. s, NH)
C13H15N3OS2
C16H13N3OS2
C24H29N3O2S2
C14H10N4O4S2
C18H14N4OS2
C12H13N3OS2
53.37
53.24
5.04
5.12
14.19
14.33
21.62
21.84
142-143
158-159
206-207
0.37 (a)
0.64 (a)
0.70 (a)
0.56 (b)
0.30 (a)
0.82 (a)
0.98 (6H, d, JMe–CН = 5.7, 2Me); 2.22 (1H, m, CH);
4.07 and 4.22 (2Н, s, СН2СО, EZ'- and EE'-conformers);
6.65 and 6.80 (1Н, s, СН=N, EZ'- and EE'-conformers);
7.84 (4H, m, H arom.); 10.22 and 10.33 (1Н, br. s, NH,
EZ'- and EE'-conformers); EE':EZ' = 70:30
4.15 and 4.34 (2Н, s, СН2СО, EZ'- and EE'-conformers),
6.92-7.04 (5H, m, Ph), 7.38 and 7.92 (1Н, s, СН=N,
EZ'- and EE'-conformers), 7.70-7.76 (4H, m, H arom.),
10.38 and 10.74 (1Н, br. s, NH, EZ'- and EE'-conformers);
EE':EZ' = 74:26
1.58 (18H, c, 2 t-Bu); 4.08 and 4.22 (2Н, s, СН2СО,
EZ' and EE'-conformers); 5.24 (1H, s, OH); 7.10 (2H, c, H arom.);
7.48-7.57 (4H, m, H arom.); 7.74 and 7.84 (1Н, s, СН=N,
EZ'- and EE'-conformers); 10.84 and 11.08 (1Н, br. s, NH,
EZ'- and EE'-conformers); EE': EZ' = 80:20
3.92 and 4.32 (2Н, s, СН2СО, EZ'- and EE'-conformers);
6.70 (1H, d, J34 = 3.4, 4-H furan); 7.40 (1H, d, J34 = 3.4, 3-Н furan);
7.65-7.70 (4H, m, H arom.); 7.90 and 8.04 (1Н, s, СН=N,
EZ'- and EE'-conformers); 10.04 and 10.33 (1Н, br. s, NH,
EZ'- and EE'-conformers); EE':EZ' = 70:30
3.81 and 4.10 (2Н, s, СН2СО, EZ'- and EE'-conformers);
7.40 (1H, d, J = 2.5, 2-Н indole); 7.52-7.75 (8H, m, H arom.);
7.94 and 8,08 (1Н, s, СН=N, EE'- and EZ'-conformers);
8.38 (1H, br. s, NH indole); 9.84 and 10.10 (1Н, br. s,
NH, EZ'- and EE'-conformers); EE':EZ' = 75:25
1.78 and 1.83 (6H, s, 2Me, EZ'- and EE'-conformers);
4.16 and 4.42 (2Н, s, СН2СО, EZ'- and EE'-conformers);
7.64-7.72 (4H, m, H arom.), 10.04 and 10.12 (1Н, br. s, NH,
EZ'- and EE'-conformers); EE':EZ' = 63:37
80
4a
4b
4c
4d
4e
58.61
58.72
4.05
3.97
12.96
12.84
19.34
19.57
74
87
74
77
75
63.42
63.30
6.28
6.37
9.09
9.23
13.92
14.06
46.29
46.41
2.87
2.76
15.62
15.47
17.45
17.68
183-184.5
(decomp.)
58.88
59.01
3.91
3.82
15.21
15.30
17.60
17.48
250-251
51.50
51.61
4.73
4.66
14.92
15.05
23.11
22.94
137-138.5
4f
_______
* Compounds were crystallized: 1 from ethanol; 3a,d from benzene, 3b,c,e from 1-propanol; 3f,g from a mixture of
hexane and toluene (4:1); 4a from a mixture of 2-propanol and water (1:1.5); 4b,c from a mixture of dioxane and water
(2:1); 4d from a mixture of ethanol and water (1:1); 4e from a mixture of DMF and water (5:1); 4f from a mixture of
benzene and hexane (2:1).
*2 The solvent system is given in brackets.
*3 The spectra of compounds 3a,b,d,e were recorded in acetone-d6, compounds 3c,g in CDCl3, and compounds 3f and
4a-f in DMSO-d6.

4-ones does not exceed 40-45%, even after refluxing for 36-40 h. With a higher boiling solvent (xylene, DMF,
o-dichlorobenzene), significant tarring of the reaction mixture occurs and as a result the yield of the target
compounds is lowered.
H
N
R
O
N
R1
R2
6a–f
HSCH2COOH
– H2O
R1R2CO
+
RNHN=CR1R2
RNHNH2
– H2O
S
3a–g,
5a–g,
1, 2
4a–f
Cl
Cl
N
;
2, 4, 6 R =
1, 3, 5 R =
SCH2CO
S
N
3, 5 a–f R2 = H, g R2 = C5H11; a R1 = Ph, b R1 = 2-HOC6H4, c R1 = 4-MeOC6H4,
d R1 = 4-Me2NC6H4, e R1 = 4-O2NC6H4, f R1 = 4-HO-3,5-(t-Bu)2C6H2, g R1 = C5H11;
4, 6 a–e R2 = H, f R2 = Me; a R1 = i-Pr, b R1 = Ph, c R1 = 4-HO-3,5-(t-Bu)2C6H2,
d R1 = 5-nitrofuryl-2, e R1 = indolyl-3, f R1 = Me
Reaction of the hydrazine 2 with isothiocyanates gives the 1-(benzothiazolyl-2-thioacetyl)-4-R-
thiosemicarbazides 7a,b and refluxing of these with chloroacetic acid and sodium acetate (molar ratio 1:1:3) in
absolute ethanol gives the 2-[N-(benzothiazolyl-2-thioacetyl)hydrazino]-3-R-thiazolidin-4-ones 8a,b in
64-68% yields.
N
ClCH2COOH
AcONa
RNCS
2
SCH2CONHNHCSNHR
S
7a,b
R
O
N
N
S
S
N
NHCOCH2S
8a,b
7, 8 a R = CH2=CHCH2, b R = Ph
The IR spectra of compounds 3a-g show strong absorption bands in the region 1625-1615 cm-1 which
are typical for the C=N stretching vibrations of hydrazones [14]. In the spectra of the N-acylhydrazones 4a-f the
absorption bands of these groups are shifted to higher frequency and appear at 1650-1630 cm-1 [15].
It is known [11, 15-17] that N-acylhydrazones can exist in four stereoisomeric forms due to geometrical
isomerism about the C=N bond (E- and Z-isomers) and rotational (conformational) isomerism due to hindered
amide rotation around the C–N bond of the acyl fragment (E'- and Z'-isomers).
It was found that the N-(benzothiazolyl-2-thioacetyl)hydrazones 4a-f exist in the solid state and in
solution as an equilibrium mixture of the two conformational forms of the more stable E-isomer (the
EZ'-isomers (A) and EE'-isomers (B)) due to the hindered rotation around the amide N–CO bond.
216

R2
R1
R2
R1
C
N
C
N
H
H
N
N
C
N
N
C
O
S
S
SCH2
CH2S
EZ'-4a–f (A)
O
EE'-4a–f (B)
In the IR spectra of the N-acylhydrazones 4a-f (solid phase and solutions) the stretching vibrations of
the C=O group appear as doublet absorption bands in the region 1695-1655 cm-1 (Table 3). Associates with an
intermolecular hydrogen bond of the type C=O···H–N are absent in solution since the appearance of the
spectrum is not changed with dilution. The doublet for the νC=O in the solid state (vaseline oil) and the same
difference in frequencies for its components in CHBr3, CH2Cl2, and dioxane point to the fact that association
with solvent is not responsible for the splitting of this band. Hence the doublet for the νC=O band is due to the
presence of the two EZ'- and EE'-rotational isomers. This is also indicated by the presence of two absorption
bands in the region for NH stretching vibrations, e.g. for compound 4a at 3350 and 3325 (CHBr3), 3362 and
3320 (CH2Cl2), for compound 4b 3365 and 3320 (CHBr3), and for compound 4f 3355 and 3315 cm-1 (CH2Cl2).
The temperature dependence (20-120°C) of the strength of the components of the νC=O doublet is small
but sufficient to assign the low frequency component to the associated C=O group. The increased intensity of
the high frequency component of the νC=O in more polar solvent (CHBr3 → CH2Cl2 → dioxane → MeCN)
allows one to assign the absorption in the spectrum of the N-acylhydrazone 4b at 1690 cm-1 to the C=O group of
the more polar EZ'-isomer and that at 1675 cm-1 to the C=O group of the less polar EE'-isomer [18, 19].
The proposal that the N-acylhydrazones 4a-f exist in solution as a mixture of two stereoisomers is also
supported by the doubling of the signals for the NH and CH2CO group protons in the 1H NMR spectra of all of
the compounds (Table 1) and the CH=N group proton in the spectra of the aldehyde N-acylhydrazones 4a-e
(which undergo coalescence when the spectra are recorded in DMSO-d6 solution heated to 120°C).
According to data in [16, 20] the chemical shift of NH and CH2CO group protons signals lie to higher
field and the CH=N group proton to lower field for the EZ'-isomers when compared with the analogous signals
for the EE'-isomers. A quantitative reckoning of the conformational isomers was carried out by a comparison of
the integral intensities of the signals for the protons of the CH=N and CH2CO groups. The data obtained
indicates that an increase in the solvent polarity leads to an increase in the proportion of the more polar
EZ'-conformer, e.g. for the N-acylhydrazone 4a in chloroform the EZ':EE' ratio is 63:37 and in DMSO 70:30 and
for the N-acylhydrazone 4f it is 54:46 and 65:35 respectively.
In the IR spectra of the thiazolidin-4-ones 5a-g, 6a-f, and 8a,b there are observed absorption bands of
varying intensity corresponding to vibrations of the thiazolidine ring [21, 22]: 1470-1450, 1445-1425 (CH2
scissoring vibrations) 1290-1280, 1085-1070 (νring), 1180-1165, and 1010-995 cm-1. The strong absorption
maxima in the region 1755-1735 cm-1 are typical of a carbonyl group stretching vibration in thiazolidinones [10,
12, 21, 22] and in the region 1670-1655 cm-1 in the spectra of compounds 6a-f to the "amide I" type vibration of
an N-acetyl group [14]. The thiazolidin-4-ones 8a,b also show strong absorption bands at 1630-1625 cm-1 which
are assigned to the stretching vibrations of the C=N group of the hydrazone fragment [14].
1
The H NMR spectra of the thiazolidin-4-ones 5a-g, 6a-f, and 8a,b (Table 2) show methylene proton
signals at position 5, typical of an AB-spin system, as two unsymmetrical doublets at 3.92-4.12 and
4.24-4.48 ppm with JAB = 16.5-18.5 Hz [14]. In the case of the 2-substituted thiazolidin-4-ones 5a-f and 6a-e
(R2 = H) the 2-H proton appears as a singlet signal at 3.32-3.58 ppm. In the spectrum of compound 6f the proton
signals for the methyl groups are seen as two singlets at 1.25 and 1.34 ppm and this is typical of gem-dimethyl
groups in cyclic systems [14, 21, 23].
217

TABLE 2. Parameters for the Synthesized Thiazolidin-4-ones 5a-g, 6a-f, and 8a,b
Found, %
1H NMR spectrum, δ, ppm, J (Hz)*3
——————
Com-
Empirical
formula
Yield,
%
Calculated, %
mp, °C*
Rf*2
pound
2-H
NH
C
3
H
4
N
5
S
6
5-CH2, d
Other protons
12
(1H, s)
(1H, br. s.)
11
1
2
7
8
9
10
13
64
C14H11Cl2N2OS 51.38 3.44 8.71 9.94
51.53 3.37 8.59 9.82
127-128
0.67 (b) 3.38
3.95, 4.34 (JAB = 17.0)
8.52
7.28-7.36 (5H, m, Ph); 7.64 (1H, d,
5a
J
46 = 2.5, 4-Н pyridine); 8.08 (1H, d,
46 = 2.5, 6-Н pyridine)
J
C14H11Cl2N2O2S 49.03 3.31 8.05 9.50 153-154.5 0.56 (a) 3.46
49.12 3.22 8.19 9.36
4.05, 4.40 (JAB = 18.5)
3.92, 4.28 (JAB = 16.5)
8.84
6.94-7.18 (4H, m, H arom.);
7.72 (1H, d, J46 = 2.4, 4-Н pyridine);
8.01 (1H, d, J46 = 2.4, 6-Н pyridine);
8.36 (1Н, s, OH)
68
73
5b
5c
C15H13Cl2N2O2S 50.34 3.52 7.98 9.15
50.56 3.65 7.86 8.99
165-166
123-124
0.60 (c) 3.34
0.55 (b) 3.50
8.74
8.80
3.66 (3Н, s, MеО); 6.97 (2H, d,
J = 7.6, Н arom.); 7.46 (2H, d,
J = 7.6, Н arom.); 7.80 (1H, d,
J
46 = 2.3, 4-Н pyridine);
8.14 (1H, d, J46 = 2.3, 6-Н pyridine)
C16H16Cl2N3OS 51.94 4.27 11.54 8.81
52.03 4.34 11.38 8.67
4.02, 4.36 (JAB = 17.5)
3.25 (6Н, s, Mе2N); 6.78 (2H, d,
J = 8.2, Н arom.); 7.28 (2H, s,
J = 8.2, Н arom.); 7.69 (1H, d,
75
5d
J
J
46 = 2.6, 4-Н pyridine); 8.21 (1H, d,
46 = 2.6, 6-Н pyridine)
C14H10Cl2N3O3S 45.16 2.60 11.18 8.81
45.28 2.69 11.32 8.63
169-170
185-186
0.56 (a) 3.60
0.70 (c) 3.42
3.92, 4.42 (JAB = 18.0)
4.10, 4.35 (JAB = 16.7)
8.87
8.94
7.38 (2H, d, J = 6.7, Н arom.);
7.67 (1H, d, J46 = 2.5, 4-Н pyridine);
7.80 (2H, d, J = 6.7, Н arom.);
8.10 (1H, d, J46 = 2.5, 6-Н pyridine)
60
58
5e
5f
C22H27Cl2N2O2S 58.28 6.05 6.29 7.17
58.15 6.14 6.17 7.05
1.58 (18Н, s, 2 t-Bu);
5.18 (1H, s, HO); 7.08 (2H, s,
Н arom.); 7.60 (1H, d,
J
46 = 2.7, 4-Н pyridine); 7.88 (1H, d,
J
46 = 2.7, 6-Н pyridine)
C18H27Cl2N2OS 55.25 7.07 7.34 8.06
55.38 6.92 7.18 8.20
88-90
0.61 (b)
—
3.98, 4.37 (JAB = 17.4)
3.92, 4.30 (JAB = 17.2)
8.85
9.82
1.18 (6H, t, 2Me);
51
64
5g
6a
1.33-1.52 (12H, m, CH2);
3.40 (4H, t, 2CH2);
7.67 (1H d, J46 = 2.6, 4-Н pyridine);
7.92 (1H, d, J46 = 2.6, 6-Н pyridine)
C15H17N3O2S3
48.87 4.72 11.27 26.27 108-109.5 0.72 (a) 3.32
49.05 4.63 11.44 26.15
1.12 (6H, d, J = 8.6, Me2CH);
2.14 (1H, m, Me2CH);
3.70 (2Н, s, СН2СО);
7.72-7.90 (4H, m, H arom.)

TABLE 2 (continued)
1
2
3
4
5
6
7
8
9
10
11
12
13
60
C18H15N3O2S3
53.72 3.62 10.70 24.11 137-138.5 0.60 (a) 3.42
53.86 3.74 10.47 23.94
4.08, 4.24 (JAB = 18.5)
10.34
3.88 (2Н, s, СН2СО);
6b
6.82-7.05 (5H, m, Ph),
7.58-7.70 (4Н, m, H arom.)
C26H31N3O3S3
C16H12N4O5S3
C20H16N4O2S3
59.14 5.72 8.17 18.04 161-162.5 0.67 (a) 3.54
58.98 5.86 7.94 18.15
4.05, 4.48 (JAB = 18.0)
3.97, 4.28 (JAB = 16.7)
4.05, 4.30 (JAB = 17.3)
10.10
10.62
10.18
1.44 (18H, s, 2 t-Bu); 3.90 (2Н, s,
СН2СО); 5.24 (1H, s, OH);
7.24 (2H, s, H arom.);
68
70
62
6c
6d
6e
7.80-7.88 (4H, m, H arom.)
43.88 2.64 12.97 22.18 188-189.5 0.51 (b) 3.38
44.04 2.75 12.84 22.02
3.85 (2Н, s, СН2СО); 6.54 (1H, d,
J
J
34 = 3.8, 3-H furan); 7.32 (1H, d,
34 = 3.8, 4-Н furan);
7.88-7.96 (4H, m, H arom.)
54.71 3.52 12.90 21.64 175-177
54.54 3.64 12.73 21.82
0.33 (c) 3.50
3.76 (2Н, s, СН2СО);
7.18-7.24 (2H, m, H arom.);
7.32 (1H, d, J = 4.0, 2-H indole);
7.46-7.52 (4H, m, H arom.);
7.67-7.72 (4H, m, H arom.);
8.36 (1H, br. s., NH indole)
C14H15N3O2S3
C15H14N4O2S3
47.67 4.17 12.07 27.33
47.59 4.25 11.90 27.20
98-99
0.85 (a)
—
—
3.96, 4.28 (JAB = 16.5)
3.92, 4.32 (JAB = 17.2)
10.50
10.28
1.25 (3H, s, 2-Me);
58
64
6f
1.34 (3H, s, 2-Me);
3.74 (2Н, s, СН2СО);
7.56-7.62 (4H, m, H arom.)
47.51 3.77 14.95 25.26 164-165
0.52 (с)
3.74 (2Н, s, СН2СО); 4.08 (2H, d,
CH2N); 5.06 (1H, d, J = 3.5,
CH2=C); 5.20 (1H, d, J = 3.5,
CH2=C); 5.56 (1H, m, =CH–);
7.66-7.72 (4H, m, H arom.)
8a
47.62 3.70 14.81 25.40
(with
decomp.)
C18H14N4O2S3
52.24 3.44 13.36 23.31 185-186
52.17 3.38 13.53 23.19
0.44 (с)
—
3.96, 4.26 (JAB = 16.5)
10.22
3.82 (2H, s, CH2CO);
68
8b
6.88-6.95 (5H, m, Ph);
7.58-7.67 (4H, m, H arom.)
_______
* Compounds were crystallized: 5a from a mixture of ethanol and water (2:1), 5b, 6f from a mixture of benzene and
hexane (1:1), 5c from a mixture of methyl cellusolve and water (2:1), 5d,g from a mixture of benzene and hexane (1:3),
5e from a mixture of chloroform and hexane (3:1), 5f from a mixture of benzene and hexane (1:1.5), 6a,c from a mixture
of benzene and hexane (5:1), 6b from a mixture of ethanol and water (1:1), and 6d,e, 8a,b from a mixture of DMF and
water (2:1).
*2 The solvent system is given in brackets.
*3 The spectra of compounds 5a-f, 6a-e and 8a,b were recorded in DMSO-d6 and compounds 5g, 6f in CDCl3.

TABLE 3. IR Spectra of N-(Benzothiazolyl-2-thioacetyl)hydrazones 4a-f
νC=O*, cm-1
Compound
in vaseline oil
in CHBr3
in CH2Cl2
in dioxan
1652, 1664
1645,1660
1642, 1652
1640, 1655
1650, 1664
1645, 1657
1668, 1688
1665, 1668
1658, 1680
1665, 1682
1665, 1685
1662, 1681
1678, 1695
1675, 1695
1670, 1690
1675, 1692
1678, 1697
1674, 1694
1679, 1700
1678, 1695
1672, 1692
1678, 1702
1684, 1705
1682, 1702
4a
4b
4c
4d
4e
4f
_______
* Solution concentration 5 mmol/l.
In the spectra of the hydrazones 3a-g and the thiazoldin-4-ones 5a-g the signals for the protons of the
3,5-dichloropyridyl fragment are seen as doublets at 7.52-7.86 (4-H) and 7.88-8.23 ppm (6-H) with
J46 = 2.4-2.7 Hz. The protons of the benzothiazole fragment in the spectra of compounds 4a-f, 6a-f, and 8a,b
appear as multiplet signals at 7.44-7.84 ppm.
EXPERIMENTAL
IR spectra were obtained on a Bruker IFS-48 instrument for KBr tablets, as a suspension in vaseline oil,
1
and in solvents (CH2Cl2, CHBr3, dioxane). H NMR spectra were recorded on a Bruker WP-250 spectrometer
(250 MHz) for 10-15% solutions with TMS internal standard. Monitoring of the reaction course and the purity
of the compounds obtained was carried out using TLC on Merck LU-074 alumina bonded layer plates with the
solvent systems chloroform–methanol, 30:1 (a), chloroform–methanol, 40:1 (b), and benzene–methanol, 20:1 (c)
and were visualized using iodine vapor.
The starting benzothiazolyl-2-thioacetic acid hydrazide (2) was prepared by a known method [24].
N-(3,5-Dichloropyridyl-2)hydrazine (1). A mixture of 2,3,5-trichloropyridine (2.45 g, 13.4 mmol),
N2H4.H2O (30%, 2.6 ml, 46.9 mmol), and propanol (1 ml) was refluxed with stirring for 4 h, cooled to 20°C, and
a solution of NaOH (0.53 g, 13.4 mmol) in water (10 ml) was added with stirring. The reaction mixture was
stirred for 30 min at 20°C, and the precipitate formed was filtered off, washed on the filter with water, and dried
at 80°C (Table 1).
N-(3,5-Dichloropyridyl-2)hydrazones of the Carbonyl Compounds (3a-g). A mixture of the
pyridylhydrazine 1 (0.89 g, 5.0 mmol) and the corresponding aldehyde or ketone (5.25 mmol) in propanol
(10 ml) was refluxed with stirring until the starting hydrazine had disappeared (monitored using TLC;
30-45 min for the preparation of hydrazones 3a-e, 3-3.5 h for hydrazones 3f,g) and then cooled to 20°C. The
precipitated solid was filtered off, dried, and crystallized from the appropriate solvent (Table 1).
N-(Benzothiazolyl-2-thioacetyl)hydrazones of the Carbonyl Compounds (4a-f). A mixture of the
hydrazide 2 (2.39 g, 10 mmol), the corresponding aldehyde or ketone (10 mmol) and acetic acid (0.5 ml) in
dioxane (40 ml) was refluxed with stirring for 3.5 h, cooled to 20°C, poured into iced water (150 ml), and held
for 3 h at 5°C. The precipitate formed was filtered off, dried, and crystallized from the appropriate solvent
(Table 2).
2-R1-2-R2-3-(3,5-Dichloropyridyl-2-amino)-
(5a-g)
and
2-R1-2-R2-3-[N-(benzothiazolyl-2-
thioacetyl)amino]thiazolidin-4-ones (6a-f). A mixture of the hydrazone 3a-g or 4a-f (8 mmol), freshly
distilled thioglycolic acid (1.47 g, 16 mmol), and anhydrous ZnCl2 (0.2 g) in 40 ml of anhydrous benzene (for
the preparation of the thiazolidin-4-ones 5a-g) or anhydrous dioxane (for the preparation of the thiazolidin-4-
220

ones 6a-f) were refluxed with stirring for 10-12 h. The solvent was removed at reduced pressure and the residue
was washed with 3% sodium bicarbonate solution (3 × 20 ml), water (2 × 20 ml), dried, and crystallized from
the appropriate solvent (Table 2).
1-(Benzothiazolyl-2-thioacetyl)-4-allylthiosemicarbazide (7a). A mixture of the hydrazine 2 (4.78 g,
20 mmol) and freshly distilled allyl isothiocyanate (1.9 g, 20 mmol) in 2-propanol (50 ml) was refluxed with
stirring for 5 h and evaporated to dryness at reduced pressure. The oil remaining was carefully triturated with
cold petroleum ether (4 × 25 ml) and held for 24 h at 0°C. The precipitate formed was filtered off and
crystallized from benzene to give the thiosemicarbazide 7a (6.1 g, 90%); mp 117-119.5°C and Rf 0.44 (a).
1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 3.92 (2H, s, CH2S); 4.08 (2H, t, CH2N); 4.88 (1H, d, JAB = 3.8,
CHAHB); 5.02 (1H, d, JAB = 3.8, CHAHB); 5.25 (1H, m, CH=); 6.84 (1H, br. s, NH). Found, %: C 46.02; H 4.05;
N 16.83; S 28.22. C13H14N4OS3. Calculated, %: C 46.15; H 4.14; N 16.57; S 28.40.
1-(Benzothiazolyl-2-thioacetyl)-4-phenylthiosemicarbazide (7b) was synthesized similarly from the
hydrazide 2 and phenylisothiocyanate in 85% yield; mp 160-162°C (ethanol) (according to data in [25]:
mp 157°C) and Rf 0.54 (b). 1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 4.14 (2H, s, CH2S): 6.79 (1H, br. s,
NH); 6.96-7.04 (5H, m, Ph); 7.50-7.58 (4H, m, Harom); 8.50 (2H, br. s, NH).
2-[N-(Benzothiazolyl-2-thioacetyl)hydrazino]-3-R-thiazolidin-4-ones (8a,b). A mixture of the
thiosemicarbazide 7a,b (10 mmol), chloroacetic acid (0.95 g, 10 mmol) and anhydrous sodium acetate (2.46 g,
30 mmol) in absolute ethanol (50 ml) was refluxed with stirring for 8 h, cooled to 20°C, poured into iced water
(120 ml), and held for 12 h at 5°C. The precipitate formed was filtered off, washed on the filter with water,
dried, and crystallized from a mixture of DMF and water (2:1).
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