Transformations of 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole

Article abstract of DOI:10.1134/S1070363208110248

Accessible 2,2-dichloro-1-p-tolylsulfonylethenyl isothiocyanate reacted with hydrazine hydrate to give 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3- thiazole whose reactions with thiols and amines followed a complicated pattern. Treatment of 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole with acetylacetone led to the formation of previously unknown 5-chloro-2-(3,5- dimethyl-1H-pyrazol-1-yl)-4-p-tolylsulfonyl-1,3-thiazole which reacted with O-, S-, and N-centered nucleophiles at the C⁵ atom with high regioselectivity.

Full text of DOI:10.1134/S1070363208110248

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 11, pp. 2132–2136. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © K.V. Turov, T.K. Vinogradova, B. S. Drach, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 11, pp. 1897–1901.
Transformations of 5-Chloro-2-hydrazino-
4-p-tolylsulfonyl-1,3-thiazole
K. V. Turov, T. K. Vinogradova, and B. S. Drach
Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
Received February 5, 2008
Abstract—Accessible 2,2-dichloro-1-p-tolylsulfonylethenyl isothiocyanate reacted with hydrazine hydrate to
give 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole whose reactions with thiols and amines followed a
complicated pattern. Treatment of 5-chloro-2-hydrazino-4-p-tolylsulfonyl-1,3-thiazole with acetylacetone led to
the formation of previously unknown 5-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-p-tolylsulfonyl-1,3-thiazole
which reacted with O-, S-, and N-centered nucleophiles at the C5 atom with high regioselectivity.
DOI: 10.1134/S1070363208110248
We previously found that 2,2-dichloro-1-p-tolyl-
sulfonylethenyl isothiocyanate (I) readily reacted with
primary and secondary amines to form the
corresponding cyclocondensation products, 2-amino-5-
chloro-4-p-tolylsulfonyl-1,3-thiazole derivatives [1].
Compound I reacted with hydrazine hydrate in a
similar way (Scheme 1), and this reaction was used as
a preparative method for the synthesis of 5-chloro-2-
hydrazino-4-p-tolylsulfonyl-1,3-thiazole (II) [1]. The
latter is sufficiently electrophilic to react with aromatic
thiols in the presence of triethylamine; however, these
reactions were not selective, and mixtures of
unidentified products were formed. On the other hand,
treatment of substituted 2-hydrazino-1,3-thiazole II
with acetylacetone readily produces electrophilic
compound III which is capable of undergoing
regioselective condensations with O-, N-, and S-
centered nucleophiles (transformations III → IV, III →
V, III → VI, and III → VII in Scheme 1).
the thiazole fragment having a tosyl group on C4 and a
p-chlorophenylsulfonyl group on C5. Interestingly, the
C4 atom in molecule IX turned out to be the most
reactive toward oxygen- and sulfur-centered
nucleophiles. We succeeded in demonstrating that the
main transformations of IX are those involving
elimination of the p-tolylsulfonyl group, IX → XI and
IX → XII. The reactivity of IX considerably differed
from the reactivity of 5-p-chlorophenylsulfonyl-2-
phenylsulfonyl-4-p-tolylsulfonyl-1,3-thiazole
which
reacted with sulfur nucleophiles at C2 and C5 [2].
To conclude, we can state that the structure of
compounds II–XII directly follows from the scheme
of their synthesis; in addition, the structure of II–XII
1
was confirmed by H NMR spectroscopy (Table 2).
For instance, the formation of 3,5-dimethyl-1H-
pyrazol-1-yl fragment in the transformation II → III is
readily revealed by the appearance of two singlets
from methyl protons in the region δ 2.2–2.6 ppm.
These nucleophilic substitution reactions always
involved the C5 atom in the thiazole ring, whereas the
tosyl group in the 4-position remained intact; the
contribution of other processes was insignificant.
Further modification of compounds VI and VII
afforded new functionally substituted 2-(3,5-dimethyl-
1H-pyrazol-1-yl)-1,3-thiazoles VIII–XII (Table 1) that
are difficult to obtain by other methods.
1
Comparison of the H NMR spectra of compounds IX
and XII shows that the latter lacks singlet at δ 2.40
ppm as a result of elimination of the tosyl group in the
reaction of IX with sodium benzenethiolate. Finally,
introduction of various R1R2N and AlkS groups into
the 5-position of the thiazole ring in the synthesis of
compounds Va–Vc, Xa, and Xb gives rise to the cor-
responding signals in the 1H NMR spectra (Table 2).
It should be specially emphasized that the
transformation VI → IX enhances electrophilicity of
2132

TRANSFORMATIONS OF 5-CHLORO-2-HYDRAZINO-4-p-TOLYLSULFONYL-1,3-THIAZOLE
2133
Scheme 1.
Cl
Ts
Cl
N
C
S
I
.
H2NNH2 H2O
Ts
Me
Me
Ts
Ts
4-MeC6H4OH,
Et3N
N
N
N
N
O
O
Me
N
Me
N
4-MeC6H4O
N
S
NH
NH2
Cl
Cl
S
S
Me
Me
III
IV
II
2 R1R2NH
NaSH
ArSH, Et3N
Ts
Ts
Ts
N
N
N
N
N
N
Me
Me
Me
R1R2N
ArS
HS
N
N
N
S
S
S
Me
Me
VIa, VIb
Me
Va_Vc
VII
H2O2, MeCOOH
Ar = 4-ClC6H4
(1) MeONa;
(2) AlkHlg
(1) EtONa; (2) 1/2 I2
H2O2, MeCOOH;
Ar = 4-ClC6H4
Ts
Ts
Ts
N
N
N
H2O2,
MeCOOH
N
N
N
Me
Me
Me
N
AlkS
N
N
4-ClC6H4SO
4-ClC6H4SO2
S
S
S
Me
Me
VIII
Me
Xa, Xb
IX
4-MeOC6H4ONa
PhSNa
Ts
N
N
N
Me
4-MeOC6H4O
4-ClC6H4SO2
PhS
S
S
N
N
N
N
Me
Me
Me
N
Me
N
4-ClC6H4SO2
S
S
S
S
N
N
Me
Me
N
XI
XII
Ts
Me
XIII
V, R1R2N =
O
N (b), PhCH2NH (c); VI, Ar = 4-MeC6H4 (a), 4-ClC6H4 (b); V, Alk = Me (a), i-Pr (b).
N (a),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

2134
TUROV et al.
Table 1. Yields, melting points, and elemental analyses of compounds II–XIII
Found, %
S
Calculated, %
S
Comp.
no.
Yield, %
mp, °C (solvent)
Formula
Cl
N
Cl
N
70
85
71
68
70
75
76
84
87
60
56
70
75
57
65
62
205–207 (EtOH)
135–136 (EtOH)
283–284 (EtOH)
183–184 (EtOH)
152–154 (EtOH)
181–182 (EtOH)
185–187 (DMF–EtOH, 1:10)
168–170 (DMF–EtOH, 1:10)
202–205
158–160 (EtOH)
140–142 (EtOH)
185–187 (EtOH)
142–144 (EtOH)
210–212 (EtOH)
138–140 (EtOH)
185–187 (DMF)
11.70
9.58
−
−
−
21.03
17.47
14.55
16.02
15.80
14.58
21.10
20.27
26.32
19.64
18.97
25.43
23.54
13.75
20.99
27.64
13.05
11.32
9.40
13.80
13.75
12.80
9.18
8.90
11.21
8.67
C10H10ClN3O2S2
C15H14ClN3O2S2
C22H21N3O3S2
C19H22N4O2S2
C19H22N4O3S2
C22H22N4O2S2
C22H21N3O2S3
C21H18ClN3O2S3
C15H15N3O2S3
C21H18ClN3O3S3
C21H18ClN3O4S3
C16H17N3O2S3
C18H21N3O2S3
C21H18ClN3O4S2
C20H16ClN3O2S3
C28H24N6O4S6
11.67
9.64
−
−
−
21.11
17.43
14.59
15.93
15.32
14.62
21.11
20.21
26.32
19.55
18.93
25.35
23.60
13.47
20.82
27.45
13.83
11.42
9.56
13.92
13.39
12.77
9.22
8.83
11.50
8.54
II
III
IV
Va
Vb
Vc
VIa
VIb
VII
VIIIа
IXb
Xa
−
−
−
−
7.50
−
7.23
7.04
−
7.45
−
7.21
6.98
−
8.41
8.27
11.21
10.18
8.52
9.25
10.95
11.07
10.31
8.83
9.09
11.99
−
−
Xb
XI
6.98
7.20
−
7.45
7.67
−
XII
XIII
Found, %: C 51.63; H 4.05. Calculated, %: C 51.26; H 3.69. b Found, %: C 49.49; H 3.62. Calculated, %: C 49.65; H 3.57.
a
Table 2. 1H NMR spectra of compounds II–XIII (DMSO-d6)
Comp.
no.
Chemical shifts δ, ppm
2.44 s (3Н, СН3), 5.03 br.s (2Н, NН2), 7.38–7.40 m (2Нarom), 7.77–7.79 m (2Нarom), 9.14 br.s (1Н, NH)
II
2.20 s (3Н, СН3), 2.44 s (3Н, СН3), 2.53 s (3Н, СН3), 5.96 s (1Н, СН), 7.34–7.36 m (2Нarom), 7.95–7.97 m (2Нarom
)
III
IV
2.12 s (3Н, СН3), 2.37 s (3Н, СН3), 2.45 s (3Н, СН3), 2.55 s (3Н, СН3), 6.07 s (1Н, СН), 7.09–7.11 m (2Нarom), 7.23–7.25 m
(2Нarom), 7.40–7.42 m (2Нarom), 7.83–7.85 m (2Нarom
2.04 m (4Н, 2СН2), 2.13 s (3Н, СН3), 2.20 s (3Н, СН3), 2.41 s (3Н, СН3), 3.53 m (4Н, 2СН2), 5.93 s (1Н, СН), 7.33–7.35 m
(2Нarom), 7.75–7.77 m (2Нarom
2.15 s (3Н, СН3), 2.38 s (3Н, СН3), 2.43 s (3Н, СН3), 3.12 m (4Н, 2СН2), 3.78 m (4Н, 2СН2), 6.00 s (1Н, СН), 7.37–7.39 m
(2Нarom), 7.81–7.83 m (2Нarom
2.10 s (3Н, СН3), 2.41 s (3Н, СН3), 2.46 s (3Н, СН3), 4.46 m (2Н, СН2), 5.94 s (1Н, СН), 7.33–7.36 m (6Нarom), 7.97–7.81 m
(2Нarom
2.09 s (3Н, СН3), 2.40 s (3Н, СН3), 2.44 s (3Н, СН3), 2.48 s (3Н, СН3), 6.01 s (1Н, СН), 7.28–7.30 m (2Нarom), 7.41–7.43 m
(2Нarom), 7.51–7.53 m (2Нarom), 7.87–7.89 m (2Нarom
2.11 s (3Н, СН3), 2.44 s (3Н, СН3), 2.49 s (3Н, СН3), 6.04 s (1Н, СН), 7.41–7.43 m (2Нarom), 7.47–7.49 m (2Нarom), 7.59–7.61 m
(2Нarom), 7.87–7.89 m (2Нarom
2.16 s (3Н, СН3), 2.44 s (3Н, СН3), 2.47 s (3Н, СН3), 6.12 s (1Н, СН), 7.43–7.45 m (2Нarom), 7.65–7.67 m (2Нarom), 7.80–7.82 m
(2Нarom), 7.93–7.95 m (2Нarom
2.20 s (3Н, СН3), 2.40 s (3Н, СН3), 2.44 s (3Н, СН3), 6.15 s (1Н, СН), 7.39–7.42 m (2Нarom), 7.72–7.74 m (4Нarom), 8.12–8.14 m
(2Нarom
2.22 s (3Н, СН3), 2.42 s (3Н, СН3), 2.54 s (3Н, СН3), 2.61 (3Н, СН3), 5.95 s (1Н, СН), 7.31–7.33 m (2Нarom), 7.95–7.97 m
(2Нarom
1.04–1.07 m (3Н, СН3), 1.74–1.76 m (2Н, СН2), 2.16 s (3Н, СН3), 2.43 s (3Н, СН3), 2.50 s (3Н, СН3), 3.01–3.05 m (2Н, СН2),
6.07 s (1Н, СН), 7.39–7.41 m (2Нarom), 7.83–7.85 m (2Нarom
2.21 s (3Н, СН3), 2.27 s (3Н, СН3), 3.78 s (3Н, ОСН3), 6.10 s (1Н, СН), 6.87–6.89 m (2Нarom), 7.01–7.03 m (2Нarom), 7.66–7.68 m
(2Нarom), 8.01–8.03 m (2Нarom
2.10 s (3Н, СН3), 2.45 s (3Н, СН3), 6.02 s (1Н, СН), 7.37–7.50 m (5Нarom), 7.60–7.62 m (2Нarom), 7.87–8.89 m (2Нarom
2.20 s (6Н, 2СН3), 2.44 s (6Н, 2СН3), 2.53 s (6Н, 2СН3), 5.87 s (2Н, 2СН), 7.34–7.36 m (4Нarom), 7.95–7.97 m (4Нarom
)
Vа
)
Vb
Vc
)
)
VIа
VIb
VIII
IX
)
)
)
)
Xа
)
Xb
XI
)
)
)
XII
)
XIII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

TRANSFORMATIONS OF 5-CHLORO-2-HYDRAZINO-4-p-TOLYLSULFONYL-1,3-THIAZOLE
2135
rogen sulfide, 0.0075 mol, was added to a suspension
of 0.0015 mol of compound III in 10 ml of methanol,
and the mixture was left to stand for 20 h at 20–25°C.
The precipitate was filtered off, the solvent was
removed from the filtrate under reduced pressure, the
residue was treated with 5 ml of water and acidified
with concentrated hydrochloric acid to pH 2, and the
precipitate was filtered off and used in further
syntheses without additional purification.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury 400 spectrometer using DMSO-d6 as solvent
and tetramethylsilane as internal reference.
5-Chloro-2-hydrazino-4-(p-tolylsulfonyl)-1,3-thia-
zole (II). A solution of 0.5 mol of hydrazine hydrate in
10 ml of THF was added dropwise over a period of 5 min
to a solution of 0.05 mol of compound I in 10 ml of
THF, cooled to 5°C. The mixture was stirred for 5 h at
20°C, the solvent was removed under reduced
pressure, and the residue was recrystallized from
ethanol.
5-(4-Chlorophenylsulfinyl)-2-(3,5-dimethyl-1H-
pyrazol-1-yl)-4-(p-tolylsulfonyl)-1,3-thiazole (VIII).
Compound VIb, 0.01 mol, was dispersed in 5 ml of
glacial acetic acid, 0.5 ml of 30% aqueous hydrogen
peroxide was added, and the mixture was heated for
0.5 h under reflux. The solvent was removed under
reduced pressure, and the residue was recrystallized
from ethanol.
5-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-(p-
tolylsulfonyl)-1,3-thiazole (III). Acetylacetone,
0.09 mol, and glacial acetic acid, 0.5 ml, were added to
a suspension of 0.03 mol of compound II in 10 ml of
ethanol. The mixture was heated for 10 h under reflux
and cooled to 20°C, and the precipitate was filtered off
and recrystallized from ethanol.
5-(4-Chlorophenylsulfonyl)-2-(3,5-dimethyl-1H-
pyrazol-1-yl)-4-(p-tolylsulfonyl)-1,3-thiazole (IX). a.
Compound VIb, 0.0015 mol, was dispersed in 5 ml of
glacial acetic acid, 1 ml of 30% aqueous hydrogen
peroxide was added, and the mixture was heated for
2 h under reflux and cooled to 20°C. The precipitate
was filtered off and purified by recrystallization from
acetic acid.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(p-tolyloxy)-
4-(p-tolylsulfonyl)-1,3-thiazole (IV). Compound III,
0.01 mol, was dissolved in 10 ml of THF, 0.02 mol of
p-methylphenol and 0.02 mol of triethylamine were
added, and the mixture was heated for 10 h under
reflux. The solvent was removed under reduced
pressure, and the residue was recrystallized from
ethanol.
b. Compound VIII, 0.001 mol, was dispersed in 7 ml
of glacial acetic acid, 1 ml of 30% aqueous hydrogen
peroxide was added, the mixture was heated for 2 h
under reflux and cooled to 20°C, and the precipitate
was filtered off and purified by recrystallization from
acetic acid. Samples of IX obtained as described in a
and b showed no depression of the melting point at
mixing.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(pyrrolidin-
1-yl, morpholino, benzylamino)-4-(p-tolylsulfonyl)-
1,3-thiazoles Va–Vc (general procedure). Pyrrolidine,
morpholine, or benzylamine, 0.1 mol, was added to a
suspension of 0.05 mol of compound III in 10 ml of
butanol, and the mixture was heated for 20 h under
reflux. The solvent was removed under reduced
pressure, and the residue was washed with water and
recrystallized from ethanol.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-(methylsulfan-
yl, isopropylsulfanyl)-4-(p-tolylsulfonyl)-1,3-thiazoles
Xa and Xb (general procedure). Compound VII,
0.05 mol, was dispersed in 5 ml of methanol, 0.05 mol
of sodium methoxide and 0.065 mol of methyl iodide
or isopropyl bromide were added, the mixture was
heated for 3 h under reflux, and the precipitate was
filtered off and purified by recrystallization from
ethanol.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-(p-tolylsulfon-
yl)-5-(p-tolylsulfanyl, 4-chlorophenylsulfanyl)-1,3-
thiazoles VIa and VIb (general procedure). p-Methyl-
or p-chlorobenzenethiol, 0.1 mol, and triethylamine,
0.1 mol, were added to a suspension of 0.05 mol of
compound III in 10 ml of ethanol, and the mixture was
heated for 15 h under reflux. The precipitate was
filtered off, the solvent was removed from the filtrate
under reduced pressure, and the residue was
recrystallized from ethanol–DMF (10:1).
5-(4-Chlorophenylsulfonyl)-2-(3,5-dimethyl-1H-
pyrazol-1-yl)-4-(4-methoxyphenoxy)-1,3-thiazole (XI).
Compound IX, 0.05 mol, was dissolved in 10 ml of
THF, 0.1 mol of sodium 4-methoxyphenoxide was
added, and the mixture was left to stand for 24 h at 20°C.
The solvent was removed under reduced pressure, and
the residue was recrystallized from ethanol.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-(p-tolylsulfon-
yl)-1,3-thiazole-5-thiol (VII). Freshly prepared hyd-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008

2136
TUROV et al.
at 20°C. The solvent was removed under reduced pres-
sure, and the residue was recrystallized from ethanol–
DMF (10:1).
5-(4-Chlorophenylsulfonyl)-2-(3,5-dimethyl-1H-
pyrazol-1-yl)-4-phenylsulfanyl-1,3-thiazole (XII).
Compound IX, 0.05 mol, was dispersed in 10 ml of
THF, 0.1 mol of sodium benzenethiolate was added,
and the mixture was left to stand for 24 h at 20–25°C.
The solvent was removed under reduced pressure, and
the residue was recrystallized from ethanol.
REFERENCES
1. Babii, S.B., Zyabrev, V.S., and Drach, B.S., Russ. J. Gen.
Chem., 2002, vol. 72, no. 11, p. 1730.
5,5′-Dithiobis[2-(3,5-dimethyl-1H-pyrazol-1-yl)-
4-(p-tolylsulfonyl)-1,3-thiazole] (XIII). Compound
VII, 0.01 mol, was dispersed in 10 ml of ethanol, a
solution of 0.01 mol of sodium ethoxide in 3 ml of
ethanol and 16 ml of a 3% solution of iodine in ethanol
were added, and the mixture was left to stand for 48 h
2. Turov, K.V., Vinogradova, T.K., Zyabrєv, V.S., and
Drach, B.S., Tezi dopovіdei XXI Ukraїns’koї konferentsії
z organіchnoї khіmії (Abstracts of Papers of the XXIth
Ukrainian Conf. on Organic Chemistry), Chernіgіv, 2007,
p. 336.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 11 2008