Reactions of 4-tosyl-2-phenyl-5-chloro-1,3-thiazole with N-, O-, and S-nucleophiles

Article abstract of DOI:10.1134/S1070363210040249

The accessible two-center electrophilic substrate 4-tosyl-2-phenyl-5- chloro-1,3-thiazole reacts regioselectively with N-, O-, and S-nucleophiles to eliminate a chloride ion. The analog of this substrate, 4-tosyl-2-phenyl-5-p- chlorophenylsulphonyl-1,3-th

Full text of DOI:10.1134/S1070363210040249

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 825–828. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © K.V. Turov, T.K. Vinogradova, V.S. Brovarets, B.S. Drach, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4,
pp. 664–667.
Reactions of 4-Tosyl-2-phenyl-5-chloro-1,3-thiazole
with N-, O-, and S-Nucleophiles
K. V. Turov, T. K. Vinogradova, V. S. Brovarets, and B. S. Drach†
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev-94, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received June 25, 2009
Abstract―The accessible two-center electrophilic substrate 4-tosyl-2-phenyl-5-chloro-1,3-thiazole reacts
regioselectively with N-, O-, and S- nucleophiles to eliminate a chloride ion. The analog of this substrate, 4-
tosyl-2-phenyl-5-p-chlorophenylsulphonyl-1,3-thiazole, reacts with “soft” and “hard” nucleophiles differently:
with the participation of С5 or С4 center, respectively, that seems to be caused by the principle of “symbiosis”
in the transition state.
DOI: 10.1134/S1070363210040249
To continue the study of nucleophilic substitution
in electron-deficient thiazole substrates [1, 2], we
investigated the reactivity of one of key trisustituted
thiazoles obtained on heating 3-tosyl-1-phenyl-1,4,4-
trichloro-2-aza-1,3-diene (I) with thiourea, as it had
been described earlier [3]. Resulting 4-tosyl-2-phenyl-
5-chloro-1,3-thiazole (II) obtained in a high yield
reacts in mild conditions with N-, O-, and S-
nucleophiles to eliminate the chloride anion and to
form the corresponding substituted thiazoles III–VI
(Scheme 1). The high reactivity of the С5 center in
substrate II originates from the electrophilic influence
of the tosyl group of the neighboring С4 center of the
thiazole ring, whereas the nature of the nucleophilic
agent practically does not affect the substitution
regioselectivity.
The analog of substrate II containing the p-chloro-
phenylsulfonyl group in position 5 (substrate VII)
reacts with the “soft” and “hard” nucleophiles dif-
ferently. “Soft” arylsulfanyl groupes are entered into
position 5 of the thiazole ring, and “hard” arylоxy
groups replace the tosyl anion at atom C4.
To introduce alkylsulfanyl groups, first a thiol
group was introduced in position 5 of the thiazole ring,
and then it was alkylated: II → III → IX. Morpholine
and benzylamine act on substrate VII similarly to
“hard” sodium phenylates (conversions VII → X or
XI, see the table).
Different reactions of VII with “soft” and “hard”
bases can be explained by a transition state stab-
ilization in the case when the number of equal in
nature groups at a reactive center increases. In this case
the initial structure A can give rise to two types of
relatively stable transition states B and C, which are
formed upon the attack of “soft” nucleophiles on С5,
and also of “hard” nucleophiles, on С4. In both cases
the number of substituents close in nature increases in
the corresponding positions: in the structure B two
“soft” substituents are at the center С5, and in the
structure C three “hard” groups are bound with the
center С4 (Scheme 2).
According to the “symbiosis” principle [4], the
formation of the transition states B and C occurs faster
as compared to alternative structures that provides a
high regioselectivity of the center С4 reaction with
“hard” bases and of center С5, with “soft” bases.
In conclusion we note that the preparative worth of
the conversions presented in Scheme 1 will be
considered later on.
EXPERIMENTAL
1
The Н NMR spectra were recorded on a Varian
Mercury-400 spectrometer in a CDCl3 solution with
TMS as the internal reference.
†
Deceased.
825

826
TUROV et al.
Scheme 1.
Ts
Ts
Ts
N
Cl
Cl
(NH2)2C=S
N
AlkHlg, MeONa
NaSH
N
Cl
Cl
Ph
S
HS
Ph
S
Ph
I
II
III
Ar1SH, Et3N
Ar2ONa
R1R2NH
Ts
Ar2O
Ts
Ts
N
N
N
R1R2 N
Ph
Ar1S
Ph
IVа, IVb
Ph
S
S
S
Vа, Vb
VIа, VIb
H2O2,
MeC(O)OH
Ar1SH, Et3N
Ar1 = 4-ClC6H4
Ts
Ts
Ts
N
N
N
PhSH, Et3N
Ar1 = Ph
4-ClC6H4SO2
Ph
AlkS
Ph
S
PhS
Ph
S
S
VII
VIII
IXа, IXb
Ar2ONa
Ar2O
R1R2N
R1R2NH
N
N
4-ClC6H4SO2
Ph
O
Ph
4-ClC6H4S
S
2
S
Xа, Xb
XIа, XIb
Ar1 = 4-MeC6H4 (IVa), 4-ClC6H4 (IVb); Ar2 = Ph (VIa, XIa), 4-MeC6H4 (VIb, XIb);
R1R2N =
PhCH2NH (Vb, Xb); Alk = Me (IXa), 4-ClC6H4CH2 (IXb).
N (Vа, Xа),
O
Scheme 2.
SO2
ArO−
ArS−
N
SO2
S
A
Ar
SO2
SO2
O
−
N
N
SO2
−
S
S
SO2
S
Ar
B
C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

REACTIONS OF 4- TOSYL-2-PHENYL-5-CHLORO-1,3-THIAZOLE
Yields, constants, and elemental analysis data for compounds II–XI
827
Found, %
Cl(N)
Calculated, %
Cl(N)
Comp. Yield,
no.
II
mp, °С (solvent for crystallization)
Formula
%
S
S
74
150–151 (EtOH)
151–152 (EtOH)
144–145 (EtOH)
195–196 (EtOH)
169–170 (EtOH)
102–103 (EtOH)
103–104 (EtOH)
168–169 (EtOH–DMF, 1:1)
102–103 (EtOH)
153–154 (EtOH–DMF, 10:1)
164–165 (EtOH–DMF, 10:1)
150–151 (EtOH)
104–105 (EtOH)
106–107 (EtOH)
9.76
(3.56)
7.58
18.17
21.76
20.89
15.89
15.09
15.84
15.36
19.57
22.67
26.49
20.45
15.02
14.42
15.05
14.23
С16H12ClNO2S2
С23H19NO2S3
С22H16ClNO2S3
С20H20N2O3S2
С23H20N2O2S2
С22H17NO3S2
С23H19NO3S2
С22H16ClNO4S3
С22H17NO2S3
10.13
(3.20)
7.74
18.33
21.98
21.00
16.01
15.25
15.74
15.21
19.63
22.71
26.61
20.38
15.23
14.54
14.99
14.51
87a
91a
72
74
73
76
85
78
72
89
73
77
74
76
IVа
IVb
Vа
(6.68)
(6.32)
(3.79)
(3.58)
7.10
(6.99)
(6.67)
(3.44)
(3.32)
7.23
Vb
VIа
VIb
VII
VIII
IXа
IXb
Xа
Xb
XIа
XIb
(3.54)
(4.12)
7.42
(3.31)
(3.87)
7.51
С17H15NO2S3
С23H18ClNO2S3
С19H17ClN2O3S2
С22H17ClN2O2S2
С21H14ClNO3S2
С22H16ClNO3S2
8.15
7.87
8.42
8.04
8.42
7.85
8.28
8.02
124–125 (EtOH)
a Yield for procedure a.
b. To a solution of 1.5 mmol of compound VII in
2-Phenyl-5-chloro-1,3-thiazol-4-yl tosylate (II).
Thiourea, 30 mmol, was added to a suspension of
10 mmol of compound I [3] in 50 ml of acetonitrile,
the mixture was boiled for 2 h, the solvent was
removed in vacuo, water, 100 ml, was added to the
residue, and the precipitate was filtered off and
10 ml of acetonitrile equimolar amounts of the
corresponding thiophenol and triethylamine were
added, the mixture was left to stand for 24 h at 20°С,
the solvent was removed in vacuo, water, 10 ml, was
added to the residue, and the precipitate was filtered
off and purified by recrystallization. The test of mixing
samples obtained by the produres a and b mode did not
show a melting point depression. 1H NMR spectrum, δ,
ppm, IVa: 2.44 s (3Н, СН3), 2.46 s (3Н, СН3), 7.26–
7.28 m (2Нarom), 7.31–7.43 m (5Нarom), 7.53–7.55 m
(2Нarom), 7.70–7.72 m (2Нarom), 8.09–8.11 m (2Нarom);
IVb: 2.46 with (3Н, СН3), 7.32–7.46 m (7Нarom), 7.54–
7.56 m (2Нarom), 7.73–7.75 m (2Нarom), 8.07–8.09 m
(2Нarom).
1
purified by recrystallization. Н NMR spectrum, δ,
ppm: 2.44 s (3Н, СН3), 7.31–7.43 m (5Нarom), 7.70–
7.72 m (2Нarom), 8.09–8.11 m (2Нarom).
5-Sulfanyl-2-phenyl-1,3-thiazol-4-yl tosylate (III).
Potassium hydrosulfite, 3 mmol, was added to a
solution of 1.5 mmol of compound II in 10 ml of THF,
the mixture was heated for 3 h at 60°С, the solvent was
removed in vacuo, water, 10 ml, was added to the
residue, the mixture was acidified with concentrated
hydrochloric acid to рН 2, and the precipitate was
filtered off and used without purification for further
conversions. Yield of unpurified compound 56 %.
5-Morpholine(benzylamino)-2-phenyl-1,3-thia-
zol-4-yl tosylates (Vа, Vb). Morpholine or benzyl-
amine, 2.5 mmol, was added to a solution of
0.85 mmol of compound II in 10 ml of dioxane, the
mixture was heated for 24 h at 100°С, the solvent was
removed in vacuo, water, 10 ml, was added to the
residue, and the precipitate was filtered off and
5-p-Tolylsulfanyl(p-chlorophenylsulfanyl)-2-phe-
nyl-1,3-thiazol-4-yl tosylates (IVа, IVb). a. To a
solution of 1.5 mmol of compound II in 10 ml of
acetonitrile equimolar amounts of the corresponding
thiophenol and triethylamine were added, the mixture
was boiled for 2 h, the solvent was removed in vacuo,
water, 10 ml, was added to the residue, and the pre-
cipitate was filtered off and purified by re-
crystallization.
1
purified by recrystallization. H NMR spectrum, δ,
ppm, Va, 2.45 s (3Н, СН3), 3.24 m (4Н, 2 СН2), 3.92
m (4Н, 2СН2), 7.30–7.45 m (5Нarom), 7.75–7.82 m
(2Нarom), 8.00–8.02 m (2Нarom); Vb: 2.44 s (3Н, СН3),
4.86 m (2Н, СН2), 7.29–7.41 m (5Нarom), 7.38–7.56 m
(8Нarom), 7.78–7.85–7.87 m (2Нarom).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

828
TUROV et al.
recrystallization. 1H NMR spectrum, δ, ppm, IXa: 2.44
s (3Н, СН3), 2.67 s (3Н, СН3), 7.30–7.46 m (5Нarom),
7.82–7.84 m (2Нarom), 8.03–8.05 m (2Нarom); IXb: 2.39
s (3Н, СН3), 4.44 s (2Н, СН2), 7.31–7.44 m (5Нarom),
7.84–7.86 m (2Нarom), 8.05–8.07 m (2Нarom).
4-Morpholino(benzylamino)-2-phenyl-1,3-thia-
zol-5-yl 4-chlorobenzenesulfonates (Xа, Xb). Mor-
pholine or benzylamine, 2.5 mmol, was added to a
solution of 0.85 mmol of compound VII in 10 ml of
dioxane, the mixture was heated for 24 h at 100°С, the
solvent was removed in vacuo, water, 10 ml, was
added to the residue, and the precipitate was filtered
off and purified by recrystallization. 1H NMR
spectrum, δ, ppm, Xa: 3.26 m (4Н, 2СН2), 3.97 m (4Н,
2СН2), 7.30–7.45 m (5Нarom), 7.75–7.82 m (2Нarom),
8.00–8.02 m (2Нarom); Xb: 4.83 m (2Н, СН2), 7.29–
7.41 m (5Нarom), 7.38–7.56 m (9Нarom), 7.78–7.80 m
(2Нarom), 7.85–7.87 m (2Нarom).
5-Phenyloxy(p-tolyloxy)-2-phenyl-1,3-thiazol-4-
yl tosylates (VIа, VIb). To a solution of 1.5 mmol of
compound II in 10 ml of THF a corresponding sodium
phenolate, 1.6 mmol, was added, the mixture was left
to stand for 24 h at 20°С, the solvent was removed in
vacuo, water, 10 ml, was added to the residue, and the
precipitate was filtered off and purified by crystal-
1
lization. H NMR spectrum, δ, ppm, VIa: 2.45 s (3Н,
СН3), 7.18–7.20 m (2Нarom), 7.28–7.30 m (1Нarom),
7.33–7.35 m (2Нarom), 7.38–7.46 m (5Нarom), 7.79–7.81
m (2Нarom), 8.01–8.03 m (2Нarom); VIb: 2.46 s (3Н,
СН3), 7.34–7.46 m (7Нarom), 7.54–7.56 m (2Нarom),
7.73–7.75 m (2Нarom), 8.07–8.09 m (2Нarom).
2-Phenyl-5-(p-chlorophenylsulfonyl)-1,3-thiazol-
4-yl tosylate (VII). To a solution of 3.5 mmol of
compound IVb in 10 ml of trifluoroacetic acid, 1 ml of
30% aqueous solution of hydrogen peroxide was
added, the mixture was boiled for 1.5 h, 1 ml more of
30% aqueous solution of hydrogen peroxide was
added, and the mixture was boiled for 1.5 h more,
cooled to 20°С, poured out in 50 ml of water, and the
precipitate was filtered off and purified by
2-Phenyl-4-phenyloxy-(p-tolyloxy)-1,3-thiazol-5-
yl 4-chlorobenzenesulfonates (XIа, XIb). To a
solution of 1.5 mmol of compound VII in 10 ml of
THF a corresponding sodium phenylate, 1.6 mmol,
was added, the mixture was left to stand for 24 h at 20°С,
the solvent was removed in vacuo, water, 10 ml, was
added to the residue, and the precipitate was filtered
1
recrystallization. H NMR spectrum, δ, ppm: 2.46 s
(3Н, СН3), 7.32–7.46 m (7Нarom), 7.54–7.56 m
(2Нarom), 7.73–7.75 m (2Нarom), 8.11–8.13 m (2Нarom).
1
off and purified by crystallization. H NMR spectrum,
2-Phenyl-5-phenylsulfanyl-1,3-thiazol-4-yl tosy-
late (VIII). To a solution of 1.5 mmol of compound
VII in 10 ml of acetonitrile equimolar amounts of
thiophenol and triethylamine were added, the mixture
was left to stand for 24 h at 20°С, the solvent was
removed in vacuo, water, 10 ml, was added to the
residue, and the precipitate was filtered off and
purified by crystallization. 1H NMR spectrum, δ, ppm:
2.46 s (3Н, СН3), 7.30–7.53 m (8Нarom), 7.62–7.64 m
(2Нarom), 7.71–7.73 m (2Нarom), 8.09–8.11 m (2Нarom).
δ, ppm, XIIа: 7.09–7.11 m (2Нarom), 7.18–7.26 m
(1Нarom), 7.31–7.59 m (7Нarom), 7.79–7.81 m (2Нarom),
8.06–8.08 m (2Нarom); XIIb: 2.39 s (3Н, СН3), 6.97–
6.99 m (2Нarom), 7.16–7.18 m (2Нarom), 7.38–7.56 m
(5Нarom), 7.79–7.81 m (2Нarom), 8.06–8.08 m (2Нarom).
REFERENCES
1. Turov, K.V. and Drach, B.S., Zh. Obshch. Khim., 2008,
vol. 78, no. 4, p. 648.
5-Methylsulfanyl(p-chlorobenzylsulfanyl)-2-phe-
nyl-1,3-thiazol-4-yl tosylates (IXа, IXb). To a
suspension of 0.85 mmol of compound III in 5 ml of
methanol equimolar amounts of sodium methylate and
methyliodide or p-chlorobenzyl chloride were added,
the mixture was left to stand for 5 h at 20°С, and the
precipitate was filtered off and purified by
2. Turov, K.V. and Vinogradova, T.K., Zh. Obshch. Khim.,
2008, vol. 78, no. 11, p. 1897.
3. Kharchenko, A.V., Seferov, S.O., Zyabrev, V.S.,
Chervonyi, V.A., Vdovenko, S.I., and Drach, B.S., Ukr.
Khim. Zh., 1993, vol. 59, no. 6, p. 637.
4. Pearson, R.J. and Zongstad, I., Usp. Khim., 1969, no. 7,
p. 1223.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010