A convenient route to new 4,5-dimercapto-1,3-thiazole derivatives

Article abstract of DOI:10.1023/A:1023380927159

A series of 2-X-4-tosyl-5-chloro-1,3-thiazoles (X = OH, OAlk, SH, SAlk, NH₂, NHAlk, NAlk₂, NHAr, etc.) were prepared from accessible 1-tosyl-2,2-dichloroethenyl isothiocyanate. Only some of these compounds containing a moderately lab

Full text of DOI:10.1023/A:1023380927159

Russian Journal of General Chemistry, Vol. 72, No. 11, 2002, pp. 1709 1713. Translated from Zhurnal Obshchei Khimii, Vol. 72, No. 11, 2002,
pp. 1813 1817.
Original Russian Text Copyright
2002 by Babii, Zyabrev, Drach.
Dedicated to the centenary of Academician A.V. Kirsanov’s birthday
A Convenient Route
to New 4,5-Dimercapto-1,3-thiazole Derivatives
S. B. Babii, V. S. Zyabrev, and B. S. Drach
Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received January 8, 2002
Abstract A series of 2-X-4-tosyl-5-chloro-1,3-thiazoles (X = OH, OAlk, SH, SAlk, NH2, NHAlk, NAlk2,
NHAr, etc.) were prepared from accessible 1-tosyl-2,2-dichloroethenyl isothiocyanate. Only some of these
compounds containing a moderately labile hydrogen atom peculiarly react with thiophenols in the presence of
triethylamine to give 4,5-di(arylthio)-2-(hydroxy- or arylamino)-1,3-thiazoles, which are difficult to prepare
by other routes. It is quite possible that, in the course of nucleophilic substitution of the chlorine atom and
tosyl residue by the corresponding arylthio groups, a significant role is played by nonaromatic tautomeric
forms of functionally 2-substituted 1,3-thiazoles formed by proton transfer to positions 3 and 5 of the hetero-
ring.
We have shown recently that the accessible poly-
centered electrophilic agent, 1-tosyl-2,2-dichloroeth-
enyl isothiocyanate I, is an indispensable synthetic
precursor of a number of 4-tosyl-5-chloro-1,3-thiazole
derivatives containing various functional groups in
position 2 (compounds II V in Scheme 1). A syste-
matic study of the lability of chlorine and tosyl group
in these compounds with respect to substitution by
arylthiolate ions suggested the possibility of formation
of eight types of 4,5-dimercapto-1,3-thiazole deriva-
tives, VI XIII; however, only five of them (VII, VIII,
and X XII) were actually prepared. It should be pri-
marily noted that, among diverse 2-amino-4-tosyl-5-
chloro-1,3-thiazole derivatives II, only some of com-
pounds containing aryl residues at the exocyclic nitro-
gen atom readily react with thiophenols on heating in
ethanol in the presence of triethylamine. The regio-
The structure of VII and VIII is confirmed by the
1H NMR spectra (Table 1) and by the transformations
VIIa
XIa
XII and IV
VIIIa
XII, which
led to the same product, 3-methyl-4,5-ditosyl-1,3-thi-
azol-2(3H)-one (Scheme 1).
It should be noted that, in contrast to III, its thione
analog V does not react under mild conditions with
arylthiolate anions and is therefore unsuitable for
preparing 2,4,5-trimercapto-1,3-thiazole derivatives
IX and XIII.
Thus, the applicability of the new route to 4,5-di-
mercapto-1,3-thiazole derivatives is apparently limited
owing to specific features of nucleophilic substitution
of readily leaving groups at the C4 and C5 centers
of the thiazole ring. To interpret these features, it is
useful to consider not only the aromatic tautomer A1
of the starting compounds but also their nonaromatic
forms B1 and C1 (Scheme 2).
selective transformation II
VI could be performed
in none of the cases, as at the equimolar ratio of the
reactants only 2-arylamino-4,5-di(arylthio)-1,3-thia-
zoles X were obtained, though in a low yield. Similar
results were obtained with 2-hydroxy-4-tosyl-5-chlo-
ro-1,3-thiazole for which the 3H-thiazolone tautomer
III is major. Its reaction with thiophenols in the pres-
ence of triethylamine at the reactant molar ratios of
1 : 1 : 1 and 1 : 2 : 2 yielded exclusively compounds
VII. It is interesting that compound IV, which is the
N-methyl analog of III, reacts with thiophenols differ-
ently. Even with an excess of thiophenols, only the
chlorine atom is substituted, and the tosyl group is not
The nucleophilic substitution of chlorine at the C5
center can hardly occur by the A1
A2 pathway, as
similar compounds (A3) with X = O, S, and PhN ap-
peared to be relatively inert toward arylthiolate ions.
The fairly low reactivity of the C5 center in the
related structures A1 and A3 is apparently due to the
conjugation of this center with the lone electron pairs
of the exocyclic O, S, or N atom at the 2-position of
the ring. The activating effect of the tosyl group at the
adjacent C4 center is undoubtedly less pronounced.
At the same time, in the cyclamide tautomer B1, iden-
tified in many cases [2], the C5 atom exhibits pro-
nounced electrophilic properties; therefore, the nucleo-
involved (cf. transformations III
VIII).
VII and IV
1070-3632/02/7211-1709$27.00 2002 MAIK Nauka/Interperiodica

1710
BABII et al.
Table 1. IR and 1H NMR data for new 1,3-thiazole derivatives II, IV, VII, VIII, and X XII
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (solvent)
IIc
IV
1150, 1325 (SO2), 3390 (NH) 2.42 s (3H, CH3), 7.53 8.25 m (8H, ArH), 11.33 s (1H, NH) (DMSO-d6)
1160, 1340 (SO2), 1690 (CO) 2.48 s (3H, CH3C6H4), 3.47 s (3H, CH3N), 7.40 d (2H, ArH), 7.85 d (2H, ArH)
(CDCl3)
VIIa 1690 (CO), 3390 (NH)
2.34 s (3H, CH3), 2.36 s (3H, CH3), 7.12 7.34 m (8H, ArH), 7.93 s (1H, NH)
(CDCl3)
VIIIa 1150, 1325 (SO2), 1685 (CO) 2.39 s (3H, CH3C6H4), 2.48 s (3H, CH3C6H4), 3.35 s (3H, CH3N), 7.20 7.47 m
(6H, ArH), 7.93 d (2H, ArH) (CDCl3)
Xa
Xd
3400 (NH)
3400 (NH)
2.30 s (6H, CH3), 7.03 7.33 m (13H, ArH), 7.77 s (1H, NH) (CDCl3)
2.28 s (3H, CH3), 2.37 s (3H, CH3), 7.19 7.56 m (10H, ArH), 8.04 d (2H, ArH),
11.15 s (1H, NH) (DMSO-d6)
XIa 1660 (CO)
2.32 s (3H, CH3C6H4), 2.33 s (3H, CH3C6H4), 3.25 s (3H, CH3N), 7.07 7.28 m
(8H, ArH) (CDCl3)
XII 1130, 1320 (SO2), 1660 (CO) 2.43 s (3H, CH3C6H4), 2.46 s (3H, CH3C6H4), 3.26 s (3H, CH3N), 7.49 7.92 m
(8H, ArH) (DMSO-d6)
Scheme 1.
1) 4-CH3C6H4SH, C5H5N;
2) H2O2 (excess); 3) NaSH
2R1NH2
Cl
Cl
Ts
N=C=S
I
1) MeOH, C5H5N;
2) HBr
2R2SH,
2Et3N
Me
2R2SH,
2Et3N
Ts
Ts
Ts
Ts
NH
N
NH
N
Et3N, MeI
(R1 = Ar)
Cl
O
Cl
S
NHR1
Cl
O
Cl
S
S
S
S
IIa IIf
III
IV
R2SH, Et3N
V
R2SH, Et3N
2R2SH, 2Et3N
R2SH, Et3N
(R1 = H, Me, Ar)
Me
Ts
R2S
R2S
Ts
Ts
NH
S
NH
O
N
O
N
R2S
R2S
R2S
NHR1
S
S
S
S
VI
VIIa, VIIb
VIIIa, VIIIb
X
H2O2 (excess)
(R2 = 4-MeC6H4)
Me
1) MeONa;
2) MeI
Me
R2S
R2S
Ts
R2S
R2S
R2S
N
NH
N
N
H2O2 (excess)
(R2 = 4-MeC6H4)
R2S
O
S
Ts
O
NHAr
S
S
S
S
Xa Xe
XIa, XIb
XII
XIII
R1 = C6H5 (IIa), 4-CH3C6H4 (IIb), 4-NO2C6H4 (IIc), 2-naphthyl (IId), CH3 (IIe), H (IIf); R2 = 4-CH3C6H4 (VIIa, VIIIa,
Xa, Xd, Xe, XIa), 4-ClC6H4 (VIIb, VIIIb, Xb, Xc, XIb); Ar = C6H5 (Xa, Xb), 4-CH3C6H4 (Xc), 4-NO2C6H4 (Xd),
2-naphthyl (Xe).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 11 2002

A CONVENIENT ROUTE TO NEW 4,5-DIMERCAPTO-1,3-THIAZOLE DERIVATIVES
1711
Scheme 2.
X = O, S, NH, AlkN, ArN, NAc.
philic substitution of chlorine by the pathway B1
B2 should occur even under mild conditions, which
was proved experimentally by the model transforma-
C1
C3
C4 cannot be made without special stud-
ies, since both the tosyl residue and the chlorine atom
at the C4 and C5 centers of C1 should be highly nu-
cleophilic.
tion B3
B4. It should be noted that, in structure B3
and hence in B1, the tosyl group at C4 shows no
noticeable lability; therefore, to account for ready
elimination of this group, we should give attention to
tautomers C1 and C2, usually disregarded when con-
sidering tautomeric equilibria in functionally 2-substi-
tuted 1,3-thiazoles (cf. [2]). On the contrary, in cyclic
enamides, such N-acylimine forms have been identi-
fied, and their significant role in manifestation of
specific properties of secondary enamides is beyond
doubt [3]. Since the B1 structure contains an enamide
Thus, the prototropy plays, apparently, an impor-
tant role in the complex transformation A1
...
A5. At the same time, too high acidity of A1 can have
an adverse effect on its reactivity. Although formation
of tautomers B1 and C1 remains possible, the action
of a base can result in formation of a stable mesomer-
ic anion (see below) whose reactivity toward nucleo-
philic agents is low.
fragment, the equilibrium B1
C1 is quite pos-
Ts
Ts
Ts
N
N
N
sible, though it is, apparently, strongly shifted toward
B1. Since the C1 form is highly electrophilic, even its
small content can be sufficient for the occurrence of
nucleophilic substitution of the labile tosyl group at
the C=N bond. Indeed, such a substitution was recent-
ly proved for acyclic analogs of C1 [4]. The choice
Cl
Cl
X
X
Cl
X
S
S
S
It is quite probable that this fact is responsible for
different behavior toward arylthiolate anions of simi-
lar representatives of A1 and B1 with X = O, S, NAr,
between the alternative pathways C1
C2
C4 and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 11 2002

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BABII et al.
Table 2. Yields, melting points, and elemental analyses of new 1,3-thiazole derivatives II, IV, VII, VIII, and X XII
Found, %
Calculated, %
Comp.
no.
Yield,
%
mp,
C
Formula
(solvent for recrystallization)
Cl
S
Cl
S
IIc
IId
IV
VIIa
VIIb
VIIIa
VIIIb
Xa
Xb
Xc
Xd
Xe
XIa
XIb
XII
85
95
65
36
53
91
88
93
75
96
70
69
65
77
79d
220 222 (ethanol acetonitrile)
140 142 (ethanol)
120 122 (ethanol)
154 155 (ethanol)
177 178 (ethanol)
169 170 (ethanol acetonitrile)
156 158 (acetonitrile)
110 112 (ethanol)
134 136 (acetonitrile)
150 151 (ethanol)
198 200 (ethanol acetonitrile)
126 127 (acetonitrile)
88 89 (ethanol)
8.62
8.50
11.65
15.63
15.39
21.04
27.72
24.83
24.52
23.38
22.83
20.86
20.28
20.70
20.37
26.80
23.98
22.74
C16H12ClN3O4S2
C20H15ClN2O2S2
C11H10ClNO3S2
C17H15NOS3
C15H9Cl2NOS3
C18H17NO3S3
C17H14ClNO3S3
C23H20N2S3
C21H14Cl2N2S3
C22H16Cl2N2S3b
C23H19N3O2S3
C27H22N2S3
8.65
8.54
11.67
15.65
15.46
21.11
27.84
24.90
24.57
23.35
22.87
20.85
20.23
20.66
20.44
26.76
24.03
22.71
a
18.20
8.64
18.35
8.61
15.30
15.00
15.37
14.91
C18H17NOS3
C16H11Cl2NOS3
C18H17NO5S3
c
94 96 (ethanol)
215 216 (acetonitrile)
17.70
17.71
e
a
b
c
Found, %: C 43.76; H 3.39. Calculated, %: C 43.49; H 3.32. Found N, %: 9.07. Calculated N, %: 9.03. Found, %: C 48.60;
d
e
H 2.80. Calculated, %: C 48.00; H 2.77. Yield by the reaction VIIIa
XII; yield by the reaction XIa
XII 50%. Found, %:
C 51.11; H 4.10. Calculated, %: C 51.04; H 4.05.
NAc (see Experimental). All these features apprecia-
bly limit the applicability of the suggested route to
new 4,5-dimercapto-1,3-thiazole derivatives; neverthe-
less, its application sphere is wider than shown in
Scheme 1.
azole IId. A solution of 20 mmol of 2-naphthylamine
in 5 ml of ethanol was added with stirring over a period
of 10 min to a suspension of 10 mmol of I, cooled to
10 15 C. The mixture was stirred at 20 25 C for
24 h, and the precipitate was filtered off and washed
with ethanol.
EXPERIMENTAL
3-Methyl-4-tosyl-5-chloro-1,3-thiazol-2(3H)-one
IV. Methyl iodide, 7.1 mmol, was added to a solution
of 7.1 mmol of III and 7.1 mmol of triethylamine in
16 ml of methanol. The mixture was stirred at 20
25 C for 72 h, and the precipitate was filtered off.
The IR spectrum of XII was taken on a UR-20
spectrometer (KBr pellet), and those of the other com-
pounds, on a Specord IR-71 spectrometer (CH2Cl2
1
solutions). The H NMR spectra were recorded on
a Varian VXR-300 spectrometer, internal reference
TMS. The yields, melting points, and analytical data
for the new compounds are given in Table 2.
4,5-Di(arylthio)-1,3-thiazol-2(3H)-ones VIIa
and VIIb. A mixture of 3.4 mmol of III, 6.9 mmol of
p-thiocresol or p-chlorothiophenol, and 10.5 mmol of
triethylamine in 10 ml of ethanol was refluxed for 6 h
and then cooled to 20 25 C; 1 ml of concentrated
HCl was added, and the precipitate was filtered off
and washed with water and ethanol.
1-Tosyl-2,2-dichloroethenyl isothiocyanate I,
2-amino(methylamino, p-tolylamino, phenylamino)-
4-tosyl-5-chloro-1,3-thiazoles IIa, IIb, IIe, and IIf,
4-tosyl-5-chloro-1,3-thiazol-2(3H)-one III, and
4-tosyl-5-chloro-1,3-thiazole-2(3H)-thione V were
prepared as described in [1, 5].
3-Methyl-4-tosyl-5-arylthio-1,3-thiazol-2(3H)-
ones VIIIa and VIIIb. A mixture of 1.1 mmol of IV,
1.1 mmol of appropriate thiol, and 1.1 mmol of tri-
ethylamine in 4 ml of ethanol was refluxed for 1 h
and then cooled to 20 25 C; the precipitate was fil-
tered off and washed with ethanol.
2-p-Nitrophenylamino-4-tosyl-5-chloro-1,3-thia-
zole IIc. A mixture of 10 mmol of isothiocyanate I,
20 mmol of p-nitroaniline, and 10 ml of acetonitrile
was stirred at 20 25 C for 48 h; the precipitate was
filtered off and washed with ethanol.
Action of thiols on 2-amino(methylamino, aryl-
amino)-4-tosyl-5-chloro-1,3-thiazoles II. A mixture
of 1.3 mmol of IIa IId, 2.6 mmol of p-thiocresol or
2-(2-Naphthylamino)-4-tosyl-5-chloro-1,3-thi-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 11 2002

A CONVENIENT ROUTE TO NEW 4,5-DIMERCAPTO-1,3-THIAZOLE DERIVATIVES
1713
p-chlorothiophenol, and 2.6 mmol of triethylamine in
5 ml of ethanol was refluxed for 6 h and then cooled
to 20 25 C; the precipitate was filtered off and
washed with ethanol. 2-Arylamino-4,5-di(arylthio)-
1,3-thiazoles Xa Xe were obtained. The reactions of
IIe and IIf with excess p-thiocresol yielded no ex-
pected products VI and X.
Reaction of p-thiocresol with 4-tosyl-5-chloro-
1,3-thiazole-2(3H)-thione V. A solution of 2 mmol of
V, 4 mmol of p-thiocresol, and 4 mmol of triethyl-
amine in 5 ml of ethanol was refluxed for 6 h and
then cooled to 20 25 C; 1 ml of concentrated HCl
was added. The starting compound V was recovered
in 55% yield.
Reactions of p-thiocresol with 2-methoxy-4-tosyl-
5-chloro-1,3-thiazole [1], 2-methylthio-4-tosyl-5-
chloro-1,3-thiazole [1], and 2-[methyl(phenyl)ami-
no]-4-tosyl-5-chloro-1,3-thiazole [1]. A mixture of
1.3 mmol of one of the above 1,3-thiazole derivatives,
2.6 mmol of p-thiocresol, and 2.6 mmol of triethyl-
amine in 5 ml of ethanol was refluxed for 6 h and
then cooled to 20 25 C; the starting compounds were
recovered in 60 80% yields.
3-Methyl-4,5-di(arylthio)-1,3-thiazol-2(3H)-ones
XIa and XIb. Methyl iodide, 1 mmol, was added to
a solution of 1 mmol of VIIa and VIIb and 1 mmol of
sodium methylate in 10 ml of methanol. The mixture
was stirred for 72 h at 20 25 C, 3 ml of water was
added, and the precipitate was filtered off and washed
with water.
3-Methyl-4,5-ditosyl-1,3-thiazol-2(3H)-one XII.
A mixture of 1.2 mmol of VIIIa or XIa, 1 ml of 30%
aqueous hydrogen peroxide, and 5 ml of acetic acid
was refluxed for 2 h and then cooled to 20 25 C. The
precipitate was filtered off and washed with water and
ethanol.
Acetylation of 2-amino-4-tosyl-5-chloro-1,3-thia-
zole IIf and reaction of the acetylation product
with p-thiocresol. A mixture of 5 mmol of IIf and
5 ml of acetic anhydride was refluxed for 1 h and then
cooled to 20 C; the precipitate was filtered off and
dried at 100 C. Analytically pure 2-acetylamino-4-
tosyl-5-chloro-1,3-thiazole was obtained; yield 83%,
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mp 228 C. IR spectrum (KBr), , cm : 1670 (CO),
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3160 (NH). H NMR spectrum (DMSO-d6), , ppm:
2.13 s (3H, CH3CO), 2.41 s (3H, CH3C6H4), 7.48 d
(2H, ArH), 7.83 d (2H, ArH), 12.85 s (1H, NH).
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 11 2002