Synthesis of 4-tosyl-5-chloro-1,3-thiazole-2-carbonitrile and its transformations

Article abstract of DOI:10.1134/S1070363210010159

Reaction of the available 1-tosyl-2,2-dichloroethenyl isothiocyanate with sodium cyanide yields new clearly electrophilic substrate of thiazole nature containing the nitrile group, the tosyl residue, and the chlorine atom at C ², C⁴, and C⁵ respectively. The direction of the reaction of this substrate with nucleophile depends significantly on the nature of the latter. It was used in regioselective syntheses of a series of the unknown previously trifunctional thiazoles.

Full text of DOI:10.1134/S1070363210010159

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 1, pp. 117–120. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © K.V. Turov, T.K. Vinogradova, B.S. Drach, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 1, pp. 123–126.
Synthesis of 4-Tosyl-5-chloro-1,3-thiazole-2-carbonitrile
and Its Transformations
K. V. Turov, T. K. Vinogradova, and B. S. Drach†
Institute of Bioorganic and Oil Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev-94, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
Received February 2, 2009
Abstract―Reaction of the available 1-tosyl-2,2-dichloroethenyl isothiocyanate with sodium cyanide yields
new clearly electrophilic substrate of thiazole nature containing the nitrile group, the tosyl residue, and the
chlorine atom at C2, C4, and C5 respectively. The direction of the reaction of this substrate with nucleophile
depends significantly on the nature of the latter. It was used in regioselective syntheses of a series of the
unknown previously trifunctional thiazoles.
DOI: 10.1134/S1070363210010159
Systematic studies of nucleophilic substitution at C4
and C5 carbon atoms of 1,3-thiazole ring which were
begun recently, were significantly complicated by the
fact that only small number of suitable objects was
known. Therefore syntheses of new highly reactive
electrophilic substrates of thiazole nature present
obvious interest. In this work we delveloped one of
such procedures carried out by means of cyclo-
condensation of the available 1-tosyl-2,2-dichlo-
roethenyl isothiocyanate I with sodium cyanide. As it
is shown in the scheme, the first step is evidently the
addition of cyanide anion to the isothiocyanate group
of the reagent I. Then the intermediate compound II or
the product of its cyclization III eliminates sodium
chloride and forms trisubstituted thiazole IV
containing the nitrile group and the tosyl residue in the
positions 2 and 4, and the reactive chlorine atom at the
C5 carbon atom.
phile adds at the C≡N bond, while in the second event
the “soft” nucleophile attacks the position 5 of the
thiazole ring (see the transformations IV → V and
IV → VI). At the same time the morpholine even at
20°C reacts with both electrophilic centers giving the
corresponding trifunctional thiazole VII.
Note that the product of condensation of the
substrate IV with thiophenol remains
a quite
pronounced electrophile as seen from the trans-
formations VI → VIII and VI → X proceeding under
mild conditions.
Consider finally the reaction of compound IV with
sodium benzenesulfinate leading to the electrophilic
substrate XI which is the most reactive compared to
the other thiazoles presented in the scheme. Similarly
to substrate IV its analog XI reacts with soft and hard
nucleophiles by different pathways. The reaction of
“soft” p-chlorothiophenol in the presence of triethyl-
amine proceeds as the nucleophilic substitution of
phenylsulfonyl group at C5 center of compound XI. At
the same time a “harder” morpholine attacks C2 carbon
atom resulting in the transformation XI → XIII
accompanied by elimination of the cyanide anion.
Electrophilic substrate IV is a yellowish crystalline
substance which is formed in high yield. It is quite
stable at storage and is suitable for the preparative
syntheses of a large number of new functionalized
thiazole derivatives. Some of them V–XIII are
presented in the scheme and in Table 1.
The introduction of the electron-donor morpholino
group in the position 2 of the thiazole ring decreases
the electrophilicity of the C5 center, and therefore
compound XIII does not take part in further reaction
with morpholine.
It is interesting that substrate IV reacts in different
manner with methanol and thiophenol in the presence
of triethylamine. In the first case the “hard” nucleo-
†
Deceased.
117

118
TUROV et al.
Ts
Cl
Cl
Ts
N
Ts
−N
NaCN
N
C
S
−
Cl
CN
Na+
CN
Na+
Cl
S
Cl
S
Cl
III
I
II
−NaCl
Ts
−NaCl
N
Cl
CN
S
IV
3
O
NH
MeOH, Et3N
PhSH, Et3N
Ts
Ts
Ts
O
N
N
N
OMe
N
N
CN
Cl
PhS
S
S
S
NH
NH
O
VII
VI
V
H2S, Py
NH4N3
Ts
Ts
Ts
N
N
BrCH2COPh
N
H
N
S
S
PhS
PhS
N
PhS
S
S
S
N
NH2
N N
Ph
IX
X
VIII
Ts
Ts
Ts
PhSO2Na, [n-Bu4N]+I−
4-ClC6H4SH, Et3N
N
N
N
CN PhSO2
PhSO2
CN
4-ClC6H4S
N
S
S
S
O
XI
XIII
XII
O
NH
2
Structures of new substrate IV and the products of
its transformations V–XIII agree with the IR and
NMR data presented in Table 2. For example, the
comparison of the IR spectra of compounds I, IV
shows that the disappearance of the broad band of
asymmetric vibrations of isothiocyanate group at
2040 cm–1 is accompanied by the appearance of a
narrow band of the C≡N bond at 2250 cm–1. These
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 1 2010

SYNTHESIS OF 4-TOSYL-5-CHLORO-1,3-THIAZOLE-2-CARBONITRILE
Table 1. Yields, constants, and elemental analysis data for compounds IV–XIII
119
Found, %
N(Cl)
Claculated, %
Comp.
no.
mp, °С
(solvent for crystallization)
Yield, %
Formula
S
S
N(Cl)
87
73
88
76
72
84
68
76
72
81
167–168 (EtOH–CH3CN, 1:1)
124–125 (МеOH)
12.31
19.24
25.64
14.54
30.92
25.14
23.02
23.49
23.11
20.48
9.12(11.32)
8.17(9.96)
7.31
C11H7ClN2O2S2
C12H11ClN2O3S2
C17H12N2O2S3
C19H24N4O4S2
C17H14N2O2S4
C25H20N2O2S4
C17H13N5O2S3
C17H12N2O4S3
C17H11ClN2O2S3
C20H20N2O5S3
12.46
19.38
25.82
14.69
31.55
25.21
23.15
23.78
23.64
20.70
9.38(11.87)
8.47(10.72)
7.52
IV
V
210–211
VI
145–146 (EtOH)
12.27
12.83
VII
VIII
IX
247–248 (EtOH–DMF, 5:1)
163–164 (EtOH–DMF, 5:1)
195–196 (EtOH–H2O, 10:1)
159–160 (EtOH)
5.94
6.89
5.21
5.51
16.17
16.85
X
6.37
6.93
XI
209–210 (EtOH)
6.21(8.34)
5.63
6.88(8.71)
6.03
XII
XIII
195–196 (EtOH)
Table 2. Spectral data of compounds synthesized IV–XIII
Comp.
no.
1H NMR spectrum, δ, ppm (DMSO-d6)
IVа
2.46 s (3Н, СН3), 7.36–7.38 m (2Нarom), 7.94–7.96 m (2Нarom
2.45 s (3Н, СН3), 3.95 s (3Н, OСН3), 7.36–7.38 m (2Нarom), 7.96–7.98 m (2Нarom), 8.76 s (1H NH)
2.34 s (3Н, СН3), 7.38–7.40 m (2Нarom), 7.56–7.78 m (5Нarom), 8.08–8.10 m (2Нarom
2.43 s (3Н, СН3), 3.46 m (8Нmorph), 3.70 m (8Нmorph), 7.34–7.36 m (2Нarom), 7.94–7.96 m (2Нarom), NHex
)
V
VIb
VIIc
)
VIIId 2.31 s (3Н, СН3), 7.34–7.36 m (2Нarom), 7.51–7.72 m (5Нarom), 7.98–8.00 m (2Нarom), 8.62 s (2Н, NH2)
2.45 s (3Н, СН3), 7.26–7.40 m (5Нarom), 7.46–7.54 m (4Нarom), 7.64–7.66 m (2Нarom), 7.80–7.82 m (2Нarom), 8.07–8.09 (2Нarom
)
IX
Xe
XI
2.44 s (3Н, СН3), 7.37–7.39 m (2Нarom), 7.47–7.57 m (3Нarom), 7.62–7.64 m (2Нarom), 8.01–8.03 m (2Нarom), NHex
2.37 s (3Н, СН3), 7.41–7.43 m (2Нarom), 7.56–7.58 m (2Нarom), 7.74 m (2Нarom), 7.88 m (1Нarom), 8.08–8.10 m (2Нarom
2.49 s (3Н, СН3), 7.44–7.46 m (2Нarom), 7.56–7.58 m (2Нarom), 7.74–7.76 m (2Нarom), 7.89–7.91 m (2Нarom
2.43 s (3Н, СН3), 3.44 m (4Нmorph), 3.68 m (4Нmorph), 7.32–7.34 m (2Нarom), 7.59–7.75 m (5Нarom), 8.02–8.04 m (2Нarom
)
)
XII
)
XIII
a
b
c
IR spectrum, ν, cm–1: 1150, 1350 (SO2); 2250 (C≡N). IR spectrum, ν, cm–1: 1150, 1375 (SO2); 2225 (C≡N). IR spectrum, ν, cm–1:
1150, 1350 (SO2); 1610 (C≡N); 3310 (NH). d IR spectrum, ν, cm–1: 1125, 1370 (SO2); 3310, 3410 (NH2). e 1125, 1325 (SO2); 3450 (NH).
data confirm the formation of a cyclic structure. On the
other hand, the addition of methanol, morpholine, and
hydrazoic acid to the C≡N bond of substrates IV, VI
leads to the disappearance of the narrow band in the
range 2250–2260 cm–1 belonging to the nitrile group.
At the same time the presence of the tosyl residue in
compound IV and its derivatives V–XIII agrees with
the fact that in 1H NMR spectra of all these compounds
a singlet of methyl group bound with the phenylene
fragment is observed in the range 2.43–2.49 ppm.
Besides this signal in the spectrum of compound V two
singlets at 3.95 and 8.76 ppm were observed. They
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120
TUROV et al.
belong to the methoxy group and the imine fragment
confirming reliably that the addition of methanol to the
C≡N bond of substrate IV takes place.
3 mmol of bromoacetophenone were added. The mix-
ture obtained was stirred for 5 h at 70°C, the solvent
was removed in a vacuum, and the residue was treated
with 20 ml of a saturated sodium hydrocar-bonate
solution. The precipitate formed was filtered off and
purified by crystallization from 5:1 ethanol–DMF.
5-[(4-Tosyl-5-phenylthio)-1,3-thiazol-2-yl]-1H-
tetrazole (X). To a solution of 1.3 mmol of compound
VI in 10 ml of THF 1.6 mmol of sodium azide and
1.6 mmol of ammonium chloride were added, and the
mixture obtained was heated for 6 h at 70°C. The
solvent was removed in a vacuum, and the residue was
treated with 10 ml of water and 0.5 ml of hydrochloric
acid. The crystals formed were filtered off and crys-
tallized from 5:1 ethanol-water mixture.
4-Tosyl-5-phenylsulfonyl-1,3-thiazole-2-carbo-
nitrile (XI). To a solution of 6 mmol of compound IV
in 20 ml of acetone 7.5 mmol of sodium sulfinate and
0.6 mmol of tetrabutylammonium iodide were added,
and the resulting mixture was heated for 10 h at 60°C.
The solvent was removed in a vacuum, and the residue
was treated with 15 ml of water. The precipitate
formed was filtered off and crystallized from ethanol.
4-Tosyl-5-p-chlorophenylthio-1,3-thiazole-2-car-
bonitrile (XII). To a solution of 0.6 mmol of com-
pound XI in 10 ml of acetonitrile 0.18 mmol of mor-
pholine was added, and the resulting mixture was
stirred for 20 h at 20°C. The solvent was removed in a
vacuum, and the residue was treated with 5 ml of
ethanol. The precipitate formed was filtered off and
crystallized from ethanol.
EXPERIMENTAL
IR spectra were recorded on an UR-20 spectrometer
1
in KBr pellets. H NMR spectra were taken on a
Varian Mercury-400 spectrometer in DMSO-d6 against
internal TMS.
1-Tosyl-2,2-dichloroethenyl isothiocyanate (I) was
prepared as described in [1].
4-Tosyl-5-chloro-1,3-thiazole-2-carbonitrile (IV).
To a solution of 45 mmol of compound I in 50 ml of
acetone 45 mmol of sodium cyanide were added, and
the mixture obtained was stirred for 24 h at 20°C. The
solvent was removed in a vacuum, the residue was
treated with 15 ml of ethanol, the precipitate formed
was filtered off and crystallized from 1:1 ethanol–
acetonitrile mixture.
Methyl 4-tosyl-5-chloro-1,3-thiazol-2-imidocar-
boxylate (V). To a suspension of 3 mmol of com-
pound IV in 10 ml of methanol 6 mmol of triethyl-
amine were added, the mixture obtained was heated for
5 h at 65°C and cooled to 20°C. The precipitate formed
was filtered off and crystallized from methanol.
4-Tosyl-5-phenylthio-1,3-thiazole-2-carbonitrile
(VI). To a solution of 1.7 mmol of compound IV in
10 ml of benzene equimolar amounts of thiophenol and
triethylamine were added, the mixture obtained was
stirred for 20 h at 20°C. The precipitate formed was
filtered off and washed with water and ethanol.
4-(4-Tosyl-5-phenylsulfonyl-1,3-thiazol-2-yl)morpho-
line (XIII). To a solution of 0.6 mmol of compound
XI in 10 ml of acetonitrile 0.8 mmol of 4-chloro-
thiophenol were added, and the resulting mixture was
stirred for 20 h at 20°C. The solvent was removed in a
vacuum, and the residue was treated with 5 ml of
ethanol. The precipitate formed was filtered off and
purified by crystallization from ethanol.
5-Morpholino-4-tosyl-1,3-thiazol-2-imidocarboxa-
morpholide (VII). To a solution of 1.7 mmol of
compound IV in 10 ml of acetonitrile 5.5 mmol of
morpholine was added, and the mixture obtained was
stirred for 20 h at 20°C. After thet solvent was
removed in a vacuum, the residue was treated with
5 ml of ethanol, the precipitate formed was filtered off
and crystallized from ethanol.
REFERENCES
4-Tosyl-5-phenylthio-1,3-thiazole-2-carbothio-
amide (VIII). A suspension of 5 mmol of compound
VI in 10 ml of pyridine was saturated with hydrogen
sulfide, the mixture obtained was stirred for 2 h at 20°C,
and poured in water. The precipitate obtained was
filtered off and crystallized from 5:1 ethanol–DMF.
1. Babii, S.B., Zyabrev, V.S., and Drach, B.S., Zh.
Obshch. Khim., 2002, vol. 72, no. 11, p. 1834.
2. Babii, S.B., Zyabrev, V.S., and Drach, B.S., Zh.
Obshch. Khim., 2002, vol. 72, no. 11, p. 1813.
3. Turov, K.B., Babii, S.B., Zyabrev, V.S., and Drach, B.S.,
Zh. Obshch. Khim., 2006, vol. 76, no. 10, p. 1757.
4-Tosyl-2-(4-phenyl-1,3-thiazol-2-yl)-5-phenyl-
thio-1,3-thiazole (IX). To a solution of 3 mmol of
compound VIII in 5 ml of DMF 10 ml of ethanol and
4. Turov, K.B. and Drach, B.S., Zh. Obshch. Khim., 2008,
vol. 78, no.14, p. 648.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 1 2010