Synthesis of 4,5-dichloro-3-cyanoisothiazole and its functional derivatives

Article abstract of DOI:10.1134/S1070428008070154

By treating with phosphorus pentoxide the 4,5-dichloroisothiazole-3- carboxamide 4,5-dichloro-3-cyanoisothiazole was synthesized whose reactions with piperidine, phenyl-and benzylthiols occurred with replacement of the chlorine atom in the position 5 by t

Full text of DOI:10.1134/S1070428008070154

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 7, pp. 1038−1042. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.I. Potkin, Yu.S. Zubenko, N.I. Nechai, A.I. Bykhovets, P.V. Kurman, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 7, pp. 1048−1052.
Synthesis of 4,5-Dichloro-3-cyanoisothiazole
and Its Functional Derivatives
V. I. Potkin, Yu. S. Zubenko, N. I. Nechai, A. I. Bykhovets, and P. V. Kurman
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, 220072 Belarus
e-mail: potkin@ifoch.bas-net.by
Received November 13, 2007
Abstract—By treating with phosphorus pentoxide the 4,5-dichloroisothiazole-3-carboxamide 4,5-dichloro-3-
cyanoisothiazole was synthesized whose reactions with piperidine, phenyl- and benzylthiols occurred with
replacement of the chlorine atom in the position 5 by the residue of the corresponding nucleophile. Reactions
with sodium thiobytylate and also with sodium methylate in methanol led to the formation both of the products of
chlorine substitution by BuS or MeO groups respectively and of addition products of methanol to the cyano
group. The reaction of butanethiol with cyanoisothiazole in 2-propanol in the presence of sodium 2-propylate
was more selective and resulted in the replacement of the chlorine atom in the position 5 by the residue of the
butanethiol.
DOI: 10.1134/S1070428008070154
established that the reaction could be carried out both
by heating the reagents without solvent at 110–120°C
and by boiling the reagents mixture in perchloroethylene.
In both cases the process was completed in 1 h, and the
yield of nitrile I was 95%.
The stable interest to the synthesis of functionally-
substituted isothiazole is stimulated by the high biological
activity of many among these compounds. A large part
of recent publications consists of patent on preparation
and application of isothiazoles as agricultural reagents
and pharmaceuticals of versatile range of application
[1, 2].
A popular procedure for nitriles preparation by
treating amides with the thionyl chloride in DMF in our
case proved to be less acceptable: The reaction proceeded
slowly, was accompanied with considerable tarring, and
the yield of nitrile I did not exceed 50%.
The functionalization of isothiazole ring is one of the
most reasonable ways to the synthesis of new compounds
promising for testing their biological action. Functional
derivatives of isothiazoles possessing a cyano group in
the position 4 of the heterocycle are known to exhibit
fungicidal, insecticide, and bactericidal activity [3–5].
No published data are available on the preparation and
properties of 3-cyano-substituted isothiazoles.
The formation in the reaction of cyanoisothiazole I
was confirmed by the presence in its IR spectrum of the
characteristic absorption band of the C≡N group at 2246
cm–1. In the 13C NMR spectrum of compound I lacked
the signal of the carbon atom of the amide group of the
initial compound II at 161.2 ppm and appeared the signal
of cyano group at δ 111.8 ppm and also three signals
with the chemical shifts 128.3, 139.7, and 151.7 ppm
belonging to carbon atoms of the heterocycle.
The target of our research consisted in the develop-
ment of preparation procedure of 4,5-dichloro-3-cyano-
isothiazole (I) and its heteroatomic derivatives. We chose
as an initial compound the available 4,5-dichloro-
isothiazole-3-carboxamide (II) [6]. 4,5-Dichloroiso-
thiazole-3-carboxylic acid is the reioisomer we have
formerly synthesized of 3,4-dichloroisothiazole-5-carb-
oxylic acid whose derivatives are endowed with a wide
range of pesticide action [7, 8].
The exhaustive proofs of the nitrile structure were
obtained by mass spectrometry. The mass spectrum of
compound I contained a group of molecular ion peaks
where the intensity ratio of isotope components
(100:65:10) indicated the presence in the molecule of
two chlorine atoms [9, 10]. The fragmentation of the
molecular ion occurred in the way characteristic of
The synthesis of cyanoisothiazole I was performed
by treating amide II with phosphorus pentoxide. It was
1038

SYNTHESIS OF 4,5-DICHLORO-3-CYANOISOTHIAZOLE
1039
N
N
Cl
Cl
N
N
N
S
RS
NH
Cl
S
IV,V
III
HN
N
O
N
N
Cl
Cl
Cl
NH2
OMe
BuSH_MeONa
MeOH
P2O5
+
N
N
N
Cl
BuS
BuS
Cl
S
S
S
S
II
I
VI
VII
HN
N
N
+
Cl
Cl
OMe
N
MeO
MeO
S
S
VIII
IX
S
Cl C C Cl +
NC CN+
+
.
+
Cl
CN
À
B
N
N
+
Cl
+
S
+
Cl C C CN
Cl C
S
C
D
isothiazoles by decomposition of the heterocycle to give
ions A–D [11, 12]. The most abundant were in the
spectrum the molecular ion peaks (m/z 178, Irel 100%),
those of the sulfur-containing ions A (m/z 126, Irel 44%)
and C (m/z 79, Irel 64%), and also of products of chlorine
elimination from these ions. The peaks of nitrogen-
containing ions B and D are of low intensity. (Here and
hereinafter the m/z values for the chlorine-containing ions
are given for the components with the isotope 35Cl).
at 40°C occurred with the substitution of the chlorine
atom in the position 5 of the heterocycle and resulted in
5-piperidin-1-yl-4-chloro-3-cyanoisothiazole (III) in
53% yield. The piperidine excess served for bonding the
evolved hydrogen chloride.
The reaction with phenyl- and benzylthiols in
methanol in the presence of sodium methylate at the
equimolar reagenta ratio at room temperature also
proceeded at the position 5 of the isothiazole molecule
and led to the formation of the corresponding 5-(phenyl-
thio)- and 5-(benzylthio)-4-chloro-3-cyanoisothiazoles
(IV and V) in 64–67% yields.
We investigated the reactions of synthesized nitrile I
with nucleophiles of different character. The reaction of
nitrile I with a double excess of piperidine in methanol
N _
NH
R C
OMe
MeO_
MeOH
R C N + MeO_
R C
OMe
R = Ph (IV), Bn (V).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

POTKIN et al.
1040
The direction of nitrile I reaction with butanethiol
protolysis constant and larger proton affinity than
methanol [15] the content of anions i-PrO– in the reaction
mixture is significantly lower and consequently the
content of thiobutylate anions higher favoring the
replacement of chlorine and impeding the reaction at the
cyano group.
strongly depended on the nature of alcohol and alcoholate
whereas for phenyl- and benzylthiols this was
insignificant. For instance, the reaction of butanethiol
with nitrile I in methanol solution in the presence of
sodium methylate occurred nonselectively giving a mix-
ture of products where alongside the expected product
of chlorine replacement, 5-(butylthio)-4-chloro-3-cyano-
isothiazole (VI) methyl 5-(butylthio)-4-chloroisothiazol-
3-imidocarboxylate (VII) was identified. Overall yield
of compounds VI and VII was 54%, and their ratio in
the mixture was ~ 1:2. The reaction of butanethiol with
nitrile I in 2-propanol solution in the presence of sodium
2-propanolate proceeded relatively selectively and
provided in 68% yield 5-(butylthio)-4-chloro-3-cyano-
isothiazole (VI) isolated in an individual state. Com-
pounds VI and VII obtained in methanol were not
separated, and their formation was confirmed by the data
The composition and structure of obtained com-
pounds III–VI were established from elemental analyses,
IR, 1H NMR, and mass spectra. In the IR spectra of the
compounds the C≡N group gave rise to the absorption
band in the region 2240–2247 cm–1, the C=C and C=N
of isothiazole ring, to three characteristic bands in the
range 1313–1528 cm–1. In the 1H NMR spectra of com-
pounds III–VI the signals of hydrogen-containing
fragments of the molecules appeared with the appropriate
multiplicity and integral intensity. The mass spectra of
compounds III–VI contained the molecular ion peaks
with the ratio of isotope components (100:33)
corresponding to the presence in the molecules of a single
chlorine atom [9, 10]. The fragmentation of molecular
ions under the electron impact proceeded in a complex
way with elimination of substituents, their fragments,
and with the cleavage of the isothiazole ring. The
maximum abundance in the spectra of alkyl(aryl)thio
derivatives IV–VI have the molecular ion peaks with
m/z 252, 266, and 232 respectively. In the mass spectrum
of compound III the most abundant peak corresponded
to the piperidine residue (m/z 84), and the intensity of
the molecular ion peak with m/z 227 was 65%.
1
of GC-MS, IR, and H NMR spectra of the reaction
mixture after its vacuum distillation, and also by
comparison of the sprctra of mixture with those of
individual compound VI. In the mass spectrum of the
mixture appeared the peaks of molecular ions with m/z
232 and 264 corresponding to compounds VI and VII
respectively. The intensity ratio of the isotope peaks of
molecular ions equal 100:33 confirmed the presence in
the molecules of a single chlorine atom [9, 10]. In IR
spectrum of compounds VI and VII mixture alongside
the absorption band of cyano group of compound VI at
2246 cm–1 absorption bands were present of N–H bonds
(3425 cm–1) and C=N (1637 cm–1) of ester VII. In the
1H NMR spectrum of the mixture alongside the signals
of the butyl groups a broadened singlet was observed at
7.15 ppm and a singlet at δ 4.10 ppm belonging
respectively to imido and methoxy groups of compound
VII.
We presumed that the reaction of nitrile I with sodium
methylate in methanol should also occur not only with
the substitution of a chlorine atom, but also with methanol
addition to the C≡N bond.Actually, the reaction of nitrile
I with MeONa in methanol solution resulted in the
formation of two main products: 5-methoxy-4-chloro-3-
cyanoisothiazole (VIII) and methyl 5-methoxy-4-
chloroisothiazol-3-imidocarboxylate (IX) in a ratio 1:3
and overall yield 40%. Compounds VIII and IX were
identified by GC-MS method, and also based on IR and
1H NMR spectra of the reaction mixture after its vacuum
distillation.
The formation of the addition product of MeOH to
the cyano group in the reaction of nitrile I with
butanethiol is apparently due to the higher basicity of
anion BuS– compared with anions PhS– and BnS– [13]
resulting in higher concentration of methoxy anions in
the mixture and catalyzing the methanol reaction at the
cyano group occurring through primary reversible addi-
tion of the methylate anion to the C≡N bond and giving
finally imidoester VII [14].
In the mass spectra of the mixture resulting from the
reaction molecular ion peaks of compounds VIII and
IX were present with m/z 174 and 206 respectively and
the ratio of isotope components (100:33), corresponding
to the presence of a single chlorine atom in the molecule.
The effect of the alcohol nature on the mode of the
nitrile reaction with butanethiol may be ascribed to the
difference in the acid-base properties of the alcohols. In
2-propanol possessing considerably smaller auto-
1
The H NMR spectrum of the mixture contained three
singlets at 4.35, 4.25, and 3.92 ppm where the first one
belonged to MeO group of compound VIII, and the other
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

SYNTHESIS OF 4,5-DICHLORO-3-CYANOISOTHIAZOLE
1041
5-Piperidyl-4-chloro-3-cyanoisothiazole (III).
A solution of 0.9 g (5 mmol) of nitrile I and 0.93 g
(11 mmol) of piperidine in 20 ml of methanol was stirred
at 40°C for 10 h, then it was poured on ice, the precipitate
was filtered off, washed with water, and dried in
a vacuum. After recrystallization from a mixture ether–
hexane, 1:3, yield was 0.61 g (53%), mp 103–104°C. IR
spectrum, ν, cm–1: 2240 (C≡N), 1528, 1390, 1313 (C=C,
two, to methoxy groups of imidoester IX. The integral
intensities of singlets at 4.25 and 3.92 ppm are equal,
and the intensity of the singlet at δ 4.35 ppm is three
times less than each of them in agreement with the data
of GC-MS analysis. The presence of =NH group in the
structure of compound IX is confirmed by the appearance
1
in the H NMR spectrum of a broadened singlet at
δ 8.5 ppm. In the IR spectrum of the products mixture
alongside the absorption bands of the isothiazole ring in
the region 1313–1532 cm–1 the absorption bands are
observed of C=N (1621 cm–1) and NH (3456 cm–1) bonds
characterizing the molecular fragments of imidoester IX.
The presence in the mixture of methoxy-substituted
nitrile VIII is confirmed by the weak absorption band of
C≡N bond in the region 2248 cm–1.
1
C=N of isothiazole). H NMR spectrum, δ, ppm: 1.8–
2.1 m (6H, 3CH2C), 3.3–3.6 m (4H, 2CH2N). Found, %:
C 47.83; H 4.58; Cl 15.85; N 18.29; S 14.02. [M]+ 227.
C9H10ClN3S. Calculated, %: C 47.47; H 4.43; Cl 15.57;
N 18.45; S 14.08. M 228.
5-[Phenyl(benzyl)thio]-4-chloro-3-cyanoiso-
thiazoles IV and V. To a solution of 0.9 g (5 mmol) of
nitrile I and 5 mmol of an appropriate thiol in 20 ml of
methanol was added dropwise 0.27 g (5 mmol) of sodium
methylate in 15 ml of methanol; the mixture was stirred
for 8 h at 20–25°C. The precipitate was filtered off, the
filtrate was evaporated in a vacuum to dryness and
washed with water. The obtained reaction product was
purified by recrystallization from a mixture ether–hexane,
1:3.
Some of compounds obtained show insecticide
activity and are interesting for further investigation as
chemical agents for plant protection.
EXPERIMENTAL
IR spectra of compounds were recorded on a Fourier-
'
'
spectrophotometer Nikolet Protege-460 from samples
1
pelletized with KBr. H and 13C NMR spectra were
5-(Phenylthio)-4-chloro-3-cyanoisothiazole (IV).
Yield 67%, mp 75–76°C. IR spectrum, ν, cm–1: 2242
(C≡N), 1441, 1378, 1356 (C=C, C=N of isothiazole).
1H NMR spectrum, δ, ppm: 7.4–7.6 m (5H, Ph). Found,
%: C 47.70; H 1.84; Cl 14.32; N 11.17; S 25.31. [M]+
252. C10H5ClN2S2. Calculated, %: C 47.52; H 1.99;
Cl 14.03; N 11.09; S 25.37. M 252.73.
registered on a spectrometer Avance-500 in CDCl3.
Chemical shifts of protons were measured with respect
to TMS, of carbon atoms, related to CDCl3 signal (δ 77.0
ppm). Mass spectra were obtained on a GC-MS
instrument Hewlett Packard 5890/5972 in the electron
impact mode at ionizing electrons energy 70 eV; capillary
column HP-5MS 30 m × 0.25 mm, stationary phase (5%
PhMe Silicone) 0.25 μm, vaporizer temperature 250°C.
5-(Benzylthio)-4-chloro-3-cyanoisothiazole (V).
Yield 64%, mp 63–64°C. IR spectrum, ν, cm–1: 2247
(C≡N), 1452, 1380, 1347 (C=C, C=N of isothiazole).
1H NMR spectrum, δ, ppm: 4.55 s (2H, CH2S), 7.4–
7.6 m (5H, Ph). Found, %: C 49.83; H 2.89; Cl 13.32;
N 11.17; S 25.31. [M]+ 266. C11H7ClN2S2. Calculated,
%: C 49.52; H 2.65; Cl 13.29; N 10.50; S 24.04.
M 266.76.
4,5-Dichloroisothiazole-3-carboxamide (II) was
prepared by procedure [6].
4,5-Dichloro-3-cyanoisothiazole (I). A mixture of
2 g (10 mmol) of dichloroisothiazole-3-carboxamide (II)
and 1.42 g (10 mmol) of phosphorus pentoxide was
heated for 1 h at 110–120°C, then the reaction mixture
was cooled to room temperature and extracted with
dichloromethane. The extract was washed with water,
dried with CaCl2, the solvent was removed, the solid
reaction product was purified by sublimation in a vacuum
(1 mm Hg). Yield 1.71 g (95%), mp 43–44°C. IR
spectrum, ν, cm–1: 2246 (C≡N), 1482, 1377, 1351 (C=C,
C=N of isothiazole), 972 (C–Cl). 13C NMR spectrum,
δ, ppm: 111.79 (C≡N), 128.25, 139.72, 151.67 (carbon
atoms of heterocycle). Mass spectrum, m/z (Irel, %): 178
(100) [M]+, 126 (44), 99 (4), 91 (53), 79 (64), 64 (5), 56
(17), 52 (5).
5-(Butylthio)-4-chloro-3-cyanoisothiazole (VI) was
prepared similarly but the nitrile reaction with butanethiol
was carried out in 2-propanol in the presence of sodium
2-propylate for 12 h. Yield 68%, mp 165–167°C. IR
spectrum, ν, cm–1: 2246 (C≡N), 1486, 1383, 1353 (C=C,
1
C=N of iso-thiazole). H NMR spectrum, δ, ppm: 0.97 t
(3H, CH3), 1.48–1.53 m (2H), 1.73–1.77 d.t (2H, CH2C),
3.06 t (2H, CH2S, 3J 7.5 Hz). Found, %: C 41.56; H 4.15;
Cl 15.42; N 12.11; S 27.62. [M]+ 232. C8H9ClN2S2.
Calculated, %: C 41.28; H 3.90; Cl 15.23; N 12.04;
S 27.55. M 232.74.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

POTKIN et al.
1042
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The study was carried out under a financial support
8. Ishikawa, K., Tanigawa, H., Kawashima, H., Kanemo-
to, Y., Shimotori, H., Yarase, J., Sekino, T., Tomura, N.,
and Kuwazuka, T., Japan Patent 05-59024, 1993; Chem.
Abstr., 1993, vol. 119, 117242kh.
of the Foundation for Basic Research of Belarus’
Republic (grant no. X04-003).
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