Synthesis and some reactions of aryl 4,5-dichloroisothiazol-3-yl ketones

Article abstract of DOI:10.1134/S1070428007100211

By acylation of benzene, toluene, and p-xylene with 4,5- dichloroisothiazole-3-carbonyl chloride the corresponding aryl 4,5-dichloroisothiazol-3-yl ketones were obtained. By reaction of 4,5-dichloroisothiasol-3-yl 4-methylphenyl ketone with piperidine, alkyl(aryl) thiolates, sodium alcoholates, and 2,4-dinitrophenylhydrazine were synthesized 4-methylphenyl 5-piperidyl-4-chloroisothiazol-3-yl ketone, 5-alkyl(aryl) sulfanyl-4-chloroisothiazol-3-yl 4-methylphenyl ketones, 5-alkoxy-4- chloroisothiazol-3-yl 4-methylphenyl ketones, and 2,4-dinitrophenylhydrazone of the initial ketone respectively.

Full text of DOI:10.1134/S1070428007100211

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1532−1536. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © V.I. Potkin, S.K. Petkevich, Yu.S. Zubenko, A.I. Bykhovets, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43,
No. 10, pp. 1536−1540.
Synthesis and Some Reactions of Aryl 4,5-Dichloroisothiazol-3-yl
Ketones
V. I. Potkin, S. K. Petkevich, Yu. S. Zubenko, and A. I. Bykhovets
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, 220072 Belarus
e-mail: potkin@ifoch.bas-net.by
Received March 18, 2007
Abstract—By acylation of benzene, toluene, and p-xylene with 4,5-dichloroisothiazole-3-carbonyl chloride the
corresponding aryl 4,5-dichloroisothiazol-3-yl ketones were obtained. By reaction of 4,5-dichloroisothiasol-3-yl
4-methylphenyl ketone with piperidine, alkyl(aryl) thiolates, sodium alcoholates, and 2,4-dinitrophenylhydrazine
were synthesized 4-methylphenyl 5-piperidyl-4-chloroisothiazol-3-yl ketone, 5-alkyl(aryl)sulfanyl-4-
chloroisothiazol-3-yl 4-methylphenyl ketones, 5-alkoxy-4-chloroisothiazol-3-yl 4-methylphenyl ketones, and
2,4-dinitrophenylhydrazone of the initial ketone respectively.
DOI: 10.1134/S1070428007100211
yield of the corresponding aryl 4,5-dichloroisothiazol-
3-yl ketones III–V was 63–86%.
Functional derivatives of isothiazole exhibit a wide
range of biological action, and therefore the development
is stimulated of studies on the synthesis and properties
of this class compounds [1, 2]. Based on isothiazoles
were obtained in particular efficient antibacterial drugs
[3], highly selective antagonists of 5-HT2Β receptors [4],
immunosupressants [5], and other pharmaceuticals, quite
a number of chemicals for plant protection was also
synthesized [6].
The composition and structure of obtained reaction
products III–V were established from elemental analysis
and IR, 1H NMR, and mass spectra. In the IR spectra of
ketones strong absorption bands of the carbonyl group
are observed in the region 1659–1672 cm–1, the vibrations
of C=C, C=N, and C–C bonds of the isothiazole ring
give rise to three characteristic absorption bands in the
1
range 1349–1579 cm–1. In the H NMR spectra of
In a series of isothiazolyl ketones compounds are
known having the keto group in the positions 4 or 5 of
the heterocycle that are obtained from 4-iodoisothiazoles
[7] and 5-aryl-substituted furans or thiophenes
respectively [8]. Some among the ketones obtained
exhibit high herbicidal activity [1, 2].
compounds III–V appear the multiplets of aromatic
protons in the region 7.27–8.03 ppm and the signals of
methyl substituents at the benzene ring with an
appropriate integral intensity. In the mass spectra of
ketones III–V groups of molecular ion peaks are
observed where the intensity ratio of the main isotope
components (100:65:1.1) indicates the presence in the
ion of two chlorine atoms [10, 11]. The fragmentation of
molecules under the electron impact is characteristic for
isothiazoles [12, 13] involving the cleavage of the
isothiazole ring and elimination of substituents (chlorine
and aryl moieties). The fragmentation process
unambiguously confirms the structure of the synthesized
aryl isothiazolyl ketones.
The target of our study was the development of
synthetic approach to preparation of previously unknown
aryl 4,5-dichloroisothiazol-3-yl ketones with a keto group
in the position 3 of isothiazole ring starting with acyl
chloride obtained from available 4,5-dichloroisothiazole-
3-carboxylic acid (I), whose preparation we had
described formerly [9].
The synthesis of ketones was performed by acylating
arenes with 4,5-dichloroisothiazole-3-carbonyl chloride
(II) under the Friedel–Krafts reaction conditions in the
presence of anhydrous aluminum chloride in
dichloromethane at 40°C. Benzene, toluene, and xylene
were used as arenes. The reaction completed in 2 h, the
It is known that in chlorine-substituted isothiazoles
the most reactive site with respect to nucleophilic
reagents is the position 5 of the heterocycle as compared
to the low reactive position 4 [2]. The molecules of
1532

SYNTHESIS AND SOME REACTIONS OF ARYL 4,5-DICHLOROISOTHIAZOL-3-YL KETONES
1533
ketones obtained contain also a carbonyl group, an addi-
tional reactive site. Therefore the synthesized ketones
III–V are promising compounds for preparation of
isothiazole functional derivatives. We studied the
behavior of the ketones in reactions with some nucleo-
philes by an example of 4,5-dichloroisothiazol-3-yl
4-methylphenyl ketone (IV). Nucleophiles of various
character were applied: 2,4-dinitrophenylhydrazine,
piperidine, thiolates, and sodium alcoholate.
lacked the absorption band of the C=O group of the initial
ketone in the region 1659 cm–1, and absorption bands
appeared characteristic of C=N bond vibrations at
1616 cm–1 and of symmetrical and anisymmetrical
vibrations of N–O bonds in the nitro groups at 1336 and
1518 cm–1. In the 1H NMR spectrum of compound VI
a broadened singlet of amino group appears at δ 11.4 ppm.
The reaction of ketone IV with piperidine at the ratio
ketone:piperidine = 1:2 occurred selectively at the posi-
tion 5 of the heterocycle with the substitution of chlorine
atom and resulted in 4-methylphenyl 5-piperidino-4-
chloroisothiazol-3-yl ketone (VII) in 85% yield.
Piperidine was used in excess to bind the liberated
hydrogen chloride.
The reaction of ketone IV with 2,4-dinitrophenyl-
hydrazine in a water-methanol mixture in the presence
of sulfuric acid took the “classic” route at the carbonyl
group and led to the formation in a preparative yield of
2,4-dinitrophenylhydrazone VI. Obtained compound VI
was identified based on IR and 1H NMR spectra and on
elemental analysis. The IR spectrum of compound VI
The reaction of ketone IV with butyl- and phenyl-
thioles in methanol in the presence of triethylamine also
O
COOH
Cl
Cl
Cl
SOCl2
N
N
Cl
Cl
S
I
S
II
AlCl
O
ArH,
3
NO2
NH
O2N
R1
Cl
H2NNHC6H3(NO2)2
R1
N
N
Cl
III_V
Cl
S
H
N
R3ONa
N
Cl
VI
S
R2SH,
O
MeONa
O
R1
Cl
R1
Cl
O
N
R3O
R1
S
N
Cl
N
X, XI
S
VII
N
R2S
S
VIII, IX
R1 = H (III), 4-Me (IV, VI–XI), 2,5-Me2 (V); R2 = Bu (VIII), Ph (IX); R3 = Me (X), Et (XI).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

POTKIN et al.
1534
occurred at the position 5 of the heterocycle and led to
the formation of the corresponding 4-methylphenyl
5-butylsulfanyl- and 4-methylphenyl 5-phenylsulfanyl-
4-chloroisothiazol-3-yl ketones VIII and IX. However
the yields of these reaction products were relatively low,
15 and 36% respectively. We succeeded in increasing
the yield to 50–60% by raising the thiols nucleophilicity
carrying out the reaction in the presence of equimolar
amount of sodium methylate.
stationary phase (5% PhMe Silicone) 0.25 μm, vaporizer
temperature 250°C.
4,5-Dichloroisothiazole-3-carboxylic acid (I) was
prepared by procedure [9], its acyl chloride II, by method
[14].
Aryl 4,5-dichloroisothiazol-3-yl ketones III–V. To
a complex of 30 mmol of acyl chloride II and 36 mmol
of AlCl3 in 30 ml of anhydrous dichloromethane was
added 75 mmol of an appropriate arene, and the reaction
mixture was stirred for 2 h at 40°C till the end of HCl
evolution, then the mixture was poured into water, the
organic layer was separated, washed with a solution of
sodium hydrogen carbonate, with water, and dried with
magnesium sulfate. On removing the solvent the residue
was purified by recrystallization from hexane
(compounds IV and V) or by column chromatography
on silica gel 100/160 μ, eluent hexane–ether, 6:1 (ketone
III).
Ketone IV cleanly reacted with sodium methylate and
ethylate in the solution of the corresponding alcohol with
substitution of chlorine in the position 5 to provide
5-alkoxy-4-chloroisothiazol-3-yl 4-methylphenyl ketones
X and XI in 70–85% yield. It was established that the
reaction should be performed in an anhydrous alcohol
for even small quantity of water led to significant tarring.
The composition and structure of compounds VII–
XI obtained were established from elemental analysis
and IR, 1H NMR, and mass spectra. In the IR spectra the
vibrations of C=C, C=N, and C–C bonds of the
isothiazole ring give rise to three characteristic absorption
bands in the range 1300–1577 cm–1, the vibrations of
the carbonyl group appear as strong absorption bands in
the region 1663–1668 cm–1. The 1H NMR spectra contain
the signals of aromatic protons and protons of
substituents of an appropriate integral intensity. In the
mass spectra of substances VII–XI groups of molecular
ion peaks are observed where the intensity ratio of the
main isotope components (100:33) indicates the presence
in the molecules of one chlorine atom [10, 11]. The
fragmentation of molecules is characteristic of
isothiazoles involving the cleavage of the isothiazole ring
[13, 14] and elimination of substituents, and it clearly
confirms the structure of compounds VII–XI.
4,5-Dichloroisothiazol-3-yl phenyl ketone (III).
Yield 86%, oily substance. IR spectrum, ν, cm–1: 1672
(C=O), 1598, 1495 (C=C), 1579, 1386, 1351 (isothia-
1
zole), 893 (C–Cl). H NMR spectrum, δ, ppm: 7.56 m
(3Harom), 8.03 m (2Harom). Found, %: C 46.11; H 1.89;
Cl 27.15; N 5.37; S 12.32. [M]+ 257. C10H5Cl2NOS.
Calculated, %: C 46.53; H 1.96; Cl 27.47; N 5.43; S 12.42.
M 258.12.
4,5-Dichloroisothiazol-3-yl 4-methylphenyl)
\ketone (IV). Yield 72%, mp 80–81°C. IR spectrum, ν,
cm–1: 1659 (C=O), 1602, 1506 (C=C), 1564, 1383, 1353
1
(isothiazole), 894 (C–Cl). H NMR spectrum, δ, ppm:
3
2.44 s (3H, CH3), 7.31 d (2Harom, J 7.2 Hz), 7.92 d
(2Harom, 3J 7.2 Hz). Found, %: C 48.90; H 2.84; Cl 26.23;
N 5.21; S 11.52. [M]+ 271. C11H7Cl2NOS. Calculated,
%: C 48.54; H 2.60; Cl 26.05; N 5.15; S 11.78. M 272.15.
Some of ketones synthesized exhibited insecticide
activity and presented an interest for testing them as
chemicals for plant protection.
2,5-Dimethylphenyl 4,5-dichloroisothiazol-3-yl
ketone (V). Yield 63%, mp 37–38°C. IR spectrum, ν,
cm–1: 1668 (C=O), 1613, 1498 (C=C), 1568, 1380, 1349
1
(isothiazole), 927 (C–Cl). H NMR spectrum, δ, ppm:
EXPERIMENTAL
2.35 s (3H, CH3), 2.45 s (3H, CH3), 7.27 d (2Harom
,
3J 7 Hz), 7.31 br.s (1Harom). Found, %: C 50.69; H 3.44;
Cl 24.95; N 4.73; S 11.46. [M]+ 285. C12H9Cl2NOS.
Calculated, %: C 50.36; H 3.18; Cl 24.77; N 4.90;
S 11.20. M 286.18.
IR spectra of compounds were recorded on a Fourier
spectrophotometer Nikolet Protege-460 from samples
pelletized with KBr (substances IV–VII, X, and XI) and
from thin films (compounds III, VIII, and IX). 1H NMR
spectra were registered on a spectrometer Tesla BS-567A
(100 MHz) in CDCl3, internal reference TMS. Mass
spectra were measured on a GC-MS instrument Hewlett-
Packard 5890/5972 in an electron impact mode, electrons
energy 70 eV; capillary column HP-5MS 30 m×0.25 mm,
4,5-Dichloroisothiazol-3-yl 4-methylphenyl ketone
2,4-dinitrophenylhydrazone (VI). In 15 ml of concn.
H2SO4 was dissolved 2.97 g (15 mmol) of 2,4-di-
nitrophenylhydrazine, 20 ml of water and 70 ml of
methanol was addede, to the solution obtained in one
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

SYNTHESIS AND SOME REACTIONS OF ARYL 4,5-DICHLOROISOTHIAZOL-3-YL KETONES
1535
4-Methylphenyl 5-phenylthio-4-chloroisothiazol-
3-yl ketone (IX). Yield 60%, oily substance. IR spectrum,
ν, cm–1: 1665 (C=O), 1604 (C=C), 1577, 1379, 1348
portion was poured a solution of 2.72 g (10 mmol) of
ketone IV in 20 ml of methanol. The mixture was stirred
for 2 h, the separated orange precipitate was filtered off,
washed with water and with ether, and dried in a vacuum.
Yield 4.34 g (96%), orange crystals, mp 206–207°C. IR
spectrum, ν, cm–1: 1616 (C=N), 1565, 1370, 1339
(isothiazole), 1518, 1336 (NO2), 892 (C–Cl). 1H NMR
1
(isothiazole), 892 (C–Cl). H NMR spectrum, δ, ppm:
2.45 s (3H, CH3), 7.40 m (7Harom), 7.97 d (2Harom
,
3J 8 Hz.). Found, %: C 59.28; H 3.76; Cl 10.49; N 4.29;
S 18.87. [M]+ 345. C17H12ClNOS2. Calculated, %:
C 59.03; H 3.50; Cl 10.25; N 4.05; S 18.54. M 345.87.
spectrum, δ, ppm: 2.43 s (3H, CH3), 7.25 d (2Harom
,
,
,
3
3J 8 Hz), 7.93 d (2Harom, J 8 Hz), 8.18 d (1Harom
5-Alkoxy-4-chloroisothiazol-3-yl 4-methylphenyl
ketones X and XI. In 50 ml of an appropriate alcohol
was dissolved 1.4 g (6 mmol) of sodium metal, 1.36 g
(5 mmol) of ketone IV was added, and the mixture
obtained was stirred at 60°C for 10 h, then it was poured
into water, extracted with dichloromethane, and dried
over CaCl2. The solvent was removed, the product was
purified by recrystallization from hexane.
3
3J 9 Hz), 8.52 d.d (1Harom, J 9 Hz), 9.28 d (1Harom
4J 3 Hz), 11.4 br.s (1H, NH). Found, %: C 45.44; H 2.47;
Cl 15.89; N 15.23; S 7.51. C17H11Cl2N5SO4. Calculated,
%: C 45.14; H 2.46; Cl 15.68; N 15.49; S 7.09.
5-Piperidyl-4-chloroisothiazol-3-yl 4-methyl-
phenyl ketone (VII). A solution of 1.36 g (5 mmol) of
ketone IV and 0.85 g (10 mmol) of piperidine in 30 ml
of ethanol was heated at reflux for 12 h, then the mixture
was poured into water, the precipitate was filtered off,
washed with water, and dried in a vacuum. After
recrystallization from hexane the yield was 1.37 g (85%),
mp 112–114°C. IR spectrum, ν, cm–1: 1668 (C=O), 1604,
1572 (C=C), 1524, 1376, 1300 (isothiazole), 895 (C–Cl).
1H NMR spectrum, δ, ppm: 1.70 m (6H, 3CH2C), 2.44 s
(3H, CH3), 3.37 m (4H, 2CH2N), 7.30 d (2Harom, 3J8 Hz),
7.94d(2Harom, 3J8Hz). Found, %:C59.90;H2.84;Cl 26.23;
N 8.53; S 10.14. [M]+ 320. C16H17ClN2OS. Calculated,
%: C 59.99; H 2.97; Cl 26.47; N 8.73; S 9.99. M 320.86.
5-Methoxy-4-chloroisothiazol-3-yl 4-methyl-
phenyl ketone (X). Yield 85%, mp 60–62°C. IR
spectrum, ν, cm–1: 1663 (C=O), 1603, 1532 (C=C), 1570,
1
1378, 1350 (isothiazole), 900 (C–Cl). H NMR spectrum,
δ, ppm: 2.43 s (3H, CH3), 4.16 s (3H, CH3O), 7.29 d
(2Harom, 3J 8 Hz), 7.93 d (2Harom, 3J 8 Hz). Found, %:
C 53.59; H 4.10; Cl 13.38; N 5.25; S 11.50. [M]+ 267.
C12H10ClNO2S. Calculated, %: C 53.83; H 3.77;
Cl 13.24; N 5.23; S 11.97. M 267.74.
4-Methylphenyl 5-ethoxy-4-chloroisothiazol-3-yl
ketone (XI). Yield 70%, mp 69–70°C. IR spectrum, ν,
cm–1: 1667 (C=O), 1605, 1527 (C=C), 1568, 1383, 1351
5-Butyl(phenyl)sulfanyl-4-chloroisothiazol-3-yl
4-methylphenyl ketones VIII and IX. To a solution of
1.36 g (5 mmol) of ketone IV and 5 mmol of an
appropriate thiol in 25 ml of anhydrous methanol was
added dropwise a solution of 5.5 mmol of sodium
methylate in 30 ml of methanol, and the mixture was
stirred at 50°C for 15 h. The formed precipitate of sodium
chloride was filtered off, the filtrate was diluted with
150 ml of water, extracted with chloroform, and dried
over CaCl2. The solvent was removed, the product was
purified by column chromatography on silica gel 100/
160 μ, eluent hexane–ether, 5:1.
1
(isothiazole), 895 (C–Cl). H NMR spectrum, δ, ppm:
1.60 t (3H, CH3, 3J 7 Hz), 2.45 s (3H, CH3), 4.30 q (2H,
CH2O, 3J 7 Hz), 7.31 d (2Harom, 3J 8 Hz), 7.94 d (2Harom
,
3J 8 Hz). Found, %: C 55.73; H 4.55; Cl 12.69; N 4.78;
S 11.44. [M]+ 281. C15H16ClNOS2. Calculated, %: C 55.41;
H 4.30; Cl 12.58; N 4.97; S 11.38. M 281.77.
The study was carried out under a financial support
of the Foundation for Basic Research of Belarus’
Republic (grants nos. X04-003 and XM07-025).
REFERENCES
5-Butylsulfanyl-4-chloroisothiazol-3-yl 4-methyl-
phenyl ketone (VIII). Yield 50%, oily substance. IR
spectrum, ν, cm–1: 1666 (C=O), 1605 (C=C), 1564, 1380,
1.Hamad, Elgazwy, A.-S.S., Tetrahedron, 2003, vol. 59,
p. 7445.
2.Kaberdin, R.V., Potkin, V.I., Usp. Khim., 2002, vol. 71,
p. 764.
3.Hara, R., Nakai, E., Hisamichi, H., Nagano, N., J. Antibiot.,
1994, vol. 47, p. 477.
4.Forbes, I.T., Ham, P., Booth, D.H., Martin, R.T., Thomp-
son, M., Baxter, G.S., Blackburn, T.P., Glen, A., Ken-
net, G.A., Wood, M.D., J. Med. Chem., 1995, vol. 38,
1
1345 (isothiazole), 890 (C–Cl). H NMR spectrum, δ,
3
ppm: 0.93 t (3H, CH3, J 6 Hz), 1.50 m (4H, 2CH2C),
3
2.44 s (3H, CH3), 2.72 t (2H, CH2S, J 7 Hz), 7.30 d
(2Harom, 3J 8 Hz), 7.93 d (2Harom, 3J 8 Hz). Found, %:
C 55.49; H 4.80; Cl 10.97; N 4.35; S 19.50. [M]+ 325.
C15H16ClNOS2. Calculated, %: C 55.28; H 4.96; Cl
10.88; N 4.30; S 19.68. M 325.89.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

POTKIN et al.
Trans. 1, 1997, p. 2247; Laaman, S.M., Meth-Cohn, O.,
1536
p. 2524.
and Rees, Ch.W., Synthesis, 1999, p. 757; Duan, X.-L. and
Rees, Ch.W., J. Chem. Soc., Perkin Trans. 1, 1997, p. 3189.
9.Kaberdin, R.V., Potkin, V.I., and Ol’dekop, Yu.A., Zh. Org.
Khim., 1990, vol. 26, p. 1560.
10. Takhistov, V.V., Prakticheskaya mass-spektrometriya
organicheskikh soedinenii (Practical Mass Spectrometry
of Organic Compounds), Leningrad: Izd. Leningrad. Gos.
Univ., 1977, p. 265.
11. Takhistov, V.V., Rodin, A.A., and Maksimova, B.N., Usp.
Khim., 1991, vol. 60, p. 2143.
12. Poite, J.C., Vivaldi, R.V., and Bonzom, A., C.r., 1969,
vol. 268, p. 12.
5.Lipnicka, U., Machon, Z., Acta Pol. Pharm., 1997,
vol. 54, p. 207.
6.Munster, P., Schefczik, E., Konig, H., Gerber, M.,
Westphalen, K-O., and Walter, H., German Patent 4328425,
1995; Ref. Zh. Khim., 1997, 14O398P; Yoshikawa, Y.,
Kawashima, H., Inami, S., Tomura, N., and Kishi, I., Japan
Patent 08-277276, 1996; Chem. Abstr., 1997, vol. 126,
47213g; Newton, T.W., Europe Patent 761654, 1995;
Chem. Abstr., 1997, vol. 126, 277469z; Anderson, R.J.,
Cloudsdale, I.S., Lamo-reaux, R.J., Schaefer, K., and
Harr, J., US Patent 5888937, 1997; Ref. Zh. Khim., 2000,
11O431P.
7.Guilloteau, F. and Miginiac, L., Synth. Commun., 1995,
p. 1383.
8.Rees, Ch.W. and Yue, T.-Y., J. Chem. Soc., Perkin
13. Naito, T., Tetrahedron, 1968, vol. 24, p. 6237.
14. Nechai, N.I., Dikusar, E.A., Potkin, V.I., and Kaber-
din, R.V., Zh. Org. Khim., 2004, vol. 40, p. 1050.
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