Synthesis of novel 3,5-disubstituted-4-isothiazolecarbonitriles

Article abstract of DOI:10.1081/SCC-200025636

α-Cyano-β-enaminones, obtained by regioselective acylation of β-enaminonitriles, were smoothly converted to thiones which on oxidative cyclization afforded 3,5-disubstituted-4-isothiazolecarbonitriles in good to excellent yields.

Full text of DOI:10.1081/SCC-200025636

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Synthesis of Novel
3,5‐Disubstituted‐4‐isothiazolecar
Manisha Mishra a , S. K. Dutta Chowdhury a b
Kumar K. Mahalanabis a
&
a Department of Chemistry , Jadavpur University ,
Kolkata, 700 032, India
b Jogesh Chandra Chaudhuri College , Kolkata,
India
Published online: 12 Jan 2011.
To cite this article: Manisha Mishra , S. K. Dutta Chowdhury & Kumar K.
Mahalanabis (2004) Synthesis of Novel 3,5‐Disubstituted‐4‐isothiazolecarbonitriles,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:14, 2681-2689, DOI: 10.1081/SCC-200025636
To link to this article: http://dx.doi.org/10.1081/SCC-200025636
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 14, pp. 2681–2689, 2004
Synthesis of Novel 3,5-Disubstituted-
4-isothiazolecarbonitriles
Manisha Mishra,1 S. K. Dutta Chowdhury,1,2 and
Kumar K. Mahalanabis1,
*
1Department of Chemistry, Jadavpur University, Kolkata, India
2Jogesh Chandra Chaudhuri College, Kolkata, India
ABSTRACT
a-Cyano-b-enaminones, obtained by regioselective acylation of b-
enaminonitriles, were smoothly converted to thiones which on oxidative
cyclization afforded 3,5-disubstituted-4-isothiazolecarbonitriles in good
to excellent yields.
Key Words: a-Cyano-b-thioenaminones; b-Enaminonitriles; Lawes-
son’s reagent; 3,4,5-Trisubstitutedisothiazoles.
INTRODUCTION
Mononuclear isothiazoles were unknown until 1956 when Adam
and Slack[1] obtained isothiazole-4,5-dicarboxylic acid by the oxidation of
*
Correspondence: Kumar K. Mahalanabis, Department of Chemistry, Jadavpur Uni-
versity, Kolkata 700 032, India; E-mail: kkmahalanabis@yahoo.co.in.
2681
DOI: 10.1080/SCC-200025636
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2682
Mishra, Chowdhury, and Mahalanabis
5-aminobenz[d]isothiazole. Since then synthesis, properties and applications of
isothiazoles have been extensively reviewed.[2] Isothiazole containing penicil-
lins and cephalosporins competed quite successfully with ampicillin.[3,4] Isothia-
zole analogs were also synthesized and tested in vitro for muscaranic receptor
activity and M1 efficacy.[5] Isothiazole derivatives are also known to act as estro-
gen synthetase inhibitors.[6] Isothiazole derived compounds are also used as
protectors for polymers, dyes, detergents, and leather goods, for decontamina-
tion of pigments, latexes, food stuffs, and stabilizer for photomaterials.[7]
Further to these applications, isothiazoles have also been reported to exhibit
insecticidal,[8] fungicidal,[9] and insect repellant[10] activities.
The most frequently used methods for construction of isothiazole ring
consists of cyclization of compounds containing preformed N–C–C–C–S
fragments. Thus, various isothiazole derivatives are prepared either by the
oxidative cyclization of 2-aminoalk-1-enethiocarboxyamides[11,12] or thioacyl-
ation of suitably substituted enamines followed by oxidative ring closure.[13]
But these methods suffer from the lack of variants particularly at C-5 and gen-
erally result in poor yields. Thioenaminones were converted to isothiazoles[14]
by treatment with hydroxylamine-O-sulfonic acid (HAS). But this approach is
severely limited to 5-aryl substituents only as the enaminones[15] were pre-
pared from aryl methyl ketones. In addition, this approach does not allow
incorporation of nitrile function at C-4.
Recent observation[16] that 3-methylthio-5-aryl-4-isothiazolecarbonitriles
show good activity against polio1 and ECHO 9 prompted us to develop a
general method for synthesis of 4-isothiazolecarbonitriles with built-in
scope for variation of substituents at C-3 and C-5 positions of isothiazole
ring. In spite of limitations thioenaminones appear to be attractive precursor
for synthesis of isothiazoles in view of their easy availability and simplicity
of oxidative cyclization. It occurred to us that limitations inherently associated
with thioenaminones prepared from aryl methyl ketones can be easily
removed if thioenaminones are prepared from a-acyl-b-enaminonitriles.
However, a severe constraint to this apparently simple approach is the lack
of a general procedure for regioselective preparation of C-acyl enaminoni-
triles.[17] Recently, we have described[18,19] regioselective acylation of enam-
inonitriles with a variety of acid chlorides in the presence of an added organic
base. Herein, we report preparation of a series of 3,5-disubstituted-4-isothia-
zolecarbonitriles 3 via oxidative cyclization of a-cyano-b-thioenaminones 2
(Sch. 1) derived from a-cyano-b-enaminones 1.[19] The structures of all these
compounds 2a–l and 3a–l are firmly secured by elemental and spectral ana-
lyses. In our case, thionation is best achieved by Lawesson’s reagent (LR).[20]
m-Chloroperbenzoic acid, hydrogen peroxide, and bromine were also used
for oxidative cyclization of thioenaminone 2e, whereby isothiazole 3e was
obtained in 84%, 82%, and 78% yields, respectively. Although hydrogen

Synthesis of Novel 3,5-Disubstituted-4-isothiazolecarbonitriles
2683
Scheme 1.
peroxide took longer time it was preferred over other reagents in view of
its easy availability, operational simplicity, and comparable yield with
m-chloroperbenzoic acid.
In conclusion, ready availability of diversely substituted thioenaminoni-
triles 2a–l (Table 1) offers an excellent opportunity to prepare 3,5-disubsti-
tuted-4-isothiazolecarbonitriles 3a–l with excellent control of regiospecificity.
In view of the inherent flexibility incorporated in the synthetic design, substitu-
ents at C-5 of isothiazole can be alkyl groups 3a–c, phenoxyalkyl groups 3d–e,
heteroaromatic groups 3g–h, as well as aryl group 3f. Variation in the nature
of C-5 substituents can also occur in the form of conjugated double bond and
triple bond unsaturation in the side chain, 3i and 3j which by themselves can
generate new functionality. Furthermore, variation of substituent at C-3 can
also be achieved by choice of appropriate enamines, 3k and 3l. It is pertinent
Table 1. Compounds 2a–l prepared.
M.p.
(8C)
Yielda
(%)
Compound
R
R1
2a
2b
2c
2d
2e
2f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
CH2CH3
152–154
130–131
64–65
70
68
65
75
78
58
62
64
48
45
55
59
CH2CH2CH3
CH2OC6H5
CH2OC6H3Cl2(2,4)
p-NO2C6H4
2-Furyl
115–116
156–157
205–207
131–132
139–141
176–177
193–195
179–180
190–192
2g
2h
2i
2-Thienyl
(CH55CH)2–C6H5
;;
C C–C6H5
CH3
2j
2k
2l
p-CH3OC6H4
CH3
aYields of isolated products.

2684
Mishra, Chowdhury, and Mahalanabis
to note that 5-alkenylisothiazoles were recently prepared[21] from 3,4,5-tribro-
moisothiazoles by cross coupling with terminal alkynes in poor to moderate
yield contaminated with undesirable byproducts. In conjunction with Krebs’
work[22] which allows introduction of various nucleophilic substituents at C-5
of 3-phenyl-5-thioalkylisothiazole-4-carbonitriles, the present work offers
unlimited opportunity for direct introduction of various non-nucleophilic substi-
tuents at C-5 position of 4-cyanoisothiazoles.
When compared with the literature documented methods[12,14,23–25] for
preparation of 4-cyano/carboxyisothiazoles, the present procedure allows
an extremely simple and highly flexible synthesis of cyanoisothiazoles with
novel variants at C-5 position which are otherwise difficult to prepare in
good to excellent yields.
EXPERIMENTAL
Melting points were determined in open capillaries. Solid compounds were
crystallized from ethyl acetate-pet. ether (60–808). IR spectra were taken in
1
Hitachi 270-30 spectrometer, H NMR and 13C NMR spectra were recorded
in Bruker DPX-300 and DPX-400 spectrometers using CDCl3 as solvent and
TMS as internal standard. Mass spectra were recorded in JEOL JMS 600 and
ANY I 08-LCMS spectrometers. Elemental analyses were done in PERKIN-
ELMER 240C Elemental Analyzer. Reported yields were of isolated materials.
a-Cyano-b-enaminones[19] and LR[26] were prepared following pro-
cedures described earlier.
General Procedure for the Preparation of
a-Cyanothioenaminones (2)
A mixture of cyanoenaminone (0.01 mol), LR (0.005 mol), and dry benzene
(40 mL) were refluxed slowly under nitrogen (4–6 hr). The course of the reac-
tion was monitored by TLC. Benzene was distilled off. The yellow mass thus
obtained was purified by column filtration (silica gel, 60–120 mesh, 5–10%
ethyl acetate–pet. ether). Removal of solvent gave solid materials which on
crystallization from a suitable solvent afforded pure products.
General Procedure for the Preparation of Isothiazoles (3)
To a solution of thioenaminone (0.001 mol) in ether (10 mL), hydrogen
peroxide (30% w/v, 10 mL) was added with continuous stirring at room

Synthesis of Novel 3,5-Disubstituted-4-isothiazolecarbonitriles
2685
temperature. On completion of addition of hydrogen peroxide stirring was
allowed to continue for 48 hr. The course of the reaction was monitored by
TLC. The reaction mixture was extracted with ether (3 ꢀ 10 mL) and
washed sequentially with water, dilute sodium bicarbonate solution and
brine. Organic layer was dried over anhydrous sodium sulphate. Removal of
the solvent afforded the desired product. The solid material thus obtained
was crystallized from suitable solvent and the liquid material was purified
by column filtration (silica gel, 60–120 mesh, 5–10% ethyl acetate-pet.
ether) and the purity of the liquid compounds were determined by observing
single GC peak.
Representative Spectral Data of Selected Compounds
1
2c. Yellow crystal. IR (KBr): cm21 3320, 2940, 2198, 1632, 1225. H
NMR (CDCl3, 300 MHz): d 1.0 (t, J 7.4 Hz, 3H, CH3), 1.8 (m, 2H,
CH2CH3), 2.45 (s, 3H, C55CCH3), 3.15 (t, J 7.4 Hz, 2H, CH2CH2CH3),
6.75 (bs, 1H, NHa), 13.5 (bs, 1H, NHb). 13C NMR (CDCl3, 75 MHz): d
13.96, 24.22, 24.94, 54.25, 97.02, 118.83, 169.95, 224.2. m/z (%): 168
(Mþ, 98), 135 (100). Anal. calcd for C8H12N2S (168.25): C, 57.11; H, 7.19;
N, 16.65. Found: C, 57.23; H, 7.20; N, 16.58.
1
2e. Yellow crystal. IR (KBr): cm21 3357, 2940, 2208, 1626, 1211. H
NMR (CDCl3, 300 MHz): d 2.48 (s, 3H, CH3), 5.15 (s, 2H, CH2), 6.80 (d, J
8.75 Hz, 1H, Ar60H), 6.88 (bs, 1H, NHa), 7.11 (dd, J 1.38 and 8.75 Hz, 1H,
Ar50H), 7.37 (d, J 1.38 Hz, 1H, Ar30H), 13.46 (bs, 1H, NHb). 13C NMR
(CDCl3, 75 MHz): d 24.42, 78.51, 96.50, 115.18, 117.56, 123.50, 126.58,
127.35, 130.16, 152.42, 171.04, 211.99. m/z (%): 300 (Mþ, 10.70), 302
(7.5), 304 (1.54), 139 (100). Anal. calcd for C12H10Cl2N2OS (301.18): C,
47.85; H, 3.35; N, 9.03. Found: C, 47.76; H, 3.37; N, 9.11.
2g. Red crystal. IR (KBr): cm21 3209, 2853, 2195, 1636, 1581, 1427,
1
1304, 1259. H NMR (CDCl3, 300 MHz): d 2.53 (s, 3H, CH3), 6.54 (dd, J
1.7 and 3.5 Hz, 1H, b-H of furan ring), 6.80 (bs, 1H, NHa), 7.47 (d, J
3.5 Hz, 1H, b0-H of furan ring), 7.66 (d, J 1.7 Hz, 1H, a-H of furan ring).
13.69 (bs, 1H, NHb). m/z (%): 192 (Mþ, 13), 191 (100). Anal. calcd for
C9H8N2SO (192.17): C, 56.25; H, 4.20; N, 14.58. Found: C, 56.64; H, 4.24;
N, 14.62.
2i. Red solid. IR (KBr): cm21 3256, 2914, 2194, 1670, 1574, 1445, 1265.
1H NMR (CDCl3, 300 MHz): d 2.53 (s, 3H, CH3), 7.14 (d, J 15.3 Hz, 1H,
CH-Ph), 7.29–7.64(m, 8H, CH55CH–CH55 and ArH), 10.35 (bs, 1H, NHa),
13.37 (bs, 1H, NHb). 13C NMR (CDCl3, 75 MHz): d 23.40, 96.67, 119.14,
127.28, 127.96, 128.82, 128.95, 135.24, 136.36, 140.62, 143.39, 172.36,

2686
Mishra, Chowdhury, and Mahalanabis
202.37. m/z (%): 254 (Mþ, 100). Anal. calcd. for C15H14N2S (254.27): C,
70.84; H, 5.95; N, 11.02. Found: C, 69.98; H, 6.02; N, 11.06.
3,5-Dimethyl-4-isothiazolecarbonitrile (3a). White crystal. Yield:
70%. M.p.: 558C (literature[13] 568C). IR (KBr): cm21 3660, 2948, 2224,
1
1668, 1530, 1502. H NMR (CDCl3, 300 MHz): d 2.57 (s, 3H, C55CCH3),
2.71 (s, 3H, CH3). m/z (%): 138 (Mþ, 100). Anal. calcd for C6H6N2S
(138.18): C, 52.15; H, 4.38; N, 20.27. Found: C, 51.93; H, 4.40; N, 20.31.
5-Ethyl-3-methyl-4-isothiazolecarbonitrile (3b). Liquid. Yield 64%.
B.p.: 80–848C/7 mm. IR (neat): cm21 3294, 2960, 2226, 1624,1423, 1373.
1H NMR (CDCl3, 300 MHz): d 1.41 (t, J 7.0 Hz, 3H, CH3), 2.57 (s, 3H,
C55CCH3), 3.10 (q, J 7.0 Hz, 2H, CH2CH3). m/z (%): 152 (Mþ, 82), 137
(100). Anal. calcd for C7H8N2S (152.21): C, 55.23; H, 5.29; N, 18.40.
Found: C, 55.34; H, 5.32; N, 18.45.
3-Methyl-5-propyl-4-isothiazolecarbonitrile (3c). Liquid. Yield 67%.
B.p.: 112–1148C/7 mm. IR (CHCl3): cm21 3432, 2942, 2226, 1520, 1435,
1364. 1H NMR (CDCl3, 300 MHz): d 1.04 (t, 3H, J 7.0 Hz, CH3), 1.99 (m, 2H,
CH2CH3) 2.53 (s, 3H, C55CCH3), 2.98 (t, J 7.0 Hz, 3H, CH2CH2CH3). m/z (%):
166 (Mþ, 100). Anal. calcd for C8H10N2S (166.24): C, 57.80; H, 6.06; N, 16.85.
Found: C, 58.03; H, 6.10; N, 16.88.
3-Methyl-5-(phenoxymethyl)-4-isothiazolecarbonitrile (3d). White
crystal. Yield 77%. M.p.: 91–928C. IR (KBr): cm21 2994, 2226, 1591,
1
1484, 1368. H NMR (CDCl3, 300 MHz): d 2.66 (s, 3H, CH3), 5.42 (s, 2H,
CH2), 6.96–7.35 (m, 5H, ArH). 13C NMR (CDCl3, 75 MHz): d 18.04, 63.63,
106.40, 112.43, 114.69, 122.33, 129.71, 157.11, 167.83, 173.74. m/z (%): 230
(Mþ, 100). Anal. calcd for C12H10N2OS (230.28): C, 62.58; H, 4.38; N, 12.16.
Found: C, 61.98; H, 4.41; N, 12.13.
5-((2,4-Dichlorophenoxy)methyl)-3-methyl-4-isothiazolecarbonitrile
(3e). White crystal. Yield 82%. M.p.: 1458C. IR (KBr): cm21 3445, 2224,
1
1542, 1485, 1364. H NMR (CDCl3, 300 MHz): d 2.63 (s, 3H, CH3), 5.47
(s, 2H, CH2), 6.95 (d, J 8.76 Hz, 1H, Ar60H), 7.24 (dd, J 2.3 and 8.76 Hz,
1H, Ar50H), 7.42 (d, J 2.3 Hz, 1H, Ar30H). 13C NMR (CDCl3, 75 MHz): d
18.13, 65.24, 107.5, 112.33, 115.22, 124.67, 127.85, 128.11, 130.55,
151.68, 167.96, 172.52. m/z (%): 298 (Mþ, 27), 300 (24), 302 (7), 156
(100). Anal. calcd. for C12H8Cl2N2OS (299.17): C, 48.17; H, 2.69; N, 9.36.
Found: C, 48.31; H, 2.72; N, 9.39.
3-Methyl-5-(4-nitrophenyl)-4-isothiazolecarbonitrile (3f ). White crystal.
Yield 56%. M.p.: 119–1208C. IR (KBr): cm21 3468, 2202, 1597, 1529, 1405.
1H NMR (CDCl3, 300 MHz): d 2.71 (s, 3H, CH3), 7.24 and 8.40 (d, J 8.73 Hz,
each 2H, Ar-H). m/z (%): 245 (Mþ, 100). Anal. calcd for C11H7N3O2S
(245.25): C, 53.87; H, 2.88; N, 17.13. Found: C, 54.11; H, 2.91; N, 17.15.
5-(Furan-2-yl)-3-methyl-4-isothiazolecarbonitrile (3g). White crystal.
Yield 60%. M.p.: 68–698C. IR (KBr): cm21 3114, 2218, 1578, 1474, 1386.

Synthesis of Novel 3,5-Disubstituted-4-isothiazolecarbonitriles
2687
1H NMR (CDCl3, 300 MHz): d 2.62 (s, 3H, CH3), 6.64 (dd, J 1.8 and 3.9 Hz,
1H, b-H of furan ring), 7.30 (dd, J 3.9 Hz, 1H, b0-H of furan ring), 7.60 (d, J
1.8 Hz, 1H, a-H of furan ring). 13C NMR (CDCl3, 75 MHz): d 18.13, 102.13,
112.29, 112.95, 113.87, 143.90, 145.06, 162.34, 168.17. m/z (%): 191 (MHþ,
100). Anal. calcd. for C9H6N2OS (190.21): C, 56.82; H, 3.18; N, 14.73.
Found: C, 56.65; H, 3.15; N, 14.77.
5-(Thiophen-2-yl)-3-methyl-4-isothiazolecarbonitrile (3h). White crystal.
Yield 69%. M.p.: 778C. IR (KBr): cm21 3212, 2222, 1612, 1543, 1440, 1362. 1H
NMR (CDCl3, 300MHz): d 2.63 (s, 3H, CH3), 7.19 (dd, J 3.73 and 5.10 Hz, 1H,
b0-H of thiophene ring), 7.58 (dd, J 1.00 and 5.10 Hz, 1H, b-H of thiophene ring),
7.70 (dd, J 1.00 and 3.73 Hz, 1H, a-H of thiophene ring). 13C NMR (CDCl3,
75 MHz): d 18.35, 104.33, 114.08, 128.20, 128.68, 129.95, 133.60, 167.23,
168.82. m/z (%): 206 (Mþ, 100). Anal. calcd. for C9H6N2S2 (206.28): C,
52.40; H, 2.93; N, 13.58. Found: C, 52.62; H, 2.95; N, 13.61.
3-Methyl-5-((1E,3E)-4-phenylbuta-1,3-dienyl)-4-isothiazolecarbo-
nitrile (3i). Light yellow crystal. Yield 72%. M.p.: 145–1468C. IR (KBr):
cm21 3452, 3025, 2222, 1606, 1486, 1373. 1H NMR (CDCl3, 300 MHz): d
2.56 (s, 3H, CH3), 6.90 (d, J 16 Hz, 1H, CH55CH–CH55CH–C6H5), 7.12–
7.20 (m, 2H, 55CH–CH55), 7.31–7.49 (m, 6H, CH–C6H5). 13C NMR
(CDCl3, 75 MHz): d 18.22, 113.72, 118.10, 126.91, 127.14, 128.46,
128.88, 129.12, 135.97, 138.65, 139.34, 168.19, 172.39. m/z (%): 252
(Mþ, 44), 251 (100). Anal. calcd. for C15H12N2S (252.32): C, 71.40; H,
4.79; N, 11.10. Found: C, 70.86; H, 4.83; N, 11.14.
3-Methyl-5-(2-phenyl-ethynyl)-4-isothiazolecarbonitrile (3j). White
crystal. Yield 66%. M.p.: 165–1678C. IR (KBr): cm21 3455, 3018, 2227,
1
1607, 1444. H NMR (CDCl3, 300 MHz): d 2.74 (s, 3H, CH3), 7.21–7.58
(m, 5H, ArH). 13C NMR (CDCl3, 75 MHz): d 22.94, 113.20, 115.19,
126.30, 126.66, 129.61, 131.51, 134.41, 151.62, 162.89, 177.18. m/z (%):
224 (Mþ, 100). Anal. calcd for C13H8N2S (224.27): C, 69.62; H, 3.59; N,
12.49. Found: C, 70.21; H, 3.61; N, 12.60.
5-Methyl-3-phenyl-4-isothiazolecarbonitrile (3k). White crystal. Yield
73%. M.p.: 768C (literature[13] 778C). IR (KBr): cm21 3312, 2970, 2216,
1486, 1435. H NMR (CDCl3, 300 MHz): d 2.78 (s, 3H, CH3), 7.48–8.03
1
(m, 5H, ArH). m/z (%): 200 (Mþ, 100). Anal. calcd for C11H8N2S (200.25):
C, 65.97; H, 4.03; N, 13.99. Found: C, 66.32; H, 3.98; N, 13.79.
3-(4-Methoxyphenyl)-5-methyl-4-isothiazolecarbonitrile
(3l). White
crystal. Yield 70%. M.p.: 87–888C. IR (KBr): cm21 3274, 2218, 1684, 1506,
1
1487. H NMR (CDCl3, 300 MHz): d 2.76 (s, 3H, CH3), 3.86 (s, 3H, OCH3),
7.00 (d, J 8.84 Hz, 2H, Ar20H), 7.99 (d, J 8.84 Hz, 2H, Ar30H). 13C NMR
(CDCl3, 75MHz): d 13.11, 55.31, 106.92, 114.16, 125.71, 129.03, 132.50,
161.19, 167.00, 174.61. m/z (%): 230 (Mþ, 100). Anal. calcd for C12H10N2OS
(230.28): C, 62.58; H, 4.38; N, 12.16. Found: C, 61.86; H, 4.41; N, 12.21.

2688
Mishra, Chowdhury, and Mahalanabis
ACKNOWLEDGMENTS
We are thankful to Dr. W. Froestl, Novartis Pharma AG, Basel, Switzerland;
Dr. V. A. Snieckus, Queens University, Ontario, Canada; Dr. R. Mukherjee,
IICB, Kolkata, India for recording spectral data of some of our compounds;
Dr. S. Chakraborty, University of Michigan, USA for recording mass spec-
troscopy of some compounds; and Dr. R. G. Bhattacharya, J. U. for running
GC of liquid samples. M. M. thanks Jadavpur University for awarding the
State Fellowship.
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Received March 10, 2004