One-pot transformation of cyano oxiranes into furo[3,2-c]isothiazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.06.083

The one-pot reactions of 2-[amino(2-cyano-3-aryloxiran-2-yl)methylene] malononitriles with thiocyanate to afford 5-amino-3-arylfuro[3,2-c]isothiazole- 6-carbonitriles in good yields.

Full text of DOI:10.1016/j.tetlet.2011.06.083

Tetrahedron Letters 52 (2011) 4724–4725
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot transformation of cyano oxiranes into furo[3,2-c]isothiazole
derivatives
⇑
Ivan N. Bardasov , Roman V. Golubev, Oleg V. Ershov, Yakov S. Kayukov, Oleg E. Nasakin
Ulyanov Chuvash State University, Cheboksary, Moskovsky pr., 15, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-pot reactions of 2-[amino(2-cyano-3-aryloxiran-2-yl)methylene]malononitriles with thiocya-
nate to afford 5-amino-3-arylfuro[3,2-c]isothiazole-6-carbonitriles in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 4 April 2011
Revised 19 May 2011
Accepted 20 June 2011
Available online 7 July 2011
Keywords:
Heterocyclic compounds
Cyano compounds
Oxiranes
Isothiazoles
Furans
One-pot synthesis
Cascade-heterocyclization reactions have a special place in
modern organic synthesis and achieve complicated chemical trans-
formations in one synthetic operation. Their use in reactions of
cyano-containing compounds allows the synthesis of functional
mono-, bi-, and polycyclic structures.1 Prospective substrates for
the synthesis of new heterocyclic compounds are 2-[amino(2-cya-
no-3-aryloxiran-2-yl)methylene]malononitriles 1,2 which are
obtained by epoxidation of arylmethylidene derivatives of malono-
nitrile dimers.3 The use of these compounds in organic synthesis has
enabled the development of one-pot syntheses of 5-amino-3-arylf-
uro[3,2-c]isothiazole-6-carbonitriles 2. The presence of enamine-
carbonitrile moieties makes them promising for further chemical
transformations. Besides some isothiazole derivatives are known
to possess cytotoxic, antiproliferative, antiviral, antibacterial, and
antipsychotic activity.4
Substituted isothiazoles are a poorly-represented class of het-
erocyclic compounds, however, several general approaches to their
synthesis have been developed. One of the main synthetic
approaches to fused isothiazoles is based on reactions between
imino-containing compounds and thiocyanates.5
Herein, we describe a new method for the preparation of
isothiazoles 2a–e (Scheme 1), fused with a furan ring. The method
involves the one-pot reaction of 2-[amino(2-cyano-3-aryloxiran-2-
yl)methylene]malononitriles 1 and sodium, potassium or ammo-
nium thiocyanates in a 1,4-dioxane-water mixture. A series of
intramolecular transformations leads to 5-amino-3-arylfuro[3,2-
c]isothiazole-6-carbonitriles 2a–e in 76–89% yields (Table 1).6
The structures of compounds 2a–e were confirmed by IR, 1H
NMR and 13C NMR spectroscopy and mass spectrometry. The 1H
NMR spectra of 2a–e exhibited singlets at d 9.02–9.12 ppm for
the amino group and expected resonances for the aryl group and
other substituents. The 13C NMR spectrum of 2a displayed reso-
nances in agreement with the structure. The structural assign-
CN
CN
CN
H2N
+ SCN-
NH2
CN
+ SCN-
NC
NC
O
NH2
N
S
O
O
H
HN
S
Ar
CN
Ar
Ar
3
2
1
Scheme 1. Synthesis of isothiazoles 2a–e.
Table 1
Synthesis of 5-amino-3-arylfuro[3,2-c]isothiazole-6-carbonitriles 2a–e
Oxirane
Ar
Product
Yielda (%)
1a
1b
1c
1d
1e
C6H5
2a
2b
2c
2d
2e
82
86
83
76
89
2-ClC6H4
4-H3CC6H4
4-FC6H4
3-ClC6H4
⇑
Corresponding author. Tel.: +7 9083030163; fax: +7 8352770979.
E-mail address: bardasov.chem@mail.ru (I.N. Bardasov).
a
Yield of isolated product.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.083

I. N. Bardasov et al. / Tetrahedron Letters 52 (2011) 4724–4725
4725
CN
CN
CN
CN
H2N
N
NC
NC
O
NH2 + SCN-
N
NH2
NH2
CN
O
O
S
S
CN
CN
S
CN
CN
O
H
O
H
H
CN
Ar
CN
Ar
6
Ar
4
Ar
1
- CN-
H2N
5
CN
CN
CN
H
H
CN
H2N
NC
HO
NC
N
N
N
- CN-
N
O
S
S
CN
- HCN
CN
CN
HO
S
CN
H
S
H
H
Ar
2
Ar
Ar
Ar
8
7
9
Scheme 2. Proposed mechanism for the synthesis of isothiazoles 2a–e.
Abd Allah, S. O.; Mohareb, R. M. Synthesis 1984, 976–978; (d) Junek, H.;
Thierrichter, B.; Wibmer, P. Monatsh. Chem. 1979, 110, 483–492; (e) Junek, H.;
Wolny, B. Monatsh. Chem. 1976, 107, 999–1006.
ments made on the basis of the mass spectra of compounds 2 dis-
played molecular ion peaks and other fragmentations, including
peaks due to [Ar–C„S+] fragments.
4. (a) Kuzuya, M.; Yamauchi, Y.; Niwa, J.; Kondo, S.; Sakai, Y. Chem. Pharm. Bull.
1995, 43, 2037–2041; (b) Singer, J. M.; Barr, B. M.; Coughenour, L. L.; Gregory, T.
F.; Walters, M. A. Bioorg. Med. Chem. Lett. 2005, 15, 4560–4563; (c) Cipollina, J.
A.; Ruediger, E. H.; New, J. S.; Wire, M. E.; Shepherd, T. A.; Smith, D. W.; Yevich, J.
P. J. Med. Chem. 1991, 34, 3316–3328; (d) Yevich, J. P.; New, J. S.; Smith, D. W.;
Lobeck, W. G.; Catt, J. D.; Minielli, J. L.; Eison, M. S.; Taylor, D. P.; Riblet, L. A.;
Temple, D. L., Jr. J. Med. Chem. 1986, 29, 359–369; (e) Raap, R.; Micetich, R. G. J.
Med. Chem. 1968, 11, 70–73; (f) Swayze, E. E.; Drach, J. C.; Wotring, L. L.;
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Zh. Org. Khim. 1996, 32, 1745–1753; (b) Schulze, B.; Kirsten, G.; Kirrbach, S.;
Rahm, A.; Heimgartner, H. Helv. Chim. Acta 1991, 74, 1059–1070; (c) Schulze, B.;
Rosenbaum, K.; Hilbig, J.; Weber, L. J. Prakt. Chem. 1992, 334, 25–33; (d) Schulze,
B.; Herre, S.; Braemer, S.; Laux, C.; Muehlstaedt, M. J. Prakt. Chem. 1977, 319,
305–312; (e) Schulze, B.; Hilbig, J.; Weber, L.; Rosenbaum, K.; Muhlstadt, M. Z.
Chem. 1988, 28, 287–288.
According to published data, ring-opening of oxiranes under the
action of thiocyanates can lead to the formation of 2-imino-1,3-
oxathiolanes 3.7 Depending on the structures of the reactants
and the reaction conditions, derivatives of various classes of het-
erocycles, such as thiiranes, 1,3-oxathiolanes and thiazoles can
be formed. The structures of the final products 2 and the proposed
mechanism for this transformation do not require formation of 3 as
an intermediate in the reaction of oxiranes 1 with thiocyanates.
Ring-opening of an oxirane ring can occur stereospecifically via
approach of a nucleophile from the rear of the C–O7 bond by an SN2
mechanism. Therefore, during the first stage we assume initial for-
mation of intermediate 4 (Scheme 2).
This intermediate undergoes intramolecular heterocyclization
with the formation of iminofuran 5, subsequent tautomerization
of which gives intermediate 6. The proximity of the imine anion
and thiocyanate group leads to formation of an isothiazole ring
accompanied by the elimination of a cyanide anion and the forma-
tion of intermediate 9.
An alternative reaction course is also possible. This involves the
formation of the isothiazole ring 8 after tautomerization of 4 into
intermediate 7. Further, intramolecular cyclization leads to forma-
tion of bicycle 9. Finally, aromatization occurs via elimination of
hydrogen cyanide.
In earlier published work the only method for the synthesis
furo[3,2-c]isothiazoles and benzofuro[3,2-c]isothiazoles involved
intramolecular nucleophilic replacement with the participation of
azido- and thione groups.8 Thus, the proposed method is the first
approach for the synthesis of polyfunctional furo[3,2-c]isothiazoles.
6. Typical procedure for the preparation of 5-amino-3-arylfuro[3,2-c]isothiazole-6-
carbonitriles 2a–e. NaSCN (0.81 g, 10 mmol) was dissolved in a solution of 2-
[amino(2-cyano-3-phenyloxiran-2-yl)methylene]malononitrile
1a
(2.36 g,
10 mmol) in a mixture of 1,4-dioxane (20 mL) and H2O (20 mL). The mixture
was stirred at 70 °C for 1 h, cooled filtered and washed with 1,4-dioxane (20 mL)
and H2O (20 mL). Compound 2a: mp 285–286 °C; 1H NMR (500.13 MHz, DMSO-
d6): d 7.48 (1H, t, J = 7.3 Hz, C6H5), 7.55 (2H, t, J = 7.5 Hz, C6H5), 7.64 (2H, d,
J = 7.7 Hz, C6H5), 9.04 (2H, s, NH2). 13C NMR (125.76 MHz, DMSO-d6): d 59.41
(C6), 113.65 (CN), 126.32, 127.42, 129.41, 129.52 (C6H5), 135.29 (C3), 138.59
(C3a), 160.36 (C6a), 175.13 (C5). IR 3334, 3258 (NH2), 2224 (C„N). MS (EI, 70 eV):
m/z (%) 241 (M+, 42), 121 ([Ar–C„S+], 100). Anal. Calcd for C12H7N3OS: C, 59.74;
H, 2.92; N, 17.42. Found C, 59.77; H, 3.03; N, 17.50. Compound 2b: mp 240–
241 °C; 1H NMR (500.13 MHz, DMSO-d6): d 7.50–7.57 (2H, m, C6H4), 7.70 (1H,
dd, 3J = 7.7 Hz, 4J = 1.6 Hz, C6H4), 7.91 (1H, dd, 3J = 7.5 Hz, 4J = 2.0 Hz, C6H4), 9.05
(2H, s, NH2). IR 3328, 3267 (NH2), 2226 (C„N). MS (EI, 70 eV): m/z (%) 277 (M+
37Cl, 24), 275 (M+ 35Cl, 78), 157 ([Ar–C„S+], 34), 155 ([Ar–C„S+], 100). Anal.
Calcd for C12H6ClN3OS: C, 52.27; H, 2.19; N, 15.24. Found C, 52.32; H, 2.22; N,
15.30. Compound 2c: mp 181–182 °C; 1H NMR (500.13 MHz, DMSO-d6): d 2.36
(3H, s, CH3), 7.35 (2H, d, J = 8.1 Hz, C6H4), 7.53 (2H, d, J = 8.2 Hz, C6H4), 9.02 (2H,
s, NH2). IR 3333, 3262 (NH2), 2226 (C„N). MS (EI, 70 eV): m/z (%) 255 (M+, 68),
135 ([Ar–C„S+], 100). Anal. Calcd for C13H9N3OS: C, 61.16; H, 3.55; N, 16.46.
Found C, 61.22; H, 3.57; N, 16.51. Compound 2d: mp 214–215 °C; 1H NMR
(500.13 MHz, DMSO-d6): d 7.39–7.43 (2H, m, C6H4), 7.67–7.70 (2H, m, C6H4),
9.07 (2H, s, NH2). IR 3336, 3257 (NH2), 2224 (C„N). MS (EI, 70 eV): m/z (%) 259
(M+, 36), 139 ([Ar–C„S+], 100). Anal. Calcd for C12H6FN3OS: C, 55.59; H, 2.33; N,
16.21. Found C, 56.08; H, 2.47; N, 16.02. Compound 2e: mp 265–266 °C; 1H NMR
(500.13 MHz, DMSO-d6): d 7.53–7.58 (2H, m, C6H4), 7.68 (2H, s, C6H4), 9.12 (2H,
s, NH2). IR 3326, 3256 (NH2), 2233 (C„N). MS (EI, 70 eV): m/z (%) 277 (M+ 37Cl,
27), 275 (M+ 35Cl, 80), 157 ([Ar–C„S+], 37), 155 ([Ar–C„S+], 100). Anal. Calcd for
Acknowledgment
This research was supported by the Federal Target Program
Research and educational personnel of innovative Russia as
research project (No. 16.740.11.0160).
C
12H6ClN3OS: C, 52.27; H, 2.19; N, 15.24. Found C, 52.39; H, 2.33; N, 15.23.
7. (a) Kleiner, C. M.; Horst, L.; Würtele, C.; Wende, R.; Schreiner, P. R. Org. Biomol.
Chem. 2009, 7, 1397–1403; (b) Vasil’eva, S. A.; Kashina, Y. A.; Kulikova, M. V.;
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Castilla, J.; Marin, I.; Matheu, M. I.; Diaz, Y.; Castillon, S. J. Org. Chem. 2010, 75,
514–517; (d) Majcen, A.; Marechal, L.; Robert, A.; Leban, I. J. Chem. Soc., Perkin
Trans. 1 1993, 351–356; (e) Baudy, M.; Robert, A.; Foucaud, A. J. Org. Chem. 1978,
43, 3732–3736.
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1873–1876; (b) Capperucci, A.; Degl’Innocenti, A.; Funicello, M.; Scafato, P.;
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