A new heterocycle: Furo[3,2-c]isoselenazole

Article abstract of DOI:10.1016/j.tetlet.2016.05.032

New heterocycles, furo[3,2-c]isoselenazoles, were obtained by the reaction of 2-[amino(2-cyano-3-aryloxiran-2-yl)methylene]malononitriles with potassium selenocyanate.

Full text of DOI:10.1016/j.tetlet.2016.05.032

Accepted Manuscript
A new heterocycle: Furo[3,2-c]isoselenazole
Ivan N. Bardasov, Denis L. Mikhailov, Anastasiya U. Alekseeva, Oleg V.
Ershov, Viktor A. Tafeenko
PII:
S0040-4039(16)30546-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.032
TETL 47651
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 April 2016
5 May 2016
9 May 2016
Please cite this article as: Bardasov, I.N., Mikhailov, D.L., Alekseeva, A.U., Ershov, O.V., Tafeenko, V.A., A new
heterocycle: Furo[3,2-c]isoselenazole, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.05.032
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A new heterocycle: furo[3,2-c]isoselenazole
Ivan N. Bardasov,* Denis L. Mikhailov, Anastasiya U. Alekseeva, Oleg V. Ershov and Viktor A.
Tafeenko

A new heterocycle: furo[3,2-c]isoselenazole
Ivan N. Bardasov a,*, Denis L. Mikhailov a, Anastasiya U. Alekseeva a, Oleg V. Ershov a and
Viktor A. Tafeenko b.
aUlyanov Chuvash State University, Moskovsky pr. 15, Cheboksary 428015, Russia
bMoscow State University, Vorob’evy gory 1, Moscow, 119992, Russia.
Abstract — New heterocycles, furo[3,2-c]isoselenazoles, were obtained by the reaction of 2-
[amino(2-cyano-3-aryloxiran-2-yl)methylene]malononitriles with potassium selenocyanate.
Keywords: Heterocyclic compounds; Cyano compounds; Furoisoselenazole; New heterocycle.
*
Corresponding
author.
Tel.:
+79083030163;
fax:
+78352450279;
e-mail:
bardasov.chem@mail.ru.
Selenorganic compounds, in particular isoselenazoles, are essential substrates in modern
organic chemistry.1 Selenazolinium salts (Se-N+) are of interest as magnetic conducting and
superconducting materials.2 Organoselenium compounds with intramolecular nonbonding Se…N
interactions have attracted interest as mimics of glutathione peroxidase (GPx) and thioredoxin
reductase (TrxR).3 Isoselenazoles, such as ebselen and its analogues, are effective anti-
inflammatory and antioxidant agents.4
Additionally isoselenazoles are widely used intermediates in organic synthesis.5 The
reactivity of organoselenium compounds is mainly associated with the ability of selenium to
stabilize adjacent positive and negative charges, as well as with the ease with which selenides to
undergo oxidation to give selenoxides. Therefore, the development of preparative methods for
the synthesis of selenium-containing heterocyclic is an area of continued interest. Currently,
methods of synthesis of selenazoles are represented by variations of electrophilic addition of
selenium-containing substrates to multiple bonds.6
Previously, we have described a new method for obtaining isothiazoles7 by the reaction
of thiocyanates with 2-[amino(2-cyano-3-aryloxiran-2-yl)methylene]malononitriles 1, which
were synthesized by the reaction of 2-amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitrile with
hydrogen peroxide.8
As part of our continued research, we found that no methods for the synthesis of furans
which were annulated with an isoselenazole ring were reported in the literature. Therefore, based
on the fact that thiocyanates and selenacyanates are isoelectronic, we extended our method to
obtain 5-amino-3-arylfuro[3,2-c]isoselenazole-6-carbonitriles 2.
The reaction of 2-[amino(2-cyano-3-aryloxiran-2-yl)methylene] malononitriles 1a-f with
potassium selenocyanate in a mixture of dioxane and water, led to the formation of 5-amino-3-
arylfuro[3,2-c]isoselenazole-6-carbonitriles 2a-f in 75-91% yields (Scheme 1, Table 1).9
Scheme 1. Synthesis of 5-amino-3-(2-chlorophenyl)furo[3,2-c]isoselenazole-6-carbonitriles 2a-
f.
Table 1. Synthesis of 5-amino-3-(2-chlorophenyl)furo[3,2-c]isoselenazole-6-carbonitriles 2a-f.a
Substrate
Ar
Product Yieldb (%)

1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
91
85
75
78
83
88
C6H5
2-ClC6H4
3-NO2C6H4
4-FC6H4
4-CH3C6H4
3-ClC6H4
a Reaction conditions: compound 1 (10 mmol), KSeCN (10 mmol), 60 °С, 1,4-dioxane (20 mL),
water (20 mL).
b Yield of isolated product.
The structures of compounds 2a-f were confirmed by IR, 1H and 13C NMR spectroscopy,
mass spectrometry as well as single crystal X-ray diffraction analysis of compound 2b (Figure
1).10
Figure 1. ORTEP diagram of 5-amino-3-(2-chlorophenyl)furo[3,2-c]isoselenazole-6-carbonitrile
2b.
The obtained furo[3,2-c]isoselenazoles 2 are crystalline products which were stable at
room temperature. Only after long-term storage in the presence of atmospheric moisture was
traces of decomposition with the formation of elemental selenium observed.
Utilization of tellurocyanates for the synthesis of the analogous furo[3,2-c]isotellurazoles
led to the formation of unstable products, that instantly decomposed with formation of elemental
tellurium.
A possible mechanism for the formation of furo[3,2-c]isoselenazoles 2 includes the
tandem formation of fused rings. It is known that the oxirane ring easily opens under the
influence of various reagents. The initial ring opening of the oxirane by the selenocyanate gives
cyanohydrin A (Scheme 2). This intermediate which is not stable in the basic medium breaks
down leading to the formation of ketone B, which tautomerizated into enol C. The proximity of
the hydroxy and cyano groups leads to formation of furan D. Next, intramolecular nucleophilic
substitution of the selenium atom leads to the annulation of furan to an isoselenazole and the
formation of final compound 2.

Scheme 2. Possible mechanism for the formation of furo[3,2-c]isoselenazoles 2a-f.
In conclusion, an approach to the previously undescribed heterocyclic system, including
annulated furan and isoselenazole rings was developed. Novel furo[3,2-c]isoselenazoles 2a-f
were obtained by a simple domino process in one synthetic operation. The resulting compounds
are crystalline substances that very slowly release elemental selenium, therefore they can
potentially be used as a source of this biologically significant element.
Acknowledgement
This work was carried out in the framework of the baseline of the State Assignment of the
Ministry of Education and Science of the Russian Federation No. 872.
References and notes
1. (a) Młochowski, J.; Kloc, K.; Lisiak, R.; Potaczek P.; Wójtowicz, H. ARKIVOC 2007, vi,
14-46; (b) Nogueira, C. W.; Zeni, G.; Rocha J. B. T. Chem. Rev. 2004, 104, 6255−6285;
Santi, C.; Santoro, S.; Battistelli, B. Curr. Org. Chem. 2010, 14, 2442-2462.
2. (a) Bagryanskaya, I. Yu.; Gatilov, Y. V.; Gritsan, N. P.; Ikorskii, V. N.; Irtegova, I. G.; Lon
chakov, A. V.; Lork, E.; Mews, R.; Ovcharenko, V. I.; Semenov, N. A.; Vasilieva, N. V.;
Zibarev, A. V. Eur. J. Inorg. Chem. 2007, 4751–4761; (b) Awaga, K.; Tanaka, T.; Shirai, T.;
Fujimori, M.; Suzuki, Y.; Yoshikava, H.; Fujita, W. Bull. Chem. Soc. Jpn. 2006, 79, 25–34;
(c) Okamoto, K.; Tanaka, T.; Fujita, W.; Awaga, K.; Inabe, T. Angew. Chem. Int. Ed. 2006,
45, 4516–4518; Angew. Chem. 2006, 118, 4628; (d) Deumal, M.; LeRoux, S.; Raw- son, J.
M.; Robb, M. A.; Novoa, J. J. Polyhedron 2007, 26, 1949–1958; e) Rawson, J. M.; Alberola,
A.; Whalley, A. J. Mater. Chem. 2006, 16, 2560–2575; (f) Rawson, J. M.; Luzon, J.;
Palacio, F. Coord. Chem. Rev. 2005, 249, 2631–2641.
3. (a) Singh, V. P.; Singh, H. B.; Butcher, R. J. Eur. J. Inorg. Chem. 2010, 637–647; (b)
Alberto, E. E.; Nascimento, V. do; Braga, A. L. J. Braz. Chem. Soc. 2010, 21, 2032–2041;
(c) Nascimento, V.; Ferreira, N. L.; Canto, R. F. S.; Schott, K. L.; Waczuk, E. P.; Sancineto,
L.; Santi, C.; Rocha, J. B. T.; Braga, A. L. Eur. J. Med. Chem. 2014, 87, 131–139; (d) Yan,
J.; Guo, Y.; Wang, Y.; Mao, F.; Huang, L.; Li, X. Eur. J. Med. Chem. 2015, 95, 220–229.
4. (a) Scholz, M.; Ulbrich, H. K.; Dannhardt, G. Eur. J. Med. Chem. 2008, 43, 1152–1159; (b)
Mugesh, G.; Singh, H. B. Chem. Soc. Rev. 2000, 29, 347– 357; (c) Sharma, B. K.; Mugesh,
G. J. Am. Chem. Soc. 2005, 127, 11477–11485; (d) Satheeshkumar, K.; Mugesh, G. Chem.
Eur. J. 2011, 17, 4849–4857.
5. (a) Patai, S.; Rappoport, Z. The Chemistry of Organic Selenium and Tellurium Compounds;
John Wiley & Sons Ltd: London, 1986; (b) Paulmier, C. Selenium Reagents and
Intermediates in Organic Synthesis; Pergamon Press, Oxford, 1986; (c) Liotta, D.
Organoselenium Chemistry; John Wiley & Sons, New York, 1987. (d) Grivas, S. Curr. Org.
Chem. 2000, 4, 707–726; (e) Ueda, T.; Kawai, S.; Sakakibara, J. Chem. Pharm. Bull. 1987,
35, 398–401; (f) Lucchesini, F.; Picci, N.; Pocci, M. Heterocycles 1989, 29, 349–354; (g)
Ralph, J. T. Synth. Commun. 1989, 19, 1381–1387.

6. (a) Arsenyan, P.; Vasiljeva, J.; Belyakov, S.; Liepinsh, E.; Petrova, M. European J. Org.
Chem. 2015, 5842–5855; (b) Mbogo, S. A.; Mcwhhie, R. J. Organometallic Chem. 1990,
395, 167–175; (c) Yavoiovskii, A. A.; Kuklenko, E. A. Chem. Het. Comp. 1997, 32, 997–
999.
7. Bardasov, I. N.; Golubev, R. V.; Ershov, O. V.; Kayukov, Y. S.; Nasakin, O. E. Tetrahedron
Lett. 2011, 52, 4724–4725.
8. Golubev, R. V.; Belikov, M. Yu.; Bardasov, I. N.; Ershov, O. V.; Nasakin, O. E. Russ. J.
Org. Chem. 2010, 46, 1883–1884. Typical procedure for the preparation of 2-(amino(3-
aryl-2-cyanooxiran-2-yl)methylene)malononitrile 1. Hydrogen peroxide (30%) (1 mL) was
added to 2-amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitrile (10 mmol) in CH3COOH (20
mL) and stirred at 80 ºС for 20 min. After cooling, H2O (20 mL) was added, and the
precipitate was filtered and washed with H2O. Recrystallized from i-PrOH (5 mL).
9. Typical procedure for the preparation of 5-amino-3-arylfuro[3,2-c]isoselenazole-6-
carbonitriles 2. 2-[Amino(2-cyano-3-aryloxiran-2-yl)methylene]malononitrile (1) (10
mmol) was dissolved in a solution of KSeCN (10 mmol) in a mixture of 1,4-dioxane (20
mL) and water (20 mL). The mixture was stirred at 60 °C for 1 h, cooled, filtered and
washed with 1,4-dioxane (20 mL) and H2O (20 mL). Recrystallized from 1,4-dioxane (20
mL). Compound 2e. mp 245-246 ºС (dec.); 1H NMR (500.13 MHz, DMSO-d6): δ 3.28 (3Н,
s, CH3), 7.86 (2Н, d, J = 8.43 Hz, C6H4), 8.05 (2Н, d, J = 8.45 Hz, C6H4), 9.13 (2H, s, NH2).
13C NMR (125.76 MHz, DMSO-d6): δ 43.36, 61.52, 113.71, 128.05, 128.13, 134.49, 135.38,
140.66, 140.81, 163.77, 175.63. IR (mineral oil, cm–1): 3232 (NH2), 2228 (CN). MS (EI, 70
eV): m/z (%) 303 [M]+ (92), 183 [Ar-C-Se]+ (100), 92 [Se-CH2]+ (34). Anal. Calcd for
C13H9N3OSe: C, 51.67; H, 3.00; N, 13.91. Found: C, 52.12; H, 6.24; N, 27.65.
10. Crystallographic data (excluding structure factors) for the structure 2b in this paper have
been deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 1446592. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44 (0) 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk]

Highlights
1. One-pot synthesis of undescribed heterocyclic system – furo[3,2-c]isoselenazoles.
2. New path of rearrangements of cyanooxiranes.
3. Gives the desired product in good yields under mild reaction conditions.
4. A plausible mechanism is proposed for the reaction.