Simple synthesis of selenium-containing 1,2-dihydro-2-oxonicotinates

Full text of DOI:10.1007/s10593-013-1221-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
LETTERS TO THE EDITOR
SIMPLE SYNTHESIS OF SELENIUM-CONTAINING
1,2-DIHYDRO-2-OXONICOTINATES
K. A. Frolov1*, V. V. Dotsenko1, and S. G. Krivokolysko1
Keywords: cyanoselenoacetamide, ethoxymethylenemalonate, pyridine-2-selenolate, vinyl substitution.
It is known that selenium-containing compounds show a unique combination of chemical properties and
biological activity, and are of great practical interest (see recent reviews [1-4]). Selenoamides appear as
universal building blocks for the preparation of a wide series of N,Se-containing heterocycles [5, 6]. Interest in
heterocyclization reactions involving cyanoselenoacetamide (1) has encouraged us to study its reaction with the
ethoxymethylenemalonate 2. Ethoxymethylene compounds are quite widely used in heterocyclic synthesis as
three-carbon 1,3-dielectrophilic synthons [7, 8], but only isolated examples are known of their use in preparing
selenium-containing compounds [9-11]. As has been noted [9], in contrast to their sulfur-containing analogs, the
preparation of Se-containing derivatives in an analytically pure state can be difficult in such reactions.
Se
H2N
OEt
O
OEt
O
Et3NH+
Et3N, abs. EtOH
argon, 20°C
CN
CN
O
EtO
+
O
Se
NH2
EtO
1
2
OEt
O
O
O
BrCH2R
CN
CN
EtOH, 
EtO
EtO
N
Se
O
N
SeCH2R
H
H
Et3NH+
4a–c
3
4 a R = CH2=СН, b R = 4-MeC6H4СО, c R = 4-MeC6H4NHСО
______
*To whom correspondence should be addressed, e-mail: ka.frolov@inbox.ru.
1"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A Molodyozhnyi Kv., Lugansk
91034, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1992-1994, December, 2012.
Original article submitted October 3, 2012.
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0009-3122/13/4812-1868©2013 Springer Science+Business Media New York

We have found that the cyanoselenoacetamide (1) can readily take part in a vinyl substitution reaction
with ester 2 under mild conditions to give the previously unknown triethylammonium 3-cyano-
5-ethoxycarbonyl-6-oxo-1,6-dihydropyridine-2-selenolate (3) in 26% yield. Attempts to optimize the method
and to increase the yield of selenolate 3 were unsuccessful. Short heating of compound 3 in ethanol in the
presence of alkylating agents gave the Se-alkylation products 4a-c. It should be particularly emphasized that the
1,2-dihydro-2-oxonicotinate fragment present in the structure of compounds 3 and 4a-c is a pharmacophore and
is found in many compounds with hypoglycemic, analgesic, cytotoxic, cardiotonic, and other types of activity.
We have previously shown that direct structural analogs of the synthesized compounds are inhibitors of
ubiquitin C-terminal hydrolase L1 (UCH-L1) [12]. The unusual combination of oxonicotinate and selenium-
containing fragments makes it highly likely that compounds 3, 4a-c will be found to be biologically active. At
this time, work is being carried out to test the obtained compounds on biological systems.
IR spectra were recorded on an IKS-29 spectrophotometer in nujol. The 1H NMR spectra were recorded
on a Bruker Avance II 400 (400 MHz) instrument using DMSO-d6 with TMS as internal standard. Elemental
analysis was carried out using a Carlo-Erba 1106 instrument. Melting points were determined on a Kofler hot
stage apparatus and were not corrected. Purity of the obtained compounds was monitored by TLC on Silufol
UV-254 plates, eluting with acetone–hexane (1:1) and using iodine vapor and UV visualization. The
cyanoselenoacetamide (1) was prepared by a known method [13]. All of the syntheses were carried out under an
argon atmosphere.
Triethylammonium 3-Cyano-5-ethoxycarbonyl-6-oxo-1,6-dihydropyridine-2-selenolate (3). Et3N
(1.42 ml, 10.2 mmol) was added dropwise with stirring to a mixture of cyanoselenoacetamide (1) (1.00 g,
6.8 mmol) and diethyl ethoxymethylenemalonate (2) (1.66 ml, 6.8 mmol) in absolute EtOH (10 ml). The
mixture was stirred for 30 min at 20°C, filtered through a fluted filter, and left for 24 h at room temperature
under an argon atmosphere. The product obtained was filtered off, washed with cold EtOH and acetone. Yield
0.66 g (26%). Yellow-green, fine crystalline powder. Mp 156-158°C. IR spectrum, , cm-1: 3390 (N–H), 2210
(C≡N), 1720, 1680 (C=O). 1H NMR spectrum, , ppm (J, Hz): 1.25 (9H, t, 3J = 7.2, N(CH2CH3)3); 1.30 (3H, t,
3
3
3J = 7.1, OCH2CH3); 3.15 (6H, q, J = 7.2, N(CH2CH3)3); 4.15 (2H, q, J = 7.1, OCH2CH3); 7.83 (1H, s, H-4);
8.82 (1H, br. s, NH). Found, %: C 48.19, H 6.29; N 11.10. C15H23N3O3Se. Calculated, %: C 48.39; H 6.23;
N 11.29.
Preparation of Compounds 4a-c (General Method). A mixture of selenolate 3 (150 mg, 0.40 mmol)
and the corresponding alkyl halide (0.40 mmol) in 70% EtOH (1 ml) was refluxed to full dissolution of the
starting reagents (over the course of 2-3 min), rapidly filtered through filter paper under an argon stream, and
left for 24 h at room temperature. The precipitate formed was filtered off and washed with EtOH and hexane to
give compounds 4a-c in an analytically pure state.
Ethyl 6-(Allylseleno)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylate (4a). Yield 90 mg (72%).
White, fine crystalline powder. Mp 118-120°C. IR spectrum, , cm-1: 3375 (N–H), 2225 (C≡N), 1691, 1672
(C=O). 1H NMR spectrum, , ppm (J, Hz): 1.33 (3H, t, 3J = 7.0, OCH2CH3); 3.99 (2H, d, 3J = 7.3, SeCH2); 4.28
3
3
3
(2H, q, J = 7.0, OCH2CH3); 5.04 (1H, d, J = 9.9, CH=CH2 cis); 5.31 (1H, d, J = 16.7, CH=CH2 trans);
5.93-6.04 (1H, m, CH=CH2); 8.26 (1H, s, H-4); 12.68 (1H, br. s, NH). Found, %: C 46.09; H 3.94; N 8.87.
C12H12N2O3Se. Calculated, %: C 46.32; H 3.89; N 9.00.
Ethyl 5-Cyano-6-{[2-(4-methylphenyl)-2-oxoethyl]seleno}-2-oxo-1,2-dihydropyridine-3-carboxylate
(4b). Yield 110 mg (68%). Yellow, fine crystalline powder. Mp 150-152°C. IR spectrum, , cm-1: 3477 (N–H),
2220 (C≡N), 1695, 1680 (C=O). 1H NMR spectrum, , ppm (J, Hz): 1.33 (3H, t, 3J = 7.0, OCH2CH3); 2.42 (3H,
s, ArCH3); 4.29 (2H, q, 3J = 7.0, OCH2CH3); 4.97 (2H, br. s, SeCH2); 7.35 (2H, d, 3J = 7.8, H Ar); 7.94 (2H, d,
3J = 7.8, H Ar); 8.29 (1H, s, H-4); 12.72 (1H, br. s, NH). Found, %: C 53.46; H 4.03; N 6.86. C18H16N2O4Se.
Calculated, %: C 53.61; H 4.00; N 6.95.
Ethyl
5-Cyano-6-({2-[(4-methylphenyl)amino]-2-oxoethyl}seleno)-2-oxo-1,2-dihydropyridine-
3-carboxylate (4c). Yield 50 mg (30%). Light-grey, fine crystalline powder. Mp 193-195°C. IR spectrum, ,
1
cm-1: 3465, 3330 (N–H), 2220 (C≡N), 1720, 1705 (C=O). H NMR spectrum, , ppm (J, Hz): 1.37 (3H, t,
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3J = 7.1, OCH2CH3); 2.29 (3H, s, ArCH3); 4.11 (2H, br. s, SeCH2); 4.31 (2H, q, 3J = 7.1, OCH2CH3); 7.04 (2H,
3
3
d, J = 8.4, H Ar); 7.43 (2H, d, J = 8.4, H Ar); 8.23 (1H, s, H-4); 9.93 (1H, br. s, CONH); 12.72 (1H, br. s,
NH). Found, %: C 51.46; H 4.12; N 9.92. C18H17N3O4Se. Calculated, %: C 51.68; H 4.10; N 10.05.
This work was carried out with support of the grant No. F47/032 of the President of Ukraine.
REFERENCES
1.
2.
3.
G. Mugesh, W. W. du Mont, and H. Sies, Chem. Rev., 101, 2125 (2001).
C. W. Nogueira, G. Zeni, and J. B. T. Rocha, Chem. Rev., 104, 6255 (2004).
D. L. Hatfield, M. J. Berry, and V. N. Gladyshev (editors), Selenium. Its Molecular Biology and Role in
Human Health, Springer, New York (2012), 598 pp.
4.
5
J. Młochowski, Phosphorus, Sulfur Silicon Relat. Elem., 183, 931 (2008).
V. P. Litvinov and V. D. Dyachenko, Usp. Khim., 66, 1025 (1997).
6.
7.
8.
9.
M. Ninomiya, D. R. Garud, and M. Koketsu, Coord. Chem. Rev., 255, 2968 (2011).
V. D. Dyachenko and R. P. Tkachev, Zh. Org. Khim., 39, 807 (2003).
V. D. Dyachenko and R. P. Tkachev, Zh. Org. Khim., 42, 167 (2006).
Ya. Yu. Yakunin, V. D. Dyachenko, and V. P. Litvinov, Khim. Geterotsikl. Soedin., 831 (2001). [Chem.
Heterocycl. Compd., 37, 766 (2001)].
10.
11.
A. M. Shestopalov, Yu. A. Sharanin, V. P. Litvinov, V. Yu. Mortikov, and V. N. Nesterov, Zh. Obshch.
Khim., 57, 959 (1987).
Yu. A. Sharanin, A. M. Shestopalov, V. P. Litvinov, G. V. Klokol, V. Yu. Mortikov, and
A. S. Demerkov, Zh. Org. Khim., 24, 854 (1988).
12.
13.
A. N. Mermerian, A. Case, R. L. Stein, and G. D. Cuny, Bioorg. Med. Chem. Lett., 17, 3729 (2007).
V. P. Litvinov, V. Yu. Mortikov, Ya. A. Sharanin, and A. M. Shestopalov, Synthesis, 98 (1985).
1870