New approach to the synthesis of 4-aryl-3,5-dicyano-6-oxo- 1,4,5,6-tetrahydropyridin-2-olates (salts of guareschi imides)

Full text of DOI:10.1007/s10593-011-0855-4

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
NEW APPROACH TO THE SYNTHESIS
OF 4-ARYL-3,5-DICYANO-6-OXO-
1,4,5,6-TETRAHYDROPYRIDIN-2-OLATES
(SALTS OF GUARESCHI IMIDES)
E. A. Chigorina1, V. V. Dotsenko2*, and S. G. Krivokolysko2
Keywords: 4-aryl-2,6-dioxopiperidine-3,5-dicarbonitriles, 1-cyanoacetyl-3,5-dimethylpyrazole, Guareschi
imides, 4-(2-chlorophenyl)-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridin-2-olate, Michael reaction.
Derivatives of 2,6-dioxopiperidine-3,5-dicarbonitrile (Guareschi imides) are of practical interest as anti-
convulsants, sedatives, and analgesics [1] as well as promising building blocks for the preparation of bispidine
(3,7-diazabicyclo[3.3.1]nonane) derivatives [2, 3] and biologically active compounds [4–6]. The most
convenient method for the preparation of these compounds is the Guareschi reaction, namely, the reaction of
ethyl cyanoacetate with ketones and ammonia [7–11] or, in an alternative variant, the reaction of
2-cyanoacrylates with cyanoacetamide [4, 6, 12, 13]. The classical Guareschi reaction has its disadvantages. The
yields and reaction times vary. Also, there are limitations related to the need to use only ketones as the carbonyl
components. Guareschi imides are known to undergo facile oxidation by atmospheric oxygen [14]. When
aldehydes are used in this reaction instead of ketones, the final products are only the oxidation products, namely,
4-alkyl- or 4-aryl-6-hydroxy-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles or their salts [15–19]. Only a few
examples of the preparation of 4-aryl-2,6-dioxopiperidine-3,5-dicarbonitriles or their salts have been reported [1,
20, 21]. As a rule, either the products are obtained in low yield or the methods require the use of exotic reagents
such as Li3N as the source of NH3.
We have found that the salt of the Guareschi imide, triethylammonium 4-(2-chlorophenyl)-3,5-dicyano-
6-oxo-1,4,5,6-tetrahydropyridine-2-olate (1), may be synthesized under mild conditions by the Michael reaction
of readily available 1-cyanoacetyl-3,5-dimethylpyrazole 2 [22, 23] with 3-(2-chlorophenyl)-2-cyanoacrylamide
3. Pyridinolate 1 is formed in 76% yield as a mixture of cis and trans diastereomers and, according to the
1H NMR spectrum, does not contain oxidation product impurities. This method is the first efficient procedure for
preparing 4-aryl-ubstituted Guareschi imides and one of the first examples of the use of azolide 2
as an active methylene compound serving as an alternative to ethyl cyanoacetate. Work on the optimization of
the method and clarification of its scope is currently underway.
_______
*To whom correspondence should be addressed, e-mail: Victor_Dotsenko@bigmir.net.
1G.S. Petrov Research Institute of Plastics, Perovsky proezd 35, Moscow 111024, Russia.
2ChemEx Laboratory, Volodimir Dahl East Ukrainian National University, 20a, build. 7 Molodezhnyi Qr.,
Lugansk 91034, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1108–1110, July, 2011. Original
article submitted March 2, 2011.
0009-3122/11/4707-0913©2011 Springer Science+Business Media, Inc.
913

Ar
O
O
Me
Et3N,
Me2CO
NC
O
CN
NC
Ar
NC
NH2
N
N
+
N
H
O
+
Me
Et3NH
3
2
1
1, 3 Ar = 2-ClC6H4
1
13
The IR spectra were obtained on an IKS-29 spectrometer in nujol mulls. The H and C NMR spectra
were taken on a Bruker DRX-500 spectrometer at 500 and 125 MHz, respectively, in DMSO-d6 with TMS as
internal standard. The elemental analysis was carried out on a Perkin-Elmer CHN analyzer.
Triethylammonium 4-(2-Chlorophenyl)-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridin-2-olate (1).
Triethylamine
dried
over
KOH
(1.2 ml,
8.6 mmol)
was
added
to
a
mixture
of
(E)-3-(2-chlorophenyl)-2-cyanoacrylamide 3 (1.20 g, 5.8 mmol) and cyanoacetylpyrazole 2 (1.10 g, 6.7 mmol)
in warm acetone (15 ml). The flask with the reaction mixture was left at 10–15°C for 72–120 h. The white
crystalline precipitate was filtered off and washed with cold acetone and ether to give 1.64 g (76%) pure salt 1;
mp >250°C; Rf 0.69 (acetone–hexane, 1:1). Attention! This compound causes sneezing. IR spectrum, , cm–1:
1
3170 (NH), 2255 (unconj. C≡N), 2175 (C≡N), 1695 (C=O). H NMR spectrum, , ppm (J, Hz): 1.16 (9H, t,
3
3J = 7.1, 3CH3CH2); 3.05 (6H, q, J = 7.1, 3CH3CH2); 4.19–4.79 (2H, m, superposition of signals of
diastereomeric H-4 and H-5); 7.27–7.50 (4H, m, H Ar); 9.71 (1H, br. s, NH). The signals of the NH+ proton are
not seen due to deuterium exchange. 13C NMR spectrum, , ppm: 9.34, 37.30, 41.78, 46.31, 128.07, 128.17,
129.10, 129.32, 129.75, 129.97, 133.13, 133.70, 138.47, 140.50, 164.32, 164.51. Found, %: C 61.14; H 6.24;
N 14.90. C19H23ClN4O2. Calculated, %: C 60.88; H, 6.18; N 14.95.
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