Method for preparing 1-allyl-4-oxo-2-thioxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile

Abstract

FIELD: organic chemistry.SUBSTANCE: invention relates to the technology of synthesizing 1-allyl-4-oxo-2-thioxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile of formula (1), which can find application as a compound with targeted biological action or a reagent for obtaining practically significant organic compounds. The method of production involves a multicomponent reaction of cyclohexanone, cyanoacetic ester, cyanothioacetamide and allyl bromide in ethanol in the presence of N-methylmorpholine under boiling.EFFECT: obtaining the target product with a yield of 63%.1 cl, 2 ex

Description

[0001] The invention relates to a method for producing 1-allyl-4-oxo-2-thioxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile of formula (1):

[0002] ,

[0003] which can find its application as a compound with targeted biological action or a reagent for obtaining practically significant organic compounds.

[0004] Hydrogenated pyridines are components of a large number of natural and synthetic biologically active compounds [Vitaku E., Smith DT, Njardarson JTJ Med. Chem. 2014, 57 (24), 10257-10274. doi 10.1021 / jm501100b; Khamitova AE, Berillo DA Drug Develop. Registr. 2023, 12 (2), 44-54. doi 10.33380 / 2305-2066-2023-12-2-44-54; De la Torre BG, Albericio F. Molecules. 2022,27(3), 1075. doi 10.3390 / molecules27031075], the search for new accessible methods for the synthesis of their derivatives is an important task in organic chemistry.

[0005] Compound 1 was previously unknown. Its isomer 2 has been described in the literature [Dyachenko VD, Mitroshin AE, Litvinov VP Chem. Heterocycl. Comp. 1996, 32(9), 1058-1065. doi 10.1007 / bf01164713]. The synthesis of this substance is carried out in two stages. First, by reacting cyclohexylidene cyanoacetic ester with cyanothioacetamide or cyclohexylidene cyanothioacetamide with cyanoacetic ester in ethanol at 20 °C in the presence of N-methylmorpholine, an organic salt, N-methylmorpholinium 1,5-dicyano-4-oxo-3-azaspiro[5.5]undec-1-ene-2-thiolate (3), was obtained in yields of 84 and 90%. It was then treated with allyl bromide in ethanol at the same temperature, which formed the 2-allylthio derivative2 in 79% yield.

[0006]

[0007] Furthermore, it is known that derivatives of hydrogenated 2-allylthio-3-cyanopyridines, when heated, are capable of undergoing a [3,3]-sigmatropic allylic rearrangement [Dyachenko VD, Baryshev BN, Nenajdenko VG Russ. Chem. Rev. 2022, 91 (8), RCR5039. doi 10.1070 / RCR5039] with the formation of hydrogenated 3-allyl-3-cyanopyridine-2(1H)-thiones, for example, a derivative5 similar in structure to compound1 was obtained from tetrahydropyridone4 in benzene [Krivokolysko SG, Dyachenko VD, Nesterov VN, Litvinov VP Chem. Heterocycl. Comp. 2001, 37 (5), 315-319. doi 10.1023 / A:1017555032309].

[0008]

[0009] The prototype of the claimed method of production can be attributed to the multicomponent condensation of cyclohexanone, cyanoacetic ester, cyanothioacetamide and piperidine in ethanol at 20 °C, as a result of which piperidinium 1,5-dicyano-4-oxo-3-azaspiro[5.5]undec-1-ene-2-thiolate (6) was synthesized with a yield of 67% [Krivokolysko SG, Frolov KA, Litvinov VP Chem. Heterocycl. Comp. 2001, 37 (5), 645-646. doi 10.1023 / A:1011673009239], and its 2-alkylthio derivatives7 were obtained upon alkylation.

[0010]

[0011] Ar = 4-ClC6H4, 4-EtC6H4

[0012] The object of the present invention is to develop a method for synthesizing 1-allyl-4-oxo-2-thioxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (1).

[0013] The technical result of the proposed invention is the expansion of the arsenal of available methods for obtaining hydrogenated pyridines.

[0014] This is achieved by a multicomponent reaction of cyclohexanone, cyanoacetic ester, cyanothioacetamide, and allyl bromide in ethanol in the presence of N-methylmorpholine under reflux. This approach involves the sequential formation of intermediate compounds 2,3 in the reaction mixture without their isolation, followed by the subsequent transformation of the latter into the target product under high temperature conditions. After filtration and washing with ethanol and hexane, compound 1 was isolated in 63% yield.

[0015]

[0016] The invention is illustrated by the following examples.

[0017] Example 1. Synthesis of 1-allyl-4-oxo-2-thioxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (1)

[0018] With continuous stirring, 0.27 ml (2.5 mmol) of N-methylmorpholine was added to a mixture of 0.52 ml (5 mmol) of cyclohexanone and 0.53 ml (5 mmol) of cyanoacetic ester in 15 ml of ethanol at 25 °C; after 10 min, 0.501 g (5 mmol) of cyanothioacetamide and 0.55 ml (5 mmol) of N-methylmorpholine were added; The reaction mixture was refluxed for 30 min, filtered through a folded paper filter and left for 24 h. The separated product was separated, washed with ethanol and hexane. Yield 0.905 g (63%), light yellow powder.

[0019] Example 2. Study of the structure of 1-allyl-4-oxo-2-thioxo-3-azaspiro[5.5]undec-1-ene-1,5-dicarbonitrile (1)

[0020] T. mp. >180 °C (initial decomposition). IR spectrum, ν, cm -1 : 3189 (NH), 2235 ff. (C≡N), 1681 (C=O). NMR spectrum 1 N, δ, ppm: 1.28-1.78 m (10H циклогексан ); 2.77-2.83 m (2H, C N2CH=); 4.61 s (1H, CHC≡N); 5.05-5.13 m (2H, =CH2); 5.71-5.74 m (1H, =CH–); 9.12 ush. s (1H, NH). NMR spectrum 13 C, δ, ppm: 20.8, 20.9, 24.6, 31.7, 31.8, 34.9 (6C циклогексан ), 36.8 ( C H2CH=), 42.3 ( C HC≡N), 93.0 ( C C≡N), 115.9, 118.2 (2C≡N), 118.6 (CH= C H2), 137.5 ( C H=CH2), 160.4 (C=O), 208.7 (C=S). Found, %: C 62.63; H 5.91; N 14.56. C 15 H 17 N3OS. Calculated, %: C 62.69; H 5.96; N 14.62.M287.4.

[0021] Based on the above, it can be concluded that the proposed technical solution is new, has distinctive features and can be scaled up for use in organic chemistry to obtain functionally substituted hydrogenated pyridines.

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