L. A. Rodinovskaya

ADVANCES IN THE CHEMISTRY OF 3-CYANOPYRIDIN-2(1H)-ONES, -THIONES, AND -SELENONES

Abstract This review is concerned with the synthesis, structure, physico-chemical properties and reactivity of 3-cyanopyridin-2(1H)-ones, -thiones, and -selenones and their derivatives. The 3-cyanopyridin-2(1H)-ones, -thiones, and -selenones being bifunctional compounds containing nitrile and amide, thioamide, or selenoamide groups with an endocyclic nitrogen atom are widely used in the synthesis of different classes of annelated heterocycles possessing practically important properties.

Cross-condensation of derivatives of cyanoacetic acid and carbonyl compounds. Part 1: Single-stage synthesis of 1′-substituted 6-amino-spiro-4-(piperidine-4′)-2H,4H-pyrano[2,3-c]pyrazole-5-carbonitriles

Abstract To develop a method of synthesis of the potentially physiologically active compounds, 1′-substituted 6-amino-spiro-4-(piperidine-4′)-2 H ,4 H -pyrano[2,3- c ]pyrazoles, we studied the three-component condensation of substituted piperidin-4-ones, malononitrile and pyrazolin-5-ones. It was found that the electrochemical method of synthesis is more regioselective, the products of the reaction are analytically pure and do not require further recrystallization.

Polyalkoxy Substituted 4H‑Chromenes: Synthesis by Domino Reaction and Anticancer Activity

A series of 4H-chromenes containing various modifications in the ring B and polyalkoxy substituents in the ring E has been synthesized by Knoevenagel-Michael-hetero-Thorpe-Ziegler three-component domino reaction with the overall yield of 45-82%. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antimitotic and microtubule destabilizing activity. The most active compounds 5{1,5} and 5{5,5} featured sesamol-derived ring B and m-methoxyphenyl or m-methoxymethylenedioxyphenyl ring E. Compounds 5{3,1}, 5{1,2}, 5{5,4}, 5{1,5}, and 5{5,5} exhibited strong cytotoxicity in the NCI60 human tumor cell line anticancer drug screen. Surprisingly, cell growth inhibition caused by these agents was more pronounced in the multidrug resistant NCI/ADR-RES cells than the parent OVCAR-8 cell line. The results suggest that polyalkoxy substited 4H-chromenes may prove to be advantageous for further design as anticancer agents.

N-Cyanochloroacetamidine — A convenient reagent for the regioselective synthesis of fused diaminopyrimidines

Abstract N-Cyanochloroacetamidin reacts wit conjugated thiolato(selenolato)nitriles to give product of regioselective S(Se) alkylation that can subsequently be involved in the Thorpe reaction. Resulting enaminocyanamidines form pyrimidine rings under acid or base catalysis forming fused diaminopyrimidines. According to this common scheme, functionally substituted thieno[3,2-d]pyrimidines, thiazolo[4,5-d]pyrimidines, pyrimido[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2-d]pyrimidine, pyrido[3′,2′4,5]thieno(selenopheno)[3,2-d]pyrimidines, their hydrogenated analogues, and pyrimido-[4′,5′:4,5]thieno[2,3-d]pyrimidine were synthesized.

One-pot synthesis of diverse 4-di(tri)fluoromethyl-3-cyanopyridine-2(1H)-thiones and their utilities in the cascade synthesis of annulated heterocycles.

Diverse substituted 4-di(tri)fluoromethyl-3-cyanopyridine-2(1H)-thiones were synthesized via the Claisen condensation of alpha-methyl(methylene)ketones with di(tri)fluoroacetate, followed by the immediate Thorpe-Guareschi reaction of the preformed di(tri)fluoromethyl-1,3-diketones with cyanothioacetamide. The procedure allows facile synthesis of the di(tri)flouromethylated pyridine-2(1H)-thiones in 50-95% yields, without the need for isolation and purification of intermediates. Resultant 4-di(tri)fluoromethyl-3-cyanopyridine-2(1 H)-thiones were subsequently utilized in domino reactions to produce first various substituted thieno[2,3-b]pyridines and, then, thienopyridines polyannulated with pyridine, pyrimidine, benzodiazocine, diazepine, and pyran rings.

Synthesis of substituted 4-hydroxy-1H-thieno[2,3-b;4,5-b′]dipyridin-2-ones

Substituted 4-hydroxy-1H-thieno[2,3-b;4,5-b′]dipyridin-2-ones were prepared by the reactions of 3-cyanopyridine-2(1H)-thiones with alkyl 4-chloroacetoacetates and by intramolecular cyclization of alkyl 4-(2-pyridylthio)acetoacetates or alkyl 3-(3-aminothieno[2,3-b]pyridin-2-yl)-3-oxopropionates under the action of bases.

Cross reactions of cyanoacetic acid derivatives with carbonyl compounds 3. One-step synthesis of substituted 2-amino-5-oxo-4,5-dihydropyrano[3,2-c]chromenes

Three-component reactions of 4-hydroxycoumarin, carbonyl compounds, and malono-nitrile or alkyl cyanoacetates in ethanol in the presence of Et3N as a catalyst give substituted 2-amino-5-oxo-4,5-dihydropyrano[3,2-c]chromenes.

Synthesis of Isomeric Isothiazolo[4′,3′:4,5]- and Isothiazolo[4′,5′:4,5]thieno[3,2-b]pyrano[2,3-d]pyridines by Combination of Domino Reactions

Isothiazolothienopyridines have been prepared by a domino reaction (the SN2 reaction → the Thorpe-Ziegler reaction → the Thorpe-Guareschi reaction type) from disodium 4-cyanoisothiazole-3,5-dithiolate. By changing the order of addition of the alkylation reagents in the reaction with disodium 4-cyanoisothiazole-3,5-dithiolate both possible isomers of the isothiazolothienopyridines are synthesized. These isomers were further used in three-component domino reaction (the Knoevenagel reaction → the Michael reaction → the hetero-Thorpe-Ziegler reaction type) to obtain wide range of isomeric isothiazolothienopyranopyridines.

Synthesis of 2,5-Asymmetrically Substituted 3,4-Diaminothieno[2,3-b]thiophenes by Domino Reaction

A convenient one pot synthesis of 2,5-asymmetrically substituted thieno[2,3-b]thiophenes is developed. The method is based on consecutive domino reactions (SN2 reaction → Thorpe-Ziegler reaction) using malononitrile and carbon disulfide as starting materials with the generation of potassium 2,2-dicyanoethene-1,1-bis(thiolate) in a solution. The high yield of the target thienothiophenes was achieved using the Ziegler dilution effect.

Cross-condensation of derivatives of cyanoacetic acid and carbonyl compounds. 2. One-pot synthesis of substituted 2-amino-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyrans in ethanol and ionic liquid [bmim][PF6]

The three-component reaction of 4-hydroxy-6-methylpyran-2(2H)-one with cyanoacetic acid derivatives and carbonyl compounds in EtOH or in the ionic liquid, viz., 1-butyl-3-methylimidazolinium hexafluorophosphate ([bmim][PF6]), affords substituted 2-amino-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyrans. The yield of substituted pyrano[4,3-b]pyrans in [bmim][PF6] is by 10—14% higher than that in EtOH.