Anatoliy M. Shestopalov

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.

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, Structure, Chemical Reactivity, and Practical Significance of 2-Amino-4H-pyrans

Publisher Summary The class of 2-amino-4H-pyrans has been known for several decades. Most of the 2-amino-4H-pyrans are colorless, pale-yellow, or pale-cream crystals with high melting points. They are readily soluble in aromatic hydrocarbons, alcohols, acetone, acetonitrile, chloroform, DMF, and DMSO, and nearly insoluble in hexane and water. This chapter focuses on the structure, synthesis, chemical properties, and applications of 2-amino-4H-pyrans. It highlights the use of computational studies, X-ray structural analysis, UV spectroscopy, IR spectroscopy, NMR spectroscopy, and mass spectrometry for the analysis of the structure of 2-amino-4H-pyrans and their physicochemical properties. The most widely known 2-amino-4H-pyrans contain a primary amino group. The general synthetic approach involves cyclization of Michael adducts via nucleophilic addition of an enolic oxygen to a nitrile group and subsequent tautomeric shift of the resultant 2-iminopyran to 2-aminopyran. Acyclic intermediates can be generated from appropriate Michael donors and acceptors, such as methylene-active carbonyl compounds and unsaturated nitriles, or from α,β-unsaturated carbonyl compounds and CH-acidic nitriles. The chapter describes the synthesis of non-annulated 2-amino-4H-pyrans 2-amino-4H-pyrans annulated with five to seven-membered carbocycles 2-amino-4H-benzopyrans, heteroannulated 2-amino-4H-pyrans, and spiro-conjugated 2-amino-4H-pyrans. 2-amino-4H-pyrans are used mainly for biological purposes, such as inhibition of smooth muscle cell proliferation, cell growth inhibition, and arterial intimal thickening after balloon angioplasty when administered systematically. Assays of acetyl- and butyrylcholine esterases inhibition, as well as of the modulation of calcium channels and nicotinic receptors have been conducted in vivo. Also among the fused aminopyrans, 2-amino-4H-chromenes draw especial attention due to their broad biological potential.

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.

One-Step Synthesis of Substituted 3,5-Dicyanospiro-4-(piperidine-4′)-1H,4H-dihydropyridine-2-thiolates and 2,6-Diamino-3,5-dicyanospiro-4-[(piperidine-4′) or (2′-oxoindole-3′)]-4H-thiopyrans

A new, one-step method for the synthesis of substituted 3,5-dicyanospiro-4(piperidine-4′)-1H,4H-dihydropyridine-3-thiolates and 2,6-diamino-3,5-dicyanospiro-4-[(piperidine-4′) or (2′ -oxoindole-3′)]-4H-thiopyrans using a multicomponent reaction of N-substituted piperidine-4-ones and isatins with derivatives of cyanoacetic acid is described. The regioselectivity of this reaction can be controlled by varying the substituents at the nitrogen atom of the piperidine-4-ones. The multicomponent reaction of N-alkylpiperidine-4-ones with malononitrile and cyanothioacetamide gives spiro-4-(1′ -alkylpiperidine-4′)-1H,4H-dihydropyridine-2-thiolates, whereas a similar reaction of N-(acyl)alkoxycarbonylpiperidine-4-ones leads exclusively to spiro-4-(1′ -(acyl)alkoxycarbonylpiperidine-4′)-4H-thiopyrans.

Synthesis of Fluorinated Pyridines

Present review contains recent literature data published since 2009 for 2012 as till 2009 four reviews on this field have been published. The methods of synthesis of 2-, 3-, 4-fluoropyridines, di-, tri-, polyfluoropyridines, perfluoroalkylpyridines and also fluoropyridines fused with carbo-, heterocycles are presented. Methods for synthesis of F18 substituted pyridines for local radiotherapy of cancer and other biological active compounds are also presented.