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.

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.

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.

New convenient four-component synthesis of 6-amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles and one-pot synthesis of 6'-aminospiro[(3H)-indol-3,4'-pyrano[2,3-c]pyrazol]-(1H)-2-on-5'-carbonitriles.

This report describes a new four-component synthesis of substituted and spiro-conjugated 6-amino-2H,4H-pyrano[2,3-c]pyrazol-5-carbonitriles directly from aromatic aldehydes or heterocyclic ketones, malononitrile, beta-ketoesters, and hydrazine hydrate. The method provides a convenient one-pot route toward divers 2,4-dihydropyrano[2,3-c]pyrazoles, whereas a modified one-step sequential protocol gives access to spiro[indoline-3,4'-pyrano[2,3-c]pyrazol]-2-ones.

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.

One-step synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')- 2H,4H-dihydropyrazolo[3,4-b]pyrans.

Three-component condensation of 4-piperidinones (7), 5-pyrazolones (8), and malononitrile (4) proceeds chemically and electrochemically and is a convenient one-step means of synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')-2H,4H-dihydropyrazolo[3,4-b]pyrans (12). The electrochemical reactions proceed under milder conditions and with yields 12-15% greater than those of the reactions catalyzed by chemical bases.