No abstract

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.

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.

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.

M u l t i c o m p o n e n t R e a c t i o n s o f C a r b o n y l C o m p o u n d s

A single step method for the synthesis of substituted 7 aminopyrano[2,3 d]pyrimidines was developed. The method involves a three component reaction of barbituric acid or 4,6 dihydroxypyrimidine with aromatic aldehydes and malononitrile in DMF in the presence of N methylmorpholine as a catalyst. Key words: malononitrile, barbituric acid, 4,6 dihydroxypyrimidine, pyrano[2,3 d]pyri midines. Scheme 1 1, 8: Ar = Ph (a), 4 ClC 6 H 4 (b) Reagents and conditions: i. DMF, N methylmorpholine, 15 min, 90-95 °C. Synthesis of 7 aminopyrano[2,3 d]pyrimidinesRuss.

No abstract

Polyfunctional 4-(3-cyanopyridin-2-ylthio)acetoacetates were used in the synthesis of 4-hydroxy-1H-thieno [2,3-b:4,5-b]dipyridin-2-ones. The latter were used in reactions with arylidenemalononitriles or in three-component reactions with aldehydes and malononitrile to give 2-amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido [3¢,2¢:4,5]thieno [3,2-b]pyridines. Utilizing 4-(3-cyanopyridin-2-ylthio)acetoacetates and arylidenemalononitriles or aldehydes and malononitrile, we developed a method for the synthesis of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans. Reactions of substituted 4-(3-cyanopyridin-2-ylthio)acetoacetates with hydrazine hydrate yielded substituted 3-hydroxypyrazoles, which were further used for the preparation of 6-amino-4-aryl-5-cyano-3-(pyrid-2-ylthiomethylene)-2,4-dihydropyrano[2,3-c]pyrazoles. Analogously, ethyl 4-(3-cyano-1,4-dihydropyridin-2-ylthio)acetoacetates were used for the synthesis of substituted 2-amino-4H-pyrans.We have previously reported that 4-(3-cyanopyridin-2-ylthio)acetoacetates (3) are convenient starting reagents for the syntheses of 4-hydroxy-1H-thieno[2,3-b:4,5-b]dipyridin-2-ones that are otherwise difficult to prepare. 1 Considering that compounds of type 3 contain several reaction centers, we decided to study the ability of these compounds to undergo a range of reactions in order to develop new routes to relatively inaccessible heterocycles, including new heterocyclic systems. Products of these reactions are of interest for several reasons, but mainly because of their similarity to the highly physiologically active hydroxy(oxo)pyridines 2,3 and 2-amino-4H-pyrans, which are licensed as drugs, pesticides, and other practically significant compounds. 4-8 It therefore seemed of practical interest to prepare substances containing simultaneously both pyridine and pyran rings.Substituted 4-(3-cyanopyridin-2-ylthio)acetoacetates 3, can be readily synthesized from 3-cyanopyridine-2(1H)-thiones 1 and 4-chloroacetates 2 and can be further transformed into 4-hydroxy-1H-thieno[2,3-b:4,5-b]dipyridin-2-ones 4 by successive Thorpe-Ziegler and GuareschiThorpe 1 intramolecular ring closures (Scheme 1).We decided to use thienodipyridinones 4 and their hydrogenated analogues for the synthesis of annealated pyrans of type 6, which represent a novel heterocyclic system. 9 Compounds 4, similar to 4-hydroxyquinolin-2(1H)-one, 10,11 react as CH-acids with arylidenemalononitriles 5 in the presence of triethylamine or N-methylmorpholine in DMF to afford 2-amino-4-aryl-3-cyano-5,6-dihydro-5-oxo-4H-pyrano[2,3-d]pyrido[3¢,2¢:4,5]thieno[3,2-b]pyridines 6a-e (method A). Compounds 6a-d were also obtained by three-component reaction of thienodipyridinones 4, aromatic aldehydes 7, and malononitrile 8 (method B) (Scheme 1).