Utility of isatin in synthesis of heterocycles of anticipated biological activity

Abstract

Isatin and some of its derivatives are used in this investigation on the hope of getting heterocyclic compounds bearing indolinone moiety to enhance their biological activities.Thus,2 - (2- oxindolin -3 - ylidene) malononitrile (1a) or (E,Z)ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate (1b) or isatin-β-thiosemicarbazone (1c) undergo reactions with prototype hydrazine hydrate itself and some of its simple congeners and gave hydrazone derivatives bearing indoline-2-one moiety (2a-d). Refluxing of (E,Z) ethyl 2-cyano-2-(2-oxindolin-3-ylidene)acetate (1b) with hydroxylamine hydrochloride in ethanol and a catalytic amount of ammonium acetate produced the oxime derivative 3.Treatment of 1a, b with o-phenylenediamine in acetic acid yielded 5H-indolo[2,3-b]quinoxaline(4) in one-pot reaction. On the other hand the reaction of 1a with o-phenylenediamine in ethanol produced di-hydroquinoxaline derivative 5 in good yield. The reaction of hydrazide derivative 6 and isatin 1 in ethanol afforded the hydrazone derivative 7 in a good yield. Refluxing of isatin1 and imidazolone derivative 8 in n-butanol produced compound 9 in a good yield. The reaction of isatin 1 with 2-benzamidoacetic acid in acetic anhydride not afforded the expected oxazolone derivative 10, instead it produced the open adduct 11. On the other hand the reaction of 1 with p-nitrobenzyl cyanide in the presence of a catalytic amount of triethyl amine gave a mixture of diastereo isomers of 12. We aimed to undergo benzoylation or acylation to compounds 1a and 1b hoping to prevent the removal of dicyano methylene of orcyanocarboethoxy methylene moieties of compounds 1a 1b by the action of hydrazines.Heating of 1a with benzoyl chloride in dry acetone in the presence of anhydrous potassium carbonate as a base yielded an adduct which was proved to be a mixture of two compounds, the 2-(1-benzoyl-2-oxindolin-3-ylidene) malononitrile (13) and ethyl 2-(2-benzamidophenyl)-3,3-dicyanoacrylate (14). Compound 14 is formed by ring opening of 13 during its crystallization with ethanol. Heating of compounds 1a and 1b in acetic anhydride furnished compounds 15a,b as a mixture of N-acetyl and O-acetyl derivatives in addition to ethyl 2-amino-3-cyanoquinoline-4-carboxylate (16) in case of the reaction with 1a. Treating an ethanolic solution of 15a with hydrazine hydrate yielded the cinnoline derivative 18 in addition to a minor amount of the hydrazone derivative 2a. Similar treatment of compound 15b with hydrazine hydrate gave the N-acetyl hydrazone 19 and small amounts of the hydrazone derivative 2a.The reactions of 15a and 15b with phenyl hydrazine furnished (Z)-1-acetyl-3-(2-phenyl hydrazono) indolin-2-one (20), beside compound 2b in minor amount.