Synthesis of 2-Aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones

Abstract

Bromination of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates gave ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazol-3-carboxylates which were used to alkylate benzenethiol and heterocyclic thiones at the sulfur atom. Reactions of the resulting S-alkylation products with hydrazine or methylhydrazine involved closure of pyridazine ring to afford 2-aryl-3-methyl-4-[phenyl(or hetaryl)sulfanylmethyl]-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.1-Arylpyrazoles having functional substituents at positions 3 and 4 attract interest as reagents for the synthesis of more complex heterocyclic assemblies, including fused heterocyclic systems [1-3], and design of new pharmacologically active agents [4-6], as well as electroluminescent materials [7]. We previously reported on effective procedure for the synthesis of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates I by reaction of arenediazonium salts II with ethyl 2-chloroacetoacetate (Japp-Klingemann reaction), followed by condensation of hydrazones III thus formed with acetylacetone (Scheme 1). It was also reported that compounds I react with hydrazine and its derivatives to give products in which pyridazine ring is fused at the c side of the pyrazole ring [2].In the present article we report on the synthesis of previously unknown pyrazole derivatives, 2-aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones. For this purpose, in the first step pyrazoles Ia-Ie were subjected to bromination of at the acetyl fragment on C 4 . The optimal bromination procedure was treatment of solutions of Ia-Ie in acetic acid with bromine in the presence of a catalytic amount of sulfuric acid. We thus obtained ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazole-3-carboxylates IVa-IVe (Scheme 2).α-Halo ketones are convenient reagents for the alkylation of various nucleophiles [8]. Such transformations of bromo ketones IV could give rise to many polyfunctional 1-arylpyrazole derivatives. We used compounds IVa-IVe to perform S-alkylation of benzenethiol (V) and various heterocyclic thiones VI-X. The reactions were carried out by heating the reactants in ethanol in the presence of triethylamine. As a result, the corresponding 4-[phenyl(hetaryl)sulfanylacetyl]-pyrazoles XI-XVI were isolated (Scheme 2). Ethyl 1-aryl-5-methyl-4-(R-sulfanylacetyl)-1H-pyrazole-3-carboxylates XI-XVI are polyfunctionalized compounds and are therefore convenient building blocks for the design of fused heterocyclic systems. By reaction of compounds XI-XVI with hydrazine or methylhydrazine we obtained previously unknown pyrazolo-[3,4-d]pyridazin-7-ones XVII-XXVII (Scheme 3).To conclude, we have developed an efficient procedure for the synthesis of functionally substituted 2-aryl-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.