Syntheses of 4-Benzylpyridones via Nucleophilic Aromatic Substitutions

Abstract

Different strategies were studied for the preparation of analogues of potent biarylmethanes non-nucleoside reverse transcriptase inhibitors. We undertook the study of the possible routes for the preparation of 3-cyano-4-(3,5-dimethylbenzyl)-5-ethyl-6-hydroxypyridin-2(1H)-one and its cyclic analogue 4-(3,5-dimethylbenzyl)- 6-oxo- 2,3,6,7 - tetrahydrofuro [2,3 - b] pyridine-5 - carboni-trile. Preparation of the former was achieved from the anion of 4-methyl-5-ethyl-2,6-dimethoxynicotinonitrile either by a nucleophilic aromatic substitution reaction on 3,5-dimethyl iodobenzene or starting with a nucleophilic addition reaction on 3,5-dimethylcyclohexanone. Cyclic analogues were prepared by an unprecedented nucleophilic aromatic substitution of, for example, 3,5-dimethyliodobenzene with the dianion of 4-methyl-6-oxo-2,3,6,7-tetrahydrofuro[2,3-b]pyridine-5-carbonitrile. None of the herein described new compounds showed anti HIV-1 activity or cytotoxicity on cellular assays (CEM-SS and MT4).

Key words

HIV-1 - pyridines - arylation - nucleophilic aromatic substitution - S_RN1

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