Syntheses of 4-benzylpyridones via nucleophilic aromatic substitutions

Different strategies were studied for the preparation of analogues of poten t biarylmethanes non-nucleoside reverse transcriptase inhibitors. We undert ook 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-ca rbonitrile. Preparation of the former was achieved from the anion of 4-meth yl-5-ethyl-2,6-dimethoxynicotinonitrile either by a nucleophilic aromatic s ubstitution reaction on 3,5-dimethyl iodobenzene or starting with a nucleop hilic addition reaction on 3,5-dimethylcyclohexanone. Cyclic analogues were prepared by an unprecedented nucleophilic aromatic substitution of, for ex ample, 3,5-dimethyliodobenzene with the dianion of 4-methyl-6-oxo-2,3,6,7-t etrahydrofuro[2,3-b]pyridine-5-carbonitrile. None of the herein described n ew compounds showed anti HIV-1 activity or cytotoxicity on cellular assays (CEM-SS and MT4).