While optimizing the synthesis of pharmaceutical building block 3  [ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate], we encountered an unusual addition of an aryllithium reagent to the ketone oxygen atom of diethyl ketomalonate. Compound 3  was ultimately prepared on large scale by a two-step sequence involving (1) annulation of a functionalized Grignard reagent with diethyl ketomalonate and (2) selective mono-reduction of a geminal diester using lithium tri-tert-butoxyaluminum hydride.

1,4-Addition of an aryllithium reagent to diethyl ketomalonate: Scalable synthesis of ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate

244th National Meeting (2012)

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