The pd-catalyzed decarboxylative allylic alkylation has found widespread utility in organic synthesis, enabling the efficient construction of sp3-sp3 carbon-carbon bonds. Since its initial discovery, it has proven most successful for enolate and other “soft” nucleophiles that possess conjugate acid pKa’s of less than 25. On the other hand, application to “harder” nucleophiles such as benzylic substrates has remained less developed. Our group recently found that aromatic benzylic nucleophiles are sufficiently softened to undergo decarboxylative coupling under relatively mild reaction conditions. The resulting C3-substituted phthalides were obtained in good yield. The specific goal of this work was to develop an efficient synthesis of substrates bearing different substitution patterns on the allyl ester fragment. We found that 2-substituted allyl esters could be synthesized via acid-catalyzed esterification, while 3-substituted allyl esters required esterification under neutral conditions to avoid isomerization and decomposition. These studies will guide efforts to access to other related substrates, which will in turn provide efficient access to medicinally relevant phthalide derivatives.

Development of an efficient synthesis of 3,3-disubstuited phthalides for DAA

ACS Spring 2022

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