2-Quinolinones are a privileged pharmacophore found in numerous examples of biologically active natural products and active pharmaceutical ingredients. While several synthetic methods currently exist to selectively N-alkylate 2-quinolinones, selective O-alkylation persists as an unmet synthetic challenge where limited success has been realized to date. As part of our ongoing collaborations between the Chemical Process Development (CPD) group at BMS and the Frantz group at UTSA, we have discovered a practical Pd-catalyzed method to O-alkylate 2-quinolinones using benzylic electrophiles with unprecedented selectivity over N-alkylation (O:N &gt; 100:1 in most examples). A broad range of substituted 2-quinolinones have been successfully implemented in this chemistry as well as several related pyridones. Preliminary mechanistic investigations along with highlights and limitation of the method will be presented.

Pd-Catalyzed O-Selective Alkylation of 2-Quinolinones

ACS Spring 2022

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