Pd-Catalyzed Chemoselective O-Benzylation of Ambident 2-Quinolinone Nucleophiles

We have discovered and developed a highly chemoselective O-benzylation of ambident 2-quinolinone nucleophiles via Pd-catalysis. Detailed reaction analysis using direct-injection high resolution mass spectrometry (DI-HRMS) combined with in situ 31P NMR implicate a phosphine mono-oxide Pd(II) eta 1-benzyl complex as a key intermediate on the catalytic cycle. Extrapolation of this method to selectively O-alkylate a series of substituted 2-quinolinones using several benzylic electrophiles is demonstrated providing 2-benzyloxy quinolines in good yields and high O:N selectivities (up to 100:1) utilizing as little as 1 mol % Pd-catalyst to achieve these results.