Pd-Catalyzed Chemoselective O-Benzylation of Ambident 2-Quinolinone Nucleophiles
Melissa Cadena, Roberto Silva Villatoro, Jyoti Shah Gupta, Cody Phillips, Jonathan B. Allen, Hadi D. Arman, Daniel Wherritt, Nicholas A. Clanton, Alexander L. Ruchelman, Eric M. Simmons, Albert J. DelMonte, John R. Coombs, Doug E. Frantz
Abstract
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) η1-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.