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Published December 21, 2005 | Supplemental Material + Accepted Version
Journal Article Open

Oxidative Cyclizations in a Nonpolar Solvent Using Molecular Oxygen and Studies on the Stereochemistry of Oxypalladation


Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different types of nucleophiles:  phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electron-rich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same is true of the acid derivatives. The racemic conditions served as a platform for the development of an enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule out a "Wacker-type" mechanism involving anti oxypalladation and suggest that the reaction proceeds by syn oxypalladation for both mono- and bidentate ligands. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation.

Additional Information

© 2005 American Chemical Society. Received August 12, 2005; Publication Date (Web): November 15, 2005. The authors wish to thank the NIH-NIGMS (R01 GM65961-01), Bristol-Myers Squibb Company and the American Chemical Society (graduate fellowship to R.M.T.), the University of California TRDRP (postdoctoral fellowship to Y.K.R.), the Dreyfus Foundation, Merck Research Laboratories, Research Corporation, Abbott Laboratories, Pfizer, Amgen, GlaxoSmithKline, Lilly, and Johnson and Johnson for generous financial support. Drs. Eric Ferreira, Jonathan Owen, and Andrew Waltman are acknowledged for helpful discussions.

Attached Files

Accepted Version - nihms63208.pdf

Supplemental Material - ja055534ksi20050930_025347.pdf


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