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Monday, January 10, 2005
Douglass Taber
University of Delaware

Best Methods for C-C Bond Formation: Part One of Three

Carbon-carbon bond formation is fundamental to all of organic chemistry. Nucleophilic displacement is still the basis for most of what we do, but over the past thirty years radical addition and organometallic coupling have both been brought to a level of practical importance.

The conventional wisdom had been that since organometallic coupling necessitates formation of a carbon-transition metal bond, it is necessarily limited to substrates that lack β-hydrogens, since β-hydride elimination would be faster than intermolecular C-C bond formation. In recent years, systems have developed for the effective coupling of primary halides having β-hydrogens. Greg Fu at MIT has now reported (J. Am. Chem. Soc. 2004, 126, 1340. ) the development of ligand systems that allow the efficient cross-coupling of secondary halides such as 1 having β-hydrogens.

Professor Fu has also developed (J. Am. Chem. Soc. 2004, 126, 82. ) ligand-free methods for the effective Pd-mediated coupling of sp2-hybridized organozirconium reagents with primary halides. This procedure is compatible with a wide range of organic functional groups. The organozirconium reagents are prepared directly from the corresponding terminal alkynes by the addition of the commercially-available Cp2ZrClH. The ability to carry out the coupling without supporting ligands obviates the needs to remove the ligand after the reaction.

The difficulty of removing the last traces of the catalytic transition metal, especially of Pd, has put limits on the use of transition metal coupling reactions in the late stages of active pharmaceutical preparation. Kyotomi Kaneeda recently reported (J. Am. Chem. Soc. 2004, 126, 1604. ) the development of dendrimer-supported Pd complexes that efficiently catalyze Heck coupling. Solvent partitioning efficiently separated the Pd dendrimer from the coupled product. Since the products in this case were hydrocarbon-soluble, a thermomorphic hexane-DMF mixture was used for the separation. What will be needed for pharmaceutical preparation will be a dendrimer that is designed to partition the other way, into the hexane, leaving the pharmaceutical product in the DMF.

D. F. Taber, Org. Chem. Highlights 2005, January 10.