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Synthesis

Palladium-Mediated Insertive Behavior

Studies pin down key intermediates in versatile migratory alkene insertion reactions

by Stephen K. Ritter
June 7, 2010 | A version of this story appeared in Volume 88, Issue 23

Two research groups have independently reported the first experimental observation of postulated highly reactive intermediates in palladium-catalyzed migratory insertion reactions of alkenes with amide ligands. By characterizing these fleeting intermediates, organic chemists have gained a better mechanistic understanding of the stereochemical control possible in alkene functionalization reactions.

During migratory alkene insertions, an alkene ligand on the metal complex serves as a reactant by migrating and inserting into a metal-ligand bond. The reaction can occur in a syn fashion, with two substituents adding to the same side of the alkene double bond, or in an anti fashion, with the substituents adding to opposite sides of the alkene. Syn insertion of alkenes into Pd–N bonds has been proposed as a key step in a number of palladium-catalyzed reactions, but chemists have not been able to prove it by direct observation until now.

In one study, Joshua D. Neukom, Nicholas S. Perch, and John P. Wolfe of the University of Michigan, Ann Arbor, identified the palladium intermediate involved in the syn intramolecular insertion of the terminal alkene of an alkenylamido ligand into its Pd–N bond (J. Am. Chem. Soc. 2010, 132, 6276). In another study, Patrick S. Hanley, Dean Markovic´, and John F. Hartwig of the University of Illinois, Urbana-Champaign, identified the palladium intermediate in the syn intermolecular insertion of an olefin into an adjacent Pd–N bond (J. Am. Chem. Soc. 2010, 132, 6302).

Observing this stoichiometric alkene insertion is an important contribution to organometallic chemistry because it aids understanding of several synthetically useful palladium-catalyzed processes, including alkene aminations and olefin polymerizations, notes Mark Stradiotto of Canada’s Dalhousie University, whose group focuses on transition-metal-catalyzed aminations. “These two reports provide a mechanistic framework that is certain to encourage the further development of novel catalytic transformations involving alkene insertion into a palladium-amido bond,” Stradiotto says.

Wolfe and coworkers treated an aryl palladium complex with an aryl pentenylamine to form a palladium arylamido complex. The pendant alkene group quickly underwent syn insertion selectively into the Pd–N amide bond, rather than into the adjacent Pd–C aryl bond, to generate the key alkylpalladium intermediate, which the team characterized spectroscopically. The species subsequently formed a 2-benzylpyrrolidine product in high yield at room temperature.

Hartwig and coworkers prepared several palladium diarylami­do complexes that add an olefin—either ethylene or 1-octene—to form the key intermediate. They were able to track the rapid syn insertion of the palladium-bound olefin into the Pd–N amide bond at low temperature and subsequent formation of the enamine products in high yields.

Both studies required carefully executed low-temperature multinuclear magnetic resonance studies of the reactive intermediates, detailed kinetic analyses that included examining substituent effects, and isotopic labeling studies to confirm the reaction pathways.

“The combination of these studies by our two groups provides a view of the reaction coordinate before, during, and after the insertion process,” Hartwig says. “The fast rates for insertion counter previous conclusions that insertions of alkenes into metal-heteroatom bonds should be slow.”

These mechanistic studies by Hartwig and Wolfe describe “a key step in catalytic amination of alkenes,” comments Tamio Hayashi of Japan’s Kyoto University, an expert in transition-metal catalysis and the mechanisms of organometallic reactions. “Although the reaction pattern is different in terms of inter- or intramolecular reactions, both succeed in establishing the syn stereochemistry at the primary aminopalladation step,” Hayashi says. “These results provide significant information on further extending catalytic functionalization of alkenes.”

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