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Synthesis

Adding Pep To PEPPSI

Cross-Coupling: Chemists develop a better catalyst for adding secondary alkyl groups to five-membered heterocycles

by Stephen K. Ritter
July 6, 2015 | APPEARED IN VOLUME 93, ISSUE 27

The secret to the palladium-catalyzed cross-coupling reactions is often the judicious choice of catalyst ligand. Michael G. Organ’s group at York University, in Toronto, in collaboration with researchers at Dow Chemical and Eli Lilly & Co., have revealed a bit more of that secret by learning how to tweak the structure of a pyridine-N-heterocyclic-carbene-based ligand system called PEPPSI to carry out selective Negishi couplings of secondary alkyl groups with five-membered heterocyclic rings, a reaction not possible before (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201503941). Negishi coupling works for adding branched alkyl groups to six-membered rings, but attempts to do the same with five-membered rings gave a mixture of linear and branched isomers. Organ’s group found that adjusting the structure of a commercial PEPPSI ligand they previously developed, by switching from isopentyl to isoheptyl substituents and adding chlorines, increases the bulk and alters the electronic properties to favor the desired branched isomers.

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Increasing the length of the phenyl alkyl groups and adding chlorines to the N-heterocyclic carbene in the PEPPSI ligand allows chemists to carry out selective secondary alkyl couplings with five-membered-ring heterocycles for the first time.
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