Saturated nitrogen-containing heterocycles are privileged structural motifs in biologically relevant compounds and are attractive structures for pharmaceutical screenings. As such, efficient methods to access these rings with reliable stereocontrol are of significant value. We targeted transition metal-catalyzed C–H functionalization to generate structural diversity and access rapidly chiral heterocycles. We have recently developed a Pd-catalyzed C(sp3)–H arylation of pyrrolidine and piperidine rings to access selectively cis-3,4-disubstituted derivatives. This was achieved using an aminoquinoline directing group at the 3-position to functionalize the unactivated C(4)–H bond. The reaction proceeded with high regioselectivity for the 4-position, despite the availability of a weaker C(2)–H bond. Excellent cis-stereoselectivity was achieved for the pyrrolidine ring, while a minor trans-derivative was observed for the corresponding piperidine system. This was found to derive from a trans-palladacyclic intermediate. This poster will present an overview on this work, with a particular focus on the investigations into the mechanism of the C–H functionalization of these substrates. Kinetic analysis, deuteration studies and DFT calculations have been undertaken to gain useful insights into the regio- and stereoselectivity of the reaction. These studies suggested the palladation step is neither rate-limiting or stereodetermining, with activation of both cis- and trans-C(4)–H bonds of pyrrolidine shown to be feasible. Subsequent stereodetermining oxidative addition of PdII to PdIV and final reductive elimination would deliver the C(4)-arylated product as a single cis-diastereomer.

Pd-catalyzed C(4)–H functionalization of pyrrolidines and piperidines with C(3)-directing groups: Mechanistic insight into regio- and stereoselectivity

2019 Fall National Meeting

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