Allylic C–H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis

Siraj Z. Ali, Brenna G. Budaitis, Devon F.A. Fontaine, Andria L. Pace, Jacob A. Garwin, M. Christina White

Research output: Contribution to journalArticlepeer-review

Abstract

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines—a common motif in pharmaceuticals—remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal–catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z).

Original languageEnglish (US)
Pages (from-to)276-283
Number of pages8
JournalScience
Volume376
Issue number6590
DOIs
StatePublished - Apr 15 2022

ASJC Scopus subject areas

  • General

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