gamma-Selective C(sp(3))-H amination via controlled migratory hydroamination

Abstract

Sequential alkene isomerization and cross-coupling enables remote functionalization, but coupling has been limited to positions at a carbon chain terminus or proximal to a functional group. Here the authors show a method to interrupt isomerization with a nickellacycle, which enables coupling at an atypical, unreactive position. Remote functionalization of alkenes via chain walking has generally been limited to C(sp(3))-H bonds alpha and beta to polar-functional units, while gamma-C(sp(3))-H functionalization through controlled alkene transposition is a longstanding challenge. Herein, we describe NiH-catalyzed migratory formal hydroamination of alkenyl amides achieved via chelation-assisted control, whereby various amino groups are installed at the gamma-position of aliphatic chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, gamma-selective amination can be achieved via stabilization of a 6-membered nickellacycle by an 8-aminoquinoline directing group and subsequent interception by an aminating reagent. A range of amines can be installed at the gamma-C(sp(3))-H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added gamma-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to delta-selective amination. The chain-walking mechanism and pathway selectivity are investigated by experimental and computational methods.