Abstract
Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)–H bonds α and β to polar-functional units, while γ-C(sp3)–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 γ-position of aliphatic chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, γ-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 γ-C(sp3)–H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added γ-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to δ-selective amination. The chain-walking mechanism and pathway selectivity are investigated by experimental and computational methods.
Highlights
Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)–H bonds α and β to polar-functional units, while γ-C(sp3)–H functionalization through controlled alkene transposition is a longstanding challenge
Remote olefin functionalization via a combination of transition-metal-catalyzed alkene isomerization and cross-coupling chemistry allows for the direct installation of functionalities into inert sp[3] C–H sites that are distant from the alkene initiation point, which would otherwise be difficult to achieve using conventional approaches
We first explored the feasibility of alkene isomerization using eightAQ-coupled alkenamide 1j by investigating possible ligand candidates (Fig. 2a)
Summary
Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)–H bonds α and β to polar-functional units, while γ-C(sp3)–H functionalization through controlled alkene transposition is a longstanding challenge. Despite significant advances in the field of alkene isomerization/functionalization, remote functionalization involving chain walking processes has been restricted to the installation of functional groups at C–H bonds α or β to polar-functional units in the substrate, as chain walking proceeds rapidly to form the most favorable α- or β-alkyl-metal intermediate prior to the cross-coupling process for product formation (Fig. 1a). In this regard, selective functionalization of remote γ-C(sp3)–H bonds through controllable alkene transposition remains a significant unexplored challenge. We a) Remote C(sp3)-H functionalization through chain walking strategy
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