γ-Selective C(sp3)–H amination via controlled migratory hydroamination

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.

Alkene Difunctionalization Directed by Free Amines: Diamine Synthesis via Nickel-Catalyzed 1,2-Carboamination

“…In recent years, directed three-component alkene difunctionalization has emerged as an effective strategy for selective synthesis of highly substituted, multifunctional, and stereochemically defined products from simple chemical inputs (Scheme A). In this context, successful amine-based directing groups have included those based on bidentate directing auxiliaries − and monodentate protecting groups (e.g., amides and sulfonamides) (Scheme B) . In these cases, attachment of an electron-withdrawing group to the amine is critical, as it attenuates Brønsted and Lewis basicity, diminishing its ability to interfere with catalysis.…”

Endo-Selective Intramolecular Alkyne Hydroamidation Enabled by NiH Catalysis Incorporating Alkenylnickel Isomerization

“…We commenced our investigation by first seeking a NiH system − that can engage alkenylnickel isomerization. Our group recently reported a NiH-catalyzed intermolecular hydroamidation of alkynes using dioxazolones as an umpolung amidating reagent (Scheme a) .…”

Ligand‐Controlled NiH‐Catalyzed Regiodivergent Chain‐Walking Hydroalkylation of Alkenes

“…On the basis of our mechanistic studies, we propose two catalytic cycles for the migratory α‐ and β‐hydroalkylation (Scheme 6). The reaction is likely to be initiated by the generation of L4 NiH and L11 NiH from the reaction between Ni II with (EtO) 3 SiH [9c, 16] . The nickel (I) hydride species L4 NiH or L11 NiH inserts into the alkene ( 1 ) to generate an alkyl‐nickel intermediate ( A or E ), which then undergoes a chain‐walking process to afford more stable five‐ or six‐membered nickelacycle ( B or F ).…”