Catalytic Arylalkylation of Alkenyl Amines at Remote Sites via Directed Nickel Catalysis

Abstract

Comprehensive Summary Directing group‐assisted, transition metal‐catalyzed three‐component difunctionalization of alkenes has emerged as a powerful tool to drive molecular complexity. However, this strategy generally works with the substrates bearing directing groups in close proximity to the alkene moieties, due to the preference for formation of kinetically stable five‐membered metallacycles. Herein, we have disclosed a complementary strategy to accomplish a nickel‐catalyzed remote arylalkylation of alkenyl amines with excellent regioselectivity and diastereofidelity, involving rare six‐ or seven‐membered metallacycles. This general protocol is compatible with a series of δ‐ and ε‐alkenyl amines, providing corresponding valuable δ,ε‐ and ε,ζ‐difunctionalized aliphatic amines that would be difficult to synthesize. The coordination of the bidentate picolinamide auxiliary and the facile oxidative addition of alkyl halides to Ni(I) species are the key to the success of the developed remote olefin dicarbofunctionalization.

Enantioselective Directed Nickel-Catalyzed Three-Component Reductive Arylalkylation of Alkenes via the Carbometalation/Radical Cross-Coupling Sequence

“…As a continuation of our interest in this area, we herein disclose the first enantioselective nickel-catalyzed reductive three-component arylalkylation between terminal or internal alkenes, aryl halides, and alkyl halides through carbonickelation/Csp 3 –Csp 3 cross-coupling sequence (Figure d). This reductive asymmetric arylalkylation of alkenes makes it reasonable to proceed with the chiral aryl–[Ni] complex in situ catalytically generated from aryl halides performing stereoselective carbonickelation of alkene ,,,− to afford the chiral α-branched Csp 3 –Ni intermediate with opposite regioselectivity to those radical relay strategies. − A coordinating-group-based chelation strategy is employed to stabilize the enantiomerically enriched Csp 3 –Ni intermediate as a transient nickelacycle followed by radical cross-coupling with alkyl halides to deliver aryl/alkyl difunctionalized products with exquisite control of regio-, chemo-, and enantioselectivity. Additionally, this reaction, devoid of the need for preprepared and sensitive organometallic reagents, is compatible with a broad range of electrophilic aryl and alkyl sources possessing various reactive functional groups.…”

“…In stark contrast to the well-established radical relay strategy, the catalytic enantioselective, three-component arylalkylation of alkenes via stereoselective migratory insertion strategy in an enantio- and regioselective manner has been largely underdeveloped so far (Figure d). Only a handful of racemic reactions have been reported relying on redox-neutral, − or reductive methods. , Thus, the development of a method for enantioselective arylalkylation via migratory insertion as a key stereoselective step is highly desirable and meaningful.…”

“…Other alkyl iodides containing functional groups such as trifluoromethyl ( 8 ), cyano ( 9 ), alkenyl ( 10 and 11 ), hydroxyl ( 12 ), ester ( 13 – 17 ), ketone ( 17 and 18 ), ether ( 19 and 20 ), amide ( 21 – 25 ), and amine ( 26 ) were also investigated, providing the corresponding products in high yields and with up to 98:2 er. Remarkably, the free hydroxyl, often sensitive to organometallic reagents, can also tolerate ( 12 ), which is highly useful for further synthetic elaboration without extra manipulations of protecting groups, showcasing the notable functional group tolerance compared to redox-neutral using harsh organometallic reagents. − Noteworthily, with this method, challenging 1,2-dialkyl-substituted internal alkenes could lead to products ( 28 – 32 ) containing two contiguous stereocenters with excellent syn -diastereoselectivity (>20:1 dr) and good enantioselectivity (76–94% ee), indicating the migratory insertion is the enantiodeterming step. However, Z -alkenes exhibited higher enantioselectivity than the analogous E -alkene ( 27 vs 28 ).…”

Auxiliary-controlled regiodivergent NiH-catalyzed gem-difluoroallylation of alkenyl amines via defluorinative olefin cross-coupling

“…In recent years, the directing group strategy has emerged as a powerful and attractive toolkit for executing functionalization of unactivated alkenes, and the auxiliaries could dictate the regioselectivity by stabilization of different sizes of metallacycles. 7 As part of our continuous interest in Ni-catalyzed functionalization of alkenyl amine compounds, 8 we speculated that the judicious selection of auxiliaries would provide regiodivergent access to structurally diverse branched amines via Ni migration 9 or non-migration. Herein, we report our discovery that auxiliary-controlled switchable site-selectivity 10 can be achieved in Ni-catalyzed gem -difluoroallylation of alkenyl amines with aryl and alkyl trifluoromethyl alkenes.…”

Nickel-Catalyzed 8-Aminoquinoline Directed Reductive Dialkylcyclization/Homodialkylation of Unactivated Alkenes

“…Despite the application of highly active coupling reagents, direct functionalization of unactivated alkene would be achieved via the coordination with the directing group. Since 8-aminoquinoline (AQ) was widely used in nickel-catalyzed cross-couplings, ,,, N -(quinolin-8-yl)­but-3-enamide ( 1a ) and 1,3-dibromopropane ( 2a ) were initially selected as model substrates to test this reductive dialkylcyclization process (Table ). We started with NiCl 2 as the catalyst and Mn as the reductant, and to our delight, a 28% yield of the cyclopentane product 3aa was obtained when reacted in DMF (entry 1).…”