Hydroalkylation of unactivated olefins with C(sp3)─H compounds enabled by NiH-catalyzed radical relay

Abstract

The hydroalkylation reaction of olefins with alkanes is a highly desirable synthetic transformation toward the construction of C(sp³)─C(sp³) bonds. However, such transformation has proven to be challenging for unactivated olefins, particularly when the substrates lack directing groups or acidic C(sp³)─H bonds. Here, we address this challenge by merging NiH-catalyzed radical relay strategy with a HAT (hydrogen atom transfer) process. In this catalytic system, a nucleophilic alkyl radical is generated from a C(sp³)─H compound in the presence of a HAT promotor, which couples with an alkyl metallic intermediate generated from the olefin substrate with a NiH catalyst to form the C(sp³)─C(sp³) bond. Starting from easily available materials, the reaction not only demonstrates wide functional group compatibility but also provides hydroalkylation products with regiodivergence and excellent enantioselectivity through effective catalyst control under mild conditions.

Fig. 1.. The hydroalkylation of olefins.

(A) The state-of-art of olefin hydroalkylation with alkanes. (B) Olefin hydroalkylation with (pseudo)halides via TM-H-catalysis. (C) Working hypothesis. (D) This work: Hydroalkylation of unactivated olefins with alkanes via NiH-catalyzed radical relay. PC, photocatalyst; DG, directing group; FG, functional group; PG, protecting group; EWG, electron-withdrawing group; X, (pseudo)halogen atom.

Fig. 2.. Substrate scope for linear products.

Reaction conditions: olefins 1 (0.1 mmol), C(sp³)─H compounds 2 (1.0 ml), NiBr₂.glyme (10 mol %), L1 (15 mol %), HAT-1 (1.5 equiv), (EtO)₂MeSiH (2.0 equiv), and LiOH (3.0 equiv), at 35°C for 3 hours. The ratio of L/B was determined by nuclear magnetic resonance (NMR) of the crude product. ^†NMR yields. ^‡Reaction conditions: 1a (0.1 mmol), C(sp³)-H compounds 2 (0.9 ml), NiBr₂.glyme (20 mol %), L1 (30 mol %), TBPB (1.5 equiv), (EtO)₂MeSiH (2.0 equiv), LiOH (3.0 equiv), and DCE (0.1 ml), at 35°C for 5 hours, then TBPB (1.5 equiv), (EtO)₂MeSiH (2.0 equiv), and LiOH (3.0 equiv), at 35°C for 12 hours. ^¶Total yields.

Fig. 3.. Substrate scope for regiodivergent hydroalkylation.

Reaction conditions: olefins 5 (0.1 mmol), C(sp³)─H compounds 2 (0.8 ml), NiBr₂.glyme (10 mol %), L3 or L8 (15 mol %), TBPB (1.5 equiv), (EtO)₃SiH (2.0 equiv), and LiOH (3.0 equiv), in PhCF₃ or DCE (0.2 ml) at 35°C for 18 hours. The ratio of B/L or L/B was determined by GC-MS. ^†Total yields. ^‡The yields in brackets is the isolated yield of major products.

Fig. 4.. Substrate scope for enantioselective hydroalkylation.

Reaction conditions: olefins 5 (0.1 mmol), C(sp³)─H compounds 2 (1.0 ml), NiBr₂.glyme (10 mol %), CL9 (15 mol %), TBPB (1.5 equiv), (EtO)₃SiH (2.0 equiv), and LiOH (3.0 equiv), at 35°C for 18 hours. The ratio of B/L was determined by GC-MS. ^†Total yields. ^‡The yields in brackets are the isolated yield of chiral products.

Fig. 5.. Preliminary mechanistic study and proposed catalytic cycle. (A) Preliminary mechanistic experiments (B) Proposed mechanism.