Nickel-catalyzed formation of quaternary carbon centers using tertiary alkyl electrophiles.

Transformation of sterically hindered tertiary alkyl electrophiles under nickel-catalyzed conditions to forge C(sp3)-C bonds and simultaneously create challenging all-carbon quaternary centers has received growing attention in the recent years. The unique nature of nickel featuring flexible oxidation states ranging from Ni0 to NiIV, allows the effective activation of tertiary alkyl electrophiles through ionic (2e) or radical pathways. In nickel-catalyzed coupling of tertiary alkyl electrophiles, the competitive ß-H elimination upon the resulting alkyl-Ni intermediate is relatively slow, thus benefiting the C-C bond forming process. Meanwhile, nickel-catalyzed radical addition of tertiary alkyl electrophiles to unsaturated C-C bonds has also advanced rapidly due to the successful incorporation of carboxylic acid and alcohol derivatives as radical precursors, and more importantly due to further interception of the intermediate radical adducts with nucleophiles and electrophiles to accomplish three-component cascade reactions. This review highlights these state-of-the-art nickel-catalyzed transformations of tertiary electrophiles, organized by reaction types with emphasis on the reaction mechanisms.

Insertion of Isolated Alkynes into Carbon-Carbon σ-Bonds of Unstrained Cyclic ß-Ketoesters via Transition-Metal-Free Tandem Reactions: Synthesis of Medium-Sized Ring Compounds.

The transition-metal-free insertion of isolated alkynes into carbon-carbon σ-bonds of unstrained cyclic ß-dicarbonyl compounds has been reported. These tandem reactions offer an efficient synthesis of medium-sized ring or fused-ring compounds through ring expansion. The methodology has the potential to be widely used throughout organic synthesis due to the easily accessible starting materials and mild reaction conditions.

Asymmetric synthesis of aryl/vinyl alkyl carbinol esters via Ni-catalyzed reductive arylation/vinylation of 1-chloro-1-alkanol esters.

We report herein an asymmetric Ni-catalyzed cross-electrophile coupling approach to prepare enantioenriched aryl/vinyl alkyl carbinol esters through arylation/vinylation of easily accessible racemic 1-chloro-1-alkanol esters with aryl/vinyl electrophiles. The method features a broad substrate scope as demonstrated by more than 60 examples including the challenging chiral allylic esters. It tolerates a wide array of functional groups including alkenyl, carbonyl and free hydroxyl groups that may not survive in conventional carbonyl reduction and addition methods. The synthetic utility of the present work was showcased by facile preparation of a few key intermediates and the modification of chiral drugs and naturally occurring compounds. Finally, we describe an efficient one-pot procedure for this method.

Alkenylation and Arylation of Peptides via Ni-Catalyzed Reductive Coupling of α-C-Tosyl Peptides with Csp2 Triflates/Halides.

A Ni-catalyzed reductive cross-coupling between α-C-tosyl peptides and Csp2 triflates/halides has been developed. This protocol enables the formation of various unnatural di- and tripeptides containing vinyl and aryl side chains, and it expands the applications of Ni-catalyzed reductive cross-coupling in late-stage diversification of peptides.

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine.

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar-Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp2) electrophile to the resultant Gly-Ni(i) intermediate gives a key Gly-Ni(iii)-Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly-Ni(i) intermediate.