NiH-Catalyzed Functionalization of Remote and Proximal Olefins: New Reactions and Innovative Strategies

Abstract

Conspectus Transition metal hydride catalyzed functionalization of remote and proximal olefins has many advantages over conventional cross-coupling reactions. It avoids the separate, prior generation of stoichiometric amounts of organometallic reagents and the use of preformed organometallic reagents, which are sometimes hard to access and may compromise functional group compatibility. The migratory insertion of metal hydride complexes generated in situ into readily available alkene starting materials, the hydrometalation process, provides an attractive and straightforward route to alkyl metal intermediates, which can undergo a variety of sequential cross-coupling reactions. In particular, with the synergistic combination of chain-walking and cross-coupling chemistry of nickel, NiH-catalyzed functionalization of remote and proximal olefins has undergone particularly intense development in the past few years. This Account aims to chronicle the progress made in this arena in terms of activation modes, diverse functionalizations, and chemo-, regio-, and enantioselectivity. We first provide a brief introduction to the general reaction mechanisms. Taking remote hydroarylation as an example, the four oxidation states of Ni have allowed us to develop two different reaction strategies to form the final product: a Ni­(I)-H/X-Ni­(II)-H platform that relies on stoichiometric reductants and a Ni­(I/II/III) cycle and a redox-neutral functional group or FG-Ni­(II)-H platform that reacts with an alkene substrate and forms the migratory products via a Ni­(0/II) pathway. We also demonstrate that diverse functionalization, including general C–C bond-forming reactions and the more challenging C–N/C–S bond-forming reactions could be realized. Moreover, the employment of appropriate chiral ligands has allowed us to successfully realize the corresponding asymmetric hydrofunctionalization reactions of olefins, including hydroalkylation, hydroarylation, hydroalkenylation, hydroalkynylation, and hydroamination. Interestingly, the enantio-determining step could be enantioselective hydronickelation, selective oxidative addition, or selective reductive elimination. To realize more challenging asymmetric migratory hydrofunctionalization, we have developed a general ligand relay catalytic strategy with a combination of two simple ligands, the first for chain-walking and the second for asymmetric coupling. This novel strategy avoids the design of a single, possibly structurally complex chiral ligand to promote both steps of chain-walking and asymmetric coupling. In addition, the success of multicomponent hydrofunctionalization provides a convenient approach to gain simple access to complex molecules. Finally, alkyl halides could be used as olefin precursors to undergo a variety of reductive migratory cross-electrophile coupling reactions. Applications of these remote hydrofunctionalization reactions are also discussed. We hope this Account will inspire future development in the field to overcome key challenges, including conceptually new catal...

Native Amides as Enabling Vehicles for Forging sp3–sp3 Architectures via Interrupted Deaminative Ni-Catalyzed Chain-Walking

“…The ability to selectively functionalize sp 3 C–H bonds has received considerable attention in medicinal chemistry programs. , Their popularity arises from the observation that drugs possessing a higher content of sp 3 -hybridized carbons are oftentimes more selective and deliver higher success in clinical trials . Recently, Ni-catalyzed chain-walking of unactivated olefins has gained momentum as a powerful, yet practical, alternative to commonly adopted sp 3 C–H functionalization strategies, allowing to promote innovative bond disconnections for forging sp 3 architectures from simple, yet abundant, precursors . Despite the advances realized, site-selectivity in Ni-catalyzed chain-walking reactions is predominantly dictated by a subtle interplay between electronic and steric effects.…”

Control of Axial Chirality through NiH-Catalyzed Atroposelective Hydrofunctionalization of Alkynes

“…Notwithstanding the recent considerable progress in the field of transition-metal-catalyzed asymmetric hydrofunctionalization of alkenes − for the streamlined construction of centrally chiral compounds, the transition-metal-catalyzed atroposelective hydrofunctionalization of alkynes for the direct and efficient construction of atropisomeric alkenes remains an underexplored subject, especially with earth-abundant metal catalysis (Figure b). On the basis of the recent advances in NiH-catalyzed asymmetric reductive hydrofunctionalization of olefins, we wondered if this strategy could be successfully extended to simple yet abundant alkyne substrates, providing a general, efficient, and attractive route to the desired atropisomeric olefins with excellent enantioselectivity and complete Z -selectivity (Figure c).…”

Merging Alkene Isomerization Enables Difunctionalization of Cyclic Enamines toward Ring-Fused Aminal Synthesis

“…Transition-metal-catalyzed alkene isomerization offers the opportunity toward introducing the chemical transformation at previous untapped position, allowing for remote functionalization that is generally difficult to access by conventional synthetic methods, thereby greatly increasing the synthetic efficiency . The aliphatic allylic amine derivatives are frequently encountered in a variety of natural products and agrochemicals, which are also versatile intermediates by the facile elaboration of both alkene and amine functional groups, which stimulate tremendous efforts for the development of a robust protocol for this skeleton synthesis .…”