NiH-Catalyzed Proximal-Selective Hydroamination of Unactivated Alkenes

Abstract

Reported herein is a modular, NiH-catalyzed system capable of proximal-selective hydroamination of unactivated alkenes with diverse amine sources. The key to the successful implementation of this approach is the promotion of NiH insertion into even highly substituted olefins via coordination of the bidentate directing group to the nickel complex. A wide range of primary and secondary amines can be installed in both internal and terminal unactivated alkenes with excellent regiocontrol under the optimized reaction conditions. This protocol is flexible and general for the preparation of a variety of valuable β- and γ-amino acid building blocks that would otherwise be difficult to synthesize. The utility of this transformation was further demonstrated by the site-selective late-stage modification of complex and medicinally relevant molecules. Combined experimental and computational studies illuminate the detailed reaction mechanism.

Nickel-Catalyzed Regio- and Diastereoselective Arylamination of Unactivated Alkenes

“…However, we consider this pathway to be less likely because the selective insertion into the Ni-C rather than Ni-N bond was suspicious and the energy barrier of reductive elimination of Ni II amido species is too high under similar catalytic system based on DFT calculations (>50 Kcal/mol). [50] An alternative pathway in which the alkene inserted into the Ni-N bond precedes transmetalation and C-C reductive elimination was also considered unlikely, because it would involve formation of thermodynamically unfavored larger nickelacycles, especially for bishomoallylic amine substrates (seven-membered nickelacycles).…”

Nickel-Catalyzed 1,2-Carboamination of Alkenyl Alcohols

“…Based on these experiments and literature precedents, a plausible catalytic cycle is proposed in Figure 3E 19,41,42 . Here we propose a Ni(I)/Ni(III) catalytic cycle based on the observation of stereospecificity erosion (3at, 3au, 3ax and 3ay), which may imply a competitive alkyl-Ni(III) homolysis/recombination process.…”

“…To evaluate the viability of these possible sequences, we analyzed the ratio of carboaminated product (3a) to hydroarylated side product (13), the latter of which was obtained in 6% yield under the standard conditions, as a function of reagent concentrations. In a sequence in which MI precedes OA, both the desired product (3a) and hydroarylated product (13) would be generated from a common alkylnickel(I) intermediate (14); in this case the product ratio should be determined by the relative rates of bimolecular oxidative addition versus protodemetalation (both of which are expected to be irreversible) 41 and should thus be dependent on the concentration of the N-O reagent. In an alternative OA-first mechanism, the thusly generated alkylnickel(III) intermediate would already bear the amido ligand, and the product ratio should be independent of the N-O reagent concentration.…”

Earth-Abundant 3d Transition Metal Catalysts for Hydroalkoxylation and Hydroamination of Unactivated Alkenes

“…Although great progress has been made in the Ni-catalyzed hydroamination of 1,3dienes and 1,2-dienes [111], there are only a few reports on the development of nickelbased catalysts for the regioselective hydroamination of an unactivated terminal and more challenging internal alkenes [112]. In 2020, the group of Hong made a breakthrough in this domain by reporting an efficient Ni-H-based system having the ability to promote a proximal-selective hydroamination of unactivated alkenes tethered to a bidentate directing group (Figure 19) [113]. Indeed, the combination of Ni(acac)2/(EtO)2MeSiH in the presence of electrophilic hydroxylamine esters as amine transfer agent provides a useful Although great progress has been made in the Ni-catalyzed hydroamination of 1,3dienes and 1,2-dienes [111], there are only a few reports on the development of nickelbased catalysts for the regioselective hydroamination of an unactivated terminal and more challenging internal alkenes [112].…”

“…Indeed, the combination of Ni(acac)2/(EtO)2MeSiH in the presence of electrophilic hydroxylamine esters as amine transfer agent provides a useful Although great progress has been made in the Ni-catalyzed hydroamination of 1,3dienes and 1,2-dienes [111], there are only a few reports on the development of nickelbased catalysts for the regioselective hydroamination of an unactivated terminal and more challenging internal alkenes [112]. In 2020, the group of Hong made a breakthrough in this domain by reporting an efficient Ni-H-based system having the ability to promote a proximal-selective hydroamination of unactivated alkenes tethered to a bidentate directing group (Figure 19) [113]. Indeed, the combination of Ni(acac) 2 /(EtO) 2 MeSiH in the presence of electrophilic hydroxylamine esters as amine transfer agent provides a useful synthetic method for the conversion of mono-, di-and trisubstituted alkenes tethered to amidelinked aminoquinoline or to amine-derived picolinamides to structurally diverse and functionalized βand γ-amino acid building blocks in moderate to good yields.…”