Regio‐ and Enantioselective Ni‐Catalyzed Formal Hydroalkylation, Hydrobenzylation, and Hydropropargylation of Acrylamides to α‐Tertiary Amides

Abstract

The development of enantioselective alkyl-alkyl cross-couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet challenging. Herein, we report the intermolecular regio-and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center a-position to the newly formed C sp3 -C sp3 bond for the first time. The use of a newly developed chiral ligand enables the electronicallyreversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary a-stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti-Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.Scheme 1. Alkyl-alkyl cross-coupling strategies to construct stereogenic carbon center.

Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

“…Based on the mechanistic results and literature precedence [28][29][30][31][32][33][34][42][43][44][45]48,49 , two tentative mechanistic pathways are proposed and depicted in Fig. 7.…”

“…In 2021, Hu group reported a hydroalkylation of vinyl boronates to give chiral secondary alkyl boronates enabled by the anchoring effect of boron 49 . These examples showcased the feasibility of building a stereogenic carbon center originating from alkenes via Ni-catalyzed hydroarylation [36][37][38] and hydroalkylation [48][49][50][51] of alkenes.…”

“…The use of unactivated alkyl halides to build stereogenic center originating from alkenes remains elusive due to the reversible Ni-H insertion onto alkenes and the propensity of chain-walking 46,47 . Recently, our group developed the Ni-H-catalyzed hydroalkylation of acrylates via anti-Markovnikov hydrometalation, giving the enantioenriched α-tertiary amides by forging a stereogenic center originating from acrylates 48 . In 2021, Hu group reported a hydroalkylation of vinyl boronates to give chiral secondary alkyl boronates enabled by the anchoring effect of boron 49 .…”

Enantioselective synthesis of N-alkylindoles enabled by nickel-catalyzed C-C coupling

“…To gain insight into the mechanism and origin of selectivity, a series of experiments well conducted. Generally, the reductive coupling process consists of π-bond insertion into L*Ni−H species, oxidative addition of the resulting L*Ni-alkyl intermediate, and reductive elimination to form product and the L*Ni-H catalyst [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] . Take the reductive coupling of N-alkenyl indoles with aryl halides as an example, competition experiments were performed to compare the reactivity between different aryl halides, indicating that (i) electron-deficent aryl bromide is more reactive than an electron-rich one (Fig.…”

“…However, catalytic enantioselective reductive coupling of N-alkenyl indoles faces several challenges. First, current asymmetric reductive coupling is largely limited to the use of liner alkyl-Ni intermediates [46][47][48][49][50][51][52][53][54][55][56][57][58] . Catalytic enantioselective coupling of branched alkyl-Ni intermediates generated from hydronickellation of olefins remains elusive [59][60][61][62][63] .…”