Nickel/SKP-Catalyzed Markovnikov Regio- and Enantioselective Hydroamination of Vinylarenes with Hydroxylamines

Abstract

A Ni-catalyzed enantioselective hydroamination of vinylarenes has been developed, affording a wide variety of α-branched chiral alkylamines in good yields with exclusive Markovnikov regioselectivity and excellent enantioselectivity. The SKP ligand was found to be crucial to both the reactivity enhancement and enantiocontrol of the reaction. The synthetic utility of the protocol was exemplified in a gram-scale reaction and late-stage modification of medicinally relevant molecules. The deuterium-labeling experiment revealed that the irreversible hydronickelation of vinylarenes is most likely the enantioselectivity-determining step.C hiral α-branched alkylamines exhibit a broad range of functionality and are a class of recurring structural units in pharmaceutical agents and natural products (Scheme 1a), 1

Nickel Catalyzed Enantioselective 1,4-Hydroamination of 1,3-Dienes

“…According to the above results and literature, − a plausible reaction mechanism was proposed (Figure c). The nickel­(I) hydride species I , generated from SKP-bound Ni precursor with a silane in the presence of a base, , would insert into the terminal double bond of the 1,3-diene, generating the corresponding π-allyl-Ni­(I) intermediate II .…”

“…Recently, metal hydride-catalyzed hydrofunctionalization of alkenes has attracted considerable attention. − It has been reported that some NiH complexes demonstrate robust catalytic activity for enantioselective C–N bond-forming processes, − wherein O-benzoyl hydroxylamines (BzO–NR 2 ) are used as electrophilic amination reagent which is compatible to the presence of reductant reagents in the reaction system . Accordingly, we commenced our studies on the Ni-catalyzed model reaction of phenylbutadiene 1a and morpholino benzoate 2a , and a preliminary parameter survey revealed that the reaction was best run at rt in 2-Me-THF with Ni­(COD) 2 as the Ni source in the presence of trimethoxysilane and K 2 CO 3 (for details, see SI).…”

NiH-catalyzed C–N bond formation: insights and advancements in hydroamination of unsaturated hydrocarbons

“…In that same year, Ding and his colleagues made significant breakthroughs by unveiling a Ni-catalyzed enantioselective hydroamination procedure tailored for vinylarenes ( Scheme 19 ). 79 This approach was instrumental in the streamlined synthesis of a vast array of α-branched chiral alkylamines. The method's standout feature was its unique Markovnikov regioselectivity paired with unparalleled enantioselectivity.…”

Silanes as a versatile hydride source for Ni–H catalysis: a promising tool for π-hydro functionalization

“…The SKP ligand was found to be crucial for receiving exclusive Markovnikov regioselectivity and excellent enantioselectivity (Scheme 15). 34…”