Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes

Abstract

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio-and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves azanickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % V bur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Mn(I)-Catalyzed Carbon-Skeleton Rearrangement of Tertiary Alcohol-Based Aldol Reaction with Aldehydes

“…Again, the Mn-catalyzed cross-coupling reaction of secondary allylic alcohol 1 – 16 with arylketone 2 – 18 and 4-methylbenzaldehyde 2 – 1 could not also bring us the desired α,β-unsaturated carbonyl compounds 4 – 17 and 4 – 18 , respectively. Switching aldehyde 2 – 1 to N -sulfonylimine 2 – 19 only furnish 11% yield of 4 – 1 in steady of β-aminoketone 4 – 19 , possibly due to that N -acylimine 2 – 19 suffered from decomposition to form benzaldehyde again under the standard reaction conditions. Notably, tertiary allylic alcohol 1 – 1 could not react with allylaldehyde 2 – 20 to produce the corresponding α, β, γ, δ-unsaturated ketone 4 – 20 .…”

“…An oven-dried Schlenk tube charged allylic alcohols 1 (0.10 mmol), aldehydes 2 or N -acylimine 2 – 19 (0.20 mmol, 2.0 equiv), Mn­(CO) 5 Br (0.02 mmol, 20 mol %), Me 2 Zn (0.10 mmol, 1.0 equiv), MgO (0.10 mmol, 1.0 equiv), ZnBr 2 (0.10 mmol, 1.0 equiv), and diglyme (0.1 mL) under an Ar atmosphere. The reaction mixture was then allowed to stir at 100 °C (heated by heating mantle) for 4 h. After the reaction mixture was cooled down, the reaction mixture was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:10) as eluent to afford the desired products 3 or 4 .…”

Catalytic transformations of alkenes via nickelacycles

“…In 2023, Xiao and co-workers reported a breakthrough: a ligand-controlled, regiodivergent nickel-catalysed hydroaminoalkylation of unactivated alkenes with N -sulfonyl amines (Scheme 54). 137 Tri- tert -butylphosphine facilitates branched regioselectivity and syn diastereoselectivity, while ethyldiphenylphosphine promotes linear selectivity. Systematic evaluations of various monodentate phosphine ligands revealed distinct regioselectivity effects, and %Vbur (min), a steric descriptor of ligands, was identified as a predictive measure of ligand structure's correlation with regioselectivity.…”

Regioselective and Enantioselective Nickel-Catalyzed Intermolecular Reductive Coupling of Aliphatic Alkenes with Imines

“…To understand the origin of enantioselectivity and regioselectivity, we performed density functional theory (DFT) calculations on the oxidative cyclization of 4-phenyl-1-butene ( 1a ) and imine 2c with nickel (Figure A). This is the step that determines rate, as well as regioselectivity and enantioselectivity (see Supporting Information for details). ,, Calculations of the oxidative cyclization transition states TS1-R and TS1-S showed that the energy for TS1-R was 2.2 kcal/mol lower than that for TS1-S . This difference aligns well with the experimental outcomes, favoring the formation of the ( R )-product.…”