Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds

Abstract

An inexpensive Ni-based catalyst, in combination with a readily recyclable 8aminoquinoline directing group, promotes efficient and regioselective addition of two different organohalides across alkenyl carbonyl compounds under mild reductive conditions. The method has broad functional group tolerance and is applicable to aryl-alkylation, alkenyl-alkylation, and dialkylation transformations. Utility of the strategy is highlighted through concise synthesis of bioactive molecules that are difficult to access by alternative procedures. Kinetic studies revealed insights into the mechanism of the multicomponent reaction.

Nickel-Catalyzed Site- and Stereoselective Reductive Alkylalkynylation of Alkynes

“…Based on our investigations and related studies, 14,60,64 a tentative mechanism is proposed in Synthetic transformations. Using redox-active esters 10 tethered to a terminal olefin, we postulated that a cascade pathway 72 commencing from alkyl radical addition to the alkyne followed by an intramolecular 5-exo-trig cyclization with the C=C bond to give a second alkyl radical species III before reassociation with the Ni complex for subsequent alkynylation could occur (Fig.…”

Alkyl Halides as Both Hydride and Alkyl Sources in Catalytic Regioselective Reductive Olefin Hydroalkylation

“…Reaction design and optimization. A hallmark of catalytic reductive transformations [48][49][50][51][52][53][54][55][56] is the use of stoichiometric amounts of an inexpensive reducing agent to drive single-electron transfer processes mediated by an appropriate (e.g. Ni-based) catalyst.…”

“…Transformations with less activated organobromides were performed at 60 o C for optimal efficiency. These include products that contain an ester (6d), an enoate (6e), an aldehyde (6h), an alkene (6n) as well as unprotected protic units (problematic with basic organometallic reagents) 56,59 such as carboxylic acid (6k), alcohol (6pq) and phenol (6r). It merits mention that previous methods which rely on hydrosilane/base to generate the hydride source may cause undesired silylation side reactions with hydroxyl groups.…”

Alkyl Halides as Both Hydride and Alkyl Sources in Catalytic Regioselective Reductive Olefin Hydroalkylation

“…Reaction design and optimization. A hallmark of catalytic reductive transformations [49][50][51][52][53][54][55][56][57] is the use of stoichiometric amounts of an inexpensive reducing agent to drive single-electron transfer processes mediated by an appropriate (e.g. Ni-based) catalyst.…”

“…Transformations with less activated organobromides were performed at 60 o C for optimal efficiency. These include products that contain an ester (9d), an enoate (9e), an aldehyde (9h), an alkene (9n) as well as unprotected protic units (problematic with basic organometallic reagents) 57,61 such as carboxylic acid (9k), alcohol (9pq) and phenol (9r). It merits mention that previous methods which rely on hydrosilane/base to generate the hydride source may cause undesired silylation side reactions with hydroxyl groups.…”