Boron‐Catalyzed α‐Functionalizations of Carboxylic Acids

Abstract

Catalytic, chemoselective, and asymmetric α‐functionalizations of carboxylic acids promise up‐grading simple feedstock materials to value‐added functional molecules, as well as late‐stage structural diversifications of multifunctional molecules, such as drugs and their leads. In this personal account, we describe boron‐catalyzed α‐functionalizations of carboxylic acids developed in our group (five reaction types). The reversible boron carboxylate formation is key to the acidification of the α‐protons and enolization using mild organic bases, allowing for chemoselective and asymmetric bond formations of carboxylic acids. The ligand effects on reactivity and stereoselectivity, substrate scopes, and mechanistic insights are summarized.

Boron-Catalyzed Michael Reaction of Donor–Acceptor Carboxylic Acid Pairs Enabling Direct Synthesis of 1,5-Dicarboxylic Acids

“…Following reactions were conducted to gain mechanistic insights into the reaction (Scheme ). In accord with our previous reports, no 3aa was obtained when the methyl ester 9 was used as the Michael donor (Scheme a), indicating that boron enolate formation was specific to carboxylic acids. In addition, 3aa was obtained in only a trace amount when methyl acrylate ( 10 ) was used instead of acrylic acid ( 2a ), showing that the in situ generated boron carboxylate of 2a is more reactive than 10 .…”

“…For the sake of expeditious analysis of the reaction outcome, crude reaction products were subjected to methyl esterification using dimethyl sulfate to obtain diester 3aa . While no reaction occurred in the absence of a boron catalyst (entry 1), addition of 10 mol % of (AcO) 4 B 2 O, which is a competent catalyst to form the diboron enediolate, caused the reaction to afford 1,5-diester 3aa in 76% yield with concomitant formation of significant amounts of tricarbonyl compounds, which seem to be produced through double Michael addition with a single molecule of 1a and two molecules of acrylic acid ( 2a ) (entry 2). BH 3 ·SMe 2 , which has also been used for catalytic reactions involving diboron enediolate intermediate formation, promoted the Michael reaction with only a 33% yield of 3aa (entry 3).…”

“…We have developed various boron-catalyzed reactions based on chemoselective enolate formation from carboxylic acids . The reversible B–O covalent bond formation between the carboxylic acids and the Lewis acidic boron catalysts increases the acidity of the α-proton, thus enabling generation of nucleophilic diboron enediolates under mild basic conditions.…”