Sustainable Synthesis of α‐Hydroxycarboxylic Acids by Manganese Catalyzed Acceptorless Dehydrogenative Coupling of Ethylene Glycol and Primary Alcohols**

Abstract

Herein, we report a straightforward synthesis of valuable α-hydroxycarboxylic acid molecules via an acceptorless dehydrogenative coupling of ethylene glycol and primary alcohols. A bench-stable manganese complex catalyzed the reaction, which is scalable, with the product being isolated with high yields and selectivities under mild conditions. The protocol is environmentally benign, producing water and hydrogen gas as the only byproducts. Methanol can also be used as a C1 source for producing the platform molecule lactic acid, with a high turnover of > 10 4 . The methodology was also used to functionalize alcohols derived from natural products and fatty acids. Furthermore, it was applied for synthesizing α-amino acid, α-thiocarboxylic acid, and several drugs and bioactive molecules, including endogenous metabolites, Danshensu, Enalapril, Lisinopril, and Rosmarinic acid. Preliminary mechanistic studies were performed to shed light on the mechanism involved in the reaction.

Alcohols as Substrates in Transition-Metal-Catalyzed Arylation, Alkylation, and Related Reactions

“…Maji also utilized a manganese catalyst in the disclosure of a method using ethylene glycol as another abundant feedstock reactant, enabling the generation of α-hydroxycarboxylic acids via a net-oxidative reaction with primary alcohols as well as methanol (Scheme 63c). 438 Isotope-labeling and mechanistic NMR experiments were used to support a mechanism proceeding by in situ oxidation of both alcohols, aldol condensation, and a hydroxide-mediated Cannizzaro reaction. Manganese was also explored by Liu in 2018 toward the generation of alkene products from the coupling of two primary alcohols, which were reduced to alkanes when making nondimeric products (Scheme 63d).…”

“…Other notable examples by Leitner (Scheme b) and Kempe, each in the presence of a manganese catalyst, feature the β-methylation of secondary alcohols with excess methanol. Maji also utilized a manganese catalyst in the disclosure of a method using ethylene glycol as another abundant feedstock reactant, enabling the generation of α-hydroxycarboxylic acids via a net-oxidative reaction with primary alcohols as well as methanol (Scheme c) . Isotope-labeling and mechanistic NMR experiments were used to support a mechanism proceeding by in situ oxidation of both alcohols, aldol condensation, and a hydroxide-mediated Cannizzaro reaction.…”

Ir(tri-N-heterocyclic carbene)-catalyzed upgrading of glycerol: C–C bond formation for the synthesis of α-hydroxy acids

“…While most chemical conversions involving glycerol tend to preserve or reduce the number of carbons in the molecule (C 3 or less than C 3 ), it is important to explore innovative chemical methods capable of yielding a broader range of products from glycerol with increased carbon units. Recent advancements have been made in the case of biomass-derived ethylene glycol, where protocols involving Ir-catalyzed dehydrogenation followed by aldol reactions have been employed to extend the carbon chain of ethylene glycol, [5][6][7][8][9][10][11] leading to the synthesis of industrially valuable α-hydroxy acids (AHAs), as depicted in Scheme 1. 12,13 Aliphatic AHAs are present in biologically interesting molecules, including lipoxazolidinone B (Scheme 1).…”