α‐Functionalization of Aliphatic Carboxylic Acid Equivalents via Direct CH Oxidation

Abstract

The α‐functionalization of aliphatic carboxylic acids and equivalents thereof including amides and esters is among the highly important synthetic transformations of organic synthesis. Traditional approaches are largely dominated by enolate chemistry demanding (over) stoichiometric quantity of a strong base with respect to the carbonyl precursor to obtain a nucleophilic enolate equivalent and an electrophilic coupling partner to form a new CC and/or C–heteroatom bond. Modern progresses demonstrate that the α‐CH bond of carboxylic acids, amides, esters, and other synthons can be also triggered in the presence or absence of a transition metal catalyst under oxidative conditions. The external oxidant is known to play a crucial role in the α‐CH bond oxidation process. The current article describes the oxidative α‐CH bond functionalizations of carboxylic acids/equivalents by nucleophiles using transition metal catalysts or organic mediators. Consequently, (i) α‐CH transformations with the participation of an enolate equivalent from the carboxylate counterpart; (ii) Lewis acid‐catalyzed α‐functionalization approaches; (iii) α‐functionalization with concomitant decarboxylation, etc. are beyond the scope of this article.

Cobalt Catalyzed α-Hydroxylation of Arylacetic Acid Equivalents with Dioxygen

“…7 Likewise, the α-functionalization of α-amino acid esters via aldimines is also not viable for arylacetic acid synthons. 8 While transition metal catalyzed directing group-assisted C− H functionalization approaches could provide a potential solution to the above challenge, they lead to orthohydroxylation of the aryl ring via the formation of a thermodynamically preferred six-membered metallacycle intermediate over that of the strained four-membered intermediate. 9 Hence, a powerful and highly chemo-and regioselective catalytic approach for the α-hydroxylation of arylacetic acid synthons, specifically amides, has long been awaited.…”

“…However, the inherent challenge in those methods, particularly for α-unsubstituted arylacetic acids, is the competitive formation of undesired α-keto acids via “over-oxidation”. , In the case of arylacetamides, the α-hydroxylation is accomplished via the α-oxyamination with 2,2,6,6-tetramethylpiperidine- N -oxyl (TEMPO) followed by N–O bond scission by employing (over)stoichiometric reagents or through the formation and subsequent hydrogenation of α-keto acid amides. , Of note, reported benzylic C–H hydroxylation approaches do not apply to α-hydroxylation of arylacetic acids functionalized with several competing benzylic groups due to chemoselectivity issues . Likewise, the α-functionalization of α-amino acid esters via aldimines is also not viable for arylacetic acid synthons …”