Utilization of C(sp³)‐Carboxylic Acids and Their Redox‐Active Esters in Decarboxylative Carbon−Carbon Bond Formation

Abstract

Over the last several years, radical‐mediated decarboxylative cross‐coupling reactions employing alkyl carboxylic acids have emerged as a powerful tool for the regiospecific construction of carbon−carbon bonds. Under thermal or photocatalytic conditions, a wide variety of C(sp3)‐carboxylic acids and their redox‐active esters undergo decarboxylative C−C bond formation with suitable reactant partners, leading to complex chemical scaffolds with wide‐ranging applications. This synthetic strategy has several advantages over the more conventional organometallic reagents, including abundant starting material availability and high functional group tolerance associated with the mild reaction conditions. This review article highlights recent developments in the functionalization of α‐heteroatom‐substituted carboxylic acids as well as the more challenging unactivated acids, with representative examples discussed against the backdrop of insightful comments on reaction mechanisms. In addition, examples of the synthesis of natural products, drug molecules, and the late‐stage modification of bioactive molecules employing this non‐traditional C−C bond formation strategy are included. This review has been categorized into three main sections that are organized around the type of C−C bond being forged: C(sp3)−C(sp2), C(sp3)−C(sp3), and C(sp3)−C(sp). Further, the reactions of carboxylic acids and their redox‐active esters have been organized separately in each section.

Organophotoredox-catalyzed semipinacol rearrangement via radical-polar crossover

“…In contrast to the above-mentioned electrochemical methods, a photochemical approach for decarboxylative semipinacol rearrangement of β-hydroxycarboxylic acid derivatives has been scarce 11 – 13 . Although various photoredox catalysis realizing decarboxylative coupling using aliphatic carboxylic acid derivatives have been presented so far 14 – 17 , a single electron oxidation of a transient alkyl radical is challenging due to the low concentration of the photooxidant 18 – 21 . Therefore, a lack of general and versatile RPC-based photochemical approaches has limited the development of decarboxylative semipinacol rearrangements.…”

Photoinduced ligand to metal charge transfer enabling cerium mediated decarboxylative alkylation of quinoxalin-2(1H)-ones

“…8 However, the main challenge associated with carboxylic acids is compensating the high redox potential to generate alkyl radicals through decarboxylation, which is commonly supplemented by highly expensive strong photocatalysts, therefore largely hampering the incorporation of carboxylic acids as a radical precursor in cost effective catalysis. 8,9 Hence, as an alternative decarboxylative alkylation, utilizing RAEs is extensively studied to generate alkyl radicals in the presence of a photocatalyst or transition metal. 8d,10 However, the generation of the alkyl radicals by the decarboxylation of carboxylic acids directly draws the attention of synthetic chemists as it obviates the requirement for prefunctionalization and makes it a step-and atom-economical process.…”

Redox inversion: A radical analogue of umpolung reactivity for C(sp3)–C(sp3) bond formation

“…[6][7][8][9][10] Various homocoupling methods to synthesize bibenzyls have been developed, with recent emphasis on the use of readily-available alcohols, aldehydes and carboxylic acids as alternatives to traditional alkyl halides. [11][12][13][14][15][16][17][18] Unfortunately, these reactions typically rely on excess external oxidant or reductant, which is often metal-based.…”

“…(single electron acceptor). 14,[24][25][26][27][28] We hypothesized that this relationship between carboxylic acids and their NHPI esters could be exploited for a redox inversion strategy. The feasibility of this transformation was especially promising, as demonstrated by the recent widespread use of alkyl radical precursors in transition metal catalysis (Figure 2a).…”

“…To begin, acid 1a was selected for optimization due to its precedent for undergoing lightinduced one-electron decarboxylation (Figure 3). 14 First, the identity of the photocatalyst (PC) was explored. Multiple well-established PCs were screened including the acridinium salt PC1 (Entry 1), the iridium photocatalyst PC2 (Entry 2), and cyanoarene 4-CzIPN PC3 (Entry 3).…”