Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis

Abstract

The development of palladium-catalyzed cross-coupling methods for the activation of C(sp²)-Br bonds facilitated access to arene-rich molecules, enabling a concomitant increase in the prevalence of this structural motif in drug molecules in recent decades. Today, there is a growing appreciation of the value of incorporating saturated C(sp³)-rich scaffolds into pharmaceutically active molecules as a means to achieve improved solubility and physiological stability, providing the impetus to develop new coupling strategies to access these challenging motifs in the most straightforward way possible. As an alternative to classical two-electron chemistry, redox chemistry can enable access to elusive transformations, most recently, by interfacing abundant first-row transition-metal catalysis with photoredox catalysis. As such, the functionalization of ubiquitous and versatile functional handles such as (aliphatic) carboxylic acids via metallaphotoredox catalysis has emerged as a valuable field of research over the past eight years.In this Account, we will outline recent progress in the development of methodologies that employ aliphatic and (hetero)aromatic carboxylic acids as adaptive functional groups. Whereas recent decarboxylative functionalization methodologies often necessitate preactivated aliphatic carboxylic acids in the form of redox-active esters or as ligands for hypervalent iodine reagents, methods that enable the direct use of the native carboxylic acid functionality are highly desired and have been accomplished through metallaphotoredox protocols. As such, we found that bench-stable aliphatic carboxylic acids can undergo diverse transformations, such as alkylation, arylation, amination, and trifluoromethylation, by leveraging metallaphotoredox catalysis with prevalent first-row transition metals such as nickel and copper. Likewise, abundant aryl carboxylic acids are now able to undergo halogenation and borylation, enabling new entry points for traditional, primarily palladium- or copper-catalyzed cross-coupling strategies. Given the breadth of the functional group tolerance of the employed reaction conditions, the late-stage functionalization of abundant carboxylic acids toward desired targets has become a standard tool in reaction design, enabling the synthesis of various diversified drug molecules. The rapid rise of this field has positively inspired pharmaceutical discovery and will be further accelerated by novel reaction development. The achievement of generality through reaction optimization campaigns allows for future breakthroughs that can render protocols more reliable and applicable for industry. This article is intended to highlight, in particular, (i) the employment of aliphatic and (hetero)aryl carboxylic acids as powerful late-stage adaptive functional handles in drug discovery and (ii) the need for the further development of still-elusive and selective transformations.We strongly believe that access to native functionalities such as carboxylic acids as adaptive handles will further inspire researchers across the world to investigate new methodologies for complex molecular targets.

Figure 1.

Development of various decarboxylative transformations under metallaphotoredox conditions, enabling arylation, alkylation, amination, and trifluoromethylation from aliphatic carboxylic acids. Inherently stable aromatic carboxylic acids were converted to electrophiles and nucleophiles.

Figure 2.

Decarboxylative arylations, pioneered by MacMillan et al., were adapted by many groups and led to diverse conditions toward smallmolecule drugs and biomolecules. Further developments led to enantioselective and vinyl halide transformations. Typical photocatalysts, bases, and solvents are displayed. The choice of ligands has a distinct effect on the nickel catalysis, and the proper ligands are highlighted. Data are from refs , , and .

Figure 3.

Decarboxylative formation of unsymmetrical ketones from α-keto carboxylic acids via a versatile acyl radical intermediate 6. Data are from ref .

Figure 4.

Unsymmetrical dialkyl ketones obtained from the CO₂ extrusion of anhydrides. Data are from ref .

Figure 5.

Decarboxylative mechanism merged with the migratory insertion of nickel into alkynes to obtain substituted olefins. Data are from ref .

Figure 6.

Decarboxylative cross-electrophile coupling between aliphatic carboxylic acids and alkyl bromides to yield the respective C(sp³)–C(sp³) coupled product. Data are from ref .

Figure 7.

Decarboxylative arylations were adapted by many groups, but no reaction generality was observed. Phenotypic screening of hundreds of additives resulted in phthalimide as a powerful and reliable reagent to improve the conversions generally. OAC: Oxidative addition complex. Data are from ref .

Figure 8.

Decarboxylative copper-catalyzed trifluoromethylation using Togni’s reagent I as an electrophilic CF3 source. Data are from ref .

Figure 9.

Decarboxylative N-alkylation of various heterocycles. Coupling proceeded either directly with the N-heterocycles or by previous interception with propellane to obtain the corresponding 1,3-disubstituted BCP derivatives. Data are from refs and .

Figure 10.

General platform for the decarboxylative halogenation of aryl carboxylic acids via copper-to-ligand charge transfer. Data are from refs and .