Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis

Abstract

Conspectus 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...

Resurgence and advancement of photochemical hydrogen atom transfer processes in selective alkane functionalizations

“…11,32 Metallaphotoredox provides a unique strategy to enforce the interaction of alkyl radicals with transition-metal complexes for various crosscoupling reactions. [33][34][35][36] The synergistic incorporation of radical-mediated HAT processes and bond-forming steps enabled by transition metals may provide new opportunities to address challenging problems such as alkane metathesis and dehydrogenation reactions. Moreover, the utilization of photonic energy provides bonus energy input to enable endothermic alkane transformations.…”

Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation

“…Alkene hydrofunctionalization methods that exploit radical intermediates are a fundamental class of synthetic reactions. Radical reactivity offers a complementary regio- and chemoselectivity profile relative to polar pathways. , Despite anti-Markovnikov hydrobromination dating back a century, , the development of radical hydrofunctionalization reactions remains a contemporary area of investigation. − Our group has a particular interest in alkene hydrocarboxylation using radical intermediates. , Carboxylic acids are a readily diversifiable functional handle − and are themselves a common motif found in natural products, pharmaceuticals, and commodity chemicals. − We envision that a broad and general radical hydrocarboxylation reaction would offer a powerful complement to transition-metal-catalyzed methods, such as the numerous established CO-based approaches − and the emerging alternative technologies that proceed through migratory insertion into CO 2 . − However, established approaches to radical hydrocarboxylation have remained largely limited to activated alkenes (Figure A). ,,− Unactivated aliphatic alkenes are an abundant and important substrate class but remain more challenging to engage due to their attenuated reactivity. Indeed, in the past year, Yu and co-workers reported the first and only synthetic methodology that engages unactivated alkenes with CO 2 •– .…”

Metallaphotoredox-Mediated Decarboxylative Cross-Coupling of α-Oxy Morpholine Carboxylic Acids and (Hetero)Aryl Halides

“…Seeking to address this gap in the synthetic literature and develop a step-economical approach for the construction of α-oxy-arylated morpholines, we turned to metallaphotoredox-mediated decarboxylative cross-couplings of carboxylic acids and aryl halides as a possible solution. , While the large body of work on carboxylic acids in metallaphotoredox chemistry affords entry to an array of diversified scaffolds, there is a striking lack of systematic study on α-oxy acids, in comparison to the much more well-studied α-amino and alkyl acid classes. ,− At the time our study concluded, to our knowledge, there had been no reported methods in the chemical literature that allow for direct use of commercially available α-oxy morpholine acids in decarboxylative metallaphotoredox cross-coupling. , …”