Bimetallic Cooperative Catalysis for Decarbonylative Heteroarylation of Carboxylic Acids via C‐O/C‐H Coupling

Abstract

Cooperative bimetallic catalysis is a fundamental approach in modern synthetic chemistry. We report bimetallic cooperative catalysis for the direct decarbonylative heteroarylation of ubiquitous carboxylic acids via acyl C‐O/C‐H coupling. This novel catalytic system exploits the cooperative action of a copper catalyst and a palladium catalyst in decarbonylation, which enables highly chemoselective synthesis of important heterobiaryl motifs through the coupling of carboxylic acids with heteroarenes in the absence of prefunctionalization or directing groups. This cooperative decarbonylative method uses common carboxylic acids and shows a remarkably broad substrate scope (>70 examples), including late‐stage modification of pharmaceuticals and streamlined synthesis of bioactive agents. Extensive mechanistic and computational studies were conducted to gain insight into the mechanism of the reaction. The key step involves intersection of the two catalytic cycles via transmetallation of the copper–aryl species with the palladium(II) intermediate generated by oxidative addition/decarbonylation.

Metal/Metal Dual Catalysis in C−H Activation

“…Recently, Szostak and co-workers established a Pd/Cu bimetallic catalysis system for heterocycles synthesis via decarbonylative heteroarylation starting from common carboxylic acids (Scheme 27). [40] This cooperative decarbonylative methodology showed a remarkably broad substrate scope (> 70 examples) and could be further applied to late-stage modification of pharmaceuticals and streamlined synthesis of relevant bioactive agents. Meanwhile, a tunable CÀ H arylation and acylation of azoles with carboxylic acids was also realized by Chen and coworkers through Pd/Cu cooperative dual catalysis.…”

Facile Conversion of Molecularly Complex (Hetero)aryl Carboxylic Acids into Alkynes for Accelerated SAR Exploration

“…The formation of amide 4 in chamber II indicates the evolution of CO gas during the reaction. Furthermore, 13 C incorporation clearly shows the origin of the formed CO gas.…”

“…We decided to focus on decarbonylative approaches, [13][14][15][16] as these reactions are described as less restricted in their substrate scope notably regarding electronic and steric effects compared to decarboxylative couplings. [14,17] Several activated carbonyl functionalities, such as acyl halides, [18][19][20] esters, [21][22][23] and amides [24][25][26] have been used as precursors for such a transformation, however we aimed to avoid unnecessary reagent preparation, focusing on the direct use of the advanced carboxylic acid already in hand.…”

“…This methodology enabled several decarbonylative transformations starting directly from carboxylic acids, for example borylations [27] or phosphorylations, [28] among others. [13,29] As a starting point for our study, we used a bimetallic Pd/Cu catalytic system with a mixture of Piv 2 O and DMAP as activator of the carboxylic acid together with TIPS protected acetylene as alkyne source, which after coupling can be conveniently deprotected giving access to the targeted terminal alkyne. To our delight, using these conditions the desired coupling product was observed.…”

Tandem C–O and C–H Activation at Palladium Enables Catalytic Direct C–H Alkenylation with Enol Pivalates

“…18 Rh catalysis involving directing-group assisted C-H activation is the major reported method. [23][24][25][26][27][28][29][30] For reactions without C-H directing groups, Ni catalysis 31 and more recently tandem Pd/Cu catalysis 32,33 have been reported. A more direct method is tandem C-O/C-H activation involving ester, ether, or carbamate leaving groups.…”