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Palladium-catalyzed Suzuki–Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the first palladium-catalyzed decarbonylative Suzuki–Miyaura cross-coupling of amides for the synthesis of biaryls through the selective activation of the N–C(O) bond of amides. This new method relies on the precise sequence engineering of the catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a mechanism involving oxidative addition, decarbonylation and transmetallation and provide insight into high N–C(O) bond activation selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki–Miyaura cross-coupling of the amide bond and should enable the design of a wide variety of cross-coupling methods in which palladium rivals the traditional biaryl synthesis from aryl halides and pseudohalides. 

Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. Herein, we describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/( ii ) catalytic cycle. The method shows a remarkably broad substrate scope, enabling to direct the classical acyl reduction towards selective decarbonylation by a redox-neutral mechanism. The utility of this reaction is highlighted in the direct defunctionalization of pharmaceuticals and natural products, and further emphasized in a range of traceless processes using removable carboxylic acids under mild, redox-neutral conditions orthogonal to protodecarboxylation. Extensive DFT computations were conducted to demonstrate preferred selectivity for the reversible oxidative addition and indicated that a versatile hydrogen atom transfer (HAT) pathway is operable. 

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.

 

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.

 

Decarbonylative borylation of carboxylic acids is reported. Carbon electrophiles are generated directly after reagent‐enabled decarbonylation of the in situ accessible sterically‐hindered acyl derivative of a carboxylic acid under catalyst controlled conditions. The scope and the potential impact of this method are demonstrated in the selective borylation of a variety of aromatics (>50 examples). This strategy was used in the late‐stage derivatization of pharmaceuticals and natural products. Computations reveal the mechanistic details of the unprecedented C−O bond activation of carboxylic acids. By circumventing the challenging decarboxylation, this strategy provides a general synthetic platform to access arylpalladium species for a wide array of bond formations from abundant carboxylic acids. The study shows a powerful combination of experiment and computation to predict decarbonylation selectivity.

 

Decarbonylative borylation of carboxylic acids is reported. Carbon electrophiles are generated directly after reagent‐enabled decarbonylation of the in situ accessible sterically‐hindered acyl derivative of a carboxylic acid under catalyst controlled conditions. The scope and the potential impact of this method are demonstrated in the selective borylation of a variety of aromatics (>50 examples). This strategy was used in the late‐stage derivatization of pharmaceuticals and natural products. Computations reveal the mechanistic details of the unprecedented C−O bond activation of carboxylic acids. By circumventing the challenging decarboxylation, this strategy provides a general synthetic platform to access arylpalladium species for a wide array of bond formations from abundant carboxylic acids. The study shows a powerful combination of experiment and computation to predict decarbonylation selectivity.