Advances in Palladium-Catalyzed Carbon-Carbon Bond Formation Via Functionalization of Carbon-Hydrogen Bonds

Abstract

In the past decade, significant advances have been made in the formation of Csp2-Csp 2 bonds by direct arylation. However, this process generally requires the use of forcing conditions at temperatures typically above 100 °C, which limits the substrate compatibility as well as large-scale applications. Inspired by the recent advances in the development of milder reaction conditions for the arylation of electon-rich arenes in an aqueous medium, we describe that such reactivity is also possible with electron-deficient polyfluorinated arenes at room temperature under biphasic conditions. Several examples are included, highlighting the application of this method to the preparation of a variety of biaryls using iodides bearing electron-poor, electron-rich and sterically encumbering substituents. Several polyfluoroarenes with different substitution patterns are also tolerated. In addition, the method can be extended to the arylation of halogenated thiophenes in a regioselective fashion. However, direct arylation conditions that are general for a broad variety of heterocyclic coupling partners are only sparsely reported and the use of a different set of conditions for each type of substrate remains the norm. As part of a program dedicated to the study of the direct arylation mechanism and the development of broadly applicable reaction conditions, we became interested in investigating the effect of electron-deficient biaryl-type phosphine ligands on the C-H bond cleavage step of this process under Pd(0) catalysis. Inspired by previous reports validating the efficiency of these types of ligands in intramomecular direct arylation, we have developed a new electron-deficient fluoroarylphosphine ligand that promotes C-H bond functionalization of a broad variety of heterocycles. The demonstrated ability of these types of ligands to facilitate the C-H bond cleavage step of this process has been assessed and experimental evidence suggests a concerted metalation-deprotonation mechanism in the presence of an electrophilic metal center. Only recently, nonetheless, has attention been paid to the formation of Csp3-Csp2 bonds by the direct arylation strategy. As an alternative to the use of aliphatic halides as an entry point to a1kylpalladium(II) intermediates, we describe the use of a Heck-like cyclization of an aryl halide as a means of intercepting the key palladium(II) species, along with the first examples of domino Heck-arylation involving intermolecular capture with heterocyclic arenes via C-H bond cleavage. Several examples are presented, demonstrating the application of this method to the preparation of diverse dihydrobenzofurans, indolines and oxindoles substituted with sulfur-containing heterocycles such as thiazoles, thiophenes and benzothiophene.