Recent Applications of Pd-Catalyzed Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process Chemistry

Abstract

Cross-coupling reactions have changed the way complex molecules are synthesized. In particular, Suzuki–Miyaura and Buchwald–Hartwig amination reactions have given opportunities to elegantly make pharmaceutical ingredients. Indeed, these reactions are at the forefront of both the stages of drug development, medicinal chemistry, and process chemistry. On the one hand, these reactions have given medicinal chemists a resource to derivatize the core compound to arrive at scaffold rapidly. On the other hand, these cross couplings have offered the process chemists a smart tool to synthesize the development candidates safely, quickly, and efficiently. Generally, the application of cross-coupling reactions is broad. This review will specifically focus on their real (pharma) world applications in large-scale synthesis appearing in the last three years.

Construction of Heterobiaryl Skeletons through Pd-Catalyzed Cross-Coupling of Nitroarenes and Heterocyclic Arylborononate Esters with a Sterically Demanding NHC Ligand

“…Heterobiaryl compounds are found in an array of pharmaceuticals, dyes, and materials, − and a large number of synthetic methods have been developed over the years for the preparation of heterobiaryls. − Transition-metal-catalyzed cross-couplings between haloarenes and (pseudo)­haloarenes and arylboronate reagents have been the most successful approach to biaryl compounds. Nitroarenes are attractive electrophiles.…”

Aryl fluorosulfates: powerful and versatile partners in cross-coupling reactions

“… 15 This coupling is one of the widely used reactions in the manufacture of pharmaceuticals and is the most common biaryl bond forming reaction. 16 …”

Structural authentication of intermediates of mechanistic significance in palladium- and nickel-catalysed cross-couplings: case studies

“…63,69 The cross-coupling has been rapidly adopted by chemists on both laboratory- and industrial-scales, as it represents a mild, efficient, and reliable strategy for accessing ubiquitous aryl amines. 70–72 The first generation approaches reported by Migita's group employed aminostannanes as nucleophiles, and [Pd{P( o -tol) 3 } 2 ] as the catalyst. 73 This was significantly improved upon by the Buchwald and Hartwig groups independently, through their development of enhanced methodology that obviated the need for stoichiometric tin reagents.…”

“…Since these early reports, this process has rapidly emerged as a general and versatile tool for the formation of C–N bonds. 69,70,72 Ligand optimisation has been a major focus, and chelating bis(phosphines) and dialkylbiaryl phosphines are now among the most frequently used systems. 63 Mechanistically, the palladium-catalysed Buchwald–Hartwig reaction commences with oxidative addition (Fig.…”