The Pursuit of Effective Catalysis for C-C and C-N Cross-Coupling under Mild Conditions

Abstract

Homogeneous transition metal-catalysis has had a great impact on the synthesis of organic molecules in recent years. The selective mono-arylation of small molecules, a class of reactions predominantly achieved via transition metal-catalyzed cross-coupling reactions, is an important transformation for converting commercially available, abundant materials into value added products. Major advancements have been made with palladium-catalysis in mono-arylation reactions with such abundant stock materials as acetone and ammonia as well as other related compounds. Notwithstanding the utility of palladium in these challenging transformations, it has become desirable to move towards more cost efficient and abundant metals for catalysis. Nickel is significantly less expensive than palladium and shows the potential to provide similar or superior reactivity. The palladium-catalyzed mono-α-arylation of acetone has been conducted at room temperature for the first time. Acetone is the smallest and simplest ketone which makes it a challenging substrate for selective mono-arylation methodologies. Palladium/JosiPhos mixtures have allowed the scope of reactivity to expand to include many (hetero)aryl halides. Ammonia is produced on a large scale and is an ideal building block for organic synthesis. Selective mono-arylation of ammonia has been accomplished through use of palladium-catalysis. Moving to nickel catalysis has allowed for the development of the new DalPhos ligand, PAd-DalPhos, which is capable of facilitating nickel-catalyzed mono-arylation of ammonia and challenging primary amine coupling-partners under mild conditions with a large substrate scope. The nickel/PAd-DalPhos catalyst system has also made possible the first mono-arylation of ammonia employing arylmesylate coupling partners. Mono-arylation of primary amines can be achieved at room temperature using many (hetero)aryl (pseudo)halides and including chemoselective reactivity. Mono-arylation of primary amides and lactams employing nickel-catalysis was made possible for the first time. Nickel is capable of reactivity beyond what has been demonstrated with palladium in transition metal-catalyzed cross-coupling. Nickel has shown the ability to utilize unique electrophiles in amination reactions such as carbamates, sulfamates, and pivalates which are largely inaccessible to palladium catalysis. These electrophiles were used for the first time in amination reactions with ammonia and primary alkyl amines.