Pharmaceuticals

Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate Structure

“…The palladium-catalyzed Suzuki–Miyaura coupling reaction has been extensively studied and widely used in both academia − and industry. , It is a particularly powerful synthetic strategy for the construction of numerous natural compounds, pharmaceuticals, agrochemicals, and polymers. − Typical systems for Suzuki coupling consist of an aryl bromide, an arylboronic acid, or ester, catalytic quantities of Pd(0) or Pd­(II) salts in the presence of a ligand, and the presence of added bases . The reactions are usually conducted in an organic medium or in a biphasic organic–aqueous media.…”

“…The palladium-catalyzed Suzuki−Miyaura coupling reaction has been extensively studied and widely used in both academia 1−7 and industry. 8,9 It is a particularly powerful synthetic strategy for the construction of numerous natural compounds, pharmaceuticals, agrochemicals, and polymers. 3−9 Typical systems for Suzuki coupling consist of an aryl bromide, an arylboronic acid, or ester, catalytic quantities of Pd(0) or Pd(II) salts in the presence of a ligand, and the presence of added bases.…”

Aqueous Suzuki Coupling Reactions of Basic Nitrogen-Containing Substrates in the Absence of Added Base and Ligand: Observation of High Yields under Acidic Conditions

“…Heterocyclic biaryl compounds, particularly those containing nitrogen, are components in many pharmaceutical and biologically active molecules . While many synthetic methods have been employed for coupling aromatic reaction partners to form biaryl products, the Suzuki coupling reaction has emerged as the most versatile of the synthetic protocols. − These Pd-catalyzed reactions are usually conducted in an organic–aqueous cosolvent in the presence of a suitable ligand. , In addition, the presence of base (e.g., K 3 PO 4 ) is considered to be crucial for the success of the reaction. − , Indeed, in his Nobel address, Professor Suzuki emphasized that no coupling reaction occurs without base . While there has been great success in a wide range of Suzuki coupling processes, reaction partners containing basic nitrogen centers often react more slowly and/or produce the desired coupled products in lower yields compared to the neutral substrates under the same reaction conditions. − In these cases, the basic nitrogen centers are postulated to coordinate with the palladium catalyst, reducing or poisoning its catalytic activity. − As a consequence, the use of additional protection/deprotection steps or expensive designer ligands is often necessary to achieve reasonable reaction rates and high yields. ,, Herein, we report the surprising observation that aqueous heterogeneous Suzuki coupling reactions of a wide variety of aryl bromides containing aliphatic 1°, 2°, and 3° amine substituents and substituted bromopyridines produce excellent yields in the absence of added base and ligand.…”