Palladium-Catalyzed Ligand-Free Suzuki Reaction In Water

Solvents generally account for the major source of the wasted mass of a given process or a synthetic pathway. Moreover, the use of solvents is a constant source of worry since it gives rise to toxicity, hazard, pollution and waste treatment issues. In a recent survey, most pharmaceutical companies are approaching green chemistry and considering water as a potentially useful and safe solvent. Water is an abundant, nontoxic, noncorrosive and nonflammable solvent, and a lot of efforts have been made to carry out organic reactions in water.Among the developed transformations, the palladium-catalyzed Suzuki reaction is an excellent example, which is one of the most versatile and powerful tools for the construction of biaryls. Although the Suzuki reaction has strongly benefited from aqueous chemistry, most of halogenated substrates are insoluble in water, resulting in poor reactivity. In this thesis, we developed simple, efficient and green palladium-catalyzed ligand-free protocols for Suzuki reaction in water and applied the protocol to synthesize the arylpyridine N-oxides. The main contents are as follows:1. We developed a fast and efficient catalytic system of Pd(OAc)2/(i-Pr)2NH/H2O for the cross-couplings of a wide range of aryl halides with arylboronic acids without any additive. With the optimized conditions (0.25mol%Pd(OAc)2, two equivalent diisopropylamine, water,100℃), various4-substituted aryl bromides bearing either electron-donating or electron-withdrawing groups, such as-OMe,-NH2,-CN,-COCH3and-NO2, provided the corresponding products in good to excellent yields in5min, resulting in a high TOF up to4752h-1. Aryl bromides with a carboxyl or hydroxyl group were successfully coupled with p-tolylboronic acid in excellent yields. This catalytic system could tolerate aryl halides with hydrophilic groups or hydrophobic groups.2. Aryl-substituted pyridines are the most common N-heteroaryl units in pharmaceutically active compounds. The catalytic system of Pd(OAc)2/(i-Pr)2NH/H2O was successfully extended for the Suzuki reaction of pyridine N-oxides with arylboronic acid, providing a green and efficient approach for arylation of pyridine N-oxides.3. A general and recyclable catalytic system for the Pd/C-catalyzed ligand-free Suzuki cross-coupling reaction is developed, which tolerates a wide range of aryl halides without any additive in water.2-Pyridyl bromide was less active in coupling with arylboronic acid in this catalytic system, providing50-86%isolated yields within24h. It is clear that this protocol is also applicable to the cross-coupling between2-bromothiophene and phenylboronic acid. As a whole, this catalytic system could tolerate a broad range of aryl bromides bearing a hydrophilic group or a hydrophobic group. The Pd/C catalyst could be reused three runs without significant loss of the catalytic efficiency.