Copper-catalyzed Radical Methylation Using Peroxides As The Methylating Reagents

Methylation is an important transformation in organic synthesis chemistry. Traditional methods apply electrophilic methylating reagents, such as dimethyl sulfate, dimethyl carbonate, methyl iodide, and diazomethane. These methodologies have several drawbacks, such as using hazardous and toxic methylating reagents, strongly basic additives and always result in the mixture of mono-and multimethylated products. So methods for efficient and selective methylation using safe reagents under mild conditions are highly desirable.Peroxides are commercially available, easy-to-handle, and environmentally friendly. Over the past decade, organic peroxides as oxidants have found widely applications in organic synthesis chemistry. In recent years, the researchers found that the thermal cleavage of peroxides could produce an alcoxyl radical. The followed cleavage of the alcoxyl radical could produce a methyl group and corresponding alcohol or ketone byproduct. This facture means that peroxides as methyl sources could be applied in methylation reactions.This thesis mainly using peroxides as methyl reagents and applications in synthesis of quinazolinones and methylsulfonyl compounds. Our research work mainly includes following two sections.Section 1:Copper-catalyzed radical methylation/C-H amination/oxidation cascade for the synthesis of quinazolinones.Quinazolinones, as an important class of N-heterocycle compounds, has been widely found in biologically and pharmacologically active molecules, natural products, and functional materials. Herein, we demonstrated a facile method for the synthesis of quinazolinones starting from anthranilamides using DCP as the methyl source. This reaction involved a tandem N-methylation/sp3 C-H amination/oxidation process in the presence of a copper catalyst. This protocol presents a broad substrate scope and has good tolerance of various functional groups. Notably, a methyl radical, generated from peroxide, was confirmed by electron paramagnetic resonance for the first time.Section 2:Copper-catalyzed radical methylation for the synthesis of methylsulfonyl compounds in water.Sulfonyl hydrazides are readily accessible and exist as stable solids. Studies on the synthesis of sulfonyl hydrazide increasingly attracted researchers’interest, and have made great improvement in recent years. We have developed a facile method for the synthesis of methylsulfonyl compounds starting from sulfonyl hydrazide using TBHP as the methyl source. This reaction has a wide substrate scope, under mild reaction conditions. Particularly, this method using environmental friendly solvent and achieving the recycling of copper catalyst could precisely meet the demands of green and sustainable chemistry. The scaled up experiment with good yield further promote its application in organic synthesis chemistry.