Buchwald-Hartwig Amination Of Aryl Chlorides Under Mechanical Milling Conditions

The C-N bond is widely existed in various bioactive molecules and functional materials.Therefore,the establishment of a highly efficient strategy for C-N bond construction has always been the research interests from both academic and industrial communities.The Pd-catalyzed Buchwald-Hartwig amination is one of the most effective ways to construct the C-N bond directly.However,the application of Buchwald-Hartwig amination of aryl chlorides is limited in industry since its low reactivity and complex operation(inert gas protection).So it is interesting and challenging to find an efficient method for activating C-Cl bond and realize BuchwaldHartwig amination of aryl chlorides under mild conditions.As a new reaction method,mechanical ball-milling can activate various chemical bonds effectively.Based on the strategy of promoting C-Cl bond activation by mechanochemistry,Buchwald-Hartwig amination of aryl chlorides had been studied under mechanical ball-milling conditions,in order to develop a highly efficient and green protocol for Buchwald-Hartwig amination.In the first chapter,the development of Buchwald-Hartwig amination was summarized and the basic conceptions of the mechanical ball-milling technique was reviewed.Then,in the second chapter,the mechanical Buchwald-Hartwig amination was studied systematically under solvent-free mechanical ballmilling conditions.The effort was paid to optimize the reaction conditions,and the scope of application of the substrate has been investigated.Finally,we established a new protocol of Buchwald-Hartwig amination with the advantages of short reaction time,high efficiency,simple operation.In addition,the role of different grinding aids was carefully examined,owing to the discovery that grinding aids have great influences on the activity and reproducibility of the reaction.Based on our previous work,it was found that the C-Cl bond in the Suzuki-Miyaura reaction was efficiently activated under liquid-assisted grinding(LAG)conditions.Thus,we examined Buchwald-Hartwig amination at LAG conditions.The main factors affecting the yield of the reaction were discussed,including ligand,base,solid and liquid additives.Then,the scope of substrate using this methodology was expanded.What's more,the mechanism of reaction system was probed with LAG effect as the focus of the research.Finally,three active pharmaceutical ingredients and key intermediates was synthesized under the solvent-free and liquid-assisted grinding conditions to validate the effectiveness of developed Buchwald-Hartwig amination.