Transition-metal Catalyzed C(sp~2)-H Etherification of Benzamide Derivatives

Author:Zuo Jian Fei

Supervisor:ding cheng rong zhang guo fu


Degree Year:2019





Ether moiety are chemical and metabolically stable functional groups that are omnipresent in various natural products and synthetic chemicals.Compared with traditional methods of ether synthesis,transition-metal catalyzed C-H etherification has attracted more attention in terms of steps-and atom-economy and the advantages of non-pre-functionalization for substrates.However,up to now,the transition-metal catalyzed C-H etherification has been mostly limited to the palladium-or copper-catalyzed system,only a few reports for other transition metals.In addition,most of C-H etherification need the assistance of various complicated directing groups,although the directing groups can be moved by simple operation,it is of great significance to develop a novel directing group which is cheap and not moved.In this paper,we have been developed a series of transition-metal catalyzed etherification of aryl C(sp~2)-H directing by N,N-dimethylethylenediamine(DMEDA)which is cheap and readily available.The main contents are as follows:1、Copper catalyzed C(sp~2)-H methoxylation of benzamide derivativesA novel copper-catalyzed ortho-C(sp~2)-H methoxylation of benzamide derivatives directing by DMEDA was developed.The reaction system occurs with high functional tolerance,and most substituted benzamide derivatives are tolerated.As a key skeleton structure of some bioactive drugs,the commercially available DMEDA did not need to be moved which could simplify the operation.The methoxylated benzamide derivatives can be used as a potential drug molecule in high throughput drug screening for new drugs.It will provide an efficient method for the synthesis of new active drug molecures.2、Iron catalyzed C(sp~2)-H ethoxylation of benzamide derivatives with cobalt co-catalystThe study further expanded the application of DMEDA as a directing group for the C-H etherification.A new method of ortho-C(sp~2)-H etherification of benzamide derivatives was realized with iron acetylacetonate as a catalyst and cobalt acetate as a co-catalyst.The reaction has a wide range of substrates,good functional group compatibility and excellent regioselectivity.It’s the first example of iron-catalyzed C-H etherification with cobalt co-catalyst.The ethoxylated benzamide derivatives can also be used as a potential drug molecule in high-throughput drug screening.3、Silver promoted C(sp~2)-H methoxylation of benzamide derivativesA silver-promoted ortho-C(sp~2)-H methylation of benzamide derivatives was carried out directing by DMEDA.This protocol is characterized by mild reaction conditions,good functional group compatibility and excellent regioselectivity,most substituted benzamide derivatives can be tolerated in this system.This is also the first example of silver-promoted sp~2 C-H etherification,which provides another fast and efficient method for high-throughput drug screening of new drug molecules.