Study On The Synthesis Of α- Ketoamides By Metal-free Catalysis

α-ketoamides,as a key skeleton of many natural products and drugs,have a wide range of important biological activities.Their unique structure exists in many molecules found so far,and it plays an extremely important role.The structure of α-ketoamides can be found in some T cell proliferation inhibitors,protease inhibitors,and drugs for the treatment of chronic hepatitis C.As early as the end of the 20 th century,the specific structural features of α-ketamides and their important biological effects successfully attracted many drug synthesis scientists’ attention,and after decades of efforts they have put forward a variety of different methods for its efficient synthesis and this work will still continue.However,in the traditional study,the methods of synthesizing these compounds have common drawbacks: the use of toxic reagents,too many synthesis steps,harsh reaction conditions,low yield and so on.In recent years,with the development of C-H bond activation,people have began to use the transition metal catalytic method to synthesize such compounds and made great progress,but trace metal residues limit the α-ketone Amide synthesis applications in the pharmaceutical industry.So the development of more consistent with the green chemistry of synthetic methods has got more and more attention by drug synthesis workers.Based on the preliminary work,the substrate of synthetic α-ketamide was screened as the principle of economic application and operability.The effects of acetophenone and secondary amine,toluene and N,N-dimethyl-Amide and almost twenty other kinds of substrate models were classified,and the possibility and operability of generating the target product were explored for different types of substrate models.After eliminating the substrate models going against the experiment,difficult to synthesis,not according with the economic principles and the basic principles of green chemistry,as well as too much by-products,we finally choose the way with simple operation,easy-to-access acetophenone together with secondary amine and toluene together with amide as model substrates to synthesize α-ketoamides.In this paper,two kinds of model substrates were used as the main lines to explore the non-metallic catalytic oxidation system which accorded with the two reactions: the first main line used acetophenone and secondary amine as the model substrates,and the orthogonal experiment was used to select the most suitable metal-free catalytic system: I2 / TBHP.On the basis of I2 / TBHP,we optimized the ideal reaction conditions and examined the suitability of the substrate under the conditions of the reaction.The second main line used toluene and amide as the model substrate,and the orthogonal experiment was used to select the most suitable metal-free catalytic oxidation system: TBAI / DTBP.On the basis of TBAI / DTBP,we optimized the ideal reaction conditions and examined the suitability of the substrate under the conditions of the reaction.In conclusion,based on the preliminary work,two different feasible methods for the synthesis of α-ketoamides were designed in this study,which not only increased the diversified methods of synthesizing α-ketamide,but also innovatively selected an unique nonmetallic catalytic oxidation system in line with the two routes.Our study provided a new feasibility idea to solve the problems of traditional methods for the synthesis of such compounds,such as the usage of toxic reagents,too many steps,harsh reaction conditions,low yield and trace metal residues in the transition metal catalytic method,and also laid the foundation for the further study of α-ketoamides.