Diversity-oriented Synthetic Methodologies Based On The Raw Materials Of Arylethanones And Diarylethanones

Diversity-oriented synthesis has become one of the research hot spots in the fields of chemistry,biochemistry and medicinal chemistry,and plays a very important role in the drug discovery.Diversity-oriented synthesis is a relatively new and rapidly developing research field in recent years,which provides an efficient method for the synthesis of complicated structures and diverse small molecules at different diversity levels.In addition,modern organic synthetic methodologies provide new reagents,new reactions and new strategies for diversity-oriented synthesis.Among the methods used in diversity-oriented synthesis,cascade reaction is known as an atom-and step-economically synthetic strategy and has become one of the very efficient tools for the diversity-oriented synthesis,to circumvent the procedures of separation and purification of the reaction intermediates,and to make possible the construction of different kinds of complicated and diverse molecular skeletons in efficient ways with the utilization of simple and easily accessible starting materials.The works in this thesis have taken use of arylethanones and diarylethanones as the key starting materials,constructed four new reaction systems featuring different cascade reaction processes,and achieved the facile syntheses of structure-diverse skeletons.The main contents are shown as follows:In chapter 1,we first briefly summarized the importance of diversity-oriented synthesis in modern organic synthesis,next introduced in detail the diversity-oriented synthesis and its design strategies,as well as the transition-metal catalyzed organic reactions including the Csp2-Csp3 coupling and C(C=O)-Csp3 cleavage.In this context,we proposed the research idea and work contents in this thesis.In chapter 2,a novel palladium-catalyzed sequential coupling and C(C=O)-Csp3 activation cascade reaction has been developed for the synthesis of various diarylmethanes with the raw materials of arylethanones and aryl halides in yield up to 91%.In this facile one-pot reaction,the arylethanone acts only as a formal methylene donor to couple with two moles of aryl bromide partners,A detailed plausible mechanism has been identified based on the experimental results from the reaction process by taking use of thin-layer chromatography and ex situ IR spectroscopy as well as a series of control experiments.In chapter 3,on the basis of the work of chapter 2,a one-pot palladium-catalyzed cascade process for the synthesis of symmetrical and unsymmetrical diarylmethanones using arylethanones and aryl bromides as raw materials has been developed.The mechanistic investigation revealed the process involves the procedure of sequential coupling,oxidation and C(C=O)-Csp3 activation.The achievement of this reaction was done through the change of the reaction atmosphere and modulation of the loading of base that were applied in the former reaction in chapter 2,and consequently,arylethanone used acts as a latent carbonyl donor instead of a methylene donor.The yields of products reached up to 86%.Moreover,a nonsteroidal anti-inflammatory drug,Ketoprofen,was able to be synthesized in a two-step procedure in 45%overall yield based on our developed method.In chapter 4,a chemoselective transformation of diarylethanones to arylmethanoic acids and diarylmethanones has been realized under two types of reaction conditions,based on the cascade reactions of Beayer-Villiger oxidation,C(C=O)-Csp3 activation,benzilic acid rearrangement and decarboxylation reactions.The method was exploited to provide a practical strategy for the syntheses of some high value-added molecules such as arylmethanoic acids,vitamin B3,diphenic acids and diarylmethanones with yields up to 97%.Furthermore,we verified the key aldehyde intermediate involved in the process of arylmethanoic acids formation by 1H NMR tracking experiment.In chapter 5,a straightforward approach to an array of novel multiaryl-substituted 1H-pyrrol-2(3H)-ones featuring a hardly accessible a-diarylated all-carbon quaternary center has been developed by the reaction of diarylethanones and primary amines as the raw materials.This one-pot,one-step strategy was achieved through a copper/TEMPO-mediated cascade process comprising oxidative enolate homocoupling,oxidative dehydrogenation,heterocyclization and Wagner-Meerwein 1,2-phenyl shift.This method was very efficient and delivered the products in up to 84%isolated yield.Interestingly,these compounds,as new AIE luminogens,showed typical aggregation-induced emission(AIE)property,and this photophysical property was explained with the help of the crystal structure of a typical multiaryl-substituted 1H-pyrrol-2(3H)-one compound.In chapter 6,all the works of this Ph.D dissertation are summarized,and the related future works are outlooked.