Selective Activation Of Inert C-H,C-F Bonds

In the development of chemistry,efficient activation of inert chemical bonds has always been a hot topic.The study of inert chemical bond activation can not only help people to further understand the mechanism of chemical bond cleavage in the reaction,but also construct C-C,C-O,C-N bonds,and other chemical bonds with high selectivity through selective activation and functionalization of inert bonds.By studying the activation of inert bonds,it is possible to construct target molecules from a simple starting material,which is of great significance for the synthesis of natural products and drug molecules.In recent years,inert bond activation has made great progress,and at the same time,remarkable results have been achieved in the actual production process,opening up ne'w research fields for the pharmaceutical,agricultural,food,materials and other industries,albeit facing the increasingly more difficulties and challenges.Since inert bonds are widely present in organic molecules,how to achieve their selective conversion is still a difficult point.The research in this thesis includes regiocontrolled direct C-H arylation of indoles at the C5 positions,asymmetric defluoroborylation of 1-(trifluoromethyl)alkenes,transition-metal-free defluorosilylation of fluoroalkenes with silylboronates,and enantioselective copper-catalyzed defliorosilylation of trifluoromethylated alkenes with silylboronates,as follows:Part I:The indole motifis aubiquitous feature of bioactive natural products and an important structural element in pharmaceutical applications.Therefore,the development of effective and regioselective C-H bond functionalization of indole has received extensive attention.There are six C-H bonds in the indole motif that can be functionalized:positions C2 and C3(pyrrole core),and C4-C7(benzene core).However,these C-H bonds are inequivalent,and it is quite difficult to access each of them.Since the benzene core of indole is more electron deficient than the pyrrole core,it is more difficult to carry out regioselective C-H bond functionalization on the benzene core.Our group has been working on the functionalization of C-H bonds on the benzene core of indole.On the basis of previous work,we introduced pivaloyl group as a direction group at the C3 position of indoles,CuTc as a catalyst,diaryliodonium salts as an aryl source,and successfully achieved C-H arylation of indoles at the C5 position.This method was successfully applied to the synthesis of Tiplaxtinin as a key step,which proved that the strategy has broad application prospects and commercial value.Part ?:Modern drug discovery relies on advance in chemical synthesis to address challenges from designing new pharmaceutical agents.As carbonyl isosteres,replacement of a carbonyl with the corresponding gem-difluoroalkene,has been demonstrated to provide bioactive substrates still recognized by their target.However,this potentially valuable carbonyl mimic has not been extensively evaluated,possibly because the conventional routes to construct the gem-difluoroethylene motif involve a functional-group interconversion relying on highly reactive intermediates,organometallic reagents,or harsh reaction conditions.We have developed an efficient asymmetric copper-catalyzed system that can activate the C-F bonds of 1-(trifluoromethyl)alkenes via a defluoroborylation process to produce a diverse array of enantioenriched gem-difluoroallylboronates.We discovered that the Josiphos family of ligands provided the best reactivity and enantioselectivity.The reaction conditions were mild,and a variety of common functional groups,such as ether,halogen,ester,cyano,sulfide,amino,and indoyl groups,were well tolerated.Furthermore,we not only applied this developed system as a powerful synthetic tool for the late-stage modification of complex compounds,but also highlighted the utility of the formed compounds in synthesis.We anticipate that this strategy based on the diversity of boron chemistry will simplify the synthesis and structural elaboration of gem-difluoroalkene targets for research in chemistry,biology,and medicine.Part ?:Silylated fluoroalkenes are important synthetic intermediates with complementary reactivity,which plays a key role in the construction of natural products,pharmaceuticals,and manmade materials.Converting the normally highly stable fluoroalkenes into silylated fluoroalkenes by selective defluorosilylation is a challenging task.Here,we report a simple,inexpensive and robust defluorosilylation of a variety of fluoroalkenes with silylboronates in the presence of alkoxy base to directly synthesize various silylated fluoroalkenes.The protocol features mild and safe reaction conditions that avoid a catalyst,a transition metal,a ligand,and high reaction temperature and tolerates a wide scope of fluoroalkene substrates without compromising the efficiency.Density functional theory calculations show that transient silyl anion complex undergoes a concerted nucleophilic substitution is responsible for this base-mediated defluorosilylation reaction.Part IV:Silylated fluoroalkenes have shown great promise as a powerful tool for the introduction of fluoroalkene motifs in organic molecules,in which given that silyl groups can be readily converted into a wide variety of other functional groups.These features have triggered the development of synthetic methods to complement existing strategies for accessing these compounds.However,enantioselective defluorosilylation of trifluromethylated alkenes remains a huge challenge.We have developed firstly an efficient asymmetric copper catalyzed system that can activate the C-F bonds of trifluoromethyl alkenes via a defluoroallysilanes.Given the ubiquity of the difluorovinyl group and its precursors in bioactive compounds,we anticipate that this strategy,based on well developed silane chemistry,will simplify the synthesis and structural elaboration of chiral difluoroalkene targets for research in chemistry,biology and medicine.