Study Of Aromatic C(sp~2)-H Bond Functionalization And Synthesis Of Benzoxazine Derivatives Based On Electrophilic Trapping Of Zwitterionic Intermediates

Metal carbenes generated from transition metal-catalyzed decomposition of diazo compounds have attracted more and more attention due to their highly reactive peculiarity in organic transformations.In recent years,our group have developed a series of novel multi-component reactions based on the electrophilic trapping of ylide intermediates,which are formed from nucleophilic attack to the metal carbenes by alcohols and amines.As the extesion of electrophilic trapping strategy,we also realize the MCRs based on trapping of zwitterionic intermediates which are generated from transfer of a carbene moiety onto nitrogen-containing aromatic heterocycles.Carbene-induced C-H functionalization is among the most valid and reliable synthetic tools for the construction of C-C bonds.However,carbene-induced functionalization of aromatic C-H bonds is generally considered to proceed through the formation of a zwitterionic intermediate,which makes it very challenging to achieve efficiently enantioselective control.In this thesis,we successfully develop a catalytically asymmetric functionalization of aromatic C-H bonds based on a novel three-component reaction.This reaction is a significant progress of MCRs on the basis of electrophilic trapping strategy.In chapter 2,we have achieved the first asymmetric functionalization of aryl C-H bonds through a three-component reaction of N,N-disubstituted anilines with diazo compounds and imines in the presence of Rh(?)/chiral phosphoric acid cocatalytic system.This transformation is proposed to proceed via the generation of zwitterionic intermediates by electrophilic addition to the aromatic ring with metal carbenes,and subsequent electrophilic trapping process with imines.This transformation not only offers an efficient way for the construction of ?,?-diaryl all-carbon benzylic quaternary stereocenters in good yields with high diastereoselectivities and excellent enantioselectivities,but also provides experimental evidence to support the electrophilic addition pathway via a zwitterionic intermediate for traditional metal carbene-induced functionalization of aromatic C-H bonds.In chapter 3,we have developed an efficient method for the construction of 3-aryl-3-substituted oxindole derivatives in good yields and high diastereoselectivities through an aromatic C-H fuunctionalization.This transformation is proposed to proceed via an intermolecular aldol-type trapping of metal-carbene-induced zwitterionic intermediates generated in situ from N,N-disubstituted anilines and metal carbenes.The intermolecular kinetic isotope effect experiment suggests that the C-H bond cleavage is not involved in the rate-determining step.This transformation offers a straightforward way for the construction of 3-aryl-3-substituted oxindole skeleton.At the same time,this reaction replenish our trapping strategy in functionalization of aromatic C-H bonds.In chapter 4,a simple,mild and efficient Rh(?)-catalyzed aromatic C-H functionalization of a-phenoxyketones by 3-diazooxindoles for the synthesis of spiro[chroman-4,3 '-oxindole]is described.A series of functionalised spiro[chroman-4,3'-oxindole]derivatives bearing two adjacent quaternary carbon centers have been obtained in a highly diastereoselective manner with very good yields.Control experiments suggested the possibility of an intramolecular aldol-type trapping of zwitterionic intermediates after the C-H functionalization.Furthermore,the applicability of this method has been tested by gram scale synthesis.Treatment of products with base enabled the transformation of syn isomers to trans isomers,thus providing a facile access to both syn-and anti-diastereomers via the isomerisation.In chapter 5,we have developed an effective method for the construction of 4-quaternary-4H-benzo[d][1,3]oxazine derivatives in high yields and good diastereoselectivities.This transformation is proposed to proceed via electrophilic trapping of metal-carbene-induced zwitterionic intermediate generated in situ from 2-diazo-2-(2-arylamidophenyl)acetate using isatins.In chapter 6,we have developed an effective method for the construction of chiral 4-quaternary-4H-benzo[d][1,3]oxazine derivatives in high yields and good enantioselectivities in the presence of Rh(?)/chiral phosphoric acid cocatalytic system.This transformation is proposed to proceed via electrophilic trapping of metal-carbene-induced zwitterionic intermediate generated in situ from 2-diazo-2-(2-arylamidophenyl)acetate using imines.This kind of zwitterionic intermediate is another supplement of our works about electrophilic trapping active intermediates.