Study On Addition Reactions To Low-activity Michael Acceptors With Alkene-derived Nucleophiles

The addition of carbon-based nucleophilc reagents to Michael acceptors,namely Michael addition reaction,is one of the most important reactions for C–C bond formation in organic synthesis,and is also one of the cornerstones in modern organic synthesis,as well as having wide applications in the synthesis of complex and bioactive molecules.In this domain,the addition of various carbon-based nucleophiles to highly reactive Michael acceptors,such as enal,enone,α,β-unsaturated ester,nitroalkene,has been widely studies.In contrast to the significant advances,the corresponding addition reaction to low-activity Michael acceptors,such as six-membered azaheteroarnes,α,β-unsaturated amide,and azaheteroaryl substituted alkenes is still rare,which might be ascribled to the aromaticity of the these azaheteroarenes,the low electron-withdrawing ability of amide and azaheteroarene groups.In addition,only few reports on the more challenging asymmetric addition of carbon-based nucleophiles to these low reactive Michael acceptors have been disclosed so far,and almost be confined to the strong organometallics（e.g.,organolithium,Grignard reagent）,which could lead to the poor functional group tolerance.Considering the importance and the challenge of these Michael addition reaction,the development of an（asymmetric）addition of carbon-based nucleophiles to these low-activity Michael acceptors under mild conditions and simultaneously averting the use of poor functional group tolerated organometallics undoubtly processes important in theory and practice.Based on the above research background,this thesis aimed to develop an（asymmetric）addition reaction of pyridiens and azaheteroaryl substituted alkenes with inexpensive,stable and readily availble alkenes as the feedstock instead of the previous stoichiometric amounts of organometallics to establish a series of important（chrial）N-containing molecules,as follows:1)Pyridine motifs are widely existing various bioactive molecules and directly regioselective C–H functionalizations have been immensely reported.However,the C4-position C–H functionalizations remain quite rare,therefore,we developed a synergistically catalytic system,that could enable a regioselective alkylation of pyridines via employing the in situ generated catalytic amounts of organoborane as the nucleophiles to react with pyridines,furnishing C4-alkylatd pyridines in moderate to excellent yields.Moreover,1,1-diaryl alkenes are also valid for this reaction and tertiary compound bearing quaternary carbon centers that are otherwise difficult to access.The proposed mechanism was also investigated via H/D scrambling experiments,¹¹B NMR studies,intermediate trapping experiments,and computational studies.This reaction is the first example of transition-metal free alkylation of pyridines,and that provides an effective reference for other alkylation reactions of olefins and aromatics without transition metal catalyst.2)Azaheteroaryl substituted alkenes are one of the lowest reactive Michael acceptors,and it is more challenging forβ-substituted azaheteroaryl substituted alkenes,owing to the steric hinderance of the substituent at theβ-position.Overrinding these challenges,the asymmetric version remains elusive.In this section,we demonstrated a CuH-catalyzed asymmetric addition ofβ-substituted azaheteroaryl substituted alkenes with styrenes as the feedstocks via the in situ generated catalytic amounts of organocopper organiated from the insertion of alkenes into CuH catalyst,to deliver a series of chiral two consecutive stereocenters-containing azaheteroarenes in good to excellent yields with excellent level of diastereo-and enantiocontrol.This reaction employs the stable and readily available alkenes as the equivalents of traditional organometallics and overcomes the drawbacks of traditional organometallics.On the other hand,we employed the steric and electron properties of the chrial liangd to tune the nucleophility of the in situ generated alkyl copper intermediate,and therefore realize the asymmetric addition to low reactive Michael acceptors without requirement of the strong conventional organometallics and Lewis acids that enhanced the reactivity.The success of this approach lays a foundation for the development of the coreresponding transformations of other low reactive Michael acceptors.