Directing Group-Assisted Intermolecular Aminative Difunctionalization Of Unactivated Alkenes

Nitrogen containing organic compounds are broadly existed in natural products,pharmaceuticals,materials science,and chemical industry.The synthesis of nitrogen containing molecules therefore has always been a hot topic in organic chemistry.Among the numerous developed synthetic protocols,the intermolecular aminative difunctionalization of readily available alkenes is undoubtedly one of the most straightforward and efficient accesses to nitrogen containing molecules.Along with the construction of C-N bond,this reaction can incorporate another functional group adjacent to the newly installed nitrogen atom,which dramatically enhances the molecular complexity and benefits the following functional group interconversion.However,currently there are two major challenges in intermolecular aminative difunctionalization of alkenes.First,the alkene substrate scope mainly focus on the styrene derivatives,and only limited examples are reported with unactivated alkenes due to the low reactivity as well as the difficulty in controlling the regioselectivity of the reaction.Second,the incorporated nitrogen atoms are usually tethered with electron-withdrawing groups.For electron-rich dialkyl amino sources,they can poison the transition metal catalyst and are also easily to be oxidized;both would hamper their application in aminative difunctionalization of alkenes.In this thesis,a strategy combining directing group and the nitrogen radical chemistry was successfully utilized to achieve the intermolecular aminative difunctionalization of unactivated alkenes with electron-rich amino sources in an excellent regio-and diastereoselective manner.In these reactions,the directing group would force the reaction centerclose to the olefin moiety,which simulates the intermolecular reaction as anintramolecular version and thus increases the chemicalreactivity of the nonactivated olefins.On the other hand,the dialkyl nitrogen radicals generated through the SET between N-halogenated dialkylamines and transition metal would combined with protons or Lewis acids to form electrophilic protonated aminium radical cations(ARCs).Subsequent radical addition of ARCs to unactivated alkenes followed by the assistance of a directing group finally achieved the regio-and diastereoselective aminative difunctionalization reactions.With this strategy,we have successively realized the intermolecular aminohalogenation(X = Br,Cl),aminoazidation,and aminofluorination of unactivated alkeneswith electron-rich amino sources.This thesis has been divided into the following five parts.In Chapter 1,we briefly summarized the development of intermolecular aminative difunctionalization of alkenes,containing the reactions for activated alkenes,unactivated alkenes and electron-rich amino sources,respectively.In Chapter 2,this thesis' s topic selection was discussed.Based on the two major limitations in current aminative difunctionalization of alkenes,we proposed a combination of directing group and the nitrogen radical chemistry to realize the intermolecular aminative difunctionalization of unactivated alkenes with electron-rich amino sources.In Chapter 3,a directed intermolecular aminohalogenation of unactivated alkenes has been realized.With the assistance of copper catalyst and directing group,N-halogenated dialkylamines were utilized as both electron-rich amino sources and halogen atom sources to achieve the intermolecular aminobromination and aminochlorination of unactivated alkenes.In Chapter 4,a directed intermolecular three-component aminoazidation of unactivated alkenes has been realized.With N-bromodialkylamines as electron-rich amino sources and external sodium/silver azide as azide source,the first example of a copper-catalyzed three-component aminoazidation of unactivated alkenes was reported by using a directing group strategy.In Chapter 5,a catalytic intermolecular three-component aminofluorination of unactivated alkenes with electron-rich amino sources has been discolosed.By employing a directing-group strategy,N-bromodialkylamines were used as electron-rich amino sources while external nucleophilic fluoride was used as fluorine source.An ion exchange between fluoride and high-valent copper species followed by the subsequent C-F reductive elimination made the first intermolecular dialkylaminofluorination of unactivated alkenes a reality.