Application Of Base-promoted Nucleophilic Aromatic Substitution Of C-F Bond

C-F bond is known as one of the most stable chemical bonds among all organic chemical bonds.It is one of the most important and interesting research topics in organic synthesis and fluorine chemistry to activate C-F bond and its further transformation.The base-promoted nucleophilic substitution reaction(S_NAr)of fluoroarenes has been well-applied in the synthesis of drugs and pesticides,as well as in the total synthesis of natural products.The purposes of this dissertation are to study the S_NAr reaction of fluoroarenes to develope the efficient routes to form C-O and C-N bonds under transition-metal-free conditions,and to develop the new synthetic methods for the formation of heterocyclic compounds based on S_NAr reaction of fluoroarenes.Firstly,this dissertation summarizes the literatures on the strategies for the activation of C-F bond of fluoroarenes,particularly the base-promoted S_NAr reactions of C-F bonds and their application in the synthesis of benzo-fused heterocyclic compounds.And then the research work and purposes of this dissertation are described.Therefore,one of the research work of this dissertation is to investigate the S_NAr reactions of 2-fluorobenzamide with methanol under different conditions.It has been found that with the use of KOH/DMSO as superbase medium,2-fluorobenzamide can efficiently undergo the S_NAr reaction with methanol to give aryl alkyl ether smoothly under mild conditions.In addition,KOH/DMSO medium system can be applied to the S_NAr reactions of other fluoroarenes with a variety of nucleophiles such as alcohols,phenols,amines,amides,providing an efficient synthetic method for the formation of aryl alkyl ethers,diaryl ether,anilines.Moreover,the S_NAr reactions also occur under the similar conditions in the cases of neutral fluoroarene and fluoroarenes bearing electron-donating group.Also on the basis of the TD-DFT calculation,the possible reason for the efficient KOH/DMSO-promoted S_NAr reaction of fluoroarenes is described.On the basis of the above-mentioned S_NAr reactions of 2-fluorobenzamide with alcohols to form C-O bond,the research work design an efficient protocol to synthesize the benzo-fused heterocyclic compounds through the S_NAr reactions of2-fluorobenzamides with 2-propyn-1-ol to give the intermediate of2-[(2-propynyl)oxy]benzamides,which is expect to undergo the intramolecular N-H Michael cycloaddition to alkynyl group.It has been found that in the case of KOH/DMSO used,the intermolecular benzannulation produces seven-membered benzo-fused heterocycles of 1,4-benzoxazepin-5(4H)-ones,whereas under the conditions of KOH/Me CN,the six-membered benzo-fused heterocycles of1,3-benzoxazin-4(4H)-ones are formed.Thus a facile and efficient solvent-controlled chemo-and regioselective synthesis of benzo-fused seven-membered and benzo-fused six-membered via the KOH-promoted intermolecular cyclization of 2-fluorobenzamides with 2-propyn-1-ol has been developed.In addition,on the basis of real-time monitoring experiments,a proposed mechanism for the formation of different heterocyclic compounds in the different solvents is explained.