Studies On β-functionalization Reaction Of Piperidine And Facile Synthesis Of 3-acylindole

Nitrogen-containing heterocyclic compounds play an integral role in drug synthesis,with approximately 60% of all marketed drugs containing this type of backbone.In addition,as a very important class of fine chemical intermediates,nitrogen-containing heterocycles are widely used in food processing,pesticide production,polymer materials,dyes and flavors and other related fields,especially compounds containing piperidine or indole skeletons play a great role in these fields.Therefore,how to construct or modify the above two types of nitrogen-containing heterocyclic compounds in an efficient and green way has become a hot research topic for researchers.The modification of piperidine derivatives has been reported for a long time,but these methods still suffer from poor functional group compatibility and the limitation of substituents on nitrogen atoms at present.In recent years,the direct functionalization of acyl-protected nitrogen heterocyclic compounds has gradually become one of the hot spots in organic synthesis research,but their low reactivity limits the rapid derivatization of this type of molecular backbone.Therefore,the development of novel and efficient catalytic systems for selective modification of amide compounds has become one of the urgent problems in organic synthesis.This article focuse on the functionalization reaction of N-acetylpiperidine and successfully achieved the dehydrogenation and β-position functionalization of cyclic amide,and also studied the synthesis of diacyl-substituted indole by the cyclization reaction involving o-alkynyl aniline.The details of the study are as follows:1.A strategy to initiate amide functionalization using oxidation reaction to reduce the C(sp~3)-H bond dissociation energy was proposed.N-hydroxy compounds were chosen as catalysts,fluorine reagent as fluorine source and oxidant,magnesium sulfate as additive and sodium bicarbonate as base for the reaction.The synthesis of β-fluoroalkenamides was achieved by successive dehydrogenation and β-site fluorine substitution of Nacetylpiperidine compounds under argon atmosphere at 80 oC.2.The nitration of the β-position of the piperidine ring was achieved by activating the inert C(sp~3)-H bond through the oxidation process.The synthesis of β-nitroenamides was achieved without catalyst in the reaction system,choosing NOBF4 as the nitration reagent,DTBP as the oxidizing agent and magnesium sulfate as an additive under argon atmosphere at 80 oC.The products can be converted to 3-piperidone or polysubstituted piperidine derivatives by reduction reactions or Michael addition.3.The copper-catalyzed radical oxidative cyclization of o-alkynylaniline under visible light irradiation was developed.Copper bromide was used as a catalyst and 1,10-phenanthroline as a ligand for the efficient synthesis of 2,3-disubstituted indoles by intramolecular oxidative cyclization/oxygen insertion of o-alkynylaniline under visible light irradiation in air with the formation of both C-C and C-O bonds.