TEMPO-Mediated Oxidative Dehydrogenative Olefination And Its Application In Organic Synthesis

2,2,6,6-Tetramethylpiperidine-1-oxyl(TEMPO),as a stable nitroxyl radical,is widely used in synthetic chemistry,especially in the chemoselective oxidation of alcohols and amines has shown great synthetic potential.In recent decades,TEMPO participated in the oxidative reaction mainly focused on the redox process of TEMPO~+/TEMPOH,while the research on the redox process using TEMPO/TEMPOH was relatively rare.In recent years,a series of useful olefin derivatives have been synthesized by utilizing the redox process of TEMPO/TEMPOH to achieve oxidative dehydrogenative olefination.In this paper,we have realized the conversion of raw materials to?,?-unsaturated carbonyl compounds through TEMPO promoted oxidative dehydrogenative olefination strategy.Thus not only efficiently realizes C-C and C-heteroatom bond formation,but also provides a novel and efficient method for the synthesis of a series of derivatives containing important structural skeletons of pyrimidine,nicotinate,triazole and pyridine with potential biological activity.This paper is divided into six chapters:Chapter 1:In this part,the types,structures,properties,and production of nitroxyl radicals and iminoxyl radicals are briefly introduced,and the chemical reactions in which nitroxyl radicals involved are briefly reviewed.Chapter 2:We have successfully developed a new and efficient strategy for the preparation of structurally important pyrimidines by Cu-catalyzed and 4-HO-TEMPO-mediated[3+3]annulation of commercially available amidines with saturated ketones.By using this protocol,pyrimidines are facilely synthesized by a cascade reaction of direct oxidative dehydrogenation?,?-C(sp~3)-H of saturated ketones followed by annulation with amidines/oxidative aromatization.Chapter 3:We developed a facile and efficient approach for the preparation of?-functionalized ketones by using cyclopropanols and nucleophiles as the readily accessible substrates and TEMPO as the oxidant under metal-free as well as additive-free conditions.This reaction involves in situ generated enones as the intermediates,which is derived from TEMPO-mediated cascade oxidative alkoxyl radical initiation/ring-opening/olefination of cyclopropanols.The subsequent TEMPH-catalyzed nucleophilic addition of amines,enamines,alcohols and phenols to enones realizes the synthesis of?-functionalized ketones through C-C/C-N/C-O bonds formation.Chapter 4:We have also developed a TEMPO-mediated intermolecular[3+3]annulation for the synthesis of structurally important nicotinate derivatives by using cyclopropanols and?-enamine esters.In this reaction,the C-C and C-N bonds has also been constructed in an atom-economy manner by using cyclopropanols and?-enamine esters as the buliding materials.Chapter 5:By using the similar tactic,we have also developed a TEMPO-mediated intermolecular[3+2]cyclization of cyclopropanols with organic azides to synthesize polysubstituted1,2,3-triazoles.This reaction not only realizes the formation of C-N bond,but also provides the first example for carbonyl?,?-diamination of cyclopropanols with oxidative ring opening.Chapter 6:On the basis of the previous work of Mengwei Wu,a graduate student in our research group,we have consummated the TEMPO-catalyzed redox strategy,realized the[3+3]annulation of cyclopropanols and oxime acetates for the synthesis of structure-important pyridine derivatives,and further investigated the applicability of cyclopropanols.In addition,the gram-scale preparation of pyridine derivative and its diverse follow-up transformation have also been explored.Moreover,the reaction mechanism has been revealed through control experiments,the intermediate separation,cyclic voltammetric analysis and DFT calculations,which indicates that the reaction experiences the redox cycle of TEMPO/TEMPOH to realize the electron and proton transfer between cyclopropanols and oxime acetates.In this way,cyclopropanols and oxime acetates are converted to enones and imines,respectively,which then undergoes cascade annulation and oxidative aromatization to yield pyridine derivatives.This tactic not only represents the first example of a TEMPO-catalyzed redox reaction,where both TEMPOH and TEMPO are active catalysts,but also broadens the new frontiers for TEMPO in catalysis.Furthermore,by using TEMPOH as the catalyst,the annulation of enones with oxime esters can take place as well to give pyridine products as the first TEMPOH-catalyzed redox-neutral reaction.