Oxidative Radical Annulation Reactions Of 1,n-Enynes

Cyclic compounds are a class of important structural motifs that widely found in numerous bioactive molecules,pharmaceuticals,natural products and functional organic materials.Given its unique structures and properties,they play important roles in the development of synthetically organic chemistry,medicinal chemistry and natural products.Therefore,developing new simple,efficient and highly atom economical synthetic methodologies for accessing cyclic compounds is still one of the most active area in organic synthesis,and also become an eternal target of synthetic organic chemists.Enynes are a type of compounds that contain a C=C bond and a C(?)C bond in a molecular unit,and serve as versatile synthetic intermediates that widely utilized in organic synthesis.Enyne annulation reaction has emerged as one of the most important tools to construct a diverse array of complex cyclic compounds.The enyne annulation reactions feature high reaction activity,excellent selectivity,mild reactive conditions and high step-economy.Recently,new synthetic methods based on oxidative radical-mediated annulation of l,n-enynes have been developed and have becoming a research hot-topic.This dissertation focuses on the annulation reactions of enynes by the oxidative radical strategy,and it begins with rational design of l,n-enyne substrates,and then successively develops several new enyne annulation methods to synthesize heterocyclic compounds,including benzofurans and quinolinones.This dissertation includes seven chapters and the details are summarized as following:In chapter 1,recent progress in the radical cyclization reactions of l,n-enynes are summarized in detail.This chapter mainly described the cyclization reactions of l,n-enynes with various radicals,including alkyl radicals,azide radicals,aryl radicals,nitral radicals,aldehyde radicals,sulfonyl radicals,fluoroalkyl radicals and other radicals.In chapter 2,a new metal-free aerobic nitrative radical cyclization of l-ethynyl-2-(vinyloxy)benzenes with tert-butyl nitrite('BuONO),air and H2O at room temperature was proposed for the synthesis of 3-carbonylated benzofuran products,in which introduced an oxygen atom into the carbon-carbon triple bond to form a carbonyl group through dioxygen activation.Most importantly,the NO2 radical produced by the 'BuONO was utilized as greener initiators and functional group incorporation strategies in the cyclization reaction.In chapter 3,a mild and efficient routes and especially metal-free strategies radical 5-exo-dig cyclization of phenol-linked 1,6-enynes with O2,TEMPO(2,2,6,6-Tetramethyl-I-piperidinyloxy),and tBuONO was described for the formation of carbonylated benzofuran scaffold.It should be noted that this method introduces two oxygen atoms into the new formed carbonyl groups of the benzofuran system from O2 and TEMPO through dioxygen activation and the N-O bond oxidative cleavage.In chapter 4,a novel metal-free oxidative radical[2+2+1]carbocyclization of benzene-linked l,n-enynes(n = 6,7)with two C(sp3)-H bonds adjacent to the same heteroatom was established.The optimized conditions was 2 equiv of TBPB at 110 0C for 12 h.This method provided efficient and general access to a variety of fused five-membered carbocyclic hydrocarbons through two C(sp3)-H bonds oxidative functionalization and annulation cascades.Moreover,the possible reaction mechanism included a 1,5-H shift process.In chapter 5,a practical Lewis acid-catalyzed radical-mediated divergent bicyclizations of l,n-enynes(n = 6,7)by a-C(sp3)-H oxidative functionalization of alkyl nitriles was developed using Ag2O as oxidant.The reaction was selectively terminated by the functionalization of the C(sp3)-H bond or the C(sp2)-H bond,which relied on the substitution effect of the acrylamide moiety,and offered a step-and atom-economical access to diverse polycycles with broad substrate scope.In chapter 6,a novel Cu(II)-catalyzed C-H oxidative radical functionalization and annulation of aniline-linked 1,7-enynes with alkyl nitriles or acetone was described using DTBP(di-tert-butyl peroxide)as oxidant.The tandem reaction provided a straightforward and practical access to important polycyclic rings system.The control deuterium-labelled experiment offered the true evidence for the occurrence of a 1,5-hydride shift process.In chapter 7,a new Cu(I)-catalyzed oxidative[2+2+1]annulation of l,n-enynes(n = 6,7)with a-carbonyl alkyl bromides through the C-Br/C-H functionalization was developed.Using Ag2CO3/tert-butyl hydroperoxide(TBHP)as co-oxidants,a-carbonyl alkyl bromides provided one carbon component,to cyclize with the l,n-enynes and Cu(MeCN)4PF6,thus forming two rings in this reaction.Moreover,silver salts were used to cleavage the C-Br bond and stabilize the radical intermediates.