Synthesis Of Functionalized Heterocyclic Compounds Based On Radical Tandem Reactions Without Transition Metal Participation

Heterocyclic compounds are prevalent in many biologically active natural products and pharmaceutical and biologically active molecules.Substantial efforts have been devoted to develop versatile methods for the synthesis of heterocyclic compounds in the past decades.Compared with the traditional strategies,the radical cascade reaction has become an attractive approach in recent years since it enables access to fused heterocycles with high reactivity,selectivity and atom economy.By using cheap and available small molecules as radical precursors,a series of heterocyclic compounds,such as 3-carbonylated benzofurans,1,3,6-benzo thiadiazepine,2-Substituted benzothiazoles and 3-Substituted imidazo[1,2-a]pyridines were synthesized via intermolecular two-or three-component radical cascade reaction under transition-metal-free conditions.The main contents were summarized as below,1.IntroductionA general review on the recent progress in synthesis functional heterocycles via radical cascade reaction,focusing on some“Drug bias”heterocyclic derivatives were summarized.2.Radical addition cascade cyclization of 1,6-enynes with DMSO to access methylsulfonylated and carbonylated benzofurans under transition-metal-free conditionsA mild and direct addition/cyclization cascade to construct methylsulfonylated and carbonylated benzofurans was accomplished using oxygen-linked 1,6-enynes as the starting materials.DMSO acted as solvent,radical source and oxidant.The process went through sulfur methylation,1,6-enyne cascade intramolecular 5-exo-dig cyclization and oxidation of thioether.Sulfur methyl radical from DMSO acted as the reaction initiator and functional group.To identify the source of oxygen in product,the isotopic labeling experiment with H₂¹⁸O was conducted.As expected,the ¹⁸O atom was introduced to both the carbonyl and methylsulfonyl.A wide range of oxygen-linked 1,6-enynes bearing various substituents were found to be suitable in this cascade process,providing benzofurans with dual functional groups in moderate to high yields.This method could also be utilized to synthesize benzothiophenes from sulfur-linked 1,6-enynes.3.Radical C-H sulfuration initiated annulation of 1-?2-aminoaryl?pyrroles,ethers with elemental sulfur to give 1,3,6-benzothiadiazepine derivativesAn efficient TBHP/TBAI promoted three-component reaction of 1-?2-aminoaryl?pyrroles,ethers,and elemental sulfur for constructing 1,3,6-benzothiadiazepines through radical dual C-H sulfuration,intramolecular amination cyclization and C-O cleavage of ethers under transition-metal-free conditions has been developed.Elemental sulfur acted as sulfur source and ethers acted as both reactants and solvent in this reaction.Through free radical capture experiment and LC-MS,three possible intermediate species were speculated.The method proceeded efficiently over a broad range of substrates with good functional group tolerance and provided new strategies for the construction of seven-member sulfur heterocycles4.Radical initiated annulation of anilines,ethers,and elemental sulfur,access to 2-aryl-,2-heteroaryl-,or 2-alkyl-substituted benzothiazolesAn efficient TBHP/KI promoted annulation of anilines with ethers and elemental sulfur has been developed through selective C-O bond cleavage of ethers under transition-metal-free conditions.Elemental sulfur acted as sulfur source and ethers acted as radical source in this reaction.The control experiments were conducted supporting the radical way of the reaction.A wide range of 2-aryl-,2-heteroaryl-,and2-alkyl-substituted benzothiazoles were easily prepared with satisfactory yields and good functional group compatibility.The method has advantages of wide raw material sources,such as a series of benzyl methyl ethers and aliphatic ethers.Notably,the method can be successfully applied to the synthesis of two bioactive compounds.5.Radical initiated heteroarylation-nitration of alkenesAn efficient and regioselective radical three-component heteroarylation-nitration of alkenes with imidazo[1,2-a]pyridines and tert-butyl nitrite under transition-metal-free conditions has been developed.The process was tolerant of a variety of functional groups under mild conditions in the absence of catalysts and additives to give nitro functionalized imidazo[1,2-a]pyridine derivatives in moderate to good yields.The reaction was successfully used in structural modification of complex molecules and also applicable for some other aza-heterocycles,such as indoles.