Study And Application Of Masked Sulfurating Reagent

Carbon-heteroatom bond formations are very important reactions in organic synthesis and have gained more and more attention of many synthetic organic chemists.Among various carbon-heteroatom bond formations,the carbon-sulfur bond formations hold a prominent position in the race for the synthesis of pharmaceuticals,agro-chemicals,food ingredients,and material molecules.Traditionally,sulfur-carbon bond formation is a cross-coupling between nucleophile thiol（ate）and electrophilic carbon.Challenging problems from naked sulfur in conventional sulfuration are the facts as follows:（a）deactivating on catalysts with thiol（ate）anion,（b）oxidizating to disulfide in the presence of oxidants,and（c）serving solely as nucleophilicity.Moreover,it generally suffers from preparation difficulties,unpleasent smell,and toxicity during the entire process.My doctorate dissertation title is "Study and Application of Masked Sulfurating Reagent".The research focused on studying masked sulfurating reagents and applied new sulfurating methodologies in the fields of life molecule,drug,material,and pesticide.Part 1 Na₂S₂O₃ 5H₂O as sulfuration reagentPd-catalyzed double C-S bond formation coupling reaction by using Na₂S₂O₃ 5H₂O as sulfuration reagent has been developed.This protocol provides an efficient method for the synthesis of substituted 1,4-benzothiazine derivates,which are structural elements of numerous bioactivity molecules.Control experiment and DFT study gave the outline of this efficient transformation.Cross-coupling of aryl halides,alkyl halide,and Na₂S₂O₃’5H₂O to deliver aromatic thioether was further described.Pyridine,furan,thiophene,benzofuran,benzoxazole,benzothiophene,benzothiazole,and pyrazine are all amenable to this protocol.In addition,active molecule could successfully furnished by this late-stage sulfuration strategy.Part 2 Oxidative cross-coupling reactionCu-catalyzed direct oxidative cross-coupling between boronic acids and masked sulfides delivering thioethers was described,in which the SO₃^-,as a mask,has shown a distinctive effect on oxidative cross-coupling condition.Disulfide could be suppressed efficiently via masked strategy under CO₂ atmosphere.A broad scope of aromatics and scalable processes indicates its practicality,which could be further applied to drug late-stage modification and unsymmetrical dibenzothiophenes（DBTs）synthesis.A divergent cross-coupling for both thioether and thioester construction from organosilicon compound has been further developed.Predominant selectivity for Hiyama-type coupling and C1 insertion reaction was achieved under the guidance of ligands.Thioether was obtained under ligand-free conditions,in which disulfide generated from homo-coupling could be prevented.Meanwhile,application of bidentate phosphine ligands under carbon monoxide atmosphere（CO balloon）afforded the thioester with little decomposition,which was revealed through the interval NMR tracking.Part 3 Novel,safe,and green thiomethyl surrogateThiomethyl,as well as methyl sulfoxide and sulfone,extensively exists in vital life molecules,natural products,pharmaceuticals,and pesticides.Especially,thiomethyl is a significant structural unit in rational design of bioactive molecules owing to abundant variations in stereoelectronic property,which alters biological phases of a drug in its pharmacodynamic and pharmacokinetic profiles with molecular recognition,solubility tuning,and metabolic control.However,thiomethylation had been facing great obstacles in organic synthesis steming from critically problematic thiomethyl-source or methyl-source.The combination of inorganic potassium thioacetate salt and dimethyl carbonate was efficiently established for thiomethylated cross coupling with aryl chlorides.Remarkably,this powerful strategy realized thiomethylation on nucleosides bearing unprotected ribose,on chloride-containing pharmaceuticals with late-stage cross coupling,and on herbicides possessing multiple heteroatoms and steric hindrance.Furthermore,this protocol is practically amenable to multigram-scale synthesis with lower catalysis loading and higher yield.