Carbon-heteroatom Bonds Formation And Their Application In Organic Synthesis

In recent years, formation of carbon-heteroatom bonds (C-S, C-N, C-O etc.) has drawn much attention and experienced an unprecedented development, which represents the key step in a wide range of preparative organic processes, such as synthesis of ethers, thioethers, amines and heterocycles. In addition, the formation of carbon-heteroatom bonds has also played an important role in the preparation of Pharmaceuticals and natural products. Traditional methods for the formation of carbon-heteroatom bonds mainly depend on transition metal catalyzed cross-coupling reactions between aryl halides and heteroatom-containing nucleophilic reagents with the use of ligands, strong bases or high boiling point solvents. With respect to the principles of Green Chemistry and the present problems of existed methods, several copper, cerium chloride, molecular iodine and small moleculars promoted synthetic systems were designed and applied for the synthesis of heteroatom-containing compounds.A highly efficient and environmentally friendly protocol for the synthesis of3-sulfenylindoles in50%-94%yield through the reaction of indoles with unsymmetric benzothiazolyl-containing disulfides (BTS-SR) has been developed using10mol%Cul as catalyst at room temperature. The byproduct2-mercaptobenzothiazole (BTSH) can be easily recovered for the preparation of activated sulfur-containing reagent, which can reduce the cost and improve atom economy of the reaction.An aerobic CeCl3·7H2O-NaI catalyzed sp3C-H bond functionalization strategy has been developed for the synthesis of3-sulfenyl imidazo[1,2-a]pyridines from easily available ketones,2-aminopyridines and disulfides in mole ratio of1:1:0.5and the products can be obtain in53%-96%yield. This three-component tandem reaction has several advantages such as easily available substrates and high atom economy. An efficient CeCl3·7H2O-catalyzed aerobic oxidative system has also been developed for the synthesis of polysubstituted pyridines in81%-92%yield from ketones and benzylamines. It was found that substituted imidazoles were selectively afforded in76%-93%yield in the presence of1equivalent of TBAC and10mol%Nal.The iodine catalyzed oxidative system for3-sulfenylation of indoles with disulfides using DMSO as oxidant has been achieved under ambient conditions and the products bearing different substituted groups were afforded in88%-97%yield using5mol%iodine and3equivalents of DMSO in the solvent dimethyl carbonate. Based on this research, iodine/DMSO oxidative system was then used for the synthesis of2-sulfenyl phenols from cyclohexanones and disulfides through dehydrogenative aromatizations strategy. In addition, the iodine catalyzed oxidative system was also applied for cyclization of primary alcohols with o-amino benzamides to quinazolinones via in situ oxidation of primary alcohols to aldehydes. The mechanism research shows that DMSO can oxidize HI formed in the reaction to iodine catalyst.An efficient methylation of ethers, thioethers and ketone oximes was explored using dimethyl carbonate as a green methylation reagent promoted by3equivalents of potassium thioacetate in the absence of catalyst. When this protocol was used for amines and indoles, carboxyl methylation products were afforded in high yields. Compared to traditional methylation reactions, this process can proceed well under mild reaction condition in the absence of catalyst and additive.A simple and efficient synthetic route for the preparation of pharmaceutical intermediate2-carbomethoxybenzenesulfonamide was designed. And the reaction condition for the synthesis of key intermediate disulfide was optimized. It was found that disulfide was formed in83%yield from the reaction between methyl anthranilate diazonium salts and thionyl chloride in water with2mol%CuSO4·5H2O as catalyst and1mol%KI as additive. The synthetic route designed above can avoid using high toxic and corrosive reactants under relatively mild reaction conditions.In conclusion, the unsymmetric benzothiazolyl-containing disulfides (BTS-SR) were selected as new-type sulfur-containing reagent, which provides a green and efficient method for sulfenylation of electron-rich aromatics. Catalytic activity, substrate scope and relative reaction mechanisms of CeCl3·7H2O-NaI/O2and I2/DMSO catalytic oxidative systems were tested, which path the way for further research of the two catalytic systems. At last, the appliction of methods for forming carbon-heteroatom bonds in organic synthesis were researched, including selective methylation and carboxyl methylation reactions promoted by potassium thioacetate, and synthetic process of2-carbomethoxybenzenesulfonamide.