Synthesis Of Thioethers, Indoles And Pyrazoles Derivatives Via C-H Functionalization

The C-H functionalization is a reaction that cleaves a carbon-hydrogen bond for direct introduction of various functional groups into the carbon atom for the formation of the carbon-carbon bonds and carbon-heteroatom bonds. The C-H functionalization can avoid the use of pre-functionalized substrate, remarkably improve the atom-economic efficiency and reduce the discharge of waste material. The C-H functionalization method has been widely applied to construct some lead skeleton of drugs and diverse bioactive compounds, thereby making it significant in the high throughput drug screening.The carbon-sulfur bond, indole and pyrazole motifs are embedded in numerous natural products and pharmaceuticals. For these reasons, many elegant methods have been delevoped for their construction. In this field, the C-H functionalization serves as one of the most important and efficient methods for direct introduction of functional groups to form diverse thioether, indole and pyrazole derivatives, which can pave the way for the design and synthesis of corresponding pharmaceuticals, as well as for organizing the bioactive molecular libraries.This dissertation focuses on the synthesis of thioethers, indoles and pyrazoles through the C-H bond oxidation strategy. The content of dissertation includes four parts:1. Recent advances in the functionalization of sp3C-H bond adjacent to a nitrogen atom via the metal-free oxidative dehydrogenation coupling reaction or transition metal-catalyzed process. The functionalization of sp3C-H bond adjacent to a nitrogen atom through oxidative dehydrogenation coupling reactions include three ways:(1) metal-free mediated sp3C-H bond functionalization,(2) metal-catalyzed sp3C-H bond functionalization, and (3) photoredox catalyzed sp3C-H bond functionalization. According to the type of reaction, the research field of transition metal-catalyzed functionalization of sp3C-H bond adjacent to a nitrogen atom was also discussed involving three parts:(1) hydroaminoalkylation of sp3C-H bond adjacent to a nitrogen atom,(2) arylation of sp3C-H bond adjacent to a nitrogen atom, and (3) some other reactions.2. A new method for metal-free molecular sieve-promoted TBHP-mediated oxidative thiolation of sp3C-H bond adjacent to a nitrogen atom in amides or to an oxygen atom in ethers has been developed for the synthesis of S,N-heterocyclic compounds and S,O-heterocyclic compounds. In the presence of4A molecular sieve and TBHP, the oxidative deprotonation of a sp3C-H bond adjacent to a nitrogen atom or an oxygen atom was achieved to produce a carbon radical. It could be trapped by the S-S bond of disulfide to form the C-S bond. The present thiolation method is general for a wide range of substrates, including amides (DMF, DMAc and1-methylpyrrolidin-2-one), ethers (tetrahydrofuran, tetrahydro-2H-pyran,2-methoxy-2-methylpropane and1,2-dimethoxyethane) and disulfides (diaryl disulfides and dibenzyl disulfide). Significantly, this tiolation method could be applied to the synthesis of benzothiozoles derivatives from2,2’-disulfanediyldianiline and amides through the thiolation and oxidative cyclization cascade process. Moveover, the present thiolation method was viable for the synthesis of pesticide fipronil analogues by the reaction of pyrazole disulfide with DMAc or THF, respectively. Indoor pesticidal activities test indicated that the two fipronil analogues have highly pesticidal activities for the mythima sepatare and aphis medicaginis.3. A new and selective C-N bond oxidative cleavage method to3-acylated indoles by Pd-catalyzed oxidative cross coupling of indoles with a-amino carbonyl compounds has been established. In the presence of Pd(OAc)2, Cu(OAc)2and HOAc, a wide range of substituted indoles successfully reacted with a-amino carbonyl compounds to form diverse3-oxoacetylindole derivatives. Importantly, the oxidative coupling method allows one-pot reaction of2-ethynylanilines with a-amino carbonyl compounds to afford the2-substituted-3-oxeacetylindoles.2-Ethynylanilines was firstly underwent an electrophilic cyclization catalyzed by PdCl2, affording a2-substituted indole, followed by reaction with a-amino carbonyl compounds, Cu(OAc)2and HOAc to yield the corresponding indole derivatives. Mechanism research on HRMS indicated that a-amino carbonyl compound was firstly oxidated to an imine cation intermediate, followed by coupling with indole in the presence of palladium catalysis. The in-situ formed intermediate was further oxidated to an imine cation, followed by hydrolysis, oxidation and deamination afforded the3-oxoacetylindoles. The isotope experiments demonstrated that the oxygen atom in carbonyl derived from water. It is noteworthy that in the presence of4-methylbenzenesulfonic acid the cyclization of indolyl diones with indole can be achieved to access polyheterocyclic compounds with good fluorescent properties, which can be employed as efficient probes for Hg2+and Fe3+ions.4. A new strategy for the synthesis of multi-substituted pyrazoles is presented by Ni-catalyzed oxidative cyclotrimerization of a-amino ketones. In the presence of (C5H5)Ni(II)Cl(PPh3), PhCO2H and air, a series of a-amino ketones smoothly underwent the oxidative cyclotrimerization to afford various multi-substituted pyrazoles (up to75%yield). The ESI-HRMS real-time analysis and control experiments were used to investigate the reaction intermediates and materials balance. A change curve chart for starting material, intermediates and products was given, and a possible reaction mechanism was discussed. The reaction mechanism displays that this unprecedented method allows three a-amino ketones to undergo sequential multiple deprotonations and deamination through two C-C bonds, one N-N bond formation, carbonyl isomerization and dehydration cascade.