Copper-mediated Synthesis Of α-trifluoromethylthio- And Seleno-α,β-unsaturated Carbonyl Compounds

α,β-Unsaturated carbonyl compounds have served as versatile intermediates in countless syntheses of biologically active natural products, pharmaceuticals, agrochemicals, and advanced materials. Particularly, α-trifluoromethyl-α,β-unsaturated carbonyl compounds are important building blocks for preparing fluorine-containing nucleosides, which have shown a broad spectrum of antiviral and anticancer activity. Their unique properties stems largely from the metabolic stability, lipophilicity, and electronegativity of fluorine group.Synthetic methods for a-trifluoromethyl-α;β-unsaturated carbonyl compounds have been sporadically reported, but the CF3S-substituted α,β-unsaturated carbonyl species are even less well known. Furthermore, these reported methods suffer serious limitations of using highly toxic and expensive reagents that preclude their practical use. Therefore, it is highly desirable and valuable to develop a new, efficient and safe approach to synthesize these compounds.The thesis consists of three parts:Part 1:The air-stable (bpy)CuSCF3 has been synthesized from CuF2, S8, CF3SiMe3, and 2,2-Bipyridine according to the reported method by our group. The trifluoromethylthiolation conditions of a-bromocinnamaldehyde with (bpy)CuSCF3 are explored by using different solvents, temperature, reaction time as well as base affecting on the reaction. The optimization study concluded that the best yields of α-bromocinnamaldehyde (lequiv) with (bpy)CuSCF3(2equiv) were obtained with the combining CH3CN and xylene (2ml,1:9) as solvent and CsF(2equiv) as the base at 140 ℃ for 24h. We extended the scope of the substrates with the optimal reaction conditions available. The α-bromo-α,β-unsaturated ketones and α-bromo-α β-unsaturated esters can react with (bpy)CuSCF3 in this method. The corresponding isolated yields of α-trifluoromethylthio-α,β-unsaturated carbonyl compounds could reach 53-69%, and the E isomers of the products were generated as the major products.Part 2:The air-stable [(bpy)Cu(SeCF3)]2 has been synthesized from KF, Seg, CF3SiMe3, and 2,2-Bipyridine according to the reported method by our group recently. The corresponding α-trifluoromethylseleno-α;β-unsaturated carbonyl compounds are synthesized by those substrates mentioned with [(bpy)Cu(SeCF3)]2. The corresponding isolated yields of a-trifluoromethylseleno-α,β-unsaturated carbonyl compounds could reach 71-88%, and the major products were the.E-isomers.Part 3:Based on the experimental results, a plausible reaction pathway is proposed. The first step involves the oxidative addition of the α-bromo-α;β-unsaturated carbonyl compounds to (bpy)CuSCF3 to form a copper(Ⅲ) species. The subsequent reductive elimination from the copper (Ⅲ) species affords the trifluoromethylthiolated product together with (bpy)CuBr. Additionally, the higher E-isomer product selectivity indicated that gem-carbonyl groups in α-bromo-α,β-unsaturated carbonyl compounds can alter trifluoromethylthiolation or trifluoromethylselenolation stereochemistry. The copper allenoates species could be involved in the formation of products with inverted configurations.