Highly Diastereoselective Synthesis Of Anti-CF₃-Substituted Oxazolines And Vicinal Amino Alcohols

Multicomponent reaction(MCR) is the one-pot method for the synthesis of compounds by taking many substrates into a reactor without separating intermediate products, which have been viewed as an indispensable tool for generating libraries of molecules for the discovery of biologically active leads and potential drug candidates, ease of execution, continuous reaction, simple operation, atom economy, and meeting the need of organic and pharmaceutical synthesis. Oxazolines are frequently encountered structural motifs in numerous natural products and biologically active molecules, and the development of new methods for the facile construction of oxazolines has long been the focus of considerable attention of chemical and biological researchers. Fluorinated units could modify the physicochemical and biological properties of an organic compound profoundly. Therefore, construction of fluorinated organic molecules especially trifluoromethyl-substituted heterocycles has been one of the highlights in pharmaceutical and agrochemical sciences.In this thesis, we designed and realized a novel, three-component C?C, C?N and C?O bonds forming reaction of CF3CHN2, nitriles, and aldehydes in the presence of 20 mol% Cu O. This multicomponent reaction could afford trifluoromethylated oxazolines in moderate to high yields(45%?86%) with excellent diastereoselectivities(> 95:5). In addition, the trifluoromethylated amides were obtained with the aldehydes that could not give the trifluoromethylated oxazolines under the optimal conditions. The absolute configurations of oxazoline 2a and amide 2r were established by single-crystal X-ray analyses. Subsequent ring-opening of oxazolines give rise to the corresponding CF3-substituted vicinal amino alcohols, which are highly important structural motifs in bioactive compounds. Finally, based on the 19 F NMR monitored experiments and deuterated experiments, the reaction mechanism was proposed that the reaction went through copper carbenoid and ammonium ylide intermediates to give the final trifluoromethylated oxazolines.