Catalytic Asymmetric1,2-addition Of Terminal1,3-diynes And3-En-1-ynes To Trifluoromethyl Ketones

Chiral α-trifluoromethylated propargyl alcohols are one of key intermediates insynthetic chemistry, which are important subunits for a great number of naturalproducts, pharmaceuticals and biologically active compounds. The catalyticenantioselective1,2-addition of alkyne nucleophiles to trifluoromethyl ketonesrepresents the most convergent and efficient approach to the synthesis of opticallyactive propargylic alcohols containing trifluoromethyl.Herein, A simple and efficient enantioselective control in the1,2-addition ofterminal1,3-diynes and3-en-1-ynes to trifluoromethyl ketones can be realized withcatalytic system （Ti（O-ⁱPr）₄-QN-BaF₂-Me₂Zn） developed by our group. Variation ofreaction parameters （solvent, temperature, additive and catalyst loading） wereinvestigated. With the optimized reaction conditions in hand, we explored the scopeof this alkynylation reaction by varying the trifluoromethyl ketones, the terminal1,3-diynes and3-en-1-ynes. A series of diynylated and eneynylated adducts weresynthesized in6593%yields with40%94%ee. Additionally, Efavirenz analogueswere synthesized starting from1-（5-chloro-2-nitrophenyl）-2,2,2-trifluoroethanone viavery simple transformations.In order to gain better insight into this reaction, DFT calculations using the hybridB3LYP method were performed with a view of delineating the detailed mechanism. Ascreening of alkaline earth halides acting as additives were proceeded. Additive BaF2gives the best performance steming from the shortest Ti-F bond in the intermediatecomplexes of IN1, along with relatively low Gibbs free energy. This leads to a higheryield and stereoselectivity which is consistent with the observed experimental result.In addition, electrospray ionization mass spectrometry （ESI-MS） methods were alsoemployed to study this1,2-addition reaction. And a base peak at881.4（m/z） wasobserved, pertaining to the existence of the asymmetric1,2-addition intermediate.Further theoretical investigation indicates that a Re-facial attack in atitanium（IV）-catalyzed enantioselective alkynylation reaction could be more favoredby the stronger repulsion of the bulky groups on the catalyst with aromatic ring of thesubstrates. Calculation results showed that the Gibbs free energies of TS_Si of thecorresponding alkynes are close to that of experimental ones according to Arrhenius Equation. And the final products prefer the R-configuration.