Studies On The Organic Synthetic Chemistry Of Trifluoromethyl Ketimines And Trifluorodiazoethane

Trifluoromethyl-containing compounds are playing an increasing important rolein the fields of chemistry, pharmaceuticals and materials etc. owing to their specialphysical and chemical properties. So the efficient construction of trifluoromethylmolecules is becoming a significant topic in organic synthetic chemistry.Chiral trifluoromethyl-containing compounds are important building blocks forthe preparation of chiral reagents and biologically active molecules. The mosteconomic and efficient approach to access these usful compounds is chemicaltransformations based on various trifluoromethyl synthons. Inspired by the structureof anti-HIV drug Efavirenz and its derivatives, we developed the enantioselectivediynylation and enynylation of cyclic N-acyl trifluoromethylketimines. Withsystematic screening on the ligands, solvents and reaction temperatures, theasymmetric addition of1,3-diynes to N-acyl trifluoromethylketimines was achieved inhigh yield and high ee with chloramphenicol-amine derivatives as chiral additives.We also obtained several analogs of anti-HIV drug DPC961after further chemicaltransformations, and carried out some initial studies on their biological activities.With BINOL derivatives as ligands, the enantioselective addition of1,3-diynes and3-en-1-ynes to cyclic trifluoromethylketimines and N-arylimines of trifluoropyruvateswere also implemented. The yields, enantioselectives and substrate tolerance are allvery good in these reactions. With this methodology, a series of optically activetrifluoromethyl-containing propargylic amines were successfully synthesized.Subsequently, we studied the enantioselective organocatalytic Strecker reactionof cyclic trifluoromethylketimines with TMSCN. Using as low as1mol%cinchonaalkaloid-based thioureas, both enantiomers of α-amino nitriles can be accessed inexcellent yields (up to99%) and enantioselectivities (90–97%ee). Furthermore, theStrecker reaction serves as a key step in the asymmetric preparation of anti-HIV drugDPC083.2,2,2-trifluorodiazoethane has emerged as an attractive synthon in theconstruction of trifluoromethyl-containing building blocks owing to its high reactivity.With our continuing interests in syntheses of fluorinecontaining compounds, westudied the cycloaddtion reaction of trifluorodiazoethane with various allenes. In the presence of Et3N, a series of trifluoromethylpyrazoles were obtained in51–92%yieldunder mild conditions. Furthermore, by controlling the reaction parameters, anotherkind of trifluoromethylpyrazoles derivatives were also delivered in50–88%yield. Themechanism of this reaction was also investigated with NMR analysis.Notablely, several trifluoromethylphosphazine intermediates were achieved withtrifluorodiazoethane and phosphines under mild conditions. A subsequent cascadereaction of allenotes with trifluoromethylphosphazines in one pot was then developedin58–94%yield. On the other hand, the N-aza Wittig reaction of aldehydes andα-ketoesters with trifluoromethylphosphazines was also accomplished in50–95%yield in a similar manner. With this methodology, we obtained a series of neworganophosphine compounds and bis-hydrazone derivatives involving trifluoromethylgroup. These findings make great sense to the diversity oriented syntheses oftrifluoromethyl chemistry.