Synthèse d’amidines et de composés trifluorométhylés par le biais de molécules hautement réactives
This work is separated in two distinct parts aiming to describe the recent advances concerning the use of highly reactive molecules such as trifluoromethanesulfonic anhydride (Tf2O) and trifluormethyldiazomethane in organic synthesis. In the first section, the amide activation strategy using triflic anhydride was applied in order to synthesize free secondary and tertiary amidines. Those molecules find numerous applications, particularly in natural product synthesis and medicinal chemistry. Although their purification on small scale is quite difficult, their synthesis and caracterization were successfully achieved. Next, investigations were conducted towards the trifluoromethylation of organic compounds. The idea was to trifluoromethylate highly electronegative activated amides in order to transform them into trifluoromethylketones. Unfortunately, this route appeared to be uneffective and was switched to another promising trifluoromethylating source : Trifluormethyldiazomethane. In the second section, the safe and efficient synthesis of trifluoromethyldiazomethane in continuous flow is described. That diazo compound was then used in the synthesis of trifluoromethylated pyrazolines. A reactivity trend was unveiled as those molecules spontaniously tautomerize (or not) depending on the nature of the substrate. Trifluoromethylated pyrazolines are interesting compounds on their own, especially for the pharmaceutical industry, but also serve as precursors to trifluoromethylated cyclopropanes. Finaly, some ideas and related future projects are discribed, in particular in what should be an efficient and possibly enantioselective synthesis of trifluoromethylated cyclopropanes in continuous flow.
Trifluoromethanesulfonic anhydride Amide activation Free amidine synthesis Trifluoromethyldiazomethane Trifluoromethylated pyrazoline synthesis Continuous flow chemistry