Transition Metal‐Free Direct Trifluoromethylation of 2,3‐Dihydropyridin‐4(1H)‐ones at Room Temperature

Abstract

A transition metal‐free, regioselective C‐5 trifluoromethylation of 2,3‐dihydropyridin‐4(1H)‐ones (cyclic enaminones) with trimethyl(trifluoromethyl)silane (TMSCF3) was developed that proceeds under mild conditions at room temperature. This direct transformation was successful with both electron‐rich and electron‐deficient cyclic enaminones. This method bypasses substrate prefunctionalization and transition metal catalysis, and allows the convenient and direct access to a variety of medicinally important 3‐trifluoromethylpiperidine derivatives. This chemistry also represents a rare example of a direct trifluoromethylation of an internal olefinic CH bond. A radical mechanism is proposed for this reaction.magnified image

Highly Site-Selective Metal-Free C–H Acyloxylation of Stable Enamines

“…Accordingly, their syntheses have attracted tremendous attention from synthetic chemists . In recent years, our group and other groups have developed efficient methods for the construction of functionalized enamides via direct sp 2 C–H bond functionalization of simple enamides. Enaminones are another class of enamine derivative that have attracted the attention of synthetic chemists since they contain additional functional groups that can be easily manipulated .…”

Synthesis of Multifunctionalized 2,3-Dihydro-4-pyridones and 4-Pyridones via the Reaction of Carbamoylated Enaminones with Aldehydes

“…Dihydropyridones bearing the CF 3 group have attracted attention as intermediates for the preparation of biologically important CF 3 -piperidines . But the range of such dihydropyridones as well as approaches to their synthesis is limited by the small number of protocols including radical trifluoromethylation . It should be noted that 6-CF 3 -2,3-dihydro-4-pyridones are hard-to-reach compounds, and in the literature, the only example of them, ethyl 6-(4-chloro­phenyl)-4-oxo-2-(trifluoro­methyl)-1,4,5,6-tetrahydro­pyridine-3-carboxylate, has been described .…”

Recent advances in direct trifluoromethylation of olefinic C–H bonds

“…The rst and only study on metal-free direct triuoromethylation of cyclic alkenes was reported by Georg and co-workers in 2014. 36 It described the regioselective introduction of a CF 3 group at the C-5 position of 2,3-dihydropyridin-4(1H)-ones (cyclic enaminones) using PhI(OAc) 2 as an oxidant and the Ruppert's reagent. A screening of reaction conditions proved that KF and MeCN were the most effective base and solvent, respectively.…”