α-(Trifluoromethyl)amine Derivatives via Nucleophilic Trifluoromethylation of Nitrones

Abstract

(Trifluoromethyl)trimethylsilane (TMSCF(3)) reacts with nitrones to afford alpha-(trifluoromethyl)hydroxylamines protected as O-trimethylsilyl ethers. Potassium t-butoxide initiates the nucleophilic trifluoromethylation. The reaction works best with alpha,N-diaryl nitrones, and the conditions are compatible with a range of substituents on the aryl groups. Acidic deprotection of the nitrone/TMSCF(3) adducts generates alpha-(trifluoromethyl)hydroxylamines. Catalytic hydrogenation of the adducts produces alpha-(trifluoromethyl)amines. Nitrone/TMSCF(3) adducts with strong electron-withdrawing groups on the alpha-aryl ring or heterocyclic alpha-aryl groups undergo an elimination/addition sequence to generate alpha,alpha-bis(trifluoromethyl)amines. Nitrones with alkyl groups bound directly to the 1,3-dipolar moiety fail to react with TMSCF(3), but trifluoromethylation of beta,gamma-unsaturated nitrones followed by reduction of the double bond can circumvent this limitation.

Nucleophilic Trifluoromethylation of C=N Bonds

“…Complete conversion of nitrones was achieved by adding 0.05-0.1 % of tBuOK at 15 min intervals and may take up to 48 h. This reaction gave good yields of products 28 for the nitrones bearing the electron rich aromatic group. [32] Eur. J.…”

Strategies for nucleophilic, electrophilic, and radical trifluoromethylations

“…Nelson and co-workers reported the nucleophilic trifluoromethylation of nitrones with Ruppert-Prakash reagent (Scheme 6) [31,32]. Since a nitrone is strongly electrophilic, it Scheme 1. readily accepts trifluoromethide ion.…”

Gas‐phase structure and new vibrational study of methyl trifluoroacetate (CF3C(O)OCH3)

“…Over the past two decades, the number of new organofluorine compounds has increased tremendously because of their different, sometimes improved, properties compared with nonfluorinated analogues. [1] The powerful electron-withdrawing ability and the relatively small size of the trifluoromethyl group can bring remarkable changes in the physical, chemical and biological properties of molecules, making them suitable for diverse applications in the areas of materials science and the pharmaceutical and agrochemical industries. [2,3] It is therefore desirable to investigate and understand the fundamental properties of such fluorinated organic compounds.…”