N-Trifluoromethoxyphthalimide: A Shelf-Stable Reagent for Nucleophilic Trifluoromethoxylation

Abstract

Due to the unique properties of the OCF3 group, trifluoromethyl ether compounds play an important role in pharmaceuticals and agrochemicals. Recently, considerable attention has been focused on the development of practical and convenient reagents for the direct incorporation of the OCF3 group into organic compounds. Herein, we reported a new trifluoromethoxylating reagent N-trifluoromethoxyphthalimide (Phth-OCF3). The reagent was a stable solid and released an OCF3 anion under mild reaction conditions. We demonstrated the application of Phth-OCF3 for the nucleophilic trifluoromethoxylation of various alkyl electrophiles.

Comprehensive Study and Development of a Metal‐Free and Mild Nucleophilic Trifluoromethoxylation

“…No alkyl chloride was tested with Phth-OCF 3 . [22] [a] Yields determined by 19 F NMR spectroscopy with PhCF 3 as internal standard.…”

“…Again, primary alkyl iodides are the key substrates used and no real rationalization regarding the choice of additive (Et 4 NI or CsF or Et 4 NI/CsF) was provided. [22] While DDPyOCF 3 was used by Sanford with a stoichiometric amount of silver salt to perform nucleophilic substitutions, primarily with benzyl bromides, [23b] we demonstrated that similar substrates could also be trifluoromethoxylated under mild, metal-free conditions. [23a] In our early work, the DNTFB/ DMAP ratio was found to be a crucial parameter: an excess of DNTFB is required to provide a reservoir of the CF 3 O À anion to perform metal free substitutive trifluoromethoxylations.…”

“…[25b] Qing applied the same approach with Phth-OCF 3 on a single example. [22] As we had previously demonstrated the ability of DDPyOCF 3 to generate difluorophosgene, [26] we considered the possibility of performing a direct dehydroxytrifluoromethoxylation, similar to Tang but in a simpler solvent and with a cheaper reagent, to extend the study of the reactivity of our DNTFB/DMAP system (Scheme 4).…”

“…Very recently, Qing et al updated the synthesis and use of Phth-OCF 3 . [22] For our part, we described, concomitantly with the Sanford group, the use of cheap 2,4-dinitro-trifluoromethoxybenzene (DNTFB) as an efficient source of a stable solution of CF 3 O À anion (DDPyOCF 3 ). [23] All of these reagents were used to perform nucleophilic substitutions, but the majority of them required a stoichiometric amount of silver salts.…”

Development and Application of Trifluoromethoxylating Reagents

“…In 2023, Qing and co‐workers disclosed the novel application of N ‐trifluoromethoxyphthalimide (Phth‐OCF 3 ) as a nucleophilic trifluoromethoxylating reagent, [ 57 ] which was initially synthesized by Togni in 2014, [ 58 ] and later used as the radical aminating reagent. [24c] Compared to previous reagents, Phth‐OCF 3 was easily synthesized in one step from cheap starting materials ( N ‐hydroxyphthalimide and CF 3 SO 2 Na).…”