A scalable and operationally simple radical trifluoromethylation

Abstract

The large number of reagents which have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge. Current state-of-the-art reagents for appending the CF3 functionality directly are highly effective; however, their use on preparative scale has minimal precedent, because they require multi-step synthesis for their preparation, and/or are prohibitively expensive for large scale application. For a scalable trifluoromethylation methodology, trifluoroacetic acid and its anhydride represent an attractive solution in terms of cost and availability; however, due to the exceedingly high oxidation potential of trifluoroacetate, previous endeavors to use this material as a CF3 source have required the use of highly forcing conditions. Here we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to effect a facile decarboxylation to the CF3 radical.

Photochemical Perfluoroalkylation with Pyridine N -Oxides: Mechanistic Insights and Performance on a Kilogram Scale

“…We recently reported such a method through the use of pyridine N -oxide as a stoichiometric redox trigger to facilitate the photochemical decarboxylation of trifluoroacetic anhydride (TFAA). 64 As a conceptual alternative to direct carboxylate oxidation, the acylation of a pyridine N -oxide derivative allows the reaction manifold to be accessed through a reductive pathway. This design expands the scope of photoredox-mediated decarboxylation to electron-poor carboxylates, and through this method, a number of electron-rich and redox-sensitive substrates have been trifluoromethylated using TFAA.…”

Biocatalysis Fueled by Light: On the Versatile Combination of Photocatalysis and Enzymes

“…In a recent contribution by Cheruzel and co‐workers the usefulness of their hybrid catalysts was further demonstrated by their application in a photo‐biocatalytic cascade reaction scenario . A previously reported method for photoredox trifluoromethylation was combined with the enzymatic C,H‐oxidation described above (Scheme ). For this purpose, several hybrid enzymes were investigated, all featuring the Ru II complex 18 e (Scheme ) as photosensitizer component attached to the non‐native single cysteine residue L407C.…”

Aluminium Chloride‐Mediated Synthesis of 1‐Chloro‐2,2,2‐Trifluoroethylidene‐Substituted Pyrrolidones

“…For example, Aniracetam is a drug with anti-depressive properties used as a mental performance enhancer. [18] Later, Schä fer and co-workers also reported the synthesis of trifluoromethylated imidazofused N-heterocyles using TFAA as trifluoromethylating reagent. This biological and medicinal importance makes pyrrolidone derivatives desirable compounds for the screening of new biological activities.…”