Direct Trifluoromethoxylation without OCF₃‐Carrier through In Situ Generation of Fluorophosgene

Abstract

Owing to the high interest in the OCF 3 group for pharmaceutical and agrochemical applications, trifluoromethoxylation received great attention in the last years with several new methods for this approach towards OCF 3 -comprising compounds. Yet, it most often requires the beforehand preparation of specific F 3 CO À transfer reagents, which can be toxic, expensive, unstable, and/or generate undesired side-products upon consumption. To circumvent this, the in-situ generation of gaseous fluorophosgene from triphosgene, its conversion by fluoride into the OCF 3 anion, and the direct use of the latter in nucleophilic substitutions is an appealing strategy, which, although recently approached, has not been fully exploited. We disclose herein our efforts towards this aim.

Development and Application of Trifluoromethoxylating Reagents

“…Therefore, in 2021, Leroux and co‐workers developed an efficient strategy to realize the trifluoromethoxylation of various alkyl iodides without the isolation of AgOCF 3 (Scheme 18b). [ 40 ]…”

Recent Advances in Visible Light‐Mediated Radical Fluoro‐alkylation, ‐alkoxylation, ‐alkylthiolation, ‐alkylselenolation, and ‐alkylamination

“…In addition, the increased lipophilicity of this unit paired with its electronegativity has rendered the trifluoromethoxy group to be nicknamed a “super halogen”. Given the attractive properties of the OCF 3 group, many protocols have been developed to generate and utilize anionic − OCF 3 [177–182] . However, given the propensity of β‐fluoride elimination, low reactivity, and need for prefunctionalization of substrates, direct C−H trifluoromethoxylation protocols remain an elusive but valuable approach to circumvent the innate shortcomings of anionic trifluoromethoxylation.…”

“…Given the attractive properties of the OCF 3 group, many protocols have been developed to generate and utilize anionic À OCF 3 . [177][178][179][180][181][182] However, given the propensity of β-fluoride elimination, low reactivity, and need for prefunctionalization of substrates, direct CÀ H trifluoromethoxylation protocols remain an elusive but valuable approach to circumvent the innate shortcomings of anionic trifluoromethoxylation. In recent years, several protocols utilizing different redox active scaffolds have enabled the generation and utilization of the trifluoromethoxy radical under visible light conditions (Scheme 47).…”

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

“…On the other hand, the vigorous development of trifluoromethoxylating reagents has laid the foundation for more efficient synthetic methods. The classical nucleophilic trifluoromethoxylating reagents mainly include trifluoromethoxide salts, such as AgOCF 3 , CsOCF 3 , tris­(dimethylmino)­sufonium trifluoromethoxide (TASOCF 3 ), R 4 NOCF 3 , PyOCF 3 , etc. (Figure , top).…”