Radical C−H Trifluoromethoxylation of (Hetero)arenes with Bis(trifluoromethyl)peroxide

Trifluoromethoxylated (hetero)arenes are of great interest for several disciplines, especially in agro- and medicinal chemistry. Radical C−H trifluoromethoxylation of (hetero)arenes represents an attractive approach to prepare such compounds, but the high cost and low atom economy of existing ^. OCF₃ radical sources make them unsuitable for the large-scale synthesis of trifluoromethoxylated building blocks. Herein, we introduce bis(trifluoromethyl)peroxide (BTMP, CF₃OOCF₃) as a practical and efficient trifluoromethoxylating reagent that is easily accessible from inexpensive bulk chemicals. Using either visible light photoredox or TEMPO catalysis, trifluoromethoxylated arenes could be prepared in good yields under mild conditions directly from unactivated aromatics. Moreover, TEMPO catalysis allowed for the one-step synthesis of valuable pyridine derivatives, which have been previously prepared via multi-step approaches.     

Recent Advances and Perspectives of Transition Metal‐Catalyzed Asymmetric Fluorination Reactions

The synthesis of fluorine‐containing molecules has received intensive attention in recent years due to the great value of fluorides, however, the transition metal‐catalyzed asymmetric construction of C—F bonds is much less developed. This review presents the recent advancement of transition metal‐catalyzed asymmetric fluorination reactions, in which the final C—F bond is from reductive elimination of organometallic complexes. In addition, the perspective of the field is also provided for the future studies of asymmetric fluorinations and the related transformations, such as trifluoromethylation, trifluoromethylthiolation and trifluoromethoxylation.     

Fluoroalkylation of Diazo Compounds with Diverse Rfn Reagents

Progress in the transition‐metal‐catalyzed or ‐free fluoroalkylation of diazo compounds with different types of fluoroalkyl (R_fn) transfer reagents is summarized in this review. Special attention is focused on the straightforward trifluoromethylation, gem‐difluoroolefination, trifluoromethoxylation, fluoroalkylthiolation, and trifluoromethylselenolation of diazo substrates. The mechanistic insights and the application of some of the products are also discussed in this article. We believe that this review will inspire both young and experienced chemists to further study the direct fluoroalkylation of diazo compounds as an efficient and convenient way to build complex fluorine‐containing molecules.     

Direct Dehydroxytrifluoromethoxylation of Alcohols

The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late‐stage trifluoromethoxylation of complex small molecules.     

Trifluoromethoxylation Reactions of (Hetero) arenes,Olefinic Systems and Aliphatic Saturated Substrates

Direct fluoroalkoxylation reactions of (hetero)arenes, carbon-carbon multiple bonds, and substitution reactions at Csp³ carbon centers by CF₃O, CHF₂O, and (CF₃)₂CFO groups are discussed. Emphasis on thermal radical, electron transfer, photocatalytic, electrochemical and redox-neutral radical methods are placed to accomplish fluoroalkoxylation reactions. All these methods employ either radical fluoroalkoxylating reagents or some nucleophilic trifluoromethoxylating sources of CF₃O. A summary of all these methods is provided in Table 2.     

Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes

The intermolecular C?H trifluoromethoxylation of arenes remains a long‐standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a novel trifluoromethoxylating reagent and redox‐active catalysts for the direct (hetero)aryl C?H trifluoromethoxylation. Our approach is operationally simple, proceeds at room temperature, uses easy‐to‐handle reagents, requires only 0.03 mol % of redox‐active catalysts, does not need specialized reaction apparatus, and tolerates a wide variety of functional groups and complex structures such as sugars and natural product derivatives. Importantly, both ground‐state and photoexcited redox‐active catalysts are effective. Detailed computational and experimental studies suggest a unique reaction pathway where photoexcitation of the trifluoromethoxylating reagent releases the OCF₃ radical that is trapped by (hetero)arenes. The resulting cyclohexadienyl radicals are oxidized by redox‐active catalysts and deprotonated to form the desired products of trifluoromethoxylation.     

Synthetic Approaches to Trifluoromethoxy‐Substituted Compounds

Because of the unique properties of the trifluoromethoxy group, molecules bearing this moiety will find applications in various fields, particularly in the life sciences. However, despite the great interest in this functional group, only a small number of trifluoromethoxylated molecules are currently synthetically accessible. Over the last few years, several innovative and promising strategies for the synthesis of trifluoromethoxylated compounds have been described. This Minireview discusses these existing methods with a particular focus on more recent advances.