Owing to its distinctive physicochemical properities, such as interesting metabolic stability, suitable lipopphilicity and specific electronic properties, the trifluoromethoxy group(O-CF3) is of high value as attractive functional subsituent in various fields, particularly in the life sciences.  Furthermore, trifluoromethoxylated arenes present highly specific structural features. for instance, compared to a methoxy group, which normally rests in plane of the arene, the confromational changes resulting from trifluoromethoxy group incorporation can be beneficial to obtain additional binding affinity by adopting an orthogonal orientation with respect to the arene plane. Some examples of OCF3-containting molecules have found applications as pharmaceuticals or agrochemicals including Riluzole( amyotrophic lateral sclerosis treatment),Celikalim(potassium channel opener), Flurprimidol(plant growth regulator) and Triflumuron(insect growth regulant), and so on.

The formation fo the O-CF3 bond as well as the carbon-OCF3 has been difficult to accomplish for two main reasons: reactivity of the trifluoromethylating reagents with carbon sites of the oxgenated nucleophile leading to formation of byproducts and the thermal instability of many trfluoromethoxide salts. Even though significant advances achieved in the past years, most of them were very resitricted in terms of the substrate scope( mainly arenes), often required harsh reaction conditions( e.g. trifluoromethyl hypofluorite),thermal instability (e.g.O-(trifluoromethyl)dibenzofuranium reagents) and aggressive reagents(e.g. HF). Therefore, despite these above-mentioned particular interests, we still  have a long way to go before we find an efficient toolbox for stable, efficient and safe synthesis of desired trifluoromethyl ethers.  

All the methods for indirect or direct introduction of O-CF3 moiety can be divided into three groups of electrophilic,radical and nucleophilic reactions. 

1. Electrophilic Trifluoromethoxylation: Two typical electrophilic trifluoromethoxylation were to use Umemoto's oxonium reagent and Togni's hypervalent iodine reagents.  The former  is currently of limited synthetic use due to the carbon trifluomethylation or the need for impractical reaction conditons with  thermally unstable O-(trifluoromethyl)dibenzofuranium salt. In contrast, O-trifluoromethylation of primary and secondary alcohols with thermally stable Togni Reagent II( kumi3F11) affords the desired trifluoromethyl ethers.

2. Radical Trifluoromethoxylation: A direct radical trifluoromethoxylation can  be accomplished with the reagent families of CF3OX( X=F,Cl,O2CF3,OCF3), but these type of reactions have one common  drawback of toxicity and potential explosiveness resulting from hypofluorite.Very recently, Hu and co-workers developped a new two-step strategy for the synthesis of aryl trifluoromethyl ethers.this indirect radical trifluoromethoxylation employs the readily available sodium bromodifluoroacetate(kumi2F26), SelectFluor II(kumi9F02) and a catalytic amount of silver salt, thus providing a practical method to introduce OCF3 moiety into target phenols. 

3. Nucleophilic Trifluoromethoxylation: Recently Qing and co-workers adopted a new oxidative trifluoromethoxylation of phenols by using nucleophilic Ruppert-Prakash reagent(CF3TMS,kumi3F01) with the promotion of a silver salt. Although the synthesis of trifluoromethyl trifluoromethanesulfonate( TFMT,kumi3F27) has been known for a long time, it has only really been used  in fluorine chemistry in the last ten years. trifluoromethyl trifluoromethanesulfonate has shown versatile reactivity in various nucleophilic trifluoromethoxylation reactions, but all these methods starting from TFMT found limited applications for further synthesis, beacuse it is still expensive ,volatile and difficult to handle with a low boiling point. An alternative approach was later proposed to generate trifluoromethoxide anions for direct trifluomethoxylation of aliphatic substrates with 2,4-Dinitro(trifluoromethoxy)benzene(kumi3F26). 

In most recent, a family trifluoromethoxylating reagents of trifluoromethyl arylsulfonate (TFMS) are introduced by Tang Pingping and coworkers, as  novel trifluoromethoxylation reagents for an asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes. Compared to other trifluoromethoxylating reagents, TFMS is easily prepared and thermally stable with good reactivity. In addition, this reaction is operationally simple, scalable and proceeds under mild reaction conditions. Some of TFMS reagents can be provided by kuimdas, including: Trifluoromethyl 4-fluorobenzene sulfonate (kumi4F03), Trifluoromethyl4-(trifluoromethyl)benzenesulfonate(kumi6F08), Trifluoromethyl4-nitrobenzenesulfonate (kumi3F28), Trifluoromethyl benzenesulfonate(kumi3F29), Trifluoromethyl4-methoxybenzenesulfonate(kumi3F30), Trifluoromethyl2,4,6-trisopropylbenzenesulfonate(kumi3F31).  

In 2018, Hu group has developped a new, easily-prepared, shelf-stable and versatile reagent of Trifluoromethyl benzoate (TFBz,kumi3F55) for nucleophilic trifluoromethoxylation reaction with broad scope of substrates. Its synthetic potency is demonstrated by trifluoromethoxylation-halogenation of arynes, nucleophilic substitution of alkyl (pseudo) halides, cross-coupling with aryl stannanes, and asymmetric difunctionalization of alkenes. etc.. The unprecedented trifluoromethoxylation-halogenation of arynes proceeds smoothly at room temperature with the aid of a crown ether-complexed potassium cation, which significantly stabilize the trifluoromethoxide anion derived from TFBz.

Trifluoromethoxylating Reagents Overview

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You can either buy our trifluoromethoxylating reagents and then introduce trifluoromethoxyl group into your  own desired compounds, or you can simply order the building blocks pre-loaded with the O-CF3 subsitituent.
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