Electrophilic trifluoromethylating

The overall trend of reactivities for t-butoxy radicals with the fluoro-olcfins more closely parallels that for methyl radicals than that for the electrophilic trifluoromethyl or trichloromethyl radicals. 

Absolute rates for the addition of the methyl radical and the trifluoromethyl radical to dienes and a number of smaller alkenes have been collected by Tedder (Table l)3. Comparison of the rate data for the apolai4 methyl radical and the electrophilic trifluoromethyl radical clearly show the electron-rich nature of butadiene in comparison to ethylene or propene. This is also borne out by several studies, in which relative rates have been determined for the reaction of small alkyl radicals with alkenes. An extensive list of relative rates for the reaction of the trifluoromethyl radical has been measured by Pearson and Szwarc5,6. Relative rates have been obtained in these studies by competition with hydrogen... 

Counteranion-bound S-, Se-, and re-(trifluoromethyl)dibenzothiophe-nium-, -selenophenium-, and -tellurophenium-3-sulfonates 42-44, 48, and 49, developed as another series of the electrophilic trifluoromethylating agents, are useful because the resultant trifluoromethylated products are easily separated from the by-product dibenzothiophene-, -selenophene-, or -tellurophene-3-sulfonic acids because these by-products are soluble in water (Eq. 17) (95JFC). 

Electrophilic trifluoromethylation is still of minor importance in synthetic applications. The limited efficiency and the cost of the reagents able to transfer a CF3 cation are important obstacles for the development of this approach. However, CF3-S" -type reagents can react with activated enolates under Lewis acid catalysis. A recent and promising result shows that, when the reaction is performed under UV irradiation, yields significantly increase. This can lead to synthetic applications, as exemplified by the recent preparation of 7-CF3 steroids (Figure 2.37). ... 

In the search for less expensive and more easily accessible reagents, a new hypervalent iodine(III)-CF3 reagent has shown a promising reactivity in the mild and selective electrophilic trifluoromethylation of active methylene compounds and free thiols (Figure 2.38). Synthesis of this reagent is easy and scalable. ... 

The oldest methods for synthesis involve the condensation-cyclization of trifluor-omethyl or fluoroalkyl pyrroles in the presence of a metal salt. These reactions afford tetrakis(fluoroalkyl) porphyrins. The electrophilic trifluoromethylation of porphyrins is selective and leads to /I-CF3 and meso-CVT, porphyrins. While condensation of meio-trifluoromethyl-dipyrromethane with an aldehyde in acidic medium is rather difficult, it proceeds with better yields and permits a selective introduction of trifluoromethyl groups in meso The Ruppert reagent (CF3TMS) has been used to... 

Jouannetaud and co-workers229 have explored electrophilic trifluoromethylation under superacidic conditions of aniline derivatives229 and /V-heterocycles. Methyl-substituted anilines and substituted acetanilides [Eq. (5.85)] react with the CC13+ cation generated from CC14 in HF-SbF5 followed by fluorination to yield the corresponding trifluoromethyl derivatives. Under similar conditions, indolines are transformed to the 6-triluoromethyl derivatives, whereas substituted indoles yield 5-triluoromethyl derivatives.230... 

Two hypervalent iodine, electrophilic trifluoromethylation (Togni) reagents, which have CF3-iodine bonds are also worth including in this section (Scheme 5.6). 

The fluorine atoms in trifluoroethylene enhance the rate of attack by the nucleophilic methyl radicals, but retard attack by the electrophilic trifluoromethyl radicals. Methyl radicals add preferentially to the most substituted end of trifluoroethylene, in direct contradiction of the resonance stabilization hypothesis. In fact we can see that the reaction of methyl radicals... 

Kieltsch, I., Eisenberger, P. and Togni, A. (2007) Mild electrophilic trifluoromethylation of carbon- and sulfur-centered nucleophiles by a hypervalent iodine(III)-CF3 reagent. Angew. Chem. Int. Ed., 46, 754-757. 

Scheme 2.141 Electrophilic trifluoromethylation of activated aromatic substrates by an HF/ CCf/SbF system and subsequent treatment with 70%...

Electrophilic Trifluoromethylation with Umemoto s Reagents A.8.1 Trifluoromethylation of the Trimethylsilyl Dienol Ether 30... 

Scheme A.12 Electrophilic trifluoromethylation with Umemoto s reagent [18].

Among a series of trifluoromethyl dibenzoheterocyclic onium salts derived from chalcogens, a small number of tellurium compounds have been prepared. As electrophilic trifluoromethylating agents, the tellurium compounds appeared as the least reactive. With a very reactive carbanion, the unsubstituted dibenzotellurophenium salt (81) gave only 9% of the trifluoromethylated product. With the p-diketone enolate, (81) did not react. However, the 3,7-dinitrotellurophenium salt (82) showed a relative activity similar to that of the unsubstituted selenium compound (47). 1... 

We have interpreted the formation of zinc triflinate by a SET process (Fig. 15). In order to test for the presence of the electrophilic trifluoromethyl radical in this reaction, we have added anilines to the medium. Indeed, alkylation at electron-rich positions of the ring was observed (Fig. 19) (ref. 26). 

Other electron-rich aromatic compounds can be employed as substrates. Pyrroles were trifluoromethylated regioselectively at the 2-position (ref. 27). Recently, the system trifluoromethyl iodide-zinc-sulfur dioxide in DMF at low temperature was used for the trifluoromethylation of aminonaphtalenes and aminoquinolines (ref. 28). Computational results support the mechanism in which the electrophilic trifluoromethyl radical intertact with the aromatic ring at the sites with the greatest electron density of the HOMO orbitals. 

Electrophilic trifluoromethylation reagents can be generated from the treatment of trifluoromethyl biphenyl sulfoxides with Tf20. These reagents will react with a wide range of nucleophiles including carbanions, aromatics, silyl enol ethers, thiolates, and phosphines (eq 90). ... 

Togni and coworkers have found that 1-trifluoromethylbenziodoxole 770 is a useful reagent for electrophilic trifluoromethylation of nucleophilic substrates. This reagent, in particular, reacts with (3-ketoesters 769 under mild conditions in the presence of potassium carbonate to give a-trifluoromethylated product 771 in good yield (Scheme 3.303) [1026, 1027]. Likewise, this mild electrophilic trifluoromethylating... 

Matcha and Antonchick prepared a series of indoles, pyrazoles, and pyrid-azinones via the functionalization of alkenes in a cascade multicomponent process. An electrophilic trifluoromethyl radical added to the terminal position of olefin 119 to give radical intermediate 121. Then, in a Fischer indolization-like process, phenylhydrazone 122, through an ene-hydrazine, cyclized to aminoindoline 123. After elimination of ammonia, indole 120 was isolated in good yield (14AG(I)11960). 

While Yu et al. [15] reported the palladium-catalyzed ortho trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent (Scheme 19.9), Liu and coworkers [69] developed a nondirected C-H trifluoromethylation method using the nucleophilic Ruppert-Prakash (TMSCFj) reagent (Scheme 19.43). Thus, indoles underwent trifluoromethylation in moderate yields at the C-2 position or, when the C-3 position was free, at the C-3 position in the presence of a Pd /bis-oxazoline catalyst, cesium fluoride, PhI(OAc)2 as the stoichiometric oxidant, and TEMPO as a radical trap. Similar to Yu s method, the mechanism was proposed to involve the formation of an Ar-Ph -CEj intermediate that reductively eliminates to form the Ar-CFj bond. 

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