Radical trifluoromethylation

Other sources of radical CF3, much less expensive than CF3I, have been discovered. These are the anodic oxidation of sodium trifluoroacetate (the decomposition being initated by a hydroperoxide or ruthenium catalyst) and trifluoromethyl bromide (CF3Br) using sodium dithionite as initiating agent.  

---

First examine the geometry of methyl radical. Is it planar or puckered Examine the geometries of 2-methy 1-2-propyl radical, trifluoromethyl radical, trichloromethyl radical and tricyanomethyl radical. Classify each of the substituents (methyl, fluoro, chloro and cyano) as a n-electron donor or as a Tt-electron acceptor (relative to hydrogen). Does replacement of the hydrogens by 7t-donor groups make the radical center more or less puckered Does replacement by Jt-acceptor groups make the radical center more or less puckered Justify your observations. 

Trifluridine is synthesized by radical trifluoromethylation of uracil, followed by coupling with the protected deoxyribose (enzymatic or chemical) or by trifluoromethylation of the protected iodonucleoside (Fig. 28) [91]. 

These molecules are prepared through radical trifluoromethylation of the base (cf. Chapters 2 and 8). 

Ruppert reagent (CF3TMS), by radical trifluoromethylation, and finally by total synthesis starting from alicyclic precursors. 

Shustova, N.B., Popov, A.A., Mackey, M.A. etal. (2007) Radical trifluoromethylation of ScsNOCgo- Journal of the American Chemical Society, 129, 11676-11677. 

Numerous alternative preparations have been described (ref. 2). They often make use of toxic (CF3SCI) or fragile (CF3CU, CF3SCU) reagents. Radical trifluoromethylation can also occur starting from the expensive trifluoromethyl iodide. 

The syntheses of 2-trifluoromethylbenzimidazoles (65, 68, and 71) are summarized in Scheme 12.9. Although condensation of phenylenediamines 64 with trifluor-oacetic acid is the most convenient method , the reaction of phenylenediamines with either trifluoroacetimidoyl derivatives 67 or 70 also provides the desired benzimidazoles 68 and 71 in good yields. A direct radical trifluoromethylation of imidazole ring 72 with trifluoromethyl iodide has a poor regioselectivity. ... 

Compound 205 can be synthesized by (i) the reaction of uracil-5-carboxylic acid 206 with an excess of sulfur tetrafluoride and small amount of water (0.5 mL per 45 g of sulfur tetrafluoride) (Scheme 12.41), (ii) radical trifluoromethylation of 187 using bis(trifluoromethyl)mercury in the presence of azoisobutyronitrile (AIBN) (Scheme 12.41), (in) an electrolysis of a solution 187 in trifluoroacetic acid (Scheme 12.41 ), (iv) the reaction of 5-trifluoromethyl-5,6-dihydrouracil 207 with bromine in acetic acid followed by heating in dimethylformamide (DMF) solution... 

Bis(perfluoroalkanoyl)peroxides were also appUed for radical trifluoromethylation of pyrrole 2b [34], Performing the reaction in freon 113 at -30 °C was found to be optimal for aU peroxides. In this way 2-CF3-pyrrole 38b was regioselectively synthesized in 72 % yield (Table 1, entry 7). Lower yields were obtained both at higher temperature and in diethyl ether as a solvent. 

The A -nitrososulfonamide 70 was shown to be a convenient reagent for radical trifluoromethylation. UV irradiation of lb with 70 in the presence of diacetyl as a sensitizer led to 38b in 51 % yield (Table 1, entry 8). Distinct advantage of this method is easy handling of the solid 70 instead of gaseous CF3I or of the quite unstable bis(perfluoro-aIkanoyl)peroxides. 70 is assessable from trifluoronitroso-methane 69 in a one-pot procedure [35]. Te(CF3)2 was also used as a trifluoromethyl radical source for trifluoromethylation. The reaction proceeded under UV irradiation and led to a 25 1 mixture of pyrroles lb and 2b (Table 1, entry 9) [36]. 

Radical trifluoromethylation of IV-trimethylsilylindole 27b with trifluoroiodometh-ane proceeded nonselectively into both 2- and 3-positions, with a preference for the 2-trifluoromethylindole formation [24], Quench of the reaction mixture with methanol afforded the 2- and 3-trifluoromethylndoles 60a and 61 in 2/1 ratio. Similarly, the trifluoromethylation using difluorodiiodomethane [25] and bis(perfluoroalkanoyl) peroxide [26] led to a mixture of the same products. In aU cases, the overall yield of isomeric indoles was moderate. 

A radical trifluoromethylation is widely used for incorporation of CF3 group into thiazole ring. This is simple and therefore promising procedure as an industrial process. Trifluoromethyl radical has electrophilic nature and can be readily generated from various sources. For example, the reaction of thiazoles with CF3I is carried out in the presence of Fe (II), H2O2 and DMSO under mild conditions [7]. In this case usual orientation of electrophilic substitution was observed. 

---