Trifluoromethyl groups formation

Trifluoromethyl groups are very resistant to hydrolysis, unless they are allylic or benzylic, or vicinal to a carbon linked to hydrogen. In the last case, elimination of hydrogen fluonde leads to the formation of a difluoromethylene group which is key to additional reactions... 

Hydrolysis of the trifluoromethyl group of 2 tnfluoiomethylimidazoles is promoted by the formation of the anion, which readily eliminates fluoride. The resultant ditluorodiazafulvene then easily adds water The remaining steps in the hydrolysis ate predictable When aqueous ammonia is used, 2-cyanoimidazoles result [40] (equation 4])... 

An unusual 1,4-migration of a trifluoromethyl group was observed when azomethine imines were synthesized from hexafluoroacetone azine and alkoxy-acetylenes The rearrangement, which occurs at temperatures as low as 0 "C, results in the formation of A-(perfluoro-ferf-butyl)pyrazoles [207] (equation 46)... 

Bischler-Napieralski reaction conditions can be attributed, again, to the destabilizing ability of the trifluoromethyl group to the cationic transition state of the acid catalyzed elimination. Formation of compound 29 was ultimately accomplished by base catalyzed methanol elimination-conditions conditions that are quite unusual for isoquinoline formation. 

Since these methoxylated and acetoxylated sulfides have an acetal structure, it is expected that Lewis acid catalyzed demethoxylation should generate a carbocation intermediate which is stabilized by the neighboring sulfur atom. In fact, nucleophilic substitution with arenes has been successfully achieved as shown in Scheme 6.7 [43], This procedure is useful for the preparation of trifluoroethyl aromatics. As already mentioned, generation of carbocations bearing an a-trifluoromethyl group is difficult due to the strong electron-withdrawing effect. Therefore, this carbon-carbon bond formation reaction is remarkable from both mechanistic and synthetic aspects. 

An alternative approach to preventing the formation of dihydroartemisinin by simple P450 metabolism is to replace the methyl function in artemether with an aryl function. Phenoxy analogues of DHA can easily be prepared in a one-step synthesis from dihydroartemisinin in a manner similar to the preparation of Ic and Id. In addition to having superior in vivo activity to artesunate and artemether, analogues substituted with a p-fluoro (71a) or trifluoromethyl group (71b), in the phenoxy ring, resist metabolism to DHA . ... 

Unexpected oxazoline formation was observed during a study to prepare nonsedating anxiolytic 1-styrylisoquinolines 27a-h from 2-(trifluoromethyl)aryl-ethylamines 25a-h under Pictet-Gams conditions (POCI3 in refluxing toluene). This deviation from the normal reaction pathway was hypothesized to result from the electron-withdrawing effect of trifluoromethyl group that inhibited the formation of a benzylic cation required for isoquinoline formation (Scheme 8.12). 

Treatment of 18 with ethylenediamine afforded the desired triazolo piperazine 3 at room temperature albeit in low yields. Attempts to improve the reaction revealed that when the oxadiazole was added to two equivalents of ethylenediamine in methanol at 0 °C, a new species crystallized directly from the reaction mixture. This solid was isolated, identified as the amidine 20, and was found to convert to 3 by refiuxing in methanol for 4h (Scheme 5.11). The formation of amidine 20 was curious since it suggested that initial attack of ethylenediamine did not occur at the carbon of the oxadiazole vicinal to the trifluoromethyl group. Of the three carbons of the oxadiazole which need to react with ethylenediamine, this would easily be rationalized as the most electrophilic. In order to understand the mecha-... 

The fluorination of allylic231 232 and benzylic positions by halogen replacement using hydrogen fluoride has found very wide interest, since trifluoromethyl groups are highly desired substituents in many applications. Some representative examples are given by the formation of 10,232 II,233- 235 and 12.236... 

Treatment of furan-2.4- and furan-2.5-dicarboxylic acid with excess sulfur tetrafluoridc and hydrogen fluoride under forcing conditions results in simultaneous conversion of the carboxylic acid groups into trifluoromethyl groups and addition of two fluorine atoms at C 2 and C5 of the furan ring to give highly fluorinated derivatives of 2.5-dihydrofuran, e.g. formation of... 

Trifluoromethyl groups are aminolyzed by ammonia to yield carbonitriles, which works especially well with electron-rich-substituted trifluoromethane derivatives (e.g., 7), even when aqueous ammonia is used.41 45 It has been proposed that these substrates might react via a fulvene-like intermediate, which could be formed via an ElcB mechanism. With less reactive substrates, sodium amide or liquid ammonia has to be used as reagent in order to achieve carbonitrile formation.3,46 49... 

Furan-2-carboxylic add reacts with sulfur tetrafluoride at 0 °C to give 2-furoyl fluoride, but attempts at further fluonnation results in resin formation [222] A second carboxylic group and/or electron withdrawing substituents, such as the nitro or trifluoromethyl group, stabilize the furan ring Thus, turandicar-... 

Reactions of unsaturated ketones 62 containing a strong a electron-withdrawing trifluoromethyl group with urea and its analogues 28, 60 and 61 usually stop at the stage of the formation of hydroxytetrahydropyrimidines 63 [69] (Scheme 3.19). 

Gassman, P. G. Hall, J. B. Testing for symmetry in neighboring group participation in car-bocation formation. An insight into doublebond participation via trifluoromethyl group substitution. /. Am. Chem. Soc. 1984, 3 06, 4267—4269. 

---