Indoles trifluoromethylation

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

A trifluoromethyl moiety is a strong electron-withdrawing group which dominates the direction of indolization in the Nenitzescu process. ... 

The directing influence of the trifluoromethyl group also competes with that of the strongly electron-donating methoxyl group. Thus 2-methoxy-5-trifluoromethyl-l,4-benzoquinone (26) was treated with ethyl 3-aminocrotonate (5) to furnish 25% of each of the two possible isomeric indoles 27 and 28. °... 

For example. 2-ethoxyindole (1 a) with the alkyne diester in refluxing dioxane yields dimethyl 2-ethoxy-3//-l-benzazepine-3,4-dicarboxylate (2) as a minor product along with a 50 % yield of a mixture of the cis- and tran.v-indol-3-ylacrylates 3.20 However, with 2-ethoxy-l-methylindole (1 b) the l//-l-benzazepine 4 becomes the major product. An analogous reaction with l,2-bis(trifluoromethyl)acetylene to yield 2-ethoxy-l -methyl-3,4-bis(trifluoroiriethyl)-1 //-1-benzazepine has been performed however, the yield was not reported.142... 

For commonly encountered heterocycles, the chemical shifts of trifluo-romethyl substituents will depend somewhat upon where in the heterocycle they are located. Examples of trifluoromethyl derivatives for a number of common heterocycles, including pyridines, quinolines, pyrroles, indoles, thiophenes, benzothiophenes, furans, benzofurans, imidazoles, and uracils are given below. 

Proton and Carbon NMR Spectra of Pyrroles and Indoles. Some examples are given in Scheme 5.48 that provide proton and carbon data for pyrroles and indoles bearing a trifluoromethyl group. 

The following scheme illustrates the synthesis of a trifluoromethyl indole derivatives via the title radical reaction. 

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

Halogenomethylpyrroles have been oxidized with lead(IV) salts or by chromium trioxide to yield the formylpyrroles, whilst catalytic hydrogenolysis or zinc-acetic acid reduction produces the 2-methylpyrroles (B-77MI30504). The methyl derivatives are also obtained by hydride reduction of trifluoromethyl-pyrroles and -indoles, and trifluoromethylindoles are converted into the carboxylic esters by ethanol under basic conditions (74JOC1836). 

A different reactivity is found for trifluoromethyl groups at the 2- or 3-position in indoles during hydrogenolysis by complex hydrides. While lithium aluminum hydride is capable of reducing trifluoromethyl groups in both 2- or 3-(trifluoromethyl)indole with almost the same result, sodium borohydride in ethanol reduces only 3-(trifluoromethyl)-l//-indole (3) to the corresponding 3-methyl-l//-indole (4, skatole).67,145... 

Methyl- or 3-Methyl-l //-indole by Reduction of the Corresponding (Trifluoromethyl)indole Typical Pro-cedures 67-145... 

Methyl-M-indole Refluxing was stopped as soon as 3-(trifluoromethyl)-l//-indole was not detected by TLC in the mixture after purification (vide supra), evaporation of F.t20. and recrystallization (hexane), the product was obtained yield 59.5 mg (42%) mp 90 92 C. 

Chloro-l-(4-fluoro-phcnyl)-4-oxo- -5-fluoro-2-oxo- EI6b. 406 (subst. Indol t snbsl. Ketenimin) 3-Chloro-4-oxo-l-phenyl- -5(or 6)-fluoro-2-oxo- EI6b, 406 (Indol-Der. + subst. Ketenimin) 3-Chloro-4-oxo-l-(4-trifluoromethyl-phenyl)- -5(or 6)-fluoro-2-oxo-EI6b. 406 (Indol-Der, + subst. Ketenimin)... 

A wide variety of nucleophiles, such as 1-alkylpyrroles, furans, thiophenls [51], phenols [52], anilmes [53, 54], indoles [55], CH-acidic compounds [56, 57], as well as organolithium [53], Gngnard [57, 59], organocadmium, and organozmc compounds [50], undergo C-hydroxyalkylation with tnfluoropyruvates to yield derivatives of a-trifluoromethyl a-hydroxy acids. 

Dandia, A., Singh, R., Sachdeva, H. and Arya, K., Microwave-assisted one pot synthesis of a series of trifluoromethyl substituted spiro [indole triazoles], /. Fluorine Chem., 2001, 111,61-67. 

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... 

Benzimidoyl chloride, N-phenyl-, Friedel-Crafts benzoylation using, 55, 195 Benz[g]indazoles. 5-trifluoroacetyl-3-trifluoromethyl-, 60, 17 Benz[c]indole, 4.5,6,7,8,9-hexafiuoro-2-phenyl-, 59, 14... 

Benz[g]indole-2-carboxylate, 5-trifluoro-acetyl-3-trifluoromethyl-, 60, 17... 

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