2-Trifluoromethylated indole

As an orthogonal approach to the direct trifluoromethylation of indole derivatives, 2-trifluoromethylated indole 93 was prepared by subjecting isonitrile 92 to the hypervalent iodide (Togni) reagent and catalytic amounts... 

Ma reported the Cu(I)-catalyzed cascade coupling-trifluoromethyl)indoles 249 (Scheme 9.88) [239, 241]. Thus, a formal [3 - - 2] annulation of trifluoroacetanilides 247 with 3-ketoesters 248... 

Muzalevsidy VM, Shastin AV, Balenkova ES, Haufe G, Nenajdenko VG (2008) New approaches to the synthesis of 2-(trifluoromethyl)indole and 2-amino-3-(trifluoromethyl)-quinoUne. Russ Chem BuU (EngJ Transl) 10 2217—2219... 

Chen Y, Wang Y, Sun Z, Ma D (2008) Elaboration of 2-(trifluoromethyl)indoles via a cascade coupUng/condensation/deacylation process. Otg Lett 10 625-628... 

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

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... 

Trifluoromethyl-indoles can be prepared in a similar manner as shown in Eq. 64. In this case, anodic oxidation provides p-benzo-quinone imine derivatives 29, which are easily converted into trifluoromethyl-indoles 30 by heating or by treatment with ceric ammonium nitrate. 

The most common dipolar cycloaddition reaction is the 1,3-dipolar cycloaddition (1,3-DCA) [1-4], and several investigators have employed this reaction in the synthesis of indoles. Kobayashi and colleagues found that 2,3-bis (trifluoromethyl)indole was assembled from the 1,3-DCA reaction between nitrone 1 and hexaflnorobnt-2-yne (Scheme 1, equation 1) [5], Intermediates 2 through 5 were each isolated and characterized, and each individually was converted to the indole product by chromatography or acid treatment. No yields were reported. The isoxazoline-to-oxazoline (2) rearrangement was proposed to involve an aziridine. Cambon and colleagues described a similar synthesis of fluorinated indoles (equation 2) [6]. 

MA(-dimethylaiiilmes (equation 3) [32]. Independently, Liang reported a similar synthesis of 3-acylindoles [33]. Hon and colleagues uncovered a novel 3-trifluoromethyl-indole synthesis that used a CuBr-promoted reaction of 2-alkynylanihne in the presence of Umemoto s reagent (5) (equation 4) [34],... 

Kobayashi et al. elaborated an unusual pathway for the synthesis of 2,3-bis(trifluoromethyl)indoles [32], Photolysis of the l-phenyl-4,5-bis(tri-fluoromethyl)-lH-l,2,3-triazole in hexane proceeded very slowly to afford the indole 68 in 44 % yield. It was proposed, that after homolytic nitrogen extrusion, the carbene 67 was formed. Intramolecular cyclization led to the indole 68. 

Rodrigues I, Bonnet-Delpon D, Begue JP (2001) 1-Trifluoromethyl epoxy ethers. Effect of hexafluoro-2-propanol on reactions with secondary aromatic amines synthesis of 3-trifluoromethyl indole derivatives. J Org Chem 66 2098-2103... 

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. 

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). 

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. 

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