Indole, 1-phenyl-, lithiation

The direct lithiation of benzo fused heterocyclic systems in the benzo ring is often less easy than in the heterocyclic ring or even at a substituent phenyl group. Thus, while A7-phenyl indole undergoes lithiation at both the 2- and the 2 -positions, /3-lithiation at the 7-position does not occur. The first observation of lithiation at the 7-position of an indole derivative was seen with tricarbonyl(T7 -l-methyl-2-trimethylsilylindole)chromium(0) 26, even though the major site of reaction was at C-4 (Scheme 28)... 

D. Pyrroles, Indoles. Carbazoles, and Pyrazoles Lithiation in an Al-Phenyl... 

C-Metallation of indoles has, in nearly all cases, been conducted in the absence of the much more acidic iV-hydrogen i.e. the presence of an iV-substituent like methyl, or if required, a removable group phenyl-sulfonyl, lithium carboxylate and f-butoxycarbonyl have been used widely also recommended are dialkylaminomethyl, ° trimethylsilylethoxymethyl and methoxymethoxy (the Ai-substituent cannot be introduced into an indole - it requires a pre-formed 1-hydroxy-indole - but it is possible to reduce it off to leave an iV-hydrogen-indole). Each of these removable substituents assists lithiation by intramolecular chelation and in some cases by electron withdrawal, reinforcing the intrinsic tendency for metallation to proceed at the a-position. 

The saltlike alkali metal compounds of indole react with electrophiles such as haloalkanes, acyl halides, sulfonyl halides and trimethylchlorosilane to form the corresponding 1-substituted indoles. 1-Benzylindole isomerizes to 2-benzylindole when heated in polyphosphoric acid [47]. 1-Phenyl-sulfonylindole is lithiated in the 2-position by n-butyllithium. Subsequent alkylation with haloalkanes and cleavage of the phenylsulfonyl residue with sodium hydroxide yields 2-alkylindole. 

The Feldman indole synthesis describes the reaction between lithiated 7V-phenyl-p-toluenesulfonamide (1) and phenyl(propynyl)iodonium triflate (2) to form indole 3 (Scheme 1, equation 1) [1, 2], The lithiated species 1 was generated from the corresponding tosylanilide with n-butyllithium (THF, -78 °C). Applications are limited thus far to the synthesis of indoles shown in equation 2. 

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