SYNTHESIS OF 2,3-DISUBSTITUTED INDOLES VIA PALLADIUM-CATALYZED ANNULATION OF INTERNAL ALKYNES

The palladium-catalyzed coupling of 2-iodoaniline and the correspondin g N-methyl, -acetyl, and -tosyl derivatives with a wide variety of int ernal alkynes provides 2,3-disubstituted indoles in good-to-excellent yields. The best results are obtained by employing an excess of the al kyne and a sodium or potassium acetate or carbonate base plus 1 equiv of either LiCl or n-Bu4NCl, occasionally adding 5 mol % PPh3. The yiel ds with LiCl appear to be higher and more reproducible than those obta ined with n-Bu4NCl. The process is quite general as far as the types o f substituents which can be accommodated on the nitrogen of the anilin e and the two ends of the alkyne triple bond. The reaction is quite re gioselective, placing the aryl group of the aniline on the less steric ally hindered end of the triple bond and the nitrogen moiety on the mo re sterically hindered end. This methodology readily affords 2-silylin doles, which can be easily protodesilylated, halogenated, or reacted w ith alkenes and Pd(OAc)(2) to produce 3-substituted indoles, 2-haloind oles, or 2-(1-alkenyl)indoles, respectively. The presence of alcohol g roups in the alkyne seems to have a particularly strong directing effe ct, perhaps due to coordination with palladium. This catalytic process apparently involves arylpalladium formation, regioselective addition to the C-C triple bond of the alkyne, and subsequent intramolecular pa lladium displacement.