Abstract

Due to the potent biological activity exhibited by various indole derivatives, there is a continuous demand for novel synthetic procedures in this area. In 1989, the reaction of vinyl magnesium halides with ortho-substituted nitroarenes was discovered to lead to indoles. In the 1990s, it has attracted much attention, as it employs simple and readily available starting materials. This reaction is now frequently reported as the “Bartoli reaction” or the “Bartoli indole synthesis” and has rapidly become the shortest and most flexible route to 7-substituted indoles, as classical indole syntheses generally fail in their preparation. The flexibility of Bartoli reaction is great as it can be extended to heteroaromatic nitro derivatives and can be run on solid support. The necessity of an ortho-substituent on the aromatic ring is the limit of the Bartoli indole synthesis, because o,o- unsubstituted nitroarenes follow a completely different pathway when reacting with vinyl Grignard reagents. Bromine, however, should be a transient group, which can enforce the sigmatropic rearrangement, as requested by the mechanism, and is easily removed. A combination of the two methodologies can give a significant reduction of steps required for the preparation of many complex 7-unsubstituted indoles, whose functions are tolerant to the reaction conditions, but not to classical indole syntheses. This review will focus both the use of the Bartoli indole synthesis as key step in many preparation of complex indoles and the improvements of the reaction.

Keywords: indole chemistry, nucleophilic reagents, nitroarenes, single electron transfer, synthesis, reductive cyclization