In Search of Simplicity and Flexibility: A Rational Access to Twelve Fluoroindolecarboxylic Acids

All twelve indolecarboxylic acids 1–12 carrying both a fluorine substituent and a carboxy group at the benzo ring have been prepared either directly from the corresponding fluoroindoles 13–16 or from the chlorinated derivatives 22, 23 and 25 by hydrogen/metal permutation (“metalation”), or from the bromo‐ or iodofluoroindoles 17–20 and 26, 27, 29 and 30 by halogen/metal permutation, the organometallic intermediate being each time trapped with carbon dioxide. In most, though not all cases, the nitrogen atom in the five‐membered ring had to be protected by a trialkylsilyl group. Some of the bromo‐ or iodofluoroindoles (26 and 27) were successfully subjected to a basicity gradient‐driven selective migration of the heavy halogen. An unexpected finding on the way to the target compounds were the rigorously site‐selective metalation of the 5‐fluoro‐N‐(trialkylsilyl)indole (14b; exclusive deprotonation of the 4‐position). The fluoroindoles 13–16, although previously known, were accessed more conveniently from suitably substituted nitrobenzenes using the Bartoli or the Leimgruber–Batcho method. A new and very attractive indole synthesis was elaborated consisting of the ortho‐lithiation of an N‐acyl‐protected aniline followed by ortho‐formylation, Wittig chloromethylenation and base‐catalyzed cyclization accompanied by dehydrochlorination. These five consecutive steps can be contracted to a convenient one‐pot protocol.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)