Scaffold preparation and parallel synthesis of arrays of 5,6,7,8-tetrahydropyrrolo-azepinones in the solution phase

An efficient synthesis of a pyrrolo-azepine scaffold for the parallel preparation of an array of (oxo-pyrrolo-azepinyl)acetamides is described. The Stetter cyclisation of 1,3-cyclohexanedione with ethyl bromopyruvate was the key reaction in the assembly of a tetrahydrobenzofuran substrate which was submitted to a rapid transformation into a tetrahydroindole by microwave-assisted cyclocondensation in the presence of glycine. The carbonyl group was then stereoselectively transformed into the corresponding (Z)-oxime which gave the pyrrolo-azepinone by Beckmann rearrangement in the presence of polyphosphoric acid. Trimethylalumimum-mediated amidation gave the corresponding amides which were finally N-alkylated at the 5-position to give 52 diverse (pyrrolo-azepinyl)acetamides, showing an appreciable exploration of the chemical space around the central heterocyclic core. ((c) Wiley-VCH Verlag GmbH & Co. KGdA, 69451 Weinheim, Germany, 2008).