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. Trimethylaluminium‐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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)