Scalable Preparation of 1-Aminoethyl Oxindoles From Simple Benzaldehydes

Oxindoles are prevalent structures in natural products and pharmaceutically active molecules. To support structure–activity-relationship (SAR) studies in a medicinal chemistry program, we developed a straightforward and scalable synthesis route to 1-aminoethyl oxindole building blocks harboring various types of substituents. Our strategy relies on an intramolecular Buchwald–Hartwig amidation of a 2-bromophenylacetic amide precursor. The cyclization substrates can be prepared from readily available benzaldehydes by ortho-selective C(sp²)−H bromination followed by homologation to the corresponding phenylacetic acid derivatives. The process was optimized to allow for preparation of 246 g of one representative example.