Novel one-step flow chemistry procedure for synthesizing isochromane derivatives

Abstract Continuous flow chemistry offers enhanced control, scalability, and safety in synthetic processes, driven by microstructured reactors that enable superior heat and mass transfer. Herein is presented a novel one-step synthesis of isochromanes via the oxa-Pictet–Spengler reaction, a reaction between a phenethyl alcohol and a benzaldehyde derivative, using acetonitrile and methanesulfonic acid under flow conditions. Optimization via design of experiments (DoE) identified ideal parameters (98 °C, 12.4 min residence time), achieving up to 98% conversion with minimal impurities. Substrate scope analysis confirmed that electron-donating groups on phenethyl alcohol component and electron-withdrawing groups on the benzaldehyde component significantly enhance reactivity. Furthermore, regiochemical effects of the substituents were explored, with ortho -, meta -, and para -chlorobenzaldehydes showing high conversions overall. A 24-h continuous run demonstrated scalability, yielding 14.6 g of product with 100% conversion. This flow-based approach has shown to offer a sustainable and scalable alternative to traditional batch synthesis, significantly reducing reaction time and enabling precise control over reaction parameters, making it a promising platform for synthesis of isochroman derivatives. • Optimization of reaction conditions with design of experiments. • Utilizing flow chemistry for synthesis of isochromanes. • Producing 0.6 g/h of product with a small-scale setup. • Best conditions with 98 °C in temperature and 12.4 min reaction time. • Synthesis of new isochromanes.