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.
Tønder et al. (Sun,) studied this question.