Continuous Flow Inter- and Intramolecular Macrolactonization under High Dilution Conditions.

An efficient continuous flow process for the macrolactonization of seco acids and diacids using diols in the presence of Mukaiyama reagent ( N -methyl-2-chloropyridinium iodide) has been developed for medium to large sized macrocyclic lactones. In comparison with other methods, the continuous flow process provided good to high yield in a short reaction time. By using this methodology, a wide range of macrocyclic lactones (11 compounds), dilactones (15 compounds), and tetralactone derivatives (2 compounds) with various ring sizes (12-26 atoms in the core) were synthesized in just 35 min of residence time. Advantageously, macrolactonization under the flow process is very elegant to handle the high dilution of reactants with a defined perfluoroalkoxy alkanes (PFA) tube reactor volume (7 mL).