Continuous-flow synthesis of prenyl chloride on-demand through surface-mediated hydrochlorination

1-Chloro-3-methyl-2-butene is an important synthetic precursor or alkylating agent in the preparation of various bioactive chemicals and essential nutrients for human beings. A flow surface-mediated HCl in situ generation and subsequent hydrochlorination of isoprene were realized in the PTFE tubing reactor and the packed-bed reactor separately. Up to 86% isolated yield of 1-chloro-3-methyl-2-butene was achieved in the packed-bed reactor by performing the flow hydrochlorination at -15 °C within a 15 min residence time in the presence of 0.5 equiv. SOCl 2 . The in-line recycling and regenerating of solid proton donor Al 2 O 3 were accomplished via simple washing with DCM and MeOH in sequence, the activity of Al 2 O 3 filled in the packed-bed reactor maintain consistent on the isolated yield of 1-chloro-3-methyl-2-butene after ten times consecutive reutilization. The flow platform consisting of two parallel packed-bed reactors were assembled for the continuous synthesis of desired 1-chloro-3-methyl-2-butene without interruption through delicate coordinating opening direction of a series of three-way valves. Long-term stability and reliability were demonstrated by continuous running the designed cyclic rotation system for 10 h, the targeted hydrochlorination product was furnished in 91–93% yield. Graphical abstract Continuous-flow synthesis of prenyl chloride was enabled by cross-sequential utilization strategy using two parallel packed-bed reactors and precise alternating a series of three-way valves opening direction.