Synthesis of Value-Added Intermediates by Continuous Flow Technology

Abstract

We present three projects linked by our use of continuous
flow chemistry in the synthesis of organic intermediates. The first is the synthesis of 1,1'-spirobiindane-7,7'-diol (SPINOL) in 6 steps and 32% overall yield. The synthesis has been improved over the previous literature protocols
as it is safer, scalable, and higher-yielding, with better robustness and reproducibility. We introduce two attempts towards the enantioselective synthesis of SPINOL. In the second project, we have developed a flow process based on the Vapourtec reactor to synthesise coumalic acid and
methyl coumalate from malic acid in concetrated sulfuric acid. A new heated rotating flow reactor is also presented for the intensified synthesis of coumalic acid, a valuable intermediate in organic synthesis derived from biorenewable sources of malic acid. Methyl coumalate has been used in two Diels-Alder reactions where the products have applications in molecular electronics and organic light-emitting diodes. Finally, the Darzens
reaction for the synthesis of epoxides is presented here for the first time in flow, providing access to a range of benzaldehyde-derived products, including precursors to the pharmaceutical compound ibuprofen.