Synthesis of an 8-membered oxygen-containing benzo-fused heterocycle using flow technologies – an exercise in undertaking research with sustainability as a driver

Abstract

Due to their natural abundance and biological properties, benzo-fused heterocycles are attractive targets in the field of drug discovery. Previously, a synthetic strategy for accessing 5-, 6-, 7- and 8-membered oxygen-containing benzo-fused heterocycles with the oxygen atom in the less commonly encountered 2-position was reported, however, the approach was hindered by long reaction times and a reliance on high boiling point solvents such as DMF. Targeting an 8-membered analogue as an exemplar, we highlighted that the adoption of basic green chemistry principles coupled with the use of flow chemistry techniques could be utilised (with limited development time) to improve day-to-day sustainability when performing synthetic research. In the case in hand, several key improvements were noted including (i) a higher overall yield (37% vs. 26%), (ii) a significantly reduced reaction time (110 min vs. 136 h) and (iii) the avoidance of the undesirable solvent DMF.