Synthesis of an 8-membered oxygen-containing benzo-fused heterocycle using flow technologies

Abstract

Flow chemistry has become an appealing alternative synthetic technology globally over the last few decades finding application in both academic and industrial laboratories driven largely by the fact that it commonly provides higher selectivity, yield and purity compared to batch chemistry that has become time-consuming, ineffective, and challenging to scale up. This dissertation describes the application and development of a flow process towards the synthesis of an 8-membered oxygen-containing benzo-fused heterocycle. The synthesis consisted of six stages that included two allylation steps, a Claisen rearrangement, an alcohol protection, an aldehyde reduction and a ring-closing metathesis step. The target molecule, (Z)-7-isopropoxy-8-methoxy-3,6-dihydro-1H-benzo[c]oxocine 25, was selected with an interest in developing an improved approach to accessing the scaffold for future structure-activity relationship screening and demonstrating that modern process technologies like flow can also be used routinely to perform fundamental research in a more sustainable and responsible manner. In summary, all six steps were successfully translated into flow and improved yields were shown with the use of greener solvents and operating at unconventionally high temperature and pressures especially when considering the Claisen rearrangement step. Design of experiment was also used in the last two stages which included i) the second allylation which required a strong base such as sodium hydride and was used as a slurry pumping through peristaltic pumps, and ii) the final ring closing metathesis stage in which two ruthenium-based catalysts were investigated with the use of a greener solvent. It was found that the flow approach yielded an overall percentage yield of 37.7 % in 105 minutes, compared to the batch approach that yielded an overall percentage yield of 0.77 % in 154 hours.