Integrated Multistep Photochemical and Thermal Continuous Flow Reactions: Production of Bicyclic Lactones with Kilogram Productivity

Combining continuous photochemistry and flow reactions in high-temperature/high-pressure water has enabled us to integrate a multistep sequence into a single process with a reduction in reaction time to <10 min compared to >24 h in batch. At the same time, applying this approach to different substrates has allowed us to increase previously low yields to levels high enough to make these reactions potentially useful for multistage synthesis. In this paper, we describe the [2 + 2] cycloaddition/fragmentation of 3,4,5,6-tetrahydrophthalic anhydride and propargyl alcohol and analogous compounds leading to bicyclic lactones to demonstrate how photochemistry and thermal chemistry can be combined using continuous flow techniques to create complex structures on a relatively large scale. We show how photochemical and high-temperature water flow reactors can be used to carry out a three-step reaction sequence as a single integrated and continuous process. The reaction time has been reduced by exploiting the enhanced acidity of high-temperature water/acetonitrile mixtures. The overall process is demonstrated on an equivalent productivity of a >1 kg/day productivity using lab-scale equipment. Our approach should be simple to scale up in an appropriate facility, for larger scale production of chemicals. Process analytical technology and modeling were used to support the reaction development, while UV and IR time-resolved spectroscopies have been used to provide a deeper understanding of the reaction mechanism.

Automated summary

The integration of continuous photochemistry and flow reactions in high-temperature/high-pressure water has allowed for the consolidation of multistep reactions into a single process, reducing reaction time and increasing yields for potential use in multistage synthesis. This approach demonstrates the capability to create complex structures on a large scale through the combination of photochemistry and thermal chemistry in a continuous flow system. The use of high-temperature water/acetonitrile mixtures has also been shown to reduce reaction time and enhance productivity, with the possibility of scaling up for larger production facilities.