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

Howie, Rowena A.; Elliott, Luke D.; Kayal, Surajit; Sun, Xue Zhong; Hanson-Heine, Magnus W.D.; Hunter, Jonathan; Clark, Charlotte A.; Love, Ashley; Wiseall, Christopher; Lee, Darren S.; Poliakoff, Martyn; Booker Milburn, Kevin I.; George, Michael W.

Abstract

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.

Citation

Howie, R. A., Elliott, L. D., Kayal, S., Sun, X. Z., Hanson-Heine, M. W., Hunter, J., Clark, C. A., Love, A., Wiseall, C., Lee, D. S., Poliakoff, M., Booker Milburn, K. I., & George, M. W. (2021). Integrated Multistep Photochemical and Thermal Continuous Flow Reactions: Production of Bicyclic Lactones with Kilogram Productivity. Organic Process Research and Development, 25(9), 2052-2059. https://doi.org/10.1021/acs.oprd.1c00089

• Journal Article Type: Review
• Acceptance Date: Aug 5, 2021
• Online Publication Date: Sep 8, 2021
• Publication Date: Sep 17, 2021
• Deposit Date: Nov 2, 2021
• Publicly Available Date: Sep 9, 2022
• Journal: Organic Process Research and Development
• Print ISSN: 1083-6160
• Electronic ISSN: 1520-586X
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 9
• Pages: 2052-2059
• DOI: https://doi.org/10.1021/acs.oprd.1c00089
• Keywords: Organic Chemistry; Physical and Theoretical Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/6607207
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.oprd.1c00089
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Process Research and Development, copyright© American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.oprd.1c00089