Multigram Synthesis of Trioxanes Enabled by a Supercritical CO₂Integrated Flow Process

Photochemical synthesis of highly reactive hydroperoxides and their conversion into useful products, such as 1,2,4-trioxanes, are of wide interest for synthetic organic chemistry and pharmaceutical manufacturing particularly because of their relevance as potential antimalarial and anticancer treatment drugs, for example, Artemisinin. One class of antimalarial drugs is based on 1,2,4-trioxane scaffolds although production of such compounds on a gram scale is challenging due to their instability in oxidizable solvents. Furthermore, current methods employ either solid oxidants, which make continuous processing problematic, or molecular oxygen, requiring long reaction times of up to 48 h. Here, we report a new multigram continuous approach using a custom-built high-pressure sapphire photoreactor to synthesize trioxanes via the dearomatization of para-substituted phenols by photogenerated singlet oxygen in supercritical CO2. CO2 also facilitates mixing with O2 and has lower viscosity, thereby improving penetration into the pores of the solid acid catalyst used for the formation of trioxanes. We show the capabilities of a 5.2 mL reactor to scale up the reaction to 67 g/day. This synthetic approach provides a platform to rapidly access high-value compounds under flow conditions, with high atom efficiencies, excellent yields, short reaction times, and without the need for isolation of hazardous intermediates.