Multigram Synthesis of Trioxanes Enabled by a Supercritical CO₂ Integrated Flow Process

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