Caffeine Alkaline Hydrolysis and in Silico Anticipation Reveal the Origin of Camellimidazoles

- Context. Camellimidazoles A–C were recently reported as new natural substances arising from what was described as new caffeine degradation pathway in Keemun black tea. - Discoveries. Under alkaline hydrolysis conditions followed by spontaneous cascade reactions with formaldehyde or dichloromethane (as the key methylene group providers), we were able to achieve the synthesis of camellimidazoles B and C. A MetWork-based pipeline was also implemented highlighting a wealth of structurally diverse compounds formed in the course of the reaction and streamlining the isolation of the newly described camellimidazoles D-F, subsequently confirmed as anticipated in silico upon extensive spectroscopic analyses. Besides demonstrating the artefactual origin of camellimidazoles, the current investigation emphasizes the fitness of MetWork-tagging to illuminate the chemical diversity associated with seemingly simple reactive conditions.- Methods. Organic synthesis, phytochemical analysis, in silico anticipation, molecular networking dereplication