Abhijit Nandy, Shibdas Banerjee
Sprayed water microdroplets often enable reaction pathways that remain inaccessible in a bulk solution. Here, we uncover a unique alchemy of aqueous microdroplets that drives the in-flight metamorphosis of indole without the need for external catalysts. When aqueous indole solutions mixed with ammonia or primary amines were aerosolized, nitrogen insertion occurred into the five-membered pyrrole ring of indole, yielding quinazolinone pharmacophores─scaffolds of significant medicinal importance. Mechanistic insights obtained through mass spectrometry, isotope-labeling experiments, and the detection of reactive intermediates revealed that reactive oxygen species, generated in situ at the air-water interface, play a pivotal role in promoting this oxidative transformation at the droplet surface. Considering the broad therapeutic relevance of quinazolinone derivatives as anticancer, antimicrobial, and CNS-active agents, this simple microdroplet-based strategy for constructing such scaffolds offers a promising new avenue for medicinal chemistry.