Expanding the Synthetic Utility of Thermal Reactions: Catalyst-Free Access to Bioactive Scaffolds in a GC-MS Microreactor

Traditional pyrone syntheses often rely on catalysts and harsh reaction conditions, raising concerns about sustainability and scalability. Herein, we present a novel, catalyst-free method for pyrone formation that utilizes gas chromatography–mass spectrometry (GC–MS) as both a reaction platform and analytical tool. Thermally induced aldol condensation of methyl, ethyl, propyl,isopropyl, and tert-butyl acetoacetates within a heated GC inlet yielded diverse pyrone derivatives, including 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one,propyl 4,6-dimethyl2-oxo-2H-pyran-5-carboxylate, isopropyl 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylate, and 4,6- dimethyl-2-oxo-2H-pyran-5-carboxylate, alongside 2,4,6-heptanetrione as a minor byproduct. This gas-phase method expands the utility of thermal reactions in organic synthesis, offering a sustainable route to pyrones, key scaffolds in medicinal chemistry and materials science. Further extending this approach, we demonstrate the gas-phase synthesis of three structurally distinct carbonyl architectures from a binary mixture of ethyl acetoacetate and ethyl 2- oxocyclopentanecarboxylate at an inlet temperature of 360 °C. The resulting compounds—6- acetyl-7-hydroxy-4H-chromen-5-one (a coumarin derivative), 8-methyl-7-oxaspiro[4.5]dec-8- ene-1,6,10-trione (a spirocyclic trione), and 1-(2-oxocyclopentyl)-1,3-butanedione (a β-diketone) were formed via spontaneous aldol condensation pathways and confirmed by mass spectrometric analysis. These results highlight the GC mass spectrometer as a dual-function microreactor and detection system, enabling rapid (less than a second), solvent-free synthesis of heteroaryl, spirocyclic, and diketone compounds.