Chemoselective Gas-Phase Interception of a Transient Acyl-Ketene Using a GC–MS Injection-Port Microreactor

The thermal decomposition of β-keto esters in the gas phase provides a versatile route to structurally complex heterocycles; however, the high reactivity of the proposed intermediates has historically precluded their direct observation. Building on our previous report describing pyrone formation via dealkylation–decarboxylation pathways, we now demonstrate the first direct interception of transient acyl-ketene intermediates using an in-port GC–MS microreactor strategy. By employing the heated GC injection port as a solvent-free reaction chamber, methyl acetoacetate was reacted with secondary amine nucleophiles—morpholine and thiomorpholine—to trap reactive intermediates prior to cyclization. 

Formation of the 4-acetylmorpholine adduct was confirmed by a 96% NIST library match corresponding to m/z 171. Mechanistic support for ketene trapping was further strengthened using thiomorpholine, where the observed molecular ion at m/z 187 displayed the characteristic sulfur isotopic pattern (M+2 at m/z 189), providing internal elemental verification. The trapping strategy was successfully extended to aniline and 2-pyrrolidinone, affording the corresponding acylated derivatives of the intercepted intermediate. Although enamine formation dominates under certain nucleophilic conditions (morpholine and thiomorpholine), complete selectivity for the acylated intermediate was observed with aniline and 2-pyrrolidinone. 

These findings demonstrate the power of reactive chromatography as a tool for capturing and characterizing otherwise elusive gas-phase intermediates.