Substituent Effects Govern the Efficiency of Isoxazole Photoisomerization to Carbonyl‑2H‑Azirines

The photoisomerization of isoxazoles is an atom-economical route to carbonyl-2H-azirines, which are valuable in both synthetic and biological applications. However, isolation of the carbonyl-2H-azirine is challenged by reverse photoisomerization back to the isoxazole and irreversible rearrangement to an oxazole. In this work, we demonstrate that substituent selection on 3,5-disubstituted isoxazoles plays a critical role in driving the photochemical isoxazole-azirine equilibrium toward the carbonyl-2H-azirine while avoiding oxazole formation. We find that substituents affect the degree of overlap in the absorption spectra of isoxazole-azirine pairs, where reducing overlap increases the efficiency of photoisomerization. We use time-dependent density functional theory to predict absorption spectra for isomer pairs with varied 3,5-disubstituents, identifying tert-butyl- and trifluoromethyl-substituted 5-aminoisoxazoles as promising structures. We then tested these predictions experimentally, revealing efficient formation of carbonyl-2H-azirines in high yields with minimal oxazole formation. This is in contrast to a phenyl-substituted 5-aminoisoxazole, which was found to readily form oxazoles, precluding isolation of the carbonyl-2H-azirine. These results demonstrate the utility of substituent-driven design for tuning photoisomerization equilibria and provide an atom-economical option for generating carbonyl-2H-azirines on synthetically useful scales.