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 the reverse photoisomerization back to isoxazole and an 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 towards 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-amino-isoxazoles as promising structures. We then test 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-amino-isoxazole, 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.