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

Document Type

Journal Article

Role

Author

Journal Title

ACS Organic & Inorganic Au

Publication Date

12-1-2025

Abstract

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.

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