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

## TL;DR

This paper shows how substituents on isoxazoles can control their photoisomerization to carbonyl-2H-azirines, improving efficiency and yield.

## Contribution

The study introduces substituent-driven design to tune photoisomerization equilibria for efficient carbonyl-2H-azirine synthesis.

## Key findings

- tert-Butyl- and trifluoromethyl-substituted isoxazoles yield carbonyl-2H-azirines efficiently with minimal oxazole formation.
- Phenyl-substituted isoxazoles readily form oxazoles, preventing carbonyl-2H-azirine isolation.
- Substituent effects reduce absorption spectrum overlap, enhancing photoisomerization efficiency.

## 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.