Claisen isoxazole synthesis

What is Claisen isoxazole synthesis?

In 1881, Claisen reported the formation of 3-hydroxyisoxazoles through the cyclization of β-keto esters and hydroxylamine. The reaction is kown as the Claisen isoxazole synthesis. The presence of R1 and R2 substituents in the β-keto ester allows for the addition of substituents in the 4- and 5-position of the heterocyclic ring.

Claisen isoxazole synthesis
Claisen isoxazole synthesis

Hydroxylamine can condense with β-keto esters in two possible directions, leading to the formation of either isoxazolin-3-ones (which mostly exist as 3-hydroxyisoxazoles) or isoxazolin-5-ones. Thus, Isoxazolin-5-ones were the products derived from 2-unsubstituted β-keto esters. However, 2-substituted analogues produced 3-hydroxyisoxazoles, and both types of products could be obtained from either type of keto ester, depending on the specific pH conditions during the reaction workup.

Claisen isoxazole synthesis - general reaction scheme - 5-isoxazolone formation
Claisen isoxazole synthesis (5-isoxazolone formation)

When ethyl acetoacetate (1, with R1 = Me, R2 = H, and R3 = Et) (see list of acronyms) was subjected to hydroxylamine at pH 6.5-8.5 (buffered), a carbinolamine intermediate (4) was formed, which then dehydrated to generate syn and anti oximes. The syn isomer (5) cyclized to form 3 within minutes, whereas the conversion of the anti form required several hours.

Claisen isoxazole synthesis - general reaction scheme - 3-isoxazolol formation
Claisen isoxazole synthesis (3-isoxazolol formation)

The impact of reaction pH on the ring closure direction of a variety of β-keto esters, including both 2-unsubstituted and 2-substituted compounds, was studied, and it was found that the yield of 3-hydroxyisoxazole was highest at pH 10.0. It was also determined that the formation of 3-hydroxyisoxazole 2 occurred through open chain hydroxamic acid 6, which exists in a dynamic equilibrium with 7. Subsequently, under highly acidic conditions, the 5-hydroxy-3-isoxazolidinone intermediate 8 was dehydrated to form 2.