Isoxazol-5-ones as Strategic Building Blocks in Organic Synthesis

Abstract

Isoxazol-5-one rings have been identified as relevant motifs in drug candidates, agrochemicals, and materials. Furthermore, this heterocycle has been also applied as a versatile building block for the preparation of a variety of densely functionalized molecules. This short review will present the most representative applications of isoxazol-5-ones in organic synthesis while discussing their properties and reactivity.1 Introduction1.1 General Aspects1.1.1 Tautomerism1.1.2 Importance: Natural Products Isolation, Biological Activity, and Materials1.1.3 Preparation Methods2 Isoxazol-5-ones in Organic Synthesis2.1 General Reactivity2.2 Specific Examples2.2.1 Alkylation Strategies2.2.2 Alkyne Synthesis2.2.3 Annulation Reactions2.2.4 N–O Bond Insertions2.2.4.1 Preparation of 1,3-Oxazin-6-ones3 Conclusions

On the Necessity of One‐Pot Tautomer Trapping in Asymmetric Michael Reactions of Arylideneisoxazol‐5‐ones

“…Isoxazol‐5‐ones are important five member heterocycles. They have been found in a variety of natural sources showing a range of biological activities , . Therefore, an increasing number of synthetic biologically active compounds have been reported in recent years (Figure ) .…”

“…In addition, several isoxazol‐5‐one based materials with useful optical properties have been developed (Figure ) . Isoxazol‐5‐ones are also versatile intermediates in the synthesis of diverse heterocycles, alkyne acyclic compounds or α,α‐difunctionalized‐β‐amino acids, exploiting rearrangement reactions, nitrosative cleavage of N–O bond, decarboxylations and hydrogenation reactions , . The main synthetic route for the preparation of isoxazol‐5‐ones is typically based on reactions of hydroxylamine with β‐ketoesters , .…”

“…Isoxazol‐5‐ones are also versatile intermediates in the synthesis of diverse heterocycles, alkyne acyclic compounds or α,α‐difunctionalized‐β‐amino acids, exploiting rearrangement reactions, nitrosative cleavage of N–O bond, decarboxylations and hydrogenation reactions , . The main synthetic route for the preparation of isoxazol‐5‐ones is typically based on reactions of hydroxylamine with β‐ketoesters , . Then, the obtained heterocycles are subjected to further functionalization due to the reactivity of the methylene group as for example in the preparation of arylideneisoxazol‐5‐ones via Knoevenagel condensations , .…”

“…The main synthetic route for the preparation of isoxazol‐5‐ones is typically based on reactions of hydroxylamine with β‐ketoesters , . Then, the obtained heterocycles are subjected to further functionalization due to the reactivity of the methylene group as for example in the preparation of arylideneisoxazol‐5‐ones via Knoevenagel condensations , . To this regard, several one‐pot methodologies have been developed, even though the two‐step synthesis remains the most widely used and reliable procedure …”

“…Despite the possibility to allow the access to a wide range of functionalized isoxazol‐5‐ones, very few Michael reactions of alkylideneisoxazol‐5‐ones have been described , , . As disclosed in the seminal works reported by Jurberg, three tautomeric forms, known as “imine‐like” CH‐form, as “enamine‐like” NH‐form and as “enol‐like” OH form (Scheme ), characterize isoxazol‐5‐ones chemistry …”