Synthesis and Reactivity of 3‐Halo‐4,5‐dihydroisoxazoles: An Overview

Abstract

The 3‐halo‐4,5‐dihydroisoxazole moiety is an interesting emerging feature in medicinal and organic chemistry fields. The properties of this nucleus are intimately correlated with the nature of the halogen substituent, ranging from inertness to instability. In between, the 3‐bromo‐Δ2‐isoxazoline scaffold stands out as a handleable and easily affordable electrophilic warhead, able to react with nucleophilic active sites of different enzymes, determining inhibitory effects. However, the importance of 3‐bromo‐Δ2‐isoxazolines does not rely only upon their biological activity. In fact, they are valuable synthetic intermediates, presenting a peculiar reactivity spectrum that allows access to useful chemical functions, ranging from variously decorated dihydroisoxazoles to β‐hydroxynitriles, β‐hydroxyesters, and γ‐hydroxyamines. The synthesis of 3‐bromo‐Δ2‐isoxazolines is predominantly based on the 1,3‐dipolar cycloaddition, a pericyclic reaction accompanied by a remarkable regio‐ and stereo‐selectivity. Thus, this intermediate lends itself especially well to the production of complex molecules with regio‐ and stereo‐chemical requirements.

Energetic Aspects and Molecular Mechanism of 3-Nitro-substituted 2-Isoxazolines Formation via Nitrile N-Oxide [3+2] Cycloaddition: An MEDT Computational Study

“…This study does not, however, conduct a systematic exploration of the main problem. It should be noted that at this point the synthesis and properties of other, simply substituted nitrile N-oxides are understood substantially better (F [44,45], Cl [46][47][48], Br [49][50][51], and CN [52][53][54]).…”

Synthesis of 3‐Haloisoxazolines by Deoxygenation of 3‐Haloisoxazoline N‐Oxides under Treatment with Acetyl Bromide

“…[3] In addition to medicinal application, 3haloisoxazolines serve as useful intermediates in the synthesis of more complex targets. [4] Thus, substitution reactions (including some cross-couplings) were demonstrated to lead to various 3-substituted isoxazolines, [5] including the use in total synthesis. [6] The prevalent synthetic strategy toward 3-haloisoxazolines, that was used for the preparation of aforementioned acivicin analogues, is based on the [3 + 2]-cycloaddition of halonitrile oxides (Scheme 1).…”

“…[6] The prevalent synthetic strategy toward 3-haloisoxazolines, that was used for the preparation of aforementioned acivicin analogues, is based on the [3 + 2]-cycloaddition of halonitrile oxides (Scheme 1). [4] Several limitations of such approach can be outlined. The first one is associated with the nature of starting materials, namely nitrile oxides.…”

“…Thus, acivicin analogues, including 3‐chloro and 3‐bromo substituted isoxazolines are studied for antitumor and other bioactivities [3] . In addition to medicinal application, 3‐haloisoxazolines serve as useful intermediates in the synthesis of more complex targets [4] . Thus, substitution reactions (including some cross‐couplings) were demonstrated to lead to various 3‐substituted isoxazolines, [5] including the use in total synthesis [6] …”