Synthetic Approaches to Nitro-Substituted Isoxazoles

Abstract

Nitro-substituted isoxazoles are of utmost interest both as versatile intermediates for targeted organic synthesis and as perspective bioactive compounds for drug development. Nevertheless, the existing approaches to them usually lack generality and strongly depend on the position of the nitro group and on the presence of other substituents in the isoxazole ring. This review provides the first systematization of all available data concerning synthetic approaches to 3-, 4-, and 5-nitroisoxazoles. There are a number of preparative approaches to 4-nitroisoxazoles based on classical heterocyclization reactions of nitro-substituted compounds and the nitration of isoxazoles. 3-Nitro- and, especially, 5-nitroisoxazoles are much less readily available. A few methods affording 3-nitroisoxazoles have been reported, often employing the heterocyclization of unsaturated compounds by treatment with sodium nitrite. The sole general preparative method for 5-nitroisoxazoles, containing a variety of functional groups, employs the heterocyclization of electrophilic alkenes by treatment with tetranitromethane activated with triethylamine.1 Introduction2 Synthesis of 4-Nitroisoxazoles2.1 Nitration of Isoxazoles2.2 Condensations of α-Nitro Ketones or Their Oximes2.3 1,3-Dipolar Cycloaddition of Nitrile Oxides to Acetylenes and Their Synthetic Equivalents2.4 Heterocyclization of Acetylene Derivatives by Treatment with Sodium Nitrite2.5 Heterocyclization of Nitro Derivatives of 1,3-Diketones and Their Synthetic Equivalents2.6 Miscellaneous Methods3 Synthesis of 3-Nitroisoxazoles3.1 Heterocyclization of Acetylene Derivatives or 1,3-Dihalogenoalkenes by Treatment with Sodium Nitrite3.2 Heterocyclization of Morita–Baylis–Hillman Acetates by Treatment with Sodium Nitrite3.3 1,3-Dipolar Cycloadditions4 Synthesis of 5-Nitroisoxazoles4.1 1,3-Dipolar Cycloadditions4.2 Synthesis Using Polynitro Compounds5 Conclusion

A Facile Approach to Bis(isoxazoles), Promising Ligands of the AMPA Receptor

“…In particular, the structures containing the phenylene-based linkers and aminoisoxazole moieties were identified among the most promising potential PAMs. Recently, we have elaborated a novel preparative method for the synthesis of 3-EWG-5-nitroisoxazoles, based on the heterocyclization of electrophilic alkenes via treatment with the tetranitromethane-triethylamine (TNM-TEA) complex [36][37][38][39]. Until now, this method has been used to produce polysubstituted isoxazoles containing one heterocyclic fragment in a molecule.…”

5-Nitroisoxazoles in SNAr Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors

“…There are two main approaches to isoxazole ring formation consisting in (1) heterocyclization of 1,3-dielectrophiles, such as 1,3-diketones, 1,3-ketoesters, 1,3-ketoenamines, α,β-unsaturated ketones and others, under the treatment with hydroxylamine or (2) in reactions of 1,3-dipolar cycloaddition of nitrile oxides to acetylenes (or the reactions of their synthetic equivalents) [24][25][26][27][28][29][30]. However, both methods are not completely chemo-and regioselective, and many efforts have been devoted to improvement of their selectivity [31][32][33][34][35][36]. The direct functionalization of the isoxazole ring also has peculiar features and limitations.…”

Development of Nitrolactonization Mediated by Iron(III) Nitrate Nonahydrate

“…12,13) Nitrones and nitrile oxides generated from nitro compounds undergo 1,3-dipole cycloaddition reaction to give various heterocycles. [14][15][16] The nitro group can be converted into a carbonyl or amino group through the Nef reaction 17,18) or reduction, respectively. 19) For these reasons, nitro compounds are heavily used as versatile starting materials in the synthesis of natural products and drugs.…”