An overview of metal-free synthetic routes to isoxazoles: the privileged scaffold

Abstract

Isoxazole, a five-membered heterocyclic moiety commonly found in many commercially available drugs. This review article presents a comprehensive overview on metal-free synthetic routes for the synthesis of isoxazoles with significant bioactivities.

Synthesis of Spirocyclic and Fused Isoxazoline Building Blocks

“…The key 1,3‐dipolar cycloaddition of chloroximes 1 and alkenes 2 was performed upon the standard conditions, [23–25] which included the use of NaHCO 3 as the base and EtOAc as the solvent at rt. According to the literature data, at basic conditions, chloroximes are transformed into nitrile oxides that readily undergo the 1,3‐dipolar cycloaddition with alkenes or other unsaturated dipolarophiles; typically, the reaction proceeds in a regioselective manner [26–29] . A competitive dimerization of nitrile oxides into furoxan derivatives is also observed, so that a 1.15–1.2‐fold excess of chloroximes was needed in some cases to reach the complete conversion of the corresponding alkene (Scheme 2, A ).…”

“…The utility of the obtained cycloadducts was demonstrated by their transformation into various functionalized isoxazoline derivatives -valuable building blocks other unsaturated dipolarophiles; typically, the reaction proceeds in a regioselective manner. [26][27][28][29] A competitive dimerization of nitrile oxides into furoxan derivatives is also observed, so that a 1.15-1.2-fold excess of chloroximes was needed in some cases to reach the complete conversion of the corresponding alkene (Scheme 2, A).…”

Crystal structure and Hirshfeld surface analysis of 5-(5-phenyl-1,2-oxazol-3-yl)-1,3,4-thiadiazol-2-amine

“…Compounds with the five-membered isoxazole, isothiazole and 1,3,4-thiadiazole heterocycles possess high potential for biological activity and are privileged scaffolds for the development of pharmaceutical agents (Das & Chanda, 2021;Kletskov et al, 2020;Khalilullah et al, 2014;Yadigarov et al, 2009;Safavora et al, 2019;Zubkov et al, 2014). In particular, isoxazoles are able to enhance the action of 'first-line' antitumor substances, which makes it possible to reduce their therapeutic doses and thus reduce toxic side effects (Khalilov et al, 2021;Kulchitsky et al, 2012;Naghiyev et al, 2020).…”

Chiral Cyclopropenimine‐catalyzed Asymmetric Michael Addition of Bulky Glycine Imine to α,β‐Unsaturated Isoxazoles

“…Many unsaturated compounds including unsaturated aldehydes, ketones and esters, vinyl phenyl sulfones, and aromatic nitroalkenes were used as Michael acceptors. In recent years, α,β-unsaturated isoxazoles [8][9][10][11][12] have been used as new type of Michael acceptor to install heterocyclic ring in organic molecules. The compounds containing isoxazole core exhibit unique bioactivities with anticancer, [13] antimicrobial [14] and anti-inflammatory effects.…”