Synthesis of new isoxazolidin-5-ones using KaMC reaction – useful method for preparing isoxazolidinyl 1,2,3-triazoles

Isoxazolidines play a very important role in organic chemistry as constituents of biologically interesting compounds or as valuable intermediates in many synthetic routes.[1] Among them, isoxazolidinyl 1,2,3-triazoles represent an important group of heterocyclic compounds, which have been found to be promising drug candidates in pharmacological research.[2],[3]

Recently, we have achieved the first entry into the synthesis of novel types of isoxazolidinyl 1,2,3-triazoles with an isoxazolidine ring hydroxylated at C-4 carbon atom.[4] In this presentation, we wish to report a new synthetic approach towards such modified triazoles bearing the biologically important hydroxymethyl group attached at C-3.

The synthesis is based on a well-known method of multicomponent Knoevenagel-aza-Michael cyclocondensation (KaMC) reaction between aldehydes, Meldrum's acid, and N-carbamate hydroxylamines leading to isoxazolidin-5-ones.[5]

The key intermediates, 4,5-unsubstituted 2,3-dihydroisoxazoles, have been prepared according to the procedure based on the elimination reaction of the 5-hydroxyisoxazolidines readily synthesized by reduction of the corresponding isoxazolidin-5-ones with Super-Hydride. Epoxidation reactions of 2,3-dihydroisoxazoles with 3,3-dimethyldioxirane (DMDO) yielded novel isoxazolidinyl epoxides, which were subjected to regiospecific epoxide ring opening reactions with thionyl bromide and lithium chloride providing 5-haloisoxazolidin-4-ols, respectively. Model 5-chloroisoxazolidine was subsequently used in nucleophilic substitution reaction with sodium azide to obtain the corresponding 5-azidoisoxazolidine. Finally, the triazole scaffold was prepared applying the 1,3-dipolar cycloaddition of 5-azidoisoxazolidine with phenylacetylene.