1,3‐Dipolar cycloaddition synthesis of 3‐bromo‐5‐substituted isoxazoles, useful intermediates for the preparation of pharmacologically active compounds

Abstract

Bromonitrile oxide 2, generated from easily available dibromoformaldoxime 1, reacts with monosubstituted acetylenic derivatives 4 to give 3‐bromo‐5‐substituted isoxazoles 5 in high yield. The experimental conditions necessary to overcome difficulties such as the low reactivity of acetylenic dipolarophiles and the high tendency to dimerization of bromonitrile oxide 2, are discussed; the regioselectivity of this 1,3‐dipolar cycloaddition is also studied. The obtained improvements in the synthesis of some pharmacologically active compounds are reported.

Base Induced Chemical Conversion of 3-Carbamoyl-2-isoxazolines

“…This experimental fact prompted us to conduct the similar reaction by using bicyclic isoxazoline derived from 2,3-dihydrofuran. As a result of the similar aromatization, 3,4-difunctionalized isoxazole was formed in 23% yield, in which the fused tetrahydrofuran ring of remained as a b-hydroxyethyl group at the 4-position [19][20][21] (…”

Structure−Activity Studies of 6-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 2. Effects of Distal Acid Bioisosteric Substitution, Absolute Stereochemical Preferences, and in Vivo Activity

“…In order to prepare amino acids substituted with an isoxazole, as is found in AMPA, we required the novel isoxazole substituted Horner−Emmons reagent 44 (Scheme ). Conversion of 3-bromo-5-(hydroxymethyl)isoxazole ( 39 , which was contaminated with about 10% of 3-bromo-4-(hydroxymethyl)isoxazole; this was removed upon purification of 42 ) to the corresponding 3-methoxy compound 42 was achieved only when the alcohol was first oxidzed to the corresponding acid 40 …”

Ruthenium‐Catalyzed Cycloadditions of 1‐Haloalkynes with Nitrile Oxides and Organic Azides: Synthesis of 4‐Haloisoxazoles and 5‐Halotriazoles

“…[27] The 1,3-dipolar cycloaddition between terminal alkynes and bromonitrile oxides is a means to provide 3-haloisoxazoles in good yield with high regioselectivity. [28] However, examples of high yielding reactions involving 1-haloalkynes and nitrile oxides remain remarkably scarce. [29] For example, thermal cycloadditions of nitrile oxides and 1-haloalkynes often either require alkynes substituted with highly activated hypervalent iodine species [30] or a large excess of one of the reactants [29c] and/or controlled addition of the nitrile oxide component.…”

“…Some of these limitation have been addressed using electrophilic cyclization of 2‐alkyn‐1‐one O ‐methyl oximes, which provides 4‐substituted isoxazoles containing halides and selenium functional groups 27. The 1,3‐dipolar cycloaddition between terminal alkynes and bromonitrile oxides is a means to provide 3‐haloisoxazoles in good yield with high regioselectivity 28. However, examples of high‐yielding reactions involving 1‐haloalkynes and nitrile oxides remain remarkably scarce 29.…”