Ruthenium‐Catalyzed Cycloaddition of Nitrile Oxides and Alkynes: Practical Synthesis of Isoxazoles

Abstract

3,4‐Disubstituted and 3,4,5‐trisubstituted isoxazoles have been formed from alkynes and nitrile oxides in a ruthenium(II)‐catalyzed process (see scheme; cod=cycloocta‐l,5‐diene, Cp*=C5Me5). These reactions are experimentally simple, proceed at room temperature, and produce isoxazoles with excellent regioselectivity in high yield.

Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents

“…41 Conversely, in the case of cyclopentadienyl ruthenium derivatives, 42 the regioselective formation of the related 4,5-disubstituted heterocycles was observed. It should be pointed out that for many applications the use of toxic transition metals is undesirable, if not prohibited.…”

Synthesis of novel 1,2,4-trizaole- and isoxazol(in)e-containing heterocycles

“…12 On the other hand, 3,4-disubstituted isoxazoles are formed as the major regioisomers in ruthenium(II)-catalyzed 1,3-dipolar cycloadditions. 13 In our synthesis, even without the aforementioned Cu(I) catalyst, 3,5-disubstituted regioisomers were observed exclusively. The connectivity of compound 16 was confirmed via X-ray crystallography (Fig.…”

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

“…We have also proposed that nitrile oxides coordinate in similar fashion via their carbon atom. [2] To explain the regioselectivity trends observed in the current study, we propose a similar sequence of key interactions and events: organic azide acts as a terminal electrophile, wherein its N3 nitrogen is attacked by the nucleophilic C2 of the alkyne component in the first covalent bond-forming step, producing Ru_intT . Similarly, we propose that C2–O bond formation occurs between the π-coordinated haloalkyne and the σ-coordinated (through carbon) nitrile oxide, likewise producing Ru_intI , which showcases the “umpolung” reactivity of nitrile oxide upon its coordination to the ruthenium catalyst.…”

“…Pentamethylcyclopentadienyl ruthenium(II) chloride, [Cp*RuCl], based catalysts were introduced in 2005 as an effective and easy means for regioselective preparation of 1,5-disubstituted 1,2,3-triazoles [1] as well as 3,4-disubstituted isoxazoles [2] from terminal alkynes and organic azides (RuAAC; ruthenium catalyzed azide alkyne cycloaddition) or nitrile oxides, respectively. RuAAC had an immediate impact on organic chemistry and related fields, [3] in that the substitution pattern of the resulting product was, and is a perfect complement to triazoles obtained by way of the well-known copper catalyzed (CuAAC), ‘click’ reaction, [4] i.e.…”