Isoxazoles and Isoxazolines

The remarkable regioselectivity of this cycloaddition reaction was further studied and explained by Emamian using computational methods (15JFC165). 

---

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

Trifluoroacetonitrile oxide has been used in the synthesis of trifluoro-methyl isoxazoles and isoxazolines (84BCJ2184 86BCJ2631). In the presence of a base it dimerizes to a dioxadiazine (84JOC919). 

A promising combination of sequential multicomponent Ugi reaction and INOC has been carried out for the preparation of fused isoxazoles and isoxazolines (413). The coupling of these two reactions (Scheme 1.38) provide access to the heterocyclic ring systems in two steps, from easily available starting materials (e.g., R = Ph, R/=PhCH2), in moderate to good overall yields (the yields of Ugi reaction products 354 were 50%-70%, those of the INOC products 355 were 27%-64%). 

Akritopoulou Zanze I, Gracias V, Moore ID, Djuric SW (2004) Synthesis of novel fused isoxazoles and isoxazolines by sequential Ugi/INOC reactions. Tetrahedron Lett 45 3421-3423... 

The introduction of a phenyl group in isoxazole and isoxazoline has the same enthalpic change and equation 45 is thermoneutral, and so the enthalpy of formation of phenylisox-azoline is 116 kJmol . ... 

Dipolar cycloaddition of nitrile oxides to olefins and acetylenes is among the most widely exploited synthetic routes towards isoxazoles and isoxazolines. It is well-known that microwave irradiation in cycloaddition reactions considerably reduces reaction times. Indeed, the use of dielectric heating (microwave-heated reactions were performed in a flask with a reflux condenser mounted outside the apparatus) allowed for a remarkable reduction of the cycloaddition reaction time from 6-12 hours to merely 3 minutes [69]. Simple aqueous workup provided the target isoxazoles and isoxazolines. The requisite nitrile oxides for the cycloaddition reaction were generated in situ from the corresponding nitroalkanes, 4-(4,6-dimethoxy [1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 4-dimethylaminopyridine (DMAP) (Scheme 22). 

The generation from furoxans of other heterocyclic systems, some of which show useful biological activity (see Section 4.22.5), has been the subject of intensive investigation. The following subsections summarize the conversion of benzofuroxans into quinoxaline and benzimidazole oxides, the rearrangement of 4-substituted benzofuroxans, and the transformation of monocyclic furoxans into isoxazoles and isoxazolines, furazans, and pyrazolines. More detailed discussion is to be found in recent comprehensive reviews (75S415, 76H(4)767, 81AHC(29)251>. 

It should be noted that it is in many cases conceivable that isoxazoles and isoxazolines are formed from chloroximes without the intermediacy of a nitrile oxide. This route could occur if the substrate acted as a nucleophile to give an intermediate, such as the alkynyloxime (25) from an acetylide, which can cyclize to the isoxazole (26). In this case, by trapping with nonnucleo-philic alkenes, the reaction has been shown to involve a nitrile oxide.60,71 However, experiments on reactions of chloroximes with other nucleophiles suggest that a nitrile oxide is not invariably involved.72,73... 

C. Ring Transformations 1. Furoxans into Isoxazoles and Isoxazolines... 

A reaction that is set to gain momentum within the field of macromolecular science over the next few years is the cycloaddition of nitrile oxides with alkynes and norbornenes to form isoxazoles and isoxazolines respectively (Scheme 2.6). Whilst strictly a catalyst-free reaction, the in situ generation of the requisite nitrile oxide from the respective oxime precursor typically makes use of a mixture of a dipole generating agent (such as Chloramine-T) and a weak base (such as aqueous NaHC03). 

Zhdankin et al. reported the iodine(III) catalyzed oxidative cycloaddition of aldoximes 60 with alkenes and alkynes to prepare isoxazoles and isoxazolines. The active hypervalent iodine(III) species was generated in situ by the oxidation of catalytic 3,5-dimethyliodobenzene using Oxone as an inexpensive and environmentally safe terminal oxidant in aqueous 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). This activated iodine(III) promoted the oxidation of the corresponding aldoximes efficiently affording nitrile oxides 61, which upon cycloaddition reaction with various alk5mes 62 and alkenes 64 resulted in isoxazoles 63 and isoxazolines 65, respectively in moderate-to-excellent yields (up to 92%). In this oxidative conversion, HFIP is believed to increase the electrophilicity of I(III) reagent (Scheme 11) [27]. 

As an example of a preparative application, the reduction of ( )-2-phenyl-l-nitropropene ( )-81 yielded (R)- 2 in 82% yield and >98% ee (Scheme 3.22). The latter was then dehydrated to the nitrile oxide 83 and submitted to 1,3-dipolar cycloaddition with various dipolarophiles with no loss of optical purity, giving useful intermediates, isoxazoles and isoxazolines [102]. 

---