Isoxazole fragmentation

The synthesis of new 11-deoxyprostaglandin analogs with a cyclopentane fragment in the oo-chain, prostanoid 418, has been accomplished by a reaction sequence involving nitrile oxide generation from the nitromethyl derivative of 2-(oo-carbomethoxyhexyl)-2-cyclopenten-l-one, its 1,3-cycloaddition to cyclopenten-l-one and reductive transformations of these cycloadducts (459). Diastereoisomers of a new prostanoid precursor 419 with a 4,5,6,6a-tetrahydro-3aH-cyclopent[d isoxazole fragment in the oo-chain have been synthesized. Reduction of 419 gives novel 11-deoxyprostanoids with modified a- and oo-chains (460). 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

Electron impact mass spectrometry has been employed to study the fragmentation patterns of isoxazolylmethyl- and bis(isoxazolylmethyl)-isoxazoles and the results are in agreement with proposed pathways (79AC(R)8l). Electron impact studies of nitrostyryl isoxazole (6) show fragmentation in a variety of ways. The standard loss of NO2 from the molecular ion... 

The fragmentation pattern of isoxazoles on electron impact has been well studied. It has been used as an important tool for the structural assignment of isoxazoles obtained from the reaction of chromones with hydroxylamine 79MI41600, 77JOC1356). For example, the structures of the isoxazoles (387) and (388) were assigned on the basis of their fragmentation patterns. Ions at mje 121 (100%) and mje 93 (19.8%) were expected, and indeed observed, for the isoxazole (388), and an ion at mje 132 (39.5%>) was similarly predicted and observed for the isoxazole (387). 

The structures of the isoxazoles (393) were all consistent with their mass spectral fragmentation patterns. The reaction of hydroxylamine with 3-phenylchromone (394) gave exclusively 5-(o-hydroxyphenyl)isoxazole (395) (78ACH(97)69). 

The thermal or photolytic fragmentation of furazans to nitriles and nitrile Af-oxides has been reported (73JOC1054, 75JOC2880). The irradiation of dimethylfurazan (419) in the presence of cyclopentene, and benzofurazan (420) in the presence of dimethyl acety-lenedicarboxylate, gave isoxazoline (421) and isoxazole (422), respectively, in good yields. The thermolysis of acenaphtho[l,2-c]furazan (423) in the presence of phenylacetylene gave isoxazole (424) in 55% yield. 

The electron impact mass spectra of 3-methyl-4-nitro-5-styryl-isoxazoles exhibit, on the contrary, only negligible loss of OH"80. This has been interpreted in terms of an isoxazole-to-azirine rearrangement80. The latter fragments directly to an abundant cinnamoyl ion as well as rearranges to oxazole and an epoxide through an intramolecular oxidation of the ethylenic bond by the nitro group80 see Scheme 10. 

Novel polycyclic heterocyclic systems including the isoxazoline ring were described. Thus, oximes 191 and 193 in the presence of sodium hypochlorite afforded heterocycles 192 or 194, respectively (equations 83 and 84). Intramolecular cycloaddition of nitrile oxide was used in the synthesis of the A-ring fragments of la,25-dihydrovitamin D3 and taxane diterpenoids, sulphur-containing isoxazoles, fluoro-substituted aminocyclopentanols and aminocyclopentitols . New gem- and vic-disubstituted effects in such cyclization reactions have been reviewed by Jung. ... 

Isoxazoles and benzisoxazoles that are unsubstituted at the 3-position readily undergo the base-reduced ring fragmentation shown above, and there are therefore no reports on the successful metalation of these types of compound. 3-substituted isoxazoles do undergo lithiation, at the 5-position, but ring fragmentation rapidly follows, even at -60°C in the case... 

In addition, there are [5 -> 3 + 2] fragmentations leading to acyclic products that result from the original fragments by rearrangement. Examples are 5-phenyl-l,2,3,4-thiatriazole (50) and related compounds with three ring heteroatoms and an exocyclic double bond (51),THF (52), y-butyrolactone (53), y-thiobutyrolactone (54), pyrroles (8,61), pyrrolidine (55), furans (56, 58), pyrazole (62), and isoxazoles (11, 63,64). Most of these molecules are thermally rather stable and their decomposition requires drastic conditions. 

A synthesis of 2-cyanocyclohexanone 4.45 from cyclohexanone is shown below. Formylation of cyclohexanone produces a mixture of keto/enol tautomers 4.42 and 4.43, the equilibrium lying to the side of the enol 4.42. Treatment with hydroxylamine affords isoxazole 4.44, and base-induced fragmentation of the isoxazole ring affords 4.45. Explain the regioselectivity of the isoxazole formation, and the mechanism of the fragmentation process. 

Ring deprotonation is also known with certain members of these series. Carbanion 8.15 is stable at low temperature (-70°C) and can be trapped with electrophiles, but on warming to room temperature it decomposes with ring fragmentation and extrusion of nitrogen. This fragmentation process is reminiscent of the base-catalysed cleavage of isoxazoles (Chapter 4). 

Reaction with hydroxylamine occurs on the aldehyde group of the more reactive minor tautomer 4.43 affording isoxazole 4.44. Methoxide-induced fragmentation as shown gives enolate 4.48 which is quenched by a proton in the workup to afford 2-cyanocyclohexanone 4.45. 

The nature of substituents in aryl fragments of 3,5-diaryl-4-nitroisoxazole practically does not influence either the nitro group vas or the band frequencies of the isoxazole ring itself (Table 3.55) [486, 1048, 1049]. 

Analysis of mass spectra of nitroisoxazoles has been carried out in a small number of works [1317-1321], In general, the mass spectra of isoxazoles are significantly different from those of oxazoles because the initial fragmentation of isoxazoles involves N-O bond cleavage. Surprisingly, we were unable to find mass spectra of nitrooxazoles in the literature. 

---