Mechanism of isoxazoline

New theoretical calculations of mechanisms of isoxazoline syntheses have been reported. 

In a number of cases the intermediate oxime has been isolated in the reaction of hydroxylamine and /3-keto esters. The reaction of ethyl acetoacetate with hydroxylamine generated an oxime which cyclized on base treatment (Scheme 144) (70MI41600). Likewise, treatment of an analogous amide with hydroxylamine generated a ring opened material which cyclized on treatment with HCl (Scheme 144) (67T831). The presence of a minor contaminant in the standard reaction of ethyl acetoacetate with hydroxylamine was discovered and identified as an isomeric isoxazolin-3-one. The mechanism of product formation has been discussed (70BSF2685). 

The generation of a nitrile oxide bearing a carbamoyl group (i.e., 16) was effected by treating 4-nitro-3-isoxazoline-5-one (15) with a mixture of acetonitrile and water (Scheme 6.5). Although the mechanism of this reaction is not clear, the method allows for the formation of a functionalized nitrile oxide (16) and subsequent cycloaddition under mild conditions (91). 

A similar effect occurs in the reaction of some pyrimidine nucleoside derivatives with hydroxylamine. Studies of the mechanism of this reaction with uridine derivatives340 shows that the initial point for nucleophilic attack is at C-6, and the resultant 5,6-dihydro-6-(hydroxy-amino)uridine derivative (86) is an intermediate in the conversion of the uridine derivative into the ribosylurea derivative 87 and 2-isoxazolin-5-one (88), as shown in Scheme 8. 

Thermal rearrangement of isoxazolines provides yet another route to aziridines. Prepared by 1,3-dipolar cycloaddition of A-methyl-C-trifluoromethylnitrone (148) to phenylacetylene, isoxazoline 149 was transformed in refluxing toluene into cA-aziridine 150 (81%)."° The clean cis stereochemistry is consistent with interpretation of the mechanism as an allowed 1,3-sigmatropic rearrangement, a four-... 

The oxidation of 3-hydroxypiperidine (15) with iodosylbenzene in water affords 2-pyrrolidinone 16 directiy in good yieid (Scheme 6.9) [28], The mechanism of this reaction probabiy invoives oxidative Grob fragmentation yielding an imino aldehyde, which upon hydrolysis affords 2-pyrrolidinone by a cyclization-oxidation sequence [28], The oxidative cyclization of aldoximes using iodosylbenzene in neutral aqueous media in the presence of surfactants has been employed in the synthesis of functionalized isoxazolines [29]. 

O-Propargyhc hydroxylamines 16 are converted to the isomeric 3,5-disubstituted isoxazohnes on treatment with K2CO3 [328]. The mechanism of this transformation is not yet elucidated. A possible explanation involves (2,3)-sigmatropic rearrangement of 16 to a N-aUenic hydroxylamine 17, which may further rearrange to a a,P-unsaturated oxime 18 in analogy to (1), cyclization gives rise to the isoxazoline system ... 

The reaction of alkyl nitro compounds with acetyl chloride in the presence of an alkenic compound produced a 2-isoxazoline. The mechanism is believed to proceed via a nitrile oxide and is illustrated in Scheme 112 (B-79MI41613). 

Rahman and Clapp decomposed dinitromethane derivatives in DMF in the presence of alkenes to obtain 2-isoxazolines. Without any alkene present, an acid and KNO2 were obtained. They proposed a mechanism which proceeded via a three-membered ring or a nitrocarbene which rearranged to a nitrile oxide (76JOC122, 75MI41612). 

RSaS stereoisomers.29 The 1,3-dipolar cycloaddition of [60]fullerene with diazomethane, nitrile oxide, and nitrone afforded fullereno-pyrazolines and -isoxazolines. These reactions were modelled at the B3LYP/6-31G(d,p)//AMl level and the reaction mechanisms, regiochemistry, and nature of addition were investigated.30... 

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