3- Isoxazolines, isomerization

The nucleophilic attack of hydroxylamine at the 5-position of 4-trifluoroacetyloxazoles (414) led to a mixture of stereoisomeric isoxazolines (415). Dehydration of these isomeric isoxazolines (415) in the presence of trifluoroacetic anhydride gave isoxazoles (416) in good yields (76JHC825). 

This small class of compounds is characterized by an N-alkyl moiety, and they are synthesized from isoxazolium salts by isomerization or by the dehydration of 2-alkyl-isoxazolidin-3-ols (Scheme 128) (74BSF1025). The reaction of isoxazolium salts that are unsubstituted in the 5-position with phenylmagnesium halides was reported to give 3-isoxazolines by 1,4-conjugate addition, and this reaction is also shown in Scheme 128 (74CPB70). 

Jurd reported the isolation of a 2//-3-isoxazoline by the reaction of the flavylium salt (488) with hydroxylamine. Gentle heating of the material caused isomerization to the more stable 2-isoxazoline. Treatment with base generated an a,/3-unsaturated oxime which on photolysis regenerated the starting flavylium salt (Scheme 129) (70CI(L)624). 

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 oxidative coupling of 3,4-dimethyl-or 3,4-diphenyl-isoxazolin-5-one by activated Mn02 produced a 4,4 -bis(isoxazolinone) (519) and 2,4 -bis(isoxazolinone) (520). Hydrogenation of (519) over Pt02/H0Ac produced a pyrrole derivative while similar reaction of (520) produced an isomeric pyrrole (80JHC763). These reactions are shown in Scheme 152. 

The reduction of 3,5-diphenylisoxazoline with sodium cyanoborohydride produced a mixture of isomeric 3,5-diphenylisoxazolidines. The H and NMR spectra were utilized to distinguish the isomers SOLAIOI). Sodium borohydride reductions likewise reduce isoxazolines to isoxazolidines (equation 56) (80JA4265). 

A highly stereocontrolled synthesis of (+) testosterone 49 was accomplished wherein the A/B ring system was constructed via INOC reaction of 47 to isox-azoline 48 (Scheme 6) [24]. The cycloaddition was assumed to be taking place via a chair-like TS 47 providing isomerically pure isoxazoline 48 in 87 % yield. 

The cu-dioxane (97) underwent cyclization to afford a single tricyclic isoxazoline in which the new 5,5-fused bicyclic system formed rapidly at 0 C (Scheme 27).45 The isomeric tranr-dioxane also gave a single tricyclic isoxazoline (96) as product but only at 20 C. The results were rationalized as follows cyclization of the nitrile oxide derived from (96) occurred with the vinyl group equatorial, while the cis isomer required an axial vinyl group in the transition state. The isoxazoline (96) was converted in several steps to a known PGF2a precursor. 

For the isomeric 2//-isoxazolin-5-ones 347, elimination of a nitrile is impossible and only CO2 is lost upon pyrolysis to give the iminocarbenes 348, which cyclize as shown to provide a useful synthesis of fused imidazoles 349. A wide range of examples has been examined as illustrated by the products 350-353, which are generally formed in almost quantitative yield using FVP at 500-600 °C165,166. 

Dicobalt octacarbonyl in anhydrous acetonitrile promoted the rearrangement of 4-isoxazolines to isomeric 2-acylaziridines with yields ranging from 39 to 92%. The optically pure isoxazoline 64 underwent a totally d iastereoselective rearrangement to give aziridino ketone 65 as a single isomer <020L1907>. 

Nitrile oxides display three types of reactivity (apart from isomerization and deoxygenation) 1,3-cycloaddition, 1,3-addition, and dimerization to furoxans. The first can give isoxazolines and isoxazoles directly. The second can give isoxazolines and isoxazoles indirectly. The third (which may be regarded as a carbenoid reaction,62 but see also Lo Vecchio et al.63) is an undesirable side reaction as far as the synthesis of isoxazoles is concerned. Thus, although many methods for generating nitrile oxides are available, and in some cases they may be isolated and used, methods capable of generating them in the presence of the substrate are preferred. 

Either intramolecular nitrile oxide cycloadditions (INOC) or intramolecular silylnitroate cycloadditions (ISOC) of /3-nitrosulfides 477 gives isomeric thieno[3,4-c]isoxazolines 478 and 479 (Equation 17) <1997SC1865>. 

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