Isoxazoline 4,5-disubstituted

This regioselectivity is practically not influenced by the nature of subsituent R. 3,5-Disubstituted isoxazolines are the sole or main products in [3 + 2] cycloaddition reactions of nitrile oxides with various monosubstituted ethylenes such as allylbenzene (99), methyl acrylate (105), acrylonitrile (105, 168), vinyl acetate (168) and diethyl vinylphosphonate (169). This is also the case for phenyl vinyl selenide (170), though subsequent oxidation—elimination leads to 3-substituted isoxazoles in a one-pot, two-step transformation. 1,1-Disubstituted ethylenes such as 2-methylene-1 -phenyl-1,3-butanedione, 2-methylene-1,3-diphenyl- 1,3-propa-nedione, 2-methylene-3-oxo-3-phenylpropanoates (171), 2-methylene-1,3-dichlo-ropropane, 2-methylenepropane-l,3-diol (172) and l,l-bis(diethoxyphosphoryl) ethylene (173) give the corresponding 3-R-5,5-disubstituted 4,5-dihydrooxazoles. 

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. ... 

Acetylenic oximes undergo in a similar manner conversion to 3,5-disubstituted isoxazoles. Thus, oximes 195 in the system K2C03/Me0H at room temperature afforded isoxazoles 196 in excellent yields (equation 85). a, S-Unsaturated ketoximes 197 can be also easily transformed to the corresponding 5-arylisoxazoles 198 (yield up to 95%) by treatment with iodine and potassium iodide. The presence of isoxazoline was detected in the reaction mixture (equation 86) . a, S-Unsaturated ketoximes in the presence of palladium catalyst afforded isoxazolines . 

The [3+2] cycloaddition of terminal alkynes has been investigated with several dipoles. These dipolarophiles are competent in the cycloaddition, however, the corresponding isoxazolines cannot be isolated. Instead, the cycloadduct undergoes spontaneous rearrangement to provide acylaziridine products (Table 2.52) (229). Disubstituted alkynes also undergo this process, however, in lower yield. This rearrangement occurs with all nitronates studied (Chart 2.3) (66,230,231). 

The cycloaddition of some nitrile oxides to trani-l,2-disubstituted alkenebor-onates afforded the respective isoxazoline-4-boronates with high regioselectivity. These products were then used to prepare the 4-hydroxy derivatives (139) complementing earlier approaches that took advantage of 4-modification (140,141) of furan cycloaddition products (20,21) (see Section 6.4.4). 

Another approach that relies on asymmetric induction from the alkene part, uses chiral auxiliaries of various types, thereby leading to enantiomerically enriched or pure isoxazoline products. The complexity of some of these auxiliaries is high, and more economical solutions are desirable since the competition is the resolution of racemic cycloadducts with an overall efficiency up to 50% yield. With chiral nitrile oxides, the situation is much less satisfactory since asymmetric induction of the 1,4-type (with 1-alkenes) is minimal, and hardly better with a 1,3-relationship of inducing-forming stereocenters, when 1,2-disubstituted alkenes are employed (Scheme 6.22). Upon separation of the two diastereomers, however, another entry to pure optically active isoxazolines is available. 

Ab initio calculations also confirm that the use of an allyl magnesium alkoxide in place of the alcohol functionality will lead to high or complete stereoselectivity (138). When homoallylic alcohols are used, the Kanemasa protocol afforded the respective isoxazolines with poor stereoselectivity ( 55 45) in the case of terminal aUcenes, but with very high diastereoselectivity (up to 96 4) in the reaction of cis-1,2-disubstituted olefins (136). Extension of this concept to the reaction of a-silyl allyl alcohols also proved feasible and produced the syn (threo) adducts as nearly pure diastereomers (>94 6) (137). Thus, the normal stereoselectivity of the cycloaddition to the Morita-Baylis-Hillman adducts (anti > syn, see above) can be reversed by prior addition of a Grignard reagent (176,177). Both this reversal... 

Analogously, the l-valine derived nitrones 103 react with methyl acrylate (104) to produce the corresponding diastereomeric 3,5-disubstituted isoxa-zolines 105-108. In the case of the dibenzyl-substituted nitrones, in addition to 3,5-disubstituted isoxazolines, the 3,4-disubstituted isoxazolines were also obtained in low yields. High pressure just served to decrease the reaction time. The major products 105 were found to have the C-3/C-6 erythro and C-3/C-5 trans relative configuration (Scheme 30) [74]. 

Nitroisoxazolines are also aromatized by the action of other oxidizing agents (Mn02, [584], CrC3 [540], HS03F [540], and C(N02)4 [585]). In some cases 4-nitroisoxazoles can be obtained by the thermolysis of the respective isoxazolines. Thus, 3,5-disubstituted 4-nitroisoxazolines form 4-nitroisoxazoles when heated in DMF. At the same time nitrous acid is eliminated during the thermolysis of the 4-nitroisoxazolines in the absence of a solvent [586] (Scheme 113). 

Unsymmetrical silaketals 201 having a 1,2-disubstituted double bond and a nitro group were prepared and transformed upon treatment with phenyl isocyanate in the presence of Et3N under mild reaction conditions into 2-oxazoline derivatives 202 by a regiospecific intramolecular 1,3-dipolar cycloaddition, as shown in Scheme 36 <1997SL1208>. The /ra r-stereochemistry of the alkene 201 was transported to the 2-isoxazoline product 202, which was confirmed by the H NMR spectroscopic data. 

Disubstituted 4-isoxazolines 65 were easily converted to a,p-enals 66 by treatment with Mel in THF at reflux temperature. When the same reaction was performed in polar solvents such MeOH, DMF or MeCN the formation of minor amounts of a,p-unsaturated amides 68 was observed. The amides 68 were obtained as sole products in high yields by heating the preformed isoxazolinium salts 67 in MeOH. The new process is believed to proceed through the heterolytic cleavage of the C3-N bond of 67 assisted by the solvent with formation of an allylic tertiary carbocation intermediate <03JOC3718>. 

When 3,4-disubstituted 4-aminoisoxazolin-5(4Af)-ones (9) are hydrogenated, and then subsequently recyclized, high yields of imidazoles (10) are obtained (Scheme 6.1.4). The starting materials can be readily made from isoxazolin-5(4Af)-ones by sequential bromination, reaction with sodium azide and conversion of azide into amino by reaction with hydrobromic acid in acetic acid. The amines are then converted into formamidine or acetamidine derivatives with DMF or dimethylacetamide under reflux in phosphoryl chloride-chloroform. Yields at this stage are 50-93%. Catalytic... 

The molybdenum-mediated cleavage reactions of a series of disubstituted-4,5-dihydroisoxazoles having aryloxy substituents at C-5 have been studied <2004RJ01003>. Isoxazolines 140 underwent molybdenum-mediated tandem reductive N-O bond cleavage-retro-aldol reactions to provide compounds 141 or 142 as a mixture of stereoisomers (Scheme 30) <2002004101 >. 

Nitrile oxide cycloaddition with mono- and trisubstituted alkenes affords almost exclusively 5-mono- and 4,5,5-trisubstituted isoxazolines, respectively, the regioselectivity being determined by steric effects. Reverse regioselectivity in nitrile oxide cycloaddition to terminal alkenes has been reported <1997CC1517> for example, 4-A t/-butylbenzoni-trile oxide was forced to reverse alignment for the cycloaddition by formation of the inclusion complex 470 with /3-cyclodextrin. Under these conditions, 90% of the 3,4-disubstituted cycloadducts were obtained, whereas in the absence of cyclodextrin the aromatic nitrile oxide afforded only the 5-substituted isoxazoline. 

Tsuge, O., Kanemasa, S, Suga, H., and Nakagawa, N., Synthesis of (diethoxyphosphoryl)acetonitrile oxide and its cycloaddition to olefins. Synthetic applications to 3.5-disubstituted 2-isoxazolines, Bull. Chem. Soc. Jpn., 60, 2463, 1987. 

After consideration of the moderate complexity of our target 10 b, it was clear that the best hope for multi-kilo preparations would still incorporate the useful [3+2] cycloaddition of an aryl nitrile oxide with a properly functionalized propylene to quickly establish the 2,5-disubstituted isoxazoline ring. Once that is assumed, there remained three conceptual routes to 10b (Fig. 8). 

IBX has also been used for the preparation of the 3,5-disubstituted isoxazolines 865. The oxidation of aldoximes 863 with IBX produces the respective nitrile oxides, which then undergo 1,3-dipolar addition with an alkene component 864 to give final products 865 (Scheme 3.345) [1182]. 

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