Isoxazoline 2-oxides

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

The synthesis of novel heterocycle-fused furo[3,4-d]isoxazoles via ring transformation of 2-isoxazoline-2-oxides by Lewis acids was reported <96H(42)289>. A practical application of the... 

Treatment of 2-bromo aldehydes and ethyl nitroacetate with alumina gives 4-hydroxy-2-isoxazoline-2-oxides with high stereoselectivity (Eq. 8.81).131... 

Keywords epoxyaldehyde, ethyl nitroacetate, alumina surface, 3-(ethoxycarbo-nyl)-4-hydroxy-5-(l-hydroxyalkyl)-2-isoxazoline-2-oxide... 

Optically pure bicyclic isoxazoline 2-oxides 55 were prepared in good yields by Pd(0)-catalyzed intramolecular cyclization of enantiopure acetates 54. The mild reaction conditions were compatible with several functional groups <07T1116>. 

Also, dianions derived from y-substituted /f-ketoesters engage in condensations with oxiranes, to afford 2-carbomethoxyethylidene-tetrahydrofurans in a stereospecific manner <92SL529>. In certain cases these types of reactions can be effected on an alumina surface without solvent. In a base-catalyzed tandem nitroaldol cyclization process <90JOC78l>, 2-isoxazoline-2-oxides are formed in... 

A new gram-scale one-pot preparation of enantiomerically pure isoxazoline 2-oxides 47 starting from 2,3-epoxy alcohols 46 was developed. The selectivity of the process was low (dr from 56 44 to 72 28) but the diastereomeric products could be separated by column chromatography. The bis-/er<-butyldimethylsily Af.oxide derivatives could be deoxygenated in very good yields by exposure to hot trimethyl phosphite to obtain the corresponding isoxazolines 48 <01OL727>. 

Rosini and co-workers reported the synthesis of 5-acyl-3-(ethoxycarbonyl)-2-isoxazoline-2-oxide 163, via conjugate addition of ethyl nitroacetate 161 to the a-bromo enones 160 followed by ring closure (Scheme 42) [143]. The reaction was performed under both homogeneous and heterogeneous conditions, but the former was found to be superior in terms of the isolated yield of the product. 

P.M. Khan, R. Wu, K.S. Bisht, Pd(0) catalyzed intramolecular alkylation stereoselective synthesis of furan and isoxazoline-2-oxide analogs. Tetrahedron 63 (2007) 1116-1126. 

Another example of oligomer preparation by C-C bond formation is outlined in Figure 16.30. In this synthesis, nitroalkyl phenyl selenides are converted into nitrile oxides in the presence of support-bound terminal alkenes, forming isoxazolines. Oxidative elimination of the selenide yields a new alkene, which can then be subjected to further 1,3-dipolar cycloaddition with a new nitrile oxide. Although this synthesis is short and easy to perform, the cycloadditions proceed with low diastereoselectivity... 

Isoxazoline oxides 11, 865 Isoximes s. Nitrones Ivanov reagent 12, 725... 

Pyrroles from 1,4-dicarbonyl compounds and ammonia isoxazolines from olefins and nitrile oxides. 

A convenient route to A -isoxazoline N-oxides has been developed from nitrostyrenes using dimethylsulfoxonium methylide. The addition of the ylide (572) to the nitrostyrene (571) was greatly facilitated by the presence of copper(I) salts, the isoxazoline N-oxide (573) being obtained in excellent yield (76JOC4033). 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

The oxygen of 1,2-benzisoxazole fV-oxides can be removed by treatment with triethyl phosphite (80CC42l), and the oxygen of 3,4,5-triphenylisoxazoline A-oxide with H2 catalysis and PCI5 (69JOC984). Isoxazoline A-oxide (272) reacts with styrene to give cycloadduct (273) (66ZOR2225). 

Nitrile A-oxides, under reaction conditions used for the synthesis of isoxazoles, display four types of reactivity 1,3-cycloaddition 1,3-addition nucleophilic addition and dimerization. The first can give isoxazolines and isoxazoles directly. The second involves the nucleophilic addition of substrates to nitrile A-oxides and can give isoxazolines and isoxazoles indirectly. The third is the nucleophilic addition of undesirable nucleophiles to nitrile A-oxides and can be minimized or even eliminated by the proper selection of substrates and reaction conditions. The fourth is an undesirable side reaction which can often be avoided by generating the nitrile A-oxide in situ and by keeping its concentration low and by using a reactive acceptor (70E1169). 

It was also found that bromonitrophenylmethane (375) reacted with sodium aryl-methanenitronate (374) in DMSO to give the isoxazoline iV-oxide (369) in 60% yield. Both reactions probably involved the formation of a vicinal dinitroethane derivative (376), which lost nitrous acid to give cfs-a-nitrostilbene (368). As mentioned, the reaction of (368) with (374) gave the isoxazoline iV-oxide (369). 

A -Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile -oxides with alkenes and from the condensation reaction of ehones with hydroxylamine. Therefore, methods of conversion of -isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

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 two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

When compound (443), which contains alkene and alkyne moieties, was reacted with benzonitrile oxide, both an isoxazoline (444) and isoxazole (445) were produced, with the former predominating. Oxidation of (444) with permanganate produced 3-phenyl-2-isoxazoline-5-carboxylic acid (446) (67ZOR82i). The reaction of 1-trimethylsilylbut-l-yne-3-ene produced only a compound which reacted at the alkenic unit. Oxidation of the adduct also produced (446) (68ZOB1820). These reactions are shown in Scheme 102. 

The reaction of benzonitrile oxide with (447) or (448) produced only (449). No isoxazoline (450) was observed in the reaction with (447) (80MI41601). 

The cycloaddition of benzonitrile oxide to cis- and rrans-l,2-dichloroethylene produced the appropriate cis- and trans-4,5-dichloro-3-phenyl-2-isoxazoline diastereomers. Base elimination produced only one compound, 4-chloro-3-phenyloxazole (Scheme 103) (70CJC3753). 

The reaction of benzonitrile oxide with the bicyclic isoxazoline (451) produced the three fused diisoxazoles shown in Scheme 105 (77JCS(Pi)2222). 

The reaction of arylnitrile oxides with 1,1-diphenylallenes gave a mixture of 4-methylene-2-isoxazolines (Scheme 106) with major attack at the C(2)—C(3) double bond (74JCS(P2)l30l, 76CSC67, 76CSC71, 72JCS(P2)1914) and not a mixture of the 4- and 5-methylene compounds. 1-Phenoxyallene and benzonitrile oxide produced a mixture of positional isomers and a spiro compound (Scheme 107) (79JOC2796). 

Acetonitrile oxide was generated from 3,4-dimethylfuroxan oxide by flash vacuum pyrolysis and trapped at -40 °C where its and NMR spectra were examined. Warming to room temperature in the presence of propane produced 3,5-dimethyl-2-isoxazoline (Scheme 108) (79TL2443). The oxide could also be generated by photolysis of furoxan (68CC977). 

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). 

Aldehydes react with a-nitroacetophenone in refluxing toluene to generate a 3-acetyl-2-isoxazoline (78USP4092327), while a-nitroacetophenone oxides react with alkenes to provide 2-isoxazolines (Scheme 121) (79ZOR735, 79ZOR2408, 80CPB479>. 

Bravo et al. studied the reaction of various ylides with monooximes of biacetyl and benzil. Dimethylsulfonium methylide and triphenylarsonium methylide gave 2-isoxazolin-5-ol and isoxazoles, with the former being the major product. Triphenylphosphonium methylide and dimethyloxosulfonium methylide gave open-chain products (Scheme 135) (70TL3223, 72G395). The cycloaddition of benzonitrile oxide to enolic compounds produced 5-ethers which could be cleaved or dehydrated (Scheme 136) (70CJC467, 72NKK1452). 

This class was first reported in 1924 and was formed 62HC(17)l) by cyclization of a-bromo-/3-aryl-y-nitroketones. The direct synthesis by oxygenation of 2-isoxazolines has not been reported. To date only 3-substituted derivatives have been prepared. Aryl-nitromethanes react with nitrostilbene to form isoxazoline A-oxide by a nitrile ion displacement (Scheme 138) <62HC(17)1, 68TL3375). 

Attempted alkylation of methyl nitroacetate in base produced an isoxazoline Af-oxide (Scheme 140) (74CPB477), and the enamine (497) gave an isoxazoline A-oxide when reacted with methyl nitroacetate (74IZV845, 74MI41605). 

The thermal decomposition of the silver salt of dinitrophenylmethane in the presence of an alkene produced an isoxazoline A-oxide via a proposed arylnitrocarbene (80JOC4158),... 

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