1,3-dipolar cycloaddition aryl nitrile oxides

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

Aryl-5-cyano-2-isoxazolines, possessing liquid crystal properties (smectic phases A or E) have been synthesized, 1,3-dipolar cycloaddition of nitrile oxides to acrylonitrile being the key step (532). For example, nitrile 462 has been obtained in 66% yield from substituted benzaldoxime and acrylonitrile via in situ generated nitrile oxides. 

Isoxazole-supported selenium resins, produced via 1,3-dipolar cycloaddition of nitrile oxides with propargyl selenium resin, were subjected to a-alkylation reactions with various electrophiles, leading to 3-aryl-5-i4-substituted ethenylisoxazoles in satisfactory yields (62-78%) and purity (90-99%). Compound 238 gave olefin 240, through selenoxide elimination from the a-alkylation product 239 (Scheme 56) <2003OL4649>. 

Methyl 3-(/>-nitrobenzoyloxy)acrylate was exploited as a methyl propiolate equivalent with reverse regioselectivity in 1,3-dipolar cycloaddition with nitrile oxides, leading to 3-aryl-4-methoxycarbonylisoxazoles in moderate to good yields <2000JHC75>. 

Recent developments in the retro-Diels-Alder reaction have been reviewed. 1,3-Dipolar cycloadditions of nitrile oxides to 4-aryl-2-alkyIthio-l-azetines gave oxadiazabicyclo[3.2.0]heptenes that undergo a 2 -i- 2-cycloreversion with the loss of a styrene to furnish 5-alkylthio-3-aryl-l,2,4-oxadiazoles (Scheme 1). ... 

In a search for new isoxazole-based liquid crystalline compounds, a 22-member library of 3,5-diaryl isoxazoles 628 was prepared by parallel synthesis on solid phase (Rink resin) through 1,3-dipolar cycloaddition of supported phenylacetylene units with suitable aryl nitrile oxides generated in situ from hydroxyiminoyl chlorides. Cleavage from the resin under acidic conditions allowed the generation of the cyano moiety <2004TL2277>. 

Thus, in the presence of an Ru-catalyst (e.g., RuCl(cod)(C5Me5)), 3,4-disubstituted isox-azoles (15, R =H) are obtained as pure regioisomers [308]. In contrast, in the presence of Cu(I) salts (i.e., via Cu(I)-acetyHdes) the regiocomplementary 3,5-disubstituted isoxazoles (15, R =H) are formed exclusively [309]. Alternatively, 3,5-disubstituted isoxazoles can be regioselectively and efficiently prepared by 1,3-dipolar cycloaddition of aryl nitrile oxides with 1,1-disubstituted bromoalkenes followed by spontaneous aromatization of the 5,5-disubstituted bromoisoxazoline intermediates by loss of HBr [310]. 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

Some features are characteristic of reactions of nitrile oxides with 2,4,6-cyclo-hep tatrien-l-imines (8-azaheptafulvenes). 1,3-Dipolar cycloaddition to the C=N double bond of N-aryl-2,4,6-cycloheptatrien-l-imines 142 (R = Ar), affording... 

The carbon-nitrogen triple bond of aryl thiocyanates acts as a dipolarophile in 1,3-dipolar cycloadditions. Reactions with nitrile oxides yield 5-arylthio-1,2,4-oxadiazoles 227 (X = O Y = S). Aryl selenocyanates behave similarly forming 5-arylseleno-l,2,4-oxadiazoles 227 (X = 0 Y = Se). Reactions of 5-aryl-... 

A more elaborate approach was taken by Kaffy et al. [94], The goal of the research was a series of compounds with greater stability and a higher affinity for endothelial cells within tumor vessels than CA-4, 7 however, the paper described a method that was purely synthetic. The synthetic strategy involved a 1,3-dipolar cycloaddition of a nitrile oxide 186 with a substituted aryl alkyne 187 to form the oxazole 188. 

Wilcox and co-workers (145) reported that the stereoselectivity of 1,3-dipolar cycloaddition reactions can be controlled in a predictable manner when ion pairs are located at a proper position near the reaction site (Scheme 11.40). He has employed an A-phenylmaleimide substrate having a chiral center in the substituent at ortho position of the phenyl group. Due to serious steiic hindrance, this phenyl group suffers hindered rotation around the aryl-nitrogen bond (rotation barrier 22 kcal/mol). Four diastereomeric cycloadducts are possible in the cycloaddition step with a nitrile oxide. When the cycloaddition reaction is carried out in... 

Other thermal 1,3-dipolar cycloadditions are the reactions between nitrile sulfides and electron-deficient aldehydes and ketones forming 1,3,4-oxathiazolines (98 Scheme 19) between aryl thioketones and thiofluorenone 5-tosylimide to yield the 1,3,4-dithiazolidines (204) and between thioketene S-oxides and imines, yielding in one case the 1,2,4-oxathiazolidine (136). 

Sequential [3+2] cycloaddition/silicon-based cross-coupling reactions allowed for the synthesis of 3,4,5-trisubsti-tuted isoxazoles. Regioselective 1,3-dipolar cycloaddition reactions between alkynyldimethylsilyl ethers 400 and ethyl or phenyl nitrile oxides, generated in situ from 1-nitropropane and A -hydroxybenzene carboximidoyl chloride, respectively, gave as predominant products after hydrolysis isoxazol-4-ylsilanols 401, converted into 4-arylisoxazoles 402 by cross-coupling with a variety of aryl iodides (Scheme 97) <2005JOC2839>. 

Dioxoindoxazenes (68 R1 = aryl or heteroaryl, R3 = alkyl), formed by 1,3-dipolar cycloaddition of the appropriate nitrile oxide to a 1,4-benzoquinone, have bactericidal and fungicidal properties.87 Apparently, optimum yields of 68 are obtained by generating the nitrile oxide in situ from the hydroxamoyl chloride. 

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