Isoxazolines—

The use of isoxazolines as synthetic intermediates continues to be a valuable approach to different classes of molecules. 

Mapp et al. have reported a versatile and efficient synthesis of substituted P-amino acids (P-AA) through diastereoselective nucleophilic addition to enantiopure isoxazolines 40. In the C=N reduction with LiAlILt in THF, the proximal hydroxymethyl substituent directed the hydride approach to the same side as the C-5 ring substituent, affording the amino diol 41 with high diastereoselectivity. In contrast, carbon nucleophiles were sterically driven and preferentially added on the opposite isoxazoline face. The facial selectivity was complete with 

The hydroximoyl chloride 45 obtained from mannitol was treated with NEt3 in 2-methylfirran to give a mixture of two separable diastereomers 46 and 47 in a 3 2 ratio. The enantiopure furoisoxazoline 46 was then converted to the natural antibiotic (+)-furanomycin 48 and to some analogues of 48 05EJ03450 . 

A synthesis and structural revision of calafianin 49, a spiroisoxazoline isolated from the sponge Aphysina gerardogreene, was described. In particular, a trawi-relationship between the epoxy and isoxazoline oxygen atoms was established 05TL1083 . 

INOC was successfully employed in the total synthesis of the 16-membered macrolactone (+)-macrosphelide B 53. Interestingly, the cycloaddition of nitrile oxide generated in situ from 51 was more stereoselective in dioxane than in CH2CI2 (dr 10 1 vs 2 1). The major isomer was then converted into 53 by reductive N-0 bond cleavage, dehydration and MEM deprotection 05OL3159 . 

Phase-switching strategy was applied to the multistep synthesis of isoxazolines 45-47. The approach exploits the boronic acid functionality as a phase-tag which can be easily immobilized on diethanolaminomethyl polystyrene (DEAM-PS) resin and then released by treatment with wet THF. Each reaction step was carried out in solution and the products were purified by addition of the scavenging resin, followed by filtration, washing of the supported material, hydrolytic release and evaporation. Finally, the boronic acid could be used to introduce additional substituents on the molecule. For example, 46 was converted into the biaryl-containing isoxazoline 47 by a Suzuki cross-coupling reaction 07JCO193 . 

5-Vinyl isoxazolines 48 can be prepared by cycloaddition of nitrile oxide to 1,3-butadiene. An alternative synthetic approach has been recently described. The method is based on domino nucleophilic addition-anionic C-O-heterocyclization of nitrile oxides with allyl organometallics derived from trans-1,4-dihalobutene and a metal such as zinc, magnesium or indium. In the case of indium an aqueous media could be used 07SL1449 . 

2-Isoxazolidines were prepared from primary nitroalkanes and alkenes in the presence of catalytic amounts of copper acetate and 1-methylpiperidine (NMP). Under these reaction conditions, adduct 49 was obtained in quantitative yield starting from nitropentane and norbomene. 

Experimental evidences suggest that nitrile oxides are not reaction intermediates and water is released from the nitro compound after reaction with the alkene 07SL2451 . A rationalization of the condensation of primary nitro compounds with alkynes and alkenes under base catalysis has been proposed 07EJO4352 . 

A study on fulleroisoxazolines showed that these adducts undergo retro-cycloaddition by heating in the presence of copper(II) triflate as a catalyst and an excess of a dipolarophile to trap nitrile oxide. The electronic nature of the isoxazoline substituents strongly influences the reaction outcome 07JOC3840 . The fulleroisoxazolines 50 functionalized with electron-donor groups have been synthesized and their photophysical properties analyzed 07EJO2175 . 

A solid-phase synthesis of 3-substituted isoxazoles 31 in good yields and purities was achieved by 1,3-DC of polymer-supported vinyl selenide with in situ generated nitrile oxides treatment of intermediate isoxazolines 30 with an excess of hydrogen peroxide resulted in the release of isoxazoles 31 while the use of Mel/Nal led to 3-substituted 5-iodoisoxazolines 

A DFT-HSAB study provides a quantitative rationalization of regioselectivity in 1,3-DC of 4-substituted benzonitrile oxides towards methyl propiolate not amenable to FMO and electron-demand theory 06CEJ1156 . 

New applications of nitrile oxide 1,3-DC have been reported. Soluble, single-wall carbon nanotubes (SWNT) 32 functionalized with pentyl esters at the tips and pyridyl isoxazoline rings along the walls were prepared using pentyl ester-SWNT as dipolarophile. The complex 

Polymeric isoxazolines were prepared by cycloaddition of nitrile oxides to norbomadiene followed by ring-opening metathesis polymerization (ROMP) 06PLM3292 06MM3147 . 

Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-t-butylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 06CEJ8571 . 

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

C3NO 0 N 5,5 -Biisoxazole 3-hydroxy-5-phenylisoxazole 3,3 -bi-2-isoxazoline 3-hydroxy-5-phenylisoxazole 3-phenylisoxazolin-5-one ... 

A -Pyrazolines and A -isoxazolines (302 Z = NH, O) are cyclic hydrazones and oximes, respectively. 2-Pyrazolines are quaternized at the 2-position (306 307) (64AHC(. ll). 1,3,4-Oxadiazolines (e.g. 308) are very easily ring-opened (66AHCi7 183). 

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). 

Dimethylsulfonium phenacylide (574) underwent C-alkylation with a-chloronitroso compounds such as (575). The intermediate (576) immediately cyclized to the isoxazoline (577). With a more basic ylide such as dimethylsulfonium methoxycarbonylmethylide the initial alkylation product underwent elimination of the sulfonium group to an alkene rather than its displacement (72T3845). 

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 chemical potentials and free energies of the 2-isoxazolines have also been studied and the electron impact and chemical ionization mass spectra determined (77MI41614). Fragmentation pathways and retrocycloadditions of various derivatives were discussed in these reports. 

Isoxazolines with alkyl substituents are also all liquids (or low melting solids) and incorporation of aryl substituents results in crystallinity. Introduction of carboxy substituents and endocyclic carbonyl or imino groups also has the anticipated effect, with crystalline products being isolated. These trends are illustrated by the data compiled in Table 2. 

Table 2 Melting Points (Boiling Points) of Various A -Isoxazoline Derivatives (62HC(i7)i, p. 95>...

Isoxazoles, isoxazolines, isoxazolidines and benzisoxazoles are all thermally stable, distilling without decomposition, but the stability of the system depends on the substitution pattern. For example, aminoisoxazoles distill unchanged but the isoxazole carboxylic acids usually decompose at or above their melting points without giving the corresponding isoxazole. 

Irradiation of the fused ring isoxazoline (27) gave the ring expanded product, oxazepine (28), in 80% yield. 

The photolysis of 4-substituted 2,3-dimethyl-3-isoxazolin-5-ones has been studied. Irradiation in methanol or ethanol with a 100 W high-pressure mercury lamp through a Pyrex filter of a 4-phenylthio compound produced a semithioacetal (Scheme 5). In contrast, an H, Cl or OPh moiety gave no reaction. The use of alkylthio substitution gave similar products. Cyclic compounds yielded cyclic products (Scheme 5), and the photolysis of (29) in benzene... 

Sodium borohydride and 3-isoxazolium salts with a 3-unsubstituted position also give isoxazolines, as do the 3-substituted 5-unsubstituted derivatives. With the latter group, further reduction occurs to the isoxazolidines (74CPB70). 

The photolysis of 3-( p-cyanophenyl)-2-isoxazoline in benzene produced a tricyclic product along with six other materials (Scheme 46) (B-79MI41616). Irradiation of the bicyclic 2-isoxazoline (155) produced benzonitrile, /3-cyanonaphthalene and polymer via a proposed biradical intermediate (156) (Scheme 47) (B-79MI41615). 

The reaction of 3,5-diphenyl-2-isoxazoline with lithium diisopropylamide produced with 2 equivalents of base a chalcone oxime, while in the presence of 1 equivalent and an alkyl iodide, ring alkylation occurred at the 4-position of the nucleus (Scheme 48) (80LA80, 78TL3129). 

Treatment of 2-isoxazolines with acid usually leads to ring rupture and formation of chalcone products 62HC(l7)l), although 5-methyl-3-phenyl-2-isoxazoline forms a quaternary salt with dimethyl sulfate in the presence of perchloric acid (Scheme 51) (73BSF1390). 

The 3-substituents in 3-nitro- and 3-phenylsulfonyl-2-isoxazolines were displaced by a variety of nucleophiles including thiolate, cyanide and azide ions, ammonia, hydride ions and alkoxides. The reaction is pictured as an addition-elimination sequence (Scheme 54) (72MI41605, 79JA1319, 78JOC2020). 

A number of manipulations on isoxazolinone can be performed with the nucleus remaining intact, and a variety of reagents cleave the ring. Isoxazolin-5-ones have also been used as synthons for the production of other heterocycles (76ZC270). 

Acyl (or 4-hydroxymethylene) isoxazolin-5-ones react with Grignard reagents to give 4-methyleneisoxazolin-5-ones (Scheme 57) 72M141613, 73UC1). In contrast, 4-acylisoxazol-ium salts under the same conditions produced tertiary alcohols (Scheme 57) (75MI41617). 

Hydroxymethylene-isoxazolin-5-ones undergo reaction with SOCI2 to form 4-chloromethylenes, with alcohols they form ethers (62HC(17)1, p. 7) and with amines aminomethylenes are obtained (Scheme 58) (73T4291, 60ZOB600). 

The treatment of ethyl Af-methyl-5-oxo isoxazoline-4-carboxylate with NaOH generated ethyl Af-methylmonomalonamide. The reaction in the case of 3-unsubstituted derivatives... 

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