4-Methylene isoxazolines

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). 

Ethyl acetoacetate and hydroxylamine with a large excess of alkali produced (516) which on heating generated 4-methylene-2-isoxazoline (517), while limited base generated the dimer (518) (80JHC763). 

In the cycloaddition of nitrile oxide 79a with 1,1-diphenyllallene, the nitrile carbon atom of 79a is selectively attached to the central carbon atom (C2) of the allene. The cycloaddition takes place at both the C1-C2 and C2-C3 double bonds of the allene to give a mixture of 4-methylene-2-isoxazolines [80],... 

Reactions of isoxazolylmethylzinc reagent 35 with aromatic (or heteroaromatic) aldehydes afforded 4-methylene isoxazolines 36. Reductive cleavage of the N—O bond of 37 provided the highly functionalized aldol-type products 38 (14CEJ14096). 

The work of Garranti and Zecchi provides additional examples in which cyclization was shown to occur with alkynes and alkenes. They have, however, identified further limitations regarding chain length and hence ring size of final products. Pocar and co-workers have illustrated the intermolecular version of this reaction by use of nitrile oxides and tran5-1,3-diaminopropenes. A base is necessary for reaction to occur, and of several tried, triethylamine proved superior. The exo-methylene isoxazolines (363) were obtained after elimination of one of the amino-functions. When sodium methoxide in methanol was used, however, the reverse elimination occurred to give the isoxazole (362) (Scheme 52). 

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]. 

IsoxazoIine, 5-isocyanato-3-phenyI-pyrolysis, 6, 39 2-Isoxazoline, 4-methylene-synthesis, 6, 91... 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

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. 

Dipolar cycloadditions of ( -phenyl-/V-methylnitrone (585) to Baylis-Hillman adducts such as ( 3-hydroxy-a-methylene esters) (608-610) proceed with complete regioselectivity in good yields to afford the corresponding diastere-omeric 3,5,5-trisubstituted isoxazolines (611-613) (Scheme 2.269). Attack by the dipole in (585) from the less sterically hindered side of dipolarophiles (608-610) affords C-3/C-5 cis isoxazolidines (611a,b-613a,b) as the major products (780). 

Methylene sugars are versatile starting compounds for the synthesis of aromatic and hydroxymethyl C-glycosyl compounds (71) and of double-ended C-glycosyl compounds (70). The double bond undergoes 1,3-dipolar cycloadditions to give isoxazoline derivatives (71), such as that used as a model for the synthesis of tunicamycin. Also, reaction with iodonium sym-... 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazolines, the application of Lewis acid catalysis to nitrile oxide cycloadditions with Achiral 3-(2-alkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ft-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

The reaction of methylene triphenylarsorane with benzonitrile oxide in DMSO gave rise to 3,5-diphenylisoxazole (53) along with the 3-phenyl-4-benzoyl-2-isoxazoline oximes 54 and 55 ( /). When the reaction took place in ether instead of DMSO, a mixture of 3,5-diphenyl-l,2,4-oxadiazole (56) and 3,5-diphenylisoxazole (53) was obtained (31). 

With 1-phenylsulfinylallene, the residual double bond is found mainly at the 5-position in the cycloadduct (85SC663), whereas nitrogen-substituted allenes afford mainly 4-methylene-substituted isoxazolines [90JCS(P1)533 91JCS(P1)1843]. The regioselectivity of addition to 1-fluoro- and 1,1-difluoro-allene depends on the nitrile oxide and is thought to reflect the... 

Yuan, C., and Li, C., SIndies on organophosphorus compounds. Part 67. Reactions of a-nitroalkenes with compounds bearing active methylene groups. A novel and convenient synthesis of 2-isoxazoline derivatives, Phosphorus, Sulfur Silicon Relat. Elem., 78, 47, 1993. 

The 1,3-dipolar cycloaddition of exocyclic methylenes with nitrile oxides has already been addressed in section 2.13.10 This work, shown in Scheme 8.4.2, is notable in that high stereoselectivity in the resulting isoxazoline can be obtained. This is presumably the consequence of the bulk of the nitrile oxide directing approach to the a face of the sugar methylene. Through the use of these reactions, C-disaccharides, bridged by isoxazoline rings have been made accessible. 

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