Cycloaddition of nitrile oxides with alkenes

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. 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

Ukaji and co-workers (379-381) described the first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrile oxides with alkenes. Upon treatment of allyl alcohol with diethylzinc and (7 ,/ )-diisopropyl tartrate followed by the addition of diethylzinc and substimted hydroximoyl chlorides 274, the isoxazoli-dines 275 are formed with enantioselectivities of up to 96% ee (Scheme 12.87). 

Pei Y, Moos WEI, Post-modification of peptoid side chains (3 + 2) cycloaddition of nitrile oxides with alkenes and alkynes on the solid-phase, Tetrahedron Lett., 35 5825-5828, 1994. 

Dipolar cycloadditions of nitrile oxides with alkenes or alkynes give isoxazolines or isoxazoles, respectively. Typically, nitrile oxides are generated in situ, and the cycloaddition reaction occurs smoothly at room temperature. Awide variety of nitrile oxide cycloadditions have been studied on solid support since Yedidia and Leznoff published their smdies in 1980. ° Dimerization of the nitrile oxides has limited the utility of nitrile oxide cycloadditions in solution. Solid-supported reactions enabled the formation of resin-bound nitrile oxide in situ and trapped the reactive 1,3-dipole with an excess of the dipolarophile in solution (Scheme 11.32). Trityl resin-bound cycloadducts were then cleaved with highly diluted trifluoroacetic acid and the products were obtained as phenols. 

Pei1994 Pei, Y. and Moos, W.H., Post-Modification of Peptoid Side Chains [3+2] Cycloaddition of Nitrile Oxides with Alkenes and Alkynes on the Solid-Phase, Tetrahedron Lett., 35 (1994) 5825-5828. 

This result prompted us to first apply the strategy to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides, which had not been developed when our research project started. The idea was presented as follows when nitrile oxide is generated in situ from hydroximoyl chloride by treatment with ethylzinc moiety as abase, the stereochemical course of nitrile oxide coordinated to the chiral zinc species 5 was anticipated to be controlled efficiently. In accordance with this hypothesis, the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allylic alcohols was realized to afford the corresponding 2-isoxazolines 6 with excellent enantioselectivity (Eq. 11.3). Even when a catalytic amount (0.2 equiv) of diisopropyl (R,/f)-tartrate [(R,/ )-DlPT] was employed, the 2-isoxazolines 6 were obtained with the selectivity of up to 93% ee by the addition of a small amount of 1,4-dioxane (Eq. 11.4). This method was the first catalytic enantioselec-tive 1,3-dipolar cycloaddition of nitrile oxides with alkenes. The method was efficiently applied to the total synthesis of (—)-Lasubine 11 (Scheme 11.2) [11]. 

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). 

Cycloaddition of nitrile oxides to alkenes with various chiral auxiliaries are summarized in Table 8.1, which shows chiral alkenes and differential excess (de). 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

One obvious synthetic route to isoxazoles and dihydroisoxazoles is by [3+2] cycloadditions of nitrile oxides with alkynes and alkenes, respectively. In the example elaborated by Giacomelli and coworkers shown in Scheme 6.206, nitroalkanes were converted in situ to nitrile oxides with 1.25 equivalents of the reagent 4-(4,6-di-methoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 10 mol% of N,N-dimethylaminopyridine (DMAP) as catalyst [373], In the presence of an alkene or alkyne dipolarophile (5.0 equivalents), the generated nitrile oxide 1,3-dipoles undergo cycloaddition with the double or triple bond, respectively, thereby furnishing 4,5-dihydroisoxazoles or isoxazoles. For these reactions, open-vessel microwave conditions were chosen and full conversion with very high isolated yields of products was achieved within 3 min at 80 °C. The reactions could also be carried out utilizing a resin-bound alkyne [373]. For a related example, see [477]. 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

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). 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

A novel class of activators for chloride conductance in the cystic fibrosis transmembrane conductance regulator protein has been identified. These 3-(2-benzy-loxyphenyl)isoxazoles and 3-(2-benzyloxyphenyl)isoxazolines have been synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with various alkene and alkyne dipolarophiles (490). 

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

Extensive work has been done to determine and understand the factors controlling diastereoselectivity in the cycloaddition of nitrile oxides to alkenes but very little is known about nitrile ylides in this regard. Work on their reactions with alkenes that are geminally disubstituted with electron-withdrawing groups (e.g., 187) has illustrated some of the difficulties in such studies. When the imidoyl chloride-base route was used to generate the nitrile ylides it was found that the products 188 epimerized under the reaction conditions. When the azirine route was used, the reaction was complicated by the photochemical isomerization of the dipolarophiles (96,97). Thus, in both cases, it proved impossible to determine the kinetic product ratio. 

G. P., Simpson, G. P., Cycloaddition Reactions of Nitrile Oxides with Alkenes, 60, 261. 

Cycloaddition Reactions of Nitrile Oxides with Alkenes... 

Finally, C. J. Easton, C. M. M. Hughes, G. P. Savage, and G. W. Simpson (Adelaide and Melbourne, Australia) review the cycloaddition reactions of nitrile oxides with alkenes. Although previous reviews of this subject have appeared, the synthetic potential of this reaction has recently been the object of intensive study. 

The Nitrile Oxides , Grundmann, C. and Griinanger, R, Springer-Verlag, Berlin and New York, 1971 Cycloaddition reactions of nitrile oxides with alkenes , Easton, C. J., Merricc, C., Hughes, M., Savage, G. P. and Simpson, G. W.,Adv. Heterocycl Chem., 1994, 60, 261. 

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