Cycloaddition /reactions nitrile oxides

It was found that 2-propenyloxymagnesium bromide reacts much more readily with nitrile oxides than other known dipolarophiles of electron-deficient, electron-rich, and strained types, including 3-buten-2-one, ethyl vinyl ether, and norbomene, respectively (147). Therefore, this BrMg-alkoxide is highly effective in various nitrile oxide cycloaddition reactions, including those of nitrile oxide/Lewis acid complexes. 

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). 

N/L recorded was 16,000 for the reactions using the magnesium aUcoxide of 3-methyl-2-buten-l-ol as a multisubstituted internal allylic alcohol substrate, which is why regiocontrol is still effective in the reactions in a highly coordinating solvent such as THE. Rate enhancement is much lower in the nitrile oxide cycloaddition reactions using homoallylic alcohol substrates. 

Many groups have tackled the development of catalytic asymmetric versions of nitrile oxide cycloaddition reactions using chiral Lewis acid catalysts. However, Ukaji is the first and the only chemist who has succeeded in the achievement of such processes involving nitrile oxide cycloaddition reactions. He studied reactions... 

N. P. Peet, E. W. Huber, and R. A. Farr, Diastereoselectivity in the intramolecular nitrone, oxime, and nitrile oxide cycloaddition reactions, Tetrahedron 47 7537 (1991). 

An intramolecular nitrile oxide cycloaddition reaction of a 1,3-dioxolane monocyclic precursor provided the construction of the two five-membered rings of the isoxazoline (32), a precursor to prostaglandin F2a (Equation (12)) <84JOC230l>. 

Aspects of the stereoselectivity of nitrile oxide cycloaddition reactions have been reviewed (89G253). The most obvious stereochemical consequence of the cycloaddition is that the configuration of the alkene is retained in the product isoxazoline and this feature continues to be exploited in asymmetric synthesis. For example, the dehydrophenylalanine derivatives (42) gave the corresponding isoxazolines (43), stereospecifi-cally (Scheme 23) (91JHC1945). 

In this chapter we have attempted to summarize recent trends in nitrile oxide cycloaddition reactions of alkenes. We hope that this overview will stimulate and encourage continued work in the field. 

The inside alkoxy effect is useful for predicting the stereoselectivity of nitrile oxide cycloaddition reactions with chiral lylic ethers. The hypothesis states that allylic ethers adopt the inside position and alkyl substituents prefer the sterically less-crowded anti conformation in transition states for these electrophilic cycloadditions . The terms inside and outside are defined in (17) for a hypothetical nitrile oxide cycloaddition transition state. Both ab initio (Gaussian 80 with 3-2IG basis set) and molecular mechanics calculations agree, each predicting the lowest-energy transition state to be the one described, i.e. (18 H outside) just above it lies one where the alkyl group is anti, OR outside and H inside (19 ). As illustrated, the former leads to a product wherein OR and the nitrile oxide oxygen are anti, the latter to one with them syn (Scheme 19). 

Other cascade sequences have also been observed to occur from the thermolysis of isoxazolines, thereby increasing the utility of the nitrile oxide cycloaddition reaction. For example, in the context of synthesizing testosterone derivatives, Guarna and coworkers reported that the reaction of a nitrile oxide derived from oxime 89 with 76 gave isoxazoline 90 (Scheme 15) (91TL6395). Hydrolysis of the ketal moiety provided cycloadduct 91, which was heated at reflux in DMF to furnish 92 in 30% yield. 

Intramolecular nitrile oxide cycloaddition reactions were found to have a widespread application in the syntheses of many different molecular frameworks. (For recent examples see references 388 397.) The stereochemical outcome of these reactions depends on ... 

There are few reports of intramolecular nitrile oxide cycloaddition reactions in which the stereochemical course is ruled by an allylic stereocenter outside the tether206 208. The following is one example207. 

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