Reactions of Nitrile Oxides 20

The addition of nitrile oxides to a,P-unsaturated carboxylic acid derivatives opens up a route to chiral, substituted isoxazoline derivatives. The nitrile oxides are generated in situ via deprotonation with a base (e.g. triethylamine) starting from the chlorinated aldoxime as the precursor (solvents CHCI3, CH2CI2, ether, benzene, toluene temperature -78°C up to 110°C). In most cases only one of two possible regioisomeric adducts is formed. 

In general, lower regioselectivities were observed with chiral p-substituted a,P-unsaturated carbonyl compounds compared to reactions involving acrylic derivatives. a,p-Unsaturated amides proved to be most effective. 

The chiral auxiliaries 9,13, 63 and 65 are easily removed with L-Selectride. 

In reactions of nitrile oxides with chiral electron-rich alkenes, e.g. vinylethers, only moderate diastereoselectivities were obtained. 

Asymmetric 1,3-dipolar cycloaddition of chiral vinylsulfoxides proceed regio- and stereoselectively. 

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The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

Table 10. Molecular mechanics calculations on the INOC reactions of nitrile oxides 98 (energies in kcal/mol)...

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. 

The reaction of nitrile oxides with nitrilium salts, which are more reactive than the corresponding nitriles, as discussed in CHEC-II(1996) <1996CHEC-II(4)179>, is the main route through to oxadiazolium salts. Further advances in this area have not been reported. 

Some routes of chemical transformations of nitrile oxides connected with the problem of their stability were briefly discussed in Section 1.2. Here only two types of such reactions, proceeding in the absence of other reagents, viz., dimerization to furoxans and isomerization to isocyanates, will be considered. All other reactions of nitrile oxides demand a second reagent (in some cases the component is present in the same molecule, and the reaction takes place intramolecularly) namely, deoxygenation, addition of nucleophiles, and 1,3-dipolar cycloaddition reactions. Also, some other reactions are presented, which differ from those mentioned above. 

Addition of C-nucleophiles to nitrile oxides is of special interest. There are examples of reactions with both carbanions and neutral carbon nucleophiles. To the former group belong reactions of nitrile oxides with organometallic... 

Dipolar cycloaddition reactions are of main interest in nitrile oxide chemistry. Recently, reviews and chapters in monographs appeared, which are devoted to individual aspects of these reactions. First of all, problems of asymmetric reactions of nitrile oxides (130, 131), including particular aspects, such as asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions (132, 133), development of new asymmetric reactions utilizing tartaric acid esters as chiral auxiliaries (134), and stereoselective intramolecular 1,3-dipolar cycloadditions (135) should be mentioned. Other problems considered are polymer-supported 1,3-dipolar cycloaddition reactions, important, in particular, for combinatorial chemistry... 

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). 

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. 

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. 

The 1,3-dipolar cycloaddition reactions of nitrile oxides to unsymmetrically substituted norbomenes (243) and to dicyclopentadiene and its derivatives (244) proceed with complete stereoselectivity. The approach of the dipole takes place exclusively from the exo-face of the bicycloheptane moiety, generally... 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

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... 

Among six-membered unsaturated nitrogen heterocycles, cycloaddition reactions of nitrile oxides at the C=N bond have been described for individual... 

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