Aromaticity, nitrile oxide cycloadditions, dipolar

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). 

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. 

A synthesis of novel spirodioxazole systems by the 1,3-dipolar cycloaddition reactions of 3,5-di-ferf-butyl-1,2-benzoquinone with aromatic nitrile oxides has been described (Scheme 1.31). Though yields are high (80%-100%), the regios-electivity is low, the regioisomer ratio 181 182 being dependent on the Ar nature (349). 

Of the 18 systems, some of which are unstable and must be generated in the reaction has been accomplished for at least 15, but not in all cases with a carbon-carbon double bond (the reaction also can be carried out with other double bonds ). Not all aUcenes undergo 1,3-dipolar addition equally well. The reaction is most successful for those that are good dienophUes in the Diels-Alder reaction (15-60). The addition is stereospecific and syn, and the mechanism is probably a one-step concerted process, as illustrated above, " largely controlled by Frontier Molecular Orbital considerations. " In-plane aromaticity has been invoked for these dipolar cycloadditions. " As expected for this type of mechanism, the rates do not vary much with changes in solvent, " although rate acceleration has been observed in ionic liquids. " Nitrile oxide cycloadditions have also been done in supercritical carbon dioxide. There are no simple rules... 

These experimental facts indicate that it is possible to synthesize differently bis-fimctionalized isoxazoles by cycloaddition of 6 with P-keto esters 34 direcdy. Among the numerous studies on nitrile oxides, only those examples in which a 1,3-dicarbonyl compound is employed as a dipolar-ophile are found in the literature (Scheme 9.14). Umesha et al. prepared 4-acetyl-3-arylisoxazoles by the cycloaddition of isolable aromatic nitrile oxides with acetylacetone 34b [59]. Suzuki and coworkers developed the cyclocondensation of hindered aromatic nitrile oxides with cyclic P-diketones, which was applied to the synthesis of natural products [60]. In these reactions, nitrile oxide was stable enough for isolation thus, a substituent at the 3-position of the cycloadducts was limited to an aromatic group. 

The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively <06JHC1045>. The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278... 

Diaz-Ortiz described the microwave-induced 1,3-dipolar cycloadditions of the me-sitonitrile oxide 10 with aliphatic and aromatic nitriles in solvent-free conditions [99]. The procedure allowed the corresponding heterocyclic adducts, the 1,2,4-oxadia-zoles 187, to be obtained in a domestic oven. The reaction times were shorter and the yields better than those seen with the classical homogeneous reactions (Scheme 9.57). 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

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). 

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2.5-/ra//.v-2.5-diphenylpyrrolidine-derived acrylamide and cinnamamide 399, efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides 400 in highly regio- and stereoselectivity (Scheme 1.47). Acid hydrolysis of these products affords enantiopure 4,5-dihydroisoxazole-5-carboxylic acids 401 (443). 

Alkynes add nitrile oxides and diazoalkanes to give isoxazoles (60) and pyrazoles (61), respectively, in 1,3-dipolar cycloadditions. If an alkene is used instead of an alkyne the non-aromatic analogues (62 Z = NH, O) result (94AHC(60)26l) yields are best when the alkene contains an electron-withdrawing substituent. 

Dipolar cycloadditions have been used successfully in assembling a number of these ring systems. Nitrile oxides, generated from a-chloro oximes and base, add to a wide range of aliphatic and aromatic aldehydes and ketones, but not to esters (Scheme 42), yielding... 

Recently, Biao et al. investigated an asymmetric induction in 1,3-dipolar cycloaddition reactions of nitrile oxides to chiral alkenes [53]. They found that the reaction between aromatic... 

Diaz-Ortiz described the microwave-induced 1,3-dipolar cycloadditions of mesi-tonitrile oxide to aliphatic and aromatic nitriles under solvent-free conditions. The adducts were obtained in shorter reaction times and better yields than with classical methods [84]. By the same approach, Corsaro reported the successful cycloaddition of arylnitrile oxides to naphthalene or aromatic polycyclic dipolaro-philes under solvent-free microwave activation [85]. In the same report, the yields of bis-cycloadducts were also improved by microwave exposure [85]. 

CAN-mediated nitration provides a convenient route for the introduction of a nitro group into a variety of substrates. Alkenes on treatment with an excess of sodium nitrite and CAN in chloroform under sonication afford nitroalkenes. When acetonitrile is used as the solvent, nitroacetamidation occurs in a Ritter-type fashion. However, the attempted nitroacetamidation of cyclo-pentene-1 -carboxaldehyde under similar conditions resulted in the formation of an unexpected dinitro-oxime compound. A one-pot synthesis of 3-acetyl- or 3-benzoylisoxazole derivatives by reaction of alkenes (or alkynes) with CAN in acetone or acetophenone has been reported. The proposed mechanism involves a-nitration of the solvent acetone, oxidation to generate the nitrile oxide, and subsequent 1,3-dipolar cycloaddition with alkenes or alkynes. The nitration of aromatic compounds such as carbozole, naphthalene, and coumarins by CAN has also been investigated. As an example, coumarin on treatment with 1 equiv of CAN in acetic acid gives 6-nitrocoumarin in 92% yield. ... 

Corsaro A, Chiacchio U, Librando V, Fisichella S, Pistara V (1997) 1,3-dipolar cycloadditions of polycyclic aromatic hydrocarbons with nitrile oxides under microwave irradiation in the absence of solvent. Heterocycles 45 1567-1572... 

Thus, in the presence of an Ru-catalyst (e.g., RuCl(cod)(C5Me5)), 3,4-disubstituted isox-azoles (15, R =H) are obtained as pure regioisomers [308]. In contrast, in the presence of Cu(I) salts (i.e., via Cu(I)-acetyHdes) the regiocomplementary 3,5-disubstituted isoxazoles (15, R =H) are formed exclusively [309]. Alternatively, 3,5-disubstituted isoxazoles can be regioselectively and efficiently prepared by 1,3-dipolar cycloaddition of aryl nitrile oxides with 1,1-disubstituted bromoalkenes followed by spontaneous aromatization of the 5,5-disubstituted bromoisoxazoline intermediates by loss of HBr [310]. 

The chemistry of the 1,3-dipole cycloaddition reaction, so elegantly elucidated by Professor Huisgen by the early 1960 s, appeared to be especially suited for the synthesis of aromatic polymers since the monomers could be recdily synthesized, and many of the dipolar additions gave high yields of 5-membered heterocyclic aromatic compounds. An inspection of the literature revealed that nitrili-mines, sydnones and nitrile oxide dipoles were especially suited. 

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