Cycloadditions of nitrile oxides

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. 

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). 

A variety of 1-azirines are available (40-90%) from the thermally induced extrusion (>100 °C) of triphenylphosphine oxide from oxazaphospholines (388) (or their acyclic betaine equivalents), which are accessible through 1,3-dipolar cycloaddition of nitrile oxides (389) to alkylidenephosphoranes (390) (66AG(E)1039). Frequently, the isomeric ketenimines (391) are isolated as by-products. The presence of electron withdrawing functionality in either or both of the addition components can influence the course of the reaction. For example, addition of benzonitrile oxide to the phosphorane ester (390 = C02Et) at... 

Zinc-tartrate complexes were applied for reactions of both nitrones and nitrile oxides with allyl alcohol and for both reaction types selectivities of more than 90% ee were obtained. Whereas the reactions of nitrones required a stoichiometric amount of the catalyst the nitrile oxide reactions could be performed in the presence of 20 mol% of the catalyst. This is the only example on a metal-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrile oxides. It should however be no-... 

The cycloaddition of nitrile oxides 574 to vinyl sulphoxides usually produces a mixture of regio- and diastereoisomers. Their ratio is dependent on the nitrile oxide used and the configuration around the double bond in the starting sulphoxide (equation 365)673. 

The stereoselectivity of conjugate addition and cyclopropanation of the chiral nitrovinyldioxolanes 17 can be effectively controlled <96TL6307>, and good selectivity is observed in the ultrasound-promoted cycloaddition of nitrile oxides to alkenyldioxolanes 18 <95MI877,95JOC7701 >. Asymmetric Simmons-Smith cyclopropanation of 19 proceeds with... 

Nitro sulfides are useful intermediates for the preparation of various heterocycles containing sulfur atoms. Synthetic applications are demonstrated in Schemes 4.25 and 4.3,6 in which biotin is prepared via cycloaddition of nitrile oxides (see Chapter 8). 

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. 

Intramolecular 1,3-cycloadditions of nitrile oxides (INOC) provide a useful tool for the construction of fused cyclic ring systems. The stereochemical outcome of this reaction is presumed to be a consequence of reaction through the transition state that minimizes allylic 1,3 strain (Scheme 8.19).103... 

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

Compared with the related reactions of nitrones, there have only appeared a few publications of metal-assisted or metal-catalyzed 1,3-dipolar cycloadditions of nitrile oxides. This is due to... 

It has recently been found that Et2Zn promotes the 1,3-dipolar cycloaddition of nitrile oxides to allyl alcohol in the presence of catalytic amounts of diisopropyl tartrate (DIPT). By this method, 2-isoxazlines are obtained in good yields and up to 96% ee (Eq. 8.73).124a A positive nonlinear effect (amplification of ee of the product) has been observed in this reaction. There is an excellent review on positive and negative nonlinear effects in asymmetric induction.124b... 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

The process has been applied to the synthesis of a A9-19-nor-10-azatesto-sterone 378 by cycloaddition of nitrile oxide 377 to MCP followed by thermal rearrangement of the adduct (Scheme 52) [94]. 

Polymeric isoxazolines were prepared by cycloaddition of nitrile oxides to norbomadiene followed by ring-opening metathesis polymerization (ROMP) <06PLM3292 06MM3147>. 

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]. 

From the 1,3-dipolar cycloaddition of nitrile oxides to azomethines (imines) 291... 

The cycloaddition of nitrile oxides to nitriles in the presence of a Pd(ll) center allowed the isolation of the previously unknown l,2,4-oxadiazole-Pd(n) species 227 (Equation 44) <2005EJI845>. 

The cycloaddition of nitrile oxides to amidoximes 234 leads to 1,2,4-oxadiazole 4-oxides which can then be deoxygenated with trimethyl phosphite (Equation 48) <1997T1787>. 

The cycloaddition of nitrile oxide 235 to the 4-iminobenzopyran-2-one 236 gave the fully conjugated 1,2,4-oxadiazole 238 directly, a reaction that most likely proceeds via loss of methanol from the intermediate 237 (Scheme 36) <1996JHC967>. Similarly, nitrile oxide 239 reacted with imine 240 to give the 1,2,4-oxadiazole 242 via the nonisolable intermediate 241 <2002PJC1137>. 

In the scope of this subsection, competitive 1,3-cycloaddition of nitrile oxides to carbon-carbon and carbon-heteroatom multiple bonds are of special interest. Competition between carbon-carbon and carbon-nitrogen double bonds in... 

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. 

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

Regio- and diastereoselectivity in 1,3-dipolar cycloadditions of nitrile oxides to 4-substituted cyclopent-2-enones was studied (238, 239). The reactions are always regioselective, while the diastereofacial selectivity depends on the nature of the substituents. Thus, 4-hydroxy-4-methylcyclopent-2-enone (75) gives preferably adducts 76a, the 76a 76b ratio warying from 65 35 to 85 15 (Scheme 1.22). 

The cycloaddition of nitrile oxides RCNO (R = alkyl, alkenyl, aryl), generated in situ from either RCH2NO2/PI1NCO or RCH=NOH/NaOCl to (R)-( + )-limonene, proceeds regioselectively at the extracyclic double bond, but not stereospecifically, to form (5R/S )-isoxazoles 78 in 64% to 81% isolated yield (241). 

Fullerenes Cycloaddition reactions are very popular for functionalization of fullerenes. Such reactions of fullerenes are compiled and discussed in detail in Reference 253. During the last 10 to 15 years, several communications appeared concerning [3 + 2] cycloaddition of nitrile oxides to fullerene C60- Nitrile oxides, generated in the presence of C60, form products of 1,3-cycloaddition, fullerene isoxazolines, for example, 89. The products were isolated by gel permeation chromatography and appear by and 13 C NMR spectroscopy to be single isomers. Yields of purified products are ca 30%. On the basis of 13C NMR, structures with Cs symmetry are proposed. These products result from addition of the nitrile oxide across a 6,6 ring fusion (254). 

There are a few communications concerning cycloadditions of nitrile oxides to unsaturated oxa and aza cage systems. Benzo- and mesitonitrile oxides RCNO give, with five substituted 7-oxanorbomenes 106, mixtures of the corresponding exo-adducts 107 and 108 in nearly quantitative yields. No traces of compounds resulting from the endo-face attack was detected (274). Substituents at positions 5 and 6 of 106 render the process highly regioselective. 

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