Nitrile oxide dipole

Dimethyl 7-10-tetrahaptotricyclo[4.2.2.02 5]deca-3,7,9-triene-7,8-dicarboxy-late tricarbonyliron reacted readily with several 1,3-dipoles nitrile oxides, at the cyclobutene double bond, to give adducts from which the tricarbonyliron group could be easily removed by oxidative decomplexation with trimethylamine N-oxide (237). 

A characteristic feature of contemporary investigations in the held under consideration, is the interest in cycloaddition reactions of nitrile oxides with acetylenes in which properties of the C=C bond are modified by complex formation or by an adjacent metal or metalloid atom. The use of such compounds offers promising synthetic results. In particular, unlike the frequently unselec-tive reactions of 1,3-enynes with 1,3-dipoles, nitrile oxides add chemo-, regio-and stereoselectively to the free double bond of (l,3-enyne)Co2(CO)6 complexes to provide 5-alkynyl-2-oxazoline derivatives in moderate to excellent yield. For example, enyne 215 reacts with in situ generated PhCNO to give 80% yield of isoxazoline 216 (372). 

We have already mentioned the synthetic versatility of silyl thioketones249 which is confirmed because they react with 1,3-dipoles (nitrile oxides, nitrile imines and nitrile ylides) to give regiospecifically silyl thiaheterocycles462. Equation 135 illustrates the reaction between phenyl trimethylsilyl thioketone and diphenyl nitrihmine. 

Far more interesting are the elimination sequences which lead to the generation of reactive heterocumulenes (ketenimines, carbodiimides, isocyanates, isothiocyanates) or 1,3-dipoles (nitrile oxides, nitrile imides, nitrile... 

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

The A-benzenesulfonyl imines of hexafluoroacetone readily react with nitrile oxides to give [3-1-2] adducts, apparently in a multistep reaction [151] (equation 36) Although only a few examples of [3-1-2] cycloaddition reactions of this type have been descnbed so far, most 1,3-dipoles should react in this way with predictable regiochemistry [5 146, ISO 151]... 

Isothiazolylphosphonate 29 (Section II.B.2) reacted with 1,3-dipoles such as diazomethane and nitrile oxides, affording regioselectively 30a,b or 32. By reacting 30b and 32 with bases, pyrazolylphosphonate 31 and isoxazolylsulfonamide 33 were obtained (01T(57)5453). 

For the reactions of other 1,3-dipoles, the catalyst-induced control of the enantio-selectivity is achieved by other principles. Both for the metal-catalyzed reactions of azomethine ylides, carbonyl ylides and nitrile oxides the catalyst is crucial for the in situ formation of the 1,3-dipole from a precursor. After formation the 1,3-di-pole is coordinated to the catalyst because of a favored chelation and/or stabiliza-... 

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

Some researchers have elaborated synthesis of PCSs employing bis(nitrile oxide)s as 1,3-dipoles and diynes, dinitriles, and a number of other compounds as dipolaro-philes154-156). 

The intermolecular dimerization of nitrile oxides has been described as a procedure to prepare Fx with identical substituent both in the 3 and 4 position (Fig. 3). This procedure is a [3 -F 2] cycloaddition where one molecule of nitrile oxide acts as 1,3-dipole and the other as dipolarophile [24-26]. Yu et al. has studied this procedure in terms of theoretical calculus [27,28]. Rearrangement of isocyanates competes with the bimolecular dimerization, with the former becoming dominant at elevated temperatures. 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

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. 

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-... 

Nitrile oxides are very reactive dipoles which, apart a few members, need to be prepared in situ for their tendency to dimerize to furoxans [86], This behaviour represents a limit to their use with alkylidenecyelopropanes that is only in part compensated by their reactivity. The cycloadditions of several nitrile oxides with alkylidenecyelopropanes were extensively studied in connection with the rearrangement process leading to dihydropyrid-4-ones 336 [64, 87],... 

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]. 

Microwave irradiation has been extensively employed to generate nitrile oxides and to promote 1,3-dipolar cycloadditions of the previously prepared dipole. 

The 1,3-dipoles were generated by the addition of Et3N in 20% excess. Only imidazole was basic enough to generate a nitrile oxide in the absence of triethy-lamine. Due to prototropic tautomerism, reactions of triazoles and tetrazoles led to mixtures of two isomers. With unsubstituted pyrazole and imidazole only one hydroximoylazole was formed (117). 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

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... 

Similarly, other cycloadducts of nitrile oxides with C6o were synthesized. The cycloadducts were characterized by 13C NMR spectroscopy and high-resolution fast atom bombardment (FAB) mass spectrometry. It should be mentioned that X-ray structure determination of the 3-(9-anthryl)-4,5-dihydroisoxazole derivative of C6o, with CS2 included in the crystals, was achieved at 173 K (255). Cycloaddition of fullerene C60 with the stable 2-(phenylsulfonyl)benzonitrile oxide was also studied (256). Fullerene formed with 2-PhSC>2C6H4CNO 1 1 and 1 2 adducts. The IR, NMR, and mass spectra of the adducts were examined. Di(isopropoxy)phosphorylformonitrile oxide gives mono- and diadducts with C60 (257). Structures of the adducts were studied using a combination of high performance liquid chromatography (HPLC), semiempirical PM3 calculations, and the dipole moments. 

The 1,3-dipolar cycloaddition reactions of the chiral 3-benzoyl-4-methylene-2-phenyloxazolidin-5-one 118 and nitrile oxides RCNO (R = Ph, Me) had the expected stereochemistry, addition of the 1,3-dipole having occurred from the less hindered n-face of the exocyclic methylene of 118 (282). 

Aldimines, Ketimines, and Related Compounds as Dipolarophiles Reactions of aldimines with nitrile oxides proceed readily to give 1,2,4-oxadiazolines independently of the nature of substituents both in dipole and dipolarophile molecules. 1,2,4-Oxadiazolines were prepared by the regiospe-cihc 1,3-dipolar cycloaddition of nitrile oxides with fluoro-substituted aldimines (295). Phosphorylnitrile oxides gave with azomethines, PhCH NR, phosphory-lated 1,2,4-oxadiazolines 129 (296). Expected 1,2,4-oxadiazolines were also obtained from azomethines, derived from 4-formylcoumarine (179) and 1,3-diphenylpyrazole-4-carbaldehyde (297). 

Cycloaddition at C=C Bonds Cycloaddition of nitrile oxides to triple carbon-carbon bonds is a rather trivial reaction. Therefore, most attention is to new types of dipoles and dipolarophiles as well as to unusual reaction routes... 

It is of interest to mention that DFT study performed, prior to experimental observations, revealed for Cu(I)-catalyzed cycloaddition of nitrile oxides to 1-alkynes, a stepwise mechanism involving unprecedented metalacycle intermediates, which appear to be common for a variety of dipoles (382). 

The intramolecular cycloaddition reactions of the nitrile oxides 357 (n = 1, 2, 3, 9), obtained in situ from the 2,5-difunctional furan hydroximoyl chlorides or nitro compounds (415) has specific features because of the 2,5-arrangement of two open chains bearing acetylenic and fulminic moieties. Only with 357 (n = 3) is the expected furanoisoxazolophane 358 formed, in acceptable yield. Compound 357 ( =9) gives a complex product mixture whereas 357 ( = 1, 2) gives rise to the exclusive reaction of the dipole with a double bond of the furan system. 

The stereoselectivity of the INOC process substantially differs from that of the ISOC process, the stereoselectivity of the ISOC process being generally much higher. Evidently, this is due to a considerable differentiation of the transition states. It gives to different stereoisomers due to higher hindrance of the nitronate dipole compared to the linear nitrile oxide dipole. 

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