Of nitrones

Fit a 3-litre rovmd-bottomed flask with a long reflux condenser and a dropping funnel (1). Place a mixture of 400 ml. of concentrated nitric acid and 600 ml. of water in the flask and heat nearly to boiling. Allow 100 g. (116 ml.) of cycZopentanone (Section 111,73) to enter the hot acid dropwise, taking care that the first few drops are acted upon by the acid, otherwise an explosion may occur the addition is complete in 1 hour. Much heat is evolved in the reaction so that the flame beneath the flask must be considerably lowered. Omng to the evolution of nitrons fumes, the reaction should be carried out in the fume cupboard or the fumes... 

The preparation of isoxazolidine derivatives was first reported by Bodforss in 1918 (18CB192). The major synthesis of isoxazolidines involves the cycloaddition of nitrones with alkenes, and isoxazolidines have also enjoyed an increasing use as key intermediates in the synthesis of natural products and other heterocycles (79ACR396, 1892CB1498, 1892CB3291, 1882CB2105). 

The chlorination of 3,5-dimethylisoxazole gave the 3,4-dichloro-4-isoxazoline (489) (77MIP41602). Additional 2-substituted 4-isoxazolines were prepared by the addition of nitrones to triple bonds (76AP1014, 77H(8)387, 70CB3196, 67AG(E)709, 69CB2346), as shown by the conversion of (490) into (491) (76AP1014). 

The addition of nitronic esters to alkynes to produce aziridines was postulated to proceed through a 4-isoxazoline as one of the intermediates (Scheme 132). A biradical intermediate (492) was also included in the mechanistic pathway for the reaction (77JA6667). 

Isoxazolin-5-imines were produced by nitrile oxide addition to cyanoacetates (62HC(17)l,p.7), by the reaction of nitrones with phenylacetonitrile (74CB13), and by base addition of nitrosobenzene to nitriles (Scheme 148) (72LA(762)154). 

The reaction of nitrones with allenes produced three main products an azepine, a pyrrolidinone and an isoxazolidine (Scheme 155) (79JOC4213). The intramolecular cycloaddition of nitrones (529) produced different products depending on the length of n (Scheme 156) (78H(10)257). 

A newer method for the preparation of nitronic esters, namely utilizing the (9-trimethyl-silyl ester, has been reported and these are prepared by the reaction of alkylnitro compounds and (V,(V-bis(trimethylsilyl)acetamide. These nitronic esters also undergo cycloaddition with alkenes to produce isoxazolidines (equation 54) (74MIP41601, 74DOK109, 78ACS(B)ll8). 

The cycloaddition of nitrones with ketenes produced 5-isoxazolidinones as well as oxazolones, as shown in Scheme 162 (78H(9)457, 79JOC2961). In a similar fashion, nitrones also react with ketenimines to generate the 5-isoxazolidinone imines (75JHC175, 68JHC881). 

A" -Isoxazolines, which are readily accessible by 1,3-dipolar addition of nitrones and nitronic esters to activated alkynes, undergo facile rearrangement upon warming (<110 °C)... 

In the discussion of some mass spectra of nitrones (41), intermediate isomerization to oxaziridines was concluded from the occurrence of aldehyde fragments. 

Oxaziridine formation by photoisomerization of nitrones was discovered almost simultaneously with the peracid procedure (58JOC65l>. The t-butyl nitrones of benzaldehyde and 4-nitrobenzaldehyde yielded about 90% of oxaziridines (254) and (255) on UV irradiation. 

From N-oxides of aromatic bases oxaziridines were obtained only at very low temperatures, but oxaziridines were often postulated as intermediates in the photoconversion of such N-oxides (Section 5.08.3.1.2). Isolation of the more stable photoisomers of nitrones also causes some problems due to their thermal and photochemical instability leading to acid amides, e.g. (69TL2281), or, by fragmentation, to carbonyl compounds and products of stabilization of nitrenes, e.g. from (260) (69ZN(B)477). 

Such syn stereoselectivity also was observed for a number of additions of nitrones to fluoroallene, such as its reaction with N-phenyl-C-phenyl nitrone [25, 26, 27] (equation 19)... 

Nitrone hydrate is converted into nitrone by boiling in benzene with azeotropic removal of water [48] (equation 50). This in situ formation of nitrone is carried out in the presence of various alkenes and alkynes, which undergo cycloaddition with the nitrone [48, 49] (equations 51 and 52). 

The cycloaddition of nitrones to enamines results in the formation of an isoxazolidine (179,180). The reaction of l-(N-pyrrolidino)- -phenyl-ethylene (133) with nitrone 134 producing isoxazolidine 135 illustrates this type of cycloaddition (180). 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

In alieyclic systems, more emphasis has been placed on oxidation of nitrones. At least one aldonitrone of the pyrroline series (62) undergoes autoxidation to the hydroxamic acid (63). This is probably a... 

Cationic complexes of rran.s-chelating tridentate ligand, (/ ,/ )-4,6-dibenzo-furandiyl-2,2 -bis(4-phenyloxazoline), with transition metal(II) perchlorates as effective catalysts for asymmetric cycloaddition of nitrones 98YGK368. 

Application in organic synthesis of optically active isoxazolidones obtained by asymmetric cycloaddition of nitrones with allenes 97T403. 

The 1,2,4-triazine 4-oxides 55 were synthesized by the reaction of nitrones 158 (generated from a-hydroxylamino ketones and aldehydes) with an excess of hydrazine, followed by the oxidation of the intermediate 4-hydroxy-2,3,4,5-tetrahydro-l,2,4-triazines 159 with lead(TV) oxide (73KGS134). 

The light sensitivity of nitrones in solution was observed by Kamlet and Kaplan, " who postulated the formation of oxaziranes. Krohnke formulated the rearrangement caused by light on a nitrone by using an oxazirane as an intermediate. Splitter and Calvin successfully isolated the rearranged products (9, 11, 12) and identified them as known oxaziranes [Eq. (6)]. 

The UV and IR spectra eliminate structures with a CN double bond. The isomerism of nitrones and oxaziranes thus cannot be a result of CIS or traris arrangement of substituents about a double bond. The carbon atoms of an oxazirane are still at the oxidation level of the carbonyl compound used in its syntheses. By acid hydrolysis, for example, 2-terf-butyl-3-phenyloxazirane (9) can be split into benzaldehyde and tert-butylhydroxylamine fEq. (8)]. ... 

Recently the synthetic method involving formation of the 1—5 and 3—4 bonds has been extended to the preparation of the completely hydrogenated system of A -substituted isoxazolidines (42). This interesting reaction results from 1,3-dipolar addition of nitrones (41) to olefins. " ... 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Further improvement of the reaction was achieved by applying ethyl vinyl ether 8a in the reaction instead of 8b (Scheme 6.12). The reactions between a series of nitrones la-d with 8a catalyzed by 10 mol% of 11b all proceeded to give the corresponding products 9 with excellent exo selectivity and with enantioselectivity of 88-97% ee in all cases [23]. 

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