N- nitrones

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. 

Enantioselective hydroxylation of the double bond in C=N nitrones with diphenylsilane, using RU2CI4-I(S)-(—)-p-tolbinap 2(NEh) [p-tolbinap = 2, 2 -bis(di-p-tolylphosphino)-1,1 -binaphthyl] as a catalyst at 0°C, gives the corresponding optically active /V,N -disubstituted hydroxylamines (482). 

Reductive Cross-Coupling of Nitrones Recently, reductive coupling of nitrones with various cyclic and acyclic ketones has been carried out electrochem-ically with a tin electrode in 2-propanol (527-529). The reaction mechanism is supposed to include the initial formation of a ketyl radical anion (294), resulting from a single electron transfer (SET) process, with its successive addition to the C=N nitrone bond (Scheme 2.112) (Table 2.9). 

Dichloro-2 -nitro-N-nitron i lino )-ethanol Nitrate, (02N)C6H2 (Cl2 ) N(N02 ) ... 

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). 

Like isomerization of oxaziridines to nitrones, acid hydrolysis of oxaziridines proceeds with conservation of the N—O bond. Both reactions are related mechanistically and are... 

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). 

Hydroxy-5a-pregn-l-ene-3,20-dione (44). To a solution of 7.7 g (15.6 mmoles) of the nitrone (43) in 300 ml of benzene is added 500 ml of 2 A hydrochloric acid, whereupon the deep-red benzene solution immediately turns green. The resulting mixture is stirred for 12 hr and the layers are then separated. The aqueous layer is extracted with three 300-ml portions of benzene the combined benzene layers are washed with 2 N hydrochloric acid and with water, and then dried over sodium sulfate. The benzene is evaporated under reduced pressure to give 4.8 g (93 %) of the diosphenol (44). 

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)... 

Nitrones are among the most highly studied and useful reagents for the synthesis of five-membered-nng heterocycles. The first fluonnated nitrone, N-methyl-C-(trifluoromethyl)nitrone, was prepared recently and used to introduce Irifluoromethyl groups into such heterocycles... 

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). 

While pyridine N-oxide does not react with enaniines in the absence of an acylating agent, other nitrone systems have formed adducts (615,616). 

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. 

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

Among the J ,J -DBFOX/Ph-transition(II) metal complex catalysts examined in nitrone cydoadditions, the anhydrous J ,J -DBFOX/Ph complex catalyst prepared from Ni(C104)2 or Fe(C104)2 provided equally excellent results. For example, in the presence of 10 mol% of the anhydrous nickel(II) complex catalyst R,R-DBFOX/Ph-Ni(C104)2, which was prepared in-situ from J ,J -DBFOX/Ph ligand, NiBr2, and 2 equimolar amounts of AgC104 in dichloromethane, the reaction of 3-crotonoyl-2-oxazolidinone with N-benzylidenemethylamine N-oxide at room temperature produced the 3,4-trans-isoxazolidine (63% yield) in near perfect endo selectivity (endo/exo=99 l) and enantioselectivity in favor for the 3S,4J ,5S enantiomer (>99% ee for the endo isomer. Scheme 7.21). The copper(II) perchlorate complex showed no catalytic activity, however, whereas the ytterbium(III) triflate complex led to the formation of racemic cycloadducts. 

Kobayashi and co-workers reported similar enantioselectivity switch in the bi-nol-yterrbium(III) triflate complex-catalyzed cycloaddition reactions [69] between N-benzylidenebenzylamine N-oxide and 3-crotonoyl-2-oxazolidinone [70]. The reaction in the presence of MS 4 A showed an exclusively high enantioselectivity of 96% ee, while that in the absence of MS 4 A (-50% ee) or in the presence of pyridine N-oxide (-83% ee) had the opposite enantioselectivity (Scheme 7.24). This chirality switch happens generally for the combination of a wide variety of nitrones and dipolarophiles. 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-l,2-oxazine N-oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at -40 °C in dichloro-methane in the presence of MS 4 A and l ,J -DBFOX/Ph-Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-fe][l,2]oxazines as the ring-fused isoxazolidines in high yields. The J ,J -DBFOX/Ph aqua complex prepared from... 

Monodentate dipolarophiles such as acrolein, methacrolein, and a-bromoacrolein could be successfully utilized in the l ,J -DBFOX/Ph-transition metal complex-catalyzed asymmetric nitrone cycloadditions [76]. The reactions of N-benzylideneani-line N-oxide with acrolein in the presence of the nickel(II) aqua complex R,R-DBF0X/Ph-Ni(C104)2 3H20 (10mol%) and MS 4 A produced a mixture of two regioisomers (5-formyl/4-formyl regioisomers ca 3 1). However, enantio-... 

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