A,N-diphenylnitrones

Spiro-(indoline-isoxazolidines) 137, exhibiting interesting biological activities, were prepared in modest yields, by the cycloaddition reaction between ethyl (3-indolylidene)-acetate 135 and various substituted a,N-diphenylnitrones 136 under solvent-free conditions (Scheme 48). The reaction conducted under conventional heating in an oil bath did not proceed even after 20 h, especially when it was carried out without solvent [87]. 

Cycloaddition of a-aryl-A-phenylnitrones to the C16-C17 n-bond in 16-dehydropregnenolone-3P-acetate (545) involves only the minor rotamer (A-form) of the nitrones. It proceeds regio-, stereo- and Jt-facial-selectively to give steroido[16,17-d]isoxazolidines (546) in high yield (Scheme 2.257), (Table 2.24) (760). Similarly the cycloaddition of a,N -diphenylnitrones proceeds with five-membered heterocyclic enones (761). 

The cyclopropane diester (800) bearing a vicinal acetylenic moiety, when treated with Co2(CO)s, affords the formation of the dicobalt hexacarbonyl complex (801). It undergoes a smooth cycloaddition with a,N -diphenylnitrone, in the presence of Sc(OTf)3, to form the corresponding dicobalt hexacarbonyl complex of tetraydro-l,2-oxazine (802). De-complexation of adduct (802) gives 6-ethynyl-tetrahydro-l,2-oxazine (803) (Scheme 2.332) (856). 

Further comparisons of experimental versus estimated values are discussed, for example, for hydroxyureas [57]. Based on new experimental K0w for substituted a,N-diphenylnitrones and benzonitrile iV-oxides, Kirchner et al. [58] evaluated contributions for several iV-oxide groups for which contribution values were so far missing in the scheme of Hansch and Leo. Similarly, Finizio et al. [35] derived new contributions for three s-triazine groups. The groups and their contributions are shown in Figures 1.7.6 and 1.7.7. 

More recently, Parmar et al. reported the cydoaddition reaction between ethyl (3-indolylidene)acetate 122 and a variety of substituted a,N-diphenylnitrones 123 [93]. The regioisomeric adducts 124 and 125 were obtained without solvent within 4-5 min at 132-140 °C in 35-36% combined yields. Conventional heating in benzene at 60 °C for 150-180 h provided products in only 10-15% combined yields (Scheme 11.31). 

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. 

In all of the above reactions, a chiral center of the alkene was located in the allylic position. However, as shall be demonstrated next, more distant chiral centers may also lead to highly selective cycloadditions with 1,3-dipoles. In two recent papers, the use of exocyclic alkenes has been applied in reactions with C,N-diphenylnitrone (165,166). The optically active alkenes 109 obtained from (S)-methyl cysteine have been applied in reactions with nitrones, nitrile oxides, and azomethine ylides. The 1,3-dipolar cycloaddition of 109 (R=Ph) with C,N-diphenyl nitrone proceeded to give endOa-1 Q and exOa-110 in a ratio of 70 30 (Scheme 12.36). Both product isomers arose from attack of the nitrone 68 at the... 

A. N,oi-Diphenylnitrone. A solution of 27.3 g. (0.25 mole) of pure N-phenylhydroxylamine2 (Note 1) in 50 ml. of ethanol is prepared in a 200-ml. Erlenmeyer flask by swirling a mixture of the two and warming it briefly to 40-60° (Note 2). To the clear, lightly colored solution is added 26.5 g. (25.3 ml., 0.25 mole) of freshly distilled benzaldehyde (exothermic reaction). The flask is stoppered and kept overnight at room temperature in the dark. The colorless needles of N,a-diphenylnitrone are collected on a Buchner funnel and washed once with 20 ml. of ethanol There is obtained 42-43 g. (85-87%) of product (m.p. 111-113°), which can be further purified by dissolving the crude material in 80 ml. of ethanol and allowing the solution to cool for several hours in the ice box. In this manner there is produced 35-39 g. (71-79%) of pure crystalline nitrone, m.p. 113-114° (Note 3). 

Moreover, biotransformation of secondary arylalkylamines also affords nitrones. Thus, N-oxygenation of a series of 4-substituted iV-benzylanilines in liver microsomal preparations from various animal species has been detected to be a minor pathway of metabolism, usually generating a,7V-diphenylnitrones (34) in a species-dependent manner26. Nitrone formation was most abundant in liver, kidney and lung53. There was a clear sex difference... 

Not only Diels-Alder cycloadditions but also 1,3-dipolar cycloaddition reactions can be subject to hydrophobic rate enhancements. For example, the reaction of C,N-diphenylnitrone with di-n-butyl fumarate at 65 °C to yield an isoxazolidine is about 126 times faster in water than in ethanol, while in nonaqueous solvents there is a small 10-fold rate decrease on going from n-hexane to ethanol as solvent - in agreement with an isopolar transition-state reaction [cf. Eq. (5-44) in Section 5.3.3] [858]. Because water and ethanol have comparable polarities, the rate increase in water cannot be due to a change in solvent polarity. During the activation process, the unfavourable water contacts with the two apolar reactants are reduced, resulting in the observed rate enhancement in aqueous media. Upon addition of LiCl, NaCl, and KCl (5 m) to the aqueous reaction mixture the reaction rate increases further, whereas addition of urea (2 m) leads to a rate decrease, as expected for the structure-making and structure-breaking effects of these additives on water [858]. 

Similar attack of methanol on the presumed oxaziridine intermediate in the photolysis of C,N-diphenylnitrone led to the formation of 2- and 4-methoxyazoben-zenes."" The reaction converting dibenz[b,f] [l,4]oxazepine 60 to 2-(2-hydroxy-phenyl)benzoxazole 62 seems better explained by a nucleophilic substitution on protonated 61 than by the electrophilic process suggested by the authors. ... 

Detailed H NMR studies together with calculated conformations using MMX have been reported on tetrahydro-l,2-oxazepine derivatives (e.g., (21)) formed from [4 + 3] cycloadditions of C,N-diphenylnitrone with 1,3-dienes. The existence of two conformers with a slow rate of interconversion is indicated by the NMR data <89JOC5774>. 

As compared to the Diels—Alder reaction, the 1,3-dipolar cycloaddition of nitrones with olefins generally exhibits lower levels of regio- and stereo-control exolendo selectivity), which is a consequence of significant contribution by both LUMOdipoie-HOMOdipoiarophiie and HOMOdipoie LUMOdipoiarophiie interactions (Scheme 5.28). The process is further complicated by the possibility of interconversion of the nitrone geometry in the case of acyclic nitrones. For example, the cycloaddition between methyl acrylate and C,N-diphenylnitrone is only marginally in favor of the exo mode. 

Reduction of nitrones such as N,a-diphenylnitrone 962 a with equivalent amounts of methyllithium/857 in HMPA/THF, again generating MesSili 1883, affords the corresponding Schiff bases such as 964a in 84% yield [82] (Scheme 7.25). 

When the enantiomerically pure ketene acetal 16 was used, cycloaddition with N,a-diphenylnitrone (11) or chalcone (12) was achieved within 3 min in 98 and 96% yield, respectively. Under the same reaction conditions the use of classical heating in the absence of solvent at 120-124 °C for 3 min caused the yields to decrease to 3-4%. These results suggest that the excellent yields achieved by use of microwave irradiation are perhaps not entirely a result of the rapid heating of the reaction mass (Scheme 9.3). 

N,a-diphenylnitrone, 46,129 N,N -Diphenylethylenediamine, condensation with triethyl orthoformate, 47,14... 

The preparation of the oily ethyl 2,3-diphenyl-5-methyl-isoxazolidine-4-carboxylate provides another example of this reaction. As in the procedure described with styrene, 10.0 g. (50.7 mmoles) of N,a-diphenylnitrone is heated under nitrogen for 24 hours at 90-100° with 35.0 g. (38.0 ml., 307 mmoles) of ethyl crotonate. The excess olefin, b.p. 45° (12 mm.) is removed on the water pump, and the red-orange residue, while still warm, is transferred to a 50-ml. Claisen flask using acetone as a rinse. 

N,a-Diphenylnitrone, by condensation of N-phenylhydroxylamine with bcnzaldehyde, 46,127 1,3-dipolar cycloaddition to styrene, 46,128... 

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