Formation of Nitrones

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 

Heterocyclic secondary amines, such as phenmetrazine or (—)-anabasine, a minor tobacco alkaloid, undergo metabolic attack at the amino groups to finally yield nitrones 37 and 38, respectively, when incubated with tissue preparations from various mammals90,91. 

Incorporation of IV-methylbenzamidine in hepatic microsomes from rabbits affords the tautomeric a-aminonitrone 39, a completely new type of metabolite50. 

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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 required nitro compounds are easy to prepare, and are useful building blocks for synthesis. Treatment with an appropriate base—e.g. aqueous alkali—leads to formation of nitronates 2. Various substituted nitro compounds, such as nitro-ketones, -alcohols, -esters and -nitriles are suitable starting materials. 

The use of m-CPBA allows the formation of nitrones in the oxidation of tertiary amines. The resulting amines A-oxides are subject to either Cope or Meisenheimer rearrangements, providing formation of nitrones. Thus, the generated corresponding nitrones in the oxidation of bicyclic aziridines give nitrones as a result of a Meisenheimer rearrangement (Scheme 2.14) (93). 

Oxidation of lappaconitine and elatine alkaloids leads to de-ethylation by a Cope reaction, with the formation of nitrones (Scheme 2.15) (94). 

Selective formation of nitrones can be achieved using Pd (II) [Pd(cod)Cl2] as a catalyst, in the reaction of oximes with allylic acetate (Scheme 2.49) (303). 

Formation of nitrones can be achieved in the first stage of a Krohnke type reaction in which p-n trosodi methy 1 an dine reacts with 2-oo-bromoacetylphenoxathiin in alkaline medium (336). The synthesis of a series of cyclic nitrones of structure (182) has been achieved by regioselective, and by an unusual [3 + 2] cycloaddition of a-nitrosostyrenes (181) to 1,3-diazabuta-l,3-dienes (180) (Scheme 2.64) (337a). Theoretical studies of the substitution effect at the imine nitrogen on the competitive [3 + 2] and [4 + 2] mechanisms of cycloaddition of simple acyclic imines with nitrosoalkenes have been reported (337b). 

Other experiments suggest that nitrone deoxygenation proceeds through intermediate formation of nitrone RC, rather than the product of its isomerization, a oxaziridine (441). 

The involvement of olefins containing vicinal alkoxy- and acetoxy groups in this synthesis always leads to the formation of nitronate (35) containing the alkoxy group at the C-6 atom. 

Evidently, this approach is not limited to the formation of nitronates, nitroso acetals or enoximes. The rearrangements of these compounds by elimination reactions, the trapping of intermediates and finally their reactions with various reagents are of equal importance. It should be emphasized that silylation of AN as a process in organic chemistry is characterized by an unrivalled completeness and diversity of transformations. Hence, the silylation can be considered as a separate field of application of AN in organic synthesis. 

Reactions of alkenes such as 120 with a-chloronitrosoalkanes of type 119 proceed under very mild conditions and result in the formation of nitrones 121 that can be easily hydrolyzed into hydroxylamines 122 (equation 86) . Chiral carbohydrate-derived a-chloronitrosoalkenes 123 possess enhanced reactivity and produce good stereoselectivity in reaction with prochiral alkenes such as 124 (equation 87) . ... 

Oxidation of secondary amines with oxaziridine 144 provides moderate yields of hydroxylamines 145, although overoxidation invariably results in formation of nitrones 146 (equation 96). ... 

The in situ formation of nitrones from oximes by 1,3-APT or 1,2-prototropy is clearly a powerful synthetic strategy but conventional nitrone generation, in particular hydroxylamine-carbonyl condensation, has been applied to numerous syntheses, in intra- and intermolecular mode (258). Accordingly, the ring systems similar to those synthesized using 1,3-APT/intramolecular nitrone-alkene cycloaddition (INAC) methodology by Heaney (313-315) (see Section 1.11.2) or Padwa and Norman (340) have been made using conventionally prepared nitrones (Scheme 1.67). As with the previous examples, once formed, the nitrones are suitably placed for a spontaneous intramolecular cycloaddition reaction with the... 

This conclusion has been confirmed by other authors (79CB2769) who examined the addition of monosubstituted hydroxylamines to various acetylenes. In most cases, they observed the formation of nitrones. With phenyl cyanoacetylene, however, the diadduct 160 was obtained due to participation of both the N—H and O—H bonds (Scheme 82). 

Influence of different PTCs and pH values on the formation of nitrones... 

Imines are oxidized by peroxy acids to oxaziridines, with the formation of nitrones as a competing process (Scheme 25).Oxaziridines are probably formed by a two-step process involving nucleophilic addition of the peroxy acid to the CWN bond, followed by elimination, as illustrated nitrones are formed by competing N-oxidation. The oxidation of chiral imines to oxaziridines by MCTBA proceeds with good, but not complete, diastereoselectivity. ... 

The formation of nitrones by reaction of aldehydes and ketones v/ith N-Methyl-N,0-bis(trimethylsilyl)hydroxylamine is accelerated when TMSOTf is used as a catalyst the acceleration is particularly pronounced when the carbonyl group is under a strong electronic influence (eq 20). ... 

Cyclization by Addition of Amines to Multiple Bonds of Carbohydrate Substrates. A versatile unsaturated aldehydic intermediate derived from D-ribose has been used to synthesize a number of potential glycosidase inhibitors (Scheme 13). Addition of hydroxylamine and then bromine to the enal resulted in the formation of nitrone 57 with 66% diastereoselectivity, and this in turn was readily transformed into various imino-alditols (e.g. 5R-60) by nucleophilic attack followed by reduction. A number of these compounds proved to be good inhibitors of a-L-fucosidases. ... 

Scale up of reaction in the case of stoichiometric reaction between 4-cyanophenyl aldehyde (5.0mmol) and Al-methylhydroxylamine hydrochloride gave limited success. Milling for 30min showed the formation of nitrone in 88% yield. However, the same experiment on 10 mmol scale showed the lower substrate conversion (68%), which might be a result of an inefficient mixing, showing that the lOmL jar was not adapted for such a scale. 

Another example of the reaction proceeding in a similar manner is the conversion of 2-(5-chloro-2-nitrophenyl)-3-phenylpropionitrile into A-hydroxyindole derivative (Scheme 71) [189]. The intermediate vinyl nitroso compound undergoes electrocyclization, resulting in the formation of nitrone (2//-indole N-oxide), which is tautomerized into A-hydroxyindole. 

Cordova and co-workers [51] have developed an elegant one-pot three component [3+2] cycloaddition catalyzed by Jprgensen-Hayashi prolinol ether 45. The protocol applies to both in situ formation of nitrone [51a] and azomethine ylides [51b] to give isoxazolidines 91 and pyrrolidines 92 in good yields and high ee (Scheme 6.21). 

Scheme 1.10 Addition of dicarboxylic acid 25 to this small library of nitrones shifts the equilibrium to favor formation of nitrone 24 that has two amidopyridine recognition groups [38].

Evidence for the intermediate formation of nitrone species during the carbonylation of nitroarenes in e s-cyclooctene as solvent catalysed by Ru3(CO)i2 have been obtained [14], Moreover, zerovalent palladium species with nitrogen donor ligands have been shown to be active catalysts in the reductive carbonylation of organic nitro derivatives [41]. The hypothesis that an intermediate having the olefinic double bond coordinated to the metal is formed during the catalytic cycle is supported by the steric effect that has been observed in the case of p,p -dimethyl-o-nitrostyrene (7f) as substrate. Moreover, such an intermediate could explain why a pentaatomic indole nucleus is preferentially formed, even when a conjugated double bond is present in the olefinic chain ... 

The stability of ARs is conditioned by tautomeric conversions and depends on the chemical structure of substituents at the N atom, temperature and solvent [5,9]. The general mechanism of AR decay is a disproportionation reaction with formation of nitrones and hydroxylamines. ARs having primary or secondary alkyl groups are short-lived species because they easily undergo disproportionation by the scheme ... 

Among the most synthetically useful 1,3-dipolar cycloaddition reactions are those involving nitrones. The nitrone shown in entry 4 is the condensation product of benzaldehyde and N-methylhydroxylamine. It reacts with alkenes to yield isoxazolines. Entry 6 shows an intramolecular cycloaddition proceeding via in situ formation of nitrone A. 

It is generally accepted that the condensation of nitroalkanes 1 with aldehydes proceeds with the nitronates 2 as the intermediates. The role of the base is to shift the tautomeric equilibrium towards the formation of nitronic acids, or ac/-nitroalkanes 3. Since 3 are much stronger acids (with a pAa range of 2 6) than 1 (with a pAa range of 9 10), they are more readily deprotonated with the base. After the deprotonation, the formed nucleophilic... 

SCHEME 1.203 Formation of nitrones from N-r-butylhydroxylamine and acetylenes. 

SCHEME 10.26 In situ formation of nitrone and reaction with cyclopropane. 

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