Nitrone reactions halogenation

Reactions of Halogenation and Nitrosation Nitrones with protons in the a-alkyl group can occur in tautomeric nitrone-hydroxylamine equilibrium (Scheme 2.117) similar to keto-enol and imine-enamine tautomerisms. 

Nitronate(47a) is not the only oxazete derivative. For example, sterically hindered nitroalkenes (42b-d) can be prepared by nitration and halogenation of readily available allenes (48). Compounds (42b-d) are rather smoothly isomerized into the corresponding four-membered cyclic nitronates (47b-d) by the first-order reaction equation (168). Storage of nitronate (47c) is accompanied by its slow transformation into acid chloride (47e) from which amide (47f) can be easily synthesized. 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

To understand the carbanion mechanism in flavocytochrome 62 it is useful to first consider work carried out on related flavoenzymes. An investigation into o-amino acid oxidase by Walsh et al. 107), revealed that pyruvate was produced as a by-product of the oxidation of )8-chloroalanine to chloropyruvate. This observation was interpreted as evidence for a mechanism in which the initial step was C -H abstraction to form a carbanion intermediate. This intermediate would then be oxidized to form chloropyruvate or would undergo halogen elimination to form an enamine with subsequent ketonization to yield pyruvate. The analogous reaction of lactate oxidase with jS-chlorolactate gave similar results 108) and it was proposed that these flavoenzymes worked by a common mechanism. Further evidence consistent with these proposals was obtained by inactivation studies of flavin oxidases with acetylenic substrates, wherein the carbanion intermediate can lead to an allenic carbanion, which can then form a stable covalent adduct with the flavin group 109). Finally, it was noted that preformed nitroalkane carbanions, such as ethane nitronate, acted as substrates of D-amino acid oxidase 110). Thus three lines of experimental evidence were consistent with a carbanion mechanism in flavoenzymes such as D-amino acid oxidase. 

Krohnke reactions. A halogen compound reacts with pyridine in ethanol to form a pyridinium salt (1), which is treated with p-nitroso-N,N-dimethylaniline and alkali to produce a nitrone (2), which on acid hydrolysis affords an aldehyde. 

It was found by Krohnke that compounds of the types ArCH=CHCH2Cl, ArCOCH2Cl, and ArCH2Cl, that contain particularly reactive halogen, form pyridinium salts whose reaction with A,iV-dimethyl-p-nitrosoaniline gives nitrones from which aldehydes are formed smoothly on hydrolysis by acids ... 

Formation of the nitrone can generally be prevented by using an excess of the methylene component. When a halogen atom is present on the methylene-carbon atom, nitrone may be formed without presence of an excess of the nitroso compound, since the primary adduct may be stabilized by loss of hydrogen halide, as occurs, for instance, in the reaction of 4-nitrobenzyl chloride with nitrosobenzene 434... 

More recently, the reductive activation of halothane (CFaCHBrCl), which is a hepatotoxic anaesthetic molecule, by human hemoglobin results in the modification of the prosthetic heme [57]. The inhibition of the reaction by adding exogeneous CO or the spin trapping agent N-t-butyl-a-phenyl nitrone to the incubation mixture indicated that (i) a reduced and free heme iron is required by Hb to activate the halogenated substrate and (ii) the formation of free radical species is responsible for Hb inactivation. However, no carbene species were detected in these reactions. The mechanism is shown in Scheme 7. 

Conventional nucleophilic substitution of halogens and other nucleofugal groups X in electron-deficient arenes, particularly nitroarenes, proceeds via addition of nucleophiles at positions occupied by X to form o -adducts. The addition is coimected with dearomatization—thus, the adducts, which are in fact nitronate anions of nitro cyclohexadienes, undergo rapid rearomatization via spontaneous departure of X" to form products of nucleophilic aromatic substitution (Sj Ar) reaction. Detailed discussion of these processes is presented in Chapter 6. 

A cycloaddition reaction of the halogen-substituted nitrone (289) with olefins in the presence of AgBp4 provides reactive iminium salts in a regio- and stereo-specific manner. These react with various nucleophiles to give 1,2-oxazine derivatives as shown. In a study of the reactions of P-enamino-esters with carbonyl compounds, WamholF et have isolated a series of acyclic and... 

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