O-Alkyl nitronates

Both C-alkylation products and the corresponding O-alkyl nitronates were detected in the reaction mixture prepared by the reactions of above mentioned salt with primary alkyl halides (Scheme 3.9, Eq. 1). However, isoxazolidines (1) are the main identified products of the reactions with secondary or tertiary alkyl halides. The possible pathway of their formation is shown in Scheme 3.9. Here, the key event is generation of the corresponding olefins from alkyl halides. These olefins can be trapped with O-nitronates that are simultaneously formed in [3 + 2]-cycloaddition reactions. Presumably, these olefins are generated through deprotonation of stabilized cationic intermediates (see Scheme 3.9). 

Diazo compounds and oxonium salts are the most efficient alkylating agents in the synthesis of alkyl nitronates. It is assumed that diazo compounds are inserted into the O-H bond in the aci forms of the corresponding AN, whereas oxonium salts generally react with AN anions. 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

However, if protons at the a-carbon atom of the O-alkyl fragment are absent, another process can occur resulting in elimination of olefin and generation of the respective aci-nitro compound (Eq.2). In particular, this anomalous decomposition was found by Nenitzescu and Isacescu (234) for nitronate 74a (Eq. 3). 

Here two facts can be mentioned. For example, cycloaddition of nitronate (Me02C)CH=N(0)0SiMe3 to ethylene was observed (203), whereas its O -methyl analog does not react with ethylene. It is hardly probable that this fact is due to the high reactivity of the silyl nitronate. More likely, the negative result for alkyl nitronate is attributed to low stability of this derivative. 

In general, nitronates undergo O-alkylation. However, some procedures have been developed that overcome the preference for O-alkylation in favour of C-alkylation. For example, the double deprotonated nitronates introduced by Seebach74 can be C-alkylated and this strategy was used for the synthesis of nitro furanosyl and pyranosyl compounds.75... 

C-Alkylation has also been observed in intramolecular reactions where the O-alkylation is not favoured.76 This property has been recently exploited in a stereocontrolled intramolecular cyclization of nitronate of nitro sugar 101 (Scheme 32), that provided the novel bicyclic nitrolactone 102, a synthetic precursor of tripeptide 103, that includes the first reported polyhydroxylated cyclopentane (3-amino acid.77... 

Poor to modest yields of trinitromethyl compounds are reported for the reaction of silver nitroform with substituted benzyl iodide and bromide substrates. Compounds like (36), (37), and (38) have been synthesized via this route these compounds have much more favourable oxygen balances than TNT and are probably powerful explosives." The authors noted that considerable amounts of unstable red oils accompanied these products. The latter are attributed to O-alkylation, a side-reaction favoured by an SnI transition state and typical of reactions involving benzylic substrates and silver salts. Further research showed that while silver nitroform favours 0-alkylation, the sodium, potassium and lithium salts favour C-alkylation." The synthesis and chemistry of 1,1,1-trinitromethyl compounds has been extensively reviewed. The alkylation of nitronate salts has been the subject of an excellent review by Nielsen." ... 

The nitroso acetals that result from the [3 + 2] cycloaddition of alkyl nitronates with dipolarophiles typically provide several characteristic spectroscopic signals for identification. As in the silyl counterparts, the O—N—O stretch in the alkyl nitroso acetals is observed in the IR ranges between 1000 and 1030 cm (Tables 2.22 and 2.23) (57,75-77). However, this resonance is usually not strong, and can be obscured by other functional group resonances with more substituted nitroso acetals. 

The intermolecular alkylation of metallo nitronates with various alkyl halides is limited. The addition of methyl iodide to the silver salt of an aryl nitro-methane provides the corresponding methyl nitronate in moderate yield (Eq. 2.13) (150), which has also been extended to the silver salt of trinitromethane (Scheme 2.16) (151-153). However, in the case of primary halides, both O- and C-alkylation are observed. For secondary and tertiary halides, only O-alkylation is observed, but in low yields. Unfortunately, under the reaction conditions, the starting alkyl halide can undergo dehydrohalogenation to provide the corresponding alkene, which then undergoes [3+2] cycloaddition with the alkyl nitronate. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEXAHYDRO-1,3,3,6-TETRAMETHYL-2,l-BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a - sec - AM IN O ALKYL ATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

R2C—N02) that can be alkylated at oxygen or carbon.427 O-Alkylation gives nitronic esters, which are generally unstable to heat but break down to give an oxime and an aldehyde or ketone. 

TV-Hydroxyglycine was obtained in 1896 by acidolysis of the nitrone resulting from the condensation of awd-benzaldoxime 17 with chloroacetic acid 22 N-Alkylation of 17 with a-bromoesters was extended much later to the synthesis of various TV-hydroxyamino acids 23,24 It is notable that syn-benzaldoxime is O-alkylated under the same conditions 25 As substitution of a-bromoacids proceeds with inversion of configuration, Liberek and Palacz 26 prepared H-D-(OH)Phe-OH from (.S )-c/.-bromo-p-phenylpropanoic acid, obtained by HN02 deamination of L-Phe in the presence of KBr. Treatment of nitrone 19 with an TV-hydrox-ylamine salt yields the corresponding TV-hydroxyamino ester 20 (Scheme 5) 24,27 ... 

Norris and Randles67,68 have largely studied the regiochemistry of the coupling between / -nitrobenzyl radicals and ambident nitronate anions, in the association step of S l reactions, and showed that it depends on steric factors. Branching at the positions adjacent to the reaction sites (Cp) causes a shift in the product distribution toward O-alkylation and away from C-alkylation. In some cases no products were formed. The authors have formulated rules which predict when C-alkylation will occur in the association step involving / -nitrobenzyl radicals and nitronate anions (equation 15). 

Steric and electronic effects on the rate and regiochemistry of the reaction between p-nitrobenzyl substrates and tertiary carbanions were also studied71. Thus, increasing the size of the alkyl groups attached to the benzylic or anionic carbons of the substrates causes substantial decrease in the proportions of C-alkylation product. In contrast with the previous reaction with nitronate anions, formation of reduction products is observed instead of a significant O-alkylation. 

Hydroxylaiiimonium O-Alkyl-N-alkyliden- -tetrafluoroborate E14a/3, 342 (O-Alkylierung von cycl. Nitron)... 

Nitronic ester The result of O-alkylation of the carbanion of the aci tautomer of a nitro compound and having the general formula R2C=N+(0-)0R. 

Hydroxyindole can be prepared in solution, but attempted purification leads to dimerisation via its nitrone tautomer, however O-alkyl derivatives can be formed easily and are stable. ... 

On the other hand a (T-alkyl nitrone complex has been obtained by reaction o-f BuV lO with ethylene coordinated to platinumdl) [44] ... 

Dialkoxyammonium salts Hydroxamic acid esters Hydroximic acids (esters) Iminocarbonic acid esters Nitronic — (O-Alkyl-... 

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