Halides hydroxylamines

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Lead dioxide Aluminum carbide, hydrogen peroxide, hydrogen sulfide, hydroxylamine, ni-troalkanes, nitrogen compounds, nonmetal halides, peroxoformic acid, phosphorus, phosphorus trichloride, potassium, sulfur, sulfur dioxide, sulfides, tungsten, zirconium... 

Hydrazine and hydroxylamine also react with acyl halides to give, respectively. 

In a similar reaction, aromatic acyl halides are converted to amines in one laboratory step by treatment with hydroxylamine-O-sulfonic acid. " ... 

Allylation of acyloyl-imidazoles and pyrazoles61 with allyl halide mediated by indium in aqueous media provides a facile regioselective synthesis of P, y-unsaturated ketones (Scheme 11.1), which has been applied to the synthesis of the monoterpene artemesia ketone. The same product can be obtained by indium-mediated allylation of acyl cyanide (Eq. 11.35).62 Samarium, gallium, and bismuth can be used as a mediator for the allylation of nitrones and hydrazones to give homoallylic hydroxylamine and hydrazides in aqueous media in the presence of Bu4NBr (Scheme 11.2).63 The reaction with gallium and bismuth can be increased dramatically under microwave activation. 

Very recently, Dongol and coworker have developed a one-pot synthesis of isoxa-zolidinones starting from O-homoallyl hydroxylamines and aryl halides. After a Heck reaction of the substrates, a subsequent C-N bond formation took place to furnish the target compounds in up to 79% yield [86]. 

Recently, a new method for synthesis of tertiary amines 326 from iV,iV-dialkyl O-benzoyl hydroxylamines 325 was proposed.425 The protocol is based on the copper-catalyzed reaction of hydroxylamines 325 with dialkyl- and diarylzinc reagents (Scheme 166). It is noteworthy that alkyl- and phenylzinc halides also reacted with compounds 325, however, yields were significantly lower than those for ZnR2 (18-29% vs. 69-98%). 

Formally, they can all be viewed as derivatives of hydroxylamine, H2N—OH indeed, oximes can be prepared by the addition of hydroxylamine to aldehydes and ketones (equations 1 and 2), and hydroxamic acids by its reactions with acetyl halides and esters (equations 3 and 4). ... 

The main advantages of preparation of hydroxylamines through Af-alkylation of other hydroxylamines are versatility and predictable stereochemical outcome that allow the introduction of the hydroxyamino group at advanced stages of multistep syntheses. The use of nucleophilic displacement is however problematic for sterically hindered alkyl halides and sulfonates. Apart from several examples mentioned below, alkylation of hydroxylamines with tertiary alkyl halides does not take place. 

Alkylation of hydroxylamine with primary halides and sulfonates is rarely used nowadays for preparation of A-alkylhydroxylamines due to the competing formation of N,N-dialkylhydroxylamines. A number of older procedures have been reported with low to moderate yields of Al-alkylhydroxylamines. Yet, in many cases the reported low yields can be attributed to workup losses during distillation and crystallization steps rather than to the polyalkylation. Use of excess of hydroxylamine in reactions with primary alkyl halides (e.g. 3) improves the yields of monoalkylation (equation 2). Most of the examples of alkylation of hydroxylamine in good yield involve a substitution of an activated halogen atom at benzylic positions as well as in haloacetamides 4 leading to alkylhydroxylamines such as 5 where dialkylation rates are lower (equation 3). 

Because of their lower hydrophilicity and higher stability to oxidation, O-protected hydroxylamines are more convenient substrates for alkylation than hydroxylamine itself. Commercially available 0-benzylhydroxylamine was successfully alkylated with alkyl halides and alkyl sulfonates ". ... 

Due to a much lower danger of dialkylation, alkylation of iV-alkyl- and Ai-alkyl-O-protected hydroxylamines (e.g. 8, equation 6) with primary alkyl halides proceeds substantially more selectively giving high yields of Al,Al-disubstituted products " of type 9. 

Alkylation of hydroxylamines with secondary alkyl halides and alkyl sulfonates like 10 (equation 7) is one of the most frequently used synthetic approaches, especially to enantiomerically pure hydroxylamines such as 11 (equation 7). The reaction proceeds with inversion of configuration and does not produce appreciable amounts of diaUcyla-tion products. Both hydroxylamine as well as N- and O-alkylhydroxylamines have been successfully used. Alkyl trillates are probably the most useful substrates for these transformations since they can be prepared from a large pool of commercially available enantiomerically pure chiral secondary alcohols. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Hydroxamic acids undergo facile nucleophilic Ai-arylation with activated aryl halides such as 31 (equation 22). While hydroxamates are known to be ambident nucleophiles in alkylation reactions, arylation of hydroxylamines results exclusively in Ai-substituted hydroxamates of type 32 (equation 22)". ... 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

As in the case of aryl halides, no polysubstitution reaction has been reported in het-eroarylion of hydroxylamines. If two or more identical chlorine atoms are present in the molecule, substitution of the first chlorine atom can be done selectively in most cases. 

The general approach to 0-arylation of hydroxylamines involves N-protection followed by O-arylation. Activated aryl halides and heteroaryl halides easily alkylate oxime salts (equation 25), N-aUcyl hydroxamic acids and N-hydroxysuccinimide . N-Hydroxyph-thalimide can be also 0-phenylated through a reaction with diphenyliodonium salt, although in lower yield . ... 

Tertiary and aromatic nitroso compounds react with aryl Grignard or aryl-lithium reagents giving the corresponding hydroxylamines . This reaction is useful for preparation of alkyl- and aiylhydroxylamines (e.g. 109, equation 80 and 110, equation 81) and can be considered as complementary to arylation of hydroxy lamines with activated aryl halides. It has been used for functionalization of cyclophanes with the hydroxy amino group. The main limitation of the reaction is the relatively restricted choice of available aliphatic nitroso components, so most of reactions were done with 2-nitroso-2-methylpropane. There is no literature data about the possibility of removal of the tert-butyl group from these compounds. 

It is not possible to carry out the reaction between hydroxylamine and an ester under neutral conditions (Scheme 49) since it always requires a pH >10. Hence, this method is not suitable for ester derivatives that contain halides, and other base-sensitive groups. 

General synthesis of pyrroles and 1-vinylpyrroles by the reaction of ketoximes with acetylenes and their synthetic equivalents (vinyl halides and dihaloethanes) in the presence of the strongly basic KOH/DMSO system (Trofimov reaction) has been reviewed ° in recent years. Therefore, in the present work this reaction will be described very shortly. In principle, pyrrole (51) synthesis can be carried out as a one-pot procedure by treating ketones (49) with hydroxylamine and then reacting the ketoximes (50) formed with acetylenes (equation 22). 

Berman and Johnson observed that amination of phenylzinc halide and n-butylzinc chloride with A-benzoyloxymorphoUne 2a and A,A-dibenzyl O-benzoyl hydroxylamine 2f, respectively, under Cu catalysis was not effective (equation 7) . 

The effect of the cyanine dye and of gelatin on the reaction rate shows that reduction of silver ions from solution is not the rate-controlling process. These influences of adsorbed components on the reaction rate speak against the concept that solution of the silver halide is the rate controlling process. Hence, the silver catalyzed reduction of silver chloride by hydroxylamine takes place substantially at the solid silver/ silver halide interface. 

Furazan- and furoxan-carboxylic acids are thermally and hydrolytically unstable decomposing to a-(hydroxyimino)nitriles, but their amide, ester, halide, and nitrile derivatives are readily accessible and all undergo the expected functional group interconversions. Dicyanofuroxan reacts with hydroxylamine to give the fused oxazino compound (63) and the pyridazino analogue (64) is similarly formed with hydrazine <82H(19)1063>. 

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