Hydroxylamine heterocyclic

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. 

Azetidines under analogous reaction conditions to those above result in six-membered ring formation. However, diketene (472), an oxetan-2-one, offers considerable promise for five-membered heterocycle formation. With hydroxylamine the 3-methylisoxazolin-5-one (473) was formed. Phenylhydrazine gave the corresponding 3-methyl-l-phenylpyrazolin-5-one. 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

At the end of the nineteenth century, Claisen described the cyclization of P-keto esters with hydroxylamine to provide 3-hydroxyisoxazoles. Substituents Ri and R2 in the P-keto ester make it possible to introduce substituents in the 4- and 5-position of the heterocyclic ring. 

The mononuclear heterocyclic rearrangement (MHR) of isoxazole-3-amidoxime 108 in the presence of a base and hydroxylamine with concomitant removal of the amide moiety affords furazan acetaldoxime 109 (Scheme 56) (91CHE651, 91KGS827). 

Transformations of nitro compounds, nitrones, nitrates, hydroxylamines, and amino-A-oxides into heterocycles 98SL939. 

The resin-bound reagents thus obtained were reacted with a variety of nucleophiles to give different heterocycles (Scheme 13). So, reaction with hydrazine or hydroxylamine gave respectively pyrazoles and isoxazoles in excellent yields (94-99%, 34 examples) and excellent purities (> 95%). Reaction with guanidines afforded 2-aminopyrimidines. 

For the preparation of the anticipated heterocyclic library compounds (Scheme 6.257), solutions of the prepared enamine synthons were split and diluted with an appropriate solvent, and 1.2 equivalents of a dinucleophile (hydrazine, hydroxylamine, amidines see Scheme 6.257 for more complex building blocks) was added. Subsequent exposure to microwave conditions in acetic acid/DMF mixtures... 

Cyclocondensation processes of p-dicarbonyl derivatives or their analogues are still widely employed for the synthesis of new isoxazoles. Non-proteinogenic heterocyclic substituted ct-amino acids have been synthesised using the alkynyl ketone functionality as a versatile building block ynone 2, derived from protected L-aspartic acid 1, reacted with hydroxylamine hydrochloride affording the isoxazole 3 with enantiomeric purity greater than 98% ee <00 JCS(P 1 )2311 >. 

Nucleophilic addition of metallated heterocyclic derivatives to AMetrahydro-pyranyl (THP) protected nitrones (361) makes it possible to synthesize a-branched hydroxylamines (362) (Table 2.13) (597). 

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

The reactions of 5-acyl-2,2-dimethyl-4,6-dioxo-l, 3-dioxanes (1373) with urea, thiourea, sulfamide, hydroxylamine, or 1-substituted hydrazines gave monocyclic six- and five-membered heterocycles (1374-1378) in good yields [79JAP(K) 106466],... 

Whenever you see a five-membered heterocycle, think 1,3-dipolar cycloaddition. The heterocyclic rings shown can be made from an intramolecular cycloaddition of a nitrone and the alkene. The nitrone must be made from the hydroxylamine and formaldehyde. 

Electrosyntheses of heterocycles from nitroso derivatives prepared in a batch cell according to Scheme 34 need two conditions. The first one is a good stability of the hydroxylamine intermediate and the second one is a very fast cyclization of the nitroso compound to avoid the formation of an azoxy compound by condensation of the generated nitroso and the hydroxylamine. Electroanalytical studies using cyclic voltammetry can give information on the rate of cyclization. 

Types of compounds are arranged according to the following system hydrocarbons and basic heterocycles hydroxy compounds and their ethers mercapto compounds, sulfides, disulfides, sulfoxides and sulfones, sulfenic, sulfinic and sulfonic acids and their derivatives amines, hydroxylamines, hydrazines, hydrazo and azo compounds carbonyl compounds and their functional derivatives carboxylic acids and their functional derivatives and organometallics. In each chapter, halogen, nitroso, nitro, diazo and azido compounds follow the parent compounds as their substitution derivatives. More detail is indicated in the table of contents. In polyfunctional derivatives reduction of a particular function is mentioned in the place of the highest functionality. Reduction of acrylic acid, for example, is described in the chapter on acids rather than functionalized ethylene, and reduction of ethyl acetoacetate is discussed in the chapter on esters rather than in the chapter on ketones. 

A seemingly complex heterocycle which on close examination is in fact a latentiated derivative of a salicylic acid shows antiinflammatory activity. It might be speculated that this compound could quite easily undergo metabolic transformation to a salicylate and that this product is in fact the active drug. Condensation of acid 134 with hydroxylamine leads to the hydroxamic acid 135. Reaction of that with the ethyl acetal from 4-chlorobutyraldehyde then leads to the cyclic carbinolamine derivative 136. Treatment... 

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