Hydroxylamines, substituted

Oximes, hydrazines and semicarbazones. The hydrolysis products of these compounds, t.e., aldehydes and ketones, may be sensitive to alkali (this is particularly so for aldehydes) it is best, therefore, to conduct the hydrolysis with strong mineral acid. After hydrolysis the aldehyde or ketone may be isolated by distillation with steam, extraction with ether or, if a solid, by filtration, and then identified. The acid solution may be examined for hydroxylamine or hydrazine or semicarbazide substituted hydrazines of the aromatic series are precipitated as oils or solids upon the addition of alkali. 

Compounds of the type R NH—OR are named (1) as alkoxyamino derivatives of compound R H, (2) as A, 0-substituted hydroxylamines, (3) as alkoxyamines (even if R is hydrogen), or (4) by the prefix aminooxy- when another substituent has priority for parent name. Examples of each type are... 

Salts of thiols (170) or of sulfinic acids (171) react like the alkoxides, giving 4-alkylthio- or 4-alkylsulfono-substituted butyrates. Alkali cyanides give 4-cyanobutyrates (172), hydroxylamine gives a hydroxamic acid (173), and hydra2ine a hydra2ide (174). 

A/-Trimethoxybora2ines are available from reaction of dichloroboranes and 0-methyl-X,X-his(trimethylsilyl)hydroxylamine (eq. 31). The B-trichloro-bora2iQes undergo substitution reactions at the B atoms to give B-tri(/ f -butoxy)- or B-tri(/ f2 -but5i)-A/-trimethoxybora2iaes (101)... 

If primary or secondary amines are used, A/-substituted amides are formed. This reaction is called aminolysis. Hydra2ines yield the corresponding hydra2ides, which can then be treated with nitrous acid to form the a2ides used in the Curtius rearrangement. Hydroxylamines give hydroxamic acids. 

Cyanopyridazines add ammonia, primary and secondary amines and hydroxylamine to give amidines or amidoximes. Substituted amides, thioamides and carboximidates can be also prepared. With hydrazine, 3-pyridazinylcarbohydrazide imide is formed and addition of methylmagnesium iodide with subsequent hydrolysis of the imine affords the corresponding pyridazinyl methyl ketone. 

The chemical consequences of /3-protonation are illustrated further by the ring-opening reactions of furans with methanolic hydrogen chloride and of (V-substituted pyrroles with hydroxylamine hydrochloride (Scheme 11) (82CC800). 

The reaction of the steroidal )3-ketoaldehyde (293) with hydroxylamine hydrochloride in acetic acid gave a mixture of the 3- and 5-substituted isoxazoles (294) and (295a). In sodium acetate buffer the reaction provided exclusively the 5-substituted isomer (29Sb) (66JOC3193). 

The reaction of )3-substituted vinyl ketones RCOCH=CHY (Y = halogen, OR or NR2) with hydroxylamine hydrochloride has been extensively investigated (63AHC(2)365, 62HC(l7)l). One would anticipate that replacement of hydroxylamine hydrochloride with hydroxylamine in these reactions would result in enhanced regiospecificity and increased... 

Since an electron-withdrawing group such as ethoxycarbonyl at the a-carbon atom enhanced the electrophilicity of the )3-carbon atom, the reaction of a-ethoxycarbonyl-)3-ethoxyvinyl ketones (298) with hydroxylamine hydrochloride gave solely 5-substituted isoxazole-4-carboxylates (299) (55JOC1342, 59YZ836). 

To synthesize isomeric 3-substituted isoxazoles (301) the reaction of ethylene acetals of )3-ketoaldehydes (300) (readily available from -chlorovinyl ketones (57IZV949)) with hydroxylamine was employed. Owing to the comparative stability of the dioxolane group, this reaction gave exclusively 3-substituted isoxazoles (301) (60ZOB954). The use of noncy-clic, alkyl S-ketoacetals in this reaction resulted in a mixture of 3- and 5-substituted isoxazoles (55AG395). 

Only in a few instances, where both phenyl groups were sufficiently different in their substitution patterns, were 3,5-diarylisoxazoles prepared regiospecifically by the reaction of 1,3-diketones (302) (R = substituted phenyl) with hydroxylamine (45JA134). Accordingly, other CCC component synthons have been employed for the regiospecific synthesis of 3,5-diarylisoxazoles. 

The reaction of hydroxylamine with 2-substituted chromones (392) where R = Me, Ph (76MI41601) or CO2H (79MI41600) gave exclusively 5-(o-hydroxyphenyl)isoxazoles (393). 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

Conversion of 2-cyano-5,5-dimethyl-3-ethoxy-2-cyclohexene (601) into (602) by hydroxylamine has been accomplished (73MI41604). Reduction of the homocyclic ring in the 3-substituted 2,1-benzisoxazole occurred with H2/Pd-C to give the tetrahydro analogs (equation 65) (74JHC395). 

Compound (253) is formed from benzaldehyde and methylhydroxylamine-O-sulfonic acid in 35% yield. With ethyl-substituted chloramine or hydroxylamine-O-sulfonic acid yields do not exceed 10%, which is assumed to be due to steric hindrance and is foreseeable for both carbonyl addition and O —N bond formation. 

Treatment of cotarnine and similar compounds with hydrogen cyanide, alkoxides, mercaptides, hydroxylamine, hydrazine, and amines has been reported to give 1-substituted derivatives of 1,2,3-tetrahydroisoquinoline (171, R = CN, OR, SP, NHOH, NHNH, NHR) (262-265). 

The condensation of P-keto esters with hydroxylamine can occur in two directions to give either isoxazolin-3-ones [which exist predominately as 3-hydroxyisoxazoles (2)] or isoxazolin-5-ones (3). Early work by Claisen, Hantzch, and others showed that the products from 2-unsubstituted P-keto esters were isoxazolin-5-ones. In the early 1960 s, Katritzky found that 2-substituted analogues give 3-hydroxyisozaoles. Jacquier later showed that both types of products could be produced from both types of keto esters depending on the precise pH variation during the reaction workup. ... 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

In addition to their reactions with amines, Zincke salts also combine with other nitrogen nucleophiles, providing various A -substituted pyridine derivatives. Pyridine A -oxides result from the reaction with hydroxylamine, as exemplified for the conversion of Zincke salt 38 to the A -oxide 39 Reactions of Zincke salts with hydrazine, meanwhile, lead... 

Some substituents such as the acylamino group are readily decomposed by many nucleophiles to give a poorer leaving group (e.g., amino). Others, such as nitroamino and sulfonylamino, are less reactive when they are anionized by the nucleophile. 3-Nitroamino-pyridazine (117) and its 6-methyl derivative are readily aminated with benzylamine (130°, short time ). 4,6-Dimethyl- and 6-methyl-2-nitroaminopyrimidine undergo 2-substitution on warming a few minutes with hydroxylamine, hydrazine, primary or secondary alkylamines, or anilines. 

A special type of ammonio group is represented by 4-( 1 -pyridinium)-pyridine and other azinium analogs. Such products often result from self-quaternization of highly reactive derivatives. A -(4-Pyridyl)-and A -(3-nitro-4-pyridyl)-pyridinium chloride hydrochlorides (121) react with aniline, chloride ion, and water to give 4-substituted pyridines plus pyridine. l-(2-Quinolyl)- and l-(4-quinolyl)-pyridinium salts undergo 2- and 4-substitution, respectively, with amines, anilines, hydroxylamine, phenols, alkoxides, mercaptans, and chloride... 

The high level of reactivity of as-triazines is also indicated by 5-substitution of 312 with ammonia or amines (110°, 20 hr, 40-65% yield) and with hydroxylamine or hydrazine (65-80°,... 

The effect of the nature of the substituent at the acetylene bond is not so noticeable. Substitution reduces the C-3 activity due to polarization effects and steric factors. As aresult, in the cyclization with hydrazines and hydroxylamines an increase in the content of 5-substituted pyrazoles and isoxazoles is observed (81UK1252). As mentioned above, nonsymmetiic nitrogen-containing binucleophiles H2N—YH (Y = O, NMe, NPh) react with l-heteroalk-l-en-3-ynes in two alternative pathways by functions H2N and YH. 

Here a typical property of three-membered rings wdth two hetero atoms is shown and this property is also found in the diaziridines. Only with the oxaziranes which are substituted by aryl groups in the 3-position does the hydrolysis by acids occur according to Eq. (14) with formation of an aromatic aldehyde and alkyl hydroxylamine. 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

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