Hydroxylamines with aldehydes

Condensation of N -substituted hydroxylamines with aldehydes and ketones is widely used in the synthesis of various spin traps and biologically active nitrones (Fig. 2.5) (161-186). 

Reaction of hydroxylamine as well as O- and A-substituted hydroxylamines with aldehydes 63 results in formation of oximes and/or oxyiminium salts of type 64 (equation 42). Subsequent reaction with carbon, nitrogen, oxygen or phosphorous nucleophiles provides A-substituted hydroxylamines of type 65. 

Oxime complexes are made by condensation of hydroxylamines with aldehydes or ketones and can be of the types... 

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

The addition of (E)- and (Z)-crotylboronates 7 to aldoximes 6 has been realized in good yield by performing the reaction under 3-6 x 10° Torr pressure10. The resulting hydroxylamines 8 can easily be reduced to yield the primary amines. The addition of E-l leads preferentially to the anh-diastereomcr 8, while (Z)-crotylboronate 7 shows a modest selectivity towards formation of the vyy -diastereomer 8 (same sense as in the reaction with aldehydes). Some effort has been made to elucidate the mechanism, but this is not yet well understood. 

Silylation of hydroxylamine or N-alkyl or N-ethoxycarbonyUiydroxylamines is usually accomphshed, in 52-84% yield, by silylation with TCS 14/NEt3 [63, 161, 162]. Whereas the reaction of N,0-bis(trimethylsilyl)methylhydroxylamine 952 with aldehydes such as benzaldehyde, or with ketones, with to adducts such as 953, has already been mentioned at the beginning of Section 7.3 thermal and other reactions of N,0-bis(trimethylsilyl)hydroxylamine 1141 or N-substituted N,0-bis(trimethylsi-lyl)hydroxylamines 1121, 1128, 1131 are discussed in this section. 

Compounds of this type with an electron-withdrawing substituent at C-a can be easily prepared by condensation of 2-(benzotriazol-l-yl)acetophenone 869 with aldehydes. Exclusively (E) isomers of a,(l-unsaturated ketones 870 are formed. Treatment with hydrazines converts derivatives 870 into pyrazolines 871. Elimination of benzotriazole from 871 in the presence of mild bases furnishes pyrazoles 872. When in these reactions hydroxylamine is used instead of hydrazines, the corresponding isoxazoles are obtained (Scheme 141) <2001JOC6787>. 

The reaction of 2-chloro-4,5-dihydroimidazole 347 with hydroxylamine-O-sulfonic acid gives 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate 348, which reacts with aldehydes and cyclic ketones to give the imidazo[l,2-f] fused 4,5-dihydro-l,2,4-oxadiazoles 350 (Scheme 58). Mechanistically, the reaction may be explained by the reaction of an imidazoline NH with the carbonyl followed by intramolecular electrophilic amination of the anionic oxygen present in the resultant intermediate 349 and elimination of the sulfate group <2003JOC4791>. 

Another synthetic approach for generating sugar-containing nitrones is by initial treatment of sugars with unsubstituted hydroxylamine. The resulting cyclic hydroxylamine of the tautomeric mixture (68a) and of the open chain oxime (68b) react with aldehydes to give the corresponding nitrones (69) (Scheme 2.24) (216-220). 

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). ... 

A small number of examples is available for the synthesis of E and Z isomers of oximes. In many cases, E isomers were obtained either from the Z forms (by the hydrochloride method) or isolated by column chromatography. Often, the reagents that have been used for oximation of aldehydes and ketones also catalyze the interconversion of Z and E isomers. The rate of equilibration of a mixture of Z and E isomers and the position of the equilibrium is temperature-dependent ". In 2001, Sharghi and Sarvani reported a convenient method for controlling the stereochemistry of the reaction of hydroxylamine hydrochloride with aldehydes or ketones in the solid state. The highly stereoselective conversion of aldehydes and ketones to their corresponding oximes... 

One of the more useful oxazir ne syntheses is that described Uy Schmitz.17 It is based on the discovery that hydroxylamitte-O-sulfDnic acids react in alkaline solution with aldehydes and ketones to term oxazir nes in 20-40% yield. Thus benzaldehyde and 2V-methyl-hydroxylamine-0-Knlfonic acid give the oxaeirane in 38% yield ... 

Isoxazoles and their partially or fully saturated analogs have mainly been prepared, both in solution and on insoluble supports, by 1,3-dipolar cycloadditions of nitrile oxides or nitrones to alkenes or alkynes (Figure 15.10). Nitrile oxides can be generated in situ on insoluble supports by dehydration of nitroalkanes with isocyanates, or by conversion of aldehyde-derived oximes into a-chlorooximes and dehydrohalogenation of the latter. Nitrile oxides react smoothly with a wide variety of alkenes and alkynes to yield the corresponding isoxazoles. A less convergent approach to isoxazoles is the cyclocondensation of hydroxylamine with 1,3-dicarbonyl compounds or a,[3-unsatu-rated ketones. 

RRjCO + NH2OH -RRiC = NOH + H20. Hydroxylamine hydrochloride (NH20H.HC1) is generally used in most cases the free base is liberated by the subsequent addition of the theoretical quantity of a basic substance (caustic potash, sodium carbonate, etc.). With aldehydes it is advisable to reduce the quantity of... 

The earliest and to date most extensively studied class of intramolecular cycloadditions involves unsaturated nitrones.4 These are most readily available from condensation of an unsaturated aldehyde with a hydroxylamine or an unsaturated hydroxylamine with an aldehyde. Another approach is simply to oxidize an unsaturated hydroxylamine. Nitronic esters are nitrones containing an alkoxy substituent attached to the N-atom they can be prepared from nitro compounds. Frequently an unsaturated nitrone can be isolated and purified, although much work has been done with the nitrone generated in situ eventual cyclization can provide three new contiguous chiral centers, often with only one diastereomer actually formed. 

In addition to the pathways described above, nitrones can derive from condensation of a primary hydroxylamine with an aldehyde or ketone140. Under simulated biological conditions, Beckett and coworkers were able to demonstrate that primary hydroxylamines metabolically formed from amphetamine, mexiletine or norfenfluramine readily combined with ketones produced by metabolic deamination of the primary amines141. Reactions can be formulated according to equation 13, where R1 = aryl, alkyl or aralkyl, and R2 = alkyl or H. 

Imines of aldehydes are relatively stable while those of ketones are unstable. Derivatives of imines that form stable compounds with aldehydes and ketones include phenylhydrazine, 2,4-dinitrophenyl-hydrazine, hydroxylamine, and semicarbazide. 

Oxime. Hydroxylamine reacts with aldehydes and ketones to form oximes. 

Hydroxylamine Hydrochloride Solution Dissolve 50 g of hydroxylamine hydrochloride (preferably reagent grade or freshly recrystallized before using) in 90 mL of water, and dilute to 1000 mL with aldehyde-free alcohol. Adjust the solution to a pH of 3.4 with 0.5 N alcoholic potassium hydroxide. 

Reaction of hydroxylamine with ketones or aldehydes yields oximes, aldoximes RHC=NOH, or ketoximes R2C=NOH. Almost all the hydroxylamine production (95%) is used for the production of either cyclohexanone oxime or caprolactam, both of which are intermediates for polyamide synthetics. The remainder of the hydroxylamine production is used as an anticreaming agent in paints and coatings, as an auxiliary in refining fats for soap production, as a regulator or inhibitor for various polymerizations, as a stabilizer for developers, and as an additive for color emulsions. Oximes are also used as pharmaceuticals or in crop protection. 

The nitroparaffins are condensed with aldehydes to yield nitro alcohols (70-80%), which on acetylation and treatment with an aqueous methanolic solution of sodium bicarbonate are converted to nitroolefins (80-84%). These compounds are reduced to the corresponding ketoximes by zinc and acetic acid (50-60%). Reduction with iron and dilute hydrochloric acid gives good yields of either ketones or ketoximes, depending upon the amount of hydrochloric acid used. The ketoximes can be hydrolyzed to ketones by refluxing with dilute sulfuric acid in the presence of formalin, which acts as a hydroxylamine acceptor (80%). The over-all yields from the nitroolefins are 40-60%. In this manner, certain otherwise difficultly obtainable ketones are prepared. Semicarbazones have been converted to ketones by treatment with sodium nitrite in glacial acetic acid, with aqueous oxalic acid, or with phthalic anhydride. ... 

Examples of reactions which have used 1,2-diketones and ammonia with or without added aldehyde include the isolation of good yields of lophine (2,4,5-triphenylimidazole) from benzil and ammonia, a rather elegant synthesis of 4,5-di-t-butylimidazole (135), and the preparation of a series of 2-aryl-5-trifluoromethyl-4-phenylimidazoles (136) from 3,3,3-trifluoro-l-phenylpropane-l,2-dione monohydrate (Scheme 74). Additionally, the formation of 1-hydroxyimidazole 3-oxides (137) from a-diketones, hydroxylamine and aldehydes (74CI(L)38), and the preparations of 2,2 -bis- (138) and 2,2, 2"-tris-imidazolyls (139) from benzil, ammonia and polyformyl aromatics provide further examples of this versatile reaction (Scheme 74). There is yet some doubt about the pathway or pathways involved in these... 

A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile addition reactions rather readily. Thus, alkaline hydrolysis produces carboxamides, then carboxylic acids, alcoholysis leads to imidates, ammonolysis to amidines, hydrazinolysis to amidhydrazines, hydroxylamine to amidoximes, and hydrogen sulfide to thioamides. Acid hydrolysis tends to give the decarboxylated acid derivative. Reduction either by sodium-ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, most of the compounds examined have been relatively non-polar derivatives. Table 28 lists some reactions and relevant literature. 

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