Oximes from hydroxylamines + ketones

Place 80 g, of hydroxylamine sulphate (or 68-5 g. of the hydrochloride), 25 g. of hydrated sodium acetate, and 100 ml. of water in a 500 ml. flask fitted with a stirrer and a reflux water-condenser, and heat the stirred solution to 55-60°. Run in 35 g (42 nil,) of -hexyl methyl ketone, and continue the heating and vigorous stirring for ij hours. (The mixture can conveniently be set aside overnight after this stage.) Extract the oily oxime from the cold mixture twice with ether. Wash the united ethereal extract once with a small quantity of water, and dry it with sodium sulphate. Then distil off the ether from the filtered extract, preferably using a distillation flask of type shown in Fig. 41 (p. 65) and of ca, 50 ml, capacity, the extract being run in as fast as the ether distils, and then fractionally distil the oxime at water-pump pressure. Collect the liquid ketoxime, b.p. 110-111713 mm. Yield, 30-32 g. 

The Doering-Moore-Skattebol method including a cyclopropylidene-allene rearrangement is often used for the synthesis of allenes. However, the reaction conditions applied are often not compatible with acceptor substituents. One of the rare exceptions is the transformation 76 —> 77 (Scheme 7.11) [122]. The oximes 77 are not accessible by the classical route starting from allenyl ketone and hydroxylamine (see Section 7.3.2). 

The analogous transformation of 125, also realized by flash vacuum pyrolysis, gave rise to allenic oximes 126 [165], which are not directly accessible by the classical route starting from allenyl ketones and hydroxylamine (see Section 7.3.2) [122], Because compounds 125 are prepared from allenyl ketones and furan by [4 + 2]-cycloaddition followed by treatment with hydroxylamine, the retro-Diels-Alder reaction 125 —> 126 is in principle the removal of a protecting group (see also Scheme 7.46). 

SYNTHESIS To a well stirred solution of 14.8 g hydroxylamine hydrochloride in 120 mL MeOH there was added 3.6 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 1.0 g sodium cyanoborohydride. The oxime, prepared from the ketone and hydroxylamine in MeOH with pyridine, may... 

In fact, the oxime formed from a ketone and hydroxylamine is just a special example of an imine. 

Benzil acts like a ketone in that it forms oximes with hydroxylamine-The oximes are of exceptional interest, since our knowledge of the stereochemistry of nitrogen proceeds from them. Benzil forms two monoximes and three dioximes. The constitution of these compounds will be discussed later, under the preparation of benzophenone-oxime ... 

Oximes - Compounds of structure R2C=NOH derived from condensation of aldehydes or ketones with hydroxylamine. Oximes from aldehydes may be called aldoximes those from ketones may be called ketoximes. [5]... 

In fact, the oxime formed from a ketone and hydroxylamine is just a special example of an imine. All imines have a C=N double bond and are formed when any primary amine reacts with an aldehyde or a ketone under appropriate conditions, for example aniline... 

It is known that cyclohexanone oxime can be formed from the ketone, ammonia, H2O2 and tungstate [192]. However, it has been found recently that titanium silicalite, TS-1, also catalyses this reaction [193]. As a heterogeneous system, this is of great interest for improving manufacture, and a pilot plant has been announced [194]. It is also disclosed that, in the absence of ketone, hydroxylamine is formed from H2O2 and ammonia... 

Dissolve 0.5 g of hydroxylamine hydrochloride in 5 mL of water and 3 mL of 3 A4 sodium hydroxide solution, and add 0.5 g of the aldehyde or ketone. If the carbonyl compound is insoluble in water, add just enough ethanol to give a clear solution. Warm the mixture on a steam bath or boiling-water bath for 10 min then cool it in an ice-water bath. If crystals do not form immediately, scratch the side of the tube with a glass rod at the air-liquid interface to induce crystallization. Recrystallize the oxime from water or aqueous ethanol. 

The study of the mechanism of Schiff base formation in aqueous solution has been approached by hydrolysis studies because of the unfavorable equilibrium constants of formation. The formation reaction can be studied directly in the presence of semicarbazide or hydroxylamine since these bases serve as a trap for the reactive Schiff base, and the rate of semicarbazone or oxime formation is identical to the rate of Schiff base formation. This technique has been used to study Schiff base formation from methylamine and acetone . Nucleophilic catalysis is also useful in synthesis. For example, certain mesitylketoximes that have not been obtained from the ketones and hydroxylamine have been synthesized fi om the appropriate keti-mines . 

The hydroxylamine method in which the mineral acid, liberated from hydroxylamine salts by oxime formation with the aldehyde, is titrated direct, requires to be modified according to the particular aldehyde or ketone being determined (Bennett and Cocking" ). The advantages of the hydroxylamine process over the absorption methods given above are recognised as (a) the hydroxylamine method is a definite determination of aldehydic or ketonic substances, whereas the absorption methods include impurities such as water-soluble organic acids and adulterants such as alcohol (d) a small quantity only of the oil is required and the determination can be completed in a much shorter time. Yet it must be pointed out... 

The plan was to prepare 55 from 70, which would be derived from an intramolecular nitrone cycloaddition of 71. Cft-octalin 71 was to be prepared from hydroxylamine 72 and formaldehyde, a standard method for nitrone preparation. The cycloaddition required that the hydroxylamine reside on the concave face of the at-octalin. It was felt that this stereochemistry could be established by hydride reduction of an oxime, which would be derived in turn from the corresponding ketone. A cycloaddition between 1,3-butadiene (73) and cyclohexenone 74 was to serve as the starting point of the synthesis. 

Since hydroxylamine is usually available only in the form of its salts, e.g., the hydrochloride or sulphate, the aqueous solution of these salts is treated with sodium acetate or hydroxide to liberate the base before treatment with the aldehyde or ketone. Most oximes are weakly amphoteric in character, and may dissolve in aqueous sodium hydroxide as the sodium salt, from which they can be liberated by the addition of a weak acid, e.g., acetic acid. 

For water insoluble aldehydes or ketones, the following alternative procedure may be used. Reflux a mixture of 0-6 g. of the aldehyde or ketone, 0 5 g. of hydroxylamine hydrochloride, 5 ml. of ethanol and 0 5 ml. of pyridine on a water bath for 15-60 minutes. Remove the alcohol either by distillation (water bath) or by evaporation of the hot solution in a stream of air (water pump). Add 5 ml. of water to the cooled residue, cool in an ice bath and stir until the oxime crystallises Filter off the solid, wash it with a little water and dry. Recrystallise from alcohol (95 per cent, or more dilute), benzene, or benzene - light petroleum (b.p. 60-80°). 

Oximes (compare Section III,74,B). The following procedure has wide application. Dissolve 0-5 g. of hydroxylamine hydrochloride in 2 ml. of water, add 2 ml. of 10 per cent, sodium hydroxide solution and 0-2 g. of the aldehyde (or ketone). If the latter is insoluble, add just sufficient alcohol to the mixture to give a clear solution. Heat the mixture under reflux for 10-15 minutes, and then cool in ice. If crystals separate, filter these off, and recrystallise from alcohol, dilute alcohol, benzene or light petroleum (b.p. 60-80°). If no solid separates on cooling, dilute with 2-3 volumes of water, filter the precipitated sohd, and recrystallise. 

Substituents R, R at the starting oxime 1 can be H, alkyl, or aryl. The reaction conditions for the Beckmann rearrangement often are quite drastic (e.g. concentrated sulfuric acid at 120 °C), which generally limits the scope to less sensitive substrates. The required oxime can be easily prepared from the respective aldehyde or ketone and hydroxylamine. 

Imine formation from such reagents as hydroxylamine and 2,4-dinitro-phenylhydrazine is sometimes useful because the products of these reactions— oximes and 2,4-dinitrophenylhydrazones (2,4-DNPs), respectively—are often crystalline and easy to handle. Such crystalline derivatives are occasionally prepared as a means of purifying and characterizing liquid ketones or aldehydes. 

The cycloaddition, reduction and oxidation reactions emanating from a,/J-unsatu-rated nitroalkenes provide easy access to a vast array of functionalities that include nitroalkanes, N-substituted hydroxylamines, amines, ketones, oximes, and a-substi-tuted oximes and ketones [73-75], Consequently, there are numerous possibilities of using these in situ generated nitroalkenes for the preparation of valuable building blocks and synthetic precursors. 

Although harmine 52 is frequently obtained by isolation (or purchase order), a synthesis of this compound as well as a number of analogs has recently appeared [47,48]. The key step to this synthesis was the thermal electrocyclization of oxime intermediate 55, which was prepared by acylation of vinylindole derivative 54 followed by treatment with hydroxylamine hydrochloride. Neither oxime 55 nor its ketone precursor were isolated— instead, the crude reaction mixture was heated at reflux in o-dichlorobenzene to ultimately yield harmine in 56% yield overall starting from 54 (Fig. 18). 

Particularly good yields of the cydoadduct 329 are obtained if R1 = R2 = H is valid for the allenyl ketone 328 [165]. The Diels-Alder products 329 can undergo many chemical transformations, for example to the oximes 330, which yield the modified allenes 331 after a subsequent flash vacuum pyrolysis. The oximes 331 generated by retro-Diels-Alder reaction are not available from ketones 328 and hydroxylamine hydrochloride directly [122] (see also Scheme 7.19). 

To a solution of 4 g. of benzophenone in 25 c.c. of alcohol, cooled solutions of 3 g. of hydroxylamine hydrochloride in 6 c.c. of water and 5 g. of potassium hydroxide in 5 c.c. of water are added and the whole is heated under reflux on the water bath for two hours. The product is then poured into 50 c.c. of water, any unchanged ketone is removed by filtration after shaking to cause aggregation, the filtrate is faintly acidified with dilute sulphuric acid, and the free oxime recrystallised from alcohol. Melting point 140°. 

Axenrod and co-workers reported a synthesis of TNAZ (18) starting from 3-amino-l,2-propanediol (28). Treatment of (28) with two equivalents of p-toluenesulfonyl chloride in the presence of pyridine yields the ditosylate (29), which on further protection as a TBS derivative, followed by treatment with lithium hydride in THF, induces ring closure to the azetidine (31) in excellent yield. Removal of the TBS protecting group from (31) with acetic acid at elevated temperature is followed by oxidation of the alcohol (32) to the ketone (33). Treatment of the ketone (33) with hydroxylamine hydrochloride in aqueous sodium acetate yields the oxime (34). The synthesis of TNAZ (18) is completed on treatment of the oxime (34) with pure nitric acid in methylene chloride, a reaction leading to oxidation-nitration of the oxime group to em-dinitro functionality and nitrolysis of the A-tosyl bond. This synthesis provides TNAZ in yields of 17-21 % over the seven steps. 

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... 

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