Hydroxylamine, reaction with carbonyl compounds

The successful synthesis of 2-thienyl and substituted 2- and 3-thienyl-acetylenes in yields as high as 60-80% opened a wide variety of synthetic applications. Various addition reactions with carbonyl compounds or epoxides could be carried out with ease. Aliphatic as well as aromatic amine addition reactions, or condensation reactions with hydrazine or hydroxylamine could be easily performed. 

Vasella [58] has shown that the hydroxy-oxime 122 (2,3-0-isopropylidene-5-0-trityl-D-ribose oxime) can be, via its tautomeric form a-alkoxy-hydroxylamine 123, converted by reaction with carbonyl compounds (formaldehyde, acetaldehyde, etc.) to N-(alkoxyalkyl) nitrones 124 which then reacts via 1,3-dipolar cycloaddition with methyl methacrylate to give the protected isoxazolidine ribosides 125, 126 epimeric at C5. This reaction proceeds in high yield (97 %) and with high stereoselectivity (84 16) (Fig. 8.35). 

I. Condensation of N-Monosubstituted Hydroxylamines with Carbonyl Compounds Condensation of N -monosubstituted hydroxylamines with carbonyl compounds is used as a direct synthesis of many acyclic nitrones. The synthesis of hydroxylamines is being carried out in situ via reduction of nitro compounds with zinc powder in the presence of weak acids (NH4CI or AcOH) (14, 18, 132). The reaction kinetics of benzaldehyde with phenylhydroxylamine and the subsequent reaction sequence are shown in Scheme 2.21 (133). 

Accordingly, diazobenzene and nitrous acid are related to each other in the same way as are phenylhydrazine and hydroxylamine the latter two substances, in fact, yield the same reaction products with carbonyl compounds as the former two do with the corresponding methylene derivatives. 

Bpgevig A, Poulsen TB, Zhuang W, Jprgensen KA (2003) Formation of optically active functionalized 3-hydroxy nitrones using a proline catalyzed aldol reaction of aldehydes with carbonyl compounds and hydroxylamines. Synlett 2003 1915-1918... 

Once the three-membered ring is opened, the rest of the reaction amounts to acid-catalysec hemiacetal hydrolysis. The alcohol is a hydroxylamine and the carbonyl compound benzaldehyde. An alternative mechanism, favoured by the original authors (J. H. Fendler ar.c group, /. Chem. Soc., Perkin Trans. 2, 1973, 1744), starts with protonation of the oxygen atom and ends up with the hydrolysis of an imine. Again, the second or the third step could be ratedetermining. 

The condensation reaction of carbonyl compounds with halogen-containing derivatization chemicals (so-called elec-trofoiic reagents like pentafluorophenyl hydrazine, 2,4,6-trichlorophenyl hydrazines) and, especially, pentafluoro-benzyl hydroxylamine that has been consid-... 

Reactions of carbonyl compounds with strong bases have been found to be apparently uncatalyzed on the acidic side of the pH-rate profile and general acid catalyzed on the basic side. Oxime (pAa hydroxylamine = 6.0) formation and Schiff base formation from aliphatic amines (pAa 10) are such reactions and can be described by mechanism (38). 

The effect of the amine on the overall equilibrium constants of condensation reactions of carbonyl compounds and amines has been discussed above (see section II.A) where it was pointed out that the thermodynamic stability of the C=N— linkage increases with the type of amine used, in the order NH3 < aliphatic amines < aromatie amines < amines containing an adjacent electronegative atom with a free electron pair. In contrast to the overall equilibrium constants, the rate and equilibrium constants for addition compound formation appear to be dependent on the basicity of the amine. In studies in which different amines have been reacted with the same earbonyl compound under the same conditions, the following observations have been made. The equilibrium constants for addition compound formation with -chlorobenzaldehyde were found to be 21 7, 9-11, 4 14 1/mole for hydroxylamine (pJiTa = 6-0) methoxyamine (pA =... 

The large values of og for the reaction of phenylhydrazine, hydroxylamine and i-butylamine with carbonyl compounds reflect the important role of catalysis played by the solvated proton in this mechanism. Values of 2 of unity for the dehydration of carbinolamines derived from semicarbazide and aniline indicate that such dehydrations appear to be only specific acid catalyzed, except in fairly basic solutions where the concentration of hydronium ion is low . 

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with A-hydroxylamines5 and the oxidation of A+V-di substituted hydroxylamines.5 9 Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.10 11 12 13. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane10 or A-phenylsulfonyl-C-phenyloxaziridine,11 and oxidations with hydrogen peroxide catalyzed by Na2W044 12 or Se02.13 All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give... 

It is much more common not to be able to isolate any intermediates at all, but this does not necessarily mean that none are formed, merely that they may be too labile or transient to permit of their isolation. Their occurrence may then often be inferred from physical, particularly spectroscopic, measurements made on the system. Thus in the formation of oximes from a number of carbonyl compounds by reaction with hydroxylamine (p. 219),... 

Table 2.5 Formation of optically active functionalized fS-hydroxy-nitroncs 95 by reaction of aldehydes 93 with activated carbonyl compounds 94 and substituted N -alkyl hydroxylamine hydrochloride in the presence of L-proline as the catalyst...

Bicyclic nitrones (132) were formed from the reaction of alkenyl carbonyl compounds (131) with hydroxylamine. The reaction requires the presence of the terminal olefinic electron withdrawing ester group CC Et. Also, the product(s) of reaction are shown to depend on the space filling capacity of substituents R1 — R4... 

There are a few reports on the use of oximes as electrophilic amination reagents. Since 1984, ketone O-sulfonyloxknes have found applicability as amino transfer reagents to car-banions. In the reaction of organometaUic compounds with oximes, carbanions attack the carbonyl carbon of the oxime, giving Af-substituted hydroxylamines as addition products (Scheme 53, path a). However, a number of scattered reports have been also published on the formation of aziridines by a-deprotonation, followed by addition (path b) or formation of azirines by a-deprotonation before addition (path c). Addition of carbanions to azirines also yields aziridines, which are hydrolyzed to a-aminoalcohols. 

Compound 63, the 2-formyl derivative of compound 61, undergoes a series of side-chain reactions at the carbonyl group including reduction with sodium borohydride and condensation reactions with hydroxylamine or malononitrile. The reactions afford the appropriately 2-substituted products in excellent yields <2004CHE1477>. 

Dicarbonyl compounds with a double bond in the 2,3-position condense with hydrazine to give pyridazines (e.g. 91 — 92). If one of the carbonyl groups in the starting material is part of a carboxyl group or a potential carboxyl group, then reactions with hydrazines or hydroxylamine lead to pyridazinones or 1,2-oxazinones (e.g. 93 — 94 Z = NH, NPh, O). Similarly a cyano group leads to an amino or imino product. 

The starting oximes (acetophenone oxime and cyclohexanone oxime) were prepared by reaction of the corresponding carbonyl compound with hydroxylamine hydrochloride. The purity of the resulting oximes was checked by GC and IR spectroscopy after recrystallisation of the samples. 

The synthesis consists in forming the oxime by reaction of a carbonyl compound ( aldehyde or ketone ) with hydroxylamine followed by reaction with an isocyanate... 

In the currently accepted mechanism, ammonia is oxidized to hydroxylamine on Ti sites in TS-1 channels and then reacts rapidly with the carbonyl compounds in solution (even with those that are too bulky to diffuse inside the channels of the catalyst), producing the corresponding oxime in an uncatalyzed reaction (Figure 25). 

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