A-hydroxylamine

Dissolve 0-5 g. of the substance in 10 ml. of 50 per cent, alcohol, add 0-5 g. of solid ammonium chloride and about 0 -5 g. of zinc powder. Heat the mixture to boiling, and allow the ensuing chemical reaction to proceed for 5 minutes. Filter from the excess of zinc powder, and teat the filtrate with Tollen s reagent Section 111,70, (i). An immediate black or grey precipitate or a silver mirror indicates the presence of a hydroxyl-amine formed by reduction of the nitro compound. Alternatively, the filtrate may be warmed with Fehling s solution, when cuprous oxide will be precipitated if a hydroxylamine is present. Make certain that the original compound does not aflfect the reagent used. 

Acid Hydrolysis. With hot concentrated mineral acids, primary nitroparaffins yield a fatty acid and a hydroxylamine salt. If anhydrous acid and lower temperatures are used, the intermediate hydroxamic acid can be recovered. 

Dutch State Mines (Stamicarbon). Vapor-phase, catalytic hydrogenation of phenol to cyclohexanone over palladium on alumina, Hcensed by Stamicarbon, the engineering subsidiary of DSM, gives a 95% yield at high conversion plus an additional 3% by dehydrogenation of coproduct cyclohexanol over a copper catalyst. Cyclohexane oxidation, an alternative route to cyclohexanone, is used in the United States and in Asia by DSM. A cyclohexane vapor-cloud explosion occurred in 1975 at a co-owned DSM plant in Flixborough, UK (12) the plant was rebuilt but later closed. In addition to the conventional Raschig process for hydroxylamine, DSM has developed a hydroxylamine phosphate—oxime (HPO) process for cyclohexanone oxime no by-product ammonium sulfate is produced. Catalytic ammonia oxidation is followed by absorption of NO in a buffered aqueous phosphoric acid... 

Figure 15.52 Structures of various S-N oxoanions (a) hydroxylamine-A-sulfonate, (b) A-nitrosohydroxylamine A-sulfonate and (c) the dimeric anion in Fremy s salt K2[0N(S03)2])2.

In general, a hydroxamic acid function results from the condensation of a hydroxylamine group with a carboxylic acid derivative. If these two groups are positioned suitably in the same molecule, spontaneous cyclization can occur. The most usual technique involves... 

Amine oxides 2, which can be prepared by oxidation of amines 1, react upon heating to yield an olefin 3 and a hydroxylamine 4. This reaction is called the Cope elimination reaction,and as a synthetic method is a valuable alternative to the Hofmann degradation reaction of quaternary ammonium salts. 

Oximes can form either an imine or a hydroxylamine, and these in turn can be reduced to an amine. 

In a reaction similar to 12-50, azoxy compounds can be prepared by the condensation of a nitroso compound with a hydroxylamine. The position of the oxygen in the final product is determined by the nature of the R groups, not by which R groups came from which starting compound. Both R and R can be alkyl or aryl, but when two different aryl groups are involved, mixtures of azoxy compounds (ArNONAr, ArNONAr, and Ar NONAr ) are obtained and the unsymmetrical product (ArNONAr ) is likely to be formed in the smallest amount. This behavior is probably caused by an equilibration between the starting compounds prior to the actual reaction (ArNO -I- Ar NHOH Ar NO - - ArNHOH). The mechanism has been investigated in the presence of base. Under these conditions both reactants are converted to radical anions, which couple ... 

Azoxy compounds can be obtained from nitro compounds with certain reducing agents, notably sodium arsenite, sodium ethoxide, NaTeH, NaBH4—PhTeTePh, and glucose. The most probable mechanism with most reagents is that one molecule of nitro compound is reduced to a nitroso compound and another to a hydroxylamine 119-42), and these combine (12-51). The combination step is rapid compared to the reduction process. Nitroso compounds can be reduced to azoxy compounds with triethyl phosphite or triphenylphosphine or with an alkaline aqueous solution of an alcohol. ... 

Additional P2 proline-containing PDF inhibitors have been reported in the patent literature by Dainippon and Questcor [95, 96]. The Dainippon examples disclosed contain an A-formyl-A-hydroxylamine group and possess good antibacterial activity against S. aureus, S. pneumoniae, Streptococcus pyogenes. Enterococcus faecium and M. catarrhalis [95]. The Questcor patent application describes various proline-containing hydroxamic acid inhibitors [96]. 

In 1975, SAR studies involving actinonin investigated an analogue in which the orientation of the Pl -P2 amide bond was reversed (13), but the compound was found to lack antibacterial activity. Since then, however, descriptions of some /i-aminohydroxamic acids and /i-amino-A-formyl-A-hydroxylamines as PDF inhibitors have appeared in the patent literature. Patent applications from Senju [97] and De Novo [98] pharmaceuticals cover Pl -P2 amides (14), ureas (15, 16) and sulfonamides (17). 

In the patent literature, Aventis has published a patent application covering hydroxamic acid containing macrocycles (39) with the same general template as the A-formyl-A-hydroxylamine macrocycles described above [114] and GlaxoSmithKline has published an application on macrocyclic PDF inhibitors containing a hydrazide scaffold (40) [115], No data has been published on these inhibitors to date. 

Asymmetric hydrogenation of nitrones in an iridium catalyst system, prepared from [IrCl(cod)]2, (S)-BINAP, NBu 4 BH4, gives with high enantioselectivity the corresponding A-hydroxylamines which are important biologically active compounds and precursors of amines (480). Further reduction of hydroxylamines to secondary amines or imines can be realized upon treatment with Fe/AcOH (479), or anhydrous titanium trichloride in tetrahydrofuran (THF) at room temperature (481). 

Scheme 49 a Hydroxylamine hydrochloride, sodium acetate/acetic acid, EtOH, reflux, 6h [92,93]... 

Scheme 52 a Hydroxylamine hydrochloride, sodium bicarbonate, CH30H/H20 3 1 b CH3PPh3+Br-, NaH, THF C CHC13, pyridine, NCS, TEA d TBAF, CH2C12 e Mn02, benzene, reflux [60]... 

The freeze-dried sediments were subjected to both a total dissolution and a selective extraction. The latter, as described in Chester Hughes (1967), is carried out in a hydroxylamine hydrochloride and acetic acid (HA) solution and designed to isolate reactive phases. With the exception of total Se, extracted metals were determined by the method described for porewaters. Total solid Se concentrations were measured by AAS with HG-FIAS (analysis ongoing). 

The first product in the oxidation of primary amines is a hydroxylamine as indicated in Figure 4.85. Hydroxylamines can be further oxidized to nitroso metabolites, which can be viewed as analogous to the oxidation of an alcohol to an aldehyde. If there is a hydrogen... 

FIGURE 4.85 Oxidation of primary amines leads to a hydroxylamine followed by a nitroso metabolite, which if there is a hydrogen on the a-carbon can rearrange to an oxime. Without such a hydrogen, as in the case of phentermine, no rearrangement is possible. 

FIGURE 4.86 Oxidation of a secondary amine to a hydroxylamine followed by nitrone formation. 

The first product in the oxidation of secondary amines is also a hydroxylamine (Fig. 4.86). Further oxidation requires the involvement of an adjacent carbon atom to form a nitrone. If there is more than one adjacent carbon with a hydrogen atom, the major product will usually involve the most substituted carbon atom (assuming at least one hydrogen such that a new bond can be formed) or one in which the nitrone is conjugated with other double bonds as shown in Figure 4.86. 

It is also useful to compare the bioactivation of aminobiphenyl and sulfamethoxazole. Aminobiphenyl is a carcinogen found in cigarette smoke. Its bioactivation is similar to that of N-acctylaminolluorcnc in which the first step is oxidation to form a hydroxylamine. The... 

Fig. 8.17. Mechanism of bioactivation of self-immolative carbamate prodrugs of cytotoxic amines. A bacterial nitroreductase coupled to a tumor-directed antibody reduces the prodrug to a hydroxylamine (Reaction a), which breaks down spontaneously to liberate the antitumor...

Scheme 9.30 Allylic substitutions with a hydroxylamine derivative as nucleophile.

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