Groups N-oxide

Triazoles can be activated towards electrophiles by the introduction of an A-oxide group. N-Oxidation gives rise to better activation of the 5-position than the 4-position. Thus, bromination of 3-benzyl-1,2,3-triazole 1-oxide (192, R = PhCH2) requires only 120 h at 20 °C and affords the 5-bromo compound (193) in quantitative yield <87ACS(B)724>. 3-Phenyl-1,2,3-triazole 1-oxide is... 

Triazoles can be activated towards electrophilic attack at carbon by the introduction of an TV-oxide group. N-Oxidation gives rise to better activation of the 5-position than the 4-position. 

A basic principle of the sol-gel process involves hydrolysis reaction of the metal alkoxides M(OR)b (M = Si, Ti, B, Zr, etc. R = alkyl group n — oxidation number) with water and subsequent polycondensation reaction by dehydration or dealcoholation to produce metaloxane sols as described below. 

Thiazole-N-oxides are prepared by the action at low temperature (-10°C) of hydrogen peroxide in acetic acid (474). 4-MethyIthiazole and 2,4-dimethylthiazole afforded the corresponding N-oxides with yields of 27 and 58%, respectively (Scheme 88). Thiazole-N-oxides without a methyl group in the 2-position are so unstable that they have a tendency to form 2-hydroxythiazoles and are decomposed by oxidation, whereas a 2-methyl group would prevent such rearrangement (474). 

Substitution Reactions. Aromatic heterocycHc A/-oxides undergo both electrophilic and nucleophilic substitution because the dipolar N-oxide group is both an electron donor and an electron acceptor, giving rise to the resonance stmctures ... 

Nucleophilic substitution occurs in positions a and y to the N-oxide group. In nearly all these reactions deoxygenation occurs giving the substituted heterocychc amine. 

Treatment of pyridazine 1-oxides with phosphorus oxychloride results in a-chlorination with respect to the N-oxide group, with simultaneous deoxygenation. When the a-position is blocked, substitution occurs at the y-position. 3-Methoxypyridazine 1-oxide, for example, is converted into 6-chloro-3-methoxypyridazine and 3,6-dimethylpyridazine 1-oxide into 4-chloro-3,6-dimethylpyridazine. 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

There are several examples of replacement of methoxy and ethoxy groups in substituted pyridazine N- oxides, with ammonia or hydrazine producing the corresponding amino and hydrazino compounds. 

Methylpyridazine can be oxidized with selenium dioxide to give 3-formylpyridazine, and methyl groups attached to any position in pyridazine N-oxides are transformed with pentyl nitrite in the presence of sodium amide in liquid ammonia into the corresponding... 

Nitropyridazines are reduced catalytically either over platinum, Raney nickel or palladium-charcoal catalyst. When an N-oxide function is present, palladium-charcoal in neutral solution is used in order to obtain the corresponding amino N-oxide. On the other hand, when hydrogenation is carried out in aqueous or alcoholic hydrochloric acid and palladium-charcoal or Raney nickel are used for the reduction of the nitro group, deoxygenation of the N- oxide takes place simultaneously. Halonitropyridazines and their N- oxides are reduced, dehalogenated and deoxygenated to aminopyridazines or to aminopyridazine N- oxides under analogous conditions. 

Although the presence of an N-oxide substituent modifies the reactivity of other groups, only reactions directly involving the Af-oxide part are discussed here. 

N-Amino and N-nitro groups N-Hydroxy groups and N-oxides N-Hatogeno groups... 

This group, which is more stable than the 2-hitrobenzenesulfenamide, has been developed to protect amino acids. It is readily introduced with the sulfenyl chloride (52-74% yield) and is cleaved with triphenylphosphine or 2-thiopyridine N-oxide. It is stable to CF3COOH but can be cleaved with 0.1 M HCl. ... 

Few other reactions of series of substituted pyridines have been investigated extensively. Dondoni, Modena, and Todesco have measured the rate of N-oxidation of a limited series of pyridines and found a good correlation with normal u-values with a p-value of — 2.23. The A-alkylation of pyridines with alkyl iodides in nitrobenzene has been studied by Brown and Cahn and by Clarke and Rothwell. Unfortunately, the only data available are for the parent compound and for alkyl derivatives, and, since the a-values for the various alkyl groups in a given position are substantially constant, this leaves a correlation of only three independent points. However, the rates of A-alkylation of the j8- and y-alkyl derivatives are so nearly equal that it appears as if no correlation existed. Clarke and Rothwell have also studied the alkylation with allyl bromide in nitromethane at various temperatures, and in this case a more extensive series is available. The authors state that no overall Hammett correlation is obtained however, the j8-substituted derivatives fall on one straight line and the y-derivatives on another one with a different slope. The data are shown in Fig. 2. The line for the j8-compounds, p = — 2.53 0.31, r = 0.95, is seen not to be very good the line for the y-derivatives, p = — 1.42 0.06, r = 0.99, is much more satisfactory. It does not seem likely that the discrepancy is due to the intervention of resonance effects, since in this case one would expect the correlation for the y-derivatives to be poorer than that for the j8-analogs. More extensive studies with a wider variety of substituents would seem very desirable. 

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