Diazonium, reaction with aminopyridine

JV-Nitraminopyridines are reducible both in acid and alkali. In hydrochloric acid the main product from 2-nitraminopyridine was the hydrazino-pyridine, formed in a six-electron reduction, but 2-aminopyridine and 2-chloropyridine were side products, the latter possibly through reaction by an intermediate diazonium compound with chloride. Contrary to nitramines of most primary amines, 2-nitraminopyridine431 is reducible in alkaline solution uptake of the first two electrons forms the 2-pyridyl-N-nitrosamine, which is further reduced to 2-aminopyridine. 

The 4-aminopyridine derivative 92, prepared from the reaction of ethyl benzoylacetate and malononitrile dimer 91, undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives such as 93. Under refluxing conditions in ethanolic sodium hydroxide, these azo compounds cyclize to pyrido[3,2-f]pyridazines and pyrido[3,2-r]-pyridazino[2, 3 - ]quinazolines (Scheme 15) <2005AP329>. 

Aminopyridines give normal diazonium salts on reaction with nitrous acid, but with a- and 7-isomers, unless precautions are taken, the corresponding pyridones are... 

The reaction of 2- and 6-amino groups with nitrous acid is similar to that of 2-aminopyridines, in that diazonium salts are produced, but relative to phenyldiazo-nium salts, these are unstable. Despite this, they can be utilised for the introduction of groups such as halide or of course oxygen by reaction with water, with loss of nitrogen. 8-Diazonium salts are considerably more stable. ... 

A few 3-cyanopyridines have been prepared, in 40-50 per cent yield, by reaction of a 3-pyridyl diazonium salt with potassium cuprocyanide or cuprous cyanide2i8, 755-7 Though 2- and 4-aminopyridines have been converted into 2- and 4-halogenopyridines via the diazonium reaction, the ready reaction of the 2- and 4-pyridyldiazonium ions with nucleophiles present in the solutions in which they are formed makes their use in cyana-tion difficult if not impossible. The difference in ease of diazotization between a 2- and a 3-aminopyridine permits the conversion of 2,5-diaminopyridine into 2-amino-5-cyanopyridine by diazotization in dilute acid is. The easier diazotization (p. 359) of 4-aminopyridine 1-oxides and the greater stability... 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

Diazotization of 2- and 4-aminopyridines leads to the corresponding diazonium salts which, as they cannot be stabilized by mesomeric donation of electrons from the heterocyclic ring, tend to be highly unstable. Under normal aqueous diazotization conditions, therefore, the major products tend to be 2-pyridones (equation 85). 2-Chloro- and 2-bromo-pyridines can be obtained in moderate to good yield if the diazotization is carried out in concentrated hydrochloric or hydrobromic acid. In contrast to this situation which pertains with simple aminopyridines, the diazonium salts obtained on diazotization of 2- and 4-aminopyridine N-oxides are stabilized by resonance and therefore undergo normal diazonium salt reactions (equation 86). 

Oxidative Coupling of Heterocyclic Hydrazones. This method has opened the way to the preparation of azo derivatives of diazo compounds unobtainable by other means, ie, heterocyclic compounds in which the diazotizable amino group is conjugated with the heterocyclic nitrogen atom as in 2- and 4-aminopyridine, compounds which do not normally yield stable diazonium salts (38). The reaction occurs as illustrated by equation 7 for the interaction of (IV-methylcarbostyryl)hydrazone [28219-37-6] and dimethylaniline the overall process is oxidation. 

When 2- or 4-aminopyridine is diazotized, a-pyridone or y-pyridone is formed. Apparently, the diazonium salt reacts immediately with water to form a hydroxypyri-dine (Section 16.10). The product of the reaction is a pyridone because the keto form of a hydroxypyridine is more stable than the enol form. (The mechanism for the conversion of a primary amino group into a diazonium group is shown in Section 16.12). 

A series of upper rim pyridyl azo calix[M]arenes ( = 4,6,8) have been synthesized by coupling calix[n]arenes with diazonium salts derived from 3-, 4-aminopyridine. In these reactions, the dizonium salt of... 

The reaction of 2- and 6-amino groups with nitrous acid is similar to that of 2-aminopyridines, in that diazonium salts are produced, but relative to... 

The kinetics of the diazotization of 4-aminopyridine in 0.0025-5.0 M perchloric acid were studied, and the reaction was believed to proceed by only one mechanism whose kinetic form is first order with respect to the amine as well as to nitrous acid. The rate of the reaction showed an exponential catalytic dependence on the concentration of added perchloric acid and sodium perchlorate. In solutions of constant ionic strength the rate was directly related to the acidity function Hq). The 4-diazonium ion was characterized as 4-(2-hydroxy-l-naphthylazo)pytidine. When 4-aminopyridine is diazotized and treated with Ar,7 A-dimethylaniline, 4-(p-dimethylaminophenylazo)pyridine (DC-95) is obtained. 2-(p-Dimethylaminophenyl)pyridine is isolated when 2-aminopyridine is used instead of 4-aminopyridine. ... 

A -oxide which is easily reduced to codeine with sulphur dioxide [303]. The 0-methylation of certain Erythrina alkaloids has been carried out in a similar manner [304]. A -Oxidation has also been used to protect tertiary ring nitrogen atoms in heteroaromatic compounds. Protonation of the ring nitrogen atom in 4- (and 2-) aminopyridines renders their diazonium salts very susceptible to hydrolysis, thus they cannot be converted into cyanides by the Sandmeyer reaction. The corresponding TV-oxides may, however, be used in the normal way and the oxide function removed at a later stage, as in the sequence (63) (64) used by Berson and Cohen in studies on ipecac... 

Under the reaetion eonditions, most electron-poor substrates efficiently generated the produet in high yields and with short reaetion times. However, strongly electron withdrawing substrates, such as 4-aminopyridine, were not successful in the reaction due to the instability of the diazonium ion. Relatively electron-rich substrates, such as 4-amino toluene, gave low yields of product. These conditions were successfully applied to the preparation of... 

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