Aminopyridine oxides, diazotization

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). 

Aminopyridines, aminopyridine oxides, and 3-aminoquinoline are obviously diazotized by analogous mechanisms. Kalatzis (1967 b) studied the diazotization of 4-aminopyridine over a very large range of acid concentrations (0.0025-5.0 m HC104). This compound is comparable to 2-aminothiazole in its acid-base properties the heterocyclic nitrogen is easily protonated at pH 10, whereas the amino group is a very weak base (pKa = -6.5). Therefore, the kinetics indicate that the (mono-protonated) 4-aminopyridinium ion reacts with the nitrosyl ion. The... 

Amine oxides, prepared to protect tertiary amines during methylation and to prevent their protonation in diazotized aminopyridines, can be cleaved by reduction (e.g., SO2/H2O, 1 h, 22°, 63% yield H2/Pd-C, AcOH, AC2O, 7 h, 91% yield Zn/HCl, 30% yield). Photolytic reduction of an aromatic amine oxide has been reported [i.e., 4-nitropyridine A-oxide, 300 nm, (MeO)3PO/CH2Cl2, 15 min, 85-95% yieldl. ... 

Neither the 2- nor 4-aminopyridine-l-oxides nor their substitution products can be protonated at the heterocyclic nitrogen. The findings regarding the diazotization kinetics of these compounds indicate that, under the reaction conditions studied by Kalatzis and Mastrokalos (1977), two simultaneous mechanisms take place. In the first of these, nitrosyl ions attack the free amine, whereas in the second they attack the protonated amine. 

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). 

Aminopyridine /V-oxides can be diazotized, and the diazonium salts undergo coupling, etc. These diazonium salts are stabilized by mesomerism (728), cf (726). Amino groups in pyridazine /V-oxides can also be diazotized and the diazonium group further replaced by other functionality. Nitrosation of 3-amino-1,2,4-triazine 2-oxides and subsequent thermolysis of the diazonium tetrafluoroborate salts afforded 3-fluoro-1,2,4-triazine 2-oxides (85H(23)1969). 

The preparation of 5-azatryptamine (192) is summarized in Scheme 61 (64FES741). It is interesting in starting from diazotized 4-aminopyridine N- oxide and important because pyrrolo[3,2-c]pyridine does not readily react at position 3. 

Amine oxides, prepared to protect tertiary amines during methylation and to prevent their protonation in diazotized aminopyridines, can be cleaved by reduction... 

Aminopyridines , aminopyridine-l-oxides, 3-aminoquinoline and 2-aminothi-azole are obviously diazotized by analogous processes. For 4-aminopyridine, 3-amino-quinoline and 2-aminothiazole it was shown that the monocation, protonated at the heterocyclic nitrogen, is nitrosated preferentially. 

Pytidylazide is formed by reaction of 3-pyridyldiazonium chloride with sodium azide. 2-Aminopyridine-l-oxides can be diazotized, and treatment of the salt with azide ion gives rise to the 2-azidopyridine-l-oxide in good yields. ... 

When 3-aminopyndine is diazotized with hydrochloric acid and sodium nitrite and then treated with acetic acid containing sulfur dioxide and cupric chloride, 3-pyridine ulfonic acid can be isolated. Similarly, 4-aminopyridine-l-oxide gives 4-pyridinesulfonic acid-1 -oxide, but the 2-isomer gives very poor yields of the corresponding sulfonic acid. The preparations and reactions of various 3-pyridinediazonium salts have been reported. 3-Amino-2,6-lutidine... 

The identification and determination of 2,4-, 2,5-, and 2,6-dinitrophenols by their color reactions with 2-aminopyridine have been reported. 2-Aminopyiidine-l-oxide gives a blue color when it is heated with 7V,7V-dimethylaniline and concentrated hydrochloric acid. On diazotization and treatment with azide ion it yields 2-azidopyridine-l-oxide. ... 

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... 

Aminopyridine 1-oxide has been diazotized and, by use of the Sandmeyer reaction, converted into 4-chloro- and 4-bromo-pyridine l-oxide" . 4-Iodo-pyridine 1-oxides have also been prepared through the diazonium reac-tion i . 

Mercaptans793, 982 and thiocyanate ion7976, 802, 983 react satisfactorily with diazotized 3- and 4-aminopyridines. Diazotized 3-aminopyridine does so likewise with potassium ethyl xanthate979a. in these reactions, diazotized 4-aminopyridine 1-oxide has not proved very usefuU ... 

Comments on the diazotization of aminopyridines and their 1-oxides have been made in connection with nucleophilic substitutions leading to cyano-(p. 226), halogeno- (p. 229) and hydroxy-pyridines (p. 239). The formation of a diazotate from 2-aminopyridine (p. 229), and of diazo oxides from 3-amino-2- and -4-hydroxypyridine (p. 270) has also been noted. 

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