Aminopyridines diazotization

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 ... 

When carried out in dilute acid, diazotization of 2-aminothia2ole may provide unstable diazohydroxides (164, 335, 336), differing in that respect from 2-aminopyridines which give 2-pyridones when the reaction is carried out in weak acids (337). 

An important early method simulated the well-known Widman-Stoermer cinnoline synthesis. 3-Aminopyridine-2- or -4-alkenes such as (348) gave pyrido-[3,2-c]- or -[3,4-c]-pyridazines on diazotization and alkaline cyclization (66JCS(C)2053>. 

The historieal aspeets of synthesis, study and applieation of heteroeyelie azoeompounds (HAC) pyridynie of a line in airalytieal ehemistry are eonsidered. Works of A.E. Chieibabin on diazotation of 2-aminopyridine and it azoeopulation with resoreinol (PAR) and 2-naphthol (PAN-2). 

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. ... 

Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

The observations that heteroaromatic amino compounds are not easily diazotized, are quite readily hydrolyzed,and often do not form Schiff bases with aldehydes have all been incorrectly interpreted as indications that these compounds exist principally in the imino form, whereas these observations can reasonably be attributed to the fact that the amino groups in compounds of the type of 4-aminopyridine are electron deficient as a result of the contribution of structures of type 36. ... 

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... 

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. 

Chan, J.K., and Anderson, B.M. (1975) A novel diazonium-sulfhydryl reaction in the inactivation of yeast alcohol dehydrogenase by diazotized 3-aminopyridine adenine dinucleotide. J. Biol. Chem. 250, 67-72. 

Aminopyridines90 91, aminopyridine-1 -oxides25, 3-aminoquinoline92 and 2-aminothi-azole93 are obviously diazotized by analogous processes. For 4-aminopyridine, 3-aminoquinoline and 2-aminothiazole it was shown that the monocation, protonated at the heterocyclic nitrogen, is nitrosated preferentially. 

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). 

A simple example of the Balz-Schiemann reaction is the preparation of 2-fluoropyridine by diazotization of 2-aminopyridine in HF-pyridine at 0°C, and then allowing the salt to warm up to 20°C [88JFC(38)435] there are many other examples [81CJC2608, 81JOC4567 82JHC1245 84H(22)1105 85H(23)1431, 85H(23)1969, 85JHC145 87LA857]. Chloro,... 

The first compound having a C — F linkage in a heterocyclic ring was reported from Russia in 1915 by Chichibabin (Knunyants mentor, see ref 46) and Rjazancev. 2-Fluoropyridine was made by diazotization of 2-aminopyridine in concentrated hydrofluoric acid. 

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. 

Nitro-2-chloropyridine, ndls (from w), mp 101-2° almost insol in cold w insol in NaOH sol in coned acids was prepd by diazotizing 3-nitro-2-aminopyridine with NaNOz in HCI soln [Ref, p (82)] ... 

By coupling of diazotized 3-aminopyridine to 2-naphthol, followed by quater-nization, dyes (e.g., 46 [41313-61-5]) are obtained that color polyacrylonitrile in fast yellow shades and exhibit excellent leveling characteristics [134],... 

Aminopyridine, and ambident reactivity, 63 bromination of. 79 by Chichibabin reaction, 12 diazotization of. 67 and HSAB, 63 nJtration of. 72... 

Treatment of the hydroxamic acid (280) with HN02 yielded the pyrido-l,2,3-triazin-4-one (281) <60JCS2157>. Diazotization of the aminopyridine (282) using amyl nitrite gave the 3//,4/f-pyrido[3,2-d]-l,2,3-triazin-4-one (283) (78JOC393). 

Diazotization of 4-acetamido-3-aminopyridine (284) using HN02 gave 3H,4H-pyhdo[3,4-d] l,2,3-triazin-4-one (285) <78JOC393). 

Proton loss. The side-chain anions from 2- and 4-aminopyridines are stabilized by resonance 761. Aminoazines are thus weak acids their anions react with electrophilic reagents preferentially at the amino nitrogen. 2-Aminopyridine 745 is thus converted by NaNH2/MeI to the 2-methylamino- 763 or 2-dimethylamino-derivatives 764. With EtONO/NaOEt, a sodium diazotate 762 is formed which will couple with phenols. 

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