3- Aminopyridines

Aminopyridines are similar to hydroxypyridines in that the 2- and 4-aminopyridines can exist in several forms. 3-Aminopyridine is considered as an aromatic amine related to aniline and behaves so on hydrogenation. Nienburg (89) found that uptake of hydrogen stopped sharply with the absorption of three molar equivalents. 3-Amino-piperidine was obtained in good yield. Another investigation confirmed his results (90). 

While Wheland (91) suggests that 4-aminopyridine is an aromatic amine little success has been achieved in hydrogenation. Orthner (92) cites failure with platinum catalysts under a variety of conditions. Very low yield (16.5%) resulted from reduction of the hydrochloride salt with platinum catalyst under 80 atm pressure (93). In the reduction of A7-(4-pyridyl)morpholine where the 4-amino nitrogen atom is tertiary, hydrogenation in alcohol was successful with ruthenium (5), but unsuccessful with rhodium on alumina or platinum oxide in acetic acid. It is possible that the pressure conditions used for reduction with ruthenium catalysts may be conducive to conversion of 4-aminopyridine, since these catalysts are less inhibited by strong nitrogen bases. 

In the hydrogenation of 2-aminopyridine under acidic conditions two equivalents of hydrogen were absorbed, giving tetrahydroaminopyridine as the hydrochloride salt, which on further reduction was converted to piperidine hydrochloride and ammonia (74). When 2-aminopyridine hydrochloride was hydrogenated in aqueous solution four equivalents of hydrogen were absorbed, yielding piperidine hydrochloride and ammonia. 

The protection against deamination when reduction is carried out as a hydrochloride salt is in contrast to the work of Grave (74) with 2-aminopyridine. Nevertheless, it seems to emphasize a combination of effects which includes that of a l-substituent. These effects suggest the possibility of hydrogenating a l-substituted-2-iminopyridine in acid solution with subsequent removal of the protecting group to obtain 2-aminopiperidine. 

Exchange of 4-aminopyridines (9.18) takes place at the 3-position on the monoprotonated species [67JCS(B)1219], as expected. In 3-aminopyr-idine, exchange occurs at the 2-position This is strongly deactivated by 

At higher acidity exchange occurs on the conjugate acid and the rate increases with increasing acidity until the H0 value corresponding to the pAa for the second protonation is reached, the rate-acidity profile slope then becoming zero [73JCS(P2)1072]. 

For 5-chloro-4-aminopyridine (9.25) and its N,)V-dimethyl derivative (9.26), exchange at 158°C took place predominantly on the free base at lower acidity and on the conjugate acid at higher acidity (the changeover point occurs at a higher acidity for 9.26 than for 9.25). The rate-acidity profile became horizontal (i.e., zero slope) at very high acidity for 9.25 due to second protonation, but this was not observed for 9.26 ]71JCS(B)2363]. 

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Fluoropyridine. This isomer can be prepared in 54—81% yield by dia2oti2ation of 4-aminopyridine in anhydrous hydrogen fluoride (370,371,400). Eree 4-fluoropyridine readily undergoes self-quaterni2ation to give pyridyl pyridinium salts (401) stabili2ation can be effected as the hydrochloride salt (371,400). Numerous 4-fluoropyridinium salts, eg, 4-fluoro-l-methylpyridinium iodide, have been converted to novel penicillins (387,402). 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

Nicotinamide [98-92-0] (26) and isonicotinamide [1453-82-3] (32) undergo Hofmann rearrangements to form 3- (33) and 4-aminopyridine (34), respectively (35). This provides an important route for the manufacture of these amines. 

Avitrol [504-24-5] (4-anHnopyridine) (24), mp 155—158°C, bp 273°C, has repeUent—toxicant properties for birds and is classed as a severe poison and irritant. This secondary bird repeUent can be used as a broadcast bait, causing uncoordinated flight and distress caUs and escape responses in nearby birds (57). A reevaluation shows lack of effectiveness of 1% baits but better control of blackbirds with 3% baits (58). Suspected contamination of drinking water with 4-aminopyridine has been reported in toxicosis of Brahman catde and horses (59). 

Aminopyridine [504-24-5] M 94.1, m 160°, b 180 /12-13mm, pK -6.55, pKj . (9.18). Crystd from benzene/EtOH, then recrystd twice from water, crushed and dried for 4h at 105° [Bates and Hetzer J Res Nat Bur Stand 64A 427 I960], Has also been crystd from EtOH, benzene, benzene/pet ether, toluene and sublimes in vacuum. 

Reaction of 2 or 3 aminopyndine with trifluoronitrosomethane forms the trifluoromethaneazo derivative directly 4-Aminopyridine fails to give the azo product [12] (equation 11)... 

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. ... 

This method is not applicable if the spectra of the potentially tautomeric compound and both alkylated derivatives are very similar, e.g., it is not suited to an investigation of the tautomerism of 4-aminopyridine 1-oxide (Fig. 3). A further limitation is that often only qualitative conclusions can be drawn because no contribution from the spectrum of the minor constituent can be found in the spectrum of the tautomeric compound. It should also be noted that, un-... 

Dipole moment data have provided valuable information for the study of the tautomerism of compounds such as isonicotinic acid, pyrid-4-one, and ethyl acetoacetate, However, this method must be used with discretion since it can lead to inconclusive results. Thus, the fact that 4-aminopyridine has a higher dipole moment than the algebraic sum of the dipole moments of pyridine and aniline was originally interpreted as proof that structure 54 exists with a strong contribution from 36, and it was stated that 55 w ould have a very low moment. Later, Angyal and AngyaF pointed out that the... 

Comparison by Gardner and Katritzky of the pKa values of the cations formed by 2- and 4-aminopyridine 1-oxide and the alkylated derivatives of both forms showed that in aqueous solution the amino form predominates for 2- and 4-aminopyridine 1-oxide (cf. 241 242) and the methylamino form for 2- and 4-methylaminopyridine 1-oxide by factors of ca. 10 and >10 in the 2- and 4-series, respectively. The ultraviolet spectra of the 4-isomer and its alkylated derivatives... 

Earlier studies of 4-aminopyridine 1-oxide were less conclusive. The solid-state infrared spectrum could be interpreted to indicate the existence of both the imino structure and/or, more probably, the amino structure. Comparison of the actual pKa value of 4-aminopyridine 1-oxide wdth the value calculated using the Hammett equation was considered to indicate that the compound existed as such or as an equilibrium mixture with l-hydroxypyrid-4-onimine, the latter possibility being considered the less likely on the basis of resonance and bond energies/ Resonance energy and ultraviolet spectral considerations have been advanced to support the 4-aminopyridine 1-oxide structure/ The presence of an infrared absorption band at... 

All existing syntheses of pyrido[4,3-d]pyrimidines from pyridines build up the pyrimidine ring from a 3-substituted 4-aminopyridine by methods closely similar to those applied for the other systems (routes i and u). The preparation of suitable 4-aminopyridines presents some... 

The 4-aminopyridine-type resonance, one of the most interesting methods by which hydration is facilitated, is illustrated by the small resonance in the neutral species of 4-aminopyridine (34) and the far greater resonance in the cation of the same substance (35). 4-Amino-pyridine owes its strongly basic properties (pA 9.2, as compared to... 

In general, electron-releasing groups (e.g. —NH2, —OH) diminish or prevent covalent hydration by decreasing the electron deficiency in the nucleus. This diminution becomes ineffective if a new kind of stabilizing resonance is facilitated by the substituent, e.g. the urea-type resonance and the 4-aminopyridine-type resonance in 2- and 6-hydroxypteridine, respectively. The reluctance of the anions of these substances to form hydrates is attributed to the stable benzenoid system, e.g. 42, in the anhydrous anion compared with the predominantly lactam form of the neutral species, e.g. 43. 

The neutral species of 1,3,6-triazanaphthalene, unlike those of its isomers, decomposes at pH 7.1 to give 4-aminopyridine-3-aldehyde, on standing at 20°. The nitrogen atom in position 5 of pteridine must confer extra stability on the hydrated cation, because 1,3,8-triaza-naphthalene (from which it is derived by replacing C-5 by a nitrogen atom) is more easily ring-opened by cold acid. 

The first amination of a halogenopyridine involving a rearrangement was carried out by Levine and Leake in 1955 in an attempt to prepare 3-phenacylpyridine. When 3-bromopyridine (27, X = Br) was allowed to react with sodium amide in liquid ammonia in the presence of sodio-acetophenone, the reaction mixture obtained consisted chiefly of amorphous nitrogenous material from which only 10% of 4-aminopyridine (34, Y = NH2) and 13.5% of 4-phenacylpyridine were isolated. 

Chloroethyl)-3-[ (2-methyl-4-aminopyridin-5-yl)methyl] urea Sodium nitrite Hydrogen chloride... 

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. 

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