Halogenopyridines amines

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. 

The independence of the composition of the reaction products from the nature and position of the halogeno substituent clearly demonstrates that the amination of the isomeric 3- (27, X = Cl, Br, I) and 4-halogenopyridines (32, X = Cl, Br, I) proceeds exclusively via 3,4-pyridine (31). It is surprising that the 4-halogenopyridines did not... 

Amination of the various four 2-halogenopyridines (24, X = F, Cl, Br, I) under analogous conditions gave 2-aminopyridine (25, Y = NH2) as the sole reaction product in greater than 85% yield.The mechanism of these reactions is discussed in Section II, A, 3. 

None of the 3-halogenopyridines yield 2-piperidinopyridine. This substance was obtained as the only product from the reaction of 2-fluoropyridine (24, X = F) with lithium piperidide under the same conditions in 97% yield. Finally, it was found that 4-chloropyridine (32, X = Cl) was converted in 95% total yield into a mixture of 0.4% of 3-piperidino- (29, Y = NC5H10) and 99.6% of 4-piperidino-pyridine (34, Y = NCsHio)- Thus, in contrast to the amination with potassium amide, 4-chloropyridine reacts with lithium piperidide almost exclusively via the addition product 33 (X = Cl, Y = NC5H10). 

Why, then, was 2,3-pyridyne not found to play a role in the amination of 2- and 3-halogenopyridines ... 

While awaiting the results of tracer experiments, the present authors prefer to desist from assuming that the route from 24 to 25 via the addition product shown is the only pathway followed in the amination of 2-halogenopyridines. This is the more so since it seems probable that in the experiments described below derivatives of 2,3-pyridyne occur as intermediates. 

In 1961 a more extensive investigation of the amination of halogenopyridines with potassium amide (4 equivalents) in liquid ammonia at -33° was published (Pieterse and den Hertog - ). From the amination of 3-chloro (27, X = Cl), 3-bromo- (27, X = Br), and... 

Nucleophilic amination by replacement of halogen is among the most important reactions of compounds of the pyridine series. The original observation of this kind of reactivity was made by Marckwald , who drew the analogy between halogenopyridines and halogenonitrobenzenes. Whilst 2-chloropyridine was insufficiently reactive, 6-chloronicotinic acid reacted with... 

Bromopyridine has been aminated by reaction with sodamide or potas-samide in liquid ammonia (see also p. 214) and, in moderate yield, with sodio-methylaniline and related compounds in this connection it is interesting that sodium or potassium salts of arenesulphonamides give 2-arenesulphonyl-aminopyridines with 2-halogenopyridines, whilst sulphanilamide itself gives... 

The following examples Oft illustrate the important point that 3-halogen atoms are less easily replaced than 2- and 4-halogen atoms. Nevertheless, 3-halogenopyridines are useful sources of 3-aminopyridines, since amination... 

Little is known of the relative abilities of halogen atoms and other groups as leaving groups in nucleophilic amination of pyridines. However, when 2-halogeno-4-nitropyridines are heated with aqueous ammonia at 130°, 4-amino-2-halogenopyridines result . In the reactions shown, a 2-bromo-substituent is in competition with two other replaceable groups. The course... 

The halogen atom in 3-chloropyridine 1-oxide is very much less activated than those in 2- and 4-halogenopyridine 1-oxides but more so than that in 3-chloropyridine (see below). 3-Fluoropyridine 1-oxide reacts with piperidine or hydrazine more readily than do the chloro- or bromo-compounds . Surprisingly, reaction of amines or hydrazine with 3-halogeno-4-nitropyri-dine 1-oxides causes replacement of halogen and not of the nitro-group " 2. 

Pyridynes also arise in the amination of halogenopyridine l-oxides ... 

Amination by replacement of the nitro group in 4-nitropyridine 1-oxide has proved surprisingly unsuccessful a, 714. With ammonia, the main product seems to be 4,4 -azopyridine l,T-dioxide. Thus, although 4-nitro-pyridine 1-oxides are important sources of a range of 4-aminopyridine 1-oxides and 4-aminopyridines, this is so only because the 4-nitropyridine 1-oxides can be efficiently converted into 4-halogenopyridine 1-oxides (p. 233) and thence into the amines. 

The difficulty of diazotizing 2- and 4-aminopyridines, and the great reactivity of the diazonium ions once they are formed (p. 226), does not prevent the use of these amines as sources of halogenopyridines. Indeed, halogenation is one of the reactions which can easily be applied to diazotized 2- and 4-aminopyridines because of the high concentrations of halogen anions which can be introduced into the reaction solution from the very beginning. 

Two other modifications of the preparation of 2- and 4-halogenopyridines from amines have been used. 2-Aminopyridines, when treated with sodium ethoxide and amyl nitrite, give diazotates which have been converted by reaction with acids into 2-chloro-, -bromo- and -iodo-pyridinesi 4-Nitraminopyridine, with sodium nitrite in concentrated hydrochloric acid,... 

Qualitatively 2- and 4-halogenopyridine 1-oxides are more reactive towards amines than are 2- and 4-halogenopyridines, and the 3-isomers are in the same order (p. 213). Quantitative studies give the order 2 > 4 > 3, but involvement of the oxide function in the transition state of the replacement occurring at the 2-position may affect the relative order of the 2- and 4-positions (p. 217). As with the pyridines themselves, the best evidence for the relative positional reactivities in the oxides comes from the reaction of halo-genopyridine 1-oxides and alkoxides (p. 245). 

Arylation of aminopyridines by reaction with halogenobenzenes, usually in the presence of copper, is well known382-4 Tertiary amines can be prepared335. The special case of reaction with halogenopyridines has been mentioned (p. 211), and also the formation of di-(2-pyridyl) amine from 2-aminopyridine and its hydrochloride (p. 210). 

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