3- Halogenopyridines

The higher reactivity of 2-halogenothiazoles with respect to halogenopyridines can be related to the different aromaticity of the two systems, less for thiazole than for pyridine, for example, the relatively stronger fixation of the tt bond in the thiazole than in the case of pyridine. As the data reported in Table V-1 (footnote a) indicates, the free thiophenol is more reactive than the thiolate anion toward the 2-halogenothiazoles. This fact should be considered when one prepares the thiazolyl sulfides. 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

Ciamician reported the formation of 3-halogenopyridines in low yield from the reaction of pyrryl potassium with chloroform, or bromo-form, in ether. Similar reactions of pyrrole with benzal chloride and methylene iodide gave 3-phenylpyridine and traces of pyridine, respectively. These reactions were later reinvestigated by Alexander... 

Whereas only one dehydrobenzene, benzyne, has been detected, two pyridynes are possible. Thus, the scheme we can write ab initio for the action of a nucleophile on the isomeric monosubstituted derivatives of pyridine involving 2,3- (26) and/or 3,4-pyridyne (31) is more complicated than that for the analogous reaction of the corresponding benzene derivative. The validity of this scheme can be checked using data available in the hterature on reactions of halogenopyridines with potassium amide and hthium piperidide involving pyridynes. 

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. 

The reactions of various halogenopyridines with lithium piperidide and piperidine have been studied by Kauffmann and Boettcher. ... 

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). 

Those reactions of halogenopyridines with potassium amide and lithium piperidide which proceed via 3,4-pyridyne form the 3- and 4-substituted pyridine derivatives in ratios of 1 2 and 1 1, respectively (see Section II, A, 1). It appears that the ring nitrogen atom has an orienting effect on these additions, but the quantitative divergence of the addition of ammonia and piperidine is not understood at present. 

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. 

Halogenopyridines can be photohydrolized efficiently. The quantum yield of photohydrolysis is independent of the pH-value (5.2) 501 a>. 

Quantum Yields of Photohydrolysis of some Halogenopyridines at Different pH Values 4>x, Disappearance of Halogenopyridine oH> Formation of Hydroxypyridine... 

It is seen from Table 1 that the series of halogenopyridines show quantum yields of photohydrolysis independent of pH in the neutral and alkaline region and decreasing only at pH-values where the pyridine nitrogen becomes protonated to a considerable percentage. 

Fig. 3.23 Oxidation of halogenated quinolines to halogenopyridine-2,3-dicarboxylic acids [260]...

Halogenopyridines can undergo metal-halogen exchange when treated with butyllithium. The lithium derivatives then behave in a similar manner to arylithiums and Grignard reagents and react with electrophiles such as aldehydes, ketones and nitriles (Scheme 2.17). Thus, aldehydes and ketones form alcohols, and nitriles yield A -lithioimines, which on hydrolysis are converted into pyridyl ketones. 

Both reactions are directed to C-2(6) and C-4 (attack at C-2 is shown below). Electrophilic reactions require the loss of a proton, whereas those for nucleophiles require the loss of hydride ion. 2(4)-Halogenopyridine A-oxides are good substrates for nucleophilic substitution, and the thus site of attack is strongly iniluenced by the position of the halogen atom. 

Determinations in this area seem mainly confined to the simple aromatic molecules, pyridines and substituted derivatives, particularly the halogenopyridines. Figure 1 shows the results of determinations for pyridine (74JST(20)119, 77JST(42)l). Features to note are the... 

Pyridine itself will substitute a- and y-halogenopyridines, giving A-(2- or 4-pyridyl)pyridinium salts. Self-quaternization of halogenopyridines can also occur and is most common with 4-fluoropyridines (58BSF424). 

Pyridynes are also commonly generated from orf/io-dihalogenopyridines by lithium exchange processes, e.g. Scheme 138, and processes not involving halogenopyridines, e.g. thermal decomposition of pyridinediazonium carboxylates. 

Stabilized carbanions will substitute a- and y-halogenopyridines and their benzo analogues. Substitution at the /3-position is much less common and requires the presence of suitable activating groups, e.g. Scheme 140 (73BCJ3144). 

Azaallyl anions, generated by treatment of arylmethylidene(arylmethylamines) with lithium diisopropylamide (LDA), react with 2-halogenopyridines to give a variety of substituted [l,7]naphthyridines (Scheme 47) <1995J(P1)2643>. 

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