Halogenopyridines halogen

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). 

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. 

The higher reactivity of 2-halogen othiazoles 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 rr 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. 

The halogen atom of 7-chloro l,2,3.4-tetrahydrobenz [c]acridine is prone to nucleophilic displacement, as expected of a y-halogenopyridine system. Ready hydrolysis yields the 7-hydroxy compound and sodiomalononitrile affords the dicyanomethyl derivative both products exist as the keto-tautomers (B.V. Lap et at, 2. heterocyclic Chem., 1983, 20, 281). 

It should be noted that lithiopyridines alternatively and frequently are prepared by halogen-metal exchange reactions of halogenopyridines with organolithiums, e.g. ... 

With 3-halogenopyridines, nucleophilic substitution takes place by an aryne mechanism. For instance, reaction of 3-chloropyridine with NaNH2/NaOtBu in tetrahydro-furan (THF) at 40 °C in the presence of pyrrolidine yields a 1 1 mixture of 3- and 4-(N-pyrrolidino)pyridines, which is indicative of a primary 1,2-dehydro-halogenation and addition of pyrrolidine to a 3,4-dehydropyridine ( hetaryne ) intermediate [85]. 

Alternatively, lithiopyridines can be obtained by halogen-metal exchange from halogenopyridines and organoUthium compounds, as shown for 37 ... 

Bas M, Gueret C, Perrio C, Lasne M, Barr6 L (2001) Oxidation of 2- and 3-halogenated quinolines an easy access to 5- and 6-halogenopyridine-2,3-dicarboxylic acids. Synthesis... 

Nuclear quadrupole resonance studies of chloro- and bromopyridines have been used to examine the charge distribution in the heterocyclic ring. The charge density at a nuclear carbon atom can be related to Hammett substituent constants, and the quadrupole resonance frequencies of halogen atoms at C(3) and C(5) in pyridines can be related satisfactorily to the Hammett constant for the heterocyclic nitrogen atom. However, the relationship breaks down for 2-halogenopyridines, and the quadrupole resonance frequencies indicate , in these cases, an increase in the carbon-halogen bond order (35). 

Nuclear alkylation by reaction of lithium alkyls with halogenopyridines is of consequence only as a side-reaction which diminishes the efficiency of halogen-metal exchange to produce pyridyl lithiums . This situation differs considerably from that found with some sodium reagents (see below). 

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... 

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. 

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. 

Nucleophilic halogen exchange has been observed frequently with 2-and 4-halogenopyridines. The commonest reaction of this type is that of a 2- or 4-chloropyridine with hydriodic acid 819-20,... 

Some cases of halogen-halogen exchange accompanying quaternization of halogenopyridines have been mentioned already (p. 180). 

Concentrated halogen hydracids convert 4-nitropyridine 1-oxide into 4-halogenopyridine l-oxides, 849 hut with dilute acids products arise from an initial hydrolysis to 4-hydroxypyridine l-oxide, 849-50 With sulphuryl chloride, 4-nitropyridine 1-oxide gives mainly 2,4-dichloropyridine (35-40 per cent) 248, 796. 

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