Halopyridines, reactivity

It should be pointed out that the existence of stable structures of the intermediate-complex type (also known as a-complexes or Wheland complexes) is not of itself evidence for their being obligate intermediates in aromatic nucleophilic substitution. The lack of an element effect is suggested, but not established as in benzene derivatives (see Sections I,D,2 and II, D). The activated order of halogen reactivity F > Cl Br I has been observed in quantita-tivei36a,i37 Tables II, VII-XIII) and in many qualitative studies (see Section II, D). The reverse sequence applies to some less-activated compounds such as 3-halopyridines, but not in general.Bimolecular kinetics has been established by Chapman and others (Sections III, A and IV, A) for various reactions. 

The A-oxidation of 3-chloropyridazines increases their reactivity toward methoxide and sulfanilamide anions.The reactivity of 4-chloro- or 4-nitro-quinoline and of chloropyridines toward methoxide ion and piperidine is less than that of the corresponding A-oxides (see Tables II and XI, pp. 270 and 338). The activating effect of the A-oxide moiety in 3-halopyridine A-oxides is greater than that of a nitro group, and in fluoroquinoline A-oxides the activation is transmitted to resonance-activated positions in the adjoining rings. 

The reactivity of 2- and 4-halopyridines toward a variety of nucleophiles is far greater than that of the 3-halo isomers (274), which are nevertheless appreciably activated. The 4-position (cf. 271) is more reactive than the 2-position (cf. 272), except when the specific factors described in Sections II, B and III, A and also below, produce an increase in the reactivity at the 2-position. Pyridine derivatives are the least reactive of the monocyclic azines (cf. Scheme I, p. 266). 

Halopyridines undergo self-quaternization on standing while the less reactive 2-halo isomers do not. However, more is involved here than the relative reactivity at the ring-positions. The reaction rate will depend on the relative riucleophilicity of the attack-ing pyridine-nitrogens (4-chloropyridine is more basic) and on the much lower steric hindrance at the 4-position. Related to this self-quatemization are the reactions of pyridine and picolines as nucleophiles with 4-chloro- and 2-chloro-3-nitropyridines. The 4-isomer (289) is. again the more reactive by 10-30-fold (Table VII, p. 276). 

Halopyridines and other re-deficient nitrogen heterocycles are excellent reactants for nucleophilic aromatic substitution.112 Substitution reactions also occur readily for other heterocyclic systems, such as 2-haloquinolines and 1-haloisoquinolines, in which a potential leaving group is adjacent to a pyridine-type nitrogen. 4-Halopyridines and related heterocyclic compounds can also undergo substitution by nucleophilic addition-elimination but are somewhat less reactive. 

Halogen atoms in pyrones and pyridones e.g. 902) are unreactive toward SAE nucleophilic displacement. 3-Halopyridines are less reactive than the a- and 7-isomers but distinctly more reactive than unactivated phenyl halides. Thus, a bromine atom in the 3-position of pyridine or quinoline can be replaced by methoxy (NaOMe-MeOH, 150°C), amino (NH3-H20-CuS04, 160°C) or cyano (CuCN, 165°C). 5-Halogens in pyrimidines are also relatively unreactive. 

The reactions of the 4-halopyridines parallel those of the corresponding 2-isomers, with the exception that 4-halopyridines polymerize much more readily (e.g. to 903) because the pyridine nitrogen atom is not sterically hindered and is more basic (cf. Section 3.2.1.3.4). As expected, the chlorine atom in the 1-position of 1,3-dichloroisoquinoline is more reactive than that in the 3-position, thus, mild treatment with sodium ethoxide gives (904). Halogens in the 9-position of acridine are more reactive, e.g. (906) — (90S), (907). 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

Of lesser relevance to this discussion are halogenation methods involving the modification of the carbon skeleton (synthesis and degradation). The Hunsdiecker reaction, as applied to certain heterocyclic acids, has had limited application for the synthesis of halogen derivatives. The preparation of 3-bromo-4,6-dimethyl-2-pyridone from the silver salt of the respective 3-carboxylic acid by treatment with bromine in carbon tetrachloride is a rare example of success.13 The interaction of carbenes with heterocycles also has been employed infrequently, but recent advances in carbene generation may reactivate this approach.14 The Ciamician-Dennstedt ring expansion of pyrrole to / -halopyridines is a case in point18 [Eq. (4)] ... 

Heteroaryl halides such as halopyridines, bromoquinolines " , furyl halides , thienyl halides and imidazolyl bromides " were found to be reactive. A particularly interesting application concerns nucleoside chemistry, since 2-iodopurine " 246 5-iodouridine , 5-halouracil2 ° 2 and 5-iodocytosine were used successfully. When the reactivity of the carbon-halogen bond is exalted, the coupling reaction can be extended to chloro derivatives, such as 6-chloropurines ", 4- and 5-chloro-pyrimidines and 2-chloropyrazines °. 

In contrast to their lack of reactivity toward electrophilic substitution, 2-and 4-substituted (but not 3-substituted) halopyridines undergo nucleophilic aromatic substitution easily. 

Chloro- and 2-bromo-pyridines undergo Ni-catalyzed coupling reactions with primary alkyl Grig-nard reagents (equation 3-halopyridines are less reactive and an ortho methyl substituent... 

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