Quinolines, activation positional reactivity

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. 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

Comparison between the reactivity of the N-oxides and the parent compounds (Table 11.1) shows that formation of the N-oxides increases the reactivity by 10-fold, except that at the 8-position of quinoline, where the reactivity remains the same. The difference between the result for the 8-position and the others probably again reflects the poor 1,5-conjugative interaction. The relatively small incremental activation for the other positions reflects the generally poor transmission of conjugative effects between one ring and the other in naphthalene-like molecules [68JCS-(B) 1112],... 

Aryl fluoroalkyl ethers have been prepared from the reaction, at room temperature in HMPA, of fluo-ro-substituted alkoxides with activated fluoro-,149 nitro-,149 and, at 150 °C, also chloro-arenes150,151 and some chloro-substituted pyrazines (equation 15), pyrimidines, quinolines,150,152 and pyridines.152 Disubstitution was observed in die presence of comparably activated leaving groups such as in 2,4- and 2,6-di-chloronitro- or cyano-benzenes, whereas regiospecific substitution took place at position 4 in 3,4-dichloronitro- or cyano-benzene and at position 2 in 2-fluoro-6-chlorocyanobenzene.151 Steric hindrance and the number of fluorine substituents in the alkoxide pose limits to the reactivity. Thus, tertiary alkoxides, or alkoxides containing more than four fluorine substituents, displace activated nitro and fluoro, but not chloro substituents.149,150 The secondary hexafluoro-2-propoxide anion does not react even with the more reactive nitro and fluoro derivatives.149... 

The electron-deficient ring of quinoline is not very reactive to electrophilic substitution, the preferred sites of attack being position 5 and 9 [24]. Nitration of CPT (best yields 70 % [25]) gives infacta mixtureofl2-and9-nitrocamptothecin (6). The latter is itself a compound (Rubitecan) endowed with potent antitumor activity [26], and is a precursor of many derivatives, as it can be easily reduced to 9-amino-CPT (7), in turn convertible into 9-hydroxy- and 9-methoxycamptothecin, minor components of the plant extract (Scheme 16.3). 

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