Pyridines 2-halo, nucleophilic substitution reactions

The 4- and 6-positions of pyrrolo[2,3-3]pyridines can be substituted via palladium-catalyzed cross-coupling reactions with the 4- or 6-halo-substituted derivatives (Scheme 3) <2001SL609>. Nucleophilic displacement of the 4-substituent of 6-chloro-4-nitro- and 4,6-dichloro-pyrrolo[2,3-/ ]pyridines takes place with phenols. Protection of the pyrrole nitrogen with a /3-trimethylsilylethoxymethyl (SEM) group affords good yields of the aryl ethers (Equation 3) <2006TL2069>. 

Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions, which compete with the desired DoM process. 

A nitro group in the 2- or 4-position of the pyridine ring is susceptible to nucleophilic substitution under relatively mild conditions, and in these reactions it competes with a 3- or 5-halogen. 3-Halo-4-nitropyridines (halo = Cl, Br, I) react with aqueous barium or potassium hydroxide to form 3-halo-4-pyridones and with alkoxides to form 4-alkoxy-3-halopyridines. However, 3-fluoro-4-nitropyridine is converted to 4-nitro-3-pyridinol or 3-alkoxy-4-nitropyri-dines. The corresponding iV-oxides react similarly. (See Section 1.6.A., p. 688). 

Pyridine is much less nucleophilic than benzene, so it undergoes electrophilic aromatic substitution reactions only under rigorous conditions. However, halo-substituted benzenes readily undergo nucleophilic aromatic substitution reactions. 

All the halo-diazines, apart from 5-halo-pyrimidines, react readily with soft nucleophiles, such as amines, thiolates and malonate anions, with substitution of the halide. Even 5-bromopyrimidine can be brought into reaction with nucleophiles using microwave heating. All cases are more reactive than 2-halo-pyridines the relative reactivities can be summarised ... 

A transition metal-free direct amination of halo(pyridine or pyrimidine) has been developed in good yields under the action of computer-controlled microwave irradiation [202]. This solvent-free reaction is useful for coupling of halo(pyridine and pyrimidine) with pyrrolidine and piperidine derivatives by nucleophilic aromatic substitution (S Ar). 

The reaction of 3-halo-4-aminopyridines with acyl chlorides in the presence of triethy-lamine gives pyridin-4-yl a-substituted acetamides in which an Al-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution resulting in a formal two-carbon insertion (Scheme 205). " ... 

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