Alkylpyridines halogenation

Halogenoalkylpyridines also result from direct halogenation of alkylpyridines. For example, the chlorination of 2-methylpyridine gives 2-chloromethylpyridine with small amounts of the di- and tri-chloromethyl compounds (Scheme 48) (63AG(E)144). 

Very little work has been done on selectivity in anodic reactions of pyridines. Selective methoxylation and acetoxylation are known for al-kylbenzenes, but such reactions have not been reported for alkylpyridines. Also, reports on the oxidation of pyridines having aldehyde, ketone, halogen, hydroxyalkyl, or aminoalkyl functionalities are sparse. 

It is possible to halogenate selectively at the methyl position of alkylpyridines to give halogenoalkylpyridines. Low to moderate yields of fluoromethylpyridines are obtained on fluorination of 2- and 4-methyl pyridines with (V-fluoro-bis[(trifluoromethyl)sulfonyl]imide 52 in the presence of sodium carbonate in dichloromethane <1996T15>. 2-Methylpyridine is fluorinated in 20% yield and 4-methylpyridine in 72% yield under these conditions. Reagent 52 also effects the selective fluorination of 2,4,6-collidine to give the 2-fluoromethylated product in moderate yield (Equation 35). 

Alkylpyridines undergo reactions analogous to benzene such as side-chain halogenation and oxidative functionalization (cf. p 291). In addition, C-H bonds directly attached to the heterocycle display a kinetic acidity which is greater by a factor of > 10 compared to the corresponding benzene derivatives. This is more pronounced in the 2- and 4-positions than in the 3-position. H/D-Exchange experiments of 2-, 3- and 4-picoline with a relative exchange rate of 130 1 1810 (MeOD/MeONa at 20°C, cf toluene 10" ) demonstrate this point. 

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