Alkylpyridines side-chain reactions

The typical reactions of alkyl groups attached to benzenoid rings involve benzyl-type radical intermediates. An azine ring can stabilize a side-chain radical just as can a phenyl ring, and thus most alkylpyridines and azines show these reactions. 

The picolyl hydrogens of 2- and 4-alkylpyridines are more acidic than the corresponding benzylic hydrogens. For that reason, the reactions of alkylpyridines with olefins occur under mild ccHiditions, and with conjugated dienes, styrenes, and vinylpyridines at below room temperatures. The mechanism of side-chain addition of alkylpyridines to olefins is very similar to that described for alkylbenzenes. 

The general process begins with Cr(CO)3L3, in which the L unit can be CO (most common),MeCN, " o-alkylpyridine, ammonia, and other donor ligands (equation 91). The rate (reaction temperature) is related to the nature of L the most reactive readily available source of Cr(CO)3 is ( ] -naphthalene)Cr(CO)3, which undergoes favorable arene exchange under mild conditions with many substituted arenes. " The most general and convenient procedure employs a mixture of THF and di-n-butyl ether at reflux. " A variety of polar and nonpolar aprotic solvents has been used and, for some purposes such as complexation of a-amino acids with aromatic side chains, water-THF mixtures are effective. 

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. 

The special properties associated with pyridine a- and 7-positions show again in the reactions of alkylpyridines the protons on alkyl groups at those positions are particularly acidified because the enaminate anions formed are delocalised. The ability to form side-chain anions provides an extremely useful means for the manipulation of a- and 7-side-chains. 

The enaminate anions produced by deprotonating a- and 7-alkylpyridines can participate in a wide range of reactions, " being closely analogous to enolate anions. Similar side-chain carbanion formation is seen in ortho- but not me/a-nitrotoluene. Side-chain metallation of 2-/-butylcarbonylamino-4-methylpyridine proceeds at room temperature. ... 

In the laboratory, selenium dioxide in organic solvents is a good reagent for the oxidation of alkylpyridines to carboxylic acids. " The intermediate aldehydes can be obtained depending on the position of the alkyl side-chain and the substrate/Se02 ratio. The reaction is selective in the case of 5-ethynyl-2-methylpyridine (X-S9) yielding 5-ethynyl-2-picolinic acid in 40% yield. ... 

In contrast, N-oxides of 2- and 4-alkylpyridines are functionalized in the side-chain (Boekelheide reaction) by acylation reagents (acid anhydrides [104] leading to acy-loxylation, sulfonyl chlorides, or POCI3 [105] leading to chlorination). For instance, 2-picoline-N-oxide on reaction with AC2O yields a mixture of acetoxy compounds (97-99), in which the methyl-acetoxylated product 97 dominates [106] ... 

Dimerization is well known to be a side reaction in the Chichibabin reaction (78RCR1042). In fact, dimerization can be the only product with certain alkylpyridines (79USP4177349 81USP4267335). Under normal Chichibabin conditions, heating a heterogeneous mixture of sodium amide in a hydrocarbon at atmospheric pressure with a branched chain alkylpyridine leads to... 

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