Pyridine reaction with alkyl-, aryl-lithiums

Reaction with alkyl- or aryl-lithiums proceeds in two discrete steps addition to give a dihydro-pyridine iV-lithio-salt which can then be converted into the substituted aromatic pyridine by oxidation (e.g. by air), disproportionation or elimination of lithium hydride. The N-lithio-salts can be observed spectroscopically and in some cases isolated as solids. Attack is nearly always at an a-position reaction with 3-substituted-pyridines usually takes place at both available a-positions, but predominantly at C-2 this regioselectivity may be associated with relief of strain when C-2 rehybridises to sp during addition. 

Table 22 Reactions of Alkyl- and Aryl-lithium Compounds (RLi) with Pyridines and Some 2- or 4-Substituted...

Pyridine reacts with lithium alkyls and aryls under rather vigorous conditions (e.g. xylene at 100°C) to afford 2-alkyl- and 2-aryl-pyridines. The reaction proceeds by way of the corresponding dihydropyridines (e.g. 275 or a tautomer), and these may be isolated at lower temperatures. The less reactive Grignard reagents give poorer yields of the same products. 

The reaction of a lithium alkyl or aryl with dry pyridine involves the formation of a dihydro derivative (103) which, on heating or on being oxidized with molecular oxygen in the cold, furnishes the 2-substituted pyridine 104. Alternatively, 103 may be treated with water to give the 1,2-dihydro derivative which is converted to 104 by oxidation with picric acid (in which case the picrate of 104 is the product isolated) or with chloranil.229 No 4-phenylpyridine could be detected by gas chromatography in the reaction with phenyllithium.230 Support for... 

There is no doubt that in these. reactions the nitrogen atom of the pyridine ring is complexed with either the lithium alkyl or aryl or with the lithium bromide which is usually present in many preparations of organolithium compounds. It has been established that, either in the presence of an excess of lithium bromide or in the total absence of this salt, phenyllithium still gives the same ortho .para ratio on reaction with 3-picoline.229 To account for the predominant formation of the 2,3-isomer in the reaction of CH3Li with 3-alkylpyridines, it was suggested261 that the transition states for these reactions were similar... 

The reaction of A -phenacylpyridinium bromide with lithium dialkylcuprates (49) results in the isolation of acetophenone. The fate of the heterocyclic moiety has apparently not been determined. It is reasonable to assume, on the basis of the soft nature of these organometallic reagents, that 4-alkylpyridines must have been produced concomitantly. Addition of chloroformate esters to a mixture of pyridine and a cuprate reagent leads predominantly to A -carbo-alkoxy-4-alkyl(aryl)- 1,4-dihydropyridines (50). 

Two features of the reaction of pyridine derivatives with lithium aryls need separate mention. First, when alkyl substituents are present in the pyridine nucleus, metalation of the alkyl group is in competition with nuclear arylation (cf. p. 327). Ziegler and Zeiser found that phenyl lithium in ether converted 2-picoline into picolyl lithium. Sometimes, attempts to metalate... 

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