Alkyl lithiums, reaction with pyridines

C-Alkylation of weakly activated methylpyridines to yield the isopropyl and tert-butyl derivatives (35-40%), which normally requires the use of strong bases, such alkyl lithiums, is earned out effectively using a phase-transfer catalyst and aqueous sodium hydroxide on the /V-methylpyridinium salts. The pyridines are regenerated by reaction with sodium acetate or sodium 4-toluenethiolate [134]. 3-Methylpyridine fails to react under these conditions and the synthesis of 2-ethylpyridines by this procedure is also unsuccessful. 

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... 

Use of Lithium Derivatives. There are only a few reports of alkylation procedures which provide a means for preparing predominately 3-substituted pyridines. Some (l6-19) involve reaction of the pyridine compound with a lithium derivative, e.g. jiienyllithium or lithium aluminum hydride (LAH), followed by reaction with an alkyl or arylhalide. The reaction steps are as follows ... 

This type of reaction could not be effected using alkyl-lithium or alkyl-Grignard reagents. Also, the products represented by 2.225 and 2.227 with presumed divalent cobalt centers as offered by Johnson and coworkers should be considered as being tentative only no conclusive data were actually given in support of the proposed formulations. There is also a discrepancy between the main textual body and the experimental section of the 1973 paper by Johnson and coworkers as to which Co(III) derivative was actually used in these reactions. In the main body, it is stated that the square planar (implying pyridine-free) Co(III) corrole is used, whereas in the experimental section, it is stated that the pyridine derivatives were used. 

Lithium aluminum hydride (LAH) reacts with pyridines and their analogs in aprotic solvents to give dihydro- and tetrahydro-pyridines. In the absence of proton sources dihydropyridines normally predominate, solutions of pyridine and LAH form lithium complexes (32 Scheme 7), which likely consist of both 1,2- and 1,4-dihydropyridlnes. This intermediate has been used as a reducing agent for ketones, and reaction with alkyl halides generates 3-substituted pyridines (33) in good yield. 

Lithium aluminum hydride (LAH) reductions are carried out in aprotic solvents and give rise to the dihydro- and tetrahydropyridine derivatives. LAH reacts with both pyridines and pyridinium salts. It has been known for some time that aged ( 24 h) pyridine and LAH solutions form complexes of lithium tetrakis(A -dihydropyridinyl)aluminate (40, LDPA), - which is believed to consist of a mixture of the 1,2- and 1,4-dihydropyridines (by NMR). Indeed, LDPA itself has been used as a selective reducing agent for ketones and affords 3-substituted pyridines (41) on reaction with alkyl halides. 2,5-Dihydropyridines have been identified as intermediates in similar reactions. Kuthan and co-workers have shown that for 3,5-dicyan-... 

Lil in boiling pyridine or other weak nucleophilic bases can cleave alkyl esters to alkyl iodides and lithium carboxylates (Scheme 28). The reaction is mainly used for mild, aprotic cleavage of esters to car-boxylates. The high degree of dissociation for Lil and the nucleophilic strength of the iodide ion explain the reaction with esters, which is not useful with the other halides. Trimethylchlorosilane and sodium iodide also give alkyl iodides from esters. ... 

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