Variations in the site of lithiation of N-acyl-3-(aminomethyl)pyridine derivatives with different N-substituents using different lithiating reagents has been investigated. Ring lithiation has been achieved by the use of t-BuLi at -78 °C followed by reaction with various electrophiles to give the corresponding 4-substituted products in high yields. The reaction was regioselective towards the side-chin with LDA at -20 to 0 °C. A mixture of ring and side-chain substitution products was obtained with n-BuLi. Smith’s group has developed several efficient lithiation procedures for preparation of various substituted aromatics and heteroaromatics that might be difficult to prepare by other means.1 As part of such studies they have successfully lithiated and substituted various N-(substituted benzyl) pivalamides and N'-(substituted benzyl)-N-N-dimethylureas selectively using n-BuLi or t-BuLi.2 Such processes have been applied for the production of substituted isoindoline and isoquinoline derivatives.3 Very recently, the Smith group has investigated the effect of an extra CH2 between the DMG and the pyridine ring.4 It was found that the lithiation and substitution of 2- and 4-substituted N-(pyridinylmethyl)amines (urea, pivalamide and carbamate containing groups) provided easy access to various side-chain (methylene) substituted derivatives in high yields.4 Ring lithiation of a series of N-acyl-3-(aminomethyl)pyridine derivatives has been achieved by the use of t-BuLi then allowed to react with various electrophiles to give the corresponding 4-substituted products in high yields.5 On the other hand, the reaction was regioselective towards the side-chin with LDA at -20 to 0 °C.5 A mixture of ring and side-chain substitution products, and also some product resulting from addition of butyllithium on the pyridine double bond followed by oxidation was obtained.5

Regioselective lithiation of various substituted pyridines

251st National Meeting (2016)

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