Control of site of lithiation of 3-(Aminomethyl)pyridine derivatives

Lithiation of N-(pyridin-3-ylmethyl)pivalamide, tert-butyl N-(pyridin-3-ylmethyl)carbamate, and N,N-dimethyl-N′-(pyridin-3-ylmethyl) urea with tert-butyllithium (3 equiv) in anhydrous tetrahydrofuran at -78 °C takes place on the nitrogen and on the ring at the 4-position. The dilithium reagents thus obtained react with various electrophiles to give the corresponding substituted derivatives in high yields. On the other hand, regioselective side-chain lithiation occurs with lithium diisopropylamide (3.3 equiv) at -20 to 0 °C. A mixture of ring and side-chain substitution products is obtained with n-butyllithium as the lithium reagent. Treatment of one of the ring-substituted products with trifluoroacetic anhydride in dichloromethane under reflux conditions led to formation of the corresponding 1H-pyrrolo[3,4-c]pyridine in high yield.