Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives

Abstract

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.

Key words

directed lithiation - side-chain lithiation - N-(pyridin-3-ylmethyl)pivalamide - N,N-dimethyl-N′-(pyridin-3-ylmethyl)urea - tert-butyl N-(pyridin-3-ylmethyl)carbamate

• References and Notes

• 1 Current address: Chemistry Department, College of Sciences and Humanities, Salman bin Abdulaziz University, P.O. Box 83, Al-Kharij 11942, Saudi Arabia.
• 2 Current address: Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt.

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