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Synthesis 2013; 45(24): 3426-3434
DOI: 10.1055/s-0033-1338547
DOI: 10.1055/s-0033-1338547
paper
Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
Further Information
Publication History
Received: 16 July 2013
Accepted after revision: 13 September 2013
Publication Date:
09 October 2013 (online)
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)carbamateSupporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.
- Supporting Information
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References and Notes
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See, for example:
Recent examples for substituted benzenes:
Recent examples for substituted heterocycles:
For discussion of aggregation level, see: