Synthesis of Substituted Pyridines via Formal (3+3) Cycloaddition of Enamines with Unsaturated Aldehydes and Ketones

An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This...

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Bibliographic Details
Published in:Journal of organic chemistry 2022-07, Vol.87 (13), p.8437-8444
Main Authors: Dai, Xi-Jie, Krolikowski, Paul, Murray, James I., Wei, Carolyn S., Dornan, Peter K., Rötheli, Andreas R., Caille, Seb, Thiel, Oliver R., Smith, Austin G., Parsons, Andrew T.
Format: Article
Language:English
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Summary:An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib. Mechanistic analysis using two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed the transformation proceeds through the reversible formation of a stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.2c00576