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DOI: 10.1055/a-2651-2367
Structurally Mapping Sodium-Mediated Synthesis of 1,4-Substituted Dihydropyridines: Nucleophilic Addition vs. Deprotonative Metalation
Supported by: Fundacion Ramon Areces
Supported by: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung 219318
Funding Information The authors acknowledge the financial support provided by the University of Bern, the Swiss National Science Foundation (SNSF) (project number 219318), and the Fundacion Ramón Areces (postdoctoral fellowship to DSR).
Dedication
This study is dedicated to Professor Paul Knochel, a true innovator in polar organometallic chemistry, on the occasion of his 70th birthday.
Abstract
The advent of organosodium reagents in organic synthesis has provided a more reactive and sustainable alternative to lithium derivatives, uncovering, in some cases, unique reactivities. Here we present the divergent reactivity of in situ generated benzyl sodium (BnNa), obtained by direct toluene sodiation, toward a selection of pyridine derivatives. Emphasizing its capacity as a nucleophile, selective C4-addition into some of these substrates followed by electrophilic interception has unlocked a new method to access 1,4-dihydropyridines. Contrastingly, when using picolines, selective benzylic metalation is observed for 2- and 4-picoline, whereas in the case of 3-picoline, a mixture of C4-addition and benzylic metalation is observed. Attempts to favor the nucleophilic addition using a borane additive revealed the formation of a sodium borate complex, which still shows a basic behavior by partial dissociation in solution. By trapping and characterizing key intermediate sodiated species, new mechanistic insights have been gained that advance the understanding of these sodium-mediated transformations.
Keywords
Organosodium reagents - Dihydropyridines - Metalation - Organometallic intermediates - Coordination effectsPublication History
Received: 24 June 2025
Accepted after revision: 08 July 2025
Accepted Manuscript online:
08 July 2025
Article published online:
21 August 2025
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For borate complexes bearing a benzyl group see: