Structurally Mapping Sodium-Mediated Synthesis of 1,4-Substituted Dihydropyridines: Nucleophilic Addition vs. Deprotonative Metalation

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 effects

Publikationsverlauf

Eingereicht: 24. Juni 2025

Angenommen nach Revision: 08. Juli 2025

Accepted Manuscript online:
08. Juli 2025

Artikel online veröffentlicht:
21. August 2025

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