Regioselective synthesis of pyridines by redox alkylation of pyridine N-oxides with malonates

Abstract

A regioselective synthesis of pyridines by the addition of malonate anions to pyridine N-oxide derivatives, which have been activated by trifluoromethanesulfonic anhydride, is reported. The reaction selectively affords either 2- or 4-substituted pyridines in good yields.Graphical abstract Electronic supplementary materialThe online version of this article (10.1007/s00706-017-2081-y) contains supplementary material, which is available to authorized users.

New Strategies for the Functionalization of Carbonyl Derivatives via α-Umpolung: From Enolates to Enolonium Ions

“…Following this initial success, we set out to unlock an intermolecular C−C bond-forming event and investigated the addition of enolates to the α-position of amides. 25 Here, potential challenges were to be overcome in order to achieve regioselective attack on the enolonium species (green circle in intermediate 7), with attack at the other electrophilic site (red circle in 7) 26 or elimination triggered by the basic reactants/ reagents being the more obvious pitfalls. Pleasingly, LDA-or NaH-preformed enolates were indeed suitable nucleophiles, reacting exclusively in the desired manner, which allowed us to generalize this metal-free method for the preparation of otherwise difficult-to-access 1,4-dicarbonyl compounds (Scheme 4).…”

Preparation of chiral DMAP derivatives and investigation on their enantioselective catalytic activity in benzazetidine synthesis and kinetic resolutions of alcohols

“…This strategy activates the electrophilic character of the substrate with a pronounced selectivity for the position 2 [44,45]. A similar procedure was recently used to functionalize pyridine rings with malonates [46]. In the synthesis of catalyst 8, the key step is the conversion of the pyridine N-oxide 5 into a reactive trifluoromethylsulfonyl-N-oxypyridinium salt (9) by treatment with triflic anhydride.…”

Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles

“…This reaction manifold would lead to the formation of the starting material and a substituted lutidine product and was previously observed by us in a different context (Figure 2c). 22 Here (Figure 2d), we report a detailed study of the reactivity of the enolonium intermediate a toward a broad range of heteroatom nucleophiles, including O-, N-, S-and halogen species. This study results in a unified approach to the αfunctionalization of amides in a fully chemoselective fashion.…”

“…This reaction manifold would lead to the formation of the starting material and a substituted lutidine product and was previously observed by us in a different context (Figure 2c). 22…”

“…While the α-position is, in principle, a “soft” electrophilic center, a problem that could arise by the use of other “hard” nucleophiles, such as alkoxides, would be attack at the 4-position of the lutidine moiety (Figure b). This reaction manifold would lead to the formation of the starting material and a substituted lutidine product and was previously observed by us in a different context (Figure c) …”