Modular synthesis of chiral 1,2-dihydropyridines via Mannich/Wittig/cycloisomerization sequence that internally reuses waste

Abstract

Abstract1,2-Dihydropyridines are valuable and reactive synthons, and particularly useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. However, the catalytic enantioselective synthesis of structurally diverse 1,2-dihydropyridines is limited to enantioselective addition of nucleophiles to activated pyridines. Here, we report a modular organocatalytic Mannich/Wittig/cycloisomerization sequence as a flexible strategy to access chiral 1,2-dihydropyridines from N-Boc aldimines, aldehydes, and phosphoranes, using a chiral amine catalyst. The key step in this protocol, cycloisomerization of chiral N-Boc δ-amino α,β-unsaturated ketones recycles the waste to improve the yield. Specifically, recycling by-product water from imine formation to gradually release the true catalyst HCl via hydrolysis of SiCl4, whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste Ph3PO from the Wittig step to modulate the acidity of HCl. This approach allows facile access to enantioenriched 2-substituted, 2,3- or 2,6-cis-disubstituted, and 2,3,6-cis-trisubstituted piperidines.

Light-Promoted Dearomative Cross-Coupling of Heteroarenium Salts and Aryl Iodides via Nickel Catalysis

“…Traditionally, synthetic access to partially saturated nitrogen heterocycles (e.g. dihydropyridines) has relied on various cyclization and cycloaddition reactions and dearomatization of heteroarenes. − For example, azatrienes prepared through condensation of carbonyl compounds and amines or through transition metal-catalyzed reactions undergo 6-π electrocyclization to deliver 1,2- or 2,3-dihydropyridines ,, and hetero Diels–Alder reactions can deliver 1,4-dihydropyridines . These cyclization and cycloaddition approaches use starting materials that require multistep synthesis and allow preparation of only certain substitution patterns on dihydropyridines due to the steric and electronic requirements of these reactions.…”

Skeletal remodeling of chalcone-based pyridinium salts to access isoindoline polycycles and their bridged derivatives

“… 2 Despite substantial advances, this strategy only modifies the periphery of the dearomatized pyridine molecules by tuning the substituents while retaining the six-membered cyclic structure. 3 Skeletal re-editing is an important complementary method that comprises two elementary steps: deconstruction of the underlying molecular skeleton to generate reactive species and subsequent reconstruction to deliver structurally distinct molecules. This method rapidly and reliably achieves skeletal diversity by modifying the core framework.…”

Cascade aza-Wittig/6π-Electrocyclization in the Synthesis of 1,6-Dihydropyridines

“… 11 Very recently, Yu, Zhou et al reported the enantioselective synthesis of 1,2-dihydropyridines, using a chiral amine catalyst. 12 Metal-free protocols that allow rapid access to substituted DHPs and their derivatives are in high demand.…”

“…Tejedor et al has developed a convenient domino access to substituted alkyl 1,2-dihydropyridine-3-carboxylates from propargyl enol ethers and primary amines by means of a Claisen rearrangement/isomerization/amine condensation/6π-aza-electrocyclization process (Scheme c) . Very recently, Yu, Zhou et al reported the enantioselective synthesis of 1,2-dihydropyridines, using a chiral amine catalyst . Metal-free protocols that allow rapid access to substituted DHPs and their derivatives are in high demand.…”