Nucleophilic Dearomatization of Pyridines under Enamine Catalysis: Regio-, Diastereo-, and Enantioselective Addition of Aldehydes to Activated N-Alkylpyridinium Salts

Abstract

Catalytic addition of chiral enamines to azinium salts is a powerful tool for the synthesis of enantioenriched heterocycles. An unprecedented asymmetric dearomative addition of aldehydes to activated N-alkylpyridinium salts is presented. The process exhibits complete C-4 regioselectivity along with high levels of diastereo- and enantiocontrol, achieving a high-yielding synthesis of a broad range of optically active 1,4-dihydropyridines. Moreover, the presented methodology enables the synthesis of functionalized octahydropyrrolo[2,3-c]pyridines, the core structure of anticancer peptidomimetics.

Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts

“…Further work from Bernardi, Fochi and co-workers used secondary amine catalysts to promote the enantioselective addition of aldehydes to N -alkyl pyridiniums via in situ generated enamines in toluene. 23 Subsequent Wittig-olefination was used to selectively generate the isolable 1,4-DHP products in generally good yields, >90 : 10 dr and >95 : 5 er. Related manuscripts from the groups of Rovis and Massi demonstrated two alternative NHC-catalysed dearomatisation processes.…”

Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts

“…Finally, a chemical transformation of compound 82a (R 1 = R 2 = H, R 3 = Bn, 98% ee) to the more complex structure 83a through a Friedlander reaction was performed in high isolated yield and without racemization (83%, 99% ee) (Scheme 25b). In 2017, Bernardi and Fochi have achieved nucleophilic dearomatization of pyridinium salts 47 under enamine catalysis using Jørgensen catalyst C17 (10 mol%) and phenyl acetic acid (10 mol%) as co-catalyst (Scheme 26) [65]. This acid co-catalyst was proposed to buffer the unreacted amount of Et 3 N at the end of the reaction thus slowing post-addition epimerization.…”

Nucleophilic Dearomatization of Activated Pyridines

“…Finally, some experimental investigations led us to propose a reaction pathway showing the catalyst involved in the double (covalent and H-bond) activation of both of the reaction partners. Shortly after, the reactivity of N-alkyl-3-nitroor 3-cyano-pyridinium halides towards asymmetric nucleophilic dearomatization was extended by employing chiral enamines as nucleophiles [61]. These were generated by the reaction of chiral secondary amine organocatalysts [62,63] with enolizable aldehydes.…”