Economical Access to Diverse Enantiopure Tetrahydropyridines and Piperidines Enabled by Catalytic Borrowing Hydrogen

Abstract

We disclose herein a catalytic borrowing hydrogen method that enables an unprecedented, economical one‐pot access to enantiopure tetrahydropyridines with minimal reagent use or waste formation. This method couples a few classes of readily available substrates with commercially available 1,3‐amino alcohols, and delivers the valuable tetrahydropyridines of different substitution patterns free of N‐protection. Such transformations are highly challenging to achieve, as multiple redox steps need to be realized in a cascade and numerous side reactions including a facile aromatization have to be overcome. Highly diastereoselective functionalizations of tetrahydropyridines also result in a general access to enantiopure di‐ and tri‐substituted piperidines, which ranks the topmost frequent N‐heterocycle in commercial drugs.

Highlighting the Rich Chemistry of the Allenone Moiety

“…Tetrahydropiperidine rings have been also recently prepared from the reaction of α-allenones 2 and chiral non-racemic aminoalcohols 462 (Scheme 79a). [213] Iridium catalyst 464 has provided substrate controlled enantioselectivity of up to 99% through a hydrogen borrowing catalytic reaction mechanism (Scheme 79a). [213] In a different work, α-allenones prepared in situ from chlorovinyl ketones 465 have generated [1,2,3]triazolo [1,5-a]quinolines 467 from the reaction with 2-azidoaryl carbonyls 466 under Ni catalysis (Scheme 79b).…”

“…Tetrahydropiperidine rings have been also recently prepared from the reaction of α‐allenones 2 and chiral non‐racemic aminoalcohols 462 (Scheme 79a) [213] . Iridium catalyst 464 has provided substrate controlled enantioselectivity of up to 99% through a hydrogen borrowing catalytic reaction mechanism (Scheme 79a) [213] .…”

“…[213] Iridium catalyst 464 has provided substrate controlled enantioselectivity of up to 99% through a hydrogen borrowing catalytic reaction mechanism (Scheme 79a). [213] In a different work, α-allenones prepared in situ from chlorovinyl ketones 465 have generated [1,2,3]triazolo [1,5-a]quinolines 467 from the reaction with 2-azidoaryl carbonyls 466 under Ni catalysis (Scheme 79b). [214] Keto-vinylidenecyclopropanes 119 a have been devised as precursors of cyclic aminoalcohols 470 through a transition metal catalyzed annulation process involving the allenone moiety (Scheme 80a).…”

Ir-Catalyzed Synthesis of Functionalized Pyrrolidines and Piperidines Using the Borrowing Hydrogen Methodology

“…Depending on the length of the diol, this strategy provided excellent results for the preparation of aza-heterocycles such as piperidines and pyrrolidines. With regard to the transition metal classically used for this transformation, Ir − and Ru − are often used as catalysts, but Feringa and Barta − among others , also showed the efficiency of Fe in this reaction. Heterogeneous catalysis using either NiCuFeO x or bimetallic Pt–Sn/γAl 2 O 3 , has also been reported.…”

B(C6F5)3-catalyzed β-C(sp3)–H alkylation of tertiary amines with 2-aryl-3H-indol-3-ones

“…It should be noted that the strategy involving redox-neutral C–H activation via hydride-transfer is a more efficient and sustainable route for the direct C(sp 3 )–H functionalization of amines. 6 In recent years, various increasing efforts have been made for the explosive development of the α-functionalization of amines. 7 However, the direct β-C–H functionalization of amines has been less explored owing to the distal bonds being less electron-rich.…”