Highly Enantioselective Catalytic Addition of Grignard Reagents to N‐Heterocyclic Acceptors

Abstract

General methods to prepare chiral N‐heterocyclic molecular scaffolds are greatly sought after because of their significance in medicinal chemistry. Described here is the first general catalytic methodology to access a wide variety of chiral 2‐ and 4‐substituted tetrahydro‐quinolones, dihydro‐4‐pyridones, and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

“…On the other hand, Grignard reagents are significantly more reactive than organoaluminium and organozinc reagents, rendering the catalytic control of both the regio-and enantioselectivity in addition reactions challenging. Nevertheless, Harutyunyan and co-workers introduced the first general catalytic methodology to access a wide variety of chiral piperidones in 2019, using Grignard reagents (Scheme 1C) [18]. Therein, a new catalytic system based on the ligand L4/Cu complex promoted the addition of Grignard reagents to N-Cbz-pyridone and N-Cbz-2,3-dihydropyridone Michael acceptors with high enantioselectivity and yield.…”

“…lytic system based on L4/Cu, which efficiently catalysed the ACA of Grignard reagents to N-protected quinolones 17 at room temperature (Scheme 6) [18]. Initially, the methodology was developed for additions to N-Cbz-4-quinolone-based substrates, and the catalytic system was demonstrated to facilitate the addition of a wide variety of reagents, including linear, α-, β-, and γ-substituted, as well as aryl Grignard reagents.…”

Recent Developments in the Synthetic Strategies of 4‐Quinolones and Its Derivatives

“…The reaction was successfully upgraded to the gram scale. [64] The organocatalyzed aza-Micheal addition has been extensively explored for the synthesis of enantiomeric nitrogen heterocycles. Inspired from these, Saito and fellow workers developed an enantioselective protocol for the synthesis of Nunprotected-2-substituted-2,3-dihydro-4-quinolones (79) via intermolecular aza-Micheal addition of N-unprotected-2-aminophenyl vinyl ketone (77) catalyzed by chiral phosphoric acid [scheme 25].…”

Ru‐NHC‐katalysierte asymmetrische Hydrierung von 2‐Chinolonen zu chiralen 3,4‐Dihydro‐2‐chinolonen

“…Die erste ist die Übergangsmetall-katalysierte asymmetrische konjugierte Addition, [5] die meisten Beispiele konzentrieren sich jedoch auf Arylierungen. Im Jahr 2019 hat Harutyunyan [6] die asymmetrische Alkylierung mit Grignard-Reagenzien erforscht, um erfolgreich alkylsubstituierte Dihydro-2-chinolone zu bilden, wobei die harschen Bedingungen und die begrenzte Substratbreite aufgrund der geringen Aktivität von 2-Chinolonen Probleme bleiben (Schema 2 a). Alternativ dazu entwickelten Cao, [7] Gong [8] und Xiao [9] eine asymmetrische [4+2]-Cycloaddition zur erfolgreichen Bildung der oben genannten Motive.…”