Highly Enantioselective Nucleophilic Dearomatization of Pyridines by Anion‐Binding Catalysis

Abstract

The asymmetric dearomatization of N-heterocycles is an important synthetic method to gain bioactive and synthetically valuable chiral heterocycles. However, the catalytic enantio- and regioselective dearomatization of the simplest six-membered-ring N-heteroarenes, the pyridines, is still very challenging. The first anion-binding-catalyzed, highly enantioselective nucleophilic dearomatization of pyridines with triazole-based H-bond donor catalysts is presented. Contrary to other more common NH-based H-bond donors, this type of organocatalyst shows a prominent higher C2-regioselectivity and is able to promote high enantioinductions via formation of a close chiral anion-pair complex with a preformed N-acyl pyridinium ionic intermediate. This method offers a straightforward and useful synthetic approach to chiral N-heterocycles from abundant and readily available pyridines.

Nucleophilic Dearomatization of Activated Pyridines

“…A recent report by Mancheño introduced organocatalysis as a platform to induce stereoselectivity in the dearomatization of pyridinium salts [35], disclosing anion binding by multiple hydrogen bond donors as a suitable approach to this type of reactions. A silylketene acetal was used as nucleophilic partner.…”

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

“…Following the aforementioned studies, the Mancheno group designed and synthesized various chiral triazole-based complexes such as L2–L4 (Scheme 2) [36–39]. It was proposed that while these triazole derivatives are conformationally flexible, upon their binding to halogen anions these complexes adopt a reinforced chiral helical conformation.…”

“…Various nitrogen-containing heterocycles such as pyridines [36], quinolines [38], isoquinolines [38], etc. were reacted with TrocCl to form the corresponding salts, and these generated in situ ion pairs were treated with silyl enol ethers in the presence of chiral catalysts L2–L4 to form chiral addition products.…”

“…Application of chiral triazole-based catalysts L3 and L4 for counterion activation of pyridinium, quinolinium and isoquinolinium salts by Mancheno and co-workers [36–39]. …”

ORCHEM‐Preis: T. Magauer und O. García Mancheño / Emil‐Fischer‐Medaille: D. Trauner / Gmelin‐Beilstein‐Denkmünze: J. P. Richmond

“…Ihr Forschungsprogramm ist der Entwicklung neuer, vor allem katalytischer Synthesemethoden gewidmet, mit einem Schwerpunkt auf dem Einsatz ionischer Verbindungen und Intermediate in der oxidativen C‐H‐Funktionalisierung und der Organokatalyse mithilfe von Wasserstoffdonoren. In der Angewandten Chemie hat sie die enantioselektive Dearomatisierung von Pyridinen vorgestellt und in Chemistry—A European Journal chirale Triazole in der Anionenbindungskatalyse …”