Easily accessible and tunable chiral triazoles have been introduced as a novel class of C−H bond-based H-donors for anion-binding organocatalysis. They have proven to be effective catalysts for the dearomatization reaction of different N-heteroarenes. Although this dearomatization approach represents a powerful strategy to build chiral heterocycles, to date only a few catalytic methods to this end exist. In this work, the organocatalyzed enantioselective Reissert-type dearomatization of isoquinoline derivatives employing a number of structurally diverse chiral triazoles as anion-binding catalysts was realized. The here presented method was employed to synthesize a number of chiral 1,2-dihydroisoquinoline substrates with an enantioselectivity up to 86:14 e.r. Moreover, a thorough study of the determining parameters affecting the activity of this type of anion- binding catalysts was carried out.

Die asymmetrische Dearomatisierung von N-Heterocyclen ist ein wichtiges Verfahren zur Synthese bioaktiver und präparativ wertvoller chiraler Heterocyclen. Allerdings stellt die katalytische, enantio- und regioselektive Dearomatisierung der einfachsten sechsgliedrigen N-Heteroarene, der Pyridine, immer noch eine Herausforderung dar. In dieser Arbeit präsentieren wir die erste hoch enantioselektive, nukleophile Dearomatisierung von Pyridinen durch Anionenbindungskatalyse mit Triazol-basierten H-Donor-Katalysatoren. Im Vergleich zu den geläufigen NH-basierten H-Bindungsdonoren zeigt dieser Organokatalysator eine sehr viel höhere C2-Regioselektivität. Er ist in der Lage, hohe Enantioselektivitäten zu induzieren, indem er einen chiralen Ionenpaar-Komplex mit einem ionischen N-Acylpyridinium-Intermediat bildet. Die Methode bietet eine direkte und nützliche Synthese von chiralen N-Heterocyclen ausgehend von kommerziell erhältlichen Pyridinen.

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.

N-carbamoyl nitrones represent an important class of reagents for the synthesis of a variety of natural and biologically active compounds. These compounds are generally converted into valuable 4-isoxazolines upon cyclization reaction with dipolarophiles. However, these types of N-protected nitrones are highly unstable, which limits their synthesis, storage and practical use, enforcing alternative lengthy or elaborated synthetic routes. In this work, a 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)-mediated formal “dehydrogenation” of N-protected benzyl-, allyl- and alkyl-substituted hydroxylamines followed by in situ trapping of the generated unstable nitrones into N-carbamoyl 4-isoxazolines is presented. A plausible mechanism is also proposed, in which the dipolarophile shows an important assistant role in the generation of the active nitrone intermediate. This simple protocol avoids the problematic isolation of N-carbamoyl protected nitrones, providing new synthetic possibilities in isoxazoline chemistry.