Exploiting Synergistic Catalysis for an Ambient Temperature Photocycloaddition to Pyrazoles

Abstract

Sydnone‐based cycloaddition reactions are a versatile platform for pyrazole synthesis, however they operate under harsh conditions (high temperature and long reaction times). Herein we report a strategy that addresses this limitation utilizing the synergistic combination of organocatalysis and visible‐light photocatalysis. This new approach proceeds under ambient conditions and with excellent levels of regiocontrol. Mechanistic studies suggest that photoactivation of sydnones, rather than enamines, is key to the successful implementation of this process.

Sydnone Methides—A Forgotten Class of Mesoionic Compounds for the Generation of Anionic N‐Heterocyclic Carbenes

“…They are widely applied as masked nitrile imines in 1,3‐dipolar cycloadditions (“Huisgen reactions” [1] ) which proceed in a copper‐catalyzed, [2] metal‐free [3] or metal‐free strain‐promoted click fashion [4, 5] with sub‐millisecond intermediates, [6] as summarized in numerous review articles and compilations about [2+3]‐cycloadditions [7] . Recent developments include the synergistic combination of organocatalysis and visible‐light photocatalysis of cycloadditions of sydnones to form pyrazoles [8] . Apart from cycloadditions, sydnones are versatile precursors for nucleophilic radiofluorination for the synthesis of [ 18 F]fluoroarenes, [9] and co‐catalysts or ligands of Pd catalysts for Suzuki–Miyaura reactions under acidic conditions [10] .…”

“…[7] Recent developments include the synergistic combination of organocatalysis and visible‐light photocatalysis of cycloadditions of sydnones to form pyrazoles. [8] Apart from cycloadditions, sydnones are versatile precursors for nucleophilic radiofluorination for the synthesis of [ 18 F]fluoroarenes, [9] and co‐catalysts or ligands of Pd catalysts for Suzuki–Miyaura reactions under acidic conditions. [10] They are of ongoing interest as biologically active compounds [11] from which the sydnone imine [12] Molsidomine [13] and Sydnocarb [14] are in clinical use.…”

Sydnonmethide – fast vergessene Mesoionen als Vorläufermoleküle von anionischen N‐heterocyclischen Carbenen

“…Diese können Kupfer‐katalysiert, [2] metallfrei [3] oder auch “klickbar” metallfrei unter Ausnutzung von Ringspannungen [4, 5] über Submillisekunden stabile Intermediate erfolgen, [6] wie in zahlreichen Übersichtsartikeln und Bibliographien über [2+3]‐Cycloadditionen zusammengefasst [7] . Die synergistische Kombination aus Organokatalyse und Photokatalyse im sichtbaren Licht, um von Sydnonen in 1,3‐dipolaren Cycloadditionen zu Pyrazolen zu gelangen, markiert eine neueste Entwicklung [8] . Abgesehen von Cycloadditionen haben sich Sydnone als wertvolle Ausgangsmaterialien für nucleophile Radiofluorierungen für [ 18 F]Fluoraromaten‐Synthesen [9] und als Co‐Katalysatoren oder Liganden von Pd‐Katalysatoren für Suzuki–Miyaura‐Reaktionen im Sauren erwiesen [10] .…”

“…[7] Die synergistische Kombination aus Organokata-lyse und Photokatalyse im sichtbaren Licht, um von Sydnonen in 1,3-dipolaren Cycloadditionen zu Pyrazolen zu gelangen, markiert eine neueste Entwicklung. [8] Abgesehen von Cycloadditionen haben sich Sydnone als wertvolle Ausgangsmaterialien fürn ucleophile Radiofluorierungen für [ 18 F]Fluoraromaten-Synthesen [9] und als Co-Katalysatoren oder Liganden von Pd-Katalysatoren fürS uzuki-Miyaura-Reaktionen im Sauren erwiesen. [10] Nach wie vor sind Sydnone als biologisch aktive Verbindungen interessant.…”

Sydnone Ribosides as a Platform for the Synthesis of Pyrazole C-Nucleosides: A Unified Synthesis of Formycin B and Pyrazofurin

“…The presented sydnone–alkyne cycloaddition swiftly provides N -protected 5-carboxy-pyrazoles with multiple orthogonal diversification points, which are challenging to generate via other methods in the context of Formycins . The reactivity of the mesoionic heterocycle sydnone is well documented with plenty of examples for the formation of multisubstituted pyrazoles. − While sydnones have many applications in synthesis and bioorthogonal chemistry, − to date, there have been no reports on the use of sydnones in the synthesis of nucleoside analogues.…”