Copper-Catalyzed Three-Component Aminofluorination of Alkenes and 1,3-Dienes: Direct Entry to Diverse β-Fluoroalkylamines

Abstract

Rapid and efficient access to structurally diverse β-fluoroalkylamines is in high demand, with their wide presence and great importance in medicinal chemistry and drug development. Direct 1,2-aminofluorination of alkenes offers an ideal strategy for one-step entry to β-fluorinated amines from readily available starting materials. Yet the synthesis of valuable β-fluorinated alkylamines remains an unsolved challenge, due to the inherent incompatibility between electrophilic fluoride sources and the electron-rich alkylamines. We report an unprecedented, catalytic, three-component aminofluorination of diverse alkenes and 1,3-dienes, which has been achieved by an innovative copper-catalyzed electrophilic amination strategy using O-benzoylhydroxylamines as alkylamine precursors. The use of Et3N·3HF is also critical, not only as a commercially available and inexpensive fluoride source to enable effective fluorination but also as an acid source for the formation of aminyl radical cations for electrophilic amination. Mechanistic experiments suggest the involvement of aminyl radical species and carbon-radical intermediates under reaction conditions. This method features high regioselectivity and good tolerance of diverse functional groups and provides a practical and direct entry to a broad range of β-fluorinated electron-rich alkylamines. Synthetic applications of this method have also been highlighted by its use for the rapid entry to β-fluoridated amine-containing pharmaceuticals, natural products, and bioactive compounds.

Development of New Reactions Driven by N–O Bond Cleavage: from O-Acyl Hydroxylamines to Tetrodotoxin

“…18 Carbon nucleophiles derived from aryl boronates or diorganozinc species are also compatible with nickel-catalyzed olefin functionalization when using an aminoquinoline directing group. 28,29 Fluoroamination, 30 amino-oxygenation, 31,32 and diamination [33][34][35] of alkenes have all been shown to be viable catalytic reactions. That so many publications and distinct approaches have relied on these R 2 N-OBz species marks them as uniquely versatile 'plug-and-play' reagents for electrophilic amination across a wide range of substrates, catalysts, and reaction conditions.…”

Regio-, Site-, and Stereoselective Three-Component Aminofluorination of 1,3-Dienes via Cooperative Silver Salt and Copper Catalysis

“…The E / Z -mixed 1,3-dienes are allowed to be processed into single E -products, providing convenience for substrate preparation. Detailed mechanistic studies illustrate a reaction sequence involving ARC generation, aziridinium formation, and nucleophilic fluorination and identify the distinct roles of the metal complexes, wherein the silver complex initiates a single-electron transfer (SET) to generate electrophilic ARCs, while the copper complex dramatically enhances 1,2-regioselectivity through aziridinium intermediates …”

Recent Advances in Non-Precious Metal Catalysis

“…Recently, Wang and colleagues developed an unprecedented synthesis of valuable β-fluorinated alkylamines via Cu-catalyzed aminofluorination of alkenes and 1,3-dienes (Scheme 25). 41 The reaction would undergo a different mechanism than previous stereoselective three component reactions using Cu catalysts, and the authors proposed a radical pathway with some experimental studies supporting this. The method features a robust Cu-catalyzed electrophilic amination using O-benzylhydoxylamines, and fluorination after the formation of an aminyl radical cation using readily available Et 3 N•3HF.…”