Generation of Tertiary Alkylamines by Photoredox Catalysis and Nickel-Catalyzed Cross-Coupling

Significance

Tertiary alkylamines are essential structural motifs frequently found in natural products, pharmaceuticals, and bioactive compounds. Research in medicinal chemistry has demonstrated that small molecules enriched with C(sp³) centers display enhanced physicochemical and pharmacokinetic properties, which improve success rates in drug discovery. However, conventional methods relying on two-electron pathways, such as carbonyl reductive amination and nucleophilic addition with highly reactive reagents, encounter limitations due to poor functional group tolerance, complicating the synthesis of these compounds. This work addresses these challenges by employing a multicomponent aminoalkylation of organohalides, using commercially available aldehydes and secondary amines via dual photoredox/nickel catalysis.

Comment

This work enables three- and four-component aminoalkylation of organohalides via photoredox catalysis, followed by nickel-catalyzed cross-coupling. In more detail, photoredox catalysis selectively generates α-amino radicals from in situ formed iminium ions, which then undergo nickel-catalyzed cross-coupling to produce the desired tertiary alkylamines. The three-component reaction has proven effective in synthesizing a range of bioactive molecules with satisfactory yields. Additionally, this approach has been applied to a four-component 1,2-aryl-aminoalkylation of activated alkenes, yielding a diverse array of γ-amino acid derivatives. By employing a suitable chiral BiIM ligand (not shown), the first enantioselective variant of this reaction was successfully achieved, enabling the synthesis of enantioenriched α-aryl-γ-amino acid derivatives.

Publication History

Article published online:
20 December 2024

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