Dual Nickel/Photoredox-Catalyzed Deaminative Cross-Coupling of Sterically Hindered Primary Amines

We report a method to activate alpha-3 degrees amines for deaminative arylation via condensation with an electron-rich aldehyde and merge this reactivity with nickel metallaphotoredox to generate benzylic quaternary centers, a common motif in pharmaceuticals and natural products. The reaction is accelerated by added ammonium salts. Evidence is provided in support of two roles for the additive: inhibition of nickel black formation and acceleration of the overall reaction rate. We demonstrate a robust scope of amine and haloarene coupling partners and show an expedited synthesis of ALK2 inhibitors.

Automated summary

This study reports a new method to activate alpha-3 degrees amines for deaminative arylation by condensing with an electron-rich aldehyde and combining this reactivity with nickel metallaphotoredox to generate benzylic quaternary centers. The reaction is accelerated by added ammonium salts, which inhibit nickel black formation and accelerate the overall reaction rate. The study demonstrates a broad scope of coupling partners and shows an expedited synthesis of ALK2 inhibitors.