Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer

Abstract

Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues. The SN2 reaction is essential in organic chemistry, but its substrate scope is limited. Now, a strategy based on halogen-atom transfer using α-aminoalkyl radicals and copper catalysis enables coupling of secondary alkyl iodides with N-nucleophiles with SN2-like programmability.