A Radical Approach to Secondary and Tertiary Amines

Keywords

tertiary amines - substitution reaction - blue LED - copper catalysis - amination

Significance

Tertiary amines have a huge impact on the bioactivity and bioavailability of many drugs and natural products, such as alkaloids. They can be prepared by various methods. The direct substitution of alkyl halides by amines is always the most attractive strategy, as these reactants are often commercially available or easy to make. However, this approach has only been efficient for reactive and unhindered reactants. In this work, Fu and co-workers describe a blue-light-mediated and copper(I)/(II)-catalyzed direct displacement of aliphatic secondary and tertiary alkyl bromides with secondary amines.

Comment

The key step in the mechanism of this reaction is the capture of a radical intermediate by the secondary amine (facilitated by the catalyst). This approach avoids the need to go through a highly hindered transition state (S_N2) or a carbocation (S_N1) under acidic conditions (acid–base incompatibility). Notably, this method and reductive amination give products with orthogonal diastereoselectivity. Unfortunately, the chiral phosphine ligand did not induce any enantioselectivity. The method has a broad functional group compatibility but fails for very hindered amines (e. g., diisopropylamine).

Publication History

Article published online:
25 February 2025