Synthesis of a Water-Soluble Tridentate (Dimethylamino)ethyl Cu(I)/Cu(II)-Ligand

Copper-catalyzed alkyne azide click chemistry (CuAAC) plays an important role in drug development and labeling of biological materials. Stabilizing ligands prevent Cu(I)-species from oxidation, increases the solubility of copper, and increases the acceleration of the catalyzed process. In this context, we report on the synthesis of a trisamine tridentate Cu-ligand (TDETA), with terminal (dimethylamino)ethyl-substitution, which can be legally synthesized as a replacement of toxic nitrogen mustard HN3 as an intermediate and is a scalable alternative to the previously found amine ligand DTEA. The class II ligand TDETA exhibits excellent solubility properties in organic solvents and aqueous solutions, outcompetes the commercial class I ligands THPTA and TBTA for a broad range of azide and alkyne combinations using Cu(I)- and Cu(II)-species, and was shown to be recoverable in a yield of 80%.