Direct Amination of BODIPY via Cu(II)-Catalyzed C-H Activation: A One-Step Method for Drug/Chelator/Biomolecule Coupling.

Conventional syntheses of amino-BODIPYs with drug/chelator/biomolecule attachment are highly challenging due to time-consuming and low-yielding multistep reactions. Few cross-dehydrogenative coupling and C-H activation methods are also known, but they lack the versatility required to synthesize a wide range of amino-BODIPYs. Herein, we developed a Cu(II)-catalyzed and expensive ligand-free, mild C-H activation method that is useful for regiospecific α-amination (C-N coupling) at the BODIPY core. Importantly, this method is useful for the coupling of a wide range of primary and secondary amines (aliphatic, aromatic, cyclic, acyclic). The methodology is also highly efficient for coupling different drug molecules, amino acids, peptides, alkaloids, and crown ethers directly at the BODIPY core in a single step with high yields. A total of 40 amino-BODIPYs were synthesized using the developed protocol. The regiospecificity and reaction mechanism were confirmed using NMR (1H, 13C, 19F, 11B), electron paramagnetic resonance (EPR), high-resolution mass spectrometry (HRMS), and X-ray crystallography analyses. The photophysical properties of the synthesized amino-BODIPYs were also evaluated. They exhibited weak fluorescence, which can be enhanced by solvent polarity as well as viscosity changes. Thus, the newly developed C-H activation methodology provides a highly efficient strategy for synthesizing amino-BODIPY dyes, which hold significant value in a wide range of chemical and biological applications.