Tandem In Situ Nitro Reduction and Cyclization for the On-DNA Synthesis of Traditionally Privileged Skeletons

The development of DNA-encoded library (DEL) technology is contingent upon robust and DNA-compatible reactions to expand accessible chemical space. Tandem transformations, which combine functional group interconversion and scaffold construction in one step, are particularly attractive for streamlining on-DNA synthesis. Herein, we report a copper-mediated tandem reaction conducted under mild, aqueous conditions that enables the in situ reduction of nitro groups followed by reductive amination with aldehydes. This DNA-compatible protocol efficiently furnishes secondary amines directly from nitro substrates, circumventing the need for prereduction. Moreover, the methodology can be extended to o -nitroaniline derivatives, providing efficient one-pot access to benzimidazole scaffolds through tandem nitro reduction and cyclization with aldehydes. Compared to conventional stepwise sequences requiring isolated intermediates, this strategy provides a more streamlined and atom-economical route for constructing privileged pharmacophores directly on DNA.