Chemoselective On-DNA N-Arylation Using Ruthenium

Keywords

amines - arylation - DNA-encoded library

Significance

DNA-encoded library (DEL) technology has revolutionized hit ID in drug discovery. The power of DEL technology is derived from the ability of the unique DNA identifier to decode hits. Successful DELs also rely on robust and selective chemical transformations, which is an ongoing challenge in the field. Amine-containing building blocks are common in DEL synthesis. Prior to this report, N-arylation of DNA-conjugated amines was restricted to S_NAr, limiting the substrate scope. Pd- and Cu-catalyzed N-arylation in a DEL format favors arylation of the amino groups in the oligonucleotide, as corroborated by experiments in this report. Given the successful implementation of S_NAr in DELs, the authors sought to expand the aryl halide scope through activation using π-arene coordination with a Ru complex. A mild and chemoselective procedure has thus been reported.

Comment

An electron-deficient RuCpAc complex successfully activates chlorobenzene for complexation with DNA-AOP-NH₂. A second light-mediated decomplexation step is necessary to yield the N-arylated product using a wavelength > 360 nm to ensure DNA stability. This transformation is chemoselective, with no observable arylation of the amino groups in adenine, guanine, or cytosine. All halides can be activated, and with multi-halide arenes the substitution order is F > Cl ~ Br > I. Substrates containing Lewis basic groups require the addition of HBF₄·Et₂O. For substrates with multiple aromatic rings, addition of a second equivalent of [Ru] can ensure productivity. As proof of concept, an 18-membered library was synthesized using a split and pool approach. All 18 members were identified by mass spectrometry.

Publication History

Article published online:
16 December 2025