Pd-Catalyzed Reductive Cyclization Using CO Surrogates: Selective N–N Bond Formation and Access to Indazolo[3,2- a ]isoquinolines

Abstract A Pd-catalyzed reductive cyclization of nitroaryl isoquinolines using phenyl formate as a carbon monoxide (CO) surrogate is reported. The method provides selective access to 5,6-dihydroindazolo[3,2-a]isoquinolines, indazolo[3,2-a]isoquinolines, and 8,13-dihydro-7H-indolo[2′,3′:3,4]pyrido[1,2-b]indazoles from precursors easily prepared in two steps. The transformation proceeds under catalytic conditions using in situ generated CO as the terminal reductant, avoiding stoichiometric metal-based reductants and producing CO2 and phenol as stoichiometric by-products. A broad range of functionalized substrates, including halogenated, fluorinated, and trifluoromethylated derivatives, is well tolerated, enabling further derivatization. Scale-up and post-functionalization experiments demonstrate the synthetic utility of the method. An N-methylation experiment confirms preferential N–N bond formation, even when alternative cyclization pathways are accessible. The resulting scaffolds may represent promising platforms for the development of G-quadruplex ligands, providing straightforward access to functionalizable heterocycles of potential biological interest.