The link between PDE4 and apoptosis prompted us to design and synthesize for the first time a series of novel 1-thienyl pyrroloquinoxalines as potential PDE4 inhibitors/apoptotic agents. A ligand-free Pd-catalyzed C–N cross-coupling/cyclization strategy has been developed for the rapid and milder access to this class of compounds some of which showed interesting pharmacological properties when tested in vitro and in zebrafish embryos.