Synthesis and convenient functionalisation of pyridazinofurocoumarins: nitrogenated isosters of potent DNA inhibitors

Abstract

Pyridazino[3,4- h]psoralens and pyridazino[3,4- j]angelicins are prepared in good yield from resorcinols through a direct, easy and generally applicable synthetic route. The key step in this route is the inverse electron-demand Diels–Alder reaction between linear or angular furocoumarins and 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine to give the dicarboxymethylated tetracycles. The ester group in the peri position with respect to the oxygen in the furan ring can be regioselectively transformed to give primary or secondary amides. Similarly, the two ester groups in the tetracycle can be transformed in a high-efficiency process to give bis-amides that can be either symmetrical (from the same amine) or unsymmetrical (from two different amines).