Synthesis of 2,3-dimethoxy-8,10-methylenedioxy benzo[c]cinnoline 7 As Potential Topoisomerase I Inhibitor

A novel and green synthesis of 2,3-dimethoxy-8,10-methylenedioxy benzo[c]cinnoline 7 is herein described. This compound is structurally related to benzo[i]phenanthridine, a class of potent topoisomerase I inhibitors such as nitidine. While nitidine was found to be toxic, the benzo[c]cinnoline derivative 7 may circumvent that by not being a Schiff base. A conveniently short synthetic plan was implemented involving a novel solvent- and catalyst-free cross-coupling biarylation of halogenated nitroarenes 2 and 5 using a high speed ball milling (HSBM) procedure. Indeed, using a copper vial as reaction vessel, and a copper ball as a collider in a shaker, we observed clean cross-coupling reactions of 2, and 5 leading up to substituted biphenyl 6 in quantitative yield. Reductive diazotization of 6 with lithium aluminum hydride produced 2,3-dimethoxy-8,10-methylenedioxybenzo[c]cinnoline 7 in good yield