Synthesis of 8‐amino‐4‐methylthio‐6‐methyl‐2‐(β‐D‐ribofuranosyl)‐2,6‐dihydro‐1,2,3,5,6,7‐hexaazaacenaphthylene and an unusual reductive ring‐opening of the 1,2,3,5,6,7‐hexaazaacenaphthylene ring system

Abstract

The tricyclic nucleoside 8‐amino‐4‐methylthio‐6‐methyl‐2‐(β‐D‐ribofuranosyl)‐1,2,3,5,6,7‐hexaazaacenaphthylene ( 3 ) was synthesized from 3‐cyano‐4,6‐ bis (methylthio)‐1‐(β‐D‐ribofuranosyl)pyrazolo[3,4‐ d ]pyrimidine ( 1 ). Attempts to synthesize 8‐amino‐6‐methyl‐2‐(β‐D‐ribofuranosyl)‐1 H ‐2,6‐dihydro‐1,2,3,5,6,7‐hexaazaacenaphthylene ( 5 ) ([an aza analog of 6‐amino‐4‐methyl‐8‐(β‐D‐ribofuranosyl)‐1,3,4,5,8‐pentaazaacenaphthylene (TCN)], which is a potent antitumor agent), by the treatment of 3 with Raney nickel did not afford the desired aza analog of TCN. Instead, it was established that a reductive cleavage of the pyridazine moiety of 3 had occurred to give 4‐methylamino‐6‐methylthio‐1‐(β‐D‐ribofuranosyl)‐1 H ‐pyrazolo[3,4‐ d ]pyrimidine‐3‐carboxamidine ( 6 ). Assuming that solubility was a problem in the reductive step, the isopropylidene derivative of 3 , 8‐amino‐6‐methyl‐4‐methylthio‐2‐(2,3‐ O ‐isopropylidene‐β‐D‐ribofuranosyl)‐2,6‐dihydro‐1,2,3,5,6,7‐hexaazaacenaphthylene ( 8 ), was treated with Raney nickel, only to observe that a similar reductive ring cleavage of 8 had occurred to afford 4‐methylamino‐6‐methylthio‐1‐(2,3‐ O ‐isopropylidene‐β‐D‐ribofuranosyl)‐1 H ‐pyrazolo[3,4‐ d ]pyrimidine‐3‐carboxamidine ( 10 ) and 4‐methylamino‐1‐(2,3‐ O ‐isopropylidene‐β‐D‐ribofuranosyl)‐1 H ‐pyrazolo[3,4‐ d ]pyrimidine‐3‐carboxamidine ( 11 ). Structural assignments for all products were established by physico‐chemical procedures.