Tetrahedron Letters,Vo1.30,No.25,pp 3287-3290,1989 0040-4039189 $3.00 + -00 Printed in Great Britain Maxwell Pergamnn Macmillan plc AN UNUSUAL REDUCTIVE RING-OPENING OF THE 1,2,3,5,6,7~HEXAAZAACENAPHT~-lYLENE RING SYSTEM Andrew M. Kawasaki and Leroy B. Townsend* Department of Medicinal Chemistry, College of Pharmacy; Department of Chemistry, College of Iditeraturc, Sciences and Arts The University of Michigan, Ann Arbor, MI 48109~1065 Abstract: Studies on an unexpected reaction involving a reductive cleavage of the pyridazine moiety of a tricyclic heterocycle are described. Structure assignments for the products obtained from the reductive cleavage were made using physicochemical methods. The pro drug’ (TCN-P, fi) of 6-amino-4-N-methyl-8-(P-D-ribofuranosyl)-I ,3,4,5&pentaaza- acenaphthylene2 (TCN, b) is currently undergoing clinical trials under the auspices of the National Cancer Insritute.3 It is generally thought that both TCN and TCN-P are acting as adenosine analogs4 but the exact biochemical mechanism has not yet been elucidated. It has been reported that a ring scissinn of the RO 0 kd HO OH OH pyrrole ring of TCN occurs in vivo, and this prompted us to initiate a synthesis of the aza analog of TCN (5) with a nitrogen being substituted for carbon at the site of the in vivo ring scission in TCN (la). We elected to use 4,6-bis(methylthio)-l-(P-n_ribofuranosyl)~~yra~olo[3,4-~~p~rimidine~ (2) as our starting material. Treatment of 2 with ten equivalents of methylhydrazine afforded a good yield of a compound which was tentatively assigned the smlcture 3-cyano-4-N-( I-methylhydrazino)6merhylthyhhio~ I- @-D-ribofuranosyl)pyrazolo[3,4-dlpyrimidine (2) based on the following data: I) a singlet (6 2-1) in the 1 H NMR spectrum for one methylthio group; 2) a strong peak at 2240 cm -1 in the IR spectrum (CN). The displacement by methylhydrazine could have conceivably occurred in two possible ways, &-_, displacement 3287