Synthesis of hydroxy‐substituted aza‐analogues of antitumor anthrapyrazoles

Synthetic routes have been developed which lead to ring‐hydroxylated aza‐analogues of antitumor anthrapyrazoles, namely, 2,5‐bis[(aminoalkyI)amino] substituted 10‐hydroxymdazolo[3,4‐ fg ]isoquinolin‐6(2 H )‐ones 1 and 7‐hydroxyindazolo[4,3‐ gh ]isoquinolin‐6(2 H )‐ones 2 . The regiospecific synthesis of 6,9‐dihalo‐4‐hydroxybenz[ g ]isoquinolines 3 and 4 has been accomplished. Intermediate 3 was constructed in a multistep process involving Diels‐Alder chemistry of benzoylacrylates whereas 4 was assembled using Ni(II) mediated coupling of methyl 3‐chloro‐5‐methoxyisonicotinate ( 15b ) with the organic zinc reagent 18 derived from 2‐fluoro‐5‐chlorobenzyl bromide ( 17 ). After protection of the hydroxy group with a p ‐methoxybenzyl moiety, the different nucleofugacities of the leaving groups present in 10 and 20 allowed sequential displacements by substituted hydrazines and amines, respectively, to lead to the desired p ‐methoxybenzyl protected analogues 12 and 22 . Deprotection led to the side arm modified compounds 1 and 2 . The displacements of 21a and 21b with N,N ‐dimethylethylenediamine also led to the tri[(aminoalkyl)amino]substituted analogues 23a and 23b , respectively, which arose from further S N Ar substitutions of the p ‐methoxybenzyloxy group.