Theoretical and experimental studies on ring closure reactions of 4(5)-chloro-5(4)-hydroxyalkylamino-6-nitro-3 (2H)-pyridazinones

Cyclization of the title compounds with sodium ethoxide may proceed in vari ous ways to afford differently fused pyridazino ring systems. Theoretical c onsiderations based on frontier molecular orbital (FMO) analysis of 4-chlor o-5-hydroxyalkylamino-6-nitropyridazinones were in agreement with experimen tal results in most cases. Formation of pyridazino[3,4] annelated systems w as predicted and observed from 5-hydroxyethylamines and their N-benzyl anal ogs. However, in the ring closure reaction of the 5-N-benzyl-N-hydroxypropy lamino derivative, besides [3,4] annelation, another cyclization also occur red to form a pyridazino[4,5-b]oxazepine derivative as minor product, where as the 5-hydroxypropylamino derivative without an N-benzyl group gave a [3, 4]-fused bicyclic compound, and a 6-ethoxy monocyclic derivative. The next homologue, i.e. the 5-hydroxybutylamino derivative, underwent only an inter molecular nucleophilic substitution reaction to give 6-ethoxypyridazinone d erivative. In the cases of the 4-regioisomers, the N-benzyl derivatives could only be cyclized, and pyridazino[4,5] annelated systems were obtained. Structures of new compounds were proven by spectroscopic methods and microa nalytical data. For a regioisomeric pair of pyridazino[4,5-b]oxazepines, X- ray analyzes were also carried out. (C) 2001 Elsevier Science B.V. Ail righ ts reserved.