Convenient Synthesis of Cycloalkene-fused Phthalazinones

Abstract

A series of cycloalkene-annelated phthalazin-1(2H)-ones (2-5) was prepared in high yields by a one-pot procedure, employing pyridazino[4,5-d]pyridazin-1(2H)-ones (1) as azadienes and cyclic enamines as dienophiles in an inverse-electron-demand Diels-Alder reaction, followed by acid-catalyzed aromatization. Phthalazin-1(2H)-ones bearing a substituent at C-4 represent key intermediates in the synthesis of various compounds with highly interesting pharmacological properties, such as the blood platelet aggregation inhibitor MY-54452 [1-(3-chloroanilino)-4-phenylphthalazine] which has been found to be also a selective phosphodiesterase VA inhibitor3 or the thromboxane A2 synthetase inhibitor and bronchodilator, 2-[2-(1imidazolyl)ethyl]-4-(3-pyridyl)phthalazin-1(2H)-one.4 Moreover, a number of established drug molecules like Hydralazine,5 Budralazine,6 Azelastine,7 Ponalrestat,8 or Zopolrestat9 are accessible starting from the corresponding phthalazinones. In general, most of the structural modifications of the parent system which have been carried out in order to optimize the biological activity of phthalazine-derived drugs can be seen as a variation of the substitution pattern at positions 1, 2, and 4, i. e. the substitution pattern of the 1,2-diazine part of the bicyclic system. Considerably less effort has been devoted to the modification of the benzene part of the phthalazine skeleton.10 In the course of a program aimed at the study of structureactivity relationships of various types of phthalazine-derived bio-active molecules by a systematic, gradual variation of the lipophilic and steric properties of the benzene part of the condensed system (without significant alteration of its electronic properties), the need arose to find a suitable access to a series of cycloalka[g]phthalazin-1(2H)-ones of variable cycloalkene ring size (five-, six-, seven-, and eightmembered). Here we wish to describe an efficient and simple synthesis of such compounds, employing an inverse-electron-demand (LUMOdiene-controlled) Diels-Alder reaction of a condensed pyridazine as the key step.11 We have previously demonstrated that 1,4-disubstituted pyridazino[4,5-d]pyridazines can be successfully employed as azadienes in interand intramolecular [4+2] cycloaddition reactions with a variety of electronrich dienophiles.12,13 Although the calculated LUMO energies for pyridazino[4,5-d]pyridazin-1(2H)-ones of type (1) (which are conveniently accessible, starting from 4-pyridazinecarboxylic acid14,15) are somewhat higher than that of the parent system,16 it was considered worthwhile to attempt the synthesis of cycloalka[g]phthalazin-1(2H)-ones via thermally induced inverse-electron-demand Diels-Alder reactions of such azadienes with simple enamines, derived from cyclic ketones, as dienophiles. When the pyridazino[4,5-d]pyridazin-1(2H)-one (1a) (R = ethyl) was heated with a fourfold excess of 1-pyrrolidino-1-cyclopentene in 1,4-dioxane at reflux temperature, immediate gas evolution was observed which obviously results from elimination of N2 from an initially formed, highly strained cycloadduct. After one hour, the starting material was completely consumed, and the resulting mixture contained according to 1H-nmr the target phthalazinone (2a) as well as smaller amounts of dihydrophthalazinone intermediates of types (A) and (B), respectively (cf. Scheme 1). Acid-catalyzed elimination of pyrrolidine from the latter compounds smoothly afforded 2a, this step is most conveniently performed in a one-pot manner by refluxing the crude cycloaddition product mixture in 1-propanol in the presence of acetic acid. Analogous reaction of the 4-phenyl-substituted azadiene (1b) with the five-membered enamine, followed by acid treatment gave the corresponding phthalazinone (2b) in 84% overall yield. This transformation of the azadienes (1a,b) into g-annelated phthalazinones gives good yields with six-, seven-, and eightmembered cyclic enamines as well, although considerably longer reaction times (48 hours and 72 hours, respectively) are required in the case of 1-pyrrolidino-1-cyclohexene as a dienophile; this observation is in agreement with previous findings.12,19,20