Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Abstract

AbstractReactions of 1,3‐disubstituted 5‐aminopyrazole‐4‐carbonitrile derivatives 3a‐o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3‐disubstituted pyrazolo[3,4‐b]pyridine‐5,6‐dicarboxylates 4a‐o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250‐300° to give 1,3‐disubstituted 4‐amino‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyridazine‐5,8(6H,7H)‐diones 7a‐s in good yields. Similarly, 1,3‐disubstituted 4‐hydroxy‐1H‐pyrazolo[4′3′:5,6]pyrido[2,3‐d]pyridazine‐5,8(6H,7H)‐diones 10a‐c were obtained from alkyl 1,3‐disubstituted 5‐aminopyrazole‐4‐carboxylates 8a‐c. These tricyclic pyridazine derivatives were alternatively synthesized from 4‐hydroxypyrrolo[3,4‐e]pyrazolo[3,4‐b]pyridine‐5,7‐diones 13a‐c prepared by reactions of 5‐aminopyrazoles (8e‐g) with methyl 1‐methyl‐4‐methylthio‐2,5‐dioxo‐1H‐pyrrole‐3‐carboxylate (11a) followed by the Gould/Jacobs reaction.1‐Methyl‐4‐methylthio‐2,5‐dioxo‐1H‐pyrrole‐3‐carbonitrile smoothly reacted with 2‐aminobenzimidazoles to give the corresponding 5‐amino‐3‐methyl‐1H‐pyrrolo[3′4′:4,5]pyrimido[1,2‐a]benzimidazole‐1,3(2H)‐diones 16a‐e, which were readily converted to the desired 12‐aminopyridazino[4′,5′:4,5]pyrimido‐[1,2‐a]benzimidazole‐1,4(2H,3H)‐diones 17a‐e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2‐aminoheterocycles with the maleimide in good yields.Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4‐phenylamino‐1‐methyl‐2,5‐dioxo‐1H‐pyrrole‐3‐carboxylates 25a‐e which were converted in good yields to 2‐methylpyrrolo[3,4‐b]quinoline derivatives 26a‐e by heating in diphenyl ether. Reaction of 26a‐c with hydrazine hydrate gave 10‐hydroxypyridazino[4,5‐b]quinoline‐1,4(2H,3H)‐diones 27a‐e in good yields. The desired 10‐aminopyridazino[4,5‐b]pyridazine‐1,4(2H,3H)‐diones 30a‐e were obtained in good yields by the chlorination of 4a‐e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide.Some pyridazino[4,5‐a][2.2.3]cyclazine‐1,4(2H,3H)‐diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6‐dimethylamino[2.2.3]cyclazine‐1,2‐dicarboxylates 34, 36, were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7‐dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd‐C in refluxing toluene.Some were found to be more efficient than luminol in light production. 4‐Amino‐3‐methylsufonyl‐1‐phenyl‐1H‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyridazine‐5,8(6H,7H)‐dione (7r), 10‐hydroxypyridazino[4,5‐b]‐quinoline‐1,4(2H,3H)‐diones 27a‐e, and 10‐aminopyridazino[4,5‐b]quinoline‐1,4(2H,3H)‐diones 30a‐e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.