Georgia Tsolomiti,, Kyriaki Tsolomiti, A. Tsolomitis
2007
Citations
0
Influential Citations
3
Citations
Journal
Heterocyclic Communications
Abstract
A simple and efficient synthesis of the novel 4-mercapto-6-phenylpyridazin-3(2H)-ones from the reaction of 6-phenyl-4,5-dihydropyridazin-3(2H)-ones with excess thionyl chloride under mild conditions, is described. 3(2H)-Pyridazinone core have an ubiquitous presence in pharmaceuticals and pesticides. Three marketed selective COX-2 inhibitors, Celebrex(celecoxib), Viox(rofecoxib) and Bextra(valdecoxib), effectively treat pain, infamation, and fever with improved gastroindestinal safety. All three of these drugs share a similar structural motif: a core heterocyclic ring substituted with a phenyl and a 4-(sulfonyl)phenyl ring on adjacent atoms. This structural motif was investigated employing 3(2H)-pyridazinone as the core heterocycle, some active regioisomers of this report are under clinical investigation. The same core is present in many pharmaceuticals used as phosphodiesterase inhibitors for treatment of different diseases among them multiple sclerosis, hypertension, Alzheimer disease, and as inhibitors of the production and transduction of cytokines. 3(2H)-Pyridazinone derivatives, have been also recently referred" as drugs for inhibiting vascular intimal hyperplasia. Norflurazon, belongs to this core heterocycle with herbicidal activity inhibiting the biosynthesis of long-chain carotenoids, effecting on protein composition and chlorophyll organization in pigmentprotein complex of photosystem II. Furtermore some 5-mercapto-pyridazinones have been reported as microbiocides and insecticides or for treating/preventing diabetic complications. Given the broad spectrum of biological activity of functionalized pyridazinones, the method desribed here could be used for the synthesis and derivatization of new compounds added to the corporate library, useful as prodrugs and/or as microbiocides or pesticides. After an extensive bibliographic research we did not find 4-mercapto-substituted 3(2H)pyridazinones and in the course of our studies on synthesis of different heterocycles and on abnormal reactions of thionyl chloride, we experimented with the incorporation of the sulfur moiety at the 4position of this core. Based on literature reports""® and our experience, on direct incorporation of chlorosulfenyl moiety, at the α-carbon atom to a carbonyl group, (ketonic or carboxylic acid's chloride), using thionyl chloride ,we proceeded by means of a mechanism which involved oxidation of a methylene carbon to the preparation of the corresponding chlorosulfenyl chloride, >C(SC1)C1. The literature reports""®'··'' refer to such reactions under drastic conditions, in the presence of pyridine, on different carbon atoms as: methyl carbon atoms adjacent to an aromatic ring, " ' methylenes adjacent both, to an aryl and a carboxyl group, active methylenesand methylenes adjacent to enolizable carbonyl groups, (ketonic or carboxylic acid's chloride). '" The former authors suggested a mechanism which proceeded through the transformation of a methylene carbon to the corresponding chlorosulfenyl chloride. The later usually reacts as an intermediate to the formation of sulfur heterocycles"'®' or other nucleophilic displacements while in only few cases it was isolated and characterized by "H NMR, and then heterocyclized. In this letter we wish to disclose a simple and convenient synthesis of 4-mercapto-6-phenylpyridazin3(2H)-ones 6 from the corresponding 6-phenyl-4,5-dihydropyridazin-3(2H)-ones 3, a reaction of mild conditions with excess thionyl chloride, (without any of base), Scheme 1. The used pyridazinones 3 have been reported (except from 3d for which there are no data), by cyclocondensation of ßbenzoylpropionic acid and the proper hydrazine. In order to overcome some experimental obscurities, perhaps connected to and/or the co-formation of the corresponding hydrazides, and to have better yields, we prepared them from the hydrazones 2, (prepared under mild condensation conditions,