Use of Polyfunctionalized Pyridazines as Reactive Species for Building Chemical Diversity

M.      Schmitt; S.      Oumouch; J.   J.   Bourguignon

Abstract

Efficient chemical pathways leading to differently substituted 3-aminopyridazines have been reviewed with the general objective to help to design the most straightforward chemical pathways to produce libraries of compounds with largest chemical diversity. Thus 3-chloropyridazines bearing at different positions halogens may offer opportunities, when submitted two tandem of selected reactions leading to the expected compounds (amination vs. palladium cross coupling reactions (PCCR)). As a result of its electron-deficient system, the commercially available 3,6-dichloropyridazine offers a large panel of reactivities in particular the access to 4-functionalized systems (vicarious nucleophilic substitution, halogenation, metalation/alkylation, arylation using Lewis acid catalyst). In other cases, the functionalized pyridazin-3- one precursors may be helpful as the free amide could also deal with PCCR by means of its O-Triflate derivative. A particular attention was given to opportunities offered by electron deficient 3,6, 3,4,6, 3,4,5, and 3,4,5,6- polychloropyridazines. However increasing the number of chlorines increased the number of possible combinations toward both amination and PCCR, and in general, led to a loss of regioselectivity. Thus introduction of different functionalities (bromine, iodine, enol, nitro, cyano, methyl and other carbon acids) at the pyridazine ring significantly increased their potentials, (increased reactivity and regioselectivity). Finally tetra-functionalized pyridazines were briefly introduced. They may constitute the most suitable scaffolds for building in an expeditive manner different 3- aminopyridazine sub-series by means of combinatorial chemistry.

Keywords: Sonogashira reaction, Diels-Alder reactions, vicarious nucleophilic substitution, benzodiazepine receptor, Anti-angiogenic, pyridazine drugs

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