Modular Enantioselective Synthesis of Tetrahydropyridazines by Palladium-Catalyzed Aminoalkenylation/Aminoarylation Reaction

Abstract

Chiral 1,4,5,6-tetrahydropyridazine core has emerged as valuable structural motifs in drug discovery, and has been recognized that the identified stereocenter of this structure has a significant impact on activity. Nevertheless, the catalytic asymmetric synthesis of such frameworks with clearly defined stereocenters remains a significant challenge, primarily due to the inherent difficulty in achieving stereo control during the cyclization process, as well as the limited availability of broadly applicable efficient catalytic system. In this work, a novel palladium-catalyzed enantioselective aminoalkenylation and aminoarylation of γ,δ-unsaturated hydrazones with aryl or alkenyl halides is described. The use of a sterically demanding Xu-Phos ligand ensures excellent chemoselectivity and enantioselectivity. This protocol provides an efficient and practical strategy for the synthesis of structurally diverse chiral tetrahydropyridazines bearing alkenyl and aryl functionalities in good yields and high enantioselectivities under mild reaction conditions. Notably, preliminary mechanistic investigations indicate that the syn-azapalladation was found to be the dominant pathway and might elucidate the high enantioselectivity in the cyclization process.

Keywords

Palladium-catalyzed / Enantioselective / Aminoalkenylation / Aminoarylation / Tetrahydropyridazines / γ,δ-Unsaturated hydrazone / syn-Azapalladation / Carboamination

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