Enantioselective Inverse Electron-Demand Hetero-Diels-Alder Reactions Of Diazadienes:Efficient Synthesis Of Chiral Pyridazines

The inverse electron-demand hetero-Diels-Alder (IEDDA) reaction has been recognized as one of the most powerful methods to efficiently construct various biologically important and synthetically valuable heterocycles. In this context, various azadienes have been widely utilized in the inverse electron-demand aza-Diels-Alder reaction for the enantioselective synthesis of nitrogen-containing heterocycles. For example, aldehyde-derived2-azadienes and N-protected1-aza-1,3-butadienes have been successfully applied in the asymmetric IEDDA reaction through Lewis acid catalysis and organocatalysis strategies, affording the corresponding tetrahydroquinoline and piperidine derivatives, respectively. Despite these impressive achievements, the use of multiazadienes as the electron-deficient component has been largely unexplored in catalytic asymmetric IEDDA reactions. Accordingly, employment of new and versatile multiazadienes for the construction of multinitrogen-containing heterocycles is a desirable but challenging task for synthetic organic chemists.Herein we present the first example of asymmetric IEDDA reaction of in-situ generated1,2-diaza-1,3-dienes and enol ethers by the use of a catalytic amount of chiral copper triflate/bisoxazoline complex. Note that this method should lead to the formation of a challenging N,O-acetal stereocenter in the products. Investigation of the protecting group in the substrate and other reaction parameters (such as the catalytic system, ratio of the metal and ligand, catalyst loading, ratio of the two substrates, temperature, reaction media and base) gave the optimal reaction conditions:20mol%of Cu(OTf)2/93c as the catalyst in DCE at-20℃. With the optimal conditions, a wide range of a-halogenated N-benzylhydrazones and enol ethers were examined to probe the generality of the catalytic asymmetric IEDDA reaction. The reaction exhibits high enantioselectivity (up to90%ee) and provides a robust and powerful method to synthesize a variety of structurally diverse and densely substituted chiral pyridazine derivatives in good to excellent yields.The products were characterized by NMR, MS, HRMS, HPLC, Optical Rotation, IR. The absolute configuration of the product was determined to be R by X-ray analysis. According to this result and previous works of hydrazone, a plausible sterochemical model was proposed.