Comprehensive Summary A highly efficient catalytic enantioselective 4+2 annulation reaction between acyclic or cyclic enecarbamates and in situ ‐generated azoalkenes (derived from α‐halohydrazones) has been successfully realized using a Cu(I)/(4R,2R p )‐Ph‐Phosferrox complex. Performed under mild reaction conditions, this robust synthetic protocol affords a structurally diverse collection of chiral tetrahydropyridazine derivatives bearing multiple contiguous stereogenic centers, with good to excellent isolated yields (48%–94%), high enantioselectivities up to 96% ee, and excellent diastereocontrol (dr > 20 : 1). This reaction also exhibits outstanding substrate generality and tolerance, accommodating a wide scope of substituted α‐halohydrazones and structurally varied enecarbamates, thereby enabling the facile construction of a diverse library of functionalized chiral tetrahydropyridazines. A gram‐scale experiment and subsequent synthetic derivatizations of the chiral products were conducted to fully verify the practical utility and scalability of this catalytic system for potential synthetic applications. Single‐crystal X‐ray diffraction analysis of a representative product unambiguously confirmed its absolute configuration, and combined with systematic control experiments, these results clarified that the annulation proceeds through a stepwise 4+2 cycloaddition pathway. Additionally, comprehensive mechanistic studies including nonlinear effect assays, UV absorption spectroscopic analyses and Job's plot measurements were performed, which together provide solid experimental evidence to firmly validate the scientific rationality of the proposed reaction mechanism.
Li et al. (Mon,) studied this question.