Palladium-Catalyzed Diastereo- and Enantioselective Allenylation of Imines with Propargyl Nitriles via Cyano-Directed Activation Assisted by Machine-Learning-Guided Condition Screening

Chiral homoallenylamines are valuable intermediates in the synthesis of bioactive molecules and serve as versatile building blocks for further transformations. However, the simultaneous control of central and axial chirality remains challenging, and efficient synthetic methods for such compounds are still limited. Herein, we report a palladium-catalyzed diastereo- and enantioselective synthesis of axially chiral homoallenylamines via the asymmetric addition of propargyl nitriles to imines. In this reaction system, the cyano group plays a critical role in the selective activation of propargyl nitriles through coordination with the palladium catalyst. Machine-learning-assisted condition screening was employed as a complementary tool to facilitate the exploration of the reaction parameters. The reaction accommodates a range of imines and propargyl nitriles, affording a variety of chiral homoallenylamines in moderate to high yields with moderate to high diastereo- and enantioselectivities (up to 99% yield, 96:4 dr, and 99:1 er). Mechanistic investigations, supported by high-resolution mass spectrometry (HRMS) and density functional theory (DFT) calculations, suggest a catalytic pathway involving palladium−ketenimide intermediates. This study provides an efficient strategy for the construction of chiral homoallenylamine frameworks bearing both central and axial chirality under mild conditions.