Chiral Monoamidines as Effective Organocatalysts for the Stereoselective Synthesis of Oxindoles under Homogeneous and Heterogeneous Conditions

The asymmetric aza-Henry reaction of aryl nitromethanes with isatin-derived ketimines promoted by chiral monoamidine catalysts is herein reported. This class of chiral Bro̷nsted bases, developed by Johnston, was first employed in the stereoselective synthesis of biologically relevant quaternary carbon-centered oxindoles. The process was first investigated under homogeneous conditions, affording a yield up to 95%, an <i>ee</i> up to 96%, and a dr up to 99:1. Next, the protocol was transposed to heterogeneous conditions using our recently developed polystyrene-supported 3-pyrrolidinol-linked catalyst <b>PS-(</b><i><b>S</b></i><b>)-Pyr-MAM</b>. The macroporous heterogeneous catalyst was tested in the synthesis of a short library of chiral oxindoles, showing activity almost comparable to that of the homogeneous counterpart, apart from an observed slight decrease in enantioselectivity (ca. 3-8% <i>ee</i>). The robustness of the synthetic protocol was confirmed on the gram-scale, and the recyclability of the catalyst was evaluated using straightforward filtration, achieving a satisfactory 84% <i>ee</i> after six cycles, with a modest decline in the conversion efficiency of approximately 2% per cycle, leading to a total turnover number of 53.1.