Abstract
<jats:p>This article describes asymmetric transfer hydrogenation of imines with benzothiazolines using a chiral phosphoric acid (CPA) catalyst immobilized on a polystyrene support. We demonstrate that the reduction of imines with immobilized Ad-TRIP CPA using 2-napthyl-substituted benzothiazoline proceeds with excellent enantioselectivities to provide 15 chiral benzylic amines in 77-99% ee. By carrying the benzothiazoline reductant optimization in continuous flow, we were able to streamline the optimization process and identify a new superior benzothiazoline reducing agent featuring 3,5-di-tert-butylphenyl substituent that facilitated the reductions with significantly higher levels of enantiocontrol (up to 99% ee). To demonstrate the scalability of this process, a 1.1 gram-scale reduction with 3,5-di-tert-butylphenyl substituted benzothiazoline was achieved in continuous flow in 99% ee and 92% yield. In addition, a computational study using the double-ended growing-string method (GSM) and DFT established a stereochemical model for this reduction. Analysis of the hydride-transfer transition states leading to the major and minor enantiomers reveals that the selectivity arises from the interplay between a stabilizing π–π interaction with the catalyst that favors the major pathway and steric repulsions with the catalyst's 3,3′-substituents that disfavor the minor one.</jats:p>