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A Dual-Catalysis Anion-Binding Approach to the Kinetic Resolution of Amines: Insights into the Mechanism via a Combined Experimental and Computational Study

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posted on 06.05.2015 by Nisha Mittal, Katharina M. Lippert, Chandra Kanta De, Eric G. Klauber, Thomas J. Emge, Peter R. Schreiner, Daniel Seidel
Racemic benzylic amines undergo kinetic resolution via benzoylation with benzoic anhydride in the presence of a dual catalyst system consisting of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine (DMAP). An evaluation of various experimental parameters was performed in order to derive a more detailed understanding of what renders this process selective. The catalyst’s aggregation behavior and anion-binding ability were evaluated in regard to their relevance for the catalytic process. Alternate scenarios, such as catalyst deprotonation or the in situ formation of a neutral chiral acylating reagent were ruled out. Detailed computational studies at the M06/6-31G­(d,p) level of theory including solvent modeling utilizing a polarized continuum model provide additional insights into the nature of the ion pair and reveal a range of important secondary interactions that are responsible for efficient enantiodiscrimination.

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