Abstract
Chiral BINOL-derived phosphoric acids catalyse the transfer hydrogenation of ketimines using Hantszch esters. In many cases the nitrogen on the imine binds to the catalyst through the catalyst hydroxyl group and the nucleophile forms a second hydrogen bond to the phosphoryl oxygen. DFT and ONIOM calculations show that the introduction of an ortho-hydroxyaryl group on the carbon atom of the ketimine leads the reaction to proceed through a 14-membered bifunctional mechanism. The transition states of these reactions involve both hydrogen bonding from the hydroxyl group on the imine and the nucleophile's proton to the phosphate catalyst. This mechanistic pathway is lower in energy than the conventional route, consistent with the experimentally observed increased rates of reaction relative to imines that are not derived from ortho-hydroxybenzophenone. To complement the high-level calculations, an accessible qualitative model has been developed that predicts the correct sense of stereoinduction for all examples.
Highlights
Chiral phosphoric acids are an important class of Brønsted acids, catalysing a wide range of transformations.[1,2,3] The addition of nucleophiles to imines is the largest substrate class for these catalysts
These transition states where calculated to be disfavoured relative to Mechanism C in which the phosphate catalyst binds to Hantszch ester and the ortho-hydroxyl aryl group
We have previously identified this as an excellent computational method for studying chiral phosphoric acid catalysed transfer hydrogenation reactions.[8,26]
Summary
Chiral phosphoric acids are an important class of Brønsted acids, catalysing a wide range of transformations.[1,2,3] The addition of nucleophiles to imines is the largest substrate class for these catalysts. The nucleophile would be delivered to the most accessible face Such a model in which only one of the reactants is activated has been known to be higher in energy compared to those involving bifunctional activation.[8] Despite this, NMR evidence suggested the phenolic proton was bound to the catalyst.[5,9] The group noted that removing the hydroxyl group at the ortho position greatly slowed the reaction, supporting the importance of a productive binding site to the catalyst via a hydrogen bond to this position.[10] The uncertainty associated with the mechanism for this important class of substrates makes prediction of the sense of enantioinduction very difficult for novel reactants.
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