Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility. Here, we report that merging hydrogen bonding and phase-transfer catalysis provides an effective mode of activation for nucleophiles that are insoluble in organic solvents. This catalytic manifold relies on hydrogen bonding complexation to render nucleophiles soluble and reactive, while simultaneously inducing asymmetry in the ensuing transformation. We demonstrate the concept using a chiral bis-urea catalyst to form a tridentate hydrogen bonding complex with fluoride from its cesium salt, thereby enabling highly efficient enantioselective ring opening of episulfonium ion. This fluorination method is synthetically valuable considering the scarcity of alternative protocols and points the way to wider application of the catalytic approach with diverse anionic nucleophiles.
Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C–F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable β-fluoroamines in high yields and enantioselectivities. This methodology employs a chiral N-ethyl bis-urea catalyst that brings solid KF into solution as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.
Hydrogen-bonding interactions have been explored in catalysis, enabling complex chemical reactions. Recently, enantioselective nucleophilic fluorination with metal alkali fluoride has been accomplished with BINAM-derived bisurea catalysts, presenting up to four NH hydrogen-bond donors (HBDs) for fluoride. These catalysts bring insoluble CsF and KF into solution, control fluoride nucleophilicity, and provide a chiral microenvironment for enantioselective fluoride delivery to the electrophile. These attributes encouraged a 1 H/ 19 F NMR study to gain information on hydrogen-bonding networks with fluoride in solution, as well as how these arrangements impact the efficiency of catalytic nucleophilic fluorination. Herein, NMR experiments enabled the determination of the number and magnitude of HB contacts to fluoride for thirteen bisurea catalysts. These data supplemented by diagnostic coupling constants 1h J NH•••F − give insight into how multiple H bonds to fluoride influence reaction performance. In dichloromethane (DCM-d 2 ), nonalkylated BINAM-derived bisurea catalyst engages two of its four NH groups in hydrogen bonding with fluoride, an arrangement that allows effective phase-transfer capability but low control over enantioselectivity for fluoride delivery. The more efficient N-alkylated BINAM-derived bisurea catalysts undergo urea isomerization upon fluoride binding and form dynamically rigid trifurcated hydrogen-bonded fluoride complexes that are structurally similar to their conformation in the solid state. Insight into how the countercation influences fluoride complexation is provided based on NMR data characterizing the species formed in DCM-d 2 when reacting a bisurea catalyst with tetra-n-butylammonium fluoride (TBAF) or CsF. Structure−activity analysis reveals that the three hydrogen-bond contacts with fluoride are not equal in terms of their contribution to catalyst efficacy, suggesting that tuning individual electronic environment is a viable approach to control phasetransfer ability and enantioselectivity.
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