Catalytic enantioconvergent nucleophilic substitution reactions of alkyl halides are highly valuable transformations, but they are notoriously difficult to implement. Specifically, nucleophilic fluorination is a renowned challenge, especially when inexpensive alkali metal fluorides are used as fluorinating reagents due to their low solubility, high hygroscopicity and Brønsted basicity. Here we report a solution by developing the concept of synergistic hydrogen bonding phase-transfer catalysis. Key to our strategy is the combination of a chiral -urea hydrogen bond donor (HBD) and an onium salt-two phase-transfer catalysts essential for the solubilization of potassium fluoride-as a well-characterized ternary HBD-onium fluoride complex. Mechanistic investigations indicate that this chiral ternary complex is capable of enantiodiscrimination of racemic benzylic bromides and α-bromoketones, and upon fluoride delivery affords fluorinated products in high yields and enantioselectivities. This work provides a foundation for enantioconvergent fluorination chemistry enabled through the combination of a HBD catalyst with a co-catalyst specifically curated to meet the requirement of the electrophile.
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| http://dx.doi.org/10.1038/s41929-024-01288-0 | DOI Listing |
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