The direct intramolecular stereospecific substitution of a hydroxyl group in stereogenic alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, S-, and N centered nucleophiles to generate enantioenriched tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydroquinoline and chromane derivatives. The five- and six-membered heterocyclic products are generated in good to excellent yields, with high stereospecificity, and water as the only by product. Mechanistic studies by both experiments and density functional theory calculations have been performed on the reaction to form five-membered heterocyclic compounds. Racemization experiments show that phosphinic acid does not promote SN1 reactivity. Rate order determination indicates that reaction follows first-order dependence in catalyst concentration. DFT calculations corroborate a reaction pathway in which the phosphinic acid operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge in an SN2-type reaction mechanism. The acidic proton of the phosphinic acid protonates the hydroxyl group enhancing the leaving group ability simultaneously as the oxo group of phosphinic acid abstracts the proton of the nucleophile enhancing the nucleophilicity in a bridging transition state.

H3PO2-catalyzed intramolecular stereospecific nucleophilic substitution of the hydroxyl group in stereogenic alcohols

254th National Meeting (2017)

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