Highly Enantioselective Synthesis of Propargyl Amides through Rh‑Catalyzed Asymmetric Hydroalkynylation of Enamides: Scope, Mechanism, and Origin of Selectivity

Chiral propargyl amides are particularly useful structural units in organic synthesis. The enantioselective synthesis of propargyl amide is highly desirable. Conventional approach involves the use of a stoichiometric amount of metal reagent or chiral auxiliary. In comparison, direct alkynylation with terminal alkyne is attractive because it avoids the use of stoichiometric organometallic reagent. The asymmetric coupling of aldehyde, amine, and alkyne (A³-coupling) provides an efficient method for the synthesis of <i>N</i>-alkyl and <i>N</i>-aryl-substituted propargyl amines, but this strategy is not amenable for the direct enantioselective synthesis of propargyl amide. We have developed a new strategy and report here a Rh-catalyzed asymmetric hydroalkynylation of enamides. Alkynylations occur regioselectively at the α position of an enamide to produce chiral propargyl amides. High yield and enantioselectivity were observed. Previous alkynylation methods to prepare chiral propargyl amine involve the nucleophilic addition to an electron-deficient imine. In contrast, our current approach proceeds through regioselective hydroalkynylation of an electron-rich alkene. Kinetic studies indicated that migratory insertion of the enamide to the rhodium hydride is turnover limiting. Computational studies revealed the origin of regio- and enantioselectivities. This novel strategy provides an efficient method to access chiral propargyl amides directly from terminal alkynes

Synthesis of Amides with Remote Stereocenters by Catalytic Asymmetric γ‑Alkynylation of α,β-Unsaturated Amides

An iridium-catalyzed enantioselective hydroalkynylation of α,β-unsaturated amides was described. The selectivity of this reaction is distinct from that observed in many catalytic hydroalkynylations of α,β-unsaturated carbonyl compounds. It occurs selectively at the γ instead of the β position. Preliminary mechanistic studies suggest that the reaction proceeds through alkene isomerization followed by hydroalkynylation. This method provides a straightforward route for the synthesis of amides with a remote stereocenter at the γ position

Synthesis of Amides with Remote Stereocenters by Catalytic Asymmetric γ‑Alkynylation of α,β-Unsaturated Amides

An iridium-catalyzed enantioselective hydroalkynylation of α,β-unsaturated amides was described. The selectivity of this reaction is distinct from that observed in many catalytic hydroalkynylations of α,β-unsaturated carbonyl compounds. It occurs selectively at the γ instead of the β position. Preliminary mechanistic studies suggest that the reaction proceeds through alkene isomerization followed by hydroalkynylation. This method provides a straightforward route for the synthesis of amides with a remote stereocenter at the γ position

<i>N</i>-Directing Group Assisted Rhodium-Catalyzed Aryl C–H Addition to Aryl Aldehydes

Direct aryl C–H addition to aryl aldehydes to produce biaryl methanols was reported <i>via</i> Rh catalysis with an <i>N</i>-containing directing group. The method is highly atom-, step-, and redox-economic. The procedure is robust, reliable, and compatible with water and air

<i>N</i>-Directing Group Assisted Rhodium-Catalyzed Aryl C–H Addition to Aryl Aldehydes

Direct aryl C–H addition to aryl aldehydes to produce biaryl methanols was reported <i>via</i> Rh catalysis with an <i>N</i>-containing directing group. The method is highly atom-, step-, and redox-economic. The procedure is robust, reliable, and compatible with water and air

<i>N</i>-Directing Group Assisted Rhodium-Catalyzed Aryl C–H Addition to Aryl Aldehydes

Direct aryl C–H addition to aryl aldehydes to produce biaryl methanols was reported <i>via</i> Rh catalysis with an <i>N</i>-containing directing group. The method is highly atom-, step-, and redox-economic. The procedure is robust, reliable, and compatible with water and air

Palladium-Catalyzed Trifluoromethylation of Aromatic C–H Bond Directed by an Acetamino Group

The first palladium-catalyzed <i>ortho</i>-trifluoromethylation of the aromatic C–H bond directed by an acetamino group is reported. This method provides an efficient and green approach to synthesize the highly biological potential key structure of <i>ortho</i>-CF₃ acetanilides and anilines