Coupling–Isomerization Synthesis of Chalcones

The Sonogashira coupling of electron‐deficient (hetero)aryl halides 1 and (hetero)aryl or alkenyl 1‐propargyl alcohols 2 does not terminate at the stage of the expected internal propargyl alcohols, but rather gives rise to the formation of α,β‐unsaturated ketones 3 with a variety of acceptor substituents. This new domino reaction, a coupling–isomerization reaction (CIR), can be rationalized as a sequence of rapid Pd/Cu‐catalyzed alkynylation followed by a slow amine‐base‐catalyzed propargyl alcohol–enone isomerization. Performing the CIR in deuterated protic solvents or with a selectively deuterated propargyl alcohol revealed that the base‐catalyzed isomerization step proceeds through a formal 1,3‐H shift with minimal H/D exchange with the surrounding solvent. Additionally, 19 F NMR kinetic measurements on the isomerization step with the fluorinated propargyl alcohol 4 r support the mechanistic rationale.