Copper Catalysis

A tandem hydroamination–alkynylation was developed as a unique mode of accessing tetrasubstituted propargylic amines. The first equivalent of an alkyne acts as the electrophile in a Markovnikov hydroamination. The resultant ketimine intermediate is attacked by the second equivalent of alkyne in its nucleophilic copper acetylide form. Studies on the role of each component indicate that the overall reaction is first-order in copper, amine, and alkyne. In addition, a tandem hydroamination–hydrovinylation provides for an unprecedented onestep synthesis of a 1-amino-1,3-butadiene from phenylacetylene and morpholine.

Catalytic asymmetric conjugate addition reactions represent a powerful strategy to access chiral molecules in contemporary organic synthesis. However, their applicability to conjugated alkenyl-N-heteroaromatic compounds, of particular interest in medicinal chemistry, has lagged behind applications to other substrates. We report a highly enantioselective and chemoselective catalytic transformation of a wide range of β-substituted conjugated alkenyl-N-heteroaromatics to their corresponding chiral alkylated products. This operationally simple methodology can introduce linear, branched, and cyclic alkyl chains, as well as a phenyl group, at the β-carbon position. The key to this success was enhancement of the reactivity of alkenyl-heteroaromatic substrates via Lewis acid activation, in combination with the use of readily available and highly reactive Grignard reagents and a copper catalyst coordinated by a chiral chelating diphosphine ligand.

Copper(II) chloride catalyzes the three-component coupling of cyclohexanone, amines, and alkynes to produce tetrasubstituted propargylamines. As a wide range of substrates react without solvent, excess starting material, or other additives, water is the sole by-product. Studies demonstrate that this reaction is first order in copper, cyclohexanone, amine, and alkyne. These mild conditions allow for the first direct, catalytic synthesis of silyl-protected tetrasubstituted propargylamines.