A copper-based catalytic technique for the regioselective ortho C-H cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper-catalyzed cyanative dearomatization mechanism is proposed to account for the regiochemical course of this reaction.

Two groups' research initiated to address two very different questions on problems of basic chemical research led, after much effort on catalyst development and studies of reaction mechanism, to the discovery and development of the coupling of amines with aryl halides in a practical fashion.

The copper-catalyzed intermolecular enantioselective addition of styrenes to imines has been achieved under mild conditions at ambient temperature. This process features the use of styrenes as latent carbanion equivalents via the intermediacy of catalytically generated benzylcopper derivatives, providing an effective means for accessing highly enantiomerically enriched amines bearing contiguous stereocenters. Mechanistic studies shed light on the origin of the preferential styrene hydrocupration in the presence of an imine with the Ph-BPE-derived copper catalyst.

Allene (C3H4) gas is produced and separated on million-metric-ton scale per year during petroleum refining but is rarely employed in organic synthesis. Meanwhile, the addition of an allyl group (C3H5) to ketones is among the most common and prototypical reactions in synthetic chemistry. Herein, we report that the combination of allene gas with inexpensive and environmentally benign hydrosilanes, such as PMHS, can serve as a replacement for stoichiometric quantities of allylmetal reagents, which are required in most enantioselective ketone allylation reactions. This process is catalyzed by copper salts and commercially available ligands, operates without specialized equipment or pressurization, and tolerates a broad range of functional groups. Furthermore, the exceptional chemoselectivity of this catalyst system enables industrially relevant C3 hydrocarbon mixtures of allene with methylacetylene and propylene to be applied directly.

The highly selective palladium-catalyzed Negishi coupling of secondary alkylzinc reagents with heteroaryl halides is described. The development of a series of biarylphosphine ligands has led to the identification of an improved catalyst for the coupling of electron-deficient heterocyclic substrates. Preparation and characterization of oxidative addition complex (L)(Ar)PdBr provided insight into the unique reactivity of catalysts based on CPhos-type ligands in facilitating challenging reductive elimination processes.

A thorough investigation of the challenging Pd-catalyzed fluorination of five-membered heteroaryl bromides is presented. Crystallographic studies and density functional theory (DFT) calculations suggest that the challenging step of this transformation is C-F reductive elimination of five-membered heteroaryl fluorides from Pd(II) complexes. On the basis of these studies, we have found that various heteroaryl bromides bearing phenyl groups in the ortho position can be effectively fluorinated under catalytic conditions. Highly activated 2-bromoazoles, such as 8-bromocaffeine, are also viable substrates for this reaction.

A copper-catalyzed, chemoselective hydrometalation process enables the use of simple allenes as allylmetal nucleophile surrogates in imine allylation reactions. By modulating the nitrogen-protecting group, either highly branched- or linear-selective addition can be achieved from the same allene. Both reactions exhibit excellent diastereoselectivity and broad functional-group tolerance. Preliminary results indicate that good enantioselectivity can also be achieved in the linear-selective reaction. Finally, a mechanistic model for the regiodivergence is proposed on the basis of density functional theory calculations.

Enantioenriched alcohols found in an array of bioactive natural products and pharmaceutical agents are often synthesized by asymmetric nucleophilic addition to carbonyls. However, this approach generally shows limited functional-group compatibility, requiring the use of preformed organometallic reagents in conjunction with a stoichiometric or substoichiometric amount of chiral controller to deliver optically active alcohols. Herein we report a copper-catalyzed strategy for the stereoselective nucleophilic addition of propargylic and other alkyl groups to ketones, using easily accessible (poly)unsaturated hydrocarbons as latent carbanion equivalents. Our method features the catalytic generation of highly enantioenriched organocopper intermediates and their subsequent diastereoselective addition to ketones, allowing for the effective construction of highly substituted stereochemical dyads with excellent stereocontrol. Moreover, this process is general, scalable, and occurs at ambient temperature.

Catalytic assembly of enantiopure aliphatic amines from abundant and readily available precursors has long been recognized as a paramount challenge in synthetic chemistry. Here, we describe a mild and general copper-catalyzed hydroamination that effectively converts unactivated internal olefins—an important yet unexploited class of abundant feedstock chemicals—into highly enantioenriched α-branched amines (≥96% enantiomeric excess) featuring two minimally differentiated aliphatic substituents. This method provides a powerful means to access a broad range of advanced, highly functionalized enantioenriched amines of interest in pharmaceutical research and other areas.

Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied to the preparation of an important drug, ( R)-procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.