Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addition complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of benchtop storage under ambient conditions. We demonstrated the utility of OACs in a variety of experiments including automated nanomole-scale couplings between an OAC derived from rivaroxaban and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.

This article describes a mechanistic study of copper-catalyzed hydroalkylation of terminal alkynes. Relying on the established chemistry of N-heterocyclic carbene copper hydride (NHCCuH) complexes, we previously proposed that the hydroalkylation reaction proceeds by hydrocupration of an alkyne by NHCCuH followed by alkylation of the resulting alkenylcopper intermediate by an alkyl triflate. NHCCuH is regenerated from NHCCuOTf through substitution with CsF followed by transmetalation with silane. According to this proposal, NHCCuH must react with an alkyne faster than with an alkyl triflate to avoid reduction of the alkyl triflate. However, we have determined that NHCCuH reacts with alkyl triflates significantly faster than with terminal alkynes, strongly suggesting that the previously proposed mechanism is incorrect. Additionally, we have found that NHCCuOTf rapidly traps NHCCuX (X = F, H, alkenyl) complexes to produce (NHCCu)2(μ-X)(OTf) (X = F, H, alkenyl) complexes. In this article, we propose a new mechanism for hydroalkylation of alkynes that features dinuclear (NHCCu)2(μ-H)(OTf) (X = F, H, alkenyl) complexes as key catalytic intermediates. The results of our study establish feasible pathways for the formation of these intermediates, their ability to participate in the elementary steps of the proposed catalytic cycle, and their ability to serve as competent catalysts in the hydroalkylation reaction. We also provide evidence that the unusual reactivity of the dinuclear complexes is responsible for efficient hydroalkylation of alkynes without concomitant side reactions of the highly reactive alkyl triflates.

We have developed a copper-catalyzed hydroalkylation of terminal alkynes using alkyl triflates as coupling partners and (Me(2)HSi)(2)O as a hydride donor. The hydroalkylation proceeds with excellent anti-Markovnikov regioselectivity and provides exclusively (E)-alkenes. We have demonstrated that both alkyl- and aryl-substituted alkynes can be used as substrates, together with 1° alkyl and benzylic triflates. Finally, the transformation can be accomplished in the presence of a wide range of functional groups. Overall, the new hydroalkylation reaction allows highly efficient and diastereospecific synthesis of (E)-alkenes from readily available terminal alkynes and alkyl triflates. On the basis of a preliminary mechanistic study, we propose that the hydroalkylation reaction involves copper hydride formation, hydrocupration of an alkyne, and alkylation of an alkenyl copper intermediate.

We have developed the first catalytic method for anti-Markovnikov hydrobromination of alkynes. The reaction affords terminal E-alkenyl bromides in high yield and with excellent regio- and diastereoselectivity. Both aryl- and alkyl-substituted terminal alkynes can be used as substrates. Furthermore, the reaction conditions are compatible with a wide range of functional groups, including esters, nitriles, epoxides, aryl boronic esters, terminal alkenes, silyl ethers, aryl halides, and alkyl halides. A preliminary study of the reaction mechanism suggests that the hydrobromination reaction involves hydrocupration of an alkyne, followed by the bromination of the alkenyl copper intermediate. This study also suggests that 2-tert-butyl potassium phenoxide functions as a mild catalyst turnover reagent and provides a better understanding of the unique effectiveness of (BrCl2C)2 among brominating reagents.