Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a challenge. We report here the first general approach to this transformation. The key to productive, selective crosscoupling is the use of a small amount of iodide or bromide along with a recently reported ligand, pyridine-2,6-bis(Ncyanocarboxamidine) (PyBCam CN ). The scope of the reaction is demonstrated with 35 examples (63 ± 16% average yield), and we show that the Br − and I − additives act as cocatalysts, generating a low, steady-state concentration of more-reactive alkyl bromide/ iodide.

The activation of carbodicarbene (CDC)-Rh(I) pincer complexes by secondary binding of metal salts is reported for the catalytic site-selective hydro-heteroarylation of dienes (up to 98% yield and >98:2 γ:α). Reactions are promoted by 5 mol % of a readily available tridentate (CDC)-Rh complex in the presence of an inexpensive lithium salt. The reaction is compatible with a variety of terminal and internal dienes and tolerant of ester, alkyl halide, and boronate ester functional groups. X-ray data and mechanistic experiments provide support for the role of the metal salts on catalyst activation and shed light on the reaction mechanism. The increased efficiency (120 to 22 °C) made available by catalytic amounts of metal salts to catalysts containing C(0) donors is a significant aspect of the disclosed studies.

A carbodicarbene (CDC)-based pincer ligand scaffold is reported, along with its application to site-selective Rh(I)-catalyzed intermolecular hydroamination of 1,3-dienes with aryl and alkyl amines. To the best of our knowledge, this is the first example of the use of a well-defined CDC complex as an efficient catalyst. Transformations proceed in the presence of 1.0-5.0 mol % Rh complex at 35-120 °C; allylic amines are obtained in up to 97% yield and with >98:2 site selectivity.

While the use of triphenylphosphine as a reductant is common in organic synthesis, the resulting triphenylphosphine oxide (TPPO) waste can be difficult to separate from the reaction product. While a number of strategies to precipitate TPPO are available, none have been reported to work in more polar solvents. We report here that mixing ZnCl2 with TPPO precipitates a TPPO–Zn complex in high yield in several common polar organic solvents. The solvent compatibility of this procedure and the reliability of the precipitation in the presence of polar functional groups were examined to show the utility and limitations of this method.

As part of intracellular copper trafficking pathways, the human copper chaperone Hah1 delivers We proposed 2-body and 3-body interaction models based on previously known structures of homologous proteins to describe both intermolecular Hah1-MBD and intramolecular MBD-MBD interactions. These interaction models and our smFRET results were then used to formulate and quantify a comprehensive Hah1-MBD34 mechanism. The enhanced interaction stability of Hah1 with the multi-MBD system, the dynamic intramolecular MBDMBD interactions, and the ability of Hah1 to interact with multiple MBDs simultaneously suggest an efficient and versatile mechanism for the Hah1-to-WDP pathway to transport Cu Last, but not least, I would like to thank my wife, Dixie, and daughter, Lilly. Their love and support was critical, and I will forever be in debt to their future vitality and happiness.

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We report the development of palladium(0)‐catalyzed syn‐selective 1,2‐carboboration and ‐silylation reactions of alkenes containing cleavable directing groups. With B2pin2 or PhMe2Si‐Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono‐, di‐, tri‐ and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2‐carboboration of electron‐rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck‐type alkene 1,2‐difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio‐ and stereocontrol.

As sp2–sp3 disconnections gain acceptance in the medicinal chemist’s toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2–sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2–sp3 bond-forming methods and suggests a path forward for further refinements.