New reaction conditions for intramolecular palladium(II)-catalyzed oxidative carbon-carbon bond formation under air are described. The use of pivalic acid as the reaction solvent, instead of acetic acid, results in greater reproducibility, higher yields, and broader scope. This includes the use of electron-rich diarylamines as illustrated in the synthesis of three naturally occurring carbazole products: Murrayafoline A, Mukonine, and Clausenine. A variety of side products have also been isolated, casting light on competing reaction pathways and revealing new reactivity with palladium(II) catalysis.

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.

Rho‐Rho‐Rho your boat: A rhodium catalyst effects the regioselective oxidative coupling of enynes with N‐aryl ureas (X=NR2) and N‐vinylacetamides (X=C(O)Me), affording the corresponding 2‐alkenylindoles and 2‐alkenylpyrroles in good yield. Simple hydrogenation delivers the C2/C3‐aliphatic‐substituted indole or pyrrole (see scheme).

Subjection of N-methyl 6- and 7-azaindole N-oxides to a Pd(OAc)2/DavePhos catalyst system enables regioselective direct arylation of the azine ring. Following deoxygenation, 7-azaindole substrates undergo an additional regioselective azole direct arylation event in good yield.

A mild and direct strategy for the construction of aryl aminooxetanes has been accomplished through the synergistic combination of photoredox and nickel catalysis. This approach represents a rare example of harnessing challenging tertiary radicals in photoredox/nickel cross-coupling. Oxetanes are often employed in medicinal chemistry as carbonyl or gemdimethyl bioisosteres, but their accessibility is hampered by the lack of practical synthetic methods. The strategy reported here utilizes a readily available oxetanyl amino acid building block in a cross-coupling manifold to rapidly access oxetane scaffolds with broad functional group tolerance. Computational studies reveal that a catalytic cycle beginning with Ni(0)−Ni(II) oxidative addition, rather than radical addition to Ni(0), is operative for reactions with aminooxetanyl radicals. Consequently, for radical-based photoredox/nickel-catalyzed cross-couplings, the preferred mechanistic pathway has a fundamental dependence on the identity of the radical.