Efficient Pd⁰-Catalyzed Asymmetric Activation of Primary and Secondary C–H Bonds Enabled by Modular Binepine Ligands and Carbonate Bases

Abstract

International audienceNew binepine ligands have been synthesized, and characterized and have been shown to induce high diastereo- and enantioselectivity in the intramolecular arylation of primary and secondary C(sp3)–H bonds, giving rise to fused cyclopentanes. The ligands were obtained as bench-stable phosphonium tetrafluoroborate salts that can be directly employed in catalysis. It was shown that a ferrocenyl P-substituent on the ligand allows achievement of high stereoselectivities in combination with potassium carbonate for the arylation of primary C–H bonds under unprecedentedly low temperature (90 °C) and catalyst loading (1–2 mol % Pd/2–3 mol % ligand). Using a base-free precatalyst, carbonate was shown to be the active base and to provide higher stereoselectivities than acetate and pivalate. The more difficult arylation of secondary C–H bonds could also be achieved and required fine-tuning of the ligand structure and the carbonate countercation. This method allowed generation of fused tricyclic products containing three adjacent stereocenters as single diastereoisomers and with moderate to high enantioselectivity. Experimental data indicated that the enantiodetermining C–H activation step involves a monoligated species. DFT (PBE0-D3) calculations were performed with a prototypical binepine ligand to understand the origin of the enantioselectivity. The preference for the major enantiomer was traced to the establishment of a more efficient network of weak attractive interactions between the phosphine ligand and the substrate

Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

“…[184] Fort he synthesis of enantiomerically enriched dihydroindene 463 from vinyl bromide 462,C lot, Baudoin, and co-workers utilized axially chiral phosphine LG13 (Scheme 87). [185] TheY uresearch group demonstrated an enantioselective palladium-catalyzed carbonyl-directed C(sp 3 )ÀHa ctivation. Thedifferentiation of the two pro-stereogenic methyl groups can be accomplished, albeit with moderate stereoselectivity in most cases,byusing amodified amino acid as achiral ligand on palladium (Scheme 88).…”

Computational Study of the Ni-Catalyzed C–H Oxidative Cycloaddition of Aromatic Amides with Alkynes

“…3,4 The C–H cleavage step in these reactions is most commonly proposed to proceed via a base-promoted concerted metalation–deprotonation (CMD) mechanism. 5 Although other C–H bond metalation pathways, such as oxidative addition (OA), 6 σ-complex-assisted metathesis (σ-CAM), 7 and ligand-to-ligand hydrogen transfer, 8 are well precedented in the literature, these alternative mechanisms have not been thoroughly investigated in C–H functionalization reactions involving N , N -bidentate directing groups. 9 Because previous computational mechanistic studies of this type of reactions all focused on the CMD mechanism, 10,11 it is not clear what conditions would promote an alternative C–H bond cleavage pathway.…”

Computational Studies of Carboxylate-Assisted C–H Activation and Functionalization at Group 8–10 Transition Metal Centers

“…. Copyright 2016, John Wiley and Sons.These intramolecular cyclisations have been extended to the diastereo-and enantioselective syntheses of indanols114 and indanes 110. With 52-Br (Figure 21, R = i Pr) reaction proceeds via the C-Br activated [Pd(52)(CO3 -)L] intermediate, where L is a chiral binepine-based phosphine ligand and carbonate is again sited trans to the vacant site.…”