Selectivity Control in the Palladium-catalyzed Cross-coupling of Alkyl Nucleophiles

Abstract

Site-selectivity remains a major challenge in metal-catalyzed C-H bond functionalization. Most existing strategies rely on the introduction of a directing group or on the intrinsic reactivity of the substrate. In this account article, we describe the development of an alternative strategy based on the migration of an organopalladium species along an alkyl chain, wherein the phosphine ligand controls the cross-coupling site. This concept was first implemented with lithium enolates, and then extended to α-zincated alkylamines obtained by directed lithiation and transmetalation. Both the direct and the migrative cross-couplings, which are controlled by simply switching the ligand, furnish synthetically useful organic intermediates.

Regiodivergent enantioselective C–H functionalization of Boc-1,3-oxazinanes for the synthesis of β2- and β3-amino acids

“…2a). 7,9,[26][27][28] This behavior might be related to the higher propensity of the 1,3-oxazinane, as compared to the piperidine ring, to reach the twist-boat conformation required to align the C-Pd and C-H bonds for the β-H elimination step initiating Pd migration. 9 Moreover, the selectivity switch exerted by ligands L 2 -L 3 can be explained by steric factors, i. e. the steric environment of the phosphorus atom and the rotation around the C-N axis, according to previous studies.…”

“…3 Migratory cross-couplings have emerged as interesting new methods to functionalize remote positions of alkyl chains and cyclic systems. [6][7][8] In particular, our group showed that the use of appropriate ligands of palladium-based catalysts allows functionalization of various positions of the same reactant in a regiocontrolled fashion through a Pd migration mechanism. 7 For instance, the Negishi coupling of racemic α-zincated Boc-piperidine, generated by Boc-directed α-lithiation of Boc-piperidine 1 with s-BuLi/TMEDA and transmetallation to zinc, leads to the C2 and C3-arylated racemic products 2-3 with good positional selectivity in the presence of appropriate phosphine ligands L 1 -L 2 (Fig.…”

One-Pot Alkene Hydroboration/Palladium-Catalyzed Migratory Suzuki–Miyaura Cross-Coupling

“…This process, termed “chain-walking”, operates via dynamic displacement of a transition-metal catalyst along an alkyl chain, often associated with the translocation of a double bond, to a terminal position, presumably due to steric effects or due to a resonance-stabilized position such as the one adjacent to an aromatic group or heteroatom . Significant progress in remote C–H functionalization through chain-walking has already been achieved with different transition metals such as Zr, Co, Ni, Ru, or Pd. − Previous reports from our research group on palladium(0)-catalyzed migratory cross-couplings relied on ligand-controlled chain-walk with enolates as nucleophiles or organozinc compounds obtained by directed lithiation and Li–Zn transmetalation or under Barbier conditions (Figure a). , To further expand and demonstrate the power of the remote C–H functionalization toolbox, we designed a benzylic-selective migratory Suzuki–Miyaura cross-coupling reaction (Figure b) . Undesired migration products were previously observed in B-alkyl Suzuki–Miyaura cross-couplings, but these migratory cross-couplings have not been synthetically exploited.…”

Reaction scope and mechanistic insights of nickel-catalyzed migratory Suzuki–Miyaura cross-coupling

“…In this context, the concept of migratory cross-coupling has been initially described by the Baudoin group in palladium-catalyzed C-H bond functionalization reactions (Fig. 1a) [19][20][21] .…”