Accounting for Strong Ligand Sensitivity in Pd-Catalyzed α-Arylation of Enolates from Ketones, Esters, and Nitroalkanes

Abstract

The mechanism of the Pd-catalyzed α-arylation of three model enolates is studied focusing on an analysis of their very different reactivities. In particular, the low reactivity of nitronates under standard arylation conditions and their high sensitivity to the nature of catalytic systems are addressed. The three canonical steps for each of the reaction systems are examined, and key trends surrounding the stability of intermediates and transition states are delineated. A framework based on molecular orbital analyses and the hard–soft acid–base (HSAB) theory is advanced to explain the observed reactivity trends. The local softness of the enolates was found to be a key parameter controlling the energy of the enolate–catalyst complexes. The low reactivity of the nitroalkane enolates is attributed to slow reductive elimination, a consequence of the hard nature of the nitronate. Analysis of reactivity of nitromethane in α-arylation with Pd catalysts containing Buchwald ligands reveals destabilization of the L2Pd species as a major non-enolate-specific acceleration mechanism as well as less electron-rich ligands accelerating reductive elimination as a nitronate-specific mechanism. The corresponding energetics and feasibility that favor C-arylation versus O-arylation are outlined.

C 2-Symmetric atropisomeric N-heterocyclic carbene–palladium(ii) complexes: synthesis, chiral resolution, and application in the enantioselective α-arylation of amides

“…Nevertheless, a recent theoretical study on palladium-catalyzed α-arylation of ketones with phosphine ligands suggested that reductive elimination is the rate-limiting step. 21 As expected, the nature of the allyl derivative ligand has no meaningful influence on the enantioselectivity (72% ee, entry 2 vs. 77% ee, entry 6) (95% ee, entries 3 and 4 vs. 92% ee, entry 7 vs. 92%, entry 8) since the generated catalytic species is the same. As isolated yields are good to excellent, the effect of the nature of the allyl derivative ligand on catalytic activity cannot be confidently addressed.…”

“…Nevertheless, a recent theoretical study on palladium-catalyzed α-arylation of ketones with phosphine ligands suggested that reductive elimination is the ratelimiting step. 21 As expected, the nature of the allyl derivative ligand has no meaningful influence on the enantioselectivity (72% ee, entry 2 vs. 77% ee, entry 6) (95% ee, entries 3 and 4…”

Copper‐Catalyzed α‐Arylation of Nitroalkanes with (Hetero)aryl Bromides/Iodides

“…Since a nitro group has stronger electron-withdrawing property, the pKa values of nitroalkanes are approximately 8.6-10.2, [31] which are similar to those for activated 1,3dicarbonyl compounds (pKa 9-13). [25] Based on this analysis, we decided to explore the possibility to apply nitroalkanes as suitable nucleophiles, [32] and subsequently revealed that their coupling with (hetero)aryl halides worked well by using our newly developed Cu/oxalamide catalytic system. [33] This result represents the first copper-catalyzed α-arylation/ alkenylation of nitroalkanes with (hetero)aryl halides and vinyl halides.…”

Palladium-Catalyzed Direct α-Arylation of Indane-1,3-dione to 2-Substituted Indene-1,3-diones

“…Although numerous α-arylation reagents have been developed, their applications are limited because they involve different strategies and transmetalation . Furthermore, major efforts toward the α-arylation of aliphatic enolates and cyclic carbonyl compounds have scantly been reported . It reveals that some shortcomings still exist in the direct α-arylation of cyclic carbonyl compounds.…”