Addressing Challenges in Palladium‐Catalyzed Cross‐Coupling Reactions Through Ligand Design

Abstract

The development of palladium-catalyzed cross-coupling reactions has revolutionized the synthesis of organic molecules on both bench-top and industrial scales. While significant research effort has been directed toward evaluating how modifying various reaction parameters can influence the outcome of a given cross-coupling reaction, the design and implementation of novel ancillary ligand frameworks has played a particularly important role in advancing the state-of-the-art. This Review seeks to highlight notable examples from the recent chemical literature, in which newly developed ancillary ligands have enabled more challenging substrate transformations to be addressed with greater selectivity and/or under increasingly mild conditions. Throughout, the importance and subtlety of ligand effects in palladium-catalyzed cross-coupling reactions are described, in an effort to inspire further development and understanding within the field of ancillary ligand design.

C-N bond forming reactions in the synthesis of substituted 2-aminoimidazole derivatives

“…In this context, palladium-catalyzed amination methodologies for the formation of C-N bonds 44 were the method of choice. This procedure has been successfully applied mainly to benzo or hetero fused imidazole derivatives.…”

Sulfur-containing DalPhos ligand variants: synthesis and application in Buchwald−Hartwig amination

“…aryl-X oxidative addition, amine substrate binding, and/or aryl-N reductive elimination) is well-established. 3 As such, the quest to address problematic substrate transformations in BHA chemistry benefits directly from innovations in ancillary ligand design. [1][2][3][4][5] Highly successful BHA catalyst systems have traditionally relied on two sterically demanding and electron rich ligand classes: (a) monodentate phosphine or NHC ligands, with Buchwald's dialkylbiarylphosphines 2,4 and Organ's Nheterocyclic carbene (NHC)-based PEPPSI catalysts [6][7] representing prototypical examples; and (b) strongly chelating bidentate bisphosphine ligands, including the JosiPhos 8 …”

“…Selected interatomic distances (251(3); C41-C42 1.393(5); C42-C43 1.372(5); P-Pd-S 87.01(3).Having prepared a small collection of new DalPhos ligand variants (L3-L7) that incorporate sulfur either as a donor atom or as part of the ligand backbone, we sought to compare the catalytic performance of these new ligands in BHA chemistry to that of Me-DalPhos (L1) and Mor-DalPhos (L2) under similar experimental conditions. We chose as a reference point the selective monoarylation of RNH 2 reagents (R = octyl, phenyl or H) using the modestly electronically deactivated coupling partner 4-chlorotoluene (110 ºC, 1 h), given the established ability of Mor-DalPhos (L2) to promote such reactions in an efficient manner.…”

CHAPTER 5. Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions

“…Notably, the ancillary ligand(s) (i.e., L n ) employed, typically phosphines or N-heterocyclic carbenes, have a direct influence on the course of the elementary transformations. [20][21][22] Electron-rich and sterically demanding ligands promote the formation of low-coordinate compounds of type A that are predisposed to undergo Ar-X oxidative addition to give B. The steric and electronic properties of the ligands can serve to discourage unwanted dimerization within low-coordinate intermediates such as B or D, in addition to providing selectivity in amine binding (for BHA) or enolate complexation (for AA) proceeding from B.…”

“…20,21 Early investigations made use of structurally simple triarylphosphine ancillary co-ligands; however, it was found subsequently that the use of more structurally complex ancillary ligands that serve to accelerate otherwise difficult segments of the catalytic cycle can enable more challenging substrate pairings to be accommodated, often with excellent functional group tolerance and under mild conditions (e.g., low Pd/L loadings, mild reaction temperatures). In this regard, a number of effective ancillary ligation strategies have emerged, including sterically demanding monodentate ligands such as biarylmonophosphines 10,14 and N-heterocyclic carbenes, 21,24 and also rigid bidentate ligands including bisphosphines 9 and heterobidentate ligands 20,25 such as those featuring pairings of phosphorus and nitrogen donors.…”