Carin C. C. Johansson Seechurn

Palladium‐Catalyzed Cross‐Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize

In 2010, Richard Heck, Ei-ichi Negishi, and Akira Suzuki joined the prestigious circle of Nobel Laureate chemists for their roles in discovering and developing highly practical methodologies for C-C bond construction. From their original contributions in the early 1970s the landscape of the strategies and methods of organic synthesis irreversibly changed for the modern chemist, both in academia and in industry. In this Review, we attempt to trace the historical origin of these powerful reactions, and outline the developments from the seminal discoveries leading to their eminent position as appreciated and applied today.

Air-Stable Pd(R-allyl)LCl (L= Q-Phos, P(t-Bu)3, etc.) Systems for C–C/N Couplings: Insight into the Structure–Activity Relationship and Catalyst Activation Pathway

A series of Pd(R-allyl)LCl complexes [R = H, 1-Me, 1-Ph, 1-gem-Me(2), 2-Me; L = Q-Phos, P(t-Bu)(3), P(t-Bu)(2)(p-NMe(2)C(6)H(4)), P(t-Bu)(2)Np] have been synthesized and evaluated in the Buchwald-Hartwig aminations in detail, in addition to the preliminary studies on Suzuki coupling and α-arylation reactions. Pd(crotyl)Q-PhosCl (9) was found to be a superior catalyst to the other Q-Phos-based catalysts, and the reported in situ systems, in model coupling reactions involving 4-bromoanisole substrate with either N-methylaniline or 4-tert-butylbenzeneboronic acid. Precatalyst 9 also performed better than the catalysts bearing P(t-Bu)(2)(p-NMe(2)C(6)H(4)) ligand; however, it is comparable to the new crotyl catalysts bearing P(t-Bu)(3) or P(t-Bu)(2)Np ligands. In α-arylation of a biologically important model substrate, 1-tetralone, Pd(allyl)P(t-Bu)(2)(p-NMe(2)C(6)H(4))Cl (15) was found to be the best catalyst. The reason for the relatively higher activity of the crotyl complexes in comparison to the allyl derivatives in C-N bond formation reactions was investigated using X-ray crystallography in conjunction with NMR spectroscopic studies.

Synthesis and X-ray structure determination of highly active Pd(II), Pd(I), and Pd(0) complexes of di(tert-butyl)neopentylphosphine (DTBNpP) in the arylation of amines and ketones.

The air-stable complex Pd(η(3)-allyl)(DTBNpP)Cl (DTBNpP = di(tert-butyl)neopentylphosphine) serves as a highly efficient precatalyst for the arylation of amines and enolates using aryl bromides and chlorides under mild conditions with yields ranging from 74% to 98%. Amination reactions of aryl bromides were carried out using 1-2 mol % Pd(η(3)-allyl)(DTBNpP)Cl at 23-50 °C without the need to exclude oxygen or moisture. The C-N coupling of the aryl chlorides occurred at relatively lower temperature (80-100 °C) and catalyst loading (1 mol %) using the Pd(η(3)-allyl)(DTBNpP)Cl precatalyst than the catalyst generated in situ from DTBNpP and Pd(2)(dba)(3) (100-140 °C, 2-5 mol % Pd). Other Pd(DTBNpP)(2)-based complexes, (Pd(DTBNpP)(2) and Pd(DTBNpP)(2)Cl(2)) were ineffective precatalysts under identical conditions for the amination reactions. Both Pd(DTBNpP)(2) and Pd(DTBNpP)(2)Cl(2) precatalysts gave nearly quantitative conversions to the product in the α-arylation of propiophenone with p-chlorotoluene and p-bromoanisole at a substrate/catalyst loading of 100/1. At lower substrate/catalyst loading (1000/1), the conversions were lower but comparable to that of Pd(t-Bu(3)P)(2). In many cases, the tri-tert-butylphosphine (TTBP) based Pd(I) dimer, [Pd(μ-Br)(TTBP)](2), stood out to be the most reactive catalyst under identical conditions for the enolate arylation. Interestingly, the air-stable Pd(I) dimer, Pd(2)(DTBNpP)(2)(μ-Cl)(μ-allyl), was less active in comparison to [Pd(μ-Br)(TTBP)](2) and Pd(η(3)-allyl)(DTBNpP)Cl. The X-ray crystal structures of Pd(η(3)-allyl)(DTBNpP)Cl, Pd(DTBNpP)(2)Cl(2), Pd(DTBNpP)(2), and Pd(2)(DTBNpP)(2)(μ-Cl)(μ-allyl) are reported in this paper along with initial studies on the catalyst activation of the Pd(η(3)-allyl)(DTBNpP)Cl precatalyst.

Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovering Hidden Species and Implications in Catalytic Cross-Coupling Reactions

The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed processes, ranging from cross-coupling, C-H activation, to Wacker chemistry. For one of the most powerful new generation phosphine ligands, PtBu3, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mechanism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the formation of the highly active precatalyst {Pd(μ-Br)(PtBu3)}2. The formation of dinuclear Pd(I), as opposed to the Pd(0) complex, (tBu3P)2Pd was shown to depend on the stoichiometry of Pd to phosphine ligand, the order of addition of the reagents, and, most importantly, the nature of the palladium precursor and the choice of the phosphine ligand utilized. In addition, through experiments on gram scale in palladium, mechanistically important additional Pd- and phosphine-containing species were detected. An ionic Pd(II)Br3 dimer side product was isolated, characterized, and identified as the crucial driving force in the mechanism of formation of the Pd(I) bromide dimer. The potential impact of the presence of these side species for in situ formed Pd complexes in catalysis was investigated in Buchwald-Hartwig, α-arylation, and Suzuki-Miyaura reactions. The use of preformed and isolated Pd(I) bromide dimer as a precatalyst provided superior results, in terms of catalytic activity, in comparison to catalysts generated in situ.

CHAPTER 3:Pd–Phosphine Precatalysts for Modern Cross-Coupling Reactions

The development and use of well-defined preformed Pd catalysts are reviewed from academic and industrial points of view. The strategies employed for the development of Pd precatalysts resulting in either L2Pd(0) or LPd(0) are discussed with examples from industry and academia on how the properties of the ligand and the nature of the precatalyst itself can precisely affect the efficiency of a number of cross-coupling reactions. The well-defined preformed Pd catalysts often improve the selectivity and activity of selected cross-coupling reactions by reducing the metal loading and the ligand-to-metal ratios. In addition, they are often more practical to handle than the corresponding in situ system containing a Pd precursor such as Pd(dba)x and a pyrophoric ligand such as t-Bu3P.

CHAPTER 1:Introduction to New Trends in Cross-Coupling

Palladium-catalyzed cross-coupling reactions have emerged as an exceptionally powerful class of reactions for the creation of carbon–carbon and carbon–heteroatom bonds in both the academic and industrial sectors of research. This chapter provides a brief history, relevant background information and a preface to the important topics discussed in the remainder of the book.

Development of concise two-step catalytic approach towards lasofoxifene precursor nafoxidine

We have elaborated a two-step catalytic approach to nafoxidine, a key precursor to lasofoxifene. Firstly, an efficient α-arylation of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one with chlorobenzene was developed, which operates at low 0.1u202fmol% Pd-132 catalyst loading in the presence of 1.9 equivalents of sodium tert-butoxide at 60u202f°C in 1,4-dioxane and provides 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one in 90% yield. Secondly, we have demonstrated that 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one can be converted to nafoxidine in 61% yield via CeCl3 promoted reaction with (4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)lithium, which is formed in-situ from the corresponding arylbromide precursor and n-butyllithium. Altogether, the shortest two-step approach to nafoxidine from simple tetralone commodity starting material has been developed with overall 55% yield. The developed synthetic approach to nafoxidine has several beneficial aspects over the one used in the synthetic route primarily developed for the preparation of lasofoxifene.