Reactions of the 21st Century: Two Decades of Innovative Catalyst

Review pubs.acs.org/Organometallics

Reactions of the 21st Century: Two Decades of Innovative Catalyst Design for Palladium-Catalyzed Cross-Couplings Peter G. Gildner and Thomas J. Colacot* Johnson Matthey Catalysis and Chiral Technologies, 2001 Nolte Drive, West Deptford, New Jersey 08066, United States ABSTRACT: A brief account of the major developments of palladium-catalyzed crosscoupling during the last two decades is highlighted chronologically, with an emphasis on the personal experiences of the corresponding author. Important contributions from both academia and industry, which have been vital to the accelerated growth of this area, are presented. The developments of new classes of ligands and the switch from in situ to preformed catalysts tailored to address the challenges in cross-coupling are reviewed, reflecting an evolution in continued growth.

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INTRODUCTION While the origins of modern cross-coupling1 can be traced back to the 1970s, the impact of this powerful technology and its significant growth over the past two decades was recognized in 2010 with the awarding of the Nobel Prize in Chemistry to Professors Heck, Negishi, and Suzuki (Figure 1).2 The exponential growth of this field did not happen by design, as many factors have influenced the overall landscape of crosscoupling. An improved understanding of the steric and electronic properties of ligands within organic chemistry as well as the binding properties of metals using the principles of coordination chemistry led to the creation and implementation of organometallic complexes as highly effective catalysts. Catalytic systems developed prior to the late 1990s were utilized for making pharmaceutical molecules such as losartan3 and valsartan (Suzuki−Miyaura coupling),4 eletriptan (Heck reaction),5 and imatinib (aminocarbonylation and Buchwald− Hartwig amination)6 as well as agrochemicals such as boscalid (Suzuki−Miyaura coupling)7 (Figure 2). More recently, applications in electronics materials, including liquid crystals and OLEDs have replaced cathode ray tube display screens and continue to advance rapidly.8 The development of technologies to remove trace amounts of metals from these organic products also spurred growth of this area from an industrial perspective.9 The need for catalysis in all of these disparate fields directly propelled the growth of cross-coupling. There is a similar relationship between the rapid development and innovation of cross-coupling and the evolution of mobile phone technology that has occurred over the last two decades (Figure 3). One can imagine a parallel between the high-value features of state of the art catalysts (e.g., high activity under mild conditions, regioselectivity, air and moisture stability, broad ligand scope, and new coupling activity) with advanced features of modern mobile phone technology (e.g., © 2015 American Chemical Society

Figure 1. Prominent historical figures in cross-coupling. The images of Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki are reproduced with permission from ref 2. Copyright 2015 John Wiley & Sons. The images of Morris S. Kharasch, Makoto Kumada, and Kenkichi Sonogashira are reproduced from ref 10. The photograph of John K. Stille is courtesy of Charles S. Henry.

Received: June 30, 2015 Published: October 16, 2015 5497

DOI: 10.1021/acs.organomet.5b00567 Organometallics 2015, 34, 5497−5508

Review

Organometallics

Matthey in late 1995. While his original projects encompassed the areas of process chemistry and non-precious-metal-based new product development, he became fascinated by the properties of the ferrocene-based 1,1′-bis(diphenylphosphino)ferrocene (dppf) ligand, on the basis of his background in phosphine chemistry and an unexpected customer inquiry.12 Although the lifespan of the project was cut short, his interest in the properties of dppf increased as he learned of the effectiveness of Pd(dppf)Cl2 for promoting reductive elimination in a striking example of a Kumada−Corriu coupling using a sec-alkyl Grignard reagent.13 In this report, investigating the utility of bisphosphines for Kumada−Corriu coupling, Hayashi and co-workers observed that the relatively large P− Pd−P angle (bite angle) in Pd(dppf)Cl2 led to an accelerated rate of reductive elimination from the transmetalation intermediate, Pd(dppf)(sec-Bu)Ph (1), in comparison to the analogous intermediate 2 using 1,1′-bis(diphenylphosphino)propane (dppp), which gave mixtures of products resulting from competitive reductive elimination and β-hydride elimination/isomerization pathways (Scheme 1). Intrigued by the

Figure 2. Early applications of cross-coupling technology in pharmaceutical and agrochemical development.

Internet access, e-mail, texting, video chat, apps). These advanced features are not essential for less challenging crosscouplings or basic communication; thus, less expensive solutions still serve a purpose. Yet in both cases the needs of the customer continue to drive innovation forward toward more elegant and creative solutions. In this brief account, we relate the evolving story of palladium-catalyzed cross-coupling from the perspective of catalyst design by considering the mutual roles of industry and academia. Since our group has recently published a comprehensive book discussing new trends in cross-coupling10 as well as several recent review articles,2,11 the following account will provide only a glimpse over the last two decades, highlighting how academia and industry have worked together to elevate the area of palladium-catalyzed cross-coupling to its current status as one of the most powerful practiced reactions of the 21st century.

Scheme 1. Effect of Bite Angle on Competing Pathways of PdII Intermediates

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A PERSONAL ACCOUNT The Colacot group’s first experiences with cross-coupling began unexpectedly when Colacot started his career with Johnson

Figure 3. Analogous evolution in technology. 5498


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Organometallics

couplings using aryl chlorides (Table 1).23 In accordance with the observations above, the best results would be obtained with

unique properties of this ligand, our group began to market Pd(dppf)Cl2 as a “magic catalyst”, highlighting its air and moisture stability coupled with high activity/selectivity in comparison to other more commonly employed palladium catalysts such as air sensitive Pd(PPh3)4. As we began to promote Pd(dppf)Cl2, Hartwig’s group started investigating the use of dppf with Pd(dba)2,14 while Buchwald and co-workers used a Pd2dba3/BINAP combination for aryl amination reactions.15 Our successful procedures for synthesizing and commercializing dppf and Pd(dppf)Cl2 in multikilogram quantities helped us to gain an early appreciation for the importance of preformed versus in situ catalysts in terms of improving activity, selectivity, scalability, and ease of handling from the perspective of process economy and environmental safety. This precept would become a crucial strategy for us in advancing the field of catalysis.

Table 1. High Reactivity of Pd/P(t-Bu)3 in Suzuki−Miyaura Coupling of Aryl Chlorides

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THE ERA OF MODERN CROSS-COUPLING: ROLE OF LIGANDS Soon, after these early critical findings, several reports and publications surfaced which proved to be ground-breaking for the burgeoning field of palladium-catalyzed cross-coupling. An important milestone in the era, the first comprehensive book, edited by Diederich and Stang, illuminated the quickly growing field of metal-catalyzed cross-coupling with an emphasis on name reactions.16 While PPh3 had been a common choice of ligand for palladium-catalyzed couplings involving aryl bromides and iodides, new catalyst combinations were beginning to increase the breadth of substrate scope. As we have previously published comprehensive reviews/book chapters covering the importance of ligand properties, the following offers only a preview of the varied classes of ligands and their origin.2,17 Two early concurrent reports of the carbonylation of aryl chlorides by Osborn18 and Milstein19 stressed the importance of both steric volume (as measured by the cone angle for phosphines and the bite angle for bidentate ligands)20 and basicity (pKa) for affecting catalytic activity (Figure 4). Osborn observed that “significant catalytic activity is

ligands possessing both sufficient steric bulk and electronrichness (P-t-Bu3 and PCy3). An optimal Pd to ligand ratio of approximately 1:1 led Fu and co-workers to propose a monoligated palladium intermediate as the active species. With bulky, electron-rich ligands such as DavePhos and P(tBu)3 (Figure 5), it became possible to overcome the large dissociation energy of the C−Cl bond,24 which, in turn, greatly increased the scope and availability of coupling partners.25

Figure 4. Steric and stereoelectronic evaluation of several phosphine ligands. Figure 5. Bulky, electron-rich ligand scaffolds.

found only with phosphines which are both strongly basic (pKa >6.5) and with well-defined steric volume, that is, the cone angle must exceed 160°.”18 From these early reports and observations of the importance of ligand properties, powerful catalysts would emerge leading to significant advances in cross-coupling. Buchwald’s group published a pivotal work highlighting the effectiveness of a new electron-rich biaryl phosphine for several room temperature C−C and C−N cross-couplings of aryl chlorides.21 Although Koie and co-workers were among the first to present the high reactivity of bulky, electron-rich P(t-Bu)3 for limited examples of C−N cross-coupling,22 research from the Fu group greatly expanded the utility of this catalyst system, first demonstrating its potential in a range of Suzuki−Miyaura

From these early findings, Buchwald and co-workers developed a family of biaryl dialkylphosphine ligands that have greatly expanded the scope of C−C and C−N couplings with continuous improvements ongoing.21,26 A convenient onepot, modular synthesis of the Buchwald biaryl monophosphines has led to the generation of a large library of ligands. An indepth understanding of the impact of key structural elements within this framework has made this ligand class exceptionally useful for a wide range of palladium-catalyzed cross-couplings. Larger biaryl monophosphine ligands favor monoligated LPd0, which has been shown to accelerate oxidative addition. Electron-donating alkyl groups on phosphorus have also been 5499


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and 4).38 Notably, the reactivity of their PCy3-derived precatalysts gave superior results in Suzuki−Miyaura couplings of aryl chlorides in comparison to the in situ catalyst formed from Pd2(dba)3 or Pd(OAc)2 with PCy3. At the same time, Herrmann’s group published the first synthesis of several preformed Pd0 dicarbene complexes. However, they found dicarbene 5 inferior to the corresponding in situ catalyst for a Suzuki−Miyaura coupling.39 Later Stahl and co-workers confirmed by various characterization techniques, including X-ray crystallography, that Herrmann and co-workers had synthesized the PdII-oxo complex 6 instead of the expected Pd0 dicarbene 5.40 These preliminary results paved the way for additional investigations into synthesizing and testing preformed catalysts. Continuing their seminal work with Pd2(dba)3/P(t-Bu)3,23 Fu and co-workers investigated the use of preformed Pd[P(t-Bu)3]2 for Negishi couplings of aryl and vinyl chlorides with aryl- and alkylzinc reagents.41 Hartwig’s group also utilized Pd[P(t-Bu)3]2 in amination reactions, observing a significant increase in reactivity in comparison to the use of Pd(dba)2 with P(t-Bu)3.42 From these initial reports, several more recent examples of the utility of Pd[P(t-Bu)3]2 can be seen in the work of Mori and co-workers with their elegant C−H arylation of heteroarenes with aryl bromides and chlorides,43 as well as the one-pot hydrogenation/C−H arylation of isoindolines to form 1-arylisoindoles from the Suginome group.44 Availability and Utility of L2Pd0. Despite the significant advancements in catalysis using L2Pd0 precatalysts, their synthesis proved challenging. For instance, though the preparation of Pd[P(t-Bu)3]2 had been reported in the literature,45 it was not commercially viable at an industrial scale. While Pd(PPh3)4 is believed to form Pd(PPh3)2 as the active catalytic species, PPh3 is generally less effective as a ligand when compared to bulky, electron-rich trialkylphosphine scaffolds. Challenging conditions involving unstable and highly volatile precursors45a or impractical recrystallization procedures45b,41 led to increased efforts to access this powerful class of precatalysts on commercial scale. To address these issues, our group developed a general route for synthesizing L2Pd0 catalysts using a wide range of bulky, electron-rich phosphines in nearly quantitative yield at large scale via an environmentally friendly, “reagent-economical” procedure (Scheme 2). Mecha-

found to accelerate oxidative addition. Transmetalation is also facilitated by a monoligated palladium intermediate due to minimized steric hindrance. Larger alkyl groups on phosphorus and substitution at the ortho position of the non-phosphinecontaining aryl ring promote reductive elimination. Many additional research groups devoted their attention toward developing highly active ligands by incorporating bulky, electron-rich groups for a wide variety of cross-coupling reactions (Figure 5). Nolan’s group utilized the strong binding of sterically hindered N-heterocyclic carbene (NHC) ligands with palladium to catalyze a wide range of cross-couplings.27 Hartwig’s pentaphenylferrocenyl di-tert-butylphosphine ligand (Q-Phos) served as a highly active catalyst for a range of αarylations28 as well as C−heteroatom bond forming reactions.29 Beller and co-workers reported a class of adamantyl-based phosphines for cross-coupling30 and carbonylation reactions.31 Later Stradiotto and co-workers developed a class of P,Nligands which were shown to be highly active for a broad range of Buchwald−Hartwig aminations32 including the monoarylation of ammonia33 and acetone.34 The latter is a challenging substrate prone to diarylation.

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EVOLUTION OF PREFORMED CATALYSTS Advantages of Precatalysts. While the development of this multitude of ligand classes greatly expanded the scope of a variety of cross-coupling reactions, several drawbacks remained. We have addressed this topic in detail in a recent review11 and in a chapter in our recent book.35 Our intention in the following sections is to present the latest developments from our group within a concise historical perspective of precatalyst development. For the majority of the examples discussed above, a palladium source such as Pd(dba)x or Pd(OAc)2 is mixed with the ligand to form the active catalyst LnPd0 in situ. The socalled innocent ligands from these palladium sources, such as dibenzylideneacetone (dba), have been found to compete with the added ligands, and, therefore, diminish catalytic activity.35,36 In addition, the purity of these Pd precursors has been found to vary on the basis of their method of preparation and the supplier.37 In some cases, off-cycle species may also form which can have a detrimental effect on activity and selectivity, and thus, reactions may require increased reaction time and/or higher temperatures. Precatalysts can also favor process economy in an industrial setting by avoiding excess ligand, simplifying workup, and reducing residual metal content in the product. Furthermore, many of the electron-rich tertiary phosphine ligands are extremely air sensitive or even pyrophoric (e.g., P(t-Bu)3), which poses challenges and safety risks especially during industrial scale-up. As mentioned previously with respect to Pd(dppf)Cl2, the potential for employing a precatalyst to obviate these significant issues became increasingly attractive. In 2000 Beller and co-workers published the isolation of the first Pd0 monophosphine complexes (Figure 6, complexes 3

Scheme 2. General Synthesis of L2Pd0

nistic studies provide evidence for the reduction of PdII to Pd0 in the absence of excess phosphine. This operationally simple method uses inexpensive and air-stable Pd(COD)X2 (X = Br, Cl) together with stoichiometric phosphine ligand in the presence of a hydroxide base in protic solvent.46 Ready access to the extended class of highly active L2Pd0 catalysts spurred research not only in our laboratory but also in academic groups for the development of new processes. Hartwig and co-workers developed several methods using Pd[P(o-tol)3]2 together with Josiphos ligand CyPF-t-Bu for the amination of aryl and heteroaryl tosylates at room temperature,47 as well as the development of a general method for the monoarylation of ammonia with a wide range of aryl halides and sulfonates.48 Our laboratory published a high-yielding

Figure 6. Early development of Pd0 complexes. 5500


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Organometallics Table 2. Lautens’ Intramolecular Carbohalogenation Using Pd(Q-Phos)2

Table 3. Effectiveness of Pd(dtbpf)Cl2 for Suzuki−Miyaura Couplings of Aryl Chlorides

a

entry

[Pd]

yield (%)

entry

[Pd]

yield (%)

1 2 3 4 5

Pd(PPh3)2Cl2 Pd(PCy3)2Cl2 Pd(dppe)Cl2 Pd(dppf)Cl2 Pd(P(o-tol)3)Cl2

2 2 5 4 7

6 7 8 9a

Pd(DPEPhos)Cl2 Pd(dippf)Cl2 Pd(dtbpf)Cl2 Pd(dtbpf)Cl2

2 9 65 100

In DMF at 120 °C.

Table 4. Mild Conditions for Amination using [Pd(μ-Br)(P-t-Bu3)]2

a

9 as catalyst.

Pd catalysts in terms of selectivity and ease of setup (Table 3).52,53 Prior to this report, catalyst 7 had not been studied in catalytic applications. Catalyst 7 later proved effective for the α-arylation of ketones with various aryl halides as disclosed by our group.54 Working in the same vein, Guram and co-workers utilized Pd(AmPhos)2Cl2 for the Suzuki−Miyaura coupling of heteroaryl chlorides,55 while Falck developed a stereospecific Suzuki− Miyaura coupling of alkyl α-cyanohydrin triflates using Pd(AmPhos)2Cl2 or Pd(dtbpf)Cl2 that proceeds with inversion to afford enantiomerically enriched alkyl nitriles.56 Lipshutz and co-workers used Pd(AmPhos)2Cl2 in aqueous media with a designer surfactant for Negishi-type couplings between sp2 and sp3 halides, thus avoiding preformed organozinc coupling partners.57 They later used catalyst 7 for room-temperature Heck reactions in aqueous micelles.58 To better understand the effects of catalyst structure and CO pressure for carbonylation reactions, Barnard published a method for the carbonylation of aryl halides and described bidentate Pd(dcypp)Cl2 (dcypp = bis(dicyclohexylphosphino)propane) as a powerful catalyst for

copper-free Sonogashira coupling (Heck alkynylation) using aryl and heteroaryl chlorides.49 New reactivity not previously realized was also enabled by this class of reactive catalysts such as intramolecular carbohalogenation to form a range of nitrogen- and oxygen-containing heterocycles developed by Lautens and co-workers using Pd(Q-Phos)2 (Table 2).50 Improved Stability with L2PdX2. While L2Pd0 catalysts are highly active and have been utilized for improving and developing a wide range of catalytic methods, their high reactivity is also reflected in their air sensitivity. Although these catalysts do pose handling concerns, with proper techniques (i.e., as in the handling of Pd(PPh3)4) they have been used effectively in several commercial processes.35,51 Alternatively, the class of L2PdX2 catalysts exhibit increased stability to atmospheric conditions even while producing L2Pd0 in situ, which has led to their frequent use especially for industrial processes at both large and small scale. Our group reported a method for the Suzuki−Miyaura coupling of unactivated, sterically hindered aryl chlorides, benefiting from the air-stable, yet highly active, Pd(dtbpf)Cl2 (dtbpf = 1,1′-bis(di-tertbutylphosphino)ferrocene) (7), which outperformed several 5501


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palladacycles formed via cyclopalladation of the ligand (Figure 7, first category). Activation to Pd0 was proposed to occur by the action of an amine and a base.71 The advantages of the palladacycle precatalyst over the in situ precursors is evident in an early example from the Buchwald group, wherein air-stable palladacycle 10 provides near full conversion in only 2 h with reduced loading and without the use of excess ligand (Scheme 4, top). In this example the palladacycle allows for more facile access to LPd0 in comparison to the in situ catalyst starting with Pd(OAc)2, where more forcing conditions are required for full conversion (Scheme 4, bottom).69 A second class of palladacycles, formed via cyclopalladation with a sacrificial backbone, proved highly effective and led to a large family of evolving precatalysts. Examples of this type include palladacycles developed by Indolese, Studer, and co-workers,72 NHC-based palladacycles from Nolan and co-workers,73 and several generations of Buchwald palladacycles (Figure 7, second category).74 For this category of precatalysts it is proposed that after transmetalation (NMe2 palladacycles) or deprotonation (Buchwald NH palladacycles) reductive elimination leads to the active LPd0 species that likely remains monoligated throughout the catalytic cycle. The increasing practicality and effectiveness of the Buchwald palladacycles is evident across four generations of commercially available, stable precatalysts that have led to increased catalytic efficiency, shorter reaction times, and the minimization of excess ligand through fast generation of the active LPd0 species (Figure 8). While first-generation Buchwald palladacycles (G1) exhibit a wide range of reactivity across an impressive array of cross-coupling reactions, they require more forcing conditions for activation, possess a short lifetime in solution, and require a multistep synthesis involving unstable organometallic intermediates which limits their scalability.75 Second-generation palladacycles (G2) possess a more acidic aromatic amine and can be activated using a weak base at room temperature; however, larger ligands such as BrettPhos and tBuXPhos cannot be incorporated.76 A third generation of palladacycles (G3) replaces the chloride in the first- and second-generation palladacycles with a less coordinating and more electronwithdrawing mesylate counterion, allowing for the incorporation of larger biaryl phosphine ligands.77 While the full scope and generality of the Buchwald palladacycles will not be covered here,74,78 the following examples highlight their advantages over the in situ components. Amination of an aryl mesylate failed to proceed under in situ conditions using

promoting oxidative addition in challenging aryl chloride substrates.59 Generating LPd0. As the understanding of catalyst and ligand effects increased, greater attention to structure and the metal to ligand ratio led to even more active catalysts. While a 14-electron L2Pd0 complex is more thermodynamically stable, 12-electron LPd0 is kinetically more active, which has been supported in reports where a 1:1 ratio of palladium to ligand gives optimal results.60 However, as mentioned earlier, there are also examples of reactions where L2Pd0 precatalysts49,50 and higher ligand to palladium ratios are superior.61 As reflected in this observation, preformed catalysts of the type LPdXn continue to evolve into some of the most active palladium catalysts to date. Dimeric [Pd(μ-Br)(P-t-Bu3)]2 (8) and [Pd(μBr)P(1-Ad)-t-Bu2]2 (9), originally identified by Hartwig, proved to be remarkably active catalysts for amination (Table 4) and Suzuki−Miyaura reactions.62 Because of the exceptionally high rates of reactivity (completion achieved often in minutes at room temperature), many previously sensitive functional groups could now be tolerated. Ryberg also demonstrated the practicality of Pd(I) dimers 8 and 9 in his report of a high-yielding, mild method for the cyanation of a hydroxy-substituted bromoindole on a multikilogram scale.63 Schoenebeck and co-workers have published several elegant computational studies investigating the unique reactivity patterns of the air-stable dimer [Pd(μ-I)(P-t-Bu3)]2 and demonstrated its utility for several cross-coupling methods.64 While the original methods to synthesize [Pd(μ-Br)(P-t-Bu3)]2 gave only moderate yields, possibly due to decomposition upon workup,65 additional process modifications and development have greatly improved the synthesis,66 leading to its current commercial availability in bulk quantities. In the modified route, notably no sacrificial ligand is required to reduce PdII to PdI (Scheme 3).67 Scheme 3. Improved Commercial Synthesis of [Pd(μ-Br)(Pt-Bu3)]2

The groups of Herrmann and Beller were the first to report the use of palladacycles as precursors to LPd0.68 After this initial discovery, the groups of Buchwald69 and Vilar70 developed

Figure 7. Generations of palladacycle precatalysts. 5502


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Organometallics Scheme 4. Notable Reactivity: Early-Generation Buchwald Palladacycle

precatalysts have focused on increasing steric bulk at the ortho positions of the N-aryl group of the NHC ligand which has been linked to improved catalyst performance. Recently our group introduced a new class of πallylpalladium precatalysts to readily access LPd0. Together with Shaughnessy and co-workers, this highly active air-stable precatalyst system was first disclosed with Pd(allyl)(DTBNpP) Cl (11) and investigated for a wide range of amine arylations and several examples of ketone α-arylation.85 Notably precatalyst 11 proved to be highly effective for challenging substrates and demonstrated significantly higher reactivity than the in situ system for the amination of aryl chlorides (Scheme 6). Subsequent investigation by our group highlighted the reactivity of 11 π-allylpalladium precatalysts across 4 different electron-rich phosphine ligands and established their broad scope for a range of amination, Suzuki−Miyaura, and αarylation couplings.84 Relative differences in reactivity based on the (π)-allyl moiety were discussed in addition to the formation of a PdI dimer as a result of “comproportionation” in varying amounts from the allyl-based precatalysts containing relatively less bulky ligands (Scheme 7). Dramatic improvements in catalytic activity were observed in amination reactions using Pd(crotyl)(L)Cl in comparison to the respective L2Pd0 scaffold containing Q-Phos (Scheme 8). However, as previously mentioned in Table 2, Pd(Q-Phos)2 proved to be the most active catalyst for Lautens’ carbohalogenation,50 demonstrating the importance of tailored catalyst design for specific reactions and substrates even when using the same ligand. Nolan and coworkers reported the preparation and high reactivity of Pd(cinnamyl)(AmPhos)Cl for the amination of a range of (hetero)aryl chlorides with both primary and secondary amines.91 More recently, we published a comprehensive study which greatly expanded the family of π-allylpalladium precatalysts to encompass an array of extremely bulky, electron-rich biaryl- and bipyrazolylphosphine ligands.92 Essential to the expansion of this precatalyst class, a Pd(R-allyl)(L)Cl scaffold was used to incorporate less bulky ligands, while a [Pd(R-allyl)(L)]OTf

Figure 8. Generations of Buchwald palladacycles.

Pd2(dba)3 and BrettPhos but proceeded to full conversion under the same reaction conditions by employing G1 BrettPhos (Scheme 5).79 Suzuki−Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids under very mild conditions were also accomplished with fast rates of activation by using G2 XPhos (Table 5).76 In addition to the extensive research performed using tertiary phosphine ligands, NHC ligands27c have also been utilized effectively in precatalyst structures to access LPd0.27b,80 Using Pd(NHC)(R-allyl)Cl complexes, Nolan and co-workers found these precatalysts to be exceptionally active for Suzuki− Miyaura couplings.81 A significant improvement in catalytic activity was observed as the size of the substituent on the allyl group increased from hydrogen to phenyl. Larger bond distances from palladium to the substituted allyl carbon were measured as the size of the substituent on that carbon increased. Presumably the resultant weakening of the Pd−allyl bond increases the propensity for activation.82 Later Balcells, Hazari, and co-workers performed experimental and theoretical studies examining the relationship between Pd(IPr)(R-allyl)Cl monomers and corresponding (μ-allyl)(μ-Cl)Pd2(IPr)2 PdI dimers83 following our earlier studies on the phosphine based catalysts84 in collaboration with Shaughnessy.85 They noted that increased steric hindrance at the 1-position of the allyl ligands in the case of the crotyl and cinnamyl precatalysts increases the kinetic barrier to comproportionation forming the deleterious Pd(I) dimers. Organ and co-workers have demonstrated the effectiveness of NHC-based Pd-PEPPSI precatalysts86 for a range of Negishi,87 Suzuki−Miyaura,88 and Kumada−Corriu89 cross-couplings and Buchwald−Hartwig aminations.90 Successive generations of these versatile Scheme 5. Superior Reactivity of G1 BrettPhos over Precursors

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Organometallics Table 5. G2 XPhos for Coupling of Unstable Boronic Acids

Scheme 6. High Activity of π-Allylpalladium Precatalyst for Amination of Aryl Chlorides

Scheme 7. Comproportionation Pathway To Form Pd(I) Dimer

Scheme 8. Comparison of L2Pd0 with Pd(crotyl)(L)Cl using Q-Phos

Figure 9. Single-crystal X-ray structure of the off-cycle Pd(I) dimer 12.

of oxidative addition product A and comproportionation product B were measured (Table 6). While Pd(I) dimer 12 was formed in an appreciable 44% yield when Pd(allyl)(SPhos) Cl was used (entry 1), the use of a crotyl group completely suppressed comproportionation to give only the oxidative addition product (entry 2). Larger ligands such as BrettPhos also proved effective for preventing dimer formation even when the allyl group was employed (entry 3), while cationic [Pd(allyl)(BrettPhos)OTf] led to even higher yields of the oxidative addition product (entry 4). Mechanistic experiments suggest that the exceptionally high reactivity of these precatalysts across a range of C−C and C−X cross couplings is the product of three critical factors: (1) fast activation to LPd0 under mild, commonly employed conditions,

scaffold was established to accommodate exceptionally bulky ligands (Scheme 9). To better understand the activity of these precatalysts, a single-crystal X-ray structure was obtained of the comproportionation product following activation of Pd(allyl)(SPhos)Cl, derived from the smallest of the biaryl ligands utilized in this study (Figure 9).92 On examination of the relatively short bond distances between the eclipsed cyclohexyl rings (3.867 Å) and the non-phosphine-containing biaryl ring (3.922 Å), it was proposed that an increase in steric bulk at either of these positions or on the allyl group would likely deter the off-cycle comproportionation leading to a Pd(I) dimer. To test this hypothesis, stoichiometric activation studies were carried out in the presence of bromobenzene (to trap LPd0) and the amounts

Scheme 9. Synthesis of Neutral and Cationic Classes of π-Allylpalladium Precatalysts

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Organometallics Table 6. Modular Precatalyst Design To Suppress Comproportionation

Scheme 10. Scope of R-Allylpalladium Precatalysts for Challenging Cross-Couplings

yield (%) entry

[Pd]

A

B

1 2 3 4

Pd(allyl)(SPhos)Cl Pd(crotyl)(SPhos)Cl Pd(allyl)(BrettPhos)Cl [Pd(allyl)(BrettPhos)]OTf

11 74 74 95

44 0 0 0

(2) suppression of an off-cycle comproportionation pathway to form a stable Pd(I) dimer, and (3) release of noninhibitory byproducts upon activation. These advantageous properties are reflected in the high reactivity of these precatalysts, which in some instances have been observed to outperform the corresponding biaryl-ligand-based palladacycles (Table 7).92 Table 7. Comparison of Reactivity: π-Allylpalladium and RuPhos Palladacycle Precatalysts

academia and industry, rational design has led to the synthesis and implementation of catalysts possessing remarkable activity. The realization of commercial materials such as drug molecules increasingly relies on the robust and efficient nature of these highly active catalysts, as described in recent reviews.94 The syntheses of several very recent promising drug molecules, including canagliflozin (Suzuki−Miyaura coupling),95 dolutegravir (aminocarbonylation),96 and ledipasvir (Miyaura borylation, Suzuki−Miyaura coupling)97 (Figure 10) together with

a

Additional 0.5 mol % RuPhos. b2.5 h reaction time. c0.5 mol % carbazole.

Additionally they have exhibited excellent reactivity in coupling a range of challenging partners, including oxazolidinones, sulfonamides, alcohols, and indoles, depicted in Scheme 10.92 The modular nature of this scaffold is highly useful for altering the steric demand of the π-allyl backbone to provide optimal activity for different ligands through suppression of the comproportionation pathway. Concurrent with our work, the Hazari group reported related studies using precatalysts featuring a tert-butyl indenyl scaffold.93

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CONCLUSION The advances disclosed in this brief account mark some of the highlights in the evolving field of palladium-catalyzed crosscoupling over the last two decades. Recognition of the potential of palladium cross-coupling and its implementation in the late 1990s were quickly followed by the design of powerful ligands for improved activity and selectivity. With increasing knowledge of the intricacies of the catalytic cycle, ligand scaffolds improved to access the active species under mild and efficient conditions. As the collective knowledge in this vital field has grown in both

Figure 10. Recent selected examples of pharmaceutical molecules developed by cross-coupling technology.

sofosbuvir98 for the treatment of hepatitis C, have all been facilitated by cross-coupling technology. Coupling partners previously deemed unreactive or functional groups that were thought to react unfavorably now appear in countless examples of elegant cross-coupling. The elevated yields, mild conditions, and improved atom economy are important factors for moving toward methods that are sustainable. The ever-present need for 5505


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more efficient synthetic methods continues to drive the search for new and improved catalysts and processes.

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AUTHOR INFORMATION

Corresponding Author

*E-mail for T.J.C.: [email protected]. Notes

The authors declare the following competing financial interest(s): While many of the palladium catalysts described in this review including R-allyl Pd, L2Pd0, and LnPdXn precatalysts are the intellectual property of Johnson Matthey and are commercially available from Johnson Matthey Catalysis and Chiral Technologies (JMCCT), the biaryl ligands and palladacycle catalysts described herein are intellectual property of MIT; they are also commercially available from JMCCT as this technology is licensed from MIT.

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ACKNOWLEDGMENTS This account is dedicated to Professor Ei-ichi Negishi on the occasion of his 80th birthday. In the final stages of revising this manuscript we were deeply saddened to learn of the passing of Professor Richard F. Heck. This account serves as a tribute to the lasting importance of his seminal findings.99

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