Review pubs.acs.org/acscatalysis
Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize Hongbo Li,† Carin C. C. Johansson Seechurn,‡ and Thomas J. Colacot†,* †
Johnson Matthey Catalysis & Chiral Technologies, 2001 Nolte Drive, West Deptford, New Jersey 08066, United States Johnson Matthey Catalysis & Chiral Technologies, Orchard Road, Royston, Hertfordshire, SG8 5HE, United Kingdom
‡
ABSTRACT: Strategies for the development of Pd catalysts based on utilization of L2Pd and LPd species, beyond the contributions of the 2010 Nobel Laureates Richard Heck, Ei-ichi Negishi, and Akira Suzuki, along with their contemporaries, are reviewed. These well-defined, preformed Pd catalysts improve the selectivity and activity of selected cross-coupling reactions by reducing the metal loading and the ligand-to-metal ratios. This review describes predominantly the development of Pd precatalysts over the last 10 years and highlights the benefits often observed when using well-defined preformed catalysts relative to those generated in situ. KEYWORDS: cross-coupling, palladium, precatalysts
1. INTRODUCTION The 2010 Nobel Prize in Chemistry for Pd-catalyzed crosscoupling was one of the most highly anticipated awards within the synthetic organic and organometallic chemistry community.1 The ongoing progress in cross-coupling2−7 has not only had a significant impact on academic research, but it has also influenced the industrial arena for a variety of real world synthetic applications, such as the synthesis of natural products,8,9 active pharmaceutical ingredients (API),10 agrochemicals,11 and materials for electronic applications.12 The impact of these monumental discoveries was well recognized by synthetic practitioners, such as Nicolaou, who in a 2005 review stated, “A new paradigm for carbon−carbon bond formation has emerged that has enhanced considerably the prowess of synthetic organic chemists to assemble complex molecular f rameworks and has changed the way we think about synthesis.”13,14 A historic perspective on the development of this area by acknowledging the individual seminal contributions of Heck, Negishi, and Suzuki, along with the contributions of other pioneers who have made a significant impact of this area, was recently reviewed by our group in collaboration with Snieckus.15 Therein, our intent was mainly to tell a story behind the evolution of cross-couplings involving successive “waves,” leading over time to Pd as the metal of choice. Although the importance of ligand properties was highlighted as a “third wave” in that review, we could not elaborate on the role of the coordination number on Pd and its influence in selectivity and activity due to space limitations. However, we did touch upon the new trends, such as decarboxylative coupling, direct arylation (also known as C−H activation), etc. Therefore, herein, we focus mainly on the strategy behind the recent developments of L2Pd- and LPd-based precatalysts and their significant reactivity and selectivity. In addition, new applications in cross-coupling chemistry are discussed, with particular emphasis on their relevance to the chemical and © 2012 American Chemical Society
pharmaceutical industries. The new trend of using appropriate, well-defined precatalysts vs catalysts generated in situ is reviewed here by using representative results from our lab, along with those from other prominent groups. We have tried our best not to duplicate the theme behind our contemporary review article in Angewandte Chemie,15 although there might be some unintentional overlaps here and there. Only after attempting the review, we realized that the topic is very vast and that we could not cite all the references, which was not intentional, but we tried our best to cover those pertaining to the precatalysts mentioned in the review. The generally accepted catalytic cycle for cross-coupling reactions is shown in Scheme 1. The first step is the oxidative addition of an organic halide, or pseudohalide, to the assumed catalytically active species, LnPd(0), where Ln is the number (n) of ligands (L) coordinated to Pd. At this point, in Negishi-, Suzuki-Miyaura, and related coupling reactions, transmetalation with an organometallic reagent occurs, followed by reductive elimination to provide the desired product. In the Heck coupling, the oxidative addition is followed by migratory insertion of an olefin, followed by a β-hydride elimination/baseassisted H−X elimination sequence to give the final coupling product. The substituents on the olefin as well as the nature of the ligand influence the formation of linear vs branched or mixed products. In addition, cis and trans isomerized products can also be formed. Since the original discoveries of these reactions, there have been significant developments in the area in terms of better understanding the reaction mechanism in which the role of the ligand is identified to be important. The electronic and steric nature of the ligand (L), and the coordination number of Pd Received: February 1, 2012 Revised: March 13, 2012 Published: April 18, 2012 1147
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Scheme 1. General Mechanism of Cross-Coupling Reactions
Figure 1. Electron-rich, bulky ligands used in palladium-catalyzed coupling reactions.
significantly influence the two most important steps: namely, oxidative addition and reductive elimination (Scheme 1).16 Until the mid-1990s, PPh3 was the most widely used ligand for palladium-catalyzed coupling reactions, in which the substrates were mostly aryl iodides and aryl bromides. The low reactivity of more challenging substrates, such as unactivated aryl chlorides, is often attributed to the relatively high bond dissociation energy of the C−Cl bond.17 It was hypothesized that the ligand may be modified or substituted for another one so as to facilitate the oxidative addition of aryl halide (or related substrates) onto Pd(0), a critical ratedetermining step in the palladium-catalyzed coupling reactions. Fu’s pioneering report in 1998 on the use of sterically hindered, electron-rich trialkylphosphine ligands such as P(t-Bu)3 and PCy3 demonstrated the possibility of using less reactive organic chlorides as coupling partners in palladium-catalyzed crosscoupling reactions,18,19 although Osborn commented about the importance of the basicity (pKa) and steric bulkiness (cone angle) as early as in 1989 for carbonylation reactions of aryl halides.20 Koie has also described the application of Pd/P(tBu)3 in a C−N bond-forming reaction of an unactivated aryl chloride.21 The utilization of such ligand systems, when combined with palladium, can facilitate C−C bond formation of more challenging substrates; for example, aryl chlorides, under milder reaction conditions.19 Figure 1 illustrates the results of some of the most notable efforts toward the development of highly active ligands for use in cross-coupling reactions during the past decade.22 Among the front runners within the field of ligand development are Buchwald and co-workers, who developed a family of biaryl dialkylphosphine ligands that has expanded the scope of C−N and C−C couplings of aryl chlorides.23−27 Hartwig and coworkers discovered pentaphenylferrocenyl di-tert-butylphosphine ligand (Q-Phos) as a powerful ligand in Pd catalyzed cross-coupling reactions28 such as α-arylations of ketones,29 esters, amides,30 and even aldehydes,31 in addition to C−N/O bond forming reactions.32 Beller’s group developed phosphines containing a bulky adamantyl group that are active for various C−C/N bond-forming reactions and carbonylation reactions,33,34 while Nolan et al. have reported catalysts based on hindered N-heterocyclic carbene ligands, which can catalyze a wide variety of cross-coupling reactions.35,36 Herrmann has also reported some noteworthy results using NHC ligands.37 Generally, great progress has been made on the use of aryl chlorides in most types of cross coupling reactions, such as Buchwald−Hartwig amination,21,38 Heck coupling,39,40 α-
arylation of ketones,29 C−O bond formation,41,42 and Stille reactions.43 Despite those significant developments, most of the catalyst systems described above are formed in situ by mixing a palladium precursor, such as Pd(dba)2 or Pd(OAc)2, with a ligand; however, the dba ligand has been reported to significantly retard the activity of the catalyst when Pd(dba)x is used (x = 1.5−2).44,45 Although Pd(OAc)2 and Pd(dba)x are readily available Pd precursors, their purities vary significantly, depending on their preparation and supplier. In addition, from a practical point of view, many of the highly active electron-rich monophosphine ligands are air-sensitive and in some cases even pyrophoric (e.g., P(t-Bu)3), which results in further complications, particularly during the scale-up of a cross-coupling reaction. In addition, depending on the way a Pd precursor is mixed with a ligand, different catalytic species may be formed, which can adversely affect the activity and selectivity of the specific coupling reaction. This problem was not anticipated in the beginning of the cross-coupling era, but was identified and highlighted only in the last 5−10 years.
2. THE DEVELOPMENT OF PREFORMED CATALYSTS For the above reasons, during the past decade, there has been a significant effort in developing “well-defined” preformed complexes. In addition to the pivotal role of the ligands, the nature of the Pd complex (1) can also impact in a significant way the activity and selectivity of a cross-coupling reaction. The size of the ligand can influence the coordination number of Pd, depending on how the complex is engineered.
The Pd complex 1 is the pictorial representation of the catalyst. The steric and electronic properties of ligand L; the number, n, of L; the oxidation state of Pd (2+, 1+, 0); and even the nature of the spectator ion X (halide, allyl, etc.) can be varied readily and independently to engineer a catalyst for a suitable coupling reaction. This permits the fine-tuning of the catalytic species to have the desired properties to enhance the different steps in a catalytic cycle. The Holy Grail in crosscoupling methodology is the development of a “universal 1148
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coupling partner (Br or I vs Cl). A chemist who decides which catalyst to be used in a reaction should think of the overall cost of the process, rather than the upfront price of the catalyst. 2.2. Second-Generation Preformed Pd Catalysts. When the development of processes employing electron-rich alkyl phosphines as ligands was pioneered by Fu and Koie, a natural succession was for research groups around the world to prepare preformed palladium complexes incorporating this new type of ligand. Possibly, one driving force behind this was that the use of these air-sensitive, often pyrophoric, ligands in industrial processes would be highly problematic. If one could find a way of getting around this problem by employing a preformed Pd catalyst, in which the Pd−PR3 bond was already in place, the use of the less reactive but more widely available organic chloride substrates could be made possible, even at a larger scale. The earliest examples of cross-coupling reactions involving organic chlorides employed the trialkylphosphine ligands, such as P(t-Bu)3 or PCy3 followed by, to some extent, JohnPhos (Buchwald’s early generation) and NHCs (Figure 1). These were also the ligands to be first incorporated in the second generation preformed palladium catalysts. Beller and Herrmann reported in 1995 the synthesis of a preformed thermally robust palladacycle dimer catalyst 2 and demonstrated its application in coupling chloroarene substrates in Heck, Suzuki, and even in amination reactions (Figure 2).57−59 This palladacycle was synthesized by combining
catalyst” that can achieve equally high conversions, regardless of the nature of coupling partners. This would be an extremely difficult feat to achieve, as there are still questions regarding many of the steps or pathways in the various catalytic cycles, despite ongoing active research in this area. Nonetheless, incremental steps have been taken to develop more robust and reproducible catalytic systems for specific reactions. In this review, our focus is to highlight the development and use of preformed Pd catalysts with the aim of improving the activity and selectivity of a particular reaction in comparison to the catalysts used in situ. 2.1. First Generation of Preformed Pd Catalysts. As early as in 1979, Kumada observed that the appropriate choice of ligand can have a profound influence on the outcome of a cross-coupling reaction.46,47 The use of PdCl2(dppf) expanded the substrate scope of Kumada reactions to include the previously problematic alkyl Grignard reagents (Table 1). Table 1. Kumada Coupling of Secondary Alkyl Magnesium Chlorides with Aryl Bromides Showing the Importance of a Bidentate Ligand with Larger Bite Angle
entry
catalyst
time (h)
bite angle (°)
sec-BuPh (%)
n-BuPh (%)
1 2 3 4 5
(PPh3)2PdCl2 dppePdCl2 dpppPdCl2 dppbPdCl2 dppfPdCl2
24 48 24 8 1
n/a 85.8 90.6 94.5 99.1
5 0 43 51 95
6 0 19 25 2
This study highlights the dramatic positive effect of a bidentate ferrocenyl phosphine ligand48 with a relatively large bite angle in catalysis (entry 5). The larger P−Pd−P angle (bite angle) is correlated in the above case to accelerate the reductive elimination of the coupled product after the transmetalation step, rather than allowing the alkyl moiety to sit on the Pd long enough to facilitate β-hydride elimination, which leads to destructive pathways such as the isomerization of s-butyl- to nbutyl-based product via the recoordination of the eliminated olefin to Pd.46 There are also a number of early examples in which the preformed Pd(II) catalyst PdCl2(PPh3)249 or the Pd(0) complex Pd(PPh3)450,51 has been used as catalyst of choice. Although they do alleviate the problems associated with potentially deleterious Pd species formed in situ, they contain the less active PPh3 ligand; therefore, it is necessary to limit the substrate scope to aryl iodides and activated aryl bromides. This does not mean that these catalysts are obsolete. On the contrary, all three aforementioned catalysts are still very commonly used in large-scale processes,52−56 mainly because of their relatively lower cost in comparison with the lately developed more advanced catalysts. Many factors can affect the choice of a catalyst; however, in a somewhat simplified argument, the lower cost of these less active catalysts needs to be weighed against the required use of a more expensive
Figure 2. Early examples of preformed Pd catalysts.
Pd(OAc)2 with P(o-tol)3, which slowly decomposes in air when stored as the free ligand. Five years later, in 2000, Beller demonstrated the preparation and isolation of the first Pd(0) monophosphine complexes 4−5 and their performance in the Suzuki coupling of aryl chlorides. These precatalysts contained electron-rich, air-sensitive phosphine ligands such as PCy3 and 2-biphenyl-PCy2. Notably, it was observed that the use of welldefined preformed catalyst 4 resulted in superior results in comparison with the use of in situ-formed catalysts Pd2(dba)3 or Pd(OAc)2/PCy3 (Table 2). Concurrently, Herrmann reported the first synthesis of a preformed Pd(0) dicarbene complex 3 (Figure 2).37 He observed, however, a 25% decrease in the product yield in a Suzuki coupling when employing the preformed catalyst as opposed to the in situ formed one. Nevertheless, this seminal work by Herrmann and Beller constitutes the beginning of the development of a second generation of preformed Pd catalysts. 1149
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Table 2. Beller’s Preformed Catalyst 4 in Suzuki Reactions
a
entry
catalyst
yield (%)a
1 2 3 4
Pd2(dba)3/PCy3 (1:1) Pd(OAc)2/PCy3 (1:1) Pd(OAc)2/PCy3 (1:2) 4
8 11 28 79
Scheme 2. Negishi Coupling Using Aryl Chlorides
Determined by GC with hexadecane as internal standard.
3. PREFORMED CATALYSTS CONTAINING TERTIARY PHOSPHINE LIGANDS As described in the introduction, until the mid-1990s, the less active triarylphosphine PPh3 and, to some extent, P(o-tol)3 were the ligands of choice for use in cross-coupling reactions. This restricted the substrate scope to the use of aryl iodides and activated aryl bromides. Fu, among others, pioneered the use of highly active trialkylphosphines in the more challenging crosscoupling reactions of organic chlorides. At the expense of the higher activity came the air-sensitive, often pyrophoric, properties of the required ligands, which greatly complicated the practical aspects of carrying out the reactions in a safe manner, particularly on large scale. This section will focus on the efforts and advances made to prepare stable preformed catalysts containing these highly active tertiary phosphine ligands. Examples will be highlighted to demonstrate that quite often the activities of the precatalysts are superior to that of the in situ generated catalysts from a Pd precursor and the free ligand. The preformed catalysts containing tertiary phosphine ligands can be categorized in two groups, depending on the nature of the proposed catalytically active Pd(0) species: L2Pd(0) and LPd(0). The L2Pd(0) catalysts can be prepared and isolated, but are moderately air-sensitive, as in the case of the well-known Pd(PPh3)4, and do not require activation in situ to form the catalytically active Pd(0) species. They can also be generated in situ in the reaction mixture from L2Pd(II)X2 precatalysts. The LPd(0) catalysts have not been isolated, but are generated in situ from the preformed Pd catalysts, such as Pd(I) dimers, (LPdX)2; Pd(II) dimers, (LPd(II)X2)2; and palladacycles. 3.1. L2Pd(0) Catalysts. Having established that Pd2(dba)3/ P(t-Bu)3 was a viable catalytic system for the Negishi coupling of 4-chloroanisole, Fu continued to investigate use of the preformed Pd(0) catalyst Pd[P(t-Bu)3]2 to understand the substrate scope for a wide range of aryl and heteroaryl chlorides with aryl and alkyl zinc reagents (Scheme 2).60 Hartwig also investigated preformed Pd[P(t-Bu)3]2 in amination reactions and observed a significant increase in activity when the precatalyst was used in comparison with the in situ generation of the catalyst from Pd(dba)2 and P(t-Bu)3 (Table 3).61 Notably, in this case, a 1:2 metal-to-ligand ratio provided results superior to a 1:1 Pd-to-ligand ratio. Generally, this is not a universally true observation, as Hartwig has demonstrated that at room temperature, a 1:0.8 Pd-to-ligand ratio has provided significantly higher activity than that of a 1:2 ratio.38 Fu also observed a similar trend in Suzuki couplings at room temperature. Use of a 1:1 ratio of P(t-Bu)3 to Pd furnishes a very active catalyst, whereas a 2:1 ratio leads to a very slow
Table 3. Amination Using Pd[P(t-Bu)3]2 vs in Situ
a
entry
catalyst
yield (%)a
1 2
Pd(dba)2/P(t-Bu)3 1:1 Pd[P(t-Bu)3]2
