Metal Catalyzed Cross-Coupling Reactions and More
By Stefan Bräse
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Metal Catalyzed Cross-Coupling Reactions and More - Armin de Meijere
The Editors
Armin de Meijere
Institut für Organische und Biomolekulare Chemie
der Georg-August-Universität
Tammannstr. 2
37077 Göttingen
Germany
Stefan Bräse
Institute of Organic Chemistry &
Institute of Toxicology and Genetics Karlsruhe Institute of Technology
Fritz-Haber-Weg 6
76131 Karlsruhe
Germany
Martin Oestreich
Institut für Chemie
Technische Universität Berlin
Strasse des 17. Juni 115
10623 Berlin
Germany
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Preface
As a quick survey of the chemical literature in the last 30 years discloses, research in the area of Organometallic Chemistry is more productive than ever, and new metal-catalyzed carbon–carbon as well as carbon–heteroatom bond-forming reactions constitute a major fraction of it. This was underscored again by the recent 17th Symposium on Organometallic Chemistry Towards Organic Synthesis (OMCOS 17)
held in Fort Collins, Colorado, USA, at which 6 out of 8 Plenary, 6 out of 12 Invited and 7 out of 12 Short lectures as well as 101 out of 347 Posters dealt with Metal-Catalyzed Cross-Coupling Reactions
in the broader sense. This series of conferences, which was initiated by Louis S. Hegedus and John K. Stille in 1981 with the first of its kind in Fort Collins, has been ever since growing in attendance record and visibility. The fact that the Nobel Prize in Chemistry was awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki in 2010 for their seminal work on such cross-coupling reactions, emphasized the necessity for producing an up-to-date monograph on this topic, after the first one came out in 1998 followed by a second completely revised and enlarged edition in 2004. As this field has grown so much and keeps growing further, the editors in consent with the Wiley-VCH publisher decided to bring out a new book under the title Metal-Catalyzed Cross-Coupling Reactions and More
to express the fact that the recent development brings forward more and more sequential reactions incorporating cross-couplings as one of the steps and that C–H bond activation has started to play a major role. The latter type of reaction certainly is not a cross-coupling in the original definition, but the outcome is the same. Accordingly, five new chapters have been incorporated in the new book, while one of the previous chapters has been dropped for lack of progress in the area. For reasons of comprehensiveness, two chapters have simply been reprinted, as other comprehensive and up–to–date reviews on the corresponding topics have recently been published in other contexts. All of the remaining 12 chapters have been updated or completely rewritten with a focus on new developments during the last 10 years. All in all, this three-volume monograph is meant to provide a useful and rather complete overlook of the particular area of Organometallic Chemistry.
It is due to all of the engaged authors that this book came into being, and the editors wish to express their sincere thanks for all the efforts by the authors as well as the team at Wiley-VCH.
Göttingen, Karlsruhe and Berlin
September 2013
Armin de Meijere
Stefan Bräse
Martin Oestreich
List of Contributors
Eric J.-G. Anctil
Champlain – St.Lawrence College
Chemistry Department
790, Nérée-Tremblay
Québec G1V 4K2
Canada
Jan-Erling Bäckvall
Stockholm University
Department of Organic Chemistry
Arrhenius Laboratory
10691 Stockholm
Sweden
Olivier Baudoin
Université Claude Bernard
Lyon 1, CNRS UMR 5246
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CPE Lyon
43 Boulevard du 11
Novembre 1918
69622 Villeurbanne
France
Stefan Bräse
Institute of Organic Chemistry Institute of Toxicology and Genetics, Karlsruhe Institute of Technology
Fritz-Haber-Weg 6
76131 Karlsruhe
Germany
Anton Bayer
Saarland University
Institute for Organic Chemistry
Campus C4.2
66123 Saarbrücken
Germany
Fabrice Chemla
Université Pierre et Marie Curie Paris 6
UMR CNRS 7201 – Institut Parisien de Chimie Moléculaire
(FR 2769), Case 183
4 Place Jussieu
75252 Paris Cedex 5
France
Scott E. Denmark
Department of Chemistry
University of Illinois
600 South Mathews Avenue
Urbana, IL 61801
USA
Antonio M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16
43007 Tarragona
Spain
Franck Ferreira
Université Pierre et Marie Curie Paris 6
UMR CNRS 7201 – Institut Parisien de Chimie Moléculaire
(FR 2769), Case 183
4 Place Jussieu
75252 Paris Cedex 5
France
Dennis G. Hall
University of Alberta
Department of Chemistry
11227 Saskatchewan Drive
4-010 Centennial Centre for Interdisciplinary Science
Edmonton, Alberta T6G 2G2
Canada
Anna Homs
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16
43007 Tarragona
Spain
Kenichiro Itami
Nagoya University
Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science
Chikusa, Nagoya 464-8602
Japan
Olivier Jackowski
Université Pierre et Marie Curie Paris 6
UMR CNRS 7201 – Institut Parisien de Chimie Moléculaire
(FR 2769), Case 183
4 Place Jussieu
75252 Paris Cedex 5
France
Rodolphe Jazzar
Université Claude Bernard
Lyon 1, CNRS UMR 5246
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CPE Lyon
43 Boulevard du 11
Novembre 1918
69622 Villeurbanne
France
Ludivine Jean-Gérard
Université Claude Bernard
Lyon 1, CNRS UMR 5246
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CPE Lyon
43 Boulevard du 11
Novembre 1918
69622 Villeurbanne
France
Hirofumi Kamada
Purdue University
Brown Laboratory of Chemistry
560 Oval Drive
West Lafayette, IN 47907-2084
USA
Uli Kazmaier
Saarland University
Institute for Organic Chemistry
Campus C4.2
66123 Saarbrücken
Germany
Eun Hoo Kim
Purdue University
Brown Laboratory of Chemistry
560 Oval Drive
West Lafayette, IN 47907-2084
USA
Milan Kivala
University of Erlangen-Nürnberg
Department of Chemistry and Pharmacy
Chair of Organic Chemistry I
Henkestrasse 42
91054 Erlangen
Germany
Jack C.H. Lee
University of Alberta
Department of Chemistry
11227 Saskatchewan Drive
4-010 Centennial Centre for Interdisciplinary Science
Edmonton, Alberta T6G 2G2
Canada
Ilan Marek
Technion – Israel Institute of Technology
Schulich Faculty of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry
Haifa 32000
Israel
Claudio Martínez
Institute of Chemical Research of Catalonia (ICIQ)
16 Avgda. Paisos Catalans
43007 Tarragona
Spain
Belén Martín-Matute
Stockholm University
Department of Organic Chemistry
Svante Arrhenius väg 16 C
10691 Stockholm
Sweden
Armin de Meijere
Georg-August-Universität Göttingen
Institut für Organische und Biomolekulare Chemie
Tammannstrasse 2
37077 Göttingen
Germany
Laurent Micouin
UMR CNRS 8601 - Laboratoire de
Chimie et Biochimie Pharmacologiques et Toxicologiques
45, Rue des Saints-Pères
75006 Paris
France
Yury Minko
Technion – Israel Institute of Technology
Schulich Faculty of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry
Haifa 32000
Israel
Terence N. Mitchell
Technische Universität Dortmund, Organische Chemie
Otto-Hahn-Str. 6
44227 Dortmund
Germany
Masahiro Miura
Osaka University
Department of Applied Chemistry
Faculty of Engineering
2-1 Yamadaoka Suita
Osaka 565-0871
Japan
Kilian Muñiz
Institute of Chemical Research of Catalonia (ICIQ)
16 Avgda. Paisos Catalans
43007 Tarragona
Spain
and
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluís Companys 23
08010 Barcelona
Spain
Ei-ichi Negishi
Purdue University
Brown Laboratory of Chemistry
560 Oval Drive
West Lafayette, IN 47907-2084
USA
Akimichi Oda
Purdue University
Brown Laboratory of Chemistry
560 Oval Drive
West Lafayette, IN 47907-2084
USA
Jan Paradies
Karlsruhe Institute of Technology (KIT)
Institute of Organic Chemistry
Fritz-Haber-Weg 6
76131 Karlsruhe
Germany
Alejandro Perez-Luna
Université Pierre et Marie Curie Paris 6
UMR CNRS 7201 - Institut Parisien de Chimie Moléculaire
(FR 2769), Case 183
4 Place Jussieu
75252 Paris Cedex 5
France
and
UMR 8601 CNRS-Paris Descartes
Laboratoire de Chimie et de Biochimie pharmacologiques
et toxicologiques 45
rue des Saints Pères
75006 Paris
France
Tetsuya Satoh
Osaka University
Department of Applied Chemistry
Faculty of Engineering
2-1 Yamadaoka Suita
Osaka 565-0871
Japan
Laurel L. Schafer
University of British Columbia
Department of Chemistry
2036 Main Mall
Vancouver, BC V6T 1Z1
Canada
Tobias A. Schaub
University of Erlangen-Nürnberg
Department of Chemistry and Pharmacy
Chair of Organic Chemistry I
Henkestrasse 42
91054 Erlangen
Germany
Victor Snieckus
Queen's University
Department of Chemistry
90 Bader Lane
Kingston, ON K7L 3N6
Canada
Ramzi F. Sweis
AbbVie Laboratories
100 Abbott Park Road
R4CP AP52-1178
Abbott Park IL 60064
USA
Kálmán J. Szabó
Stockholm University
Department of Organic Chemistry
Svante Arrhenius väg 16 C
10691 Stockholm
Sweden
Shiqing Xu
Purdue University
Brown Laboratory of Chemistry
560 Oval Drive
West Lafayette, IN 47907-2084
USA
Junichiro Yamaguchi
Nagoya University
Department of Chemistry
Graduate School of Science
Chikusa-ku, Nagoya 464-8602
Japan
Jacky C.-H. Yim
University of British Columbia
Department of Chemistry
2036 Main Mall
Vancouver, BC V6T 1Z1
Canada
Neal Yonson
University of British Columbia
Department of Chemistry
2036 Main Mall
Vancouver, BC V6T 1Z1
Canada
Volume 1
Chapter 1
Mechanistic Aspects of Metal-Catalyzed C,C- and C,X-Bond Forming Reactions
Antonio M. Echavarren and Anna Homs
1.1 Mechanisms of Cross-Coupling Reactions
Cross-coupling reactions comprise a group of transformations for the formation of C–C bonds based on the transmetallation of nucleophilic organometallic compounds with organic electrophiles in the presence of late-transition metals as catalysts [1]. In most cases, cross-coupling reactions are based on palladium(0) catalysis [2–7], although nickel catalysts were actually involved in the initial discovery of cross-coupling methods by Kumada et al. [8] and are currently receiving renewed attention [9]. These transformations were later extended to the use of heteronucleophiles, such as amines, alcohols, and thiols, for the formation of C-X bonds.
The first palladium-catalyzed cross-coupling reactions of organostannanes were reported in the 1976–1978 period by the groups of Eaborn [10], Kosugi et al. [11], and Stille [12]. This transformation is usually known as the Stille coupling [13–17] and, together with the Suzuki–Miyaura cross-coupling of organoboron compounds [18–21], has been established as the most general and selective palladium-catalyzed cross-coupling reaction [1, 22–24] (Scheme 1.1). Synthetically, the Stille reaction takes prevalence over the Suzuki–Miyaura coupling in substrates bearing a stannane and a boronic ester as reactive sites [25]. Mechanistically, these reactions are closely related to other transmetallation-based cross-couplings of organometallic nucleophiles [26] such as the Negishi [27, 28], Hiyama [29, 30], Sonogashira [31, 32], Kumada (or Kumada–Corriu), and other related couplings [33–36].
Scheme 1.1 Representative palladium-catalyzed cross-coupling reactions.
c01scy001The first thorough mechanistic studies centered on the Stille reaction [13, 14]. Although some important differences exist between this reaction and related cross-couplings, the main mechanistic conclusions that arose from work done on this reaction pertain to other related cross-couplings proceeding through Pd(0)/Pd(II) catalytic cycles. Although nickel, copper, iron, cobalt, and occasionally platinum have also been used as catalysts for cross-coupling processes, most of the detailed mechanistic studies concern palladium chemistry. Cross-coupling reactions share important mechanistic details with the Heck alkenylation of organic electrophiles [37, 38]. Indeed, the 2009 Nobel Prize for chemistry recognized both the Heck and cross-coupling reactions as the most important contributions from palladium organometallic chemistry inorganic synthesis [39].
In this chapter, we update our previous review on this topic [22], centering most of the discussion on palladium-catalyzed transformations, although the most significant mechanistic aspects of other cross-couplings are also included. To keep the length of the review within reasonable limits, the coverage is not exhaustive, although key references are provided for all important aspects. The mechanism of the palladium-catalyzed direct arylation of arenes, which is a practical alternative to cross-coupling methods for the formation of biaryls [40–51], is not covered in this review.
1.1.1 The Earlier Mechanistic Proposal: The Stille Reaction
The extensive synthetic and mechanistic work carried out by Stille [12, 13] established this reaction as a mature synthetic method for organic synthesis [40, 52, 53]. In the first comprehensive mechanistic proposal, a [PdL2] (L = PPh3) complex was proposed to react with the organic electrophile R-X to form complex 1 (Scheme 1.2). Complex 1 was the only observable species in the catalytic cycle, even in the presence of excess organostannane, which demonstrated that the slow step is the transmetallation reaction with the organostannane. This transmetallation was believed to give rise directly to the Pd(II) complex 2. Then, a trans-to-cis isomerization would give complex 3, from which the reductive elimination immediately ensued to afford the final coupling product R–R′.
Scheme 1.2 The original proposal for the mechanism of the Stille reaction.
c01scy002This mechanistic interpretation of the Stille reaction has been the base for the formulation of the mechanisms of other cross-coupling reactions. Model studies on the coupling of alkynes with vinyl triflates with [Pt(PPh3)4] were in overall agreement with that proposal [54], although involvement of cationic complexes in the transmetallation step was strongly suggested by this work. Farina [55] and Brown [56] also found that the intermediates formed upon oxidative addition of organic triflates to Pd(0) are cationic complexes such as [PdR¹(S)L2]+ and [PdR¹L3]+.
Although these studies shed light on the transmetallation step, this transformation was initially mechanistically obscure. Thus, for example, either inversion [57] or retention [58] of the configuration of alkylstannanes has been found. Inversion has also been observed in other processes as a result of an SN2 oxidative addition process [59, 60]. In addition, theoretical studies and experimental results were in contradiction with several aspects of the mechanistic model of Scheme 1.2. In effect, intermediates of the type trans-[PdR¹R²L2] (2) [61] might be expected to be quite long-lived, as trans-to-cis isomerizations in this type of complexes are not facile processes [62–64].
1.1.2 The Oxidative Addition
The oxidative addition of organic electrophiles (halides, sulfonates, and related activated compounds) to palladium(0) is the first step in the cross-coupling and Heck reactions. Much work has been done on the mechanisms of the oxidative addition reactions of aryl and alkenyl halides and triflates (C(sp²)-X electrophiles) [65], the most common organic electrophiles in cross-coupling reactions.
The oxidative addition of C(sp³)-X electrophiles to Pd(0) complexes PdL4 (L = phosphine) takes place usually by an associative bimolecular process (SN2 reaction). The anion then adds to the metal to give the product. However, the reaction of allylic electrophiles is more complex, because, in addition, SN2′ substitutions are conceivable pathways. The coupling of the trans-configurated allylic chloride 4 with PhSnBu3 proceeded with overall retention of configuration when the reaction was performed in benzene with a Pd(0) complex made in situ from [Pd(η³-C3H5)Cl] and maleic anhydride, while clean inversion was observed in polar, coordinating solvents (Scheme 1.3) [66]. The observed configuration is a consequence of the oxidative addition step. This reaction proceeds with complete or predominant retention in noncoordinating solvents [66, 67], which is in agreement with theoretical studies on the oxidative addition of CH3X to Pd(0) [68]. On the other hand, in coordinating solvents such as MeCN or DMSO, complete or nearly complete inversion was observed [66]. Syn oxidative addition has also been observed in related substrates [69]. However, the usual inversion of configuration in the oxidative addition was observed with [Pd(PPh3)4, 66, 70].
Scheme 1.3 Retention or inversion of configuration in the oxidative addition as a function of solvent polarity.
c01scy003Allylic fluorides react with sodium dimethyl malonate (the Tsuji–Trost reaction) to form initially tight ion pairs [71]. Interestingly, the reaction does not follow the normal double-inversion mechanism, which has been explained by the competitive reaction of the intermediate ion pair with neutral [PdL2].
An earlier study on the mechanism of the oxidative addition of aryl iodides to [PdL2] was consistent with an aromatic nucleophilic substitution [72]. Accordingly, electron-withdrawing substituents on aryl electrophiles lead to rate acceleration [73, 74]. In general, increasing the bite angle of bidentate ligands leads to a decrease in the rate of the oxidative addition [74, 75]. However, the opposite effect has also been observed [76], although in this case ligands of very different basicity were considered [77].
Contrary to the general thought that palladium-catalyzed couplings of alkenyl halides are always stereoretentive; the Suzuki–Miyaura coupling of (Z)-alkenyl halides with boronic acids can give significant amounts of coupled products with (E)-configuration [78]. The best stereoretention was achieved with [Pd(P(o-Tol)3)2] as the catalyst.
1.1.2.1 Cis-Complexes in the Oxidative Addition
The intermediates that are usually observed after the oxidative addition are trans-[PdRXL2] complexes (2, Scheme 1.2), an observation which has led to the general proposal that these complexes are the primary products of the reaction. However, the oxidative addition for the most common C(sp²)-X electrophiles proceeds by a concerted interaction of a reactive [PdL2] or [Pd(L-L)] (L-L = diphosphine) species with the substrate R-X via a three-center transition state that should necessarily lead to cis-[PdRXL2] complexes (Scheme 1.4). In the cis-isomers, a destabilizing interaction exists between the mutually trans-positioned phosphorus donor and aryl ligands [79]. Therefore, in the case of complexes with monodentate phosphines, the initially formed cis-[PdRXL2] (5) complexes undergo isomerization to form the more stable trans-[PdRXL2] complexes [80]. Such isomerization is obviously not possible for complexes 6 with cis-coordinating bidentate phosphines.
Scheme 1.4 Oxidative additions of C(sp²)-X electrophiles to Pd(0).
c01scy004The isomerization process was analyzed in detail by the group of Espinet [81] in the case of complex 7, formed by the oxidative addition of C6Cl2F3I to [Pd(PPh3)]4 (Scheme 1.5). The isomerization of cis-7 to trans-8 is a rather complex process that can take place by four major competitive pathways. Two of these pathways involve associative replacements of PPh3 by an iodide ligand of a second palladium complex. Two additional routes involve two consecutive Berry pseudorotations on pentacoordinated species formed by coordination of the solvent tetrahydrofuran (THF) [81].
Scheme 1.5 Cis-to-trans isomerization of a primary oxidative addition product.
c01scy0051.1.2.2 The Role of Alkene and Anionic Ligands
The complex [Pd2(dba)3·S] (dba, dibenzylideneacetone; S = dba or solvent molecule)¹ [82] has been used as a source of Pd(0) in many palladium-catalyzed reactions [23]. Early work by Roundhill [83], and subsequent detailed studies by Amatore and Jutand [76, 84–86], established that the dba ligands are not completely substituted in the reactions of [Pd2(dba)3·S] with phosphines under mild conditions. With PPh3, mixtures of [Pd(PPh3)3] in equilibrium with [Pd(dba)(PPh3)2] are formed (Scheme 1.6) [83, 87]. As a result, starting from [Pd2(dba)3] and 2 equiv. of PPh3, the oxidative addition of PhI proceeds at an overall rate that is about 10 times less than that starting from [Pd(PPh3)4]. Similar equilibria were found for other ligands [88, 89].
Scheme 1.6 Equilibrium resulting from [Pd2(dba)3·S] and PPh3.
c01scy006The double bond of certain sterically encumbered alkenylstannanes can undergo insertion into the oxidative addition intermediates leading to products of cine substitution (Scheme 1.7) [90]. Mechanistic studies suggest the involvement of palladium carbenes 10 as intermediates, which are formed by evolution of intermediates 9 [90c,d].
Scheme 1.7 Insertion of the double bond of alkenylstannanes into the oxidative addition intermediates.
c01scy007Anionic ligands play a very significant role in oxidative and transmetallation addition reactions [91, 92]. Thus, for example, Amatore and Jutand [93, 94] concluded that in the presence of acetate, the tricoordinated anionic species [PdL2(OAc)]− are the effective complexes in oxidative addition [94], instead of the usually postulated neutral [PdL2] complex. In the presence of halide anions, anionic complexes are also formed [95–97]. In general, the following order of stabilization of the anionic Pd(0) species is observed: I− > Br− > Cl− [98].
1.1.2.3 Cross-Couplings in the Presence of Bulky Phosphines
It may be risky to raise mechanistic conclusions on qualitative observations regarding rate accelerations upon changes on any reaction variable in complex catalytic processes such as cross-coupling reactions. Nevertheless, some interesting hints can be obtained from work aimed at developing new conditions for the coupling of the less reactive organic substrates such as aryl chlorides [99, 100] and alkyl electrophiles [101].
Aryl chlorides react more sluggishly in cross-coupling reactions than bromides, iodides, and triflates because of their aversion toward oxidative addition to Pd(0) [102]. Initially, the focus was on the development of sterically encumbered, chelating ligands to activate these substrates. Thus, Milstein [74, 103] reported that [Pd(dippp)2] (dippp, 1,3-bis(diisopropylphosphino)propane) was an efficient catalyst for the carbonylation, formylation, and Heck reactions of aryl chlorides. The groups of Hartwig and Buchwald also demonstrated the importance of a variety of sterically congested, chelating ferrocenyl- or biphenylphosphines in palladium-catalyzed transformations. In particular, the amination and etherification of aryl electrophiles [104], as well as the ketone and malonate arylation processes [105–108], benefit greatly from the use of this type of ligands.
Relatively simple, bulky monodentate phosphines that form [PdL] or [PdL2] complexes, promote the coupling of the less reactive substrates under relatively mild conditions [109, 110]. This accelerating effect on the oxidative addition was demonstrated in the context of the formation of (η³-allyl)palladium complexes [111]. Particularly useful for the activation of aryl chlorides are palladium complexes of the bulky phosphine P(tBu)3 [109, 112–115]. Bulkier phosphines such as (1-Ad)P(tBu)2 (Ad, adamantyl) have been used in the palladium-catalyzed arylation of malonates and cyanoesters [116]. The related bulky phosphine P(tBu)2(o-biphenyl) and many variations on this theme have been developed by Buchwald as ligands for the palladium-catalyzed reaction of amines with aryl bromides, chlorides, and triflates [117–119] and in the Suzuki–Miyaura coupling reactions [117a,120]. Bulky, monodentate phosphines are also the ligands of choice for the coupling of organotrifluoroborates [121].
Highly reactive palladium catalysts based on this type of bulky biphenylphosphines can be readily generated from phenylethylamine-derived palladacycles [122] or, even more conveniently, from biarylamine-derived precatalysts [123]. Complexes PdL2 can also be conveniently prepared in situ by the reaction of Pd(η³-1-PhC3H4)(η⁵-C5H5) with tertiary phosphines L [124].
Coordinatively, unsaturated [(1,6-diene)PdL] (L = phosphine) complexes are also efficient catalysts for the Suzuki–Miyaura coupling of aryl chlorides with phenylboronic acid [125, 126].
Fu reported that the complex [Pd(PCy3)2] (Cy, cyclohexyl), formed in situ from [Pd(OAc)2] and PCy3, catalyzes the room-temperature coupling of primary alkyl bromides that possess β-hydrogens with alkyl-BBN (BBN, 9-borabicyclo[3.3.1]nonane) [127, 128]. A similar complex, formed from [Pd2(dba)3] and PCy3 (1 : 2 ratio of Pd to phosphine), allowed couplings of primary alkyl chlorides that possess β-hydrogens with alkylboranes [129]. The complex [Pd(PCy3)2] and the related complexes with other monodentate bulky phosphines are catalysts for the Kumada coupling of alkyl chlorides [130].
For the coupling of primary alkyl tosylates, the bulkier phosphine P(tBu)2Me gave the best results [131]. As expected, the oxidative addition of an alkyl tosylate to Pd(0) results in predominant inversion of configuration, while the transmetallation occurs with retention [131]. The complex [Pd(P(tBu)2Me)2] is also a catalyst for the room-temperature coupling of primary alkyl bromides that possess β-hydrogens with boronic acids [132]. Complex 11, the oxidative addition product of an alkyl bromide to [Pd(P(tBu)2Me)2], has been isolated and structurally characterized [132] (Scheme 1.8). The Stille coupling of alkenylstannanes with alkyl bromides that possess β-hydrogens is possible at room temperature, with [Pd(P(tBu)2Me)2] as the catalyst [133]. In this case, the addition of fluoride was required to enhance the reactivity of the stannane.
Scheme 1.8 Oxidative addition of a primary alkyl bromide to the palladium complex [Pd(P(tBu)2Me)2].
c01scy008Interestingly, while with isolated [Pd(P(tBu)3)2] high temperatures are required for the activation of aryl halides in the Suzuki–Miyaura coupling [134], as well as the amination [113d] and Heck reaction [112], the complex that results from the reaction between [Pd2(dba)3·dba] and 1 equiv. of P(tBu)3 allows performing these reactions at room temperature [105d,112, 135–137]. Under these conditions, aryl chlorides are coupled in preference to aryl triflates [135]. The less bulky PCy3 could be used for the Suzuki–Miyaura reaction of aryl triflates. Related bulky phosphines also allow performing the Suzuki–Miyaura couplings under relatively mild conditions [118].
Secondary alkyl halides are a much more challenging class of electrophiles for cross-coupling reactions [138]. The use of nickel catalysts allows coupling of these substrates with organoboranes in the presence of a 1,2-diamine ligand (Scheme 1.9) [139]. Similar results have been obtained in the Negishi couplings with nickel catalysts [140].
Scheme 1.9 Cross-coupling of a secondary alkyl halide with an organoborane reagent catalyzed by NiBr2·diglyme.
c01scy009Interestingly, the use of nickel catalysts with chiral ligands allows performing the stereoconvergent Suzuki–Miyaura or Negishi cross-couplings of racemic electrophiles with organometallic nucleophiles. Thus, the stereoconvergent cross-coupling of racemic α-halonitriles has been achieved by nickel-catalyzed Negishi arylations and alkenylations (Scheme 1.10) [141]. For this reaction and the other related nickel-catalyzed Negishi, Hiyama, and Suzuki–Miyaura reactions of unactivated secondary alkyl halides, radical intermediates may be involved [140, 142–144].
Scheme 1.10 Ni-catalyzed stereoconvergent reaction of a racemic α-halonitrile.
c01scy010All the experimental evidence points to the involvement of Ni(I)–Ni(III) catalytic cycles in Ni-catalyzed Kumada-type and related couplings [144a,b,c –146]. A theoretical study on the Ni-catalyzed cross-coupling of unactivated secondary alkyl halides with alkylboranes confirms that the reaction proceeds through a catalytic cycle involving a Ni(I)–Ni(III) transformation [144c]. This catalytic cycle involves a rate-determining transmetallation of [Ni(L)Br] with K[B(Me)2(Et)(OiBu)] to form [Ni(L)Et], followed by the oxidative addition of iPrBr with [Ni(L)Et] by bromine abstraction and radical recombination to give [Ni(L)(iPr)(Et)Br]. The C–C reductive elimination of [Ni(L)(iPr)(Et)Br] leads to [Ni(L)Br] and the coupled product. On the other hand, the oxidative addition of tBuBr generates a tBu radical and singlet [Ni(L)(Et)Br], which equilibrates to the triplet [Ni(L)(Et)Br] through facile spin crossover, which raises significantly the overall activation barrier of the reductive elimination. This explains why tertiary halides are not reactive in the title cross-coupling [144c].
The Pd/P(tBu)3 system was also applied for the Stille reaction with aryl electrophiles using CsF as the activator for the stannane [147]. Mechanistic work suggested that a palladium monophosphine complex [PdL] is the active catalyst in the cross-coupling of aryl halides [135, 136]. Accordingly, Hartwig [147–149] proposed that the oxidative addition of an aryl bromide to the complex [Pd(P(o-Tol)3)2] involved prior dissociation of a phosphine ligand giving a 12e-complex [Pd(P(o-Tol)3)] (Scheme 1.11). Addition of a second equivalent of ligand then leads to the dimeric complexes. This process involves the dissociative ligand substitution and cleavage to the monomers, before the reductive elimination [150].
Scheme 1.11 Oxidative addition from [PdL2] complexes with very bulky monodentate phosphines.
c01scy011Brown et al. [151] reported that [Pd(PCy3)2] reacts with PhOTf according to an associative mechanism. Reaction of PhI with [Pd(PCy3)2] or [Pd(PCy2(tBu))2] also proceeded associatively. In contrast, complexes [Pd(P(tBu)3)2] or [Pd(PCy(tBu))2] with bulkier phosphines behaved like [Pd(P(o-Tol)3)2].
Hartwig [152] also reported the isolation of formally tricoordinated, T-shaped, Pd(II) complexes 12 in the oxidative addition of ArX to [PdL2] or [Pd(dba)L], bearing very bulky phosphines (Scheme 1.12). Two of these complexes 12a,b showed agostic interactions with C–H bonds of the phosphine resembling distorted square-planar Pd(II) complexes. A related platinum complex shows a seemingly three-coordinate Pt(II) core [153], although the metal is actually stabilized by an agostic interaction with one of the methyl groups of the phosphine ligand.
Scheme 1.12 Formation of tricoordinated Pd(II) complexes from [PdL2] with very bulky monodentate phosphines.
c01scy012The Suzuki–Miyaura cross-coupling of 4-chlorophenyl triflate led regioselectively to different products using PCy3 or PtBu3 as the ligands for Pd(0) (Scheme 1.13) [135, 151, 152, 154, 155]. The oxidative addition of the C–Cl bond is promoted selectively by [PdP(tBu)3], formed in situ from [Pd2(dba)3] and P(tBu)3 [135], whereas reaction through the triflate occurs with [Pd(PCy3), 156]. The reason for this regiocontrol was rationalized by computation analyzing the bond dissociation energies (BDEs) [157]. On the basis of this analysis, monocoordinated palladium species preferentially react with the C–Cl bond, which is easier to distort and, therefore, would be of higher reactivity than the C–OTf bond. On the other hand, the most nucleophilic species, PdL2, reacts through a more distorted transition state with the C–OTf bond, which is the site of lowest LUMO (lowest unoccupied molecular orbital) energy.
Scheme 1.13 The Suzuki–Miyaura cross-coupling of 4-chlorophenyl triflate leading regioselectively to different products using PCy3 or PtBu3 as the ligands for Pd(0).
c01scy0134-Bromophenyl triflate reacted in the Stille coupling with vinyl tributylstannane through the Ar–Br bond in the absence of additives, whereas in the presence of LiCl, the Ar–OTf bond was selectively activated [158]. In the Kumada couplings, bulky monophosphine palladium catalysts favor the reaction of bromides over triflates, while a chelating diaryldiphosphine activates the bromide [159]. The Negishi coupling occurred at the triflate site [155]. Theoretical studies and experimental results using [Pd2(dba)3]/PtBu3 as the catalytic system and 4-chlorophenyl triflate as the substrate provided strong support of a change in the catalytically active species in polar solvents depending on the additives (Scheme 1.14) [160]. Calculations show a preference for the oxidative addition of the Ar–Cl bond to [Pd(P(tBu)3)2], although in the presence of CsF, activation of the Ar–OTf bond is observed. These results suggest that the active species under such conditions in polar solvents is [Pd(P(tBu)3)2F]− in agreement with the proposals of Amatore and Jutand of anionic palladium as the active catalytic species [91, 92], in line with conclusions by Hartwig [161].
Scheme 1.14 The Stille cross-coupling of 4-chlorophenyl triflate leading regioselectively to different products using KPF6 or CsF as additives.
c01scy014In support of the involvement of [Pd(PR3)] in the oxidative addition, Pd(I) dimers 13a,b have been found to catalyze the room-temperature amination and the Suzuki–Miyaura couplings of aryl chlorides and bromides (Scheme 1.15) [162]. These palladium dimers decompose to form the palladium dibromide [Pd(PR3)Br2] and a highly reactive Pd(0) complex [Pd(PR3), 162, 163].
Scheme 1.15 Formation of highly reactive [PdL] complexes from Pd(I) dimers.
c01scy015The highly reactive catalyst [PdPtBu3] can be generated by fast 1 : 1 micromixing of [Pd(OAc)2] and PtBu3 and can be quickly transferred to the reaction vessel using a flow system to perform the Suzuki–Miyaura couplings [164].
In the quest for coordinatively unsaturated palladium catalysts, the more radical approach uses ligandless conditions
[165, 166] following the work pioneered by Beletskaya [38b,167]. However, the mechanism of cross-coupling reactions under these conditions is not known [168].
1.1.2.3.1 Scrambling with the Phosphine
Exchange between R residues on palladium and the phosphine ligand can take place under very mild conditions (Scheme 1.16), which may lead to homocoupling [169–171]. In a study with complexes such as 14 [169], the rate was not affected by the added Ph3. However, the rearrangement of arylpalladium(II) complexes 15 was nearly completely inhibited by Ph3 [170]. The contradiction has been addressed by Novak [172], who demonstrated that the aryl–aryl interchange reaction of [PdArL2X] proceeds first through a reductive elimination to form a phosphonium salt followed by an oxidative addition of a different phosphorus–carbon bond. The interchange and phosphonium salt formation reactions alike are facilitated by the predissociation of either phosphine or iodide.
Scheme 1.16 Scrambling of alkyl/aryl iodide residues with those on the phosphine ligands.
c01scy0161.1.2.4 N-Heterocyclic Carbenes as Ligands
N-heterocyclic carbenes (NHCs) have demonstrated their utility as ligands in a variety of cross-coupling reactions [173–176]. The oxidative addition of aryl halides to [PdL2] (L = N-heterocyclic carbene) has been shown to furnish the expected trans-square-planar complexes such as 16 and 17 (Scheme 1.17) [177, 178].
Scheme 1.17 Oxidative addition products with N-heterocyclic carbenes as ligands.
c01scy017Interestingly, NHC–palladium(II) complexes 18 with unconventional pyridazine- and phthalazine-derived carbene ligands can be directly obtained by oxidative addition of pyridazinium or phthalazinium salts to [Pd(PPh3)4] (Scheme 1.18) [179].
Scheme 1.18 Oxidative addition of pyridazinium or phthalazinium salts to [Pd(PPh3)4].
c01scy018Interestingly, while selective couplings through the more reactive alkyl bromides over alkyl chlorides can be achieved by performing the Kumada couplings at low temperature [180], similar selectivities can also be obtained by playing with the solvent in the Negishi couplings [181]. Thus, using a 1 : 2 ratio of DMI to THF (DMI, dimethylimidazolidinone) and NHC-Pd complex 19 as the catalyst [182], the coupling through the bromide was carried out at room temperature, while increasing the polarity of the medium allowed performing the coupling through the chloride (Scheme 1.19). Related palladium complexes with bulkier NHC ligands allow for the selective coupling of secondary zinc reagents with aryl halides and triflates by favoring the reductive elimination that competes with the β-hydride elimination [183].
Scheme 1.19 The selective Negishi couplings through the more reactive alkyl bromide over alkyl chloride by playing with the solvent.
c01scy0191.1.2.5 Palladacycles as Catalysts
Many palladacycles have also been described as useful catalysts for cross-coupling and the related reactions [184–192]. However, strong evidence has been accumulated indicating that the palladacycles merely act as a reservoir of Pd(II), which requires reduction to Pd(0) to enter into the catalytic cycle [189, 190, 193]. Thus, in a detailed study of the Heck reaction catalyzed by palladacycles 20 and 21 (Figure 1.1), Pfaltz and Blackmond [193] concluded that the resting state of the catalyst within the catalytic cycle was a Pd(II) intermediate derived from oxidative addition, while the majority of Pd remained outside the catalytic cycle as a dimer in equilibrium with the oxidative addition species.
Figure 1.1 Palladacycles used in the Heck reaction.
c01fgy001Palladium nanoparticles and other heterogeneous catalysts are often invoked as catalysts in cross-coupling processes [194, 195]. Direct evidence in support of an oxidative-addition-promoted leaching mechanism has been recently obtained in the Suzuki–Miyaura reactions with nanoparticle catalysts, suggesting that true surface catalysis remains largely unknown with these heterogeneous catalysts [196].
1.1.2.6 Involvement of Pd(IV) in Catalytic Cycles
Formation of Pd(IV) intermediates by oxidative addition of alkyl halides to Pd(II) complexes [197, 198] and in other oxidative processes [199] is a well-known process. However, C(sp²)-X electrophiles, such as aryl halides, are much less reactive in the oxidative addition to Pd(II) complexes, and therefore, the formation of Pd(IV) species from these electrophiles is less likely. The hypothetical mechanism for the Heck reaction based on Pd(II)/Pd(IV) has been analyzed computationally [200].
Reaction of [Ph2I]OTf with Pd(II) and Pt(II) gives metal(IV) species by formal transfer of Ph+ to the metal center [201, 202]. Intramolecular oxidative additions of C–C bonds to Pt(II) to form hexacoordinated Pt(IV) complexes is also known [203].
The first direct, clear-cut experimental evidence for the formation of Pd(IV) species by oxidative addition of an aryl iodide to Pd(II) was provided by the group of Vicente [204] (Scheme 1.20). The oxidative addition occurs intramolecularly on a palladacycle 22 with a particularly electron-rich Pd(II) center to form 24 via intermediate 23. Although Pd(IV) complexes related to 24 can undergo insertion reactions with styrene and alkyl acrylates in a Heck process, the catalytic cycle involved is probably not particularly pertinent to most Heck catalytic Heck reactions [204b].
Scheme 1.20 First experimental evidence for the formation of Pd(IV) species by the oxidative addition of an aryl iodide to 22.
c01scy020A Pd(IV) intermediate has also been proposed in the Negishi coupling using the pincer-Pd(II) complex 25 as catalyst [205]. Experimental and computational results suggested that a T-shaped 14e pincer complex 26 was the key intermediate, which undergoes oxidative addition with aryl bromides to yield the pentacoordinated Pd(IV) aryl bromide complex 27 (Scheme 1.21). Subsequent transmetallation of 27 with Zn(Ar′)2 followed by reductive elimination gives the coupling products.
Scheme 1.21 Proposed pincer-Pd(II) 25 and 26 intermediates that undergo oxidative addition.
c01scy021A genuine coupling based on a group 10 M(II)/M(IV) catalysis is probably involved in the nickel-catalyzed coupling of alkyl halides and tosylates with the Grignard reagents discovered by Kambe (Scheme 1.22) [206]. A similar system has been developed for the catalytic C–C-bond-forming reaction using nonactivated alkyl fluorides by coupling of the alkyl Grignard reagents with CuCl2 or NiCl2 as the catalysts [206b]. In this system, a bis(η³-allyl)nickel(II) complex 28 formed by an oxidative dimerization of butadiene is involved in the catalytic cycle (Scheme 1.22). The oxidative addition of the alkyl halide or tosylate to the electron-rich intermediate 29 probably forms the Ni(IV) complex 30, which leads to the C–C bond formation by reductive elimination.
Scheme 1.22 Ni-catalyzed coupling of alkyl halides and tosylates with the Grignard reagents.
c01scy0221.1.2.7 Oxidative Addition of Stannanes to Pd(0)
Oxidative addition of certain stannanes to Pd(0) complexes is also possible. Thus, alkynylstannanes have been shown to react with Pd(0) complexes [207, 208]. In addition, the Pd(0)-catalyzed reaction of allylstannanes with alkynes has been found to afford allylstannylation products 31 (Scheme 1.23) [209]. A likely mechanism involves oxidative addition of the allylstannanes to Pd(0) to give (η³-allyl)palladium complexes 32 (L = alkyne) (Scheme 1.23). In this transformation, the usually nucleophilic allylstannanes behave as electrophiles. Complexes of type 32 are probably formed by transmetallation of (η³-allyl)palladium complexes with hexamethylditin [210]. An oxidative addition to form complexes 32 has been proposed in the Pd(0)-catalyzed carboxylation of allylstannanes with CO2 [211]. Although complexes 32 have not been isolated as stable species, work on the intramolecular reaction of allylstannanes with alkynes and theoretical calculations give support to the formation of these complexes by the oxidative addition of allylstannanes to Pd(0) [212].
Scheme 1.23 Allylstannylation of alkynes by oxidative addition of allylstannanes to Pd(0).
c01scy0231.1.3 The Transmetallation in the Stille Reaction
1.1.3.1 Isolation of the Transmetallation Step
The transmetallation step was studied for an intramolecular case with systems 33 (X = Br, I), which undergo oxidative addition to [Pd(PPh3)4] to give intermediate complexes that suffered transmetallation to form palladacycles 34 that do not undergo reductive elimination because of the high ring strain of the expected four-membered-ring heterocycles [213] (Scheme 1.24). The product of oxidative addition 35 was isolated presumably because the sterically demanding dppf (bis(1,1′-diphenylphosphino)ferrocene) ligand prevents the necessary alignment of the Pd–I and C–Sn bonds in the transition state of the transmetallation. However, smooth transmetallation was achieved by formation of the carbonate by reaction with Ag2CO3 to form palladacycle 36, presumably through an open transition state [213b]. Similar systems were used in a study on the transmetallation of silanes with Pd(II) [214] and stannanes with Pt(II) [215].
Scheme 1.24 Isolation of transmetallation intermediates in the Stille reaction.
c01scy024The reaction of pincer triflato complex 37 with 2-(tributylstannyl)furan allowed isolating the transmetallation product 38 as a stable compound (Scheme 1.25) [216]. Furthermore, by performing the reaction at low temperature, intermediate 39 was observed in which the furan is η²-coordinated to the palladium center.
Scheme 1.25 Isolation of a η²-furyl palladium(II) complex in a transmetallation reaction.
c01scy025In a study on the transmetallation of the bimetallic complex 40 with alkynylstannanes, a different precoordinated palladium intermediate 41 was observed, which evolved to the alkynyl-Pd(II) complex 42 (Scheme 1.26) [217, 218].
Scheme 1.26 Transmetallation intermediates in the palladium-catalyzed metal–carbon bond formation.
c01scy0261.1.3.2 Dissociative Mechanistic Proposals
It has been shown that the addition of a neutral ligand L retards the coupling [219, 220]. In addition, ligands such as trifurylphosphine [221, 222] and triphenylarsine [55, 220, 223], which are of lower donicity than PPh3, have a beneficial effect in the Stille reaction. These results have been taken as an indication that ligand dissociation is a key step in the transmetallation.
Thus, the simplified mechanism in Scheme 1.27, involving a dissociative X-for-R² substitution (X = I, Br) with preservation of the configuration at Pd, was proposed for vinyl- and arylstannanes. It was assumed that 44 cannot undergo transmetallation, probably because it is too electron rich, and ligand dissociation occurs prior to the transmetallation to form coordinatively unsaturated 45 or, more likely, 46, with a coordinated solvent molecule. The more electrophilic complex 46 would then be involved in the transmetallation with stannane to give 47, which could then afford the trans-configured complex 48.
Scheme 1.27 Mechanistic scheme for the dissociative transmetallation in the Stille reaction.
c01scy027Although the preceding interpretation has been disputed (Sections 1.1.3.3 and 1.1.3.4), a dissociative transmetallation probably takes place with complexes bearing very bulky ligands. Thus, Hartwig found that for the transmetallation of dimers [PdArBr{P(o-Tol)3}]2 49 [149], the rate depended on the square root of the concentration of dimer (Scheme 1.28). This is consistent with a dissociative mechanism, in which T-shaped monomers 50 [219] react with the organostannane, presumably through 51, to give the coupled product Ar-R.
Scheme 1.28 Transmetallation of T-shaped Pd(II) complexes with organostannanes.
c01scy0281.1.3.3 Cyclic and Open Associative Transmetallation
The proposals for a dissociative transmetallation assume that the trans configuration of complex 44 to give a trans-[PdR¹R²L2] complex 48 is preserved (Scheme 1.27). As the reductive elimination of R¹–R² is well established to occur on cis-configured derivatives, a fast isomerization of trans- to cis-[PdR¹R²L2] needs to be postulated (Scheme 1.29). An important additional problem with mechanisms based on ligand dissociation is that this type of substitution is rare for Pd(II) [224].
Scheme 1.29 Mechanism of the Stille reaction based on an open/cyclic associative transmetallation.
c01scy029Kinetic studies on the palladium-catalyzed coupling of substrates such as 1-iodo-3,5-dichlorotrifluorobenzene with vinyl- or (4-methoxyphenyl)tributyltin carried out by the group of Espinet [225–228] led to a comprehensive proposal for the mechanisms of the Stille reaction that includes both open and cyclic transmetallation steps (Scheme 1.29). The transmetallation in the cyclic mechanism involves an associative substitution (L for R²) through intermediate 54 and transition state TS54,55 to give directly a cis-R¹/R² complex 55, from which the coupled product will immediately lead to the formation of R¹–R² by reductive elimination. A posttransmetallation intermediate cis-[PdR¹R²L(ISnBu3)] in the cyclic mechanism was spectroscopically detected [229].
The proposal in Scheme 1.29 explains the observed dependence on L and produces immediately the cis arrangement needed for fast R¹–R² coupling. The known inverse relationship between ligand donor ability and transmetallation rate [14, 52, 219, 220] supports the dissociative model because ligands of modest donicity (such as AsPh3) would be more easily displaced in an associative substitution process.
The coupling of iodobenzene and vinyltributylstannane with [Pd(dba)(AsPh3)2] in dimethylformamide (DMF) was examined by Amatore and Jutand (Scheme 1.30) [89, 230]. In this study, the transmetallation was proposed to occur on intermediate 58, formed by consecutive ligand substitutions via 57.
Scheme 1.30 Coordination to Pd(II) for the selective alkenyl transmetallation.
c01scy030The open transition state operates in cases where no bridging groups are available on the coordination sphere of Pd(II) to produce a cyclic intermediate [227]. The SE(open) transmetallation mechanism, proceeding through transition state TS53–56 (Scheme 1.30), is the only possible path in the absence of bridging ligands, but it can also operate in the presence of the ligands. It implies X-for-R² or L-for-R² replacement at the Pd center, leading competitively to cis and trans arrangements to give complexes 56a,b and produces inversion of configuration at the α-carbon transferred from the stannane. This mechanism is favored by the use of polar, coordinating solvents, lacking bridging ability. It might also operate in the presence of an excess of L and with easily leaving anionic ligands lacking bridging ability, in which case transmetallation proceeds from cationic complexes. This mechanism also occurs in the coupling of aryl triflates with vinyltributylstannane in the presence of dppe (bis(1,2-diphenylphosphino)ethane) as the ligand [228].
The fact that the transmetallation step in the Stille reaction can follow two different paths, SE2(cyclic) and SE2(open), has important stereochemical consequences, as this transformation determines the stereochemical outcome of the overall coupling reaction with C(sp²)-X electrophiles. Therefore, retention of the configuration would be expected for an SE2(cyclic) pathway, while an SE2(open) mechanism would result in overall inversion of configuration. This clarifies the contradictory stereochemical results reported in the literature. Thus, Falck [58] reported 98% retention of configuration in the coupling of chiral α-alkoxystannanes with acyl chlorides in toluene, which would proceed along a cyclic pathway. On the other hand, Labadie and Stille [57] found inversion (≥65%) in the coupling of a chiral benzylic stannane to an acyl chloride in HMPA (hexamethylphosphoric triamide). In the last example, the use of a highly polar and coordinating solvent favors the open pathway, even in the presence of a potentially bridging chloride ligand.
This comprehensive mechanistic proposal advanced by the group of Espinet [231] was supported theoretically. This study shows that both transmetallations with alkenylstannanes occur in two steps. First, a ligand substitution takes place, followed by an intramolecular transmetallation. In the cyclic mechanism, this second step requires the highest activation energy. In the open process, the transmetallation occurs by an SN2 reaction at the tin center with the X− as the incoming group and the alkenyl as the leaving group. In this case, in contrast to the cyclic mechanism, the first step has the highest energy barrier in the process.
An in-depth study of the Stille reaction of alkynylstannanes with aryl iodides reveals the high complexity of many cross-coupling processes, in which the often ignored isomerization reactions can compete with the oxidative addition or the transmetallation as the slow steps in the overall process [232]. The effect of ligands as well as that of fluoride anion in the Stille reaction has been studied in detail computationally within this overall mechanistic scenario [233].
However, when very bulky ligands are used, a dissociative mechanism probably operates through T-shaped intermediates such as 50 (Scheme 1.31) [149, 219]; these intermediates may then evolve by SE2 (cyclic) transmetallation with the organostannane via 59.
Scheme 1.31 Transmetallation from T-shaped Pd(II) complex 50.
c01scy031The open-associative mechanism probably operates in the Stille reaction carried out in the presence of additives such as fluoride [147] and hydroxide anion [234]. Similarly, coordination of tin to the nitrogen of benzylamines 60 [235] and stannatrane derivatives 61 [236, 237] (Figure 1.2) presumably leads to transmetallation by an SE2(open) mechanism.
Figure 1.2 Internal coordination to tin favors transmetallation to Pd(II).
c01fgy002A different type of coordination is involved in a system developed by Yoshida for the selective transfer of the Me3SiCH2− group from 62 (Scheme 1.32) [238]. In this case, coordination of the pyridine nitrogen to Pd(II) as shown in 63 favors the intramolecular transmetallation through an SE2(cyclic) intermediate. However, a trans-to-cis isomerization is now required for the reductive elimination of complex 64.
Scheme 1.32 Coordination to Pd(II) for the selective alkyl transmetallation.
c01scy032In a model study for the Stille reaction using platinum instead of palladium, the transmetallation reaction between trans-[PtPh(OTf)(PMe2Ph)2] and PhSnMe3 was found to give simultaneously trans-[PtPh2(PMe2Ph)2] and cis-[PtPh2(PMe2Ph)2] (Scheme 1.33) [239]. In THF, the intermediate trans-[PtPhMe(PMe2Ph)2] was also detected in the pathway involving the formation of cis-[PtPh2(PMe2Ph)2]. In this mechanism, the initial attack takes place trans to the phenyl ligand leading to 64a,b. Interestingly, the stannanes actually function as catalysts for the cis–trans isomerization.
Scheme 1.33 Transmetallation reaction between trans-[PtPh(OTf)(PMe2Ph)2] and PhSnMe3 gives both trans-[PtPh2(PMe2Ph)2] and cis-[PtPh2(PMe2Ph)2].
c01scy0331.1.3.4 The Copper Effect
An interesting phenomenon in the Stille couplings is the acceleration observed upon the addition of Cu(I) salts [52, 55, 58, 240–245].
Farina and Liebeskind [242] initially suggested that in highly polar solvents, a Sn/Cu transmetallation could take place, leading to the in situ formation of organocopper species, a proposal that later developed into effective coupling systems. Thus, Piers demonstrated that the intramolecular coupling of alkenyl iodides with alkenylstannanes can be carried out using CuCl in stoichiometric quantities [246, 247]. A new procedure of broad scope for the Stille reaction has been developed using both CuI and CsF as additives [248].
This copper effect was rationalized by Espinet within the framework provided by the associative mechanism. Accordingly, Cu(I) captures part of the free neutral ligand L released during the oxidative addition of [PdL4] that yields the species actually undergoing transmetallation, trans-[PdR¹IL2]. Therefore, Cu(I) would mitigate the autoretardation
produced by the presence of free L on the rate-determining associative transmetallation [249].
Better results were later obtained using other Cu(I) salts, which allow the reaction to proceed under catalytic conditions [58b,250–256].
Oxidation of the Pd(0) catalyst [Pd(PtBu3)2] to dinuclear Pd(I) complexes takes place in the presence of Cu(I) and Ag(I) salts [257]. For the Suzuki–Miyaura cross-coupling reactions with ArCl, the effect of oxidants depends on the anion. If X = I (i.e., CuI), the highly stable dinuclear complex [{(PtBu3)PdI}2] is formed, which leads to slow transformations in cross-couplings. However, when X = Br, a more active precatalyst [{(PtBu3)PdBr}2] is formed, which leads to [PdPtBu3], a highly reactive species in the oxidative addition. In the case of Sonogashira couplings, the Pd(I) complexes react with the alkynes leading to products of polymerization, which explains the inhibitory effect of Cu salts in reactions with ArCl. Alternative cycles involving bimetallic Pd(I) were also suggested in this study [257]. The highly selective Pd-catalyzed Csp–Csp Sonogashira coupling of bromoalkynes has been achieved with very low loadings of palladium nanoparticles generated from Pd(OAc)2 and tetrabutylammonium bromide, in the presence of CuI and iPr2NH [258].
1.1.3.5 Transmetallation in the Suzuki–Miyaura Reaction
Owing to the low nucleophilicity of the borane reagents (compared with organostannanes, for example), the Suzuki–Miyaura, reaction in order to take place, requires the addition of a base. Stronger bases such as NaOH, TlOH, and NaOMe perform well in THF/H2O solvent systems, whereas weaker bases such as K2CO3 and K3PO4 are usually more successful in DMF. The base is involved in several steps of the catalytic cycle, most notably in the transmetallation process. Soderquist [259] performed detailed mechanistic studies on the coupling of trialkylboranes and alkoxy(dialkyl)boranes with aryl and alkenyl electrophiles (Scheme 1.34). This study allowed determining the stereochemistry of the transmetallation step [259, 260] and the role of the base in the catalytic cycle. The main role of the base is to generate a more reactive boranate 66 by coordination of hydroxide to boron, which will react with the intermediate R-Pd(II)-X complex. On the other hand, in the case of the alkoxyboranes 67, the base also reacts with the intermediate R-Pd(II)-X derivatives to form the more reactive R-Pd(II)-OH species (Scheme 1.34).
Scheme 1.34 Catalytic cycles for the coupling of trialkylboranes (top) and alkoxy derivatives (bottom).
c01scy034A detailed study of the transmetallation in the Suzuki–Miyaura reaction by the group of Amatore and Jutand shows that hydroxide [261] and fluoride anions [262] form the key trans-[ArPdX(L)2] complexes that react with the boronic acid in a rate-determining transmetallation. In addition, the anions promote the reductive elimination. Conversely, the anions disfavor the reaction by formation of nonreactive anionic [Ar′B(OH)3−nXn]− (n = 1–3). Countercations M+ (Na+, K+, and Cs+) of anionic bases in the palladium-catalyzed Suzuki–Miyaura reactions decelerate the transmetallation step in the following decreasing reactivity order: nBu4NOH > KOH > CsOH > NaOH; this is due to the complexation of the hydroxy ligand in [ArPd(OH)(PPh3)2] by M+[263].
The two main mechanistic proposals for the role of the base in the transmetallation step of the Suzuki–Miyaura cross-coupling reaction, first attack at the palladium complex or at the boronic acid, were studied computationally by the group of Maseras [264]. These calculations were fully consistent with the experimental data and strongly suggested that the main pathway for the Suzuki–Miyaura catalytic cycle starts with the attack of the base on the organoboronic acid. The transmetallation can actually proceed by dissociative or associative mechanisms depending on the different nature of the ligands and other experimental conditions [265]. A theoretical study of the full catalytic cycle of the Suzuki–Miyaura coupling between bromobenzene and PhB(OH)2 was carried out depending on the ligand in [PdL2] complexes and demonstrated that electron-poor ligands such as P(CF3)2 greatly facilitated the transmetallation step [266]. A theoretical study of the Suzuki–Miyaura reaction using diimine palladium complexes has also been reported [267].
Several intermediates in the Suzuki–Miyaura coupling of bromopyridines with arylboronic acids have been identified by in situ analysis of the reaction by electrospray ionization mass spectrometry (ESI-MS) [268]. Interestingly, monitoring the coupling by ESI-MS demonstrates that, at the end of the reaction, there is an accumulation of binuclear Pd(0)-Pd(II) halide clusters, which are still catalytically active [269].
Chiral secondary boronic esters react with aryl iodides in the palladium-catalyzed Suzuki–Miyaura couplings with high retention of configuration, as expected in a transmetallation proceeding through a four-membered transition state [270, 271]. The cross-coupling of secondary organotrifluoroborates is also a stereospecific process that occurs with complete retention of the configuration [272]. In contrast, cross-coupling of potassium β-trifluoroboratoamides and α-(acylamino)alkylboronic esters proceeds with inversion of configuration as a result of the presence of a strongly coordinating group that binds to the boronate during the transmetallation [273, 274].
Base-free C–C couplings of organoboron reagents have been carried out starting from perfluoroalkenes and fluorinated arenes [275]. In this reaction, the transmetallation occurred directly between the fluoride [RPdL2F] and the organoboron compound. The first [RPdL2F] complexes were reported by Grushin [276, 277] formed by reaction of organopalladium hydroxides with Et3N(HF)3 in the presence of free phosphine or by reaction of [RPdL2I] with AgF. Related platinum fluoride complexes had been prepared before by reaction of liquid HF with [Pt(PR2Ph)4] complexes [278]. Fluoroarenes were also coupled with arylboronates using a Ni(0)/NHC catalyst [275]. Benzylic fluorides undergo the Suzuki–Miyaura coupling, presumably through intermediates of the type [RPdL2F, 279].
Transmetallation products between arylboronic acids and platinum(II) halides or palladium(II) halides were isolated and characterized spectroscopically as well as by X-ray diffraction [280]. As expected, the reductive elimination of cis-diarylpalladium(II) complex 68a was considerably faster than that of 68b with a more electron-deficient fluorinated aryl ring (Scheme 1.35) [280a]. However, a kinetic study of the transmetallation between para-substituted arylboronic acids and cationic [Pd(Ph)(PPh3)(dppe)]BF4 showed a small negative ρ value (−0.54) [281]. It is interesting that the Hammett analysis of the palladium-catalyzed allyl–aryl coupling using aryl silicate derivatives revealed that the reaction is facilitated by electron-withdrawing groups on the arylsiloxane [282]. This result is consistent with either the transmetallation or the reductive elimination being the rate-determining step.
Scheme 1.35 Reductive elimination of cis-diarylpalladium(II) complexes 68a,b.
c01scy035The transmetallation in the γ-selective Suzuki–Miyaura coupling between potassium allyltrifluoroborates with haloarenes is rate-determining and was shown to occur on [Pd(Ar)(L-L)]+ through an SE2′ (open) transition state according to experimental and theoretical studies [283].
Complexes of other metals have recently been found to catalyze the Suzuki-type reactions. Thus, platinum complexes catalyze the coupling between arylboronic acids and aryl halides [215], and [Ni(PCy3)2Cl2] is effective in the cross-coupling of arylboronic acids and aryl tosylates [284]. In this case, the usual mechanism involving oxidative addition of the aryl tosylate to [Ni(PCy3)2], followed by transmetallation and reductive elimination, has been proposed. The study of the effects of the substituents on the electrophile and the boronic acid indicates that transmetallation is the rate-determining step. The mechanism of the Pd-catalyzed homocoupling of arylboronic acids has also been studied [285].
1.1.3.6 Transmetallation in the Negishi Reaction
The transmetallation step in a palladium-catalyzed Negishi reaction is a complex transformation that has been investigated combining experimental and theoretical studies (Scheme 1.36) [286]. The reaction between trans-[PdMeCl(PMePh2)2] and ZnMe2 in THF shows that in the absence of added phosphine, an ionic intermediate [PdMe(PMePh2)2(THF)]+ leads to an ionic transmetallation pathway. In contrast, an excess of phosphine retards the reaction because of the formation of a highly stable cationic complex with three phosphines [PdMe(PMePh2)3]+. The ionic pathway via cationic complexes with one weak ligand is faster than the concerted pathways via neutral intermediates.
Scheme 1.36 Transmetallation in the Negishi reaction in the presence/absence of added phosphine.
c01scy036This work demonstrated the existence of some competitive transmetallation pathways in the Negishi coupling reaction that had not been invoked before [286b]. Another experimental and theoretical investigation of the palladium-catalyzed Negishi coupling also showed the importance of a secondary transmetallation reaction between the intermediate [PdAr¹Ar²(L)2] and the organozinc reagent Ar²-ZnX to form [Pd(Ar²)2(L)2] and Ar¹ZnCl [287, 288]. The possible involvement of Pd-Zn species of type L2Pd-ZnRX(S) in the Negishi coupling has been examined computationally [289].
A cyclic associative transmetallation of 69 to 70 through a low-energy transition state was proposed based on density functional theory (DFT) calculations for the Negishi coupling using [{Pd(allyl)Cl}2] and a bulky monodentate phosphabarrelene ligand (Scheme 1.37) [290].
Scheme 1.37 Transmetallation of 69 to 70.
c01scy037Transmetallation has been demonstrated to be the rate-limiting step in the Sonogashira coupling reaction [291]. The transmetallation is also rate-determining in the nickel-catalyzed reaction between arylzinc reagents and α-chloro carbonyl compounds that proceeds via ArNi(II)R intermediates [292].
1.1.3.7 Transmetallation in the Hiyama Reaction
The lower reactivity of the Si–C bond requires the use of activating reagents to enhance the reactivity of silanes and to promote the Si-Pd transmetallations. Fluoride is the common additive, although other nucleophiles such as hydroxide, metal oxides, and alkoxides are also effective [30, 293, 294]. Fluoride converts the starting silanes into pentacoordinate fluorosilicates, which are the actual transmetallation reagents.
Transmetallation of alkenylsilanes takes place with retention of the double bond configuration, as in other cross-coupling reactions [295]. Owing to the lower transmetallation rate, competing 1,2-insertion of the alkene in the intermediate organopalladium complex (as a Heck type reaction) may take place, which affects the regioselectivity of the Hiyama reaction in some cases (Scheme 1.38) [296]. This results in cine substitution, a process also observed in the Stille coupling reactions of some hindered alkenylstannanes [90].
Scheme 1.38 The Hiyama reaction involving alkene insertion (as a Heck type reaction) before transmetallation.
c01scy038Hiyama studied the stereoselectivity of alkyl transmetallation in the [Pd(PPh3)4]-catalyzed reaction of aryl triflates with enantiomerically enriched (S)-1-phenylethyltrifluorosilane in the presence of TBAF (tetrabutylammonium fluoride) [297]. At 50 °C, there was retention of the configuration, but at higher temperatures, a linear decrease in the degree of retention took place and finally, inversion was observed above 75 °C. A significant solvent effect was also observed. Thus, the reaction in THF resulted in retention. On the other hand, inversion was found in HMPA-THF (1 : 20) (Scheme 1.39).
Scheme 1.39 Solvent effect on the stereoselectivity of Si-Pd alkyl transmetallation.
c01scy039The retention of configuration at low temperatures in THF can be explained assuming a fluorine-bridged SE2(cyclic) transition state (71), analogous to that proposed for the Stille reaction formed from a pentacoordinate silicate (Scheme 1.40).
Scheme 1.40 Formation of arylpalladium