Table of Contents
Related Titles
Title Page
Copyright
Preface
List of Contributors
Chapter 1: Mechanistic Aspects of Metal-Catalyzed C,C- and C,X-Bond Forming Reactions
1.1 Mechanisms of Cross-Coupling Reactions
1.2 Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles
1.3 Formation of C–X (X = N, O, S) Bonds in Metal-Catalyzed Reactions
1.4 Summary and Outlook
List of Abbreviations
References
Chapter 2: State-of-the-Art in Metal-Catalyzed Cross-Coupling Reactions of Organoboron Compounds with Organic Electrophiles
2.1 Introduction
2.2 Advances in Cross-Coupling Reactions for the Formation of C(sp2)–C(sp2) Bonds
2.3 Advances in the Cross-Coupling Reactions for the Formation of C(sp3)–C(sp2) or C(sp3)–C(sp3) Bonds
2.4 Experimental Procedures
2.5 Summary and Outlook
References
Chapter 3: Pd-Catalyzed Cross-Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances
3.1 Background and Discovery
3.2 Discovery of the Pd- or Ni-Catalyzed Cross-Coupling Reactions of Organometals Containing Zn, Al, Zr, and B
3.3 The Current Scope of the Pd- or Ni-Catalyzed Cross-coupling and Its Application to the Synthesis of Natural Products and Other Complex Organic Compounds
3.4 Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA) ZACA–Pd- or Cu-Catalyzed Cross-Coupling Sequential Processes as a General Route to Enantiomerically Enriched Chiral Organic Compounds
3.5 Representative Experimental Procedures
Acknowledgments
References
Chapter 4: Carbon–Carbon Bond Forming Reactions Mediated by Organozinc Reagents
4.1 Introduction
4.2 Methods of Preparation of Zinc Organometallics
4.3 Uncatalyzed Cross-Coupling Reactions of Organozinc Reagents
4.4 Copper-Catalyzed Cross-Coupling Reactions of Organozinc Reagents
4.5 Transition-Metal-Catalyzed Cross-Coupling Reactions of Organozinc Reagents
4.6 Conclusions
4.7 Experimental Procedures
Acknowledgments
List of Abbreviations
References
Chapter 5: Carbon–Carbon-Bond-Forming Reactions Mediated by Organomagnesium Reagents
5.1 Introduction
5.2 Methods of Preparation of Magnesium Organometallics
5.3 Transition-Metal-Catalyzed Cross-Coupling Reactions of Organomagnesium Reagents
5.4 Conclusions
5.5 Experimental Procedures
Acknowledgments
List of Abbreviations
References
Chapter 6: Organotin Reagents in Cross-Coupling Reactions
6.1 Introduction
6.2 Mechanism and Methodology
6.3 Natural Product Synthesis
6.4 Organic Synthesis
6.5 Polymer Chemistry
6.6 Inorganic Synthesis
6.7 Conclusions
6.8 Experimental Procedures
List of Abbreviations
References
Chapter 7: Organosilicon Compounds in Cross-Coupling Reactions
7.1 Introduction
7.2 Modern Organosilicon Cross-Coupling
7.3 Mechanistic Studies in Silicon-Based Cross-Coupling Reactions
7.4 Applications to Total Synthesis
7.5 Summary and Outlook
7.6 Experimental Procedures
List of Abbreviations
References
Chapter 8: Cross-Coupling of Organyl Halides with Alkenes – The Heck Reaction
8.1 Introduction
8.2 Principles
8.3 Cascade Reactions and Multiple Couplings
8.4 Related Palladium-Catalyzed Reactions
8.5 Enantioselective Heck-Type Reactions
8.6 Syntheses of Heterocycles, Natural Products, and Other Biologically Active Compounds Applying Heck Reactions
8.7 Carbopalladation Reactions in Solid-Phase Syntheses
8.8 The Heck Reaction in Fine Chemicals Syntheses
8.9 Conclusions
8.10 Experimental Procedures
Acknowledgments
List of Abbreviations
References
Chapter 9: Cross-Coupling Reactions to sp Carbon Atoms
9.1 Introduction
9.2 Alkynylcopper Reagents
9.3 Alkynyltin Reagents
9.4 Alkynylzinc Reagents
9.5 Alkynylboron Reagents
9.6 Alkynylsilicon Reagents
9.7 Alkynylmagnesium Reagents – The Kumada–Corriu Reaction
9.8 Other Alkynylmetals
9.9 Concluding Remarks
9.10 Experimental Procedures
Acknowledgments
List of Abbreviations
References
Chapter 10: Carbometallation Reactions
10.1 Introduction
10.2 Carbometallation of Alkenes
10.3 Carbometallation of Alkynes
10.4 Carbometallation Reactions of Allenes
10.5 Conclusions
10.6 Experimental Procedures
References
Chapter 11: Palladium-Catalyzed 1,4-Additions to Conjugated Dienes
11.1 Introduction
11.2 Palladium(0)-Catalyzed Reactions
11.3 Palladium(II)-Catalyzed Reactions
References
Chapter 12: Cross-Coupling Reactions via π-Allylmetal Intermediates
12.1 Introduction
12.2 Palladium-Catalyzed Allylic Alkylations
12.3 Allylic Alkylations with Other Transition Metals
12.4 Experimental Procedures
List of Abbreviations
References
Chapter 13: Palladium-Catalyzed Aromatic Carbon–Nitrogen Bond Formation
13.1 Introduction
13.2 Mechanistic Considerations
13.3 General Considerations
13.4 Arylation
13.5 Amination with C–H Bond Activation
13.6 Troubleshooting
13.7 Conclusions
13.8 Experimental Procedures
References
Chapter 14: The Directed Ortho Metallation (DoM)–Cross-Coupling Nexus. Synthetic Methodology for the Formation of Aryl–Aryl and Aryl–Heteroatom–Aryl Bonds
14.1 Introduction
14.2 Content of this Review
14.3 Synthetic Methodology Derived from the DoM–Cross-Coupling Nexus
14.4 Application in Synthesis
14.5 Conclusions and Prognosis
14.6 Selected Experimental Procedures
Acknowledgments
List of Abbreviations
References
Chapter 15: Transition-Metal-Catalyzed Hydroamination Reactions
15.1 Introduction
15.2 Early Transition Metal Catalysts
15.3 Late Transition Metal Catalysts
15.4 Hydroamination in Synthesis
15.5 Summary and Future Directions
15.6 Example Experimental Procedures
References
Chapter 16: Oxidative Functionalization of Alkenes
16.1 Introduction
16.2 Palladium-Catalyzed Nucleopalladation: General Features
16.3 Wacker-Type Reactions
16.4 Other Oxygenation Reactions Involving Wacker-Type Chemistry
16.5 Metal-Catalyzed Difunctionalization of Alkenes
16.6 Summary
References
Chapter 17: Biaryl Synthesis through Metal-Catalyzed C–H Arylation
17.1 Introduction
17.2 C–H/C–X Coupling
17.3 “Special” Coupling Partners: Phenol Derivatives and Arylcarbonyl Compounds
17.4 C–H/C–M Coupling [160]
17.5 C–H/C–H Coupling
17.6 Enantioselective C–H Coupling
17.7 Experimental Procedures
References
Chapter 18: C–H Bond Alkenylation
18.1 Introduction
18.2 Oxidative C–H Bond Alkenylation with Alkenes
18.3 Direct C–H Bond Alkenylation with Alkenyl Halides and Alkenylmetal Reagents
18.4 C–H Bond Addition across Alkynes
18.5 Experimental Procedures
18.6 Summary
References
Chapter 19: C–H Bond Alkylation (Including Hydroarylation of Alkenes)
19.1 Introduction
19.2 C–H Alkylation with Electrophilic Reagents
19.3 C–H Alkylation with Alkylmetal Reagents
19.4 Hydroarylation and Hydroalkenylation of Alkenes
19.5 Experimental Procedures
19.6 Summary and Outlook
References
Index
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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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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
Volume 1
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.
The 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.
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.
This 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].
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.
Allylic 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.
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).
The 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.
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.
The 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.
Anionic 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].
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].
Interestingly, 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.
Interestingly, 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.
All 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.
Brown 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.
The 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).
4-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.
In 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.
The 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].
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.
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.
Interestingly, 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].
Interestingly, 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.
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.
Palladium 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].
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.
A 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.
A 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.
31Scheme 1.23332Scheme 1.2332332232