Palladium and Copper in CâN Cross-Coupling Reactions - American

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The Complementary Competitors: Palladium and Copper in C−N Cross-Coupling Reactions Irina P. Beletskaya* and Andrei V. Cheprakov Department of Chemistry, Moscow State University, Moscow, Russia ABSTRACT: The C−N cross-coupling chemistry intensely developed since the late 1990s has supplied synthesists with an overwhelming number of methods to effectively combine carbon and nitrogen residues. This new chemistry relies on complexes of mainly two metals, copper and palladium, used as catalysts or stoichiometric agents. The development of new methods has revealed both similarities and differences in the principles used for the design of new catalytic systems and analysis of their reactivity and selectivity. The discussion of cross-coupling chemistry of these two metals can be performed within a common mechanistic paradigm, helping to elucidate the key factors governing the behavior of the transition-metal complexes involved.

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the intermediate σ-bonded complexes forming the target products via reductive elimination (Figure 1). Such reactions are commonly recognized as cross-coupling.

INTRODUCTION During the last 20−30 years the arsenal of synthetic methods of organic chemistry as a whole was dramatically expanded by transition-metal-catalyzed reactions, in which one of the most prominent roles is played by so-called cross-coupling chemistry, enabling the formation of C−C and C−heteroatom σ bonds from two fragments of complementary (electrophile−nucleophile) or the same (nucleophile−nucleophile) types of reactivity. The area which seems to benefit the most from the development of cross-coupling methods is the chemistry of nitrogen compounds, both because of the utmost importance of these compounds in organic chemistry and because of the surprising weakness of common organic chemistry in its lack of truly flexible means of creation of new C−N bonds, which impeded progress in the synthesis of nitrogen compounds for a century. Even more surprising is the fact that the classical Ullmann and Goldberg reactions are actually the oldest known transition-metal-catalyzed cross-coupling reactions known for more than a century, though a realization of the true nature and vast synthetic potential of these classical reactions was adopted in organic chemistry only very recently, after the introduction and rapid development of modern cross-coupling methods (post-Ullmann chemistry) which eventually permitted chemists to overcome the shortages and limitations of the classical methods. An overwhelming number of new transition-metal-assisted methods have been introduced for the synthesis of nitrogencontaining compounds, and the major two metals which make up the lion’s share of new developments are palladium and copper. In this review we attempt to compare palladium- and copper-catalyzed reactions for the construction of new C−N bonds. We confine the discussion to the processes in which the C−N bond is formed by transition-metal-assisted substitution reactions (σ-bond metathesis), which are believed to involve © XXXX American Chemical Society

Figure 1. Common step in cross-coupling reactions.

The formation of a carbon−nitrogen bond, mediated by transition-metal complexes such as copper and palladium, can take place within three distinctly different types of stoichiometries, (i) regular cross-coupling, (ii) oxidative cross-coupling, and (iii) inverse or Umpolung cross-coupling, with the regular and inverse cross-coupling being catalytic with respect to the transition metal, while the oxidative cross-coupling is by default a noncatalytic process, which however can be made catalytic by attaching a secondary redox process for recycling of the main transition-metal reagent, thus turning it into a catalyst (Figure 2). There is certainly a fourth alternativereductive coupling which is the reaction of two electrophiles in the presence of a two-electron reductant. Such a process is well-known as homocoupling, while its realization as cross-coupling would face the competition of homocoupling of one or both reagents, therefore making the realization of a selective process a challenge and, as far as we know, so far remains unresolved. Regular cross-coupling is the reaction between an organic electrophile and an NH nucleophile, thus being a transitionSpecial Issue: Copper Organometallic Chemistry Received: October 3, 2012

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dx.doi.org/10.1021/om300683c | Organometallics XXXX, XXX, XXX−XXX

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via a concerted transition-metal-mediated nucleophilic substitution.

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REGULAR CROSS-COUPLING Regular cross-coupling, that is, the metathesis reaction of an organic electrophile bearing a univalent nucleofugal leaving group with a σ-bonded organometallic compound, is apparently the predominant type of reaction in modern transition-metalcatalyzed C−N bond formation methods. Currently it is generally accepted that such reactions involve catalytic cycles in which metal is bonded in a stepwise fashion to an organic residue and a nucleophile, followed by reductive elimination of the final product and regeneration of a lowvalent metal complex ready to enter the next step of the catalytic cycle. The differences between Cu and Pd are due to variations in the order of individual stages, the oxidation states involved, the coordination properties of metal centers and ligands, etc. One of the most crucial features of such catalytic cycles stems from the possibility of controlling the coordination shell of the metal through a proper choice of ancillary ligands, which requires an understanding of their role in the reaction. In this respect, the difference between palladium- and copper-catalyzed reactions seems to be the most dramatic and truly fundamental. The vast majority of palladium-catalyzed C− N cross-coupling processes seem to belong to catalytic reactions involving the so-called well-defined complexes in which the coordination sphere is controlled, often precisely, through the use of special ligands and proper choice of reaction conditions, allowing suppression of the undesirable coordination events as fully as possible. Unlike many other palladiumcatalyzed reactions such as the Mizoroki−Heck reaction or various C−C cross-coupling methods, there seem to be no proven cases of the so-called “ligand-free” C−N cross-coupling processes, at least among the intermolecular processes (though in the intramolecular C−N cross-coupling such cases have been identified, see below). Palladium-catalyzed C−N cross-coupling reactions critically depend on the proper choice of ancillary ligands. On the other hand, copper-catalyzed reactions are more likely to belong to catalytic processes with poorly controlled and largely undefined complex intermediates, and the outcome of a given process is defined more by a haphazard interplay of complex equilibria, some of which lead to the realization of the desired reaction, while others are nonproductive. A pool of interconvertible complex species of poorly predictable nature is formed instead of well-defined intermediates. In the first instances of this chemistry, the pioneers of the field discovered that the use of some copper complexes allowed for a dramatic softening of reaction conditions and expansion of the preparative scope, in comparison to the classical Ullmann− Goldberg methods, insisting that the essence of new methods is the use of “well-defined copper catalysts”. Further studies, however, challenged the validity of this point. First, the preformed complexes gave way to mixtures of Cu(I) salts and ligands, the selection of which (the “toolbox”1) grew to include chelating and monodentate compounds of perplexing variety, apparently having nothing in common (no common trends in variation of electronic properties, bite angles, stability constants, and all other ligand properties commonly involved in considerations of the effects of ancillary ligands on catalytic activity) except the very ability to somehow bind to copper. Even some weak ligands could do the job if taken in good excess; thus, coordinating solvents were often revealed to be

Figure 2. Three major types of stoichiometries in cross-coupling reactions.

metal-catalyzed nucleophilic substitution. Such reactions usually require the presence of an equimolar amount of base, formally in order to quench the liberated acid, but actually to serve more specific roles in the catalytic cycle (vide infra). Inverse crosscoupling in this case can be regarded as the catalyzed electrophilic substitution between an organic nucleophile (an organometallic compound) and a nitrogen electrophile, a compound in which the nitrogen atom is bonded to a nucleofugal leaving group. An apparent ad hoc advantage of inverse cross-coupling is that no base is required, which simplifies the reaction system and increases the tolerance to functionality in substrates. Oxidative cross-coupling is different from the two other types of processes in many respects. As it is a reaction between nucleophile and nucleophile, this process cannot altogether take place in the absence of the third reagent or a system of reagents required to withdraw two electrons. This process can be viewed as if the transition-metal complex of higher oxidation state which readily undergoes reductive elimination is obtained by oxidation of a preceding transition-metal complex of lower oxidation state reluctant to undergo reductive elimination. Both palladium and copper are now known to be able to deliver the reactivity required to drive all three versions of cross-coupling. Regular and inverted cross-coupling reactions rely on the ability of low-valent metal complexesPd(0) or Cu(I)to take part in the oxidative addition to the activated bond of the electrophilic coupling partner (C−X in normal cross-coupling and N−X in inverse cross-coupling). Such reactivity is well-known for both metals, though in practice the extents of involvement of copper and palladium are dramatically different. Oxidative cross-coupling relies on two propertiesthe availability of the oxidation state with reasonable oxidative power in a two-electron process and the feasibility of the in situ oxidative regeneration of higher oxidation states. Both copper and palladium have such oxidation states, the main difference being that coppermediated systems rely on the Cu(I)/Cu(III) pair, while palladium chemistry revealed so far seems to rely on the Pd(II)/Pd(IV) pair instead of the Pd(0)/Pd(II) pair involved in regular or inverted cross-coupling. It should be emphasized that a given reaction which conforms to any of these stoichiometric types (Figure 2) is not guaranteed to proceed via the respective cross-coupling mechanisms involving all the prescribed major steps (see below). These standard mechanisms should be regarded as major mechanistic paradigms rather than as the obligatory real mechanisms. Deviations from the standard mechanisms are indeed possible. Thus, for example, Umpolung cross-coupling is sometimes viewed as transition-metal-mediated electrophilic substitution, as regular cross-coupling can be readily depicted B


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Table 1. Roles of Ancillary Ligands in Pd- and Cu-Catalyzed C−N Cross-Coupling Reactions in the Main Steps of the Catalytic Cycle step of catalytic cycle preactivation oxidative addition ligand exchange reductive elimination

Pd

Cu

generation of stable Pd(0) species and protecting Pd(0) against Cu(I) is stable without special ligands, but ligation is required to deactivation solubilize simple precatalysts (CuI, Cu2O, etc.) required for less reactive subtrates such as deactivated aryl bromides, aryl not required chlorides, sulfonates, etc. similar rolerestricting from binding more than one molecule of NH nucleophile, which is believed to poison the catalyst, as well as from multidentate binding of NH nucleophiles capable of chelation (amides, amino heterocycles, etc.) required for “pushing out” the product from the coordination shell of Pd, not required as this is often a limiting stage of the cycle

quite effective. Therefore, a growing number of “ligand-free” (that is, not using such explicitly added good ligands but instead involving implicit ligands, the components of reaction mixtures, such as solvents, innocent additives, bases, and sometimes even substrates) protocols have been announced. This situation bears a striking likeness to what is observed in the domain of palladium-catalyzed Suzuki−Miyaura and Mizoroki−Heck reactions, for which an enormous number of catalytic systems of amazing variety and uncertain functions (once even ironically dubbed as “cocktails”) has been introduced.2 An analysis of these systems revealed that those targeted on challenging cases (aryl chlorides and sulfonates, normally unreactive hindered olefins, room-temperature reactions, enantioselective or regioselective reactions, etc.) rely on specific palladium complexes bearing special ligands. At the same time, simpler tasks (reactions of aryl iodides and activated bromides with reactive olefins etc.) can be performed with a variety of catalytic systems not requiring special ligands but instead relying on such formulations of the catalytic system as a whole (combination of precatalyst, additives, base, solvent, etc.), which sustain a good level of catalyst activity and suppress or delay catalyst deactivation. Interestingly, a similar dichotomy can be revealed between Pd- and Cu-catalyzed C−N crosscoupling, the former being driven by the design of special ligands while the latter is dependent on the optimization of all components of the catalytic system (copper source, ligands, base, additives, solvent). Accordingly, Pd-catalyzed systems easily cope with challenging tasks (aryl chlorides, sulfonates, less reactive NH nucleophiles, room-temperature reactions, low catalyst loading), while copper-catalyzed systems are good for less challenging but still very useful synthetic tasks involving more reactive aryl iodides or bromides and a narrower scope of NH nucleophiles. The comparison of palladium- and copper-catalyzed C−N cross-coupling processes should highlight differences and similarities in the functions of the main components of catalytic systems: in the first place the ancillary ligands, which are believed to be the key to the catalyst design. In recent years, many relevant details of the mechanisms of these processes have been revealed, so that it may become possible to trace essential features of both types of catalytic processes to the differences in reactivity and coordination chemistry of the two metals. Roughly, these differences, with respect to the roles of the ancillary ligands, are concisely enumerated in Table 1. Of the three main coordination events involved in C−N cross-coupling the order of the first twooxidative addition and ligand exchange with NH nucleophileis not fixed. Thus, two instantiations of the C−N cross-coupling catalytic cycle are feasible, which is roughly illustrated in Figure 3. In cycle A oxidative addition precedes ligand exchange, while in cycle B

Figure 3. Two catalytic cycles in C−N cross-coupling (the lower oxidation state is denoted by a plain blue “M” and the higher oxidation state by a red italic “M”). NHRZ denotes a generic NH nucleophile and B a base.

ligand exchange takes place in a pre-equilibrium before oxidative addition. Given that the mechanisms of crosscoupling reactions for Pd and particularly for Cu are known at best fragmentarily and have been studied only for a few arbitrarily chosen “easy” models, the discussion of differences of mechanisms might appear as a scholastic exercise having little to do with synthetic practice. Nevertheless, the combined synthetic and mechanistic evidence gained so far shows that these different instantiations indeed seem to set two distinct paradigms, which describe rather well particular features of both palladium- and copper-catalyzed C−N cross-coupling reactions. These paradigms reveal the specific roles played by ancillary ligands, bases, and other components of a given catalytic system, as well as account for how both catalytic processes can be controlled. The catalytic cycle A conforms better to typical palladiumcatalyzed C−N cross-coupling reactions. This cycle is controlled mainly by ancillary ligands in a fairly predictable manner, while the roles of other components of reactions mixtures are auxiliary, so that each realization of this paradigm is a common protocol suitable for a wide series of substrates. On the other hand, the cycle B better reflects the behavior of copper-catalyzed systems. In this case the N-nucleophile itself plays the role of important ancillary, while the role of stable ancillary ligands is not as critical as that in cycle A. Pd-Catalyzed C−N Cross-Coupling: An Overview. The factor in which Pd- and Cu-catalyzed domains are distinguished most radically is the role of ligands. Pd-catalyzed C−N crosscoupling is among the clearest cases of transition-metalcatalyzed processes controlled by ligand design. The advances of this chemistry since its birth have relied on introducing new generations of ligands and understanding their role in defining catalytic activity, selectivity, scope. In these reactions ligands serve several critical roles. C


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other weak nucleophiles for which reductive elimination becomes the bottleneck of the catalytic cycle. These goals were effectively pursued by the introduction of third-generation ligands, which are based on the discovery that cross-coupling reactions (not only C−N, but C−C, C−O, etc. as well) benefit from electron-rich and bulky monodentate ligands, the archetypical representatives of which are tris(tertbutyl)phosphine6 and the monodentate heterocyclic carbenes IPr/SIPr and IMes/SIMes.7 These electron-rich ligands furnish high activity in oxidative addition reactions, thus allowing for an extension of the scope of substrates to aryl chlorides, and improve the activity of catalytic systems, allowing for processing of aryl bromides at moderate temperatures. However, as such ligands are monodentate ligands with very large cone angles but with symmetrical and compact shapes, they cannot precisely control the coordination sphere of Pd, and up to three molecules of these ligands can be bonded, with the respective complexes being involved in the dissociation and isomerization equilibria. Further development of this design principle gave many useful ligands, such as Beller’s diadamantylalkylphopshines of the cataCXium A series, such as 1,8 Verkade’s triaminophosphines 2 and 3,9 and many others, showing very high activity and improved catalytic efficiency and handling (Chart 1).

(i) Preactivation of initially loaded precatalyst is secured to supply monoligated complex of Pd(0) in as high an extent relative to the initial loading as possible. Hence, strongly bonding but sterically bulky mono- and bis-phosphine ligands as well as some heterocyclic carbenes are used. (ii) The Pd center is activated toward oxidative addition, which is particularly important for mild (e.g., room-temperature) protocols and involvement of less reactive substrates (chlorides). Hence, electron-rich ligands are preferred. (iii) The coordination shell is protected from harmful binding of wrong ligands which may suppress the main cycle: e.g. prevention of premature binding of NH nucleophile, binding of several molecules of the NH nucleophile, or prevention of multidentate binding of substrates (e.g., amides prone to form bidentate N,O complexes). Hence, either a fine balance between the donicity and the bulk of monophosphines is sought, or chelating PP, PN, and PO ligands are designed so that temporary chelation controls the side processes. (iv) Steric strain is increased in the coordination shell of the metal, which is likely to serve as the main driving force of the product-forming step reductive elimination. Hence, bulky ligands are preferred. The Pd0/Pd2+ catalytic cycle in C−N cross-coupling relies on specific ancillary ligands, either phosphines or heterocyclic carbenes. When first introduced in 1994−1995,3 the reaction was shown to be catalyzed by Pd complexes with simple triarylphosphines, the then common ligands in Pd catalysis. Modestly bulky tris(o-tolyl)phosphine was used as the first common ligand. The use of such ligands could not enforce a good level of control over the coordination sphere of Pd; thus, the first generation of Hartwig−Buchwald reaction systems employed ill-defined catalysts, which accounted for the rather modest scope of both electrophiles and nucleophiles, harsh conditions, and competition of side reactions, particularly of the reductive dehalogenation of aryl halides. The second-generation catalytic systems employed chelating bis-phosphines with two equal chelating sites, the most popular of which are BINAP and dppf.4 These ligands normally form homoleptic bis-chelates which can be forced to undergo thermal dissociation into reactive monochelates, which enter the catalytic cycle.5 Thus, as the activation process is a thermal spontaneous dissociation, these catalysts show a reasonable activity only at elevated temperatures where the concentration of the active monochelate becomes relatively high. These catalytic species possess a good level of reactivity in the oxidative addition of aryl bromides and aryl iodides, as well as aryl triflates. Diphosphine solidly controls two coordination sites, thus quite effectively suppressing one of the nastiest side reactionsthe inner-sphere hydride elimination from the Nligand, which leads, as a net result, to the reductive dehalogenation of aryl halides. As a result, diphosphines, and particularly BINAP, won a major place in palladium-catalyzed amination chemistry and became the ligands of first choice, effectively applied to an overwhelming number of published syntheses. Still, these ligands fail to serve for more specific goals: (i) processing of less reactive electrophiles such as chlorides and ordinary nonfluorinated sulfonates (tosylates, mesylates, etc.); (ii) increasing the selectivity, e.g. of monoarylation vs diarylation of primary amines; (iii) increasing the net efficiency and rate of catalytic processes (TOF and TON values), which are rather modest in the common protocols involving the firstand second-generation ligands; (iv) processing amides and

Chart 1. Bulky Electron-Rich Monophosphines

Further progress in the area is associated with the introduction of a vast series of ligands furnishing a precise control of the coordination shell of palladium but exploiting the same principlesteric bulk plus high donicity, with special attention paid to designing molecules which, under reaction conditions, spontaneously form only monoligated species, so that equilibria with higher order complexes may not noticeably interfere. The third-generation ligands share a common feature, as all of them can form stablize monodentate complexes with the second coordination site in the shell being temporarily screened off by hemilabile or labile bonding of the second ligation center in the ligand or simply by steric effects. The ligands of this generation can be roughly classified into several groups: (i) bidentate ligands with the same phosphine binding sites and very large bite angles, making cis-chelation thermodynamically unfavorable, the most popular of which are DPEPhos (4) and particularly its rigidized version in Xantphos (5) family ligands; (b) bidentate ligands with two different phosphine binding sites and large bite angles as in the Josiphos family of ligands11 such as 6 (Chart 2); (iii) bidentate ligands with a strongly bonded phosphine site and labile secondary site (O or N n-basic substituent or electron-rich benzene ring serving as a labile η2 ligand),12 such as e.g. DavePhos (7),13 MOP (8), or phenanthrene derivative14 monodentate ligands (Chart 3), the steric bulk of which is not defined solely by the formal Tolman cone angle15 but rather by the specific irregular shape of the molecule, effectively screening the second coordination site.10 The best known and most thoroughly developed ligands of the last type are biphenyl derivatives with bulky alkyl groups at D


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Chart 4. QPhos (16),26 BippyPhos (21),20 Beller’s Phosphines (18, 19),17 Kwong’s Phosphines (20),19 Takasago Ligand cBRIDP (17),27 KITPHOS (22),21 and Mor-DalPhos (23)22

Chart 2. Large-Bite-Angle Diphosphines: DPEPhos (4), Xantphos (5), and a Typical Representative of JosiPhos Ligands (6, CyPF-tBu, R = Cy)

Chart 3. Diphenylmonophosphine Ligands DavePhos (7), JohnPhos (9), CyJohnPhos (10), BrettPhos (13),12 SPhos (14),23 XPhos (11),24 and RuPhos (15)25

Pd(II) source reduction to Pd(0) takes place spontaneously if the NH nucleophile (e.g., alkylamine) bears hydrogen atoms capable of β-hydride elimination. Otherwise, preactivation can be achieved by the addition of reductants, e.g. PhB(OH)2.28 These spontaneous techniques work well in most cases. However, when maximum activity is desired, the coordination shell of Pd should be devoid of interfering ligands left from precatalysts and contain only a single active ancillary ligand. Though the structure of the third-generation ligands itself accounts for proper composition of the coordination shell, in the most demanding cases special techniques can be used to enforce the optimum shell configuration. One of the most commonly used methods for in situ generation of monoligated complexes employs the cleavage of an η3-allylic ligand from the respective heteroleptic complex by nucleophiles (Figure 4).29

phosphorus (JohnPhos (9) and CyJohnPhos (10)) and additional bulky groups in the second phenyl ring (Xphos (11), tBuXPhos (12), BrettPhos (13), SPhos (14), RuPhos (15), etc.), which, in addition to other beneficial effects, suppress the formation of palladacycles by intramolecular ortho palladation of the ligand, an undesirable side reaction decreasing the activity of the catalyst.16 Many phosphines of similar design, typical representatives of which are given in Chart 4, were synthesized on the basis of different scaffolds, such as ferrocene (QPhos (16)), cyclopropane (Takasago ligands, e.g. 17), N-arylpyrroles (e.g., cataCXium PCy (18)),17 N-arylindoles (cataCXium PinCy (19)),17 N-arylimidazoles,18 2-arylindoles (20),19 N-pyrazolylpyrazoles (BippyPhos (21)),20 caged structures (e.g. KITPHOS (22)),21 and Stradiotto’s very bulky aminophosphines (e.g. Mor-DalPhos (23)).22 The last generation of ligands gave the most spectacular results and effectively solved almost all challenges of C−N cross-coupling. Numerous phosphine ligands taking advantage of the same design principles appeared in the 2000s, showing comparably high activity with challenging substrates (aryl chlorides, hindered aryl halides, etc.). The activation of catalysts usually takes place as spontaneous coordination transformations using either Pd2(dba)3 or Pd(OAc)2 as the palladium source, each of which has its own advantages and drawbacks; thus, in particular cases optimization is usually required to identify the right catalyst. With a

Figure 4. Generation of monoligated species by nucleophilic cleavage of allylic ligands.

An ingenious technique for in situ generation of monophosphine Pd complexes through base-induced reductive elimination from a stable palladacyclic intermediate was used for the safe generation of monoligated Pd(0) complexes in the absence of any potentially interfering auxiliary ligands (Figure 5).30 It should be noted, however, that though such activation indeed initially generates the highly active well-defined PdL complexes; their longevity in real catalytic systems is often limited because of deterioration of such complexes due to various side reactions. Therefore, in order to achieve better E


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new ancillary ligands. An overwhelming number of such ligands has been proposed, so that it might seem that none of the known NN, NO, OO, or other chelators has been missed, but no useful guidelines as to which one to use in any particular case has appeared. However, an analysis of the published protocols brings forward the conclusion that the success of a given protocol in solving some preparative problem depends not mainly on the ancillary ligand used but rather on the optimization of the catalytic system as a whole, with the choice of copper source, base, solvent, concentrations, etc. being of prime importance. Real breakthroughs (e.g., lowering the catalyst loading, softening the conditions, widening the scope, running the reactions in aqueous or other unusual media, etc.) are achieved also through finding some new recipe of combining the components of reaction mixtures, not through the introduction of some new special ligand. The number of “ligand-free” protocols is large and steadily growing, particularly among the most recent additions. One of the main questions in this respect is how Cu(I) can effect the oxidative addition, or put even more dramatically whether the oxidative addition of aryl iodides, the most common substrates of Cu-catalyzed C−N cross-coupling, to Cu(I) can take place altogether. The analogy with Ni(0) and Pd(0) is not straightforward, as there is at least one essential differencethese metals go to stable Ni(II) and Pd(II) oxidation states, represented by thousands of well-characterized and stable complexes, while Cu is transformed into the Cu(III) state, which is normally rather unstable and a potent oxidizer, if not properly stabilized by ligands, and which is known in only a handful of unambiguously characterized complexes, in which the Cu(III) state is stabilized by so special polydentate chelators.35 Thus, the natural question appears whether Cu(III) is not a regular oxidation state of this metal but rather a very rare exception requiring extraordinary efforts for stabilization. Moreover, if we consider the oxidative addition of ArI to Cu(I) species, the reverse reaction, the reductive elimination of ArI from the ArCuIIII intermediate, is a very likely process, unlike what is expected in similar Pd or Ni chemistry, where the oxidative addition is rarely treated as reversible. The reversibility of oxidative addition to Cu(I) was drawn attention to already in early studies by Cohen and co-workers on the classical Ullmann reaction.33c This problem was brightly highlighted by Wang and co-workers, who showed that not only iodide ion but also bromide and chloride are reducing nucleophiles effecting fast reductive elimination even from highly stabilized arylcopper(III) intermediates formed by an independent pathway (Figure 6).36 Stahl, Ribas, and co-workers even succeeded in directly observing reversible oxidative addition/reductive elimination of aryl bromide embedded in a macrocyclic ligand able to stabilize the Cu(III) state (Figure 7). Cleavage of the amine ligand by protonation led to reductive elimination, while restoring it by deprotonation gave the Cu(III) complex.37 Therefore, the mechanism of copper-catalyzed cross-coupling involving an oxidative addition step, formulated by analogy with the respective Pd chemistry, cannot be fully trusted. In fact, while the respective oxidative adducts of Pd(0) are trivial complexes, hundreds of which have been isolated and characterized, only a few arylcopper(III) complexes have been obtained using special macrocyclic polydentate ligands and none (except for that shown in Figure 7) contained halide ligands or counterions (more unambiguous data have, however, been obtained for C−C cross-coupling with sp3 carbon

Figure 5. Generation of monophosphine complexes from hybrid palladacycle−phosphine complexes.

TON values, an additional amount of the ligand is usually added. Thus, the overall status of the field is such that there are a few common ligands such as BINAP and tBu3P which serve well a majority of purposes and a wide selection of special ligands targeting specific tasks. In spite of a rather good understanding of the chemistry of C−N cross-coupling, it remains impossible to find a universal recipe for any given reaction, which for example led to the introduction of multipleligand systems.31 Therefore, the number of ligands reported is enormous, though a rather limited toolbox including roughly a dozen commercial ligands serves most purposes quite well,32 which allows us to state that Pd-catalyzed C−N cross-coupling has achieved a state of solid maturity and become a fundamentally important general method of fine organic synthesis with enviably broad scope unmatched by any traditional noncatalytic method of the vast synthetic arsenal. Cu-Catalyzed C−N Cross-Coupling: An Overview. The status of copper-catalyzed C−N cross-coupling is different and is still very far from maturity, as it is a rapidly growing area of research with almost monthly announcements of new breakthroughs and unexpected developments. The mechanism of copper-catalyzed C−N cross-coupling is much less understood, though essential facts about this chemistry have been elucidated already for classical Ullmann−Goldberg reactions,33 and the basic steps of the catalytic cycle have been established by the groups of Buchwald, Hartwig, and Taillefer.34 Currently, there likely is a consensus that in general the process follows the common cross-coupling mechanistic paradigm including oxidative addition, ligand exchange, and reductive elimination, though the order of the steps very probably conforms to cycle B of Figure 3. The catalytic cycle is serviced not by M0/M2+ oxidation states as for Pd (and Ni)-catalyzed reactions, but by M+/M3+ oxidation states. On comparison of the analogous transformations effected by Pd(0) on one hand and Cu(I) on the other, it is important to realize the most likely main source of differences. Cu(I) is formally isoelectronic not with 4d10 Pd(0) but with Ni(0), being a smaller metal center which can be expected to form shorter bonds and, due to positive charge and smaller size, to retain a substantial and harder Lewis acidity and thus a higher affinity for ligands based on second-period elements such as O and N. On the other hand, it is less electron rich and nucleophilic (again due to its smaller size and positive charge) than Pd(0). Also, due to its smaller size and shorter metal-toligand bonds, the effective size of the coordination shell in the vicinity of the metal center is smaller, leaving less space for huge ancillary ligands and thus fewer possibilities for control through sophisticated ligand design. Steric congestion and strain and tuning of the ligand donicity, which are very effective design principles for ancillary ligands in the palladium catalysts, are not highly useful in copper catalysis. The novel Cu-catalyzed C−N cross-coupling chemistry (post-Ullmann chemistry) developed in parallel with its Pdcatalyzed peer but somewhat lagging behind it may, at first glance, also appear as an area advanced through the design of F


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The interaction of a copper amide complex with aryl iodide was explicitly observed by Buchwald and co-workersthe reaction was fast, and no observable intermediates were traced (Figure 9).34b

Figure 9. Model stoichiometric amidation.

The arylcopper(III) intermediates of the cross-coupling catalytic cycle should be transient. In fact, they can be transient to an extent that it becomes meaningless to consider them as true intermediates, and the transformation can be regarded as a concerted metathesis reaction simply avoiding the dubious high-energy distinct Cu(III) state (Figure 10). Unfortunately it

Figure 6. Fast reductive elimination of aryl halides from arylcopper(III) complex.

Figure 7. Direct observation of oxidative addition/reductive elimination reversibility.

residues35b,38). Any hypothetical [ArCuIIIX] (X = I, Br) intermediate should be very unstable toward the reverse reductive elimination reaction. A high propensity toward reductive elimination from [ArCuIIII] can also be traced as a driving force for well-known Br to I exchange reactions in the presence of CuI.39 This observation teaches an important lessondue to reversibility the oxidative addition of Cu(I) particularly to aryl iodides can be hardly expected to take place to any practical extent and account for productive transformation in a given cross-coupling reaction if the intermediate Cu(III) state is stabilized only by neutral ligands, disregarding what effective chelators they make. The doubts that oxidative addition leading to a Cu(III) intermediate is a real pathway in the C−N cross-coupling catalytic cycle were recently emphasized by computational evidence showing that oxidative addition is a high-energy route which can be circumvented by lower energy single electron transfer or atom transfer pathways, formally leading to the same products.40 The attempts to trap radical intermediates by various “radical clocks” failed, however. Therefore, copper-catalyzed cross-coupling cannot follow the same mechanism as its Pd-catalyzed counterpartthe Cu(I) oxidative adduct is by default highly transient and cannot take part in any process other than reductive elimination. In the first place, it cannot take part in ligand exchange processes as ArPdX intermediates do. This apparent controversy can be resolved only if it is assumed that the nucleophilic coupling partner is present in the coordination shell before the oxidative addition, in which case oxidative addition becomes the rate-limiting step while the reductive eliminations are fast (Figure 8).

Figure 10. Can Cu-catalyzed C−N cross-coupling be a concerted process?

Figure 8. Reversibility of oxidative addition of ArX to Cu(I) dictating the pre-equilibrium binding of a nucleophile.

Figure 11. Two types of amide complexes in copper-catalyzed C−N cross-coupling.

is usually close to impossible to elucidate the degree of transiency and real lifetime of such intermediates, and such questions usually remain unanswered. The controversies whether this or that organic reaction should be regarded as concerted or stepwise involving highly transient intermediates are abundant in common organic chemistry, and for decades such disputes served as a pastime for generations of scholars. The transition-metal chemistry can hardly be simpler. Thus, the properties of copper complexes engaged in the catalytic cycle dictate that the interaction with aryl halide be postponed to the last product-forming step (be it concerted or involve a distinct transient Cu(III) complex), and on entering this step the NH nucleophile should be present in the coordination shell in the deprotonated form. What is then the role of the ancillary ligand? Apparently it is different from what is observed in the Pd-catalyzed cycle. It is not critical for oxidative addition and reductive elimination. One of its major roles is a bit paradoxicalto compete with the NH nucleophile for coordination sites at the copper center. In the absence of a competing ancillary ligand copper prefers to bind not one but two or more molecules of NH nucleophile to form homoleptic anionic bis-amidate complexes (Figure 11). This property is certainly not unique for copper; instead, the phenomenon of binding one ligand to a metal center, facilitating binding the other until a homoleptic complex is formed, is a common

G


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coordination bonding interaction with the leaving group is likely to be much more important, and the whole process in this case involves the attack of the less nucleophilic metal center at the C−X bond loosened by coordination of X to the Cu(I) center, or in other words, the leaving group in the process is required to lend a substantial assistance so that the Cu(I) center is able to break the C−X bond. The intrinsic mechanism of this transformation is closer to atom (X) transfer from the aromatic residue to the metal center than to regular nucleophilic displacement. Thus, the oxidative addition to Cu(I) should be more dependent on the properties of the leaving group than on substituent effects in the aromatic residue. Copper-catalyzed processes are indeed highly effective for aryl iodides. Though particularly in the last 5−6 years good protocols suitable for aryl bromides have been published in good numbers, iodo derivatives retain the status of the par excellence substrates for copper catalysis. Thus, it is no surprise that aryl chlorides remain challenging substrates for copper catalysis, and practically no reliable protocols have been developed so far for nonactivated chloro derivatives. Substantial contribution of Lewis acidity in the interaction of copper amide complexes with the electrophile explains several obvious abnormalities of this chemistrythe inertness of anionic bisamidate complexes (in which the acidity of the Cu center should be fully suppressed) and the reluctance of sulfonates to take part in the reactions. The sulfonates, even those such as triflates and nonaflates, remain the terra prohibitanot a single copper-catalyzed protocol can boast even modest results here (very recently the formation of an arylcopper reagent from arenesulfonate was demonstrated to take place via the intermediate organocobalt compound44), while only a few occasional examples of the use of triflates for arylation in modest yields can be found (Figure 12).45

feature of the coordination chemistry of all multiply charged metal ions. Thus, the interaction of the Cu(I) precatalyst with one molecule of NH nucleophile in the presence of base gives a very active neutral copper amide complex, which very readily binds the second molecule of NH nucleophile to form a homoleptic bis-amidate. The most important discovery corroborated independently by major contributors of the area was that such complexes are absolutely inert in oxidative addition even with highly reactive aryl iodides.34 Certainly, this is not an absolute rule and exclusions do exist,41 but in general this behavior seems to describe very well the reactivity of copper systems. The monoamidate Cu(I) complexes are highly reactive not only in the cross-coupling chemistry but also in other reactions, which was demonstrated for example by trapping them by diynes via an aminocupration pathway.42 This discovery is not only highly essential for understanding the principles of operation of copper-catalyzed cycles but also sets a sharp border between palladium and copper catalytic transformations. Indeed, in the palladium chemistry, the formation of electron-rich anionic complexes formed by bonding an extra anion to Pd(0) species was established to be an essential pathway of activation toward oxidative addition.43 Why does copper behave differently? The oxidative addition of low-valent metal to C−X bonds is a concerted process in which this bond is cleaved by an electronrich metal center, with the leaving group being transferred to the metal to become a new ligand. A substantial involvement of M−X interaction distinguishes this process from regular nucleophilic aromatic substitution involving σ complexes. As in any concerted reactions involving simultaneous transformations of two or more bonds, a broad variation of intimate structure of the transition state between nonconcerted boundary mechanisms should be possible. Relevant to this discussion, the oxidative addition is a rupture of the C−X bond in concert with the formation of M−C and M−X bonds. A fully synchronous three-centered interaction is an ideal mechanism for this reaction, hardly conceivable for real processes involving three reaction centers (carbon, transition metal, and a leaving group to become ligand). In reality, one might deal with nonsynchronous cases, where some interactions lag behind the othersthe metal center can interact more strongly with carbon or the leaving group. Thus, in the transition state either the nucleophilicity or the Lewis acidity (electrophilicity) of the metal center may be the predominant interaction. The difference between palladium and copper in oxidative addition seems likely to be associated with such mechanistic dichotomy. Pd(0), particularly such bearing electron-rich ancillary ligands, is a nucleophilic center, which means that the attack of Pd(0) complexes at the C−X bond is governed by the nucleophilicity of the metal. Therefore, palladium reactivity is readily tuned up by the electronic properties of ancillary ligands. The relatively lesser importance of the interaction of the metal with the leaving group to create a new ligand accounts for the applicability of palladium-catalyzed procedures for a vast variety of leaving groups, including chloride as well as various sulfonates, which behave as counterions and not as true ligands for palladium. On the other hand, Cu(1+), an intermediate species between nucleophilic Ni(0) and acidic Zn(2+), is a smaller and less electron-rich center than Pd(0), which is likely to possess a substantial Lewis acidity while retaining a modest level of nucleophilicity. In the oxidative addition of Cu(I) the

Figure 12. A very rare example of Cu-catalyzed arylation by an aryl triflate.

Probably the only successful and systematic study on the use of triflates in copper-catalyzed C−N cross-coupling was performed by Hattori and co-workers for bis-triflate esters of calixarenes (Figure 13). This exception actually speaks in favor of the miserable reactivity of Cu(I) toward triflates, as in this

Figure 13. Amination and amidation of calixarenes via bis-triflate esters. H


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case the oxidative addition of the triflate C−O bond to Cu(I) is assisted by the proximal hydroxyl group, which thus compensates for the lack of interaction between the metal center and the triflate's own oxygen atom.46 Moreover, this can be regarded as a more general hintunreactive or less reactive leaving groups (chloride, triflate, etc.) can be made reactive toward Cu(I) species if the attack is directed by a proximal nucleophilic center in an intramolecular fashion. Indeed, the cases of Cl displacement, for example, are more abundant in heterocyclization (see below). In this respect, an important question is whether copper can be additionally activated toward oxidative addition through the use of inert ancillary ligands, in a sense similar to that employed in palladium catalysis. In other words, can the role of ancillary ligands in copper catalysis be wider than just controlling coordination sites from overpopulation and poisoning by the nucleophile? Though the already published data on the development of catalytic systems give few clues as to whether this is indeed possible, there are a few indications that phosphine ligands may play the same role for copper as they do for palladium, though the choice of good phosphine ligands for copper is likely to be a challenge. Employment of the same bulky and electron-rich phosphine ligands apparently is not useful. The relative dimensions of the coordination sphere of copper are smaller than those of the 4d element Pd; thus, even from trivial steric reasons such huge ligands cannot adequately fit into it and leave space for ligands directly engaged in the transformations. A few reports on the use of phosphine ligands have appeared. Thus, the CuI−nBu3P system for diarylation of anilines by unactivated aryl chlorides was reported.47 Unfortunately, no development of this interesting protocol followed. Probably the success in this case was accounted for not by the ligand but by the rather harsh and strongly basic conditions, enabling the elimination−addition aryne pathway (Figure 14).

Figure 15. Taillefer’s phosphine ligand in mild copper-catalyzed arylation of azoles by unactivated aryl bromides.

the ligand to fit well into the smaller coordination shell of copper, and due to its effective steric bulk it helps to maintain coordination unsaturation of the copper center at lower temperatures. Such copper is reactive enough to bind the anion of azole in a regular way, but the resulting complex bearing not only amidate but also phosphine probably increases the electron density and nucleophilicity of copper. Side-by-Side Comparison of Pd- and Cu-Catalyzed C− N Cross-Coupling. Scope and Substrate Selectivity. One of the most interesting features of Pd- and Cu-catalyzed C−N cross-coupling is the well-known complementarity toward NH nucleophiles, first highlighted by Buchwald and co-workers.48 With much more data on the reactivity toward various classes of NH nucleophiles accumulated since then, it would be more correct to consider not exactly the complementarity, but more or less distinct preferences of either of the metals, differences in substrate selectivity. The differences are definitely rooted in the mechanistic models of both catalytic cycles. In copper-catalyzed C−N cross-coupling, as described by a mechanistic model of the catalytic cycle (Figure 16), binding of NH nucleophile takes place in the beginning of the process (a new turn of the catalytic cycle). The binding occurs as a competitive reversible ligand exchange process belonging to a complex manifold of equilibria with ancillary ligand(s), solvent, and NH nucleophile competing for the Cu(I) center according

Figure 14. Electron-rich phosphine ligands in copper-catalyzed crosscoupling of aryl chlorides.

Nevertheless, a search for new ligands of wider functional targeting could bring results. Probably the most relevant evidence was disclosed by Taillefer and coauthors, who showed that the reaction of azoles with aryl bromides can be facilitated by special ligands of the phosphine class (Z)-4-phenylbutadienyldiphenylphosphine (Figure 15).34a In the presence of this ligand, the oxidative addition of PhBr takes place at room temperature, while similar phosphinesPh3P, Ph2PMe, and Ph2PCHCH2are ineffective. Thus, the effect of this unusual ligand is not due to electronic effects but rather is likely to be associated with its spatial demandsthe molecule is not sterically bulky in the sense of formal bite angle, but it effectively screens off coordination sites due to its irregular shape and a certain degree of flexibility and free rotation, which seems to be quite similar to the mode of functioning of Buchwald’s diphenyl-scaffolded phosphine ligands and their descendants. The smaller cone angle, at the same time, allows

Figure 16. Factors defining the substrate selectivity in the catalytic cycle of Cu-catalyzed C−N cross-coupling. I


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acidity (azoles with two or more N atoms, amides, and similar compounds) can be bonded as anions to directly generate amide (azolate, amidate, etc.) complexes engaged in further transformation; NH acids that are too weak, on the other hand, cannot be deprotonated to any substantial extent by the bases employed in Cu-catalyzed reactions, and therefore the formation of the amide complex becomes a bottleneck. The third key stage of the cross-coupling catalytic cycle reductive eliminationis the product-forming step. The differences between Pd and Cu with respect to this stage are essential. While in Cu-catalyzed processes reductive elimination from Cu(III) intermediates containing σ-bonded ligands which are to form the product of cross-coupling is fast and spontaneous, not critically depending on ancillary ligands, in Pd-catalyzed processes this step critically depends on proper ancillary ligands and can be a bottleneck, at least with some NH nucleophiles. In Pd-catalyzed reactions the reductive elimination poses interesting problems, because the requirements of this stage are in contradiction with those of oxidative addition, which is favored for electron-rich metal centers bearing electron-rich dative ligands. Reductive elimination, on the other hand, should be favored by electron-withdrawing ligands.50 Though this is indeed so, this principle does not work for C−N crosscouplingvery probably because such ligands would have failed in the coordination competition with NH nucleophile. Fortunately, this tendency can be overpowered by either bidentate ligands with increased bite angles or bulky monodentate ligands, which force the residues to be eliminated to move closer to each other. Probably even more important is that such ancillaries impart steric strain to the intermediate complexes, which can be relieved by reductive elimination, thus being a driving force for catalytic transformation. Such an influence, as has been demonstrated by Hartwig and Roy, may cause reductive elimination in the absence of other nucleophilic ligands to take place from the ArPdX intermediate itself, thus leading to the reversibility of the oxidative addition step.51 Thus, combining high donicity with steric bulk satisfies both the oxidative addition and reductive elimination steps of the catalytic cycle. This has become the working principle of ligand design in C−N cross-coupling. As to the Cu-catalyzed processes, an understanding of the factors governing the reductive elimination might seem inessential, as this stage is spontaneous and fast and does not depend on ancillary ligands. However, since the coordination sphere of copper in such reactions is not properly controlled, the factors which govern reductive elimination should determine the net chemoselectivity of the reactions. Moreover, this factor is important for selecting the ancillary ligands, because many of these are potential NH or OH nucleophiles, and a competition between a productive nucleophile and the ligand can interfere with the due course of the reaction. Unique evidence on what triggers the reductive elimination in Cu-catalyzed reactions was obtained recently in the investigation of an ArCuIII intermediate obtained by electrophilic cupration. Though this method of generation of ArCuIII intermediates pertains to oxidative cross-coupling rather than regular cross-coupling, these two types of processes are hypothesized to involve a common type of intermediate, so that the evidence is of common relevance in both contexts. Very important results throwing light on the trends in reductive elimination were reported in a series of papers by Stahl and coworkers.52 An important and the only truly distinguishing

to the values of the involved equilibrium constants. As these constants are unknown even as rough estimates, only an approximate tentative description can be made. The main working hypothesis is that reactive species are only monoamide complexes of Cu(I) formed by deprotonation of monoamine complexes. In any given system many Cu(I) complexes (a pool of Cu(I) complexes) would be formed; only a few of which (monoamide complexes with or without a stable ancillary ligand denoted as L) are reactive. In Pd-catalyzed reactions the interplay of factors (Figure 17) is likely to be simpler. The roles of the factors involved are represented in Table 2 in an oversimplified way, showing the major trends, which are further elaborated below.

Figure 17. Factors defining the substrate selectivity in the catalytic cycle of Pd-catalyzed C−N cross-coupling.

Table 2. Main Factors Accounting for Substrate Selectivity (Substrate Preferences) in C−N Cross-Coupling Reactions factor nucleophilicity of NH nucleophile steric bulk of NH nucleophile

Pd catalyzed

Cu catalyzed

important

less important

strong negative influence

very strong negative influence positive effect positive effect

NH acidity positive effect nucleophiles capable negative effect (requires special of chelated binding ligands to suppress bidentate binding) leaving group in RX reflects the ease of oxidative addition steric bulk in RX small influence (often even strong negative beneficial) influence

During such speculations, we should be aware that the parameters used are rather loosely defined subjects. The equilibrium constants involved, usually unknown, are replaced by quantitative consideration of trends in the affinity of ligands toward metal centers. Such considerations are always tricky and error prone, as such affinity is dependent on many factors, including the nature of ligands already present in the coordination shell. In view of the overwhelming complexity of such considerations, only rough trends can be analyzed. The affinity of the nitrogen ligand for the metal center can be roughly referred to as nucleophilicity (the equally ambiguous term Lewis basicity can be used instead), with all reservations required not to misuse the notion. The second important factor is NH acidity. In contrast to the nucleophilicity, this factor can be reliably quantified for free NH acids in aprotic polar solutions.49 Nothing qualitative, however, is known as to how the coordination to Cu(I) affects the acidity, though it can safely be assumed that the acidity is increased by several pK steps. Nevertheless, two obvious tendencies can be noted: nucleophiles possessing high NH J


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feature of the ArCuIII intermediate obtained by the electrophilic cupration−oxidation pathway from those generated by oxidative addition to aryl halides is the lack of halide in the coordination shell of Cu, which ensures the stability of such a ArCuIII complex, as otherwise the reverse reductive elimination of aryl halide takes place as was noted above. The ArCuIII complex 24 bears three N ligands included in a macrocycle, forming a roughly square-planar coordination of the Cu center. This complex is stable, in spite of two sites being NH nucleophiles of secondary aliphatic amine nature. Reductive elimination is triggered by the addition of NH nucleophiles of higher NH acidity. Interestingly, the most NH acidic nucleophiles used (sulfamides, phthalimide, 2-pyridone) give exclusively the products formed by these external nucleophiles, while somewhat less NH acidic simple carboxamides give a mixture of two products, one formed by an external nucleophile and the second formed by an internal tertiary amine nucleophile.52b The easy formation of imidate complexes from imides in the absence of base is similar to what is observed in Pd(II) chemistry, with the essential difference that there such complexes are stable.53 This finding clearly shows that not a more nucleophilic but rather a more NH acidic nucleophile is what is preferentially eliminated (Figure 18).

the equilibration between ArPd(NHRZ) intermediates immediately precedes the reductive elimination step triggered by the deprotonation of the bonded NHRZ ligand, thus conforming to the classical Curtin−Hammett kinetic regime.54 In Figure 19 the trends in nucleophile preferences are roughly delineated. The Cu-catalyzed reactions show prefer-

Figure 19. Nucleophile preferences in Pd- and Cu-catalyzed C−N cross-coupling.

ences for nucleophilic aliphatic amines and ammonia, probably bonded as neutral molecules, andto an even greater extent for NH acidic amides and azoles, which are very likely to be bonded as the respective anions, formed in the prototropic equilibria in reaction mixtures. On the other hand, aromatic amines, which neither are good nucleophiles nor can be effectively deprotonated by bases used for Cu-catalyzed reactions, are rather poor substrates, avoided in competitive runs. In Pd-catalyzed reactions nucleophile preferences are roughly complementary. The preferred nucleophiles are those which furnish higher rates of reductive elimination, which depend on two factorsNH acidity of the bonded nucleophile and a decent level of nucleophilicity. Similar considerations apply to the choice of bases (or, more accurately, the basicity of the reaction environment defined by the combination of base, counterion effects, and media) in C− N cross-coupling. The behavior of copper-catalyzed systems is different from that of palladium-catalyzed systems. Palladiumcatalyzed systems require strongly basic environments, and unless a few special ligands are used, sodium tert-butylate in aprotic media is the base of choice in common protocols. At the same time, the reactions with base-sensitive reagents (triflates and other sulfonates, reagents containing base-cleaved groups such as ester, acyl, etc.) can be effectively run in the presence of Cs2CO3, though the reactions are usually slower than those in the presence of tert-butoxide.55 The third-generation ligands can be used in the systems with milder bases; not only Cs2CO3 but also K 2 CO 3 , K 3 PO 4 , KOH, etc. have been used successfully.20,56 On the other hand, with less NH acidic substrates, such as e.g. primary alkylamines, the use of the strong base LiHMDS can afford the reaction under milder conditions (Figure 20).57

Figure 18. Modeling the reductive elimination step.

The importance of this work52b in understanding the trends in Cu-catalyzed cross-coupling and the real source of differences from Pd-catalyzed counterparts cannot be overestimated. It should be stressed that in regular cross-coupling with Cu(III) intermediates the ligand to be eliminated is already in the coordination shell of Cu when the aryl group enters via oxidative addition, and this ligand is in the anionic deprotonated state (otherwise, oxidative addition does not take place at all); therefore, oxidative addition immediately leads to an intermediate undergoing fast reductive elimination, and ancillary ligands are not important for this process to take place. Thus, chemoselectivity and nucleophile preferences are defined by and only by the coordination equlibria of Cu(I) complexes which are able or not able to supply the reactive Cu-NRZ complex in a reasonable concentration. Once formed, the CuNRZ intermediate slowly enters the product-forming step (stepwise or concerted oxidative addition−reductive elimination), which defines the rate of the catalytic reaction overall but not the substrate preferences. Such behavior differs essentially from that observed in the Pd-catalyzed transformation, in which

Figure 20. Base dependence of the cross-coupling with electron-rich aryl chloride. K


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while the magnitude of the basicity itself is of lesser importance. Such bases enable the arylation of primary aliphatic and cyclic amines by aryl iodides and bromides at room temperature (Figure 23), as well as the arylation of anilines, azoles, and

In copper-catalyzed chemistry, only the early works employed similarly strong bases, while in further research the choice of bases shifted to moderate basicity. The most common choice is Cs2CO3, which delivers rather high basicity (a “naked” carbonate anion) in strictly anhydrous aprotic media but still is much less basic than of tert-butylate. Many copper-catalyzed reactions run well in the presence of even more modest bases, such as K2CO3, K3PO4, etc., though such bases are often used in basicity-enhancing aprotic environments (anhydrous polar solvents such as DMSO, DMF, NMP, etc. are particularly useful for carbonate bases). None of these bases is capable of appreciably deprotonating free amines, because the acidity of such substrates should be decreased by the same media, since the basicities of the respective conjugate bases (N− anions) are also enhanced in polar aprotic media. On the other hand, if the deprotonation takes place in the bonded nucleophile, this effect should not operate, as the product of deprotonation is formally a neutral complex, while the liberated halide ions are not as susceptible to solvent effects. Moreover, a few recent studies showed that the use of rather weak bases such as KHCO3 and KOAc is quite possible, at least in the arylation of amides by aryl iodides to afford high yields of target products. The same work reveals that the best choice is CsF, which not only furnishes high yields but also leads to a radical shortening of reaction times to 2 h instead of 16−20 h or the possibility of carrying out the reactions at room temperature with longer exposure times (Figure 21).58 The

Figure 23. Example of “naked” carboxylates in copper-catalyzed crosscoupling of deactivated aryl bromides with primary amines.

ammonia (water-free solution in dioxane) by aryl iodides, also at room temperature. One of the most effective bases in this approach is the less basic oxalate, which, if taken as its tetrabutylammonium salt, showed comparably high performance in the arylation of benzylamine in the presence of the different standard auxiliary ligands DMEDA, phananthroline, and N,N-dimethylglycine (DMG). Similar results were obtained with resin-immobilized quaternary ammonium salts (phosphates, acetates, carbonates).61 The mechanistic considerations discussed throw light on the dependence on steric effects. Both methods are very sensitive to these effect, but the patterns are different and very characteristic. Pd-catalyzed reactions are less sensitive to steric bulk in the electrophile, as this is bonded first when the coordination shell has enough free space. In fact, bulky aryls often have a remarkably positive effect on the yields and reaction rates, likely because the additional strain brought in by the aryl group facilitates reductive elimination. On the other hand, Pdcatalyzed reactions are very sensitive to the steric bulk of the NH nucleophile, apparently because of the negative effect on the ligand exchange equilibrium and therefore on the concentration of the respective intermediate. Cu-catalyzed reactions are extremely sensitive to steric bulk in both the NH nucleophile (because of the negative effect on ligand binding) and electrophile (low reaction rate of the product-forming step). These trends are elaborated below in the section devoted to particular types of substrates. An interesting consequence of ligand control and relative slowness of reductive elimination in Pd-catalyzed C−N crosscoupling is the possibility of trapping a Pd amide intermediate by an intramolecular aminopalladation and thus triggering a short cascade process, discovered and developed into a powerful synthetic method by Wolfe and co-workers (Figure 24).62

Figure 21. Example of Cu-catalyzed C−N cross-coupling in the presence of fluoride base.

beneficial action of this base is very probably accounted for by the low affinity of Cu for fluoride, which thus does not interfere with proper coordination events belonging to catalytic transformation. The other interesting system in line with the current context was developed by Fukuyama et al. to depend on cesium acetate in DMSO, enabling an effective “ligand-free” protocol of intraand intermolecular amination and amidation (Figure 22).59

Figure 22. Example of “ligand-free” acetate-promoted C−N coppercatalyzed cross-coupling.

This important observation is in line with work by Fu and coworkers60 showing that the well-known amination protocols using DMEDA or amino acid ligands can be dramatically boosted if anionic carboxylate bases (acetate, adipate, malonate, oxalate) are used in the form of tetrabutylammonium or, even better, tetrabutylphosphonium salts in organic solvents (DMSO, DMF, dioxane), that is, under conditions ensuring the maximum concentration of free (“naked”) basic anions,

Figure 24. Pd-catalyzed cascade process beginning as C−N crosscoupling but involving intramolecular trapping of a Pd amide intermediate. L


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direction of this competition in particular cases is dependent of the ligand and, more generally, the system.71 Most probably the outcome in each particular case depends on the interplay of prototropic and coordination equilibria, which is unfortunate because the coordination behavior of copper is very poorly studied, and thus this chemistry is doomed to be hardly predictable. It should be mentioned that such a situation prompted researchers to seek rationalizations of ligand dependence of N/O selectivity in considering mechanistic pathways outside of the common cross-coupling paradigm and altogether excluding the intermediacy of organocopper(III) intermediates via computational modeling (ref 40 vs ref 72). The computational evidence and sophisticated interpretations inferred thereof should, however, be accepted with reservations, because even if the most up to date high-level theoretical approaches are used, the accuracy of calculations of model systems involving transition metals is rather low, and simplifications necessarily invoked when building the model representations of real reaction systems are usually too drastic to promise a truly realistic description of the pathways involved. In fact, the data so far accumulated are rather scarce, and a side by side comparison of various catalytic systems has been done only for chelating amino alcohols (Figure 26). Several highly

Depending on the ligand, which most probably accounts for the shorter or longer lifetime of the Pd amide intermediate, either normal N-arylation or the cascade can be realized, thus giving a good degree of flexibility and control (Figure 25).63

Figure 25. Wolfe’s aminopalladation cascade vs regular C−N crosscoupling: pathway selection by ligand.

The cascade was developed mainly by Wolfe and co-workers to become an effective method of stereoselective synthesis of various five- and six-membered heterocycles.62b,64 On the other hand, no cascade transformation involving the analogous intermediates of Cu-catalyzed C−N cross-coupling has been so far disclosedmost probably the respective intermediates are too short-lived to be trapped. N/O Selectivity Issue. The OH nucleophiles are legitimate substrates for both Cu- and Pd-catalyzed cross-coupling reactions. Therefore, the competition between the O and N centers may become an important issue. Generally, Cucatalyzed reactions are more suitable for C−O cross-coupling, because OH nucleophiles can effect ligand exchange in Cu(I) complexes, the reductive elimination from ArCuIII intermediates is very facile even with less dative O ligands, and this process is not dependent on special ancillary ligands. Arylation of phenols, aliphatic alcohols, and even free hydroxide ion65 are effectively performed using simple Cu-catalyzed methods. A C−O bond is often preferentially formed in the presence of NH nucleophilic centers. In contrast, in the Pd-based systems, the reductive elimination of the C−O coupling product can be enabled only by highly bulky ancillary ligands.66 In addition, OH bases are rather poor ligands for palladium, probably because Pd−O binding lacks additional π bonding with unoccupied d orbitals of the metal,67 and their competitive binding in the presence of NH nucleophiles is practically improbable. Moreover, the latter are known to effectively displace OR ligands from the coordination shell.68 Nevertheless, due to their higher acidity OH nucleophiles exist and participate in ligand exchange equilibria as anionic species, while the much less acidic NH nucleophiles remain in the neutral form. Such a temporary advantage in nucleophilicity was used, for example, by Hartwig and co-workers in a mechanism explaining the purported special role of tert-butoxide in C−N cross-coupling.69 Though the general validity of such a pathway was later not corroborated, the chemistry of ligand exchange revealed preferential binding of NH nucleophiles by Pd(II) centers. In the context of C−N cross-coupling this feature is a blessing, as O arylation70 practically never competes with N arylation in Pdcatalyzed reactions, and the examples of selective n-arylation of various multifunctional compounds containing either alcoholic or phenolic OH groups are multiple. In the case of Cu-catalyzed reactions the competition of C− O and C−N cross-coupling is a common phenomenon. The

Figure 26. N/O arylation of amino alcohols.

selective complementary protocols were indeed developed for these ambident nucleophiles. It is noted that N arylation is usually achieved under milder conditions, in “ligand-free” systems or with rather ineffective O,O chelating ancillary ligands:73 that is, under conditions in which the amino alcohol itself is likely to serve as a chelating ligand. The reductive elimination in that case should indeed involve the less electronegative N center (cf. Figure 28). On the other hand, O arylation is observed either in the presence of a strong N chelator73b or a strongly coordinating solvent73a at markedly higher temperature: that is, under conditions disfavoring chelation of the amino alcohol, which can be bonded via the O center because of higher OH acidity vs NH acidity. The acidity of bonded ligands is higher due to stabilization of the ligand by the metal center. It is likely that the differences in acidity of bonded ligands are therefore markedly smaller than the differences of acidity of free molecules. A good demonstration of this can be found in the results obtained by Buchwald and coauthors on the competitive arylation of phenol−aniline mixtures.74 Usually, phenols are much more acidic than anilines; thus, the outcome is the arylation of phenol via binding of phenolate. However, the introduction of even the rather weak electron-withdrawing substituent p-CN into aniline M


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as the proton abstraction by base is the factor triggering the reductive elimination. Thus, relative NH acidities of the chelating ancillary and NH nucleophile reagent define the direction. Lowering the NH acidity by N monomethylation thus is an effective means to widen the scope of the ligand. Catalyst Loading. Palladium-catalyzed amination reactions typically require 0.5−1 mol % palladium and a comparable amount of phosphine or carbene ligand, thus belonging to catalytic processes of moderate effectiveness with TON values around 100. The use of third-generation ligands allows for a substantial increase in catalytic activity and stability of catalytic species. With select third-generation ligands the catalytic systems are stable enough to survive 10 000 and more catalytic cycles. With aryl chlorides the use of the ligand BrettPhos (13) made it possible to lower Pd loading to 0.05 and even 0.01 mol % (Pd:BrettPhos = 1, tBuONa, Bu2O, 80−110 °C).12 The ligand Josiphos (6) is effective at the 0.005 mol % level and sometimes even lower.11 The precatalysts based on heterocyclic carbene ligands allowed carrying out the amination reactions even at the 0.001 mol % level, though only with selected bulky substrates, aryl bromides, and a long reaction time of 30 h.29c In contrast, copper-catalyzed processes generally rely on a much higher catalyst loading, from 5 to 10−20 mol % and higher, thus formally being capable of only a few catalytic cycles. Moreover, pseudostoichiometric protocols in which the loading of copper compounds is equimolar or taken in excess are not rare, though the reactions realized in such systems most probably remain catalytic, because the Cu sources used (copper oxides or the like) are generally heterogeneous, only partially dissolved during the reaction; thus, only a part of the initial loading is utilized. High loadings of copper used in coppercatalyzed cross-coupling may reflect the lower reactivity of copper complexes in the oxidative addition reactions as compared to palladium complexes. The reaction rate is further limited because, as was discussed above, only a small fraction of loaded copper can be present in the system as active monoamide complex, as the whole copper pool is distributed among various complexes existing in poorly controlled equilibria (Figure 16). Thus, the amount of precatalyst loaded, which is formally used to estimate TON/TOF and other parameters characterizing the catalytic performance, almost certainly gives a very poor description of how much copper is indeed engaged in the catalytic process. It is therefore quite possible that the actual reactivity of copper catalysts is indeed no less impressive than the reactivity of the best Pd systems. Unfortunately, no reliable means exist to estimate the amount of active catalyst in the overall pool of Cu species existing in a given catalytic system. Some insights can be made, however. Recently, Norrby and co-workers showed that copper-catalyzed amination can be performed using a low loading of copper precatalyst down to 0.001 mol %, though really good results were obtained only with selected azoles, which are among the most reactive NH nucleophiles in Cu-catalyzed C−N cross-coupling, and PhI, using an enormous excess of ligand (DMEDA:Cu = 20 000!) at quite high temperature (Figure 29).76

leads to a dramatic inversion of the chemoselectivity. It is rather unlikely that this can be caused by substituent effects on acidity (OH vs NH) in the free moleculesthe difference between the acidities of the parent molecules (OH acidity of phenol vs NH acidity of aniline) is too large to be leveled off by a single para substituent (Figure 27).

Figure 27. Competition of N and O arylation depending on the substituent effect in anilines.

However, if both N and O ligands are simultaneously present in the coordination shell, as in chelates, the reductive elimination involves exclusively the amide ligand (Figure 28).74,75

Figure 28. Preferential arylation of amine group in o-aminophenol.

Preferential reductive elimination of a N ligand makes it possible to successfully use clelating ligands bonded through oxygen atoms in various C−N coupling protocols. It is quite interesting that, apparently, no reductive C−O elimination takes place from chelated phenols or alcohols, such as e.g. 8hydroxyquinoline, its 1,2,3,4-tetrahydro analogue, o(dimethylamino)phenol, and enolates, a considerable number of which are used as ligands in Cu-catalyzed cross-coupling reactions. Such a property enables the use of such ligands without side reactions of self-arylation which result in ligand depletion and contamination of the target products by the arylated ligand. More interestingly, this behavior is in contrast with the reactivity of chelated NH nucleophiles, which do undergo selfarylation as a side reaction. Mainly because of this, simple ligands such as EDA and CyDA are often of little use and are replaced by their N,N′-dimethyl derivatives (DMEDA, DMCyDA), which are much less prone (but still not totally reluctant) to undergo self-arylation. In this respect, it could be safe to note that if not all but many chelated NH nucleophiles are also quite resistant toward self-arylation, suffice it to note Ma’s family of amino acid ligands, most of which contain free NH2 groups. It can also be argued that the behavior of chelated NH nucleophiles and their ability to serve as ligands in a given reaction is associated with competitive deprotonation, as soon

Figure 29. Low-loading Cu-catalyzed C−N cross-coupling. N


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reactions of sulfonates.20,48,83 On the other hand, coppercatalyzed systems generally prefer polar aprotic solvents, such as DMF, DMA, NMP, DMSO, and the like, though examples of the use of nonpolar solvents are not rare. Most probably, solvent preferences are defined by solubility considerations, as most of the common copper precursors are simple salts or oxides (CuI, CuCl, CuO, Cu2O, etc.), the solubility of which is enhanced by polar coordinating solvents, as well as the need to increase the basicity of rather weak bases commonly employed in this domain. An interesting problem associated with the choice of media is the effect of water and the possibility of realizing some C−N cross-coupling protocols in aqueous environments, generally considered as environmentally benign or “green”. Both types of reactions were long considered to be moisture sensitive, and not suitable for aqueous media, though for different reasons. In Pd-catalyzed reactions the need for quite strong bases (tert-butylate or anhydrous cesium carbonate) was considered a prerequisite for effective deprotonation of NH nucleophile, and thus the presence of water, which very strongly limits the basicity, is inappropriate (the only exclusion had long remained the early Boche protocol using sulfonated triphenylphosphine as the ligand in an aqueous system84). The use of some third-generation ligands allowed for the use of milder bases and precise control of the coordination sphere of Pd center; therefore, the ban on aqueous media was partially lifted and a few effective aqueous protocols were recently described,48,85 the latest and most spectacular being proposed by Lipshutz et al. using the proprietary Takasago ligand cBRIDP (17) in the presence of the proprietary nonionic surfactant PTS (PEGylated sebacoyltocopherol), allowing for arylation of arylamines in micellar aqueous solution at room temperature (Figure 31).86

Thorough optimization and kinetic measurements revealed that DMEDA is indeed a unique ligand for this system.77 Further examples of low-loading Cu-catalyzed cross-coupling were reported by Fu, Ling and co-workers for aryl bromides and iodides containing directing o-substituent. The effect of directed oxidative addition furnished the reactions under very mild conditions (room temperature).78 The need to apply a huge loading of ancillary ligand can hardly be accounted for by suppression of deactivation of catalyst due to aggregation, which is the main factor governing the behavior of “homeopathic palladium catalysis”.79 Unlike Pd(0), which is prone to form inactive Pd metal sediments, Cu(I) cannot be expected to behave similarly. Thus, the behavior of low-loading Cu systems is most likely due to an unfavorable interplay of equilibria when several ligands compete for a very low concentration of copper. As soon as NH nucleophile is naturally present in a huge excess over Cu, the equilibrium of formation of homoleptic anionic biscomplexes, which are known to be inactive in oxidative substitution, should be shifted to the right, and the only means to generate a significant concentration of active monoamide complexes is to add an ancillary ligand, which binds to copper a little more strongly (e.g., because of chelation), in which case it can compete with the second molecule of NH nucleophile and form active complex. However, if a much stronger chelator is used, the formation of useless homoleptic CuL2 complex can be envisaged, which will not allow NH nucleophile to altogether enter the coordination sphere of Cu. It would be certainly excellent to find a ligand which can control the coordination sphere of copper more precisely by selectively binding one ancillary ligand and one amide ligand, similarly to what we have in palladium catalysis, but this task has not been solved so far, nor does it seem highly probable that it can be solved. The ability of copper species to catalyze cross-coupling using very low loadings of precatalysts was demonstrated to account for, at least partially, recently discovered iron-catalyzed crosscoupling reactions (Figure 30).80 The reactions are actually

Figure 31. Mild aqueous palladium-catalyzed C−N cross-coupling protocol.

Moreover, a small amount of water was found to exert a catalyst preactivating effect in a number of special tasks: e.g., amidation of chloroarenes12 or aryl mesylates.83a As to the copper-catalyzed C−N cross-coupling reactions, water spawns hydroxide, which is a good ligand for Cu(I), thus spoiling the coordination shell and effectively competing with the NH nucleophiles65 and causing the formation of phenols and diaryl ethers as byproducts. In most of the copper-catalyzed C−N cross-coupling reactions water is excluded and reactions are performed in dry solvents, sometimes in the presence of molecular sieves. Still, recently a few systems containing water were disclosed. However, it should be borne in mind that almost all organic halides and NH nucleophiles are not soluble in water and form a separate organic phase if the reaction is conducted in an aqueous environment. The systems therefore actually employ phase-transfer conditions even if no phasetransfer agent is explicitly used. It is highly likely that the heterogeneity of such systems, in which the process itself probably runs in an organic phase, is thus protected from the

Figure 30. Amidation catalyzed by copper traces in iron salts.

catalyzed by copper impurities in iron salts.81 Only 5 ppm of copper is sufficient to perform the arylarion of pyrazole or benzamide by aryl iodide, and the presence of iron is not required. Bimetallic Fe−Cu catalytic systems, in which the effect of two metals is likely to be synergistic, were reported by Taillefer and co-workers.82 Reaction Media. For palladium-catalyzed reactions the choice of solvents is similar in C−C and C−N (and generally C−heteroatom) cross-couplingthe basic choice is solvents of low polarity which can dissolve the substrates well and the base reasonably well and permit heating to around 100 °C without technical sophistication. Common choices are 1,4-dioxane and toluene (other useful solvents include DME, THF, and xylenes), and new protocols using advanced ligands often make use of tert-butyl alcohol or tert-amyl alcohol as solvents, which markedly enhance the reactivity particularly, in the O


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species (bromides, iodides, fluorinated sulfonates) processed using common protocols with second-generation ligands and less reactive species (chlorides, nonluorinated sulfonates) requiring special ligands and advanced protocols. The development of such ligands and protocols, however, resulted in such a spectacular advance of this area, that the less reactive substrates are no longer regarded as a challenge. There is a specific problem with iodides, which are more reactive than all other substrates but often exhibit low turnover values and incomplete conversions because of poisoning of the catalyst by the liberated iodide.4b,95 On the other hand, the scope of Cu-catalyzed methods is much narrower, involving as standard substrates only iodides and bromides, with the former being the first and often the only choice. Copper catalysts are in general insufficiently active for efficient involvement of aryl chlorides, likely because of low reactivity in the oxidative addition reaction. So far there have been only a few instances of involvement of aryl chlorides in C−N cross-coupling, and practically in all cases the aryl chlorides used are activated toward nucleophilic attack by electron-withdrawing groups. In these cases the reactions are very likely not true cross-coupling but instead an aromatic nucleophilic substitution, with Cu(I) probably playing the role of lending assistance through coordination of leaving chloride. Otherwise there are cases in which the reaction is facilitated by an ortho-directing effect, similar to what is observed in the Hurtley reaction of copper-catalyzed arylation of CH acids by o-bromobenzoic acids.96 Thus, the arylation of anilines by ochlorobenzoic acids in the system Cu/Cu2O (9 + 4 mol %) in ethylene glycol in the presence of KOH at 130 °C was described. The ortho-directing effect results in a highly unusual preference of chlorine over bromine, if the former is in a position ortho to the directing group.97

competition with hydroxide nucleophile, which is well-known as such a highly hydrophilic species that it cannot be altogether transferred into the bulk organic phase by any phase-transfer agent. For example, an interesting ligand system composed of oxalyl dihydrazide and ketones, such as hexane-2,5-dione, was however shown to control the coordination of copper species even in aqueous environments using a rather complex system (CuO (5 mol %)−L (50 mol %)−KOH, TBAB, H2O) with either microwave or conventional heating. This heterogeneous phase-transfer-assisted system was useful for coupling a broad range of NH nucleophiles (primary aliphatic and aromatic, secondary cyclic, and azoles) with aryl bromides.87 An effective “ligand-free” and solvent-free system for the arylation of primary aliphatic amines and pyrrole in the presence of CuCl and a huge excess of aqueous tetrabutylammonium hydroxide (40% solution) was also disclosed (Figure 32).88 Other PTC systems also appeared.89

Figure 32. Example of “ligand-free” aqueous copper-catalyzed arylation of primary amine.

An overly simple protocol was disclosed by Wei and coworkers, using copper powder as precatalyst (requiring the presence of some residual air to furnish Cu(I) species in situ) and no added base, except for a large excess of primary amine to be arylated (Figure 33). The protocol works best for small

Figure 33. Simple aqueous protocol for arylation of small aliphatic primary amines.

primary amines, particularly methylamine, which is generally considered as an inconvenient substrate for C−N crosscoupling (in the Pd-catalyzed domain, special ligands are required12,90), and a broad range of aryl halides, including activated aryl chlorides.91 It should be noted that the simplest NH nucleophile, ammonia, is apparently the reagent that can effectively compete with water and hydroxide, as for this nucleophile many systems containing water have been described (cf. Ammonia and Ammonia Equivalents) The other example is the use of 8-oxyquinoline as a ligand for the arylation of imidazole and benzimidazole using an unusually broad scope of aryl halides, including iodides, bromides with both electron-withdrawing and -donating substituents, and even aryl chlorides, including m-dichlorobenzene, if soluble base (Et4N)2CO3 is used as base in aqueous DMF at 130 °C.92 The other wide-scope protocol used hydrazides of pyrrole-2carboxylic acid.93 Intramolecular reactions in aqueous solvent were also developed.94 The Scope: Electrophilic Coupling Partners. Palladiumcatalyzed C−N cross-coupling has been applied to a much wider scope of electrophiles, including halides (chlorides, bromides, and iodides) and sulfonates (triflates, nonaflates, mesylates, tosylates, etc.), which are divided into highly reactive

There are also a few cases in which unactivated chlorides are reported to react. Such reactions are usually implemented in the presence of strong bases in polar aprotic solvents. A typical example of such a protocol was reported by Xu and Wolf,98 where PhCl was made to react with primary or secondary aliphatic amines or Ph2NH in the presence of 5 mol % Cu2O and 2 equiv of tBuONa in NMP at 100 °C for 24 h to give high yields of the respective triarylamines. The use of superbasic media may enable the nucleophilic substitution by an aryne mechanism. A notable exception was reported by Wan and coworkers using an aqueous system with a phase-transfer agent and a weak base, fully excluding the aryne alternative. The protocol using a large excess (5−10-fold over Cu) of two ligands furnished reasonable to good yields in the crosscoupling of even deactivated aryl chlorides with primary amines, anilines, ammonia, and diazoles (Figure 34).99 This example shows that an understanding of the reactivity of Cu species is very far from complete. Below, a few specific problems with electrophilic substrates are discussed. Aryl Fluorides. Aryl fluorides are probably the most challenging substrates for transition-metal-catalyzed crossP


Organometallics

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effectiveness of which was however established by all relevant comparative and blind runs. Also, it was explicitly proven that the reaction in the presence of such a Pd system is markedly faster than a noncatalyzed nucleophilic substitution reaction. Examples of copper-catalyzed reactions are more frequent, though all of them cannot be considered as adequately proven catalyzed cross-coupling. In fact, as Cu(I) is a better Lewis acid than Pd(0), it is quite probable that Cu-catalyzed reactions do occur as a regular nucleophilic substitution, with Cu(I) lending electrophilic assistance to the cleavage of fluoride. It is not surprising that there are “ligand-free” systems among those reported, as electrophilic assistance does not require any ligands. Copper complex of the sulfonated salen ligand catalyzes the arylation of azoles and piperidine by activated aryl fluorides and chlorides in the system Cu complex (1 mol %)−K2CO3 in DMF at 110 °C, notable for unusually low catalyst loading.104 Very similar activity was noted for a “ligand-free” system based on nanocrystalline CuO (10 mol %) (K2CO3, DMF, 120 °C)105 or on synthetic copper-exchanged apatites (K2CO3, DMF, 120 °C).106 Those fluoroarenes bearing strong mesomeric acceptors such as NO2, CN, SO2R, etc. are commonly regarded as “activated fluorides”, but the scope of fluoroarenes capable of taking part in noncatalyzed nucleophilic substitution is actually wider. A few simple halogen (F, Cl, Br, I) atoms can as readily serve as activating groups, best located in a position ortho to the fluorine being substituted. Such fluorine atoms can be reactive in noncatalyzed addition−elimination nucleophilic aromatic substitution under rather mild conditions, usually below 100 °C in polar solvents (cf. ref 107 for examples). Moreover, in some cases fluorine can be substituted even in unactivated fluoroarenes (fluorobenzene, fluorotoluene), also below 100 °C.107a Of direct relevance to the discussed subject is a recent study of the arylation of azoles by 2,4-difluoroiodobenzene, in which a comparison of catalyzed vs noncatalyzed substitution was made under otherwise identical conditions (Figure 37). The o-fluorine was shown as a primary target of nucleophilic attack in the absence of copper catalysts. The reaction in Taillefer’s system using Salox ligand in this case resulted in

Figure 34. Arylation by activated and deactivated aryl chlorides in aqueous system.

coupling reactions.100 Still, a few reports have described successful C−N cross-coupling using aryl fluorides bearing electron-withdrawing substituents. Oxidative addition, if altogether possible, in such cases is apparently very close to normal nucleophilic substitutionas fluoride is a rather poor ligand for soft transition-metal centers, the attack should take place without proper electrophilic assistance. In fact, an unambiguous demonstration of the possibility of C−F bond activation by Cu(I) reagent was recently demonstrated by Ribas and co-workers using an effective chelator able to support the well-defined complexes of Cu(III) (Figure 35). In this case, halogen exchange via the established Cu(III) intermediates took place, including the exchange of F with Cl.101

Figure 35. Oxidative addition of C−F bond to Cu(I) complex, assisted by chelation.

In discussing and interpreting such reactions, it is very important to understand whether we are dealing with true transition-metal-catalyzed cross-coupling or a regular noncatalyzed nucleophilic substitution. Unfortunately, not all reports in this area have explicitly tested the possibility of noncatalyzed reactions under the conditions used. On the other hand, all published reports work with activated fluorides bearing electron-withdrawing substituents, which are known as very good substrates for noncatalytic addition−elimination aromatic substitution. Thus, the role of transition metals in these reactions is not to switch on a full-scale cross-coupling catalytic cycle but rather to lend electrophilic assistance to the leaving fluoride, a terribly bad nucleofuge when released as a free ion. Electrophilic activation of aromatic F (and Cl) toward substitution and formation of a carbon−metal bond by coordination with transition metal is known (cf. ref 102, for example). There seems to be only a single report of palladium-catalyzed arylation of NH nucleophiles by aryl fluorides.103 A rather exotic feature of the proposed method is the use of Pd(PPh3)4 as palladium precatalyst in the presence of DavePhos ligand, thus using an unusual ligand-redundant system (Figure 36), the

Figure 37. Competition of copper-catalyzed vs noncatalyzed aromatic substitution.

Figure 36. Pd-catalyzed arylation by activated aryl fluoride. Q


Organometallics

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competition of copper-catalyzed iodine substitution and direct fluorine substitution.108 Alkenyl and Alkynyl Derivatives. Besides arylation, both Pdand Cu-catalyzed C−N cross-coupling can be applied to vinylation (alkenylation) using roughly the same protocols as those used for arylation. Palladium-catalyzed protocols can be employed for vinylation of azoles and secondary and primary amines.109 A major advantage of Pd-based systems is the wider scope of leaving groups, as such systems can employ readily available enol sulfonates, not only triflates110 but also trivial tosylates.48,111 Moreover, in the palladium-catalyzed amidation enol sulfonates are apparently more useful substrates than alkenyl halides, for which the number of protocols published is scarce.112 On the other hand, copper-catalyzed protocols, though confined to alkenyl bromides and iodides, are abundant and involve cross-coupling with primary and secondary amines, amides, sulfonamides, hydrazides, and azoles.113 Generally milder conditions of copper-catalyzed reactions using weaker bases are advantageous for alkenyl halides, which are often highly prone to undergo elimination in the presence of stronger bases, resulting in the production of various side products formed from acetylenes.114 On the other hand, an important special application of copper systems is cross-coupling of haloacetylenes leading to ynamines and ynamides. Ynamides can be formed by the reaction of preformed potassium salts of amides in the presence of stoichiometric CuI.115 The catalytic protocol was realized using the system CuCN/DMEDA with K3PO4 in toluene at reflux116 or in the presence of copper diketonates.117 The use of preparatively inconvenient bromoacetylenes can be avoided through the use of tandem elimination−cross-coupling reactions from 1,1-dibromoalkenes. The method is applicable to amides, lactams, and sulfonamides, as well as azoles.118 Primary amines can be used as well if transformed into N-tosyl derivatives (Figure 38).119

Figure 39. Macrocyclization by copper-catalyzed alkynylation of amides.

thesis. The classical Sandmeyer reaction, however, uses stoichiometric amounts of copper salts and is not catalytic with respect to the metal (though there is recent evidence that it can be performed in a catalytic mode123). So far, in C−N cross-coupling reactions there have been no proven successful examples of the application of arenediazonium salts using copper or palladium catalysts. Given the rapid growth of research on other transition-metal-catalyzed transformations of arenediazonium salts, the application to C−N cross-coupling is likely to appear soon. In any event, arenediazonium salts are indeed rather challenging substrates prone to undergo uncontrolled decomposition and side reactions. The derivatives of hypervalent main-group elements are natural substitutes for them, known to possess enhanced electrophilicity because of ready cleavage of such element-centered leaving groups enabled by formal two-electron reduction: R−Mn + + Y − → R−Y + M(n − 2) +

In addition to the best known representatives of this type, the derivatives of hypervalent iodine (iodonium salts124), the maingroup metals (Tl(III), Pb(IV), Bi(V)) are known to be capable of such transformations (Sb(V) was recently added125). The derivatives of these three metals are known as mild arylating agents for a number of nucleophiles, in this respect resembling the hypervalent iodine compounds. Some of these reactions are spontaneous, while the others require copper or palladium catalysts to enable reasonable rates. In the context of this review, in the arylation of NH nucleophiles such organometallic reagents are modest arylating agents, and so far copper catalysts have been exclusively used, which probably can be accounted for more by tradition than by actual reactivity. These reactions involving aryllead(IV) and diarylbismuth(V) compounds were described by Barton and co-workers as mild and quite versatile methods of amine synthesis.126 Aryllead(IV) triacetates were formed either by direct plumbylation or transmetalation by Pd(OAc)4 transfer aryl groups in the presence of copper catalysts under mild conditions, though examples are still scarce (Figure 40).126b,127 It should be noted, however, that these systems were among the earliest examples of transition-metal-catalyzed amination and amidation chemistry, realized well before practically all Pd- and Cu-catalyzed protocols emerged. The arylation of azoles, amides, and aromatic and aliphatic amines were realized by Barton and co-workers under mild base-free conditions in the presence of a catalytic amount of cupric acetate. The method is chemoselective toward aromatic amino groups in the presence of azole or carboxamido residues; thus, this method is complementary to copper-catalyzed arylation by aryl iodides.

Figure 38. Copper-catalyzed alkynylation of sulfonylamide by in situ formed bromoacetylene.

A general protocol using a cupric sulfate pentahydrate− phenanthroline catalytic system to effect cross-coupling of bromoalkynes with various amides, including N-tosylamines, was developed by Hsung and co-workers.120 The method is useful not only for intermolecular reactions but also for intramolecular macrocyclization (Figure 39). The method was applied to the synthesis of a new class of N-phosphorylynamides, thus showing an outstanding potential of the strategy to access entirely new targets.121 A “ligand-free” protocol for Nalkynylation of azoles using PEG400 media and microwave heating was added to the arsenal by Burley, Davies, and coworkers.122 Substrates with Enhanced Electrophilicity. The archetypal substrates of this class are arenediazonium salts. The transformation of arenediazonium salts in the presence of copper and cuprous salts, the classical Sandmeyer reaction, is, along with the Ullmann and Goldberg reactions, among the most ancient incarnations of transition-metal-assisted organic synR


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cross-coupling, other ways to solve this challenge are appearing; vide infra). Interestingly, the methods reported often use both Pd and Cu catalysts, the distribution of roles among which is vague. Thus, the arylation of benzotriazole was realized using water as solvent, in which both diaryliodonium salts and the sodium salt of benzotriazole are soluble. The catalyzed as compared to noncatalyzed reaction is regiospecific to afford exclusively 1-arylbenzotriazole derivatives.132 The reaction can also be done with cheaper PdCl2(dppe) catalyst in nonaqueous solvent, though under harsher conditions. Interestingly, in both methods both aryl groups from the iodonium salt are utilized in the reactions.133 A similar copper−palladium system allowed for arylation of the even weaker nucleophiles 5-aryltetrazoles selectively at the 2-position. The presence of both Pd and Cu catalysts was essential for achieving high yields, high regioselectivities, and fast reactions (Figure 42).134

Figure 40. Example of chemoselective arylation by aryllead(IV) triacetates.

Intermediate formation of aryllead(IV) triacetate was used by Finet and co-workers in a protocol employing arylboronic acids as primary arylating agents for arylamines, which allowed the use of catalytic amounts of cupric acetate under very mild basefree conditions (Figure 41).128 Interestingly, if the net

Figure 42. Arylation of 5-phenyltetrazole by diaryliodonium salts.

Kang et al. developed a general protocol allowing for the use of diaryliodonium salts to arylate amines at room temperature and azoles and amides at 50 °C in the presence of only copper catalysts (5 mol % Cu as CuI or Cu(acac)2) and a cheap base such as K2CO3 under mild conditions.135 The method has been applied to the mono- and diarylation of uracyl, thymine, and 6methyluracyl136 and to 5-aryltetrazoles.137 Interesting analogues of iodonium salts, alkynyltriarylbismuthonium salts, were introduced by Sueda and co-workers as highly potent electrophiles for copper-catalyzed cross-coupling with the very weak nucleophiles phthalimide and other imides (Figure 43). Due to the extremely high reactivity, the reactions take

Figure 41. Example of copper-catalyzed arylation of amines by aryllead(IV) derivatives formed in situ from arylboronic acids and stoichiometry (dashed box).

stoichiometry of this process is considered, it corresponds not to regular but to oxidative cross-coupling, with Pd(IV) serving the role of stoichiometric oxidant (vide infra). This analogy indeed highlights a very close relation between the two types of cross-coupling. The potential of organolead(IV) compounds and other hypervalent derivatives of non-transition metals is undoubtedly underestimated, and further research will appear, though such compounds can hardly become widely popular because of a common nasty featuretheir extreme toxicity. Much more popular and synthetically exposed are the derivatives of hypervalent iodine, particularly the iodonium salts. These highly reactive electrophiles can transfer one aryl group onto good nucleophiles, e.g. amines,129 even in the absence of catalysts. However, in C−N cross-coupling reactions the presence of catalyst is desirable to improve yields and broaden the scope of this valuable transformation. Diaryliodonium salts in many respects resemble arenediazonium salts, the nucleophilic substitution of which is well-known to be facilitated by copper and its salts and complexes130 (one of the earliest examples of N-arylation131). Though this analogy is transparent, the development of synthetically relevant catalytic protocols for the use of diaryliodonium salts was started only quite recently. These reagents are definitely not suitable for common tasks, because of their apparent noneconomic nature (a stoichiometric amount of expensive and heavy iodine and waste of one of the organic groups) but can be quite useful in solving specific problems where other methods fail. For example, diaryliodonium salts are useful for arylation of very weak nucleophiles which cannot be accessed by more common electrophiles within the regular C−N cross-coupling paradigm (however, with the development of oxidative and Umpolung

Figure 43. Alkynylation of phthalimide by alkynyltriphenylbismuthonium salts.

place at −40 °C, probably the lowest temperature recorded in C−N cross-coupling reactions of all sorts. Either an alkynyl or aryl residue is transferred to imide, depending on the structure of the latter.138 The Scope: NH Nucleophiles. Primary Aliphatic Amines. Primary aliphatic amines are well-established NH nucleophiles for both Pd- and Cu-catalyzed methods. In the Pd-catalyzed domain, the reactions of primary aliphatic amines have been known from the very beginning, though the entry-level firstgeneration ligand (o-tol)3P gave rather poor results due to side reactions (reductive dehalogenation and diarylation).3b,d With the introduction of second-generation ligands (dppf, BINAP) these problems were overcome, and primary aliphatic amines became standard targets.4,55,139 Amines such as n-butyl-, nhexyl-, benzyl-, and cyclohexylamine are considered as model amines for the development of new methods. The thirdgeneration ligands allowed for broadening of the scope of both S


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chelators are 1,3-diketones, the most effective of which were found to be 2-acylcyclohexanones useful for the arylation of piperidine, morpholine, N-methylpiperazine (CuCl (10 mol %)−L (Cu:L = 2.5:1), K2CO3 or Cs2CO3, NMP, 130 °C).146 More effective are 2-pyridyl β-ketones, particularly 8-acetyl5,6,7,8-tetrahydroquinoline (25), described by Wang and Ding, showing quite versatile and impressive performance under mild conditions, enabling room-temperature arylation of various amines (primary amines, including multifunctional and heteroaryl derivatives, as well as some secondary amines and aqueous ammonia) by aryl iodides. Aryl bromides require modest heating to 65 °C (CuI (10 mol %)−L (Cu:L = 1:2), Cs2CO3 (2 equiv), DMF).147 Jiang and coauthors described the use of 8-hydroxyquinoline-N-oxide (26) as a ligand for arylation of various NH nucleophiles, including primary amines, by aryl iodides and bromides and activated aryl chlorides using only 1 mol % of CuBr (Figure 45).148 Similar results under the

amines (toward branched-chain sterically congested molecules) and electrophiles (to aryl chlorides, tosylates, etc.).7a,13,56,140 Sterically hindered amines such as tert-butylamine,8b,11,90a,141 αphenylethylamine,141b,d,142 1-adamantylamine,8b,90b,143 and functionalized branched amines144 were successfully arylated. The low reactivity of N-alkylanilines in almost all published protocols makes the diarylation a problem of little concernin most cases the effective suppression is achieved by using just a 20% excess of primary amine. With the introduction of bulky third-generation ligands, steric differentiation became an important factor in increasing the selectivity of monoarylation using even lower excess ratios, which is particularly important for complex and expensive amines. Among various ligands of this kind, the performance of Josiphos ligands, particularly CyPF-tBu (6), was particularly impressive, allowing for monoarylation of primary amines by aryl chlorides and bromides with 100% monoselectivity.11 The other record of spectacular absolute mono- vs diarylation selectivity was achieved using the ligand BrettPhos (13) and a preactivation protocol allowing in situ generation of monophosphine complex, which allowed selective monoarylation of even the smallest methylamine and a clean discrimination of primary amine over secondary or cyclic amine sites in polyamine nucleophiles (Figure 44).12 The use of special bulky ligands allows for clean monoarylation of very small amines, particularly methylamine.12,90

Figure 45. Low-loading CuBr catalyzed arylation.

same conditions were achieved using 3-acetylcoumarin as ligand.149 Among very rare “ligand-free” protocols the use of mixed Cu−Fe hydrotalcite was reported by Wakharkar and coworkers. This protocol is additionally base-free and quite broad in scope (applicable to deactivated aryl bromides and primary aliphatic and aromatic amines and azoles), such unusual performance probably being due to the unidentified promoting influence of iron.150 The other Cu−Fe cocatalyzed system, developed by Fu and co-workers and also applicable to a wide scope of NH nucleophiles, relied on the BINOL ligand (CuO (10 mol %), FeCl3 (10 mol %), BINOL, Cs2CO3, DMF, 80− 110 °C).151 Fukuyama and co-workers developed a “ligandfree” protocol using Cu(II) acetate as a precatalyst and phenylhydrazine as reducing agent to effectively generate active Cu(I) species in situ.152 The problem of mono-/bis-arylation selectivity in coppercatalyzed reactions seems so far to have never been explicitly investigated, though this probably is not needed, as secondary amines are generally not reactive at all. Nevertheless, in practically all post-Ullmann protocols reported, primary amines are used in no less than 50% and often in huge (200−600%) excess. The reasons for such noneconomical precautions are not clear, and it could be hypothesized that the product amine is capable of competitively binding to copper and decreasing the effective concentration of catalyst and poisoning the catalyst. The chemoselectivity of copper-catalyzed methods enabled selective arylation of polyamines containing both primary and secondary amine groups by bromo- and iodoarenes.153 Moreover, the reactions with dihalobenzenes were also selective with respect to substitution of only one halide (Figure 46).154 Secondary Aliphatic Amines and Cyclic Amines. The current status of secondary dialkylamines in Pd- and Cucatalyzed C−N cross-coupling is dramatically different. For Pdcatalyzed methods the factor of prime importance is steric hindrance. Therefore, cyclic amines (nonaromatic heterocycles)

Figure 44. Chemoselective arylation of a primary amine center.

On the other hand, in Cu-catalyzed C−N cross-coupling aliphatic amines are regular but still rather challenging nucleophilesso far the number of protocols described in this area is rather modest, and only a few of them were demonstrated to be useful for a more or less broad selection of substrates. In the majority of published papers the scope is limited to a few standard molecules. Due to the high nucleophilicity and low acidity of such molecules, such amines can be expected to easily overload the coordination sphere of copper and form inactive complexes. Therefore, effective ancillary ligands can be expected to be prerequisite in order to control the coordination sphere of copper. “Ligand-free” techniques relying on a happy interplay of coordination events can hardly be expected to have a wide scope and be useful for anything more but reactions of a few well-behaving simple amines. Indeed, among the procedures reported, the use of good effective chelators can be noted as a common recipe. For example, 1,2,3,4-tetrahydro-8-hydroxyquinoline was shown to effect arylation of primary amines (CyNH2, BnNH2) and morpholine by aryl bromides in the system CuBr (10 mol %)− L (2:1), Cs2CO3, and DMSO at 80 °C. A strong dependence on chelator is demonstrated as e.g. o-(dimethylamino)phenol showed lower but comparable activity, while the standard 8hydroxyquinoline was markedly inferior.145 The other good T


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to account for the ineffective formation of monoamide complex required for oxidative addition. More work is definitely required to clarify this problem, as the amount of research already done is negligible as compared with that for the Pd-catalyzed peer domain. Anilines. In Pd-catalyzed C−N cross-coupling aromatic amines are among the most favorable substrates, with numerous protocols described using all sorts of electrophiles. Arylation by bromides, triflates, and iodides can be carried out using the standard ligands BINAP and dppf.4b,55,139,157 A multitude of specific protocols dealing with special tasks or providing alternatives were reported, thus making anilines one of the best studied NH nucleophiles in the domain, to mention only a small share of the published methods.7a,b,18,48,56b,85b,90a,140a,141d,142b,c,155a,h,158 As discussed in the Introduction, anilines give the highest conversion rates, in spite of their modest nucleophilicity and low binding constants to the Pd(II) center, because of high NH acidity and high rate of transformation into products via fast deprotonation of intermediate complex and fast reductive elimination. The same reasons account for the competitive chemoselective arylation of aromatic amines over other reaction centers (aliphatic amines, azoles, amides).48 Diarylation is controlled by using a small excess of aniline or by the use of special bulky ligands, e.g. BrettPhos,12 though if need be it can be performed preparatively to access triarylamines directly from anilines.27,159 Cross-coupling of sterically hindered anilines, such as 2,6dimethylaniline, 7b,8b,9a,c,d,29c,83b,86,155h,158f,160 mesitylamine,7a,141f,143a,b,158a,h,160f,161 and even 2.6-diisopropylamine,8b,29c,141f,143a,b,155d,158n,160c,d,f,161c,162 can be performed by an impressive number of protocols. Rodriguez, Tang, and coworkers developed oxaphosphole ligand 27, related to the known SPhos (28),163 finely tuned for optimal steric bulk and furnishing high-yield cross-coupling between highly hindered aniline and aryl bromide (Figure 48).160f This case highlights an

Figure 46. Selective arylation of polyamine.

are among the best NH nucleophiles, and morpholine is undoubtedly the number one substrate, invariably used as the entry model for developing new methods. Also highly reactive are N-methylamines. Practically any ligand except for a few specially developed for chemoselective arylation of primary amines (see above) can be used, so that the list of citations would contain hundreds of references. On the other hand, longer chain dialkylamines, even such simple ones as dibutylamine and dibenzylamine, are considered as challenging, and dialkylamines with branched chains are among the hardest problems. Such tasks were resolved only with the introduction of the third-generation phosphine and heterocyclic carbene ligands.7a,b,8b,9d,48,56b,85b,141a,143b,155 A few remaining challenging tasks, e.g. the reaction of aryl chlorides with volatile dimethylamine, was solved using palladium monophosphine precatalysts, and the reactions can be performed either at room temperature in the presence of a strong base or at toluene relux in the presence of the weak base K3PO4·H2O.30 In general, noncyclic secondary amines and primary amines require different protocols for effective processing. Fors and Buchwald suggested the use of a two-phosphine catalytic system (BrettPhos-RuPhos) for a common protocol covering most such targets without the need to additionally optimize the system for each new amine.90b In the Cu-catalyzed domain, the situation with secondary aliphatic amines is dramatically different. While typical cyclic amines (piperidine, morpholine, and the like) can be processed using a few systems, such as e.g. the one developed by Twieg and coauthors using (dimethylamino)ethanol (deanol) as ligand and solvent (e.g. Figure 47),153 noncyclic secondary amines are among the most challenging NH nucleophiles.

Figure 47. Selective monoarylation of cyclic secondary amine by diiodobenzene.

Figure 48. Cross-coupling of highly sterically congested coupling partners.

There are only a few mentions of attempts to arylate a few such amines, Et2NH and Bu2NH, usually in miserable yields of 2−21%.147,153,156 Given that NH acidities, which are very low for secondary aliphatic amines, are nevertheless very close for cyclic and noncyclic amines, cannot solely explain such results, the only reasonable factor left is steric bulk (and therefore nucleophilicity toward the Cu center). Cyclic amines are wellknown in coordination chemistry to be better ligands for metals than the open-chain secondary amines. Therefore, it have to be assumed that the highly unfavorable combination of low NH acidity and low nucleophilicity due to steric congestion is likely

impressive capacity of the coordination shell of palladium, which can adopt three huge ligands (it is noteworthy that steric congestion caused by 2,6-diisopropyl substituents on the NH2 group is practically the same as that of 2,6-dimethyl substituents, but the overall steric bulk of such ligands in the coordination shell is substantially greater) in the productforming stage. In addition, the ability to cross-couple sterically hindered aniline and electrophile once again shows the unique position of anilines among the NH nucleophiles in Pd-catalyzed amination, as in all other nucleophile types (secondary amines of all kinds, amides) steric restrictions are much more rigorous, U


Organometallics

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possible involvement of a direct nucleophilic aromatic substitution (dehydrobenzene) pathway. Several Cu−Fecocatalyzed systems were reported for arylation of anilines by aryl bromides.150,151,169 Secondary N-Alkylanilines. Secondary amines, N-alkylanilines, are poor NH nucleophiles in Pd-catalyzed cross-coupling. The problem is not the diminished NH acidity but rather the steric congestion around the nitrogen center. In fact, the smallest representatives, N-methylanilines, possess roughly the same reactivity as primary anilines, and N-methylaniline belongs to the commonly used set of model NH nucleophiles for developing and testing new methods. Already with Nethylaniline the problems emerge, and only a handful of methods reported were applied to this substrate.142b,160e,161b−d,170 Bulkier N-alkylanilines (e.g., isopropyl, cyclohexyl, and benzyl derivatives) are mentioned in only a few papers.18,141f,171 Buchwald and co-workers developed a protocol of in situ sequential diarylation of primary aliphatic amines, which includes, as the second step, the arylation of Nalkylaniline performed with DavePhos or Xantphos ligands (depending on the electron-donating or -withdrawing nature of the aryl groups).170b In fact, tBu3P ligand was found by Prashad and co-workers to serve reasonably well for such amines, which makes them similar to diarylamines.172 The ligand enables the arylation of a wide range of N-alkylanilines, including an N-tertbutyl derivative. However, the protocol remains highly affected by steric congestion, and an o-methyl group in an aryl bromide dramatically retards the reaction (Figure 50). As was already noted, with the primary anilines the effect of ortho substituents in the electrophile is negligible or even positive.

and bulky nucleophiles of other families are generally disallowed (vide infra). In the copper-catalyzed cross-coupling, the status of anilines is in many respects the opposite. Anilines can be arylated using a number of protocols (indeed a miserable number as compared with that reported in the Pd-catalyzed peer domain). In competition with other NH nucleophilic centers (primary aliphatic amines, azoles, amides), anilines fail.48 As was discussed above, this negative preference is likely due to low nucleophilicity interfering with binding of neutral forms by Cu(I) and still insufficient NH acidity, precluding the formation of reasonable amounts of conjugate base under the conditions commonly used for Cu-catalyzed reactions. A judicious choice of ancillary chelators for copper is thus required to fit into the narrow requirements of the process, the most essential of which is not to suppress the Lewis acidity of the copper center needed to bind a poor nucleophile. “Ligand-free” protocols cannot be expected to play an essential role in the arylation of anilines. So far, only a few protocols targeting the arylation of anilines have been reported, usually based on bidentate chelators containing a nitrogen atom and a secondary carboxylic or phosphonic site. Thus, the system CuI (10 mol %)−L-proline, K2CO3 in DMSO at 90 °C is useful for monoarylation of electron-rich anilines by aryl iodides and bromides. The method fails with less nucleophilic anilines bearing electronwithdrawing groups.156,164 A phospho analogue of proline, phenyl pyrrolidine-2-phosphonate (PPAPM, 29) showed a markedly better performance applicable to anilines bearing either electron-withdrawing or electron-donating substituents, even sterically hindered ones.165 The comparison of the steric tolerance of Pd catalysis (Figure 48) and Cu catalysis (Figure 49) speaks for itself.

Figure 50. Steric factor in Pd-catalyzed arylation of sterically congested N-alkylamine.

In the Cu-catalyzed domain the status of N-alkylanilines can be defined as practically total negligence. Only N-methylaniline received some attention, being quite reactive in the same systems used for anilines, e.g. (CuI (5 mol %), 9-azajulolidine (30), tBuONa, toluene, 110 °C;167d CuI (10 mol %), PPAPM (29), K3PO4, DMF, 110 °C165,173). The only notable exclusion is the use of a formally “ligand-free” system for o-hydroxy-Nmethylaniline, in which the hydroxy group lends assistance in directed oxidative addition (Figure 51). Diarylamines. The synthesis of triarylamines by the classical Ullmann method by heating iodoarenes with diarylamines in the presence of K2CO3 and copper powder at high temperature in high-boiling solvents174 has long been the only practical access to triarylamines. A few modifications were made to perform the reactions under milder conditions, though this

Figure 49. Cu catalysis of a sterically hindered aniline.

Similar results are achieved using readily available pyrrole-2carboxylic acid as ligand (CuI (10 mol %), 2L, K3PO4, DMSO, 80−100 °C) for arylation of anilines by aryl iodides and bromides. Ortho substituents (but not 2,6-substituents) are tolerated in both coupling partners.166 Several other papers scarcely mention only a few cases of the arylation of anilines and N-alkylanilines,167 so that no definite conclusions can be made as to the generality and scope of the method. An apparent exception to the general trend is a very interesting “ligand-free” protocol using commercial CuO nanoparticles proposed168 for arylation of anilines, aliphatic amines, and azoles by aryl iodides. The reactions are performed in superbasic media (KOH, DMSO, 110 °C) and are unusually fast (1.5−5 h versus 15−45 h required in other reported protocols) and use a very low loading of copper precatalyst (1.26 mol %). Moreover, the system turned out to be suitable for PhBr and PhCl, showing remarkable results (60% yield of Ph2NH in the reaction of chlorobenzene with aniline), apparently deserving further investigation to evaluate the

Figure 51. Intramolecular assistance in “ligand-free” arylation of a secondary N-methylaniline group. V


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bromides and iodides but also aryl chlorides,9c,17,85b,158c,k aryl triflates and simpler sulfonates,48 heteroaryl halides,180 etc. have been developed. Reactions can be run at room temperature,56b,155a,c,181 in the presence of water,85b using simple cheap bases such as aqueous KOH85b etc.182 Overall, in the arylation of diarylamines tri-tert-butylphosphine is the ligand of choice to afford good to high yields in the majority of cases.155c,183 Cross-coupling of aniline with an equimolar mixture of chloro- and bromoarene using the JohnPhos ligand was shown by Harris and Buchwald to directly afford triarylamines with three different aryl groups.184 The high practical importance and reliability of Pd-catalyzed methods of triarylamine synthesis is excellently illustrated by the vast popularity of this chemistry for the synthesis of triarylamine-based materialsoligomers, polymers,171,185 dendrimers,183,186 electroluminophors and other OLED materials,187 etc. Azoles. Thus, in the arylation of various amines Pd-catalyzed methods are invariably ahead of the Cu-catalyzed peers in effectiveness, versatility, preparative scope, and other factors of importance for synthetic chemists. For some groups (primary aliphatic and aromatic amines) the advantage is relative, and for others (all kinds of secondary amines) Cu is so far behind that no appreciable influence of this chemistry for solving preparative tasks can be perceived. There are, however, important classes of NH nucleophiles for which coppercatalyzed methods are a much stronger competition. Aromatic heterocycles involving NH centers, primarily azoles, are the first such types of substrates. Palladium-catalyzed cross-coupling with azoles was discovered much later than the arylation of amines. Azoles were considered as challenging nucleophiles for several reasons. The parent systems, pyrrole and indole, are altogether not nucleophilic at N, but due to rather high NH acidity they readily form the respective N-nucleophilic anions. The real problem is that the nucleophilicity of these substrates is ambident, with an additional sophistication of possible interconversion of palladium intermediates involving N1, C2, and C3 centers. Using indole as the most typical and best studied substrate in the presence of “ligand-free” palladium systems or systems involving small phosphines (PPh3, PCy3),188 C-arylation takes place, while the systems with bidentate or bulky special phosphines give both N- and Carylation products, and by careful choice of ligands and conditions N-arylation can be made the main course.189 The amount of C-arylation products was established to increase in scaled up preparative runs.190 Such an interesting dichotomy is likely to be associated with reversibility of the electrophilic attack of the ArPd(L)X intermediate at the N and C sites of azoles. Attack at nitrogen can take place only in the presence of a strong base, furnishing an N nucleophilic anion, as there is no lone pair available for coordination bonding in monoazoles. The C−N cross-coupling is realized only in the presence of bulky ancillary ligands, enabling reductive elimination of N-arylation product. If the basicity is lower and a competent ancillary ligand is not present, the C−N route becomes ineffective, and instead a more electrophilic ArPdX intermediate attacks the C3 site, often followed by a palladotropic shift to the C2 site,191 giving the products of regular C−C coupling, which is much less dependent on the nature of ancillary ligands and can take place even in “ligand-free” systems (Figure 53).

could be done only for selected specific substrates: e.g., orthosubstituted aryl iodides bearing electron-withdrawing directing substituents.175 Such a modified procedure has been successfully used to prepare various diaryl- and triarylamine materials in the post-Ullmann epoch.176 Recently it was shown that the temperature of the “ligand-free” reaction can be lowered to 145 °C through the use of the unusual solvent Si(OEt)4 and the stronger base Cs2CO3.177 Unfortunately, for such an important subclass of substrates in the post-Ullmann epoch relatively modest progress was made. In new copper-catalyzed C−N cross-coupling diarylamines remain very difficult types of substrates, suffering from an unlucky combination of poor nucleophilicity and insufficient NH acidity, thus probably being unable to compete effectively for a coordination site of copper. Only a very limited number of protocols deal with diarylamines, the major part of which were published at early stages of development of post-Ullmann chemistry, in the early 2000s. Interestingly, early methods use phosphines as ancillary ligands, usually as preformed complexes[Cu(neocuproine)(PPh3)Br] (tBuOK, toluene, reflux)178 and Cu(PPh3)3Br (Cs2CO3, toluene, reflux).167a The use of the more electron rich tri-n-butylphosphine was reported to enable the use of aryl chlorides, though this intriguing and apparently very promising result seems to have never been further developed into a practical method.47 A rather recent addition to this arsenal makes use of a copper(II) complex with dipivaloylmethane (tBuOK, toluene, reflux),167c and a rather exotic tricyclic analogue of DMAP (CuI, 9azajulolidine (30), tBuONa, toluene, reflux).167d It should be noted that the methods developed for arylation of diarylamines use strong bases, particularly alkali-metal tert-butylates, generally not required for copper-catalyzed reactions of other substrates. Such bases are likely to effect deprotonation of diarylamines and to enable binding by copper of the respective anions instead of poorly nucleophilic neutral amines. In some special cases when the substrate itself can furnish chelation, the arylation can be run in a “ligand-free” mode, as e.g. in the arylation of o-aminophenols.75 Monnier, Taillefer, and coworkers, however, succeeded in developing a very simple “ligand-free” protocol to obtain both diaryl- and triarylamines by arylation of lithium amide by aryl iodides. The selection of a di- or triarylation pathway is done simply by changing the ratio of substrates and extra base (Figure 52).179 In the synthesis of triarylamines palladium catalysis has so far been far more efficient, with dozens of protocols involving all major types of substrates on both sides: i.e,, not only aryl

Figure 52. Selective di-/triarylation via a single protocol. W


Organometallics

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Figure 55. Pd-catalyzed arylation of diazoles, an example.

and tetrazoles currently are outside of the scope of Pd-catalyzed C−N cross-coupling, except for a few specific examples using highly activated heteroaryl halides.200 In contrast to the modest performance and scope of Pdcatalyzed systems, in Cu-catalyzed processes heterocyclic NH nucleophiles, particularly azoles, are among the best studied and most useful substrates. Bonding of the NH nucleophile prior to oxidative addition creates azoles, particularly di- and triazoles, due to substantial NH acidity nearly optimal for such a mode of catalytic process. Furthermore, Cu(I) (unlike Cu(II); see the CH Activation section) was never noticed as electrophile capable of attack at carbon centers of aromatic systems; thus, the competing C-arylation is not a problem in Cu-catalyzed cross-coupling. The last but not least reason is the ease of the reductive elimination from Cu(III) intermediates, which is spontaneous, disregarding which N-ligand is in the coordination shell, and does not depend on ancillary ligands. All these factors account for the ease of catalytic arylation of azoles in the presence of Cu(I) catalysts and make these NH nucleophiles (particularly the diazoles) the most convenient substrates for developing new methodologies and testing new catalytic systems. However, it should be borne in mind that azole NH nucleophiles are “easy” types of reagents for Cucatalyzed C−N cross-coupling, and the systems optimized for such substrates can fail with more demanding types of NH nucleophiles. The arsenal of published methods on the Cu-catalyzed arylation of azoles is impressive, including both protocols using chelating ancillaries and “ligand-free” protocols. The basic protocol developed by Buchwald and co-workers employs diamine ligands, preferably DMEDA and DMCyDA, in the system CuI (5 mol %)−L (Cu:L = 1:4), K2CO3 or K3PO4, toluene at reflux, using aryl iodides directly and aryl bromides through Cu-catalyzed Br with I exchange201 (see also refs 201 and 202). The use of other ligands, e.g. sparteine, as preformed complex 31 allows for direct processing of aryl bromides (system CuI2L2 (5 mol %)−K2CO3, DMSO at 115 °C).203 A systematic and thorough screening of a large series of chelators was performed by Taillefer and co-workers, who succeeded in identifying very effective and practical ligands for Cu-catalyzed cross-coupling reactions. Either of these ligands was capable of driving the arylation of azoles by ArI or ArBr under mild conditions (Cu2O (10 mol %)−L (Cu:L = 2:1), Cs2CO3, MeCN, 50 °C for ArI, or reflux for ArBr).204 In fact, screening of a large set of various chelators, including the oximes and Schiff bases derived from salicylic aldehyde and its analogues, bis-oximes, carbohydrazones, etc., revealed a very weak dependence of results on the intimate structural features and electronic effects in the ancillary ligandalmost any of the polydentate ligands tested gave good results.204 Such data highlight an auxiliary role of the ligand in Cu-catalyzed C−N coupling, discussed in the Introductionthe ancillary ligand exerts no or negligible influence on the reactivity of the Cu center. The ligands play no definite role in the modulation of

Figure 53. Competition of C−C and C−N cross-coupling pathways in the arylation of a typical azole.

The N-arylation of monoazoles (pyrroles, indoles, carbazoles) is relatively well developed. Earlier protocols employed the systems Pd(OAc)2 (1 mol %)−dppf (Pd:L = 2:3)−Cs2CO3 or tBuONa in toluene at 100−120 °C.192 More flexible protocols are based on the use of bulky electron-rich phosphines, which allow for the use of milder conditions.155c,189,193 The scope of arylating agents can be extended to sulfonates (system Pd(OAc)2 (2 mol %)−XPhos (Pd:L = 2:5)−K3PO4 in toluene−tBuOH at reflux).48 The reaction can be run in water with KOH as base.48 Heteroaryl tosylates can be used in dppf-based systems to afford heavily substituted indoles.194 A similar situation exists in the arylation of heterocycles containing two or more hereroatoms, for various azoles and their benzo derivatives, which unlike their mononitrogen relatives are quite good N-nucleophiles not only as anions but also as neutral molecules.195 Recent years have shown a dramatic increase in methods for Pd-catalyzed C-arylation,191 applicable to pyrroles, indoles,188,196 imidazoles,197 pyrazoles,198 triazoles,188f etc. Interestingly, some of this chemistry involves “ligand-free” dual-metal Pd−Cu systems (Figure 54).188e The role of Cu(I) is likely to coordinate iodide ion and lend assistance to enhancement of the electrophilicity of the ArPdI intermediate.

Figure 54. Pd−Cu “ligand-free” system, favoring C-arylation over Narylation.

The N-arylation of diazoles was enabled after the introduction of XPhos (11) and its analogues tBuXPhos (12) and Me4tBuXPhos could enable reductive elimination in the arylation of diazoles (Figure 55). 57 Even with such sophisticated ligands, the process requires high precatalyst loading and Pd:L ratio. Examples of the application of Pdcatalyzed diazole arylation in synthesis are extremely rare (Figure 55).199 More NH acidic and less nucleophilic triazoles X


Organometallics

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haphazard interplay of complexing equilibria, just as “ligandfree” systems do (see below). Moreover, as azoles themselves are good ligands for copper, it is almost inevitable that most monodentate ancillaries would be effectively displaced from the copper coordination shell by azoles; thus, the exact role of monodentate ligands is very likely to be close to ephemeral. Among the monodentate ligands used were DBU, 216 benzotriazole (CuI, L, tBuONa, DMSO, 110 °C),221 etc. The use of very complex ligands is thus hardly justifiable. Thus, a tris-carbene complex forming a beautifully sophisticated hexacopper cluster structure was found to exhibit a standard level of activity in the arylation of azoles and amides by aryl iodides and activated bromides (3 mol % Cu, Cs2CO3, DMSO, 100 °C).222 A few supported systems showing limited recyclability were reported using polymeric supports involving monodentate binding sites. The operation of such precatalysts is almost certainly accounted for by the gradual leaching of copper complexes in solution, similarly to what is known for Pd catalysis.2 Thus, CuI supported on polyaniline was used for arylation of imidazole and other azoles (Cs2CO3, MeCN or DMF, 80−100 °C). The catalyst is readily recyclable for aryl iodides but rapidly loses activity with aryl bromides.223 Similar behavior was demonstrated by Cu(II) immobilized on aminopropyl-modified silica.224 Arylation of azoles can be achieved using “ligand-free” conditions, a good number of which have been reported. The effectiveness of “ligand-free” protocols for azole arylation is likely to be associated with the specific ligand properties of the azoles. In some cases, as e.g. the arylation of 5- or 7-azaindoles (system CuI (10 mol %), LiCl, K2CO3, DMF, 120 °C), the nucleophile itself apparently serves as an ancillary ligand.225 In fact, any azole containing more than one N atom can be suspected to be able to form complexes with different modes of binding, which may be active in oxidative addition (Figure 57).226

reactivity of the metal center, serving simply as a “disposable wrapper”, a concept which we have earlier revealed in Pdcatalyzed cross-coupling and Mizoroki−Heck reactions of reactive iodo- and bromoarenes.205 In this respect, a wise strategy is to select such “disposable” ancillaries from an assortment of cheap commercial chelators, which can be used as such or modified by simple means, and not to design new custom-made, expensive ligands. The ligands identified by Taillefer and co-workers illustrate this nicely, as indeed picolinic and salicylic aldehydes, diaminocyclohexane, and their simple derivatives, e.g. ligands 32−34 obtained by one-step procedures, were very effective, thus being good choices from a performance/cost standpoint. With catalytic systems based on such ligands, for example, a clean stepwise substitution of two halogens by two different NH nucleophiles becomes possible (Figure 56).34g

Figure 56. Cross-coupling with two different azoles using ligand 32.

Mild vinylation of azoles (CuI (10 mol %)−32 (Cu:L = 2:1), Cs2CO3, MeCN, 35−80 °C) was described for (E)-βbromostyrene.113c Additional useful protocols use other chelator ligands, e.g amino acids,156,164,206 histidine,207 and proline derivatives,208 or more complex molecules, e.g. benzimidazole linked through CyDA (10 mol % CuI at 100 °C)209 or 2-pyridylbenzimidazole (CuI (5 mol %), L, K3PO4, DMF, 110 °C),210 1,2,3,4-tetrahydro-8-hydroxyquinoline (CuBr (10 mol %)−L (Cu:L = 2:1), Cs2CO3, DMSO at 80− 90 °C, effective for aryl bromides),145 8-hydroxyquinoline Noxide,89b aminothiols,211 per-6-amino-β-cyclodextrin (CuI (20 mol %)−L (8 mol %)−K2CO3, DMSO, 110 °C, aryl bromides),212 phenanthrolines ((CuOTf)2·PhH−Cs2CO3, NMP, 125 °C, aryl bromides),213 (CuI (20 mol %)−L, KF/ Al2O3, 130−140 °C, aryl iodides and bromides),214 Cu2O nanoparticles,215 2,2′-bis(dimethylamino)dinaphthyl, 2,2′-diaminodiphenyl,216 diimines,217 dendrimerized Schiff bases of picolinic aldehyde,218 acylhydrazines and acyl hydrazones,219 tetrahydroquinolone oxime (CuI (1 mol %), L, NaOH, Bu4NBr, H2O, 120 °C),89b etc.34d,220 The use of monodentate ancillary ligands can be regarded as a transitional strategy between catalysts supported by chelators and “ligand-free” systems. It is obvious that monodentate ligands cannot control the coordination sphere of copper as reliably as chelators do, and thus the catalytic systems formed with monodentate ancillaries by default have to rely on a

Figure 57. Prototropic equilibria of Cu(I) azole complexes.

Of the three complexes shown in Figure 57, only the one in the middle is likely to be active in oxidative addition. As the NH acidities and N basicities of di- and triazoles are known to be modest, such equilibria are trivial prototropic transformations which should take place in the media of moderate basicity commonly used for Cu-catalyzed reactions, with insoluble base serving as a terminal scavenger of liberated acidity. Thus, it is not surprising that very simple “ligand-free” systems can be spectacularly effective. Thus, You and co-workers noticed that a Y


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arylation of azoles by aryl bromides and activated chlorides in the system CuTC or Cu2O-TC (25 mol %), K2CO3, DMSO at 135 °C.234 Another borderline system is that using complexing solvents. Nitriles can serve as good ligands for copper; thus, the arylation of azoles by aryl iodides can be performed in nitrile solvents (MeCN, EtCN, PrCN) at reflux temperatures using CuI or, better, Cu powder as catalyst. Cu powder was shown to slowly dissolve in the reaction media, probably due to the interaction with ArI giving a catalyst more active than the commercial CuI reagent. This protocol is specific for iodides, and in bromoiodobenzene only iodine is substituted.235

40% excess of azole substrate leads to substantial acceleration of the arylation reaction in the system CuI (20 mol %)−Cs2CO3, in DMF solvent at 120 °C. Interestingly, this system served well for aryl bromides, including electron-rich and hindered ones, as well as activated aryl chlorides. Good results were obtained even with p-bromophenol and p-bromoaniline, the reaction being highly chemoselective to afford only the target Narylazoles without the formation of oligomers (Figure 58).227

“Ligand-free” systems can use supported copper precatalyst, as e.g. Cu(II) on zeolite (K2CO3, DMF, 120 °C)236 or copperexchanged apatite106 were used for arylation of azoles by aryl iodides, bromides, and activated chlorides. Copper-doped silica (copper nanoparticle-doped silica cuprous sulfate, CN-DSCS) was reported by Rad, Behrouz, and co-workers to serve as a heterogeneous precatalyst for the arylation of not only azoles but also purine and pyrimidine nucleobases. The system uses the neutral organic base DBU and is highly chemoselective (Figure 60).237

Figure 58. Chemoselective arylation of imidazole by p-bromoaniline.

A similar “ligand-free” system employing a 2-fold excess of imidazole in the arylation by aryl bromides under microwave heating in tetraethoxysilane as solvent was proposed.228 Ligandfree arylation of simple azoles by aryl iodides can be achieved in the presence of a phase-transfer agent in the system CuI− Bu4NBr−NaOH, in toluene at reflux229 as well as in other systems.230 The positive influence of iron(III) compounds on the Cucatalyzed arylation of azoles was first discovered by Taillefer and coauthors, who showed that the addition of Fe(acac)3 (30 mol %) to copper compounds (CuI, Cu powder, CuO, Cu(acac)2) (10 mol %) gave an effective catalytic system for the arylation of azoles (pyrrole, diazoles, triazoles, indole, and pyrrolidone) by aryl iodides and bromides, as well as activated chlorides in the presence of Cs2CO3 in DMF at 100 °C (120 °C for electron-rich ArBr, 140 °C for ArCl) (Figure 59).82

Figure 60. “Ligand-free” chemoselective arylation of purine base in a system involving supported copper nanoparticles.

“Ligand-free” arylation of substituted pyrazoles using Cu(OAc)2·H2O precatalyst was reported to be regioselective, with the incoming aryl group attached to the remote N atom, with respect to the substituents already present in the molecule.226 Amides and Related Weak NH Nucleophiles. The use of amides in C−N cross-coupling reactions (often dubbed amidation) is a particularly important application of the methodology, not only because it affords a multitude of valuable N-aryl and N-alkenylamide derivatives but also because acyl and sulfonyl residues serve as convenient auxiliary substituents, enabling substitution at otherwise less reactive NH nucleophilic centers. The performances of palladium and copper catalysts in this area are dramatically different. Amides and related NH nucleophiles bearing mesomeric electron-withdrawing substituents (sulfamides, carbamates, ureas, etc.) are poor nucleophiles, but their NH acidity is substantially high enough to enable at least partial deprotonation by many bases utilized in cross-coupling reactions. Therefore, these nucleophiles are most probably bonded as conjugate bases directly into amidate complexes, either monodentate or bidentate (Figure 61). This feature is likely to have different effects in Cu- and Pd-catalyzed processes. In the Pd domain the nucleophile binding takes place directly before the reductive elimination, which is believed to be strongly suppressed if the binding mode is bidentate.238 Special ligands are required to disallow bidentate binding and enable reductive elimination.238,239 In the Cu-catalyzed domain,

Figure 59. Fe(III) promoted “ligand-free” Cu-catalyzed arylation of azoles.

Briefly after Bolm et al. showed that Fe(III) alone can serve as an effective catalyst for C−N cross-coupling reactions,80,231 but only in the presence of TMEDA as ligand and limited to aryl iodides, a controversy followed about the role of copper impurities in iron salts as the true source of catalytic activity.81a Thus, most probably this system should be categorized as “ligand-free” copper catalysis with Fe(III) lending some sort of auxiliary promoting assistance of uncertain nature. Copper ferrite nanoparticles were recently described as recyclable precatalysts for arylation of azoles by bromoarenes, though under harsh conditions and at high basicity (CuFe2O4 (10 mol %), t-BuOK, DMF, 150 °C).232 Other Fe−Cu-cocatalyzed systems, both “ligand-free” and involving chelator ancillaries, were reported.233 A borderline system between “ligand-free” and chelateassisted was developed using Liebeskind’s salt CuTC (TC = thiophene-2-carboxylate anion). This precatalyst, either as is or as a mixture with Cu2O, made quite a good catalyst for Z


Organometallics

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Figure 61. Amidate complexes in C−N cross-coupling.

amidate binding takes place early in the process. Bidentate binding increases the equilibrium constant and the concentration of the monoamidate intermediate responsible for crosscoupling. At the same time, the reductive elimination in Cu chemistry is not likely to depend on the binding mode of the amidate ligand. Consequently, amides are among the best nucleophiles for Cu-catalyzed C−N cross-coupling, and amidation is a thriving area with new protocols and improvements continuing to arrive almost monthly. In the amidation, Cu-catalyzed methods are often given an advantage before the respective Pd-catalyzed processes, particularly in intramolecular reactions. In the Pd-catalyzed C−N cross-coupling the problem of the development of a common protocol for amidation (except for the arylation of lactams,240 which are more reactive than openchain amides for the same reasons as those accounting for the enhanced reactivity of cyclic amines) was resolved with the introduction of the Xantphos ligand, which became the de facto standard ancillary for cross-coupling of NH nucleophiles capable of bidentate binding. . The system (Pd(OAc)2 or Pd2(dba)3−Xantphos (1 mol % Pd, Pd:L = 1:1.5), Cs2CO3, dioxane or THF, 45−110 °C, 6−44 h) , developed by Yin and Buchwald served for cross-coupling of both activated and unactivated aryl bromides, iodides, and triflates, as well as activated aryl chlorides with primary amides and sulfonamides, lactams, carbamates, secondary N-methylamides, and Nmethylsulfonamides.241 This system would actually serve as the reference protocol in the development of amidation and related chemistry. The ligands of XPhos and BrettPhos families enabled the arylation of amides by less reactive electrophiles (aryl chlorides, mesylates, tosylates, etc.).83a,242 Noncyclic secondary amines remained elusive targets, the low reactivity of which is likely to be associated with poor ligand properties due to low nucleophilicity and steric bulk. The resolution of this task can be regarded as one of spectacular achievements of rational ligand design based on an understanding of the catalytic machinery involved. The ligand developed, JackiePhos (35), retained the backbone of the BrettPhos phosphine which proved its effectiveness in the amidation overall but enhanced its π-acidity by substituting electron-withdrawing aryl groups in the phosphine residue (Figure 62).243 A similar modification of the Xantphos ligand was first demonstrated by Beletskaya and co-workers to favorably enhance the reactivity of the catalyst toward ureas and enable cross-coupling with less reactive sterically hindered aryl bromides.244 The Pd center ligated by such a phosphine is more acidic, which results in an increase of the ligand exchange rate with poor nucleophiles. Unfortunately, such a modification has its price, as it leads to a decrease of reactivity toward arylating agents. The method is best applicable to aryl triflates and nonaflates.243 The importance of the ligand exchange stage for overall catalytic efficiency is very well demonstrated by this process. Iodide and bromide ions compete with poorly nucleophilic amide, whch makes aryl iodides altogether unreactive and aryl bromides capable of only a few turnovers, upon which the accumulated bromide ion suppresses the exchange with amide.

Figure 62. Example of Pd-catalyzed arylation of secondary amides.

In the Cu-catalyzed domain amides are favorable targets. Cu(I) complexes in the presence of bases readily bind amides to form amidate complexes, which then react with aryl iodides and bromides, generally on heating. An immense number of protocols have been developed for the arylation of amides and similar NH nucleophiles by aryl iodides and bromides. Almost all common chelators such as amino acids,245 phenanthroline,246 and particularly Buchwald’s diamines (DMEDA, CyDA, DMCyDA)202b,247 perform highly reliably and can be regarded as the first choice ligands for preparative work. The same ligands serve effectively and selectively for alkenylation (e.g., Figure 63)248 and alkynylation116 of amides and carbamates.

Figure 63. Chemoselective alkenylation of amide.

In addition to Buchwald’s diamines, Taillefer’s family of chelators (32−34) were used to furnish well-developed stable protocols for different arylation reactions, including the arylation of amides by aryl iodides (system Cu2O (5 mol %)−L (Cu:L = 2:1), Cs2CO3, in DMF or MeCN at 82 °C) in the presence of molecular sieves to suppress hydrolysis. Reactions are selective and allow for e.g. the use of iodoaniline as arylating agent for 2-pyrrolidone, giving a high yield of target product with outstanding chemoselectivity without byproducts of O-arylation or oligomerization of aniline (Figure 64).34g

Figure 64. Chemoselective arylation of pyrrolidone by m-iodoaniline.

Due to the strong binding of amides and related NH nucleophiles by Cu(I) in the presence of bases, effective chelators are required to avoid binding two molecules of amide and controlling the coordination shell, and therefore “ligandfree” systems are generally not effective. Among a few exceptions is the use of Liebeskind’s catalyst CuTC,249 which in fact is a preformed copper monochelated complex. Even so, AA


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nucleophilic amidines.255 No Pd-catalyzed method has been reported so far for the intermolecular arylation of such strong nucleophiles. Ammonia and Ammonia Equivalents. At the beginning of the development of both Pd- and Cu-catalyzed C−N crosscoupling, and for quite a while since then, ammonia had not been regarded as a legitimate NH nucleophile, which spawned a number of ammonia surrogates, nucleophiles capable of being monoarylated to give products further cleaved to release primary amines. The number of such synthetic equivalents in the Pd-catalyzed domain is particularly large, benzophenone imine being apparently the best studied compound. It should be noted that this imine is a highly reactive NH nucleophile in Pd-catalyzed C−N cross-coupling. Its very close relative, benzhydrylamine, is among the most challenging amines, requiring for arylation the use of special ligands, such as BippyPhos (21).256 The arylation of benzophenone imine can be achieved by almost any protocol developed for reactive secondary amines: that is, practically by any protocol known.48,140b,141e,142c,g,155b,d,192,257 Such a dramatic difference between two closely related compounds, the main difference being a more rigid, flattened shape of the imine in comparison with the conformationally flexible amine, is a bright manifestation of the crucial role of steric effects in Pd-catalyzed cross-coupling, where each essential component of the coordination shell must fit within its share of space in the overcrowded intermediates, as if the Pd center provided several irregularly shaped sockets for ligands to be plugged into them. A very useful ammonia surrogate is the readily available LiHMDS, which, being a potent nucleophile, is reactive under mild conditions using tBu3P258 or Xantphos.259 The zinc derivative of HMDS was found to be useful for the conversion of phenol triflates to anilines.260 Other useful surrogates are allyl-261 and benzylamine,262 giving products cleavable by Pdcatalyzed hydrogenolysis or isomerization to enamines followed by hydrolysis. Simplified solutions continue to appear, e.g. solvent-free reactions of aryl bromides or triflates with various amides (acetamide, benzamide, etc.) using the now practically obsolete first-generation precatalyst Pd(tol3P)2Cl2 followed by harsh hydrolysis of the resulting arylamides.263 It should be clearly stated that the later introduction of protocols allowing for the use of neat ammonia in direct arylation does not mean that ammonia surrogates are now an obsolete choice. In complex syntheses the use of neat ammonia can be rather inconvenient, and in addition, many surrogates are reactive using simple catalytic systems, while neat ammonia requires special expensive ligands and equipment allowing for pressurization of reaction mixtures. Nevertheless, the introduction of unmasked ammonia into C−N cross-coupling264 was a serious breakthrough. Hartwig and Shen established that the reactions can be run in the presence of Josiphos ligands,265 followed by Buchwald and Surry, who disclosed a similar approach based on the ligands JohnPhos (9), DavePhos (7), and tBuXPhos (12).266 Further improvements of the method were targeted at improving the selectivity, broadening the scope, or simplifying the hardware by eliminating the need to work with pressurized ammonia gas.267 The very bulky aminophosphine ligand developed by Stradiotto and co-workers gave a system with exceptionally high chemoselectivity, in which none of the primary or secondary amine groups interfere with the cross-coupling with ammonia.22,90a

this catalyst is often used in conjunction with stronger chelates, most often the diamines DMEDA and CyDA.250 Such system were used e.g. for cross-coupling of allenyl iodides with amides, carbamates, ureas, and lactams. Recently, a very simple “ligandfree” and solvent-free system using a phase-transfer agent was developed by Punniyamurthy and co-workers for arylation of amides by aryl iodides (Figure 65).251

Figure 65. “Ligand-free” solvent-free arylation of primary amides.

Secondary acyclic amides are considered as challenging NH nucleophiles for both Pd- and Cu-catalyzed C−N crosscoupling, but probably for diffent reasons. Palladium-catalyzed chemistry is highly sensitive to steric congestion in the NH nucleophile, bonded after the oxidative addition of the electrophile, while Cu-catalyzed chemistry in which the nucleophile is bonded first is less sensitive to steric problem but more sensitive to variations in NH acidity and nucleophilicity. Therefore, the prospects for widening the scope are generally better in the Cu-catalyzed chemistry, as steric congestion is a rather unchangeable factor, while the nucleophility and the affinity of metal center for the ligand can be tuned by varying media components. A protocol to accomplish the arylation of N-arylamides was developed by Monnier, Taillifer, and co-workers to employ the diketonate ligand dipivaloylmethane (Figure 66). The method is ligandspecific and failed with other diketones, though quite reasonable results were obtained also with DMEDA.252

Figure 66. Arylation of N-arylamides.

Diarylation of urea was shown by Nandakumar to take place similarly to reaction with amides using Buchwald’s diamine ligands.253 Later, Mane and co-workers showed that monoarylation of phenylurea can be performed in a “ligand-free” solvent-free system. Intriguingly, in this protocol even deactivated aryl chlorides are reactive, even if in modest yields (Figure 67).254 Nitrogen analogues of amides, amidines, are among the strongest nucleophiles and bases. A proline system was used for monoarylation of protected guanidine by aryl iodides,45 and a “ligand-free” system was applied for the arylation of highly

Figure 67. Arylation of phenylurea by deactivated aryl chlorides. AB


Organometallics

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Still, as is evident from the reaction conditions, direct Pdcatalyzed arylation of ammonia is a rather sophisticated and resource-consuming chemistry in want of further elaboration and simplification. The need for rather high loading of palladium and a good excess of monodentate phosphine ligand clearly shows that, in the processes involving ammonia, there is a strong competition of this nucleophile for the coordination shell of metal, which can be shifted to the formation of the catalytically active monophosphine Pd complexes only by brute forcethe use of extra amounts of effective phosphine ligand. The behavior of copper-catalyzed systems is markedly different. Such systems are very rarely applied to ammonia surrogates, which are often poor NH nucleophiles for Cu catalysis, with a few exceptions such as benzylamine often used as a test primary amine in the respective protocols. The same can be said about simple amides. Unexpectedly, azide ion is emerging as a good ammonia surrogate in the Cu-catalyzed domain. An interesting protocol using sodium azide was shown recently to afford anilines even from aryl chlorides or bromides, but only those containing ortho-directing functional groups, a rare case of involvement of chloride substrates in coppercatalyzed reactions (Figure 68). The use of ethanol as solvent

Figure 69. Probable intermediacy of mixed ammonio−amide complexes in Cu-catalyzed “ligand-free” arylation of ammonia.

peer Pd-catalyzed processes, which usually require customprepared solutions of ammonia in organic solvents and rely upon sophisticated expensive ligands. The first system described by Kim and Chang used ammonia generated in situ from NH4Cl (system CuI (20 mol %)− proline, K2CO3, aqueous DMSO, room temperature) in a reaction with aryl iodides and activated bromides.272 Fast development came soon from Taillefer and Xia with a system based on 1,3-diketones, e.g. acetylacetone, which are very simple and cheap ligands, though they were used in substantial amounts (40 mol %). The reaction takes place in a biphasic system formed by DMF and an aqueous solution of Cs2CO3 (Figure 70).273

Figure 68. Synthesis of anilines by copper-catalyzed cross-coupling with azide ion. Figure 70. Arylation of ammonia in the presence of copper diketonates.

accounts for in situ reduction of initially formed azide.268 An alternative protocol using sodium azide or trimethylsilyl azide with aminoethanol as ligand was reported by Monguchi, Sajiki, and co-workers.269 A similar protocol involving Cu metal powder in the presence of pipecolinic and ascorbic acids acid is of even broader utility, being applicable not only to a wider series of aryl bromides and iodides but also to 3bromocoumarins and similar heterocyclic substrates.270 Amination by azide ion was used in an intramolecular tandem process leading to indazoles.271 Thus, until recently Cu-catalyzed C−N cross-coupling has not been regarded as a good methodology for the synthesis of primary anilines by arylation of unmasked ammonia, at least partially because of the tacit prejudice that such a transformation is too simple to be true. The barrier, however, was overcome and many effective protocols appeared within a few years. Moreover, many of the disclosed protocols were shown to work well using the simplest imaginable ammonia source the aqueous solution. The great success of copper-based chemistry with ammonia apparently shows that the coordination properties of this nucleophile meet the requirements of Cu-based catalytic machinery exceptionally well. The processes are usually run under very mild conditions and can function not only using effective chelators but also in the “ligand-free” mode. It is therefore very likely that ammonia is capable of forming mixed ammonio−amide complexes (Figure 69). All the published protocols of arylation of ammonia have yet another intriguing common featurethe reaction systems contain water introduced via either aqueous ammonia or solvent, making the processes operationally very simple, particularly if conducted in “ligand-free” mode. Therefore, Cu-catalyzed arylation of ammonia compares favorably with the

An alternative protocol uses more sophisticated chelators, such as 8-isobutyryl-5,6,7,8-tetrahydroquinoline, useful for amination of a broad range of aryl iodides by aqueous ammonia in DMSO in the presence of the cheap base K3PO4 at room temperature.274 A large excess of two ligands (oxalyl hydrazide and hexane-2,5-dione) was shown by Zhu and coworkers to support the arylation of ammonia by aryl iodides and bromides in an aqueous system.275 4-Hydroxyproline is effective as a ligand in aqueous DMSO; in this solvent the cheap base K2CO3 is as effective as Cs2CO3.276 Almost simultaneously with chelator-based systems, it was disclosed that the arylation of ammonia can be run as or even more effectively in “ligand-free” systems. One protocol uses Cu2O (5 mol %) in aqueous NMP at 80 °C, an incredibly simple system which includes no components with substantial ligand properties except ammonia itself, thus serving as an excellent token of the possibility of controlling this reaction through the nucleophile itself. Moreover, this system allows for the use of aryl chlorides to be converted to anilines, though this reaction is enabled only by prolonged microwave heating (Cu2O, 5 mol %, NMP−water 1:1, 110 °C, microwave, 10−20 h) but fails to give any conversion under drastic conditions on prolonged conventional heating (160 °C, 36 h).277 The other simple protocol employs aqueous ethylene glycol as solvent in the presence of an equivalent amount of CuI and 20 mol % of Cu bronze.278 Another recent addition to this arsenal revealed that iodoarenes and some bromoarenes can be cleanly transformed into anilines by aqueous ammonia in the presence of 10 mol % CuI, K3PO4 in DMF at room temperature (elevated AC


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NH2 group, though the reversal of selectivity is rarely quantitative (system CuI, phenanthroline, Cs2CO3, DMF, 90 °C)281 and is not observed in other catalytic systems.276 A few other systems were proposed for aryl iodides (CuI (5 mol %)− L, Cs2CO3 in DMF at 80 °C282) and bromides (CuI (5 mol %)−hydroxyproline, Cs2CO3, DMSO, 80 °C).276 On the other hand, the arylation of N-aryl-N′-acylhydrazines by aryl iodides in a “ligand-free” system (CuI (10 mol %), K2CO3, DMSO, 60 °C, 20−30 h) was shown by Ma and co-workers to be selectively directed not at the amido but at the amino group, regardless of the substituent and steric effects in the aryl iodide.283 In Pd-catalyzed systems the scope of hydrazine derivatives tested is wider, and the situation overall partially resembles that with ammoniathere is a plethora of protected hydrazines (hydrazine surrogates), introduced because free hydrazine was not believed to be able to serve as an NH nucleophile, as it is known from school-level textbooks to be decomposed in the presence of Pd compounds. Nevertheless, well-designed ancillary ligands can work miracles. Lundgren and Stradiotto applied very bulky aminophosphine ligands to afford a useful protocol for monoarylation of hydrazine hydrate or hydrochloride (Figure 73).284

temperatures were in fact shown to be an adverse factor) (Figure 71).279 Xu, Feng, and co-workers discovered that

Figure 71. Room-temperature arylation of ammonia.

selective arylation of ammonia takes place in the presence of CuI nanoparticles in an aqueous system using Bu4NOH as base and phase-transfer agent. In the absence of ammonia phenols are formed in this same system.280 An interesting form of ammonia nucleophile is lithium amide, which appears in both Pd- and Cu-catalyzed arylation. The use of this reactive nucleophile directly affords di- and triarylamines, depending on either the steric demand of the aryl halide in Pd-catalyzed process259 or the ratio of LiNH2 and extra base in the Cu-catalyzed process (cf. Figure 52).179 Selective Pd-catalyzed monoarylation is also possible through the use of a bulky ligand and a high excess of the nucleophile.265 Hydrazines and Similar Strong Nucleophiles Enhanced by the α-Effect. Hydrazines, hydroxylamines, and azides constitute a special subclass of N nucleophiles characterized by enhanced nucleophilicity due to the α-effect, the repulsion of lone pairs at adjacent heteroatoms. Such nucleophiles are easily involved in C−N cross-coupling reactions using both Cu and Pd catalysts. Many such substrates contain two different nucleophilic centers, thus presenting interest for studying ambident reactivity and revealing the interplay of various factors affecting the direction of cross-coupling. Following the general trends identified above, one may suppose that copper-based systems would prefer more NH acidic sites, while Pd-based systems would attack more nucleophilic sites, but the actual picture is not so unambiguous. Steric factors expectedly play a major role. Copper-based systems were used in a number of useful protocols. Thus, the arylation of free arylhydrazines was achieved using the ligand PPAPM (29), to give the expected products of attack at the more NH acidic internal atom (Figure 72). Interestingly, the use of sterically hindered orthosubstituted aryl bromide gave instead the terminal product.165

Figure 73. Pd-catalyzed monoarylation of unprotected hydrazine.

Information on cross-coupling with hydrazine derivatives is abundant. The arylation of tert-butyl carbazate in the presence of Pd catalysts follows a pattern similar to arylation with the Cu catalysts. The primary site of attack is the amide nitrogen, which is rather interesting, as amides are overall challenging NH nucleophiles for Pd catalysis, requiring special bulky ligands such as Xantphos (Figure 74).285 The involvement of the amide nitrogen center in the presence of more common ligands is most probably accounted for by the enhancement of nucleophilicity due to the α-effect.

Figure 72. Regioselectivity of Cu-catalyzed arylation of phenylhydrazine.

Figure 74. Regioselectivity of Pd-catalyzed arylation of tertbutylcarbazate.

Most often in cross-coupling reactions N-acylated hydrazines are used, the standard substrate being tert-butyl carbazate (BocNHNH2). This substrate also behaves as an ambident nucleophile, the preferred site of attack being the more acidic amide atom, but the aryl halides bearing ortho-substituents usually give more of the product of attack at the unsubstituted

tert-Butyl carbazate can be effectively arylared by aryl bromides in the presence of the ligand dppf. Ortho-substituted aryl bromides show a reversal of site selectivity to afford arylation at the free NH2 group.285 Later it was shown that the use of Xantphos is indeed beneficial for the arylation of hydrazides.286 Other derivatives of hydrazine studied were NAD


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aryl-N-Boc-hydrazines,286,287 N,N′-bis-Boc-hydrazine,288 N,Ndimethylhydrazine, N-aminopiperidines, and morpholines.289 Extensive studies were carried out on the arylation of hydrazones using not only aryl bromides and iodides (BINAP, dppf, Xantphos, and other ligands)290 but also chlorides291 and sulfonates (using XPhos ligand48). The arylation of the azide anion was achieved only as a copper-catalyzed reaction. Copper-catalyzed formation of azides has been known since 1980; thus, it can be performed even under standard Ullmann conditions at high temperatures, which shows that organic azides are stable in the presence of copper salts, even under harsh conditions.292 Recent studies revealed several useful protocols in the presence of proline ligand, applicable to aryl iodides,293 and a milder method involving diamine ligands DMEDA and DMCyDA in aqueous ethanol, applicable to aryl bromides, including electron-rich ones (Figure 75).294

definite meaning and proper usage. Briefly, in the tandem process sequential steps are self-contained reactions, each of which generates substrate(s) for the next step. The steps are thus coupled via isolable half-products. In the cascade process the sequential steps are coupled by reactive intermediates of the same naturethus the cascade is not a sequence of reactions but a sole multistep reaction. The cascade processes rely on a single catalytic system in which the catalyst generates a live reaction center which is next involved in one or several consecutive catalytic steps (usually involving migratory insertions to double or triple bonds), eventually terminated by another catalytic step quenching the active intermediate. The domino process is actually a redundant term usually referring to a well-tuned cascade, and therefore it can safely be omitted, at least from the present discussion. The tandem processes refer to successive multistage reactions running in reaction mixtures containing more than one catalyst, which can be generated from one or several precatalysts. The steps in the tandem process can be closely or loosely related, as e.g. a transition-metal-catalyzed reaction can run in tandem with a base-catalyzed aldol condensation etc. Each step of a tandem process is separate from the otherthe reaction center is created anew and quenched at the end, not to be transferred alive to the next stage. There is a proposal for a more precise classification of tandem processes into autotandem, orthogonal tandem, and assisted tandem processes,297 but such discrimination is based on a precise knowledge of the catalytic species involved, the timing of bond-forming events, and other such delicate matters, which are almost never explicitly known. In the case of tandem processes involving C−N crosscoupling steps there is an ambiguity associated with the uncertain ordering of steps. Indeed, in the case of a two-bondforming tandem process, C−N cross-coupling can precede or follow the formation of the other bond (Figure 77). Therefore,

Figure 75. Copper-catalyzed cross-coupling with azide.

Copper-catalyzed azidation is tolerant to the trifluoroboronate group to afford compounds bearing both azide and boronate groups useful for further transformations (e.g. coppercatalyzed click 2 + 3 cycloaddition or palladium-catalyzed Suzuki−Miyaura arylation).295 The reduction of azides, e.g. by NaBH4, affords amines; thus, azide ion can be regarded as another ammonia equivalent (see above). Palladium-catalyzed azidation was not described, probably because azides may take part in palladium-catalyzed follow-up reactions, as both Pd(0) and phosphines are known to cause the decomposition of azides. For example, the reaction of alkenyl bromides with sodium azide in the presence of palladium catalyst affords triazoles (Figure 76), with the respective alkenyl azides being likely intermediates.296

Figure 76. Palladium-catalyzed alkenylation of azide.

C−N Cross-Coupling in the Heterocyclization: Intramolecular Reactions and Tandem and Cascade Processes. Intramolecular C−N cross-coupling reactions are extremely flexible routes to a vast manifold of nitrogencontaining heterocycles. Both Pd- and Cu-catalyzed processes have been massively exploited in the synthesis of heterocycles; therefore, in this field a rough parity between the two domains is established. However, when it comes to discussing C−N cross-coupling reactions in the synthesis of heterocycles, a broader view that is not just limited to intramolecular amination and amidation is more relevant. Heterocycles are often formed not via a single-stage C−N bond forming ring closure but via multistep procedures with two or more of the bond-forming events. Such processes are described as cascade, domino, or tandem reactions, with all these terms often being used indiscriminately. Such a situation is confusing but can be readily avoided, as actually each of these terms has its own fairly

Figure 77. Two scenarios in tandem heterocyclization processes involving intermolecular or intramolecular C−N cross-coupling steps.

the process can involve either intermolecular or intramolecular C−N cross-coupling, and the knowledge of which one actually takes place is often missing or uncertain. In the palladium-catalyzed domain intramolecular C−N cross-coupling is not just a variant of general methodology; rather, it is a distinct, separate type of reaction. The mechanism of the catalytic cycle is seemingly the same, involving the same basic steps (Figure 78). However, the oxidative addition here is a directed process leading to the palladacycle; the ligand exchange is therefore not a separate step but a part of the directed oxidative addition, and reductive elimination is facilitated due to the formation of a favorable cyclic product (particularly facile when it is aromatic, e.g. indole), with release AE


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The use of simple triarylphosphines is often encountered in the intramolecular amination and even amidation reactions, e.g. in the synthesis of indolines,257f,299 indoles,300 imidazoles,301 quinolines,302 quinoxalines,299b,303 quinozalines,304 etc.305 Moreover, intramolecular C−N cross-coupling reactions (alone or in tandem with other processes) can in some cases be effectively realized in “phosphine-free” mode,306 which is altogether prohibited for intermolecular Buchwald−Hartwig reactions (Figure 81). An interesting “phosphine-free” protocol

Figure 78. The catalytic cycle for intramolecular Pd-catalyzed C−N cross-coupling.

of strain necessarily brought in by the conflict between the demands of coordination shell geometry and the conformation of the backbone, which are rarely similar. As a result, all steps are dramatically facilitated in comparison with the intermolecular reaction, and the need for special ancillary ligands is thus relaxed or altogether lifted. Very simple legacy ligands can perform adequately, which is almost never the case in the intermolecular C−N cross-coupling. Curiously enough, intramolecular C−N cross-coupling was discovered 10 years earlier than the main Buchwald−Hartwig reaction. Boger and co-workers described the synthesis of carbolines via the oxidative addition of Pd(0), taken as a typical precatalyst broadly used in early C−C cross-coupling chemistry. The basefree conditions used accounted for the stoichiometric noncatalytic process (Figure 79).

Figure 81. Example of phosphine-free intramolecular C−N crosscoupling.

was recently reported described by Orito and co-workers to employ Cu(II) acetate as a cocatalyst of uncertain function. The validity of this simple but effective protocol was demonstrated for an impressive set of targets, involving both amination and amidation and five- and six-membered rings.307 It should be stressed that the composition of the catalytic system may resemble the systems used for oxidative crosscoupling (see below), but both the formal stoichiometry and the substoichiometric loading of both Pd and Cu acetates, affording near-quantitative yields, show that the process is indeed a regular catalytic cross-coupling. This intriguing discovery clearly demonstrates that the potential of intramolecular C−N cross-coupling remains to be disclosed. Certainly, the special phosphine and heterocyclic carbene ligands common in intermolecular Buchwald−Hartwig reactions are extensively used also in heterocyclization, particularly when less reactive substrates (chlorides, sulfonates, etc.) are used, and in tandem processes which involve intermolecular C−N cross-coupling preceding the ring closure, e.g. in the synthesis of indoles by tandem intermolecular amination followed by intramolecular hydroamination, reported by Ackermann and co-workers (Figure 82).308

Figure 79. Noncatalytic early prototype for intramolecular C−N cross-coupling.

Catalytic C−N cross-coupling was discovered by the Buchwald and Hartwig groups in 1995 along with the intermolecular version,3b,298 and since then it has been extensively used for the synthesis of almost all kinds of nitrogen-containing heterocycles. It is indeed dramatically more facile and is not subject to the common restrictions of its intermolecular counterpart. Thus, e.g. intramolecular amination involving secondary amine and iodine (each of these requires advanced phosphines in the intermolecular case) takes place using the legacy precatalyst and very mild conditions (Figure 80).

Figure 82. Tandem amination/hydroamination synthesis of indoles.

The true cascade processes are not as frequent. Two major and well-developed types are (i) Wolfe’s hydroamination cascade and (ii) the norbornene-relayed cascade. The first type takes advantage of a long lifetime of Pd amidate intermediates, which can be trapped intramolecularly by a proximate double bond, with the short cascade being terminated by reductive eliminationthus, this process runs exactly as a regular C−N cross-coupling, only with the hydroamination step inserted into the catalytic cycle between the formation of amidate and the reductive elimination (cf. Figure 25).309

Figure 80. Mild intramolecular amination involving secondary amine and iodine leaving group. AF


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Figure 83. Norbornene-relayed cascade involving intramolecular amidation as a cascade-termination step.

The other type of cascade, originated by Catellani and coworkers and further developed by others,310 relies on reversible insertion of norbornene, which allows for the organopalladium reaction center to be involved in a chain of migratory insertions and Pd(II)/Pd(IV) C−C cross-couplings bringing the reactive center to proximal sites, where it can be quenched e.g. by C−N cross-coupling (Figure 83).311 Thus, the extremely versatile chemistry served by Pd catalysis brings forward an immense variety of heterocyclic structures. The synthetic and combinatorial potential of this chemistry is very far from being exhausted. In the Cu-catalyzed domain the status is different. The intramolecular version of C−N cross-coupling is not different from the intermolecular reactionboth share the same protocols and similar restrictions and substrate preferences. Therefore, in the intramolecular version so far there is a strong domination of amidation (cf. examples in the synthesis of alkaloids312). Certainly, this limitation is rather formal, as any substrate containing a NH2 group can be converted to a reactive amide by transformation into N-acyl (most often Nformyl,247 N-acetyl, N-Boc, N-tosyl, or N-phosphoryl245b) derivatives and such facilitator groups are easily removed after the cyclization. Such intamolecular amidation is very flexible, employs very simple catalytic systems, and gradually becomes the method of choice for the synthesis of heterocycles, often outperforming the respective Pd-catalyzed methods. As an interesting example, the formation of a four-membered ring can be cited, as there is no Pd-catalyzed method leading to an azetidine ring, and an attempt to perform such a cyclization gave tandem dimerization instead.313 On the other hand, the intramolecular cyclization of N-tosylamide onto chloroalkene or bromoalkene moieties readily takes place in a simple system (CuI (20 mol %)−dimethylglycine, Cs2CO3, dioxane, 100 °C). Moreover, the closure of the four-membered ring takes place preferentially, even if alternative closure to five- or sixmembered rings is available (Figure 84).314

Examples of cyclizations onto other than amides are rare and are contained in nondedicated papers describing mainly intermolecular protocols. Thus, the cyclization of an aliphatic primary amine onto o-Br or o-Cl in the presence of salicylamide,315 1,3-diketone (2-isobutyrylcyclohexanone),316 or L-proline156 as ligands to give indulines or tetrahydroquinolines under very mild conditions was reported. The “ligandfree” but noncatalytic cyclization (system CuI (200 mol %), CsOAc, DMSO, room temperature to 90 °C) to give five- to seven-membered rings using o-bromo-ω-(N-benzylamino)alkylbenzenes (and the respective iodides) is a rare example of intramolecular amination using secondary amine,59a later used in a number of successful complex syntheses.317 Yurovskaya and co-workers described the cyclization under very mild “ligand-free” conditions onto a secondary enamine residue, activated by a carboxylate group (Figure 85), located so that such an enamine can be regarded as a vinylogous carbamate.318

Figure 85. Synthesis of indoles by intramolecular vinylogous amidation.

The cyclization of o-iodo (o-bromo) benzoic acid hydrazides (CuI, L-proline) involves the second N atom to afford indazolones319(cf. intermolecular Cu-catalyzed reactions which always involve the acylated NH center of Nacylhydrazides). Cyclization involving azole arylation leading to a quinoline system fused to azoles can be performed in good yields even with chloro derivatives because of the orthodirecting activation of the halogen atom by the proximate carbonyl group.320 Various kinds of sequential multistep processes (tandem, cascade, domino) are much rarer in copper-catalyzed chemistry, because the arsenal of copper-catalyzed processes which can be coupled with C−N cross-coupling is much narrower. In fact, in the Cu-catalyzed domain only true tandem processes are known, because to take part in the cascade (domino) processes Cu(III) intermediates are too short-lived, highly transient, or nonexistent because of the hypothetically concerted character of the C−N bond-forming step (see above) to be trapped by proximate reactive groups, though migratory insertion, the most

Figure 84. Selective formation of a four-membered ring by Cucatalyzed amidation. AG


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common cascade propagation reaction (carbapalladation, aminopalladation in the Pd domain) does exist in the Cucatalyzed domain as a separate noncascaded reaction. Even the tandem processes in the Cu domain are still quite rare in comparison with the rich assortment of such processes involving Pd-catalyzed C−N cross-coupling, but these are interesting enough to stimulate further development, as the combinatorial potential of such approaches seems considerable. The tandem processes may involve inter- and intramolecular C−N cross-coupling (usually amidation), as in the synthesis of pyrroles or carbazoles from (Z,Z)-1,4-diiodobutadienes (Figure 86) or o,o′-diiododiphenyls.113a,321 The inter-/intramolecular aminations were coupled in tandem in the synthesis of benzimidazoles.322

Figure 88. Example of tandem intermolecular Cu-catalyzed amidation (red bond)/intramolecular addition to the CN group (bold bond) and tautomerization/intramolecular amidation (blue bond).

azole ring (Figure 89). In this process both of the tandemcoupled reactions are Cu(I) catalyzed. The method is also

Figure 86. Tandem inter-/intramolecular amidation.

Various base-catalyzed nucleophilic reactions are often run in tandem with intra- or intermolecular C−N cross-coupling, as e.g. aldol condensation coupled with arylation of azole, reported by Nagarajan and co-workers.323 The high tolerance of copper-catalyzed C−N cross-coupling to air was exploited by Xu and Fu in a multistep tandem synthesis of quinazolinones involving intermolecular arylation of unprotected amino acid in an air atmosphere, followed by oxidative dehydrogenation and intramolecular nucleophilic addition.324 As in the Pd-catalyzed domain, it is often difficult or impossible to guess which step comes first and whether intra- or intermolecular cross-coupling takes place. In many cases there are direct analogues between Cu- and Pd-catalyzed protocols, as e.g. in tandem C−N crosscoupling/alkyne hydroamination to afford indoles developed by Ackermann and co-workers (Figure 87 vs Figure 82).308,325

Figure 89. Tandem Cu-catalyzed [2 + 3] cycloaddition (blue bonds) and intramolecular C−N cross-coupling.

interesting, because it gives good yields also with aryl chloride substrates bearing no activating substituents.329 the good efficiency of cross-coupling at the C−Cl bond in this case is apparently due to the directed intramolecular character of the cross-coupling step. An interesting case of a tandem process, in which the amidate nucleophile does not exist in the starting reagent but is generated by nucleophilic ring opening of aziridine, was reported by Sekar and co-workers (Figure 90).330

Figure 90. Tandem aziridine SN2 ring opening coupled with intramolecular amidation.

In the Pd-catalyzed domain the assortment of C−C bondforming methods to be coupled within a tandem process is enormous, not to be compared with what Cu can manage, but still for the latter the choices are appearing and growing. An interesting example of such complex transformations was described by Dong, Zhao, and co-workers, who coupled copper-catalyzed C−C cross-coupling (Hurtley reaction) with nucleophilic addition to a cyanide group to give an amidine residue which is further involved in the intramolecular amidation (Figure 91). The processes are served by a single catalytic system using hydroxyproline ligand.331 The other interesting recent trend is to couple Cu- and Pdcatalyzed reactions in a tandem process, or at least a one-pot protocol. Thus, Bao and co-workers performed Cu-catalyzed intramolecular amidation, followed by Pd-catalyzed direct arylation (C−N/C−C cross-coupling) to access 1,1′-carbonyl2,2′-biindolyls (Figure 92).332

Figure 87. Tandem intermolecular amination/hydroamination.

A few other tandem processes were discovered involving Cucatalyzed C−N cross-coupling coupled with SN2 substitution,326 oxidative cross-coupling (cf. Figure 121),327 etc. A tandem process involving both inter- and intramolecular amidation was discovered by Fu and co-workers. The method uses cyanamide, the molecule of which provides three different reaction centers. Chloroarene residues can be successfully involved as electrophilic partners for the intramolecular amidation step, in which case attack by the Cu(I) center at the C−Cl bond is facilitated by intramolecular chelation (Figure 88).328 The other recent report by Cai and co-workers discloses how the most popular of all Cu-catalyzed reactions, the “click” reaction, can be coupled with intramolecular arylation of the AH


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processes and the way two ligands are attached to the lower oxidation state metal center also may be different, though it is seen even from the formal scheme that such processes should not change the oxidation state of the metal; thus, this is most probably electrophilic substitution. The use and nature of the external stoichiometric oxidant are not essential for chemistry involved in the main product-forming step. The participation of the external oxidant and the attachment of the regeneration pathway make the whole process catalytic in the transition metal directly involved in the bond-forming chemistry. It should, however, be clearly realized that this circumstance (the involvement of extra oxidant and the possibility to use a substoichiometric amount of transition metal) is of minor importance for understanding the mechanism of transformation, though it is highly essential from preparative and economic viewpoints. The oxidative cross-coupling pathways are known for both Pd and Cu, but so far only copper has been truly productive in serving this mode of reactivity in the context of C−N crosscoupling processes. As we have discussed above, Pd(II) reductive elimination of C−N product requires assistance from special bulky ligands, which are hardly compatible with oxidative pathways, being readily oxidizable themselves. However, there is the higher oxidation state Pd(IV), which in many respects resembles Cu(III), particularly in what concerns the ease of reductive elimination. Thus, Pd(II)/Pd(IV) may function as a peer to Cu(I)/Cu(III)-driven processes. The examples of such chemistry are very fresh but are already showing good promise for further development. Copper is involved in two distinct types of oxidative crosscoupling processes. In the first one the lower oxidation state intermediates are formed from diorganocuprates of organocopper reagents by reaction with amines or lithium amides, and the amidocuprates thus formed are oxidized to Cu(III) intermediates with subsequent fast spontaneous reductive elimination. This transformation was discovered as early as in 1980 by Yamamoto and Maruoka.335 The formation of amidocuprate, a typical cross-coupling intermediate with two σ-bonded ligands at the metal atom, by either Cu−R/N−H metathesis or the formation of an ate complex was postulated. The oxidation was performed by oxygen. It should be noted that this approach was much later successfully used for C−C cross-coupling or homocoupling of two aryl or alkyl groups by oxidation of diorganocuprates (Figure 94).336

Figure 91. Tandem intermolecular Hurtley reaction (blue bond), intramolecular nucleophilic addition (black bold bond), and intramolecular C−N cross-coupling (red bond).

Figure 92. One-pot Cu-catalyzed intramolecular amidation (blue bond) coupled with Pd-catalyzed intramolecular C−C cross-coupling (red bond).

■

OXIDATIVE CROSS-COUPLING REACTIONS Oxidative cross-coupling reactions (or oxidative nucleophilic substitution) have been known for a long time, but only recently has a growing understanding of regularities helped to advance this chemistry toward real application in synthesis.333 The recent studies of mechanisms41a,52a,72,334 unambiguously revealed the relationship between the regular and oxidative cross-coupling. From a formal point of view oxidative crosscoupling is a variation of oxidative substitutionthe reaction between two nucleophiles enabled by a two-electron oxidant. In terms of cross-coupling, it could be useful to regard, at least as the first approximation, such reactions as taking place from intermediates similar to those common for regular crosscoupling, but formed through the oxidation of the central metal in the derivatives of the same metal in lower oxidation states, in turn formed via isohypsic ligand exchange. The oxidation enables reductive elimination from higher oxidation states of the central metal (Figure 93).

Figure 94. Stoichiometric oxidative C−N cross-coupling via diorganocuprates.

Figure 93. Oxidation-enabled reductive elimination.

The reaction is selective toward N−H nucleophilic site in the presence of OH groups, e.g. (Figure 95).335 The lower order cuprates RCu(CN)Li were used in place of higher order cuprates in a similar protocol developed by

The intermediate complex undergoing reductive elimination is the same type of complex taking part in the regular crosscoupling, though ancillary ligands may and usually must be different, because the intermediates are born through entirely different processes and precursors. From the formal scheme it is seen that (a) oxidative cross-coupling is not catalytic with respect to the metal involved in the C−N bond-forming step and (b) a stoichiometric oxidant is required. The process also may or may not involve auxiliary reactions responsible for the regeneration of the main metal in the active form (shown by the dashed arrow in Figure 93). The nature of regeneration

Figure 95. Chemoselective oxidative C−N cross-coupling. AI


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Dembech, Ricci, and co-workers.337 This protocol is applicable also to the preparation of enamines (Figure 96). The other

A useful variation of this protocol uses intermediate organozinc compounds prepared by direct zincation and phenyliodosodiacetate as oxidant. The use of an organozinc reagent further improves the tolerance of the method to functional groups and widens its preparative scope.342 The other interesting recent extension of this chemistry was disclosed by Evano and co-workers, who showed that alkynylcopper reagents enter the cross-coupling with various amides (pyrrolidone and oxazolidones) under an oxygen atmosphere (Figure 99).343 The reaction is highly sensitive to

Figure 96. Enamines through oxidative C−N cross-coupling.

strong point of this strategy is that the reaction with sp3 coupling partners takes place as readily as with sp 2 substrates.337 In regular cross-coupling reactions the transfer of alkyl groups and synthesis of alkylamines remains a challenge. This protocol usually gives modest to good yields, which can be significantly improved by the addition of zinc chloride to the cuprate solution.338 Instead of using lithium amides and organocuprates, the order of nucleophiles can be inverted by using copper amides and organolithium reagents, as was developed by Snieckus and co-workers, who applied readily available ortho-lithiated benzamides (Figure 97).339

Figure 99. Oxidative alkynylation of amides.

the ancillary ligand used; no reaction was observed in the absence of such, while many N or P monodentate or chelate ligands gave poor selectivity. The best ligand was found to be TMEDA, which makes this system a direct analogue of Collmann’s catalytic oxidative arylation (see below).343 The method was successfully extended to alkynylation of other sensitive NH nucleophiles, such as imines (1,2-dimethylimidazole identified as the best ligand).344 This chemistry bridges the gap between purely stoichiometric methods involving preformed organocopper compounds and methods employing copper salts in catalytic amounts in the presence of stoichiometric oxidants treated below (Figure 100).

Figure 97. Oxidative cross-coupling of organolithium compounds with amidocuprates.

The method has been further developed and extended into a very useful synthetic protocol by Knochel and co-workers by introducing a number of preparatively effective improvements: in the first place the more conveniently handled, cheap oxidant chloranil. Organocopper compounds generated by transmetalation from organolithium or organomagnesium reagents with CuCl·2LiCl react with lithium amides to give lithium amidocuprates, which are oxidized by chloranil to afford the cross-coupling products in high yields.340 The strategy is very flexible, as it involves the generation of reactive organometallics via either metalation or transmetalation; thus, halogen atoms, even ones reactive as iodine, in the substrate can either be used or spared for further use as necessary (Figure 98).341 LiHMDS serves as an ammonia equivalent, giving access to primary amines.341

Figure 100. Oxidative alkynylation of imine: cross-coupling with stoichiometric alkynylcopper344 vs cross-coupling with alkyne in the presence of a catalytic amount of cupric salt.345

The Chan−Evans−Lam Reaction. The other realization of the oxidative cross-coupling strategy is the reaction of organometallic compounds with NH nucleophiles in the presence of Cu(II) salts or complexes, recently developed into a very useful and flexible synthetic protocol, often now referred to as the Chan−Evans−Lam reaction.346 In these reactions NH nucleophiles (amines, amides, azoles, etc.) are

Figure 98. Examples of oxidative amination via organocopper(I) compounds. AJ


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between liquid and gas phases by all reasonable means (fast stirring, small volume of reaction mixture thrown by stirrer as a thin film over the walls of the flask, etc.).350 This method gave good results for rarely used NH nucleophiles such as aziridines, in which case the mild conditions of this reaction avoiding the use of strong bases and nucleophiles are very important for success.351 A few other oxidants, such as pyridine N-oxide and TEMPO, can be applied.352 Such reoxidants are more effective and controlled than oxygen or air, thus enabling the reactions to be carried out under milder conditions, as in the protocol applicable to a vast variety of NH nucleophiles, including very weak ones (e.g. quinazolinediones).353 An interesting variation is the use of an Fe(III) salt, making possible an effective protocol using air as the main oxidant with as low as 3 mol % copper and 3 mol % iron loadings in the cross-coupling of azoles with aryl- or vinyltrialkoxysilanes,354 The scope of Chan−Evans−Lee oxidative cross-coupling is very wide, with respect to both the organometallic compound and NH nucleophiles. The latter is particularly impressive, as a sole procedure with minimal variations is applicable to aliphatic and aromatic amines, azoles, amides, ureas, sulfonamides, etc.; thus, the nucleophilicity of the NH nucleophile apparently does not play a critical role, in contrast to what is observed in regular C−N cross-coupling (vide infra). The higher reactivity toward NH nucleophiles is likely to be accounted for by the higher reactivity (Lewis acidity) of the Cu(II) state involved in ligand exchange in the oxidative cross-coupling vs Cu(I) involved in the regular cross-coupling. Recently the scope was successfully extended to aqueous ammonia.355 Poor nucleophiles, such as triazinones,356 sterically congested lactams (Figure 102),357 and

reacted with various non-transition-metal organometallic compounds (the derivatives of Bi, B, Sn, and Si), the most useful of which are boronic acids, in the presence of simple copper(II) salts, the most effective of which is anhydrous cupric acetate. The mechanism of such reactions is hypothetical, based on indirect evidence.346c,347 Similar reactions of oxidative substitution effected by cupric salts were investigated by Kochi and co-workers in the 1970s and were interpreted as involving inner-sphere redox processes accompanied by ligand transfer onto a free radical.348 In the context of the process under discussion, a very similar pathway (with free radicals formed by single-electron oxidation of organometallics) can be drawn; an alternative mechanism which takes into account an analogy with regular cross-coupling and utilizes similar intermediates can be regarded (Figure 101). Cu(II) is very likely to effect

Figure 101. Tentative mechanism of the oxidative C−N crosscoupling in the presence of Cu(II) and secondary oxidant.

electrophilic transmetalation of organometallic compounds to give rise to transient Cu(II) complexes, which, due to apparently higher Lewis acidity, should readily bind NH nucleophiles. Single-electron oxidation of the emerging Cu(II) intermediates by either a second Cu(II) (such disproportionation is quite likely, as the redox properties and stability of transition-metal complexes vary strongly depending on the ligands; see e.g. ref 349) or any concomitant oxidant such as oxygen gives the same Cu(III) intermediate as that already postulated in regular Cu(I)-catalyzed cross-coupling. Such a mechanism explains the important features of oxidative crosscouplingthere is no need for special ligands to control the reactivity of copper and no need for strong base. The reactions are carried out in the presence of modest or weak amines, such as Et3N or pyridine, and in some cases the reactions are performed in the absence of base. The latter is particularly interesting, as oxidative amination is accompanied by liberation of protic acidity, but in sharp contrast to regular cross-coupling, this acidity does not necessarily need to be scavenged. In such a pathway, the role of the second oxidant can be played by oxygen or some other reagent, though it is likely that these nonobligatory external oxidants are only spent for reoxidation of Cu(I) to Cu(II). Thus, in the absence of the secondary oxidant, the stocihiometry of the oxidative crosscoupling implies 2 equiv of Cu(II) per 1 equiv of substrate. The performance of the system is critically dependent on the copper salt used: in the most cases anhydrous Cu(OAc)2 is the only effective choice. Buchwald and Antilla have shown that the addition of a long-chain fatty acid increases the effectiveness further, if the non-nucleophilic weak base 2,6-lutidine is used. In this case the reaction can be performed with catalytic loadings of copper precursors, under conditions for effective diffusion of oxygen in the liquid phase by increasing the surface

Figure 102. Synthesis of sterically congested lactams.

quinazolinediones,353 can be arylated. The scope was extended to nucleophiles as poor as tetrazoles, which otherwise could be arylated only by diaryliodonium salts. Han and co-workers described a base-free protocol of oxidative cross-coupling between phenyltetrazoles and a wide range of aryl- and heteroarylboronic acids (Figure 103).358 Among the most recent extensions is the arylation of cyanate ion leading to carbamates, formed in alcoholic solvent (Figure 104).359 On the other hand, though the process is commonly applied to arylboronic acids, the scope was recently extended to trialkylboranes formed by hydroboronation of styrenes.360 Oxidative cross-coupling of alkynyl trifluoroborates with cyclic carbamates and secondary amines was shown by Evano and co-

Figure 103. Base-free oxidative arylation of 5-phenyltetrazole. AK


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species which are likely to be initially formed by disproportionation of Cu(II) species.367 Contrary to what is expected, imidazole is the first coupling partner to enter the coordination shell of copper, and transmetalation with arylboronic acid takes place after the disproportionation. Overall, the mechanism established for Collman’s system is likely to be relevant in the broader context of the Chan−Evans−Lam reaction. This mechanism apparently shows a very high degree of similarity between oxidative and regular cross-coupling chemistry concerning the main intermediates, the order of appearance of the coupling partners in the coordination shell (N nucleophile first, followed by C reagent), and the statement of reductive elimination from Cu(III) species as the productforming step. TMEDA can be used as an ancillary as well with other copper precursors to resolve synthetic challenges. Thus, e.g. the coupling with hindered substrates has long remained a weak spot of copper-catalyzed C−N cross-coupling reactions. A new protocol enabling the reaction of hindered arylboronic acids (2,6-diortho-substituted phenylboronic acids and 2-substituted naphthyl-1-boronic acids) involving TMEDA as ligand and CuOTf, Cu(OTf)2, or Cu(NO3)2 hydrate (20 mol %) in the presence of oxygen (Figure 107).368

Figure 104. Oxidative arylation of cyanate as a route to carbamates.

workers to take place under mild conditions in the absence of base (Figure 105).361

Figure 105. Oxidative alkynylation.

The base-free reaction of aryl azides with arylboronic acids in the presence of indium metal to afford diarylamines is an interesting case of the simultaneous use of both reducing and oxidizing agents in the same reaction system.362 However, there is a serious penalty in this generality, as no understandable trends in the rate of reactions and yields are observed, and the variations of yields even within series of very close substrates are very uneven.363 This feature is not surprising but quite typical for multistep reactions of complex kinetics depending on the innate reactivity of reagents and having no clear means of control over the reactivity of catalysts by tuning the component reaction system, particularly the ancillary ligands. The latter is simultaneously an important advantage and a very serious drawback of oxidative cross-coupling reactions. Undoubtedly, such systems are very simple and inexpensive, not requiring expensive ligands and additives. On the other hand, no means for tuning and adjusting reactivity, selectivity, and other important parameters of the catalytic system are inherent to these methods. There are, however, a few systems where ancillary ligands are not absolutely incompatible with this type of reactivity, and some can be used and afford a certain degree of control over the performance of such systems. The best known of these systems is Collman’s method using the complex [Cu(OH)(TMEDA)]Cl generated in situ from the dimeric complex (Figure 106). This complex is efficient in

Figure 107. Oxidative arylation involving sterically congested arylboronic acids.

Another interesting application of TMEDA-based protocol is a one-pot sequential realization of oxidative and regular crosscoupling (Figure 108).368

Figure 106. Mild oxidative arylation of imidazole. Figure 108. One-pot sequential oxidative/regular C−N crosscoupling.

catalytic amounts, though at the expense of the scope. The reaction is best suited for arylation of imidazole and benzimidazole.347a TMEDA was shown to be an optimal ligand by screening a number of other bidentate diamines; thus, it becomes evident that the ancillary ligand in this system is a critical factor.364 Unlike the standard Chan−Evans−Lam procedure, the process using a TMEDA complex can be run in aqueous systems.365 Further optimization of the system by van Strijdonck and co-workers arrived at aqueous NMP as the best solvent, in which the reaction takes place at room temperature in the absence of base.366 Careful examination of the mechanism by Tromp et al. showed that the catalytic cycle actually involves Cu(I)/Cu(III)

Apart from TMEDA, phenanthroline and its derivatives were seen to be able ancillaries.366 The use of this ligand was shown to afford a high regio- and chemoselectivity in the oxidative arylation of purines (Figure 109).369 Another interesting example of copper systems employing ancillary ligands is the use of a bipyridyl ligand, enabling oxidative cyclopropylation of a broad range of primary and secondary amines (Figure 110). The process is not suppressed by steric hindrance in the amine substrate, which allows for dicyclopropylation of primary amines.370 AL


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undergoes a fast disproportionation to give a pincer-type Cu(III) NCN-cuprabicycle (37) and a simple Cu(I) complex (Figure 112).372

Figure 109. Phenanthroline as ancillary ligand in oxidative arylation of purines.

Figure 110. Example of oxidative cyclopropylation of amines.

Further insight into the use of ligands in oxidative arylation was disclosed by Chen and coauthors with the introduction of several multinuclear complexes containing heterocyclic carbene residues supported in a pincer manner by imidazole and pyridine sites (Figure 111). Such complexes were capable of

Figure 112. Directed cupration of benzene ring by Cu(II) salt, followed by disproportionation to Cu(III) and Cu(I) complexes.

In the presence of strong stoichiometric oxidants, a different mechanism can be operative involving a clean Cu(I)/Cu(III) catalytic cycle without intervention of Cu(II) species (Figure 113).373 The mechanism involves prior oxidation of Cu(I)

Figure 111. Multinuclear copper carbene complexes as precatalysts for aerobic oxidative cross-coupling.

Figure 113. Cu(I)/Cu(III) mechanism of oxidative cross-coupling drawn for the amidation of N-methylindole.

sustaining the oxidative arylation of azoles and anilines with as low as 0.5 mol % precatalyst and in the absence of base under very mild conditions. CH Activation. A useful generalization of the oxidative cross-coupling pathway is the direct activation of CH bonds without the need to use organometallic reagents.334g,371 So far, Cu(II) derivatives have not been unambiguously proven to be capable of direct electrophilic cupration reactions of simple arenes. In this respect, a few recent works showing that Cu(II) can take part in electrophilic cupration of arenes containing ortho-directing substituents can be regarded as an invaluable breakthrough, showing so far unexploited reserves of reactivity of this metal. CH activation, similarly to what is well-known in Pd chemistry, is facilitated by the ortho-directing effect, and the formation of cupracycles analogous to palladacycles was observed. An important difference from Pd(II) stems from the open-shell character of the Cu(II) state, sitting between the two closed-shell states Cu(I) and Cu(III), to which it can disproportionate. Therefore, isohypsic cupration by Cu(II) can be regarded as an entry to the Cu(III)/Cu(I) cross-coupling cycle and such complexes are readily oxidized to ArCuIII cupracycles. Oxidation in the absence of other oxidizers is performed by the same Cu(II) complex (36), which thus

precatalyst by strong oxidant capable of oxidative addition to the Cu center to generate a highly reactive Cu(III) complex, which further isohypsically binds NH nucleophile and metalates the electron-rich arene. Such a mechanism can hardly be common for various oxidative C−N-cross-coupling reactions because of the involvement of highly unstable Cu(III) complexes at three different steps, which implies substantial lifetimes for such species. The extant sparse data on the chemistry of Cu(II) complexes are insufficient to corroborate such hypotheses. In some cases, including that described in Figure 113, it can be operative. Worthy of note is that binding of the NH nucleophile can take place not only before but also after the oxidation of Cu(II) to Cu(III), the latter being a more active Lewis acid capable of binding of weak nucleophiles such as phthalimide and sulfonamides in the absence of base, which is most probably in a neutral form. A model realization of this chemistry was performed with a macrocyclic ligand containing three pyridine residues (Figure 114). In this case the Cu(III) complex generated upon action of Cu(ClO4)2 was found to be highly reactive in the substitution with many useful nucleophiles, such as hydroxide, cycanide, carboxylate, and halide ions, though no AM


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Figure 117. Oxidative amidation of polyfluoroarene.

Particularly interesting is the oxidative amidation protocol reported by Li and co-workers.373a The protocol involved a directed cupration of 2-phenylpyridine and related arenes and 2-methylinole and is quite general in scope with regard to the amides, being applicable to secondary N-arylamides (e.g., Figure 118). Such sterically hindered poor nucleophiles are

Figure 114. Model copper-assisted oxidative nucleophilic substitution.

N-nucleophile was tested. Importantly, in the presence of oxygen this protocol was shown to involve less than 2 equiv of Cu(II) per 1 equiv of substitution product, thus making a further step in modeling the oxidative cross-coupling in the presence of external oxidant.36,374 Examples of preparative protocols involving CH activation in oxidative cross-coupling with NH nucleophiles are still rare but show that this mode of reactivity is real and potentially very useful. Thus, Schreiber and Wang recently showed that some CH acidic heterocycles undergo oxidative cross-coupling with amides using catalytic amounts of Cu(OAc)2 in air in the presence of Na2CO3 base (Figure 115).375

Figure 118. Oxidative amidation by sterically congested Narylacetamide.

practically unreactive in regular Pd-catalyzed cross-coupling chemistry and require special protocols in regular Cu-catalyzed cross-coupling (vide infra). The ability of the oxidative protocol to involve such poor nucleophiles is apparently due to early binding of the nucleophile by highly reactive Cu(III) species (cf. Figure 113), which are likely to possess Lewis acidity much higher than that of Cu(I) species involved in the regular crosscoupling at the time of NH nucleophile binding. Therefore, in general the oxidative cross-coupling protocols can be expected to be developed toward complementing regular cross-coupling chemistry to involve poorly mucleophilic sterically congested substrates. Oxidative cross-coupling of 2-phenylpyridine with primary amides and sulfonamides was described by John and Nicholas to take place in a very simple system (20 mol % Cu(OAc)2 in DMSO under an O2 atmosphere, at 160 °C for 48 h).377 Intramolecular CH activation via a Cu(III) cupracycle is likely to be behind the method of the synthesis of benzimidazoles by oxidative cyclization of N-arylbenzamidines.378 This reaction readily takes place without added base, and instead acetic acid is used, probably to ensure electrophilic activation of Cu(II). CH activation within the oxidative cross-coupling scheme is likely to be responsible for reactions of terminal acetylenes with amides, sulfonamides, lactams, cyclic ureas, carbamates, and azoles (Figure 119).379 Though this method appears to be a very interesting, direct, and simple approach to enymines, it needs further refinement to improve the selectivity and suppress oxidative dimerization. An alternative, proposed recently, exploits the generation of alkynylcopper intermediates through oxidative decarboxylation,

Figure 115. Oxidative amidation of a CH acidic heterocycle.

The reaction is likely to involve electrophilic cupration via an in situ generated carbanion (heterocyclic carbene). The conditions are rather harsh, which is most likely due to slow cupration. Oxidative homocoupling is the main side reaction. Intramolecular amination that likely takes place via the respective cupracycle gives better yields (Figure 116).

Figure 116. Intramolecular oxidative amidation.

The cross-coupling of the same sort of heterocycle with pnitroanilines was recently shown to take place under milder conditions.376 An even more interesting result is that the protocol is applicable to polyfluorobenzenes, the CH acidity of which is apparently too low to account for cupration via a carbanion (Figure 117). A similar protocol, though employing a catalytic amount of copper salt, was developed for arylation of electron-deficient anilines by polyfluoroarenes and pentachlorobenzene.376

Figure 119. Oxidative C−N cross-coupling with terminal acetylenes. AN


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the Pd(II)/Pd(0) pair but the Pd(IV)/Pd(II) pair.35a The Pd(IV) oxidation state boasts a much higher driving force for reductive elimination of two σ-bonded ligands than Pd(II); thus, Pd(IV) is more like Cu(III). It is therefore not surprising that oxidative cross-coupling using palladium complexes may rely on this oxidation state. Therefore, two distinct major strategies to enable reductive elimination from Pd complexes are available for development: the use of special bulky ligands operating through introduction of strain in the intermediate RPd(L)-NRZ complex in the regular cross-coupling and oxidation of Pd(II) into Pd(IV) not dependent on special ancillary ligands, as in the oxidative cross-coupling. Very recently the intermediacy of Pd(IV) in a number of oxidative cross-coupling reactions leading to the formation of C−C, C−Cl, C−Br, C−Se, and C−O bonds (e.g. ref 384 and references therein) has been firmly established, and these findings promise new entries to cross-coupling chemistry. The outstanding ability of Pd(IV) toward reductive elimination has a dark side, however, as it is not simple to predict which ligands are to be eliminated from the intermediate, and there are no less than four of them in the coordination shell. Thus, intermolecular oxidative cross-coupling reactions have so far been rarely selective, and there are only a few proven examples of C−N bond formation. However, things are dramatically different with intramolecular reactions. The use of palladium chemistry becomes a highly appealing subject in view of very facile ortho palladation. Ortho palladates themselves are complexes of Pd(II), very stable toward reductive elimination, but the oxidation of palladium to the +4 oxidation state enables reductive elimination, one of the products of which in the case of CN cyclopalladates can be ring closure via the formation of a C−N bond. A few reports appearing recently show that a good potential of CH activation via oxidative substitution can be thus unleashed. It should be noted that the authors of some of the protocols under discussion prefer to draw different mechanisms for particular reactions (see for example ref 385), and it indeed can be so, though no detailed studies on the mechanisms of any such processes have so far appeared. Still, the profound similarity between all such oxidative intramolecular aminations and amidations does show that we deal with similar phenomena. The first realization was disclosed by Buchwald and coauthors in the protocol of intramolecular oxidative amidation to afford N-acetylcarbazoles386 (Figure 122) (see also ref 387). The process is serviced by catalytic amounts of Pd(OAc)2, and

thus introducing yet another electrofugic leaving group for oxidative cross-coupling reactions (Figure 120).380

Figure 120. Oxidative alkynylation of amides by carboxylic acids.

Xu and Fu described a tandem process in which intermolecular arylation of imidazole is followed by intramolecular oxidative amidation. The process is served by a single catalytic system using L-proline ligand, originally developed by Ma and co-workers for intermolecular C−N cross-coupling. Switching to the oxidative mode is achieved by a simple change of atmosphere from inert to oxidative (Figure 121).327

Figure 121. Tandem regular cross-coupling (blue bond)/oxidative cross-coupling (red bond).

Further examples of oxidative cross-coupling with CH activation involve similar transformations.381 Tandem oxidative C−N/C−C cross-coupling was successfully applied to the modification of C60-fullerene with a heterocyclic residue.382 Oxidative Cross-Coupling Involving Pd Complexes. Oxidative cross-coupling reactions and the respective mode of reactivity are known for Pd chemistry, but the application of this chemistry toward C−N cross-coupling has not been known until very recently. A direct counterpart of the respective Cuassisted C−N oxidative cross-coupling process has so far not been revealed for the Pd(II) state. The reasons for this are multiple, starting with suppression of oxidative and electrophilic properties of Pd(II) complexes in the presence of aminesside reactions involving the oxidation of amine by Pd(II) would prevail if such reagents were forced to coexist in the same reaction mixture. Second, as was already mentioned, the special ligands required to enable reductive elimination from Pd(II) intermediates are readily oxidizable and also hardly compatible with oxidative conditions. Nevertheless, with regard to the individual steps, the chemistry is well-known for Pd(II). Organometallic compoundseven inert species such as organomercurialsare readily transmetalated by Pd(II) compounds to give essentially the same types of intermediates as those formed by oxidative addition of Pd(0) to organic halides. It should be mentioned that this reaction was used by Heck in the first noncatalytic version of what was to become the famous Heck reaction.383 A similar reaction involving CH activation (the Fujiwara reaction) was discovered simultaneously with the Mizoroki−Heck reaction and is now intensely developed. However, with regard to the C−N cross-coupling, a projection of oxidative cross-coupling chemistry involving Cu(III) intermediates onto the Pd domain hinges upon not

Figure 122. Intramolecular oxidative C−N cross-coupling. AO


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oxidation is performed by cupric acetate in an aerobic atmosphere. The latter is important because normally Cu(II) is a single-electron oxidant; thus, the use of 1 equiv of this salt would not be sufficient (though one cannot rule out that the intermediate is not a Pd(IV) but a Pd(III) complex). Effective air reoxidation of Cu(I) makes it possible to also use cupric salt in catalytic amounts. Such systems are particularly interesting, as both title metals are involved, with Pd serving the main role in oxidative crosscoupling and copper(II) salt serving as a secondary reoxidant. Further optimizations revealed the most unusual system in which no cupric salt is used at all, and the reaction takes place under an oxygen atmosphere in DMSO.385a A similar approach applied to diarylamines and using PhI(OAc)2 as oxidant afforded carbazoles in high yields. The mild conditions of the reaction enable the use of this protocol for the synthesis of functionalized carbazoles: e.g., carbazole−carbohydrate conjugates (Figure 123).388

The synthesis of indolines can be achieved via oxidative intramolecular amination of N-tosylphenylethylamines, in which case a judicious choice of oxidant is a crucial factor. Good yields were achieved in the presence of anhydrous cerium(IV) sulfate, but the best choice allowing development of a general and versatile protocol was N-fluorocollidinium tosylate. In this case side reactions, such as oxidative acetoxylation and halogenations, were suppressed.392 Diarylacrylamides are similarly cyclized into 2-quinolones393 and Ntosyleneamines of diarylacetaldehydes into N-tosylindoles (Figure 126).394

Figure 126. Oxidative amidation synthesis of N-tosylindoles.

The extraordinary capability of Pd to form palladacycles not only with aromatic but also with aliphatic CH bonds opened the possibility of developing a beautiful intramolecular amidation protocol, in which ring closure takes place with the participation of normally totally inert remote alkyl groups (Figure 127).395 In this case the mild single-electron oxidant AgOAc was shown to be the optimal choice.

Figure 123. Intramolecular oxidative C−N cross-coupling in the synthesis of carbazole−-carbohydrate conjugates.

Ortho palladation of N-methoxyamides was used for intramolecular oxidative amidation reported by Wasa and Yu (Figure 124).389

Figure 127. Intramolecular oxidative amidation of an alkyl group.

The first, and until recently the only, example of intermolecular oxidative C−N cross-coupling was observed by Sanford and Whitfield, who studied the decomposition of the Pd(IV) intermediate formed by oxidative addition of Nchlorosuccinimide to cyclopalladate formed from 2-phenylpyridine. Under the best conditions found, the yield of amidation product did not exceed 8%, with major products being those of oxidative chlorination and homocoupling formed via the same intermediate.396 This work clearly shows the obstacles to be overcome if a practical protocol of Pd-catalyzed oxidative amination is desired, as N ligands are not the first that Pd(IV) selects to get rid of (Figure 128). In this context, the results of Yu, Che, and co-workers, who developed an oxidative amidation protocol using substrates capable of ortho palladation and various amides as external nucleophiles in the presence of catalytic Pd(OAc)2 and the potent single-electron oxidant K2S2O8, seem to reflect the same reactivity pattern, though the authors put forward another hypothesis of nitrene insertion into the Pd−C bond (Figure 129).397 In any event, at least formally this protocol meets the oxidative cross-coupling paradigm. The reaction can be applied to the activation of both aromatic and aliphatic CH bonds.

Figure 124. Intramolecular oxidative amidation using a Pd/Cu pair.

Cyclization of analogous N-tosylamides also afforded oxindoles.390 A similar system was applied by Inamoto, Hiroya, and co-workers to obtain indazoles from tosylhydrazones (Figure 125).391

Figure 125. Indazole synthesis via oxidative intramolecular amidation. AP


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Figure 131. Tentative mechanism of directed oxidative C−N crosscoupling involving benzamide possessing enhanced NH acidity and Nbenzoyloxyamines.

Figure 128. Nonselective reductive elimination from a Pd(IV) complex.

Figure 129. Directed oxidative amination interpereted as nitrene insertion.

Later, Yu and co-workers described an effective protocol of directed oxidative cross-coupling with secondary amines (cyclic and dialkylamines) using their N-benzoyloxy derivatives (Figure 130).398 Figure 132. Hypothetical catalytic cycle for the inverted (Umpolung) C−N cross-coupling: (A) oxidative addition; (B) transmetalation or electrophilic metalation; (C) reductive elimination. The blue M denotes a low-valent metal (e.g., Pd(0) or Cu(I)) complex, and the red M denotes an increase in the oxidation state by +2 (Pd(2+) or Cu(3+)). Figure 130. Directed palladium-catalyzed oxidative amination.

subsequent transmetalation by an organometallic compound or electrophilic substitution by an activated arene, giving the same sort of intermediate complex bearing both residues to be coupled in the coordination shell, as is formed (or hypothesized to be formed) in regular and oxidative cross-coupling, which then should give the cross-coupling product by reductive elimination. Such a rough description of this catalytic cycle seems so obvious that it would be a rather hard task to understand why this has not already become a well-developed, fruitful strategy boasting hundreds of useful protocols. Instead, we can pick only a handful of examples. The possibility of realization of the Umpolung cross-coupling catalytic cycle, as depicted in Figure 132, faces challenges from alternative pathways of the transformation of the same reagents, in the first place with a rather trivial electrophilic substitution pathway (Figure 133). Nitrogen derivatives used for such reactions are by default electrophilic,399 though their electrophilicity is too weak to effect direct substitution. Copper or palladium precatalysts, at the same time, are usually taken as low-valent forms, which are also overly weak electrophiles. However, the same nitrogen reagents are often quite potent oxidants, which can oxidize the initial precatalyst form and generate an electrophilic metal derivative. Therefore, two successive electrophilic substitutions can take place, and such assisted electrophilic substitution would be catalytic in the transition metal, while inside the catalytic cycle the metal does

This discovery is particularly important in the context of palladium-catalyzed oxidative amination, as it takes place without external oxidant (the addition of silver acetate is facultative, as it only marginally improves yields but is not obligatory for the reaction to take place; thus, its function is a certain kind of electrophilic assistance, rather than oxidation), and N−O reagent is apparently capable of oxidative addition to the Pd(II) center. Thus, the Pd(IV) intermediate is likely to be generated by oxidative addition of nitrogen electrophile (Figure 131). In this respect this process is closely related to another type of cross-coupling, the Umpolung cross-coupling described in the following section.

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INVERTED OR UMPOLUNG CROSS-COUPLING The third paradigm in the cross-coupling chemistry relies on the inversion of the reactivity mode of the parties being coupledC residue is transferred as a nucleophile, while N residue is transferred as an electrophile. Thus, the overall reaction can be regarded as a catalyzed electrophilic substitution. Though reactions of this type have so far been very scarce, and their mechanism has not been investigated, this pathway can be tentatively regarded as an inversion of regular cross-coupling cycle (Figure 132) with the low-valent metal taking part in oxidative addition of the N−X bond, with AQ


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An even earlier example of a stoichiometric transformation of this kind was described by Ricci, Seconi, and co-workers. N,OBis(trimethylsilyl)hydroxylamine served as an ammonia equivalent to afford primary amines (Figure 135).402

Figure 135. Umpolung ammonia surrogate reagent.

Narasaka and co-workers probably described the earliest example of a catalytic version of Umpolung amination with organocuprates generated in situ from Grignard reagents (Figure 136). In this case, the reaction of a nucleophile

Figure 133. Alternative mechanisms for Umpolung C−N crosscoupling: (D, E) electrophilic substitution steps. The red M and blue M are defined in Figure 132, and the green M corresponds to the highest oxidation state, e.g. Pd(IV). The boxed part of the scheme denotes an alternative oxidative cross-coupling pathway.

not change its oxidation state. The relevance of such a mechanism in the reaction of arylboronates with Oacylhydroxylamines was supported by Hirano, Miura, and coworkers by studying individual stages of the transformation.400 In a broader context both mechanisms can be coexistent, and more studies are required to understand the real reactivity of the types of reagents involved. Moreover, in the case of Pd, the transformation of the arylpalladium(II) intermediate into the product can take place following the oxidative cross-coupling route via a Pd(IV) intermediate, if nitrogen electrophile is capable of oxidative addition to ArPdII. Such a multiplicity of possible ways of transformation using the same starting set of reagents (reactive ArM′ or ArH, nitrogen electrophile RZNX, catalytic amount of Cu or Pd precatalyst, optional base) makes possible at this stage only tentative mechanistic conclusions and does not allow for reliable identification of available modes of reactivity required for targeted research of new systems and protocols. So far, examples of transformations formally complying with the Umpolung C−N cross-coupling catalytic cycle are very scarce. Similar to the situation in oxidative cross-coupling, copper chemistry again takes the lead. The stoichiometric reaction of benzophenone oxime mesylate with dialkylcuprates or butylcopper described by Narasaka and coauthors unambiguously reveals the chemistry involved in the Umpolung cross-coupling. The adduct with dialkylcuprates should be oxidized by air, but the reaction with butylcopper spontaneously leads to the cross-coupling product (Figure 134).401

Figure 136. Catalytic Umpolung C−N cross-coupling involving in situ generated organocuprates.

(RMgX) with the copper complex obviously precedes the oxidative addition of nitrogen electrophile; thus, the order of steps should be inverse in comparison with the catalytic cycle depicted in Figure 132. The very high nucleophilicity of Grignard reagents apparently accounts for swapping of the transmetalation and oxidative addition steps. As we have seen in the discussion of regular cross-coupling, the order of these two common steps of the cross-coupling catalytic cycle can indeed vary depending on the relative reactivities of the coupling partners. The catalytic efficiency of this catalytic cycle was modest, with a TON value not exceeding 5.401 Erdik and Daskapan developed a protocol for the synthesis of primary aromatic amines by cross-coupling of hydroxylamine derivatives (O-methylhydroxylamine or acetone O-2,4,6trimethylbenzenesulfonyloxime) by organozinc reagents in the presence of CuCN catalyst under mild conditions in modest to good yields (Figure 137).403

Figure 137. Acetone oxime derivative as ammonia surrogate in catalytic Umpolung C−N cross-coupling.

Berman and Johnson developed a powerful protocol enabling a combination of secondary amines (including cyclic amines) and Grignard reagents of organolithium compounds to afford tertiary amines under mild conditions. Cross-coupling of Obenzoylhydroxylamines, which can be readily obtained from the respective amines by benzoyloxylation with benzoyl peroxide, with organozinc reagents was developed as a very mild, versatile, and convenient method of the synthesis of tertiary dialkylaryl and trialkyl amines, as well as some secondary amines, when sterically hindered primary amine is used in

Figure 134. Stoichiometric Umpolung C−N cross-coupling. AR


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copper is better represented by a diphenylphosphinate salt, which is requiresd in an amount of 2 equiv, the second equivalent providing a good ligand for tin.407 Interestingly, the choice of Cu(I) vs Cu(II) reagent can direct the reaction toward either inverted or oxidative crosscoupling (Figure 141).407

benzoyloxylation (Figure 138). Zinc salt also can be used in catalytic amounts if a Grignard reagent is added to a mixture of

Figure 141. Competition of the oxidative and Umpolung crosscoupling.

Umpolung cross-coupling with CH substrates is among the latest additions to the arsenal. The first protocol was described for N-chloroamines (Figure 146), and this protocol was later shown to be applicable to cross-coupling of heteroarenes and polyfluoroarenes with O-acylhydroxylamines. The protocol employs a strong base, used probably to assist CH cupration, and NN chelate ligand, typical in regular C−N cross-coupling. The reaction takes place under mild conditions and is applicable to a range of O-benzoyloxy derivatives of dialkylamines and cyclic amines, with a single example of a derivative of a primary amine (Figure 142).408

Figure 138. Mild and highly selective Umpolung C−N cross-coupling protocol.

benzoylhydroxylamine and zinc chloride. The process also marks a further step forward regarding copper precatalyst loading.404 In some cases Grignard reagents can be directly coupled to O-benzoylhydroxylamines in the presence of CuCl2 catalyst in the absence of zinc reagents.405 Liebeskind and coauthors extended the scope to less reactive nucleophiles, organotin compounds and boronic acids, which were coupled with Oacyloxyimines under mild conditions in the presence of 10 mol % CuTC (of Cu(OAc)2) (Figure 139).406

Figure 142. Umpolung cross-coupling with CH substrates.

Thus, as the new chemistry is unfolding, a better understanding is gained about the means of controlling the reactivity, and more sophisticated and specialized protocols have been developed. Hirano, Miura, and co-workers announced an optimized method for cross-coupling of arylboronates, readily available through powerful palladium and iridium borylation reactions, and O-benzoylhydroxylamines (Figure 143).400 The

Figure 139. Umpolung cross-coupling of O-acyloximes with organotin and organoboron compounds.

This approach was further extended to develop an Umpolung counterpart for amidation. Acyl- or O-alkylhydroxamic acid reacts with boronic acids in the presence of an equivalent amount of CuTC or CuOAc to afford an alternative base-free amidation strategy (Figure 140). The requirement of 100 mol % loading of Cu catalyst is most probably accounted for by the formation of strong amidate copper complexes which will not let copper go for the next catalytic cycle. Organotin reagents can be used in the same process, but in this case

Figure 143. Selective Umpolung cross-coupling of cyclic boronates with O-benzoylhydroxylamines (L = o-bis(diphenylphosphino)benzene).

system involves a copper salt and a chelating diphosphine, quite an unusual choice, as it had a very modest history of use in cross-coupling of all types and is probably the first diphosphine ligand proven to be useful in copper-catalyzed cross-coupling. A specific base is also required for the activation of boronates. Therefore, the protocol is not only preparatively valuable but it

Figure 140. Umpolung amidation. AS


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nitrosoarenes, followed by the already discussed inverted copper catalyzed cross-coupling.412 With regard to palladium, Umpolung C−N cross-coupling until recently remained an elusive mode of reactivity. Zerovalent palladium is known to be capable of oxidative addition of N−X bonds. The oxidative addition of Pd(0) to N− O bonds of oxime derivatives was discovered by Murahashi and coauthors 413 and extensively studied by Narasaka and coauthors, though almost exclusively the intermediates thus generated were engaged in intramolecular exo,trig addition reactions, leading to various heterocycles (known as amino− Heck reaction or Narasaka−Heck reaction;414 e.g. Figure 147).

also definitely highlights a new path to follow through an understanding that copper-catalyzed C−N cross-coupling can benefit from as yet unexplored ancillary ligands. In fact, simultaneously, Lalic and co-workers described an even more breathtaking discovery. Arylboronates were shown to react with O-benzoylhydroxylamines, including the derivatives of very bulky N,N-dialkylhydroxylamines using a copper system involving ligands with an outstanding record in palladium-catalyzed C−N cross-coupling but no proven achievements in copper cross-coupling catalysisXantphos and the heterocyclic carbene IMes (Figure 144).409 The

Figure 144. Example of Umpolung cross-coupling as a route to sterically congested dialkylarylamines.

outstanding tolerance to steric bulk in the amine residue brings this system far ahead of its competitors and clearly shows that studying Umpolung cross-coupling is not a leisure-time-filling game but rather an unexplored mine for long-awaited synthetic solutions and ideas in tuning catalytic systems. In addition to N−O bonds, N−Cl bonds are also reactive under Cu-catalyzed conditions. The arylation of N-chloroamides by arylboronic acids was recently described by Lei and coauthors (Figure 145). The reaction is run under mild

Figure 147. Heterocyclization via aminopalladation effected by oxidative addition of activated oxime derivatives.

Oxidative addition of N-halosuccinimides or N-bromophthalimide to Pd(0) phosphine complexes was reported by Fairlamb, Taylor, and co-workers in 2005 to afford stable amidate complexes.415 The complexes were shown to serve as effective precatalysts for the Stille reaction, which implies the ability to take part in transmetalation with a stannane. Of relevance to this discussion is the fact that Ni(0), which is a close relative and in many respects an intermediate between Pd(0) and Cu(I), is quite effective in catalyzing such Umpolung amination reactions. Barker and Jarvo described the crosscoupling of N-chloroamines with organozinc reagents under very mild base-free conditions (Figure 148).416

Figure 145. Umpolung cross-coupling of N-chloroamides.

conditions in the presence of CuCl and is tolerant to iodine and bromine substituents, which are reactive in regular crosscoupling.410 However, the addition of mild base is required to quench the liberated protic acidity. Recently cross-coupling with chloroamines was extended by Miura and co-workers to the amination of C−H bonds in 1,3,4oxadiazoles and similar five-membered heterocycles, the first example of such a mode of reactivity in the domain of Umpolung cross-coupling: e.g., Figure 146.411

Figure 148. Nickel-catalyzed Umpolung amination.

Quite recently, Tan and Hartwig reported the first unambiguous case of palladium-catalyzed Umpolung crosscoupling in an intramolecular variant.417 O-Acetates of oximes of benzyl ketones were shown to undergo cyclization into indoles in the presence of Pd(0) precatalyst and base (Figure 149). The phosphine-free system was proven to be more effective than the system employing a Pd(0) phosphine complex. The intermediacy of oxidative addition of the N−O bond was proven by isolation of the respective complex, stabilized by phosphine ligands. The complex, stable enough to allow for X-

Figure 146. Example of CH amination via Umpolung cross-coupling.

Substrates with unusual leaving groups such as nitrosoarenes react with arylboronic acid in the presence of copper catalyst and mild reducing agent (ascorbic acid of hydroquinone) to give diarylamines. The role of the reducing agent is most probably to generate hydroxylamine derivatives in situ from

Figure 149. Intramolecular Umpolung C−N cross-coupling. AT


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ray structure elucidation, is transformed into indole on heating in the presence of base (Figure 150).

Figure 152. Probable case of intermolecular Umpolung C−N crosscoupling.

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CONCLUSIONS In less than two decades a new potent chemistry of C−N bond formation through transition-metal-mediated substitution reactions have appeared and undergone a vigorous, and in many respects spontaneous, development. Two metals, palladium and copper, have been the most prominent players in this development. In spite of fundamental differences in the chemistry and behavior of these metals, more and more similarities in the reactivity have been revealed, which led to an understanding that a large number of reactions taking place in the presence of their complexes are similar in nature and actually belong to the same paradigm, described as crosscoupling. Each of the metals is capable of taking part in any of the realizations of the cross-coupling paradigmregular crosscoupling (transition-metal-catalyzed nucleophilic substitution), Umpolung cross-coupling (transition-metal-catalyzed electrophilic substitution), and noncatalytic oxidative cross-coupling. Major efforts have gone into the development of regular crosscoupling, the Pd-catalyzed version of which (the Buchwald− Hartwig reaction) has become a mature and versatile method of formation of C−N bonds. The avalanche advance of the Buchwald−Hartwig reaction was mainly due to the realization of rational ligand design through an understanding of the mechanism and ways to control the reactivity of the catalyst through properly selected ancillary ligands. The simultaneous and also very fast development of Cu-catalyzed cross-coupling, first trying to mimic the peer Pd chemistry, arrived at a different result. In spite of the great variety of ancillary ligands announced for Cu-catalyzed cross-coupling and a fair understanding of the mechanism, this area is advancing not via rational ligand design but rather by the elaboration of substratespecific catalytic systems, the role of ancillary ligands in which is reduced to fine-tuning the involved coordination equilibria. A good share of Cu-catalyzed protocols are “ligand-free”. Coppercatalyzed cross-coupling is more economical, though limited to a narrower subset of substrates and tasks, particularly amidation, reactions with nitrogen heterocycles, and heterocyclization, where it serves as an indispensable complement of Pd-catalyzed cross-coupling. The complementarity principle works not only in the regular cross-coupling where the metals compete but also through the addition of oxidative and Umpolung cross-coupling methods, which show promise in extending the chemistry to weak and sterically congested nucleophiles, direct CH activation, and the development of operationally simpler protocols excluding ancillary ligands and bases. In these two areas copper thus far has dominated the scene, but the first steps of palladium chemistry are interesting and promising future breakthroughs. As a result, recent advances in cross-coupling chemistry not only filled many gaps in the organic synthesis but also supplied rich material for understanding the coordination and catalytic chemistry of copper and palladium, as the differences in behavior and goals reached highlight the advantages and

Figure 150. Oxidative addition of the N−O bond and indole ring closure in Umpolung C−N cross-coupling.

The first instantiation of intermolecular Pd-catalyzed Umpolung cross-coupling was probably discovered recently by Yu and co-workers, though the chemistry was described largely as a special case of oxidative cross-coupling taking place in the presence of Pd(II) precatalyst and silver salt.398 However, in a single example the reaction was shown to take place in a quite high yield (70%) in the presence of Pd(0) precatalyst and base, in the absence of silver salt. The process is therefore catalytic in Pd(0) with as many as 7 turnovers registered. The observed stoichiometry therefore allows for an alternative Pd(0)/Pd(II) mechanism (Figure 151) in place of

Figure 151. Probable intermolecular directed Pd-catalyzed Umpolung C−N cross-coupling: protocol and tentative mechanism.

the oxidative pathway involving Pd(II)/Pd(IV) (cf. Figures 130 and 131). Further studies and searches for realizations of Umpolung cross-coupling are required to elucidate the mechanism and resolve the alternatives. A protocol which could involve undirected intermolecular Umpolung cross-coupling was described by Liu and co-workers (Figure 152).418 The interpretation in this case is particularly ambiguous, as the system described uses both Pd and Cu precatalysts but can be run with each of the metals taken alone, though in lower yields. AU


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disadvantages of each of the key players much better than an analysis confined to a single metal.

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AUTHOR INFORMATION

Notes

The authors declare no competing financial interest. Biographies

Andrei V. Cheprakov graduated from the Department of Chemistry of Moscow State University in 1983 and joined Professor I. Beletskaya’s Laboratory of Organoelement compounds. His Ph.D. theses were devoted to the oxidative halogenation of aromatic compounds and were defended in 1989. Currently he is a docent at the Chair of Organic Chemistry of Moscow University. His research interests include the methodology of transition-metal-catalyzed reactions, reactions in nonconventional aqueous microheterogeneous media, the chemistry and application of brassinosteroids, and the chemistry of extended porphyrins and fluorogenic oligopyrrins.

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REFERENCES

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Irina P. Beletskaya received her Diploma degree in 1955, her Ph.D. degree in 1958, and her Doctor of Chemistry degree in 1963 from Moscow State University. The subject for the latter was Electrophilic Substitution at Saturated Carbon. She became a Full Professor at Moscow State University in 1970, and in 1974 she became a Corresponding Member of the Academy of Sciences (USSR), of which she became a full member (Academician) in 1992. She is currently Head of the Laboratory of Organoelement Compounds, Department of Chemistry, Moscow State University. She is Chief Editor of the Russian Journal of Organic Chemistry. She was President of the Organic Chemistry Division of IUPAC from 1989 to 1991. She was a recipient of the Lomonosov Prize (1979), the Mendeleev Prize (1982), the Nesmeyanov Prize (1991), the Demidov Prize (2003), and the State Prize (2004). She is the author of more 600 articles and 4 monographs. Her current scientific interests are focused on (i) transition-metal catalysis in organic synthesis, (ii) organic derivatives of lanthanides, and (iii) carbanions and nucleophilic aromatic substitution. AV


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Organometallics

Review

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Organometallics

Review

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Organometallics

Review

(322) Chen, M. W.; Zhang, X. G.; Zhong, P.; Hu, M. L. Synthesis 2009, 1431. (323) Kumar, A. S.; Rao, P. V. A.; Nagarajan, R. Synthesis 2011, 3878. (324) Xu, W.; Fu, H. J. Org. Chem. 2011, 76, 3846. (325) Ackermann, L.; Barfusser, S.; Potukuchi, H. K. Adv. Synth. Catal. 2009, 351, 1064. (326) Wang, R. H.; Qian, W. X.; Bao, W. L. Tetrahedron Lett. 2012, 53, 442. (327) Xu, H.; Fu, H. Chem. Eur. J. 2012, 18, 1180. (328) Yang, D. S.; Wang, Y. Y.; Yang, H. J.; Liu, T.; Fu, H. Adv. Synth. Catal. 2012, 354, 477. (329) Yan, J. J.; Zhou, F. T.; Qin, D. G.; Cai, T.; Ding, K.; Cai, Q. Org. Lett. 2012, 14, 1262. (330) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11, 1923. (331) Jiang, M.; Li, J.; Wang, F.; Zhao, Y.; Zhao, F.; Dong, X.; Zhao, W. Org. Lett. 2012, 14, 1420. (332) Wang, Z. J.; Yang, F.; Lv, X.; Bao, W. L. J. Org. Chem. 2011, 76, 967. (333) Liu, C.; Zhang, H.; Shi, W.; Lei, A. W. Chem. Rev. 2011, 111, 1780. (334) (a) Casitas, A.; Poater, A.; Sola, M.; Stahl, S. S.; Costas, M.; Ribas, X. Dalton Trans. 2010, 39, 10458. (b) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068. (c) Ribas, X.; Calle, C.; Poater, A.; Casitas, A.; Gomez, L.; Xifra, R.; Parella, T.; Benet-Buchholz, J.; Schweiger, A.; Mitrikas, G.; Sola, M.; Llobet, A.; Stack, T. D. P. J. Am. Chem. Soc. 2010, 132, 12299. (d) Wang, M. Y.; Fan, T.; Lin, Z. Y. Organometallics 2012, 31, 560. (e) Lefevre, G.; Franc, G.; Adamo, C.; Jutand, A.; Ciofini, I. Organometallics 2012, 31, 914. (f) Casitas, A.; Ioannidis, N.; Mitrikas, G.; Costas, M.; Ribas, X. Dalton Trans. 2011, 40, 8796. (g) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062. (335) Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739. (336) Surry, D. S.; Spring, D. R. Chem. Soc. Rev. 2006, 35, 218. (337) Alberti, A.; Cane, F.; Dembech, P.; Lazzari, D.; Ricci, A.; Seconi, G. J. Org. Chem. 1996, 61, 1677. (338) Cane, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G. Synthesis 1997, 545. (339) Iwao, M.; Reed, J. N.; Snieckus, V. J. Am. Chem. Soc. 1982, 104, 5531. (340) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 7838. (341) Boudet, N.; Dubbaka, S. R.; Knochel, P. Org. Lett. 2008, 10, 1715. (342) Kienle, M.; Dunst, C.; Knochel, P. Org. Lett. 2009, 11, 5158. (343) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756. (344) Laouiti, A.; Jouvin, K.; Bourdreux, F.; Rammah, M. M.; Rammah, M. B.; Evano, G. Synthesis 2012, 44, 1491. (345) Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrott, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14, 6. (346) (a) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937. (d) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. (e) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829. (347) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044. (348) Jenkins, C. L.; Kochi, J. K. J. Org. Chem. 1971, 36, 3095. (349) Poater, A.; Cavallo, L. Inorg. Chem. 2009, 48, 2340. (350) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (351) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org. Chem. 2003, 68, 2045. (352) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415. (353) Guy, C. S.; Jones, T. C. Synlett 2009, 2253. (354) Song, R. J.; Deng, C. L.; Me, Y. X.; Li, J. H. Tetrahedron Lett. 2007, 48, 7845.

(355) Rao, H. H.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Angew. Chem., Int. Ed. 2009, 48, 1114. (356) Kumar, K. S.; Adepu, R.; Sandra, S.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Misra, P.; Pal, M. Bioorg. Med. Chem. Lett. 2012, 22, 1146. (357) Tan, D. Q.; Martin, K. S.; Fettinger, J. C.; Shaw, J. T. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6781. (358) Li, Y.; Gao, L. X.; Han, F. S. Chem. Commun. 2012, 48, 2719. (359) Kianmehr, E.; Baghersad, M. H. Adv. Synth. Catal. 2011, 353, 2599. (360) Naya, L.; Larrosa, M.; Rodriguez, R.; Cruces, J. Tetrahedron Lett. 2012, 53, 769. (361) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272. (362) Reddy, B. V. S.; Reddy, N. S.; Reddy, Y. J.; Reddy, Y. V. Tetrahedron Lett. 2011, 52, 2547. (363) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979. (364) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem. 2001, 66, 7892. (365) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528. (366) van Berkel, S. S.; van den Hoogenband, A.; Terpstra, J. W.; Tromp, M.; van Leeuwen, P.; van Strijdonek, G. P. F. Tetrahedron Lett. 2004, 45, 7659. (367) Tromp, M.; van Strijdonck, G. P. F.; van Berkel, S. S.; van den Hoogenband, A.; Feiters, M. C.; de Bruin, B.; Fiddy, S. G.; van der Eerden, A. M. J.; van Bokhoven, J. A.; van Leeuwen, P.; Koningsberger, D. C. Organometallics 2010, 29, 3085. (368) Wentzel, M. T.; Hewgley, J. B.; Kamble, R. M.; Wall, P. D.; Kozlowski, M. C. Adv. Synth. Catal. 2009, 351, 931. (369) Bakkestuen, A. K.; Gundersen, L. L. Tetrahedron Lett. 2003, 44, 3359. (370) Benard, S.; Neuville, L.; Zhu, J. P. Chem. Commun. 2010, 46, 3393. (371) Zhang, M.; Zhang, A. Q. Synthesis 2012, 44, 1. (372) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahia, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P. Angew. Chem., Int. Ed. 2002, 41, 2991. (373) (a) Shuai, Q.; Deng, G. J.; Chua, Z. J.; Bohle, D. S.; Li, C. J. Adv. Synth. Catal. 2010, 352, 632. (b) Santoro, S.; Liao, R. Z.; Himo, F. J. Org. Chem. 2011, 76, 9246. (374) (a) Wang, Z. L.; Zhao, L.; Wang, M. X. Org. Lett. 2011, 13, 6560. (b) Yao, B.; Wang, Z. L.; Zhang, H.; Wang, D. X.; Zhao, L.; Wang, M. X. J. Org. Chem. 2012, 77, 3336. (375) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (376) Zhao, H. Q.; Wang, M.; Su, W. P.; Hong, M. C. Adv. Synth. Catal. 2010, 352, 1301. (377) John, A.; Nicholas, K. M. J. Org. Chem. 2011, 76, 4158. (378) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (379) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (380) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000. (381) (a) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. J. Org. Chem. 2011, 76, 5295. (b) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 3694. (c) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071. (d) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996. (e) Jin, X.; Yamaguchi, K.; Mizuno, N. Chem. Commun. 2012, 48, 4974. (382) Chuang, S.-C.; Rajeshkumar, V.; Cheng, C.-A.; Deng, J.-C.; Wang, G.-W. J. Org. Chem. 2011, 76, 1599. (383) Heck, R. F. J. Am. Chem. Soc. 1969, 91, 6707. (384) (a) Canty, A. J. Dalton Trans. 2009, 10409. (b) Nieto, S.; Arnau, P.; Serrano, E.; Navarro, R.; Soler, T.; Cativiela, C.; Urriolabeitia, E. P. Inorg. Chem. 2009, 48, 11963. (385) (a) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (b) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243. (386) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. BC


Organometallics

Review

(387) Youn, S. W.; Bihn, J. H.; Kim, B. S. Org. Lett. 2011, 13, 3738. (388) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (389) Wasa, M.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 14058. (390) Miura, T.; Ito, Y.; Murakami, M. Chem. Lett. 2009, 38, 328. (391) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (392) Mei, T. S.; Wang, X. S.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, 10806. (393) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75, 3900. (394) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. Synlett 2008, 3157. (395) Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 6892. (396) Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142. (397) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006, 128, 9048. (398) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. (399) Barker, T. J.; Jarvo, E. R. Synthesis 2011, 3954. (400) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 3642. (401) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 317. (402) Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58, 5620. (403) Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139. (404) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219. (405) Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521. (406) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947. (407) Zhang, Z. H.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2008, 10, 3005. (408) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2860. (409) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. Angew. Chem., Int. Ed. 2012, 51, 3953. (410) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. W. Angew. Chem., Int. Ed. 2008, 47, 6414. (411) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (412) Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631. (413) Hosokawa, T.; Shimo, N.; Maeda, K.; Sonoda, A.; Murahashi, S. I. Tetrahedron Lett. 1976, 383. (414) (a) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45. (b) Tsutsui, H.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2002, 75, 1451. (c) Kitamura, M.; Kudo, D.; Narasaka, K. Arkivoc 2006, 148. (d) Narasaka, K. Pure Appl. Chem. 2002, 74, 143. (e) Faulkner, A.; Bower, J. F. Angew. Chem., Int. Ed. 2012, 51, 1675. (f) Kitamura, M.; Moriyasu, Y.; Okauchi, T. Synlett 2011, 643. (g) Zhu, J. L.; Su, Y. L.; Chan, Y. H.; Chen, I. C.; Liao, C. C. Heterocycles 2009, 78, 369. (415) Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Kapdi, A. R.; Taylor, R. J. K.; Whitwood, A. C. Tetrahedron 2005, 61, 9736. (416) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598. (417) Tan, Y. C.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (418) Liu, X. Y.; Gao, P.; Shen, Y. W.; Liang, Y. M. Org. Lett. 2011, 13, 4196.

BD


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