Ruthenium(II)-Catalyzed CâH Bond Activation and Functionalization

Review pubs.acs.org/CR

Ruthenium(II)-Catalyzed C−H Bond Activation and Functionalization Percia Beatrice Arockiam, Christian Bruneau,* and Pierre H. Dixneuf* Laboratoire Organométalliques, Matériaux et Catalyse, Institut Sciences Chimiques, UMR 6226 CNRS−Université de Rennes1, Campus Beaulieu, 35042 Rennes, France 3.5. Oxidative Dehydrogenative Cross-Coupling Reactions: Alkenylation of Arenes and Heterocycles 3.5.1. First Ruthenium(II)-Catalyzed Alkenylations of Arenes 3.5.2. Oxidative Dehydrogenative Alkenylation of Heteroarenes 3.5.3. Alkenylation of Arene C−H Bonds with Alkynes and Syntheses of Heterocycles 4. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Ruthenium(0) Catalysts and sp2C−H Bond Functionalization 3. Ruthenium(II)-Catalyzed sp2C−H Bond Activation/ Functionalization 3.1. Catalytic Arylation Reactions of (Hetero)arenes and Alkenes with Aryl and Heteroarylhalides 3.1.1. Profitable Influence of Phosphine on Ruthenium(II) Catalysts 3.1.2. Allylation or Homocoupling of C−H Bonds with Ru(II)−PPh3 Catalysts 3.1.3. Arylation of Arene and Alkene sp2C−H Bonds with R2P(O)H as Ruthenium(II) Partner 3.2. Carbonate and Carboxylates As C−H BondActivation Partners of Ruthenium(II) Catalysts 3.2.1. First Steps of sp2C−H Bond Deprotonation with Ruthenium(II) Catalysts 3.2.2. Arylation with Ruthenium(II)−Carboxylate Catalysts in Green Solvents 3.2.3. Autocatalytic Process of C−H Bond Activation with Carboxylate− Ruthenium(II) Catalysts 3.2.4. Few Arylation Examples and Exotic Ruthenium Catalysts 3.2.5. Monoarylation Leading to Biorelevant Functional Biaryl Derivatives 3.3. Alkylation of Arene and Heteroarene sp2C−H Bonds 3.3.1. Catalytic Hydroarylation of Alkenes 3.3.2. Catalytic Alkylation of sp2C−H Bonds with Alkylhalides 3.3.3. Alkylation of Alkene and Arene sp2C−H Bonds with Alcohols 3.4. Electrophilic Substitutions of Arene C−H Bonds with Ruthenium(II) Catalysts i. Aminocarbonylation and Alkoxycarbonylation Reactions ii. Acylation Reaction iii. Sulfonation Reaction © XXXX American Chemical Society

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1. INTRODUCTION The catalytic functionalization of unreactive C−H bonds has recently brought a revolution in synthetic methodologies for the production of pharmaceuticals and natural products and for opening new routes to molecular materials and polymers. The regioselective direct conversion of C−H bonds into C−C bonds offers the challenge to replace several classical catalytic cross-coupling reactions involving the coupling of organohalides with an organometallic intermediate RM (M = Li, MgX, ZnX, BR2, SnR3, SiR3, etc.) or with a functional alkene as in the Heck reaction. Transition metal catalysts initially based on palladium or rhodium complexes1,2 have been found to promote C−C bond formation via direct C−H bond activation under mild conditions. A large variety of metal catalysts3 and especially the cheaper ruthenium catalysts4,5 are now useful for the efficient catalytic conversion of C−H bonds. The catalytic C−H bond activation/functionalization still offers many challenges to overcome. In spite of the stability of sp2C−H bonds, early studies have revealed the relatively easy metal C−H bond activation to form metal−carbon bond and cyclometalated species via oxidative addition to electron-rich metal centers or σ-bond metathesis.6,7 However, further activation steps for catalytic C−C bond formation via oxidative addition of organohalides or insertion of unsaturated substrates also need to be favored. More substrate combinations have to be found including new tolerated functional or directing groups. New regioselectivities with respect to those occurring at the ortho position of most functional directing groups need to be explored. Although these selective C−H bond reactions

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Received: April 14, 2012

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dx.doi.org/10.1021/cr300153j | Chem. Rev. XXXX, XXX, XXX−XXX

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phenol by ethylene in the presence of catalytic amounts of potassium phenoxide and the tetraphosphite complex Ru(II)(P(OPh)3)(P(OPh2)(OC6H4))((PhO)2POC6H3OP(OPh)2) featuring two ortho-metalated ligands.19 However, the pioneering work in ortho-directed C−H bond activation/functionalization with ruthenium(0) catalysts was initiated by Murai with Chatani and Kakiuchi.10 This was the first example of chelationassisted and directed regioselective catalytic alkylation of aromatic ketones with alkenes in the presence of RuH2(CO)(PPh3)3, a stable precursor of Ru(0) catalyst.4 On the basis of DFT calculations, it was proposed that in this catalytic reaction the metal precursor is first reduced into a ruthenium(0) species simply by H2 elimination on heating and the C−H bond cleavage proceeds on oxidative addition via directed nucleophilic attack of the ruthenium(0) onto the ortho-carbon atom of the aromatic ketone, followed by migration of the hydrogen to the ruthenium center (Scheme 1).20 The hydrogen is more efficiently trapped with vinylsilane to generate the Ru(0) species.20c

constitute a contribution to green chemistry by producing less waste than the cross-coupling reaction, the catalyst loading is still high and the conditions require often high boiling point organic solvents rather than greener solvents such as dialkyl carbonates or even water at lower temperatures. Whereas many sp2C−H bonds have been successfully functionalized, it will be another challenge to develop sp3C−H bond-activation processes, including those of simple alkanes.8,9 The initial contributions for sp2C−H bond conversion brought by palladium and rhodium catalysts1,2 have motivated the search for cheaper, active catalysts and are also able to lead to different evolutions of reactions. The use of ruthenium(0) catalyst precursors, especially with the contribution of the Murai−Chatani−Kakiuchi group since 1993,10 has led to the discovery of new reactions based on initial ruthenium(0) insertion into the C−H bond and further reactivity of generated C−Ru−H species especially via unsaturated substrate insertion processes.4 Recently the use of easy-to-prepare and more stable ruthenium(II) catalysts has tremendously contributed to the discovery of cheaper and efficient catalytic systems, milder reaction conditions, and new reactions in various media, following the pioneering work of Oi and Inoue11 initiated in 2001, as well as that of Ackermann,12 Bruneau and Dixneuf.13 The success of ruthenium(II) catalysts is likely due to their easy transformation into cyclometalated species via C−H bond cleavage,7 their compatibility with currently used oxidants, and the stability of some of them to both air and water. The success of Ru(II) catalysts is also related to a quite different C−H bond-activation mechanism, with respect to the ruthenium(0) catalysts, which facilitates the deprotonation of C−H bonds, before any oxidative addition. This latter mechanism has some resonance with the C−H bond activation with Pd(II) species, by C−H bond deprotonation assisted by both the metal and the coordinated ligand.14,15 This Ru(II) C−H bond-activation process was shown to occur via assistance of Ru(II) site and in situ coordinated carbonate13 and carboxylate16,17 or by intermolecular deprotonation by carboxylate of C−H bonds activated by Ru(II) species.18 Within the last few years the use of ruthenium(II) catalysts has tremendously contributed to the discovery of sp2C−H activation processes and useful applications for cross-coupling C−C bond formation. It is the objective of this review to show the progressive discoveries of ruthenium(II)-catalyzed C−H bond functionalizations and to show their potential for the years to come. The current review will focus on ruthenium(II)-catalyzed transformations of C−H bonds into C−C bonds and describe their developments until the end of 2011, including the contributions of the first quarter of 2012, thus for almost a decade. As several reviews have presented the advantages of ruthenium(0) catalyst precursors for sp2C−H bond functionalization,4 this aspect will be only briefly presented at the beginning to show later how it contrasts with ruthenium(II) chemistry. Then the review will summarize direct catalytic sp2C−H functionalization via C−C bond formation with ruthenium(II) catalysts: arylation reactions associated with various directing groups and oxidative dehydrogenative crosscoupling reactions, including reactions performed in water.

Scheme 1. Ruthenium(0) C−H Bond-Activation Mechanism

This reaction involving aromatic or vinylic sp2C−H bond activation by low-valent ruthenium catalysts and formal insertion of a double bond into a carbon−hydrogen bond leading to alkylated products with atom economy are now described under the general name of Murai reaction. The scope of this reaction involves a wide range of alkenes including ethylene, vinylsilanes, and styrenes and could be applied to a variety of aromatic aldehydes, ketones, and esters.4 The reaction was extended to heterocycles such as pyrroles, furans, and thiophenes substituted by an acyl group in 2- or 3-position, which led to 3- or 2-alkylated products, respectively, in almost quantitative yields. Aldimines, ketimines, and nitriles also exhibited efficient directing effects (eq 1).21

2. RUTHENIUM(0) CATALYSTS AND sp2C−H BOND FUNCTIONALIZATION One of the first significant results in ruthenium-catalyzed sp2C−H bond activation consisted of the ortho-alkylation of

By contrast, under the same conditions, the reaction of aryloxazoline with triethoxyvinylsilane led to formal ortho-vinylation B


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of the arene ring. This product was assumed to be produced via insertion of the olefin into the ruthenium−carbon bond (carbometalation) followed by β-H elimination (eq 2).22

When the substrate contained both acetyl and imine directing groups, the nature of the formed product depended on the catalyst nature, and different olefins could be involved in sequential transformations. Thus, Ru3(CO)12 revealed the imine directing group efficiency, whereas RuH 2 (CO)(PPh3)3 catalytic alkylation was directed by the ketone group (Scheme 2).23

functional arenes occurred for substrates featuring a coordinating sp2N atom. The corresponding acylation reaction took place at the α, β, γ, or δ position with respect to the nitrogen atom and required a sp2C−H bond activation.25 The carbonylation of ortho-C−H bonds of chelating amides with Ru3(CO)12 leading to phthalimides has also been performed.25b

Scheme 2. Ru(0) Catalysts Selecting Their Preferred Directing Group

Scheme 3. Ruthenium(0)-Catalyzed Carbonylation of C−H Bonds with Alkene Insertion

The same catalysts are able to form C−C bonds by alkylation with alkenes of conjugated enones and enals via directed vinyl sp2C−H bond activation (eq 3).4h,24

Ortho-directed arylation of aromatic ketones with arylboronates derivatives has also been successfully performed with RuH2(CO)(PPh3)3.26 The Murai reaction was first investigated with a variety of substrates with RuH2(CO)(PPh3)3 and Ru3(CO)12 precatalysts. Other ruthenium(0) catalyst or precursors were also evaluated, such as Ru(CO)2(PPh3)3, Ru(CO)3(PPh3)2, and RuH2(PPh3)4, and it was found that RuH2(CO)(PPh3)3 showed a high catalytic efficiency when an oxygen-containing directing group was used (ketone, aldehyde, or ester), whereas Ru3(CO)12 was more suited for nitrogen-directing groups (imines, hydrazones, pyridines, and oxazolines). It is noteworthy that RuH2(H2)(CO)(PCy3)2 was also an efficient catalyst, which made the alkylation possible at room temperature.27 Recently ruthenium(0) species have been very easily in situ generated by reduction of the ruthenium(II) complex [RuCl2(p-cymene)]228 or the ruthenium(III) salt RuCl329 by sodium formate in the presence of a phosphine,

The proposed mechanism for all the previous reactions involves the formal insertion of the ruthenium(0) into the sp2C−H bond and insertion of the olefin into the ruthenium− hydride bond followed by reductive elimination. On the basis of a similar mechanism, it was also possible to perform this reaction with alkynes to obtain styrene derivatives from aromatic ketones and conjugated dienones from enones (eq 4).4e,h Most of these reactions have been investigated under CO pressure in the presence of Ru3(CO)12 and carbonylation of C


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or from Ru(O2CH)2(PPh3)(p-cymene) as catalyst precursor.30 This reaction with formate actually offers a fast way to generate ruthenium(0) catalysts from air- and water-stable ruthenium(II) complexes. The above selected examples show that the Murai−Chatani−Kakiuchi reaction4,10 has become a powerful method for the functionalization of sp2C−H bonds of a variety of substrates associated to a large range of tolerated functional directing groups.

apparently inert sp2C−H bond. It was shown that other ruthenium(II) catalyst precursors such as RuCl2(PPh3)3 and [RuCl2(COD)]n/4 PPh3 showed similar activity. The association of PPh3 ligand appeared to give the best results with respect to phosphites or diphosphines, likely to favor an oxidative addition step of ArBr. The arylation rate corresponded to the arylhalide sequence PhBr > PhI > PhOTf ≫ PhCl. The monoarylation of several substituted 2-pyridylarenes was selectively obtained in good yields for which the substituents, likely for steric reasons, inhibited diarylation. One example of monoalkenylation of phenylpyridine with E-PhCHCHBr was obtained (62%) along with 17% of dialkenylation product (eq 7). This new arylation and alkenylation reactions showed that the 2-pyridyl group was an efficient directing group for functionalization of sp2C−H bonds at the neighboring ortho position.

3. RUTHENIUM(II)-CATALYZED sp2C−H BOND ACTIVATION/FUNCTIONALIZATION 3.1. Catalytic Arylation Reactions of (Hetero)arenes and Alkenes with Aryl and Heteroarylhalides

3.1.1. Profitable Influence of Phosphine on Ruthenium(II) Catalysts. By contrast to the in situ generated ruthenium(0) species, ruthenium(II) and (III) complexes are frequently stable to air and water and thus were rapidly adopted for many catalytic organic syntheses,31 but only recently for C−H bond functionalization. An early example of C−H bond activation involved the carbon−carbon cross-coupling of furan and thiophene initiated by alkylation with ethanol using [RuCl2(C6H6)]2 and RuCl2(norbornadiene)2 catalysts or, even better, the simple precursor RuCl3·xH2O (eq 5).32 The

The efficiency of stable Ru(II) catalyst was surprising and suggested a different process than with Rh(I), Ru(0), or Pd(0) catalysts. The proposed mechanism involved an electrophilic substitution with a Ru(IV) intermediate, although the initial formation of a metalacycle intermediate was quite possible.7 In 2002, Oi and Inoue showed the direct arylation of imines with arylhalides using a similar ruthenium(II) catalyst.11b The ortho-arylated imines were obtained on reaction with phenylbromide in the presence of [RuCl2(η6-C6H6)]2/4 PPh3 catalyst, using 2 equiv of K2CO3 as a base in NMP (eq 8).

reaction involved the initial formation of a (heteroaryl)C2−Ru bond, as shown by carbonylation, followed by insertion of aldehyde, but the yield remained low. The first example of direct efficient arylation with arylhalides using ruthenium(II) catalyst was shown by Oi and Inoue11a in 2001 in the ortho-arylation of 2-pyridylbenzene. The use of [RuCl2(C6H6)]2 catalyst, in the presence of 2 equiv of PPh3 per ruthenium atom with 2 equiv of K2CO3 in NMP, led to the ortho-monoarylation of 2-pyridylbenzene with PhBr (1 equiv) or its diarylation (3 equiv of PhBr) (eq 6).

Although previous direct arylations of functional arenes were performed with Rh(I) catalyst and tetraarylstannanes,33or with Pd catalysts and aryl halides,34−36 this simple ruthenium(II) catalyst allowed the direct cross-coupling reaction of an

When N-(4-methoxyphenyl)-1-phenylethylimine was reacted with 1.2 equiv of bromobenzene, it provided total yield of 90%, with the ratio 81:19 of mono-/diphenylated products. With an D


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excess of bromobenzene, the ratio of diphenylated product was increased; however, the formation of monophenylated product remained predominant. By contrast, the aldimine underwent preferentially diarylation. With 3 equiv of PhBr it gave a 92% yield of diphenylated product. Steric hindrance played a crucial effect. meta-Methylsubstituted imines exclusively provided 74−85% of monophenylated product. Oi and co-workers have also investigated the catalytic Z-selective arylation of (E)-2-alkenylpyridines with arylhalides in the presence of [RuCl2(C6H6)]2/4 PPh3, in NMP at 120 °C. This catalytic system was found to be compatible with a large variety of substituted 2-alkenylpyridines and led to a different stereoisomer than that of the Heck reaction. High yields of products were obtained, for a variety of substituents on the aromatic ring of halides (eq 9).37

Scheme 5. Ruthenium(II)-Catalyzed Arylation of Aryloxazolines

coordination of nitrogen atom to the ruthenium complex. The presence of a methyl group or trifluoromethyl group in the meta position of the phenyl ring favored the monoarylated product. The catalytic reaction of aryloxazolines with alkenyl halides allowed the direct orthoalkenylation, often affording mixtures of E/Z products (eq 10).38 With this catalytic system the arylation was found to be compatible with N-acylimidazoles, providing good to excellent yields of arylated products (eq 11).38

The reaction was proposed to occur via initial oxidative addition of the arylhalide to Ru(II), followed by β-cis-ruthenation of the olefinic moiety and reductive elimination. However, on the basis of more recent mechanistic studies,13 the other proposed option seems more realistic via β-cis-ruthenation assisted by carbonate taking place first, followed by Ar−X oxidative addition (Scheme 4). Scheme 4. Proposed Mechanism of Arylation of Functional Alkenes

At this stage38 it was anticipated for the first time that cyclometalation took place first before oxidative addition, followed by the reductive elimination (Scheme 6). Such a mechanism is consistent with the recently proposed C−H bond-activation mechanisms.13,17 The Oi−Inoue group has extended the Ru(II)-catalyzed heteroarylation of 2-phenylpyridine and 2-phenyloxazolines with thiophenyl-, furanyl-, thiazolyl-, and pyridinylbromides in the presence of 2.5 mol % of [Ru(C6H6)Cl]2 and 10 mol % of PPh3. The monoarylated product was obtained with the use of 1/1.2 equiv of arylhalides, whereas the diarylated product was obtained in good yield with 2.2 equiv of the latter at 120 °C for 20 h (eq 12).39

Arenes containing 2-oxazoline function have been successfully arylated with a variety of arylhalides. The catalytic reaction between 2-phenyl-2-oxazoline and bromobenzene, in the presence of 2.5 mol % of [Ru(C6H6)Cl2]2 and 10 mol % of PPh3, using 2 equiv of K2CO3 in NMP at 120 °C, afforded 60% total yield of the mixture of mono- and diarylated products in the ratio of 25:75.38 With excess of bromobenzene, the diarylated phenyloxazoline was obtained as the sole product (Scheme 5). By contrast substitution on the oxazoline ring disfavored arylation. This phenomenon is due to the steric interaction between two methyl groups present in the 5- or 4-position on the oxazoline ring, thereby preventing the E


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3.1.2. Allylation or Homocoupling of C−H Bonds with Ru(II)−PPh3 Catalysts. A selective ruthenium(II)-catalyzed ortho-allylation has been achieved using also PPh3 as ligand at 120 °C.41 The branched allyl acetates afforded linear products exclusively (Scheme 7). The reaction is expected to proceed via cyclometalation followed by allyl acetate oxidative addition.

Scheme 6. Mechanism for Ruthenium(II)-Catalyzed Arylation of Aryloxazolines

Scheme 7. Examples of Allylation of Functional Arenes

Ortho-homocoupling of heterocycle-containing arenes has the potential to offer new bidentate ligands. Oi and co-workers demonstrated the homocoupling of 2-aryloxazolines and 2-arylimidazoles by choosing allyl acetate as an appropriate sacrificial oxidant, in the presence of 5 mol % of [RuCl2(cod)]n and 10 mol % of PPh3, at 120 °C in the presence of the base K2CO3 (eq 14).42

Oi and co-workers reported that imidazoles and thiazoles act as directing groups for the ruthenium(II)-catalyzed orthoarylation of phenylthiazole with bromobenzene in the presence of PPh3 and K2CO3 in NMP. The mono- or diarylated products were obtained exclusively by the use of 1.2 equiv or 2.5 equiv of bromobenzene with a wide variety of functional groups. The present catalytic system showed a broad scope for the arylbromides, having both an electron-donating or -withdrawing group and 2-bromonaphthalene, and afforded the coupled products in good yields (eq 13).40

The authors noticed that the use of allyl acetate was crucial using labeled substrates.42 The cleavage of C−D bonds occurred at the expense of two deuterium atoms, thereby producing deuterated α-methyl styrene with a quantitative yield of the coupled product (eq 15). The direct allylation of aromatic compounds such as benzene, toluene, p-xylene, anisole, phenol, and heterocycles such as furans and thiophenes has been performed by Nishibayashi and co-workers with allylic alcohol derivatives activated by cationic thiolate-bridged diruthenium(III, II) complexes (eqs 16 and 17).43 3.1.3. Arylation of Arene and Alkene sp2C−H Bonds with R2P(O)H as Ruthenium(II) Partner. A breakthrough in arylation of functional arenes with ruthenium(II) catalysts was brought by Ackermann12b by the introduction of phosphine

The above-described ruthenium(II)-catalyzed arylation of functional arenes or alkenes can be viewed as taking place via a cyclometalated ruthenium(II) species, followed by oxidative addition of (hetero)arylhalides and reductive elimination. The key role of the PPh3 ligand is to favor the difficult oxidative addition step. It also appears to disfavor diarylation in some specific examples. F


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appeared to be more efficient than the first one revealed by Oi and Inoue11 using Ru(II)/2 PPh3 catalyst.

In this study12b the role of R2P(O)H was considered simply as a preligand, as a possible anionic phosphorus ligand precursor. Later when the C−H bond activation with ruthenium(II) was established as a C−H deprotonation by the coordinated base (carbonate),13 leading initially to a ruthenacycle, as for the Pd(OAc)2 catalyzed C−H bond activation,14 Ackermann et al. proposed that R2P(O)H plays the role of a Ru(II) coordinating ligand for deprotonation of arene C−H bonds in a similar way as carboxylate.17 This active ruthenium catalyst, associated with the air-stable heteroatom-substituted secondary phosphine oxide (HASPO), allowed the direct arylation of 2-aryloxazolines with the less reactive aryl tosylates in NMP at 120 °C. The catalytic system tolerated a number of important functional groups such as alkene, ester, nitrile, and ketone (eq 20).12a

oxide R2P(O)H additives that were shown to activate the ruthenium(II) catalyst more efficiently than the phosphine ligand11 in such a way that it allowed effective arylation with the less reactive but readily available arylchlorides. Especially (adamantyl)2P(O)H (Ad2P(O)H) (10 mol %) associated with [RuCl2(p-cymene)]2 (2.5 mol %) led to diarylation using K2CO3 as a base in NMP at 120 °C for 5 h (72%) or 24 h (98%). Various arylchlorides were efficient to diarylate 2-phenylpyridine12b (eq 18). This catalytic system was used for the monoarylation with arylchlorides of ketimines that were hydrolyzed after C−H bond functionalization into the corresponding ketones12b (eq 19). For the ketimine monoarylation, this catalytic system

Interestingly, the selective formation of either mono- or diarylated products can be controlled through the choice of G


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electrophiles. The use of arylchlorides gave the diarylated product, whereas the reaction in the presence of aryl tosylates selectively yielded the monoarylated product (eq 21).12a

of substituted alkenes was performed with arylchlorides and has a broad scope with both the electron-deficient and electron-rich arylchlorides (eq 24).46

A more direct approach was used for the dehydrative coupling of heterocyclic arenes with inexpensive phenols as an arylating agent, but in the presence of p-tolylsulfonylchloride to in situ generate the tosylate. The reaction was successful in the presence of 2.5 mol % of [RuCl2(p-cymene)]2 and 10 mol % of HASPO ligand along with 1.2 equiv of p-toluenesulfonyl chloride in N,N-dimethylacetamide at 120 °C (eq 22).44

Sequential C−H activation/hydrosilylation was also achieved with ketone-containing arylchloride. A one-pot catalytic reaction sequence consisting of a direct arylation followed by a hydrosilylation was performed with the same catalyst. The sequential catalysis was not restricted to alkenes but also proved to be efficient with other heteroarenes like pyridines, oxazolines, and pyrazoles (eq 25).46

A broad functional group tolerance was shown for phenols bearing an ester, ketone, alkyl, aryl fluoride, or ether group. The catalytic system was also operative with other arene-containing heterocycle directing groups like pyridine and pyrazole.

The arylation of functional arenes by in situ-generated aryltosylates with carboxylate−ruthenium(II) catalyst has now been performed by Ackermann et al. in water.45 The reaction of arenes with phenols in the presence of p-TsCl and K2CO3 leads to the arylation of the ortho-C−H bond directed by a variety of nitrogen-containing functional groups (eq 23). Ackermann et al. illustrated the stereoselective C−H bond functionalization of alkenes containing a heterocycle directing group, in the presence of the Grubbs I ruthenium(IV) alkylidene as catalyst commonly used for alkene metathesis. The arylation

3.2. Carbonate and Carboxylates As C−H Bond-Activation Partners of Ruthenium(II) Catalysts

3.2.1. First Steps of sp2C−H Bond Deprotonation with Ruthenium(II) Catalysts. The evidence for sp2C−H bond activation has been revealed to take place under mild conditions in arene H/D exchanges.47 In the first steps of ruthenium(II) catalytic arylation of arene C−H bonds, to selectively form C−C bonds, the mechanism was thought to involve first an oxidative addition of ArBr to the Ru(II) center, by analogy with Pd(0) catalysts, followed by arene electrophilic substitution by the resulting Ru(IV) species. Very soon it appeared that, for arene containing a functional directing group, the initial formation of a metalacycle,7 taking place at moderate temperature with Ru(II) complexes, was more plausible as H


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illustrated by the reaction of phenylpyridine with [RuCl2(arene)]2 (eq 26).7e

Second, all the sp2C−H bond arylations were made in the presence of a base, usually a carbonate salt, and it was demonstrated that on reaction of [RuCl2(arene)]2 with M2CO3 not only the expected coordination of NHCarbene ligand from imidazolium occurred but more surprisingly the coordination of carbonate took place48 (eq 27). from Pd(OAc)2, the OAc ligand interacted with the ortho-C−H bond.50 The influence of both carbonate and acetate ligands was evaluated by the Rennes team13,16 by association with [RuCl2(p-cymene)]2 of K2CO3 and KOAc on catalytic arylation of phenylpyridine under conditions to reach complete conversion of phenylpyridine (eq 30). Thus, the role of the carbonate on ruthenium(II) C−H bond activation of phenylpyridine was investigated first with a variety of RuCl2(NHC)(arene) catalysts in Rennes,13 by Ö zdemir, Ç etinkaya, and co-workers,49a and by Peris and co-workers.49b The diarylation of phenylpyridine was easily achieved, and carbonate was shown to participate in the C−H bond activation/cleavage. Density functional theory (DFT) calculations by Maseras and co-workers showed that coordination of phenylpyridine to a RuCl2(NHC) unit led to a species containing an ortho-C−H agostic bond (A) and that the oxidative addition of the C−H bond (B) was not realistic as its energy is +28.2 kcal·mol−1 above that of (A) (eq 28).13

• In the presence of imidazolium salt NHC−H+Cl−, the NHC (N-heterocyclic carbene) precursor, 100% diarylation in the presence of PhBr was reached but after 10 h.13

Then DFT calculations showed that when the coordinatively unsaturated (NHC)Cl2Ru(PyPh) fragment interacted with HOCO2− an adduct (C) was formed with an energy of 22.9 kcal·mol−1 below that of the separated fragments. The coordinated oxygen atom of (C) already interacted with the ortho-(C−H) hydrogen and led to its deprotonation by concerted interaction of the Ru(II) center with the ortho-carbon, as in the transition state (D) via a barrier of 13.9 kcal·mol−1. The formation of the ruthenacycle (E) from (C) is exothermic by 13.7 kcal·mol−1 (eq 29).13 Thus, it appeared that the activation of sp2C−H bond with a Ru(II) site to give the expected metalacycle is actually a C−H bond deprotonation assisted by the concerted action of the coordinated base and the Ru(II) center. This ruthenium(II)−carbonate C−H bond deprotonation/activation process has some analogy with that observed with Pd(II)−OAc species14f,15h arising from initial oxidative addition of aryl halide (ArBr) to Pd(0) species in the presence of acetate.14,15 It was previously observed that, in the formation of palladacycle

• In the presence of K2CO3 (3 equiv), without phosphine or NHC ligand, 100% conversion was obtained at 120 °C in only 2 h, more importantly using the less reactive PhCl, but 21% monoarylated product remained.16 • After addition of only 10 mol % of KOAc (2 KOAc per Ru atom) with 3 equiv of K2CO3, complete conversion and diarylation with PhCl were reached in only 1 h at 120 °C.16 Thus, K2CO3 alone promotes more efficiently the C−H arylation than phosphine,11 NHCarbene13 or R2P(O)H.12b The influence of acetate in addition to the base M2CO3 to promote the C−H bond activation/arylation, even with PhCl, was shown to be crucial. I


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Scheme 8. Synthesis of Polyheterocycles from Phenylpyridine with In Situ Prepared Ru(OAc)2(p-cymene)

The in situ prepared catalyst Ru(OAc)2(p-cymene), by stirring [RuCl2(p-cymene)]2 with 4 KOAc in NMP at room temperature, was almost as active as the isolated complex but was preferentially used.16 It allowed the efficient preparation of various polyheterocyclic compounds or tridentate ligands in the presence of K2CO3 as a base (Scheme 8).16 Tripodal tris-1,2,3-(2-pyridyl)benzene was prepared by the reaction of 2-bromopyridine. The dithiophenylated products could be obtained quantitatively in milder conditions from 2-chlorothiophenes (Scheme 8). It is noteworthy that the catalyst based on RuCl2(NHC)(arene)/2 KOAc is also very efficient for deuteriation in MeOH-d4 of ortho-C−H bonds of a variety of functional arenes.49b As early as 2008, Ackermann and co-workers demonstrated that the selective arylation of triazoles with arylhalides in the presence of 2.5 mol % of [RuCl2(p-cymene)]2 was activated with 30 mol % of a carboxylic acid MesCO2H as additive in the presence of the base K2CO3 in toluene at 120 °C. The improved catalytic efficiency was attributed to a more effective C−H bond ruthenation through a transition state involving a concerted metalation and deprotonation (eq 31).17

The triazoles were cleanly monoarylated with a broad range of arylbromides including electron-deficient, electron-rich, and heteroarylbromides. This catalytic system was proved to be efficient for other functional directing groups like oxazoline, pyridine, and pyrazole with less reactive arylchlorides. Furthermore, the use of a functional alkene as a substrate allowed for the stereoselective formation of trisubstituted alkene (eq 31).17 Monoarylation of triazoles but with arylchlorides in the presence of ruthenium(II) catalyst can be achieved in the presence of the electron-donating ligand PCy3 but in more drastic conditions than by addition of carboxylic acid additive. The in situ-generated catalyst was active enough to perform the monoarylation with electron-deficient as well as electron-rich arylchlorides (eq 32).51 In the presence of PCy3 the arylchlorides selectively gave monoarylated products, whereas the aryl bromides provided the diarylated products under similar conditions (eq 33).51 The electron-donating ligand PCy3, if it does not favor the C−H bond deprotonation with respect to carbonate and carboxylate, is expected to favor the further Ar−X oxidative addition to the cyclometalated species, which is faster with ArBr (diarylation) than with ArCl.

The improvement in the direct arylation of triazoles with arylhalides has been shown in the presence of Ru(II) catalyst associated with MesCO2H in toluene. At 120 °C for at least 20 h the reaction provided the diarylated products, while the monoarylated products were selectively obtained from the J


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ortho-substituted triazoles (eq 34).52 Various valuable functional groups like ester or ketone on the arylhalides were tolerated by the catalytic system and conditions. The reaction did not occur between an ortho-substituted arylchloride and a metasubstituted triazole.

The ortho-mono(hetero)arylation of arenes containing a nitrogen directing group has been efficiently performed with the well-defined Ru(O2CMes)2(arene) catalyst precursor. Nitrogen-directed arylation proceeded efficiently at 120 °C for 18 h in toluene, and the substrate scope was highly complementary, allowing synthesis of biphenyls containing diverse aromatic halides substituents. Interestingly, alkenes were very easily arylated and gave the stereoselective formation of the trisubstituted alkene derivative (eq 36).53

Interestingly, when the reaction was performed in the presence of ortho-substituted arylchlorides, homocoupling of the arene took place. The halides act as a sacrificial oxidant, which plays a key role in homocoupling. The ortho-trifluoromethylchlorobenzene was found to be the best oxidant. Under the optimized conditions, a variety of heteroarenes were homocoupled together at the aryl group ortho position. However, the coupling of arenes with methoxy functionality in the ortho-position failed (eq 35).52 An analogous homocoupling was observed with allyl acetate as a sacrificial electrophile (eq 14).42 In the present case, the oxidative addition of ortho-(CF3)C6H4Cl likely does not occur easily with respect to the second C−H bond deprotonation. K


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The isolated complex Ru(O2CMes)2(p-cymene) was found to be inert during the reaction with arylchloride, whereas at 80 °C in toluene with phenylpyridine it readily provided the cyclometalated complex on additional action of carbonate (eq 37).53 This interesting reaction revealed already that

decoordination of one carboxylate should take place first to allow the coordination of 2-phenylpyridine before its deprotonation.18 Competitive experiments were made with an excess amount of heteroarenes. They showed that the electron-deficient arylhalides reacted preferentially as oxidative addition is favored, whatever the nature of the solvent. Surprisingly, arylchlorides were more reactive than arylbromides (eq 38).

2-phenoxypyridine with arylbromides and arylchlorides was successfully obtained in the presence of 2.5 mol % of [RuCl2(pcymene)]2 assisted by 30 mol % of MesCO2H in toluene at 120 °C (eq 41). It involves a six-membered ruthenacycle intermediate after C−H bond deprotonation. The directing group can be easily removed yielding the arylated phenols.55

The direct arylation of substituted indoles bearing a strongly N-chelating group that is easily removable has been demonstrated. The reaction of 2-pyrimidylindole with 4-methoxybromobenzene in the presence of [RuCl2(p-cymene)]2, 30 mol % of AdCO2H, and K2CO3 in m-xylene at 120 °C led to the selective C2 arylation.54 Notably, the reaction was not operative with H2O or the frequently used NMP. Under the optimized conditions, the catalytic system showed a broad scope for the aryl(hetero) halides and also tolerated valuable functional groups as well as additional heteroaromatic moieties (eq 39).54 One-pot synthesis of free (NH)indoles was obtained by taking advantage of the removable group from the substituted indoles in good yield, on reaction with NaOEt in dimethylsulfoxide (DMSO).54 The present catalytic system is able to functionalize the unprotected pyrroles and thiophenes, but on reaction with arylbromides (eq 40).54 The ortho-arylation of phenols protected by removable directing groups as just been reported. Direct arylation of

The efficiency of ruthenium(II) catalysts motivated the search for other ruthenium catalysts. Diarylation of heterocyclic arenes was performed with [RuH(cyclooctadienyl)2]BF4 in the presence of carboxylate salt in NMP at 120 °C.56 This Ru(IV) precursor is deprotonated into Ru(II) species only in the presence of a base. Various additives such as the carboxylate salts KOAc, KOPiv, and potassium phthalimidate (KPI) were able to completely promote diarylation of 2-phenylpyridine with chlorobenzene in 1 h at 120 °C. The efficiency of the L


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electron-deficient as well as electron-rich arylbromides, and with less reactive aryl chlorides but with extended reaction time. The reaction proceeded very well with the heterocyclic halides like 2-bromothiophene and with excess of 3-bromopyridine (eq 44).57

catalytic system was the best in the presence of KPI with chlorobenzene. For other halides like 2-chlorotoluene, 2-chlorothiophene, and 6-methyl-2-bromopyridine, the best yields were observed with KOAc in NMP and with Ru(OPiv)2(p-cymene) in diethyl carbonate (DEC) (eq 42).

The above results show that the combination of a ruthenium(II) catalyst with a carboxylate, usually 2 MO2CR per Ru atom, leads to the best catalytic system for arylation of arenes and alkenes with a nitrogen-containing directing heterocycle. However, it cannot be applied yet to weak coordinating functional groups for arylation. This system leads to a better diarylation catalyst than those arising from addition of a simple phosphine to ruthenium(II) complex. 3.2.2. Arylation with Ruthenium(II)−Carboxylate Catalysts in Green Solvents. Whereas most previous arylations with ruthenium(II) complexes were performed in organic solvents such as NMP and toluene, conditions were searched for successful arylation in more environment-tolerant solvents. Ruthenium(II) catalysts can perform the C−H bond arylation of heteroarenes in the green solvent diethyl carbonate (DEC). In DEC, the complete conversion of 2-phenylpyridine was obtained in the presence of [RuCl2(p-cymene)]2 and 4 equiv of KOAc in 9 h at 120 °C, and it was further improved in the presence of acetamide or pivalamide additive (2 h at 120 °C). Thus, in DEC diarylation is slower than in NMP (120 °C, 1 h), but the use of nontoxic DEC offers a global advantage. Better catalytic activity was obtained by using KOPiv instead of KOAc. The catalytic system allowed the reaction to be done even at 80 °C. Hence, the reaction of phenylpyridine with other heteroarenes was perfomed with [RuCl2(p-cymene)]2 and KOPiv as cocatalyst in DEC for 2 h at 120 °C (eq 45).58 The efficient catalytic system allowed for the preparation of tridentate ligands with thiophene and pyridine in good yield. The arylated compounds were also obtained with phenylpyrazole, phenyloxazoline, and benzoquinoline. The intermolecular metalation/C−H bond deprotonation by Ru(II)−O2CR catalyst is a process that should not be poisoned by water on the condition that the Ru(II) catalyst is stable. Indeed, the Rennes team59 showed that ruthenium(II)-catalyzed

Diarylated phenylpyrazole and phenyloxazoline were prepared with KOPiv in reasonable reaction time. The diarylation with 1,4-dihalobenzene allowed the formation of dichloro derivatives under mild conditions (eq 43).56

Pozgan and co-workers, have reported the C−H bond functionalization of 2- and 4-phenylpyrimidine with arylhalides, using [RuCl2(p-cymene)]2 catalyst associated with a sterically hindered 1-phenyl-1-cyclopentanecarboxylic acid (PCCA) as additive, with K2CO3 as base at 150 °C, affording the monoand disubstituted products. The arylation was performed with M


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NMP (M/D = 25/75) or diethyl carbonate (M/D = 45/55) at 100 °C. The in situ-prepared catalyst is only slightly less efficient than the isolated [Ru(OPiv)2(p-cymene)] complex, and thus this easily in situ-prepared catalyst in water can be preferentially used. Tris-1,2,3-heteroarylbenzenes were prepared in good yield with longer reaction time (eq 47).59

Polydentate ligands containing pyridyl coordinating groups were synthesized with the efficient catalytic system in water. The reaction of 1,3,5-trichlorobenzene with 2-tolylpyridine afforded the trispyridyl ligand in 77% yield, and the reaction with benzoquinoline provided 45% yield under reflux condition in 24 h, whereas the same reactions in NMP gave lower yield (eq 48).59

sp2C−H bond arylation could be performed in water as solvent. 2-Phenylpyridine with 2.5 equiv of phenylchloride, in the presence of [RuCl2(p-cymene)]2/4 KO2CR catalytic system, led at 100 °C for 2 h to a complete ortho-arene diarylation in water without any surfactant. The complete diarylation was obtained in the presence of KOPiv (2 equiv/ruthenium), whereas KOAc and K2CO3 led to a less active catalyst. The reaction can take place at 60 °C and even at room temperature for longer reaction times. The efficiency of the base was observed in the following sequence, K2CO3 > KHCO3 > K3PO4, and for phenylhalides, PhCl > PhBr > PhI, corresponding to their solubility in water (eq 46).59

Previously Ackermann12b performed the reaction of PhCl with phenylpyridine by using 2.5 mol % of [RuCl2(p-cymene)]2 with 10 mol % of Ad2P(O)H in NMP containing water, NMP/ H2O (2 mL/1 mL) at 120 °C for 20 h, and obtained 61% yield of diarylated product. This experiment revealed that the ruthenium(II) C−H bond-activation catalyst tolerated water and that pure NMP solvent allowed for a higher yield of 72% (5 h)

It is noteworthy that this ruthenium(II)−pivalate catalytic system was more efficient in water (M/D = 0/100) than in N


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and water makes possible the diarylation of oxazolines (eqs 50 and 51).

and 98% (24 h) than the mixture NMP/H2O (eq 49). The above results show that arylation of sp2C−H bonds with arylchlorides can be performed best in water with Ru(II)− pivalate catalysts under mild conditions.

The diarylation of imines has been used for the direct access to bulky amines. Imines have been transformed into amines by sequential ruthenium(II) catalysis: diarylation of imines followed by hydrosilylation. The diarylation with ArBr of aldimines is performed by in situ-prepared Ru(OAc)(X)(p-cymene) catalyst (X = Cl, Br, or OAc) in the presence of PPh3 at 100 °C (Scheme 9).60 Then the hydrosilylation is performed with Ph2SiH2 in the presence of [RuCl2(p-cymene)]2 catalyst and occurs at room temperature. Scheme 9. Sequential Arylation/Hydrosilylation of Imines

3.2.3. Autocatalytic Process of C−H Bond Activation with Carboxylate−Ruthenium(II) Catalysts. Previously it was established that the carbonate ligand associated to a coordinatively unsaturated ruthenium(II) catalyst favors the C−H bond deprotonation13 and that a catalytic amount of carboxylate (acetate, pivalate, MesCO2H, ...) in addition to the base M2CO3 dramatically enhanced the overall C−H bond activation/C−C bond formation, even in the presence of water.16,17,59 The kinetics of the reaction of Ru(OAc)2(arene) F with phenylpyridine was studied at 27 °C in acetonitrile to understand better the role of carboxylate and carbonate by Jutand and co-workers.18 The kinetics revealed (i) the easy formation of the metalacycle intermediate G, via C−H bond deprotonation, and (ii) the existence of an autocatalytic process,62 as AcOH that is one of the reaction products enhances the rate (eq 52).18

The diarylation of ketimines is more difficult to perform in high yield. Actually the presence of PPh3 favors only monoarylation, likely because the bulky Ru(II)−PPh3 catalyst and the first introduced aryl group in the ortho position inhibit the formation of a second planar cyclometalated intermediate. Therefore, the complete diarylation is performed with Ru(II)−OAc catalyst at 160 °C for 48 h without PPh3 ligand (Scheme 9).60 Ortho-diarylation of arylimines can also be performed in water61 by using [RuCl2(p-cymene)]2/4 KOAc/2 PPh3 as catalyst, and with K2CO3 as a base. Although water does not increase diarylation of arylaldimines as compared to NMP,60 water does improve the catalyst for diarylation of arylketimines

The disappearance of Ru(OAc)2(arene) and consecutive formation of G are accelerated by addition of 1 equiv of AcOH, and formation of cationic metalacycle H takes place (Figure 1). It is demonstrated that AcOH enhances the transformation of F into G: t1/2 = 45 min in the absence of AcOH and t1/2 = 5 min in the presence of 1 equiv of AcOH at 27 °C (Figure 1).18 O


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reactions are more efficient when the rates of two successive steps are closer to each other.18,63 The present study reveals that, when the Ru−O2CR complex is coordinatively saturated, easy decoordination of carboxylate allows the interaction of the Ru(II) site with the substrate. The C−H bond deprotonation is promoted by action of both the Ru(II) site and the external carboxylate to generate under mild conditions the metalacycle intermediate. 3.2.4. Few Arylation Examples and Exotic Ruthenium Catalysts. i. Arylation of Arene C−H Bonds with RuCl3 and Ruthenium(II)−Phosphine Catalysts. Ackermann and coworkers reported the arylation of heteroarenes in the presence of economically attractive and stable catalyst RuCl3·xH2O. Regioselective direct arylation with arylbromides of 2-substituted pyridines and substitued oxazolines were successfully performed at 120 °C for 20 h. Functional groups such as enolizable ketones, esters, and nitriles were tolerated by the catalytic system (eq 54).64 In that case the role of carbonate is crucial.

Figure 1. Disappearance of catalyst Ru(OAc)2(p-cymene) F with time on reaction with PhPy in CD3CN at 27 °C.

This metalacycle G formation is slightly favored by acetate and strongly retarded by K2CO3. The acetate reforms G from H, and its influence indicates that acetate is involved in the ratedetermining step. The carbonate deprotonates the cocatalyst AcOH, and its coordinating ability disfavors the interaction of the Ru(II) center with phenylpyridine and, thus, C−H bond activation (Figure 1). Pivalic acid also accelerates the formation of G but to a lesser extent than acetic acid. For both acids the addition of a small amount of water favors the reaction; thus, it is consistent with an increase of the acidity of both acids. The metalacycle G formation can be explained as in Scheme 10 by generation of a coordinatively unsaturated ruthenium species, allowing the addition of PhPy, and deprotonation of the C−H bond by external acetate, likely via a SE3 mechanism. This phenomenon is expected to take place with 18-electron ruthenium(II) catalyst. Scheme 10. Mechanism for Autocatalytic C−H Bond Activation/Deprotonation with Acetate

Zhang and co-workers also demonstrated the regioselective arylation of 2-phenylpyridine but with aryliodides with 5 mol % of the same easily available RuCl3 catalyst at 150 °C for a shorter time of 6 h. They showed that the arylated products were obtained in higher yields in the presence of benzoyl peroxides, in NMP at 150 °C, rather than with benzoic acid (eq 55).65 It is shown that complex H+PF6− leads to oxidative addition of phenyliodide (2.5 equiv). The diarylation product was isolated after 20 h at 120 °C in NMP without addition of any base (eq 53). The C−H bond activation is much faster (27 °C) than the following oxidative addition (120 °C) that becomes the ratedetermining step. In most catalytic systems based on [RuCl2(arene)]2/4 KO2CR, the presence of 1−3 equiv of M2CO3 regenerates the carboxylate from the freed HO2CR. This carbonate was shown to decrease the rate of the C−H bond-activation process (Figure 1). Thus, it is expected to bring this rate closer to that of the oxidative addition. Indeed catalytic

Arylation of benzoquinoline and 2-phenylpyridine with arylchlorides was performed in the presence of the inexpensive and readily available RuCl3·xH2O catalyst but with both PPh3 and Na2CO3 at 140 °C in NMP.66 Surprisingly, K2CO3 was less efficient with this catalytic system (eq 56). A trisbenzoquinoline P


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was obtained from the reaction of benzoquinoline with 1,3,5trichlorobenzene in decent yield (eq 57).

or iodides using [RuCl2(p-cymene)]2 catalyst in the presence of only the base K2CO3 (3 equiv). The reaction requires 18 h at 120 °C as no carboxylate additive has been used, but it occurs without decarboxylation of esters or formyl groups as with palladium catalysts (eq 59).68

ii. Synthesis of Heterocycles via Arene C−H Bond Functionalization. The heteroannulation of anilines with alkanolammonium or allylammonium chlorides and trialkylamines to form quinolines or indoles has been achieved by Cho, Shim, and co-workers in the presence of RuCl3·nH2O, RuH2(PPh3)4, or RuCl2(PPh3)3 as catalyst at 180 °C (eqs 60 and 61).69

Selective monoarylation of functional arenes is difficult to reach as usually the rates for mono- and diarylation are similar. An unsaturated alkenyl phosphane−ruthenium(II) complex was demonstrated by Xi and co-workers to be a selective catalyst for monoarylation with arylchlorides.67 2-Phenylpyridine on reaction with an equimolar amount of chlorobenzene in the presence of [(1,2-diphenylvinyl)diphenylphosphine]/rutheniumdichloride complex and K2CO3 in NMP at 120 °C for 20 h led to the controlled formation of monophenylated product. The possible explanation for this selectivity is related to both the electron-richness and the steric hindrance of the (1,2-diarylvinyl)diphenylphosphine. The reaction of 2-phenylpyridine and 2-o-tolylpyridine was successfully performed with both electron-rich and electron-deficient arylchlorides with good selectivity toward monoarylated products (eq 58). C4-arylation of a variety of 2,3,5-trisubstituted furans, especially those containing a formyl or an acyl group at the C5 position, has been successfully performed with arylbromides

The reaction takes place with arene C−H bond functionalization, and in most cases it requires the presence of SnCl2 as promoter. The mechanism involves ortho-C−H bond activation Q


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The reaction involves formal Markovnikov addition to activated alkynes. The mechanism is likely to initially proceed via cationic LnRu−H+ species to generate a LnRu−CC−R+ species. Amine Markovnikov addition to activated alkyne is then expected to produce a vinylated amine directing ortho-cyclometalation. This cyclometalation likely takes place via deprotonation rather than via C−H bond oxidative addition. Then insertion of alkyne into the Ru−C bond affords the quinoline derivatives according to Scheme 11.71 This mechanism is based on deuterium-labeling studies with Ph−CC−D showing the second insertion of alkyne and the deuteriation by alkyne of the built methyl group. The reaction was explored to perform the sequential hydroamination of alkynes and alkylation with alkyne (eq 64).71

of an aniline fragment in situ-generated via initial rutheniumcatalyzed formation of an imine, or a bidentate amine−imine derivative.69c Formal alkenylation of the aromatic C−H bonds of benzocyclic amines with terminal alkynes has been demonstrated by Yi and co-workers,70,71 using ruthenium(II) catalyst precursors. First [RuH(CO)(PCy3)2(NCMe)2]BF4 and then the more efficient system Ru3(CO)12/NH4PF6 catalyzed the reaction of indolines with terminal alkynes to produce quinoline derivatives in good yields (eq 62).70

The reaction can be extended to a variety of meta-substituted anilines and benzocyclic amines.71 The meta substituent favors its para-C−H bond activation not only for electronic influence but by steric inhibition of the ortho-C−H bond activation between the substituent and the amino group (eq 63).

3.2.5. Monoarylation Leading to Biorelevant Functional Biaryl Derivatives. The monoarylation with a fluorinated arylbromide of a phenyloxazoline derivative has been successfully achieved using Ru(II) catalyst to obtain a biaryl derivative that is a key intermediate in the synthesis of anacetrapib (MK-0859), a protein inhibitor.72 This selective monoarylation was carried out at a kilogram scale (eq 65). The catalytic reaction was performed with [RuCl2(benzene)]2/2 PPh3/10 KOAc catalytic system at 120 °C in NMP for 9 h in the presence of K3PO4. The addition of 1 PPh3 per Ru atom likely favored the oxidative addition of ArBr to the ruthenacycle but also decreased the diarylation rate. A Ru(II)- and Ru(III)-catalyzed monoarylation of a phenyltetrazole, as a key step in the production of angiotensin II Scheme 11. Proposed Mechanism for Catalytic Reaction of Anilines and Alkynes

R


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(eq 67) but in drastic conditions (120 °C, 30 h) as no carboxylate was associated to Ru(II) catalyst, but in the presence of K2CO3. The above results illustrate some required catalytic systems and conditions to produce functional unsymmetrical biaryl derivatives with biological activity, via selective monoarylation and without protection of one ortho-C−H bond by substituent or steric hindrance. 3.3. Alkylation of Arene and Heteroarene sp2C−H Bonds

3.3.1. Catalytic Hydroarylation of Alkenes. The catalyzed hydroarylation of olefins is a method to alkylate arenes as an alternative to Friedel−Crafts-type reaction. Ruthenium(II) catalysts have been used for this formal addition of aromatic C−H bonds across an olefin CC bond, especially by Gunnoe’s group.75 They have demonstrated the efficiency of catalytic addition of benzene to ethylene to produce ethylbenzene, using TpRu−R(L)(NCMe) type catalysts (Tp = hydrotris(pyrazolyl)borate) (Scheme 12)76

receptor blockers (ARBs),73 has been achieved using the simple catalyst RuCl3·xH2O in the absence of a carboxylate but in the presence of K2CO3 and PPh3 at 140 °C for 12 h (eq 66).73a

Scheme 12. Proposed Mechanism for Ruthenium(II) Hydroarylation of Alkenes

This stable catalyst appeared to be more efficient than the Ru(II) catalysts [RuCl2(arene)]2 and [RuCl2(COD)]2. The initial key intermediate based on cyclometalated Ru(II) complex formation, after C−H bond cleavage, followed by ArBr oxidative addition, is also proposed to explain the reaction.73b The preferential monoarylation of purine derivative (R = Bn) was shown on action of both aryliodides and bromides with [RuCl2(benzene)]2/8 PPh3 in the presence of K2CO3 in NMP at 120 °C (eq 67).74

Kinetic studies have revealed the reversible dissociation of acetonitrile, reversible coordination of benzene, and C−H bond activation of coordinated benzene as the rate-determining step, leading to Ru−Ph bond intermediate. The insertion of ethylene into the later Ru−C bond and the C−H bond activation of benzene affords ethylbenzene and regenerates the catalyst containing a Ru−Ph bond. Calculations support that the C−H bond activation does not involve a Ru(IV) intermediate arising from C−H bond oxidative addition. (Scheme 12)76 Electron-donating ligands L = PMe3 and P(OCH2)3CEt favor C−H bond activation, but electron-withdrawing ligand L = CO behaves as a more efficient catalyst for hydrophenylation of ethylene, as donating groups increase the energy barrier to olefin insertion.76b,c,77The hydrophenylation of propene under similar conditions is regioselective and leads to propylbenzene and isopropylbenzene in the ratio 1.6:1.76,77 The catalytic C−H bond addition of furan and thiophene to ethylene is also promoted by the TpRu−R(L)(NCMe) catalysts78 (eq 68).

Sames and co-workers79 reported the intramolecular hydroarylation of arene−ene substrates with the RuCl3/AgOTf catalytic system. This catalyst is compatible with various functional groups

The reaction was then successfully applied to 3′,5′-di-O-silyl6-arylpurine, and monoarylation preferentially took place S


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and reductive elimination with C−C bond formation were proposed as the key steps of the catalytic cycle. 3.3.2. Catalytic Alkylation of sp2C−H Bonds with Alkylhalides. Alkylation with benzylbromide of heteroarenes catalyzed by ruthenium(II) catalysts or better with RuCl3·xH2O was performed in pentane or neat and led to preferential 2-benzylation with respect to 3-benzylation of benzofuran and benzothiophene (eq 72).81

of substituted homoallylic aryl ethers including halides, methoxy, phenol, and protected amines. The formation of chromane, tetralin, terpenoid, dihydrocoumarin, tetrahydroquinoline, and indolocyclohexane or cyclopentane are obtained. This reaction proceeds via an electrophilic alkene activation with Ru(III), electrophilic substitution with C−C bond formation, and the protonation of a C−Ru intermediate, rather than involving arene C−H bond activation (eq 69).

The previous alkylation with benzylbromide does not allow β-elimination process. Better ruthenium(II) catalyst systems for general alkylation of arenes with alkyl halides allowing possible β-elimination were recently proposed by Ackermann. It is thus shown that reductive elimination from Ru(Ar)(CH2CH2R) species takes place faster than the β-elimination process. Thus, ruthenium-catalyzed sp2C−H alkylation of arylpyridine derivatives has been achieved with unactivated alkyl halides bearing β-hydrogen. The reaction was performed in the presence of 2.5 mol % of [RuCl2(p-cymene)]2, 30 mol % of 1-AdCO2H, and 2 equiv of K2CO3 in NMP.82 Appreciable yields of alkylated products were obtained when AdCO2H was used in the place of MesCO2H. These direct alkylations took place with excellent chemoselectivities and produced only the monoalkylated products. It is noteworthy that alkylation occurred without the formation of undesired products via β-elimination. Regioselective intermolecular alkylation of phenylpyridine and pyrazole with primary as well as cyclic secondary alkylhalides was successful (eq 73).

Terpenoids were prepared in good yield (99%) from polyenes with low catalyst loading of 1 mol % of RuCl3 and 2 mol % of AgOTf at 60 °C in 4 h (eq 70).

Unprecedented intermolecular hydroarylations of highly strained methylenecyclopropanes were performed by Ackermann and co-workers with 5 mol % of [RuCl2(cod)]n catalyst and 10 mol % of monophosphine biphenyl ligand. The challenging hydroarylation of cyclopropylidene with arylpyridine derivative leads to the formation of cis adducts in high isolated yields (eq 71).80

Regioselective heterocycle-directed ortho-alkylation with benzylhalides has also been applied to 2-arylpyridine and 2-aryloxazoline derivatives. The reaction with benzylchloride, in the presence 2.5 mol % of [RuCl2(p-cymene)]2, 30 mol % of (1-Ad)CO2H, and K2CO3 in toluene at 100 °C, provided the diarylmethane compounds in good yield. It is noteworthy that benzylchlorides were found to be more efficient than benzylbromides (eq 74).83 Intermolecular experiments between different substituted arenes showed that the less nucleophilic pyridine derivatives were preferentially benzylated. Moreover, meta-fluoropyrazolesubstituted arenes were functionalized at their more acidic ortho-C−H bond (eq 75).83

The deuteriated substrate led to partial deuterium retention in the resulting alkyl group. Thus, a surprising ruthenium(II) insertion into the ortho-C−H bond followed by alkene insertion T


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bulky adamantyl carboxylate from AdCO2H was a more efficient cocatalyst than acetate in this alkylation.

Several meta-substituted aryl ketimines have been alkylated, and the product nature showed that the alkylation was largely controlled by steric interactions except for the electrondeficient meta-fluoro derivative (eq 78). Intermolecular competition experiments gave evidence for the alkylation to be favored by the electron-withdrawing substituent (eq 79).84

Alkylation of imines with carboxylato−ruthenium(II) catalysts was also performed. Aromatic ketimines were efficiently monoalkylated in NMP, and subsequent stoichiometric reduction yielded the secondary amines (eq 76).82

The direct monoalkylation of C−H bond of aromatic imines with alkylbromides in the presence of [RuCl2(p-cymene)]2/ KOAc catalyst system84 was shown to be efficient in m-xylene at 120 °C for 20 h and was followed by a sequential stoichiometric reduction into ortho-alkylated amines using ZnCl2/ NaBH3CN/MeOH−THF (THF = tetrahydrofuran) stoichiometric reagent (eq 77).84 No β-elimination occurred, and the

The influences of both the carboxylate ligand and the solvent were highlighted in the Ru(II)-catalyzed alkylation of 2-(pMeOC6H4)pyridine as shown in eq 80.84 1-AdCO2H more U


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efficiently activated the Ru(II) catalyst than MesCO2H, but the latter in water or in neat condition revealed the partial metaalkylation whereas in NMP only the ortho-alkylation took place. Thus, water does not inhibit the reaction but modif ies the regioselectivity of alkylation. The proposed mechanism is based on K2CO3 intermolecular deprotonation of the C−H bond followed by oxidative addition of alkylbromide and reductive elimination. 3.3.3. Alkylation of Alkene and Arene sp2C−H Bonds with Alcohols. Yi and Lee have shown the profitable use of the ionic [RuH(CO)(PCy3)(C6H6)]BF4 catalyst for alkenylation/ alkylation with alkenes of aromatic ketones85 and amides.86 The reaction involves initial ruthenium arene sp2C−H bond activation followed by alkene insertion or cross-coupling reaction with alkene sp2C−H bonds.86 These competitive reactions will be presented in alkenylation of sp2C−H bonds in section 3.5.1 (eqs 97−103). They have now succeeded, using the same catalyst [RuH(CO)(PCy3)(C6H6)]BF4, to alkylate alkenes simply with primary alcohols87 (eq 81). The reaction takes place in CH2Cl2 or PhCl at a moderate temperature of 75−110 °C with high turnover number (TON) for cyclic olefins, indene, or heterocycles such as N-methylindole and benzopyrene with aliphatic and benzylic alcohols. followed by alcohol coordination to the electrophilic cationic ruthenium(II) site to favor C−O bond cleavage and C−C formation (eq 84).

The same RuH(CO)(PCy3)(C6H6)]BF4 catalyst has been used for the ortho sp2C−H bond alkylation of phenols with alcohols.88 In that reaction the OH phenol group is tolerated and directs the alkylation at its ortho position with both primary and secondary alcohols (eq 85). The alkylation with chiral (R)-PhCHOHMe leads to the racemic alkylated product, and that with (R)-PhCH(Me)CH2OH occurs without racemization.

Terminal alkenes can also be alkylated with high regioselectivity, and intramolecular alkylation occurs from geraniol to generate para-cymene (eq 82)87 This reaction was applied to several biological active molecules containing an alkene group with high regioselectivity and function tolerance (eq 83).87 12 C/13C kinetic isotope effects are consistent with the C−C bond formation as the rate-limiting step for this alkylation. Although the mechanism is not demonstrated, the initial formation of a Ru−alkenyl bond from the alkene is proposed V


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3.4. Electrophilic Substitutions of Arene C−H Bonds with Ruthenium(II) Catalysts

It is noteworthy that alkylations with the alcohol of cyclohexenone and α-tetralone lead to alkylated arene products resulting from the dehydrogenation of substrates (eq 86).88

i. Aminocarbonylation and Alkoxycarbonylation Reactions. Formal Friedel−Crafts-type reactions of arenes can be performed using a ruthenium(II) catalyst, without stoichiometric Lewis acid reagent to activate the acylchloride or carbamoylchloride. The first example was described by Kakiuchi and co-workers using RuCl2(PPh3)3 catalyst for the aminocarbonylation and alkoxycarbonylation of phenylpyridine.89 Thus, the reaction of phenylpyridine with N,Ndialkylcarbamoyl chlorides led to diaminocarbonylation at the ortho position of the 2-pyridyl function at 120 °C for 24 h in toluene (eq 89).89

The attempts to alkylate phenols with cyclic secondary alcohols using cyclopentene as hydrogen acceptor actually lead to their alkenylation via tandem alkylation/dehydrogenation (eq 87).

This methodology has been applied to the synthesis of benzofurans via the alkylation of the ortho-C−H bond of phenols or naphthols with diols (eq 88). This diol C−H bond alkylation and C−O bond formation has been extended to the synthesis of biologically active products that illustrates their functional group tolerance.88

As ruthenium(II) catalysts tolerate ester groups, the similar reaction with chloroformates has been attempted. It afforded at 120 °C for 12 h only the monoester derivative, whereas Friedel−Crafts reactions are not possible with chloroformate due to decarboxylation (eq 89). Analogously, the same reactions with benzoquinoline led to mono-aminocarbonylation and -alkoxycarbonylation at the C10 position. It is noteworthy that the competitive alkoxycarbonylation of phenylpyridines containing a CF3 group at the meta position, versus a CH3

The proposed mechanism is based on the initial ortho-aryl C−H bond deprotonation of phenols with ruthenium, followed by electrophilic activation of alcohols on coordination to the ruthenium species followed by C−C bond formation (eq 85).88 W


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group, led to a faster reaction that is consistent with an increased acidity of the C−H bond in electron-deficient arenes. The proposed mechanism is based on initial cyclometalation with C−H bond deprotonation with the help of carbonate, oxidative addition of ClCO2R or ClCONR2, and reductive elimination, as for direct arylation of C−H bonds. However, the previous examples show that a strongly coordinating 2-pyridyl group is required. ii. Acylation Reaction. The ruthenium(II)-catalyzed orthoacylation of arylpyridines with arylchlorides has been performed using RuCl2(PPh3)3 catalyst, without a stoichiometric amount of a Lewis acid (eq 90).90

reaction raises the question on the possible regioselectivity change by Ru−C bond of metalacycle intermediate. 3.5. Oxidative Dehydrogenative Cross-Coupling Reactions: Alkenylation of Arenes and Heterocycles

3.5.1. First Ruthenium(II)-Catalyzed Alkenylations of Arenes. Alkenylarenes and heteroarenes are conveniently produced by Heck-type reaction between (hetero)arylhalides and alkenes usually with palladium catalysts. The Heck-type reaction with arylhalides has been performed with ruthenium(II) precursors such as [RuCl2(arene)]2 catalyst in the presence of NaOAc in dimethylformamide (DMF) at 130−150 °C, but it was demonstrated that under these conditions Ru(0) colloids were produced that catalyzed the reaction.92 Alkenylated arenes have also been obtained from arylboronic acid derivatives and alkenes. Ruthenium(II) derivatives have been shown to catalyze this reaction. Brown and co-workers93 reported that the coupling of arene boronic acids with unsaturated esters can be catalyzed by [RuCl2(p-cymene)]2 in the presence of Cu(OAc)2 as oxidant (eq 94). In this reaction the Ru(II) catalyst tolerates halides on the arenes in contrast to palladium catalysts.

Selective monoacylations were controlled. Similarly, monoacylation of benzoquinoline with aromatic acylchlorides and α, β-unsaturated acyl chlorides at the C10 position were performed selectively (eq 91).

iii. Sulfonation Reaction. A catalytic sulfonation of phenylpyridines with arylsulfonyl chloride was shown for the first time to occur selectively at the meta position of the directing 2-pyridyl group (eq 92).91

The catalytic oxidative dehydrogenative alkenylation of (hetero)aromatic C−H bonds, as initially demonstrated by Fujiwara, Moritani, and co-workers,3p,94 presents a higher potential for the access to alkenylarenes, via the cross-coupling C−C bond formation from two different C−H bonds, thus under greener conditions than the classical cross-coupling reaction (eq 95).

The observed surprising regioselectivity is reasonably explained via the expected formation of the ruthenacycle and the SEAr electrophilic substitution at the para position with respect to the electron-releasing Ru−C bond (eq 93). These four examples illustrate that ruthenium(II) catalysts can perform Friedel−Crafts-type reactions and that decarboxylation does not take place with chloroformate. The sulfonation X


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Several catalytic systems have already been efficiently used for this oxidative alkenylation, using palladium95 and rhodium96,97 catalytic systems for a variety of directing groups such as amides, imines, heterocycles, and carboxylates. The use of cheaper ruthenium catalysts and especially the easily available and more stable Ru(II) systems was thus very attractive to perform this useful reaction. The pioneer example of dehydrogenative coupling of an alkene with an aromatic C−H bond was reported by Milstein and co-workers98 using RuCl3·xH2O, [RuCl2(CO)3]2, or [RuCl2(C6H6)]2 catalyst precursors under atmosphere of CO (6.1 atm) and O2 (2 atm) at 180 °C for 48 h (eq 96). Yields of

alkenylation product with low yield (35%), showing that, in that case, insertion of styrene and β-elimination was a fast process (eq 99).85b The H/D exchange from C6D5COCD3 and 1-hexene was shown to take place very rapidly exclusively at the orthobenzene position with negligible isotope effect kH/kD = 1.13 (110 °C, 1 h), suggesting a reversible process. The mechanism was consistent with the formation of a metalacycle from arylketone, promoted by the formation of an alkylruthenium species, successive insertions of the alkene and of the carbonyl group, and water elimination (Scheme 13).85

30−47% of alkenylated arenes were obtained, and it was shown that Ru(II, III) catalysts had similar activity whereas the Ru(0) precursor Ru3(CO)12 was much less active. Directing groups were not required under these conditions. Yi and Lee have shown that the reaction of 1-hexene with arylmethylketones led to the formation of the product arising from the formal insertion of the alkene into the ortho-C−H aryl bond (b) and to an indene derivative (a).85b The reaction took place in the presence of [RuH(CO)(PCy3)(C6H6)]BF4 catalyst, arising from protonation of [RuH(CO)(PCy3)]4(μ4-O)(μ3-OH)(μ2-OH) with HBF4·OEt285a and additional HBF4·OEt2 at 120 °C for 15 h (eq 97). High regioselectivity was observed in the formation of indene, but a mixture of the double-bond isomers was obtained.

Scheme 13. Mechanism for Catalytic Indene Formation from Arylketones

Yi and Lee have also shown that the ruthenium(II) complex [RuH(CO)(PCy3)(C6H6)][BF4] (5 mol %)/2 HBF4·OEt2 catalyzed the coupling of arylmethylketones with cyclic olefins, such as cyclopentene, to give a 1:1 mixture of two alkene isomers. These arose from the dehydrative coupling of the ketone with the unactivated alkene, and it involved a cycloalkene C−H bond activation (eq 100).85a Whereas 1-hexene and 2-hexenes yielded The reaction of the naphthylketone with ethylene or 2-butene with the same catalyst in acidic medium led to the same two products, very rapidly at 110 °C for 1 h, thus illustrating the fast dimerization of ethylene into butene and isomerization of 2-butene (eq 98).85b Styrene led preferentially to the ortho-

the ortho-C−H bond-insertion products,86 the use of cyclopentene and cyclohexenes preferentially led to a variety of the unsaturated cyclic hydrocarbon derivatives (eq 100). Thus, this time the formal cycloalkene sp2C−H bond activation is faster than the ortho-aryl C−H bond.85b The mechanism is thought to involve first the formation of a cyclopentenyl−ruthenium species via vinyl C−H bond Y


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activation with the Ru+−H species, followed by ketone carbonyl insertion and reductive dehydration (Scheme 14).85b Scheme 14. Proposed Mechanism for the Coupling of Cycloalkene with Arylketone

Scheme 15. Mechanism for Dehydrogenative Coupling of Cyclic Olefin with Arylketone These reactions (eqs 98 and 99) indicate that a simple ketone can act as a C−H bond-activation directing group with a ruthenium(II) catalyst (Scheme 13). The reaction of cyclopentene with arylamides in the presence of [RuH(CO)(PCy3)(C6H6)][BF4] catalyst at 80 °C afforded predominantly the ortho oxidative coupling product. A small amount of the product arising from the formal alkene insertion into the ortho-amide C−H bond or from hydrogenation of the previous product was also formed (eq 101).99

either insertion of cyclopentene into the C−Ru bond and β-elimination or the C−H bond oxidative addition of the cyclopentene followed by reductive elimination to give the oxidative coupling product. The catalyst [RuH(CO)(PCy3)(C6H6)][BF4] is used by Yi and co-workers87,88 for the direct catalytic alkylation of alkenes, cyclic alkenes, and phenols by primary or cyclic secondary alcohols or diols. It formally corresponds to the formal alkylation by alcohol of alkene sp2C−H bonds with water elimination. In some specific cases, alkenylation from alcohols occurred (see section 3.3.3). These examples reveal that ketone and amide functions are now able to direct ruthenium(II)−hydride catalyst to perform ortho-C−H bond activation and alkenylation via dehydrogenative cross-coupling reaction. 3.5.2. Oxidative Dehydrogenative Alkenylation of Heteroarenes. i. Carboxylate Directing Groups. Following the principle of oxidative dehydrogenative alkenylation by Milstein and co-workers,98 an innovative and general method of heterocycle vinylation with ruthenium(II) catalyst has been first described in 2011 by Satoh, Miura, and co-workers.100 Whereas

The same reaction performed with 1,1-disubstituted and terminal alkenes gave a higher yield of the formal insertion product versus oxidative dehydrogenative coupling (eq 102). However, the reaction of arylketones with 2-methylpropene, in the presence of the [RuH(CO)(PCy3)(C6H6)]BF4 catalyst, predominantly generated the naphthalene derivative beside the formation of the insertion product (eq 103).99 All these reactions show the effective directing capability of the amide group (or ketone) under rather mild conditions (80 °C). Stoichiometric reactions shed light on the mechanism by the initial formation of the intermediate RuH(CO)(PCy3)(C6H5CONMe2)+ (Scheme 15).99 This intermediate is expected to lead to the amide cyclometalated product, the precursor for Z


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the alkenylation of heterocycles containing the carboxylic acid directing group took place with further decarboxylation with palladium catalysts,101 the dehydrogenative alkenylation with [RuCl2(p-cymene)]2 catalyst, even with stoichiometric amounts of Cu(OAc)2·H2O as oxidant under nitrogen in the presence of LiOAc (3 equiv), occurred without decarboxylation.100 Thus, a variety of heterocycles containing the CO2H functionality were regioselectively alkenylated for the first time with an excess of alkyl acrylates at the neighboring position of the carboxylic group (eq 104).100

alkyl acrylates or acrylonitrile. It shows the directing ability of the carboxylate group for alkenylation at the neighboring carbon atom and it leads directly to annulated lactones.102 Experiments with D-labeled benzoic acid showed that the reaction proceeds without benzene H/D exchange in water, with a kinetic isotope effect of kH/kD = 3.6, which is in favor of an irreversible C−H bond-activation process (eq 107).

Under the same conditions, the 1-methylindol-3-carboxylic acid led to regioselective alkenylation at the C2 position, whereas the thiophene-3-carboxylic acid underwent the dialkenylation at both C2 and C4 positions, thus showing the directing ability of the carboxylate group to activate its two different ortho-C−H bonds (eq 105).

ii. Heterocycle Directing Groups. Oxidative monoalkenylation of arenes directed by a nitrogen-containing heterocycle such as N-arylpyrazoles has been performed with a nonactivated styrene by the Rennes group.103 It was promoted by Ru(OAc)2(p-cymene) catalyst, with a catalytic amount of Cu(OAc)2·H2O (20 mol %) at 100 °C in air (eq 108). This time the reaction was performed in acetic acid solvent as the latter autocatalyzed the ortho-C−H bond deprotonation of functional arenes by Ru(II)−OAc catalyst.18

It is noteworthy that, for the alkenylation with electrophilic alkenes such as alkyl acrylates or acryl amide, the monoalkenylation is slower than with styrene but takes place almost quantitatively with a stoichiometric amount of Cu(OAc)2·H2O in acetic acid (eq 109).103

The second general example of oxidative alkenylation with Ru(II) catalyst has just been reported by Ackermann and Pospech102 with two major innovations: the performance of alkenylation in water under mild conditions and the alkenylation of benzoic acid derivatives leading directly to the oxaMichael reaction products (eq 106).

This cross-dehydrogenative C−H bond functionalization takes place with a variety of benzoic acid derivatives with 2 equiv of Cu(OAc)2·H2O in water at 80 °C for 16−24 h using AA


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The reaction can be performed with a variety of arylpyrazole derivatives and acrylates. With N-(p-methoxy-substituted) aryl groups, the ortho-dialkenylation can take place in a significant amount (eq 110).103

iii. Ketone and Formyl Directing Groups. By modifying the ruthenium(II) catalyst [RuCl2(p-cymene)]2 on addition of AgSbF6 to free the ruthenium(II) sites from chlorides, Padala and Jeganmohan recently succeeded for the first time to achieve the Ru(II)-catalyzed ortho-E-alkenylation of arenes directed by a methylketone group. The reaction needed the presence of oxidant Cu(OAc)2·H2O (25 mol %), under very mild conditions in DCE (110 °C, 12 h).106 Under similar conditions, benzophenone led to ortho-mono- and dialkenylated products (eq 114). It is noteworthy that, in the absence of styrene or in the presence of nonreactive alkenes such as methyl methacrylate or N,N-dimethylacryl amide, the reaction afforded quantitatively the C−H ortho-homocoupling product. Actually this reaction constitutes a straightforward access to bidentate heterocyclic ligands (eq 111).103

Dehydrogenative homocoupling of arenes directed by a heterocycle has also been performed in the presence of Ru(II) catalyst and a stoichiometric amount of sacrificial oxidant such as methallyl acetate for aryloxazolines,42 2-chlorotrifluoromethylbenzene for 1,2,3-triazolylarenes,52 and FeCl3 for 2-arylpyridines.104 The use of Ru(OAc)2(p-cymene) with 20 mol % of Cu(OAc)2·H2O offers the mildest conditions to achieve such ortho-C−H bond homocoupling.103 Recently, the monoalkenylation of arylpyrazoles has also been performed with [RuCl2(p-cymene)]2 catalyst with 2 equiv of Cu(OAc)2·H2O in DMF under nitrogen atmosphere (eq 112).105

The monoalkenylation of acetophenone was successful with styrene; by contrast with p-bromostyrene the ortho-dialkenylation product was preferentially obtained and p-bromoacetophenone favored the dialkenylation with styrene (eq 114). The mechanism (Scheme 16) is thought to generate after abstraction of chlorides a cationic ruthenium(II) species leading to the cyclometalated complex via C−H bond deprotonation,

The benzylanilide was found to react with n-butyl acrylate in o-xylene on activation with Ru(II) catalyst and Cu(OAc)2·H2O (2 equiv) as oxidant. The reaction afforded directly after monoalkenylation and nucleophilic cyclization the corresponding lactam (eq 113).105 AB


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Scheme 16. Proposed Mechanism for the Ru(II) Alkenylation of Arylketones

followed by alkene insertion and β-elimination.106 The role of Cu(OAc)2 is likely to regenerate without hydride Ru(II) species from the freed Ru(H)(OAc) species. The in situ formation of Ru(OAc)n(arene) is postulated. However, the coordination of acetate is not required for metalacycle formation.18 Ru(OAc)2(pcymene) does not catalyze this reaction. Padala and Jeganmohan using a similar catalytic system based on RuCl2(p-cymene)]2/AgSbF6 showed that the formyl group could be as well tolerated and direct the alkenylation at their ortho position.107 Thus, the alkenylation of piperonal and other aromatic aldehydes afforded substituted alkene derivatives in a highly regio- and stereoselective manner under open atmosphere. This catalytic reaction is highly sensitive to the nature of the substituent. Electron-rich substituents such as OMe and NMe2 on the aromatic ring gave the highest product yield, with respect to the electron-withdrawing Cl and CN substituents (eq 115).

performed in CF3CH2OH with a large excess of NaOAc (200 mol %) at 50 °C, 3,4-dihydroisoquinolinones were obtained (eq 117).108

iv. Amide Directing Groups. N-Methoxybenzamides have been used as starting products for ortho-C−H bond alkenylation with electrophilic alkenes on catalysis using [RuCl2(pcymene)]2 by Li, Wang, and co-workers.108 N-Methoxybenzamide reacts readily with alkyl acrylate in the presence of NaOAc (30 mol %) in methanol at 60 °C to give the Heck-type product resulting also from methoxide elimination (eq 116).108 According to the conditions, the alkenylation can be followed by nucleophilic intramolecular addition to the formed CC bond. The same reaction cannot be applied to alkenylation with styrene and norbornene. However, when the reaction was

A proposed mechanism is shown in Scheme 17 suggesting that after alkene insertion into the C−Ru bond electronwithdrawing groups favor β-elimination, whereas an alkyl or aryl group favors reductive elimination. These processes are also controlled by the nature of the solvent: methanol (βelimination) and CF3CH2OH (reductive elimination). Miura and co-workers109 recently reported the alkenylation of N,N-dimethylbenzamides and phenylazoles with alkenes via regioselective C−H bond cleavage, which proceeded efficiently AC


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Scheme 17. Mechanism for Oxidative Alkenylation of N-Methoxybenzamides

It was shown that the chemoselectivity was altered with Nbenzoyl anilines as the C−H bond alkenylation of the aromatic ring linked to the amide carbonyl was observed (eq 121).110

in the presence of the [RuCl2(p-cymene)]2/AgSbF6 catalytic system and Cu(OAc)2·H2O in t-AmOH at 100 °C for 4 h under inert atmosphere (eqs 118 and 119).

This efficient catalytic system in water was applied to the mono-alkenylation of benzamides, and lactams were obtained from N-pentafluorophenyl benzamides by the sequential reactions of oxidative alkenylation and intramolecular aza-Michael addition (eq 122).110

Ackermann et al. have demonstrated that the alkenylation of anilides and benzamides can take place in water as a green solvent.110 The high catalytic efficiency was obtained by a cationic ruthenium(II) complex generated in situ from [RuCl2(p-cymene)]2 and a catalytic amount of KPF6 with 1 equiv of Cu(OAc)2·H2O as oxidant, at 120 °C for 20 h. The alkenylated products of para- and meta-substituted anilides were obtained, and the electron-rich anilides provided the best yields as compared to the electrondeficient ones (eq 120).

The results on oxidative dehydrogenation processes show that ruthenium(II) catalysts are now able to activate C−H bonds when they are directed by weak coordinating groups such as carboxylate, ketone, formyl, or amide groups. These Ru(II) catalysts are regenerated with Cu(II) oxidant in air. 3.5.3. Alkenylation of Arene C−H Bonds with Alkynes and Syntheses of Heterocycles. i. Insertion of Alkynes into C−H Bond and Vinylation Reactions. Zhang and co-workers111 first reported a new catalytic method for the alkenylation of arylpyridines at the ortho-C−H bond with terminal alkynes in the presence of 5 mol % of RuCl3 and 1 equiv of benzoyl peroxide or benzoic acid in NMP at 150 °C, with high stereoselectivity toward (E)-stereoisomers. The same alkenylation led to naphthylpyridine, phenylpyrimidine, and phenylpyridazine AD


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alkenylated benzamides was obtained in the presence of AcOH as additive, whereas in its absence lower conversion was obtained (eq 126).

derivatives. It is noteworthy that the internal alkynes were inactive under these reaction conditions. A reasonable mechanism involves the initial formation of a cyclometalated intermediate, regioselective insertion of alkyne, and protonation of the resulting Ru−C bond. Actually the peroxide is not required as benzoic acid alone allows the reaction although with lower yield (eq 123).

This efficient catalytic system allowed the hydroarylation of diphenylacetylene with phenylpyrazole in 85% yield in the presence of AcOH as additive (eq 127).113

The alkenylation of pyrroles with terminal alkyne has been performed by Fan and co-workers112 using the binuclear ruthenium(II) catalyst [RuBr2(CO)2(PPh3)]2 in chloroform at 50 °C. The reaction that corresponds to a Markovnikov addition tolerates alkyne functional groups (R2 = Ph, CH2OH, C(Me)(Et)OH, ...) (eq 124). This reaction can lead to

The proposed mechanism involves the initial cyclometalation via ortho-C−H bond deprotonation, insertion of alkyne into C−Ru bond, and protonolysis of the Ru−C bond. The role of AcOH likely favors the C−H bond activation via an autocatalytic process18 and the Ru−C bond protonolysis, as when deuteriated substrates are used no deuterium is incorporated into the alkenyl group.113 ii. Insertion of Alkynes into C−H Bond and Heteroatom− Hydrogen Bonds. Whereas the previous alkenylation with alkynes required drastic conditions, Ackermann’s group succeeded in inserting disubstituted alkynes into arene C−H bond with ruthenium(II) catalyst under milder conditions in the presence of an oxidant.114 Dehydrogenative annulations of functional arenes on reaction with alkynes, especially with rhodium catalysts,97b,115,116 have already led to isoquinolones. Recently, Ackermann has performed this dehydrogenative annulation of benzamides with alkynes in the presence of cheaper ruthenium(II) catalysts. The regioselective reaction formally involves the functionalization of both ortho-C−H and amide N−H bonds to produce isoquinolones. The reaction requires the use of an oxidant Cu(OAc)2·H2O (2 equiv) in tAmOH but at only 100 °C (eq 128).114

divinylation and to addition of pyrrole to the first introduced vinyl bond (eq 125). The mechanism of the reaction is consistent with an electrophilic activation of the alkyne followed by nucleophilic addition of pyrrole.

The presence of additional base or carbonate is not required, but acetate from the copper salt is present to favor the C−H bond cleavage. The reaction with MeO- and F- metasubstituted benzamides led to a mixture of products arising from C2−H and C6−H bond activation. The formation of the

Satoh, Miura, and co-workers113 demonstrated the catalytic hydroarylation of alkynes with benzamides in the presence of [RuCl2(p-cymene)]2 and AgSbF6 catalysts. The formation of AE


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Scheme 18. Mechanism for Ru(II)-Catalyzed Synthesis of Isoquinolones from Arylamides

major product is consistent with the enhanced acidity of the activated C−H bond (eq 129).114

with excellent yields (eq 131). It requires 1 equiv of Cu(OAc)2· H2O oxidant117 and offers improved substrate scope with respect to the similar reaction reported with rhodium catalyst.

Competition experiments with different alkynes (1:1) show that diphenylacetylene is much more reactive than diethylacetylene and only the diphenyl isoquinolone was obtained in 49% yield. Electron-deficient alkynes preferentially react with benzamides to give isoquinolones (eq 130).

The reaction is applicable to dialkylacetylenes. Alkylphenylacetylenes lead to regioselective annulations with a N−C linkage always involving the alkyne carbon bonded to the phenyl group (eq 132).

Mechanistic studies involving labeled experiments suggest an irreversible C−H bond deprotonation by acetate ligand, and the proposed mechanism is shown in Scheme 18.114 Actually, the deprotonation of both C−H and N−H bonds can take place on interaction with the Ru(II) center and by intermolecular action of acetate. This reaction with the same ruthenium(II) catalytic system was applied to acrylamides to generate 2-pyridones by C−H and N−H bond functionalization and annulation with alkynes

The ruthenium(II)-catalyzed dehydrogenative annulation was then applied to 2-aryl-substituted pyrroles and indoles118 for a variety of alkynes. However, with indoles the use of 1 or 2 equiv of oxidant Cu(OAc)2·H2O was no longer necessary, on AF


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the condition that the reaction was performed under air; then only 10 mol % of Cu(OAc)2·H2O was efficient (eq 133).

NaOAc. The reaction can be extended to heteroarylcarboxamides such as indoles (eq 137).119

The reaction can be used for the direct transformation of pyrroles into isoquinoline derivatives with dialkyl-, diaryl-, or alkylarylacetylenes with an excellent regioselectivity (eq 134).

Intermolecular competition experiments with differently substituted indoles yielded the fluoro-substituted indoles as the sole product (eq 135).118 Furthermore, it was shown that the more acidic C−H bond activation is favored and that the annulation reaction is faster with electrophilic alkynes (eq 136).118 The regioselectivity of C−H bond functionalization is sensitive to steric hindrance as a meta substituent on the benzamide disfavored functionalization on the neighboring C−H bond, except when this meta substituent bears an electronegative heteroatom (MeO). Ackermann and co-workers reported the synthesis of isocoumarins via ruthenium(II)-catalyzed oxidative annulations involving insertion of alkynes into both aryl C−H and carboxylic O−H bonds.120 Isocoumarin synthesis was obtained from various aromatic acids with 2.5 mol % of [RuCl2(pcymene)]2 with a catalytic amount of KPF6 in the presence of 1 equiv of Cu(OAc)2·H2O in t-AmOH at 120 °C (eq 138).

The cationic ruthenium(II) catalyst also allows the oxidative annulation of alkynes by acrylic acid derivative providing access to α-pyrone (eq 139).120 iii. Catalytic Synthesis of Indoles and Isoquinolones in Water. The above reaction with a modified Ru(II) catalytic system has been adapted for the synthesis of indoles using 2-pyrimidyl or 2-pyridyl protected anilines and alkynes in

Isoquinolones were obtained by ruthenium(II) catalytic addition of alkynes to benzamides on much milder conditions by the introduction of an oxidizing N-methoxy group. Li, Wang, and co-workers reported that these benzamides led to isoquinolones in high yield at room temperature (8 h) in methanol using [RuCl2(p-cymene)]2 catalyst, without the usual oxidant Cu(OAc)2·H2O, but in the presence of 20 mol % of AG


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As for other isoquinolone Ru-catalyzed syntheses, C−H bonds that are not sterically hindered by a neighboring substituent and electron-withdrawing groups provide better reactivity (eq 142).122

water.121 The catalytic reaction took place with [RuCl2(pcymene)2]/KPF6 system with Cu(OAc)2·H2O in water at 100 °C, and the reaction is not improved by the use of surfactant (eq 140). The isolated catalyst [Ru2Cl3(p-cymene)][PF6] was

shown to be very efficient as well. The regioselectivity was high with the N−C bond formed involving the arylalkyne carbon atom. Intermolecular competition revealed that diarylacetylene was again more reactive than dialkylacetylenes.

This reaction can be applied to free hydroxamic acid, which leads to isoquinolones under slightly more drastic conditions at 60−100 °C for 16 h in water (eq 143).122

Aromatic and heteroaromatic ketoximes have been transformed in one step into isoquinoline derivatives on reaction with alkynes by Jeganmohan and co-workers.123 The catalyst for annulation is based on [RuCl2(p-cymene)]2 assisted by NaOAc in methanol (eq 144).

Isoquinolone ruthenium(II) syntheses could also be performed in water from both N-methoxybenzamides and free hydroxamic acid on annulation with disubstituted alkynes.122 In water KPF6 was not operative with [RuCl2(p-cymene)]2, and KO2CMes (30 mol %) had to be used as cocatalyst for the reaction to take place at 60 °C for a variety of electron-rich or -poor benzamides and alkynes (eq 141).122

iv. Catalytic Insertion of Alkynes into C−H Bonds Directed by Halide-Free Ruthenium(II) Catalysts. Yi and co-workers85,86,99 and Padala and Jeganmohan106 have succeeded to use AH


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Scheme 19. Mechanism for Ru(II)-Catalyzed Synthesis of Indenes from Arylketones

ketones as directing groups for the functionalization of C−H bond with ruthenium(II) catalysts.106 Padala and Jeganmohan generated a chloride-free ruthenium(II) catalytic system by addition of 2 AgSbF6 per RuCl2Ln moiety able to trigger ruthenacycle intermediate formation with a coordinated ketone directing group. They have now used this system for the insertion of alkynes into C−H and carbonyl group, as well as the further formation of indenols and benzofurans.124 A variety of methylarylketones react with diphenylacetylene in the presence of Cu(OAc)2·H2O (25 mol %) to give the functional indenols (eq 145). With alkylarylacetylene a perfect regioselectivity

This catalytic system [RuCl2(p-cymene)]2/2 AgSbF6 with oxidant Cu(OAc)2·H2O was used to perform the coupling of aromatic carboxylic acids with alkynes that lead to a regioselective synthesis of isocoumarins125 with the oxygen atom bonded to the alkyne phenyl-bearing carbon atom (eq 146). DCE and tBuOH are both highly effective solvents. The presence of AgSbF6 is essential to control the regioselectivity of the reaction and to suppress decarboxylation. The reaction is suitable for the synthesis of indole and thiophene derivatives as well as for the addition of alkynes to the acrylic and methacrylic acids (eq 147).125

was observed, with the alkyne alkyl carbon bonding the ortho-aryl carbon. This is consistent with the preferred addition of the Ru(II) site to the alkyne aryl carbon atom.124

When the amount of silver salt was increased to 20 mol % in the presence of 2 mol % of [RuCl2(p-cymene)]2, the selective dehydration of indenol took place to give the corresponding benzofulvene (eq 146).

The mechanism likely involves the initial formation of the ruthenacycle (Scheme 19), with subsequent alkyne insertion into the Ru(II)−C bond, and insertion of the carbonyl group into the Ru(II)−C bond, which gives indenols on protonation with the in situ-formed AcOH. The latter are dehydrated with silver salt into benzofulvenes.124

Carboxylic acids containing ether protecting phenol groups are operative, but the nature of the ether group strongly AI


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4. CONCLUSION Simple ruthenium(II) catalysts can now be considered as essential in the catalytic activation of sp2C−H bonds for a variety of C−C bond-forming reactions. These catalysts are relatively inexpensive with respect to other efficient metal catalysts for C−H bond transformations, and some of them are rather stable to air, usual oxidants, and water. The direct arylations with (hetero)arylhalides of arenes and alkenes containing a directing group have been discovered first with the association of Ru(II)−PPh3 catalytic systems. They appear now more efficiently performed by the combination carboxylate−ruthenium(II) catalytic systems that effectively favor diarylation. The most efficient directing groups for arylation usually consist of a heterocycle with a strongly coordinating nitrogen atom such as 2-pyridyl, imines, oxazoline, pyrazole, etc. The diarylation can be performed in nontoxic dialkyl carbonate and very efficiently in pure water in the presence of both carboxylate cocatalysts and base M2CO3 without surfactant, even at moderate temperature. The ruthenium(II)-catalyzed arylation leading to polyheterocycles is now very well documented. The arylation and alkenylation of sp2C−H bonds with organic halides, performed with Ru(II)−O2CR catalyst and with M2CO3 as a base, have led to the establishment of a mechanism involving as the first step the C−H bond activation via a Ru(II) center and base-assisted C−H bond deprotonation. It occurs more generally via an intermolecular process by C−H bond deprotonation with the decoordinated carboxylate, leading easily to a ruthenacycle even at room temperature. It is followed by organic halide oxidative addition, as a ratedetermining step, and reductive elimination. The easy sp2C−H bond deprotonation by action of Ru(II)+ and RCO2− is now allowing a variety of alkylations with alkylhalides without β-elimination, as well as a few regioselective electrophilic substitutions. By contrast, hydrido−ruthenium(II) catalysts are promoting the direct alkylation with alcohols of alkenes and phenols. A tremendous recent development, demonstrated only since 2011, consists of the ruthenium(II)-catalyzed oxidative dehydrogenative cross-coupling reactions, in the presence of simple oxidants. The alkenylation of functional arenes with simple olefins are now taking place under very mild conditions and are allowing for the development of new bifunctional derivatives. The insertion of alkynes into both C−H and N−H bonds offer new routes to useful heterocycles. The regioselectivity of these catalytic reactions is directed by weak coordinating functionalities such as ketones, amides, heterocycles, and especially carboxylic acids without decarboxylation with ruthenium(II) catalysts. The success recently obtained with ruthenium(II) catalysts, the activity of which is strongly modified by the addition of very simple cocatalysts or oxidant or by creating halide-free ruthenium(II) catalysts, will probably motivate the synthesis of new efficient ruthenium catalysts for C−H bond activation, as the ruthenium(II) catalysts used presently are most of the time derived from [RuCl2(arene)]2. There are still many challenges to overcome, such as the control of regioselectivity at other C−H sites than at the ortho position of functional groups or the efficiency of new directing groups. Whereas the sp2C−H bond activation has been successfully transferred into C−C bond formation, the activation of sp3C−H bond with ruthenium(II) catalysts is certainly

influences the regioselectivity of C−H bond activation (eq 148). With low hindrance of methylene-bridged diether, the neighboring C−H bond is more reactive than when the phenol is protected by the methyl group.

The mechanism is based on the formation of the carboxylato alkenyl ruthenium(II) species, by insertion of alkyne into the ruthenacycle C−Ru bond, before reductive elimination to form the isocoumarin C−O bond. The role of Cu(OAc)2 is important to reoxidize the Ru(0) center generated by the C−O bond formation, but Cu2+ may also favor this reductive elimination step (eq 149).125

A variety of alkyne insertions into directed C−H bonds are now possible with stable ruthenium(II) catalysts. The use of an oxidant such as Cu(II) derivative is often required. It has been applied to a variety of heterocycle syntheses under the directing influence of moderately Ru(II)-coordinating functional groups such as ketone, formyl, amide, or carboxylate. Some of these catalytic reactions can be profitably performed in water as unique solvent. The use of halide-free ruthenium(II) catalysts allows for the use of rather mild reaction conditions. AJ


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attractive. Although there is already much evidence for stoichiometric sp3C−H bond activation with ruthenium complexes,8,9 only a few catalytic sp3C−H bond functionalizations are appearing. The use of ruthenium(II) catalysts for sp3C−H bonds remains a challenge for this decade.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]; pierre.dixneuf@ univ-rennes1.fr. Notes

The authors declare no competing financial interest. Biographies

Pierre H. Dixneuf initially studied ferrocene chemistry (Ph.D.) with René Dabard (Rennes) and N-heterocyclic carbene complexes with Michael F. Lappert (Brighton). As Professor in Rennes since 1978, his interests focused on organometallic chemistry (conjugated carbon-rich system, vinylidene−ruthenium and allenylidene−ruthenium complexes) and on homogeneous catalysis (C−C bond formation from alkynes and vinylidenes, alkene metathesis, and C−H bond functionalization with ruthenium(II) catalysts including metal catalysis in water). He has been research advisor at CNRS chemistry headquarters and at the University of Rennes, where he set up the Research Institute of Chemistry in 2000. He is the recipient of Le Bel Prize Grignard−Wittig prize (GDCh), Sacconi medal (Italy), and IFP− Académie des Sciences grand prix.

ACKNOWLEDGMENTS The authors are grateful to the CNRS, the French Ministry for Research, the Institut Universitaire de France (P. H. D.), and the ANR program 09-Blanc-0101-01 for support and for a Ph.D. grant to P.B.A.

Percia Beatrice Arockiam was raised in Manapparai, Tamilnadu, India. She received her M.S. degree in Catalysis, Molecules and Green Chemistry from the University of Rennes (France) in 2009. She is currently a third-year Ph.D. student under the supervision of Dr. C. Bruneau and Prof. P. H. Dixneuf at the University of Rennes. Her current research is focused on ruthenium(II)-catalyzed C−H bond functionalization and metal catalysis in water.

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Dr. Christian Bruneau graduated in chemistry from the Institut National Supérieur de Chimie Industrielle de Rouen (France, 1974) and obtained his Ph.D. at the University of Rennes (1979). He obtained a CNRS position in 1980 and since 1986 has been working in the field of transition metal catalysis. He is mainly involved in ruthenium-catalyzed selective transformations (metathesis, allylation, sp2- and sp3-C−H bond activation/functionalization, asymmetric catalysis, and bioresources transformations). From 2000 to 2011, he has been the head of the CNRS−University of Rennes research group “Organometallics and Catalysis”. AK


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