Ruthenium-catalyzed direct arylations with aryl chlorides

Abstract

Aryl chlorides are readily available at lower cost than the corresponding bromides and iodides, but are much more challenging as substrates in metal-catalyzed cross-couplings. Using arenes as nucleophilic partners by means of C–H activation instead of arylorganometallics also carries significant cost and environmental advantages. Finally, Ru catalysts, characterized by lower metal cost, excellent chemoselectivity, and high activity in C–H functionalization even in “green solvents” such as water, compound the economic and environmental benefits of chelation-assisted direct arylation. The current state-of-the-art of the Ru-catalyzed direct aryl–aryl coupling with chloroarenes will be reviewed.

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Gao-Feng Zha

Gao-Feng Zha was born in Hubei Province, P. R. China. He received his B. S. and M. S. degrees in pharmaceutical engineering from Wuhan University of Technology in 2007 and 2015, respectively. He worked as a research scientist in the pharmaceutical industry from 2007 to 2013. He is currently a Ph. D. student in Prof. Hua-Li Qin's group at Wuhan University of Technology. His research is focused on the development of powerful synthetic methodologies for synthesis of bioactive molecules.

Hua-Li Qin

Hua-Li Qin received a B. E. in chemical engineering from Anhui University and M. S. in organic chemistry from University of Science and Technology of China in 2000 and 2004, respectively. In early 2009, he received his Ph. D. in Chemistry from Boston University under the direction of Prof. James S. Panek. After working in Singapore and China as a medicinal chemist, he started his academic career at Wuhan University of Technology focusing on new synthetic method development, bioorganic, and medicinal chemistry. In 2015, he joined The Scripps Research Institute as Visiting Professor with Nobel Laureate Prof. K. B. Sharpless.

Eric A. B. Kantchev

Eric A. B. Kantchev, a native of Bulgaria, has been Green Chemistry Group Leader and Professor at the School of Chemistry and Chemical Engineering, Hefei University of Technology, P. R. China since 2014. His current research interests center on combining computational and experimental approaches to design new and improve existing transition metal catalysts. After obtaining a B. S. (University of Sofia, 1996) and a Ph. D. (The Ohio State University, 2001) in organic chemistry, he undertook research roles both in academia and industry in Taiwan, Canada, and Singapore. Since 1999, he has co-authored 50 peer reviewed articles cited >2900 times.

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Introduction

The 2010 Nobel Prize in Chemistry¹ for Pd-catalyzed cross-coupling² has been the strongest testament to the astounding impact this class of reactions has had in organic synthesis. Despite many spectacular advances, research efforts in this field continue unabated.³ One industrially-important, major advance was the successful coupling of unactivated aryl chlorides by means of Pd ligated with bulky, highly electron-rich tertiary phosphanes and N-heterocyclic carbenes.⁴ A considerably larger number of chloroarenes are commercially available at lower cost than bromo- and iodoarenes used in the classical cross-coupling protocols. However, they are more challenging as reacting partners. In the early years of the field, only aryl chlorides bearing strongly electron withdrawing p-substituents (e.g., NO₂ or CN) could be cross-coupled, typically under harsher conditions and in lower conversions than aryl bromides and iodides. The continuing efforts of catalyst design have dramatically changed this situation to the point where the choice of the halide is no longer a reactivity bottleneck.⁵ Herein we will give just one example: p-chloroanisole (an electronically-deactivated arene) can be coupled with pre-formed sodium phenylborate in methanol, without additional base, by 5 mol% of cyclo(chloropalladated) acetanilide ligated with a bulky N-heterocyclic carbene in 96% yield at 0–4 °C being the first example of Pd-catalyzed Suzuki–Miyaura coupling below ambient temperature.⁶

The typical cross-coupling methodologies rely on aryl organometallic derivatives such as organoboron reagents⁷ to smoothly introduce the nucleophilic coupling partner into the coordination sphere of the metal. However, such derivatives are handicapped by non-trivial synthesis, low stability, and low air, moisture and functional group tolerance. In the course of cross-coupling, a stoichiometric amount of salt is generated, providing thermodynamic driving force for the process but also generating waste. These drawbacks can be circumvented by the recruitment of C–H bonds as reactive sites. In the recent years, numerous examples of C–H activation methodologies catalyzed by Pd,⁸ Rh,⁹ and Ru¹⁰ have emerged. However, coupling of aryl halides with arenes by C–H activation (“direct arylation”)¹¹ is typically performed only with Pd and Ru (Fig. 1). The Ru(II)-catalyzed direct arylation with aryl halides, even though mechanistically distinct, has only been reviewed in the general context of Ru-catalyzed C–H activation. Herein, we will focus only on coupling of aryl chlorides due to their challenging substrate nature and economic and environmental significance as we anticipate important future breakthroughs in this area.

Fig. 1 Transition metal-catalyzed directed arylation vs. cross-coupling methods for biaryl synthesis. Only metals that are most commonly used as catalysts are shown. The scope of this review is shown in red.

Synthetic studies on the Ru-catalyzed direct arylation with aryl chlorides

Substrate scope: the aryl chlorides. Oi, Inoue, and co-workers were the first to report¹² (Scheme 1) the Ru-catalyzed direct arylation of 2-phenylpyridine (1) with aryl electrophiles (2–5) giving mono- and di-o-arylated products 6 and 7. Among other important findings, this paper established the reactivity order of the halide substrates as PhI > PhBr > PhOTf ≫ PhCl. Unsurprisingly, numerous subsequent studies have focussed on coupling of aryl bromides. A number of such papers^13–18 also include sporadic use of aryl chlorides, sometimes only^19–21 with activated representatives such as p-chloroacetophenone. Ackermann's group was the first (Scheme 2) to address specifically arylations with deactivated aryl chlorides^22,23 (as well as tosylates,²² another class of challenging electrophiles).

Scheme 1 The first Ru-mediated direct arylation.

Scheme 2 The first high yielding Ru-mediated direct arylations with unactivated aryl chlorides.

The key to success were the bulky, air-stable secondary phosphane oxides 8 and 9 used as “additives” (ligands) in conjunction with the common, commercially available, inexpensive [RuCl₂(p-cymene)₂] precatalyst under the Oi/Inoue conditions. The hydrolysis of the directing p-methoxyphenyl imine group gave acetophenones (e.g., 13, 14) after aqueous hydrolysis.²³ Interestingly, despite the use of 2.2 equiv. of o-chlorotoluene, only the monoarylation product 14 was isolated. Subsequently, the same group found that the 2nd generation Grubbs' metathesis catalyst (10) carrying the bulky, electron-rich tricyclohexylphosphane (Cy₃P) performed even slightly better in the same reaction.²⁴ Preformed complexes by the reaction of [RuCl₂(p-cymene)] and tertiary phosphanes prepared by zirconophosphanation/protonolysis by Tang, Xi et al.²⁵ (Scheme 3, 17), and by the Diels–Alder reaction of phosphane oxides carrying 1-alkyne substituent with anthracene and subsequent reduction by Doherty and co-workers²⁶ (KITPHOS; e.g., 18) were also competent catalysts under the Oi/Inoue conditions. These complexes were competent catalysts for the arylation of a wide range of o- and p-substituted chlorobenzenes. Particularly, the use of tertiary amino-substituted chloroarenes is noteworthy (products 20, 21, 22, 23). Exchange of the η⁶-complexed arene from p-cymene in 18 to a β-Ph from the phosphane in 19 had no significant effect on arylation yields. Two studies in 2010 explored in situ prepared Ru : PPh₃ = 1 : n catalysts (Scheme 4) for arylation of benzo[h]quinoline (25) with a wide range of aryl and heteroaryl chlorides. Yu's group²⁷ utilized 5 mol% RuCl₃·xH₂O (the most inexpensive commercial source of Ru) and 10 mol% PPh₃. The impressive 3-fold coupling of 35 with 3.5 equiv. 25 proceeded in 58% yield of 36 with 15 mol% RuCl₃·xH₂O and 30 mol% PPh₃ at 140 °C. Wada et al.²⁸ explored a range of solid supported catalysts, the most active of which was prepared from [RuCl₂(CO)₃] on CeO₂ (precipitated by KOH) followed by impregnation with 3 equiv. PPh₃ under atmosphere of H₂. These solid phase catalysts were recyclable, exhibiting no loss of yield over 3 runs. Li et al.²⁹ have demonstrated the coupling of an extended range of aryl- and heteroaryl chlorides, with 5 mol% of [RuCl₂(p-cymene) (p-MeOC₆H₄)₃P] and 20 mol% of acetamide as an additive in refluxing 1,4-dioxane. Under these milder conditions, even the use of 2.2 equiv. of m- and p-substituted chlorobenzenes resulted in the mono arylated product being the major in all but one case. Chloro benzenes carrying o-substituents gave only mono arylated products in low to moderate yields (Scheme 5). On the other hand the use of heterocyclic aryl chlorides was capricious: 4-chloropyridine failed to react whereas 2-chloroquinoline attained 98% conversion, with 77% yield of the di-arylated product. Surprisingly, electron withdrawing o-substituents had in most cases a deleterious effect on reactivity: coupling yield for o-chloroacetophenone was 0% and for methyl o-chlorobenzoate less than 5%.

Scheme 3 Direct arylations with unactivated aryl chlorides catalyzed by well-defined Ru complexes of bulky vinylphosphanes.

Scheme 4 Direct arylations with unactivated aryl chlorides mediated by in situ prepared PPh₃–Ru catalysts.

Scheme 5 Selective mono-arylations of 2-chloropyridine with unactivated aryl chlorides.

Ackermann et al. explored the couplings of a range of aryl chlorides in toluene as the solvent with a catalyst prepared either in situ from [RuCl₂(p-cymene)]₂ and MesCOOH (Mes = 2,4,6-trimethylphenyl)³⁰ or from the preformed complex 51³¹ (Scheme 6). Overall, both catalytic protocols gave similar yields within the experimental error over a range of o-, m-, and p-substituted chlorobenzenes. In the case of the 2-aryloxypyridines, the pyridine was removed after hydrolysis of the corresponding N-methylpyridinium triflate formed after treatment with MeOTf, revealing much more synthetically useful o-arylphenols. The Ru–carboxylate catalyst tolerates Ar-OTs and Ar-F functionalities (e.g., 55). Dixneuf, Fischmeister, and co-workers performed highly efficient o,o-diarylations of a range of aryl and heteroaryl chlorides with Ru–pivalate catalysts in neat water³² or diethyl carbonate³³ (Scheme 7), both of which are “geener” solvents than NMP or toluene and permit lower reaction temperatures, typically 100 °C. Importantly, it was found that in water the reactivity order of phenyl halides was reversed (5 > 3 > 2), attributed to the better solubility of chlorobenzene. Remarkably, 1,3,5-trichlorobenzene (35) underwent 3-fold arylation with 25 in refluxing water over 36 h to yield 45% of 36 (analogous to Scheme 4, bottom). The catalytic activity was slightly inferior in diethyl carbonate than water, as suggested by conversions and mono : di arylation ratios. Gimeno et al. published arylations of 2-phenylpyridine (1) with an extensive range of chloroarenes catalyzed by a ligandless Ru(II) carboxylate catalyst prepared in situ by reduction of RuCl₃·xH₂O (5 mol%) with Zn or H₃PO₂ in water containing 3 equiv. NaOAc as the base (Scheme 8).³⁴ In contrast to the catalyst derived from [RuCl₂(p-cymene)]₂, the monoarylated products predominated. The reaction proceeded well also under microwave conditions. Challenging substrates such as o-chloroaniline and p-chlorophenol gave low yields of only the monoarylated product.

Scheme 6 Mono-arylations with unactivated aryl chlorides catalyzed by (MesCOO)₂Ru catalysts.

Scheme 7 Selective di-arylations of 2-phenylpyridine with unactivated aryl chlorides in water or diethyl carbonate.

Scheme 8 Selective di-arylations of 2-phenylpyridine with unactivated aryl chlorides in water or diethyl carbonate.

Substrate scope: the C–H activation substrate. Unlike Pd, Ru(II) has so far not been reported to effect C–H activation without the presence of a directing group. Since the initial report of Oi and Inoue, 2-pyridyl has performed as an excellent directing group, 2-phenylpyridine (1) being most typical C–H activation reaction partner. Beyond the works discussed above, a number of other studies detail the use of 1 as a substrate for direct arylation with a small range of aryl chlorides, with very similar results.^{15,17,19,27,35–40} Ru catalysts also exhibit strong preference for C(sp²)–H over C(sp³)–H arylation⁴¹ as demonstrated by Ackermann et al.^17,18,24 (e.g., Scheme 2, 15). 1-Phenyl-1H-pyrazole^{24,26–28,31–33,35–37,40} (e.g., Scheme 2, 11; Scheme 3, 24; and Scheme 6, 57 and 58) and 2-phenyloxazoline^{18,24,27,31,33,37} (e.g., Scheme 6, 52) are other popular substrates, albeit less than 1. A few other heterocyclic directing groups have also been used sporadically (Scheme 9). Ackermann et al. successfully used 4-aryl-1,2,3-trazoles easy accessible by “click chemistry” as C–H activation partners in the coupling with aryl chlorides (products 70, 71) with both in situ prepared⁴² and preformed³¹ [Ru(OOCMes)₂(p-cymene)]. The couplings proceeded at the o-carbons of the phenyl ring, in contrast to Pd, which selectively arylated C-5 of pyrazole. Despite the use of 3 equiv. of p-chloroanisole, product 70 was obtained⁴² only in moderate yield (58%), indicating 1,2,3-pyrazoles are more challenging as C–H activation partners. Three successful arylations of N-(2-pyrimidyl)indole with aryl chlorides at C-2 mediated by 9 (10 mol%) and [RuCl₂(p-cymene)]₂ (2.5 mol%) were also reported (e.g., 72).¹⁶ Two examples of arylation of 4-phenylpyrimidine mediated by a catalyst prepared in situ from 1-phenylcyclopentane-1-carboxylate (10 mol%) + [RuCl₂(p-cymene)]₂ (2.5 mol%) were reported by Požgan et al. under rather forcing conditions (dioxane, 150 °C).²¹ A mixture of mono- and di-arylated products in various ratios was observed depending on the substituents in the chloroarene (e.g.73). Charette group published an interesting two-stage C–H functionalization of 2-aryl-imidazo[1,5-a]azines, where the C–H arylation of the o-aryl positions (C-2′/C-6′) was performed with in situ prepared [Ru(OOCMes)₂(p-cymene)]; two of the examples were with chloroarenes (e.g., product 74).¹⁴ Thereafter, a Pd catalyst was used to arylate the imidazole ring, which did not occur with Ru despite incubation of the substrate with the Ru catalyst in the presence of D₂O showed deuterium incorporation at all three positions (C-1, 70%; C-2′ and C-6′ both 90%). Finally, a very recent work by Tanimori et al.⁴³ disclosed a single example of o-arylation of N-methyl-2-phenylbenzimidazole with o-chloroanisole with rather high catalyst loading (10 mol%, t-Bu₃P : Ru = 3 : 1). Despite the forcing conditions, only 41% of 75 were isolated (21% with PPh₃). Among the non-heteroaryl directing groups, Ackermann group investigated only acetophenone N-(p-methoxyphenyl)imines.²³ The same group also demonstrated the only high-yielding examples of arylation proceeding via a 6-membered ruthenacycle in the case of 2-pyridylaryl ethers (Scheme 6, 54 and 55).³⁰

Scheme 9 Arylations of substrates with rare directing groups.

Mono- vs. di-arylation selectivity: substrate vs. catalyst control. Even since the seminal Oi/Inoue paper, a mixture of o-mono- and o,o-diarylation products is most commonly observed even in the presence of >2 equiv. of aryl chloride with the majority of catalysis when the C–H activation substrate has no other substituents in the phenyl ring besides the directing group. Unsurprisingly, di-arlyation is usually facilitated by longer reaction times and higher temperatures (Scheme 10).²² The products distribution with time is consistent with di-arylation product arising from arylation of the mono-arylated one, presumably with similar reaction rates. However, completion of the second arylation step with unactivated aryl chlorides resulting in mono : di selectivities > 5 : 95 and yields close to quantitative can be achieved at reasonable catalyst loadings for reasonable reaction times only with the most highly active catalysts. One such system comprises the bulky secondary phosphane oxides 8 or 9 with [RuCl₂(p-cymene)]₂ (Scheme 2, products 7 and 12).²² Detailed studies by Dixneuf et al. showed that [Ru(OPiv)₂(p-cymene)] (and other carboxylate analogs) is an excellent choice as a di-arylation catalyst in either water³² or diethyl carbonate³³ (Scheme 7, products 37, 46, 60, 63; Scheme 10b). The analogous carboxylate catalyst derived from MesCOOH was found by Ackermann group⁴² to mediate diarylation of 4-phenyl-1,2,3-triazoles in good yields (58–78%). However, the yield of the mono-arylated product was not listed, nor the selectivity issue discussed. In one of the most extensive studies, Yu's group²⁷ published a number of examples of diarylation of 2-phenylpyridine, 2-phenyloxazoline, and 1-phenylpyrazole with 20 mol% PPh₃ and 10 mol% RuCl₃·xH₂O (40/20 mol% for the latter). However, despite the high loading yields close to quantitative were recorded only for the easiest pairs of substrates, 2-phenylpyridine and chlorobenzene or p-chloroacetophenone. For the remaining examples, yields were only good to moderate (no product was obtained for 4-chloronitrobenzene). Dixneuf et al. extended their aqueous medium-carboxylate catalyst protocol to [RuCl(p-cymene) (L)] complexes (L = anions of tropolone, kojic acid (78) or glycine) (Scheme 11, products 7, 83, and 84).³⁶ The same group also investigated [RuH(codyl)₂](BF₄) (codyl = η⁵-cyclooctadienyl) as a ruthenium source to be combined with a number of anionic additives under the Oi/Inoue conditions.³⁷ The highest activity was attained with potassium acetate and potassium phthalimide: conversion of 1 with 2.5 equiv. chlorobenzene reached 100% with only 1 hour at 120 °C in NMP (mono : di selectivity 6 : 94 and 98 : 2, respectively). Designer N-heterocyclic carbene–Ru complexes by Peris (79,³⁵80¹⁵) and Özdemir (81,³⁸82³⁹) were also quite capable of delivering diarylated products (7 and 12) in high yields under the Oi/Inoue conditions.

Scheme 10 Effect of temperature and time on arylation mono : di selectivity. Isolated yields shown in brackets.

Scheme 11 Additional catalytic diarylation protocols.

Next, approaches towards mono arylation will be discussed. Having one o-substituent naturally precludes di-arylation (Scheme 2, 22; Scheme 4; Scheme 6, 52–57; Scheme 9, 72) as does the use of vinyl instead of aryl C–H activation substrate (Scheme 2, 16). Ackermann et al.^24,31 and Yu et al.²⁷ demonstrated that a m-methyl or m-methoxy substituent in 2-phenylpyridine or 1-phenylpyrazole resulted in a complete monoarylation, most likely by virtue of increasing steric hindrance unless that substituent is fluorine (Scheme 12). However, it should be noted that Ackermann's group experiments (products 87–90) were conducted with 2-fold excess of the C–H activation compound. As it can be expected, p-substituents generally do not preclude double arylation.

Scheme 12 Mono arylation under the influence of the m-substituent in the C–H activation substrate.

Using catalysts and/or reaction conditions to control the mono/di selectivity is a much more powerful and useful approach. As mentioned above, lower temperatures, shorter reaction times (Scheme 10), and lower catalyst loadings all result in increasing mono-arylated product percentage. However, tedious optimization of the reaction conditions may be necessary to maximize the yield of mono-arylated product. Whereas such undertaking may be justified in process chemistry/manufacturing, the time pressures during discovery/medicinal chemistry campaigns make it rather unattractive. Fortunately, a number of studies have demonstrated that synthetically useful mono-arylations can be reliably attained by using tertiary phosphanes as ligands (Schemes 3, 5 and 8). Particularly, the inexpensive PPh₃ was explored by the groups of Yu²⁷ and Dixneuf⁴⁰ as a mono-directing ligand in combination with RuCl₃·xH₂O and [RuCl₂(p-cymene)]₂, respectively. The monoarylated products (Scheme 13; 37, 40, 58, 91–93) were obtained in moderate yields when the C–H activation partner was used in stoichiometric or slightly larger, amount.

Scheme 13 Ligand (PPh₃)-controlled mono arylation.

Sequential (one-pot) synthetic applications. The mild and selective nature of the Ru-mediated directed arylation makes it quite suitable for integration into sequential catalysis or one pot transformations. The most common of these incorporate another Ru-mediated transformation. The selective monoarylations discussed above are naturally enhanced by performing a second arylation on the remaining o-hydrogen with a different chloroarene. Yu group's²⁷ extensive investigation on the RuCl₃·xH₂O/2PPh₃ catalyst includes one example of sequential, two-fold arylation (Scheme 14). Along with the targeted product 94, the two symmetrical diarylated products were also detected (94 : 7 : 77 = 73 : 20 : 7, 100% conversion). Peris' group successfully combined³⁵ directed hydroarylation of alkenes with directed o-arylation of 2-phenylpyridine (1) catalyzed by a di-NHC-Ru complex 95 in the presence of MesCOOK, including one example with an aryl chloride (Scheme 15, product 96). Utilizing a simpler, mononuclear NHC-Ru complex (97), Peris' group also performed¹⁵ (Scheme 16) a dehydrogenation of the secondary alcohol 98 to produce much more active 4-chloroacetophenone, which underwent in situ di-o-arylation of 2-phenylpyridine (giving 77) and 1-phenylpyrazole. Unlike with bromoarenes, up to 10% of mono-arylated products were also isolated. Ackermann et al. telescoped²⁴ (Scheme 17) direct o-arylation with 3- and 4-chloroarylketones and subsequent Ru-catalyzed hydrosilylation to 1-arylethanol TES ethers (e.g., product 99) catalyzed by the Ru(IV)–alkylidene complex 10. The resulting TES ethers could be deprotected with TBAF in situ to free secondary alcohols. Only one example of one pot Ru-catalyzed directed o-arylation and Pd-mediated direct arylation was disclosed very recently by Charette group,¹⁴ and in that case the only aryl chloride tested gave a very low yield compared to aryl bromides and iodides.

Scheme 14 One-pot, sequential arylation.

Scheme 15 One-pot, chelation-assisted hydroarylation and arylation sequence.

Scheme 16 One-pot transfer dehydrogenation/directed arylation sequence.

Scheme 17 One-pot directed arylation/hydrosilylation sequence.

Mechanism of the Ru-catalyzed direct arylation with unactivated aryl chlorides

The seminal Oi and Inoue paper¹² proposed a catalytic cycle (Scheme 18a) consisting of an oxidative addition of the aryl chloride to Ru(II) to produce Ru(IV) followed by a C–H activation, reductive elimination and base-promoted halide removal. Notably, the C–H activation step was postulated to proceed by electrophilic aromatic substitution (S_EAr) via a zwitterionic (Wheland) intermediate (100). This cycle features the same sequences of steps as the cycle of Pd-catalyzed directed arylation, which is a modification of the ubiquitous aryl–aryl cross-coupling cycle with the C–H activation taking the place of transmetalation (Scheme 18b). This initial mechanistic proposal was found to be inconsistent with stoichiometric experiments published by Ackermann's group.³¹ Importantly, [Ru(MesCOO)₂(p-cymene)] (51) did not react with p-chloroanisole in toluene at 110 °C (Scheme 18c), ruling out oxidative addition as the first step in the cycle. On the other hand, treating 2-(4-methoxyphenyl)pyridine with 51 at 80 °C gave a neural cyclometalated Ru(p-cymene) complex with one monodentate MesCOO anion retained in the inner coordination sphere of the metal (101). Complex 101 reacted with p-chloroanisole to give 67% yield of 102 in the presence of K₂CO₃ at 80 °C. Both 51 and 101 were competent catalysts for direct arylation to give 102. The above results suggest that the cycle commences with C–H activation instead of C–Cl oxidative addition. This is also consistent with the observation that unreactive (e.g., o-substituted) aryl chlorides promote the dimerization (homocoupling) of the C–H activation component in synthetically useful yields.⁴² The recent interest in C–H activation chemistry^8–10 has led to intense investigations of its mechanism. However, studies for Ru are relatively sketchy next to those for Pd and Rh. The main difference between Pd and Ru (Rh-catalyzed direct arylations are very scarce,⁴⁴ hence will not be discussed here) lies in the C–H activation step. Extensive studies⁸ have shown that C–H activation in Pd(II)-catalyzed proceeds by a number elementary reactions in a substrate- and catalyst-dependent manner, with as well as without chelation assistance (Scheme 18d).⁴⁵ Studies with Pd(OAc)₂-based catalysts suggest an inner sphere (bimolecular) concerted metallation-deprotonation (CMD-S_E2).⁴⁶ In certain cases, carbopalladation/β-hydride elimination (“Heck-type”)⁴⁷ or direct transmetalation (“carbanion arylation type”),⁴⁸ are known. As a consequence, the substrate scope for Pd is much wider than Ru. Dixneuf, Jutand et al. conducted a more detailed investigation on Ru(II) dicarboxylate-catalyzed arylations of bromoarenes.⁴⁹ The C–H activation was concluded to proceed by outer sphere (trimolecular) chelation-assisted CMD (CMD-S_E3). In this elementary step, free carboxylate acts as a base abstracting o-H from the Ph ring in 1 after the pyridine nitrogen forms a Wheland complex with the cationic [Ru(RCOO) (p-cymene)] (96). This conclusion is consistent with the observed auto-catalytic effect of the liberated RCOOH, attributed to facilitating the dissociation of a carboxylate from the initial precatalyst, thus providing an explanation for the higher activity of this type of catalysts. Based on these studies, a revised catalytic cycle comprising CMD-S_E3 C–H activation, oxidative addition, and reductive elimination has been established (Scheme 18e). The oxidative addition (giving 97) has been accepted as the rate-determining step for the whole cycle, as corroborated by numerous observations described above that aryl halides bearing electron-withdrawing groups are more active than those bearing electron-donating ones. This conclusion was made based on observations that: (1) the carboxylate-assisted cycloruthenation is facile even at room temperature⁵⁰ whereas the arylation reaction as a whole is not; (2) deuterium labelling experiments point at the C–H activation being reversible.^14,31

Scheme 18 (a) Initially proposed catalytic cycle for the Ru-catalyzed chelation-assisted direct arylation. (b) Accepted catalytic cycle for the Pd-catalyzed direct arylation. (c) Stoichiometric experiments that refute the initially proposed catalytic cycle. (d) Comparison of the C–H activation mechanisms for Pd and Ru-catalyzed direct arylation. The elementary steps are shown in a simplified manner. (e) Currently accepted catalytic cycle for the Ru-catalyzed chelation-assisted direct arylation.

Conclusion and future directions

Aryl chlorides are cheaper and more easily available than aryl bromides and iodides, but pose greater challenge due to the relatively low reactivity of the C–Cl bond. The use of Ru(II) catalysts has been very successful in inducing even deactivated (electron-rich) aryl chlorides to couple with arenes containing a pendant chelating substituent in the course of the direct arylation reaction.

Despite the significant progress evidenced in this comprehensive mini review, a number of issues remain. Some of those are briefly discussed next: (1) even though high yields have been attained using a large number of Ru catalysts, the majority of these have come from simple aryl chlorides such as chlorobenzene, m- and p-chlorotoluenes, or m- and p-chloroanisoles. It remains to be seen whether more complex substrates such as those used in pharmaceutical or agrochemical industries, or materials sciences can be converted in similarly high yields and which catalysts would enable that. (2) The scope is even more limited on the C–H activation side and warrants further investigations. Notably, many substrates that have been successfully C–H activated in other Ru-catalyzed reactions have not been demonstrated to participate in direct arylation yet. Therefore, the issue of the C–H component reactivity may be quite complex. (3) With respect to the catalysts, the work carried out to date has shown a great diversity in Ru complexes capable of catalyzing direct arylations in good yields as well as mono : di selectivity. The “ligandless” catalysts prepared from [RuCl₂(η⁶-arene)] complexes and anionic “additives” (such as carboxylates) have been systematically optimized. These catalysts have shown excellent levels of activity, particularly being the top choice for attaining high diarylation yields. On the other hand, large-scope, systematic exploration of the multitude of phosphane ligands available, particularly those that are bulky and highly sterically hindered, is still lacking. The situation with NHCs is similar. Both of these ligands classes are indispensable for activation of aryl chlorides in palladium catalysis. (4) More detailed mechanistic studies by both experiment and computation are overdue, particularly for phosphane- and NHC-ligated Ru catalysts. Investigating the molecular basis of the pronounced inclination of phosphane ligands to selectively catalyze mono-arylation may pave the way for improved catalyst design.

Acknowledgements

Financial support from Wuhan University of Technology (to GFZ and HLQ) and Hefei University of Technology (to EABK) is gratefully acknowledged.

Notes and references

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