Direct C–H bond arylations and alkenylations with phenol-derived fluorine-free electrophiles

Abstract

Significant progress has been accomplished in direct C–H bond arylations of arenes and heteroarenes with readily accessible, inexpensive phenol derivatives. Thus, ruthenium biscarboxylate complexes and inexpensive cobalt compounds allowed for challenging C–H bond derivatizations of arenes. Further, palladium, nickel and cobalt catalysts set the stage for step-economical C–H/C–O bond functionalization with electron-rich as well as electron-deficient heteroarenes.

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Sergei I. Kozhushkov

Sergei I. Kozhushkov was born in 1956 in Kharkov, USSR. He studied chemistry at Lomonosov Moscow State University, where he obtained his doctoral degree in 1983 under the supervision of Professor N. S. Zefirov and performed his “Habilitation” in 1998. From 1983 to 1991, he worked at Moscow State University and then at Zelinsky Institute of Organic Chemistry. In 1991, he joined the research group of Professor A. de Meijere (Georg-August-Universität Göttingen, Germany) as an Alexander von Humboldt Research Fellow; since 1993 he has worked as a Research Associate, since 1996 he has held a position of a Scientific Assistant, and since 2001 a permanent position as a Senior Scientist at the University of Göttingen. Since 2007, he has been working in the research group of Professor L. Ackermann (Georg-August-Universität Göttingen, Germany). His current research interests focus on the chemistry of highly strained small ring compounds under transition metals catalysis. The results of his scientific activity have been published in over 200 original publications, review articles, book chapters and patents. From 2003–2007, he won eight awards from InnoCentive, Inc.

Harish Kumar Potukuchi

Harish Kumar Potukuchi was born in 1982 in Chilakaluripet, India. He studied chemistry at Sri Sathya Sai Institute of Higher Learning in Prasanthinilayam, India, where he obtained his master degree in 2004. From 2004 to 2006, he worked as Project Assistant at National Chemical Laboratory in Pune, India, under the supervision of Dr P. Manikandan and Dr K. V. Srinivasan, and from 2006 to 2007 as Research Assistant at the University of Paderborn, Germany, under the supervision of Karsten Krohn. In 2007, he joined the research group of Professor Ackermann (Georg-August-Universität Göttingen, Germany) as a PhD Student and obtained his PhD degree in 2011 for research under the supervision of Lutz Ackermann. Currently he is a postdoctoral fellow in the group Prof. Thorsten Bach at the Technische Universität Muenchen, Garching.

Lutz Ackermann

Lutz Ackermann (1972) studied Chemistry at the Christian-Albrechts-University Kiel, Germany, and obtained his PhD degree from the University of Dortmund in 2001 for research under the supervision of Alois Fürstner at the Max-Plank-Institut für Kohlenforschung in Mülheim/Ruhr. He was a postdoctoral fellow in the research group of Robert G. Bergman at the University of California at Berkeley before initiating his independent career in 2003 at the Ludwig-Maximilians-University München supported within the Emmy Noether-programme of the DFG. In 2007, he became Full Professor at Georg-August-University Göttingen, and since 04/2011 he has been serving as Dean of the Faculty of Chemistry at the Georg-August-University Göttingen. His recent awards and distinctions include an ORCHEM-price (2006), a Dozentenstipendium (2007), a JSPS visiting professor fellowship (2009), an AstraZeneca Excellence in Chemistry Award (2011) and an ERC Independent Researcher Starting Grant (2012) as well as visiting professorships at the Universita degli Studi di Milano, Italy (2007), the University of Wisconsin at Madison (2008), and the Osaka University, Japan (2009). The development of sustainable catalytic C–H bond functionalizations for organic synthesis constitutes one of his major current research interests.

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Introduction

Bi(hetero)aryls are the key structural motifs of different compounds with activities of relevance to among others crop protection, medicinal chemistry or material sciences.^1,2 Based on pioneering studies by Ullmann and by Goldberg,³ regioselective syntheses of bi(hetero)aryls have predominantly exploited transition metal-catalyzed⁴ cross-coupling reactions between organic (pseudo)halides and stoichiometric amounts of organometallic reagents (Scheme 1a).⁵ Thereby, metal-catalyzed cross-coupling reactions have matured to being reliable tools for the formation of C_sp²–C_sp² bonds.

Scheme 1 Strategies for sustainable biaryl synthesis.

With the aim of expanding the scope of cross-coupling reactions, significant efforts have been made in recent decades. Prior to the late 1990s, aryl iodides and bromides were usually employed as electrophilic coupling partners in cross-coupling reactions due to their relatively high inherent reactivity.^1,2,4 However, the synthesis of non-commercially available aryl halides may involve multiple steps and relatively harsh reaction conditions, and leads to undesired waste production. The development of pseudo-halides as an attractive alternative to halides as the electrophiles in cross-coupling reactions began in the late 1970s.⁶ Given that phenols are inexpensive and readily available, practical methods that allow for the arylations with phenol derivatives are extremely desirable. The bond-dissociation energies in Ph–H, Ph–OH, Ph–OAc, Ph–OMe, Ph–Cl, Ph–Br and Ph–I moieties are equal to 112.9, 112.4, 106.0, 101.0, 97.1, 84.0 and 67.0 kcal mol⁻¹, respectively.⁷ Typically, phenols are converted into the corresponding sulfamates, phosphates, carboxylates, or carbamates to facilitate the cleavage of the otherwise challenging C–O bonds.⁸ However, the use of the phenol-derived (fluoro)sulfonated hydroxyl group as pseudo-halide electrophiles is the most attractive.⁹ Thus, the reactivity of aryl halides and sulfonate electrophiles toward transition metals typically follows the trend ArI > ArBr ≈ ArOTf ≫ ArCl > ArOTs.¹⁰ In spite of their lower reactivities, the fluorine-free sulfonates, tosylates and mesylates are particularly valuable coupling partners for cross-coupling reactions (Table 1).

Table 1 Aryl triflates versus aryl tosylates and mesylates: comparison of their fundamental properties

Property	Aryl triflates	Aryl tosylates/mesylates
	Ar–OSO2CF3	Ar–OSO2-p-Tol/Me
Reactivity	Very high	Low
Accessibility	Difficult	Easy
Hydrolytic stability	Unstable	Stable
Costs	Expensive	Inexpensive
Common aggregate state	Liquid	Crystalline

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First, they are more easily accessible from phenols or carbonyl enolates and less expensive than the corresponding triflates or nonaflates. Second, aryl tosylates are usually crystalline and more convenient to use because they are more stable towards hydrolysis than are the corresponding triflates. The relatively low activity of tosylates toward oxidative addition as the crucial step in metal-catalyzed coupling reactions can be addressed by the choice of the supporting stabilizing ligands in metal-catalyzed coupling reactions.¹¹ Therefore, a number of synthetically useful protocols for cross-coupling reactions of tosylates and mesylates (Scheme 1b) have been devised during the last decade.^8,12

The required organometallic nucleophilic reagents, particularly when being functionalized, are, however, often not commercially available or are relatively cost-intensive. Their preparation from the corresponding (hetero)arenes usually involves a number of synthetic operations, during which undesired byproducts are formed, as are during the traditional cross-coupling reactions themselves. On the contrary, direct arylation reactions through cleavages of C–H bonds¹³ represent an environmentally benign and economically more attractive strategy (Scheme 1c). Importantly, this strategy is not only advantageous with respect to the overall minimization of by-product formation, but also allows for a streamlining of organic syntheses by significantly reducing the number of reaction steps (Scheme 1d).¹⁴

Herein, we summarize catalytic direct arylations by C–H/C–O bond cleavages with challenging fluorine-free phenol derivatives as well as mechanistically related C–H bond alkenylations until summer 2012.¹⁵

Direct arylations

Due to the general importance of bi(hetero)aryl derivatives,² direct arylations of arenes and heteroarenes have attracted significant attention in recent years.

Direct arylations of arenes

Almost all known direct arylations of arenes with arylsulfonates proceed under catalysis with ruthenium.¹⁶ Thus, the first direct arylation reactions through C–H bond activation using aryl tosylates (Scheme 2)¹⁷ has been accomplished employing a first generation ruthenium catalyst derived from an air-stable HASPO (heteroatom-substituted secondary phosphine oxides)¹⁸ bifunctional preligand (Scheme 3).

Scheme 2 First generation catalyst for direct arylations with tosylates 2 using preligand 4.

Scheme 3 Ligands employed in catalyzed direct arylations of (hetero)arenes with challenging tosylates and mesylates.

The highly efficient and chemoselective C–H bond transformations tolerated pronucleophiles with different directing groups, including pyrazole derivatives, and a wide variety of important electrophilic functional groups. The selective formation of either mono- or diarylated products was controlled through the judicious choice of the electrophile. The development of carboxylates as most efficient ligands in ruthenium-catalyzed C–H bond functionalization by our research group set the stage for second generation catalysts¹³ utilizing substoichiometric amounts of carboxylic acids¹⁹ such as MesCO₂H (8), which enabled ruthenium-catalyzed direct arylations with organic halides and aryl tosylates even in apolar solvents (Scheme 4).¹⁹ With respect to both electrophiles and pronucleophiles, this catalytic system displayed an unparalleled broad scope, which allowed inter alia for the use of arenes displaying oxazolines in ruthenium-catalyzed direct arylations with aryl tosylates.

Scheme 4 Direct arylations with tosylates 2 using substoichiometric amounts of carboxylic acid MesCO₂H (8).

With respect to the step economy, it is important that the corresponding tosylates 2 could also be prepared in situ. Thus, phenols were directly employed as proelectrophiles in operationally simple ruthenium-catalyzed formal dehydrative direct arylations, proceeding through chemo- and regioselective functionalizations of C–H and C–OH bonds in a non-sequential fashion. Employing HASPO preligand 4, direct arylations of simple arenes as pronucleophiles with inexpensive and readily available phenols 9 proved viable (Scheme 5).²⁰ Notably, this user-friendly formal dehydrative arylation was achieved with a highly chemo- and regioselective ruthenium catalyst and allowed for a remarkable improvement of the overall step-economy.

Scheme 5 Step-economical direct arylations using phenols 9 as proelectrophiles.

This highly attractive C–H/C–OH bond functionalization strategy was realized even more successfully, when employing well-defined ruthenium(II) carboxylate complex [Ru(O₂CMes)₂(p-cymene)] (10)²¹ as the catalyst.

Thereby efficient direct arylations of unactivated C–H bonds with easily available, inexpensive phenols were achieved (Scheme 6).²² The extraordinary chemoselectivity of the ruthenium pre-catalyst 10 set the stage for challenging C–H/C–O bond functionalizations to occur in toluene as well as under solvent-free reaction conditions, and allowed for first direct C–H bond arylations with most user-friendly diaryl sulfates as the electrophiles.

Scheme 6 Direct C–H/C–OH bond arylations with well-defined complex 10.

Moreover, the extraordinary chemoselectivity of well-defined ruthenium complex 10 further enabled direct C–H/C–OH bond arylations to be performed in water as a green solvent (Scheme 7).^22,23 Notably, the protocol proved to be tolerant of a wide diversity of functional groups, and chemoselectively delivered the monoarylated products not only when employing ortho-substituted arenes but, importantly, also with para-substituted substrates.

Scheme 7 Formal dehydrative arylations with water as a green solvent.

On the basis of our experimental results of mechanistic studies on carboxylate-assisted ruthenium(II)-catalyzed direct alkylations and arylations,^13c the working mode for these direct arylations involves initial reversible carboxylate-assisted cycloruthenation (Scheme 8).

Scheme 8 Mechanistic rationalization for the formal dehydrative C–H/C–OH bond arylation (X = O₂CR, OTs).

Subsequently, the thus formed cyclometalated complex B^13ff–ii undergoes a formal oxidative addition with the in situ formed aryl tosylate. Thereby, a ruthenium-(aryl)(aryl) complex C is formed as a precursor for a final reductive elimination, which regenerates the catalytically active ruthenium species and provides the desired product 12.

Seminal contributions by the research groups of Nakamura and Yoshikai highlighted the power of inexpensive cobalt catalysts for direct C–H bond alkylations.²⁴ Recently, Ackermann and Song reported the first use of inexpensive cobalt catalysts for direct C–H bond arylations and benzylations with phenol-derived organic electrophiles through challenging C–H/C–O bond cleavage (Scheme 9).²⁵

Scheme 9 Cobalt-catalyzed direct arylations with aryl sulfamates 14.

The high catalytic efficacy of the versatile cobalt catalyst set the stage for unprecedented metal-catalyzed direct arylation and benzylation of arenes 13 with easily accessible fluorine-free aryl sulfamates 14, carbamates, and phosphates. Interestingly, intermolecular competition experiments with differently substituted arenes provided strong support for a non-S_EAr-type reaction manifold for this catalytic transformation.

Direct arylations of heteroarenes

In contrast to the direct arylation of aromatic carbocycles, arylations of heterocycles with arylsulfonates proceed mostly under palladium catalysis. Hence, the first direct arylation of azoles 16 through C–H bond functionalization with aryl tosylates 2 as electrophiles was performed with a palladium catalyst derived from Pd(OAc)₂ and the ligand X-Phos (5) (Scheme 10).²⁶ This highly active palladium complex enabled a broadly applicable C–H bond functionalization of various heterocycles with aryl tosylates 2, and also proved to be applicable to the unprecedented direct arylations using mesylates.

Scheme 10 Palladium-catalyzed direct arylations of heteroarenes.

The use of 1,2,3-triazoles 18 as the pronucleophiles in the palladium-catalyzed direct arylation using tosylates 2 turned out to be viable with the palladium complex derived from X-Phos (5), proceeding with excellent chemo- and site-selectivities through C–H bond functionalizations on the heterocyclic moieties. Monosubstituted 1,2,3-triazoles 18 gave rise to the 1,5-disubstituted compounds 19 as the sole products (Scheme 11).²⁶

Scheme 11 Direct arylations of 1,2,3-triazoles 18 using tosylates 2.

According to the generally accepted mechanism of palladium (0)/(II)-catalyzed direct arylations, these functionalizations are proposed to occur through initial oxidative addition of the aryl tosylate, along with subsequent C–H bond metalation and reductive elimination (Scheme 12).

Scheme 12 Proposed mechanism of direct arylations of 1,2,3-triazoles 18 using tosylates 2.

The significantly lower molecular weights of the corresponding aryl mesylates 21 render processes utilizing these electrophiles more atom-economical than those employing tosylates 2. However, as a result of the decreased inherent activity of aryl mesylates 21, metal-catalyzed direct C–H bond arylations with these sulfonates as electrophilic substrates have remained elusive until very recently. Hence, in the presence of substoichiometric amounts of pivalic acid, a catalytic system comprising Pd(OAc)₂ and the ligand X-Phos (5) allowed for the efficient functionalization of benzoxazole (20) with mesylates 21, thereby regioselectively yielding heterocycles 22 (Scheme 13).²⁶

Scheme 13 Direct arylations of benzoxazole (20) using mesylates 21.

Arylation of electron-deficient heteroarenes was considered a particular challenge in C–H-bond activation chemistry.^13r–t,27 Yet, the high catalytic efficacy of the optimized palladium complex was found to enable direct arylations of electron-deficient arenes and heteroarenes with aryl and alkenyl tosylates or mesylates. Under the reaction conditions described above, but applying CsF as the base, direct arylations of pyridine N-oxides 23 with both electron-deficient as well as electron-rich aryl tosylates 2 as electrophiles did selectively provide the desired products 24 (Scheme 14).²⁸ Furthermore, intramolecular competition experiments indicated a dependence of the site-selectivity on the kinetic C–H bond acidity. Thus, the 2-arylated products 24 were exclusively formed when employing 3-fluorosubstituted substrate 25.

Scheme 14 Direct arylations of electron-deficient N-oxides 23 with tosylates 2.

Importantly, the optimized palladium catalyst also enabled general direct functionalizations of electron-deficient heteroarene 25 with more atom-economical aryl mesylates 21 (Scheme 15).²⁸ In contrast to the direct arylation of benzoxazole 20, a wide variety of mesylates, including electron-rich and/or ortho-substituted derivatives 21, furnished the arylated products 26.

Scheme 15 Direct arylations of N-oxide 25 with aryl mesylates 21.

More recently, the use of CM-phos (7) in lieu of X-Phos (5) as the ligand in palladium-catalyzed direct arylations with aryl mesylates was reported by Kwong et al.²⁹ It is particularly noteworthy that the palladium catalyst derived from CM-phos (7) smoothly catalyzed direct arylations without the use of cesium fluoride (Scheme 16).

Scheme 16 CM-phos (7) as the ligand for direct arylations with aryl mesylates 21.

Caffeine, 1-(4-methoxyphenyl)-1,2,3-triazole, and benzothiazole were effectively functionalized to give the desired products in moderate to good yields. Specifically, the direct arylation of 1-(4-methoxyphenyl)-1,2,3-triazole with 3,5-dimethylphenyl mesylate occurred in a highly regioselective manner, and only the 5-arylated product was thus obtained.

A catalytic system consisting of Pd(OAc)₂ and bidentate ligand dppe was, on the contrary, found to be the optimal one for the first direct arylations of heteroarenes with moisture-stable aryl imidazolyl sulfonates 20 as electrophiles (Scheme 17).³⁰ This protocol was found not to be restricted to benzoxazoles, but could also be applied to C–H bond functionalizations on oxazoles. Competition experiments between differently substituted benzoxazoles 20 revealed that more electron-deficient heteroarenes reacted preferentially, and indicated the following series in the order of decreasing reactivity of electrophiles: ArOSO₂Im > ArBr > ArCl.

Scheme 17 Direct arylations with imidazolylsulfonates 27.

Notably, this catalytic system proved to be applicable to unprecedented C–H bond functionalizations with easily accessible alkenyl as well as benzyl phosphates, thus allowing for direct benzylations and alkenylations as well (see below).^30,31

Recently, elegant nickel-catalyzed C–H bond arylations of azoles with phenol derivatives were developed by Itami and coworkers.^8c

The catalytic system based on Ni(cod)₂ and the ligand dcype [dcype = Cy₂P(CH₂)₂PCy₂] was found to be active for the coupling of various phenol derivatives, such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates (Scheme 18). Using the C–H/C–O biaryl coupling, a series of privileged 2-arylazoles 31, including biologically active alkaloids, were step-economically accessed. Moreover, the power of the optimized catalytic system was illustrated by directly functionalizing estrone and quinine.

Scheme 18 Nickel-catalyzed coupling of azoles 20 and 29 with phenol-derived electrophiles.

Contrarily, Song and Ackermann recently disclosed inexpensive cobalt catalysts for direct C–H bond arylations of heteroarenes through C–H/C–O bond cleavages. Thus, the inexpensive catalyst was not limited to arylations of arenes (vide supra), but also allowed for cobalt-catalyzed C–H bond arylations of heteroarenes with readily accessible aryl sulfamates 14. Indeed, mono-N-substituted indoles 32 were selectively arylated at the C2 position (Scheme 19).²⁵

Scheme 19 Cobalt-catalyzed direct arylations of indoles 32 with aryl sulfamates 14.

This allowed for the synthesis of among others sterically encumbered heterobiaryls, a feature that should prove instrumental for future applications to asymmetric C–H bond arylations.

Direct alkenylations

The catalytic system consisting of Pd(OAc)₂ and the ligand dppe (vide supra) was also found to be suitable for direct C–H bond alkenylation reactions of benzoxazoles 20.³⁰

Indeed, readily available and moisture-stable phosphates 34 turned out to be alkenylation reagents of choice. Thereby, various alkenylated products could be obtained in good yields and with excellent chemoselectivities (Scheme 20).³⁰

Scheme 20 Direct alkenylation with phosphates 34.

Moreover, Hirano, Miura and co-workers discovered efficient copper-catalyzed allenylations of oligofluoroarenes 36 with propargyl phosphates 37 for the synthesis of highly fluorinated arylallenes 38 (Scheme 21).³¹ While smaller primary alkyl groups R gave satisfactory γ-selectivities, the use of bulky tert-butyl-substituted propargyl phosphate resulted in the α-substituted allene as the major isomer.

Scheme 21 Copper-catalyzed coupling of polyfluoroarenes with propargyl phosphates 37.

Under ruthenium catalysis, arenes 1 bearing different directing groups were site-selectively alkenylated with alkenyl acetates and butyrates 39 to give π-conjugated aromatic compounds 40 (Scheme 22), as reported by Kakiuchi and co-workers.³²

Scheme 22 Ruthenium-catalyzed direct alkenylation with alkenyl acetates and butyrates 39.

These ruthenium-catalyzed direct C–H bond alkenylation reactions proceeded under ligand- and base-free reaction conditions.

Conclusions

Recent years have witnessed a tremendous development in catalytic C–H bond functionalizations. Thus, challenging C–H/C–O have proven to be viable with ruthenium(II) biscarboxylate complexes as well as with palladium catalyst derived from electron-rich phosphine ligands. Furthermore, inexpensive nickel and cobalt complexes were very recently discovered as highly efficient catalysts for direct arylations with easily accessible phenol derivatives as arylating agents.

While direct C–H-bond arylations with inter alia sodium arylsulfinates,^33a aryltrimethoxysilanes^33b or arylsulfonyl hydrazides^33c were recently reported, fluorine-free sulfonates, such as aryl tosylates and mesylates, are undoubtedly among the most synthetically useful reagents for direct arylations. Thus, it does not come as a surprise that applications of these easily accessible, moisture-stable and inexpensive electrophiles were devised in the recent years (Fig. 1). Given the user-friendly nature of readily available, inexpensive phenol derivatives, the use of challenging aryl tosylates and mesylates in the direct arylation reactions could open a new horizon for future C–H bond transformations. Considering the practical importance of atom- and step-economical C–H bond catalytic arylations for natural product synthesis,³⁴ drug discovery and crop protection, further progress is expected in this rapidly developed research area.

Fig. 1 Recent progress in direct C–H bond arylations with challenging phenol-derived fluorine-free organic electrophiles.

Notes and references

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13. For selected recent reviews on C–H bond functionalization, see: (a) Acc. Chem. Res., 2012, 45, 777–958, Special Issue 6 “C–H Functionalization”; (b) L. Ackermann, A. R. Kapdi, H. K. Potukuchi and S. I. Kozhushkov, in Handbook of Green Chemistry, ed. C.-J. Li, Wiley-VCH, Weinheim, 2012, pp. 259–305; (c) L. Ackermann, Chem. Rev., 2011, 111, 1315–1345; (d) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215–1292; (e) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293–1314; (f) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902–4911; (g) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068–5083; (h) Y. Nakao, Synthesis, 2011, 3209–3219; (i) L. Ackermann and H. K. Potukuchi, Org. Biomol. Chem., 2010, 8, 4503–4513; (j) Chem. Rev., 2010, 110, 575–1211, Special Issue 2 “Selective Functionalization of C–H Bonds”; (k) M. Livendahl and A. M. Echavarren, Isr. J. Chem., 2010, 50, 630–651; (l) L. Ackermann, R. Vicente and A. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–9826; (m) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094–5115; (n) F. Bellina and R. Rossi, Tetrahedron, 2009, 65, 10269–10310; (o) A. A. Kulkarni and O. Daugulis, Synthesis, 2009, 4087–4109; (p) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009, 351, 673–714; (q) L. Ackermann, Top. Organomet. Chem., 2007, 24, 35–60; (r) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–238; (s) D. R. Stuart and K. Fagnou, Aldrichimica Acta, 2007, 40, 35–41; (t) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173–1193; (u) L. Ackermann, Synthesis, 2007, 1557–1571; (v) T. Satoh and M. Miura, Chem. Lett., 2007, 200–205. For mechanistic insight into transition metal-mediated or -catalyzed C–H functionalizations, see: with palladium: (13k) and (w) D. I. Chai, P. Thansandote and M. Lautens, Chem.–Eur. J., 2011, 17, 8175–8188; (x) Y. Boutadla, D. L. Davies, S. A. Macgregor and A. I. Poblador-Bahamonde, Dalton Trans., 2009, 5820–5831; (y) D. García-Cuadrado, P. de Mendoza, A. A. C. Braga, F. Maseras and A. M. Echavarren, J. Am. Chem. Soc., 2007, 129, 6880–6886; (z) D. García-Cuadrado, A. A. C. Braga, F. Maseras and A. M. Echavarren, J. Am. Chem. Soc., 2006, 128, 1066–1067; (a a) D. L. Davies, S. M. A. Donald and S. A. Macgregor, J. Am. Chem. Soc., 2005, 127, 13754–13755. With ruthenium: see (13bb) and (a b) B. Li, H. Feng, N. Wang, J. Ma, H. Song, S. Xu and B. Wang, Chem.–Eur. J., 2012, 18, 12873–12879; (a c) B. Li, T. Roisnel, C. Darcel and P. H. Dixneuf, Dalton Trans., 2012, 41, 10934–10937; (a d) E. F. Flegeau, C. Bruneau, P. H. Dixneuf and A. Jutand, J. Am. Chem. Soc., 2011, 133, 10161–10170; (a e) D. L. Davies, O. Al-Duaij, J. Fawcett, M. Giardiello, S. T. Hilton and D. R. Russell, Dalton Trans., 2003, 4132–4138.
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16. For a review, see: (a) L. Ackermann and R. Vicente, Top. Curr. Chem., 2010, 292, 211–229. For representative examples of ruthenium-catalysed direct arylations, see: (b) L. Ackermann, E. Diers and A. Manvar, Org. Lett., 2012, 14, 1154–1157, and references cited therein; (c) L. Ackermann and A. V. Lygin, Org. Lett., 2011, 13, 3332–3335 , and references cited therein.
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21. (a) L. Ackermann, R. Vicente, H. K. Potukuchi and V. Pirovano, Org. Lett., 2010, 12, 5032–5035; (b) L. Ackermann, P. Novák, R. Vicente and N. Hofmann, Angew. Chem., Int. Ed., 2009, 48, 6045–6048.
22. L. Ackermann, J. Pospech and H. K. Potukuchi, Org. Lett., 2012, 14, 2146–2149.
23. For the selected ruthenium-catalyzed C–H bond functionalizations with water as the reaction medium, see: (a) L. Ackermann and A. V. Lygin, Org. Lett., 2012, 14, 764–767; (b) L. Ackermann and J. Pospech, Org. Lett., 2011, 13, 4153–4155; (c) L. Ackermann and S. Fenner, Org. Lett., 2011, 13, 6548–6551; (d) P. B. Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf, Angew. Chem., Int. Ed., 2010, 49, 6629–6632; (e) L. Ackermann, Org. Lett., 2005, 7, 3123–3125 , and references cited therein.
24. A review: (a) N. Yoshikai, Synlett, 2011, 1047–1051. For examples of cobalt-catalyzed direct alkylations, see: (b) P.-S. Lee, T. Fujita and N. Yoshikai, J. Am. Chem. Soc., 2011, 133, 17283–17295; (c) L. Ilies, Q. Chen, X. Zeng and E. Nakamura, J. Am. Chem. Soc., 2011, 133, 5221–5223; (d) K. Gao and N. Yoshikai, Angew. Chem., Int. Ed., 2011, 50, 6888–6892; (e) Q. Chen, L. Ilies and E. Nakamura, J. Am. Chem. Soc., 2011, 133, 428–429; (f) K. Gao and N. Yoshikai, J. Am. Chem. Soc., 2011, 133, 400–402; (g) K. Gao, P.-S. Lee, T. Fujita and N. Yoshikai, J. Am. Chem. Soc., 2010, 132, 12249–12251.
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Footnote

† Current address: Lehrstuhl fuer Organische Chemie I, TU Muenchen, Lichtenbergstrasse 4, 85747 Garching, Germany. E-mail: harish.potukuchi@tum.de; Tel: +49 89-289-14535.

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