1 Introduction
1.1 Transition Metal-Catalyzed C–H Bond Functionalization
Sustainability was declared as one of the major goals within synthetic chemistry.1 The design of environmentally benign synthetic methods is guided by the ‘12 Principles of Green Chemistry’.2 Besides safe and non-toxic processes, waste-prevention, as well as atom- and step-economy in combination with catalysis, are all essential requirements for sustainable organic synthesis. From this point of view, transition metal catalysis is an essential step into the desired direction. Thereby, the efficiency of carbon–carbon (C–C) or carbon–heteroatom (C–Het) bond formation can be considerably improved.
For almost half a century, selective transition metal-catalyzed C–C bond formation reactions have attracted significant attention among various research groups around the world. Even in the field of industrial synthesis of pharmaceuticals, these transformations gain more and more attention over classical reaction routes.3 Certainly, one of the most famous transformations in this research area is the transition metal-catalyzed cross-coupling reaction.4
Today, traditional cross-coupling chemistry is a powerful synthetic tool in preparative organic chemistry. This is, for instance, illustrated by the fact that Heck, Negishi and Suzuki have been awarded the Nobel Prize of Chemistry in 2010 for the palladium-catalyzed formation of C–C single bonds via cross-coupling chemistry. The major features of these reactions are presented in Scheme 1.1. In general (for the cross-coupling), a (pseudo)halide as an electrophile and an organometallic species as a nucleophile are coupled via a Palladium (0)-Palladium (II)-catalytic cycle. The key steps include an oxidative addition, a transmetalation and a reductive elimination (Scheme 1.1, a). For Mizoroki-Heck-type couplings (Scheme 1.1, b) a mechanism consisting of a syn-insertion followed by
-bond-rotation and final -H elimination is generally accepted.5
1 Essen, M.; Metzger, J. O.; Schmidt, E.; Schneidewind, U. Angew. Chem. Int. Ed. 2002, 41, 414–436.
2 (a) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2000, 35, 686–694. (b) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: Oxford, 1998, p. 30.
3 Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H. Adv. Synth. Cat. 2011, 353, 1825–1864.
4 (a) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062–5086. (b) Metal-Catalyzed Cross-Coupling Reactions (Eds. de Meijere, A.; Diederich, F.), 2nd ed., Wiley-VICHY: Weinheim, 2004. (c) Transition Metals for Organic Synthesis (Eds. Beller, M.; Bolm, C.), 2nd ed., Wiley-VCH: Weinheim, 2004.
5 Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710.
Scheme 1.1: General catalytic cycles for the cross-coupling (a) and the Mizoroki-Heck (b) reaction.
The formation of stoichiometric amounts of potentially harmful metal salts as by-products and the necessity to use prefunctionalized substrates proves to be disadvantageous for the transition catalyzed cross-coupling reaction. To avoid the expensive prefunctionalization steps, transition metal-catalyzed direct functionalizations of C–H bonds represent an excellent alternative (Scheme 1.2).
Scheme 1.2: General comparison of transition metal-catalyzed transformations.
During the last 20 years, direct C–H bond functionalization has become a complementary synthetic tool in organic chemistry, even in the field of the total synthesis of complex natural products and pharmaceuticals.6
The classical synthetic routes towards the derivatization of arene would for example include electrophilic aromatic substitution (SEAr
) or directed ortho-metalation (DoM)7 (see below: Chapter
6 (a) Chen, D. Y.-K.; Youn, S. W. Chem. Eur. J. 2012, 18, 9452–9474. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed.
2012, 5, 8960–9009. (d) Tran, L. D.; Daugulis, O. Angew. Chem. Int. Ed. 2012, 51, 5188–5191. (e) McMurray, L.; O'Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885–1898.
7 Snieckus, V. Chem. Rev. 1990, 90, 879–933.
1.2). These reactions are often complicated by harsh reaction conditions and/or side-product formation.
The site-selectivity of catalytic C–H bond functionalizations can be controlled by employing either the enhanced acidity of a specific heteroaromatic C–H bond in substrates of the type 1 or by the directing group (DG) approach for the conversion of substrates 4 into their ortho-functionalized derivatives 3 or 5, respectively (Scheme 1.3, see also Chapter: 1.2).8 Stoichiometric amounts of bases are necessary in both cases.
Scheme 1.3: Two variants for C–H bond functionalizations.
The C–H bond metalation step can be accomplished by the active metal species LnM, according to four generally accepted mechanisms (Scheme 1.4). The results of computational studies of these mechanisms on different theoretical levels have been summarized by Eisenstein and co-workers.9
Scheme 1.4: Possible mechanisms for C–H bond metalation by transition metal complexes.
Oxidative addition (a) is a common process that can mainly be performed by electron-rich, low-valent complexes of late transition metals (Fe, Ru, Os, Ir, Pt, Re). Due to the impossibility of such oxidative transformations for early transition metals with d0-configuration, -bond metathesis (b) appears to be the predominant activation pathway for these metals. In a highly polar reaction medium, late transition metals (e.g. Pd, Pt) might metalate the C–H bond through an electrophilic substitution (c)
8 (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (b) For a review on removable DG’s see: Wang, C.; Huang, Y. Synlett 2013, 24, 145–149.
9 Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010, 110, 749–823.
replacing a former ligand on a metal atom with the organic substituent. Alkylidene or amido complexes of early transition metals further possess the possibility to perform the C–H bond activation via 1,2-additions (d).9,10
Since the aromatic C–H bonds feature enhanced thermodynamic stabilities [DH289 (benzene) = 112.9±0.5 kcal·mol-1)11 and low acidities [pKA (DMSO) = 44.7],12 marginal differences in reactivity were observed for the different C–H bonds within the same aromatic molecule. Therefore, different strategies have been probed in order to improve the selectivity of transition metal-catalyzed C–H functionalization reactions. Thus, site-selectivity can be achieved via chelation, employing Lewis basic directing groups (DG). Alternatively, this effect can be accomplished by the addition of a supplementary reaction partner, for example a base. Pioneering work in the field of stoichiometric base-assisted metalations has been accomplished by the groups of Shaw13 and Reutov14 in the 1970s.
Concerning catalytic base-assisted metalations, it has been proposed that a bidentate base is operating by the concerted-metalation-deprotonation pathway (CMD, Fagnou)15 or by the ambiphilic metal-ligand activation (AMLA, Davies & Macgregor) mechanism.10 Both principles favor a six-membered transition state including very little charge on the aromatic ring. Theoretical calculations on palladium- and iridium- catalyzed10,16 metalation mechanisms disclose that the metal-acetate complexes have an ambiphilic character due to an intramolecular electrophilic activation of a C–H bond followed by deprotonation with an internal base (Figure 1.1). Furthermore, the function of the transition metal center was also speculated about,15 as several irida-, rhoda- and ruthenacycles were isolated by Davies and co-workers in 2009 upon acetate-assisted C–H-activation reaction of 2-phenylpyridine.17
Figure 1.1: Possible transition states during concerted metalation-deprotonation (CMD) or ambiphilic metal-ligand activation (AMLA) pathways.
10 Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans. 2009, 5820–5831.
11 Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255–263.
12 Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63, 1568–1576.
13(a) Duff, J. M.; Shaw, B. L. J. Chem. Soc., Dalton Trans. 1972, 2219–2225. (b) Duff, J. M.; Mann, B. E.; Shaw, B.
L.; Turtle, B. J. Chem. Soc., Dalton Trans. 1974, 139–145. (c) Gaunt, J. C.; Shaw, B. L. J. Organomet. Chem.
1975, 102, 511–516.
14Sokolov, V. I.; Troitskaya, L. L.; Reutov, O. A. J. Organomet. Chem. 1979, 182, 537–546.
15 Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118–1126.
16 Ess, D. H.; Bischof, S. M.; Oxgaard, J.; Periana, R. A.; Goddard, W. A., III Organometallics 2008, 27, 6440–6445.
17 Boutadla, Y.; Al-Duaij, O.; Davies, D. L.; Griffith, G. A.; Singh, K. Organometallics 2009, 28, 433–440.
The mode of action of monodentate anionic ligands has been explored by the research groups of Goddard as well as Gunnoe.18 DFT-studies favor an internal electrophilic substitution (IES) prior to traditional σ-bond metathesis (Figure 1.2).
Figure 1.2: Proposed transition state during the internal electrophilic substitution (IES).
During the last decades, the research interest in transition metal-catalyzed C–H bond functionalization as a tool for a variety of C–C bond forming reactions has increased rapidly, especially in the field of biaryl-synthesis.19
Among other metals, ruthenium (II) catalysts not only include the remarkably broad substrate scope and the extraordinarily high chemo- and site-selectivity, as reflected by the outstanding functional group tolerance and excellent catalytic activity with water as the reaction medium,20 but also are significantly less expensive than other transition metal sources. Thus, in 2012, the prices of gold, platinum, rhodium, iridium, palladium and ruthenium were 1730, 1600, 1100, 1050, 669 and 110 US$
per troy oz, respectively.21
The Ackermann group and others have focused on the application of ruthenium complexes for chelation-assisted direct arylations.19,22,23 Starting from easily available aryl chlorides as electrophiles and a ruthenium-complex derived from a (hetero-atom-substituted) secondary phosphine oxide [(HA)SPO], they have elaborated the preparative methods for ortho-selective direct mono- and
18(a) Oxgaard, J.; Trenn, W. J., III; Nielsen R. J.; Periana, R. A.; Goddard, W. A., III Organometallics 2007, 26, 1565–1567. (b) Conner, D.; Jayaprakash, K. N.; Cundari, T. R.; Gunnoe, T. B. Organometallics 2004, 23, 2724–
2733. (c) for a review, see: Webb, J. R.; BolaÇo, T.; Gunnoe, T. B. Chem. Sus. Chem. 2011, 4, 37–49.
19 Selected reviews: (a) Ackermann, L.; Kapdi, A. R.; Potukuchi, H. K.; Kozhushkov, S. I. In Handbook of Green Chemistry (Ed. Li, C.-J.), Wiley-VCH: Weinheim, 2012, 259–305. (b) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087–4109; (c) Modern Arylation Methods (Ed.: Ackermann, L.), 1st ed., Wiley-VCH: Weinheim, 2009.
(d) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086. (e) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174–238. (f) Bellina, F.; Rossi R. Chem. Rev. 2010, 110, 1082–1146. (g) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173–1193. (h) Brückl, T.; Baxter, R. D.; Ishihara, Y.;
Baran, P. S. Acc. Chem. Res. 2012, 45, 826–839. (i) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068–5083.
20 (a) Ackermann, L. Org. Lett. 2005, 7, 3123–3125. (b) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev.
2012, 112, 5879–5918.
21 http://www.platinumgroupmetals.org/
22 (a) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–229. (b) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem. Int. Ed. 2006, 45, 2619–2622.
23 (a) Oi, S.; Funayama, R.; Hattori, T.; Inoue, Y. Tetrahedron 2008, 64, 6051–6059; (b) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783–1785; (c) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y.
Org Lett. 2001, 3, 2579–2581.
arylation of 2-arylsubstituted pyridines, pyrazoles and ketimines. Even unprecedented direct arylation using tosylates as electrophiles appeared to be successful with a mono-selective outcome (Scheme 1.5).22
Scheme 1.5: Ruthenium-catalyzed direct arylation with tosylate 7a as the electrophiles.
The direct arylation could also be performed via initial one-pot in-situ tosylation of inexpensive phenol derivatives.24
Intensive screening in less polar solvents revealed that sterically demanding carboxylic acids can act in a fashion comparable to the HASPO preligands (Scheme 1.6).25
Scheme 1.6: Comparison of C–H metalation transition states between HASPO-preligands and carboxylates.
Mechanistic studies could demonstrate that the direct arylation using carboxylic acids as additives proceeds via the in-situ formation of a ruthenium-carboxylate complex 12, which can perform reversible C–H bond functionalization with the substrate. An isolated cycloruthenated complex 14 proved to be catalytically active and is thus expected to participate in the proposed catalytic cycle (Scheme 1.7).25,26
24 (a) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043–5045; (b) Review: Kozhushkov, S. I.; Potukuchi, H. K.;
Ackermann, L. Catal. Sci. Technol. 2013, in press. DOI: 10.1039/C2CY20505.
25Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299–2302.
26 (a) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035. For recent reports highlighting the participation of similar ruthenacycles 14 in ruthenium-catalyzed C–H bond functionalizations, see: (b) Li, B.; Feng, H.; Wang, N.; Ma, J.; Song, H.; Xu, S.; Wang, B. Chem. Eur. J. 2012, 18, 12873–12879. (c) Li, B.; Roisnel, T.; Darcel, C.; Dixneuf, P. H. Dalton Trans. 2012, 41, 10934–10937.
Scheme 1.7: Proposed mechanism for carboxylate-assisted ruthenium-catalyzed direct arylation.
In 2011, Seki reported an alternative catalytic system for the ruthenium-catalyzed direct arylation reactions. The use of inexpensive RuCl3·xH2O/PPh3 catalyst resulted in elaborated efficient protocols towards the synthesis of the biaryl unit 18 in angiotensin II receptor blockers like valsartan.27 Very recently, the group of Ackermann showed a carboxylate-assisted complementary ruthenium-catalyzed procedure using mono-protected aryl-tetrazoles as substrate (Scheme 1.8).28
Scheme 1.8: Ruthenium-catalyzed direct arylation towards the synthesis of pharmaceutically important biaryl-structures 18.
27 (a) Seki, M. ACS Catal. 2011, 1, 607–610. For RuCl3·xH2O as catalyst, see also: (b) Ackermann, L.; Althammer, A.; Born, R. Synlett 2007, 2833–2836. (c) Ackermann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115–6124.
28 Diers, E.; Kumar, N. Y. P.; Mejuch, T.; Marek, I.; Ackermann, L. Tetrahedron 2013, in press, DOI:10.1016/
j.tet.2013.01.006.