1 Introduction
1.2 Site-Selectivity in C–C Bond Formations
When employing classical synthetic methods, such as electrophilic aromatic substitution, the site-selectivity of aromatic C–H bond functionalizations strongly relies on the substitution pattern of the substrate 19. Depending on the electronic and steric properties of these substituents, the substrate can get para- (21), ortho- (22) or meta-substituted (20)(Scheme 1.9).
Scheme 1.9: Usual site-selectivity of the electrophilic aromatic substitution.
The research aim of discovering reaction conditions that provide pathways which do not depend on the substitution pattern of the substrate, or in which one can directly functionalize a specific C–H bond remains to be of prime importance.29 One approach for such a site-selective insertion of a substituent is the use of main group metals in combination with directing groups. This so called
‘Directed ortho Metalation’ (DoM) approach has been independently developed in the 1940ies by Gilman30 and Wittig31, and furnished usually ortho-functionalized products. Recently, Knochel could demonstrate that the use of DoM with organomagnesium compounds in combination with a variety of removable directed-metalation groups (DMG) could be employed for the functionalization of meta and para C–H bonds as well (Scheme 1.10).32,33
Simultaneously, the group of Brown reported the site-selective meta-substitution using DoM applying organolithiums, and a removable sulfoxide group as DMG.34 Two simplified examples are shown in Scheme 1.10.
29 Mahatthananchai, J.; Dumas, A. M.; Bode, J. W. Angew. Chem. Int. Ed. 2012, 51, 10954–10990.
30 Gilman, H.; Bebb, R.L. J. Am. Chem. Soc. 1939, 61, 109–112.
31 Wittig, G.; Fuhrmann, G. Chem. Ber. 1940, 73, 1197–1218.
32 Rohbogner, C. J.; Clososki, G. C.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 1503–1507.
33 Monzón, G.; Tirotta, I.; Knochel, P. Angew. Chem. Int. Ed. 2012, 51, 10624–10627.
34 Flemming, J. P.; Berry, M. B.; Brown, J. M. Org. Biomol. Chem. 2008, 6, 1215–1221.
Scheme 1.10: Examples for site-selective C–H deprotonations via DoM.
In spite of the generally high selectivities and efficiency of this DoM strategy, the necessity to use stoichiometric amounts of highly reactive main group metal compounds, such as n-BuLi, the low reaction temperatures and the need for the removal of the DMG group certainly restricts this approach from the viewpoint of step- and atom-economy.35
As an opportunity to avoid disadvantageous stoichiometric amounts of main group metal sources as reactants, transition metal-catalyzed C–H bond functionalization could give access to site-selective incorporations of substituents into arenes.
Due to its high ability for selective C–C bond formations, palladium, one of the most often applied transition metals in catalysis, has been studied intensively by the Sanford group. Thus, recently this group has published an overview on the predictive control of site-selectivities in oxidative palladium-catalyzed transformations.36 The authors differentiate between three the types of control possibilities (Scheme 1.11): Substrate-based through directing groups (a), substrate-based through electronic properties (b), and catalyst-controlled (c).
Scheme 1.11: Three possible ways to influence the regioselectivity of palladium-catalyzed C–H bond functionalization according to Sanford.
35 Atom economy: (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
36 Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936–946.
These three presented possibilities have been used not only in oxidative couplings, but also in plenty of other transformations. The directing group approach thus usually leads to an ortho-functionalization of the substrate. An innovative approach, using carboxylic acids (13) as traceless directing groups for formal meta-arylation, has been published in 2011 by Larossa (Scheme 1.12).37
Scheme 1.12: Larossa’s formal meta-arylation.
An important example of ortho-selective palladium-catalyzed transformation is the so called Catellani reaction, in which one can replace both hydrogen atoms in ortho-positions to an iodine substituent with diverse nucleophiles followed by Mizoroki-Heck-type reaction at the iodine location itself (Scheme 1.13).38
Scheme 1.13: The Catellani-reaction in general.
The corresponding cascade mechanism will not be discussed herein.38 However, it has to be mentioned that a catalytic or stoichiometric amount of norbornene is necessary and that the substrate scope is rather limited, since only iodo arenes (15a’), or recently published heteroarenes, can be used exclusively. 39,40
Besides these approaches for site-selective transition metal-catalyzed functionalization reactions, a recent example for direct meta-selective palladium-catalyzed alkenylations using an end-on template have been reported by Yu and co-workers in 2012 (Scheme 1.14).41
37 Cornella, J.; Righi, M.; Larossa, I. Angew. Chem. Int. Ed. 2011, 50, 9429–9432.
38 Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr. Chem. 2010, 292, 1–34.
39 Catellani, M.; Frignani, F.; Rangoni, A. Angrew. Chem. Int. Ed. 1997, 36, 119–122.
40 Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990–12993.
41 (a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518–522; (b) Highlighted in: Truong, T.; Daugulis, O.
Angew. Chem. Int. Ed. 2012, 51, 11677–11679.
Scheme 1.14: First example of direct meta-alkenylation as reported by Yu.
This Fujiwara-Moritani-type reaction involves the formation of rigid six- or seven-membered cyclic transition states and the use of easily removable nitrile-containing directing groups. In 2009 Yu et al.
have also reported an approach for meta-alkenylation of electron-deficient arenes, wherein the meta-selectivity was achieved not due to the meta-directing group-effect, but by applying sterically demanding pyridine ligands.42,43
Nevertheless, only several meta-selective reactions catalyzed by other transition metals, than palladium, have been reported until now. In 2009, the Gaunt group has published their findings in the field of copper-catalyzed meta-arylations of anilides 38 (Scheme 1.15).44,45
Scheme 1.15: Copper-catalyzed meta-arylation according to Gaunt.
The reaction mechanism has been discussed controversially and intensively,46 and in 2011 the group of Park has shown the reaction to occur in a meta-selective fashion also with heterogeneous recyclable copper catalyst [Cu/AlO(OH)], which was composed from metal nanoparticles.47 The reaction could proceed smoothly only by raising the temperature (80 °C) and by adding an over-stoichiometric amount (2.0 equiv) of the arylating reagent. It is important to note that even in the absence of a copper-source a high conversion has been detected.
42 Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072–5074.
43 For mechanistic DFT calculations, see: Zhang, S.; Shi, L.; Ding, Y. J. Am. Chem. Soc. 2011, 133, 20218–20229.
44 (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597. (b) Highlighted in: Maleczka, R. E. Jr. Science 2009, 323, 1573.
45 For meta-alkylation of aromatic -carbonyl compounds: Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R.
J.; Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 463–466
46 For mechanistic DFT calculations, see: (a) Zhang, S.-I.; Ding, Y. Chin. J. Chem. Phys. 2011, 24, 711–723; (b) Chen, B.; Hou, X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem. Soc. 2011, 133, 7668–7671.
47 Young, E.; Park, J. Chem. Cat. Chem. 2011, 3, 1127–1129.
Simultaneously, Gaunt and co-workers reported also on the copper-catalyzed para-selective arylations of phenol and aniline derivatives.48 The influence of copper in this reaction for the site-selective outcome can be discussed controversially and still remains under question, due to the fact that simple electrophilic aromatic substitution would lead to the observed para-selectivity as well.
Another transition metal-catalyzed meta-selective functionalization of C–H bonds in simple arenes 40 has been invented by the groups of Marder and Hartwig and consisted of a two-step one-pot procedure. In this particullar case, a stereoselective iridium-catalyzed borylation49 followed by a Suzuki-Miyaura-type cross-coupling reaction was applied (Scheme 1.16). This approach has been used for meta-selective arylations,50 alkylations, allylations, benzylations51 and halogenations.52
Scheme 1.16: Two-step meta-selective alkylation of simple arenes 40.
Obviously, although this transformation can be performed as a one-pot procedure, it needs various reagents and therefore should not be designated as an atom-economical reaction.
Concerning the ruthenium-catalyzed regioselective C–H bond functionalization, only ortho-directed reactions, mainly arylations (see above, Chapter 1.1), have been known until recently. In 2011, Frost and co-workers have published the first example of a ruthenium-catalyzed meta-selective C–S bond formation reaction in sulfonylations of 2-phenylpyridines 6 (Scheme 1.17).53 The authors proposed a combined C–H activation/SEAr
mechanism, details of which will be discussed below in chapter 1.1.
Scheme 1.17: Ruthenium-catalyzed meta-selective sulfonylation by Frost et al..
Nevertheless, the analogous meta-selective ruthenium-catalyzed direct C–C bond formation reactions still remains ellusive.