The defined construction of molecular building blocks for the development of various functionalized materials and pharmaceuticals posed major challenges to organic chemists for centuries. Therefore, the discovery of catalytic processes set the stage for the selective formation of carbon–carbon (C–C) and carbon–heteroatom (C–Het) bonds, which constituted one of the most important developments for organic syntheses.
Early works by GLASER,[8] ULLMANN,[9] as well as GOLDBERG[10] indicated the potential of these catalytic methods. In particular, the copper-catalyzed formation of new C–C bonds, especially on arene C(sp2)–H bonds, enabled the synthesis of biaryl motifs, an omnipresent scaffold in natural occurring compounds, which are otherwise hard to access.[11] Indeed, this method suffered from harsh reaction conditions, low selectivities and moderate yields and, therefore, its applications was found to be limited. A major breakthrough in the field of selective C–C/C–Het coupling was achieved with the development of palladium-catalyzed cross-coupling reactions, processes that tremendously expanded the toolbox of modern organic synthesis.[12]
In this context, a range of well-known named reactions, such as the KUMADA -CORRIU,[13] NEGISHI,[14] MIGITA-KOSUGI-STILLE,[14a, 15] SUZUKI-MIYAURA[16] and HIYAMA[17]
cross-couplings enabled the highly efficient and selective synthesis of biaryls, while the MIZOROKI-HECK[18] reaction allowed for the selective alkenylation of aryl halides, and the SONOGASHIRA-HAGIHARA[19] reaction represents a unique alkynylation strategy. These methods have found widespread applications in the pharmaceutical, agrochemical and chemical industry and, moreover, this research was recognized with the Nobel Prize in 2010 awarded to A. Suzuki, E.-i. Negishi and R. Heck.[20]
Indisputably, these remarkable achievements changed the world of organic chemists, but still significant drawbacks are directly linked to cross-coupling reactions. Thus, prefunctionalizations of the starting materials are necessary. Besides the organic (pseudo)halides, the employed organic nucleophiles, such as Grignard reagents,
organozinc and toxic organotin compounds, require multistep syntheses and, in addition, these compounds are often difficult to handle and store. Therefore, the development of alternative methodologies such as C–H activation is highly desirable.[21]
Scheme 1.1: Comparison of traditional cross-coupling vs. C–H activation.
While cross-dehydrogenative C–H activation strategies in principle constitute the most efficient approach, which formally only generate hydrogen as by-product, stoichiometric oxidants are needed, resulting in additional waste generation (Scheme 1.1c).[21] Traditional cross-coupling, although very efficient, does not only require an electrophilic coupling partner, but also an additional nucleophilc organometallic reagent, which leads to the formation of stoichiometric amounts of partially toxic waste (Scheme 1.1a).
Therefore, the direct functionalization of C–H bonds is extremely desirable in terms of step- and atom-economy,[22] and bears great potential for the construction of C–C and C–Het bonds without the requirement of any prefunctionalization steps (Scheme 1.1b).[23]
Thus, C–H activation would provide the most favourable access for the synthesis of highly-functionalized organic molecules, but some key challenges have to be addressed. Whereas, in traditional cross-coupling reactions the regioselectivity of the C–C or C–Het bond forming step is clearly defined by the substitution pattern of the electrophile and nucleophile, for direct C–H functionalization reactions the control of selectivity is of major importance.
As C–H bonds are omnipresent in organic molecules, exhibiting almost identical bond dissociation energies, there are mainly three ways how to control the selectivity: i) the electronic distinction of C–H bonds caused by the differences in kinetic acidity, ii) the use of bulky substituents, that are blocking adjacent positions and thereby resulting in a steric control (Scheme 1.2a), and iii) the introduction of Lewis-basic directing groups to coordinate transition metal complexes in close proximity to the C–H bond to be activated (Scheme 1.2b).[23b] Furthermore, the introduction of directing groups generates a huge variety of different substrate classes, and in many cases the directing group can be removed after the desired transformation, even in a traceless fashion.
Scheme 1.2: Strategies for site-selectivity in C–H activation.
While the achievements in the field of C–H activation grew rapidly within the last decades, extensive investigations on the nature of the key-step, the initial C–H bond cleavage, have been conducted.[24] Therefore, excluding radical-type outer-sphere mechanisms,[25] five different pathways for the C–H bond dissociation, depending on the nature of the metal catalyst and oxidation state, have been identified (Scheme 1.3): a) oxidative addition for electron-rich late transition metals in low oxidation states, such as ruthenium(0), rhodium(I) and palladium(0),[24a] b) electrophilic substitution in case of late transition metals in higher oxidation states,[24c] c) σ-bond metathesis for early transition metals and lanthanoids,[24b] d) 1,2-addition to unsaturated M=X bonds, such as metal imido complexes, and e) base-assisted metalation.[24a]
Scheme 1.3: Different modes for organometallic C–H activation.
The base-assisted C–H cleavage was further investigated in detail and upon intensive research in this area several transition states were proposed, describing the activation mode of C–H activation events more precisely (Scheme 1.4).[24a]
Scheme 1.4: Transition state models for base-assisted C–H activation events.
The concerted metalation-deprotonation (CMD)[26] and ambiphilic metal-ligand activation (AMLA)[27] were independently disclosed and describe the interaction of the metal center, carboxylate-ligand and the C–H bond via a six-membered transition
state. These activation modes are especially used to describe C–H activation events of electron-deficient substrates with relative high kinetic acidity. In contrast, the intermolecular electrophilic substitution (IES)[28] proceeds via a strained four-membered transition state and has been proposed for C–H activation mechanisms relying on alkoxide bases. On the other hand, base-assisted internal substitution (BIES)[29] has been proposed to explain the preferred reactivity of electron-rich substrates.