Transition Metal-Catalyzed C–H Activation

“A dream of organic chemists has been the discovery of coupling reactions with no prefunctionalization of the coupling partners.” (V. Snieckus)^[4]

Organic synthesis, including catalytic reactions, has long been dominated by the transformation of functional groups, hence requiring pre-functionalized starting materials. In this context, a major achievement of catalysis in the past five decades

has been the development of transition metal-catalyzed cross-couplings, forming carbon–carbon (C–C) and carbon–heteroatom (C–Het) bonds.^[4] Interestingly, pioneering results were obtained as early as in the late 19^th century by, inter alia, Glaser^[5] and Ullmann^[6] using stoichiometric or catalytic amounts of copper.

Nevertheless, transition metal-mediated coupling reactions have only found broad applications since the development of palladium-catalyzed cross-couplings between organometallic reagents with organic electrophiles.^[4]

Major successes in this field have been realized for the formation of C–C bonds using diverse coupling partners, resulting in the development of numerous name reactions, such as the Suzuki–Miyaura,^[7] Negishi,^[8] Mizoroki–Heck,^[9] Kumada–

Corriu,^[10] Hiyama,^[11] Stille^[12] and Sonogashira–Hagihara^[13] cross-coupling reactions. Additionally, while not always C–C bond forming processes, the Tsuji–

Trost reaction^[14] as well as the Buchwald–Hartwig amination^[15] should be mentioned as other significant milestones in palladium coupling catalysis. Palladium-catalyzed cross-couplings are nowadays a routine tool in organic synthesis, with applications ranging from material sciences to the late-stage diversification of biologically active compounds,^[16] and their importance was recognized by the Nobel Prize in Chemistry awarded collectively to Heck, Negishi and Suzuki in 2010.^[4,17]

However, those processes still suffer from various drawbacks which significantly affect their ecological footprint. Indeed, the need for rare noble transition metal catalysts, pre-functionalized substrates and sensitive organometallic reagents, as well as the generation of stoichiometric amounts of harmful waste, render those processes hazardous and harmful to the environment.

Significant achievements have been made to address those limitations, which include the use of sustainable non-noble metal catalysts such as nickel^[18] and iron,^[19] the use of biomass-derived solvents,^[20] and the development of reusable^[21]

or highly active catalysts operating at low loadings.^[22] However, those approaches do not tackle the main issues of cross-coupling chemistry, namely the need for pre-functionalized starting materials and the generation of stoichiometric waste byproducts.

Therefore, the direct functionalization of omnipresent C–H bonds would appear as a highly desirable alternative to conventional cross-couplings due to the improved step- and atom-economy (Scheme 1.1). In this context, catalytic C‒H activation has experienced a tremendous development in recent years,^[23] and has now surfaced as a transformative tool for molecular syntheses, with notable applications in pharmaceutical industries,^[24] as well as the synthesis of complex bioactive natural products^[25] and material sciences,^[26] among others. Nevertheless, the direct functionalization of C–H bonds with organic electrophiles still requires the prefunctionalization of one of the coupling partners, generating a stoichiometric amount of (pseudo)halogenated byproducts (Scheme 1.1b). In contrast, hydroarylations^[27] would be perfectly atom-economical, redox-neutral, and more step-economical as well since no pre-functionalization is required. Cross-dehydrogenative C–H activation would also, in theory, be a fully atom-economical approach, as only molecular hydrogen is formally generated as a byproduct (Scheme 1.1c). However, those reactions usually require a stoichiometric oxidant, which results in stoichiometric waste generation, and typically suffer from a rather narrow substrate scope.

Scheme 1.1. Comparison of traditional cross-coupling vs. C–H activation.

Nevertheless, several challenges which need to be overcome are associated with synthetically useful C–H activation. First, the C–H bond is typically significantly more

stable than the C–X bond of common cross-coupling partners (e.g. BDE(Ph–H) ≈ 113 kcal mol^–1 vs. BDE(Ph–Cl) ≈ 97 kcal mol^–1,

BDE(Ph–Br) ≈ 84 kcal mol^–1, BDE(Ph–I) ≈ 67 kcal mol^–1).^[28] While early examples of C–H activations required harsh reaction conditions which strongly limited their applications to the synthesis of complex and sensitive molecules, recent progress has focused on the development of milder^[29] and more selective processes. The mechanism of the key C–H cleavage step has been studied extensively as its understanding is particularly important for the design of efficient catalytic processes.

Excluding outer-sphere mechanisms (e.g. carbene/nitrene insertions^[30] or radical reactions^[31]), five general modes of action have been proposed for the C–H metalation step depending on the nature of the substrate, the metal catalyst, its ligands and oxidation state (Scheme 1.2).^[32] These pathways consist of oxidative addition, electrophilic substitution, σ-bond metathesis, 1,2-addition and base-assisted metalation. The oxidative addition pathway is typical for electron-rich, low-valent complexes of late transition metals, such as rhenium, ruthenium, osmium, iridium, platinum and even iron,^[32b] from which higher oxidation states are readily accessible (Scheme 1.2a). While this mechanism has also been proposed for early transition metals, later findings provided support for σ-bond metathesis, typically involving an alkyl- or hydride-metal complex (vide infra). Late transition metals in high oxidation states, such as Pd(II), Pt(II), Pt(IV), or Hg(II), tend to undergo C–H activation by an electrophilic substitution in which the metal acts as a Lewis acid. In those processes, the putative intermediate is formed by electrophilic attack of the metal, usually in a strongly polar medium (Scheme 1.2b). For early transition metals, as well as lanthanides and actinides, σ-bond metathesis tend to be the preferred pathway. A key feature this mechanism is the concerted formation and breaking of C–H and C–M bonds in the transition state (Scheme 1.2c).^[32b] The 1,2-addition route is observed for metals with an unsaturated M=Y bond, typically imido, oxo and alkylidene complexes. Those transformations occur via a [2σ+2π]-type reaction where the Y group serves as the formal hydrogen acceptor (Scheme 1.2d). Finally,

another category of C–H cleavage processes is the base-assisted C–H activation.

Here, the base, most commonly a carboxylate,^[32a] facilitates the proton abstraction during the C–H scission step.

Scheme 1.2. Different pathways for organometallic C–H activation.

Further investigations on base-assisted C–H activations unravelled several different possible pathways (Scheme 1.3). Following the pioneering theoretical studies of Sakaki,^[33] the synergistic interaction between the metal center, carboxylate-ligand and C–H bond was rationalized by Gorelsky and the late Fagnou, leading to the

concept of concerted metalation-deprotonation (CMD) occurring via a six-membered transition state.^[34] Subsequent computational studies by Macgregor suggested the relevance of an agostic metal-hydrogen interaction in a mechanism named ambiphilic metal-ligand activation (AMLA).^[32c,35] Those processes are typically characterized by a considerable kinetic isotope effect (KIE) and a preference for electron-deficient substrates. In contrast, the term internal electrophilic substitution (IES)^[36] describes a mechanism occurring through a highly strained four-membered ring transition state. This process has been proposed for reactions involving alkoxide bases. Recently, the concept of base-assisted internal electrophilic substitution (BIES)^[37] has emerged in order to explain the preference for electron-rich substrates in several catalytic transformations.

Scheme 1.3. Proposed transition states for base-assisted C–H metalations.

Another challenge of C–H activation chemistry is the fact that C–H bonds are omnipresent in organic compounds and have almost identical bond dissociation energies. The control of selectivity in those transformations is therefore a task of key importance. Various approaches have been developed to tackle this issue, namely the use of substrate’s electronic bias, steric control, or a Lewis-basic group that coordinates to the transition metal catalyst and directs the C–H activation at the desired position (Scheme 1.4). Since electronic and steric biases depend on the substrate itself, those approaches usually result in a rather narrow substrate scope.

In contrast, the introduction of a directing group^[38] (DG) allows for a broad variety of substrates to be selectively functionalized. Nevertheless, a major limitation of this approach is the need to incorporate the directing group in the substrate. However,

the use of weakly coordinating,^[39] removable^[40] or transient^[41] directing groups has considerably expanded the possibilities of this approach.

Scheme 1.4. Methods to achieve positional selectivity in C–H activation.

Major progress in the field of C–H activation has been achieved with late transition metal catalysts. However, due to their high cost,^[42] low abundance^[43] and high toxicity,^[44] this approach is rather not sustainable. Therefore, the development of catalytic methods for the functionalization of otherwise inert C–H bonds employing non-noble 3d metals has attracted considerable interest in the last decade.^[45] Inter alia, the development of cobalt-,^[46] iron-,^[47] nickel-,^[48] manganese-^[49] and copper-catalyzed^[50] C–H activations has been particularly successful.

Despite those major advances, full selectivity control in enantioselective C–H functionalizations continues to heavily rely on precious 4d and 5d transition metals, prominently featuring toxic and expensive palladium, rhodium, and iridium complexes.^[51] Indeed, only a few extremely rare examples of enantioselective C–H functionalizations utilizing first-row transition metal catalysts had been published at the outset of this thesis. However, several additional contributions to this burgeoning field of research would later be disclosed in the course of the present work, by Ackermann and Cramer, among others (vide infra).^[52] In this context, it should be noted that the development of catalytic enantioselective methodologies in organic synthesis is a topic of extremely high interest, as best exemplified by the Nobel Prize in Chemistry awarded in 2001 to Noyori, Knowles and Sharpless for their seminal contributions to asymmetric catalysis.^[53] Therefore, given the sustainable nature and transformative power of 3d metal-catalyzed C–H activations, further exciting

developments are expected in the near future in this rapidly-evolving research area.^[52]