1 Introduction
In the last century, organic synthesis has made tremendous progress, which has affected the daily lives of billions of people. Valuable products of organic synthesis are used for a wide range of applications ranging from pharmaceuticals and crop-protection agents to functional materials, such as OLEDs, coloring agents and polymers.[1] Although these products unarguably present a huge benefit in their diverse applications, their synthesis is associated with a number of drawbacks, for example a huge amount of toxic waste, the depletion of limited natural resources and overall high energy consumption.[2]
Therefore, in 1998, Anastas and Warner proposed their 12 Principles of green chemistry,[3] which outlined ways to reduce the ecological footprint of organic synthesis and minimize the amounts of byproducts and waste. Among them are the use of catalytic transformations, avoidance of unnecessary prefunctionalization and auxiliaries to increase the atom economy, use of mild reaction conditions (e.g. ambient temperature) and renewable sources for chemicals and the use of nontoxic reagents and solvents.
1.1 Transition Metal-Catalyzed C–H Activation
Although the beginnings of transition metal-catalyzed coupling chemistry[4] can be traced back to inter alia the early copper-catalyzed reactions by Glaser[5] and Ullmann,[6] it was not until the discovery of palladium-catalyzed cross-couplings that these transformations found considerable use in organic synthesis.[7] However, once established, palladium-catalyzed cross-coupling chemistry soon became the benchmark process for the formation of C–C and C–Het bonds. In time, a wide range of methods using different organometallic coupling partners were realized, resulting in a range of well-known named reactions, such as Suzuki-Miyaura,[8] Negishi,[9]
Kumada-Corriu,[10] Hiyama,[11] Stille[12] and Sonogashira-Hagihara[13] cross coupling reactions. Furthermore, although not a cross coupling reaction its traditional sense, the Mizoroki-Heck[14] reaction and the Buchwald-Hartwig amination[15] should be mentioned as milestones in palladium-catalyzed chemistry. These important
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contributions were recognized with the award of the Chemistry Nobel Prize to Heck, Negishi and Suzuki in 2010.[16]
Despite recent efforts to render cross-coupling chemistry more environmentally benign and cost effective by the use of earth-abundant metals, such as iron[17] or nickel,[18] and the use of renewable solvents,[19] the major drawback of cross-coupling chemistry remains, namely the need for prefunctionalized starting materials. Moreover, these materials are in most cases either not stable under ambient conditions (Grignard reagents, organolithium and organozinc compounds) or toxic (organotin compounds).
Therefore, the direct functionalizations of C–H bonds is extremely desirable in terms of the step- and atom-economy of organic syntheses (Scheme 1.1).[20]
Scheme 1.1. Comparison of traditional cross-coupling chemistry versus C–H activation.
While the most atom efficient reaction is in principle the cross-dehydrogenative C–H activation, which formally only generates hydrogen as a byproduct, these reactions suffer from the need for a stoichiometric oxidant, resulting in additional waste (Scheme 1.1c). Moreover, common oxidants include expensive and toxic silver(I) and copper(II) salts. While direct C–H functionalization using organic electrophiles requires a degree of prefunctionalization in one coupling partner (Scheme 1.1b), the substance classes most often employed, organic halides and phenol derivatives are accessible within a reasonable number of steps and largely stable under ambient conditions.[21] Traditional cross-coupling meanwhile (Scheme 1.1a) does not only require an electrophilic coupling partner, but also an additional nucleophilic organometalic reagent.
In contrast to traditional cross-coupling reactions, C–H functionalization faces an additional challenge besides the activation of otherwise inert C–H bonds. While the new connection in cross-coupling chemistry is clearly defined by the substitution
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pattern of the electrophile and nucleophile, organic molecules contain a large number of C–H bonds with similar bond dissociation energies (113.5 kcal/mol for C(sp2)−H bonds in benzene).[22] This problem can be overcome in mainly three ways: (i) the use of electronically activated substrates, where one C–H bond has a higher kinetic acidity than the others, (ii) steric shielding of C–H bonds where the reaction is undesired and (iii) the use of lewis-basic directing groups (DG) to coordinate to the transition metal catalyst in close proximity to the C–H bond to be functionalized (Scheme 1.2).[23]
Scheme 1.2. a) Differentiation of C–H bonds. b) Influence of the directing group.
While the first two options are severely limited in substrate scope, the directing group approach shows tremendous potential. This holds especially true if the directing group is an important building block of the target molecule or is easily removed or modified.[24]
The key step for C–H functionalization reactions is often the cleavage of the C–H bond itself. Therefore, C–H bond cleavage was and still is studied in close detail, resulting in different modes of action being identified (Scheme 1.3).[25]
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Scheme 1.3. Modes of action for various C–H cleavage mechanisms under transition metal assistance.
Oxidative addition to cleave C–H bonds was mostly observed with electron-rich complexes of late transition metals.[25a] For early transition metals with d0-configuration, this mode of action is obviously not feasible. In contrast, σ-bond metathesis and 1,2-addition are possible ways to achieve C–H activation with early transition metals,[25b]
while electrophilic substitution was proposed for cationic complexes of late transition metals.[25c] In recent years, base-assisted C–H activation has gained traction as a model for C–H cleavage in C–H functionalizations using basic additives.[25a]
This base-assisted C–H cleavage was the object of further research, resulting in the proposal of several transition states (Scheme 1.4).
Scheme 1.4. Transition state models for base-assisted C–H metalation.
Intramolecular electrophilic substitution (IES),[26] the mechanism for alkoxide bases relies on a highly strained, thus high-energy four-membered ring transition state.
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Concerted metalation-deprotonation (CMD)[27] and ambiphillic metal-ligand activation (AMLA)[28] were disclosed independently and describe the interaction of metal, carboxylate-ligand and C–H bond especially for electron-deficient substrates. In contrast, base-assisted internal substitution (BIES)[29] was proposed to explain the preferred reactivity of electron-rich substrates in several transformations.
Despite tremendous progress in the recent decades regarding C–H activation,[4, 30]
most of these advances were realized using cost-intensive and toxic 4d and 5d transition metals, such as rhodium,[31] iridium,[32] palladium[33] and ruthenium.[34] Here, new opportunities remain for the development of 3d transition metal-catalyzed C–H activation with possible benefits due to the significantly lower toxicity, abundance and lower price of the employed metal catalysts.