Conspectus To improve the efficacy of molecular syntheses, researchers wish to capitalize upon the selective modification of otherwise inert C–H bonds. The past two decades have witnessed ...considerable advances in coordination chemistry that have set the stage for transformative tools for C–H functionalizations. Particularly, oxidative C–H/C–H and C–H/Het–H transformations have gained major attention because they avoid all elements of substrate prefunctionalization. Despite considerable advances, oxidative C–H activations have been dominated by precious transition metal catalysts based on palladium, ruthenium, iridium, and rhodium, thus compromising the sustainable nature of the overall C–H activation approach. The same holds true for the predominant use of stoichiometric chemical oxidants for the regeneration of the active catalyst, prominently featuring hypervalent iodine(III), copper(II), and silver(I) oxidants. Thereby, stoichiometric quantities of undesired byproducts are generated, which are preventive for applications of C–H activation on scale. In contrast, the elegant merger of homogeneous metal-catalyzed C–H activation with molecular electrosynthesis bears the unique power to achieve outstanding levels of oxidant and resource economy. Thus, in contrast to classical electrosyntheses by substrate control, metalla-electrocatalysis holds huge and largely untapped potential for oxidative C–H activations with unmet site selectivities by means of catalyst control. While indirect electrolysis using precious palladium complexes has been realized, less toxic and less expensive base metal catalysts feature distinct beneficial assets toward sustainable resource economy. In this Account, I summarize the emergence of electrocatalyzed C–H activation by earth-abundant 3d base metals and beyond, with a topical focus on contributions from our laboratories through November 2019. Thus, cobalt electrocatalysis was identified as a particularly powerful platform for a wealth of C–H transformations, including C–H oxygenations and C–H nitrogenations as well as C–H activations with alkynes, alkenes, allenes, isocyanides, and carbon monoxide, among others. As complementary tools, catalysts based on nickel, copper, and very recently iron have been devised for metalla-electrocatalyzed C–H activations. Key to success were detailed mechanistic insights, prominently featuring oxidation-induced reductive elimination scenarios. Likewise, the development of methods that make use of weak O-coordination benefited from crucial insights into the catalyst’s modes of action by experiment, in operando spectroscopy, and computation. Overall, metalla-electrocatalyzed C–H activations have thereby set the stage for molecular syntheses with unique levels of resource economy. These electrooxidative C–H transformations overall avoid the use of chemical oxidants and are frequently characterized by improved chemoselectivities. Hence, the ability to dial in the redox potential at the minimum level required for the desired transformation renders electrocatalysis an ideal platform for the functionalization of structurally complex molecules with sensitive functional groups. This strategy was, inter alia, successfully applied to scale-up by continuous flow and the step-economical assembly of polycyclic aromatic hydrocarbons.
To improve the atom- and step-economy of organic syntheses, researchers would like to capitalize upon the chemistry of otherwise inert carbon–hydrogen (C–H) bonds. During the past decade, remarkable ...progress in organometallic chemistry has set the stage for the development of increasingly viable metal catalysts for C–H bond activation reactions. Among these methods, oxidative C–H bond functionalizations are particularly attractive because they avoid the use of prefunctionalized starting materials. For example, oxidative annulations that involve sequential C–H and heteroatom–H bond cleavages allow for the modular assembly of regioselectively decorated heterocycles. These structures serve as key scaffolds for natural products, functional materials, crop protecting agents, and drugs. While other researchers have devised rhodium or palladium complexes for oxidative alkyne annulations, my laboratory has focused on the application of significantly less expensive, yet highly selective ruthenium complexes. This Account summarizes the evolution of versatile ruthenium(II) complexes for annulations of alkynes via C–H/N–H, C–H/O–H, or C–H/N–O bond cleavages. To achieve selective C–H bond functionalizations, we needed to understand the detailed mechanism of the crucial C–H bond metalation with ruthenium(II) complexes and particularly the importance of carboxylate assistance in this process. As a consequence, our recent efforts have resulted in widely applicable methods for the versatile preparation of differently decorated arenes and heteroarenes, providing access to among others isoquinolones, 2-pyridones, isoquinolines, indoles, pyrroles, or α-pyrones. Most of these reactions used Cu(OAc)2·H2O, which not only acted as the oxidant but also served as the essential source of acetate for the carboxylate-assisted ruthenation manifold. Notably, the ruthenium(II)-catalyzed oxidative annulations also occurred under an ambient atmosphere of air with cocatalytic amounts of Cu(OAc)2·H2O. Moreover, substrates displaying N–O bonds served as “internal oxidants” for the syntheses of isoquinolones and isoquinolines. Detailed experimental mechanistic studies have provided strong support for a catalytic cycle that relies on initial carboxylate-assisted C–H bond ruthenation, followed by coordinative insertion of the alkyne, reductive elimination, and reoxidation of the thus formed ruthenium(0) complex.
Ruthenium(II) complexes have emerged as effective catalysts for C–H arylations of tetrazolyl-substituted arenes by chelation assistance. Particularly, bifunctional additives, such as carboxylates or ...phosphates, set the stage for versatile C–H functionalizations with organic halides, which allowed for the step-economical synthesis of angiotensin-II-receptor blockers (ARBs) with unprecedented levels of efficacy and substrate scope. The outstanding robustness of the ruthenium(II) complexes was among others illustrated by remarkably low catalyst loadings and applications of this technology on a preparative scale.
CO2 in a fix: Gold and copper complexes of N‐heterocyclic carbenes recently enabled efficient direct carboxylation of (hetero)arenes having moderately acidic CH bonds under remarkably mild reaction ...conditions (IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene).
Carboxylate assistance proved to be the key for the success of efficient cobalt(III)‐catalyzed CH cyanations. Thus, an in situ generated cationic cobalt complex was identified as a versatile ...catalyst for the site‐selective synthesis of various aromatic and heteroaromatic nitriles with ample substrate scope.
As directed: The title reactions were accomplished with in situ generated cobalt(III) carboxylate complexes for highly efficient CH activations. The direct cyanation proved viable with removable directing groups and displayed a broad substrate scope and mild reaction conditions.
The development of methods for the functionalization of otherwise inert C–H bonds is one of the major foci in molecular syntheses. Recent advances have significantly improved the arsenal of synthetic ...chemistry, enabling the use of less functionalized starting materials, a reduction of energy consumption, and a minimization of waste production. Despite undisputable progress, the main challenge associated with synthetically meaningful C–H activations is achieving positional selectivity. Thus far, the most common approach to address site selectivity in transition-metal-catalyzed intermolecular transformations is constituted by chelation assistance through directing groups. The installation and removal of these directing groups adds additional steps, compromising the step-economical nature of the overall C–H activation strategy. In contrast, here we discuss the emergence of transient directing group approaches through the in situ installation and deconstruction of a Lewis-basic entity with the aid of co-catalytic additives for selective C–H functionalizations.
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Transition-metal-catalyzed C–H activation enables the use of easily accessible feedstocks for molecular syntheses, which holds great potential for sustainable syntheses. These C–H functionalizations are largely achieved by proximity-induced reactivity, exploiting strongly coordinating directing groups to ensure the required positional selectivity in intermolecular transformations. Since the installation and removal of the strongly coordinating directing groups calls for additional reaction steps, undesired waste is formed, which compromises the overall step- and atom-economical nature of C–H activation technology. Further, performing C–H activations with weakly coordinating functional groups continues to represent a formidable challenge. In this review, we discuss strategies to overcome these limitations, highlighting the recent developments in transient directing group approaches through the in situ formation and deconstruction of strongly coordinating directing groups in synergistic C–H activation catalysis.
C–H activation chemistry facilitates the use of common feedstocks for chemical reactions, which is important for developing more sustainable organic syntheses. One inherent difficulty for C-H functionalization in organic compounds is ensuring positional selectivity. That issue can be addressed by utilization of directing groups, in particular transient ones. This review highlights the transient directing group approach in transition-metal-catalyzed positional-selective C–H functionalizations.
Syntheses of substituted anilines primarily rely on palladium‐catalyzed coupling chemistry with prefunctionalized aryl electrophiles. While oxidative aminations have emerged as powerful alternatives, ...they largely produce undesired metal‐containing by‐products in stoichiometric quantities. In contrast, described herein is the unprecedented electrochemical C−H amination by cobalt‐catalyzed C−H activation. The environmentally benign electrocatalysis avoids stoichiometric metal oxidants, can be conducted under ambient air, and employs a biomass‐derived, renewable solvent for sustainable aminations in an atom‐ and step‐economical manner with H2 as the sole byproduct.
Zapping N: Electrochemical C−H aminations were realized in a biomass‐derived renewable solvent under mild reaction conditions. The method exploits electricity as a sustainable oxidant and H2 is the sole byproduct
Ruthenium-catalyzed isoquinolone syntheses with ample scope were accomplished through carboxylate assistance in environmentally benign water as a reaction medium. The high chemoselectivity of the ...ruthenium(II) carboxylate complex also set the stage for the direct use of free hydroxamic acids for annulations of alkynes.
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