Chelation-Assisted Iron-Catalyzed C-H Activations: Scope and Mechanism.

ConspectusTo improve the resource economy of molecular syntheses, researchers have developed strategies to directly activate otherwise inert C-H bonds, thus avoiding cumbersome and costly substrate prefunctionalizations. During the past two decades, remarkable progress in coordination chemistry has set the stage for developing increasingly viable metal catalysts for C-H activations. Despite remarkable advances, C-H activations are largely dominated by precious 4d and 5d transition metal catalysts based primarily on palladium, ruthenium, iridium, and rhodium, thus decreasing the inherent sustainable nature of the C-H activation approach. Therefore, advancing catalytic reactions based on Earth-abundant and less toxic 3d transition metals, especially nontoxic and inexpensive iron, represents a desirable and attractive alternative. While research had previously focused on 8-aminoquinoline directing groups in C-H activations, we have devised easily accessible, tunable, and clickable triazoles, which feature widespread applications in bioactive compounds and drugs, among others, as peptide isosteres. Thus, in contrast to other directing groups, the triazole group is a highly desirable structural motif and functions as a bioisostere in medicine and biology, where it is exploited to mimic amide bonds.This Account summarizes the evolution of chelation-assisted iron-catalyzed C-H activations via C-H, C-H/N-H, and C-H/N-H/C-C bond cleavages, with a topical focus on the most recent contributions of our team. Thus, the triazole-enabled iron catalysis has surfaced as a transformative platform for a large variety of C-H transformations, including arylations, alkylations, alkenylations, allylations, annulations, and alkynylations, achieved through C-H activations with organometallic reagents, organohalides, alkynes, alkenes, allenes, and bicyclopropylidenes among others. Consequently, we developed widely applicable methods for the versatile preparation of decorated arenes and heteroarenes, providing access to benzamides, isoquinolones, pyrrolones, pyridones, phenones, indoles, and isoindolinones, among others. Most of these reactions employed 1,2-dichloroisobutane (DCIB) as an oxidant. Notably, chemical-oxidant-free strategies were also developed, with the major breakthroughs being the use of internal oxidants in oxidative annulations, the use of resource-economic electrocatalysis, and the development of well-defined iron(0)-mediated catalysis. In addition, a highly enantioselective inner-sphere C-H alkylation of (aza)indoles was developed by designing novel remotely decorated N-heterocyclic carbene ligands with dispersion energy donors. In addition, detailed mechanistic experiments including kinetic analyses, intermediate isolation, Mößbauer spectroscopy, and computation provided strong support for the mode of catalysis operation, enabling unprecedented C-H activations. Thereby, low-valent iron catalysts paved the way toward weakly coordinating ketones and enantioselective iron-catalyzed C-H activations through organometallic intermediates.

Electrochemical Late-Stage Functionalization.

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical or biological activities. LSF can thus greatly accelerate the development of medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical molecular synthesis has emerged as an environmentally friendly platform for the transformation of organic compounds. Over the past decade, electrochemical late-stage functionalization (eLSF) has gained major momentum, which is summarized herein up to February 2023.

Palladium-Catalyzed Electrooxidative Double C-H Arylation.

The electrochemical transition metal-catalyzed cross-dehydrogenative reaction has emerged as a promising platform to achieve a sustainable and atom-economic organic synthesis that avoids hazardous oxidants and minimizes undesired byproducts and circuitous functional group operations. However, a poor mechanistic understanding still prevents the widespread adoption of this strategy. In this regard, we herein present an electrochemical palladium-catalyzed oxidative coupling strategy to access biaryls in the absence of a stoichiometric chemical oxidant. The robust palladaelectrocatalysis considerably suppresses the occurrence of homocoupling and oxygenation, being compatible even with electron-deficient arenes. Late-stage functionalization and Boscalid precursor synthesis further highlighted the practical importance of our electrolysis. Remarkably, mechanistic studies including the evaluation of the reaction order of each component by variable time normalization analysis (VTNA) and initial rate analysis, H/D exchange experiment, kinetic isotope effect, and stoichiometric organometallic experiments provided strong support for the involvement of transmetalation between two organopalladium complexes in the turnover limiting step. Therefore, matching the concentrations or lifetimes of two distinct organopalladium intermediates is revealed to be a pivot to the success of electrooxidative catalysis. Moreover, the presence of cationic copper(II) seems to contribute to the stabilization of the palladium(0) catalyst instead of playing a role in the oxidation of the catalyst.

Nickel-Catalyzed Atroposelective C-H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands.

The catalytic asymmetric construction of axially chiral C-N atropisomers remains a formidable challenge due to their low rotational barriers and is largely reliant on toxic, cost-intensive, and precious metal catalysts. In sharp contrast, we herein describe the first nickel-catalyzed atroposelective C-H alkylation for the construction of C-N axially chiral compounds with the aid of a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni-Al bimetallic catalyst. A wide range of alkenes, including terminal and internal alkenes, were well compatible with the reaction, providing a variety of benzimidazole derivatives in high yields and enantioselectivities (up to 97:3 e.r.). The key to success was the identification of novel HASPOs as highly effective chiral preligands. Mechanistic studies revealed the catalyst mode of action, and in-depth data science analysis elucidated the key features of the responsible chiral preligands in controlling the enantioselectivity.

Well-Defined Highly-Coordinated Copper(III) Iodide and Pincer Tris(trifluoromethyl)copper Complexes.

Copper(III) iodide and bromide complexes representing a unique combination of highly-coordinated metal and soft polarizable anions were synthesized and fully characterized, including X-ray crystallography. Ligand substitution in well-defined highly-coordinated copper complex PyCu(CF3)3 with pincer ligands was achieved to give formally octahedral copper(III) complexes.

The crucial role of silver(I)-salts as additives in C-H activation reactions: overall analysis of their versatility and applicability.

Transition-metal catalyzed C-H activation reactions have been proven to be useful methodologies for the assembly of synthetically meaningful molecules. This approach bears intrinsic peculiarities that are important to be studied and comprehended in order to achieve its best performance. One example is the use of additives for the in situ generation of catalytically active species. This strategy varies according to the type of additive and the nature of the pre-catalyst that is being used. Thus, silver(I)-salts have proven to play an important role, due to the resulting high reactivity derived from the pre-catalysts of the main transition metals used so far. While being powerful and versatile, the use of silver-based additives can raise concerns, since superstoichiometric amounts of silver(I)-salts are typically required. Therefore, it is crucial to first understand the role of silver(I) salts as additives, in order to wisely overcome this barrier and shift towards silver-free systems.

Photo-Induced Ruthenium-Catalyzed C-H Arylation Polymerization at Ambient Temperature.

Transition metal-catalyzed C-H arylation polymerization (CHAP) is an attractive tool for constructing π-conjugated polymers in a sustainable manner. However, the existing methods primarily rely on palladium catalysis, which usually entails harsh reaction conditions and branching/cross-linking. Here we report the first example of an ambient-temperature ruthenium-catalyzed C-H arylation polymerization induced by visible light irradiation. The present polymerization can produce various meta- and para-linked polymers in excellent yields with high molecular weights. The remarkable feature of our mild reaction platform is represented by high chemoselectivity, leading to polymers that are otherwise inaccessible under conventional reaction conditions at high temperatures.

Ruthenium(II)-Catalyzed Late-Stage Incorporation of N-Aryl Triazoles and Tetrazoles with Sulfonium Salts via C-H Activation.

The late-stage functionalization of active pharmaceutical ingredients is a key challenge in medicinal chemistry. Furthermore, N-aryl triazoles and tetrazoles are important structural motifs with the potential to boost the activity of diverse drug molecules. Using easily accessible dibenzothiophenium salts for the ruthenium-catalyzed C-H arylation, these scaffolds were introduced into a variety of bioactive compounds. Our methodology uses cost-efficient ruthenium, KOAc as a mild base and gives access to a plethora of highly decorated triazole and tetrazole containing drug derivatives.

Iron-Catalyzed C-H Alkylation/Ring Opening with Vinylbenzofurans Enabled by Triazoles.

We report an unprecedented iron-catalyzed C-H annulation using readily available 2-vinylbenzofurans as the reaction pattern. The redox-neutral strategy, based on cheap, non-toxic, and earth-abundant iron catalysts, exploits triazole assistance to promote a cascade C-H alkylation, benzofuran ring-opening and insertion into a Fe-N bond, to form highly functionalized isoquinolones. Detailed mechanistic studies supported by DFT calculations fully disclosed the manifold of the iron catalysis.

Electrocatalytic Formal C(sp2)-H Alkylations via Nickel-Catalyzed Cross-Electrophile Coupling with Versatile Arylsulfonium Salts.

Producing sp3-hybridized carbon-enriched molecules is of particular interest due to their high success rate in clinical trials. The installation of aliphatic chains onto aromatic scaffolds was accomplished by nickel-catalyzed C(sp2)-C(sp3) cross-electrophile coupling with arylsulfonium salts. Thus, simple non-prefunctionalized arenes could be alkylated through the formation of aryldibenzothiophenium salts. The reaction employs an electrochemical approach to avoid potentially hazardous chemical redox agents, and importantly, the one-pot alkylation proved also viable, highlighting the robustness of our approach.

Cobaltaelectro-Catalyzed C-H Activation for Central and Axial Double Enantio-Induction.

In recent years, enantioselective electrocatalysis has surfaced as an increasingly-effective platform for sustainable molecular synthesis. Despite indisputable progress, strategies that allow the control of two distinct stereogenic elements with high selectivity remain elusive. In contrast, we, herein, describe electrochemical cobalt-catalyzed C-H activations that enable the installation of chiral stereogenic centers along with a chiral axis with high levels of enantio- and diastereoselectivities. The developed electrocatalysis strategy allowed for C-H/N-H activations/annulations with cyclic and non-cyclic alkenes providing expedient access to various central as well as atropo-chiral dihydroisoquinolinones paired to the valuable hydrogen evolution reaction. Studies on the atropo-stability of the obtained compounds demonstrated that the exceedingly mild conditions ensured by the electrocatalytic process were key for the achieved high stereoselectivities.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Electrochemical Rearrangement for Remote Functionalizations of Unactivated Alkenes.

An electrochemical strategy for the dual functionalizations of unactivated alkenes through an intramolecular migration process was realized in the absence of sacrificial chemical oxidants and noble-metal catalysts under mild reaction conditions. The electrochemistry enabled a (hetero)aryl migration while providing access to alkenyl/alkynyl-migration products. Thus, electricity was employed for the formation of functionalized fluoroalkyl radicals through activation of C-H/C-Br bonds from fluorinated esters. Thereby, we obtained a variety of di and mono-fluorinated alkyl products with good functional group tolerance as well as chemo, and regioselectivities. Likewise, defluorinative allylation of α-carbonyl alkyl bromides proved viable. The reaction mechanism was established by experiments and computations.

Ruthenium-Catalyzed Aminocarbonylation with Isocyanates Through Weak Coordinating Groups.

Introducing amide functional groups under mild conditions has growing importance owing to the prevalence of such moiety in biologically active molecules. Herein, we disclose a mild protocol for the directed ruthenium-catalyzed C-H aminocarbonylation with isocyanates as the amidating agents developed through high-throughput experimentation (HTE). The redox-neutral and base-free reaction is guided by weakly Lewis basic functional groups, including anilides, lactams and carbamates to access anthranilamide derivatives. The synthetic utility of this transformation is reflected by large-scale synthesis and late-stage functionalization.

Bridging Chemical Knowledge and Machine Learning for Performance Prediction of Organic Synthesis.

Recent years have witnessed a boom of machine learning (ML) applications in chemistry, which reveals the potential of data-driven prediction of synthesis performance. Digitalization and ML modelling are the key strategies to fully exploit the unique potential within the synergistic interplay between experimental data and the robust prediction of performance and selectivity. A series of exciting studies have demonstrated the importance of chemical knowledge implementation in ML, which improves the model's capability for making predictions that are challenging and often go beyond the abilities of human beings. This Minireview summarizes the cutting-edge embedding techniques and model designs in synthetic performance prediction, elaborating how chemical knowledge can be incorporated into machine learning until June 2022. By merging organic synthesis tactics and chemical informatics, we hope this Review can provide a guide map and intrigue chemists to revisit the digitalization and computerization of organic chemistry principles.

Photoelectrocatalyzed undirected C-H trifluoromethylation of arenes: catalyst evaluation and scope.

During the last few years, photoelectrocatalysis has evolved as an increasingly viable tool for molecular synthesis. Despite several recent reports on the undirected C-H functionalization of arenes, thus far, a detailed comparison of different catalysts is still missing. To address this, more than a dozen different mediators were employed in the trifluoromethylation of (hetero-)arenes to compare them in their efficacies.

Template Synthesis to Solve the Unreachable Ortho C-H Functionalization Reaction of Aryl Iodide.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho-site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Triazole-enabled, iron-catalysed linear/branched selective C-H alkylations with alkenes.

Iron-catalysed C-H alkylations with alkenes were achieved on benzamides by N-triazole assistance. A notable switch of the regioselectivity from linear to branched was observed depending on the nature of the olefin employed. The approach allowed for the synthesis of a family of decorated benzamides with ample scope and high levels of chemo-, regio- and site-selectivity.

Ruthenium-Catalyzed Remote Difunctionalization of Nonactivated Alkenes for Double meta-C(sp2 )-H/C-6(sp3 )-H Functionalization.

Twofold distal C-H functionalization was accomplished by difunctionalization of nonactivated alkenes to provide rapid access to multifunctionalized molecules. The multicomponent ruthenium-catalyzed remote 1,n-difunctionalization (n=6,7) of nonactivated alkenes with fluoroalkyl halides and heteroarenes in a modular manner is reported. The meta-C(sp2 )-H/C-6(sp3 )-H distal functionalization featured mild conditions, unique selectivity, and broad substrate scope with a domino process for twofold remote C(sp2 )-H/C(sp3 )-H activation of the sequential formation of three different carbon-centered radicals. A plausible mechanism was proposed based on detailed experimental and computational studies.

Domino meta-C-H Ethyl Glycosylation by Ruthenium(II/III) Catalysis: Modular Assembly of meta-C-Alkyl Glycosides.

Glycosyl anomeric radical addition reactions have been well-explored and proved efficient for the C-alkyl glycosides synthesis, but multicomponent Domino transformations for the rapid and controllable construction of structurally diversified C-alkyl glycosides in a single step are still rare. In contrast, we, herein, report a ruthenium(II)-catalyzed Domino meta-C-H ethyl glycosylation, enabling the construction of challenging meta-C-alkyl glycosides. Our ruthenium(II) catalysis was reflected by the mild reaction condition, exclusive meta-site selectivity and high levels of anomeric selectivity. In addition, the ruthenium(II)-catalyzed Domino meta-C-H glycosylation allowed for the synthesis of versatile 1,2-trans-C-alkyl glycosides with commercially available vinyl arenes, acrylates and easily accessible glycosyl bromides.