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.

Late-stage meta-C-H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step.

Catalysed C-H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)-H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C-H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.

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.

Iron-catalyzed stereoselective C-H alkylation for simultaneous construction of C-N axial and C-central chirality.

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C-H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C-N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity.

Fluorescent coumarin-alkynes for labeling of amino acids and peptides via manganese(I)-catalyzed C-H alkenylation.

The late-stage fluorescent labeling of structurally complex peptides bears immense potential for molecular imaging. Herein, we report on a manganese(I)-catalyzed peptide C-H alkenylation under exceedingly mild conditions with natural fluorophores as coumarin- and chromone-derivatives. The robustness and efficiency of the manganese(I) catalysis regime was reflected by a broad functional group tolerance and low catalyst loading in a resource- and atom-economical fashion.

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.

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.

Stereoselective assembly of C-oligosaccharides via modular difunctionalization of glycals.

C-oligosaccharides are found in natural products and drug molecules. Despite the considerable progress made during the last decades, modular and stereoselective synthesis of C-oligosaccharides continues to be challenging and underdeveloped compared to the synthesis technology of O-oligosaccharides. Herein, we design a distinct strategy for the stereoselective and efficient synthesis of C-oligosaccharides via palladium-catalyzed nondirected C1-H glycosylation/C2-alkenylation, cyanation, and alkynylation of 2-iodoglycals with glycosyl chloride donors while realizing the difunctionalization of 2-iodoglycals. The catalysis approach tolerates various functional groups, including derivatives of marketed drugs and natural products. Notably, the obtained C-oligosaccharides can be further transformed into various C-glycosides while fully conserving the stereochemistry. The results of density functional theory (DFT) calculations support oxidative addition mechanism of alkenyl-norbornyl-palladacycle (ANP) intermediate with α-mannofuranose chloride and the high stereoselectivity of glycosylation is due to steric hindrance.

Electrochemical assembly of isoxazoles via a four-component domino reaction.

Multicomponent domino reactions via electrochemical annulations have emerged as a robust strategy for the rapid assembly of heterocyclics. Herein, an electrochemical annulation via a [1 + 2 + 1 + 1] four-component domino reaction was accomplished in a user-friendly undivided cell setup to assemble valuable five-membered isoxazole motifs. Our approach is characterized by a high level functional group tolerance and operational simplicity, avoiding the tedious and time-consuming preparation of pre-functionalized substrates. Detailed mechanistic studies were conducted including isotopic labeling, kinetic studies, cyclic voltammetry (CV) analysis, and intermediate characterization, providing support for a radical pathway.

A dual-targeted drug inhibits cardiac ryanodine receptor Ca2+ leak but activates SERCA2a Ca2+ uptake.

In the heart, genetic or acquired mishandling of diastolic [Ca2+] by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac death. Strategies to avoid these risks include decrease of Ca2+ release by drugs modulating RyR2 activity or increase in Ca2+ uptake by drugs modulating SR Ca2+ ATPase (SERCA2a) activity. Here, we combine these strategies by developing experimental compounds that act simultaneously on both processes. Our screening efforts identified the new 1,4-benzothiazepine derivative GM1869 as a promising compound. Consequently, we comparatively studied the effects of the known RyR2 modulators Dantrolene and S36 together with GM1869 on RyR2 and SERCA2a activity in cardiomyocytes from wild type and arrhythmia-susceptible RyR2R2474S/+ mice by confocal live-cell imaging. All drugs reduced RyR2-mediated Ca2+ spark frequency but only GM1869 accelerated SERCA2a-mediated decay of Ca2+ transients in murine and human cardiomyocytes. Our data indicate that S36 and GM1869 are more suitable than dantrolene to directly modulate RyR2 activity, especially in RyR2R2474S/+ mice. Remarkably, GM1869 may represent a new dual-acting lead compound for maintenance of diastolic [Ca2+].

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.

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.

Cobaltaelectro-Catalyzed C-H Annulation with Allenes for Atropochiral and P-Stereogenic Compounds: Late-Stage Diversification and Continuous Flow Scale-Up.

The 3d metallaelectro-catalyzed C-H activation has been identified as an increasingly viable strategy to access valuable organic molecules in a resource-economic fashion under exceedingly mild reaction conditions. However, the development of enantioselective 3d metallaelectro-catalyzed C-H activation is very challenging and in its infancy. Here, we disclose the merger of cobaltaelectro-catalyzed C-H activation with asymmetric catalysis for the highly enantioselective annulation of allenes. A broad range of C-N axially chiral and P-stereogenic compounds were thereby obtained in good yields of up to 98% with high enantioselectivities of up to >99% ee. The practicality of this approach was demonstrated by the diversification of complex bioactive compounds and drug molecules as well as decagram scale enantioselective electrocatalysis in continuous flow.

Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation.

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C-H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.

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.

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.

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.

Bifurcated Rhodaelectro-catalyzed C-H Activation for the Synthesis of Pyrroles and Lactones.

While electrocatalyzed alkyne annulations of arenes represent a powerful strategy for the assembly of heteroaromatic motives, electrochemical C(sp2)-H activations of alkenes remain scarce. Herein, a strategy for the rhodaelectro-catalyzed functionalization of enamides is presented for the efficient construction of pyrroles using electricity as a sustainable oxidant. Moreover, the tuning of the solvent system allowed a fascinating switch in chemoselectivity, which is not possible with traditionally used chemical oxidants, giving rise to lactone architectures. The rhoda-electrocatalysis features a broad scope as well as high regio- and chemoselectivities.

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.