Photoelectrocatalytic [4+2] Annulation for S-Heterocycle Assembly Enabled by Proton-Coupled Electron Transfer (PCET).

Cross-dehydrogenative couplings (CDC) present an efficient strategy for the assembly of biorelevant heterocycles, but are thus far largely limited to toxic transition metals and rather harsh reaction conditions. In sharp contrast, we, herein report on a mild photoelectrocatalyzed CDC-[4+2] annulation enabling the synthesis of functionalized isothiochromenes enabled by a proton-coupled electron transfer (PCET) strategy. The transformative photoelectrocatalysis obviated toxic transition-metal, high reaction temperatures, and stoichiometric chemical redox reagents. This approach was characterized by exceedingly mild conditions, ample substrate scope, and a commercially available catalyst. Gram-scale reactions and a telescoped synthesis route reflected the unique potential in the green synthesis of important S-heterocycles.

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.

C-S-Selective Stille-Coupling Enables Stereodefined Alkene Synthesis.

A palladium-catalyzed highly C‒S-selective Stille cross-coupling between aryl thianthrenium salts and tri- or tetrasubstituted alkenyl stannanes is described. Herein, critical challenges including site- and chemoselectivity control are well addressed through C‒H thianthrenation and C‒S alkenylation, thereby providing an expedient access to stereodefined tri- and tetrasubstituted alkenes in a stereoretentive fashion. Indeed, the palladium-catalyzed Stille-alkenylation of poly(pseudo)halogenated arenes displays privileged capability to differentiate C‒S over C‒I, C‒Br, C‒Cl bonds, as well as oxygen-based triflates (C‒OTf), tosylates (C‒OTs), carbamates and sulfamates under mild reaction conditions. Sequential and multiple cross-couplings via selective C‒X functionalization should be widely applicable for increasing functional molecular complexity. Modular installation of stereospecific alkene motifs into pharmaceuticals illustrated the synthetic application of the present protocol in drug discovery.

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.

Direct Synthesis of C4-Acyl Indoles via C-H Acylation.

The direct synthesis of C4-acyl indoles deprived of C2 and C3 substituents has proven to be challenging, with scarce efficient synthetic routes being reported. Herein, we disclose a highly site-selective palladium-catalyzed C-H acylation for the construction of C4-acyl indoles via a Catellani-Lautens cyclization strategy. In addition, we systematically studied the ortho C-H acylation mechanism of iodoaniline through density functional theory (DFT) calculations and combined experimental results to elucidate the principle of high chemoselectivity brought by triazine benzoate as an acylation reagent.

Electrochemical Enantioselective C-H Annulation by Achiral Rhodium(III)/Chiral Brønsted Base Domino Catalysis.

Rhodium(III)-catalyzed enantioselective C-H activation has emerged as a powerful tool for assembling enabling chiral molecules. However, this approach is significantly hampered by the cumbersome synthetic routes for preparing chiral rhodium catalysts. In sharp contrast, we herein report on an electrochemical domino catalysis system that exploits an achiral Cp*-rhodium catalyst along with an easily accessible chiral Brønsted base for an enantioselective C-H activation/annulation reaction of alkenes by benzoic acids. Our strategy offers an environmentally benign and most user-friendly approach for assembling synthetically useful chiral phthalides in good enantioselectivity, employing electricity as the sustainable oxidant.

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.

Photoinduced C-H arylation of 1,3-azoles via copper/photoredox dual catalysis.

The visible light-induced C-H arylation of azoles has been accomplished by dual-catalytic system with the aid of an inexpensive ligand-free copper(i)-catalyst in combination with a suitable photoredox catalyst. An organic photoredox catalyst, 10-phenylphenothiazine (PTH), was identified as effective, cost-efficient and environmentally-benign alternative to commonly-used, expensive Ir(iii)-based complexes. The method proved applicable for the C-H arylation of various azole derivatives, including oxazoles, benzoxazoles, thiazoles, benzothiazoles as well as more challenging imidazoles and benzimidazoles. Moreover, the derivatization of complex molecules and the gram scale synthesis of the natural product balsoxin reflected the synthetic utility of the developed strategy. Mechanistic studies were indicative of a single electron transfer-based (SET) mechanism with an aryl radical as key intermediate.

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.

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.

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.

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.

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.

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.

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.

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.

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+].

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.