Metallaelectro-catalyzed alkyne annulations via C-H activations for sustainable heterocycle syntheses.

Alkyne annulation represents a versatile and powerful strategy for the assembly of structurally complex compounds. Recent advances successfully enabled electrocatalytic alkyne annulations, significantly expanding the potential applications of this promising technique towards sustainable synthesis. The metallaelectro-catalyzed C-H activation/annulation stands out as a highly efficient approach that leverages electricity, combining the benefits of electrosynthesis with the power of transition-metal catalyzed C-H activation. Particularly attractive is the pairing of the electro-oxidative C-H activation with the valuable hydrogen evolution reaction (HER), thereby addressing the growing demand for green energy solutions. Herein, we provide an overview of the evolution of electrochemical C-H annulations with alkynes for the construction of heterocycles, with a topical focus on the underlying mechanism manifolds.

Copper(0)-Catalyzed Reductive Coupling of Disulfurating Reagents and (Hetero)aryl/Alkyl Halides.

Herein, we reported a copper(0)-catalyzed reductive coupling of disulfurating reagents and (hetero)aryl/alkyl halides. Copper(0) can be directly inserted into tetrasulfide and then undergoes reductive coupling with (hetero)aryl Iodides to construct disulfide. The method features the unprecedented use of copper(0)-catalyzed disulfurating reagents (tetrasulfides) in cross-coupling chemistry and is convenient with broad substrate scopes, even applicable to different halogenated hydrocarbons. It is worth noting that the methodology is practical with the late-stage modification of bioactive scaffolds of pharmaceuticals. In the meantime, the synthesis of disulfides is successfully achieved on a gram scale, indicating the approach is highly valuable.

Ruthenium(II)-Catalyzed Remote C-H Alkylation of Arenes Using Diverse N-Directing Groups through Aziridine Ring Opening.

An efficient approach for the remote C-H alkylation of arenes, employing a variety of N-directing groups is described. This method facilitates the straightforward synthesis of valuable phenylethylamine derivatives by exclusively cleaving the benzylic C-N bond in aziridines. Furthermore, these products can easily remove the protecting groups, resulting in a variety of meta-substituted compounds, such as amines and ketones, which hold significance in synthetic chemistry.

Anodic Commodity Polymer Recycling: The Merger of Iron-Electrocatalysis with Scalable Hydrogen Evolution Reaction.

Plastics are omnipresent in our everyday life, and accumulation of post-consumer plastic waste in our environment represents a major societal challenge. Hence, methods for plastic waste recycling are in high demand for a future circular economy. Specifically, the degradation of post-consumer polymers towards value-added small molecules constitutes a sustainable strategy for a carbon circular economy. Despite of recent advances, chemical polymer degradation continues to be largely limited to chemical redox agents or low energy efficiency in photochemical processes. We herein report a powerful iron-catalyzed degradation of high molecular weight polystyrenes through electrochemistry to efficiently deliver monomeric benzoyl products. The robustness of the ferraelectrocatalysis was mirrored by the degradation of various real-life post-consumer plastics, also on gram scale. The cathodic half reaction was largely represented by the hydrogen evolution reaction (HER). The scalable electro-polymer degradation could be solely fueled by solar energy through a commercially available solar panel, indicating an outstanding potential for a decentralized green hydrogen economy.

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.

Enantioselective Cobaltaphotoredox-Catalyzed C-H Activation.

The quest for sustainable strategies in molecular synthesis has spurred the emergence of photocatalysis as a particularly powerful technique. In recent years, the application of photocatalysis in this context has greatly promoted the development of asymmetric catalysis. Despite the impressive advances, enantioselective photoinduced strong arene C-H activations by cobalt catalysis remain unexplored. Herein, we report a strategy that merges organic photoredox catalysis and enantioselective cobalt-catalyzed C-H activation, enabling the regio- and stereoselective dual functionalization of indoles in an enantioselective fashion. Thereby, the assembly of various chiral indolo[2,3-c]isoquinolin-5-ones was realized with high enantioselectivities of up to 99%. The robustness of the cobaltaphotoredox catalysis was demonstrated through enantioselective C-H activation and annulations in a continuous flow to provide straightforward access to central and axially chiral molecules.

Electrochemical Glycosylation via Halogen-Atom-Transfer for C-Glycoside Assembly.

Glycosyl donor activation emerged as an enabling technology for anomeric functionalization, but aimed primarily at O-glycosylation. In contrast, we herein disclose mechanistically distinct electrochemical glycosyl bromide donor activations via halogen-atom transfer and anomeric C-glycosylation. The anomeric radical addition to alkenes led to C-alkyl glycoside synthesis under precious metal-free reaction conditions from readily available glycosyl bromides. The robustness of our e-XAT strategy was further mirrored by C-aryl and C-acyl glycosides assembly through nickela-electrocatalysis. Our approach provides an orthogonal strategy for glycosyl donor activation with expedient scope, hence representing a general method for direct C-glycosides assembly.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.