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.

Electrooxidative tricyclic 6-7-6 fused-system domino assembly to allocolchicines by a removable radical strategy.

Natural allocolchicine and analogues derived thereof a tricyclic 6-7-6-system have been found as key scaffold of various biologically relevant molecules. However, the direct preparation of the allocolchicine motif remains difficult to date. Herein, we report on an electrooxidative radical cyclization of biarylynones with various carbon- and heteroatom-centered radical precursors via a sequential radical addition/7-endo-trig/radical cyclization domino reaction. This approach provides a step-economical and strategically novel disconnection for the facile assembly of a wide range of carbocyclic 6-7-6 fused ring systems. Remarkably, the sulfonyl group on the products could be easily removed by photocatalysis at room temperature with high yields.

Synthesis and in vitro Study of Artemisinin/Synthetic Peroxide-Based Hybrid Compounds against SARS-CoV-2 and Cancer.

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 and leukemia cell lines. Several artesunic acid-derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81-83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid-quinoline hybrids also show inhibitory activity against SARS-CoV-2 in vitro (EC50 13-19 µm) and no cytotoxic effects on Vero E6 cells (CC50 up to 110 µM). These results provide a valuable basis for design of further artemisinin-derived hybrids to treat both cancer and SARS-CoV-2 infections.

C-H activation by immobilized heterogeneous photocatalysts.

During the last decades, the merger of photocatalysis with transition metal chemistry has been surfaced as a sustainable tool in modern molecular syntheses. This Account highlights major advances in synergistic photo-enabled C‒H activations. Inspired by our homogenous ruthenium- and copper-catalyzed C‒H activations in the absence of an exogenous photosensitizer, this Account describes the recent progress on heterogeneous photo-induced C‒H activation enabled by immobilized hybrid catalysts until September 2021, with a topical focus on recyclability as well as robustness of the heterogeneous photocatalyst.

Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]trienones.

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules. We report the use of electrochemistry to perform an oxidative dearomatization of biaryls leading to tri- and difluoromethylated spiro[5.5]trienones in a user friendly undivided cell set-up and a constant current mode. The catalyst- and chemical oxidant-free dearomatization procedure features ample scope, and employs electricity as the green and sole oxidant.

Photo-Induced Ruthenium-Catalyzed C-H Benzylations and Allylations at Room Temperature.

The ruthenium-catalyzed synthesis of diarylmethane compounds was realized under exceedingly mild photoredox conditions without the use of exogenous photocatalysts. The versatility and robustness of the ruthenium-catalyzed C-H benzylation was reflected by an ample scope, including multifold C-H functionalizations, as well as transformable pyrazoles, imidates and sensitive nucleosides. Mechanistic studies were indicative of a photoactive cyclometalated ruthenium complex, which also enabled versatile C-H allylations.

Dibenzocycloheptanones construction through a removable P-centered radical: synthesis of allocolchicine analogues.

Dibenzocycloheptanones containing a tricyclic 6-7-6-system are present in numerous biologically active natural molecules. However, the simple and efficient preparation of derivatives containing a dibenzocycloheptanone scaffold remains difficult to date. Herein, we report a versatile strategy for the construction of these challenging seven-membered rings using a 7-endo-trig cyclization which is initiated by a phosphorus-centered radical. This approach provides a step-economical regime for the facile assembly of a wide range of phosphorylated dibenzocycloheptanones. Remarkably, we also have devised a traceless addition/exchange strategy for the preparation of dephosphorylated products at room temperature with excellent yields. Therefore, this protocol allows for the concise synthesis of biorelevant allocochicine derivatives.

Regiodivergent C-H and Decarboxylative C-C Alkylation by Ruthenium Catalysis: ortho versus meta Position-Selectivity.

Ruthenium(II)biscarboxylate complexes enabled the selective alkylation of C-H and C-C bonds at the ortho- or meta-position. ortho-C-H Alkylations were achieved with 4-, 5- as well as 6-membered halocycloalkanes. Furthermore, the judicious choice of the directing group allowed for a full control of ortho-/meta-selectivities. Detailed mechanistic studies by experiment and computation were performed and provided strong support for an oxidative addition/reductive elimination process for ortho-alkylations, while a homolytic C-X cleavage was operative for the meta-selective transformations.

Photo-Induced Ruthenium-Catalyzed C-H Arylations at Ambient Temperature.

Ambient temperature ruthenium-catalyzed C-H arylations were accomplished by visible light without additional photocatalysts. The robustness of the ruthenium-catalyzed C-H functionalization protocol was reflected by a broad range of sensitive functional groups and synthetically useful pyrazoles, triazoles and sensitive nucleosides and nucleotides, as well as multifold C-H functionalizations. Biscyclometalated ruthenium complexes were identified as the key intermediates in the photoredox ruthenium catalysis by detailed computational and experimental mechanistic analysis. Calculations suggested that the in situ formed photoactive ruthenium species preferably underwent an inner-sphere electron transfer.

Nickela-electrocatalyzed Mild C-H Alkylations at Room Temperature.

Direct alkylations of carboxylic acid derivatives are challenging and particularly nickel catalysis commonly requires high reaction temperatures and strong bases, translating into limited substrate scope. Herein, nickel-catalyzed C-H alkylations of unactivated 8-aminoquinoline amides have been realized under exceedingly mild conditions, namely at room temperature, with a mild base and a user-friendly electrochemical setup. This electrocatalyzed C-H alkylation displays high functional group tolerance and is applicable to both the primary and secondary alkylation. Based on detailed mechanistic studies, a nickel(II/III/I) catalytic manifold has been proposed.

Rhodium-Catalyzed Electrooxidative C-H Olefination of Benzamides.

Metal-catalyzed chelation-assisted C-H olefinations have emerged as powerful tools for the construction of functionalized alkenes. Herein, we describe the rhoda-electrocatalyzed C-H activation/alkenylation of arenes. The olefinations of challenging electron-poor benzamides were thus accomplished in a fully dehydrogenative fashion under electrochemical conditions, avoiding stoichiometric chemical oxidants, and with H2 as the only byproduct. This versatile alkenylation reaction also features broad substrate scope and used electricity as a green oxidant.

Nickela-electrocatalyzed C-H Alkoxylation with Secondary Alcohols: Oxidation-Induced Reductive Elimination at Nickel(III).

Nickela-electrooxidative C-H alkoxylations with challenging secondary alcohols were accomplished in a fully dehydrogenative fashion, thereby avoiding stoichiometric chemical oxidants, with H2 as the only stoichiometric byproduct. The nickela-electrocatalyzed oxygenation proved viable with various (hetero)arenes, including naturally occurring secondary alcohols, without racemization. Detailed mechanistic investigation, including DFT calculations and cyclovoltammetric studies of a well-defined C-H activated nickel(III) intermediate, suggest an oxidation-induced reductive elimination at nickel(III).

Micellar Catalysis for Ruthenium(II)-Catalyzed C-H Arylation: Weak-Coordination-Enabled C-H Activation in H2 O.

Chemoselective C-H arylations were accomplished through micellar catalysis by a versatile single-component ruthenium catalyst. The strategy provided expedient access to C-H-arylated ferrocenes with wide functional-group tolerance and ample scope through weak chelation assistance. The sustainability of the C-H arylation was demonstrated by outstanding atom-economy and recycling studies. Detailed computational studies provided support for a facile C-H activation through thioketone assistance.

Cobaltaelectro-Catalyzed C-H Activation with Carbon Monoxide or Isocyanides.

Electrochemical oxidative C-H/N-H activations with isocyanides have been realized with a versatile cobalt catalyst. The widely applicable cobalt catalysis manifold further enabled electrooxidative C-H/N-H carbonylations with carbon monoxide under ambient conditions. The C-H functionalizations were efficiently realized with ample scope and outstanding functional group tolerance in a user-friendly undivided cell setup.

Catalyst- and Reagent-Free Electrochemical Azole C-H Amination.

Catalyst- and chemical oxidant-free electrochemical azole C-H aminations were accomplished via cross-dehydrogenative C-H/N-H functionalization. The catalyst-free electrochemical C-H amination proved feasible on azoles with high levels of efficacy and selectivity, avoiding the use of stoichiometric oxidants under ambient conditions. Likewise, the C(sp3 )-H nitrogenation proved viable under otherwise identical conditions. The dehydrogenative C-H amination featured ample scope, including cyclic and acyclic aliphatic amines as well as anilines, and employed sustainable electricity as the sole oxidant.

Electrooxidative Rhodium-Catalyzed C-H/C-H Activation: Electricity as Oxidant for Cross-Dehydrogenative Alkenylation.

Rhodium(III) catalysis has enabled a plethora of oxidative C-H functionalizations, which predominantly employ stoichiometric amounts of toxic and/or expensive metal oxidants. In contrast, we herein describe the first electrochemical rhodium-catalyzed C-H activation that avoids hazardous chemical oxidants. Environmentally benign twofold C-H/C-H functionalizations were accomplished with weakly coordinating benzoic acids and benzamides, employing electricity as the terminal oxidant and generating H2 as the sole byproduct.