Unlocking the Potential of Oxidative Asymmetric Catalysis with Continuous Flow Electrochemistry.

In the field of catalytic asymmetric synthesis, the less-treated path lies in oxidative catalytic asymmetric transformations. The hurdles of pinpointing the appropriate chemical oxidants and addressing their compatibility issues with catalysts and functionalities present significant challenges. Organic electrochemistry, employing traceless electrons for redox reactions, is underscored as a promising solution. However, the commonly used electrolysis in batch cells introduces its own set of challenges, hindering the advancement of electrochemical asymmetric catalysis. Here we introduce a microfluidic electrochemistry platform with single-pass continuous flow reactors that exhibits a wide-ranging applicability to various oxidative asymmetric catalytic transformations. This is exemplified through the sulfenylation of 1,3-dicarbonyls, dehydrogenative C-C coupling, and dehydrogenative alkene annulation processes. The unique properties of microfluidic electrochemical reactors not only eliminate the need for chemical oxidants but also enhance reaction efficiency and reduce the use of additives and electrolytes. These salient features of microfluidic electrochemistry expedite the discovery and development of oxidative asymmetric transformations. In addition, the continuous production facilitated by parallel single-pass reactors ensures straightforward reaction upscaling, removing the necessity for reoptimization across various scales, as evidenced by direct translation from milligram screening to hectogram asymmetric synthesis.

Electrochemical Azidocyanation of Alkenes.

The difunctionalization of alkenes-a process that installs two functional groups in a single operation and transforms chemical feedstocks into value-added products-is one of the most appealing synthetic methods in contemporary chemistry. However, the introduction of two distinct functional groups via two readily accessible nucleophiles remains a formidable challenge. Existing intermolecular alkene azidocyanation methods, which primarily focus on aryl alkenes and rely on stoichiometric chemical oxidants. We report herein an unprecedented electrochemical strategy for alkene azidocyanation that is compatible with both alkyl and aryl alkenes. This is achieved by harnessing the finely-tuned anodic electron transfer and the strategic selection of copper/ligand complexes. The reactions of aryl alkenes were rendered enantioselective by employing a chiral ligand. Crucially, the mild conditions and well-regulated electrochemical process assure exceptional tolerance for various functional groups and substrate compatibility with both terminal and internal alkyl alkenes.

Continuous Flow Electrochemistry Enables Practical and Site-Selective C-H Oxidation.

The selective oxygenation of ubiquitous C(sp3 )-H bonds remains a highly sought-after method in both academia and the chemical industry for constructing functionalized organic molecules. However, it is extremely challenging to selectively oxidize a certain C(sp3 )-H bond to afford alcohols due to the presence of multiple C(sp3 )-H bonds with similar strength and steric environment in organic molecules, and the alcohol products being prone to further oxidation. Herein, we present a practical and cost-efficient electrochemical method for the highly selective monooxygenation of benzylic C(sp3 )-H bonds using continuous flow reactors. The electrochemical reactions produce trifluoroacetate esters that are resistant to further oxidation but undergo facile hydrolysis during aqueous workup to form benzylic alcohols. The method exhibits a broad scope and exceptional site selectivity and requires no catalysts or chemical oxidants. Furthermore, the electrochemical method demonstrates excellent scalability by producing 115 g of one of the alcohol products. The high site selectivity of the electrochemical method originates from its unique mechanism to cleave benzylic C(sp3 )-H bonds through sequential electron/proton transfer, rather than the commonly employed hydrogen atom transfer (HAT).

Photoelectrochemical Asymmetric Catalysis Enables Enantioselective Heteroarylcyanation of Alkenes via C-H Functionalization.

The asymmetric difunctionalization of alkenes, a method transforming readily accessible alkenes into enantioenriched chiral structures of high value, has long been a focal point of organic synthesis. Despite tremendous efforts in this domain, it remains a considerable challenge to devise enantioselective oxidative dicarbofunctionalization of alkenes, even though these transformations can utilize stable and unfunctionalized functional group donors. In this context, we report herein a photoelectrocatalytic method for the enantioselective heteroarylcyanation of aryl alkenes, which employs unfunctionalized heteroarenes through C-H functionalization. The photoelectrochemical asymmetric catalysis (PEAC) method combines photoredox catalysis and asymmetric electrocatalysis to facilitate the formation of two C-C bonds operating via hydrogen (H2) evolution and obviating the need for external chemical oxidants.

Photoelectrochemical Asymmetric Catalysis Enables Direct and Enantioselective Decarboxylative Cyanation.

The development of efficient and sustainable methods for decarboxylative transformations is of great importance due to the ease of availability and nontoxicity of carboxylic acids. Despite tremendous efforts in this area, it remains challenging to develop enantioselective transformations direct from carboxylic acids. Herein we disclose a photoelectrocatalytic method for the direct and enantioselective decarboxylative cyanation. The photoelectrochemical reactions convert carboxylic acids to enantioenriched nitriles by employing cerium/copper relay catalysis with a cerium salt for catalytic decarboxylation and a chiral copper complex for stereoselective C-CN formation.

Electrochemical aromatic C-H hydroxylation in continuous flow.

The direct hydroxylation of arene C-H bonds is a highly sought-after transformation but remains an unsolved challenge due to the difficulty in efficient and regioselective C-H oxygenation and high reactivity of the phenolic products leading to overoxidation. Herein we report electrochemical C-H hydroxylation of arenes in continuous flow for the synthesis of phenols. The method is characterized by broad scope (compatible with arenes of diverse electronic properties), mild conditions without any catalysts or chemical oxidants, and excellent scalability as demonstrated by the continuous production of 1 mol (204 grams) of one of the phenol products.

Cu-Electrocatalytic Diazidation of Alkenes at ppm Catalyst Loading.

The 1,2-diamine motif is prevalent in natural products, small-molecule pharmaceuticals, and catalysts for asymmetric synthesis. Transition metal catalyzed alkene diazidation has evolved to be an attractive strategy to access vicinal primary diamines but remains challenging, especially for practical applications, due to the restriction to a certain type of olefins, the frequent use of chemical oxidants, and the requirement for high loadings of metal catalysts (1 mol % or above). Herein we report a scalable Cu-electrocatalytic alkene diazidation reaction with 0.02 mol % (200 ppm) of copper(II) acetylacetonate as the precatalyst without exogenous ligands. In addition to its use of low catalyst loading, the electrocatalytic method is scalable, compatible with a broad range of functional groups, and applicable to the diazidation of α,ß-unsaturated carbonyl compounds and mono-, di-, tri-, and tetrasubstituted unactivated alkenes.

Electrocatalytic Allylic C-H Alkylation Enabled by a Dual-Function Cobalt Catalyst.

The direct functionalization of allylic C-H bonds with nucleophiles minimizes pre-functionalization and converts inexpensive, abundantly available materials to value-added alkenyl-substituted products but remains challenging. Here we report an electrocatalytic allylic C-H alkylation reaction with carbon nucleophiles employing an easily available cobalt-salen complex as the molecular catalyst. These C(sp3 )-H/C(sp3 )-H cross-coupling reactions proceed through H2 evolution and require no external chemical oxidants. Importantly, the mild conditions and unique electrocatalytic radical process ensure excellent functional group tolerance and substrate compatibility with both linear and branched terminal alkenes. The synthetic utility of the electrochemical method is highlighted by its scalability (up to 200 mmol scale) under low loading of electrolyte (down to 0.05 equiv) and its successful application in the late-stage functionalization of complex structures.

Organoelectrocatalysis Enables Direct Cyclopropanation of Methylene Compounds.

Cyclopropane is a prevalent structural unit in natural products and bioactive compounds. While the transition metal-catalyzed alkene cyclopropanation of functionalized compounds such as α-diazocarbonyl derivatives has been well established and provides straightforward access to cyclopropanes, cyclopropanation directly from the more stable and simpler methylene compounds has remained an unsolved challenge despite the highly desirable benefits of minimal prefunctionalization and increased operational safety. Herein we report an electrocatalytic strategy for the cyclopropanation of active methylene compounds, employing an organic catalyst. The method shows a broad substrate scope and excellent scalability, requires no metal catalyst or external chemical oxidant, and provides convenient access to several types of cyclopropane-fused heterocyclic and carbocyclic compounds. Mechanistic investigations suggest that the reactions proceed through a radical-polar crossover process to form the two new carbon-carbon bonds in the nascent cyclopropane ring.

Two-Dimensional Metal-Organic Framework Nanosheets: Synthesis and Applications in Electrocatalysis and Photocatalysis.

Two-dimensional metal-organic nanosheets (2D MONs) are an emerging class of ultrathin, porous, and crystalline materials. The organic/inorganic hybrid nature offers MONs distinct advantages over other inorganic nanosheets in terms of diversity of organic ligands and metal notes. Compared to bulk three-dimensional metal-organic frameworks, 2D MONs possess merits of high density and readily accessible catalytic sites, reduced diffusion pathways for reactants/products, and fast electron transport. These features endow MONs with enhanced physical/chemical properties and are ideal for heterogeneous catalysis. In this Review, state-of-the-art synthetic methods for the fabrication of 2D MONs were summarized. The advances of 2D MONs-based materials for electrocatalysis and photocatalysis, including hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), carbon dioxide reduction reaction (CO2 RR), and electro-/photocatalytic organic transformations were systematically discussed. Finally, the challenges and perspectives regarding future design and synthesis of 2D MONs for high-performance electrocatalysis and photocatalysis were provided.

Electrochemical C-H phosphorylation of arenes in continuous flow suitable for late-stage functionalization.

The development of efficient and sustainable methods for carbon-phosphorus bond formation is of great importance due to the wide application of organophosphorus compounds in chemistry, material sciences and biology. Previous C-H phosphorylation reactions under nonelectrochemical or electrochemical conditions require directing groups, transition metal catalysts, or chemical oxidants and suffer from limited scope. Herein we disclose a catalyst- and external oxidant-free, electrochemical C-H phosphorylation reaction of arenes in continuous flow for the synthesis of aryl phosphorus compounds. The C-P bond is formed through the reaction of arenes with anodically generated P-radical cations, a class of reactive intermediates remained unexplored for synthesis despite intensive studies of P-radicals. The high reactivity of the P-radical cations coupled with the mild conditions of the electrosynthesis ensures not only efficient reactions of arenes of diverse electronic properties but also selective late-stage functionalization of complex natural products and bioactive compounds. The synthetic utility of the electrochemical method is further demonstrated by the continuous production of 55.0 grams of one of the phosphonate products.

Electrocatalytic C(sp3)-H/C(sp)-H cross-coupling in continuous flow through TEMPO/copper relay catalysis.

Electrocatalytic dehydrogenative C(sp3)-H/C(sp)-H cross-coupling of tetrahydroisoquinolines with terminal alkynes has been achieved in a continuous-flow microreactor through 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)/copper relay catalysis. The reaction is easily scalable and requires low concentration of supporting electrolyte and no external chemical oxidants or ligands, providing straightforward and sustainable access to 2-functionalized tetrahydroisoquinolines.

Discovery of a tetraarylhydrazine catalyst for electrocatalytic synthesis of imidazo-fused N-heteroaromatic compounds.

The development of electrocatalytic synthetic methods hinges on efficient molecular catalysts. Triarylamines are well-known redox catalysts because of the good stability of their corresponding amine radical cations. Herein we show that tris(4-(tert-butyl)phenyl)amine decomposes unexpectedly during electrolysis in MeOH/THF to afford a tetraarylhydrazine, 1,1,2,2-tetrakis(4-(tert-butyl)phenyl)hydrazine. In addition, we have applied this tetraarylhydrazine, which is either preprepared or formed in situ from tris(4-(tert-butyl)phenyl)amine, as an electrocatalyst for the synthesis of imidazopyridines and related N-heteroaromatic compounds through intramolecular [3 + 2] annulation. This metal-free electrocatalytic method provides straightforward access to the N-heteroaromatic compounds from readily available materials without the need for external chemical oxidants.

Electrocatalytic Dehydrogenative Cyclization of 2-Vinylanilides for the Synthesis of Indoles.

Indole is prevalent in bioactive compounds and natural products. The development of efficient and sustainable methods to access this privileged structural scaffold has been a long-standing interest of synthetic chemists. Herein, we report an electrocatalytic method for the synthesis of indoles through dehydrogenative cyclization of 2-vinylanilides. The reactions employ an organic redox catalyst and do not require any external chemical oxidant, providing speedy and efficient access to 3-substituted and 2,3-disubstituted indoles.

Tailored cobalt-salen complexes enable electrocatalytic intramolecular allylic C-H functionalizations.

Oxidative allylic C-H functionalization is a powerful tool to streamline organic synthesis as it minimizes the need for functional group activation and generates alkenyl-substituted products amenable to further chemical modifications. The intramolecular variants can be used to construct functionalized ring structures but remain limited in scope and by their frequent requirement for noble metal catalysts and stoichiometric chemical oxidants. Here we report an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C-H amination and alkylation by employing tailored cobalt-salen complexes as catalysts. These reactions proceed through a radical mechanism and display broad tolerance of functional groups and alkene substitution patterns, allowing efficient coupling of di-, tri- and even tetrasubstituted alkenes with N- and C-nucleophiles to furnish high-value heterocyclic and carbocyclic structures.

Catalyst- and Reagent-Free Formal Aza-Wacker Cyclizations Enabled by Continuous-Flow Electrochemistry.

The development of efficient and sustainable methods to access saturated N-heterocycles is of great importance because of the prevalence of these structures in natural products and bioactive compounds. Pd-catalyzed aza-Wacker type cyclization is a powerful method and provides access to N-heterocycles bearing an alkene moiety available for further synthetic manipulations from readily available materials. Herein we disclose a catalyst- and reagent-free formal aza-Wacker type cyclization reaction for the synthesis of functionalized saturated N-heterocycles. Key to the success is to conduct the reactions in a continuous-flow electrochemical reactor without adding supporting electrolyte or additives. The reactions are characterized by broad tolerance of di-, tri- and tetrasubstituted alkenes.

Electrochemically Driven Radical Reactions: From Direct Electrolysis to Molecular Catalysis.

Organic radicals are versatile synthetic intermediates that provide reactivities and selectivities complementary to ionic species. Despite its long history, electrochemically driven radical reactions remain limited in scope. In the past few years, there have been dramatic increase in research activity in organic electrochemistry. We have been developing electrochemical and electrophotocatalytic methods for the generation and synthetic utilization of organic radicals. In our studies, various radical species such as alkene and arene radical cations and carbon- and heteroatom-centered radicals are generated from readily available precursors through direct electrolysis, molecular electrocatalysis or molecular electrophotocatalysis. These radical species undergo various inter- and intramolecular oxidative transformations to rapidly increase molecular complexity. The simultaneous occurrence of anodic oxidation and cathodic proton reduction allows the oxidative reactions to proceed through H2 evolution without external chemical oxidants.

Electrochemical Synthesis of Benzimidazoles via Dehydrogenative Cyclization of Amidines.

The development of efficient and sustainable methodologies for the synthesis of N-heterocycles is a constant focus of organic synthesis. Herein an electrochemical method is reported for the synthesis of benzimidazoles through dehydrogenative cyclization of easily available N-aryl amidines. The reactions were conducted under simple constant current conditions in an undivided cell without need for catalysts, chemical oxidants, or additives, and produced H2 as the only theoretical byproduct.

Recent advances in organic electrosynthesis employing transition metal complexes as electrocatalysts.

Organic electrosynthesis has been widely used as an environmentally conscious alternative to conventional methods for redox reactions because it utilizes electric current as a traceless redox agent instead of chemical redox agents. Indirect electrolysis employing a redox catalyst has received tremendous attention, since it provides various advantages compared to direct electrolysis. With indirect electrolysis, overpotential of electron transfer can be avoided, which is inherently milder, thus wide functional group tolerance can be achieved. Additionally, chemoselectivity, regioselectivity, and stereoselectivity can be tuned by the redox catalysts used in indirect electrolysis. Furthermore, electrode passivation can be avoided by preventing the formation of polymer films on the electrode surface. Common redox catalysts include N-oxyl radicals, hypervalent iodine species, halides, amines, benzoquinones (such as DDQ and tetrachlorobenzoquinone), and transition metals. In recent years, great progress has been made in the field of indirect organic electrosynthesis using transition metals as redox catalysts for reaction classes including C-H functionalization, radical cyclization, and cross-coupling of aryl halides-each owing to the diverse reactivity and accessible oxidation states of transition metals. Although various reviews of organic electrosynthesis are available, there is a lack of articles that focus on recent research progress in the area of indirect electrolysis using transition metals, which is the impetus for this review.