Enantioselective Reductive Cross-Couplings of Olefins by Merging Electrochemistry with Nickel Catalysis.

The merger of electrochemistry and transition metal catalysis has emerged as a powerful tool to join two electrophiles in an enantioselective manner. However, the development of enantioselective electroreductive cross-couplings of olefins remains a challenge. Inspired by the advantages of the synergistic use of electrochemistry with nickel catalysis, we present here a Ni-catalyzed enantioselective electroreductive cross-coupling of acrylates with aryl halides and alkyl bromides, which affords chiral α-aryl carbonyls in good to excellent enantioselectivity. Additionally, this catalytic reaction can be applied to (hetero)aryl chlorides, which is difficult to achieve by other methods. The combination of cyclic voltammetry analysis with electrode potential studies suggests that the NiI species activates aryl halides by oxidative addition and alkyl bromides by single-electron transfer.

C(sp3)-H Aerobic Alkenylation of Tetrahydroisoquinolines via Organic Electrosynthesis.

A method for the C(sp3)-H alkenylation of N-aryl-tetrahydroisoquinoline (THIQ) has been developed by the combination of electrooxidation and a copper catalyst. The corresponding products were obtained with good to excellent yields under mild conditions. Besides, the addition of TEMPO as an electron mediator is crucial to this transformation, since the oxidative reaction could proceed under a low electrode potential. In addition, the catalytic asymmetric variant has also been demonstrated with good enantioselectivity.

TEMPO-Enabled Electrochemical Enantioselective Oxidative Coupling of Secondary Acyclic Amines with Ketones.

An electrochemical asymmetric coupling of secondary acyclic amines with ketones via a Shono-type oxidation has been described, affording the corresponding amino acid derivatives with good to excellent diastereoselectivity and enantioselectivity. The addition of an N-oxyl radical as a redox mediator could selectively oxidize the substrate rather than the product, although their oxidation potential difference is subtle (about 13 mV). This electrochemical transformation proceeds in the absence of stoichiometric additives, including metals, oxidants, and electrolytes, which gives it good functional group compatibility. Mechanistic studies suggest that proton-mediated racemization of the product is prevented by the reduction of protons at the cathode.

Site-Selective C-H Functionalization via Synergistic Use of Electrochemistry and Transition Metal Catalysis.

Electrochemical synthesis of organic compounds has emerged as an attractive and environmentally benign alternative to conventional approaches for oxidation and reduction of organic compounds that utilizes electric current instead of chemical oxidants and reductants. As such, many useful transformations have been developed, including the Kolbe reaction, the Simons fluorination process, the Monsanto adiponitrile process, and the Shono oxidation, to name a few. Electrochemical C-H functionalization represents one of the most promising reaction types among many electrochemical transformations, since this process avoids prefunctionalization of substrates and provides novel retrosynthetic disconnections. However, site-selective anodic oxidation of C-H bonds is still a fundamental challenge due to the high oxidation potentials of C-H bonds compared to organic solvents and common functional groups. To overcome this issue, indirect electrolysis via the action of a mediator (a redox catalyst) is regularly employed, by which the selectivity can be controlled following reaction of said mediator with the substrate. Since the redox potentials of transition metal complexes can be easily tuned by modification of the ligand, the synergistic use of electrochemistry and transition metal catalysis to achieve site-selective C-H functionalization is an attractive strategy. In this Account, we summarize and contextualize our recent efforts toward transition metal-catalyzed electrochemical C-H functionalization proximal to a suitable directing group. We have developed C-H oxygenation, acylation, alkylation, and halogenation reactions in which a Pd(II) species is oxidized to a Pd(III) or Pd(IV) intermediate by anodic oxidation, followed by reductive elimination to form the corresponding C-O, C-C, and C-X bonds. Importantly, improved monofunctionalization selectivity is achieved in the Pd-catalyzed C(sp3)-H oxygenation compared to conventional approaches using PhI(OAc)2 as the chemical oxidant. Physical separators are sometimes used to prevent the electrochemical deposition of Pd black on the cathode resulting from reduction of high valent Pd species. We skirted this issue through the development a Cu-catalyzed electrochemical C(sp2)-H amination using n-Bu4NI as a redox cocatalyst in an undivided cell. In addition, we developed Ir-catalyzed electrochemical vinylic C-H functionalization of acrylic acids with alkynes in an undivided cell, affording various substituted α-pyrones in good to excellent yield. More importantly, chemical oxidants, including Ag2CO3, Cu(OAc)2, and PhI(OAc)2, resulted in much lower yields in the absence of electrical current under otherwise identical conditions. As elaborated below, progress in the area of electrochemical transition metal-catalyzed synthesis provides an effective platform for environmentally friendly and sustainable selective chemical transformations.

Esterification of Carboxylic Acids with Aryl Halides via the Merger of Paired Electrolysis and Nickel Catalysis.

Electrochemistry has been successfully applied in metal catalysis to avoid the usage of chemical redox agents. This strategy proved to be a powerful approach to construct carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds. However, most of the developed methods are based on either anodic oxidation or cathodic reduction, in which a sacrificial reaction occurs at the counter electrode. Paired electrolysis merging with metal catalysis is underdeveloped, wherein both anodic and cathodic processes are taking place simultaneously. Herein, we demonstrated that by using esterification of carboxylic acids with aryl halides via paired electrolysis using nickel as the catalyst the respective aryl esters were obtained in good to excellent yields at room temperature in an undivided electrochemical cell.

Nickel-Catalyzed N-Arylation of NH-Sulfoximines with Aryl Halides via Paired Electrolysis.

A novel strategy for the N-arylation of NH-sulfoximines has been developed by merging nickel catalysis and electrochemistry (in an undivided cell), thereby providing a practical method for the construction of sulfoximine derivatives. Paired electrolysis is employed in this protocol, so a sacrificial anode is not required. Owing to the mild reaction conditions, excellent functional group tolerance and yield are achieved. A preliminary mechanistic study indicates that the anodic oxidation of a NiII species is crucial to promote the reductive elimination of a C-N bond from the resulting NiIII species at room temperature.

Enantioselective Ni-Catalyzed Electrochemical Synthesis of Biaryl Atropisomers.

A scalable enantioselective nickel-catalyzed electrochemical reductive homocoupling of aryl bromides has been developed, affording enantioenriched axially chiral biaryls in good yield under mild conditions using electricity as a reductant in an undivided cell. Common metal reductants such as Mn or Zn powder resulted in significantly lower yields in the absence of electric current under otherwise identical conditions, underscoring the enhanced reactivity provided by the combination of transition metal catalysis and electrochemistry.

Copper-Catalyzed Electrochemical Selective Bromination of 8-Aminoquinoline Amide Using NH4Br as the Brominating Reagent.

A simple and mild protocol for copper-catalyzed bromination of quinoline at the C5 site of quinoline by anodic oxidation was developed, affording the desired remote C-H activation products with isolated yields of up to about 90%. The reaction proceeds with low-cost NH4Br and shows mild and green conditions (electricity as a green oxidant; NH3 and H2 as byproducts). At the same time, a gram-scale bromination reaction was also successfully fulfilled, showing its potential applicable value in organic synthesis. Moreover, the CV chart further demonstrated the proposed catalytic cycle.

Enantioselective construction of remote quaternary stereocentres.

Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted ß-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

Nickel-Catalyzed Electrochemical Reductive Relay Cross-Coupling of Alkyl Halides to Aryl Halides.

A highly regioselective Ni-catalyzed electrochemical reductive relay cross-coupling between an aryl halide and an alkyl halide has been developed in an undivided cell. Various functional groups are tolerated under these mild reaction conditions, which provides an alternative approach for the synthesis of 1,1-diarylalkanes.

Intermolecular Dearomatization of Naphthalene Derivatives by Photoredox-Catalyzed 1,2-Hydroalkylation.

An intermolecular hydroalkylative dearomatization of naphthalenes with commercially available α-amino acids is achieved via visible-light photoredox catalysis. With an organic photocatalyst, a series of multi-substituted 1,2-dihydronaphthalenes are obtained in good-to-excellent yields. Intriguingly, by tuning the substituents at the C2 position of naphthalenes, formal dearomative [3+2] cycloadditions occur exclusively via a hydroalkylative dearomatization-cyclization sequence. This overall redox-neutral method features mild reaction conditions, good tolerance of functionalities, and operational simplicity. Diverse downstream elaborations of the products are demonstrated. Preliminary mechanistic studies suggest the involvement of a radical-radical coupling pathway.

CuII /TEMPO-Catalyzed Enantioselective C(sp3 )-H Alkynylation of Tertiary Cyclic Amines through Shono-Type Oxidation.

A novel strategy for asymmetric Shono-type oxidative cross-coupling has been developed by merging copper catalysis and electrochemistry, affording C1-alkynylated tetrahydroisoquinolines with good to excellent enantioselectivity. The use of TEMPO as a co-catalytic redox mediator is crucial not only for oxidizing a tetrahydroisoquinoline to an iminium ion species but also for decreasing the oxidation potential of the reaction. A novel bisoxazoline ligand is also reported.

Nickel-catalyzed Enantioselective Hydroarylation and Hydroalkenylation of Styrenes.

We have developed a Ni-catalyzed enantioselective hydroarylation of styrenes with arylboronic acids using MeOH as the hydrogen source, providing an efficient method to access 1,1-diarylalkanes, which are essential structural units in many biologically active compounds. In addition, Ni-catalyzed enantioselective hydrovinylation of styrenes with vinylboronic acids is also realized with good yields and enantioselectivities. The synthetic utility was demonstrated by the efficient synthesis of ( R)-(-)-ibuprofen.

Electrochemistry-Enabled Ir-Catalyzed Vinylic C-H Functionalization.

Synergistic use of electrochemistry and organometallic catalysis has emerged as a powerful tool for site-selective C-H functionalization, yet this type of transformation has thus far mainly been limited to arene C-H functionalization. Herein, we report the development of electrochemical vinylic C-H functionalization of acrylic acids with alkynes. In this reaction an iridium catalyst enables C-H/O-H functionalization for alkyne annulation, affording α-pyrones with good to excellent yields in an undivided cell. Preliminary mechanistic studies show that anodic oxidation is crucial for releasing the product and regeneration of an Ir(III) intermediate from a diene-Ir(I) complex, which is a coordinatively saturated, 18-electron complex. Importantly, common chemical oxidants such as Ag(I) or Cu(II) did not give significant amounts of the desired product in the absence of electrical current under otherwise identical conditions.

Nickel-Catalyzed Thiolation of Aryl Halides and Heteroaryl Halides through Electrochemistry.

Transition-metal-catalyzed coupling reactions are useful tools for synthesizing aryl sulfur compounds. However, conventional transition-metal-catalyzed thiolation of aryl bromides and chlorides typically requires the use of strong base under elevated reaction temperature. Herein, we report the first examples of nickel-catalyzed electrochemical thiolation of aryl bromides and chlorides in the absence of an external base at room temperature using undivided electrochemical cells.

Copper-Catalyzed Electrochemical C-H Amination of Arenes with Secondary Amines.

Electrochemical oxidation represents an environmentally friendly solution to conventional methods that require caustic stoichiometric chemical oxidants. However, C-H functionalizations merging transition-metal catalysis and electrochemical techniques are, to date, largely confined to the use of precious metals and divided cells. Herein, we report the first examples of copper-catalyzed electrochemical C-H aminations of arenes at room temperature using undivided electrochemical cells, thereby providing a practical solution for the construction of arylamines. The use of n-Bu4NI as a redox mediator is crucial for this transformation. On the basis of mechanistic studies including kinetic profiles, isotope effects, cyclic voltammetric analyses, and radical inhibition experiments, the reaction appears to proceed via a single-electron-transfer (SET) process, and a high valent Cu(III) species is likely involved. These findings provide a new avenue for transition-metal-catalyzed electrochemical C-H functionalization reactions using redox mediators.

Activation of remote meta-C-H bonds assisted by an end-on template.

Functionalization of unactivated carbon-hydrogen (C-H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C-H bonds are present in the target molecule. The usual approach is to use σ-chelating directing groups, which lead to ortho-selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C-H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta-C-H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C-H activation to a weak 'end-on' interaction between the linear nitrile group and the metal centre. The 'end-on' coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C-H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

Palladium-Catalyzed C(sp3)-H Oxygenation via Electrochemical Oxidation.

Palladium-catalyzed C-H activation/C-O bond-forming reactions have emerged as attractive tools for organic synthesis. Typically, these reactions require strong chemical oxidants, which convert organopalladium(II) intermediates into the PdIII or PdIV oxidation state to promote otherwise challenging C-O reductive elimination. However, previously reported oxidants possess significant disadvantages, including poor atom economy, high cost, and the formation of undesired byproducts. To overcome these issues, we report an electrochemical strategy that takes advantage of anodic oxidation of PdII to induce selective C-O reductive elimination with a variety of oxyanion coupling partners.

γ,δ,ε-C(sp(3))-H Functionalization through Directed Radical H-Abstraction.

Aliphatic amides are selectively functionalized at the γ- and δ-positions through directed radical 1,5 and 1,6 H-abstractions, respectively. The initially formed γ- or δ-lactams are intercepted by N-iodosuccinimide and trimethylsilyl azide, leading to double and triple C-H functionalizations at the γ-, δ-, and ε-positions. This new reactivity is exploited to convert alkyls into amino alcohols and allylic amines.

Synthesis of 1,2-Benzothiazine via Nickel-Catalyzed Electrochemical Intramolecular Amination.

Constructing a C-N bond by merging electrochemistry and nickel catalysis is considered a powerful strategy. Herein, we investigate highly efficient intramolecular amination at room temperature with excellent functional group tolerance. Mechanistic studies suggest that the rapid ligand exchange may lead to the NiI/NiIII catalytic cycle. This method not only provides a new perspective for intramolecular amination but also offers a novel approach for constructing the benzothiazine scaffold.