Electroreductive Cross-Electrophile Coupling of Aziridines and Aryl Bromides.

Herein, a nickela-electrocatalyzed cross-electrophile coupling of readily available aryl aziridines and aryl bromides under mild and sustainable electrochemical conditions to access synthetic useful ß-arylethylamines is developed. This protocol is characterized by its exquisite chemo- and regioselectivity, broad substrate scope and good functional group compatibility. Mechanistic studies confirmed that the regioselectivity and reactivity observed are a result of electro-induced ring-opening of aziridines under electroreductive conditions to generate a benzyl radical intermediate as the active species. Furthermore, this strategy also enables cross-coupling with CO2 to access ß-amino acids under mild conditions.

Selective Electroreductive Hydroboration of Olefins with B2pin2.

Organoboron showed great potential in the synthesis of various high-value chemical compounds. Direct hydroboration of olefins has been witnessed over time as a mainstream method for the synthesis of organoboron compounds. In this work, an electroreductive anti-Markovnikov hydroboration approach of olefins with readily available B2pin2 to synthesize valuable organoboron compounds with high chemo- and regioselectivities under metal catalyst-free conditions was reported. This protocol exhibited broad substrate scope and good functional-group tolerance on styrenes and heteroaromatic olefins, providing synthetically useful alkylborons with high efficiency and even various deuterium borylation products with good D-incorporation when CD3CN was employed as solvent. Furthermore, gram-scale reactions and extensive functional derivatization further highlighted the potential of this method.

Organo-Mediator Enabled Electrochemical Deuteration of Styrenes.

Despite widespread use of the deuterium isotope effect, selective deuterium labeling of chemical molecules remains a major challenge. Herein, a facile and general electrochemically driven, organic mediator enabled deuteration of styrenes with deuterium oxide (D2 O) as the economical deuterium source was reported. Importantly, this transformation could be suitable for various electron rich styrenes mediated by triphenylphosphine (TPP). The reaction proceeded under mild conditions without transition-metal catalysts, affording the desired products in good yields with excellent D-incorporation (D-inc, up to >99 %). Mechanistic investigations by means of isotope labeling experiments and cyclic voltammetry tests provided sufficient support for this transformation. Notably, this method proved to be a powerful tool for late-stage deuteration of biorelevant compounds.

Electroreductive Cross-Electrophile Coupling (eXEC) Reactions.

Electrochemistry utilizes electrons as a potent, controllable, and traceless alternative to chemical oxidants or reductants, and typically offers a more sustainable option for achieving selective organic synthesis. Recently, the merger of electrochemistry with readily available electrophiles has been recognized as a viable and increasingly popular methodology for efficiently constructing challenging C-C and C-heteroatom bonds in a sustainable manner for complex organic molecules. In this mini-review, we have systematically summarized the most recent advances in electroreductive cross-electrophile coupling (eXEC) reactions during the last decade. Our focus has been on readily available electrophiles, including aryl and alkyl organic (pseudo)halides, as well as small molecules such as CO2 , SO2 , and D2 O.

Electrochemical NiH-Catalyzed C(sp3 )-C(sp3 ) Coupling of Alkyl Halides and Alkyl Alkenes.

Herein, an electrochemically driven NiH-catalyzed reductive coupling of alkyl halides and alkyl alkenes for the construction of Csp3 -Csp3 bonds is firstly reported. Notably, alkyl halides serve dual function as coupling substrates and as hydrogen sources to generate NiH species under electrochemical conditions. The tunable nature of this reaction is realized by introducing an intramolecular coordinating group to the substrate, where the product can be easily adjusted to give the desired branched products. The method proceeds under mild conditions, exhibits a broad substrate scope, and affords moderate to excellent yields with over 70 examples, including late-stage modification of natural products and drug derivatives. Mechanistic insights offer evidence for an electrochemically driven coupling process. The sp3 -carbon-halogen bonds can be activated through single electron transfer (SET) by the nickel catalyst in its low valence state, generated by cathodic reduction, and the generation of NiH species from alkyl halides is pivotal to this transformation.

Site-Selective Electrochemical C-H Carboxylation of Arenes with CO2.

Herein, a direct, metal-free, and site-selective electrochemical C-H carboxylation of arenes by reductive activation using CO2 as the economic and abundant carboxylic source was reported. The electrocarboxylation was carried out in an operationally simple manner with high chemo- and regioselectivity, setting the stage for the challenging site-selective C-H carboxylation of unactivated (hetero)arenes. The robust nature of the electrochemical strategy was reflected by a broad scope of substrates with excellent atom economy and unique selectivity. Notably, the direct and selective C-H carboxylation of various challenging arenes worked well in this approach, including electron-deficient naphthalenes, pyridines, simple phenyl derivatives, and substituted quinolines. The method benefits from being externally catalyst-free, metal-free and base-free, which makes it extremely attractive for potential applications.

Electrochemical Desaturative ß-Acylation of Cyclic N-Aryl Amines.

Herein, we disclose a straightforward, robust, and simple route to access ß-substituted desaturated cyclic amines via an electrochemically driven desaturative ß-functionalization of cyclic amines. This transformation is based on multiple single-electron oxidation processes using catalytic amounts of ferrocene. The reaction proceeds in the absence of stoichiometric amounts of electrolyte under mild conditions, affording the desired products with high chemo- and regioselectivity. The reaction was tolerant of a broad range of substrates and also enables late-stage ß-C(sp3 )-H acylation of potentially valuable products. Preliminary mechanistic studies using cyclic voltammetry reveal the key role of ferrocene as a redox mediator in the reaction.

Electrocarboxylation of Aryl Epoxides with CO2 for the Facile and Selective Synthesis of ß-Hydroxy Acids.

Herein, an efficient and facile approach to valuable ß-hydroxy acid derivatives from readily available aryl epoxides and CO2 with high chemo- and regioselectivity under mild and sustainable electrochemical conditions is described. This approach showed broad substrate scope and good functional-group compatibility. In addition to aryl epoxides, four- to six-membered aryl cyclic ethers could all be tolerated in the reaction to provide synthetically useful hydroxy acids with high efficiency. Further late-stage carboxylation of complex molecules and drug derivatives demonstrated its potential application in the pharmaceutical industry. Mechanistic studies disclosed possible reaction pathways.

Metal-Free Electrochemical Carboxylation of Organic Halides in the Presence of Catalytic Amounts of an Organomediator.

Herein, an electroreductive carboxylation of organic carbon-halogen bonds (X=Br and Cl) promoted by catalytic amounts of naphthalene as an organic mediator is reported. This transformation proceeds smoothly under mild conditions with a broad substrate scope of 59 examples, affording the valuable and versatile carboxylic acids in moderate to excellent yields without the need of costly transition metal, wasted stoichiometric metal reductants, or sacrificial anodes. Further late-stage carboxylations of natural product and drug derivatives demonstrate its synthetic utility. Mechanistic studies confirmed the activation of carbon-halogen bonds via single-electron transfer and the key role of naphthalene in this reaction.

Electrophotocatalytic Undirected C-H Trifluoromethylations of (Het)Arenes.

Electrophotochemistry has enabled arene C-H trifluoromethylation with the Langlois reagent CF3 SO2 Na under mild reaction conditions. The merger of electrosynthesis and photoredox catalysis provided a chemical oxidant-free approach for the generation of the CF3 radical. The electrophotochemistry was carried out in an operationally simple manner, setting the stage for challenging C-H trifluoromethylations of unactivated arenes and heteroarenes. The robust nature of the electrophotochemical manifold was reflected by a wide scope, including electron-rich and electron-deficient benzenes, as well as naturally occurring heteroarenes. Electrophotochemical C-H trifluoromethylation was further achieved in flow with a modular electro-flow-cell equipped with an in-operando monitoring unit for on-line flow-NMR spectroscopy, providing support for the single electron transfer processes.

Electro-Oxidative C-C Alkenylation by Rhodium(III) Catalysis.

Electrochemical C-C activations were accomplished by expedient oxidative rhodium(III) catalysis. Thus, oxidative C-C alkenylations proved viable with the aid of electricity, avoiding the use of toxic and/or expensive transition-metal oxidants. The chelation-assisted C-C functionalizations proceeded with ample scope and excellent levels of chemo- and position selectivities within an organometallic C-C activation manifold. Detailed mechanistic studies provided support for a kinetically relevant C-C scission, and a well-defined organometallic rhodium(III) complex was identified as a catalytically competent intermediate. The electrochemical C-C functionalization was devoid of additional electrolytes, could be conducted on a gram scale, and provided position-selective access to densely 1,2,3-substituted arenes, which are not viable by C-H activation.

Control of Selectivity in Palladium(II)-Catalyzed Oxidative Transformations of Allenes.

Oxidation reactions play a central role in organic synthesis, and it is highly desirable that these reactions are mild and occur under catalytic conditions. In Nature, oxidation reactions occur under mild conditions via cascade processes, and furthermore, they often occur in an enantioselective manner with many of them involving molecular oxygen or hydrogen peroxide as the terminal oxidant. Inspired by the reactions in Nature, we have developed a number of Pd(II)-catalyzed cascade reactions under mild oxidative conditions. These reactions have an intrinsic advantage of step economy and rely on selectivity control in each step. In this Account, we will discuss the control of chemo-, regio-, and diastereoselectivity in Pd(II)-catalyzed dehydrogenative cascade coupling reactions. The enantioselective version of this methodology has also been addressed, and new chiral centers have been introduced using a catalytic amount of a chiral phosphoric acid (CPA). Research on this topic has provided access to important compounds attractive for synthetic and pharmaceutical chemists. These compounds include carbocyclic, heterocyclic, and polycyclic systems, as well as polyunsaturated open-chain structures. Reactions leading to these compounds are initiated by coordination of an allene and an unsaturated π-bond moiety, such as olefin, alkyne, or another allene, to the Pd(II) center, followed by allene attack involving a C(sp3)-H cleavage under mild reaction conditions. Recent progress within our research group has shown that weakly coordinating groups (e.g., hydroxyl, alkoxide, or ketone) could also initiate the allene attack on Pd(II), which is essential for the oxidative carbocyclization. Furthermore, a highly selective palladium-catalyzed allenic C(sp3)-H bond oxidation of allenes in the absence of an assisting group was developed, which provides a novel and straightforward synthesis of [3]dendralene derivatives. For the oxidative systems, benzoquinone (BQ) and its derivatives are commonly used as oxidants or catalytic co-oxidants (electron transfer mediators, ETMs) together with molecular oxygen. A variety of transformations including carbocyclization, acetoxylation, arylation, carbonylation, borylation, ß-hydride elimination, alkynylation, alkoxylation, and olefination have been demonstrated to be compatible with this Pd(II)-based catalytic oxidative system. Recently, several challenging synthetic targets, such as cyclobutenes, seven-membered ring carbocycles, spirocyclic derivatives, functional cyclohexenes, and chiral cyclopentenone derivatives were obtained with high selectivity using these methods. The mechanisms of the reactions were mainly studied by kinetic isotope effects (KIEs) or DFT computations, which showed that in most cases the C(sp3)-H cleavage is the rate-determining step (RDS) or partially RDS. This Account will describe our efforts toward the development of highly selective and atom-economic palladium(II)-catalyzed oxidative transformation of allenes (including enallenes, dienallenes, bisallenes, allenynes, simple allenes, and allenols) with a focus on overcoming the selectivity problem during the reactions.

Diastereoselective Cyclobutenol Synthesis: A Heterogeneous Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenols.

A highly selective and efficient oxidative carbocyclization/borylation of enallenols catalyzed by palladium immobilized on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was developed for diastereoselective cyclobutenol synthesis. The heterogeneous palladium catalyst can be recovered and recycled without any observed loss of activity or selectivity. The high diastereoselectivity of the reaction is proposed to originate from a directing effect of the enallenol hydroxyl group. Optically pure cyclobutenol synthesis was achieved by the heterogeneous strategy by using chiral enallenol obtained from kinetic resolution.

Highly Diastereoselective Palladium-Catalyzed Oxidative Carbocyclization of Enallenes Assisted by a Weakly Coordinating Hydroxyl Group.

A highly diastereoselective palladium-catalyzed oxidative carbocyclization-borylation of enallenes assisted by a weakly coordinating hydroxyl group was developed. The reaction afforded functionalized cyclohexenol derivatives, in which the 1,3-relative stereochemistry is controlled (d.r. > 50:1). Other weakly coordinating oxygen-containing groups (ketone, alkoxide, acetate) also assisted the carbocyclization toward cyclohexenes. The reaction proceeds via a ligand exchange on Pd of the weakly coordinating group with a distant olefin group. The high diastereoselectivity of the hydroxyl-directed reaction could be rationalized by a face-selective coordination of the distant olefin. It was demonstrated that the primary coordination of the close-by oxygen-containing functionality was necessary for the reaction to occur and removal of this functionality shut down the reaction.

Highly Selective Palladium-Catalyzed Hydroborylative Carbocyclization of Bisallenes to Seven-Membered Rings.

A highly selective palladium-catalyzed hydroborylative carbocyclization of bisallenes to afford seven-membered rings has been established. This ring-closing coupling reaction showed good functional group compatibility with high chemo- and regioselectivity, as seven-membered ring 3 was the only product obtained. The extensive use of different linkers, including nitrogen, oxygen, malononitrile, and malonate, showed a broad substrate scope for this approach. A one-pot cascade reaction was realized by trapping the primary allylboron compound with an aldehyde, affording a diastereomerically pure alcohol and a quaternary carbon center by formation of a new C-C bond. A comprehensive mechanistic DFT investigation is also presented. The calculations suggest that the reaction proceeds via a concerted hydropalladation pathway from a Pd(0)-olefin complex rather than via a pathway involving a defined palladium hydride species. The reaction was significantly accelerated by the coordination of the pendant olefin, as well as the introduction of suitable substituents in the bridge, due to the Thorpe-Ingold effect.

Chemodivergent and Diastereoselective Synthesis of γ-Lactones and γ-Lactams: A Heterogeneous Palladium-Catalyzed Oxidative Tandem Process.

A palladium-catalyzed oxidative tandem process of enallenols was accomplished within a homogeneous/heterogeneous catalysis manifold, setting the stage for the highly chemodivergent and diastereoselective synthesis of γ-lactones and γ-lactams under mild conditions.

Mechanistic Insight into Enantioselective Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenes.

The asymmetric palladium-catalyzed oxidative carbocyclization-borylation of enallenes, employing a chiral phosphoric acid as co-catalyst, constitutes an efficient and convenient entry into functionalized building blocks with cyclopentene scaffolds in high enantiopurity. Up till now there has been a lack of knowledge concerning the origin of enantioselectivity of this reaction as well as the absolute configuration of the product. Herein, we report the crystal structure of one of the compounds generated via this carbocyclization, providing the link between the configuration of the products and the configuration of the chiral phosphoric acid used in the reaction. Furthermore, the origin of the enantioselectivity is thoroughly investigated with density functional theory (DFT) calculations. By careful examination of different possible coordination modes, it is shown that the chiral phosphoric acid and the corresponding phosphate anion serve as ligands for palladium during the key stereoselectivity-determining cyclization step. In addition, we examine reactions wherein an extra chiral reagent, a p-benzoquinone containing a chiral sulfoxide, is used. The combined experimental and theoretical studies provide insight into the details of complexation of palladium with various species present in the reaction mixture, furnishing a general understanding of the factors governing the stereoselectivity of this and related catalytic reactions.

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 Ruthenium-Catalyzed C-H/O-H Annulation by Weak O-Coordination.

Electrocatalysis has been identified as a powerful strategy for organometallic catalysis, and yet electrocatalytic C-H activation is restricted to strongly N-coordinating directing groups. The first example of electrocatalytic C-H activation by weak O-coordination is presented, in which a versatile ruthenium(II) carboxylate catalyst enables electrooxidative C-H/O-H functionalization for alkyne annulations in the absence of metal oxidants; thereby exploiting sustainable electricity as the sole oxidant. Mechanistic insights provide strong support for a facile organometallic C-H ruthenation and an effective electrochemical reoxidation of the key ruthenium(0) intermediate.

Iridium-Catalyzed Electrooxidative C-H Activation by Chemoselective Redox-Catalyst Cooperation.

Iridium-catalyzed electrochemical C-H activation was accomplished within a cooperative catalysis manifold, setting the stage for electrooxidative C-H alkenylations through weak O-coordination. The iridium-electrocatalyzed C-H activation featured high functional-group tolerance through assistance of a metal-free redox mediator through indirect electrolysis. Detailed mechanistic insights provided strong support for an organometallic C-H cleavage and a synergistic iridium(III/I)/redox catalyst regime, enabling the use of sustainable electricity as the terminal oxidant with improved selectivity features.