Electrogenerated Cationic Reactive Intermediates: The Pool Method

Review pubs.acs.org/CR

Electrogenerated Cationic Reactive Intermediates: The Pool Method and Further Advances Jun-ichi Yoshida,* Akihiro Shimizu, and Ryutaro Hayashi Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan ABSTRACT: Electrochemistry serves as a powerful method for generating reactive intermediates, such as organic cations. In general, there are two ways to use reactive intermediates for chemical reactions: (1) generation in the presence of a reaction partner and (2) generation in the absence of a reaction partner with accumulation in solution as a “pool” followed by reaction with a subsequently added reaction partner. The former approach is more popular because reactive intermediates are usually short-lived transient species, but the latter method is more flexible and versatile. This review focuses on the latter approach and provides a concise overview of the current methods for the generation and accumulation of cationic reactive intermediates as a pool using modern techniques of electrochemistry and their reactions with subsequently added nucleophilic reaction partners.

CONTENTS 1. Introduction 2. Background 3. Carbocations 3.1. R2(R′2N)C+ Ions 3.1.1. Cation Pool Method 3.1.2. Cation Flow Method 3.1.3. Use of Auxiliaries 3.1.4. Reactions with Carbon Nucleophiles 3.1.5. Reactions with Aromatic and Olefinic Compounds 3.1.6. Redox-Mediated Reactions 3.2. R2(R′O)C+ Ions 3.2.1. Cation Pool Method 3.2.2. Indirect Cation Pool Method 3.2.3. Indirect Cation Flow Method 3.3. Stabilized Glycosyl Cations 3.4. Aryl-Substituted Carbenium Ions 3.4.1. Ar2CH+ Ions 3.4.2. Dendritic Ar2CH+ Ions 3.4.3. Stabilized ArCH2+ Ions 4. Stabilized Silyl Cations 5. Nitrogen Cations 6. Phosphorus Cations 7. Sulfur Cations 7.1. R3S+ Ions 7.2. R2(R′O)S+ Ions 7.3. R2(R′2N)S+ Ions 7.4. R2CS+R′ Ions 7.5. Stabilized RS+ Ions 8. Halogen Cations 8.1. R2X+ Ions 8.2. Stabilized X+ Ions 9. Cationic Transition-Metal Complexes 10. Radical Cations 10.1. Radical Cations of Aromatic Hydrocarbons © 2017 American Chemical Society

11. Outlook Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

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1. INTRODUCTION The concept of reactive intermediates1,2 plays a major role in understanding and designing organic reactions because it was accepted by synthetic organic chemists in the middle of the last century.3 For example, SN1 reactions proceed through the intermediacy of unstable short-lived carbocationic intermediates, the existence of which was confirmed by Olah’s extensive work using super acids.4,5 Glycosylation reactions, which are widely used for making polysaccharides, are believed to proceed through glycosyl cations, although the existence of such species has not yet been confirmed experimentally.6−8 Although various methods have been used for the generation of such reactive intermediates, organic redox chemistry9 serves as a powerful and straightforward method. One-electron oxidation of neutral organic molecules generates radical cations that are converted to either radicals or cations in the subsequent reactions. The short-lived reactive intermediates generated by these processes can be used for further transformations to give desired molecules. Therefore, redox Special Issue: Electrochemistry: Technology, Synthesis, Energy, and Materials Received: August 5, 2017 Published: October 27, 2017 4702

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far, here, we briefly touch on some modern strategies for controlling electrochemical redox reactions.15 (1) New reaction media: It is well-known that reaction media such as solvents and supporting electrolytes play important roles in organic electrochemistry, because solvation and the behavior of ions often play major roles in electron-transfer processes in solution. Recently, ionic liquids16,17 and supercritical fluids18−22 have been used as new reaction media, and they can be employed as solvents for electrolysis as well. Solidsupported electrolytes23−25 and mediators26,27 have also been developed. (2) Low-temperature electrolysis:28 Conventionally, electrochemical reactions for organic synthesis have been carried out at room temperature or higher temperatures. However, recent developments have enabled electrolysis to be performed at very low temperatures, such as −78 °C. Low-temperature electrolysis is beneficial from the viewpoint of generating and accumulating unstable reactive intermediates.29 Scheme 2 shows a typical undivided cell that enables electrolysis at low temperatures under an inert atmosphere.

chemistry has been widely used for the performance of chemical transformations involving reactive intermediates. The methods for performing redox chemistry can be categorized as chemical, photochemical, and electrochemical methods. In chemical methods, chemical oxidizing agents are used for oxidation, and chemical reducing agents are used for reduction. In photochemical methods, photoexcitation initiates the subsequent redox processes. In electrochemical methods, the oxidation process occurs on the surface of the anode, and the reduction process occurs on the surface of the cathode, and notably, these two processes should occur simultaneously in the same reaction system. Photochemical and electrochemical methods enable redox reactions under mild conditions without the use of hazardous chemical reagents, providing benign ways of performing transformations involving reactive intermediates. In particular, electrochemical oxidation serves as an effective method of generating cationic reactive intermediates. In this review article, we discuss the principles and applications of electrochemical methods for generating cationic reactive intermediates. There are two ways to generate reactive intermediates (see Scheme 1): (1) generation in the presence of a reaction

Scheme 2. Typical Undivided Cell for Low-Temperature Electrolysis

Scheme 1. In Situ Method and Pool Method for the Electrochemical Generation of Reactive Intermediates

(3) Electroauxiliaries:30 Attachment of suitable functional groups to control the reactivity of substrate molecules and reaction pathways has often been used in organic synthesis. Such an approach based on intramolecular control includes use of directing groups, protecting groups, and chiral auxiliaries. A similar method has also been developed in organic electrochemistry: A functional group that promotes electron transfer and controls the reaction pathway is introduced prior to the electrochemical transformation. Such a functional group is called an electroauxiliary. Electroauxiliaries enable highly selective electrochemical transformations that are difficult to achieve or even impossible by conventional approaches. In other words, an electroauxiliary promotes electron-transferdriven reactions in a more selective and predictable manner. For example, the introduction of a silyl group on the carbon adjacent to a heteroatom or a π-electron system decreases the oxidation potential by virtue of orbital interactions between the CSi σ orbital and the unshared p orbital, making the oxidation easier.31,32 Also, the CSi bond in the resulting radical cation is selectively cleaved without affecting the CH bonds, making the transformation highly selective. The example shown in Scheme 3 demonstrates the power of a silyl group as an electroauxiliary in the anodic oxidation of carbamates.33 Arylthio groups can also serve as electroauxiliaries for the

partner, called the in situ method, and (2) generation in the absence of a reaction partner, called the pool method. The former approach is more popular because reactive intermediates are usually short-lived transient species, and therefore, in situ trapping is more effective. This review article, however, focuses on the latter approach because it is more flexible and versatile. The reactive intermediates can be reacted with subsequently added reaction partners that cannot be survive under electrolytic conditions. This leads to the easy integration of reactions using electrogenerated reactive intermediates.10

2. BACKGROUND Electrochemical reactions11 of organic compounds have a long history, and various applications of electrochemistry to organic synthesis12,13 have been developed in both academia and industry,14 because electrochemical methods serve as powerful, straightforward, and tunable methods for oxidizing and reducing organic compounds to generate a wide variety of reactive species that are difficult to generate by other methods. Factors governing the processes that occur on and near the surface of electrodes have been extensively studied to provide useful information for designing and developing electrochemical redox reactions. Although various methods for controlling electrochemical processes have been developed so 4703

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are widely utilized for carbon−carbon bond formation in organic synthesis. Carbenium and onium ions are usually generated in the presence of nucleophiles, although carbanions are generated and accumulated in solution in the absence of electrophiles and an electrophile is added after the generation process is complete. Carbanions are usually generated as organometallic species such as organolithiums and -magnesiums, and the interaction with such metals stabilizes the carbanions. In contrast, carbenium and onium ions should be trapped in situ by nucleophiles immediately after their generation because of their transient nature in conventional reaction media (Scheme 5). This limitation on the chemistry of carbenium and onium

Scheme 3. Trimethylsilyl Group as an Electroauxiliary for the Anodic Oxidation of Carbamates

oxidation of heteroatom compounds, although the principle is different.34 (4) Flow microreactors: There are still some problems inherent in conducting organic electrochemical reactions on a preparative scale. Such problems can be solved by the use of flow microreactors,35−37 which emerged very recently as a promising science and technology (Scheme 4a). For example,

Scheme 5. Comparison of Carbanions and Carbenium Ions

Scheme 4. Combination of Electrochemistry and Flow Microreactors

ions is an obstacle to their use in organic synthesis. For example, nucleophiles that do not survive under the generation conditions cannot be used as reaction partners. The “cation pool” method using low-temperature electrochemical oxidation provides a solution to this problem (section 3.1.1). In the conventional chemical method, carbenium and onium ions are generated by acid-promoted cleavage of a carbon−heteroatom bond. This process is usually reversible, and the equilibrium usually favors the starting material. Therefore, it is very difficult to accumulate carbenium and onium ions in solution. However, electrooxidative generation serves as an irreversible method (Scheme 6). A neutral starting

the high surface-to-volume ratios of microscale chambers are advantageous for increasing the efficiency of reactions on the surface of the electrodes, and the short distances between the electrodes in microreactors can solve the problem of low conductivity encountered with many organic solvents. Also, flow microreactors are quite effective for controlling extremely fast reactions of highly reactive species generated by batch electrolysis (Scheme 4b). In the following sections, we discuss the electrooxidative generation, accumulation, and reactions of cationic reactive intermediates including carbon, nitrogen, phosphorus, sulfur, halogen, and some other cationic species that play important roles in organic synthesis. Although electrogenerated acids can be categorized as pools of electrogenerated cationic species, we do not consider them in this article, because they have not yet been fully characterized and the mechanism of their generation is not clear at present.38,39

Scheme 6. Electrooxidative Generation of Carbenium Ions

3. CARBOCATIONS Carbenium and onium ions are important reactive species in organic chemistry and are widely used as intermediates in organic synthesis.40 For example, nitrogen-substituted carbenium ions [R2(R′2N)C+ ions], which have a hybrid nature involving iminium/carbenium ion resonance, react with various nucleophiles at carbon, serving as a useful means of making nitrogen-containing compounds. Oxygen-substituted carbenium ions [R2(R′O)C+ ions] also have a hybrid nature, in this case involving oxonium/carbenium ion resonance, and react with nucleophiles at carbon. These cationic intermediates

material is oxidized to generate the radical cation species, and subsequent bond cleavage such as cleavage of a CH bond (Y = H in Scheme 6) gives a carbon radical, although there is another possibility for the fate of the radical cation.41,42 The resulting carbon radical species is often further oxidized under the reaction conditions to give the corresponding cations. These steps are essentially irreversible, and therefore, carbenium ions and onium ions can be accumulated in solution. Of course, the feasibility of the cation pool method depends on the stability of the cations, the natures of the counterions and solvent, and the reaction temperature. Usually, 4704

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electrolysis is carried out at low temperatures such as −78 °C, which is the lowest temperature in practical laboratory synthesis. In the next step, a nucleophile is added to obtain the final product. Therefore, nucleophiles that have oxidation potentials lower than those of the precursors of the cations can be used as reaction partners. We begin our discussion of the cation pool method with its use for the generation and accumulation of nitrogen-substituted carbenium ions [R2(R′2N)C+ ions], which are among the most widely used carbenium ions or onium ions in organic synthesis.

generation and accumulation of N-acyliminium ions in the absence of nucleophiles by using low-temperature electrolysis.50 For example, the electrochemical oxidation of N(methoxycarbonyl)pyrrolidine in Bu4NClO4/CH2Cl2 in a divided cell at −72 °C gives a solution of the corresponding N-acyliminium ion as a single species that can be characterized by NMR and IR spectroscopies at low temperatures (Scheme 8). The NMR chemical shifts indicate a strong positive charge Scheme 8. Cation Pool Method Using Bu4NBF4/CH2Cl2

3.1. R2(R′2N)C+ Ions

In nitrogen-substituted carbenium ions, the vacant p orbital of the carbenium ion interacts with the nonbonding p orbital of the neighboring nitrogen atom, and this interaction greatly stabilizes the cation. This interaction gives the CN bond significant double-bond character. Therefore, the structural formula is usually drawn having a CN double bond with a positive charge on the nitrogen atom such as R2CN+R′2, and such species are called iminium ions (Scheme 7). If the

at the carbon next to nitrogen, which is consistent with the generation and accumulation of the N-acyliminium ion as an ionic species. In the next step, allyltrimethylsilane, which has an oxidation potential lower than that of pyrrolidine carbamate, is added to the solution to obtain the corresponding allylated product in a high yield. Chiba and co-workers generated and accumulated Nacyliminium ions by electrolysis using the LiClO4/CH3NO2 and LiClO4/C2H5NO2 systems in an undivided cell at higher temperatures such as 0 °C (Scheme 9).51 Presumably, these

Scheme 7. Resonance Structures of Iminium Ions and NAcyliminium Ions

Scheme 9. Cation Pool Method Using LiClO4/Nitroalkane substituents on the nitrogen atom are alkyl groups or hydrogen, iminium ions are generally stable and easy to manipulate by conventional methods. However, if an electron-withdrawing group is attached to the nitrogen atom, the cation is highly unstable and is difficult to accumulate in solution. Thus, we focus on the latter type of iminium ions, in particular, Nacyliminium ions that have a carbonyl group on the nitrogen atom. N-Acyliminium ions generally react with nucleophiles at the carbon atom, and the use of carbon nucleophiles leads to effective carbon−carbon bond formation next to the nitrogen atom. In this context, N-acyliminium ions serve as useful reactive intermediates for the construction of nitrogencontaining organic compounds that often exhibit important biological activities. In fact, α-functionalization or CC bond formation at the α-carbon of amine derivatives serves as one of the key methods for constructing nitrogen-containing compounds.43 Carbamates are often used for this purpose. The oxidation of carbamates and their derivatives leads to the formation of N-acyliminium ions44,45 through the dissociation of the CH bond α to nitrogen. The electrochemical,46,47 metal-catalyzed,48 and chemical49 oxidation methods are all effective for this transformation. However, N-acyliminium ions should usually be generated in the presence of nucleophiles with high oxidation potentials such as methanol and cyanide ion. Compounds with oxidation potentials lower than those of carbamates cannot be used as nucleophiles because they are preferentially oxidized. 3.1.1. Cation Pool Method. Yoshida and co-workers developed the cation pool method, which enables the

special supporting electrolyte/solvent pairs are responsible for the higher stability of the resulting N-acyliminium ions. This method has been successfully applied to the synthesis of azanucloeoside derivatives.52,53 Lessard, Li, and co-workers reported the controlled-potential electrolysis of N-phenylamines in the ionic liquid 1-butyl-3methylimidazolium tetrafluoroborate ([BMIm][BF4]) (Scheme 10).54 The resulting N-phenyliminium ions can be reacted with subsequently added nucleophiles such as nitromethane and diethylphosphite with the aid of triethylamine. 3.1.2. Cation Flow Method. Flow microelectrochemical systems are also effective for generating unstable cationic intermediates that are subsequently reacted with nucleophiles in the flow system (Scheme 4a). This method is called the “cation flow” method.55,56 In principle, the method enables the manipulation of highly reactive cationic intermediates. An outstanding feature of the cation flow method is its ability to 4705

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cation pool method and a chiral auxiliary (Scheme 12).60 The use of β-cyclodextrin as a host/guest supramolecular cocatalyst

Scheme 10. Cation Pool Method Using Ionic Liquid

Scheme 12. Cation Pool Method Using Chiral Auxiliary

allow continuous sequential combinatorial synthesis by simple flow switching. Atobe and co-workers developed a different and effective protocol for the cation flow method based on the laminar flow regime in flow systems.57 Because of the laminar flow, the solution of the nucleophile in such a system is not exposed to the anode, and therefore, undesired oxidation of the nucleophile is prevented. The use of ionic liquids as electrolyte/solvent systems dramatically improves the selectivity of such systems. 3.1.3. Use of Auxiliaries. The use of a silyl group as an electroauxiliary is effective for the cation pool method. For example, preintroduction of a silyl group onto a carbon α to nitrogen gives rise to the selective introduction of a nucleophile onto the carbon to which the silyl auxiliary has been attached. The introduction of a silyl group decreases the oxidation potentials of carbamates, making them more easily oxidized. The silyl group also controls the position at which a cationic carbon is generated. This is also advantageous when unsymmetrical carbamates are used. The example shown in Scheme 11, in which two silyl groups are used for the control of the

improved the selectivity. The use of methanol instead of dichloromethane (CH2Cl2) for the electrolysis gave better enantioselectivity (91% ee), but in this case, the covalent methoxylated compound should be the intermediate. 3.1.4. Reactions with Carbon Nucleophiles. In addition to cyanide ion, allylsilanes, silyl enol ethers, ketene silyl acetals, Grignard reagents, and organozinc compounds are effective as carbon nucleophiles toward N-acyliminium ion pools.61 1,3Dicarbonyl compounds can be used as nucleophiles as well. A wide range of nucleophiles enables parallel combinatorial synthesis using N-acyliminium ion pools (Scheme 13). Scheme 13. Parallel Combinatorial Synthesis Based on the Cation Pool Method

Scheme 11. Cation Pool Method Using an Electroauxiliary

According to this approach, a solution of a cation pool generated by low-temperature electrolysis is divided into several portions. To the various portions are added different nucleophiles to obtain products of different coupling combinations. This protocol can be performed using automated synthesizers. 3.1.5. Reactions with Aromatic and Olefinic Compounds. N-Acyliminium ion pools also react with aromatic compounds to give Friedel−Craft-type alkylation products. However, reactions with electron-rich aromatic compounds, such as 1,3,5-trimethoxybenzene, suffer from the problem of dialkylation (Scheme 14). The use of flow microreactor systems equipped with micromixers solves this problem. Micromixing of a cation pool and a solution of aromatic compounds leads to the selective formation of monoalkylation products.62,63 Extremely fast micromixing is responsible for solving the problem of “disguised chemical selectivity”64,65 and achieving high selectivity close to that based on the kinetics.

regiochemistry, demonstrates the power of the combination of electroauxiliaries and the cation pool method.58,59 The anodic oxidation of pyrrolidine carbamate having two silyl groups on the same carbon gives rise to the cleavage of one CSi bond to generate the N-acyliminium ion regioselectively. A Grignard reagent then attacks the carbon to which the silyl group has been attached selectively. The second oxidation leads to the cleavage of the second CSi bond and the introduction of the second organic group on the same carbon. If the two organic groups are olefinic, ring-closing metathesis gives a spirocyclic structure. Shankaraiah et al. reported the enantioselective synthesis of biologically active compounds based on a combination of the 4706

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Scheme 14. Friedel−Crafts-Type Reactions of NAcyliminium Ions

Scheme 17. [4 + 2] Cycloaddition of N-Acyliminium Ions with Alkenes

N-Acyliminium ion pools can be reacted with the carbon− carbon double bonds of alkenes as well. The example shown in Scheme 15 demonstrates the diastereoselective carbohydroxylation of vinyltrimethylsilane to give an enantiomerically pure α-silyl-γ-amino alcohol.66

place. However, the formation of such polymeric byproducts can be suppressed by extremely fast mixing of the two reaction components using a micromixer in a flow microreactor system. N-Acyliminium ion pools are also effective as initiators of cationic polymerizations of vinyl ethers (Scheme 18).74 In

Scheme 15. Carbohydroxylation of Alkenes with NAcyliminium Ions

Scheme 18. Carbocationic Polymerization Using an NAcyliminium Ion as an Initiator in a Flow Microreactor

Sequential one-pot multicomponent coupling reactions of Nacyliminium ion pools serve as a powerful method for constructing nitrogen-containing compounds (Scheme 16).67 Scheme 16. Three-Component Coupling Based on the Cation Pool Method conjunction with a flow microreactor system, this method effects living cationic polymerization without the use of capping agents. Usually, the use of capping agents inherently decelerates propagation because of the dynamic equilibrium between active and dormant species, which is essential for conventional living cationic polymerization.75 Extremely fast micromixing that enables fast initiation, precise residence time control (0.5 s), and rapid trapping of the growth polymer end is responsible for a high level of control over both the molecular weight and the molecular weight distribution (Mw/Mn = 1.14 at −78 °C). The molecular weight was found to increase linearly with an increase in the amount of the monomer, indicating that transfer reactions did not play a significant role. NMR analysis indicated that the growth polymer end was really living. 3.1.6. Redox-Mediated Reactions. Another intriguing aspect of the cation pool method is the generation of freeradical species by the reduction of cation pools. For example, the electrochemical reduction of the N-acyliminium ion pool generated by the low-temperature electrolysis of N(methoxycarbonyl)pyrrolidine gave the corresponding homocoupling product as a mixture of two diastereomers and a small amount of simply reduced product (Scheme 19).76,77 Presumably, radical coupling is the major pathway in the electrochemical reduction, although the simply reduced product is likely produced by two-electron reduction to the carbanion followed by trapping with a proton.

The reaction of an N-acyliminium ion pool with an electronrich carbon−carbon double bond generates a new cation pool, which is then allowed to react with a carbon nucleophile. The approach to three-component coupling based on the cation pool method is the umpolung of anionic three-component coupling, which consists of the addition of a carbon nucleophile to an electron-deficient carbon−carbon double bond followed by trapping with a carbon electrophile.68 In some cases, the second cation pool decomposes very quickly because of its instability, but the use of a flow microreactor solves the problem by virtue of a short residence time. N-Acyliminium ions generated by the cation pool method undergo [4 + 2] cycloaddition reactions69−71 to give the corresponding cycloadduct (Scheme 17).72,73 However, the reactions with styrene derivatives suffer from the formation of significant amounts of byproducts. Presumably, cationic polymerization initiated by the N-acyliminium ions takes 4707

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Scheme 19. Reduction of N-Acyliminium Ions

hexabutyldistannane to give the final product. The resulting radical cation of hexabutyldistannane collapses to regenerate the tin radical. Single-electron transfer also plays a key role in the reactions of the N-acyliminium ion pool with benzylsilanes (Scheme 22).

The electrochemical reduction of the N-acyliminium ion pool in the presence of methyl acrylate leads to the addition of the radical intermediate to the carbon−carbon double bond (Scheme 20), indicating that cation pools can be used as precursors of free-radical species. This approach opens a new aspect of free-radical chemistry.

Scheme 22. Chain Mechanism Proposed for the Reactions of N-Acyliminium Ions with Benzylsilanes

Scheme 20. Radical Addition Using N-Acyliminium Ions

N-Acyliminium ions react with carbon free radicals. For example, heptyl iodide reacted with an N-acyliminium ion pool in the presence of hexabutyldistannane (slow addition) to give the corresponding coupling product.78,79 The following mechanism is proposed (see Scheme 21): In the first step, the heptyl radical is generated by abstraction of an iodine atom from heptyl iodide by the tin radical. In the next step, the heptyl radical adds to the N-acyliminium ion to generate the radical cation, which undergoes an electron-transfer reaction with

Although benzylsilanes of higher oxidation potentials do not react with N-acyliminium ions, benzylsilanes of lower oxidation potentials react with N-acyliminium ions to give the corresponding coupling products.80 The initial single-electron transfer from a benzylsilane to an N-acyliminium ion gives the radical cation of the benzylsilane and the radical of the carbamate. Although this process is energetically unfavorable, it seems to be promoted by the subsequent exoergonic reaction: collapse of the radical cation to benzyl radical and a formal silyl cation that reacts with BF4− to give the fluorosilane. The benzyl radical thus generated adds to the N-acyliminium ion to give the radical cation, which undergoes a single electron-transfer reaction with benzylsilane to give the coupling product and the radical cation of benzylsilane. Notably, the use of a catalytic amount of benzylstannane, which is more easily oxidized than benzylsilane, as an initiator leads to an effective chain reaction of benzylsilanes of high oxidation potentials. Arylthiomethylsilanes and aryloxymethylsilanes also react with N-acyliminium ion pools similarly.81

Scheme 21. Mechanism for Free-Radical Addition to NAcyliminium Ions

3.2. R2(R′O)C+ Ions

In this section, we discuss oxygen-substituted carbenium ions [R2(R′O)C+ ions], which are often used as intermediates in organic synthesis. The vacant p orbital of the carbenium ion interacts with the nonbonding p orbital of the neighboring 4708

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oxygen atom, and this interaction greatly stabilizes the cation. This interaction is represented by the resonance form having a carbon−oxygen double bond with a positive charge on the oxygen atom (R2CO+R′ ions) (Scheme 23).

Scheme 25. Generation and Accumulation of Carboxonium Ions as a Cation Pool

Scheme 23. Oxygen-Substituted Carbenium Ion and Its Resonance Form Carboxonium Ion

The terminology of this species is rather confusing. The most commonly used name is “oxocarbenium ion”. According to the IUPAC Gold Book, oxo indicates the presence of an oxo substituent, which is a double-bonded oxygen. However, in the present case, if one draws a carbon−oxygen double bond, the positive charge should be located on the oxygen atom, in which case the species is no longer a carbenium ion. The term “carboxonium ion” has also been used. Although this terminology is wider, it is consistent with the most commonly used structural formulas having a double bond between the carbon and the positively charged oxygen. We have used the term “alkoxycarbenium ion”, but this terminology indicates that R″ is limited to an alkyl group. Therefore, in this review article, we use the term carboxonium ion. Notably, such species normally react with nucleophiles at carbon. Therefore, they can be regarded as oxygen-substituted carbenium ions. Carboxonium ions are transient reactive intermediates that are believed to be involved in acid-promoted reactions of carbonyls and related compounds such as acetals. For example, a mechanism involving a carboxonium ion intermediate has been proposed for the Lewis-acid-catalyzed reaction of acetals (Scheme 24).82,83 It should be noted that carboxonium ions do

generated and accumulated by the anodic oxidation of ethers having an arylthio group as an electroauxiliary.85 Carboxonium ions can also be generated and accumulated by oxidative CC bond dissociation without using electroauxiliaries.86 For example, the electrochemical oxidation of meso-1,2-dimethoxy-1,2-diphenylethane at −48 °C in Bu4NBF4/CH2Cl2 gave the corresponding carboxonium ion, which reacted with allyltrimethylsilane to give the allylated product in a good yield (Scheme 26). A major advantage of CC bond dissociation is the easy generation of dications through the use of cyclic compounds as starting materials. The electrochemical oxidation of trans-9,10dimethoxy-9,10-dihydrophenanthrene gave the dication (Scheme 27). NMR analysis indicated that the two cationic centers are equivalent. The dication reacted with carbon nucleophiles to give disubstituted products. Carboxonium ions having no substituent on the cationic carbon are difficult to accumulate as cation pools because of their instability. However, the use of ethers as stabilizing additives enables the accumulation of such species.87 In the presence of 5 equiv of Et2O or tetrahydrofuran (THF), the carboxonium ion generated from (trimethylsilyl)methyl octyl ether can be accumulated as a stabilized cation pool (Scheme 28). Presumably, the oxygen atom of the additive coordinates the cationic carbon to stabilize the cation. Intramolecular participation is also effective. A carboxonium ion having an ether tether can be accumulated as a cation pool. 3.2.2. Indirect Cation Pool Method. Yoshida and coworkers developed the indirect cation pool method for the generation, accumulation, and reactions of carboxonium ions (Scheme 29).88,89 In the indirect cation pool method, an active reagent is generated and accumulated electrochemically in the first step. In the second step, the active reagent is reacted with a precursor of the cation to generate and accumulate the cation. In the third step, the resulting cation pool is allowed to react with a nucleophile. The following example shows that ArS(ArSSAr)+ is effective as an active reagent and an ArS group is effective as an electroauxiliary for oxidation of ethers. The electrochemical oxidation of ArSSAr in Bu4NBF4/CH2Cl2 at −78 °C (using 0.67 F/mol of electricity) gives ArS(ArSSAr)+, which can be characterized by 1H NMR spectroscopy and the cold-spray ionization mass spectrometry (CSI-MS). The reaction of electrogenerated ArS(ArSSAr)+ ions with ethers having an ArS group as an electroauxiliary gave the carboxonium ion, which was characterized by the signal of methine proton at 9.53 ppm (1H NMR spectroscopy) and the signal of methine carbon at 230.6 ppm (13C NMR spectroscopy). The advantage of the

Scheme 24. Lewis-Acid-Promoted Reactions of Acetals with Allyltrimethylsilane

not accumulate in solution as a pool in this case. They are generated in the presence of carbon nucleophiles such as allytrimethylsilanes, and therefore, they are continuously trapped upon generation. 3.2.1. Cation Pool Method. Yoshida and co-workers reported the generation and accumulation of carboxonium ions as cation pools through the anodic oxidation of α-silylsubstituted ethers at −72 °C (Scheme 25).84 Notably, dialkyl ethers are usually difficult to oxidize, and therefore, the use of a silyl group as an electroauxiliary is crucial to achieve this transformation. Also, the silyl electroauxiliary controls the regiochemistry. The cationic carbon is selectively generated as the carbon atom to which the silyl group has attached. The carboxonium ion can be characterized by NMR analysis. For example, the carboxonium ion generated for methyl 1(trimethylsilyl)nonylether exhibits methine proton at 9.55 ppm and methine carbon at 231.0 ppm, and these chemical shifts indicate the strong cationic character of the carbon. Carboxonium ions, which are usually stable at temperatures lower than −50 °C, react with various carbon nucleophiles at the carbon to give the corresponding carbon−carbon bond formation products. The carboxonium ion can also be 4709

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Scheme 26. Generation and Accumulation of Carboxonium Ions by CC Bond Dissociation

Scheme 27. Generation and Accumulation of Dicarboxonium Ions

Scheme 28. Stabilized Carboxonium Pools

Scheme 30. Reactions of Carboxonium Ion Pools with Alkenes

3.2.3. Indirect Cation Flow Method. In principle, the cation flow method enables the use of highly unstable cationic intermediates that are difficult to accumulate in solution by the cation pool method. Short residence times in a flow system should make it possible for subsequently added nucleophiles to react with the cationic intermediates before they decompose. However, because electrochemical reactions take place only on the surface of the electrode, the electrochemical process for generating cationic intermediates at reasonable concentrations is rather slow. To solve this problem, Yoshida and co-workers developed the indirect cation flow method, which involves the flash generation of highly unstable cationic intermediates using electrochemically generated ArS(ArSSAr)+ in the absence of nucleophiles and their reaction with subsequently added nucleophiles in a flow microreactor system.91 For example, the reaction shown in Scheme 31 was performed with a residence time of 0.17 s in reactor R1 at −28 °C, which is much higher than the temperature required for the batch reaction, to give the desired product in quantitative yield.

Scheme 29. Indirect Cation Pool Method

3.3. Stabilized Glycosyl Cations

As stated in the Introduction, glycosyl cations are believed to be the intermediates of glycosylation reactions, but their existence Scheme 31. Indirect Cation Flow Method for the Generation and Reaction of Carboxonium Ions Using ArS(ArSSAr)+

indirect cation pool method is its fast generation of carboxonium ions. The generation of carboxonium ions requires only 5 min at −78 °C. Alkenes also serve as nucleophiles (Scheme 30).90 For example, trans-stilbene derivatives react with carboxonium ions generated by the reaction of ArS-substituted ethers with ArS(ArSSAr)+ to give benzylic cations, which are trapped by ArSSAr. Then, elimination of the alkoxy group leads to the formation of other benzylic cations, which undergo an intramolecular Friedel−Crafts reaction to give thiochromans as a mixture of two diastereomers. cis-Stilbene also reacts to give a similar diastereomixture, indicating a stepwise mechanism rather than a concerted mechanism. 4710

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of thioglycosides and [ArS(ArSSAr)]+ were reacted with alcohols or glycosyl acceptors using a flow microreactor system. Studies on the effects of temperature (T) and residence time in reactor R1 (tR) indicated that the lifetime of the intermediate was on the order of 1 s even at −78 °C. For preparative purposes, the reactions were carried out with a residence time of 0.17 s at −48 °C. Under these conditions, several thioglycosides (glycosyl donors) and glycosyl acceptors were successfully reacted to obtain the corresponding glycosylation products in good yields. The use of Bu4NOTf as a supporting electrolyte enables the generation and accumulation of a glucosyl triflate as a pool through the anodic oxidation of thioglucosides (Scheme 35).92 The NMR analysis showed that the glucosyl triflate is covalent rather than ionic because the anomeric proton and carbon were observed at 6.10 and 106.9 ppm, respectively. This method can also be applied to the generation and accumulation of a galactosyl triflate pool and a mannosyl triflate. The glycosyl triflate pool reacts with subsequently added carbohydrate acceptors to give the corresponding disaccharides. Therefore, solutions of glycosyl triflates can be regarded as stabilized glycosyl cation pools. Stereoselective glycosylation was achieved using 2,3oxazolidinone glycosyl triflates generated by the electrochemical oxidation of 2,3-oxazolidinone thioglycosides.93 Reaction of the glycosyl triflates with alcohols showed high β-selectivity. The acid-mediated anomerization of β to α took place, indicating that the β-glycosides are kinetic products. Nokami and co-workers developed an iterative one-pot solution-phase synthesis of oligosaccharides using electrochemically generated glycosyl triflates (Scheme 36).94 The electrochemical oxidation of thioglycosides to generate the corresponding triflates, followed by reaction with other thioglycosides having a free hydroxyl group, gives the corresponding elongated thioglycosides. The sequence of the electrochemical oxidation and glycosylation can be repeated using an automated synthesizer developed for the method to give oligosaccharides up to hexasaccharides. This method was successfully applied to the synthesis of protected potential N,N,N-trimethyl-D-glucosaminyl- (TMG-) chitotriomycin precursors (Scheme 37).95 Nokami, Itoh, and co-workers96 developed a benzyl ethertype ionic-liquid tag (IL tag97) for electrochemical glycosylation based on the glycosyl triflate pool method (Scheme 38). The electrochemical glycosylation of tagged thioglycosides gives αisomers as major products, indicating that the stereoselectivity is opposite to that of thioglycosides without the IL tag. Also, the IL tag enables easy extraction of the products after the reaction. The reaction of glycosyl triflates with dimethyl disulfide gives glycosyl sulfonium ions as a pool (Scheme 39).98 Although glycosyl triflates are usually a single stereoisomer, a mixture of α- and β-glycosyl sulfonium ions is produced. The glycosyl sulfonium ions react with MeOH, and the reaction can be monitored by 1H NMR analysis. The α-glycosyl sulfonium ion is more reactive than the β-glycosyl sulfonium ion. A mixture of two stereoisomers is obtained from a single stereoisomer of the sulfonium ion, indicating that the reaction proceeds not by an SN2 mechanism, but by the intermediacy of a glycosyl cation. From a synthetic point of view, glycosyl sulfonium ions can be used as storable intermediates for glycosylations.99

has not yet been confirmed experimentally, despite many painstaking searches.6−8 Although glycosyl cations can be categorized as carboxonium ions, they are much more unstable than the typical carboxonium ions described above, presumably because of multiple oxygen substituents on the ring. Such electron-withdrawing substituents destabilize the cation and make the accumulation of glycosyl cations in solution extremely difficult. An attempt to accumulate glycosyl cations in solution was made by the cation pool method (Scheme 32).85 The anodic Scheme 32. Generation of Glycosyl Cations or Their Equivalents by the Cation Pool Method

oxidation of β-tetra-O-benzyl-1-phenylthioglycoside and βtetra-O-methyl-1-phenylthioglycoside in Bu4NBF4/CH2Cl2 at −78 °C followed by the addition of methanol did not give the methoxylated products, but instead, the corresponding glycosyl fluorides were obtained. Presumably, a fluoride derived from BF4− attacks the glycosyl cation. As described above, simple carboxonium ions can be accumulated in solution using BF4− as a counteranion, indicating that glycosyl cations are more reactive than simple carboxonium ions. The use of other supporting electrolytes (Bu4NClO4, Bu4NOTf, Bu4NSbF6) gave the corresponding methoxylated products, although the yield depended on the nature of the anion. The glycosyl cation intermediates were not observed spectroscopically even for these cases, but this method serves as a new approach to glycosylation, which constitutes the electrochemical generation of glycosyl cations or their equivalents followed by the addition of glycosyl acceptors after electrolysis. This method enables the use of acceptors that are easily oxidized during the application of the in situ method. For example, the use of a thioglycoside leads to the formation of a disaccharide, which can be used as a substrate for the next cycle of electrochemical glycosylation (Scheme 33). The stability of glycosyl cations or their equivalents was estimated using the indirect cation flow method (Scheme 34). Glycosyl cations or their equivalents generated by the reaction Scheme 33. One-Pot Electrochemical Glycosylation Using a Thioglycoside as an Acceptor

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Scheme 34. Glycosylation Based on the Indirect Cation Flow Method

Scheme 35. Use of Glycosyl Triflates as Stabilized Glycosyl Cation Pools

pool method enables the use of diarylcarbenium ions, including relatively unstable ones, as reagents for organic synthesis. The anodic oxidation of diarylmethanes in Bu4NBF4/CH2Cl2 at −78 °C gives a solution of the corresponding diarylcarbenium ions, which can be characterized by NMR and CSIMS analyses (Scheme 40).101,102 The resulting diarylcarbenium ions react with subsequently added nucleophiles such as allylsilanes, ketene silyl acetals, electron-rich aromatic and heteroatomatic compounds, and organozinc compounds. Another important transformation of diarylcarbenium ion pools occurs by reductive homocoupling (Scheme 41). For example, the reduction of a diarylcarbenium ion pool at −78 °C gives the homocoupling product in 81% yield, presumably through the free-radical mechanism. The reverse transformation can also be accomplished electrochemically. Anodic oxidation of the dimer at −78 °C leads to oxidative CC bond dissociation to give the diarylcarbenium ion, which can be trapped by allyltrimethylsilane. The use of diarylcarbenium ions pools for the synthesis of highly sterically demanding silyl group is interesting.103 Silyl

Scheme 36. Iterative Glycosylation Using Electrochemically Generated Glycosyl Triflate Pools

3.4. Aryl-Substituted Carbenium Ions

3.4.1. Ar2CH+ Ions. Diarylcarbenium ions, in particular, stable diarylcarbenium ions, serve as powerful tools for mechanistic investigations of cationic reactions.100 The cation 4712

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Scheme 37. Synthesis of Oligosacchirides Based on the Glycosyl Triflate Pool Method

Scheme 40. Reactions of Diarylcarbenium Ion Pools with Various Nucleophiles

Scheme 41. Reduction of Diarylcarbenium Ion Pools

Scheme 38. Ionic-Liquid Tag for the Glycosyl Triflate Method bromosilane (TEDAMS-Br), which can be used for the silylation of organic molecules. Scheme 42. Electrophilic Multisubstitution of Tris(diphenylmethyl)silane Using Diarylcarbenium Ion Pools

Scheme 39. Generation and Reactions of Glycosyl Sulfonium Ion Pool

3.4.2. Dendritic Ar 2 CH + Ions. Another intriguing application is synthesis of dendrimers. Dendritic structures can be constructed by repeating the generation of diarylcarbenium ions (Ar = p-FC6H4, p-BrC6H4) using the cation pool method followed by electrophilic reactions on the two phenyl rings of diphenyl(trimethylsilyl)methane (Scheme 43).104 In this case, the use of a silyl group as an electroauxiliary plays a crucial role. The silyl auxiliary at the benzylic position activates diarylmethane toward oxidation, enabling facile and

groups bearing extremely bulky substituents have received significant research interest from the viewpoint of sterically demanding substituents that can kinetically stabilize highly unstable species. For example, electrophilic multiple substitution on tris(diphenylmethyl)silane with di(p-fluorophenyl)carbenium ion afforded the highly sterically demanding hydrosilane tris(extended diarylmethyl)silane (TEDAMS-H) (Scheme 42). TEDAMS-H was converted to the corresponding 4713

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copolymerization of two vinyl ethers followed by trapping with nucleophiles gave structurally well-defined macromolecules. The peripheral modification of both the initiating and dendritic terminating ends leads to the formation of dendritic− linear−dendritic (D−L−D) hybrid polymers.109 3.4.3. Stabilized ArCH2+ Ions. Benzyl cations serve as useful intermediates in organic synthesis. However, the cation pool method cannot be applied to benzylic cations without the presence of other stabilizing substituents on the cationic carbon because benzyl cations are usually too unstable to accumulate in solution even at low temperatures. To overcome this problem, the stabilized cation pool method was developed (Scheme 46).110 The choice of the stabilizing agent Y is crucial. The requirements for Y include (a) an oxidation potential higher than those of toluene derivatives, which enables selective oxidation to generate benzyl cations; (b) the absence of a proton, making the stabilized form cationic and preventing overoxidation; and (c) sufficient nucleophilicity to stabilize benzyl cations and sufficient leaving ability for subsequent nucleophilic substitution. N-Tosyldiphenylsulfilimine was found to be effective as a stabilizing agent. Thus, the anodic oxidation of toluene derivatives in the presence of Ntosyldiphenylsulfilimine gives the corresponding benzylaminosulfonium ions, which can be accumulated in solution as stabilized benzyl cation pools. The reactions with various aromatic nucleophiles give the corresponding cross-coupling products, diarylmethanes (Scheme 47). This transformation serves as a powerful method for achieving benzylic CH/ aromatic CH cross-coupling without the use of metal and chemical oxidants.

Scheme 43. Iterative Molecular Assembly Based on the Cation Pool Method: Convergent Synthesis of Dendritic Molecules

site-selective oxidation to generate the diarylcarbenium ion. The silyl group also activates the aromatic ring toward electrophilic reactions with diarylcarbenium ions. The resulting dendritic diarylcarbenium ions, which can be characterized by NMR spectroscopy, react with electron-rich aromatic compounds.105 For example, dendritic diarylcarbeniun ions react with the aromatic rings of polystyrene to effect the dendronization of polystyrene (Scheme 44).106 The dendronized polymers obtained using the first- and second-generation dendritic diarylcarbenium ions, [G-1]+ and [G-2]+, respectively, were well-characterized by MALDI-TOF MS and SEC-MALLS analyses and observed by AFM. The use of the dendritic diarylcarbenium ions having peripheral bromo groups enables the synthesis of dendronized polymers having peripheral redox functionalities.107 Dendritic diarylcarbenium ion pools serve as initiators of cationic polymerizations of vinyl ethers using flow microreactor systems to give dendritic−linear (D−L) polymers (Scheme 45).108 The carbocationic polymer growth end can be effectively trapped by various nucleophiles such as allylsilanes and ketene silyl acetals to give polymers with very narrow molecular weight distributions. For example, the block

4. STABILIZED SILYL CATIONS Silyl cations (R3Si+),111,112 which are silicon analogues of carbenium ions (R3C+), are known to be extremely unstable and difficult to accumulate in solution. Silyl cations having appropriate donor ligands are, however, reasonably stable and amenable to accumulation in solution.113 The electrochemical method is also effective for the generation and accumulation of such stabilized silyl cations. The electrochemical oxidation of a disilane having a 2pyridylphenyl group on each silicon atom gives a solution of the corresponding silyl cation (Scheme 48). The nature of the counteranion is very important. The use of BF4− leads to the introduction of fluoride on the silicon atom. However, the use of B(C6F5)4− enables the generation and accumulation of the silyl cation. Significant low-field shifts of the protons on the

Scheme 44. Dendronization of Styrene with Dendritic Diarylcarbenium Ion Pool [G-2]+

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Scheme 45. Cationic Block Copolymerization of Vinyl Ethers Initiated by a Diarylcarbenium Ion Pool

Scheme 46. Stabilized Cation Pool Method for Benzyl Cations

Scheme 48. Generation of Stabilized Silyl Cation Pool

Scheme 47. Benzylic CH/Aromatic CH Cross-Coupling Based on the Stabilized Cation Pool Method The stabilized silyl cation reacts with nucleophiles such as Grignard reagents. For example, p-tolylmagnesium bromide reacts with the cation to give the product in 90% yield. Two moles of the cation are produced from 1 mol of the disilane with the consumption of 2 mol of electrons.

5. NITROGEN CATIONS We already discussed N-acyliminium ions that react with nucleophiles on the carbon instead of the nitrogen in the section on carbocations (section 3.1). This section deals with the electrochemical generation and accumulation of nitrogencentered cations. Lund reported that the controlled-potential electrochemical oxidation of anthracene in the presence of pyridine in NaClO4/ CH3CN yielded a water-soluble 9,10-dihydroanthranyldipyridinium diperchlorate, which can be converted to 9anthrylpyridinium perchlorate upon treatment with 1 equiv of a cold base (Scheme 49).114 Masui and co-workers reported the anodic oxidation of aromatic compounds in the presence of pyridine to give the

SiCH3 groups and the pyridyl ring in the 1H NMR spectrum indicates the formation of the silyl cation, which is consistent with CSI-MS analysis (spray temperature = 0 °C). 4715

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Scheme 49. Generation and Accumulation of 9-Anthrylpyridinium Ions

pyridinated ionic compound.115 For example, N-methyl-4′methoxybenzanilide was oxidized in the presence of pyridine in NaClO4/CH3CN under controlled-potential electrolysis conditions (Scheme 50). Evaporation of the solvent followed by column chromatography yielded 1-(3-N-methylbenzamido-6methoxyphenyl)pyridinium perchlorate as yellow crystals.

The intramolecular version of CH amination gives bicyclic heteroatom compounds.120 For example, the anodic oxidation of 2-pyrimidyloxybenzene, which is easily prepared from phenol and 2-bromopyrimidine, affords the cyclized pyrimidinium ion (Scheme 52). Treatment with piperidine gives 2-aminobenzoxazole, which serves as a key scaffold in therapeutically important molecules. A similar transformation using 2pyrimidylthiobenzene as a substrate gives 2-aminobenzothiazoles. N-Mesylimidazole is also effective for CH amination. The anodic oxidation of aromatic compounds in the presence of Nmesylimidazole gives a solution of N-aryl-N’-mesylimidazolium ions, which can be treated with piperidine to afford Narylimidazoles. This method is also applicable to amination of benzylic positions.121 The synthesis of an antifungal agent involving the regioselective amination of the benzylic CH bond next to the electron-rich aromatic ring bearing a methoxy group demonstrates the power of the method (Scheme 53). The anodic oxidation of aromatic compounds in the presence of N-tosyl-2-methylimidazole followed by hydrolysis of the imidazolium ions with aqueous NaHCO3 leads to the introduction of the 2-(tosylamino)ethylamino group (Scheme 54).122 The use of 2-methyloxazoline leads to the introduction of the 2-acetoxylethylamino group. In addition to fivemembered-ring heterocycles, six-membered-ring heterocycles can also be used. Because such heterocycles can be easily synthesized by the heterocylization of functional alkylamines, this reaction serves as a method for introducing functionalized alkylamino groups onto aromatic rings.

Scheme 50. Generation and Accumulation of Aromatic Pyridinium Ions

Iyoda and co-workers used electrochemically generated πradical cations such as pyrene and perylene for reaction with pyridine derivatives to obtain N-arylpyridines.116 This reaction provides a powerful and versatile method for synthesizing pyridinium-conjugated assemblies in which redox-active pyridinium moieties can be integrated into π-conjugated systems. It is known that N-arylpyridinium salts (Zincke salts) can be converted into aminoarenes by the attack of suitable nucleophiles.117,118 Therefore, the combination of the electrooxidation preparation of N-arylpyridinium salts followed by nucleophilic reactions serves as a powerful method for the C H amination of aromatic compounds.119 For example, the anodic oxidation of 2-iodoanisole at 25 °C followed by treatment of the resulting N-arylpyridium salts with piperidine at 80 °C gave 4-amino-2-iodoanisole in a good yield (Scheme 51). Notably, the iodo group was not affected during the transformation, although this group is often not compatible with the oxidation of aromatic compounds and the reduction of nitro groups to amino groups.

6. PHOSPHORUS CATIONS Ohmori and co-workers studied the electrochemical oxidation of R3P extensively.123 The oxidation potential of R3P is usually as low as 1 V vs SCE in CH3CN, enabling the selective oxidation of R3P in the presence of various nucleophiles.124 The anodic oxidation of R3P with aromatic compounds gives aryl phosphonium salts.125,126 For example, the anodic oxidation of a mixture of Ph3P and benzene in NaClO4/CH3CN gave Ph4P+ ClO4− with byproducts such as Ph3PH+ ClO4 and Ph3PO (Scheme 55). The electrochemical oxidation of Ph3P in the presence of acyclic and cyclic alkenes using 2,6-lutidinium perchlorate in CH2Cl2 using an undivided cell under constant-current conditions gives alkenyltriphenylphosphonium ions (Scheme 56).127,128 The phosphonium salts are probably generated through radical cations generated by the reaction of the triphenylphosphine radical cation with alkenes. Reaction of the phosphonium salts with sodium hydroxide gives corresponding phosphine oxides.

Scheme 51. Electrochemical CH Amination of 2Iodoanisole

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Scheme 52. Electrochemical Intramolecular CH Amination

Scheme 53. Regioselective CH Amination for the Synthesis of an Antifungal Agent

Scheme 55. Electrochemical Oxidation of Ph3P in the Presence of Benzene

Scheme 56. Electrochemical Oxidation of Ph3P in the Presence of Alkenes

Scheme 57. Electrochemical Oxidation of Ph3P in the Presence of Allylsilanes

The electrochemical oxidation of Ph3P in the presence of allylsilanes gives allyltriphenylphosphonium ions (Scheme 57).129,130 A cyclic voltammetric study suggested that the reaction proceeds through the oxidation of Ph3P. Presumably, the resulting radical cation of Ph3P attacks the γ-position of allylsilanes to give allyltriphenylphosphonium ions. Ohmori and co-workers also revealed that the anodic oxidation of Ph3P in the presence of cyclic enol silyl ethers, enol phosphates, and enol acetates gives 2-oxocycloalkyltriphenylphosphonium salts.131 Acyclic acetate can also be used for the transformation. The use of isopropenyl acetate affords (2oxopropyl)triphenylphosphonium salt. The Wittig reaction of (2-oxocycloalkyl)triphenylphosphonium salts with formaldehyde or acetaldehyde gives the corresponding (E)-2-alkylidenecycloalkan-1-ones (Scheme 58).

The electrochemical oxidation of Ph3P in the presence of 1,3dicarbonyl compounds in CH 3 CN with HClO 4 gives phosphonium salts, whereas the corresponding oxidation in CH2Cl2 with 2,6-lutidinium perchlorate (LutClO4) gives phosphoranes (Scheme 59).132,133

Scheme 54. Introduction of Functional Alkylamino Groups by the Electrochemical Method

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Scheme 58. Synthesis of Alkylidenecycloalkanones

Ohmori and co-workers also found that the constant-current electrolysis of a mixture of Bu3P and RSSR using LiClO4/ PhCO2H as a supporting electrolyte in CH3CN gave Bu3P+SR ClO4− in good yields (Scheme 62).136 The reaction of Bu3P+SR ClO4− with primary, secondary, benzyl, and allylic alcohols R′OH in the presence of DBU also gives unsymmetrical sulfides RSR′. Presumably, R′OH attacks the cationic phosphine to give RS− (or RSH) and Bu3P+OR′. Because Bu3P+O is a good leaving group, RS− undergoes SN2 displacement at the alcoholic carbon atom of R′OH to give Bu3PO and RSR′. The reaction of Bu3P+SR ClO4− with carboxylic acids R′CO2H gives thioesters R′COSR. Notably, Ph3P+SR ClO4− serves as a source of RS+ (vide infra).

Scheme 59. Electrochemical Oxidation of Ph3P in the Presence 1,3-Dicarbonyl Compounds

7. SULFUR CATIONS Organosulfur cations are categorized as sulfonium ions having the structure R3S+ and sulfenylium ions (or sulfanylium ions, sulfenium ions) having the structure RS+. Many sulfonium ions are stable, although some sulfonium ions such as episulfonium ions are unstable. In contrast, sulfenylium ions are usually highly unstable, and therefore, it is difficult to accumulate sulfenylium ions in solution. However, sulfenylium ions can be accumulated in solution in the presence of a suitable stabilizing agent. This section deals with the electrochemical generation and accumulation of R3S+ and stabilized RS+.

Trialkylphosphines such as Bu3P also give phosphorane in the anodic oxidation with 1,3-dicarbonyl compounds. Phosphoranes prepared from Bu3P and cyclic 1,3-diketones undergo thermal reactions leading to the formation of the cycloalkynones through an intramolecular Wittig-type reaction (Scheme 60). This interesting species having a carbon−carbon triple bond can be trapped by Diels−Alder reactions. The electrochemical oxidation of R3P in the presence of alcohols gives corresponding alkoxyphosphonium salts. The reactions of the alkoxyphosphonium salts prepared from β- and α-cholestanol suggested that hard nucleophiles such as F−, N3−, and PhOH react at the phosphorus to regenerate the cholestanol (Scheme 61, path a), whereas soft nucleophiles such as PhSH, SCN−, Cl−, and Br− react at the carbon next to the oxygen to give the corresponding SN2 reaction products (Scheme 61, path b).134 Alkoxyphosphonium salts can also be used for fluorination reactions. Heating the alkoxyphosphonium tetrafluoroborate gave alkyl fluoride.135 A fluorine atom derived from BF4− attacks the carbon through an SN2 mechanism.

7.1. R3S+ Ions

The electrochemical oxidation of diarylsulfides in the presence of aromatic compounds is expected to lead to the formation of triarylsulfonium ions presumably through the formation of radical cation of diarylsulfides followed by nucleophilic attack by the aromatic compounds. However, Magno and Bontempelli reported this process is prevented by self-coupling to give dimeric, trimeric, and tetrameric products if diphenylsulfide is used as the substrate (Scheme 63).137

Scheme 60. Generation and Reactions of Cycloalkynones

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Scheme 61. Electrochemical Oxidation of Ph3P in the Presence of Cholestanol

coupling product can be precipitated with sodium tetraphenylborate or hexachloroplatinate. The use of triorganosulfonium ions as stabilized glycosyl cations was already discussed in the section on stabilized glycosyl cations (section 3.3).

Scheme 62. Electrochemical Generation and Accumulation of Bu3P+SR

7.2. R2(R′O)S+ Ions

Trapping of carbenium ions with sulfoxides leads to the formation of alkoxysulfonium ions,140,141 which serve as intermediates of Swern−Moffatt142 and Komblum143 oxidations. Thus, the integration of electrooxidative generation of carbenium ions and the reaction with sulfoxides provides a method for generating and accumulating alkoxysulfonium ions. 144 For example, the anodic oxidation of di(pfluorophenyl)methane in Bu4NBF4/CH2Cl 2 at −78 °C generated the di(p-fluorophenyl)carbenium ion pool (Scheme 65). The addition of dimethyl sulfoxide (DMSO) gives the di(p-fluorophenyl)methyloxysulfonium ion, which was characterized by NMR analysis at −78 °C. Treatment with triethylamine gave the corresponding di(p-fluorophenyl) ketone in 91% yield. If a substrate has a lower oxidation potential than DMSO, in situ trapping of electrogenerated carbocations by DMSO is also effective. This in situ method is useful for cases in which the carbocations are too unstable to accumulate in solution. For example, the electrochemical oxidation of 4-methoxytoluene in DMSO/CH2Cl2 (1:2) gave alkoxysulfonium ion, which was characterized by NMR spectroscopy (Scheme 66). Notably, the electrolysis could be carried out at 24 °C in this case, because alkoxysulfoniuim ions are more stable than carbenium ions. Treatment with triethylamine gave the corresponding aldehyde

Scheme 63. Electrochemical Self-Coupling of Diphenylsulide

Hoffelner and co-workers found that di(p-methoxyphenyl)sulfide as the substrate leads to the effective formation of tri(pmethoxyphenyl)sulfonium ion.138,139 The anodic oxidation of a mixture of 0.1 M di(p-methoxy)sulfide and 1 M anisole in NaClO4/CH3CN was conducted in a divided cell under constant-potential conditions (Scheme 64). The reaction seems to proceed by the initial formation of the radical cation of di(p-methoxy)sulfide, which reacts with anisole. The

Scheme 64. Electrochemical Coupling of Di(p-methoxy)sulfide and Anisole

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Scheme 65. Electrochemical Generation and Accumulation of Alkoxysulfonium Ions from (p-FC6H4)2CH2

Scheme 66. Electrochemical Generation and Accumulation of Alkoxysulfonium Ions from p-Methoxytoluene

Scheme 67. Electrochemical Generation and Accumulation of Di(alkoxysulfonium) Ions

Scheme 68. Electrochemical Generation and Accumulation of Alkoxysulfonium Ions with Cyclization

in 86% yield. Treatment with aqueous NaOH gave the corresponding alcohol in 85% yield.145 The in situ method is also applicable to the oxidation of alkenes. For example, the anodic oxidation of 4,4′-dichlorotrans-stilbene in the presence of DMSO gave the corresponding di(alkoxysulfonium) ion, which was characterized by NMR spectroscopy (Scheme 67). Treatment with triethylamine gave the diketone in 83% yield through Swern−Moffatt-type oxidation. Treatment with aqueous NaOH gave the diol in 86% yield.

The electrochemical oxidation of alkenes bearing a nucleophilic group in an appropriate position that can participate in the electrochemical oxidation leads to effective cyclization. For example, the electrochemical oxidation of an alkene having a tosyl amide group in the presence of DMSO gave the cyclized alkoxysulfonium ion (Scheme 68). The nitrogen atom of the tosyl amide group attacks the olefinic carbon, whereas DMSO attacks the other carbon. Treatment with triethylamine gave the corresponding cyclized carbonyl 4720

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Scheme 69. Electrochemical Generation and Accumulation of N-Tosylbenzylaminosulfonium Ions

NMR spectroscopy and CSI-MS at 0 °C (Scheme 71).156 The generation of ArS(ArSSAr)+ by the anodic oxidation of ArSSAr

compound, whereas treatment with aqueous NaOH gave the cyclized alcohol. 7.3. R2(R′2N)S+ Ions

Scheme 71. Generation and Accumulation of ArS(ArSSAr)+ by Electrochemical Oxidation of ArSSAr

Sulfilimines, sulfur analogues of sulfoxides, are also effective. For example, trapping of electrogenerated benzyl cations with N-tosylsulfilimine gives the corresponding N-tosylbenzylaminosulfonium ion pool (Scheme 69).146 The NS bond can be reductively cleaved by I− to give the benzylamines. This transformation serves as a metal- and chemical-oxidant-free method for benzylic CH amination. 7.4. R2CS+R′ Ions

Thionium ions (R2CS+R′ cations),147 which are sulfur analogues of carboxonium ions, behave as carbenium ions stabilized by neighboring sulfur atom. Nucleophiles usually attack the carbon. Thionium ions can be generated and accumulated in solution by the indirect cation pool method.148 For example, ArS(ArSSAr)+ generated by the anodic oxidation of ArSSAr (Ar = p-FC6H4) at −78 °C in Bu4NBF4/CH2Cl2 was reacted with dithioacetal of benzaldehyde (Scheme 70). The Scheme 70. Generation and Reactions of Thionium Ions by the Indirect Cation Pool Method

could be monitored by in situ Raman spectroscopy at 195 K.157 A band that can be attributable to the SS vibrations of ArS(ArSSAr)+ was observed at 427 cm−1. The intensity of the band increased with increasing electricity until 2/3 F of electricity was consumed. A further increase in the electricity led to a decrease of the intensity, indicating the decomposition of ArS(ArSSAr)+. The ArS(ArSSAr)+ pools generated by the anodic oxidation of ArSSAr can be used for the indirect cation pool method to make carboxonoium ion pools as described in previous sections of this article (sections 3.2.2 and 3.2.3). The ArS(ArSSAr)+ pools can also be used as reagents for the introduction of ArS groups into organic molecules. For example, ArS(ArSSAr)+ reacts with various carbon nucleophiles.158 Electrophilic substitution with electron-rich aromatic compounds gives the corresponding ArS-substituted aromatic compounds. Reactions with allylsilanes and ketene silyl acetals give ally sulfides and αArS-substituted esters, respectively. The reactions with alkenes are interesting, because the products depend on the nature of the quenching agent (Scheme 72).159 Quenching with soft nucleophiles such as allylsilanes and ketene silyl acetals leads to the trans addition of two ArS groups onto the carbon−carbon double bond. Triethylamine is also effective as a soft nucleophile. The use of hard nucleophiles such as methanol and water leads to the addition of one ArS group and the nucleophile onto the carbon−carbon double bond. ArS(ArSSAr)+ pools also react with alkynes. Two ArS groups add across the carbon−carbon triple bond to give diarylthio-

resulting solution of the thionium ion was characterized by NMR spectroscopy. The thionium ion reacted with various carbon nucleophiles including ketene silyl acetals, enol silyl ethers, allylsilanes, and electron-rich aromatic compounds. 7.5. Stabilized RS+ Ions

The electrochemical oxidation of disulfides (RSSR) should lead, in principle, to the formation of RS+ through radical cation formation followed by SS bond cleavage. Extensive studies on the anodic oxidation of RSSR have been reported in the literature.149−155 In fact, ArS+ has been assumed to be generated as an intermediate in the anodic oxidation of ArSSAr in CH2Cl2, although some doubts have been advanced on the existence of ions in this form in the solution phase. Yoshida and co-workers studied the species generated by the anodic oxidation of ArSSAr (Ar = p-FC6H4) in Bu4NBF4/ CH2Cl2 at −78 °C and identified it as ArS(ArSSAr)+ by 1H 4721

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Scheme 72. Reactions of ArS(ArSSAr)+ with Alkenes

Scheme 75. Addition of ArSSAr to an Alkene in the Presence of a Catalytic Amount of ArS(ArSSAr)+

Scheme 76. Diene Cyclization Using a Catalytic Amount of ArS(ArSSAr)+ and a Stoichiometric Amount of ArSSAr

substituted alkenes, if triethylamine is used as the quenching agent (Scheme 73). Scheme 73. Reactions of ArS(ArSSAr)+ with Alkynes cyclization was not obtained. Presumably, ArS+ reacts with the more nucleophilic trisubstituted carbon−carbon double bond to give the episulfonium ion, which reacts with the other carbon−carbon double bond to give the cyclized product. ArS-substituted ethers having a carbon−carbon double bond in an appropriate position undergo chain reaction by the action of ArS(ArSSAr)+ (Scheme 77).162 The reaction proceeds Scheme 77. ArS(ArSSAr)+-Promoted Cyclization of Olefinic α-ArS-Substituted Ethers

Reactions at higher temperatures such as 0 °C without quenching lead to the addition of an ArS group and F derived from BF4− onto carbon−carbon multiple bonds (Scheme 74).160 This transformation serves as a useful method for introducing fluorine atoms into organic molecules. Scheme 74. Introduction of a Fluorine Atom into Alkenes and Alkynes Using ArS(ArSSAr)+

through the initial formation of a carboxonium ion intermediate, which reacts with the carbon−carbon double bond to generate the cyclized carbenium ion. When Bu4NBF4 is used as the supporting electrolyte, BF4− attacks the carbenium ion to give the corresponding organofluorine compounds as the product. However, when Bu4NB(C6F5)4 is used as the supporting electrolyte, ArSSAr attacks the cyclized carbenium ion to give ArS+ and products containing the ArS group (Scheme 78). Because the regenerated ArS+ reacts with the substrate, the reaction proceeds with a catalytic amount of ArS(ArSSAr)+ in the presence of an excess amount of ArSSAr. ArS+ stabilized by DMSO can be generated and accumulated in solution.163 For example, the electrochemical oxidation of PhSSPh in the presence of DMSO in Bu4NBF4/CH2Cl2 at −78 °C gives a solution of PhS+ stabilized by DMSO (Scheme 79). This species is stable at −50 °C for 30 min and adds to the carbon−carbon double bond of alkenes. Subsequent treatment with triethylamine gives the corresponding α-PhS-substituted ketones. A similar transformation can also be achieved using PhSeSePh. PhSe+ stabilized by DMSO is somewhat more stable than PhS+ stabilized by DMSO.

The use of a catalytic amount of ArS(ArSSAr)+ with B(C6F5)4− as the counteranion with a stoichiometric amount ArSSAr leads to the effective introduction of two ArS groups to alkenes (Scheme 75).161 A cation chain mechanism has been suggested. Notably, the use of B(C6F5)4− as the counteranion is essential for the success of this catalytic process. Nonconjugate dienes cyclize through the action of a catalytic amount of ArS(ArSSAr)+B(C6F5)4− in the presence of ArSSAr. For example, 1-phenyl-7-methyl-4,4-dimethylocta-1,6-diene reacts with 0.2 equiv of ArS(ArSSAr)+B(C6F5)4− in the presence of ArSSAr (Ar = p-MeOC6H4) to give the cyclized product in 77% yield as a mixture of two diastereomers (Scheme 76). The product derived from another mode of 4722

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Scheme 78. ArS(ArSSAr)+-Initiated Cyclization of Olefinic α-ArS-Substituted Ethers

Scheme 81. Electrochemical Synthesis of Diphenyliodonium Ions

unsymmetrical diaryliodonium ions can be prepared using this method. Nishiyama and co-workers reported that phenyliodine(III)bis(trifluoroethoxide) (PIFE) can be synthesized by anodic oxidation of iodobenzene in LiClO4/2,2,2-trifluoroethanol under constant-current electrolysis conditions (Scheme 82).169,170 PIFE was used for the synthesis of the bioactive tetrahydropyrroloiminoquinone-, carbazole-, and pyrroloindoleclass natural products.

Scheme 79. DMSO-Stabilized ArS+ and ArSe+ Ions

Scheme 82. Electrochemical Synthesis of Hypervalenet Iodine Compound (PIFE)

Ohmori and co-workers found that the constant-current electrolysis of a mixture of Ph3P, RSSR, and HClO4 (1:2:2) in CH3CN gave Ph3P+SR ClO4− in good yields.164 The reaction of Ph3P+SR ClO4− with R′SH in the presence of Et3N at room temperature gives unsymmetrical disulfides RSSR′ and Ph3P in good yields (Scheme 80). Presumably, the nucleophilic attack Scheme 80. Reactions of Electrogenerated Ph3P+SR with R′SH

of R′SH on the sulfur atom of Ph3P+SR cleaves the PS bond, indicating that Ph3P+SR serves as stabilized RS+. Notably, the reactivity of Ph3P+SR is quite different from that of Bu3P+SR (vide supra). This transformation serves as a good method for synthesizing asymmetric disulfides.

8.2. Stabilized X+ Ions

Halogen cations such as I+, Br+, and Cl+ are often used as intermediates in electrochemical oxidation, but they are difficult to accumulate in solution because of their instability. However, some halogen cations stabilized by coordinating agents can be accumulated in solution and used as reagents for organic synthesis. For example, (pyridine)2I+ is well-known as an iodination reagent.171,172 In this section, we discuss the electrochemical generation of stabilized halogen cation pools and their use in synthetic reactions. Miller and co-workers reported that the electrochemical oxidation of I2 in CH3CN gives I+ stabilized by CH3CN (Scheme 83).173,174 Although this reagent was not characterized spectroscopically, it serves as a good iodinating reagent for aromatic compounds. Romakhin and co-workers also reported that I+/CH3CN was obtained as a cream-colored powder by the anodic oxidation of I2 in CH3CN, but no detailed information was available, although the powder did not exhibit IR absorption due to the vibrations of the CN triple bond.175

8. HALOGEN CATIONS Halogen cations can be classified as halonium ions having the structure R2X+ and cations having the structure X+. The latter are very unstable, although they are assumed to be generated in situ in various reactions including electrochemical reactions. 8.1. R2X+ Ions

Hypervalent iodine compounds serve as useful oxidizing reagents in organic synthesis. Hoffelner and co-workers165 reported the anodic coupling of iodobenzene and benzene in CH3CN to give the diphenyliodonium salt (Scheme 81), which provides a simple and general one-step method for the synthesis of diaryliodonium salts.166 Peacock and Pletcher reported the synthesis of diaryliodonium salts in acetic acid/ 25% acetic anhydride/5% sulfuric acid.167 Wirth and coworkers showed that flow synthesis using the electrochemical microreactor is quite effective for this purpose.168 Various 4723

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Scheme 83. Electrochemical Generation and Accumulation of I+ Stabilized by CH3CN

Scheme 85. Electrochemical Generation and Accumulation of I+/TMOF

Scheme 86. Electrochemical Generation of X+/DMSO Pools and Their Reactions with Alkenes

Yoshida and co-workers characterized the positive iodine species generated by the anodic oxidation of I2 in Bu4NBF4/ CH3CN at 0 °C.176 A signal that could be assigned to (CH3CN)I+ was observed in addition to one that could be assigned to (CH3CN)2I+ in CSI-MS. The intensity of the signal for (CH3CN)I+ increased at the expense of (CH3CN)2I+ at higher ionization temperature, suggesting that I+ is mainly existing as (CH3CN)2I+ and CH3CN is partially liberated to give (CH3CN)I+. The I + stabilized by CH 3 CN reacts with aromatic compounds to give the corresponding aryl iodides. Electronrich aromatic compounds suffer from the diiodination, but the monoselectivity can be significantly improved by using a flow reactor equipped with a micromixer (Scheme 84). Extremely fast micromixing solves the problem of disguised selectivity.

electrolyte at −78 °C gave a solution of a positive iodine species that showed peaks due to DMSO−I+ and (DMSO)2−I+ species in CSI-MS analysis at 0 °C. These results are consistent with DFT calculations, which indicated that I+ forms a complex with DMSO in the gas phase. The interaction with the oxygen atom of DMSO (IO distance = 2.09 Å) stabilizes I+ by 118.9 kcal/mol. Coordination by a second DMSO molecule causes further stabilization (36.1 kcal/mol). Interaction with a third DMSO molecule somewhat stabilizes I+ (7.5 kcal/mol), but the third DMSO molecule does not directly coordinate to I+. DMSO−I+ adds across a carbon−carbon double bond. The resulting α-iodoalkoxysulfonium ion can be characterized by NMR spectroscopy. Treatment of the α-iodoalkoxysulfonium ion with triethylamine gives the corresponding α-iodoketone by a mechanism similar to that proposed for Swern−Moffatt-type oxidation. DMSO also stabilizes Br+ generated by electrochemical oxidation of Br−, and DMSO−Br+ reacts with alkenes. The treatment of the resulting α-bromoalkoxysulfonium ions with triethylamine gives the corresponding α-bromoketones. α-Haloalkoxysulfonium ions can also be converted to halohydrins by treatment with aqueous NaOH.180 OH− attacks the sulfur atom, and the OS bond is cleaved. The use of NaOMe as a base leads to the formation of the corresponding epoxide. Use of 18O-labeled DMSO leads to the formation of the corresponding 18O-labeled epoxide. Because 18O-labeled DMSO can be easily synthesized from 18O-labeled water, the transformation serves as a useful method for obtaining 18Olabeled epoxides, which can be utilized for various mechanistic and biological studies.

Scheme 84. Iodination of Aromatic Compounds

The I+ stabilized by CH3CN can also be generated by using H2SO4 as the supporting electrolyte, which is much less expensive than Bu4NBF4.177 This protocol serves as a practical method for the iodination of aromatic compounds. Lines and Parker reported that the anodic oxidation of I2 in the presence of 10% CF3CO2H (TFA) gives a highly reactive positive iodine species I+/TFA, although it is produced in situ in the presence of aromatic substrates.178 The reactivity depends strongly on the solvent. For example, 3-iodonitrobenzene is produced in 78% yield from nitrobenzene when 1,2dichloroethane is used as the solvent, whereas the use of dichloromethane leads to 47% yield and no iodination product is obtained when CH3CN is used as a solvent. Shono and co-workers reported that a positive iodine species is generated by the anodic oxidation of I2 in trimethyl orthoformate (TMOF) (Scheme 85).179 Although there is no structural information on this species, it can also be used as a useful iodinating agent for aromatic compounds. I+/TMOF is more chemoselective than I+/CH3CN and I+/TFA. For example, I+/TMOF reacts selectively with toluene in the presence of benzene (selectivity = 600/1). Also, I+/TMOF exhibits higher para-selectivity in the iodination of toluene, tertbutylbenzene, and anisole than I+/CH3CN. Dimethyl sulfoxide (DMSO) also serves as a stabilizing agent for I+ (Scheme 86).163 The electrochemical oxidation of Bu4NI in DMSO/CH2Cl2 (1:9 v/v) using Bu4NBF4 as the supporting

9. CATIONIC TRANSITION-METAL COMPLEXES Mitsudo, Tanaka, and co-workers reported that the electrochemical oxidation of Pd(OAc)2 in Bu4NBF4/CH3CN gave the cationic Pd complex [Pd(CH3CN)4][BF4]2.181 The use of Bu4NPF6 and Bu4NClO4 as supporting electrolytes gave [Pd(CH3CN)4][PF6]2 and [Pd(CH3CN)4][ClO4]2, respectively (Scheme 87). A mechanism involving the Kolbe-type 4724

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ethylbenzene and naphthalene radical cation followed by oneelectron oxidation. The latter process requires another molecule of naphthalene radical cation. Also, naphthalene radical cation is accumulated as a complex with a neutral naphthalene. Consequently, 4 mol of naphthalene is necessary to produce 1 mol of the product. The radical cation pool method can be applied to radical cations of other aromatic compounds such as 2-bromonaphthalene, pyrene, and fluoranthene. Electron-rich aromatic compounds such as 1,3,5-trimethoxybenzene, benzothiophenes, and indole derivatives are effective as counterparts. The regiochemistry of the coupling is predictable using DFT calculations. Shine and co-workers prepared solid perylene cation radical perchlorate by anodic oxidation of perylene as small crystals (Scheme 89).184 The perylene radical cation reacts with water

Scheme 87. Electrochemical Generation of Cationic Pd Complexes and Their Use in Electrooxidative Wacker-Type Reactions

Scheme 89. Electrochemical Generation of Perylene Radical Cation Pool reaction of the acetate ion was proposed. The cationic Pd species can be used as a catalyst for the electrooxidative Wacker-type reaction using 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) as a mediator.

10. RADICAL CATIONS 10.1. Radical Cations of Aromatic Hydrocarbons

Schubert and co-workers reported that the electrochemical oxidation of naphthalene in Bu4NPF6/CH2Cl2 at −45 °C in an undivided cell afforded red-violet needles with an approximate composition of (C 10 H 8 ) 2 PF 6 .182 X-ray analysis of the compound revealed that two naphthalene molecules interact with each other and that the distance between the two naphthalene planes is 320 pm, indicating the stabilization of the radical cation of naphthalene by neutral naphthalene. Yoshida and co-workers reported the CH/CH crosscoupling of aromatic compounds using electrochemically generated radical cations of aromatic compounds.183 For example, the anodic oxidation of naphthalene in Bu4NB(C6F5)4/CH2Cl2 in an H-type divided cell at −78 °C was carried out to accumulate the radical cation dimer of naphthalene (Scheme 88). Then, petamethylbenzene and dimethoxyethane as an additive were added at −90 °C. The mixture was stirred at −90 °C for 3 h. The desired crosscoupling product was obtained in 91% yield. The crosscoupling product is produced by the reaction of pentam-

to give a mixture of perylene and the quinone. The reaction with pyridine gives a mixture of perylene and N-(3-perylenyl)pyridinium perchlorate.

11. OUTLOOK The electrochemical method enables the generation and accumulation of unstable cationic reactive intermediates as a pool that reacts with subsequently added nucleophilic reaction partners to give desired products. In addition to the pool method, the flow method can also be used for this purpose. This review describes the current status of this ongoing fascinating research field. It is hoped that the pool method and related methods will be used together to enhance the capability of organic synthesis.

Scheme 88. Aromatic CH/Aromatic CH CrossCoupling Using the Radical Cation Pool Method

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Jun-ichi Yoshida: 0000-0001-8439-2272 Akihiro Shimizu: 0000-0001-9392-2087 Notes

The authors declare no competing financial interest. 4725

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Biographies

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Jun-ichi Yoshida obtained his Ph.D. degree (1981) under the supervision of Prof. Makoto Kumada at Kyoto University. In 1979, Yoshida joined the faculty at Kyoto Institute of Technology as an assistant professor. In 1982−1983, he visited University of Wisconsin, where he joined the research group of Prof. B. M. Trost as a postdoctoral researcher. In 1985, he moved to Osaka City University, where he was promoted to an associate professor in 1992. In 1994, he was appointed as a full professor at Kyoto University. His research interests include integrated organic synthesis on the basis of reactive intermediates, organic electron-transfer reactions, organometallic reactions, and flow microreactors. Akihiro Shimizu received his Ph.D. degree (2009) from Osaka University under the supervision of Professor Takashi Kubo. He spent three months with Professor Benoit̂ Champagne at Facultés Universitaires Notre-Dame de la Paix (FUNDP) in Namur, Belgium, as a visiting researcher in 2007. He was appointed as an assistant professor at the Graduate School of Engineering Science of Osaka University in 2010. In 2011, he moved to the Graduate School of Engineering of Kyoto University as an assistant professor. His current research focuses on electroorganic synthesis, organic active materials for organic batteries, and novel π-conjugated molecules. Ryutaro Hayashi graduated from Kyoto University in 2013. He received his M.Sc. in 2015 from Kyoto University. Currently, he is working on his Ph.D. under the supervision of Professor Jun-ichi Yoshida at Kyoto University.

ACKNOWLEDGMENTS This work was partially supported by the Grant-in-Aid for Scientific Research (S) (no. 26220804) ABBREVIATIONS AFM atomic force microscopy BMIm 1-butyl-3-methylimidazolium CSI-MS cold-spray ionization mass spectrometry DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DFT density functional theory D−L dendritic−linear D−L−D dendritic−linear−dendritic DMSO dimethyl sulfoxide IL ionic liquid IR infrared Lut 2,6-lutidinium MALDI-TOF MS matrix assisted laser desorption/ionization mass spectrometry NMR nuclear magnetic resonance PIFE phenyliodine(III)bis(trifluoroethoxide) SCE saturated calomel electrode SEC-MALLS size-exclusion chromatography-multiangle light scattering SN2 bimolecular nucleophilic substitution TEDAMS tris(extended diarylmethyl)silyl TEDAMS-H tris(extended diarylmethyl)silane TEMPO 2,2,6,6-tetramethylpiperidin-1-oxyl THF tetrahydrofuran TMOF trimethyl orthoformate REFERENCES (1) Moss, R. A., Platz, M. S., Jones, M., Jr., Eds. Reactive Intermediate Chemistry; Wiley: Hoboken, NJ, 2004. 4726

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