DOI: 10.1002/cctc.201402366

Carbon–Carbon Bond Formation via Electron Transfer:Anodic CouplingHans J. Sch�fer*[a]

Introduction

Reactive intermediates (radicals, radical ions, carbocations andcarbanions) for carbon–carbon bond formation can be gener-ated by electron transfer. Electrosynthesis is a useful andwidely applicable method to do that at ambient temperatureand pressure.[1]

For an electrosynthesis one needs a beaker-type cell, a sol-vent and a supporting electrolyte for dissolving the substrateand to conduct the electrical current. In the cell are placedtwo electrodes, an anode for oxidation, frequently made ofplatinum, graphite or glassy carbon, and a cathode for reduc-tion, often made of steel or graphite. Direct current is suppliedby a power supply, at which the current and the voltage at theworking electrode are adjusted. All these items are commer-cially available and can be assembled in a short time.[2a,b] In-creasingly, both electrodes are applied for performing a usefulreduction and an oxidation simultaneously in one cell (pairedelectrolysis). Electrosynthesis meets many of the requirementsof green chemistry.[3a,b]

Today, a broad scope of electrochemical reductions and oxi-dations by direct and indirect electrolysis are available and thenumber of reactions is continuously being extended.[1, 4a–g] Ina direct electrolysis, electrons are directly transferred from theelectrode to the substrate; in indirect electrolyses, electronsare transferred from an electrocatalyst (mediator), the activeform of which is regenerated at the electrode. This procedurecan facilitate the electron transfer leading to lower potentialsfor the conversion; furthermore, a higher or different selectivitycan be achieved. In addition, passivation resulting from insulat-ing deposits at the electrode surface can be decreased.[5]

As the field of electrochemical reactions is too broad to befully reviewed here, the following reactions have been chosento provide readers with a highlight of selected conversionsthat can be accomplished; for extended reviews, see Ref. [4] .

Coupling and cross-coupling of aromaticcompounds

Anodic oxidation can be used to couple alkyl-substituted aro-matic hydrocarbons to diphenyls and diphenylmethanes. Forexample, on oxidation of mesitylene (1), the radical cation isformed, which can undergo a radical–radical coupling to the

dimer dication that is deprotonated to diphenyl 2. As an alter-native, the radical cation 1+ · can react in an electrophilic addi-tion with 1 to form a dimer radical cation 2+ ·, which leads toa deprotonation–1 e� oxidation–deprotonation to diphenyl 2(Scheme 1 a).[6] Similarly, 1,2,4,5-tetramethylbenzene (3) yieldsdiphenylmethane 4 by deprotonation–oxidation of the radicalcation 3+ · to a benzyl cation 3(�H)+ that reacts in an electro-philic substitution with 3.[6]

Naphthalene (5) and pentamethylbenzene (6) undergoa cross-coupling reaction in good selectivity to form 7.[7]

The carbon–hydrogen/carbon–hydrogen cross-coupling oftwo unactivated aromatic compounds was performed by gen-erating the radical cation of one aromatic compound at lowtemperature (�78 8C) in over-stoichiometric amounts. There-after, the second aromatic compound was added to the radicalcation solution at �90 8C. In this way, eight different radicalcations could be added to four different aromatic compoundsthat acted as acceptors. In these reactions, the cross-couplingproduct could be obtained in high selectivity and mostly 70–87 % yield with efficient suppression of further oxidation of theproduct.[8]

Scheme 1. Anodic coupling of a) mesitylene to dimesitylene (2) and b) tetra-methylbenzene (3) to diphenylmethane 4 ; c) cross-coupling of naphthaleneand pentamethylbenzene to 7. AcOH = Acetic acid.

[a] Prof. Dr. H. J. Sch�ferOrganisches-Chemisches InstitutWestf�lische Wilhelms-Universit�tCorrens-Strasse 40, 48149 M�nster (Germany)

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Anodic coupling of phenols

Phenols can be coupled via phenoxyl radicals and phenol radi-cal cations formed by oxidation and deprotonation. The phen-oxyl radicals react by carbon–carbon and carbon–oxygen cou-pling to form dimers that can be further oxidised. Blocking ofthe 2, 4 or 6-position makes the coupling reaction more selec-tive. Phenols with an unsubstituted p-position usually formp,p’-coupling products as the major dimer (Figure 1): 8 inmethanol, dichloromethane and lithium perchlorate with a plat-inum anode.[9] If the 4-position is blocked, o,o’-coupling be-comes the main reaction, as found for 9 at a platinum anodein sodium methoxide–methanol[10] or for 10 and 11 in hexa-fluoroisopropanol at a boron-doped diamond anode.[11]

The procedure with the boron-doped diamond anode wasdeveloped further to allow the application of the less expen-

sive electrode material graphite and the cheaper fluorinatedsolvent trifluoroacetic acid; both permitted the selective o,o’-coupling with broad scope.[12] In a recently reported cross-cou-pling reaction, 4-methylguajacol and 2-methoxynaphthalenewere oxidised in N-methyl-N,N,N-triethylammonium methyl sul-fate, hexafluoroisopropanol and methanol in an undivided cellat a boron-doped diamond anode and a nickel cathode. Theheterocoupling product was obtained in 42 % yield and 42 %current efficiency and the ratio of unsymmetrical to symmetri-cal product was greater than 100:1 (Scheme 2). The largescope of the reaction was demonstrated with thirteen differentphenols and eight different arenes and a mechanism was pro-posed.[13]

Aryl ethers

Intermolecular coupling

Aryl ethers couple more selectively than phenols. Amixture of trifluoroacetic acid (TFA) and dichlorome-thane was found to be a useful electrolyte.[14] Select-ed examples are shown in Figure 2. Anisole was di-merised to 12 in TFA–dichloromethane (1:2) and [n-Bu4N][BF4] at a platinum anode.[14] 9-Methoxyanthra-cene afforded the dimer 13 in acetonitrile, TFA and[n-Bu4N][BF4] .[15] From a catechol ketal in acetonitrileand [n-Bu4N][BF4] , the cyclotrimer 14 was obtained

on a 20 g scale;[16a] 14 was applied as a platform structure forthe synthesis of rigid receptors.[16b]

Intramolecular coupling

The anodic cyclisation of benzyltetrahydroisoquinolines 15(Scheme 3) to the morphinan skeleton is particularly interest-

ing from a preparative point of view. The cyclisation cannot beachieved in a simple and selective way with chemical oxidants.The flavinantines 16 with three ether groups can be obtainedin 43–85 % yield in acetonitrile and sodium bicarbonate in a di-vided cell[17a,b] or in an undivided cell with an acidic electro-lyte.[18]

Figure 1. Anodic coupling of phenols.

Scheme 2. Highly selective cross-coupling of 4-methylguajacol with 2-me-thoxynaphthalene. HFIP = Hexafluoroisopropanol.

Figure 2. Intermolecular anodic coupling of aryl ethers to dimers andtrimers.

Scheme 3. Anodic cyclisation of benzyltetrahydroisoquinolines 15 to flavi-nantines 16. R1 = CH3; R2 = CH3 ; R3 = CH3 ; R4 = CH3, C6H5CH2, H.

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Intermolecular coupling of olefins

Styrene and indene derivatives are dimerised to 1,4-dime-thoxy-1,4-diphenylbutanes or 1,4-diphenylbutadienes by ho-mocoupling of the radical cations followed by methanolysis ordeprotonation of the dimer dication.[19a,b] The product distribu-tion depends to some extent on the anode potential and thesupporting electrolyte.

Anodic oxidation of enol ethers in methanol with eithersodium iodide or sodium perchlorate provides, in 30–60 %yield, acetals or ketals from 1,4-dicarbonyl compounds(Scheme 4).[20a,b] Likewise, silyl enol ethers can be dimerised to1,4-dicarbonyl compounds in good yield (Scheme 4).[20c]

Intramolecular coupling of olefins

The intramolecular anodic coupling of olefins involving radicalcations derived from enol ethers, vinyl sulfides and ketene ace-tals that react with carbon, oxygen and nitrogen trappinggroups has been reviewed.[21] The reaction is applied to con-struct five-membered rings that can be used for the synthesisof tricyclopentanoid ring systems, core structures in biological-ly active natural products.

The key step in the synthesis of the arteannuin ring skeletonis the intramolecular anodic coupling of a ketene acetal anda furan (Scheme 5).[22a] In a related cyclisation to the sesquiter-

pene lactone (�)-alliacol, the electrolysis could be accom-plished with simple, cheap and readily available equipment,namely a three-necked round-bottom flask, graphite electrodesand a 6 V lantern battery.[22b]

Anodic cycloaddition of olefins

cis-Cyclooctene cannot be oxidised in the electrolyte dichloro-methane–[n-Bu4N][B(C6F5)4] because its oxidation potential ismore anodic than that of the electrolyte. However, under thesame conditions in the presence of catalytic amounts of[ReCp(CO)3] , cis-cyclooctene is oxidised to form the cyclodimerin a few minutes in 70–80 % yield. Presumably, [ReCp(CO)3]acts as a mediator; it is oxidised to [ReCp(CO)3]+ , which con-verts the cycloolefin to a radical cation that undergoes cyclodi-merisation with cis-cyclooctene as donor (Scheme 6).[23]

Conclusions

Electrolysis provides a short and green access to dimers ofalkyl aromatic compounds and allows highly selective cross-couplings of different phenols and cyclisations of aryl ethersand enol ethers in mostly high yields. The mechanistic coursecan be explained with radical cations as intermediates. Abroad scope of the reactions is demonstrated and they pro-ceed at ambient pressure and temperature with electrical cur-rent as the only “reagent” in inexpensive and readily availableequipment.

Keywords: C�C coupling · enol ethers · intramolecularcoupling · electrosynthesis · phenols

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Scheme 4. Anodic coupling of enol ethers at the b position to the alkoxyand silyloxy group with yields of the dimer.

Scheme 6. Anodic cyclodimerisation of cis-cyclooctene mediated by[ReCp(CO)3] .

Scheme 5. Anodic intramolecular coupling of a ketene acetal with a furan asthe key step in the synthesis of the arteannuin ring skeleton. RVC= Reticu-lated vitreous carbon, Ts = tosyl, TsOH = toluene sulfonic acid, TIPSO = triiso-propylsilyl ether.

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Received: May 22, 2014

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HIGHLIGHTS

H. J. Sch�fer*

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Carbon–Carbon Bond Formation viaElectron Transfer: Anodic Coupling

Electrochemical carbon–carbon cou-pling: Electrolysis is a facile and greenroute to dimers of alkyl aromatic com-pounds, enabling cross-couplings ofphenols and cyclizations of aryl ethersand enol ethers in high selectivities andyields. This Highlight describes thebroad scope and simplicity of anodiccoupling. HFIP = Hexafluoroisopropanol.

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