DOI: 10.1002/adsc.201300865 Transition Metal …szolcsanyi/education/files/Chemia... · ed C H bond...

DOI: 10.1002/adsc.201300865

Transition Metal-Mediated Direct C�H Arylation ofHeteroarenes Involving Aryl Radicals

H�l�ne Bonin,a,* Mathieu Sauthier,a and FranÅois-Xavier Felpinb,*a Universit� de Lille, UMR CNRS 8181, Unit� de Catalyse et Chimie du Solide, USTL–ENSCL, BP 90108, 59652

Villeneuve d’Ascq cedex, FranceFax: (+33)-320-436-585; phone: (+ 33)-320-434-893; e-mail: [email protected]

b Universit� de Nantes, UFR Sciences et Techniques, UMR CNRS 6230, CEISAM, 2 rue de la Houssini�re, BP 92208,44322 Nantes Cedex 3, FranceFax: (+33)-251-125-402; phone: (+ 33)-251-125-422; e-mail: [email protected]

Received: September 25, 2013; Revised: November 18, 2013; Published online: January 31, 2014

Abstract: This review gives an overview of the gener-ation of aryl radicals, mediated by transition metals,and their use for the C�H arylation of heteroarenes.The different sources of aromatic derivatives able togenerate aryl radicals via a metal-assisted reductionor oxidation are discussed, with a critical view of thedeveloped systems. The radical arylations of nitro-gen-, oxygen- or sulfur-containing heterocycles arethen described and mechanistic considerations arediscussed as well.

1 Introduction

2 Generation of Aryl Radicals using a Reductant2.1 Phenyliodonium Salts2.2 Aromatic Halides2.3 Arenediazonium Salts3 Generation of Aryl Radicals using an Oxidant3.1 Arylhydrazines3.2 Arylboronic Acids4 Conclusion

Keywords: aryl radicals; arylation; boronic acids; di-azonium salts; heterocycles

1 Introduction

The metal-catalyzed direct C ACHTUNGTRENNUNG(sp2)�H arylation of het-erocycles has attracted considerable attention as suchan approach saves a pre-functionalization step of theheterocyclic structure.[1] The activation of the hetero-arene moiety, usually consisting in a halogenation,borylation or stannylation step, proved to be some-times perilous due to the higher sensitivity towardboth acidic and basic conditions compared to morerobust arenes. The numerous direct C�H arylationmethodologies developed during the past years havechanged the way chemists draw up synthetic routesand opened the door to higher molecular diversity.[2]

Most direct C ACHTUNGTRENNUNG(sp2)�H arylations are initiated throughan oxidative addition of a transition metal includingPd,[3] Ru,[4] Fe,[5] and Cu[6] onto a haloarene for themost representative ones, followed by a metal-mediat-ed C�H bond activation. However, the high inertnessof the C�H bond requires, in most cases, rather ele-vated temperatures as well as elaborate ligands.

On the other hand, the metal-mediated C ACHTUNGTRENNUNG(sp2)�Harylation of heteroarenes involving aryl radicals hasrecently emerged as a promising alternative, allowingprocesses at room temperature and under relatively

simple experimental conditions. Although this ap-proach has been known for a long time with the workof Meerwein,[7] it only recently turned out to be effi-cient with the development of novel catalytic systems.This review aims to provide a picture of the actualstate-of-the-art involving the arylation of heteroar-enes or by extension, olefin-containing heterocycles,with aryl radicals generated by transition metals. De-pending on the nature of the reagent, the aryl radicalformation mechanism might obviously be different.Whereas iodonium salts, aromatic halides and diazo-nium salts have to be reduced to generate the corre-sponding aryl radicals, their formation from arylhy-drazines and boronic acids requires the use of oxi-dants. It should be noted that transition metal-free ap-proaches have also shown promising results and read-ers interested by this field can find excellent recentreviews on this topic.[8] We also excluded from thisreview any non-transition metal-mediated arylationprocesses involved in a radical chain mechanism withBu3SnH, (Me3Si)3SiH as well as SmI2. This field of re-search has been already reviewed by Vaillard andStuder.[9]

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2 Generation of Aryl Radicals usinga Reductant

2.1 Phenyliodonium Salts

Diaryliodonium salts have recently emerged as highlyreactive, non-toxic synthetic intermediates.[10] Thesesalts are usually more reactive than their correspond-ing aromatic halides, due to the excellent leavinggroup ability of the aryl iodide. Even though theyhave been mostly used for transition metal-catalyzedcarbon-carbon cross-coupling reactions,[11] many otherapplications have been developed over the past fewyears: racemic or enantioselective arylation of car-bonyl compounds, metal-free electrophilic arylationof heteroatom-containing nucleophiles, photochemicalpolymerization, etc.[12] Direct C�H arylations ofarenes and heteroarenes involving hypervalent iodidederivatives have been recently reported with[13] orwithout[14] transition metal catalysts.

Diaryliodonium salts are considered as mild oxi-dants [for example, E0

1/2 (Ph2IPF6)= 0.04 V vs. NHE]able to generate aryl radicals in the presence of a re-ductant or by photodecomposition.[15] They representan important source of radicals for various applica-tions such as photoinitiated cationic polymerization[16]

or electrochemical grafting on glassy carbon sur-ACHTUNGTRENNUNGfaces.[17] An interesting property of radicals arisingfrom diaryliodonium salts is that they can be generat-ed at room temperature, allowing the use of mild re-action conditions. Based on this principle, Sanford de-veloped a new strategy, merging Pd-catalyzed C�Hfunctionalization and visible-light photocatalysis, toproduce biaryls at a remarkably low temperature.[18]

Zhang and Yu reported the metal-free arylation ofpyrroles, pyridine and pyrazine, used in excess (>50–70 equiv.), in the presence of NaOH at 80 8C withmoderate to excellent yields.[19]

Only a few examples of the arylation of heteroar-enes using iodonium salts as radical source have beendescribed until now, and only two examples useda transition metal catalyst.[20] Xue and Xiao published

H�l�ne Bonin was born in 1980in Dunkerque (France). Sheobtained a Masters degreefrom the University of Houstonand CPE Lyon, before movingto the University of Toulouseto work under the supervisionof Dr. Gras on the synthesis ofdioxazaborocanes and thedesign of palladium catalysts.After getting her Ph.D. in 2009,she held a post-doctoral fellowship bridged betweenthe group of Prof. Malacria at UPMC Paris and thegroup of Prof. Curran at the University of Pitts-burgh, working on NHC-borane complexes. In 2011,after a second brief post-doctoral position at theUniversity of Rennes 1, working on metathesis reac-tions with Drs. Bruneau and Fischmeister, shejoined the University of Lille as assistant professorin the group of Prof. Mathieu Sauthier, working oncarbonylation reactions and homogeneous catalysis.

Mathieu Sauthier was born in1974 in Dole (France). Heworked on the synthesis of 2-pyridylphospholes and theiruse as ligand in homogeneouscatalysis during his Ph.D. stud-ies which were completed in2001 at the University ofRennes 1 under the supervisionof the Prof. R�gis R�au. He

moved to the University of Amsterdam (UVA) fora post-doctoral position working on the chemistry ofamphiphilic phosphines in the laboratory of Prof.Piet W. N. M. Van Leuween and Prof. Joost Reek.In 2002, he was appointed assistant professor inProf. Andr� Mortreux�s laboratory at the Universityof Lille 1 and was promoted to professor in 2011.His current research interests are dedicated to ho-mogeneous catalysis, carbonylation reactions and tothe chemistry of 1,3-butadiene.

FranÅois-Xavier Felpin wasborn in Villefranche-sur-Sa�ne (France) in 1977. Hereceived his Ph.D. degree in2003 from the University ofNantes under the supervisionof Prof. Jacques Lebretonworking on the synthesis ofalkaloids. After his Ph.D., heheld a post-doctoral positionwith Prof. Robert S. Colemanat The Ohio State Universityworking on the synthesis of mitomycin. In 2004 hejoined the University of Bordeaux 1 as assistant pro-fessor and he received his habilitation in 2009. Infall of 2011 he moved to the University of Nanteswhere he was promoted to full professor. His re-search interests include heterogeneous and homoge-neous sustainable catalysis as well as medicinalchemistry.

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the room temperature photoredox-catalyzed arylationof various heteroarenes with diaryliodonium salts.[20a]

They combined the use of a ruthenium catalyst[Ru ACHTUNGTRENNUNG(bpy)3Cl2]·6 H2O with blue LED light (460�15 nm) to generate the radical. The reaction condi-tions were optimized for the arylation of N-methyl-pyrrole with diphenyliodonium salt, highest yieldsbeing obtained using 50 equiv. of N-methylpyrroleand 1 mol% of Ru catalyst at 25 8C for 12 h in aceto-nitrile (Scheme 1).

The amount of catalyst could be decreased to0.05 mol%, but the reaction time had to be increasedto 36 h. The counterion of the diphenyliodonium saltshowed an influence on reaction yields. The trifluoro-methanesulfonate and hexafluorophosphate deriva-tives gave the highest yield (84%), while tetrafluoro-borate, trifluoroacetate or bromide derivatives led toabout 70% yield. Using the optimized conditions, theauthors subsequently investigated the scope of the re-action. The C�H arylation of N-methylpyrrole wasfirst examined with various substituted symmetricaldiaryliodonium salts. Higher yields were obtained inthe presence of electron-withdrawing substituents,even at the ortho-position (Scheme 2). This trend isdue to the increasing redox potentials of electron-poor aromatic rings. The reaction is regioselective,since pyrrole was arylated only at C-2, as well as che-moselective, since halide groups on the aryl moietywere tolerated.

When unsymmetrical diaryliodonium salts wereused, the authors noticed that the less hindered arylgroup was preferentially transferred. However, onlyarylmesityliodonium salts were tested, and the un-reactive mesityl group is not only hindered but alsoelectron-rich so that the electronic properties of themesityl group might be predominant over the sterichindrance to explain this reactivity. Arylated N-meth-ylpyrroles were thus obtained after radical couplingswith unsymmetrical iodonium derivatives, albeit withlower yields than those obtained with the correspond-

Scheme 1. Optimized conditions for the arylation of N-methylpyrrole with diphenyliodonium salt catalyzed bya ruthenium photoredox catalyst.

Scheme 2. Radical arylation of N-methylpyrrole with varioussymmetrical diaryliodonium salts.

Scheme 3. Radical arylation of N-methylpyrrole with variousunsymmetrical diaryliodonium salts.

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REVIEW Transition Metal-Mediated Direct C�H Arylation of Heteroarenes


ing symmetrical salts (Scheme 3). Electron-withdraw-ing substituents on the aryl moiety increased the reac-tion yields.

The C�H arylation with diaryliodonium salts wasthen extended to other electron-poor and electron-rich heteroarenes, such as pyrrole, substituted pyr-roles, furan, thiophene, benzofuran, benzothiopheneand pyrazine. It is worth noting that no protection ofthe nitrogen was required for the couplings with pyr-role or substituted pyrroles. Electron-rich heteroar-enes coupling with electron-deficient aryl radicalsprovided heterobiaryls in higher yields. Whatever thenature of the heteroarene, the monoarylation only oc-curred at C-2 with good to excellent yields. Theamount of heteroarene could be reduced to 10 equiv-alents without a noticeable reduction in the yields.The methodology was also applied to electron-defi-cient arenes with moderate to good yields(Scheme 4).

Finally, the mechanism of the reaction was exam-ined and preliminary investigations were reported.

When the arylation of N-methylpyrrole with dipheny-liodonium triflate is conducted in the presence of theradical trapping TEMPO, the isolated yield of arylat-ed pyrrole decreases significantly from 81% to 22%,while the TEMPO-trapped O-aryl intermediate is iso-lated in 17% yield. These observations support thehypothesis of a radical mechanism (Scheme 5).

Tosibu and Chatani recently reported the roomtemperature, visible light-mediated arylation ofhetero ACHTUNGTRENNUNGarenes using an iridium photoredox catalystwith various symmetrical diaryliodonium salts.[20b]

Under the optimized conditions the radical arylationof pyridine, pyrazine, pyrimidine, N-methylpyrrole orNH-free pyrrole, imidazole and thiophene withdiphenylACHTUNGTRENNUNGiodonium hexafluorophosphate led to the for-mation of the desired products in moderate to goodyields (Scheme 6).

Heteroarenes were used as both solvent and reac-tant in a large excess (~40 equiv.). The best yieldswere obtained using pyrrole and pyrimidine (63–88%)while other heterocycles gave coupling products inlower yields (33–55%). The arylation occurred exclu-sively a to the heteroatom, except with pyridine andpyrazine which led to a mixture of regioisomers. Thearylated adducts were isolated in higher yields withelectron-poor diaryliodonium salts (68–76%) thanwith electron-rich ones (0–61%). A reaction mecha-nism, starting from a single-electron transfer (SET) ofthe excited Ir ACHTUNGTRENNUNG(III)* catalyst to the iodonium salt, isdescribed by the authors (Scheme 7, path a). A singu-

Scheme 4. Radical arylation of various heteroarenes with di-(4-acetylphenyl)iodonium triflate.

Scheme 5. Mechanism of the transition metal photocata-lyzed arylation of N-methylpyrrole with diphenyliodoniumtriflate salt.




lar reactivity was observed, however, with N-methyl-pyrrole, since the reaction could surprisingly be suc-cessfully conducted in the presence of white LEDlight but without a photoredox catalyst. The 2-phenyladduct was isolated in a non-negligible yield of 54%at room temperature under these conditions. The au-thors suggested the generation of a charge-transfercomplex (CTC), whose formation is supported by theobservation of a new band in the UV-vis spectrum ofa mixture of pyrrole and diphenyliodonium hexafluor-ophosphate. The excitation of the CTC generates thearyl radical and the pyrrole radical cation, which re-combine to form the 2-arylated pyrrole cation. Itsrearomatization by loss of a proton generates the ary-lated adduct (Scheme 7, path b). Both mechanismsare thus complementary in the arylation of N-methyl-pyrrole with diaryliodonium salts. However, the for-mation of the aryl radical by SET seems to be pre-dominant with electron-rich diaryliodonium salts,since yields of arylated pyrroles are much lower inthe absence of the photoredox catalysts (see yields inparenthesis in Scheme 7), while the CTC formationprevails for the electron-poor iodonium salts.

Only two examples of transition metal-catalyzed ar-ylation of heteroarenes with diaryliodonium saltshave been published until now. The arylated productswere isolated with moderate to excellent yields, butimproved methodologies using equimolar amounts ofreactants are still highly desired. Even though theproduction of aryl iodide as by-product might be con-sidered as a limitation, its purification and recyclingcan be envisaged.

2.2 Aromatic Halides

Aromatic halides are among the most commonly usedreagents in organic chemistry, especially for the con-struction of carbon-carbon bonds. A wide variety ofhalogenated starting materials is commercially avail-able, and many efforts have been made to developnew methodologies to activate the less reactive butless expensive chloride derivatives. The transitionmetal-catalyzed cross-couplings of electrophilic arylhalides with nucleophilic organometallic reagents,known as the Suzuki–Miyaura, Stille, Hiyama orKumada–Corriu reactions,[21] are among the mostpowerful existing methods for the synthesis of(hetero) ACHTUNGTRENNUNGbiaryls. More recently, the direct arylation ofaromatic compounds by C�H activation with aryl hal-ides has emerged as a very attractive atom-economi-cal method, especially for the synthesis of heterobiar-yls, directly from the heteroarenes, such as furans, thi-ophenes, pyrroles, oxazoles, thiazoles, etc.[22]

Different methods have been used to generate arylradical from aryl halides, including visible-light irradi-ation,[23] electrochemical reduction[24] or activation by

Scheme 6. Iridium-catalyzed radical arylation of various het-eroarenes with symmetrical diaryliodonium salts.

Scheme 7. Mechanisms of the iridium photocatalyzed aryla-tion of N-methylpyrrole with diaryliodonium salts.




organic derivatives, such as potassium tert-but-ACHTUNGTRENNUNGoxide[8a,25] or silicon derivatives.[26] The transitionmetal-mediated radical C�H arylation of (hetero)ar-enes has the advantage of requiring only a catalyticamount of radical initiator, but it usually requires sev-eral equivalents of a strong base and a very largeexcess of (hetero)arene. Iridium,[27] cobalt,[28] nickel[29]

and iron[30] catalysts have been used to carry out thedirect C�H arylation of unactivated arenes with goodto excellent yields, starting from aryl iodides, bro-mides and even chlorides, although with lower yieldsin the latter case.[29]

Li and Hua described the first transition metal-mediated radical arylation of electron-poor pyridineusing an Au(I) catalyst.[31] The reaction was examinedwith pyrazine as well, but mechanistic investigationsusing 1,2-dihydroxybenzene as radical inhibitorshowed that a radical pathway was probably not in-volved with this substrate. The optimization of the re-action conditions was done with pyrazine, and thesame conditions could be applied to pyridine. Amongthe different Au(I) catalysts and bases tested, thecombination of PCy3AuCl and t-BuOK proved to bethe best. t-BuOK alone is able to generate aryl radi-cals from aryl halides, but when the reaction was car-ried out without the Au catalyst, the yield droppeddramatically. It is worth noting that the reaction ishighly base dependent since t-BuOK is the only basethat led to the formation of the desired product. Thereaction with pyridine required a 5 mol% catalystloading, a moderate to high temperature (60–100 8C)as well as a large excess of pyridine (~25 equiv.) andled to mixtures of 2-, 3- and 4-arylpyridines with mod-erate yields, the ortho-derivative being always themajor compound (Scheme 8).

The reaction is sensitive to steric hindrance, sincethe isolated yield of arylpyridine was 26% when 2-bromotoluene was used, whereas it increases to 48%with 4-bromotoluene. When electron-poor 1-bromo-4-chlorobenzene was used, the reaction temperaturehad to be decreased to 60 8C to avoid the formationof the 1-chloro-tert-butoxybenzene side-product. Fi-nally, use of 2-bromo-6-chlorotoluene led to the ex-clusive formation of the corresponding 2-arylpyridine,albeit in a low yield.

To prove the free radical mechanism, the authorscarried out the reaction using bromobenzene and pyr-idine in the presence of 10 mol% of the radical inhibi-tor 1,2-dihydroxybenzene, and the desired phenylpyri-dine could not be detected under these conditions.However, the mechanism of the aryl radical formationwas not detailed.

The Ni-catalyzed C�H arylation of electron-defi-cient pyridine was described with various aryl bro-mides.[29] The optimized reaction conditions useda combination of 5 mol% of bis(cyclopentadienyl)-nickel and PPh3, with one equivalent of t-BuOK, inpyridine (60 equiv.) at 100 8C for 12 h. The reactiontemperature was higher than that required for the ar-ylation of benzene and naphthalene with the corre-sponding aryl bromides. With these conditions inhand, mixtures of 2-, 3- and 4-arylpyridines could beisolated with good yields (Scheme 9). Due to the pres-ence of 3- and 4-substituted pyridines, the arylationmechanism seems to proceed through a radical path-way rather than ortho-metallation that would lead tothe exclusive formation of the 2-substituted adduct.The observed ratios differing from that observed withthe Au-catalyzed radical arylation,[31] the authors con-sidered that the mechanism is more complex andmight not be proceeding only via a radical pathway.

Scheme 8. Gold-catalyzed radical arylation of pyridine witharyl bromides.

Scheme 9. Nickel-catalyzed radical arylation of pyridinewith aryl bromides.




Finally, Chan et al. recently reported the C�H ary-lation of both electron-rich and electron-poor hetero-arenes with aryl halides catalyzed by a cobalt(II) por-phyrin.[32] The optimization of the reaction conditionswas not detailed, but authors used a catalytic amountof 5 mol% of cobalt(II)-tetrakis-4-anisylphorphyrin-ACHTUNGTRENNUNGato dianion, combined with 10 equivalents of KOHand t-BuOH and a large excess of heteroarene(100 equivalents) serving both as reactant and solvent,at 200 8C (Scheme 10). Under these conditions, 2-ary-lated furans or pyrroles were obtained in good yields(50–70%) with short reaction times (15–60 min). Asusually observed for coupling reactions with aromatichalides, yields were higher and reaction times shorterwhen iodide derivatives were used instead of bro-mides. The scope of the reaction was thus extendedusing aryl iodides. It is worth noting that the reactionwas regioselective since only 2-arylated products wereisolated, as well as chemoselective since no competingreaction was observed at the nitrogen-free atom. Pyr-role reacted faster than furan and consistently led tothe formation of arylated products in higher yields.

In contrast to the regioselective arylation of pyrroleand furan, the arylation of thiophene and pyridine ledto a mixture of isomers (Scheme 11).

The formation of two isomers for the thiophene ar-ylation was explained by the stabilization of the radi-cal intermediate. Due to the available d orbital of the

sulfur atom which can participate in mesomericforms, the 3-arylthiophenium radical intermediate canindeed be stabilized by resonance, whereas this phe-nomenon is not possible with oxygen- or nitrogen-containing 5-membered rings (Scheme 12).

Concerning the mechanism, authors suggested a ho-molytic aromatic substitution (HAS), as described byCurran and Studer for the organocatalytic C�H aryla-tion of arenes and heteroarenes.[8a] Competition reac-tions with an equimolar mixture of benzene and a het-eroarene (pyridine, furan, thiophene and pyrrole)showed that the radical consistently reacted fasterwith electron-richer substrates, demonstrating theelectrophilic nature of aryl radicals. The SOMO-HOMO energy level difference was also examined fordifferent substrates and confirmed the electrophilicnature of the radical. Based on these data, Chan et al.proposed the mechanism shown in Scheme 13.

The wide variety of commercially available substi-tuted aryl iodides or bromides makes them promisingcandidates for the synthesis of arylated heteroarenes.A quite high catalyst loading is, however, required fortheir reduction into the corresponding aryl radical.The development of more efficient catalysts seemsthus to be essential to make the use of aromatic hal-ides even more attractive for these arylations, espe-

Scheme 10. Cobalt-catalyzed radical arylation of pyrrole andfuran with aryl iodides.

Scheme 11. Cobalt-catalyzed radical arylation of thiopheneand pyridine with 4-iodotoluene.

Scheme 12. Stabilization of the 3-arylthiophenium radical byresonance.




cially to reduce the reaction temperature as well asthe amount of base and heteroarene.

2.3 Arenediazonium Salts

Arenediazonium salts are well known species discov-ered at the end of the 19th century by Peter Griesswho worked on dyes and pigments. They can be clas-sified as “super-electrophiles” and highly reactive arylhalide surrogates.[33] Although diazonium ions havebeen occasionally exploited for transformations in-volving aryl cations, they have attracted much moreimportant interest as aryl halide substitutes for palla-dium-catalyzed coupling reactions including Heck-[34]

and Suzuki-type[35] transformations.However, depending on the reaction conditions, di-

azonium ions can also follow a homolytic pathway.Indeed, they are well known aryl radical precursorsthrough homolytic C�N bond cleavage.[36] The highredox potential of these species (Ered> 0.5 V vs.NHE) allows rapid electron transfer processes froma reducing agent capable of supplying a single elec-tron. Electron-withdrawing substituents on the arylmoiety increase the redox potential of diazoniumsalts, favouring thereby, the homolytic C�N bondcleavage. Electrochemical,[37] photo-induced[38] andmetal-catalyzed reductions are the main pathways forgenerating aryl radicals from diazonium salts. Therole of the counterion in the redox process has notbeen rationalized nor thoroughly studied although

one can expect that it does not act as a spectator re-garding the reaction outcome.

A number of transformations involving aryl radicalsgenerated from diazonium salts has been developedfor many years and includes the Sandmeyer,[39]

Pschorr,[40] Gomberg–Bachmann[41] and Meerwein re-actions. The Meerwein reaction,[7] a copper-catalyzedredox transformation between diazonium ions andolefins, can be formally classified as a C�H arylationsince the products are usually synthetically equivalentto those obtained through a Pd-catalyzed Heck reac-tion. However, the generally low efficiency of theMeerwein reaction precluded its development fromfurther synthetic relevant applications. It has been es-sentially studied with acrylates, methyl vinyl ketonesand styrenes as olefinic partners under copper(II)chloride catalysis in aqueous conditions.[42] Alterna-tively, the use of stoichiometric amount (2–3 equiv.)of Fe(II) and TiACHTUNGTRENNUNG(III) as reducing metals has been suc-cessfully reported for the arylation of various ole-fins.[43] More recently, Kçnig et al. reported visible-light mediated arylations with Ru ACHTUNGTRENNUNG(bpy)3Cl2 as cata-lyst[44] while arylation of heteroarenes under metal-free photocatalyzed reactions were also successful.[45]

On the other hand, the C�H arylation of heteroar-enes following a Meerwein-type reaction has beenmuch less explored, although a few successful ap-proaches should be mentioned.

In their seminal publication,[7] Meerwein and co-workers reported the arylation of coumarins undera copper-catalyzed process. Under the optimized con-

Scheme 13. Mechanism of the cobalt-catalyzed arylation of heteroarenes with aryl halides.




ditions equimolar amounts of coumarin and diazoni-um chlorides were mixed in aqueous acetone at roomtemperature in the presence of a rather high copperloading (30 mol%) (Scheme 14). As diazonium saltshaving a chloride counterion are very unstable intheir dry form, an in situ preparation was preferred.However, in this case, aqueous HCl was used as a sol-vent and the use of an excess of NaOAc as a base wasrequired to buffer the reaction media. Althoughrather synthetically useful yields (40–50%) were ob-tained with para-substituted electron-deficient diazo-nium salts, ortho-substituted, neutral and electron-richdiazonium salts were much less reactive. This resultreflects the easier homolytic C�N bond cleavage ofelectron-poor diazonium salts due to higher redox po-tentials.

The photo-Meerwein arylation of a five-fold excessof coumarin with benzenediazonium tetrafluoroboratehas been described, on a single example, using[Ru ACHTUNGTRENNUNG(bpy)3]

2+ as photocatalyst and visible light inDMSO as solvent.[44a] Under these conditions, a muchimproved yield was obtained compared to the proce-dure described by Meerwein (63% vs. 26%). This ele-gant chemistry has been very recently extended to thesurface patterning of cellulose.[44b] Indeed, coumarin-functionalized cellulose sheets were grafted with 4-methoxybenzenediazonium tetrafluoroborate usinga visible light (455 nm) photocatalyzed Meerwein ary-lation. The use of a photomask to pattern the cellu-lose sheets produced a writing observable by thenaked eye.

Besides coumarin, furans and thiophenes have beenthe most studied heteroarenes as substrates for theMeerwein arylation. The C-5 arylation of furans bear-ing formyl,[46] acetyl,[47] carboxylic[48] and othergroups[49] at C-2 have been described as privilegedstructures, due to their good reactivity with arenedia-zonium salts and the suppression of unwanted C-2/C-5 diarylation processes. Obushak and co-workers haveextensively studied these kinds of couplings (>45 ex-amples). The arylations were typically conducted ina mixture of aqueous HCl and acetone with an equi-molar amount of diazonium salts and furans in thepresence of copper(II) chloride as copper source atroom temperature. Contrary to the original conditionsreported by Meerwein, a base was not required withthese heterocycles although aqueous HCl was usedfor the in situ preparation of the diazonium salt. It is,however, rightful to question the potential influenceof a base and a detailed study for a deeper under-standing of its role would be helpful, especially foracid-sensitive substrates. In most cases, syntheticallyuseful yields, considered as rather high for the Meer-wein arylation (40–70%), were obtained with 2-CO2Me-, 2-COCH3- and 2-CO2H-substituted furans(Scheme 15). The authors noticed a lower reactivityfor arenediazonium salts bearing electron-donor sub-stituents, a trend which was, however, not always re-flected by the yields reported. The arylation of 2-ace-tylfuran provided 2,5-diarylfurans as unusual side-products upon in situ deacetylation as previously ob-served.[50] It is interesting to note that all examples re-ported by Obushak and co-workers were run ona multi-gram scale (0.2 mol) highlighting the scalabili-ty and the robustness of this transformation.

Although the role of the counterion associated tothe diazonium function has not been extensively stud-ied, Obushak and co-workers reported on a single ex-ample, describing for the arylation of furfural, itsstrong influence on the reaction yield (Table 1).[51]

The use of commercially available 4-nitrobenzenedia-zonium tetrafluoroborate was preferable to in situgenerated 4-nitrobenzenediazonium chloride and sul-

Scheme 14. Cu-catalyzed Meerwein arylation of coumarinwith diazonium salts.




fate (entry 1 vs. entries 2 and 3). Although this trendmight not be general to other diazonium salts and/orheterocycles, it could reflect the peculiar role of thecounterion. Moreover, a closer look at the results re-

ported by this group suggested that the influences ofthe catalyst and counterion are strongly and thinlytied (entries 1 and 2 vs. entries 4 and 5). Contrary totheir previous reports, they reported that aqueousDMSO was superior to aqueous acetone or water assolvent media.

Studies directed at the improvement of the reactionhave been scarce and this point should stimulate fur-ther innovative catalytic systems.

Recent studies showed that reaction yields could besignificantly improved, providing that a stoichiometricamount of copper(I) chloride was used as reductant,under water-only conditions for the coupling of diazo-nium chlorides with furfural (Scheme 16).[52] These re-sults suggest that the search for a more robust cata-lyst, having a higher turnover number should defini-tively improve the Meerwein arylation, especially forheterocyclic structures. Although examples workingwith electron-rich diazonium salts were not provided,it should be noted that ortho-substituted aryls werewell tolerated.

When an excess of the heteroarene moiety(5 equiv.) was used with TiCl3 (2 equiv.) as reducingagent, excellent yields of the corresponding arylfuranwere obtained (Scheme 17).[53] Interestingly, the useof pure water as solvent allows a control of the mono-arylation at C-2 of furan due to the insolubility of thediarylated congener. The use of an organic solventconsiderably increased the formation of unwanted di-arylated product. The extension of these reaction con-

Scheme 15. Cu-catalyzed arylation of furans with diazoniumsalts.

Table 1. Arylation of 2-furfural with 4-nitrobenzene diazoni-um salts.

Entry Counterion X� [Cu] Yield [%]

1 BF4� CuCl2 75–80

2345

Cl�

HSO4�

BF4�

Cl�

CuCl2

CuCl2

Cu ACHTUNGTRENNUNG(OAc)2

Cu ACHTUNGTRENNUNG(OAc)2

50–600061–66 Scheme 16. Arylation of furfural by diazonium salts with

a stoichiometric amount of copper(I) chloride.




ditions to the arylation of benzofuran, indole and pyr-idine led to lower yields.

Obushak and co-workers observed that 2-thio-ACHTUNGTRENNUNGphenecarbaldehydes[54] and 2-acetylthiophene[55] dis-played a lower reactivity (20–55%, Scheme 18)toward the radical arylation with arenediazoniumsalts, under copper-catalyzed reaction conditions, thandid their corresponding furan congeners (compareScheme 15 with Scheme 18). It should be noted thata similar trend was previously briefly communicatedduring the preparation of compounds having potentialfluorescent properties.[56] Although modest yieldswere usually obtained, when a catalytic amount ofcopper and an equimolar amount of heterocycleswere used, the Meerwein reaction remains attractivedue to the simplicity of the experimental conditionsand the inexpensive reagents and catalyst required. Ascreening of solvents showed that an organic-aqueousmedium was required for optimal results, with DMSObeing superior to acetone, acetonitrile and DMF asthe organic solvent. The reaction was consistentlyfully regioselective at C-5 for all cases studied, the 4-

nitrobenzenediazonium chloride being the only ex-ception to this trend, giving 27% of the C-3 arylatedproduct.

Applications of the Meerwein arylation of furansand thiophenes for the preparation of high value com-pounds are rare. In the search for H2 receptor hista-mine antagonists, a series of arylated furans, obtainedthrough the Meerwein methodology, has been de-scribed, with albeit limited success.[57] On the otherhand, organic materials incorporating an arylfuran orthiophene skeleton prepared via a Meerwein ap-proach and displaying fluorescent properties havebeen reported a few years ago.[58]

The C�H arylation of maleimide was studied byRondestvedt in the middle of 1950s (Scheme 19).[59]

In most cases, the crude product appeared to be a mix-ture of the expected 3-arylmaleimide along with the3-aryl-4-chlorosuccinimide. However, the latter waseasily converted into the former by a simple base-mediated treatment with 2,6-lutidine or 2,4,6-colli-dine. Sodium acetate was used as a buffer additivebringing the solution to pH 3, due to the excess of

Scheme 17. TiCl3-mediated arylations of various heterocy-cles with diazonium salts.

Scheme 18. Cu-catalyzed arylation of thiophenes with diazo-nium salts.




HCl used for the diazonium salt preparation. Al-though yields were rather modest (20–50%), a surpris-ing effect was observed with electron-rich diazoniumsalts. Indeed, while diazonium salts bearing electron-donating substitutents usually displayed a low reactiv-ity, Rondestvedt observed an inverse phenomenonwith maleimide, leading to a prominent side diaryla-tion process. This unusual behaviour has not beenclearly rationalized and should stimulate further in-vestigations. As a note is the surprising compatibilityof the free NH function with diazonium salts thatallows protecting group-free arylations.

We recently reported a significant breakthrough inthis field with the copper-catalyzed C�H arylation ofpyrroles with in situ generated arenediazonium saltsunder neutral conditions.[60] When we started ourstudies, the metal-catalyzed arylation of pyrroles withdiazonium salts was unknown since their high nucleo-philicity strongly favoured the addition over the di-azonium function, leading to the corresponding azocompound. This unwanted process was even rein-forced in the acidic conditions required for the Meer-wein arylation (pH <3). We reasoned that an N-pro-

tecting group decreasing the nucleophilicity of thepyrrole would disfavour the azo formation. In thesame time, the development of neutral conditionswould also be useful for conserving the integrity ofacid-sensitive pyrroles. Toward this end, we took in-spiration from our publications on metal-catalyzedtransformations involving arenediazonium salts,where we reported unprecedented mild and neutralcondition through in situ activation of anilines.[61]

We modulated the nucleophilicity of the pyrrolewith the evaluation of electron-withdrawing N-pro-tecting groups including carbamates (CO2-t-Bu,CO2Me), sulfonate (Ts) and amide (COPh). Fromthese optimization studies, we learned that stronglyelectron-withdrawing groups such as Ts and COPhdeactivated too much the heterocycle, thereby, de-creasing the reaction yield while carbamates realizeda good balance. The drop of reaction yields with elec-tron-deficient pyrroles might reflect the electrophiliccharacter of aryl radicals. Arenediazonium salts weregenerated in situ from an equimolar amount of ani-line, t-BuONO and MeSO3H. We had previously ob-served that the nature of the counterion surroundingthe diazonium cation greatly influenced the reactionoutcome, and we observed that sulfonates wereanions of choice for Pd-catalyzed Heck-type reaction-s.[61a] Although mechanisms involved were likely verydifferent for copper-catalyzed reactions, a similar be-haviour was observed in this study, since the use ofcommercially available diazonium tetrafluoroboratesconsiderably hampered reaction yields. In order totrap MeSO3H generated during advancement of thereaction and thereby exclude any acid-mediated azoside-products, we selected CaCO3 as a mild base. Thecopper source proved to be crucial for obtaining goodreaction yields. Indeed, with CuCl2, traditionally usedin the Meerwein-type arylation, significant amountsof aryl chlorides were observed due to the trapping ofchlorine by highly reactive aryl radicals. To avoid di-ACHTUNGTRENNUNGarylation side-products at C-2/C-5, a slight excess ofthe pyrrole moiety was required. These optimizedconditions proved to be very efficient with a varietyof anilines, giving yields significantly higher thanthose usually encountered for the Meerwein arylationof heterocycles (Scheme 20). The process was compat-ible with a variety of substituents including esters,ethers, nitriles, nitro, ketones and halogens, revealingthe mild conditions used in this study. The pyrrolemoiety can even react with unusual anthraquinonesand heteroarene nuclei in very synthetically usefulyields.

The mechanism of the Meerwein reaction is stillthe subject of a debate, more than 70 years after itsdiscovery. Meerwein�s classical conditions involveaqueous acetone as solvent and CuCl2 as catalyst. It isusually admitted that CuCl2 is reduced into CuCl byacetone, providing chloroacetone as by-product.[62]

Scheme 19. Cu-catalyzed arylation of maleimides with diazo-nium salts.




Then, CuCl reduces the diazonium salt into an arylradical with concomitant loss of nitrogen. Whilst thismechanism could be acceptable in many cases, itcannot explain why in acetone-free solvents, e.g.,water, acetonitrile or NMP, the reaction still takesplace nor why using directly CuCl tends to be less ef-ficient than starting with CuCl2.

[63] On the other hand,the formation of an arenediazonium tetrachlorocup-ACHTUNGTRENNUNGrate(II) has been suggested when starting from CuCl2

and arenediazonium chlorides, but this complex wasnot reduced by acetone.[64]

In 2009, another mechanism was proposed and in-volved the reduction of CuCl2 into CuCl by the ole-finic substrate giving a radical cation.[65] Then cop-per(I) chloride reduces the arenediazonium salt andthe generated aryl radical reacts with the olefin. Inthe same year this mechanism was criticized, since ap-parently nitrogen cannot be eliminated by reductionof the diazonium salt in the ground singlet state.[66] In-stead, it was postulated that tetrachlorocuprate plays

a key role in the formation of the diazonium salt ina triplet state. In that framework, we underlined thatthe latter previous theoretical work relied on a quitelow level of theory (investigation of molecular orbi-tals with semi-empirical approaches), and did not pro-vide any reaction path (no transition states have beenlocated). On top of that, it cannot explain whyCu ACHTUNGTRENNUNG(OAc)2 gave identical and even sometimes betterresults.

On the basis of literature precedents and with thecomplement of our experimental observations, a cata-lytic cycle was proposed (Scheme 21).

The Cu(I)-catalyzed homolytic dediazoniation ofthe diazonium salt A provides the corresponding arylradical B, quickly intercepted by the heteroarene C.The radical intermediate D is likely quickly oxidizedby Cu(II) species into the corresponding cation Ewhich upon deprotonation provides the expected cou-pling products. With the support of labelled experi-ments we suggested that a base, such a carbonate(CaCO3), could facilitate the deprotonation of thepyrrolo cation E, diminishing, thereby, undesirablepathways.

Although the metal-catalyzed arylation of heterocy-cles with arerediazonium salts had been discovereda long time ago by Hans Meerwein, relatively fewstudies have been undertaken to improve the original

Scheme 20. Cu-catalyzed arylation of pyrroles with diazoni-um salts.

Scheme 21. Proposed catalytic cycle of the Cu-catalyzed ary-lation of heterocycles with diazonium salts.




experimental conditions. We have, however, recentlyshowed that the nature of the diazonium salt as wellas the pH of the media could have a significantimpact on the reaction outcome. The simplicity of theexperimental procedures as well as the high reactivityof diazonium salts, allowing for mild conditions, makethis transformation of high synthetic value. There is,however, still room for improvement to design cata-lytic systems with high turnover numbers, and work-ing with diversely decorated heterocycles.

3 Generation of Aryl Radicals using anOxidant

3.1 Arylhydrazines

Arylhydrazines, known for their genotoxicity and car-cinogenicity,[67] have been mainly used for the synthe-sis of heterocycles such as indoles,[68] indazoles[69] orpyrazoles,[68b,70] as well as electrochemical graftingonto carbon or metal surfaces.[71] Another recent ap-plication is their utilization as arylating agent for thepalladium-catalyzed C�C coupling with heteroar-enes[72] or alkenes[73] via a C�N bond cleavage.

Arylhydrazines are reductants easily oxidized byoxygen or metallic oxidizing agents such as mercury,lead, copper, manganese or iron salts, to generate thecorresponding aryl radicals via the formation of un-stable diazenes. Their oxidation was initially devel-oped for the synthesis of biaryls from arylhydrazinesand aromatic solvents, albeit with moderate yields,using stoichiometric amounts of silver oxide[74] orlead(IV) acetate.[75] More recently, manganese deriva-tives have emerged as powerful oxidants for free-radi-cal generation from arylhydrazines. For instance, thegroup of Demir reported the reaction of phenylhydra-zines with benzene with high yields, using 3 equiva-lents of manganese triacetate either preformed[76] orin situ generated from a KMnO4/CH3COOH mix-ture.[77] More recently, Heinrich et al. extended thescope of this reaction to the synthesis of 2-aminobi-phenyls from arylhydrazines and anilines, by exploit-ing the strong directing effect of the free unprotectedamino group.[78] Finally, the environmentally-friendlyoxidative aryl radical addition into alkenes usingcopper[79] or iron[80] salts was also reported.

The first radical C�H arylation of heterocycles witharylhydrazines was described by Hardie and Thom-son, who reported two examples of arylation of pyri-dine and thiophene, respectively by phenyl- and 4-ni-trophenylhydrazines, with a stoichiometric amount ofsilver oxide as oxidant (Scheme 22).[74] Pyridine wasused as both reactant and solvent, and a mixture of2-, 3- and 4-phenylpyridines was isolated, suggestinga radical mechanism. On the other hand, the arylation

of thiophene was regioselective since only the 2-ary-lated product was isolated. Among the several oxi-dants tested (yellow mercury oxide, cupric oxide, leadoxide), silver oxide proved to be the most efficientone, although oxidation was never quantitative andyields were very low.

The mechanism of the reaction is thought to pro-ceed via the oxidation of the arylhydrazine to the cor-responding unstable hydrazene which decomposesspontaneously to form the aryl radical (Scheme 23).

The mechanism of the reaction between the radicaland the heteroarene was not discussed.

Demir et al. published in 2002 the first mangan-ese ACHTUNGTRENNUNG(III)-mediated radical arylation of thiophene andfuran,[81] using the conditions optimized earlier for thearylation of arenes.[76] Only the 2-substitued furan andthiophene were isolated, demonstrating the regiose-lectivity of the radical reaction. The scope of the reac-tion was then extended to electron-rich and electron-poor substituted phenylhydrazines in moderate togood yields (22–70%), usually higher for thiophenederivatives (Scheme 24). The lowest yields were ob-tained for the arylation of furan with electron-rich 4-methoxyphenylhydrazine (30%) and electron-poorpentafluorophenylhydrazine (22%), whereas the steri-cally-hindered 2-bromophenylhydrazine led to thecorresponding arylated furan or thiophene with good

Scheme 22. First radical arylation of heteroarenes with aryl-hydrazines.

Scheme 23. Mechanism of the arylation of heteroarenes witharylhydrazines.




yields (~60%). It has to be noticed, however, thata high temperature and a large excess of manganeseacetate (3 equiv.) as well as heteroarene(~200 equiv.), used as both reactant and solvent, arerequired.

The formation of the aryl radical was explained bythe formation of the unstable phenyldiazene inter-mediate after two successive Mn ACHTUNGTRENNUNG(III)-mediated oxida-tions (Scheme 25). The continuation of the mecha-nism was not described, but one can assume that theattack of the radical on the heteroarene generatesonly the corresponding 2-arylated 3-radical intermedi-ate, whose stability is greater than that of the 2-radi-cal intermediate. This radical is probably oxidized by

a third equivalent of Mn ACHTUNGTRENNUNG(III) to generate the corre-sponding cation, followed by the rearomatization ofthe arene concomitant with the loss of H+.

Finally, Heinrich et al. developed a manganese-mediated regioselective radical C�H arylation of ani-lines with arylhydrazines and reported, in this paper,one example of arylation of furan (Scheme 26).[78]

MnO2 was used as oxidant, with the hydrochloridesalt of 4-chlophenylhydrazine (to enhance its stability)and 40 equivalents of furan, leading to the exclusiveformation of the 2-(4-chlorophenyl)furan in a yieldsimilar to that obtained by Demir with manganese-ACHTUNGTRENNUNG(III) acetate.[81] The reaction mechanism is not men-tioned but is probably similar to that described byDemir.[81]

Only a few examples of radical arylation of hetero-arenes with arylhydrazines have been published untilnow, probably due to the moderate yields of arylatedproducts and the amount of both oxidizing agent andheteroarene required. The development of new meth-odologies might thus be useful, for instance, to extendthe scope to nitrogen derivatives, such as pyrroles orindoles, and to make more attractive the use of aryl-hydrazines as aryl radical source.

3.2 Arylboronic Acids

Arylboron derivatives are highly stable, non-toxiccompounds, than can be easily synthesized, especiallyby electrophilic trapping with trialkyl borates of or-ganometallic compounds[82] or C�H borylation.[83] Awide variety of derivatives is thus commercially avail-able. They have been extensively used as couplingpartners in the transition metal-catalyzed Suzuki–Miyaura cross-coupling reactions, and much progresshas been achieved to carry out reactions under verymild conditions and with short reaction times, evenwhen challenging partners are used.[84]

Arylboronic acids as well as potassiumaryltrifluoro ACHTUNGTRENNUNGborates are known to decompose intoaryl radicals through a single-electron transfer[85] inthe presence of an oxidant. Aryl radicals derivingfrom boronic acids were initially generated by

Scheme 24. Mn ACHTUNGTRENNUNG(III)-mediated arylation of thiophene andfuran by protonated phenylhydrazines.

Scheme 25. Mechanism of the Mn ACHTUNGTRENNUNG(III)-mediated arylation ofthiophene and furan by phenylhydrazines.

Scheme 26. Arylation of furan with 4-chlorophenylhydrazinecatalyzed by manganese oxide.




manganeseACHTUNGTRENNUNG(III) and used for the C�H arylation ofbenzene. Whatever the source of Mn ACHTUNGTRENNUNG(III), either Mn-ACHTUNGTRENNUNG(OAc)3

[86] or a KMnO4/AcOH mixture,[77,86b] 3 equiva-lents of oxidant and a large excess of refluxing ben-zene, used as both solvent and reactant, were re-quired. It is worth noting that arylboronic esters wereunreactive toward oxidation. Later on, the combina-tion of an organic oxidant with a catalytic amount oftransition metal has been used for the radical aryla-tion of quinones[85c,87] and biaryls.[88,89] For instance,Baran et al. developed a new synthesis of fluorenonesthrough intramolecular radical cyclisation, using0.2 equivalent of AgNO3 and 3 equivalents of K2S2O8

as radical initiators,[88] whereas Shirakawa andHayashi rather used a 10 mol%Fe ACHTUNGTRENNUNG(III)/10 mol% phenanthroline/2 equiv. (t-BuO)2

mixture for the oxidative coupling of boronic acidswith arenes.[89]

Demir et al. , who had reported the Mn ACHTUNGTRENNUNG(III)-mediat-ed radical arylation of heteroarenes with arylhydra-zines in 2002,[81] extended their methodology to aryl-boronic acids as radical source, using the optimizedconditions previously reported.[86a] Aryl radicals weregenerated by reaction with Mn ACHTUNGTRENNUNG(OAc)3 and trappedwith furan or thiophene, used as both solvent and re-actant (>300 equiv.), to produce exclusively the cor-responding 2-arylated heteroarenes (Scheme 27). Var-ious electron-rich and electron-poor arylboronic acidscould be used, and the presence of a sterically hin-dered substituent at the ortho-position did not de-crease the reaction yield. From a general point ofview, thiophene (55–77%) gave better results thanfuran (19–67%), and a slight improvement of yields

compared to that obtained with arylhydrazines couldbe noticed. It is worth noting that 2-, 3- and 4-formyl-benzeneboronic acids led to the formation of the cor-responding 2-arylated thiophene and furan adductswithout any oxidation side-product being isolated. Nomechanism was detailed in this publication.

A few years later, the same group published theMn ACHTUNGTRENNUNG(III)-mediated radical arylation of thiophene witharylboronic acids under 800 W microwave irradiationin the presence of zeolite, using Mn ACHTUNGTRENNUNG(OAc)3 orKMnO4/AcOH systems.[86b] The exact procedure was,however, not clearly detailed, since the temperaturewas not reported and the exact role of the zeolite notdescribed. Reaction yields were higher than thosepreviously reported under traditional heating, buta larger excess of thiophene was used (>600 equiv.)and the scope was rather limited (Scheme 28). Elec-tron-rich, electron-poor and heteroarylboronic acidsled to the corresponding heterobiaryls in good to ex-cellent yields (65–95%). No oxidation side-productwas isolated when 3-formyl-4-methoxybenzeneboron-ic acid was used. Finally, when the reaction was car-ried out in furan instead of thiophene, the desiredarylated adducts could not be isolated.

A more efficient microwave-promoted, Mn ACHTUNGTRENNUNG(III)-mediated C�H arylation of heteroarenes with arylbor-onic acids was published almost at the same time bythe group of Guchhait.[90] The single-electron transferoxidative radical cross-coupling could be carried outwith electron-rich as well as electron-poor heterocy-cles thanks to the microwave activation. Phenylboron-ic acid and electron-deficient pyridine were chosen asmodel substrates for the optimization of the reactionconditions (Scheme 29).

Among the different oxidants tested, such asCe(IV), Cu(II), Fe ACHTUNGTRENNUNG(III), Ag(I) and V(V), Mn ACHTUNGTRENNUNG(OAc)3

Scheme 27. Mn ACHTUNGTRENNUNG(III)-mediated arylation of thiophene andfuran by arylboronic acids.

Scheme 28. Mn ACHTUNGTRENNUNG(III)-mediated arylation of thiophene by ar-ylboronic acids under microwave irradiation.




proved to be the most efficient, and 3 equivalentswere required since all attempts to use it in a catalyticamount with a co-oxidant failed. However, the largeexcess of heteroarene, usually used as both solventand reactant, could be reduced to only 10 equivalentsin the presence of EtOH as solvent. Under these con-ditions, the reaction, carried out at 170 8C, was com-plete in less than 10 min. The importance of the acti-vation by microwaves was demonstrated by the highyield of arylated adduct (78%) and low yield of ho-mocoupling side-product (4%) (Scheme 29), whereasthe same compounds were isolated respectively in28% and 26% yields when using a conventional heat-ing method. Finally, addition of a base to increase thereactivity of the aryl moiety resulted in a lower yieldof 2-phenylpyridine (46%) and a higher yield of bi-phenyl (18%).

The scope of the reaction was then explored, anda wide variety of both electron-rich and electron-defi-

cient heteroarenes underwent successful arylationwith phenylboronic acid: thiophene, furan, N-methyl-pyrrole, thiazole, benzofuran, benzothiazole, pyridine,pyrimidine, quinolone and isoquinoline (Scheme 30).Whatever the heteroarene, the arylation exclusivelyoccurred a to the heteroatom, even with pyridine orthiophene.

Various para-substituted arylboronic acids, andeven 4-pyridineboronic acid, also led to the formationof the 2-arylated furan adducts in modest yields (43–65%) (Scheme 31).

The formation of the intermediate aryl radical wasdemonstrated, for the reaction between furan or thio-phene with phenylboronic acid, since 20 mol% ofTEMPO as radical scavenger caused a dramatic de-crease of the reaction yield.

The first room-temperature direct radical C�H ary-lation of pyridines and electron-deficient heteroareneswith arylboronic acids was developed by Baran usingan inorganic oxidant, namely K2S2O8, in combinationwith a catalytic amount of silver(I) nitrate.[91] It isworth noting that, in this procedure, the heteroareneis the limiting reagent. The optimization of the condi-tions was not detailed, but authors used 1 equiv. of tri-fluoroacetic acid, to generate in situ the protonatedheterocycle, in combination with 1.5 equiv. of arylbor-onic acid, 3 equiv. of K2S2O8, 0.2 equiv. of AgNO3 ina biphasic 1:1 DCM/H2O mixture (Scheme 32). Theprotonation of the heterocycle was not essential butimproved both reaction rates and conversions, proba-bly by reducing the electron density of the pyridineC-2 and enhancing its electrophilicity. The reactionscould be carried out in open flasks. The C�H aryla-tion of 4-tert-butylpyridine with various arylboronicacids proceeded in moderate to good yields. Electron-rich arylboronic acids exhibited a higher reactivityand shorter reaction times, whereas electron-poor

Scheme 29. Arylation of pyridine with phenylboronic acidmediated by Mn ACHTUNGTRENNUNG(OAc)3 under microwave irradiation (opti-mized conditions).

Scheme 30. Mn ACHTUNGTRENNUNG(III)-mediated arylation of various heteroar-enes by phenylboronic acid under microwave irradiation.

Scheme 31. Mn ACHTUNGTRENNUNG(III)-mediated arylation of furan by variousarylboronic acids under microwave irradiation.




boronic acids required the addition of additionalK2S2O8/AgNO3 to drive the reaction to completion.The presence of electron-donating ortho-substituentswas tolerated but led to the formation of the arylatedadducts in low yields.

The reaction with 4-methylphenylboronic acid dis-plays a broad scope with respect to electron-deficientheteroarenes with yields ranging from 30% to 96%,but a lack of regioselectivity was observed for mostsubstrates, the 2- and 4-arylated adducts being pre-dominant (Scheme 33). It was, however, chemoselec-tive since the presence of halide substituents was tol-erated. Electron-withdrawing substituents enhancethe reactivity to the detriment of the selectivity. Elec-tron-rich heteroarenes such as indole or imidazole didnot undergo successful arylation.

A mechanism was proposed for the radical aryla-tion, starting with the disproportionation of the per-sulfate anion into sulfate dianion and sulfate radicalion. The reaction between the radical ion and the bor-onic acid generates the aryl radical involved in thehomolytic aromatic substitution. The silver catalystplays two roles in the catalytic cycle. Silver(I) speciesreduces S2O8

2� into SO4C�, and the generated silver(II)

oxidizes the radical cation pyridine intermediate(Scheme 34). The reaction fails if a stoichiometricamount of silver(II) is used instead of K2S2O8, or inthe absence of silver(I), demonstrating the impor-tance of SO4C

� as oxidant.The same group reported later on an intramolecu-

lar version of this K2S2O8/AgNO3-catalyzed arylation,starting from potassium trifluoroborates, and leading

Scheme 32. Arylation of 4-tert-butylpyridine by various aryl-boronic acids catalyzed by K2S2O8/AgNO3.

Scheme 33. Arylation of various heteroarenes with 4-methyl-phenylboronic acid catalyzed by K2S2O8/AgNO3.

Scheme 34. Mechanism of the radical arylation of pyridinewith phenylboronic acid catalyzed by K2S2O8/AgNO3.




to the formation of fluorenones.[88] One example ofarylation of a pyridine derivative is described, anda mixture of 2- and 4-arylated adducts was isolated ingood overall yields (Scheme 35). Dichloromethanewas substituted by trifluorotoluene, and a temperatureof 60 8C was required.

The room-temperature C�H arylation of heteroar-enes with arylboronic acids catalyzed by K2S2O8/AgNO3 was then extended by Mai and Li to pyridineand pyrazine N-oxides.[92] The methodology was ap-plied to these particular substrates, since Baran�s con-ditions required the use of 1 equivalent of trifluoro-acetic acid to block the nitrogen atom of pyridine.Whilst a number of parameters was evaluated in theoptimization studies including the metal, oxidant andsolvent, the slightly modified Baran�s conditions re-mained the most efficient for the arylation of pyridineN-oxide (Scheme 36).

The scope of the reaction was successfully extendedto various pyridine and pyrazine N-oxides with substi-tuted arylboronic acids (Scheme 37). Pyrazine N-oxides led to the arylated adduct in higher yields (80–87%) than the corresponding pyridine derivatives.The same reaction with pyrazine led to a yield as lowas 30%. It is worth noting that the arylation occurredexclusively at the 2-position of the pyridine or pyra-zine.

The postulated mechanism is the same as the oneproposed by Baran earlier. To support the formationof the aryl radical intermediate, the authors carriedout the reaction in the presence of 2 equivalents ofTEMPO as a radical scavenger, and noted that onlya trace amount of the arylated pyridine could be de-tected.

Very recently, Patel and Flowers examined themechanism of the cross-coupling of arylboronic acidswith pyridines using kinetic and spectroscopic meth-ods, in order to improve the catalytic system andbroaden the substrate scope of the reaction.[93] 4-Tri-fluoromethylpyridine and p-tolylboronic acid werechosen as model substrates for this study(Scheme 38).

It was noticed that the use of degassed solvent andthe exclusion of oxygen from the reaction were im-portant factors to reach a higher yield of arylated pyr-

Scheme 35. Intramolecular radical arylation of a potassiumpyridine trifluoroborate catalyzed by K2S2O8/AgNO3.

Scheme 36. Arylation of pyridine N-oxide with phenylboron-ic acid catalyzed by K2S2O8/AgNO3.

Scheme 37. Arylation of pyridine and pyrazine N-oxides byvarious arylboronic acids catalyzed by K2S2O8/AgNO3.




idine. A kinetic study allowed them to determine therate order for each substrate: 1 for AgNO3 and pyri-dine derivative, 0 for K2S2O8 (but 1 for the more solu-ble Na2S2O8) and, more surprisingly, �0.5 for the bor-onic acid, indicating an overall decrease in reactionrate when the boronic acid concentration increases.The first order observed for pyridine compared to thenegative one observed for the boronic acid suggesteda mechanism more complicated than the one startingfrom oxidation of the boronic acid to form the radi-cal, followed by its addition onto pyridine. The au-thors thus investigated the possible formation of a pyr-idine-silver(I) complex using 1H NMR studies. Thespectra of pyridine, pyridine and 1 equivalent of TFAor AgNO3, as well as a mixture pyridine/TFA/AgNO3

1:1:1 in D2O were compared, and showed an equilib-rium complexation between the pyridine derivativeand silver(I). In order to confirm this hypothesis, re-actions with stoichiometric amounts of boronic acidand silver nitrate, with or without pyridine, were car-ried out. Almost 60% of para-tolylboronic acid wasconverted into toluene in the presence of pyridine,whereas the conversion decreased to 15% only in theabsence of pyridine. It had been shown that aromaticboronic acids react with silver(I) salts in ammoniacalsolution to form the corresponding arene, boric acidand Ag2O.[94] The higher conversion of para-tolylbor-onic acid into toluene in the presence of pyridine sug-gested thus that a pyridine-silver(I) complex is likelyinvolved, in the same way, in the homolytic deborona-tion of para-tolylboronic acid and this complex is de-graded to pyridine and inactive Ag2O. The use of anadditive capable of preventing the formation of thiscatalytically inactive Ag2O, such as HNO3, allowedthe isolation of 2-tolyl-4-trifluoromethylpyridine in anexcellent 90% yield (vs. 76% with Baran�s condi-tions), with only 10 mol% AgNO3 and 2 equivalentsof K2S2O8.

Another important point is the identity of the spe-cies oxidizing the arylboronic acid. Baran and otherssuggested that the SO4C

� intermediate was the oxidiz-ing agent but one cannot rule out the role of theAg(II) species, as suggested by Kochi for the homo-lytic decarboxylation of carboxylic acids usinga Ag(I)/persulfate system.[95] The arylation was thus

Scheme 38. Arylation of 4-trifluoromethylpyridine with p-tolylboronic acid catalyzed by K2S2O8/AgNO3.

Scheme 39. Mechanism of the radical arylation of 4-trifluoromethylpyridine with p-tolylboronic acid catalyzed by K2S2O8/AgNO3 described by Patel and Flowers.




carried out in the presence of 6 equivalents of allylacetate which is known as a radical trap for SO4C

�, butno impact on reaction yield was observed, indicatingthat arylboronic acid is more likely oxidized byAg(II). Authors also suggested that boron “ate” de-rivatives might be more susceptible to single-electronoxidation than trigonal boron species, and a solventor a pyridine molecule might interact with the boronatom to facilitate the process.

Based on these data, the authors proposed a mecha-nism (Scheme 39) involving the formation of the pyri-dine-silver(I) complex, followed by the oxidation ofsilver(I) into silver(II). This complex oxidizes the bor-onic acid or the “ate” complex to form the aryl radi-cal that add to the radicophile pyridinium.

Yu et al. described the first iron-mediated arylationof nitrogen heterocycles with arylboronic acids usinga methodology inspired from the work of Baran, butreplacing AgNO3 by cheaper and non-toxic iron(II)sulfide.[87a] The reaction is, however, not catalytic any-more since one equivalent of FeS was required, andlonger reaction times were necessary (40 h instead of12 h). No optimization study was described nor wasany attempt made to use a catalytic amount ofiron(II). Substituted pyridines, mostly bearing elec-tron-withdrawing groups at C-3 or C-4, were success-fully arylated with various arylboronic acids(Scheme 40). The reaction was not regioselective,however, since mixtures of products were isolated inmost cases, but it was chemoselective since halidesubstituents on the arylboronic acid or on the pyri-dine ring were tolerated. Yields were higher withelectron-rich arylboronic acids (80–97%) than withelectron-poor derivatives (41–78%). The presence ofan electron-donating group at C-4 of pyridine led tothe formation of the 2-arylated adduct exclusively,albeit in lower yields (36–68%). Other nitrogen-con-taining heterocycles could be arylated as well. Pyrimi-dine underwent arylation in very high yield (93%),whereas pyrazine, quinoline, quinoxaline, pyridazine,thiazole or benzothiazole were less reactive (17–53%). Imidazole, pyrrole, indole, benzoxazole, caf-feine and quinine were unreactive.

The mechanism of the reaction was investigatedusing a radical scavenger, and only a trace amount of4-cyano-2-phenylpyridine was detected when the reac-tion of 4-cyanopyridine and phenylboronic acid wascarried out in the presence of 2 equiv. of TEMPO.The authors proposed thus a reaction mechanismquite similar to that described by Baran. However, inthe light of the work previously discussed(Scheme 38), one cannot rule out another reactionpathway. Moreover, the mechanism is described asa catalytic cycle with the regeneration of the initialFe(II) species, whereas 1 equiv. of FeS is required toachieve good yields (Scheme 41).

Finally, Singh and Vishkarma improved theiron(II)-mediated radical C�H arylation of electron-deficient heteroarenes with arylboronic acid by reduc-ing the iron(II) quantity to a catalytic amount.[87b] Theoptimization of the conditions, using pyrazine andphenylboronic acid as model substrates in the pres-ence of 1 equiv. of trifluoroacetic acid (Scheme 42),started by varying the nature of the metal catalyst.Fe ACHTUNGTRENNUNG(acac)2 proved to be the best among several Fe,

Scheme 40. Arylation of various heteroarenes with arylbor-onic acid mediated by K2S2O8/FeS.




Mn, Ag or Cu salts tested, with an optimal amount of20 mol%. Several peroxides were tested as oxidantsbut none of them gave better results than K2S2O8.The solvent system proved to be an important param-eter as well, since the biphasic DCM/H2O systemgreatly enhanced the yield of 2-phenylpyrazine. Dueto the immiscibility of dichloromethane and water,the authors tested the use of the phase-transfer cata-lyst tetrabutylammonium bromide (TBAB) that ledto the formation of the desired product in an im-proved 84% yield. The reaction could be carried outat room temperature in an open flask, making the re-action easy to handle under very mild conditions.

Under the optimized conditions, the scope of thereaction with pyrazine was investigated and extendedto a wide variety of arylboronic acids (Scheme 43).

Whatever the nature and the position of substituentson the aryl moiety, ortho-, meta-, para-electron-donat-ing or electron-withdrawing groups, 2-arylated pyra-zines were exclusively isolated in moderate to goodyields (30–86%). As already observed in the previousmethodologies, the reaction is chemoselective, sincehalide substituents are tolerated. Dimethylpyrazinegave the corresponding product in a lower yield thanthat observed with the non-substituted pyrazine (64%vs. 86%). Heteroarylboronic acids were also testedbut led to the corresponding arylated adducts in verylow yields (0–15%), even after prolonged reactiontimes.

The substitution of phenylboronic acid by potassi-um phenyltrifluoroborate led to the formation of the2-phenylpyrazine in 78% yield, whereas only 30%yield could be isolated when the reaction was carriedout with the phenylboronic acid pinacol ester(Scheme 44).

The reactivity of various arylboronic acids towardsquinoxalines was investigated as well, and 2-monoary-lated adducts could be isolated in synthetically usefulyields (45–65%), (Scheme 45). The reaction of 2-

Scheme 41. Mechanism of the radical arylation of pyridinewith phenylboronic acid mediated by K2S2O8/FeS.

Scheme 42. Arylation of pyrazine with phenylboronic acidcatalyzed by K2S2O8/Fe ACHTUNGTRENNUNG(acac)2 (optimized conditions).

Scheme 43. Arylation of pyrazine by various (hetero)aryl-boronic acids catalyzed by K2S2O8/Fe ACHTUNGTRENNUNG(acac)2.




methylquinoxaline with p-tolylboronic acid led to thecoupling product in a much lower yield (45% vs.65%).

Finally, other electron-deficient heteroarenes, suchas pyridines, quinoline and isoquinoline were coupledwith arylboronic acids, and led exclusively to the ary-lation a to the nitrogen atom furnishing adducts inmoderate yields yet (Scheme 46).

The presence of an electron-donating substituenton the aryl moiety of the boronic acid only slightly in-creases the yields of arylated pyridine or quinoline.The authors used TEMPO as radical scavenger todemonstrate the involvement of radical intermediates.The addition of TEMPO drastically decreased theyield of 2-phenylpyrazine, even though no value wasreported.

Based on the developed methodology, the authorsdescribed the short synthesis of the bioactive naturalproduct botryllazine A (Scheme 47). The 5-step syn-thesis includes the radical arylation of 2,3-dimethyl-pyrazine.

Boronic acids are very promising arylating agentsin radical reactions with heteroarenes, mainly due totheir wide commercial availability and their tolerance

Scheme 44. Arylation of pyrazine by potassium phenyltri-fluoroborate and phenylboronic acic pinacol ester catalyzedby K2S2O8/Fe ACHTUNGTRENNUNG(acac)2.

Scheme 45. Arylation of quinoxaline by various arylboronicacids catalyzed by K2S2O8/Fe ACHTUNGTRENNUNG(acac)2.

Scheme 46. Arylation of pyridines, quinoline and isoquino-line by various arylboronic acids catalyzed by K2S2O8/Fe ACHTUNGTRENNUNG(acac)2.




to sensitive functional groups. They can be oxidizedunder very mild conditions and with easy-to-carry-outprotocols, using simple, cheap and non-toxic metalliccatalysts, such as iron, to generate aryl radicals. Thescope of the reaction with catalytic amounts of ironhas been, however, limited to nitrogen heteroarenes,whereas a stoichiometric amount of manganese wasused with oxygen- or sulfur-containing heterocyclicstructures.

4 Conclusion

These last years, at the instigation of societal con-cerns, the development of sustainable chemistry hasbecome an intensively studied area of research. Inthis context, the direct C ACHTUNGTRENNUNG(sp2)�H arylation of(hetero) ACHTUNGTRENNUNGarenes has been proposed as an interesting al-ternative to traditional cross-coupling reactions. Mostmethodologies developed so far proceed through anoxidative addition of a transition metal onto a haloar-ene, followed by a C�H bond activation step. Howev-er, the high inertness of the C�H bond usually pre-cludes any simple experimental procedures and mildreaction conditions. These limitations can be circum-vented through another mechanistic approach involv-ing aryl radicals. These latter possess a high reactivityallowing arylations under mild conditions, and theirambivalent character (nucleophilic and electrophilic)make them suitable with a variety of heterocyclicstructures. In radical CACHTUNGTRENNUNG(sp2)�H arylations, the rate-de-termining factor is no longer the addition step, butrather the radical generation. Thereby, the develop-

ment of innovative and simple methodologies to gen-erate aryl radicals under mild conditions is highly de-sirable. A broad variety of aromatic derivatives canbe used as aryl radical sources, and efficient transitionmetal-based systems have been developed for thegeneration of these radicals. Unpredictable regioselec-tivity[96] as well as modest yields are still recurrentissues with radical chemistry, but some works de-scribed in this review clearly demonstrate that upona deep mechanistic understanding impressive im-provements can be achieved.

Acknowledgements

The authors are thankful to the “Universit� de Nantes”, the“Universit� de Lille”, the “CNRS”, and the “R�gion Pays dela Loire” in the framework of a “Recrutement sur poste strat-�gique” for the funding. FXF is member of the “Institut Uni-versitaire de France”.

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DOI: 10.1002/adsc.201300865 Transition Metal …szolcsanyi/education/files/Chemia... · ed C H bond...

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Transcript of DOI: 10.1002/adsc.201300865 Transition Metal …szolcsanyi/education/files/Chemia... · ed C H bond...