aryl−aryl bond formation one century after the discovery of the ullmann reaction.pdf

ArylAryl Bond Formation One Century after the Discovery of the UllmannReaction

Jwanro Hassan, Marc Sevignon, Christel Gozzi, Emmanuelle Schulz, and Marc Lemaire*,

Laboratoire de Catalyse et Synthe`se Organique, UMR 5622, Universite Claude Bernard Lyon 1, CPE, 43 Bd du 11 Novembre 1918,69622 Villeurbanne Cedex, France, and Laboratoire de Catalyse Moleculaire, UPRESA, CNRS 8075, Institut de Chimie Moleculaire dOrsay,

Universite Paris-Sud, 91405 Orsay Cedex, France

Received July 9, 2001

ContentsI. Introduction 1360II. ArylAryl Bond Formation Using Copper as

Reagent or Catalyst1362

1. Reductive Coupling of Aromatic Halides (TheUllmann Reaction)

1362

A. Aromatic Coupling Using StoichiometricAmount of Copper

1362

B. Aromatic Coupling Using CatalyticAmounts of Copper

1365

2. Coupling of Aromatics via Aryl Carbanion 1366A. Use of Stoichiometric Amounts of Copper 1366B. Catalytic Amounts of Copper 1371

3. Oxidative Aromatic Coupling Using CopperSalts

1372

A. Use of Stoichiometric Amount of Copper 1372B. Use of Catalytic Amounts of Copper 1374

4. Aromatic Coupling via Radicals (The PschorrReaction) Using Copper Salts

1376

5. Synthesis of Oligomers and Polymers UsingCopper as a Reagent

1376

A. The Ullmann Reaction 1377B. Oxidative Coupling of an Activated Aryl 1377C. Chemical Polymerization Induced by Iron 1378

III. Nickel-Promoted ArylAryl Bond Formations 13781. Aromatic Coupling Involving Stoichiometric

Amounts of Nickel1379

A. Nickel(0) Used as a Preformed Reagent 1379B. Use of Additional Zinc or Other Reducing

Agents1379

2. Aromatic Coupling Involving CatalyticAmounts of Nickel

1380

A. Homocoupling of Aryl Halides 1381B. Cross-Coupling Reactions between Aryl

Halides and Organometallic Reagents1383

3. Use of a Nickel Catalyst without CoreducingAgent

1389

4. Nickel-Promoted Oligomerization andPolymerization

1389

IV. Aromatic Coupling Using Palladium as theCatalyst

1392

1. Palladium-Catalyzed Coupling of GrignardReagents

1393

2. Palladium-Catalyzed Coupling of ZincDerivatives

1394

A. Aryl Homocoupling of Zinc Derivatives 1394

B. Aryl Cross Coupling of Zinc Derivatives 1395C. Use of New Technologies in ArylAryl

Bond Formation Using Zinc Derivatives1397

D. Applications of Zinc Derivatives inMultistep Synthesis

1398

3. Palladium-Catalyzed Coupling of MercuryDerivatives

1399

4. Palladium-Catalyzed Coupling of SiliciumDerivatives

1399

A. Homocoupling of Aryl Silanes 1399B. Cross Coupling of Aryl Silanes 1399C. Use of New Technologies in ArylAryl

Bond Formation Using Aryl Silanes1402

5. Palladium-Catalyzed Coupling of GermaniumDerivatives

1402

6. Palladium-Catalyzed Coupling of LeadDerivatives

1402

7. Palladium-Catalyzed Coupling of BismuthDerivatives

1402

8. Palladium-Catalyzed Coupling of AntimonyDerivatives

1403

9. Palladium-Catalyzed Coupling of CopperDerivatives

1403

10. Manganese Derivatives 140311. Palladium-Catalyzed Coupling of Zirconium

Derivatives1403

12. Palladium-Catalyzed Coupling of IndiumDerivatives

1404

13. Tin Derivatives and the Stille Reaction forAromatic CarbonCarbon Bond Formation

1404

A. Synthesis of C2-Symmetric Biaryls Usingthe Stille Reaction

1404

B. Dissymmetrical Coupling of AromaticRings Using the Stille Reaction

1405

C. Recent Improvement of AromaticCoupling via the Stille Reaction

1407

14. Aromatic CC Bond Formation UsingOrganoboronic Derivatives (The SuzukiReaction)

1409

A. Homocoupling of Aryl Boronic AcidsCatalyzed by Palladium

1411

B. Suzuki Cross Coupling of Aryl BoronicAcids with Aryl Halides

1412

C. Recent Improvements in the SuzukiReaction for ArylAryl Bond Formation

1419

D. Use of New Technologies in SuzukiCross Coupling of Aromatic Substrates

1427

1359Chem. Rev. 2002, 102, 13591469

10.1021/cr000664r CCC: $39.75 2002 American Chemical SocietyPublished on Web 03/08/2002

15. ArylAryl Bond Formation Using PalladiumCatalyst without Additional Organometallic

1435

A. Oxidative Coupling of Aromatic RingsUsing Palladium

1435

B. Reductive Coupling of Aromatic RingsUsing Palladium

1436

C. Coupling of Aryl Halide ontoNonfunctionalized Aromatic PositionCatalyzed by Palladium

1438

16. Application of Palladium-Catalyzed ArylCoupling to the Synthesis of ConjugatedPolymers

1442

A. Polymerizations of Aromatic SubstratesInvolving Magnesium Derivatives

1442

B. Polymerizations of Aromatic SubstratesInvolving Zinc Derivatives

1443

C. Polymerizations of Aromatic SubstratesInvolving Mercury Derivatives

1443

D. Oligo- and Polymerizations of AromaticSubstrates Using OrganostannylDerivatives

1444

E. Suzuki ArylAryl Cross Coupling Appliedfor Oligo- or Polymerization

1447

F. Oligothiophene Synthesis in aPalladium-Catalyzed Reaction withoutAdditional Organometallics

1454

V. Aromatic Ring Coupling Using NucleophilicSubstitution as well as Radical and OxidativeProcesses

1455

1. ArylAryl Bond Formation by NucleophilicAromatic Substitution

1455

2. ArylAryl Bond Formation UsingPhotochemistry and/or Radical Initiation

1455

A. Photochemistry 1455B. ArylAryl Bond Formation with Radical

Initiation1456

3. Formation of ArylAryl Bonds by OxidativeCouplings

1458

4. Formation of ArylAryl Bonds via AryneIntermediates

1460

VI. Conclusion 1461VII. Notations and Abbreviations 1461VII. References 1461

I. Introduction

Aryl-aryl bond formation is one of the mostimportant tools of modern organic synthesis. Thesebonds are very often found in natural products suchas alkaloids as well as in numerous biologically activeparts of pharmaceutical and agrochemical speciali-ties. Many commercial dyes contain several aromaticrings bound together. Polyaromatics also possessoriginal physical properties which could lead toapplications as organic conductors or semiconductors.Last but not least, di- or triaromatic rings are thebackbone of some of the most efficient and selectiveligands for asymmetric catalysis, especially whenatropisomery is possible. As a consequence, over thelast 10 years more than 700 articles have dealt withnew results in the area of aryl-aryl bond formation.

On the other hand, few reviews are devoted to aryl-aryl bond formation, and to our knowledge, none ofthem deals with all types of methodology. Indeed, thepalladium-catalyzed Stille and Suzuki reactions havebeen the most studied over the past few years, butmany specific synthetic problems of aryl-aryl bondformation could be (and are) solved by using othermetals as the catalyst or as the reagent. In addition,oxidative methods appear to be competitive in somecases as do reactions with radicals as chemicalintermediates. The present article aims to propose alarger scope than the last few reviews by includingboth older methods that are still competitively ef-ficient and less common new concepts in the field of

Universite Claude Bernard Lyon 1. Universite Paris-Sud.

Jwanro Hassan was born in Suleimaniya, Kurdistan-Irak, in 1971. Hereceived his B.S. degree in Chemistry from Salahaddin University in 1994.In 1997, he was awarded his Master of Science degree in OrganicChemistry at the University of Reims, where he worked on access tooptically active carbonyl compounds under the guidance of Dr. JacquesMuzart. In 1997, he began his Ph.D. studies at the University of ClaudeBernard Lyon 1, joining the research group of Professor Marc Lemaire.This doctoral research focused on developing new catalytic methods foraryl-coupling reactions. His interests include synthetic methods develop-ment, carboncarbon bond formation, and polymer and heterocyclicsyntheses.

Marc Sevignon was born in Rennes, France, in 1974. He entered theChemistry program at the Ecole Superieure de Chimie-Physique-Electronique de Lyon (CPE Lyon) in 1994. He preformed two six-monthinternships in organic synthesis at the Rhone-Poulenc Rorer ResearchCenter of Dagenham (England) in the laboratory of Dr. D. Lythgoe andin heterogeneous catalysis at the Rhone-Poulenc Industrialization ResearchCenter (Saint-Fons, France) in the team of Dr. P. Metivier. He graduatedfrom CPE Lyon in 1998. Interested in the preparation of organic materials,he joined the group of Professor M. Lemaire at Lyon and first worked onthe synthesis of organic conducting polymers of asymmetric electroca-talysis. He is currently pursuing doctoral studies in the area of synthesisof specific molecules and resins for deep desulfurization of gasoil.

1360 Chemical Reviews, 2002, Vol. 102, No. 5 Hassan et al.

aryl-aryl bond formation. The diversity of the ap-proaches also shows that none of them is self-sufficient in practical organic synthesis. Aryl-arylbond formation has been known for more than acentury and was one of the first reactions using atransition metal (copper in its higher oxidation statesshould be considered a transition metal). The evolu-tion of this field is also a good illustration of thedevelopment of modern organic chemistry, particu-larly the increasing importance of transition-metalcatalysis. Indeed, during the first 70 years of the 20thcentury, copper was almost the only metal usable foraryl-aryl bond formation, initially as copper metal

in the reductive symmetrical coupling of aryl halides(the Ullmann reaction). Several modifications andimprovements of this reaction still justify today theuse of copper derivatives in several synthetic cases.The most important case may be the association ofcopper salts with aryl anions in an oxidative process.This last modification allows cross coupling and, inmany cases, the use of substoichiometric (if not trulycatalytic) amounts of metal. With some specificsubstrates, oxidative methods using copper(II) in thepresence of chiral nitrogen-containing ligands giverise to the formation of biaryl with good diastereo-or enantioselectivities. Historically, the major tech-nological breakthrough could be the use of nickelinstead of copper, first in stoichiometric amounts inan Ullmann-like procedure and then under catalyticconditions with diphosphine complexes and Grignardreagent. The latter method launched a number ofchanges allowing the use of more and more efficientcatalysts, including palladium complexes and simul-taneously less reactive, more selective nucleophilicreagents. Many organometallic reagents were testedwith success using this general methodology. Themost fruitful among them are zinc, tin, and boronderivatives. Zinc derivatives compared with magne-sium are much more compatible with various func-tional groups and strongly increase the scope ofapplication of organometallic cross couplings of arylsubstrates and reagents. The last two heteroelements(tin and boron) possess an electronegativity close tothat of carbon, and their derivatives can tolerate thepresence of almost any functional group. Over thelast 10 years, interesting and useful results havebeen published using all these types of methodolo-gies. Interestingly, the most recently used transitionmetals have generated the greatest number of pub-lications. Nowadays, many more syntheses use pal-

Christel Gozzi was born in 1969 in Valence (France). She graduated fromEcole Superieure de Chimie Industrielle de Lyon in 1991. She receivedher Ph.D. degree from the University of Lyon in 1994 for studies concerningnew potential Thromboxane antagonists bearing a 7-azanorbornaneskeleton under the direction of Professor J. Gore. Since 1995, she hasworked in the group of Professor M. Lemaire, especially on contract workfor various companies. Apart from industrial studies, her research interestslie in palladium-catalyzed aryl cross couplings with application in thesyntheses of biologically active molecules and conducting polymers.

Emmanuelle Schulz was born in Cayenne. She graduated from EcoleSuperieure de Chimie Industrielle de Lyon in 1989 and received her Ph.D.degree from the University of Lyon in 1992 for studies concerning thetotal synthesis of Strigol, under the direction of Professor P. Welzel atthe Ruhr-Universitat Bochum, RFA. After an industrial postdoctoral positionat the Research Center La Dargoire (Rhone-Poulenc Agrochimie), shejoined the group of Marc Lemaire in 1993. In 1997, she obtained apermanent position at the Centre National de la Recherche Scientifique(CNRS). Since September 2000 she has worked at the Institut de ChimieMoleculaire dOrsay in the Laboratoire de Catalyse Moleculaire ofProfessor J.-C. Fiaud. Her research topics include the preparation oforganic materials for various applications: chiral ligands for thehomogeneous and heterogeneous asymmetric catalysis, organic conduct-ing polymers for asymmetric electrocatalysis, and specific resins fordepollution (especially useful for the petroleum industry).

Professor Marc Lemaire was born in 1949 in Paris. He was employedseveral years in the pharmaceutical industry as a technician, and thenhe obtained the engineer level (CNAM Paris 1979) and his Ph.D. degreeat the Paris VI University (Professor J.P. Guette; New chlorinatingreagent). In 1983 he obtained a postdoctoral position in the University ofGroningen (The Netherlands; Professor F.M. Kellogg; Thiamacrocyclesas ligand for asymmetric catalysis). He returned to Paris and obtainedan assistant position at CNAM, and then he became a professor at theUniversity of Lyon. His group is working in five main areas: (1)heterogeneous catalysis in fine chemistry, (2) asymmetric catalysis, (3)separation science, including new ligands for liquidliquid extraction, newionoselective materials, new complexing agents of nanofiltrationcom-plexation systems, (4) organic conductors, including poly(thiophenes) andpoly(pyrroles), and (5) deep desulfurization of gasoil.

ArylAryl Bond Formation Chemical Reviews, 2002, Vol. 102, No. 5 1361

ladium catalysts than their nickel and copper coun-terparts. The Suzuki reaction is the most exemplified,even using modern technologies (polymer-supportedreagent, biphasic catalysis, supercritical conditions,etc.). Increasing the scope of the Suzuki reaction (and,to a lesser extent, the Stille reaction) has probablybeen one of the most popular aims of research inacademic institutions over the past few years.

One of the noteworthy applications of the methodsfor aryl-aryl bond formation lies in the synthesis ofoligomers and polymers with long conjugated chains.Originally, such materials were formed by usingelectrochemical or chemical oxidative coupling withrelatively low regularities in the case of substitutedmonomers (head-to-head or head-to-tail junctions, forexample). The application of new methods of catalyticaryl-aryl bond formation has given rise to longer,more regular, less dispersed materials and will bedescribed with examples in this review.

We have collected the results obtained in the fieldof aryl-aryl bond formation using all types of tech-nologies and reactions. We believe that this enormousdiversity has few equivalent with any other type ofchemical transformation. Although this article cannotbe exhaustive, we have attempted to draw a completepicture of the current efforts of organic chemists inthis area. We hope that this analysis will be usefulin encouraging further studies in less popular typesof reactions. We have chosen to organize the articleby the type of transition-metal used (copper, nickel,palladium). It is noteworthy that this classificationis also historically consistent.

II. ArylAryl Bond Formation Using Copper asReagent or Catalyst

Copper is the most ancient transition metal usedfor the synthesis of biaryls and it is still employednowadays. This part will deal with recent develop-ments in aryl-aryl bond formation using copperderivatives as reagents or catalysts. Reactions in-volving cuprates and other metals (nickel, palladium)as catalysts will be discussed later.

The use of copper in order to obtain the couplingof aromatic species can involve several types ofmechanisms. Due to the numerous possibilities ofintermediates and to the different oxidation andcoordination states of copper, it is not always easyto ascertain an accurate mechanism of this reaction.Nevertheless, we propose to distinguish four typesof couplings of aromatic rings, using copper deriva-tives, which may overlap.

The first type implies the use of aromatic halides,generally iodides or bromides, as substrates andcopper metal as the reagent. The reaction, whichinvolves the formation of a cuprate as the intermedi-ate and copper halide as a byproduct, is the reductivecoupling known as the Ullmann reaction. Althougha few results have been obtained using catalyticamounts of copper, these reactions are still studieddue to the fact that in several cases unsymmetricaland asymmetrical couplings are achieved.

The second type is closely related to the first butinvolves the formation of an aryl carbanion as theintermediate. As oxidative addition to the copper is

the limiting step in the classical Ullmann reaction,preparation of the carbanion provides milder condi-tions with a higher rate. With this methodologycatalytic amounts of copper (generally Cu(I)) can beused, but conversely a stoichiometric (or greater)amount of base or organometallic is required. Thereaction requires the reduction of the substrate(formation of the carbanion) and a transmetalationfollowed by a reductive elimination of the copperintermediate complex.

The third type is clearly an oxidation of two C-Haromatic bonds to form a C-C bond. These reactionsare performed thanks to the oxidative properties ofcopper(II), and the use of substrates with a lowoxidation potential is required. Both catalytic andstoichiometric amounts of Cu(II) have been used.

The fourth type and last one is the Pschorr reactionwhich involves the decomposition of diazonium in thepresence of copper (generally Cu(I)) into radicals.This reaction, discovered before the Ullmann reac-tion, is limited by the access to the required diazo-nium salt.

1. Reductive Coupling of Aromatic Halides (TheUllmann Reaction)

A. Aromatic Coupling Using Stoichiometric Amount ofCopper

The Ullmann reaction, initially reported in 1901,1has long been employed by chemists to generate aC-C bond between two aromatic nuclei. Typicallytwo molecular equivalents of aryl halide are reactedwith one equivalent of finely divided copper at hightemperature (above 200 C) to form a biaryl and acopper halide. This procedure and variants werecomprehensively reviewed several decades ago.2,3,4Considerable improvements have been made throughthe last century. Dimethylformamide is a solventwhich permits the use of lower temperatures and alower proportion of copper. Besides, the use of anactivated form of Cu powder, made by the reductionof copper(I) iodide with potassium, allows the reactionto be carried out at even lower temperatures (about85 C) with improved yields. As the reaction isheterogeneous, it can be accelerated considerablyusing ultrasound.5

Regarding the relationship between the structureof an aryl halide and its reactivity, electron-with-drawing groups such as nitro and carboxymethyl,especially in the ortho-position to the halogen atom,provide an activating effect. On the other hand, thepresence of substituents which provide alternativereaction sites, such as amino, hydroxyl, and freecarboxyl groups, greatly limit or prevent the reaction.Furthermore, bulky groups in the ortho-position exertan inhibitive influence.

Obviously the major limitation of the originalUllmann reaction was the obtention of only sym-metrical biaryls. Several attempts to synthesizeunsymmetrical biaryls have been made, and somesuccess has been achieved by associating aryl halidesof different reactivities. These extensions of theoriginal Ullmann reaction to unsymmetrical biarylsformation did however require the use of a significa-tive excess of the activated aryl.


We will present recent uses of stoichiometricamounts of copper to perform first symmetrical andthen unsymmetrical couplings.

a. Symmetrical Couplings. Symmetrical cou-pling of substituted benzene rings and aromaticheterocycles using copper as the reducing and cou-pling agent can be performed in both inter- andintramolecular reactions. There are many more ex-amples of the former than the latter.

Sessler et al.6 developed an efficient procedure forthe preparation of alkyl-substituted 2,2-bipyrroles.It involved first the protection of the nitrogen atom(with di-tert-butyl-dicarbonate), then an Ullmann-type coupling, followed by the deprotection of theresulting 2,2-bipyrroles (Scheme 1).

The only byproduct was the substituted 2-pyrroledue to the reduction of the C-I bond of the startingmaterial. The key step was the protection of thepyrrolic nitrogen. Since it has been shown that higheryields of substituted 2,2-bipyrroles are typicallyobtained when one or more electron-withdrawinggroup is present in the pyrrolic system, the authorshave protected the pyrrolic nitrogen with a labileelectron-withdrawing group (tert-butoxycarbonyl) inorder to avoid any coupling between the nitrogen andthe 2-position of a second pyrrole. Using appropriateN-protection, the yields of 2,2-bipyrrole were en-hanced by 20-30%.

Using copper(I)-thiophene-2-carboxylate (CuTC,see below) as a promoter, Liebeskind et al.7 reporteda CuTC-mediated Ullmann-reductive coupling ofsubstituted aromatic iodides and bromides, 2-io-doheteroaromatics, at room temperature. As depictedin Schemes 2 and 3, the CuTC-mediated reaction was

quite general and tolerant of various functionalgroups.

Efficient reductive coupling of the aromatic sub-strates required the presence of an ortho-ligating,electron-withdrawing or electron-donating, substitu-ent while 2-iodoheteroaromatics did not. The reduc-

tive coupling required a polar, coordinating solventsuch as N-methylpyrrolidinone, probably to generatereactive Cu(I) monomers from the insoluble Cu(I)carboxylate polymer.

The authors assume that the efficiency of CuTC isprobably not due to internal coordination from thesulfur atom to the metal but may be due to aninherent ability of carboxylate as a ligand to stabilizethe oxidative addition product (Scheme 4).

The intramolecular reductive coupling has alsobeen successfully studied (Scheme 5).

The easy preparation of CuTC, its handling in air,and the high yields of reductively coupled productsachieved under mild reaction conditions could makeCuTC or other Cu(I) carboxylates the reagents ofchoice for many Ullmann-like reductive couplingreactions.

Hauser et al. performed the first total synthesis ofthe 7,7-linked bianthraquinone biphyscion.8 The keystep was the preparation of symmetrical biphenylthrough traditional Ullmann coupling of a protectediodoresorcinol (Scheme 6).

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6


Although steric hindrance can be a problem inUllmann reactions, coupling proceeded to afford thebiphenyl in a good yield (73%).

Recently a new trend has appeared using copper-mediated reactions for asymmetrical Ullmann cou-plings, mainly developed by Meyers et al. This wasbased on the fact that in many of the natural orsynthetic biaryls, bulky ortho-substituents lead tohindrance of free rotation around the biaryl axis andthus to the existence of stable atropisomers. Thus,depending on the substituent, an aryl halide can beconverted to a diastereomerically enriched productunder equilibrating conditions. This process is re-ferred to as a first-order asymmetrical transforma-tion.

Meyers et al.9 reported that a thermodynamicallycontrolled resolution appeared to be operative undertheir reaction conditions so that diastereomericallyenriched biaryls are formed (93(S)/7(R)) and maybe readily purified to 100% diastereomeric purity(Scheme 7).

Two factors are mainly responsible for this reason-ably effective asymmetrical synthesis. First, althoughthe biaryl is tetrasubstituted, under the reactionconditions rotation is possible around the biaryl axis.Second, the final diastereomeric ratio is the resultof chelation control with a Cu(I) and/or Cu(II) speciesunder equilibrating conditions. Indeed, severe sterichindrances between the isopropyl groups of the twooxazoline moieties occur.

Using this methodology, Meyers et al.10 reportedthe synthesis of a pure biphenyl diol (S), which hasfunctioned as a chiral catalyst in the asymmetricalreduction of unsymmetrical ketones (Scheme 8).

With the same first steps, the authors also de-scribed the first asymmetrical synthesis of (S)-4,4,5,5,6,6-hexamethoxy-2,2-diphenic acid, a ubiq-uitous subunit in ellagitannins11 (Scheme 9).

Moreover, Meyers et al.12 reported the asym-metrical synthesis of a class of chiral binaphthylswhich contains substitution in the 8 and 8 positions.The metal is chelated between the two ligands,embedded closer to the binaphthyl framework thanin the case of 1,1,2,2-binaphthyls (BINAP, BINOL),

perhaps providing a much more stereochemicallybiased environment.

Indeed, an oxazoline (S), subjected to classicalUllmann conditions, led to bis(oxazoline) (aSS) as asingle diastereomer and debrominated naphthylox-azoline as a byproduct (Scheme 10).

The rotational barrier of atropisomers is less than20-25 kcal/mol. The difference in stability betweenthe two diastereoisomers appears to be due to thesteric interaction of the tert-butyl groups. The authorsassumed that the addition of steric factors, such assubstituents at the 2 and 2 positions of the binaph-thyl ring system, could raise the rotational barrierof this system to that of BINAP-type ligands and

Scheme 7

Scheme 8

Scheme 9

Scheme 10


could make it usable as a chiral ligand. Thus, Meyerset al.13 applied their method to binaphthyls substi-tuted in positions 2 and 2 with several oxazolines(Scheme 11).

The diastereomeric ratio of products was found tobe sensitive to the size of the (R)-substituent in theoxazoline ring. Examining the transition states andcopper intermediates, the authors explained that oneof the two diastereomeric copper complexes was freeof any severe steric interaction due to the closeproximity of the (R)-substituents of the two oxazo-lines.

This route was employed to synthesize enantio-merically pure binaphthyl diester or the correspond-ing acid (Scheme 12) for use as a chiral stationary

phase in HPLC and GC as well as a selective chiralhost for stereoselective inclusion and as a chiralligand for palladium-catalyzed cyclization.

The authors applied their method to the firstasymmetrical total synthesis of (S)-(+)-gossypol14,15(Scheme 13).

b. Unsymmetrical Couplings. To synthesizepolynitrobenzanthrones, a new class of suspectedmutagens in the atmospheric environment, Suzukiet al.16 reported an Ullmann cross coupling betweennitro-substituted iodobenzoates and iodonaphtha-lenes (Scheme 14).

To obtain those high yields of unsymmetricalcoupling (based on methyl-iodobenzoates), a largeexcess of iodonaphthalene has to be used. Moreover,the reaction temperature is crucial: below or above

optimal temperature, the heterocoupling becomesless competitive and the homocoupling is predomi-nant.

B. Aromatic Coupling Using Catalytic Amounts of Copper

During the past few years, reductive couplings,using catalytic amounts of copper to create aryl-arylbonds, have drawn little attention from the scientificcommunity.

Two methods for constructing C-N bonds arecommonly used: (1) nucleophilic aromatic substitu-tion,17 which requires that the aryl halide substratepossesses electron-withdrawing substituents, and (2)Ullmann-type coupling of imidazoles with aryl ha-lides, which has a broader substrate scope withrespect to the aryl halide. Buchwald et al. used thelatter method reporting a copper-catalyzed N-aryla-tion of imidazoles.18 They found that the couplingproceeds fairly mildly in the presence of 1,10-

Scheme 11

Scheme 12

Scheme 13

Scheme 14


phenanthroline (phen) and trans,trans-dibenzylide-neacetone (dba) as additives, with (CuOTf)2benzeneas the copper source and Cs2CO3 as the base, inxylenes at 110-125 C (Scheme 15).

The inclusion of additives is one key to the successof the process, and the authors discussed their role.As ligands are known to inhibit copper-assistedcoupling reactions,19,20 it is interesting that thisreaction is promoted by adding a 10-fold excess ofchelating ligand (relative to the amount of copper).The effect of dba is not easy to explain, and theauthors assumed that dba prevents undesirabledisproportionation or in some way stabilizes thecatalytically active copper(I) species.

The reaction proceeds cleanly with little, if any,formation of arene or symmetrical biaryl byproducts.Aryl iodides undergo coupling with imidazole at 110C, and the reactions are completed in 24-30 h, whilethe use of aryl bromides requires a higher reactiontemperature, a higher concentration of the sub-strates, and longer reaction times. As is usually thecase with Ullmann-type coupling processes, the pro-tocol works for both electron-rich and electron-pooraryl halides (the opposite of what would be expectedfrom a nucleophilic aromatic substitution reaction).

2. Coupling of Aromatics via Aryl CarbanionThis type of coupling is closely related to the

Ullmann reaction but involves the formation of anaryl carbanion as the intermediate. As oxidativeaddition to the copper is the limiting step in theclassical Ullmann reaction, preparation of the car-banion provides milder conditions with a higher rate.With this methodology catalytic amounts of copper(generally Cu(I)) can be used, but conversely astoichiometric (or greater) amount of base or orga-nometallic is required. The reaction requires thereduction of the substrate (formation of the carban-ion) and a transmetalation followed by a reductiveelimination of the copper intermediate complex.

A. Use of Stoichiometric Amounts of Coppera. Symmetrical Couplings. During the past

decade, various activating groups have been used. Wepropose to distinguish three families based on the

nature of the atom which is substituting the initialhalogen atom of the substrate. This atom can be a(1) Si, (2) Sn, or (3) Li atom.

The activation of the substrate with silicon deriva-tivessfluorosilanes, siloxanes, or silyloxyl groupssand trialkylstannane groups leads to smoother condi-tions and, in most cases, to higher yields.

The lithium derivatives present the additionalopportunity of introducing asymmetry to the couplingreactions.

i. Coupling of Silicon Derivatives. Mori et al.21centered their research interest on the homocouplingreaction of aryl silanes under mild conditions. Usinga copper(I) salt in an aprotic polar solvent and underaerobic conditions, they succeeded in homocouplingvarious aryl silanes (Scheme 16).

The number of fluorine atoms on silicon is highlycrucial: two or three fluorine atoms are essential forthe success of homocoupling. Likewise, counterionsand the oxidation state of the copper salt dramati-cally affect the yield of biaryl. CuCl and CuOTfefficiently accelerate the homocoupling reaction. Theuse of a polar solvent is crucial to promote thereaction. It is assumed that it coordinates with anorganosilicon reagent to form the pentacoordinatedbut tetravalent species, which may behave as apentavalent organosilicate that is formed by theaddition of a fluoride ion to the organosilane and isknown to be highly active to transmetalation (Scheme17).

Although mechanistic details of the homocouplingprocess remain unclear, since the organocopper spe-cies could neither be isolated nor detected, theseresults should give a clue as to the formation of theorganocopper species by the transmetalation fromsilicon to copper.

ii. Coupling of Tin Derivatives. Piers et al. devel-oped an intramolecular Cu(I)-mediated coupling oftwo aryl trimethylstannane functions.22 Treatmentof various substances with an excess of CuCl in dryDMF at room temperature for 30-60 min effects, ineach case, oxidative coupling between the two sp2carbon centers bearing the Me3Sn functions (Scheme18).

Scheme 15

Scheme 16

Scheme 17


The authors used a protocol that gives good yieldsand avoids the production of polymeric material.Referring to the works of Farina et al.,23 Scheme 19

outlines a possible pathway via the oxidative couplingprocess.

The routine use of 5 equiv of CuCl would facilitatethe overall process by shifting the initial equilibriumreaction toward the bis-copper(I) species.

Quayle et al.24 reported a general method for thepreparation of highly substituted buta-1,3-dienesbased upon a copper(II)-promoted coupling reactionof alkenyl stannanes. They extended their methodto the homocoupling of benzofused heterocyclic sys-tems (Scheme 20).

This formation of the bis-benzofuran is operation-ally simple to carry out and occurs at ambienttemperature over short reaction times (10-40 min).

According to the same methodology, Iyoda et al.synthesized in a moderate yield the 1,8-(1,8-naph-thalendiylbis(4,4-biphenyldiyl))naphthalene,25 a verystable strained cyclophane potentially interesting forhost-guest chemistry (Scheme 21).

The same team has found another method for thesynthesis of biaryls and their heteroaromatic ana-logues using the coupling of diarylmethyltins withcopper(II) nitrate.26 They applied the reaction, whichproceeds smoothly at room temperature under ambi-ent atmosphere, to various kinds of diaryldimeth-yltins (Scheme 22).

The reaction has also been carried out in the caseof diaryldimethyltins containing para- or meta-sub-stituents. The coupling occurs but the yields arelower. Moreover, it should be noticed that couplingof dibromothiophenes affords biaryl products withoutloss of the bromo substituents.

Scheme 18

Scheme 19

Scheme 20

Scheme 21

Scheme 22


The authors assume that the first step of thecoupling involves an electron-transfer process andtransmetalation to generate an organocopper(II) spe-cies and dimethyltindinitrate.

iii. Coupling of Lithium Derivatives. The use ofphenylcoppers stabilized by sulfur ligands at theortho-benzylic position for the cross coupling wasdeveloped by Ziegler et al.27 several years ago. Toyotaet al. reported the results of the reaction and theeffects of the intramolecular thioether ligands on thestability and reactivity of organocopper compounds.282-(Alkylthiomethyl)phenyllithium was reacted witha copper(I) halide to form homocoupled compounds,2,2-bis(alkylthiomethyl)biphenyl, benzyl ethyl sul-fide, and traces of a copper halide complex of thebiphenyl ligand (Scheme 23).

Several copper(I) salts were tested, but CuCl gavethe best results, which suggests that CuCl has a lowability to form a complex with the difunctionalsulfane ligand as a stable form. With CuBr, the majorproduct is the copper halide complex of a difunctionalthioether ligand, an interesting molecule from thestandpoint of coordination chemistry because copper-(I) ions are able to take a variety of aggregation formsdepending on the nature of the ligands. Therefore,the authors investigated the structure and propertiesof the copper halide complexes.

Lipshutz et al.29 developed a synthesis of biarylsby intramolecular oxidative couplings of cyanocu-prate intermediates. They achieved an asymmetricalintramolecular reaction with the help of opticallyactive auxiliary bridges (lactic, mandelic, or tartaricacid derivatives). They used their method for syn-thesizing 2,2-binaphthol (Scheme 24).

Treatment with t-BuLi followed by addition ofCuCN presumably leads to the in situ formation of ahigher order cyanocuprate, which produces the bi-naphthyl upon exposure to oxygen. It is interestingthat aryl bromide precursors are readily available,nonracemic tethers are derived from inexpensivemembers of the chiral pool, and couplings take placeat practical temperatures.

Moreover, this method applies equally to 2,2-C-substituted binaphthyls and appears suited to thesynthesis of biaryl portions of several natural prod-ucts. An approach toward the ellagitannins wasachieved by subjecting a dibromodiether to cuprate-induced coupling (Scheme 25).

Lin et al.30 used this asymmetrical intramolecularoxidative coupling to achieve the asymmetrical syn-thesis of the naturally occurring (+)-kotanin.

b. Unsymmetrical Couplings. i. Coupling ofSilicon Derivatives. Using silyloxyl groups, Hosomiet al.31 achieved a new fluoride ion-free cross-couplingreaction between aryl- or heteroarylsilanes and aryl

Scheme 23

Scheme 24

Scheme 25


halides mediated by a copper(I) salt. They examinedseveral substrates, copper salts, and solvents, andtheir best results are depicted in Scheme 26.

CuOC6F5 is the best promoter for this reaction. Thepentafluorophenoxide ion reveals strong affinity tothe silicon atom of arylsilanes and accelerates thetransfer of the Ar1 group. Moreover, the authorsnoticed that other copper(I) alkoxides and aryl oxidessuch as methoxide, tert-butoxide, and phenoxide reactfaster with the organic halides than the organosiliconcompounds (Scheme 27).

Hosomi et al. also demonstrated the syntheticutility of their fluoride-free cross coupling by expedi-ent reaction of a substrate containing a silyl ethermoiety which is easily cleaved by a fluoride ion(Scheme 28).

Lam et al. described an interesting copper-medi-ated C-N bond cross-coupling reaction. They firstdiscovered a new aryl/heteroaryl cross-coupling reac-tion via the aryl boronic acid/cupric acetate arylationof N-H containing heteroarenes.32 This reactionproceeds at room temperature when exposed to airfor 2 days and provides good yields (50-88%) butneeds the presence of a base (either pyridine ortriethylamine depending on the substrate).

They recently improved their methodology usinghypervalent aryl siloxanes instead of aryl boronicacids and tetrabutylammonium fluoride (TBAF) forC-N bond formation33 (Scheme 29).

Their new methodology offers the advantage ofperforming a room-temperature N-arylation in the

absence of a base. Water does not appear to interferewith this reaction.

The authors believe the mechanism is similar tothat postulated for N-arylation with aryl boronicacids32 (Scheme 30).

With this method, the authors performed a one-pot N-arylation of benzimidazoles using variousiodobenzenes as arylating agents via in situ genera-tion of phenyl trimethylsiloxane through the Masudamethod.34 The cross-coupling product is obtained inmoderate yields (40-44%).

ii. Coupling of Lithium Derivatives. Nilsson et al.35found that the reaction of 2-pyridylcopper in thepresence of triphenylphosphine gives 50-80% yieldsof 2-arylpyridines using nonactivated iodoarenes(Scheme 31).

The optimal ratio of triphenylphosphine/pyridyl-copper is slightly above 1. The presence of triph-enylphosphine seems to stabilize 2-pyridylcopperwith respect to thermal decomposition and formationof symmetrical biaryl. With this method, even acrowded trimethyliodobenzene can react in 2 h in anacceptable yield.

Scheme 26

Scheme 27

Scheme 28

Scheme 29

Scheme 30


Harrowven et al.36 described a short synthesis ofthe pyrrolophenanthridone alkaloid hippadine usinga low-temperature Ullmann cross coupling as the keystep (Scheme 32).

An intramolecular coupling, akin to this modifiedUllmann reaction, allows them to construct thepentacyclic skeleton.

Their interest for the coupling of aryls throughoxidation of cyanocuprate intermediates has ledLipshutz et al.37 to perform the first controlledunsymmetrical biaryl cuprate oxidation. Indeed, at-125 C in 2-methyl-tetrahydrofuran, they kineti-cally generated high-order mixed diarylcuprates.Oxidation at -125 C gives the desired cross-couplingproducts. They first applied their procedure to thesynthesis of biphenyls with good yields (70-90%)(Scheme 33).

Neither steric nor stereoelectronic factors appearto play an important role in these couplings. Variouscuprates were tested, but cyanocuprates gave thebest results in terms of selectivity. Moreover, the

temperature is a far more critical parameter than theconcentration at which the cuprate is oxidized.

Extension of the method to both naphthalene andbinaphthyl derivatives was investigated. Here againa small steric effect is observed. Likewise, an electron-deficient benzene ring or a heteroaromatic moiety canbe attached to the naphthalene ring with good yields(Scheme 34).

Lipshutz et al. also developed the potential for oneor both ligands of copper in the cyanocuprate inter-mediate (Ar, Ar) to be of an heteroaromatic nature.38For the coupling of heterocycles, results are found tobe mixed. Very good isolated yields are obtained (87-97%), but the ratio of cross-coupled/homocoupledproducts is not always advantageous. Upon switchingto a benzothiazole reagent, cross-coupled biaryl isformed in good yield and selectivity (Scheme 35).

Couplings under these controlled conditions in thebipyridyl series are unexpectedly random. This is dueto the over-riding influence exerted by the pyridylmoiety in perturbing the normally highly orderedmode of kinetic cuprate behavior toward oxidation.The corresponding intramolecular variant is far moreconsistent and rewarding (Scheme 36). Similar treat-

Scheme 31

Scheme 32

Scheme 33

Scheme 34

Scheme 35


ment of a thienyl analogue leads to the expectedproduct with a good yield (72%).

Results obtained with these intramolecular cou-plings provided strong justifications for applyingthese concepts to targets containing atropisomers.The asymmetrical synthesis of biaryls by intramo-lecular symmetrical oxidative coupling has alreadybeen discussed (see section II.2.A.a). Lipshultz et al.then applied this method with success to the synthe-sis of unsymmetrical biaryls29 (Scheme 37).

B. Catalytic Amounts of Coppera. Symmetrical Couplings. i. Coupling of Silicon

Derivatives. Kang et al. reported copper(I)-iodide-catalyzed homocoupling of substituted chloro- orfluoro-dimethylsilanes to form biaryls39 using tet-rabutylammonium fluoride (TBAF) (Scheme 38).

Of the catalysts tested, CuI gave the best results.The presence of TBAF is essential as an acceleratorfor transmetalation40 in this homocoupling. In con-sidering the likely mechanism, it is presumed thatoxidative addition of activated organosilane to CuIsalts results in the formation of organo ArCuSiMe2X.This is then ready for transmetalation with thepentacoordinate silicate, formed from TBAF andorganosilane, to give Ar2CuI. This latter moleculeundergoes reductive elimination to generate the Ar-Ar bond with the liberation of CuI.

ii. Coupling of Tin Derivatives. Kang et al. alsocarried out an efficient catalytic homocoupling oforganostannanes with CuCl2 slowly adding iodine asthe oxidant41 (Scheme 39).

Of the suitable catalysts, CuI, CuCl, CuCl2, andCuF22H2O tested, CuCl2 was the best choice.

b. Unsymmetrical Couplings. i. Coupling of TinDerivatives. Kang et al.42 reported a cuprous-iodide-catalyzed cross coupling of aryl stannanes with aryliodides in the presence of sodium chloride (Scheme40).

Initially a series of experiments were performedusing different salts. KCl and NaCl are the mostpreferable. Kang et al. noticed that the addition ofNaCl is crucial in these cross couplings. It is pre-sumed that the transmetalation of ArSnBu3 withcuprate is reversible. n-Bu3SnI, formed from trans-metalation of ArSnBu3 with CuI, can be convertedto n-Bu3SnCl by adding NaCl. n-Bu3SnCl does notparticipate in a back-reaction with cuprate and thusdrives the transmetalation favorably.

ii. Coupling of Boron Derivatives. Collman et al.developed a copper-catalyzed N-arylation of azolesusing aryl boronic acids,43 akin to a modified Ullmannreaction. Since readily available Cu(OH)ClTMEDAhas been successfully employed in aerobic oxidativecoupling of 2-naphthols,54,57 the authors assumed thatthis catalyst could be an excellent replacement forthe Cu(II) salts and tertiary amines that are used inChan and Lams system.32 They successfully em-ployed and optimized this catalytic system for thecross-coupling reaction of aryl boronic acids withimidazoles (Scheme 41).

Scheme 36

Scheme 37

Scheme 38

Scheme 39

Scheme 40


Although a lower yield is found compared to theuse of O2, the reactions also succeeded under ambientconditions. The authors speculated on a mechanismstemming from Evans postulate for coupling arylboronic acids with phenols.44

In addition to these examples based on the Ull-mann reaction, several couplings of other activatedaryls under mild conditions have also been estab-lished. Lopez-Alvarado et al.45 described N-arylationof imidazoles with p-tolyllead using a catalytic amountof Cu(OAc)2 at 90 C in good yields. However, thismethod is limited to p-tolyllead and produces toxicorganolead byproducts.

3. Oxidative Aromatic Coupling Using CopperSalts

Copper-mediated or -catalyzed oxidative couplingsare one of the ways to obtain biaryls. For the pastdecade, oxidative couplings of 2-naphthols have beenlargely employed for the preparation of binaphthols.Due to this, extensive efforts have been made toincrease the scope of these methodologies for sym-metrical and unsymmetrical couplings includingenantioselective reactions.4,46

A. Use of Stoichiometric Amount of Coppera. Symmetrical Couplings. Smrcina et al. per-

formed a very large study on the synthesis of sym-metrical and unsymmetrical binaphthyls. First theydeveloped a facile synthesis of the racemic 2,2-diamino-1,1-binaphthyl47 by oxidation of 2-naphthy-lamine using (PhCH2NH2)4CuCl2 (Scheme 42).

The complexation of copper(II) chloride is a keypoint in the reaction, since uncomplexed CuCl2 gaveonly a 34% yield.

They extended this procedure to the synthesis ofenantiomerically pure binaphthyls using inexpensiveand commercially available chiral amines.48,49

Coupling of 1 equiv of 2-naphthol,48 using an in-situ-generated complex of 1 equiv of CuCl2 and 2equiv of (-)-sparteine, results in the formation ofprecipitate and mother liquor. The precipitate leadsto the isolation of enantiomerically pure (-)-binaph-thol with a 14% yield, while the mother liquor gives42% of (-)-binaphthol of 20% ee.

Similarly, a stoichiometric coupling of 9-phenan-throl with CuCl2 and (-)-sparteine has been achievedleading to (-)-biphenanthrol of 76% ee with an 80%isolated yield49 (Scheme 43).

However, in both cases, Smrcina et al. observedthat the pure (-)-enantiomer could be best obtainedby a second-order asymmetrical transformation fromracemic species in good yields. Thus, the authorsconcluded that, in these cases, the enantioselectionwas mainly controlled via a second-order asym-metrical transformation of the binaphthyl.

Coupling of 1 equiv of 2-naphthylamine48 with 1.5equiv of (-)-sparteine and 1 equiv of CuCl2 gives aprecipitate which leads, after crystallization, to pure(-)-2,2-diamino-1,1-binaphthyl with a 13% yield.The mother liquor from the reaction furnishes 41%of (+)-2,2-diamino-1,1-binaphthyl of 31% ee. Furtherresolution leads to pure (+)-enantiomer.

Likewise, the coupling of methyl 3-hydroxy-2-naphthoate49 with CuCl2 and (S)-(-)-methylbenzy-lamine (1:4) leads to the isolation of 47% of (-)-binaphthylester (44% ee) from the precipitate, whilethe mother liquor furnishes (+)-enantiomer of 43%ee with a 40% yield (Scheme 44).

In these cases, the stereodifferentiation can beascribed to a diastereoselective crystallization of thecorresponding Cu(II)-amine-binaphthyl complex.

b. Unsymmetrical Couplings. Hovorka et al.studied the direct oxidative coupling of substituted2-naphthols as a key step toward binaphthol-derivedsystems. They investigated oxidative cross couplingof various substituted 2-naphthols mediated by dif-ferent Cu(II) salts.50 First cross couplings wereperformed with an excess (4 equiv) of in-situ-formedcopper(II) chloride/tert-butylamine complex (1:4) inmethanolic media under strictly anaerobic conditions

Scheme 41

Scheme 42

Scheme 43

Scheme 44


at temperatures of 25-50 C and with reaction timesof 5-150 min. They achieved 12 couplings from 10substituted 2-naphthols (Scheme 45) with good to

excellent yields (70-97%). In each case, the couplingoccurs at the R-position of the hydroxyl group.

Nevertheless, under comparative oxidative condi-tions, the selectivity of the cross coupling is dramati-cally influenced by the substitution of the aromaticrings. At one extreme, the selectivity is excellent (92%for cross coupling of 1 and 3; 91% for 1 and 2), whilein the other extreme the selectivity does not exceedlimits of statistical distribution (47% for 2 and 3).Using methyl 3-hydroxy-2-naphthoate (1) and 2-naph-thol (2), the influence of the reaction variables on theselectivity of the cross-coupling reaction was exam-ined. It was found that neither temperature andsolvent variations nor the structure of the amineligand had a significant effect.

Cross couplings were performed next with 4 equivof CuCl(OMe) synthesized in or ex situ. Thus, 1 and2 were coupled selectively to give 86% yield ofisolated crossed product. The main advantage of thisprotocol is its simplicity: the amine which had to beused in excess is not needed and the formation of avoluminous precipitate of Cu(II)-amine complex isavoided, enabling a substantial reduction of thereaction volumes.

Hovorka et al. were also interested in the mecha-nism of CuCl2-mediated oxidative couplings.51 Themechanism is not clear, and essentially three possibleroutes have been proposed in the literature: (1)homolytic coupling of two radicals (X +Y), (2) ionicreaction (X+ + Y-), and (3) radical insertion of one ofthe aryls into the C-H bond of another aryl molecule(X + Y). Hovorka et al. showed that the modelreaction between 2-naphthol and methyl 3-hydroxy-2-naphthoate can be controlled to give either thecross-coupled product or a nonselective mixture of thecross- and homo-coupled products. The copper/ligandratio was found to be the main controlling factor.They devised a plausible model of a binuclear Cu(II)complex explaining the preferential cross coupling:if dimeric complexes (ArOCuL)2 are considered asintermediates, the coupling would occur as an in-

tramolecular process and the differentiation betweenpathway 1, 2, and 3 would be meaningless.

Using the same procedure as for symmetricalcoupling (see section II.3.A.a), Smrcina et al.47 achievedthe cross coupling of 1 equiv of 2-naphthol and 1equiv of 2-naphthylamine by means of 2.5 equiv ofcopper(II) chloride in the presence of benzylamine (1:4) at room temperature over 24 h. The racemic cross-coupled product was obtained pure with an isolatedyield of 45%.

They then carried out the synthesis of enantio-merically pure 2-amino-2-hydroxy-1,1-binaphthyl48using enantiopure (R)-(+)-R-methylbenzylamine (10equiv) with CuCl2 (2.5 equiv). The stereodifferentia-tion was ascribed to a diastereoselective crystalliza-tion of the Cu(II)-amine-product complex. Theprecipitate and the mother liquor, after crystalliza-tion, respectively, led to 23% of pure (-)-cross-coupledproduct and 24% of pure (+)-cross-coupled product(Scheme 46).

A new situation was encountered for the highlychemoselective cross coupling of 2-naphthol withmethyl 3-hydroxy-2-naphthoate49 which displayed afairly good enantioselectivity (Scheme 47).

Indeed, the stereodifferentiating process is neithera diastereoselective crystallization nor a second-orderasymmetrical transformation. Another mechanismoperates in this system: asymmetrical induction inthe coupling reaction has been proposed as the mostlikely one.

Smrcina et al. then extended their method to theselective cross coupling of 2-naphthol and 2-naph-thylamine derivatives leading to racemic 2,2,3-trisubstituted and 2,2,3,3-tetrasubstituted 1,1-binaphthyls52 (Scheme 48).

Each product has been synthesized from its respec-tive precursors by the CuCl2/t-BuNH2-mediated oxi-dative cross coupling. Binaphthyls, resulting from theself-coupling, and carbazoles have been identified asbyproducts. The nature and number of substituentson the naphthyl derivatives dramatically influencetheir propensity to cross-couple.

Frontier orbital theory and electrochemical mea-surements have been employed to explain the ob-served selectivity. In a coupling reaction with twopotential partners A and B, both of them capable ofgenerating a radical, three possible products can be

Scheme 45

Scheme 46

Scheme 47


expected, namely, A-A, B-B, and A-B. Assumingthat the coupling proceeds as an orbital-controlledprocess, the choice of the reacting partner for theinitially formed radical, e.g., A, will be determinedby the energy difference between the SOMO of A andthe HOMOs and LUMOs of A and B. The high-energySOMO (a nucleophilic radical) is likely to interactwith the LUMO of the reaction partner, while thelow-energy SOMO (an electrophilic radical) shouldmix with the HOMO. If the stabilization is greaterfrom the interaction between ASOMO and BHOMO/LUMO,then preferential formation of the cross-coupledproduct A-B can be anticipated. Thus, to obtain ahigh proportion of cross coupling, one partner mustbe relatively easily oxidized to an electrophilic radicalwhile the acceptor molecule should be capable ofelectron donation (preferably in an anionic form) withthe HOMO close in energy to the SOMO of theradical. Although the mechanism is more complexand the coupling probably occurs in the coordinationsphere of copper, it seems that the basic propertiesof the reaction partners can be approximated by thisfrontier orbital theory.

B. Use of Catalytic Amounts of Copper

a. Symmetrical Couplings. Smrcina et al.49 car-ried out one of the first examples of a catalytic,oxidative asymmetrical coupling that creates a bi-naphthyl system. They proposed a catalytic cycle inorder to lend further credence to their mechanisticconclusions (see section II.3.A.a). The crucial pointfor the design of the catalytic cycle was the reoxida-tion of Cu(I) to Cu(II). Hovorka et al. reportedconditions50 that were the solution to this issue.

The catalytic self-coupling of 2-naphthol (in formof its sodium salt) is carried out in MeOH with 10mol % of CuCl2, 20 mol % of (-)-sparteine, and 1.1equiv of AgCl. The reaction mixture, stirred at roomtemperature for 72 h, gives rise to (+)-binaphthol(70%; 14 turnovers) of only ca. 3% ee. Although theenantiomeric excess is very low, this experimentdemonstrates that the reaction conditions allow fora catalytic process to operate. In this experiment, theoxidation of the copper(I) is performed by the sto-ichiometric amount of silver, which is the majordrawback of this method from an economical pointof view.

Koga and Nakajima53 first developed an efficientcatalytic process for the aerobic oxidative couplingof naphthol derivatives by the use of a catalyticamount of CuCl-TMEDA (1 mol %) under molecularoxygen or even under ambient conditions (Scheme49).

The authors then extended this method to theasymmetrical aerobic coupling54 of 3-hydroxy-2-naph-thoate with a chiral copper-amine complex as acatalyst. They used diamines derived from L-prolinebecause of their availability and their sterically rigidconformation in chelation with various metals (Scheme50).

They screened several types of ligands and esters,leading them to the conclusion that a secondarynitrogen in the pyrrolidine ring is crucial for asym-metrical induction: the extent of enantioselection isdependent on the bulkiness of R substituents on thisnitrogen.

They achieved the isolation of a copperdiaminecomplex by precipitation in hexane. The isolatedcomplex possesses slightly better reactivity, whichmakes it possible to conduct the reaction at roomtemperature55 (Scheme 51).

Scheme 48

Scheme 49

Scheme 50

Scheme 51


They also carried out an oxidation of naphtholswith ketone, amide, alkyl, or alkoxy moieties at the3-position. Unfortunately it generates the corre-sponding binaphthols in low enantioselectivities,which implies that the ester moiety is essential forthe asymmetrical induction. As the mechanism ofthis oxidative coupling is unknown, they postulatedthat their coupling reaction consists of three succes-sive processes: (1) exchange of the hydroxy group onthe copper complex for a phenolic hydroxy groupfollowed by the additional coordination of the estercarbonyl to the copper atom, (2) oxidative couplingaffording a diketone with central chirality, and (3)transfer of central chirality to axial chirality throughketo-enol isomerism along with dissociation of thecopperamine complex.

Pac et al. achieved the coupling of 2-naphtholscatalyzed by alumina-supported copper(II) sulfate(SCAT) under aerated conditions56,57 (Scheme 52).

The supported catalyst can be easily prepared. Theremarkable simplicity of both the reaction and theworkup procedures is of synthetic significance. Airis essential for the catalysis of the coupling reaction.However, CuSO4/Al2O3 can also act as an efficientstoichiometric reagent for the coupling reaction underdeaerated conditions. Other similar catalysts wereprepared by using solid supports such as acidic andbasic alumina, Florisil, Celite, silica gel, and molec-ular sieves and by supporting Cu(OAc)2 and CuF2 onneutral alumina. Nevertheless, their catalytic activi-ties were substantially lower, in most cases, thanthose of SCAT. What is of interest is that the catalyticactivity of SCAT might be restored by appropriatereactivation treatment after oxidation reactions.

The authors then attempted the SCAT-promotedintramolecular dehydrogenative coupling of 5,5-diacenaphthene57 as an easy access to perylene witha low yield (Scheme 53).

This appears to reflect general limitations of theSCAT catalysis which would arise from steric and

electronic requirements, e.g., adsorption of the reac-tants on the SCAT surface without steric hindrance,lower oxidation potentials than the limit for one-electron oxidation by Cu(II) of SCAT, and reactivitiesof the radical cations for the follow-up processes.However, the choice of the metal ions and inorganicsolids associated with improvements in preparationof supported catalysts and/or reagents might be ableto increase synthetic applicability.

Lakshmi Kantam et al. also developed couplingsof 2-naphthols under aerated conditions using Cu-exchanged montmorillonite as a catalyst58 with simi-lar results to those of Pac et al.56,57

b. Unsymmetrical Couplings. To lend furthercredence to their mechanistic conclusions (see sectionII.3.A.a), Smrcina et al.49 carried out a catalytic crosscoupling of 2-naphthol and methyl 3-hydroxy-2-naphthoate under conditions similar to those em-ployed for the self-coupling of 2-naphthol (see sectionII.3.B.a). It produced a (-)-cross-coupled product of32% ee (41%; eight turnovers). This was the firstexample of catalytic asymmetrical oxidative crosscoupling (Scheme 54).

c. Oxidative Coupling with FeCl3. Similar tooxidative couplings with copper(II), iron(III) is alsoused as an oxidative reagent. Indeed, because of itsoxidating properties and its low cost, iron(III) hasbeen used for many years to perform the homocou-pling of substrates with low oxidation potential, inparticular for the synthesis of 1,1-binaphthol. Typi-cally the reactions were carried out in organic mediausing solutions with more than equimolar amountsof FeCl3.59

Several variants were developed, such as the useof K3Fe(CN)4 by Feringa et al.,60 but all of thesemethods suffered from difficulties in the separationof organic and inorganic products, from the formationof quinones as byproducts, and from the disadvantageof requiring (over)stoichiometric amounts of reagent.

Toda et al. reported a solid-state oxidative proce-dure for the preparation of binaphthol derivatives.61They found that the reaction proceeded faster andmore efficiently (91-95% yields) in the solid statethan in solution and that it could be accelerated byirradiation with ultrasound. Taking advantage of thefact that oxidation of Fe2+ to Fe3+ in air occurredeasily in the solid state, the authors carried out thecoupling reaction at 50 C over 24 h in the presenceof catalytic amounts of FeCl36H2O (0.2 equiv) witha 89% yield. Similarly, Villemin et al. used stoichio-metric amounts of FeCl3 without solvent undermicrowave irradiation.62

Ding et al. carried out the reaction in water.63Indeed, the oxidative coupling of 2-naphthols sus-pended in aqueous Fe3+ (2 equiv) gave the corre-sponding 1,1-binaphthols with yields of 91-95% andproceeded much faster than in homogeneous solution.

Scheme 52

Scheme 53

Scheme 54


Considering the insolubility of 2-naphthol in water,the authors suggested that the reaction occurs at thesurface of the crystalline 2-naphthol via a solid-liquid process.

As they had done with copper,58 Lakshmi Kantamet al. used heterogeneous catalysis for the oxidativecoupling of 2-naphthols.64 The catalysts were ironsupported either on a montmorillonite clay (23.4%Fe2O3) or an acid-treated mesoporous clay (Fe-K10;20.4% Fe2O3). Although both Fe-clays gave highyields of homocoupling products (88-95%), Fe-K10appeared to have the highest activity. This activitywas attributed to the easier access of the catalyticsites on this clay. In both cases the catalyst could berecycled without loss of catalytic properties and theprocedure is easy and simple.

4. Aromatic Coupling via Radicals (The PschorrReaction) Using Copper Salts

The major use of the copper-mediated reaction isto obtain symmetrical biaryls mainly via intermo-lecular procedures. Nevertheless, a few cases ofintramolecular couplings have been developed, basedon the Pschorr reaction. The Pschorr reaction65 hasan even longer history than the Ullmann reaction.It involves the intramolecular substitution of arenesby aryl radicals which are generated by the reductionof arene diazonium salts usually with a copper(I) ion.Aryl diazenyl radicals, intermediates in the reaction,rapidly eliminate nitrogen giving rise to the requiredaryl radicals for C-C bond formation3 (Scheme 55).

The Pschorr reaction has two main weaknesses:starting compounds are not always easily preparedand the yields of ring-closed product are often modest.

In the last step of the synthesis of 4,6-dimethyl-dibenzothiophene, Meille et al. achieved an intramo-lecular cyclization with a suspension of Cu(0)66(Scheme 56).

After recrystallization, a 26% yield is obtainedwhich represents the usual low yield of this method.

5. Synthesis of Oligomers and Polymers UsingCopper as a Reagent

The synthesis of films of polyacetylene,67 with anexcess of Ziegler-Natta catalyst, was the discoverywhich stimulated research into organic conducting

polymers. Exposing these films to iodide vapor,Shirakawa et al.68 observed a considerable increasein conductivity. This discovery, which represents thebeginning of the tremendous story of organic conduc-tive polymers, earned Shirakawa, MacDiarmid, andHeeger the Nobel Prize in Chemistry for the year2000. Since then, studies have been extended to awide range of other macromolecules69,70,71 with thesame conjugated structure such as polythiophenes,72polypyrroles, poly-p-phenylenes, etc. Over the pastfew years, organic conducting oligomers or polymershave been intensively studied, owing to their funda-mental optoelectronic properties and their potentialapplications ranging from photodiodes73 to light-emitting devices (LEDs)74 and thin film transistors(TFTs).75

It is now well established that the physical proper-ties of conducting polymers are closely linked to thestructure of their monomeric precursor and to theirpolymerization conditions. The polymerization oforganic monomers can be classified into two catego-ries, i.e., the oxidative electrochemical or chemicalpolymerization and the organometallic couplings.

The electrochemical anodic polymerization hasbeen extensively studied.76 This method presents theadvantage that the doped conducting polymer isdirectly grafted onto the electrode surface, which isof particular interest for electrochemical applicationsor in situ characterization by electrochemical analy-ses. Many of the chemical polymerizations are basedon the oxidative coupling of monomeric precursorsusing oxidants such as FeCl3 or CuCl2. The polymersobtained by these methods are often high-molecular-weight polymers with a rather low amount of ir-regular couplings.

On the other hand, organic conductive polymerscan be synthesized by organometallic couplings. TheUllmann, Kumada-Corriu, Stille, Heck, or Suzuki-coupling reactions have been performed to obtainpolymers and will each be discussed in a section ofthe review. Usually these methods generate moreregioregular head-to-tail polymers with high molec-ular weights and conductivities.

Among conjugated oligomers or polymers, polypyr-roles and polythiophenes have attracted great atten-tion for their chemical stability, ease of functional-ization, and variety of useful properties. This sectionwill deal with the synthesis of such polymers andoligomers using copper as the reagent. Since itsbehavior for oxidative coupling is similar to that ofcopper and since it is largely used for chemicalpolymerization, iron will also be discussed as areagent.

The classical Ullmann reaction (see section II.1)has allowed the synthesis of various polymers, espe-cially polymers from monomers bearing an electron-withdrawing group.

The oxidative coupling of activated aryls usingcopper or iron has also been performed to obtainmainly oligomers.

Last but not least, chemical polymerization withFeCl3 has been widely developed. Nowadays thismethodology suffers from its lack of regioregularity(only 80% of the synthesized polymers are regioregu-

Scheme 55

Scheme 56


lar). Nevertheless, this method is also suitable for thesynthesis of well-defined oligomers.

A. The Ullmann ReactionIn an effort to maximize the extended -conjuga-

tion in polymers and to study their correspondingoptical and electronic properties, Tour et al.77 per-formed the synthesis of a zwitterionic pyrrole-derivedpolymer using the Ullmann reaction (Scheme 57).

The use of DME as the solvent was crucial sincecommon solvents of the classical Ullmann coupling(DMF, pyridine) did not allow polymerization. After18 h of reaction, fractional precipitation produced apolymer with a polydispersity (PD) of 1.15-1.25 witha number-average molecular weight of 3910 g/mol(i.e., 26 zwitterionic repeating units were formed). Nobromide content was detected, which is a commonlyobserved feature of Ullmann reactions78 since theexcess Cu(0) carries out oxidative additions on arylbromide locations with subsequent end-group proto-nations on workup or from the solvent.

To study and synthesize well-defined 2,5-linkedpolypyrroles, Groenendaal et al.79 also used theUllmann coupling reaction. They first synthesizedthree N-t-BOC-protected monomers of various sizes:2,5-dibromopyrrole, 5,5-dibromo-2,2-bipyrrole, and5,5-dibromo-2,2:5,2-terpyrrole. The polymerizationof the monomers was carried out at 100 C underinert atmosphere (Scheme 58).

After analyses by HPLC, they found that in thecase of the pyrrole monomer 25 different oligomerswith up to 25 pyrrole repeating units were formedwhile 8 different oligomers with up to 16 repeatingunits were obtained starting from bipyrrole monomerand up to 24 units starting from terpyrrole monomer.This difference may be due to the lower reactivityand the higher stability of the longer monomers.Their observations have led the authors to proposea chain-reaction mechanism for the oligomerizationof N-t-BOC-2,5-dibromopyrrole.

Looking for a general synthesis of polythiophenesbearing a carbonyl group (or other strongly electron-

withdrawing substituents) directly attached to the3-position of the thiophene ring, Pomerantz et al.80naturally thought about using the Ullmann reaction(Scheme 59).

Furthermore, the authors showed that polymersobtained by this route had better properties (i.e.,lower polydispersity and longer conjugation lengths)than polymers prepared by a Ni(0) coupling reaction.

B. Oxidative Coupling of an Activated Aryla. Using Copper as the Oxidative Reagent.

Interested in the synthesis of structurally definedconjugated oligomers with dimensions on the nanom-eter scale, Bauerle et al.81 performed the synthesisof a homologous series of isomerically pure R-linkedoligo(alkylthiophenes). In particular, they synthe-sized and isolated a sedicithiophene which should be64 when extended. Their monomeric precursor, aquaterthiophene, was synthesized using a nickel-catalyzed coupling. The conversion of this monomerto higher homologues was carried out by oxidativedimerization of the lithiated compound with CuCl2(Scheme 60).

Owing to their solubility, each oligomer was ob-tained in pure form by repeated chromatography. Theauthors then studied their physical properties andobtained the first STM images of physisorbed two-dimensional crystalline layers of the oligomers withsubmolecular resolution.

Scheme 57

Scheme 58

Scheme 59

Scheme 60


b. Using Iron as the Oxidative Reagent. Look-ing for new organic conductors for thin film transistor(TFT) applications, Li et al. produced the dimeriza-tion of a fused thiophene derivative82 using ferricacetylacetonate as the oxidative coupling reagent(Scheme 61).

This dimer, R,R-bis(dithieno[3,2-b:2,3-d]thiophene),was found to have an unusual -stacked structureand a wide HOMO-LUMO gap, which induces ahigh mobility and a very high On/Off ratio for thematerial.

C. Chemical Polymerization Induced by IronIn the 1980s, conducting polymers raised huge

interest. However, their insolubility in any solventhas been a serious restriction to their practicalapplications. That is the reason many teams haveworked to synthesize soluble polythiophenes, mainlyobtained with monomeric thiophene precursors bear-ing an alkyl chain in the 3-position.

In 1986, a few months after Sato et al.83 andLemaire et al.84 reported the electrochemical polym-erization of polythiophene, Sugimoto et al.85 achievedthe first chemical polymerization of 3-alkylthiopheneutilizing 4 equiv of FeCl3 as the oxidative reagent inchloroform. From this experiment, chemical polym-erization of various 3-alkylthiophenes has been per-formed. Nevertheless, the reaction mechanism of thechemical polymerization is still unclear and subjectto controversial interpretations.86,87 Wegner et al.88,89carried out a complete study of several well-charac-terized poly(3-alkylthiophenes) concentrating theirattention on the structural regularity and molecularweight of the polymers. Indeed, those two factorsdrastically influence the overall performance of apolymer with regard to conductivity in combinationwith useful mechanical properties. Thus, Wegner etal. synthesized soluble high-molecular-weight poly-mers which have rather a low amount of irregularcouplings (ca. 20%).

To bypass this lack of regioregularity, Zagorska etal.90 performed the chemical polymerization of 4,4-dialkyl-2,2-bithiophenes using the classical condi-tions of Sugimoto. With this kind of monomer, thecoupling results in a regular structure equivalent toalternating tail-to-tail and head-to-head couplings ofmonomeric 3-alkylthiophenes. However, since theregioregularity of polymers synthesized by oxidativechemical polymerization can hardly exceed 80%, thismethod is not used very much for the synthesis ofpolymers but is used for the synthesis of well-definedoligomers.

Barbabella et al.91 made a remarkable study ofthe regioselective oligomerization of 3-(alkylthio)-thiophenes with ferric chloride. Whereas in the sameexperimental conditions 3-alkylthiophenes alwayslead to high-molecular-weight polymers,92 the au-

thors observed the formation of regioregular R-con-jugated oligothiophenes, from trimer to octamer,depending on the length of the alkyl chain and thesolvent used (Scheme 62).

Theoretical calculations of the coefficients of theHOMO orbitals of the monomer and of the corre-sponding head-to-head, head-to-tail, and tail-to-tail2,2-bithiophenes and calculations of the coefficientsof the SOMO orbitals of the corresponding radicalcations showed that the regioselectivity of the oligo-mers is due to the strong orienting effect of thesubstituent and to the stability of the radical cationsformed during the oxidative process.

Working on the dodecyl and hexyl derivatives of1,3-dithienylbenzo[c]thiophene, Mohanakrishnan etal.93 achieved their oligomerization to dimers andtrimers (with yields of, respectively, 62.5% and 12.5%for the dodecyl derivative and 43% and 23% for thehexyl one).

The same reaction with a dithienylbenzo[c]thiophenefunctionalized with silyl groups on the R-position ateach end leads to a dimer with a good yield (66%).

III. Nickel-Promoted ArylAryl Bond FormationsNickel-catalyzed aryl-aryl bond formations have

been studied especially since the discovery by Ku-mada94,95 and Corriu,96 in 1972, of an efficient methodfor the formation of C-C bonds by nickel-catalyzed

Scheme 61

Scheme 62


coupling of Grignard reagents with organohalides.This reaction, further developed by using complexesof Pd and other group-VIII metals, is highly selective,allowing the formation of symmetrical and unsym-metrical biaryls in high yields, and is furthermorerun under mild conditions. These types of reactionshave since been widely studied with, for example,organozinc, organoboron, and organotin reagentsshowing similar high efficiency as well as improvedcompatibility with many functional groups presentin the substrates. Kalinin97 extensively reviewed theapplication of these methods to the functionalizationof heterocyclic compounds in 1991. We will focus hereon the use of nickel complexes as promoters for thecoupling of two aromatic rings over the past 10 years.We will first describe reactions where nickel is usedin stoichiometric amounts (Ni(0) as the preformed orin situ prepared reagent) and then transformationsinvolving catalytic amounts of nickel. Here againthese reactions involve an additional reducing agentor the use of organometallic aromatic derivatives (see,as described above, the Kumada-Corriu reaction).

1. Aromatic Coupling Involving StoichiometricAmounts of Nickel

Ni(0)-mediated aryl-aryl bond formations havebeen described for the homocoupling of haloarylcompounds and proved to be very efficient for thepreparation of bi-, oligo-, and polyaryls. Exampleswhere stoichiometric amounts of preformed Ni(0)reagents have been used were reported by Semmel-hack et al.98 This procedure was later extended tothe preparation of the in situ active form of nickel(use of Ni(II) and an additional reducing agent) byKende et al.99 Such examples are now seldom foundin the literature because the pendant reaction, i.e.,nickel used in catalytic amounts, offers much moreinterest in terms of both cost and ease of preparation.

A. Nickel(0) Used as a Preformed ReagentTo illustrate this reaction, we mention the homo-

coupling experiments, reported by Scherf et al.,100 of2-carbonyl-substituted bromobenzenes with Ni(COD)2(bis(1,5-cyclooctadiene)nickel(0)). This reagent had tobe used in excess (1.2-2.2 equiv of per aryl-arylbond formed) to allow high yields of the desiredproduct. Interestingly, the use of Ni(0) allowed theformation of a subsequent cis-pinacol cyclization(Scheme 63) according to the experimental procedure

(amounts of the metal introduced or the rate ofaddition of the coupled material).

B. Use of Additional Zinc or Other Reducing AgentsMany recent examples use Ni(0) prepared in situ,

for example, by using stoichiometric amounts of a Ni-(II) salt in the presence of a reducing agent. Indeed,

zerovalent nickel reagents are air-sensitive, need tobe prepared by sophisticated techniques, and thusremain difficult to handle. As already mentioned,Kende et al.99 reported a simple method to generatein situ tris(triphenylphosphine)nickel(0), the reactivespecies undergoing further oxidative additions witharyl halides. They were able to reduce bis(triph-enylphosphine)nickel(II) dichloride with zinc in thepresence of stoichiometric amounts of triphenylphos-phine and to use the solution of zerovalent nickelcomplex for biaryl formations (Scheme 64).

This procedure was tested for the homocoupling ofbromo- and iodobenzene derivatives in DMF to givethe expected biaryls with a modest to good yield (upto 85%). Tiecco and Testaferri101 further improvedthis procedure by preparing the active Ni(0) complexdirectly from nickel(II) chloride, triphenylphosphine,and zinc, avoiding the ex situ preparation of thecomplex Ni[P(C6H5)3]2Cl2. They then applied thismethod to the synthesis of various symmetricalbipyridines and biquinolines. They successfully testedthe homocoupling of bromo and chloro derivativeswith good yields (up to 89%, Scheme 65). The major

drawback of the above-described method is certainlythe necessity for large amounts of triphenylphosphinethat require subsequent separation by chromatogra-phy. A transposition of this method to the industrialscale is therefore hardly conceivable.

This method has been widely used for the synthesisof symmetrical nitrogen-containing aromatic deriva-tives. Queguiner et al.102 tested this homocouplingreaction to build the 2,2-bipyridyl structure of thealkaloid orelline (Scheme 66). The target molecule

was obtained via the nickel-phosphine complex-mediated homocoupling of 2-iodo-3,4-dimethoxypy-ridine in a 80% yield.

Zhang and Breslow103 used this methodology toprepare 5,5-diamino-2,2-bipyridine. This intermedi-ate was further modified to act as a linker betweena -cyclodextrin dimer (Scheme 67). This catalyst

Scheme 63

Scheme 64

Scheme 65

Scheme 66


precursor was then used as an enzyme mimic with ametallobipyridyl-linking group for ester hydrolysiswith good turnover.

Recently, Janiak et al.104 described the preparationof 6,6-diamino-2,2-biquinoline derivatives by cou-pling the corresponding 6-chloroquinolines (Scheme68) in the presence of NiCl2.6H2O/PPh3/Zn in DMF

(called NiCRA for nickel-containing complex reducingagent).

Chan used this method for the synthesis of a newtype of chiral atropisomeric 2,2-bipyridine for ap-plication in asymmetric cyclopropanation.105

This type of coupling was very recently performedby Howarth et al.106 employing the ionic liquid[bmim]PF6, where [bmim]+ is the 1-butyl-3-meth-ylimidazolium cation. These types of liquids mayprovide an alternative to classical solvents for mini-mizing industrial wastes, since they are nonvolatileand immiscible with a wide range of organic solvents(thus easily reusable). The authors tested the cou-pling of a variety of aryl bromides (bearing electron-donating or -withdrawing substituents) to occur inthe ionic liquid [bmim]PF6 with a mixture of (PPh3)2-NiCl2, Zn and PPh3 as the catalyst. The yieldsobtained were comparable to those generally obtainedin the more classical DMF, but the ionic liquidcontaining the spent catalyst could be reused byreforming the Ni(0) active species without addingfurther (PPh3)2NiCl2, although there was a smalldecrease in the yield of the coupling reaction.

Fort et al.107 prepared a number of nitrogen-,sulfur-, or oxygen-containing bis-heteroaromatic or

bis-heterocyclic derivatives by homocoupling the cor-responding halogenated compounds using a similarprocedure. In these cases, the authors assumedmixtures of sodium hydride, sodium alkoxide, and Ni-(OAc)2 to be the best activating agents to performthese couplings of organic halides. In Scheme 70,

some examples of biaryl structures obtained by thisprocedure are given. Couplings occurred in good toexcellent yields whatever the nature of the halide,the main side reaction being the reduction of theC-halogen bond.

Attempts to use these reagents in catalytic amountsfailed, due to the significant reduction of the startingmaterial by excess sodium alkoxide or sodium hy-dride added to regenerate the catalytic system.

This list of examples is certainly not exhaustive butis however representative of the large use of theNiCl2/Zn system for the preparation of symmetricalbiaryls, especially pyridine derivatives.

2. Aromatic Coupling Involving CatalyticAmounts of Nickel

In recent years, many more methods involve theuse of nickel in catalytic amounts to promote efficientbiaryl cross coupling. The aforementioned methodol-ogy, i.e., the homocoupling of aryl halides, has beenadapted to the use of Ni(II) in catalytic amountsthrough the presence of a chemical reducing agent(mostly zinc) or the help of electrons provided by acathode. We will first report some examples toillustrate the coupling reactions leading to the syn-thesis of symmetrical biaryls classified according tothe nature of the reducing species used. Subse-quently, we will examine cross-coupling reactionsbetween aryl halides, organometallic derivatives, andcatalytic amounts of Ni(II) species for providingunsymmetrical compounds. Recent examples will besummarized according to the nature of the couplingaryl nucleophiles (organozinc, Grignard, or boranederivatives).

Scheme 67

Scheme 68

Scheme 69

Scheme 70


A. Homocoupling of Aryl Halidesa. Use of Zinc as the Reducing Agent. Since the

discovery of Kende that Ni(0) generated in situ wasefficient for the homocoupling of aryl bromides, manyalternatives and improvements to this nickel-cata-lyzed coupling reaction have been performed.108 Ku-mada and Tamao109 were, for example, able toperform this transformation by using catalyticamounts of Ni(II) complex and stoichiometric amountsof zinc in the presence of triphenylphosphine. Iyodaet al.108 further improved this methodology by gen-erating the active Ni(0) complex from NiX2(PPh3)2and zinc in the presence of Et4NI. This nickel catalystwas efficiently prepared in THF without additionaltriphenylphosphine and allowed the homocoupling ofaryl chlorides, bromides, and iodides. The authorstested their procedure for the coupling of numerousbiaryls and bipyridines with good yields (Scheme 71).

A larger amount of catalyst had to be used for thecoupling of halopyridines since the correspondingbipyridines formed stable complexes with nickel.

The authors discussed the possible mechanismsinvolved in the transformations which remain still,however, controversial. As key steps, the simplestmechanism involved the oxidative addition of arylhalides to Ni(0), the formation of diaryl-nickel(II)species via metathesis, and reductive elimination.Colon,110 Amatore, and Jutand111 proposed nickel(I)and nickel(III) species as privileged intermediates.The role of the ammonium iodide is also not wellunderstood, but iodide anions accelerate couplingreactions markedly. It has been proposed that iodidemay act as a bridging ion between nickel and zinc inthe electron-transfer processes.111

The aforementioned procedure described by Iyodaet al. has been applied for the homocoupling of2-chloro(trifluoromethyl)pyridines toward the prepa-ration of bis(trifluoromethyl)-2,2-bipyridines.112 Theyields remained moderate (up to 34%, Scheme 72),probably because of the reduced electron density onthe pyridine ring. Constable et al.113 reported studiesconcerning the synthesis of dinucleating ligands forcopper, including 3,3-bipyridine units. These com-

pounds were prepared according to Iyodas procedurefor the coupling of substituted 3-bromopyridines.Yields of desired products (Scheme 72) were higherthan in the preceding example. The halopyridinederivatives tested bore an electron-donating substitu-ent and gave rise to bipyridines with lower complex-ing properties. It is interesting to note that thehomocoupling was not successfully achieved when thehalopyridine was functionalized with a sulfur-con-taining group. The authors observed that the cou-pling of 5-bromo-2-ethylsulfanylpyridine led to alarge number of organic products, most of themarising from desulfurization processes. These rela-tively mild coupling conditions were thus not com-patible with the coupling of thioethers, probably dueto the desulfurization capabilities of the active cata-lytic nickel species.

This procedure has been performed with aryltriflates in the presence of zinc powder114 either witha palladium(II) or nickel(II) complex. The synthesisof 1,1-binaphthyl was reported in a good yield (82-92%) from 1-naphthyl triflate using either NiCl2-(PPh3)2 or NiCl2(dppe) as a catalyst in the presenceof zinc and potassium iodide as additives. Interest-ingly, both complexes were also able to catalyze thehomocoupling of 1-naphthyl tosylate. The scope ofthis methodology has been studied with the synthesisof functionalized symmetrical biaryls. In most cases,nickel was found to be more efficient than palladium,especially when the aryl derivative was substitutedwith an electron-donating group (Scheme 73).

Jutand and Mosleh studied this reaction andproposed a mechanism115 (see Scheme 74) for thenickel dimerization of aryl triflates with zinc as anelectron supplier.

They suggested the single-electron reduction of theintermediate ArNiIIXL2 complex by zinc to be therate-determining step. Iodides should be effectiveboth for forming a pentacoordinated species ArNiII-XIL2- and for stabilizing the Ni(0) species. This groupalso tested less reactive 1-naphthol derivatives forthe homocoupling under these conditions and founda decreasing reactivity for NiCl2(dppe) as the catalyst

Scheme 71

Scheme 72

Scheme 73


The authors attempted to perform the synthesis ofenantiopure atropoisomers by using optically activeligands on the metal in order to perform asymmetrichomocoupling. They were, however, unable to runsuch a reaction with ortho-substituted aryl triflatesand BINAP as the chiral ligand due to steric hin-drance around the metal.

Percec et al.116 demonstrated that aryl mesylateswere able to undergo Ni(0)-catalyzed homocouplingreactions under mild conditions. The highest yieldswere obtained when the aryl group had electron-withdrawing substituents in the para-position (Scheme75).

The authors studied in detail the influence of theelectronic and steric effects of substituents attachedto the aryl sulfonates as well as the effects of thepolarity and dryness of the solvent, halide ion source,and concentration of the catalyst and ligand. In allcases, high yields were obtained with aryl mesylates,but they remained less reactive than aryl triflates.

b. Other Chemical Reducing Agents. Recently,Fort et al.117 reported that lithium hydride could beefficiently used as a reducing agent in the ligandedNi(0)-catalyzed homocoupling of haloaryls. They foundthat biphenyls were obtained in good to excellentyields (up to 92% isolated yield) by refluxing variousaryl halides in THF, in the

aryl−aryl bond formation one century after the discovery of the ullmann reaction.pdf

Documents

oxidative coupling

oxidative aromatic coupling

crosscoupling reactions

cross coupling of aryl

aryl silanes14025

activated aryl

aryl carbanion

homocoupling of aryl