Synthesis of biaryls using aryne intermediates

José-Antonio García-López *a and Michael F. Greaney *b
aDpto. Química Inorgánica, Universidad de Murcia, Campus de Espinardo, Murcia, 30100, Spain. E-mail:
bSchool of Chemistry, University of Manchester, Oxford Rd, Manchester M13 9PL, UK

Received 16th March 2016

First published on 18th October 2016

The synthesis of biaryls from benzyne intermediates offers an alternative strategy to conventional metal-catalyzed cross-coupling approaches. The concept is as old as benzyne itself, being the basis of Wittig's seminal observations on biphenyl synthesis from phenyl lithium and fluorobenzene in 1940. In the intervening 75 years, the transformation has grown to encompass a remarkable scope of reaction classes, and continues to develop as new benzyne precursors enable inventive biaryl syntheses under mild conditions. This review will cover all aryne methods relevant to biaryl synthesis, drawing together key ideas from the older literature involving halobenzene precursors, with a more comprehensive coverage of modern methods using 2-(trimethylsilyl)phenyl triflates and tri-ynes as the source of benzyne. Collectively, we hope to highlight the power of aryne chemistry to access a huge range of biaryl structures from a versatile and highly customizable set of substrates.

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José-Antonio García-López

Dr José-Antonio García-López received his BSc and PhD from the University of Murcia (Spain), working on the synthesis and reactivity of novel palladacycles under the supervision of Profs. José Vicente and Isabel Saura-Llamas. In 2012 he moved to Manchester as a postdoctoral researcher with Prof. Michael Greaney, where he worked on ruthenium-catalyzed cascade processes and aryne chemistry. In 2015 he returned to Spain as an associate researcher at the University of Murcia, where his research interests involve C–H activation and transition metal-catalyzed cascade reactions.

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Michael F. Greaney

Prof. Michael Greaney undertook his chemistry degree at the University of Oxford, completing his part II research project in the group of Prof. Sir Jack Baldwin in 1996. He then moved to London to carry out PhD work with Prof. William Motherwell at UCL, followed by postdoctoral work with Prof. Jeffrey Winkler at the University of Pennsylvania as a GlaxoWellcome fellow. He returned to the UK in early 2002, to a lectureship position at the University of Edinburgh, and in 2011 moved to the University of Manchester to a personal chair in organic chemistry. His laboratory focusses on new synthetic methods for organic chemistry.

1. Introduction

The biaryl structure is fundamental to diverse molecules across the chemical sciences, being prevalent in natural products, pharmaceuticals, agrochemicals, ligands, polymers and organic materials (Scheme 1). As a consequence, the synthesis of biaryls has played a major role in the development of carbon–carbon bond forming chemistries, from the earliest days of the discipline. Numerous methods have been developed for biaryl synthesis, with transition-metal catalyzed cross coupling being especially prominent in recent years. This superbly applicable and versatile approach was recognized with the award of the Nobel Prize to Negishi, Suzuki and Heck in 2010,1 and continues to create new reaction systems such as C–H arylation (Scheme 2).2
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Scheme 1 Some examples of functional biaryls.

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Scheme 2 Selected transition metal (TM)-catalyzed approaches to biaryl synthesis.

The aryne approach to biaryls offers an alternative pathway, drawing from a rich diversity of chemistry associated with aryl C–C bond formation. The roots of aryne biaryl synthesis reach back to the birth of benzyne chemistry, with Wittig's observations on biphenyl formation from phenyl lithium in 1940 (vide infra). From this point, numerous pathways have developed to encompass pericyclic reactions, multi-component coupling, sigma insertions, and transition-metal catalyzed processes as productive aryne routes to the biaryl structure, creating a palette of reactions readily adaptable to different substrate classes. This chemistry has undergone rapid growth in recent years, driven by the availability of new benzyne precursors that function under mild conditions, opening up new ways of manipulating the strained triple bond.

The recent growth in aryne chemistry has led to a number of excellent reviews on various aspects of aryne reactivity and application,3–14 which build on older, general accounts of benzyne chemistry.15,16 Here, we will focus exclusively on aryne methodology for biaryl and heterobiaryl synthesis, concentrating on those processes which afford a distinct C–C biaryl axis, including terphenyls, tetraphenyls and other polybiaryls. Applications of these methods to biaryls embedded in extended aromatic structures such as naphthalenes, phenanthrenes, triphenylenes or larger polyaromatics has been recently reviewed in the context of organic materials, so will not be discussed here.17–19 Similarly, the application of aryne methods to natural products has been comprehensively addressed in the recent litertaure,6,7 so biaryl examples in total synthesis will not be covered to avoid unnecessary duplication.

The aryne route to biaryls often entails the addition of a suitable aryl nucleophile to the electrophilic benzyne intermediate. Accordingly, this review will be structured around the different classes of aryl nucleophile used to forge the biaryl C–C bond.

2. Addition of organolithium reagents to arynes

Wittig observed the formation of biphenyl by reaction of phenyl lithium with fluorobenzene as early as 1940, in what was the first experimental evidence for aryne reactivity (Scheme 3).20 The phenyl lithium has a double role in this reaction, initially acting as a base to deprotonate the fluorobenzene ortho to the fluorine atom. Following elimination of LiF to generate benzyne from ortho-lithiated fluorobenzene 3, it then traps the intermediate through nucleophilic addition. Finally, protonation of the lithiated biphenyl intermediate 5 takes place to give 6. The triple bond character of benzyne was not ascertained at the time, with Wittig suggesting a zwitterionic structure 4 to account for the observed behavior. This work established a new type of arene reactivity that was extensively investigated in the subsequent decades, culminating in Roberts' identification of the strained triple bond structure of benzyne using isotopic labelling studies. His initial report concerned amination of chlorobenzene using potassium amide,21 which was followed by a study of Wittig's biphenyl synthesis using labelled fluorobenzene22 with the equal distribution of radiolabel (i.e.8 and 8′) being ascertained by a series of clever chemical degradation processes.
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Scheme 3 Generation of biphenyl from fluorobenzene and PhLi.

Wittig's seminal paper also exemplified the idea of trapping the intermediate biphenyl anion (e.g.5 in Scheme 3) with an electrophilic component other than H+. They added benzophenone to the reaction mixture and isolated the carbinol 7, having formed two C–C bonds to the arene nucleus. This three-component coupling idea has grown into a major strand of benzyne chemistry, enabling 1,2-difunctionalized arene synthesis across a very broad range of chemistries. In another early embodiment of the concept, Huisgen used carbon dioxide to trap the addition product of phenyl lithium with 3-methoxybenzyne (11, Scheme 4), demonstrating that nucleophilic addition could be highly regioselective for substituted benzynes.23–25

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Scheme 4 Regioselective three component coupling of 3-methoxybenzyne, phenyl lithium, and carbon dioxide.

Gilman and co-workers observed the formation of biphenyl in the reactions of 2-halobromophenyl derivatives (14) with n-BuLi,26 reporting the formation of 2,2′-dibromobiphenyl (16) in good yield from the reaction of n-BuLi with two equivalents of o-dibromobenzene at −78 °C in THF (Scheme 5).27 The authors proposed a simple aromatic substitution process of the o-lithiated bromobenzene with another molecule of o-dibromobenzene, since they had not observed the formation of isomers when performing the reaction with 4-chloro-bromobenzene and 1,4-dibromobenzene.

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Scheme 5 Initial observations from Gilman on the reaction of o-dibromobenzene with n-BuLi.

Nearly fifty years later, Schlosser and Leroux reinvestigated this reaction, and proved that the reaction mechanism did involve aryne intermediates.28 A careful GC-MS analysis of the reaction of 1,4-dibromobenzene with n-BuLi identified the formation of the two 4,4′ and 3,4′-dibromobiphenyl isomers (19 and 20, Scheme 5), indicative of the aryne pathway. Hence, the ortho lithiated bromobenzene 15 (generated by either halogen-lithium exchange for o-dibromobenzene or o-lithiation for the p-dibromobenzene substrate) can evolve through the elimination of LiBr to afford benzyne (22), which can be trapped by another molecule of o-lithiated bromobenzene giving rise to an intermediate lithiated biaryl 23 (Scheme 6). Finally, 23 can undergo a halogen-lithium exchange with a molecule of the starting o-dibromobenzene, affording 2,2′-dibromobiaryl 16 and regenerating the o-lithiated bromobenzene.

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Scheme 6 Proposed aryne mechanism for the reaction of o-dibromobenzene with n-BuLi.

The fact that lithium–halogen exchange is faster for iodine than for bromine allowed the use of o-iodobromo arenes as starting materials, affording non-symmetrical biaryls with impressive levels of control (e.g.25 and 26).

These concepts have been extended by Leroux and co-workers in a series of papers on cross-coupling of dihaloarenes, whereby aryne generation can be controlled through an appreciation of the different thermal stabilities of the appropriate lithiated intermediates (Scheme 7). The metal–halogen exchange reactions were generally carried out at low temperature, but when the reaction mixture was subsequently warmed, the less stable o-halo lithiated species (e.g.15) evolved to give benzyne through the loss of LiX, while the more stable (29) acted as the nucleophile.29–31

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Scheme 7 Regioselective aryne generation from iodinated substrates.

As an alternative to lithium–halogen exchange, the nucleophilic component can also be generated by direct deprotonation of suitable arenes. When 1,3-dimethoxy benzene 37 was treated with n-BuLi at 0 °C, followed by the addition of 1,2-dibromo-4,5-dimethoxybenzene 39, biaryl 44 was obtained in good yield (Scheme 8).29 The ortho-bromo biphenyl structures can be a useful starting material for further functionalization via lithium/bromine exchange reactions, followed by quenching with suitable electrophiles such as chlorophosphines32,33 or arylsulfinates.30

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Scheme 8 Generation of arene nucleophiles through deprotonation.

The use of 1,2-dibromo arenes symmetrically substituted at the 3 and 6 positions afforded hindered o,o′-tetrasubstituted biaryls (45 and 46) when 1,3-dimethoxybenzene was used as the nucleophilic coupling partner.31 An increase in temperature from the standard −78 to 0 or 25 °C was necessary due to the additional steric hindrance of the ortho substituents (Scheme 9). Nucleophilic trapping of 3-substituted arynes depended on both electronic and steric effects of the substituents present in the aryne moiety. Hence, 1,2-dibromo-3-substituted aryne precursors underwent preferentially (R = Me) or exclusively (R = TMS, Ph) attack at the distal position of the strained triple bond. In the case of the 1-methoxy-4-methylaryne substrate 53, the nucleophilic attack occurs ortho to the methyl group, since the resulting lithiated arene is stabilized by the interaction of the methoxy group with the lithium atom.

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Scheme 9 3,6- and 3-substitued arynes reaction with aryl lithiums.

The regioselectivity of aryllithium addition to benzynes generated from aryl halides has been studied in detail by Wagner and Mioskowski.34 They found that the presence of a methoxy group ortho to the halide led to a switch from benzyne to an ipso nucleophilic substitution mechanism, depending on the nature of the halide (Scheme 10). Hence the reaction of a lithiated arene with ortho-Br- or ortho-Cl-anisole afforded the ipso-substitution products 57, regioselectively. However, for the ortho-F-anisole substrate 9 only the meta-substituted biaryl 58 was obtained, pointing to an aryne reaction pathway. Similarly, the meta-F- or meta-Cl- anisole substrates 59 gave the meta-substituted biaryls 60. Several mechanistic experiments pointed to lithium coordination of the OMe group as the crucial factor for the nucleophilic substitution pathway to occur in the cases of o-Br and o-Cl-anisole. The higher acidity of the meta-proton in the case of o-F-anisole, however, afforded the m-lithiated arene 10, which evolved to give the corresponding aryne. Other groups such as Me or NMe2 did not induce the nucleophilic substitution pathway, in agreement with the early findings of Chlebowski.35

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Scheme 10 Arylation mechanism switch for anisole derivatives.

The group of Meyers advanced the aryne three component coupling idea in biaryl synthesis in the 1980s, using the oxazoline moiety as an effective directing group for ortho-metalation.36–38 The treatment of 3-chloro-benzene-oxazoline 61 with n-BuLi in THF at −78 °C gave the 3-chloro-2-lithio-benzeneoxazoline 62, regioselectively, due to the directing effect of the oxazoline ring. When the temperature was raised to −10 °C the elimination of LiCl took place, generating a 3-oxazolyl benzyne 63. A nucleophile such as PhLi can regioselectively add to the aryne, again leaving the lithium atom in close proximity to the coordinating oxazoline moiety, with an aqueous work up afforded 3-phenyl oxazoline 65. The authors then expanded the procedure to organocuprate reagents such as Ph2CuLi and simple electrophilic reagents. Regioselective addition to the aryne gave an ortho cuprate 66 which underwent subsequent trapping to give 2,3-substituted oxazolines 67–69 in good yields (Scheme 11), and the oxazoline moiety could further be hydrolyzed to obtain 2,3-disubstituted benzoic acids or esters.

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Scheme 11 Arylation of 3-oxazolyl arynes.

Recent work from Daugulis and co-workers describes the arylation of arenes and heteroarenes with chloro- or fluoroarenes in the presence of a strong base such as TMPLi (Scheme 12).39,40 The reaction proceeds through the deprotonation of both the arene and the ortho position of the chloro-/fluoroarene at low temperature. Raising the temperature provokes the elimination of LiCl or LiF with concomitant generation of the aryne 74, which in turn is trapped by the deprotonated arene 71. This method allows the arylation of a wide range of arenes and heteroarenes such as diphenylether, thiophene, N-substituted indoles, benzothiazole or pyridines in good yields (e.g.77–85). In contrast to the results found by Wagner and Mioskowski,34 the arylation of 2-chloroanisole proceeded through an aryne pathway under these reaction conditions.

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Scheme 12 Arylation of lithiated arenes with chloroarenes.

The use of arylchlorides as starting materials, while desirable on economic grounds, required specific optimization of the reaction temperature, solvents and stoichiometry for each substrate. The Daugulis group were able to expand the methodology to the use of aryltriflates 88 as aryne precursors (Scheme 13), with aryne generation operating at −78 °C, and the process displaying improved functional group tolerance.

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Scheme 13 Use of aryl triflates as aryne precursors.

Introduction of a third hetero-atomic component to trap the lithiated biaryl of type 5 (i.e. X+ rather than a carbon electrophile or simple protonation) was first demonstrated by Miller and Adejare in 1984, who reported the condensation of lithiated 1-fluoro-3-methoxybenzene 98, followed by a quench with B(OMe)3 and subsequent oxidation with H2O2 to afford the o-arylated phenol 100 (Scheme 14).41

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Scheme 14 Trapping of the lithiated biphenyl intermediate with B(OMe)3.

Daugulis and co-workers also demonstrated three-component coupling chemistry in which the aryl lithium intermediate 75 (Scheme 12), generated upon the attack of the deprotonated arene to the aryne, could be trapped by a suitable electrophile (Scheme 15) to afford ortho-substituted biaryls. In an interesting extension, they showed that increasing the amount of aryne precursor from 1.25 to 2.4 equiv. relative to the arene allows the formation of terphenyls (102), since the intermediate aryl anion 75 can attack another aryne molecule prior to the quench of the reaction with the electrophile.

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Scheme 15 Three component reactions via arynes.

Yoshida et al. have recently developed the addition of aryllithiums to arynes in flow (Scheme 16).42 This method has the advantages of reducing possible side reactions that occur in the simultaneous generation of several aryllithium species in batch, which may compete with each other. It also enables the smooth introduction of a third electrophilic coupling partner. The methodology calls for the lithiation of 2-iodo-bromobenzene 21 (benzyne precursor) and the iodoarene to be carried out in separated flow reactors at the appropriate temperature. Then the flows of both reagents are mixed and allowed to warm up to −30 °C, generating the benzyne which is instantaneously trapped by the lithiated arene 111. Subsequently, the new ortho-lithiated biaryl 112 is quenched with an electrophile in a separate reactor. Interestingly, the method allows the presence of cyano or nitro groups in the arene that would be expected to react deleteriously with organolithium reagents under batch conditions. A range of different electrophiles such as MeOTf, PhCHO, PhCNO, I2 or NFSI can be employed in this three-component reaction protocol. The utility of this methodology was exemplified in the synthesis of the fungicide boscalid in 88% yield from para-chlorobromobenzene, 2-iodo-bromobenzene, and tosylazide as the electrophilic component.

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Scheme 16 Three-component coupling of arynes in flow.

Bailey and co-workers reported an interesting intermolecular variant of the three component benzyne coupling, leading to the arylated indoline derivatives 124 (Scheme 17).43 The treatment of 2- or 3-fluoro N,N-diallylaniline 119 with an excess of PhLi at room temperature gave rise to the aryne intermediate 121, which upon addition of PhLi lead to the formation of the lithiated biphenyl intermediate 122. The presence of the tethered allyl group enables an intermolecular carbolithiation, which affords the indoline 123. Finally, quenching of the reaction mixture produces the arylated indoline 124 in moderate yield.

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Scheme 17 Intramolecular three-component coupling of arynes.

Given the versatility of aryl lithium addition to arynes, it is a natural step to apply these methods to the synthesis of axially chiral biaryl compounds, important components of natural products, chiral auxiliaries and ligands in asymmetric catalysis. Leroux et al. assessed the atropo-diastereoselective synthesis of biaryls using the coupling of arynes with lithiated arenes bearing a chiral auxiliary in the ortho position (125, 127) (Scheme 18)44–46 This strategy was applied to arenes bearing sulfoxide, tartrate ether or oxazoline moieties as chiral auxiliaries, giving rise to the corresponding biaryls 126 and 128 in moderate diastereoselectivity. In the case of the pro-nucleophile bearing a chiral oxazoline moiety, the reaction generated the fluorenone 129 as a by-product, decreasing the yields of the expected chiral biaryl 128. The formation of the fluorenone 129 could be minimised using sterically hindered iodinated aryne precursors.

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Scheme 18 Atropo-diastereoselective synthesis of biaryls based on the coupling of arynes.

The intramolecular cyclization of carbanions and heteroatoms onto benzyne is well-exemplified as the ‘benzyne cyclization’, first introduced by Huisgen and Bunnett in the 1960s and a powerful route into heteroarene compounds.47,48 The use of aryl organometallics in this process is far less common; Barluenga and Sanz et al. described the synthesis of phenanthridine, dibenzopyran and dibenzothiopyran derivatives, through benzyne cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers and thioethers respectively (Scheme 19).49,50 The treatment of compounds 133 with t-BuLi in THF at −110 °C produced the doubly lithiated intermediate 134, which upon warming to 20 °C underwent intramolecular addition of the benzyl lithium moiety to the strained triple bond, giving rise to the cyclic structures 136. Finally, the reaction mixture could be quenched with a range of carbon- or heteroatom-based electrophiles to afford structures 137.

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Scheme 19 Intramolecular trapping of arynes with tethered lithiated arenes.

Most of the reactivity of organolithium reagents towards arynes described so far has been carried out using haloarenes as the aryne precursors. In an alternative approach, the groups of Andersen and Oae reported the reactions of diarylsulfoxides with excess of aryllithium reagents to give biaryls via aryne intermediates (Scheme 20).51–53 The reaction involves the formation of triarylsulfonium oxide intermediate 145, which could be deprotonated by another equivalent of aryllithium, giving the aryne 146 and the diarylsulfide 147. The aryne is then trapped by the starting aryllithium to give the biaryl after reaction work up, with the formation of mixtures of isomers 148 and 149 when di(p-tolyl)sulfoxide and p-tolyllithium were used as starting materials supporting the involvement of aryne intermediates. The amount of p,p′-ditolyl was slightly higher than that of p,m′-ditolyl due to the existence of an additional reaction pathway involving tetraaryl sulfur species which lead exclusively to the p,p′-isomer. Similar results were observed by Kataoka in the reaction of alkynyl-diaryl- and triarylselenonium salts with lithiated arenes.54,55

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Scheme 20 Use of diarylsulfoxides as an aryne source for biaryl synthesis.

3. Addition of Grignard reagents to arynes. Synthesis of Buchwald ligands, terphenyls and tetraphenyls

Hart and co-workers investigated the addition of aryl Grignard reagents to arynes as a controlled method for terphenyl synthesis56 Initially, they carried out halogen–magnesium exchange of an o-bromo-iodoarene derivative 21 with one equivalent of an aryl Grignard reagent, affording the 2-bromoaryl Grignard 150 (Scheme 21). This organometallic intermediate can easily eliminate MgBr2 to give the reactive aryne, which undergoes addition with a second equivalent of aryl Grignard to give the novel 2-biaryl Grignard 151. Quenching with water or iodine gave the dissymmetrical biaryls 153–158.
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Scheme 21 Addition of aryl Grignard reagents to arynes.

The Hart group then adapted this chemistry to double aryne precursors 159, enabling the regio-controlled synthesis of terphenyls.57 Reacting 1,4-dibromo-2,5-diiodobenzene 159 as the aryne precursor with an excess of pheylmagnesium bromide at rt generated the intermediate 160, which can eliminate MgX2 to give the aryne 161 (Scheme 22). A further equivalent of PhMgBr traps the aryne to afford the biphenyl intermediate 162, a process which is repeated via the second aryne intermediate 163 and trapping by PhMgBr. The final quench of the reaction mixture with water or molecular iodine affords the 1,4-terphenyls 164–169 in moderate yields. The addition of PhMgBr to the second aryne intermediate 163 takes place regioselectively, under electronic control, since it generates a doubly magnesiated arene where the carbon atoms with higher electron density are as far as possible from each other.

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Scheme 22 Aryne synthesis of 1,4-terphenyls.

The formation of 1,2,4,5-tetraphenylbenzene 177 from hexabromobenzene and phenylmagnesium bromide had been reported in the older literature in very low yields.58–60 Hart et al. re-investigated this system and found that the addition of eight equivalents of phenylmagnesium bromide to a solution of either hexabromobenzene 170 or 1,2,4,5-tetrabromo-2,6-dichlorobenzene in THF, followed by stirring at rt for 12 h, afforded good yields of 1,2,4,5-tetraphenylbenzene 177 after aqueous work up (Scheme 23).61 The scope could be successfully extended to other aryl Grignard reagents bearing tolyl, mesityl, naphthyl or biphenyl groups, and the reaction mixture could also be quenched with bromine in CCl4 to give 1,2,4,5-tetraaryl-3,6-dibromobenzene 178. As observed previously, the Grignard addition to 174 is regioselective to give the intermediate 175 selectively.62,63

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Scheme 23 Synthesis of tetraphenyls through arynes.

Hart also explored the synthesis of 1,3-terphenyls from 1,2,3-trihalobenzenes (Scheme 24).64 2,6-Dibromo-iodobenzene 28 undergoes preferential magnesium–halogen exchange at the iodinated position upon addition of an aryl Grignard reagent, then readily eliminates MgBr2 to give 3-bromo aryne 185. Regio-controlled addition of a further equivalent of Grignard to the distal position generates 186, that evolves to the aryne 187, undergoing the regioselective addition of another equivalent of aryl Grignard to give 188, which can be quenched with HCl, I2 or an isocyanate. This synthetic route has been widely used for the synthesis of 1,3-terphenyls substituted at the 2 position65,66 with different groups such as –SiMe2,67 –CO2H,68,69 –SR,70 –CHO,71 and –PCl2.72,73

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Scheme 24 Synthesis of 1,3-terphenyls through arynes.

The palladium-catalyzed amination of arylhalides (Buchwald–Hartwig reaction) is now a general tool for C–N bond formation, and has led to the development of highly active catalyst systems that employ hindered biaryl phosphines as ligands.74 These catalysts have not only shown excellent performance in C–N couplings but also in challenging C–O and C–C coupling reactions. Synthesis of these biaryl phosphines was initially achieved using a multistep process involving palladium-catalyzed cross coupling of an aryl boronic acid and 2-iodo-bromobenzenes.75 In 2000, the Buchwald group reported an improved synthetic route to access this ligand class using benzyne chemistry (Scheme 25).76 By refluxing an arylhalide and o-chloro-bromobenzene as the benzyne precursor in THF, in the presence of magnesium, they could successfully obtain the ortho-magnesiated biaryl 151. This method is advantageous over the one reported previously by Hart since the benzyne precursor is activated by direct reaction of o-bromo-iodobenzene with simple Mg, without the need to use an additional equivalent of the aryl Grignard reagent. Optimization of parameters such as the arylhalide/o-chloro-bromobenzene molar ratio as well as the reaction time minimized the formation of terphenyl by-products from 151 reacting further with benzyne. The subsequent addition of stoichiometric amounts of CuCl and a dialkyl-chlorophosphine to the reaction mixture allowed the synthesis of the desired phosphine ligand 199 containing the biaryl unit in moderate yield and in a one-pot overall process. This method allows the straightforward tuning of the substituent in ortho position to the biaryl link of the phosphine, giving direct access to a wide variety of ligands, representing an important advantage in the development of more efficient catalysts for coupling reactions. The scope of the reaction includes the use of o-mono- or di-substituted aryl bromides such as o-N,N-dimethylamino-phenylbromide or mesityl bromide. This methodology was extended to the synthesis of polystyrene-supported phosphine ligands,77 and optimized to use catalytic amounts of CuCl in the phosphination step.78

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Scheme 25 Synthesis of Buchwald phosphine ligands.

The Beller laboratory reported the synthesis of 2-fluoro-biaryls through an intermolecular domino reaction based on the trapping of benzyne (generated in situ from o-bromo-chlorobenzene and magnesium) by an aryl Grignard reagent (Scheme 26).79 The intermediate biaryl Grignard could be reacted with a source of electrophilic fluorine to produce the fluorinated biaryls 207. The use of N-fluoro-2,4,6-trimethylpyridinium 206 in heptane or CH3OC4F9 as the solvent provided superior activity compared to other fluorinating agents such as NFSI or selectfluor, whilst the use of two equivalents of benzyne precursor lead to the fluorinated 1,2-terphenyl 209. The synthesis of related o-iodinated biaryl derivatives via addition of an aryl Grignard to benzyne was reported by Hartmann et al.,80 however in this case the aryne was generated from o-bromo fluorobenzene and n-BuLi at low temperature.

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Scheme 26 Three-component synthesis of fluorinated biphenyls.

Hu and co-workers developed an interesting approach to fluorene derivatives 222 based on the reaction of hindered aryl Grignard reagents 217 and palladium-bound arynes (Scheme 27).81–83 The method used 1-chloro-2-haloarenes or 2-haloaryl tosylates which underwent an initial oxidative addition to Pd(0) to give aryl palladium(II) complexes 218, which can evolve to form Pd-bound aryne complexes 219. Further transmetalation of the mesityl group from the Grignard 217 induced the carbopalladation of the aryne to give 221, followed by an intramolecular C–H activation step and oxidative C–C bond formation to give the fluorene derivatives 222. This is a notable early example of metal-catalyzed C–H activation being incorporated into an aryne reaction cycle. The use of dissymmetrical starting haloarenes gave the expected mixture of isomers, and the possibility of a non-aryne, domino cross-coupling reaction was ruled out by control experiments.

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Scheme 27 Synthesis of fluorene derivatives through Pd-bound arynes.

4. Aryne dimerization reactions: pseudo-multicomponent reactions

Multicomponent reactions (MCRs) where two of the components are identical can be called pseudo-MCRs,84 and have been extensively investigated in aryne chemistry whereby two benzyne units are incorporated into an extended biaryl structure. Transition metal-catalysis is common in this area, enabled by Kobayashi's introduction of 2-trimethylsilylphenyl triflates 228 as fluoride-activated precursors of benzyne.85 The mild reaction conditions, functioning at ambient temperature or above, are generally compatible with typical Noble metal catalytic cycles, and have been widely exploited in aryne reaction design in recent years.

Low-valent transition metal complexes are known to catalyze the oxidative cyclization of arynes. Yoshida, Kunai and co-workers took advantage of this approach in the synthesis of 2,2′-distannylbiaryls by performing the oxidative dimerization of arynes in the presence of hexamethyldistannane 229 (Scheme 28).86 The proposed mechanism involves the initial formation of an η2-benzyne–Pd(0) complex which undergoes oxidative cyclization with a second equivalent of aryne to generate the biaryl C,C-palladacycle 231. The hexamethyldistannane 229 then adds oxidatively to form a Pd(IV) intermediate, evolving to the final 2,2′-disubstituted biaryl 232 and regenerating the Pd(0) catalyst. The reaction generated the 1,2-distannylated arenes 233 by-products as a consequence of alternative ordering of the reaction sequence with the two components and the palladium catalyst.

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Scheme 28 Palladium-catalyzed synthesis of 2,2′-distannylbiaryls through arynes.

Zhang and co-workers developed an Au and Cu co-catalyzed coupling of arynes and terminal alkynes leading to 2-alkynylated biaryl scaffolds (Scheme 29).87 The proposed catalytic cycle involves the initial coordination of the aryne to the gold catalyst, while an alkynylcopper intermediate 239 formed in situ can add to benzyne giving a 2′-alkylylated aryl copper species 240. Finally, the nucleophilic addition of 240 to the aryne-gold complex affords intermediate 242, which would readily undergo protonolysis giving the 2-alkynyl biaryl structure 243.

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Scheme 29 Pseudo-MCR of arynes and terminal alkynes.

Soon after, Yoshida et al. communicated a similar coupling reaction of two arynes and a terminal alkyne catalyzed by Cu(I) salts using slightly different reaction conditions (Scheme 30).88 The authors proposed attack of the alkynyl copper intermediate 239 on the aryne, followed by insertion of a second molecule of aryne into the aryl–Cu bond before the final protonation leading to the 2-alkynyl biaryl product 243. The reaction generated the alkynylated arene 244, as a result of the early protonolysis of the aryl-copper intermediate previous to the second aryne addition step.

image file: c6cs00220j-s30.tif
Scheme 30 Copper-catalyzed pseudo-MCR of arynes and terminal alkynes.

The Yoshida group also studied the copper-catalyzed bromo alkynylation of arynes, leading to 2-bromo-2′-alkynyl-biphenyls (Scheme 31).89 The reaction was proposed to proceed through the bromocupration of the aryne by CuBr2. Insertion of an aryne molecule into the Cu–C bond leads to a cuprated-biphenyl intermediate 266, that can undergo further coupling with the bromo-alkyne to furnish the functionalized biaryl 257, with the reaction generating a small amount of 2-bromo-alkynylated arenes 258 as by products. The use of substituted propargylbromide 259 or allyl bromides 262 as starting materials gave mixtures of regioisomers of 2-bromo, 2′-alkyl-substituted biphenyls 260 and 261 or 263 and 264 respectively.

image file: c6cs00220j-s31.tif
Scheme 31 Synthesis of 2-bromo-2′-alkynyl-biaryls.

The palladium-catalyzed trimerization of benzyne to triphenylene, reported by the Guitian group in 1998, marked the beginning of the modern era of benzyne chemistry, using precursor 228 to explore new aryne chemistries under mild conditions.90 The co-trimerization of two arynes and an alkyne to yield aromatic phenanthrene products was likewise foundational to the development of transition-metal catalyzed aryne chemistry, with the Guitián, Yamamoto and Larock groups pioneering a number of systems in this area.91–94 For biaryl synthesis, the Guitian group demonstrated that co-trimerization of arynes and acyclic alkenes bearing electron-withdrawing groups could afford 9,10-dihydrophenanthrenes 273 or ortho-olefinated biphenyls 274 (Scheme 32).95 The ratio of cyclized/non-cyclized products was dependent on the Pd(0) or Ni(0)/phosphine catalytic systems, as well as the choice of starting alkene.

image file: c6cs00220j-s32.tif
Scheme 32 Pd-Catalyzed co-trimerization of arynes with acyclic alkenes.

Sato et al. reported the [2+2+2] cycloaddition of two aryne molecules and an alkene catalyzed by Ni(0) (Scheme 33).96 The reaction was specific for 1,6-dialkenes 277 as substrates, giving rise to 9,10-dihydrophenanthrenes 278 as the main products, along with small amounts of the starting diene functionalized with a biphenyl group at one of the double bonds 279. Mechanistic studies suggested that one of the alkene groups acts as an intramolecular ligand to stabilize the reaction intermediate 282. The Ni(0) complex 280 is proposed to undergo an oxidative cycloaddition with an aryne and one of the alkene moieties to give a five-membered nickelacycle 282. Insertion of the second aryne into the Ni–C bond affords a seven-membered nickelacycle 283, which then could evolve through the intramolecular C–C coupling process leading to 9,10-dihydrophenantrene 278, or undergo a β-hydride elimination to afford the alkenylated biphenyl 279. The intermediate 283 could alternatively arise by initial oxidative cycloaddition of two aryne molecules to Ni(0).

image file: c6cs00220j-s33.tif
Scheme 33 [2+2+2] cycloaddition of arynes and 1,6-dialkenes.

The co-cyclotrimerization of two aryne molecules and an allene was reported by Cheng et al. (Scheme 34).97 The reaction was efficiently catalyzed by NiBr2(dppe) in the presence of metallic zinc, although significant amounts of product were formed when [NiBr2(PPh3)2] or [Pd(PPh3)4] were used as catalysts. The reaction proceeds presumably via oxidative cyclization of one molecule of aryne and another one of the allene to give the five-membered nickelacycle 294. The insertion of one molecule of aryne in the Ni–C bond could afford a seven membered nickelacycle 295 that would furnish the final dihydrophenanthrene derivate 292 upon reductive elimination of Ni(0). Alternatively, the intermediate 295 can be produced by oxidative cyclization of two molecules of aryne and Ni(0) first, followed by insertion of the allene. Interestingly, only the internal double bond participates in the cyclization process for monosubstituted allenes, and mixtures of regioisomers are produced when 1,1-disubstituted allenes are employed. The exocyclic C–C double bond in the 10-methylene-9,10-dihydrophenanthrene 292 does not undergo a 1,3 hydrogen shift to give the corresponding phenanthrene derivatives. Following this study, the Li group described a similar cyclization process catalyzed by Pd and using allenes bearing electron-withdrawing groups, to give mainly the aromatic phenanthrene analogues.98

image file: c6cs00220j-s34.tif
Scheme 34 Ni-Catalyzed co-cyclotrimerization of arynes and allenes.

The oxidative dimerization of arynes can be achieved in a stepwise fashion, through the thiostannylation of arynes with stannyl sulfides 302 (Scheme 35).99 The Yoshida group carried out a σ-insertion of benzyne into (tributylstannyl)phenyl sulfide, creating the 2-thioaryl-phenylstannyl derivative 303. Subsequent Stille cross-coupling with aryl iodides, and oxidative dimerization catalyzed by [Pd(PPh3)4] in the presence of stoichiometric copper salts, gave the biaryls 304 and 305.

image file: c6cs00220j-s35.tif
Scheme 35 Oxidative dimerization of thio-stannylated arynes.

A one pot equivalent of the dimerization process was reported by Greaney et al., through the nucleophilic attack of magnesiated thiolates and amidates to benzyne,100 followed by copper mediated oxidative dimerization of the resulting aryl Grignard intermediate 308 (Scheme 36).101 When the aryne precursors bear a substituent in the ortho position, this procedure is capable of generating sterically hindered 2,2′,6,6′-tetrasubstituted biaryls. The Studer group described a similar approach to symmetrical 2,2′-substituted biaryls, but using a catalytic amount of CuLi2Cl4 with O2 as the oxidant, to produce the homo-coupled products of Grignard 308 in low to medium yield.102

image file: c6cs00220j-s36.tif
Scheme 36 Synthesis of hindered biaryls through oxidative dimerization of arynes.

5. Cross coupling reactions involving arynes and other arene sources

The Cheng group were the first to show that aryl boronic acids could react with arynes in biaryl synthesis, introducing the exceptionally versatile Suzuki–Miyaura cross-coupling into benzyne chemistry. Their first report described the palladium-catalyzed three component coupling of allyl chlorides, benzyne precursor 228, and a boronic acid to give the ortho-allyl biaryl 319 in good yield (Scheme 37).103 Following on from this work, they developed a nickel-catalyzed coupling of arynes with enones and boronic acids leading to biaryl structures 326 with an alkyl chain in the ortho position.104 The transformation was proposed to involve initial cyclometalation to form five-membered nickelacycle 327. The boronic acid has a double role in this reaction (as checked by experiments with deuterated substrates), it first protonates the α carbon to the ketone in the intermediate 327 and then transmetallates the aryl group to the nickel atom. Finally, the aryl–aryl linkage is formed upon reductive elimination of Ni(0) (Scheme 37).
image file: c6cs00220j-s37.tif
Scheme 37 MCR of arynes and boronic acids catalyzed by Pd and Ni.

Greaney and co-workers described the palladium-catalyzed synthesis of 2-alkenyl biaryls through the three-component reaction of arynes, acrylates and aryl iodides (Scheme 38).105 Optimization of the reaction was necessary to minimize the formation of the simple Heck product from aryl iodide and acrylate, and could be achieved using a Pd(dba)2 and diphenylphosphinobutane (dppb) catalyst system. The reaction of aryl halides with arynes in metal-catalyzed processes presents the mechanistic dichotomy of carbometallation versus metal-aryne complex formation as the first step, i.e. arylpalladium intermediate 338 can arise either through oxidative addition of Pd(0) to the aryl halide followed by carbopalladation of benzyne (path A), or via Pd(0) capturing free benzyne to give intermediate 337, which can then react with aryl iodide to give 338 (path B). Path B is often more plausible a priori,94 as the first pathway requires two reactive intermediates (336 and benzyne) present in low concentrations to react. However, detailed mechanistic studies have yet to be reported on this type of catalytic transformation.

image file: c6cs00220j-s38.tif
Scheme 38 Pd-Catalyzed MCR of arynes, acrylates and aryl iodides.

Li and co-workers described an aryl iodide coupling with benzynes for the synthesis of 6H-benzo[c]chromenes 344, via palladium-catalyzed intramolecular annulation using 2-(2-iodophenoxy)-1-arylethanones 343 (Scheme 39).106 The reaction was envisaged to proceed through the aryl-palladium intermediate 345, which could evolve through two possible pathways: (a) trapping of the aryne and oxidative cyclization with the active methylene moiety, or (b) formation of a five membered C,C-palladacycle 348 followed by the aryne trapping and oxidative coupling leading to the cyclic compounds 344.

image file: c6cs00220j-s39.tif
Scheme 39 Intramolecular annulation of arynes with 2-(2-iodophenoxy)-1-arylethanones.

The phenanthridinone heterocycle features in numerous compounds with interesting biological and pharmaceutical properties, and several aryne routes to these compounds have been reported. Larock et al. described phenanthridinone synthesis through palladium-catalyzed annulation of arynes with N-monosubstituted o-halobenzamides 354 (Scheme 40).107 As for the systems described above, the reaction pathway could proceed via aryne insertion into the intermediate palladacycle 356, with the possibility of alternative reaction involving η2-benzyne–Pd(0) intermediate 337 being noted.

image file: c6cs00220j-s40.tif
Scheme 40 Pd-Catalyzed annulation of arynes with o-halobenzamides.

Liang et al. developed the carbocyclization of arynes and N-substituted-N-(2-halophenyl)formamide derivatives 367 leading to phenanthridinones 355 (Scheme 41).108 Contrastingly, this process forms two new C–C bonds, rather than one C–C and one C–N as described above. Carbopalladation of the aryne was proposed as the first step in the catalytic cycle, followed by nucleophilic attack of the new aryl–Pd bond on the carbonyl group, followed by β-hydride elimination to give the cyclic biaryl products 355.

image file: c6cs00220j-s41.tif
Scheme 41 Pd-Catalyzed annulation of arynes and N-(2-halophenyl)formamides.

Jiang et al. reported an alternative aryne approach to phenanthridinone synthesis through the multicomponent reaction of benzynes, CO, and 1-iodoanilines 381 (Scheme 42).109 Choice of fluoride proved pivotal in controlling product distribution, with CsF/TBAI in 10% aqueous MeCN generating benzyne relatively quickly and out-competing CO for initial insertion into the aryl–Pd bond. Switching to KF and using a diphosphine ligand created conditions for slow benzyne generation, leading to initial CO insertion and generation of isomeric acridone products.

image file: c6cs00220j-s42.tif
Scheme 42 Pd-Catalyzed MCR of arynes, CO and aryl iodides.

The palladium-catalyzed carbocyclization reaction of arynes, aryliodides and bicyclic alkenes (such as norbornene) to yield 9,10-dihydrophenanthrene derivatives 394 was described by Cheng et al. (Scheme 43).110 Given precedent from the well-established Catellani–Lautens system, the reaction was thought to proceed via formation of the intermediate palladacycle 396 upon norbornene insertion into the initial Pd–aryl bond of complex 336, followed by intramolecular C–H activation. Aryne insertion and reductive elimination then gave the annulated products as single regio-isomers.

image file: c6cs00220j-s43.tif
Scheme 43 Pd-Catalyzed MCR of arynes, cyclic alkenes and aryl iodides.

The Knochel group have developed diarylsulfonates 306 as useful aryne precursors, activated on treatment with i-PrMgCl and undergoing smooth addition with a variety of magnesium thiolates, selenates or amidates. The resulting ortho-substituted aryl Grignard 403 may then be further functionalized in situ by the addition of an electrophile.100 For application to biaryl synthesis, Knochel showed that Negishi-coupling was feasible via transmetalation of 403 with zinc bromide, and subsequent palladium-catalyzed reaction with aryl halides (Scheme 44).111

image file: c6cs00220j-s44.tif
Scheme 44 Knochel system for aryne functionalization.

The Greaney group explored the synthesis of 2-amino biaryls 408 through a benzyne Truce–Smiles rearrangement (Scheme 45).112 In contrast to the preceding examples, the reaction is metal-free and does not require organometallic intermediates to form the biaryl axis. This is achieved through nucleophilic attack of N-substituted arylsulfonamides 407 to benzyne to give the intermediate 409, which undergoes Truce–Smiles rearrangement with SO2 extrusion leading to the desired 2-amino biaryl scaffold. The rearrangement requires some stabilization of the Meisenheimer intermediate 410, such as –NO2, –Cl or –Br groups in ortho or para positions to the sulfonamide moiety, and has also been extended to heteroaromatic substrates (e.g.416).

image file: c6cs00220j-s45.tif
Scheme 45 Aryne Truce–Smiles rearrangement.

6. Direct C–H arylation of arenes using arynes

Synthesis of biphenyls through simple SEAr attack onto benzyne from nucleophilic arenes was investigated in the early years of the field. The Dow phenol process, first commercialized in the 1920s, involves treatment of chlorobenzene with aq. NaOH at 300 °C and affords various biphenyl side-products which are now understood to arise through benzyne mechanisms.113 Stiles and Miller showed that thermal decomposition of benzenediazonium 2-carboxylate 417 in benzene produces small amounts of biphenyl, amongst other aromatic addition compounds.114 Friedman, initially, and then Oda made the interesting observation that biphenyl formation from benzyne and benzene could be promoted by silver.115,116 Although yields were still quite low, silver salts enhanced the selectivity for biphenyl possibly due to the increased electrophilicity of a proposed benzyne–Ag complex 419 (Scheme 46, which could also be drawn as the silver carbene complex 420, vide infra).
image file: c6cs00220j-s46.tif
Scheme 46 Electrophilic aromatic arylations promoted by Ag(I).

A more synthetically tractable strategy for aryne arylation is to harness a pericyclic mode such as an ene or cycloaddition reaction. The ene reactivity of benzyne was established in the 1960s,117 and first investigated for aromatic substrates in the 1970s by Friedman and subsequently Oda, who reported the reactions of several alkyl-substituted benzenes with benzyne generated from diazotized anthranilic acid 417 upon moderate heating (Scheme 47).118,119 Substrates such as toluene or ethyl benzene gave rise to a mixture of products (mainly [4+2] adducts), from which the double-ene ortho-benzyl biphenyl products 422 could be isolated in low yield. Despite the inefficiency, the reactions stand as an important demonstration of a fundamental benzyne pericyclic pathway for biaryl synthesis.

image file: c6cs00220j-s47.tif
Scheme 47 Double benzyne ene reaction.

Aryne cycloaddition to yield biaryls is possible through Diels–Alder reaction with styrenes. Biju and co-workers recently reported an effective illustration of this idea,120 building on early reports from Dilling and Heaney.121,122 Using the silyl precursor 228, a variety of styrenes reacted smoothly to give the 9-aryldihydrophenanthrenes 425 through a cascade Diels–Alder/ene reaction; the initial Diels–Alder adduct 427 is able to react with another aryne molecule in a concerted ene-reaction, as shown by deuterium-labelling experiments. The second ene reaction was found to be suppressed for styrenes containing electron-withdrawing groups in the para-position, yielding the aromatized Diels–Alder adducts 426 (Scheme 48).

image file: c6cs00220j-s48.tif
Scheme 48 Diels–Alder-ene reactions of arynes and styrenes.

The Liu group reported a variation of this Diels–Alder/ene process using benzylidenephthalan derivatives 437 as the styrenoid starting materials. Reaction with 228 under simple conditions of CsF gave the phenanthro[10,1-bc]furan products 438 as the trans diasteroisomers (Scheme 49).123

image file: c6cs00220j-s49.tif
Scheme 49 Diels–Alder reaction of arynes with benzylidenephthalan derivatives.

Hetero-ene reactions are also possible for benzyne,124 with Yamamoto and co-workers reporting the formation of the N-biphenyl-triptycene amine 448 in low yield from treatment of 447 with a large excess of the diazonium benzyne precursor 417.125 It appears that the aniline formed in situ is too sterically hindered to undergo a second N-arylation, a reaction that would normally be fast, and instead reacts at the ortho carbon position.126 From this precedent, the Greaney group developed a transition metal-free direct C–H arylation method for N-tritylated anilines using the 2-trimethylsilylphenyl triflate precursor 228 (Scheme 50).127 The reaction affords exclusive C-monoarylated material for a range of para and meta-substituted substrates, but does not proceed for ortho-substituted anilines. This reactivity can be understood through the reaction mechanism proceeding via a hetero-ene pathway, a conjecture proven by deuterium-labelling experiments. An ortho-substituent would create a destabilizing steric clash with the trityl group in the ene transition state, so no reaction is possible. A second arylation for para and meta substrates, producing bis-arylated products, does not occur for the same reason.

image file: c6cs00220j-s50.tif
Scheme 50 C-Arylation of bulky N-trityl anilines.

Soon thereafter, Daugulis and Truong reported the ortho-arylation of unprotected primary and secondary anilines and naphthylamines (Scheme 51).128 They noted that minor amounts of C-arylation had been observed in older studies of N-arylation using benzyne generated from haloarenes,129,130 and were able to develop a selective process using chlorobenzenes and a strong lithium base. The C/N-arylation ratio varied considerably according to solvent, temperature and reaction stoichiometry, e.g. reaction in THF or ether gave the N-arylated material 464, but switching to hydrocarbon/ether solvent mixtures gave the C-arylated products 465–474 in good yield.

image file: c6cs00220j-s51.tif
Scheme 51 C-Arylation of unprotected anilines and naphthalenes.

The Daugulis group extended this concept to the C-arylation of phenols, again using chloroarenes as aryne precursors, but switching to t-BuONa as the base at high temperature in the presence of silver salts (Scheme 52).131 Control of the phenol/ chlorobenzene ratio enabled mono or di-arylation, and the method was successfully applied to the mono and diarylation of binol 478. As with the aniline arylation, the method is notable for reaction tuning C-arylation at the expense of the more common heteroatom addition.

image file: c6cs00220j-s52.tif
Scheme 52 C-Arylation of phenols and naphthols.

The intramolecular direct arylation of phenol derivatives was demonstrated in the classical era of aryne chemistry by Hey and co-workers.132 They treated 2-bromo-N-ethyl-3′-hydroxybenzanilide 488 with potassamide and isolated the phenanthridones 490 and 491 as a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of regioisomers. A related benzyne cyclization of an aniline derivative was described by Kessar and co-workers in the 1970s, where the (2-chloro-benzyl)-aniline compound 492 cyclized to the 5,6-dihydrophenanthridine 493 upon benzyne generation through deprotonation with potassium amide (Scheme 53).133The dihydrophenanthridine derivative could be further oxidized to obtain the phenanthridine derivative 494.

image file: c6cs00220j-s53.tif
Scheme 53 Direct C–H intramolecular arylation of phenols.

More recently, Daugulis et al. expanded this concept through the use of aryl C-nucleophiles tethered to benzyne to form biaryl bonds intramolecularly (Scheme 53).134 Treatment of 3-((2-bromobenzyl)oxy)phenol 495 with t-BuOK at 140 °C afforded mixtures of the biaryls 497 (major isomer) and 498 (minor isomer), with the ortho-arylation product predominating across a range of substrates.

The Xu and Jegenmohan groups recently described an alternative benzyne approach to phenanthridones using palladium catalysis.135,136 In simultaneous reports, they demonstrated that ortho C–H activation of the amide 504 using Pd(II) gave a palladacycle 507 that could undergo aryne insertion to the assumed intermediate 508. Reductive elimination then gave the biaryl products 505, along with Pd(0) that was re-oxidized with Cu(OAc)2 (Xu) or K2S2O8 (Jegenmohan). Alternatively, amino-palladation of 22 could happen in the first instance, followed by a C–H activation step to access the palladacycle 510 (Scheme 54).

image file: c6cs00220j-s54.tif
Scheme 54 Intramolecular amino-arylation of arynes through C–H activation.

Okuma et al. explored the hetero-Diels Alder reaction of diarylthiones 516 with benzyne, using Kitamura's phenyl-(2-trimethylsilylphenyl)iodonium triflate precursor137515 and TBAF (Scheme 55).138,139 A mixture of the two cycloadduct isomers 517 and 518 was isolated, with the major compound arising from a 1,3-H shift. Higher temperatures promoted the 1,3-H shift, enhancing the yield of the biaryl isomer 518. Interestingly, the reaction did not proceed using the benzenediazonium 2-carboxylate aryne precursor 417.

image file: c6cs00220j-s55.tif
Scheme 55 Thio-Diels–Alder reaction of arynes and diarylthiones.

A major recent advance in aryne chemistry is Hoye's development of the triyne hexadehydro-Diels–Alder (HDDA) cyclization as an entrypoint to benzyne. Precursors such as 521 undergo cyclization to aryne intermediates on simple heating, which can then react in a rich variety of inter- and intramolecular reaction modes, including arylation. In their first communication on the topic, the Hoye group showed that phenol could trap aryne 522 in a C-arylation to give the biaryl 523 in good yield (Scheme 56).140 Whilst there is some commonality in the trapping step with the reactivity of conventional precursors, the reagent-less generation of 522 has also led to alternative pathways and new reactivities being identified.

image file: c6cs00220j-s56.tif
Scheme 56 Direct C–H arylation of phenol via HDDA reaction.

Lee and Xia reported the synthesis of biaryls through HDDA reaction and intramolecular nucleophilic attack of a tethered aryl ring in the presence of silver salts (Scheme 57).141 The tethering chain could include heteroatoms such as nitrogen, oxygen or silicon, giving rise to interesting heterocycles 526. The trapping of the aryne could also be performed intermolecularly in the presence of benzene, xylene or mesitylene to give the derivatives 529. The silver catalyst is believed to enhance the electrophilicy of the aryne (vide supra, Scheme 46), facilitating the attack of the arene, a catalysis mode that the Lee group has also exploited for alkane C–H functionalisation in HDDA chemistry.142

image file: c6cs00220j-s57.tif
Scheme 57 Intramolecular arylation of tethered arenes to HDDA substrates.

The Hoye group have also demonstrated the HDDA-ene reaction, in which the intermediate aryne undergoes intramolecular ene-reaction with a tethered aromatic ring bearing a methyl group in the meta position (Scheme 58).143 The reaction generates an isotoluene intermediate 540 which can undergo a [1,3-H] shift mediated by water to afford the cyclic biaryl structure 541. Interestingly, the intermediate isotoluene 540 was long-lived enough to be trapped by another enophile present in the reaction mixture, undergoing a further Alder-ene reaction. Remarkably, in these processes four C–C bonds are formed, creating challenging polycyclic structures in a single step from triyne precursors 538.

image file: c6cs00220j-s58.tif
Scheme 58 Intramolecular arylation through HDDA-ene reactions.

7. Synthesis of heterobiaryls

A number of aryne heterobiaryl syntheses are known, with almost all of them featuring a benzyne reacting with a functionalized heteroarene. The converse approach, using a hetaryne such as 3-pyridyne, is rare, although increasing recent interest in the hetaryne field suggests developments can be expected in this area.12 A notable early example was reported by Kessar, in a related system to their benzyne cyclization described in Scheme 53. Treatment of the pyridyl bromide 553 with potassium amide generated the pyridyne, which underwent intramolecular cyclization to the biaryl 555, an intermediate in the synthesis of the alkaloid perlolidine 556 (Scheme 59)144,145
image file: c6cs00220j-s59.tif
Scheme 59 Intramolecular arylation of pyridyne.

Yoshida et al. reported the insertion of arynes into the C–Cl bond of chlorotriazines to give 2,4,6-tris(2-chlorophenyl)-1,3,5-triazines 558. Yields were moderate overall, but did account for up to three separate biaryl C–C bond formations (Scheme 60).146 Electron-withdrawing groups in the triazine ring were required for the reaction to proceed, with the first step in the mechanism proposed as an SNAr reaction with fluoride as nucleophile. Addition of the displaced chloride to benzyne would generate the 2-chloroaryl anion 559, that could subsequently add to the trihalogenated triazine generating 560. The successive addition of 2-chloroaryl anions would give the polyarylated triazine 558.

image file: c6cs00220j-s60.tif
Scheme 60 Arylation of 1,3,5-triazine derivatives.

Aryne dipolar cycloaddition chemistry is a powerful method for heterocycle synthesis; first being described by Huisgen and Knorr for nitrone addition to benzyne,147 and subsequently grown to encompass a rich variety of 1,3-dipoles. Its application to biaryl synthesis requires a fragmentation step subsequent to the initial cycloaddition, and is best illustrated with heteroaromatic N-oxide substrates. Takahashi and Kano reported the 1,3-dipolar cycloaddition of benzimidazole N-oxides 567 with several dipolarophiles, including benzyne generated form the benzenediazonium-2-carboxylate precursor 417, in 1964 (Scheme 61).148 Under the reaction conditions, the cycloadduct 568 rapidly aromatizes to the arylated benzimidazole 569 in moderate yield.

image file: c6cs00220j-s61.tif
Scheme 61 1,3-Dipolar cycloaddition to benzimidazole N-oxide.

Abramovitch and Shinkai then described the arylation of pyridine 1-oxides 570 with benzyne generated from 417 under thermal conditions (Scheme 62).149 In contrast to the benzimidazole N-oxide example above, the pyridine N-oxide can fragment via two separate pathways to give 2-o-hydroxyphenylpyridine 574 and 3-o-hydroxyphenylpyridine 573, respectively, in moderate yield and generally isolated as mixtures. The 3-arylated pyridine 573 was the major product, and arises from a sigmatropic rearrangement of the initial 3+2 cycloaddition intermediate 571 leading to the formation of a spirodienone 572. Re-aromatization then gives the 3-arylated product 573, a process that is blocked for 3,5-disubstituted substrates, forming the 2-aryl isomers exclusively. Some years later, Larock and co-workers studied this reaction using the o-trimethylsilylphenyl triflate precursor 228 in MeCN at room temperature. Under these mild conditions they found the reaction to be highly regioselective, forming the 3-arylated pyridines exclusively in good yield.150

image file: c6cs00220j-s62.tif
Scheme 62 3-Arylation of pyridine N-oxide with different aryne precursors.

Liu et al. subsequently reported a switch in the regioselectivity of pyridine N-oxide arylation with 228 by changing the solvent and fluoride source to DCM/THF (4[thin space (1/6-em)]:[thin space (1/6-em)]1) and TBAF (Scheme 63).151 Screening of the conditions revealed that an excess of the pyridine N-oxide or the fluoride source could possibly act as a base, facilitating the deprotonation of the intermediate 571 to give the 2-arylated pyridine 574 as the major product. Interestingly, the presence of an electrophile such as diethylacetylene dicarboxylate or ethyl propiolate reversed the regioselectivity, giving the 3-arylated derivatives 583.

image file: c6cs00220j-s63.tif
Scheme 63 Arylation of pyridine N-oxide reported by Liu et al.

The reaction was extended to quinoline N-oxides by Okuma and co-workers, affording mainly the 2-arylated product 593 (Scheme 64).152 When the reaction was performed in the presence of an excess of benzyne precursor, a further arylation took place, affording oxazepino[4,5-a]quinoline derivatives 594.

image file: c6cs00220j-s64.tif
Scheme 64 Arylation of quinoline N-oxide.

Similarly to pyridine N-oxides, zwitterionic aza-heteroaromatic ylides can undergo 1,3-dipolar cycloaddition reactions with benzyne. Hasegawa et al. reported the reaction of benzyne with N-acetyliminopyridazinium ylides 598 to give the 1,3-dipolar cycloaddition adducts 600, which were stable under the reaction conditions (Scheme 65).153 Photolysis of some of these intermediates bearing alkoxy groups in the ring afforded 3-(2-acetoamidophenyl)-pyridazines 601 and 602 in moderate yield. The reactions of pyridinium N-imines, however, afforded the expected 2-o-aminophenylpyridines 606 under similar reaction conditions in moderate to good yields.154 More recently, Shi and Larock observed similar results in the reactions of N-Boc-aminopyridinium ylides with benzyne generated from the o-trimethylsilylphenyltriflate precursor 228.155,156

image file: c6cs00220j-s65.tif
Scheme 65 Arylation of aza-heteroaromatic ylides.

The powerful reactivity of arynes as Diels–Alder dienophiles suggests that heteroatom-containing dienes could be harnessed for heterobiaryl syntheses. Sha and Wu recently exemplified this idea with the formation of benzo[c]carbazole derivatives, via Diels–Alder reaction of 2-alkenylindoles 607 with arynes (Scheme 66).157 The outcome proved to be quite sensitive to solvent, stoichiometry, temperature and presence of oxygen, with optimal conditions being carried out in a MeCN/toluene (1/4) mixture at 80 °C under an inert atmosphere to give good yields of 608. The presence of oxygen or excess aryne precursor led to fully aromatized benzocarbazoles/doubly arylated products, respectively.

image file: c6cs00220j-s66.tif
Scheme 66 Synthesis of arylated indoles through Diels–Alder carbocyclization.

Rodriguez, Coquerel, and co-workers recently reported the aza-Diels–Alder reaction of N-pyrazolyl aldimines 616 with excess benzyne (Scheme 67).158 The electronic nature of the starting aldimine was crucial in dictating the outcome of the reaction after the initial Diels–Alder adduct 617 has been formed. Electron-rich aldimines underwent a further N-arylation to give the 1,2-dihydro-isoquinoline derivatives 618, whereas “push–pull” aldimines underwent a 1,4-dehydrogenation reaction in the presence of excess of benzyne, generating the isoquinoline derivatives 619.

image file: c6cs00220j-s67.tif
Scheme 67 Arylation of N-pyrazolyl aldimines.

Chandrasekhar et al. have recently reported the reaction of 2-sulfonyliminoindolines 627 with arynes to give 3-arylated indole derivatives 630 (Scheme 68).159 The reaction proceeds through arylation at the 3-position of the indole derivative, then further N-arylation with a second equivalent of the aryne, as confirmed by deuterium labelling experiments in CD3CN. Performing the reaction in THF, however produced mainly the benzazepine 631 arising from [2+2] cycloaddition/fragmentation reaction.

image file: c6cs00220j-s68.tif
Scheme 68 Arylation of 2-sulfonyliminoindolines.

Huang and co-workers developed an alternative approach to pyridine arylation via de novo construction of the heterocyclic ring through multicomponent reaction of arynes, isocyanides and terminal alkynes (Scheme 69).160,161 Isocyanides effectively add to arynes and have been used in a number of multi-component coupling reactions162 – here the zwitterionic adduct 633 is trapped by the terminal alkyne giving 634. This intermediate evolves through a 1,5-hydride shift to the allenyl imine intermediate 635, which can further react with either another aryne or alkyne equivalent depending on the ratio of the reagents. If the intermediate 635 reacts with an equivalent of the aryne, the arylated quinolines 641 are produced. However when an excess of the alkyne is used, the reaction affords the arylated pyridines 638.

image file: c6cs00220j-s69.tif
Scheme 69 MCR of arynes, isocyanides and terminal alkynes.

The same authors published an extension of this multicomponent reaction, employing propargyl bromide as the terminal alkyne (Scheme 70).163 In this case the intermediate 652 can undergo a 1,3-hydride shift to give the azatriene 653, with pericyclization and HBr elimination finally leading to the arylated pyridine 650.

image file: c6cs00220j-s70.tif
Scheme 70 MCR of arynes, isocyanides and propargyl bromides.

8. Miscellaneous – biaryls in organometallic complexes and polymers

Wenger and Bennett et al. disclosed the use of σ-halophenylboronic esters as benzyne precursors in the context of preparing aryne transition metal coordination complexes.164,165 Treatment of 2-bromo phenylboronic ester 662 with a stoichiometric amount of Pd(dba)2 in the presence of various phosphine ligands afforded the Pd(II) complex 663 (Scheme 71), which upon treatment with t-BuOK in toluene at 50 °C produced the complex 664, bearing a benzyne molecule coordinated in η2 mode to palladium. When the dcpe analog was heated to 50 °C, the new complex 665 containing a bidentate biaryl ligand was isolated and characterized by X-ray crystallography, along with other palladated species.
image file: c6cs00220j-s71.tif
Scheme 71 Synthesis of biaryl palladium complexes from boronic esters as aryne precursors.

To obtain the analogous Ni and Pt complexes to 665, the Bennett group used chlorobenzene/LiTMP as the benzyne source.165,166 When LiTMP was added to a solution of chlorobenzene and complex 667 in THF at 0 °C, the Ni complex containing the chelating biaryl scaffold 669 could be isolated (Scheme 71).

Johnson et al. reported an interesting Ni(0)-catalyzed dimerization of the aryne complex 670 into a biaryl structure 671 (Scheme 72).167,168 The treatment of the aryne–Ni(0) complex 670 with a catalytic amount of Ni(PEt3)2 (generated in situ from [Ni(PEt3)2Br2] in sodium amalgam) initiated dimerization of the aryne complex to give a dinuclear intermediate containing the biaryl ligand 672, which evolves through a 1,4-H shift to give the complex 671.

image file: c6cs00220j-s72.tif
Scheme 72 Synthesis of fluorinated-biaryl Ni complexes through arynes.

As discussed in Section 5 above, there has been considerable development in transition-metal catalyzed reactions involving arynes, predominately using palladium and the triflate precursor 228. In many of these reactions a benzyne carbopalladation is proposed as a key step in the catalytic cycle, but rarely have these intermediates been isolated and characterized. The Vicente group have studied this transformation through the reactions of benzyne with cyclopalladated phenethylamines (Scheme 73).169,170 The insertion of benzyne into the Pd–C of bond of palladacycles 673 resulted in enlarged palladacycles which were stable enough to be isolated and characterized. When the molar ratio of benzyne/complex was 2[thin space (1/6-em)]:[thin space (1/6-em)]1 a double insertion took place generating a ten-membered metallacycle bearing the 1,2 terphenyl moiety 682. The new Pd–C bond was still reactive to undergo a further insertion of unsaturated molecules such as CO or RNC giving eight- or ten-membered heterocyclic structures.171

image file: c6cs00220j-s73.tif
Scheme 73 Isolation of carbopalladated benzyne complexes.

Aryne chemistry has been utilized to synthesize biaryl monomers for further polymerization processes. Swager et al. made use of the 1,4-terphenyl synthesis developed by Hart (vide supra, Scheme 22) in the production of fluorinated poly(fluorenes) (Scheme 74).172 The reaction of 2,5-dibromo-1,4-diiodobenzene with PhMgBr lead to the formation of the terphenyl Grignard 162, which could be trapped with hexafluoroacetone and further transformed into 686, a suitable monomer to produce 9,9-bis-(trifluoromethyl)-poly(fluorene) 687. This fluorinated polymer displays a high fluorescence quantum yield and enhanced stability toward photooxidation.

image file: c6cs00220j-s74.tif
Scheme 74 Synthesis of monomer terphenyls for further polymerization.

The direct polymerization of arynes was recently achieved by Uchiyama et al. for the synthesis of poly(o-arylenes) 691, using copper catalysis to control the assembly of ortho-linked arene structures (Scheme 75).173 Their method employed standard conditions of o-trimethylsilylphenyl triflates 688, CsF, and 18-crown-6 in THF to generate the monomer arynes, with polymerization taking place in the presence of Cu(I) salts such as CuCN, CuCl, n-Bu2Cu(CN)Li2 or copper mesitylate. Alternative metal salts such as CuBr2, KCN, AuCl, or Pd2(dba)3 were not successful when used as initiators. The polymeric parameters such as Mn, Mw and PDI depended on the aryne precursor/Cu(I) initiator ratio, with low amounts of the Cu(I) salt forming poly-(o-arylenes) with higher average molecular weights.

image file: c6cs00220j-s75.tif
Scheme 75 Synthesis of poly(o-arylenes) using arynes.

9. Conclusions

The aryne route to biaryls features an impressively versatile range of methods for capturing the electrophilic aryne moiety in a C–C bond forming event. Benzyne will efficiently react with hard organometallics such as aryllithiums and Grignards, participate in multi-component couplings mediated by transition metals such as copper, palladium and nickel, whilst having a rich pericyclic chemistry on hand that can be exploited in biaryl synthesis. The inherent reactivity of the strained triple bond can also be harnessed in metal-free aryl bond formation, either directly in the intramolecular mode, or through suitably-designed intermolecular heteroatom additions followed by rearrangement. Collectively, this vast scope of chemistry effectively compliments cross-coupling methods for biaryl bond construction, whilst offering the extra dimension of further functionalization in situ through the addition of a third component.

The enduring relevance of arynes to biaryl synthesis suggests that the field will continue to grow, as chemists address challenges in sustainability, atom economy, and new patterns of reactivity for highly-functionalized biaryl synthesis. Potential areas for future development include the introduction of radical and single electron transfer processes, currently conspicuous by their absence from the benzyne landscape, but pivotal to current thinking in contemporary synthesis. Transformations involving hetarynes show exciting promise, with recent work demonstrating ample scope for harnessing these valuable intermediates, which were previously considered to be quite intractable to intermolecular C–C bond formation.12,174 Overall, the recent growth of benzyne chemistry has been driven in large part by the availability of new precursors,85,100,137 including some from quite unexpected sources;140 further progress in this area175–186 promises to open up new reaction regimes for biaryl synthesis under mild and operationally-simple conditions.


J.-A. G.-L. thanks the University of Murcia for the award of a postdoctoral fellowship and MINECO (grant CTQ2015-69568-P) and Fundación Séneca (grant 19890/GERM/15) for financial support and MFG thanks the EPSRC for support.


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