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Recent advances in transition-metal-free carbon–carbon and carbon–heteroatom bond-forming reactions using arynes

Downloaded by National Chemical Laboratory, Pune on 26 January 2012 Published on 26 January 2012 on http://pubs.rsc.org | doi:10.1039/C2CS15310F

Anup Bhunia, Santhivardhana Reddy Yetra and Akkattu T. Biju* Received 14th November 2011 DOI: 10.1039/c2cs15310f This tutorial review is aimed at highlighting recent developments in transition-metal-free carbon–carbon and carbon–heteroatom bond-forming reactions utilizing a versatile class of reactive intermediates, viz., arynes, which hold the potential for numerous applications in organic synthesis. Key to the success of the resurgence of interest in the rich chemistry of arynes is primarily the mild condition for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. Consequently, arynes have been employed for the construction of multisubstituted arenes with structural diversity and complexity. The versatile transitionmetal-free applications of arynes include cycloaddition reactions, insertion reactions and multicomponent reactions. In addition, arynes have found applications in natural product synthesis. Herein, we present a concise account of the major developments that occurred in this field during the past eight years.

Introduction Arynes are highly reactive intermediates poised to offer numerous applications in organic synthesis.1 Although speculation for the existence of arynes first occurred more than a century ago, arynes were proposed as intermediates by Wittig only in 19422 and their structure was confirmed by Roberts and co-workers in 1953 by the reaction of 14C labelled chlorobenzene with sodium amide.3 Arynes are uncharged Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune-411008, India. E-mail: [email protected]; Fax: +91-20-25902629; Tel: +91-20-25902441

Anup Bhunia

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Anup Bhunia was born in 1988 in Midnapore (West Bengal), India. He received his BSc in chemistry from Midnapore College, in 2009. Subsequently, he moved to the Indian Institute of Technology (IIT), Guwahati, where he obtained his MSc in 2011. At present, he is a PhD student in the research group of Dr A. T. Biju at the CSIRNational Chemical Laboratory, Pune. His research interests are focused on the development of novel organocatalytic 1,6-addition reactions and related chemistry.

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transient intermediates derived from aromatic systems by the formal abstraction of two hydrogen atoms from adjacent positions. Due to the presence of the CRC triple bond in a six-membered ring in arynes, the unhybridized p-orbitals are distorted and they are no longer parallel to each other as in normal alkynes. This strain created by the triple bond in the ring makes them highly reactive. Hence, this kinetically unstable intermediate can react with a wide variety of anionic and uncharged nucleophiles leading to a direct approach to access 1,2-disubstituted arenes. The purpose of this review is to provide an account of the recent developments in transitionmetal-free carbon–carbon and carbon–heteroatom bondforming reactions employing arynes.

Santhivardhana Reddy Yetra

Santhivardhana Reddy Yetra was born in 1988 in Guntur (AP), India. He completed his BSc in chemistry at the Acharya Nagarjuna University, Guntur, in 2008 and MSc from Andhra University in 2010. Currently, he is a PhD student in the research group of Dr A. T. Biju at the CSIR-National Chemical Laboratory, Pune. His research focuses on organocascade catalysis and related chemistry.

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Scheme 1


Fig. 1

Possible modes of action of arynes.

The phenomenal success of arynes in organic synthesis can be attributed primarily to their electron deficient nature leading to different modes of action in various bond-forming reactions (Fig. 1). The pronounced electrophilicity of arynes renders them excellent dienophiles in pericyclic reactions. Consequently, arynes found application in Diels–Alder reactions (A), [2+2] cycloaddition reactions with electron-rich olefins (B) and as excellent dipolarophiles in dipolar cycloaddition reactions (C). In addition, arynes have been extensively utilized in transition-metal-catalyzed reactions (D).4 Intriguingly, however, recent developments in aryne chemistry have been devoted to transition-metal free reactions, which mainly include the initial addition of nucleophiles to arynes and subsequent trapping of the aryl anion intermediate with electrophiles. If the nucleophile and electrophile do not belong to the same molecule, the overall process is a unique three component coupling, where the aryne is inserted between the other two coupling partners (E). Furthermore, arynes can insert into element–element (X–Y) s-bonds and p-bonds (F). Insertion reactions are synthetically very useful because both elements can be introduced into the CRC triple bond simultaneously in a formal [2+2] fashion leading to polysubstituted arenes. Thus arynes are known to insert into the carbon–carbon, carbon–heteroatom, and heteroatom–hydrogen bonds.

Akkattu T. Biju received his BSc and MSc (both first rank) from Mahatma Gandhi University, Kerala, India, and PhD under the guidance of Dr Vijay Nair at the CSIRNIIST, Trivandrum, India. Subsequently, he has been a post-doctoral fellow with Prof. Tien-Yau Luh at the National Taiwan University, Taipei, and an Alexander von Humboldt fellow with Prof. Frank Glorius at the Westfa¨lische Wilhelms-Universita¨t Akkattu T. Biju Mu¨nster, Germany. In June 2011, he began his independent research career at the CSIRNational Chemical Laboratory, Pune, India. His research focuses on the development of transition-metal-free carbon– carbon and carbon–heteroatom bond-forming reactions and their application in organic synthesis. Chem. Soc. Rev.

Mild method for the generation of arynes.5

In view of the extreme reactivity of arynes, they have to be generated in situ. Traditionally, arynes have been generated by the treatment of aromatic halides with strong bases like sodium amide. The highly basic reaction condition is however unfavourable in the case where the molecule contains basesensitive functional groups. In 1983, Kobayashi and co-workers developed a facile method for the generation of arynes 2 by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates 1 (Scheme 1).5 The mild reaction conditions involved in this procedure are compatible with a variety of reagents, substrates, functional groups and even transition metal catalysts are well tolerated. Because of these reasons, today, this approach is the most widely used and the most efficient one for the generation of arynes. The introduction of 1 as mild aryne precursors led to growing research in this area, resulting in the development of new aryne-based reactions for the preparation of complex 1,2-disubstituted arenes. In the following sections, we provide a concise report on major transition-metal-free applications of arynes in pericyclic reactions, insertion reactions and multicomponent reactions thereby shedding light on the synthetic utility of these highly reactive intermediates. Although arynes have found considerable applications in transition-metalcatalyzed reactions, these are not discussed here since excellent reviews are available on the topic.4

Pericyclic reactions Due to the high electrophilicity of their CRC triple bond, arynes act as excellent dienophiles in various pericyclic reactions. Consequently, pericyclic reactions are used both as a method for the detection of arynes and as a valuable tool for the synthesis of various benzene derivatives. The different aspects of pericyclic reactions of arynes have received a lot of attention and a number of reviews have addressed various aspects of these reactions.1a,b In view of these excellent reviews, detailed discussion on these reactions of arynes is not attempted in this review and the following section consists of selected reports, which appeared in the literature after 2003. Diels–Alder reactions The Diels–Alder reaction is the most important reaction of arynes, which is a powerful tool for constructing various carbocycles and heterocycles of synthetic importance. Due to their high electrophilicity, arynes have been shown to react with a wide variety of dienes. In addition, the Diels–Alder reaction can be combined with various intermolecular processes in tandem to synthesize molecules that are otherwise difficult to obtain. In 2007, Xie and Zhang reported the reaction of arynes with N-substituted imidazoles, which proceeds via a tandem process involving a Diels–Alder reaction and an intermolecular coupling reaction leading to the formation of aryl amines incorporating anthracene in moderate to good This journal is

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Scheme 5 Generation and subsequent Diels–Alder reaction of indolyne (Buszek et al.).9a

Tandem reaction of arynes with imidazoles.6

Scheme 2

Scheme 6 Generation and Diels–Alder reaction of 3-boryl benzynes.10

Scheme 3 Aza-Diels–Alder reaction of arynes.7

Scheme 4 Domino Diels–Alder reaction of arynes.8

yields (Scheme 2).6 The initially formed Diels–Alder adduct 3 between the aryne and imidazole undergoes a retro Diels– Alder reaction to generate the intermediate 4, the latter undergoes a second Diels–Alder reaction with the aryne to generate 5; ring opening of the latter and intermolecular nucleophilic addition to excess aryne afforded the final product. Interestingly, Wang and co-workers developed the three-component cascade synthesis of phenanthridine derivatives by the azaDiels–Alder reaction of arynes generated from benzenediazonium-2-carboxylates and the imines generated from aromatic aldehydes and aniline derivatives (Scheme 3).7 The noteworthy features of this reaction include the efficient process involving easily available starting materials and the one-pot procedure under metal-free and mild conditions. Recently Guitiań and co-workers developed the synthesis of polycyclic aromatic hydrocarbons by a domino Diels–Alder cycloaddition involving arynes (Scheme 4).8 Two successive Diels–Alder reactions proceed simultaneously in a stereoselective manner leading to the cycloadduct 6, which on treatment with acid afforded perylene derivatives, thus opening a new pathway to access elusive polyarenes. Generation of arynes from 1,2-dihalogenated indoles by treatment with butyl lithium and its Diels–Alder reaction with furan was developed by Buszek and co-workers (Scheme 5).9a In addition, they applied the intermolecular indole–aryne cycloaddition in the synthesis of indole natural products including cis-trikentrin A and Herbindole A.9b Subsequently, they provided experimental and theoretical support for the regioselectivity in indole-derived aryne cycloadditions.9c This journal is

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Scheme 7 Highly diastereoselective aryne Diels–Alder reaction with acyclic dienes.11a

These studies revealed that 6,7-indolynes showed remarkable regioselectivity in their cycloaddition reactions with 2-substituted furans, whereas 4,5- and 5,6-indolynes showed no regioselectivity. The generation of 3-boryl benzyne and its subsequent Diels–Alder reaction with substituted furans or pyrroles providing highly functionalized boronic acid derivatives has been uncovered by Akai and co-workers.10 The 2-boryl-6iodophenyl triflate 7 upon treatment with iPrMgClLiCl generates the 3-boryl benzyne, which immediately undergoes Diels–Alder reaction affording the products in good yields (Scheme 6). In an attempt to expand the scope and utility of Diels–Alder reaction of arynes with acyclic dienes, Lautens and co-workers used 1,4-disubstituted acyclic dienes as the coupling partner for arynes leading to a straightforward synthesis of 1,4-dihydronaphthalene derivatives with excellent levels of selectivity (Scheme 7).11 The reaction worked well with electron-releasing and electron-withdrawing substituents on the diene system. They also applied this methodology to a short synthesis of racemic sertraline. [2+2] cycloaddition reactions Arynes react with a wide range of olefins via [2+2] cycloaddition, leading to the formation of benzocyclobutane derivatives, which are useful synthetic intermediates. Due to the electrophilic nature of arynes, these reactions proceed Chem. Soc. Rev.

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1,3-Dipolar cycloaddition reactions

Scheme 8

[2+2] cycloadditions of arynes (Suzuki et al.).12

faster with alkenes containing electron-donating substituents. The regioselective [2+2] cycloaddition of 3-methoxybenzyne with ketene silyl acetal has been reported by Suzuki and co-workers.12a The methoxy group on the aryne precursor was the key to success for the high regioselectivity (Scheme 8A). Subsequently, the same group developed the synthesis of polyoxygenated tricyclobutabenzenes by the consecutive [2+2] cycloaddition between aryne and ketene silylacetal (Scheme 8B).12b The iodotriflate 8 generates aryne upon treatment with a base and instant [2+2] cycloaddition with 9 afforded the benzocyclobutane 10, which was transformed into the bromotosylate 11 in three steps. The aryne generated from 11 undergoes two more iterative [2+2] cycloadditions affording the tricyclobutabenzene derivative 12. They also developed a dual aryne cycloaddition method starting from bis(sulfonyloxy) diiodobenzene 13, which is a synthetic equivalent of 3-methoxy 1,4-benzdiyne.12d Treatment of 13 with silyl acetal 14 in the presence of excess base afforded the bis cycloadduct 15 exclusively in 72% yield (Scheme 8C). The [2+2] cycloaddition of arynes with enamides has been developed by Hsung and co-workers.13 When the enamide was connected to an unactivated double bond by a carbon tether, the reaction led to a rapid assembly of nitrogen heterocycles (Scheme 9). In this case, the reaction proceeds via a tandem process involving [2+2] cycloaddition followed by the pericyclic ring opening and an intramolecular N-tethered [4+2] cycloaddition.

A variety of 1,3-dipoles can add to arynes leading to the formation of benzofused five-membered heterocyclic systems. In 2006, Larock and co-workers reported the [3+2] cycloaddition of pyridine N-oxides with arynes to generate a cycloadduct, which undergoes rearrangement leading to the formation of 3-(2-hydroxyaryl) pyridines in good yields.14a Mechanistically, the initially formed cycloadduct 16 undergoes a rearrangement to generate the fused cyclopropane 17, which furnishes the product through a ring fragmentation (Scheme 10). Interestingly, an analogous reaction using the aryne generated from benzenediazonium 2-carboxylate was reported by Abramovitch and Shinkai as early as 1974.14b A related [3+2] cycloaddition of in situ generated isoquinolineN-oxide with arynes has been recently uncovered by Wu and co-workers.14c An efficient and general method for the synthesis of N-unsubstituted indazoles and N-aryl indazoles by the 1,3dipolar cycloaddition of arynes with diazomethane derivatives has been reported independently by the groups of Yamamoto and Larock (Scheme 11).15 The N-unsubstituted and N-arylated indazole formation depends on the amount of diazomethane derivative used. Additionally, the synthesis of various benzotriazole derivatives by the [3+2] cycloaddition of azides with arynes has been demonstrated by Larock and co-workers.16a The reaction has good substrate scope and tolerates broad range of functional groups. Recently, Zhang and Moses extended the azide–aryne dipolar cycloaddition by in situ generation of the aromatic azides from aromatic amines.16b The 1,3-dipolar cycloaddition of a,b-unsaturated nitrones 18 with arynes leading to the formation of benzoisoxazoline derivatives 19 was developed by Danishefsky and co-workers (Scheme 12).17 Additionally, they applied this methodology to the synthesis of the oxa[3.2.1]octane core of cortistatin A. Furthermore, the 1,3-dipolar cycloaddition of nitrile oxides with arynes furnishing benzisoxazoles was reported independently by the groups of Moses,18a Larock18b and Browne.18c Since arynes and nitrile oxides are highly reactive intermediates,

Scheme 10 1,3-Dipolar cycloaddition of pyridine N-oxides with arynes.14a

Scheme 9 Tandem aryne–enamide [2+2]-retro [2+2]–[4+2] sequence (Hsung et al.).13

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Scheme 11 [3+2] cycloaddition of diazocompounds and azides with arynes.15,16

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Scheme 14 [3+2] cycloaddition of sydnones with arynes.20


Scheme 12 1,3-Dipolar cycloaddition of nitrones and nitrile oxides with arynes.17,18

Scheme 15 Ene reaction of arynes with alkynes.21

Scheme 13 [3+2] cycloaddition of arynes with various 1,3-dipoles.19

they are generated in situ. Nitrile oxides were generated in situ from chlorooximes 20 by reaction with a fluoride source. The [3+2] cycloaddition of stable azomethine imines 21 with arynes under mild reaction conditions affording tricyclic pyrazoloindazolone derivatives 22 has been reported by Larock and co-workers (Scheme 13).19a The same group also developed the facile dipolar cycloaddition of oxaziridines 23 with arynes.19b This reaction involves the cleavage of the C–O bond of oxaziridine leading to the formation of dihydrobenzisoxazoles. Recently, Moses and co-workers developed the 1,3-dipolar cycloaddition of arynes with nitrile imines.19c The nitrile imines were generated in situ from the corresponding hydrazonyl chlorides 24 and the reaction afforded disubstituted indazole derivatives in moderate to excellent yield. Furthermore, aryne [3+2] cycloaddition with N-tosylpyridinium imides 25 furnishing pyridoindazole derivatives has been reported very recently by Shi and co-workers.19d Recently, Larock, Shi and co-workers incorporated cyclic 1,3-dipoles in aryne cycloadditions. The [3+2] cycloaddition reaction of sydnones 26 with arynes resulted in the formation of 2H-indazole derivatives.20 The initially formed cycloadduct 27 undergoes spontaneous extrusion of CO2 in a retro [4+2] fashion to form the product (Scheme 14).

Scheme 16 Intramolecular aryne–ene reaction.22

Scheme 17 Aryne aza–Claisen rearrangement.23

used a deprotonation-based method for the aryne generation where the aryne and the ene component were connected by a tether (Scheme 16). The reaction afforded a direct access to benzofused heterocycles and carbocycles. The aza-Claisen rearrangement of arynes with tertiary allylamines leading to the formation of functionalized anilines has been reported by Greaney and co-workers (Scheme 17).23 The reaction proceeds via the nucleophilic attack of the tertiary amine on the aryne generating the zwitterion 28, which gets protonated to the ammonium salt 29. The latter 29 undergoes an aza-Claisen rearrangement to produce the aniline product.

Insertion reactions Miscellaneous reactions Due to the low-lying LUMO of arynes, they are expected to be powerful enophiles in ene reactions with alkynes possessing a propargylic hydrogen. In 2006, Cheng and co-workers reported the ene reaction of arynes with alkynes affording phenylallenes under mild reaction conditions (Scheme 15).21 This ene reaction worked smoothly with a variety of alkyl substituted alkynes and differently substituted arynes. Very recently, Lautens and co-workers developed a high yielding and highly selective intramolecular aryne–ene reaction.22 They This journal is

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Due to the pronounced electrophilicity and highly strained carbon–carbon triple bond, arynes undergo facile insertion into element–element bonds. Even neutral nucleophiles that are inert towards activated alkynes can add to arynes. If the nucleophilic and electrophilic sites of a molecule are connected (Nu–E), then the initially formed zwitterion 30 undergoes nucleophilic attack on the electrophilic site of Nu–E to form the insertion product (eqn (1)). This mode of action of aryne has found numerous applications in carbon–carbon and carbon–heteroatom bond-forming reactions. Chem. Soc. Rev.

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ð1Þ

In their seminal report, Shirakawa, Hiyama and co-workers described the addition of ureas to arynes leading to the formation of benzodiazepines and 2-aminobenzamides.24 The insertion of arynes into the N–CO bond of cyclic and acyclic ureas resulted in the incorporation of two different functional groups into the adjacent position of the aromatic system (Scheme 18). The reaction proceeds via the addition of the urea nitrogen atom to aryne generating the zwitterion 31, which furnishes the product by an intramolecular nucleophilic substitution on the amide carbonyl leading to intermediate 32 followed by ring rupture. In their efforts to synthesize quaternary stereocentres by the a-arylation of a-substituted b-ketoesters using arynes, Tambar and Stoltz developed a mild and efficient procedure for the acyl-alkylation of arynes leading to interesting 1,2-disubstituted arenes.25 The reaction results in the formation of two new C–C bonds by the insertion of arynes into the a,b C–C bond of the b-ketoester (Scheme 19A). Interestingly, cyclic b-ketoesters undergo ring expansion to generate medium-size carbocycles. The reaction proceeds through a formal [2+2] cycloaddition between the aryne and the caesium enolate of the b-ketoester to generate the aryl anion intermediate 33, followed by intramolecular nucleophilic substitution to generate the intermediate 34. The fragmentation of 34 afforded the product. Later Stoltz and co-workers applied this methodology to the enantioselective synthesis of amurensinine, which is a member of the isopavine family of alkaloids, and the macrolactone natural product curvularin.26 Independent investigations carried out by Yoshida, Kunai and co-workers demonstrated a facile insertion of arynes into the C–C s-bond of various b-dicarbonyl compounds under extremely mild reaction conditions (Scheme 19B).27 In this context, it is important to note that a-arylation of 1,3-diketones using arynes in the presence of catalytic amounts of CuBr and trichloroacetic acid has been achieved by Wang and co-workers.28 Transition-metal-free insertion of arynes into the C–N bond of amides and the S–N bond of sulfinamides leading to a mild and efficient protocol for the synthesis of 1,2-disubstituted arenes has been achieved by Liu and Larock (Scheme 20).29a A variety of functional groups are well tolerated under the reaction conditions. Intriguingly, however, the presence of a CF3 moiety is crucial for this insertion reaction, presumably because this group increases the acidity of the amide and also increases the electrophilicity of the carbonyl carbon of the

Scheme 18 Insertion of arynes into ureas.24

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Scheme 19 Acyl-alkylation of arynes and its application.25–27

Scheme 20 Insertion of arynes into C–N and C–S s-bonds.29a

amide and the sulfinyl sulfur of the sulfinamide. In the context of insertion of arynes into the carbon–heteroatom s-bonds, it may be mentioned that highly selective insertion of arynes into the C–O s-bond of ethoxy acetylene leading to 2-ethoxyethynylaryl derivatives was reported by Penã, Guitiań and co-workers.29b In view of their success in efficient insertion of arynes into the C–C bond of b-dicarbonyl compounds, Yoshida, Kunai and co-workers accomplished a facile insertion of arynes into the C–C s-bond of a-cyanocarbonyl compounds 35 leading to the direct introduction of cyanomethyl and carbonyl functionalities into the aromatic ring (Scheme 21).30a Subsequently, they developed the insertion of arynes into a-tosylnitriles 36 and malononitrile affording diarylmethane derivatives.30b It is noteworthy that two molecules of aryne can be successively inserted into C–C and C–H bonds of nitriles under mild conditions. Additionally, the same group reported the insertion of arynes into the C–C bond of fluorenyl ketones 37 leading to unique acylfluorenylation reactions.30c It is important to note, however, that the fluorene skeleton was crucial for this insertion reaction. Recently, Liang, Li and co-workers reported the efficient insertion of arynes into the C–C s-bond of b-ketophosphonates 38 leading to 2-acylbenzylphosphonates in moderate to good yields.30d The insertion of arynes into the C–C s-bond of acyclic and cyclic a-sulfonyl ketones 39 has been developed by Huang and co-workers furnishing 1,2-disubstituted arenes and benzannulated carbocycles, which are difficult to access using other synthetic routes.30e Very recently, Yoshida and co-workers reported the insertion of arynes into the C–C s-bond of trifluoromethyl ketones 40 affording diverse trifluoroacetophenone derivatives in good yields.30f This journal is

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Scheme 23 Insertion–cyclization benzoates.32

Scheme 21 Insertion of arynes to various C–C s-bonds.30

Scheme 22 Insertion of arynes into N–H and O–H bonds.31

An efficient, mild and transition-metal-free method for the N-arylation by the insertion of arynes into the N–H bond of amines and sulfonamides furnishing N-arylated products with excellent yield and high regioselectivity has been reported by Liu and Larock (Scheme 22).31a Interestingly, monoarylated and diarylated amines can be obtained from primary amines by the simple control of the ratio of reactants. Subsequently, the same group reported the O-arylation by the insertion of arynes into the O–H bond of phenols and arylcarboxylic acids leading to the formation of diaryl ethers, and aryl esters with excellent functional group compatibility.31b It is noteworthy that analogous insertion of indole-derived arynes into the N–H, O–H and S–H bonds has been recently developed by Garg and co-workers.31d Additionally, the N-arylation of N-tosylhydrazones using arynes followed by treatment with a Lewis acid in one-pot leading to the efficient synthesis of N-tosylindoles has been recently achieved by Greaney and co-workers.31e This methodology was subsequently applied by the Larock group for the synthesis of biologically interesting xanthone, thiaxanthone and acrydone derivatives by a tandem insertion– cyclization sequence of arynes with 2-substituted benzoates (Scheme 23).32 The reaction proceeds via the insertion of arynes into the O–H, S–H or N–H bond of the benzoate derivative leading to the formation of the aryl anion intermediate 41, which undergoes cyclization to form the product. Furthermore, they applied this method to the insertion of arynes into the N–H bond of indole-2-carboxylates providing indole–indolone scaffolds under mild reaction conditions.33 This journal is

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arynes

and

2-substituted

Scheme 24 Insertion–cyclization cascade of arynes.35,36

Related insertion of arynes into the N–H bond of amino acid esters followed by cyclization affording diverse indoline-3-ones has been recently uncovered by Okuma and co-workers.34 Additionally, the reaction of arynes with salicylaldehydes under basic conditions proceeding via the O–H insertion followed by subsequent cyclization affording 9-hydroxy xanthenes 42 was reported by Okuma and co-workers (Scheme 24).35 Moreover, the insertion of arynes into the O–H/N–H bond of phenols/anilines having a Michael acceptor at the 2-position via an addition–cyclization cascade leading to the formation of 9-functionalized xanthenes/ acridines 43 was uncovered by Huang and Zhang.36 Apart from this, insertion of arynes into various element– element s-bonds has been achieved by Yoshida, Kunai and co-workers (Scheme 25). In 2004, they developed the thiostannylation reaction by the insertion of arynes into the Sn–S s-bond leading to the formation of versatile 2-(arylthio) arylstannanes 44 amenable for further transformations.37a Subsequently, the same group uncovered the facile aminosilylation reaction by the insertion of arynes into the N–Si s-bond resulting in a straightforward access to 2-silylaniline derivatives 45.37b Additionally, the carbo-phosphinylation reaction by the insertion of arynes into the P–C s-bond of cyanomethyldiphenylphosphine oxide 46 has been achieved.37c Insertion of arynes into the C-halogen s-bond of acid halides affording benzophenone derivatives 47 with perfect regioselectivity was also reported by the same group.37d

Scheme 25 Insertion of arynes into element–element s-bonds (Yoshida, Kunai et al.).37

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Scheme 26 Insertion of arynes into C–H bond of b-enaminoesters and ketones.38

The C-arylation of b-enaminoesters and ketones via formal insertion of arynes into the b C–H bond provides direct access to substituted aromatic b-enamino compounds.38 The reaction proceeds via the addition of enaminones to arynes generating the zwitterionic intermediate 48, which gets protonated to the imine intermediate 49 (Scheme 26). Subsequent tautomerization affords the product. Alternatively, a concerted aza–ene type reaction can also generate the imine intermediate 49. Additionally, the N-heterocyclic carbene (NHC)-catalyzed formal insertion of arynes into the Cformyl–H bond of aldehydes, the intermolecular hydroacylation of arynes, has been recently uncovered by Biju and Glorius.39 This method reveals the rare compatibility of nucleophilic carbenes with electrophilic arynes. The reaction proceeds via the formation of a nucleophilic Breslow intermediate from aldehyde and NHC, which adds to the aryne to generate the alkoxide 51 via the intermediate 50. Alternatively, a concerted transition state in analogy to the reaction of 1,3-dipoles can also lead to the alkoxide 51. Release of the NHC catalyst closes the catalytic cycle and results in the formation of the observed ketone product (Scheme 27). In this context, it is noteworthy that efficient synthesis of phosphonium salts by the addition of phosphines to arynes has been reported by Juge´ and co-workers.40 Although the insertion of arynes into the CQC bonds via [2+2] cycloaddition is known, analogous insertion into CQO bonds is very rare. In the context of their interest in the insertion reactions of arynes, Yoshida, Kunai and co-workers developed a 2 : 1 coupling of arynes with aryl aldehydes leading to the formation of 9-aryl xanthene derivatives (Scheme 28).41 The key to the success of this reaction is the high electrophilicity of arynes, allowing even nucleophilic attack of aldehydes generating the intermediate 52, which cyclizes to 53. Thus, in principle, the aldehyde underwent a

Scheme 27 Insertion of arynes into the Cformyl–H bond of aldehydes.39a

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Scheme 28 2 : 1 coupling of arynes with aryl aldehydes.41

formal [2+2] cycloaddition with arynes to afford 53. Subsequent ring opening to the o-quinonemethide 54 followed by [4+2] cycloaddition with another molecule of aryne furnished the xanthene derivative. Intrigued by the possibility of trapping the arynes with aldehydes, Miyabe and co-workers recently found that arynes can be inserted even into the carbonyl group of formamides. The reaction of arynes with formamides followed by the sequential addition of dialkyl zinc afforded 1,2-disubstituted arenes in moderate to good yields (Scheme 29A).42 However, the insertion of arynes into aryl amides 55 proceeds via the C–N s-insertion leading to the formation of amino benzophenone derivatives 56 (Scheme 29B).43 This method has been applied to the one-pot synthesis of biologically active acridones and acridines. In this context, it may be noted that a facile N-arylation of acetanilides with arynes has been uncovered very recently by Lynch and co-workers.44 Interestingly, the insertion of arynes into the C–O s-bond of aliphatic acids 57 leading to the straightforward access to o-hydroxyaryl ketones 58 has been recently reported by the Larock group (Scheme 29C).45a Very recently, the addition of 2,3-allenoic acids to arynes leading to the formation of chromones was reported by Ma and co-workers.45b Recent studies by the Greaney group revealed that the insertion of arynes into thioureas possessing one N–H bond proceeds in contrast with that in ureas.46 In this case, the reaction takes place via aryne insertion into the CQS bond of thiourea furnishing the intermediate 59, which undergoes ring opening to afford 60. Insertion of another molecule of aryne into the S–H bond of 60 leads to an operationally simple method for the synthesis of amidines (Scheme 30). Insertion of arynes into the PQN bond of P-alkenyl phosphazenes has been reported recently (Scheme 31).47 The p-insertion

Scheme 29 Insertion of arynes into amide derivatives and acids.

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Scheme 30 Insertion of arynes into thioureas.46

Scheme 32 MCR involving arynes, isocyanides and either aldehydes or activated imines.48,49

Scheme 31 Insertion of arynes into PQN bond.47

followed by retro [2+2] cycloaddition/6p electrocyclization and a subsequent protonation leads to the formation of 4-benzazaphosphorinium triflate derivatives.

Multicomponent reactions (MCRs)

Scheme 33 MCR involving arynes, imines (or amines) and CO2.50,51

Another important aspect of aryne chemistry that received much attention recently is multicomponent reactions, which mainly include the initial addition of nucleophiles to arynes and subsequent trapping of the aryl anion intermediate with electrophiles. If the nucleophile and electrophile do not belong to the same molecule, the overall process is a unique three-component coupling, where the aryne is inserted between the other two coupling partners (eqn (2)). This versatile transition-metal-free methodology has been applied to the synthesis of valuable heterocycles and in natural product synthesis. ð2Þ

In 2004, Yoshida, Kunai and co-workers developed a unique three-component reaction of arynes with isocyanides and aldehydes leading to the formation of benzannulated iminofurans in good yields (Scheme 32A).48 The reaction is initiated by the nucleophilic addition of isocyanide to aryne to form the 1,3-zwitterionic intermediate 61, which is trapped by the aldehyde, and a subsequent intramolecular cyclization to furnish the product. This protocol demonstrates that a suitable combination of nucleophiles and electrophiles allows arynes to undergo selective three-component coupling. Further studies showed that the reaction is not only limited to aldehydes as the electrophilic component, but instead activated imines (Scheme 32B), ketones and benzoquinones can be used as the third component.49 This journal is

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The use of CO2 as a coupling partner was uncovered by Yoshida, Kunai and co-workers. The zwitterion generated by the addition of imines to arynes can be intercepted using CO2 leading to the formation of pharmacologically important benzoxazinone derivatives (Scheme 33A).50 Subsequently, the Yoshida group developed the three-component coupling of arynes, amines and CO2, which furnished anthranilic acid derivatives (Scheme 33B).51 The reaction proceeds via the formation of a 1,3-zwitterionic intermediate between an aryne and an amine, which was quenched using CO2 to afford the product. It is noteworthy that these studies demonstrate the utility of CO2 as a C1 source. Further studies from the Yoshida group revealed a threecomponent reaction of arynes, aminosilanes and aldehydes leading to the formation of 2-amino benzhydrol derivatives (Scheme 34).52a Activated imines can also be used as the electrophilic coupling partner enabling the introduction of both amino and aminomethyl moieties into the contiguous position of the benzene ring.52b It is important to note, however, that catalytic amounts of benzoic acid play a crucial role in the reaction by in situ generating the free amines. The reaction of arynes and N-heteroaromatic compounds with pronucleophiles including terminal alkynes, nitriles and ketones having a-hydrogen atoms has been investigated by Cheng and co-workers. When nitriles are used as the third component, this method allows the one-pot formation of new C–C and C–N bonds (Scheme 35A).53a With terminal alkynes Chem. Soc. Rev.

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Scheme 34 MCR involving arynes, aminosilanes and aldehydes (or activated imines).52


Scheme 38 MCR involving arynes, isocyanides and terminal alkynes.56

Scheme 35 MCR involving arynes, N-heteroaromatics and nitriles (or terminal alkynes).53

Scheme 36 MCR involving arynes, pyridine and a-bromo carbonyls.54

as the third component, this protocol affords 1,2-dihydroaromatic alkynes in good yields (Scheme 35B).53b Independent investigations carried out by Zhang and Huang disclosed a three-component reaction of arynes with pyridine and an a-bromo carbonyl compound leading to the formation of pyrido[2,1-a]isoindoles (Scheme 36).54 The reaction proceeds with the formation of the pyridinium salt, which generates the azomethine ylide by the release of HBr. The ylide undergoes a [3+2] cycloaddition with the generated aryne followed by aromatization affording the product. The three-component reaction of arynes, b-sulfonyl acetates or b-ketosulfones with Michael acceptors was reported by Huang and Xue.55 With b-sulfonyl acetate, naphthol derivatives were formed (Scheme 37), whereas b-ketosulfones afforded naphthalene derivatives. The reaction proceeds via the nucleophilic attack of the b-sulfonyl compound on aryne, intramolecular nucleophilic substitution followed by Michael addition, ring closure and elimination.

Scheme 37 MCR involving arynes, b-sulfonyl acetates and Michael acceptors.55

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Recently, Sha and Huang demonstrated a multicomponent reaction of arynes, isocyanides and terminal alkynes, which provided a direct access to polysubstituted pyridines and isoquinolines with excellent selectivity.56 The key to success for the observed selectivity arose from the appropriate reaction conditions: with excess of terminal alkynes, pyridines 63 were formed and with excess of arynes, isoquinolines 64 were formed (Scheme 38). The reaction proceeds with the formation of a 1,3-zwitterionic intermediate from the aryne and isocyanide, which is intercepted by the terminal alkyne to generate the allenyl imine intermediate 62. The successive cycloaddition of 62 with another molecule of terminal alkyne or aryne afforded either 63 or 64. In their attempt to develop an aryne-intercepted version of the Passerini reaction, Stoltz and co-workers uncovered a novel three-component reaction of arynes, isocyanides and phenyl esters that provided the phenoxy iminoisobenzofuran 65 in good yield (Scheme 39).57 Acidic hydrolysis of 65 afforded o-ketobenzamides. It is important to note that the combination of this MCR and subsequent hydrolysis can be carried out in a single sequence leading to a one-pot synthesis of o-ketobenzamides. When the ester component of this MCR was replaced by an electron deficient alkyne, the reaction afforded carbocyclic imino indenones 66. Recently, the research groups of Miyabe and Yoshida independently disclosed the three-component coupling reaction involving aryne, dimethyl formamide (DMF) and an active methylene compound.58 The underlying principle is the generation of o-quinone methides 67 via the 1 : 1 reaction of aryne and DMF, which proceeds with the insertion of the carbonyl group of DMF into the aryne. In the presence of cyclic or acyclic 1,3-diketones as the third component, the reaction afforded 2H-chromenes 69 and coumarin derivatives 70 were formed when b-ketoesters or a-(hetero)aryl esters were used as the third component (Scheme 40).

Scheme 39 MCR of arynes and isocyanides with either phenyl ester or electrophilic alkynes.57

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Miscellaneous reactions


Scheme 40 MCR of arynes and DMF with active methylene compounds.58

Scheme 41 MCR of arynes and isocyanides (or cyclic ethers) with organic bromides.59

In the context of their continued interest in the aryne chemistry, the Yoshida group, very recently, incorporated alkynyl (or polyfluorinated aryl) bromides as the third component in aryne reactions.59 The 1,3-zwitterionic intermediate generated from isocyanide and aryne reacts with alkynyl bromides leading to o-functionalized bromoarenes 71 with the formation of two C–C bonds and a C–Br bond (Scheme 41A). Interestingly, cyclic ethers can also be used as the nucleophilic trigger to generate the 1,4-dipole, which can be intercepted with polyfluoro aryl or alkynyl bromides with good functional group compatibility (Scheme 41B). In 2006, Barrett and co-workers utilized the powerful threecomponent coupling of arynes in the total synthesis of entclavilactone B. The key benzyl alcohol fragment 75 was assembled by the three-component coupling involving arynes generated from the fluoride 72, the methylallyl Grignard reagent 73 and the epoxy aldehyde 74 (Scheme 42).60a The addition of Grignard reagent 73 to aryne generates the aryl anion intermediate, which was trapped by the aldehyde 74 to afford the key fragment 75. Subsequently, they applied the four-component coupling involving arynes in the total synthesis of Dehydroaltenuene B.60b

Scheme 42 Three-component coupling route to ent-clavilactone B (Barrett et al.).60

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Besides the methods discussed above, arynes are also employed for various other carbon–carbon and carbon– heteroatom bond-forming reactions. In 2008, Stoltz and co-workers developed an efficient method for the synthesis of indolines and isoquinolines by the reaction of arynes with N-acyl dehydroamino esters (Scheme 43).61a With N-carbamoyl dehydroalanine esters 76, the nitrogen-centred addition of 76 to arynes generates the aryl anion intermediate 77, which cyclizes to the indoline. The overall process is a formal [3+2] cycloaddition. With N-acyl enamides 78, the reaction afforded the isoquinoline derivatives proceeding via a formal [4+2] cycloaddition. The reaction is initiated by the enaminetype addition of 78 to aryne generating the aryl anion intermediate 79, which cyclizes to the isoquinoline. In addition, they applied this methodology to the total synthesis of opiate alkaloid papaverine and tetrahydroisoquinoline antitumour antibiotic ()-quinocarcin.61b The reaction of arynes with 2-azidoacrylates in the presence of PPh3 resulted in the formation of indole derivatives in good yields (Scheme 44).62 The reaction involves the formation of iminophosphorane 80 by the addition of PPh3 to 2-azidoacrylates and a subsequent cyclization affords the intermediate 81, which on hydrolysis followed by air-oxidation results in the formation of an indole derivative. Additionally, an efficient method for the addition of arynes to iodonium ylide leading to the formation of benzofurans was developed by Liang, Li and

Scheme 43 Synthesis of indolines and isoquinolines via aryne annulations.61

Scheme 44 Indole formation from arynes and 2-azidoacrylates.62

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Scheme 45 Benzofurans synthesis from arynes and iodonium ylides.63

co-workers (Scheme 45).63 The reaction proceeds via the addition of iodonium ylide 82 to arynes generating the alkoxy ylide 83, which undergoes intramolecular cyclization followed by release of iodobenzene affording the product.

Conclusions This tutorial review exposes the rich and fascinating chemistry of arynes, especially from the standpoint of transition-metalfree carbon–carbon and carbon–heteroatom bond-forming reactions. Arynes have found multitude of applications in pericyclic reactions, insertion reactions and multicomponent reactions. Some of these reactions result in the formation of valuable heterocycles with interesting biological activity. Thus, arynes have developed from being laboratory curiosities to efficient synthetic tools in organic chemistry. However, many aspects of the chemistry of these reactive intermediates are not well understood yet. Further developments in this area will provide a deeper understanding of the mechanism of many of these transformations and the application of arynes in enantioselective transformations. It is reasonable to believe that the aryne chemistry will continue to flourish and lead to surprising developments in the years to come.

Acknowledgements Generous financial support from CSIR-NCL in the form of a start-up grant for a new faculty is kindly acknowledged. AB and SRY would like to thank CSIR-New Delhi for the award of Junior Research Fellowship. We are grateful to Dr Vijay Nair, Raja Ramanna Fellow, Organic Chemistry Section, CSIR-NIIST for careful proof-reading of the manuscript and for providing insightful comments.

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