Employing Arynes in DielsâAlder Reactions and Transition-Metal-Free

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Employing Arynes in Diels−Alder Reactions and Transition-MetalFree Multicomponent Coupling and Arylation Reactions Sachin Suresh Bhojgude, Anup Bhunia, and Akkattu T. Biju* Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune-411008, Maharashtra, India CONSPECTUS: Arynes are highly reactive intermediates having several applications in organic synthesis for the construction of various ortho-disubstituted arenes. Traditionally, arynes are generated in solution from haloarenes under strongly basic conditions. However, the scopes of many of the aryne reactions are limited because of the harsh conditions used for their generation. The renaissance of interest in aryne chemistry is mainly due to the mild conditions for their generation by the fluorideinduced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. This Account is focused on the Diels−Alder reaction of arynes and their transition-metal-free application in multicomponent couplings as well as arylation reactions. The Diels−Alder reaction of arynes is a powerful tool for constructing benzo-fused carbocycles and heterocycles. In 2012, we developed an efficient, broad-scope, and scalable Diels−Alder reaction of pentafulvenes with arynes affording benzonorbornadiene derivatives. Subsequently, we accomplished the Diels−Alder reaction of arynes with dienes such as 1,2-benzoquinones and tropones. Moreover, we uncovered a transition-metal-free protocol for the synthesis of 9,10-dihydrophenanthrenes by the reaction of arynes with styrenes that proceeds via a Diels−Alder/ene-reaction cascade. In addition, we demonstrated the reaction of arynes with indene/benzofurans, which proceeds via a tandem [4 + 2]/[2 + 2] sequence. Multicomponent coupling (MCC) involving arynes mainly comprises the initial addition of a nucleophile to the aryne followed by interception of the aryl anion intermediate with an electrophile (provided the nucleophilic and electrophilic moieties do not belong to the same molecule). We have disclosed aryne MCCs initiated by N-heterocycles such as (iso)quinoline, pyridine, and aziridines. When (iso)quinoline is used as the nucleophilic trigger and N-substituted isatin as the third component, the reaction affords spirooxazino(iso)quinolines via 1,4-dipolar intermediates. Unexpectedly, using pyridine affords indolin-2-ones, where the reaction proceeds via the pyridylidene intermediate. Additionally, we developed the phosphine-triggered aryne MCCs for the synthesis of functionalized benzooxaphospholes. In another phase of our work, we studied the synthetic utility of CO2 as a onecarbon synthon in aryne MCCs for the synthesis of phthalimides. Engaging arynes as an aryl source is one of the transition-metal-free methods for arylation reactions. We have demonstrated the N-arylation of aromatic tertiary amines and O-arylation of aliphatic alcohols using arynes. It is anticipated that the chemistry of arynes will continue to prosper and will lead to surprising developments for the synthesis of various 1,2-disubstituted arenes of molecular complexity and structural diversity. Future challenges in this area include the utility of arynes in enantioselective transformations and the synthesis and reactions of exotic heterocyclic arynes.

1. INTRODUCTION Aryne chemistry has witnessed a resurgence of interest in the last three decades for the synthesis of various 1,2-disubstituted benzenes.1 Employing arynes is a convenient method for double functionalization of arenes and the synthesis of benzofused heterocycles.2 The existence of these highly reactive intermediates was speculated in 1902 by Stoermer and Kahlert3 in the reaction of 3-bromobenzofuran to 2-ethoxybenzofuran under basic conditions, and the reaction was assumed to proceed via the 2,3-didehydrobenzofuran intermediate. However, arynes were proposed as intermediates in the reaction of fluorobenzene with phenyllithium by Wittig only in 1942.4 Later, Roberts and co-workers in 1953 confirmed the structure by treating potassium amide with 14C-labeled chlorobenzene.5 Because of the installation of the carbon−carbon triple bond in a six-membered ring, compared with normal alkynes, the © XXXX American Chemical Society

unhybridized p orbitals in arynes are no longer parallel to each other. The high reactivity of arynes is due to this ring strain. Consequently, arynes are useful as valuable intermediates for the functionalization of arenes. The important transition-metal-free reactions of arynes include cycloaddition reactions, multicomponent couplings (MCCs), and insertion reactions. Arynes are excellent electrophiles in pericyclic reactions, including Diels−Alder reactions, [2 + 2] cycloaddition reactions, and dipolar cycloaddition reactions, because of the presence of the highly electrophilic carbon−carbon triple bond. Moreover, because of the low-lying lowest unoccupied molecular orbital (LUMO) of arynes, various nucleophiles such as isocyanides, N-heterocycles, and Received: April 18, 2016

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DOI: 10.1021/acs.accounts.6b00188 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

aryne generation has substantially developed this field for enhancing the yield as well as expanding the scope of many of the classical aryne reactions and uncovering new aryne reactions. Another recent method for the generation of arynes involves intramolecular cycloaddition of triynes, which proceeds via a hexadehydro Diels−Alder reaction developed by Hoye and co-workers (eq 4).10 The inter- and intramolecular interception of arynes generated using this method can afford complex benzo-fused compounds. In a single operation, aryne chemistry can be utilized for the rapid construction of molecular complexity through the formation of multiple carbon−carbon and carbon−heteroatom bonds in a selective manner. With the advent of mild methods for aryne generation, various substituted arynes9 and even heterocyclic arynes are accessible.11 The applications of arynes in Diels−Alder reactions, MCCs, and arylation reactions developed in our laboratory are presented in the following sections.

phosphines can add to arynes, and the resultant aryl anion intermediates can be trapped by an electrophilic third component, resulting in MCCs.6 Additionally, a convenient method for direct access to various 1,2-disubstituted benzenes is possible by the insertion of arynes into element−element bonds.7 In addition, arynes undergo several transition-metalcatalyzed transformations. The purpose of this Account is to describe recent developments in our laboratory (after 2011) in transition-metal-free aryne reactions for the construction of carbon−carbon and carbon−heteroatom bonds, but adequate explanation of closely related work carried out by others in the last four years is also given. Because of their high reactivity, arynes are not isolable, and they have to be generated in situ in solution. Arynes are traditionally generated by the action of strong bases such as sodium amide on aromatic halides (Scheme 1, eq 1). Scheme 1. Methods for the Generation of Arynes

2. DIELS−ALDER REACTION OF ARYNES The Diels−Alder reaction involving arynes is a convenient protocol for the construction of benzo-fused carbocycles and heterocycles and is also used as a tool to detect aryne generation. Because of their low-lying LUMO, arynes add to various dienes. Moreover, the aryne Diels−Alder reaction can be employed in tandem reactions by combination with other intermolecular processes. To enhance the yield and scope of many of the traditional aryne reactions, these reactions have been revisited using Kobayashi’s procedure for aryne generation. Since the first report on the Diels−Alder reaction of benzyne with furan,12 the electrophilic carbon−carbon triple bond of arynes has been widely used as a dienophile component to react with various dienes in Diels−Alder reactions. Interesting olefins such as pentafulvenes, 1,2benzoquinones, tropones, styrenes, indene, benzofurans, etc. have been utilized in aryne Diels−Alder reactions with limited success. However, the yields are only moderate, and the substrate scope is very narrow (Figure 1). A systematic study of

Intriguingly, the harsh conditions are not suitable for basesensitive substrates. Additionally, the decomposition of benzenediazonium 2-carboxylates (derived from the aprotic diazotization of anthranilic acids) can generate arynes in solution by the liberation of nitrogen and carbon dioxide (eq 2).8 A serious drawback of this method is the explosive nature of diazonium compounds. In 1983, Kobayashi and co-workers demonstrated a mild and efficient method for aryne generation by the fluoride-triggered 1,2-elimination of 2-(trimethylsilyl)aryl triflates (eq 3).9 A wide variety of base-sensitive functional groups are well-tolerated under these conditions. Aryne generation from 1 can be accomplished using KF (with 18crown-6 as an additive) in THF, CsF in CH3CN, and tetrabutylammonium fluoride (TBAF) in THF. Moreover, the rate of aryne generation can be controlled by careful selection of the fluoride source and solvent. The introduction of 1 for

Figure 1. Interesting dienes for aryne Diels−Alder reactions.

aryne Diels−Alder reactions with these challenging dienes has been performed with a view to develop a practical, scalable, and high-yielding synthesis of complex benzo-fused compounds. 2.1. Diels−Alder Reaction of Arynes with Pentafulvenes

Pentafulvenes act as either 2π, 4π, or 6π components in cycloaddition reactions.13 The Diels−Alder reaction of pentafulvenes with arynes generated using traditional methods, leading to the synthesis of benzonorbornadienes, was reported by Muneyuki and Tanida as early as 1966.14 However, the scope of this reaction is limited, and the product yields are not optimal. To address the limitations of this reaction, we carried B


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Accounts of Chemical Research Table 1. Diels−Alder Reactions of Pentafulvenes with Arynes15

out the reaction of pentafulvenes with arynes generated from triflates 1. The reaction of 6-monosubstituted pentafulvenes 2 with arynes generated from 1 in the presence of CsF in CH3CN afforded benzonorbornadienes 3 in excellent yields (Table 1).15 The reaction worked well with electron-releasing and -withdrawing groups at the 6-aryl moiety, and heteroaromatic and alkyl functionalities were well-tolerated. Moreover, 6,6-disubstituted pentafulvenes 4 also underwent smooth cycloaddition reactions furnishing the desired cycloadducts 5 in excellent yields. These reactions were found to be scalable and worked well under mild conditions.

Table 2. Diels−Alder Reactions of 1,2-Benzoquinones with Arynes18

2.2. Diels−Alder Reaction of Arynes with 1,2-Benzoquinones

1,2-Benzoquinones offer multiple reactive sites in Diels−Alder reactions.16 They can act as either carbodienes, heterodienes, carbodienophiles, or heterodienophiles. Despite the widespread application of 1,2-benzoquinones as a 4π component in Diels− Alder reactions, there is only one report on the Diels−Alder reaction of arynes with 1,2-benzoquinones.17 The narrow scope and low yield of this transformation prompted us to investigate the aryne Diels−Alder reaction with 1,2-benzoquinones. The reaction of 1,2-benzoquinones 6 with arynes generated from triflate 1 using KF and 18-crown-6 furnished dioxobenzobicyclooctadienes 7 in moderate to excellent yields (Table 2).18 Several substituted benzoquinones and a variety of (un)symmetrical arynes underwent smooth Diels−Alder reaction under the optimized conditions. The high selectivity for the carbodiene reactivity of 6 in aryne Diels−Alder reactions needs further investigation. The dioxobenzobicyclooctadienes are valuable scaffolds and are found to be amenable to further synthetic transformations in one-pot operations. The one-pot, two-step procedure involving the reaction of 6 with 1 and a subsequent addition of 1,2-phenylenediamine afforded benzoquinoxalinobarrelenes

8 in good yields (Scheme 2, eq 5). Moreover, generation of cycloadducts 7 in solution followed by irradiation at 254 nm furnished naphthalenes 9 in one pot (eq 6). 2.3. Diels−Alder Reaction of Arynes with Tropones

Tropones exhibit different reactivity profiles in pericyclic reactions. They react as 4π, 6π, or 8π components in cycloaddition reactions, and a specific mode of action depends on the coupling partner and reaction conditions. The Diels− Alder reaction of tropones, engaging them as 4π components, can result in the synthesis of intriguing bicyclo[3.2.2] systems. Surprisingly, the Diels−Alder reaction of tropones with arynes has received only limited attention. In 1967, Kende and coC


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Accounts of Chemical Research Scheme 2. One-Pot Synthesis of Benzoquinoxalinobarrelenes and Naphthalenes18

Table 4. Cascade Diels−Alder/Ene Sequence Involving Arynes and Styrenes22

workers reported an aryne Diels−Alder reaction with tropones affording the cycloadduct in 40% yield.19 We have carried out the reaction of tropones with arynes generated from triflate 1. The reaction of tropones 10 with 1 in the presence of CsF resulted in the synthesis of benzobicyclo[3.2.2]nonatrienones 11 in good yields (Table 3).20 Notably, the reaction took place

molecules of aryne, whereas electron-poor styrenes afford the dihydrophenanthrenes. Mild conditions, broad scope, and high selectivity for dihydrophenanthrene formation are the notable features of this reaction. The formation of 9-aryldihydrophenanthrenes from styrenes and arynes can be rationalized by the initial Diels−Alder reaction of styrene with the aryne generated from 1 to form cycloadduct 14 followed by a concerted ene reaction with a second molecule of aryne (Scheme 3). Moreover, a stepwise

Table 3. Diels−Alder Reactions of Tropones with Arynes20

Scheme 3. Proposed Mechanism of the Reaction of Styrenes with Arynes

under mild conditions and was found to be scalable. With tropone as the 4π component, the reaction worked well with various symmetrical and unsymmetrical aryne precursors. Moreover, 2-substituted tropones reacted with arynes to form mixtures of regioisomeric cylcoadducts (11 and 11′). Interestingly, tropolone also afforded the cycloadduct in 55% yield upon reaction with benzyne.

pathway proceeding via deprotonation of 14 followed by nucleophilic attack of another molecule of aryne to generate aryl anion 15 with subsequent protonation can also be invoked. 2.5. Reaction of Arynes with Indene/Benzofurans

With a view to inhibit the Diels−Alder/ene cascade pathway, aryne reactions have been performed using indene and benzofurans. Surprisingly, treatment of arynes with indene/ benzofurans 16 afforded dihydrobenzocyclobutaphenanthrenes 17 in moderate to good yields (Table 5).23 This reaction proceeds via the initial Diels−Alder reaction of arynes generated from 1 using CsF and 16 to generate the cycloadducts 18, which undergo a stereoselective [2 + 2] cycloaddition to afford 17. A variety of substituted arynes and several benzofurans underwent efficient tandem reaction to furnish the desired products. Moreover, this method was utilized for the one-pot synthesis of benzo[b]fluoranthene, which is a potent carcinogenic pentacyclic hydrocarbon.

2.4. Reaction of Arynes with Styrenes

Styrenes are used as 4π components in Diels−Alder reactions by employing a carbon−carbon double bond that is involved in aromaticity. The Diels−Alder reaction of styrene with arynes was known as early as 1966, but the reaction suffers from poor yields, limited scope, and the formation of side products.21 We found that the reaction of styrenes 12 with arynes generated from 1 using CsF in CH3CN afforded 9-aryldihydrophenanthrene derivatives 13 in moderate to good yields (Table 4).22 Electron-rich and -neutral styrenes react with arynes to form 9aryldihydrophenanthrenes by the incorporation of two D


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Accounts of Chemical Research 2.6. Miscellaneous Aryne Diels−Alder Reactions

Table 5. Tandem [4 + 2]/[2 + 2] Cycloaddition Involving Arynes and Indene/Benzofurans23

The Diels−Alder reaction of arynes with methyleneindolinones as diene components was reported by Li, Jia, and co-workers.24 Arynes generated from 1 using CsF reacted with isatilidenes 19 to form naphtho-fused oxindoles 20 in moderate to good yields (Scheme 4, eq 7). The reaction proceeds via [4 + 2] cycloaddition followed by isomerization and dehydrogenation. Moreover, Liu and co-workers developed the reaction of arynes with functionalized benzylidenephthalans 21 leading to the synthesis of phenanthro[10,1-bc]furans 22, which proceeds via the Diels−Alder reaction between 21 and arynes generated from 1 using CsF followed by nucleophilic addition of the cycloadduct to another molecule of aryne (eq 8).25 Additionally, the reaction of arynes with 3-alkenylindoles 23 to furnish benzo[a]carbazole-5-carboxylates 24 was recently disclosed by Wu, Sha, and co-workers (eq 9).26 The reaction worked well with various substituents on the 3-alkenylindole, and even Nunprotected indoles are well-tolerated. Furthermore, the monoselective Diels−Alder reaction of the aryne generated from bis(aryne) precursor 25 with perylene to form triflate 26 was recently accomplished by Peña and co-workers (eq 10).27 Pd-catalyzed [2 + 2 + 2] cycloaddition of the aryne generated from triflate 26 using CsF afforded threefold-symmetric 22-ring aromatic hydrocarbon 27 in 46% yield.

Scheme 4. Miscellaneous Aryne Diels−Alder Reactions

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Table 7. MCCs Using Arynes, Isocyanides, and H2O29

3. MCCS INVOLVING ARYNES MCCs involving arynes result when a nucleophile adds to an aryne to generate the aryl anion intermediate, which is intercepted by an electrophilic third component (Scheme 5).6 Scheme 5. Aryne Multicomponent Coupling

This is one of the transition-metal-free methods to access complex 1,2-disubstituted benzenes. The commonly used nucleophilic triggers in aryne MCCs are isocyanides, amines, imines, and solvents such as DMF, THF, and DMSO, and the electrophilic partners usually used are carbonyls, including CO2. Scheme 6. Proposed Mechanism of the Reaction of Arynes and Isocyanides with CO2/H2O29

3.1. Isocyanide-Triggered Aryne MCCs Using CO2/H2O as a Third Component

Isocyanides are frequently used nucleophilic initiators in aryne MCCs. The aryne MCCs induced by isocyanides are utilized for the construction of benzo-fused carbocycles and heterocycles such as iminoisobenzofurans, iminoindenones, highly substituted pyridines and isoquinolines, etc.28 We have developed aryne MCCs triggered by isocyanides by utilizing CO2/H2O as the third component. When CO2 is used as the third component, the reaction furnishes N-substituted phthalimides 28 (Table 6).29 The product formation takes Table 6. Aryne MCCs Using CO2 Triggered by Isocyanides29

3.2. Aryne MCCs Triggered by N-Heterocycles

The application of N-heterocycles such as pyridine and (iso)quinoline in aryne MCCs was disclosed by the Cheng group in 2006.32 The reaction of N-heterocycles with arynes and nitriles bearing an α-hydrogen affords 2-aryl isoquinoline derivatives 32 in good yields (Scheme 7). Notably, nitriles act Scheme 7. Aryne MCCs Triggered by Heterocycles

place via the formation of two new C−C bonds and a new C− N bond. Moreover, a transition-metal-free route to benzamides 29 is possible when H2O is used as the third component (Table 7).30 Notably, Yoshida, Kunai, and co-workers demonstrated the synthetic utility of CO2 as a one-carbon source in aryne MCCs using amines and imines as the nucleophilic trigger.31 The proposed mechanism for the formation of phthalimides and benzamides is shown in Scheme 6. The addition of the isocyanide to the aryne generates the 1,3-zwitterionic intermediate 30, which can add to CO2 in a concerted pathway or in a stepwise manner to generate isoimide 31. The fluorideinduced rearrangement of 31 can afford the phthalimide 28. In the presence of H2O, protonation of 30 followed by nucleophilic attack of hydroxide anion can result in the formation of the benzamide 29.

as the solvent as well as the third component. The 1,4zwitterionic intermediate 33 initially formed from the isoquinoline and aryne is protonated by the nitrile, thus forming isoquinolinium salt 34. Nucleophilic attack of the nitrile anion on 34 affords the product 32. Moreover, they used terminal alkynes and methyl ketones as the third component in aryne MCCs triggered by N-heterocycles. We envisioned the interception of the N-heterocycle−aryne zwitterion with an electrophilic third component with a view to F


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Accounts of Chemical Research Table 8. MCCs Using Arynes, Isoquinolines, and Isatins33

the synthesis of complex heterocycles. Gratifyingly, the reaction of isoquinolines 35 and N-substituted isatins 36 with arynes generated from 1 using KF and 18-crown-6 afforded spirooxazinoisoquinoline derivatives 37 as inseparable mixtures of diastereomers in good yields with moderate to good dr (Table 8).33 Various N-substituted isatins and electronically different arynes were well-tolerated. Moreover, quinoline was also used as the nucleophilic trigger and trifluoroacetophenone was used as the electrophilic carbonyl component. Subsequently, we employed various carbonyl compounds in this aryne MCC triggered by N-heterocycles. Treatment of (iso)quinoline and aryne with various aldehydes afforded benzoxazino(iso)quinoline derivatives 38 in good yields and diastereoselectivity.34 Under the optimized reaction conditions, the (iso)quinoline−aryne zwitterion was intercepted with several aldehydes (Table 9). Additionally, ketones such as 1,4-benzoquinone, benzophenone, benzil, and α-keto esters were used as carbonyl surrogates in this reaction.35 A plausible mechanism of the aryne MCCs using carbonyls triggered by (iso)quinoline is shown in Scheme 8. The 1,4zwitterionic intermediate 33 generated from the aryne and isoquinoline can add to the CO bond of the ketone to afford oxazinoisoquinoline derivative 38 in a concerted pathway.

Scheme 8. Mechanism of Aryne MCCs with (Iso)quinoline and Carbonyls33,34

Alternatively, 33 can add to the carbonyl in a stepwise manner to generate intermediate 39, which cyclizes to furnish 38. Encouraged by the aryne MCCs triggered by (iso)quinolines, we then focused our attention on pyridine as the nucleophile, anticipating the synthesis of pyridooxazino derivatives. Surprisingly, treatment of pyridines and N-substituted isatins 36 with arynes generated from 1 using KF and 18-crown-6 afforded indolin-2-ones 40 instead of pyridooxazino derivatives (Table 10).33 Interestingly, a simultaneous heteroarylation Table 10. MCCs Using Arynes, Pyridines, and Isatins33

Table 9. MCCs Using Arynes, (Iso)quinolines, and Carbonyls34

followed by an arylation of isatin took place via an uncommon C−H functionalization of pyridine and an intramolecular aryl transfer. Electronically different isatins readily underwent this transformation to afford the 3,3-disubstituted oxindoles 40. On the basis of several mechanistic experiments,33 we have proposed a mechanism for the pyridine-triggered aryne MCCs (Scheme 9). Addition of the pyridine to the aryne generates 1,4-zwitterionic intermediate 41. An intramolecular proton transfer in intermediate 41 generates the highly nucleophilic G


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Accounts of Chemical Research Scheme 9. Mechanism of Pyridine-Triggered Aryne MCCs33

Table 11. MCCs Involving Aziridines/Azetidines, Arynes, and Carboxylic Acids38

pyridylidene intermediate 42. The generation of the carbene intermediate 42 was confirmed by a sulfur quenching experiment, and the insight on the intramolecular proton transfer came from the reaction using pyridine-d5. Addition of nucleophilic carbene 42 to the isatin derivative forms tetrahedral intermediate 43. The desired indolin-2-one 40 is formed by an intramolecular nucleophilic aromatic substitution (SNAr) reaction via σ-complex intermediate 44. It is likely that the conversion of 43 to 40 takes place via the Smiles rearrangement. It may be noted that Rodriguez, Coquerel, and co-workers disclosed closely related results on pyridinetriggered aryne MCCs using isatins as the third component.36 The synthetic utility of aziridines as a nucleophilic trigger in aryne MCCs was demonstrated by Larionov and co-workers in 2013.37 The use of CH3CN as the solvent and third component afforded N-aryl-γ-aminobutyronitriles 45 in good yields (Scheme 10). The reaction proceeds via the generation of aziridine−aryne zwitterion 46.

Table 12. MCCs Involving Aziridines, Arynes, and Water39

Scheme 10. Aryne MCCs Triggered by Aziridines

protocol constitutes a transition-metal-free synthesis of these molecules using arynes as the aryl source. Mechanistically, these reactions proceed via initial nucleophilic addition of the aziridine to the aryne to generate zwitterion 46, which is subsequently protonated by carboxylic acid or TFA/H2O to form quaternary ammonium salt 50 and the carboxylate or trifluoroacetate anion (Scheme 11). Nucleophilic attack of the conjugate base of the corresponding acid on intermediate 50 results in ring opening to afford N-arylβ-amino alcohol acyl derivative 48. Only the trifluoroacetyl derivative of N-aryl-β-amino alcohols underwent hydrolysis under the reaction conditions to give N-aryl β-amino alcohols 49, while other acyl derivatives were stable. Intriguingly, aryne three-component coupling triggered by electron-deficient aziridines 51 with aldehydes as the third component resulted in the formation of trisubstituted N-aryl-αamino epoxides 52 in moderate to good yields and diastereoselectivity (Table 13).40 α-Amino epoxides are key

We envisioned that the interception of 46 with carboxylic acids could result in functionalized amino alcohol derivatives. Gratifyingly, the three-component coupling involving Nsubstituted aziridines/azetidines 47, arynes, and carboxylic acids furnished N-aryl-β/γ-amino alcohol derivatives 48 under mild conditions (Table 11).38 These reactions afforded the products in good yields with broad substrate scope and resulted in the formation of two new carbon−nitrogen and carbon− oxygen bonds. In addition to carboxylic acids as the third component, phenols are also successfully employed as acid surrogates in this MCC. Interestingly, the use of water as the third component in the aziridine/azetidine-triggered MCCs promoted by trifluoroacetic acid (TFA) directly afforded N-aryl-β/γ-amino alcohols 49 in moderate to good yields (Table 12).39 Notably, N-aryl-β-amino alcohols are medicinally important scaffolds, and the present H


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phosphonium salts thereof were demonstrated by Wittig and co-workers as early as 1970.41 Recently Jugé and co-workers utilized triflate precursor 1 for aryne generation, and the scope of this reaction was expanded for the synthesis of valuable Pstereogenic phosphonium triflates (Scheme 13).42 However, the utility of the aryne−phosphine zwitterion in MCCs for the construction of phosphorus heterocycles remained untapped until recently.

Scheme 11. Mechanism of Aziridine/Azetidine-Triggered Aryne MCCs38,39

Scheme 13. Formation of Phosphonium Triflates from Arynes and Phosphines Table 13. Three-Component Coupling Involving Arynes, Aziridines, and Carbonyls40

We have demonstrated highly efficient and mild phosphinetriggered aryne MCCs using aldehydes as the third component. The reaction affords functionalized benzooxaphospholes 56 in moderate to excellent yields (Table 14).43 The reaction Table 14. MCCs Involving Phosphines, Arynes, and Aldehydes43

building blocks for the synthesis of amino sugars and polyoxygenated α-amino acids. The present transition-metalfree three-component coupling allows straightforward access to these scaffolds in a single step under mild reaction conditions. Moreover, we explored the scope of this aziridine-triggered MCC with N-substituted isatins as the third component, resulting in the formation of spiroepoxy oxindoles. Mechanistically, this reaction proceeds via the generation of cyclic nitrogen ylide intermediate 54 formed by intramolecular proton transfer in aziridine−aryne zwitterion 53 (Scheme 12). The presence of an electron-withdrawing group on the aziridine is crucial for the generation of strained aziridinium ylide 54, which adds to the aldehyde to generate alkoxide intermediate 55. Subsequent ring opening of the aziridinium species by alkoxide furnishes 52.

proceeds via a formal [3 + 2] cycloaddition of the initially generated phosphine−aryne zwitterion with the carbonyl moiety of the aldehyde. A wide variety of aldehydes, symmetrical and unsymmetrical arynes, and several alkyl and aryl phosphines are well-tolerated under the optimized reaction conditions. The reaction using triphenylarsine (instead of phosphine) as the nucleophilic trigger did not afford the corresponding

3.3. Phosphine-Triggered Aryne MCCs

The generation of phosphine−aryne zwitterions by the reaction of triarylphosphines with arynes and the synthesis of the Scheme 12. Mechanism of the Formation of Amino Epoxides40

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intermediate 59 initially generated from the phosphine and aryne could undergo a formal [3 + 2] cycloaddition reaction with the carbonyl group of the aldehyde/ketone, resulting in the formation of benzooxaphosphole 56 or 58. The expected product can also be formed by a stepwise pathway proceeding through alkoxide intermediate 60.

annulation product. Surprisingly, this reaction afforded arsonium triflate 57 in 52% yield (Scheme 14). Scheme 14. Synthesis of Arsonium Triflates from Arynes and Arsines43

3.4. Aryne MCCs Initiated by Aromatic Tertiary Amines

In 2007, Yoshida and co-workers reported aryne MCCs triggered by silyl-protected amines in which either aldehydes or activated imines were employed as the third component.45 The use of protected amines excluded the possibility of Narylation. Apart from the work of the Yoshida group, the use of tertiary amines as the nucleophilic trigger in aryne MCCs has received limited attention. We have recently reported MCCs involving arynes, aldehydes, and aromatic tertiary amines 61 leading to the rapid construction of 2-functionalized tertiary amines 62 (Table 16).46 This tandem three-bond-forming

Moreover, we found that the phosphine-triggered aryne MCCs are not limited to aldehydes as the third component. Various activated ketones such as trifluoroacetophenone, diaryl 1,2-diones, α-keto esters, and β,γ-unsaturated α-keto esters can be used as the third component in this reaction to afford benzooxaphospholes 58 in moderate to good yield (Table 15).44 Additionally, N-substituted isatins can also be used as the

Table 16. MCCs Involving Arynes, Carbonyls, and Tertiary Amines46

Table 15. MCCs Involving Phosphines, Arynes, and Acyclic and Cyclic Ketones44

electrophilic component in these MCCs, giving rapid access to spirobenzooxaphospholes. In all cases, variation of the three components is easily possible, demonstrating the versatility of the present reaction. A proposed mechanism of the phosphine-triggered aryne MCCs is shown in Scheme 15. The 1,3-zwitterionic

process proceeds via aryl-to-aryl amino group migration, which is mechanistically similar to the Smiles rearrangement. The reaction is not limited only to aldehydes, as various cyclic and acyclic ketones also efficiently engaged as the third component in the present method. Mechanistically, the aryne−amine zwitterion 63 adds to the electrophilic carbonyl group, generating the key tetrahedral intermediate 64. Intermediate 64 in the absence of a proton source can undergo an SNAr reaction followed by aryl-to-aryl migration of the NMe2 group to furnish the desired product 62 via σ complex 65, resembling the Smiles rearrangement.

Scheme 15. Mechanism of Phosphine-Triggered Aryne MCCs43,44

4. ARYLATION USING ARYNES In 2003, Liu and Larock47 demonstrated the arylation of primary/secondary amines using arynes as the aryl source via J


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In 2004, Liu and Larock47b,49 reported a mild method for the O-arylation of phenols and aryl carboxylic acids using arynes for the synthesis of diaryl ethers and aryl esters. However, this method was not applicable to aliphatic alcohols. Considering the importance of installing the alkoxy group directly on the aromatic ring, we have developed a temperature-dependent and switchable reaction of arynes with aliphatic alcohols in THF solvent for the synthesis of alkyl aryl ethers. At −20 °C, the aryne smoothly inserts into the O−H bond of the alcohol to form alkyl aryl ether 67 (Table 18).50 Interestingly, at 60 °C, highly selective multicomponent coupling occurs with the THF solvent acting as the nucleophilic trigger, affording (4(alkoxy)butoxy)arenes 68. Both reactions tolerate a broad range of functional groups, and the desired products are formed in moderate to good yields with high selectivities.

N−H insertion reactions. However, this protocol was not applicable to the arylation of tertiary amines. In 2013, we reported the highly monoselective N-arylation of aromatic tertiary amines using arynes to form various diarylamines.48 A series of aromatic tertiary amines were smoothly arylated under the optimized conditions (Table 17). This method was Table 17. N-Arylation of Tertiary Amines Using Arynes48

5. CONCLUSION This Account has outlined the rich potential of arynes in Diels−Alder reactions and transition-metal-free multicomponent coupling and arylation reactions. We have developed aryne Diels−Alder reactions with potential diene systems such as pentafulvenes, 1,2-benzoquinones, tropones, styrenes, and indene/benzofurans. Moreover, transition-metal-free aryne MCCs using N-heterocycles and phosphines as nucleophilic triggers have been uncovered. In addition, N-arylation of tertiary amines and O-arylation of aliphatic alcohols have been demonstrated. The mild and operationally simple aryne reactions presented in this Account are expected to find potential applications in organic chemistry. Further developments in aryne Diels−Alder reactions may be directed toward the synthesis of valuable polycyclic hydrocarbons with potential material applications.1c,27 In addition, exploration of arynes in

applicable to various halogen-containing substrates, dyes, and donor−acceptor systems. Mechanistic studies indicated the role of the fluoride source and the basic medium in the demethylation step leading to 66.

Table 18. Temperature-Dependent Reaction of Arynes with Aliphatic Alcohols50

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brovskiy, A. V.; Markina, N. A.; Larock, R. C. Use of Benzynes for the Synthesis of Heterocycles. Org. Biomol. Chem. 2013, 11, 191−218. (3) Stoermer, R.; Kahlert, B. Ueber das 1- und 2-Brom-cumaron. Ber. Dtsch. Chem. Ges. 1902, 35, 1633−1640. (4) Wittig, G. Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen. Naturwissenschaften 1942, 30, 696− 703. (5) Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. Rearrangement in the Reaction of Chlorobenzene-1-C14 with Potassium Amide. J. Am. Chem. Soc. 1953, 75, 3290−3291. (6) (a) Bhunia, A.; Biju, A. T. Employing Arynes in Transition-MetalFree, N-Heterocycle-Initiated Multicomponent Reactions. Synlett 2014, 25, 608−614. (b) Bhojgude, S. S.; Biju, A. T. Arynes in Transition-Metal-Free Multicomponent Coupling Reactions. Angew. Chem., Int. Ed. 2012, 51, 1520−1522. (7) (a) Yoshida, H.; Takaki, K. Aryne Insertion Reactions into Carbon-Carbon σ-Bonds. Synlett 2012, 23, 1725−1732. (b) Peña, D.; Pérez, D.; Guitián, E. Insertion of Arynes into σ-Bonds. Angew. Chem., Int. Ed. 2006, 45, 3579−3581. (8) Friedman, L.; Logullo, F. M. Benzynes via Aprotic Diazotization of Anthranilic Acids: A Convenient Synthesis of Triptycene and Derivatives. J. Am. Chem. Soc. 1963, 85, 1549−1549. (9) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-Induced 1,2Elimination of o-Trimethylsilylphenyl Triflate to Benzyne Under Mild Conditions. Chem. Lett. 1983, 1211−1214. (10) (a) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. The Hexadehydro-Diels−Alder Reaction. Nature 2012, 490, 208−212. (11) Goetz, A. E.; Garg, N. K. Regioselective Reactions of 3,4Pyridynes Enabled by the Aryne Distortion Model. Nat. Chem. 2013, 5, 54−60. (12) Wittig, G.; Pohmer, L. Ü ber das intermediäre Auftreten von Dehydrobenzol. Chem. Ber. 1956, 89, 1334−1351. (13) Bergmann, E. D. Fulvenes and Substituted Fulvenes. Chem. Rev. 1968, 68, 41−84. (14) Muneyuki, R.; Tanida, R. Cycloaddition of 6,6-Dimethylfulvene with Benzynes. J. Org. Chem. 1966, 31, 1988−1990. (15) Bhojgude, S. S.; Kaicharla, T.; Bhunia, A.; Biju, A. T. A Practical and General Diels−Alder Reaction of Pentafulvenes with Arynes. Org. Lett. 2012, 14, 4098−4101. (16) Nair, V.; Menon, R. S.; Biju, A. T.; Abhilash, K. G. 1,2Benzoquinones in Diels−Alder Reactions, Dipolar Cycloadditions, Nucleophilic Additions, Multicomponent Reactions and More. Chem. Soc. Rev. 2012, 41, 1050−1059. (17) Ried, W.; Eng, J. T. S. Reaktionen mit DiazocarbonylVerbindungen, XXXIV: o-Chinonediazide und o-Chinone als Dehydrobenzol-Fänger. Justus Liebigs Ann. Chem. 1969, 727, 219−221. (18) Kaicharla, T.; Bhojgude, S. S.; Biju, A. T. Efficient Diels−Alder Reaction of 1,2-Benzoquinones with Arynes and Its Utility in One-Pot Reactions. Org. Lett. 2012, 14, 6238−6241. (19) Ciabattoni, J.; Crowley, J. E.; Kende, A. S. Reaction of Tropone with Benzyne. Formation and Photoisomerization of 6,7Benzobicyclo[3.2.2]nona-3,6,8-trien-2-one. J. Am. Chem. Soc. 1967, 89, 2778−2779. (20) Thangaraj, M.; Bhojgude, S. S.; Bisht, R. H.; Gonnade, R. G.; Biju, A. T. Diels−Alder Reaction of Tropones with Arynes: Synthesis of Functionalized Benzobicyclo[3.2.2] nonatrienones. J. Org. Chem. 2014, 79, 4757−4762. (21) Dilling, W. L. The Reaction of Benzyne with Styrene. Tetrahedron Lett. 1966, 7, 939−941. (22) Bhojgude, S. S.; Bhunia, A.; Gonnade, R. G.; Biju, A. T. Efficient Synthesis of 9−Aryldihydrophenanthrenes by a Cascade Reaction Involving Arynes and Styrenes. Org. Lett. 2014, 16, 676−679. (23) Bhojgude, S. S.; Thangaraj, M.; Suresh, E.; Biju, A. T. Tandem [4 + 2]/[2 + 2] Cycloaddition Reactions Involving Indene or Benzofurans and Arynes. Org. Lett. 2014, 16, 3576−3579. (24) Li, J.; Wang, N.; Li, C.; Jia, X. Construction of Naphtho-Fused Oxindoles via the Aryne Diels−Alder Reaction with Methyleneindolinones. Org. Lett. 2012, 14, 4994−4997.

enantioselective transformations, syntheses and reactions of heterocyclic arynes, and applications in the total synthesis of natural products appear to be the future goals in this area.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Sachin Suresh Bhojgude was born in 1986 in Osmanabad, Maharashtra, India. He completed his M.Sc. from Dr. BAMU, Aurangabad in 2010. Currently, he is a Ph.D. student in the research group of Dr. A. T. Biju at CSIR-NCL, Pune, India. His research focuses on cycloaddition reactions of arynes and related chemistry. Anup Bhunia was born in 1988 in Midnapore, West Bengal, India. He received his M.Sc. in chemistry in 2011 from the Indian Institute of Technology (IIT), Guwahati, Subsequently, he moved to CSIR-NCL, where he is presently a Ph.D. student in the research group of Dr. A. T. Biju. His research focuses on aryne MCRs and organocatalysis using N-heterocyclic carbenes. Akkattu T. Biju received his Ph.D. under the guidance of Dr. Vijay Nair at CSIR-NIIST, Trivandrum, India. Subsequently, he was a postdoctoral fellow with Prof. Tien-Yau Luh at National Taiwan University, Taipei and an Alexander von Humboldt fellow with Prof. Frank Glorius at Westfälische Wilhelms-Universität Mü nster, Germany. In June 2011, he began his independent research career at CSIR-NCL, focusing on the development of transition-metal-free carbon−carbon and carbon−heteroatom bond-forming reactions and their applications in organic synthesis.

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ACKNOWLEDGMENTS We are grateful for the generous financial support provided by CSIR-New Delhi (ORIGIN, CSC0108), CSIR-OSDD (HCP0001), CSIR-NCL (startup grant, MLP022426) for our work on aryne chemistry. We thank Mr. Trinadh Kaicharla, Mr. Tony Roy, and Mr. Manikandan Thangaraj for experimental and intellectual contributions. S.S.B. and A.B. thank CSIR-New Delhi for senior research fellowships.

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REFERENCES

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