Transition-Metal-Catalyzed Reactions Involving Arynes

Abstract

The plethora of transformations attainable by the transition-metal-catalyzed reactions of arynes has found immense contemporary interest in the scientific community. This review highlights the scope and importance of transition-metal-catalyzed aryne reactions in the field of synthetic organic chemistry reported to date. It covers transformations achieved by the combination of arynes and various transition metals, which provide a facile access to a biaryl motif, fused polycyclic aromatic compounds, different novel carbocycles, various heterocycles, and complex natural products.

1 Introduction

2 Insertion of Arynes

3 Annulation of Arynes

4 Cycloaddition of Arynes

5 Multicomponent Reactions of Arynes

6 Miscellaneous Reactions of Arynes

7 Total Synthesis of Natural Products Using Arynes

8 Conclusion

Key words

arynes - transition metal - multicomponent - insertion - natural products - cycloaddition - annulation

Biographical Sketches

Mr. Ranjeet A. Dhokale obtained his B.Sc. and M.Sc. (Nowrosjee Wadia College, Pune) degrees from the University of Pune, India­. After completing his M.Sc. in organic chemistry he worked at Sai Life Sciences Ltd. as a research chemist (2008–2010). He also qualified the Council of Scientific and Industrial Research­-UGC (NET) exam for a doctoral research fellowship and lectureship at national level. Now he is pursuing his doctoral studies under the supervision of Dr. S. B. Mhaske at CSIR-National Chemical Laboratory, Pune. His research interests include development of novel methodologies in aryne chemistry and their application in the total synthesis of bioactive natural products.

Dr. Santosh B. Mhaske completed his Ph.D. from CSIR-National Chemical Laboratory, Pune India in February 2005. He completed his postdoctoral studies in the USA followed by Humboldt Postdoctoral studies at University of Hannover, Germany. He joined CSIR-NCL as a Ramanujan Fellow from 2010, and in 2013 he became a Senior Scientist at the same institute. His research interest includes; total synthesis of bioactive natural products and their analogues for SAR studies, development of novel methodologies useful in the synthesis of natural products and drugs, synthesis and bio­logical­ evaluation of computationally designed molecules, interdisciplinary research directed towards novel, efficient and affordable treatment of diseases.

1

Introduction

Arynes find prime applications in organic synthesis due to the presence of a highly electrophilic strained triple bond.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] The energy gap between the HOMO and the LUMO of arynes is less compared to that of unstrained alkynes, which makes them superior electrophiles, hence arynes smoothly react even with weak nucleophiles under milder reaction conditions.[12] The existence of aryne intermediates was first indicated after experiments performed by Stoermer and Kahlert in 1902.[16] Wittig observed the formation of biphenyl by reacting fluorobenzene and phenyllithium via a zwitterionic intermediate.[17] Furthermore, Roberts and co-workers confirmed the formation of an aryne by a classical ¹⁴C-labeling experiment.[18] Several methods to generate arynes from varyingly substituted aromatics or alkynes have been well documented in the literature.[5] ^, [19] [20] [21] [22] [23] [24] [25] However, the generation of arynes from o-(trimethylsilyl)aryl triflate developed by Kobayashi and co-workers[26] remains the most convenient and one of the most highly utilized methods, which enables various carbon–carbon and carbon–heteroatom bond-forming processes. This mild method of aryne generation is also compatible with transition metals, thus enabling enhanced reactivity giving rise to novel transformations. Such transformations of arynes to multifunctionalized arenes, heteroarenes, and polycyclic rings in the presence of transition metals have found immense contemporary interest in the scientific community. Transition-metal-catalyzed reactions of arynes have also been found useful in the total synthesis of bioactive natural products. Reactions involving an aryne, a nucleophile, and an electrophile, referred as a multicomponent reaction, provide diverse 1,2-difunctionalized arenes and heteroarenes in the presence of a transition metal. Polyaromatic rings, which find prime applications in materials chemistry, are constructed by transition-metal-catalyzed cyclotrimerization and cocyclotrimerization reactions of arynes. The transition-metal-catalyzed annulation of arynes with substituted aromatic rings bearing heteroatoms provides varyingly substituted heterocycles. The general chemistry of arynes has been covered in many reviews.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Larock and co-workers have reviewed Pd-catalyzed aryne reactions reported until 2011.[27] Yoshida has a book chapter that highlights transition-metal-catalyzed aryne reactions reported until 2013.[28a] The present review focuses on transition-metal-catalyzed reactions of arynes reported to date that are not covered in these previous reports. Interestingly, a review on a similar topic appeared online after submission of this review.[28b]

2

Insertion of Arynes

Insertion of arynes into an element–element bond is a facile and very well explored reaction of high synthetic importance.[7] The reactants, which otherwise would be unreactive/less reactive with arynes are further activated by transition-metal catalysis.[27] [28]

The first reported example of the coupling of an alkyne and an aryne in the presence CuI under microwave-assisted conditions was in 2009 by Biehl and Akubathini; this was the first example of aryne chemistry under microwave conditions. The reaction was performed under microwave heating in acetonitrile/toluene (1:1) solvent. Various symmetric and unsymmetric disubstituted alkynes were synthesized (Scheme [1]).[29]

Scheme 1 Cu-catalyzed alkyne–aryne coupling

The insertion of an aryne into an ArS–CN bond to give substituted 2-(arylthio)benzonitriles 1 was successfully carried out by Werz and co-workers using a Pd catalyst. The reaction did not work in the absence of a Pd(II) catalyst because the sulfur in thiocyanate is positively polarized to undergo nucleophilic attack, therefore, the activation of aryl thiocyanates by Pd(OAc)₂ was necessary. The active [Pd(0)] catalyst generated by the combination of Pd(OAc)₂ and Xantphos undergoes oxidative addition to the ArS–CN bond to give intermediate 1a. The Pd complex 1a coordinates with in situ generated aryne affording 1b. Further, thiomet­alation and reductive elimination of 1b affords substituted 2-(arylthio)benzonitrile 1. It was observed that an oxygen atmosphere was crucial to obtain high yields of the expected products. Differently substituted aryl thiocyanates and aryne precursors were utilized (Scheme [2]).[30]

Scheme 2 2-(Arylthio)benzonitriles from insertion of arynes into aryl thiocyanates catalyzed by Pd(OAc)₂

The insertion of indolynes 2 into a symmetrically substituted B–B bond was successfully achieved by the Oestreich group in 2015 by employing the catalyst Pt(dba)₂ and the ligand tBuNC (Scheme [3]).[31] The resulting diborane products 3 were utilized in further C–C bond forming organometallic Suzuki–Miyaura coupling reactions. Excellent regioselectivity was achieved with the first Suzuki–Miyaura coupling reaction occurring unexpectedly at C7 to give 4. Further, Suzuki­–Miyaura coupling was carried out on monocoupled product 4 with bulky aryl iodides at C6 position giving very good yields of the 6,7-difunctionalized indoles 5.

Scheme 3 Pt(0)-catalyzed indolyne insertion into bis(pinacolato)diboron

In 2016, García-López and Pérez-Gómez synthesized spirobiaryls by reacting N-(2-phenylallyl)sulfonamide 6 (X = NTs) with an in situ generated aryne in the presence of Pd(OAc)₂ catalyst and PPh₃ ligand in toluene/acetonitrile (1:1) solvent (Scheme [4]).[32]

Scheme 4 Spirobiaryls through a Pd-catalyzed cascade reaction

Mechanistically, the intramolecular Heck arylation of complex 6a affords the intermediate 6b. Path A suggests C–H activation of 6b furnishing five-membered palladacycle 7. The insertion of the aryne into complex 7 produces intermediate 7a and further reductive elimination furnishes spiro product 8. Alternatively, substrates with a longer tethering chain undergo C–H activation producing palladacycles of type 6f, which undergo insertion with the aryne and finally reductive elimination providing the product 6g. In alternative path B, the formation of intermediate 6e via trapping of the aryne by intermediate 6b is suggested, followed by C–H activation and C–C coupling to afford the spirocyclic compound 8. The compatibility of the optimized protocol was tested on various substrates containing alkene, aryl, and heteroaryl moieties and different aryne precursors.

Chen and co-workers reported the insertion of an aryne into the H–P(O) bond of a secondary phosphine oxide using catalytic CuI (Scheme [5]). The optimized protocol was tested on various aryne precursors and afforded a diverse range of arylphosphine oxides. These arylphosphine oxides are a useful source of ligands that also find prime applications in medicinal chemistry and material science.[33]

Scheme 5 Insertion of an aryne into a H–P(O) bond through a Cu-catalyzed reaction

The synthesis of spirodehydrobenzofuran 10a and spirooxindoles 10b from alkene 9 via Pd-catalyzed domino Heck reaction was established by Lautens and co-workers (Scheme [6]). The reaction consists of a Pd-catalyzed domino-Heck spirocyclization via C–H activation and benzyne insertion sequence. A wide range of spirooxindoles and spirodihydrobenzofurans were synthesized in good to excellent yields.[34]

Scheme 6 Pd-catalyzed spirocyclization

The synthesis of heterocycle-fused 9,10-dihydrophenanthrenes 13 from 1-iodo-2-[(2-methylallyl)oxy]benzene 11 and in situ generated aryne was demonstrated by Yao and He (Scheme [7]).[35] Intramolecular Heck reaction of 1-iodo-2-[(2-methylallyl)oxy]benzene generates σ-alkyl–palladium(II) intermediate 12, which is intercepted by the aryne followed by C–H activation to afford the product 13. This protocol involves the formation of three new C–C bonds and the generation of a quaternary carbon center. Overall 26 different substituted heterocycle-fused 9,10-dihydrophenanthrenes including regioisomers were synthesized in moderate to excellent yields.

Scheme 7 Synthesis of heterocycle-fused 9,10-dihydrophenanthrenes

The above-mentioned examples demonstrate the importance of transition metals for controlled reactivity of the substrates in the expected transformation utilizing highly reactive aryne species.

3

Annulation of Arynes

The annulation reaction of arynes catalyzed by transition metals is an important reaction in organic synthesis. Syntheses of various novel heterocycles, which find prime application in the pharmaceutical field, have been achieved by the annulation of arynes in a single-step transformation. The annulation process has been efficiently used for the synthesis of various bioactive natural products.[36]

In 2010, Huang and co-workers reported the carboannulation of arynes with vinyl iodides in the presence of a Pd catalyst. The substrate scope of the optimized protocol was studied on various allyl-substituted iodocycloalkenones 14 and iodofuranones 15 with substituted aryne precursors for the synthesis of dihydrophenanthren-1(2H)-ones 16 and naphtho[2,1-c]furan-3(1H)-ones 17, respectively. Methyl- and fluorine-substituted aryne precursors gave a mixture of regioisomers in ~1:1 ratio, whereas the meth­oxy-substituted aryne precursor gave high regioselectivity (Scheme [8]).[37]

The mechanism in path A suggests the formation of palladacycle 15a by coordination of Pd(0) with benzyne. The oxidative addition of vinyl iodide 15 to palladacycle 15a leads to arylpalladium(IV) complex 15b, which on reductive elimination generates arylpalladium intermediate 15c. However, alternatively in path B, the complex 15a′ formed via oxidative addition undergoes insertion with the aryne to generate intermediate 15c. Intramolecular Heck coupling of intermediate 15c furnishes 15d, which on subsequent β-hydride elimination and aromatization affords the product 17. A similar mechanism is proposed for 16.

Scheme 8 Pd-catalyzed synthesis of dihydrophenanthren-1(2H)-ones and naphtho[2,1-c]furan-3(1H)-ones from arynes

Scheme 9 Phenanthridinones by annulation of o-halobenzamides with arynes

Larock and co-workers introduced a novel protocol for the synthesis of diverse phenanthridinones 19 by simultaneous C–C and C–N bond formation. The reaction involved an aryne precursor, o-halobenzamides 18, a Pd catalyst, CsF, and a base in toluene/acetonitrile (4:1) solvent. Mechanistically, the palladacycle 18a (path a) undergoes oxidative addition with 18 to generate Pd(IV) intermediate 18b. Further reductive elimination affords the arylpalladium(II) intermediate 18c. Alternatively, in path b the oxidative addition of Pd(0) with 18, followed by carbopalladation of the aryne produces intermediate 18c. The intermediate 18c, under basic condition cyclizes to 18d, which undergoes reductive elimination affording the product 19. A total of 25 phenanthridinones were obtained in moderate to good yields (Scheme [9]).[36]

The highly electrophilic nature of arynes has been used for the construction of diverse carbazoles 21 by annulation with 2-haloacetanilides 20 in the presence of Pd(dba)₂ catalyst, dppf ligand, CsF, and toluene/acetonitrile (4:1) as the solvent. Both C–C and C–N bonds were formed simultaneously. A diverse range of carbazoles was prepared from inexpensive starting materials using this methodology (Scheme [10]).[38]

Scheme 10 Carbazoles by annulation of o-haloacetanilides with arynes

Wang and co-workers demonstrated insertion of arynes into the C–S bond of α-carbamoyl ketene dithioacetals 22 catalyzed by Pd(OAc)₂ and dppf as the ligand. Mechanistically, the palladacycle 22a undergoes insertion into the C–S bond to afford intermediate 22c via 22b. The seven-membered palladacycle 22d is formed at the expense of the thioanisole derivative through intramolecular substitution of 22c; reductive elimination of 22d offers the expected product 23. The alternative path B suggests the oxidative addition of the Pd complex to one of the C–SR bonds, followed by aryne insertion leading to palladacycle 22c, which finally provides product 23. Various alkylthio-substituted quinolines 23 were synthesized in moderate to good yields (Scheme [11]).[39]

Scheme 11 The reaction of α-carbamoyl ketene dithioacetals with arynes in the presence of Pd(OAc)₂

Ma and Yuan developed an efficient method for the synthesis of 2,3-disubstituted benzofuran derivatives 25 containing a trisubstituted alkene functional group from the preinstalled alkyne in 24. In the proposed mechanism, intramolecular ene reaction of the preinstalled alkyne with the aryne precursor in the presence of Pd(PPh₃)₄ catalyst and CsF leads to the formation of allene intermediate 24a. In situ formed ArPdI undergoes insertion with 24a furnishing π-allyl–palladium complex 24b. Finally β-H elimination affords the isomeric benzofuran derivative 25 in moderate yields (Scheme [12]).[40]

Scheme 12 2,3-Disubstituted benzofurans from the reaction of aryl iodide with arynes in the presence of Pd(PPh₃)₄

A novel protocol was developed by Liang and co-workers in 2014 for the synthesis of various substituted phenanthridinones 27 by Pd-catalyzed annulation of a benzyne with an N-substituted N-(2-halophenyl)formamide 26. Pd(OAc)₂ was the most successful catalyst for this reaction along with P(o-Tol)₃ as the ligand. This protocol was general and various substituted N-(2-halophenyl)formamides as well as arynes were tolerated. Regioisomeric products in the ratio 1.6:1 were observed for an unsymmetrical chloroaryne precursor (Scheme [13]).[41]

Scheme 13 Phenanthridinones from Pd-catalyzed annulation of N-substituted N-(2-halophenyl)formamides with arynes

In 2014, Sha and co-workers reported the synthesis of phenanthridines 29 via Pd-catalyzed C–H activation from aryl ketone O-acetyloximes 28 and arynes (Scheme [14]).[42] In general, preactivated substrates are used for the synthesis of such heterocycles using aryne chemistry, but in this case, the synthesis of phenanthridines was carried out through C–H bond activation involving a directing group. The protocol was established successfully using Pd catalyst, CuCl₂ as an oxidant, and Cs₂CO₃ as the base. The reaction worked well for different combinations of substituted O-acetyloximes and substituted aryne precursors.

Scheme 14 Phenanthridines from ketoximes and aryne precursors

Scheme 15 Annulation between benzamides and arynes

Transition-metal-catalyzed C–H functionalization is a very powerful synthetic strategy in building complex molecules. The Xu group[43] and Jeganmohan and Pimparkar[44] both reported this concept in aryne chemistry independently in 2014. This methodology involves the Pd N–H/C–H activation of amides 30, aryne insertion, and cyclization in the presence of catalytic Pd(OAc)₂ to provide a tricyclic phenanthridinone core 31. The Xu group used Pd(OAc)₂ as the catalyst, Cu(OAc)₂ as the oxidant, and DMSO/dioxane solvent,[43] whereas Jeganmohan and Pimparkar optimized the protocol using Pd(OAc)₂ as the catalyst in combination with adamantane-1-carboxylic acid as the ligand and K₂S₂O₈ as the oxidant.[44] The Xu group extended the methodology to cyclooctynes, which also yielded the expected products in good yields (Scheme [15]).[43] Mechanistically, the five-membered palladacycle intermediate 30a is formed via coordination of nitrogen with Pd followed by orthometalation. The in situ generated aryne undergoes insertion to form a seven-membered palladacycle intermediate 30b. The reductive elimination of complex 30b furnishes the product 31 (Scheme [15]).[44]

In 2015, the Xu group extended (Scheme [15])[43] their methodology by reacting acrylamides 32 with arynes delivering diverse quinolinones 33. The optimized protocol was developed in which Pd(OAc)₂, Cu(OAc)₂, and tetrabutylammonium bromide (TBAB) in DMSO/dioxane (1:9) was used to give quinolinones 33 in moderate to good yields. A variety of quinolinones were synthesized using substituted aryne precursors (Scheme [16]).[45]

Scheme 16 Quinolinones from annulation between acrylamides and arynes

In 2016, Yao and co-workers developed a protocol for the synthesis of substituted 9,10-disubstituted phenanthrenes by annulation of o-halostyrenes with an aryne in the presence of a Pd catalyst. Various substituted o-halostyrenes 34 reacted with simple aryne precursors giving moderate to good yields of 9,10-disubstituted phenanthrenes 35. The substrate scope for variously substituted aryne precursors was also examined (Scheme [17]).[46]

Scheme 17 9,10-Disubstituted phenanthrenes by Pd-catalyzed aryne annulation by o-halostyrenes

Gogoi and co-workers reported the synthesis of biologically important diverse coumestans 37 from arynes and 4-hydroxycoumarins 36 (Scheme [18]). The reaction proceeds through C–H activation of the 4-hydroxycoumarin. Mechanistically, the anion species 36a undergoes C–H activation at 3-position to give intermediate 36b, which undergoes carbopalladation with the aryne precursor to give intermediate 36c that converts into 37 in the presence of a base. The catalyst was regenerated by Cu(OAc)₂, which acts as an oxidant (Scheme [18]).[47] In total, 20 substituted coumestans were synthesized in moderate to good yields. Moreover, the protocol was compatible with halo-substituted 4-hydroxycoumarins.[47]

Scheme 18 Coumestans via Pd-catalyzed C–H activation/C–C and C–O bond formation

In 2017, Zhang and co-workers reported the annulation of directing group containing benzamides 38 by benzynes in the presence of Cu(OAc)₂ catalyst. The resulting ortho-C–H/N–H annulations afforded the biologically important phenanthridinone compounds 39. The reaction was performed using TBAI in DMF/CH₃CN solvent under an oxygen atmosphere. The optimized protocol was tested on a wide range of benzamides and substituted aryne precursors to afford 44 substituted phenanthridinone compounds (Scheme [19]).[48]

Scheme 19 Phenanthridinone by Cu-catalyzed annulations of aryne, and benzamides; Q = 8-quinolinyl

Several reports[36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] on the synthesis of biologically relevant heterocycles such as naphthofurans, phenanthridinones, carbazoles, using the aryne annulation process suggest its importance for their construction and structure–activity relationship studies.

4

Cycloaddition of Arynes

The cycloaddition of arynes is a well-known reaction that furnishes scaffolds of biological interest, however, the control of both regio- and chemoselectivity remained a great challenge. Transition-metal catalysis has advantages over traditional methods as it improves these important aspects of the reaction. The cyclotrimerization of arynes and alkynes/alkenes/allenes has been reviewed reviewed in detail by Peña and co-workers.[49]

In 2005, Cheng and Hsieh reported the first Ni-catalyzed [2+2+2] cocyclotrimerization of arynes with diynes 40 providing substituted naphthalenes 41 containing five- to seven-membered rings (Scheme [20]).[50] NiBr₂(dppe) was the most appropriate catalyst for this transformation, while zinc promoted the reduction of the Ni(II) species to a Ni(0) species, which initiates the reaction. In the proposed mechanism, the complex 40a formed by the coordination of both C≡C bonds of the diyne to the Ni(0) center, undergoes cyclometalation furnishing 40b. The in situ generated aryne is inserted into complex 40b affording nickelacycloheptatriene intermediate 40c, which on reductive elimination generates 41 and regenerates the Ni(0) catalyst. The established protocol was sensitive to substituents on both the diyne and aryne.

Scheme 20 Substituted naphthalenes by Ni-catalyzed cocyclotrimerization of arynes with diynes

Scheme 21 Ni-catalyzed [2+2+2] cycloaddition of arynes with alkynes and nitriles

In 2008, Cheng and Hsieh employed o-dihaloarenes as aryne precursors for the Ni-catalyzed [2+2+2] cycloaddition with alkynes or dialkynes 40a and nitriles to give substituted naphthalene, phenanthridine 29a, or triphenylene derivatives (Scheme [21]).[51] The key step of this transformation is the Ni-assisted generation of the aryne. The cycloaddition reaction also worked well with various diynes, nitriles, disubstituted acetylenes, and o-diiodoarenes.

There are few reports on the [2+2+2] cycloaddition of arynes and activated alkene moieties. Sato and co-workers were the first to report the [2+2+2] cycloaddition of an aryne and unactivated alkene catalyzed by a Ni catalyst. The aim of the [2+2+2] cycloaddition of an aryne and α,ω-diene 42 was to synthesize the 1,2,3,4-tetrahydronaphthalene skeleton, but it afforded 9,10-dihydrophenanthrene derivatives 43 in good yield together with a low yield of the dien­yl-substituted biphenyl 44 (Scheme [22]).[52] Reaction of various dienes with the unsubstituted aryne precursor gave moderate yields of 9,10-dihydrophenanthrenes. Good yields were obtained when a diene (X = cyclic acetal) was reacted with an aryne precursor bearing an electron-donating group.

Scheme 22 9,10-Dihydrophenanthrenes by Ni-catalyzed [2+2+2] cycloaddition of arynes and unactivated alkenes

The transition-metal-mediated [2+2+2] cycloaddition of alkynes and alkenes is an asset for building complex structures. Prior to aryne methodology, Xie and Qiu reported the Ni-mediated [2+2+2] cycloaddition of carboryne (1,2-dehydro-o-carborane), alkynes, and alkenes.[53] Due to the similar reactivity pattern between carboryne and aryne, they extended it to afford diverse dihydronaphthalenes that are difficult to prepare from simple starting materials. After optimization of the reaction conditions, the use of Ni(cod)₂ (5 mol%) and CsF (6 equiv) in acetonitrile at room temperature afforded the dihydronaphthalenes in very good yield together with trace amounts of a regioisomer. Using different substituted aryne, alkynes, and alkenes gave a total of 19 differently substituted dihydronaphthalenes (Scheme [23]).[54]

Scheme 23 Dihydronaphthalenes by Ni-catalyzed cycloaddition of arynes, activated alkenes, and alkynes

Mechanistically, the five-membered Ni complex I is formed by co-ordination of Ni(0) with the benzyne and alkene through oxidative coupling. Further alkyne insertion with complex I produces the seven-membered intermediate II followed by reductive elimination affording the dihydronaphthalenes (Scheme [23]).[54]

The use of arynes in stereoselective reactions is very rare­. In 2011, Lautens and Candito reported the stereoselective Ni-catalyzed [2+2+2] cycloaddition of arynes and 1,6-enynes 45. The substituent near to the C=C bond proved to be a crucial factor for diastereoselectivity. The proposed mechanism involves the formation of an enyne complex by coordination with the Ni(0) catalyst followed by oxidative addition. The complex then coordinates with the aryne by insertion into one of the carbon–metal bonds followed by reductive elimination resulting in 46. The trans stereochemistry is set at the stage where enyne complex is formed with the Ni(0) catalyst. A model study suggests two diastereotopic complexes, which can cyclize in an irreversible step, but the transition step having lower 1,3-allylic strain favors the trans product (Scheme [24]).[55]

Scheme 24 Ni-catalyzed [2+2+2] cycloaddition of enynes and arynes

In 2011, Wu and co-workers reported the [3+2] cycloaddition of an aryne with (diarylmethylene)cyclopropa[b]naphthalenes 47 in the presence of a Pd catalyst (Scheme [25]);[56] isopropylidenecyclopropa[b]naphthalenes (replacement of Ar in 47 by Me) gave geometrical isomers in 1:1 ratio. The synthetic utility of the obtained 11-(diarylmethylene)-11H-benzo[b]fluorenes 48 was demonstrated by treating them further under different transition-metal-catalyzed reaction conditions.

Scheme 25 Pd-catalyzed [3+2] cycloaddition reaction of (diarylmeth­ylene)cyclopropa[b]naphthalenes with arynes

Argade and Patel reported the synthesis of differently substituted arylnaphthalenes 50 by metal-catalyzed [2+2+2] cocyclization of arynes with unsymmetrical conjugated dienes 49 in the presence of Pd₂(dba)₃ catalyst and a N-heterocyclic carbene ligand (Scheme [26]).[57] In the mechanism, the oxidative insertion of the Pd catalyst with aryne and diene affords five-membered palladacycle 49a which rearranges to 49b via insertion of a double bond into the Pd–C (alkyl bond). Finally, reductive elimination of the Pd catalyst gives intermediate 49c which is oxidized, producing arylnaphthalene 50. Six different substituted arylnaphthalenes were synthesized in good yields by reaction of variously substituted aryne precursors with unsymmetrical dienes.

Scheme 26 Arylnaphthalenes by Pd-promoted [2+2+2] cocyclization of arynes and unsymmetrical conjugated dienes

In 2012, Cheng and co-workers reported the synthesis of isochromenones 53 and oxepines 54 by reacting 2-iodobenzyl 3-phenylpropynoates 51 and 1-iodo-2-[2-(phenylethynyl)benzyloxy]benzenes 52, respectively, with arynes in the presence of Pd(dba)₂ catalyst and Tl(OAc) (Scheme [27]).[58] The reaction proceeds by Pd insertion into the iodo compound followed by C–H activation and then insertion of benzyne leading to the expected product. Mechanistically, intermediate 51b is formed via Pd(0) oxidative addition and insertion into the C≡C bond through palladium complex 51a. Intermediate 51b undergoes C–H activation to form a palladacycle 51c. Further insertion of aryne with palladacycle 51c gives the seven-membered intermediate 51d, which undergoes reductive elimination producing 53. This protocol produces two new rings. Various substituted iodo compounds and aryne precursors were compatible with the optimized protocol.

Scheme 27 Cascade cyclization of alkynes and arynes in the presence of Pd(dba)₂

Ma and co-workers reported the synthesis of 9-vinylphenanthrenes 56 by reacting two molecules of benzyne with propargylic carbonate 55 in the presence of Pd(OAc)₂ catalyst and tris(2-furyl)phosphine (TFP) ligand (Scheme [28]).[59] Mechanistically, it is proposed that an intermolecular reaction takes place between benzyne and an allenylpalladium complex. The allenylpalladium complex 55a, formed via oxidative addition of Pd with intermediate 55, is inserted into the aryne leading to 55b, subsequently another aryne insertion with 55b and carbopalladation of intermediate 55c furnishes intermediate 55d. Finally, β-hydride elimination from 55d produces the expected phenanthrene products 56.

Scheme 28 9-Vinylphenanthrenes by Pd(OAc)₂-catalyzed reaction of a propargylic carbonate with an aryne

Greaney and co-workers reported the synthesis of triphenylenes by trimerization of arynes, which were derived from ortho-substituted arylboronates 57. The reaction was carried out in the presence of Pd(dba)₂ catalyst, DPEphos ligand, and potassium tert-butoxide in toluene as a solvent at 100 °C; various substituents were tolerated (Scheme [29]).[23] The metal-bound aryne intermediates are formed and these undergo trimerization.

Scheme 29 Triphenylenes by Pd-catalyzed trimerization of arynes

In 2015, Chen and co-workers were the first to report the cyclotrimerization of arynes using (Ph₃P)AuCl. The mechanism for this reaction is very similar to Pd(0)-catalyzed cyclotrimerization. These results provide an efficient protocol for the synthesis of triphenylene derivatives by gold catalysis, which should also lead to the discovery of new applications of gold complexes in aryne chemistry (Scheme [30]).[60a]

Scheme 30 Triphenylenes by Au(I)-catalyzed cyclotrimerization of arynes

In 2014, Peña and co-workers elegantly applied the Pd-catalyzed [2+2+2] cycloaddition trimerization concept of arynes to the synthesis of the 22-ring fused aromatic ring hydrocarbon nanographene (Scheme [31]). The synthesis of nanographene was achieved by cyclotrimerization of a polycyclic aryne, which was synthesized from perylene. This example shows the application of arynes in materials chemistry.[60b]

Scheme 31 Synthesis of nanographene from a polycyclic aryne

Garg and co-workers reported a novel class of heteroatomic indole-based trimers (Scheme [32]). The synthesis of these unique scaffolds was achieved by reacting in situ generated indolyne intermediates in the presence of a Pd catalyst. Further computational studies were performed for structural and photophysical properties of the conjugated trimeric scaffolds.[60c]

Scheme 32 Conjugated trimeric scaffolds accessible from indolyne

It is evident from the above examples that the scope of the simple cycloaddition reaction of arynes has been tremendously enhanced by transition-metal catalysis to obtain the desired scaffolds more efficiently.

5

Multicomponent Reactions of Arynes

Multicomponent reactions (MCR) of arynes in the presence of a transition metal provide easy access to 1,2-difunctionalized arenes. The two new bonds are constructed simultaneously on the aryne intermediate. The resulting product of the MCR can further be used for the construction of natural products or bioactive pharmaceuticals.

Snowden and Ganta elegantly carried out the difunctionalization of substituted arynes by reaction of in situ generated lithium bis[3-(trimethylsilyl)prop-1-enyl]cuprate and appropriate electrophiles, such as allyl bromide and ethyl chloroformate. Three equivalents of the lithiated allyltrimethylsilane were generated in situ, one equivalent was utilized to generate the aryne from the 1-iodo-3-(triflyl­oxy)arene. The aryl anion generated was trapped with ethyl chloroformate and various alkyl or allyl halides. This protocol afforded exclusively E-diastereoselective functionalized homobenzylic vinylsilanes 58 (Scheme [33]).[61]

Scheme 33 One-pot preparation of ortho-substituted [(E)-3-phenylprop-1-enyl]silanes

Pineshi and co-workers successfully carried out the aryl­ation of vinylaziridines by using an aryne and a terminal alkyne in the presence of CuI–PPh₃. The reaction is initiated by attack of the terminal alkyne onto the aryne to generate an arylcopper(I) species, which opens the vinylaziridine to provide allylic amines such as 59. The reaction was S_N2′ regioselective in the case of acyclic vinylaziridines. Various vinylaziridines reacted with benzyne to give the product allylic amines (8 examples) in moderate to good yields (Scheme [34]).[62]

Scheme 34 Three-component coupling of benzyne, terminal alkyne, and vinylaziridine in the presence of CuI

The introduction of the CF₃ group into an aromatic ring is a challenging and highly desired transformation. The vicinal difunctionalization of arenes using trifluoromethylated reagents was first reported by Hu and co-workers in 2013, who ingeniously reacted an aryne with 1-iodophenylacetyl­ene, 2,2,6,6-tetramethylpiperidine (TMP) and AgCF₃ (Scheme [35]).[63] The TMP plays an important role in the difunctionalization of the aryne. Mechanistically, intermediate I is formed via the reaction between the aryne and AgCF­₃·TMP; I further hydrogen bonds with another TMP molecule to provide II. Abstraction of a proton from II and coordination with iodophenylacetylene produces III. The ‘ate’ complex IV is formed by intramolecular nucleophilic attack, which rearranges to afford the expected product, a 1-iodo-2-(trifluoromethyl)benzene. Methyl- and phenyl-substituted aryne precursors gave product mixtures of regioisomers in 1:1 ratio. However, excellent regioselectivity was observed for the methoxy-substituted aryne precursor.

Scheme 35 Ag-mediated trifluoromethylation–iodination of arynes

Isocoumarins are basic key structures found in various natural products. Kobayashi and co-workers synthesized substituted isocoumarins 60 in a single-step transformation using arynes (Scheme [36]).[64] The in situ generated aryne reacts with copper acetylide, generated from phenylacetylene and NHC–copper hydroxide or carbonate. Mechanistically, the intermediate 60a is intercepted by CO₂ producing copper carboxylate 60b; the copper heterocycle 60c is formed via 6-endo-dig cyclization of 60b. Finally, transmetalation with a cesium salt furnishes 60d, which is then converted into the isocoumarin. The substrate scope was demonstrated on substituted aryne precursors as well as on aryl/alkyl-substituted terminal alkynes.

Scheme 36 NHC–copper complex catalyzed three-component coupling of aryne, terminal alkyne, and carbon dioxide

Nishihara and co-workers reported the synthesis of cyano-substituted iminoisobenzofurans by one-pot reaction of arynes, isocyanides, and cyanoformates in the presence of catalytic [Pd(NCPh)₂(dppf)](BF₄)₂ (Scheme [37]).[65] Along with iminoisobenzofurans 61, minor amount of α-iminonitriles 62 were also formed. The iminoisobenzofurans were then converted into α-iminonitriles using DIBAL-H or the Lewis acid AlMe₃. In these reactions, the formation of three new C–C bonds at the expense of one C–C bond cleavage and migration of a cyano group was observed.

Scheme 37 Iminoisobenzofurans by Pd-catalyzed three-component coupling of aryne, isocyanide, and cyanoformate

Wu and co-workers synthesized various substituted pyrazolo[5,1-a]isoquinolines 64 by reaction of 2-alkynylbenzaldehyde 63, sulfonylhydrazine, and benzyne in the presence of silver triflate (Scheme [38]).[66] An intermediate isoquinolium-2-ylamide, generated from the 2-alkynylbenzaldehyde and sulfonylhydrazine in the presence of Lewis acid, undergoes [3+2] cycloaddition with the aryne to give the pyrazolo[5,1-a]isoquinoline.

Scheme 38 Pyrazolo[5,1-a]isoquinolines by three-component coupling of aryne, benzaldehyde, and sulfonylhydrazine

Scheme 39 Pd-catalyzed three-component coupling of aryne, terminal alkyne, and 2-vinylcyclopropane-1,1-dicarboxylate

Scheme 40 Ligand-controlled regiodivergent C₁ insertion of an aryne for the construction of phenanthridinones and acridones

2-Vinylcyclopropane-1,1-dicarboxylate was utilized as an electrophile for the first time in a three-component coupling reaction with an aryne; a terminal alkyne was employed as the nucleophile (Scheme [39]).[67] The reaction conditions utilized catalytic Pd(dba)₂, with dppp as the ligand, and CuI for the synthesis of difunctionalized arenes 65. The terminal alkyne undergoes addition to the aryne to generate a carbocopper intermediate, which then attacks the cyclopropanedicarboxylate ring activated by the transition metal. Regioisomers were observed in the case of unsymmetrical aryne precursors.

Jiang and co-workers reported the construction of variously substituted phenanthridinones 19a and acridone alkaloids 66 by Pd-catalyzed and ligand-controlled regiodivergent C1 insertion involving an aryne, CO, and a 2-iodoaniline (Scheme [40]).[68]. Mechanistically, the Pd catalyst without a bulky ligand undergoes oxidative addition with iodoaniline. The in situ generated aryne co-ordinates with the complex 19a′ followed by insertion to provide the intermediate 19c′. The insertion of CO provides acyl–Pd species 19d′, which on reductive elimination delivers the phenanthridinone product 19a. When the bidentate phosphine ligand bis(diphenylphosphino)methane (dppm) was employed, complex 66a′ coordinates with CO instead of the aryne due to steric hindrance, giving intermediate 66c′. Further interception of 66c′ with aryne followed by reductive elimination of Pd affords the acridone product 66. Optimization showed that for phenanthridinone synthesis the conditions required were Pd(OAc)₂ as catalyst and TBAI as the additive; to avoid the formation of the minor product acridone 10% H₂O was added to the acetonitrile solvent. The optimized synthesis of acridones also used Pd(OAc)₂ as catalyst, but the addition of the ligand dppm was crucial; the slow release of aryne was also important, and was achieved by using KF.

Jiang and co-workers extended their previous methodology (Scheme [40]) to the synthesis of phenanthridinone 19b through C–H activation. The reaction was carried out in the presence of unactivated anilines, aryne, and CO. The use of CuF₂·2H₂O for the slow release of aryne was found to be crucial to obtain high yields of products. Diverse phenanthridinones were synthesized in moderate to good yields (Scheme [41]).[69]

Scheme 41 Phenanthridinones from arynes, anilines, and carbon monoxide

Xu and co-workers successfully carried out a one-pot difunctionalization of arynes via C–C and C–S bond formation by reacting terminal alkynes, arynes, and benzenesulfonothioates in the presence of catalytic CuI to give 1-alkynyl-2-(arylthio)benzenes 67 (Scheme [42]).[70] Various substituents on the aryne precursors, terminal alkynes, and benzenesulfonothioates were tolerated.

Scheme 42 Cu-catalyzed three-component coupling of aryne, terminal alkyne, and benzenesulfonothioate

Hu and Zeng extended their previous methodology (Scheme [35]) for the one-pot trifluoromethylthiolation–iodination of arynes with (trifluoromethylthio)silver and 1-iodo-2-phenylacetylene (Scheme [43]).[71] The in situ generated aryne undergoes insertion in the Ag–S bond to provide an o-SCF₃-substituted arylsilver intermediate, which is further trapped by 1-iodo-2-phenylacetylene to afford 1-iodo-2-(trifluoromethylthio)arenes in good yields. These products are important precursors for Yagupolskii–Umemoto-type electrophilic trifluoromethylation reagents.

Scheme 43 Ag-mediated trifluoromethylthiolation–iodination of arynes

Multicomponent reactions of arynes thus provide an efficient and elegant access to novel disubstituted arenes, which otherwise would require multistep transformations.

6

Miscellaneous Reactions of Arynes

Arynes have also been used in the synthesis of large-ring-size structures and biphenyls. The use of arynes in polymerization reaction has also been reported.

The ortho-palladated derivatives of α,α-dimethylphenethylamine (phentermine) 68 (R = Me, X = H) and homoveratrylamine 68 (R = H, X = OMe) were reacted with benzyne to give eight-membered palladacycles 69. This is the first report of the isolation of an aryne-inserted palladacycle. The palladacycle on reaction with CO in methanol produced unnatural amino acids 71 (Scheme [44]).[72]

Scheme 44 Synthesis of unnatural amino acids

The 10- and 11-membered palladacycles were also synthesized by reacting the ortho-palladated derivative of homoveratrylamine 68a with insertion of two molecules of benzyne. The palladacycle 72 reacted with CO or RNC to afford products 75 and 76, respectively (Scheme [45]).[73]

Scheme 45 Synthesis of 10- and 11-membered palladacycles

Knochel and co-workers utilized 2-iodophenyl arenesulfonate precursors 77 for the generation of arynes using iPrMgCl.[19] Studer and co-workers used this aryne precursor for the synthesis of 2,2′-disubstituted biphenyls 78. Li₂CuCl₄ was a suitable catalyst for the homocoupling under an oxygen atmosphere. Moderate yields of 2,2′-disubstituted biphenyls 78 were obtained (Scheme [46]).[74]

Scheme 46 2,2′-Disubstituted biphenyls from arynes and anilines or benzenethiols

Arynes have been extensively used in organic chemistry, but there are very rare reports in polymer chemistry. Uchiyama­ and co-workers performed the polymerization of an aryne for the synthesis of a poly(o-arylene) that consisted of aromatic rings connected through the ortho-position (Scheme [47]).[75] The initiator for polymerization was a copper ‘ate’ complex, which was prepared from CuCN and n-BuLi. The obtained polymer has potential in new areas for nanocarbon and materials science.

Scheme 47 Synthesis of a poly(o-arylene)

7

Total Synthesis of Natural Products Using Arynes

Arynes have been used to generate key synthetic intermediates for the synthesis of different bioactive natural products. Various complex natural products have been synthesized by employing arynes in metal-catalyzed MCR, σ-bond insertion, [4+2] and [2+2] cycloaddition reactions.[5] [6]

Argade and Patel reported a concise synthesis of justicidin B, retrojusticidin B, and the formal synthesis of analogous natural products (Scheme [48]) by using their well-established Pd-catalyzed [2+2+2] cocyclization of arynes and unsymmetrical conjugated dienes in the presence of an N-heterocyclic carbene ligand (Scheme [26]).[57]

Scheme 48 Synthesis of justicidin B and retrojusticidin B

Jeganmohan and Pimparkar extended their methodology (Scheme [15]) for the synthesis of bioactive natural products phenaglydon, 6(5H)-phenanthridin-5(6H)-one, and N-methylcrinasiadine in moderate to good yields (Scheme [49]).[44]

Scheme 49 Synthesis of phenaglydon, 6(5H)-phenanthridin-5(6H)-one, and N-methylcrinasiadine

Jiang and co-workers extended their well-established methodology (Scheme [40]) to the synthesis of the phenanthridinone alkaloids; N-methylcrinasiadine, N-isopentylcrinasiadine, and N-benzylcrinasiadine in excellent yield. The protocol was also applied to the synthesis of the acridone alkaloid 10-methyl-2,3-(methylenedioxy)acridin-9(10H)-one in moderate yield (Scheme [50]).[68]

Scheme 50 Synthesis of N-methylcrinasiadine, N-isopentylcrinasiadine, and N-benzylcrinasiadine

Yao and co-workers extended their protocol (Scheme [17]) to the formal synthesis of the phenanthrene-based natural product (±)-tylophorine. A good yield was observed for the key step of the synthetic route wherein the Pd-catalyzed annulation furnished the desired phenanthrene core of the natural product (Scheme [51]).[46]

Scheme 51 Formal synthesis of the phenanthrene-based natural product (±)-tylophorine

In continuation of their research interest, Jiang and co-workers developed a methodology for the synthesis of phenanthridinones (Scheme [41]). The same methodology was applied as a key step in the total synthesis of natural products N-methylcrinasiadine, N-isopentylcrinasiadine, and N-benzylcrinasiadine (Scheme [52]).[69]

Scheme 52 Synthesis of N-methylcrinasiadine, N-isopentylcrinasiadine, and N-benzylcrinasiadine

Gogoi and co-workers applied their methodology (Scheme [18]) to the total synthesis of the biologically active natural product flemichapparin C. The developed protocol was performed using 4-hydroxy-7-methoxycoumarin and 4,5-(methylenedioxy)benzyne to afford the desired natural product (Scheme [53]).[47]

Scheme 53 Synthesis of flemichapparin C

Zhang and co-workers utilized their Cu-catalyzed methodology (Scheme [19]) for the synthesis of phenaglydon and crinasiadine natural products. The removal of the directing group in the presence of BBr₃ and PhI(TFA)₂ afforded the respective natural products (Scheme [54]).[48]

Scheme 54 Cu-catalyzed synthesis of phenaglydon and crinasiadine; Q = 8-quinolinyl

Diversity oriented natural product synthesis is a rapidly developing area of research.[5] [6] In this context, aryne chemistry paves a new pathway to achieve this goal through various types of transition-metal-catalyzed reactions.

8

Conclusion

This review highlights the scope and importance of the transition-metal-catalyzed aryne reactions in synthetic organic chemistry. The highly reactive aryne species in combination with a transition metal made it possible to construct biaryl motifs, fused polycyclic aromatic compounds, different novel carbocycles, various heterocycles, and complex natural products. From a laboratory curiosity to a highly explored reactive intermediates; arynes have travelled a long path. To cross the barrier from basic to applied research, a completely ‘off the shelf’ practical method of aryne generation is essential. The current rate at which this area of research is growing, we have no doubt that aryne chemistry might occupy an important position in combination with transition metals as a key step in the synthesis of drugs and advanced materials.

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