Transition-Metal-Catalyzed Reactions Involving Arynes

1

R. A. Dhokale, S. B. Mhaske ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2018, 50, 1–16reviewen

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Transition-Metal-Catalyzed Reactions Involving ArynesRanjeet A. Dhokale Santosh B. Mhaske*

Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, [email protected]

M

Reactants

Insertion

Multicomponent

Natural products

Cycloaddition

Annulation

M = Metal

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Received: 04.08.2017Accepted after revision: 29.08.2017Published online: 22.11.2017DOI: 10.1055/s-0036-1589517; Art ID: ss-2017-e0508-r

Abstract The plethora of transformations attainable by the transition-metal-catalyzed reactions of arynes has found immense contemporaryinterest in the scientific community. This review highlights the scopeand importance of transition-metal-catalyzed aryne reactions in thefield of synthetic organic chemistry reported to date. It covers transfor-mations achieved by the combination of arynes and various transitionmetals, which provide a facile access to a biaryl motif, fused polycyclicaromatic compounds, different novel carbocycles, various heterocycles,and complex natural products.1 Introduction2 Insertion of Arynes3 Annulation of Arynes4 Cycloaddition of Arynes5 Multicomponent Reactions of Arynes6 Miscellaneous Reactions of Arynes7 Total Synthesis of Natural Products Using Arynes8 Conclusion

Key words arynes, transition metal, multicomponent, insertion, natu-ral products, cycloaddition, annulation

1 Introduction

Arynes find prime applications in organic synthesis dueto the presence of a highly electrophilic strained triplebond.1–15 The energy gap between the HOMO and theLUMO of arynes is less compared to that of unstrainedalkynes, which makes them superior electrophiles, hencearynes smoothly react even with weak nucleophiles undermilder reaction conditions.12 The existence of aryne inter-mediates was first indicated after experiments performedby Stoermer and Kahlert in 1902.16 Wittig observed the for-mation of biphenyl by reacting fluorobenzene and phenyl-lithium via a zwitterionic intermediate.17 Furthermore,Roberts and co-workers confirmed the formation of an

aryne by a classical 14C-labeling experiment.18 Severalmethods to generate arynes from varyingly substituted aro-matics or alkynes have been well documented in the litera-ture.5,19–25 However, the generation of arynes from o-(trimethylsilyl)aryl triflate developed by Kobayashi and co-workers26 remains the most convenient and one of the mosthighly utilized methods, which enables various carbon–car-bon and carbon–heteroatom bond-forming processes. Thismild method of aryne generation is also compatible withtransition metals, thus enabling enhanced reactivity givingrise to novel transformations. Such transformations ofarynes to multifunctionalized arenes, heteroarenes, andpolycyclic rings in the presence of transition metals havefound immense contemporary interest in the scientificcommunity. Transition-metal-catalyzed reactions of aryneshave also been found useful in the total synthesis of bioac-tive natural products. Reactions involving an aryne, a nucle-ophile, and an electrophile, referred as a multicomponentreaction, provide diverse 1,2-difunctionalized arenes andheteroarenes in the presence of a transition metal. Polyaro-matic rings, which find prime applications in materialschemistry, are constructed by transition-metal-catalyzedcyclotrimerization and cocyclotrimerization reactions ofarynes. The transition-metal-catalyzed annulation ofarynes with substituted aromatic rings bearing heteroat-oms provides varyingly substituted heterocycles. The gen-eral chemistry of arynes has been covered in many re-views.1–15 Larock and co-workers have reviewed Pd-cata-lyzed aryne reactions reported until 2011.27 Yoshida has abook chapter that highlights transition-metal-catalyzedaryne reactions reported until 2013.28a The present reviewfocuses on transition-metal-catalyzed reactions of arynesreported to date that are not covered in these previous re-ports. Interestingly, a review on a similar topic appearedonline after submission of this review.28b

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1–16

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2 Insertion of Arynes

Insertion of arynes into an element–element bond is afacile and very well explored reaction of high synthetic im-portance.7 The reactants, which otherwise would be unre-active/less reactive with arynes are further activated bytransition-metal catalysis.27,28

The first reported example of the coupling of an alkyneand an aryne in the presence CuI under microwave-assistedconditions was in 2009 by Biehl and Akubathini; this wasthe first example of aryne chemistry under microwave con-ditions. The reaction was performed under microwaveheating in acetonitrile/toluene (1:1) solvent. Various sym-metric and unsymmetric disubstituted alkynes were syn-thesized (Scheme 1).29

Scheme 1 Cu-catalyzed alkyne–aryne coupling

The insertion of an aryne into an ArS–CN bond to givesubstituted 2-(arylthio)benzonitriles 1 was successfullycarried out by Werz and co-workers using a Pd catalyst. Thereaction did not work in the absence of a Pd(II) catalyst be-cause the sulfur in thiocyanate is positively polarized to un-dergo nucleophilic attack, therefore, the activation of arylthiocyanates 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 bondto give intermediate 1a. The Pd complex 1a coordinateswith in situ generated aryne affording 1b. Further, thiomet-alation and reductive elimination of 1b affords substituted2-(arylthio)benzonitrile 1. It was observed that an oxygenatmosphere was crucial to obtain high yields of the expect-ed products. Differently substituted aryl thiocyanates andaryne 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 sub-stituted B–B bond was successfully achieved by the Oestreichgroup in 2015 by employing the catalyst Pt(dba)2 and theligand tBuNC (Scheme 3).31 The resulting diborane products3 were utilized in further C–C bond forming organometallicSuzuki–Miyaura coupling reactions. Excellent regioselectiv-ity was achieved with the first Suzuki–Miyaura coupling re-action occurring unexpectedly at C7 to give 4. Further,

R

OTf

TMS

CsF

MWR + R1 CuI (2.8 mol%)

CsF, 150 °C, 30 minMW, CH3CN/toluene (1:1)

R

R1

25 examples, 59–97% yield

SiMe3

OTf

Pd(OAc)2/Xantphos

CsF, CH3CN, O2

SCN+

40 °C, 24 h

R1SR1

CN

R2R2

19 examples, 5–81% yield1

Pd(OAc)2 + Xantphos [Pd(0)]ArSCN

ArS-[Pd(II)]-CN

ArS-[Pd(II)]-CNSR1

CN

R2

1

R2

R2

1a

1b

nloa

ded

Biographical Sketches

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Mr. Ranjeet A. Dhokale obtainedhis B.Sc. and M.Sc. (NowrosjeeWadia College, Pune) degreesfrom the University of Pune,India. After completing his M.Sc.in organic chemistry he workedat Sai Life Sciences Ltd. as a re-search chemist (2008–2010).
He also qualified the Councilof Scientific and IndustrialResearch-UGC (NET) exam for adoctoral research fellowship andlectureship at national level.Now he is pursuing his doctoralstudies under the supervision ofDr. S. B. Mhaske at CSIR-National

Chemical Laboratory, Pune. Hisresearch interests include devel-opment of novel methodologiesin aryne chemistry and their ap-plication in the total synthesis ofbioactive natural products.

Dr. Santosh B. Mhaske complet-ed his Ph.D. from CSIR-NationalChemical Laboratory, Pune Indiain February 2005. He completedhis postdoctoral studies in theUSA followed by Humboldt Post-doctoral studies at University ofHannover, Germany. He joinedCSIR-NCL as a Ramanujan Fellow

from 2010, and in 2013 he be-came a Senior Scientist at thesame institute. His research in-terest includes; total synthesisof bioactive natural productsand their analogues for SARstudies, development of novelmethodologies useful in thesynthesis of natural products

and drugs, synthesis and bio-logical evaluation of computa-tionally designed molecules,interdisciplinary research direct-ed towards novel, efficient andaffordable treatment of diseas-es.


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Suzuki–Miyaura coupling was carried out on monocoupledproduct 4 with bulky aryl iodides at C6 position giving verygood yields of the 6,7-difunctionalized indoles 5.

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

In 2016, García-López and Pérez-Gómez synthesizedspirobiaryls by reacting N-(2-phenylallyl)sulfonamide 6(X = NTs) with an in situ generated aryne in the presence ofPd(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 ofcomplex 6a affords the intermediate 6b. Path A suggests C–Hactivation of 6b furnishing five-membered palladacycle 7.The insertion of the aryne into complex 7 produces inter-mediate 7a and further reductive elimination furnishesspiro product 8. Alternatively, substrates with a longer teth-ering chain undergo C–H activation producing palladacyclesof type 6f, which undergo insertion with the aryne and fi-nally reductive elimination providing the product 6g. In al-ternative path B, the formation of intermediate 6e via trap-ping of the aryne by intermediate 6b is suggested, followedby C–H activation and C–C coupling to afford the spirocycliccompound 8. The compatibility of the optimized protocolwas tested on various substrates containing alkene, aryl,and heteroaryl moieties and different aryne precursors.

Chen and co-workers reported the insertion of an aryneinto the H–P(O) bond of a secondary phosphine oxide usingcatalytic CuI (Scheme 5). The optimized protocol was testedon various aryne precursors and afforded a diverse range ofarylphosphine oxides. These arylphosphine oxides are auseful source of ligands that also find prime applications inmedicinal chemistry and material science.33

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

The synthesis of spirodehydrobenzofuran 10a andspirooxindoles 10b from alkene 9 via Pd-catalyzed dominoHeck reaction was established by Lautens and co-workers(Scheme 6). The reaction consists of a Pd-catalyzed domi-no-Heck spirocyclization via C–H activation and benzyneinsertion sequence. A wide range of spirooxindoles andspirodihydrobenzofurans were synthesized in good to ex-cellent yields.34

Scheme 6 Pd-catalyzed spirocyclization

The synthesis of heterocycle-fused 9,10-dihy-drophenanthrenes 13 from 1-iodo-2-[(2-methylal-lyl)oxy]benzene 11 and in situ generated aryne wasdemonstrated by Yao and He (Scheme 7).35 IntramolecularHeck reaction of 1-iodo-2-[(2-methylallyl)oxy]benzenegenerates σ-alkyl–palladium(II) intermediate 12, which isintercepted by the aryne followed by C–H activation to af-ford the product 13. This protocol involves the formation ofthree new C–C bonds and the generation of a quaternary

KF (2.0 equiv)18-crown-6 (2.0 equiv)

Pt(dba)2 (5.0–7.5 mol%)tBuNC (25–35 mol%)

(pinB)2 (1.5 equiv)

NMe

TfOTMS

NMe

BpinBpin

(dppf)PdCl2 (10 mol%)Ar1-I (1.0 equiv)KOH (1.7 equiv)

DME/H2O (30:1)45 °C

short reaction time (h)

NMe

BpinAr1

(dppf)PdCl2 (10 mol%)Ar2-I (4.0 equiv)KOH (2.0 equiv)

DME/H2O (23:1)90 °C

long reaction time (overnight)

NMe

Ar2

Ar1

4 examples 70–90% yield


23 4

5

DME, 85 °C

XBr

PhR1

R2

OTf

TMSPd(OAc)2, PPh3, CsF

CH3CN/toluene (1:1), 90 °C

X

PdL L

X

19 examples, 28–91%

6

7

8

R1

R1

R2

Pd(0)Ln

X

PhR1

Br-PdLn

X

PdLn

R1

X

PdLn

R1

X

PdL

XR1

PdLn

+

C–Hactivation

X

PdLn

X

PdLn

X

LnPd

R1

X

PdLn

path A

XR1

XR1

R2

R2

R2

R2

R2

R2 R2

R2

R2

path B

6a

6b

7

7a 8

6e

6f

6f

6g

6

X = NTs, NMe, O, CH2

+

TMS

OTf

R1 CuI (5 mol%)

CsF, CH3CN


PH

R2 R2

O

R2 = aryl, alkyl

PAr

R2 R2

O

R1 R3

OTf

TMS CH3CN/toluene 80 °C, 20 h

I

X+

Pd(PPh3)4 (10 mol%)CsF (2.0 equiv)

R2Cs2CO3 (1.5 equiv)

XOR1 R2

R3

33 examples, 50–96% yield9 10a (X = O)10b (X = N)

O


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carbon center. Overall 26 different substituted heterocycle-fused 9,10-dihydrophenanthrenes including regioisomerswere synthesized in moderate to excellent yields.

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

The above-mentioned examples demonstrate the im-portance of transition metals for controlled reactivity of thesubstrates in the expected transformation utilizing highlyreactive aryne species.

3 Annulation of Arynes

The annulation reaction of arynes catalyzed by transi-tion metals is an important reaction in organic synthesis.Syntheses of various novel heterocycles, which find primeapplication in the pharmaceutical field, have been achievedby the annulation of arynes in a single-step transformation.The annulation process has been efficiently used for thesynthesis of various bioactive natural products.36

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

The mechanism in path A suggests the formation of pal-ladacycle 15a by coordination of Pd(0) with benzyne. Theoxidative addition of vinyl iodide 15 to palladacycle 15aleads to arylpalladium(IV) complex 15b, which on reductiveelimination generates arylpalladium intermediate 15c.However, alternatively in path B, the complex 15a′ formedvia oxidative addition undergoes insertion with the aryneto generate intermediate 15c. Intramolecular Heck couplingof intermediate 15c furnishes 15d, which on subsequent β-hydride elimination and aromatization affords the product17. A similar mechanism is proposed for 16.

Larock and co-workers introduced a novel protocol forthe synthesis of diverse phenanthridinones 19 by simulta-neous C–C and C–N bond formation. The reaction involvedan aryne precursor, o-halobenzamides 18, a Pd catalyst, CsF,and a base in toluene/acetonitrile (4:1) solvent. Mechanisti-cally, the palladacycle 18a (path a) undergoes oxidative ad-dition with 18 to generate Pd(IV) intermediate 18b. Furtherreductive elimination affords the arylpalladium(II) interme-diate 18c. Alternatively, in path b the oxidative addition ofPd(0) with 18, followed by carbopalladation of the aryneproduces intermediate 18c. The intermediate 18c, underbasic condition cyclizes to 18d, which undergoes reductiveelimination affording the product 19. A total of 25 phenan-thridinones were obtained in moderate to good yields(Scheme 9).36

R1R2

OTf

TMSCsOPiv (1.2 equiv)

CH3CN/toluene, 90 °C16 h


I

AB

Rn

R1

AB

RPdI

n

R1

AB

R

n

R2

+

Pd2(dba)3 (2.5 mol%)P(o-Tol)3 (10 mol%)

CsF (2.0 equiv)

12

1311A,B = -NR', -O-, -CO, -CH2, -CH

n = 0,1

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

Pd2(dba)3⋅CHCl3 (5 mol%)dba (5 mol%)Cs2CO3, CsF

CH3CN/toluene (1:1)

TMS

OTf14 examples, 49–75% yield

R +

R1R1

O

I

R2

R2

n

or

O

O R3

R2

R1

I

R1R1

O R2

R2O

O

R1 R2

R3

or

R R

14

15

16 17

n

Pd(0)

R

path A

Pd R

1515a

Pd

O

O R3

R2

R1

I

R15bO

O

R3

R2R1

PdI

R15c

O

O

R2R1

R3

PdI

R15d

O

O

R2R1

R3

R

17

O

O R3

R2

R1

PdI

15

R

path B

Cs2CO3

15a'

Scheme 9 Phenanthridinones by annulation of o-halobenzamides with arynes

Br(I)

Pd(OAc)2 (5 mol%) dppm (10 mol%)

CsF, Na2CO3, 110 °C

toluene/CH3CN (4:1), 16–24 hR1 NHR2

O

+

TMS

OTf

NR1

OR2

R3

R325 examples, 36–87% yield18 19

Pd(0)

R3

path a

R3 Pd

18a

PdBr

R3

O

NHEtR1

18b

NHEtR1

PdBr

O

R3

18c

– HBr

O

NEtR1

PdL

R3

18d

19

O

NHEtR1

PdBr

18path b

R318a'

18


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The highly electrophilic nature of arynes has been usedfor the construction of diverse carbazoles 21 by annulationwith 2-haloacetanilides 20 in the presence of Pd(dba)2 cata-lyst, dppf ligand, CsF, and toluene/acetonitrile (4:1) as thesolvent. Both C–C and C–N bonds were formed simultane-ously. A diverse range of carbazoles was prepared from in-expensive 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 arynesinto the C–S bond of α-carbamoyl ketene dithioacetals 22catalyzed by Pd(OAc)2 and dppf as the ligand. Mechanisti-cally, the palladacycle 22a undergoes insertion into the C–Sbond to afford intermediate 22c via 22b. The seven-mem-bered palladacycle 22d is formed at the expense of the thio-anisole derivative through intramolecular substitution of22c; reductive elimination of 22d offers the expected prod-uct 23. The alternative path B suggests the oxidative addi-tion of the Pd complex to one of the C–SR bonds, followedby aryne insertion leading to palladacycle 22c, which finallyprovides product 23. Various alkylthio-substituted quino-lines 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 syn-thesis of 2,3-disubstituted benzofuran derivatives 25 con-taining a trisubstituted alkene functional group from the

preinstalled alkyne in 24. In the proposed mechanism, in-tramolecular ene reaction of the preinstalled alkyne withthe aryne precursor in the presence of Pd(PPh3)4 catalystand CsF leads to the formation of allene intermediate 24a.In situ formed ArPdI undergoes insertion with 24a furnish-ing π-allyl–palladium complex 24b. Finally β-H eliminationaffords the isomeric benzofuran derivative 25 in moderateyields (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-work-ers in 2014 for the synthesis of various substituted phenan-thridinones 27 by Pd-catalyzed annulation of a benzynewith an N-substituted N-(2-halophenyl)formamide 26.Pd(OAc)2 was the most successful catalyst for this reactionalong with P(o-Tol)3 as the ligand. This protocol was generaland various substituted N-(2-halophenyl)formamides aswell as arynes were tolerated. Regioisomeric products inthe ratio 1.6:1 were observed for an unsymmetrical chloro-aryne 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 ofphenanthridines 29 via Pd-catalyzed C–H activation fromaryl ketone O-acetyloximes 28 and arynes (Scheme 14).42 Ingeneral, preactivated substrates are used for the synthesisof such heterocycles using aryne chemistry, but in this case,the synthesis of phenanthridines was carried out throughC–H bond activation involving a directing group. The proto-col was established successfully using Pd catalyst, CuCl2 as

HN

I

Pd(dba)2 (5 mol%) dppf (10 mol%)

CsF (5 equiv), 110 °C

toluene/CH3CN (4:1), 24 h

R1 +

TMS

OTf R1

R2

O

N

O R2

R3

R3

27 examples, 30–77% yield20 21

TMS

OTf

Pd(OAc)2/dppf

CsF, toluene/CH3CN+

80 °C, 18 h

R1

RS

SR

NHR2O N

SRR1

OR2

R3R3


R3

R3 Pd

R1RS

PdSR

R1

SR

OPdRS

R3

PhSR

R1

RS

O

NR2

Pd

R1

SR

O

PdRS

Pd(0)

path B 22

22

R3

23

path A

22a

22b

22c

22d

OR2N

NR2

NR2

OTf

TMSO

+

Pd(PPh3)4 (5 mol%) CsF (3.0 equiv)

CH3CN, refluxO

R1

R2

R1

R3

R2

I

R3


24 25

O

R1

R2

ene reaction

O

•

R2

R1

OR2

R1Ar

PdI

HPdI

Pd(0)

ArIArPdI

HI

24

24a

24b

25

N

I

Pd(OAc)2, P(o-Tol)3, CsF

toluene/CH3CN (1:1)110 °C

R1+

TMS

OTf


Ph

H

OR2

N O

Ph

R2

R1

26 27


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an oxidant, and Cs2CO3 as the base. The reaction workedwell for different combinations of substituted O-acetylox-imes and substituted aryne precursors.

Scheme 14 Phenanthridines from ketoximes and aryne precursors

Transition-metal-catalyzed C–H functionalization is avery powerful synthetic strategy in building complex mole-cules. The Xu group43 and Jeganmohan and Pimparkar44

both reported this concept in aryne chemistry independent-ly in 2014. This methodology involves the Pd N–H/C–H acti-vation of amides 30, aryne insertion, and cyclization in thepresence of catalytic Pd(OAc)2 to provide a tricyclic phenan-thridinone core 31. The Xu group used Pd(OAc)2 as the cata-lyst, Cu(OAc)2 as the oxidant, and DMSO/dioxane solvent,43

whereas Jeganmohan and Pimparkar optimized the proto-col using Pd(OAc)2 as the catalyst in combination with ada-mantane-1-carboxylic acid as the ligand and K2S2O8 as theoxidant.44 The Xu group extended the methodology to cy-clooctynes, which also yielded the expected products ingood yields (Scheme 15).43 Mechanistically, the five-mem-bered palladacycle intermediate 30a is formed via coordi-nation of nitrogen with Pd followed by orthometalation.The in situ generated aryne undergoes insertion to form aseven-membered palladacycle intermediate 30b. The re-ductive elimination of complex 30b furnishes the product31 (Scheme 15).44

In 2015, the Xu group extended (Scheme 15)43 theirmethodology by reacting acrylamides 32 with arynes deliv-ering diverse quinolinones 33. The optimized protocol wasdeveloped in which Pd(OAc)2, Cu(OAc)2, and tetrabutylam-monium bromide (TBAB) in DMSO/dioxane (1:9) was usedto give quinolinones 33 in moderate to good yields. A vari-ety of quinolinones were synthesized using substitutedaryne precursors (Scheme 16).45

Scheme 16 Quinolinones from annulation between acrylamides and arynes

In 2016, Yao and co-workers developed a protocol forthe synthesis of substituted 9,10-disubstituted phenan-threnes by annulation of o-halostyrenes with an aryne inthe presence of a Pd catalyst. Various substituted o-halosty-renes 34 reacted with simple aryne precursors giving mod-erate to good yields of 9,10-disubstituted phenanthrenes35. The substrate scope for variously substituted aryne pre-cursors 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 biologi-cally important diverse coumestans 37 from arynes and 4-hydroxycoumarins 36 (Scheme 18). The reaction proceedsthrough C–H activation of the 4-hydroxycoumarin. Mecha-nistically, the anion species 36a undergoes C–H activationat 3-position to give intermediate 36b, which undergoescarbopalladation with the aryne precursor to give interme-diate 36c that converts into 37 in the presence of a base.The catalyst was regenerated by Cu(OAc)2, which acts as anoxidant (Scheme 18).47 In total, 20 substituted coumestanswere synthesized in moderate to good yields. Moreover, theprotocol was compatible with halo-substituted 4-hydroxy-coumarins.47

In 2017, Zhang and co-workers reported the annulationof directing group containing benzamides 38 by benzynesin the presence of Cu(OAc)2 catalyst. The resulting ortho-C–H/N–H annulations afforded the biologically importantphenanthridinone compounds 39. The reaction was per-formed using TBAI in DMF/CH3CN solvent under an oxygenatmosphere. The optimized protocol was tested on a wide

Pd(OAc)2, PPh3 Cs2CO3/CuCl2, CsF

toluene/CH3CN (3:1)80 °C, 36 h

+

TMS

OTf


R2

NOAc

R1

HR3

R3

N

R3R3

R1 R1

28 29

Scheme 15 Annulation between benzamides and arynes

Pd(OAc)2 (5 mol%)Cu(OAc)2 (2 equiv)

DMSO/dioxane (1:9)80 °C, 15 h


H

N

OOMe/Me

H +N

OOMe/Me

Pd(OAc)2 (5 mol%)Adm-1-CO2H (20–30 mol%)

K2S2O8, CsF, CH3CN100 °C, 12 h

R2

R1

R1R2


30 31

R1

N

OOMe/Me

R2

R131

PdLn

N

OOMe/Me

R2

N

OOMe/Me

R2 PdLn

Pd(II)(L)n

RCOOH + K2S2O8

L = OCOR, CH3CN

30a

30

30b

N

OOMe

H+

N

OOMe

Pd(OAc)2 (5 mol%)Cu(OAc)2 (2 equiv)

DMSO/dioxane (1:9)80 °C, 15 h

R3

R3


R2

R1 R1

R2

32 33

TBAB (1 equiv)

I

Pd(dba)2 (5 mol%) dppm (10 mol%) CsF (3.5 equiv)

toluene/CH3CN, 110 °CR1 +

TMS

OTf

EWG

R2

R1

EWG

R2



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range of benzamides and substituted aryne precursors toafford 44 substituted phenanthridinone compounds(Scheme 19).48

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

Several reports36–48 on the synthesis of biologically rele-vant heterocycles such as naphthofurans, phenanthridi-nones, carbazoles, using the aryne annulation process sug-gest its importance for their construction and structure–ac-tivity relationship studies.

4 Cycloaddition of Arynes

The cycloaddition of arynes is a well-known reactionthat furnishes scaffolds of biological interest, however, thecontrol of both regio- and chemoselectivity remained agreat challenge. Transition-metal catalysis has advantagesover traditional methods as it improves these important as-pects of the reaction. The cyclotrimerization of arynes andalkynes/alkenes/allenes has been reviewed reviewed in de-tail 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 pro-viding substituted naphthalenes 41 containing five- to sev-

en-membered rings (Scheme 20).50 NiBr2(dppe) was themost appropriate catalyst for this transformation, whilezinc promoted the reduction of the Ni(II) species to a Ni(0)species, which initiates the reaction. In the proposed mech-anism, the complex 40a formed by the coordination of bothC≡C bonds of the diyne to the Ni(0) center, undergoes cyclo-metalation furnishing 40b. The in situ generated aryne isinserted into complex 40b affording nickelacyclohepta-triene intermediate 40c, which on reductive eliminationgenerates 41 and regenerates the Ni(0) catalyst. The estab-lished protocol was sensitive to substituents on both thediyne and aryne.

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

In 2008, Cheng and Hsieh employed o-dihaloarenes asaryne precursors for the Ni-catalyzed [2+2+2] cycloadditionwith alkynes or dialkynes 40a and nitriles to give substitut-ed naphthalene, phenanthridine 29a, or triphenylene deriv-atives (Scheme 21).51 The key step of this transformation isthe Ni-assisted generation of the aryne. The cycloadditionreaction also worked well with various diynes, nitriles,disubstituted acetylenes, and o-diiodoarenes.

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

O O

OH

R1 +OTf

TMSR2

Pd(OAc)2 (5 mol%)Cu(OAc)2·H2O (1.2 equiv)

CsF (2 equiv)

NaOAc (1.2 equiv), CH3CN120 °C

O

O

O

R2

R1


36

37

O O

O

R1

Pd(OAc)

O O

OPd(OAc)

R1

O O

OH

R1

Pd(OAc)

O O

O

R1

H PdO O

CH3

R2

O O

ONa

R1

NaOAc

Pd(OAc)2

Pd(0)

Cu(OAc)2

NaOAc

C–H insertion

NaOAc

36a

36b

36c

H

N

OQ

H+

N

OQCu(OAc)2, CsF

DMF/CH3CN, O2, 80 °C12 h

OTf

TMSR1 R2 TBAI R1

R2


38 39

+

OTf

TMS

R3

R4X

R1

R2

NiBr2(dppe)/Zn

CsF, CH3CN, 80 °CX

R1

R2

R3

R4


XR1

R240

X

R1

R1

NiP

P

XNiP

PR3

R4

R3

R4

Ni

XP

P

X

R1

R2

R3

R4

41

R1

R1

R1

R1

Ni

Ni(0)P

P

Zn

40a

40b

40c

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

I/Br

I/Br+

X

Ni(dppe)Br2/dppe/Zn

CH3CN, 100 °C


R4

R2

R3

R4

R1R1

R4

R2

R3

R4

R1

R1

R1

R1or

R5

R5

R4

R2

R3

R4

R5

R5

or

XNi(dppe)Br2/ZnRCN, 100 °C

36 h

NR

R2

R3 R3

R2 5 examples, 34–76% yield

40a

29a

41a


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There are few reports on the [2+2+2] cycloaddition ofarynes and activated alkene moieties. Sato and co-workerswere the first to report the [2+2+2] cycloaddition of anaryne and unactivated alkene catalyzed by a Ni catalyst. Theaim of the [2+2+2] cycloaddition of an aryne and α,ω-diene42 was to synthesize the 1,2,3,4-tetrahydronaphthaleneskeleton, but it afforded 9,10-dihydrophenanthrene deriva-tives 43 in good yield together with a low yield of the dien-yl-substituted biphenyl 44 (Scheme 22).52 Reaction of vari-ous dienes with the unsubstituted aryne precursor gavemoderate yields of 9,10-dihydrophenanthrenes. Goodyields were obtained when a diene (X = cyclic acetal) wasreacted with an aryne precursor bearing an electron-donat-ing group.

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

The transition-metal-mediated [2+2+2] cycloaddition ofalkynes and alkenes is an asset for building complex struc-tures. Prior to aryne methodology, Xie and Qiu reported theNi-mediated [2+2+2] cycloaddition of carboryne (1,2-dehy-dro-o-carborane), alkynes, and alkenes.53 Due to the similarreactivity pattern between carboryne and aryne, they ex-tended it to afford diverse dihydronaphthalenes that aredifficult to prepare from simple starting materials. After op-timization of the reaction conditions, the use of Ni(cod)2 (5mol%) and CsF (6 equiv) in acetonitrile at room temperatureafforded the dihydronaphthalenes in very good yield to-gether with trace amounts of a regioisomer. Using differentsubstituted aryne, alkynes, and alkenes gave a total of 19differently substituted dihydronaphthalenes (Scheme 23).54

Mechanistically, the five-membered Ni complex I isformed by co-ordination of Ni(0) with the benzyne andalkene through oxidative coupling. Further alkyne insertionwith complex I produces the seven-membered intermedi-ate II followed by reductive elimination affording the dihy-dronaphthalenes (Scheme 23).54

The use of arynes in stereoselective reactions is veryrare. In 2011, Lautens and Candito reported the stereoselec-tive Ni-catalyzed [2+2+2] cycloaddition of arynes and 1,6-enynes 45. The substituent near to the C=C bond proved tobe a crucial factor for diastereoselectivity. The proposedmechanism involves the formation of an enyne complex bycoordination with the Ni(0) catalyst followed by oxidativeaddition. The complex then coordinates with the aryne byinsertion into one of the carbon–metal bonds followed byreductive elimination resulting in 46. The trans stereo-chemistry is set at the stage where enyne complex isformed with the Ni(0) catalyst. A model study suggests twodiastereotopic complexes, which can cyclize in an irrevers-ible step, but the transition step having lower 1,3-allylicstrain 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] cycload-dition of an aryne with (diarylmethylene)cyclopro-pa[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 isomersin 1:1 ratio. The synthetic utility of the obtained 11-(diaryl-methylene)-11H-benzo[b]fluorenes 48 was demonstratedby treating them further under different transition-metal-catalyzed reaction conditions.

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

Argade and Patel reported the synthesis of differentlysubstituted arylnaphthalenes 50 by metal-catalyzed[2+2+2] cocyclization of arynes with unsymmetrical conju-gated dienes 49 in the presence of Pd2(dba)3 catalyst and aN-heterocyclic carbene ligand (Scheme 26).57 In the mecha-nism, the oxidative insertion of the Pd catalyst with aryneand diene affords five-membered palladacycle 49a whichrearranges to 49b via insertion of a double bond into thePd–C (alkyl bond). Finally, reductive elimination of the Pdcatalyst gives intermediate 49c which is oxidized, produc-

OTf

TMS+X

Ni(cod)2 (10 mol%)SIMes⋅HBF4 (10 mol%)

CH3CN, 50 °C, 6 h

X X+

major minor


43 44X = CH(CO2Me), cyclic acetal, NTs, O

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

OTf

TMS

CsF (6 equiv)

CH3CN, rt+

[Ni(cod)2] (5 mol%)R2

R3 R4

R2

R4R3

R1 R1


R2

R3 R4

R2

R4R3 R1

R1

Ni O

OMe

R2 = CO2Me

R1 Ni

R3 R4

CO2Me

Ni0

+

I

II

OTf

TMS+

R2R3

R4

X

R1

R5

Ni(cod)2 (20 mol%)CsF (3 equiv)

CH3CN, 24 h

13 examples, 35–100% yield up to >20:1 dr

45

X

R1 R2

R3

R4

R5 46R H

Pd(dba)2 (5 mol%)PPh3 (10 mol%)

CsF, CH3CN, rt+

TMS

OTf


Ar

Ar

ArAr

R

R47 48


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ing arylnaphthalene 50. Six different substituted arylnaph-thalenes were synthesized in good yields by reaction of var-iously substituted aryne precursors with unsymmetricaldienes.

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

In 2012, Cheng and co-workers reported the synthesisof isochromenones 53 and oxepines 54 by reacting 2-iodo-benzyl 3-phenylpropynoates 51 and 1-iodo-2-[2-(phenyl-ethynyl)benzyloxy]benzenes 52, respectively, with arynesin the presence of Pd(dba)2 catalyst and Tl(OAc) (Scheme27).58 The reaction proceeds by Pd insertion into the iodocompound followed by C–H activation and then insertion ofbenzyne leading to the expected product. Mechanistically,intermediate 51b is formed via Pd(0) oxidative addition andinsertion into the C≡C bond through palladium complex51a. Intermediate 51b undergoes C–H activation to form apalladacycle 51c. Further insertion of aryne with palladacy-cle 51c gives the seven-membered intermediate 51d, whichundergoes reductive elimination producing 53. This proto-col produces two new rings. Various substituted iodo com-pounds and aryne precursors were compatible with the op-timized protocol.

Ma and co-workers reported the synthesis of 9-vinyl-phenanthrenes 56 by reacting two molecules of benzynewith propargylic carbonate 55 in the presence of Pd(OAc)2catalyst and tris(2-furyl)phosphine (TFP) ligand (Scheme28).59 Mechanistically, it is proposed that an intermolecularreaction takes place between benzyne and an allenylpalla-dium complex. The allenylpalladium complex 55a, formedvia oxidative addition of Pd with intermediate 55, is insert-ed into the aryne leading to 55b, subsequently anotheraryne insertion with 55b and carbopalladation of interme-diate 55c furnishes intermediate 55d. Finally, β-hydrideelimination from 55d produces the expected phenanthreneproducts 56.

Greaney and co-workers reported the synthesis oftriphenylenes by trimerization of arynes, which were de-rived from ortho-substituted arylboronates 57. The reactionwas carried out in the presence of Pd(dba)2 catalyst, DPEphosligand, and potassium tert-butoxide in toluene as a solventat 100 °C; various substituents were tolerated (Scheme29).23 The metal-bound aryne intermediates are formedand these undergo trimerization.

+

[Pd2(dba)3]

CH3CN, reflux, 24 h

O

OMeMeO

O H

Ar

R

RAr

O

OMe

O

OMe


CsF

49 50

OTf

TMS

R

R

Pd

Pd

CO2Me

Pd0

+

R

RAr

O

OMe

O

OMe

49c

R

R

R

R

HAr

O

OMe

CO2MeAr

CO2MeR

R

rearrangement

reductive elimination oxidative

addition

49

49a

49b

air oxidation50

IMes·HCl

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

SiMe3

OTf

Pd(dba)2/Tl(OAc)

CsF, CH3CN/toluene

R

R

O

R1 O

PhI

+

85 °C, 8 h

OR1

OPh

R

R

or

O

R1

I

R2

OR1

R

R

R2

or


51

52

53

54

OR1

OPh

R

R

51

53O

R1

PdL

I

O

Ph

R1

O

O

PhPd

L

R1

O

O

PhPd

R1

O

O

PhPd

Pd(0)

51a

51b

51c

51d

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

SiMe3

OTf

Pd(OAc)2 (5 mol%)

CH3CN, 60 °C, 22–35 h

TFP (5 mol%)CsF (6 equiv)

R1

OCO2Me

R2

+

R1 R2

R3 R3


R1

PdOMe

R2 R3

•R2

R3 R1

PdOMe

R1

•R3

R2

PdOMe

R1 •

R3

R2

PdOMe

R1 R2

R3

PdOMe

Pd(0)

HPdOMe56

55

CO2

formaldehyde

55a

55b 55c

55d


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Scheme 29 Triphenylenes by Pd-catalyzed trimerization of arynes

In 2015, Chen and co-workers were the first to reportthe cyclotrimerization of arynes using (Ph3P)AuCl. Themechanism for this reaction is very similar to Pd(0)-cata-lyzed cyclotrimerization. These results provide an efficientprotocol for the synthesis of triphenylene derivatives bygold catalysis, which should also lead to the discovery ofnew applications of gold complexes in aryne chemistry(Scheme 30).60a

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

Garg and co-workers reported a novel class of heteroat-omic indole-based trimers (Scheme 32). The synthesis ofthese unique scaffolds was achieved by reacting in situ gen-erated indolyne intermediates in the presence of a Pd cata-lyst. Further computational studies were performed forstructural and photophysical properties of the conjugatedtrimeric scaffolds.60c

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

5 Multicomponent Reactions of Arynes

Multicomponent reactions (MCR) of arynes in the pres-ence of a transition metal provide easy access to 1,2-difunc-tionalized arenes. The two new bonds are constructed si-multaneously on the aryne intermediate. The resultingproduct of the MCR can further be used for the constructionof natural products or bioactive pharmaceuticals.

Snowden and Ganta elegantly carried out the difunc-tionalization of substituted arynes by reaction of in situgenerated lithium bis[3-(trimethylsilyl)prop-1-enyl]cuprateand appropriate electrophiles, such as allyl bromide andethyl chloroformate. Three equivalents of the lithiated allyl-trimethylsilane were generated in situ, one equivalent wasutilized to generate the aryne from the 1-iodo-3-(triflyl-oxy)arene. The aryl anion generated was trapped with ethylchloroformate and various alkyl or allyl halides. This proto-col afforded exclusively E-diastereoselective functionalizedhomobenzylic vinylsilanes 58 (Scheme 33).61

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

Pineshi and co-workers successfully carried out the aryl-ation of vinylaziridines by using an aryne and a terminalalkyne in the presence of CuI–PPh3. The reaction is initiatedby attack of the terminal alkyne onto the aryne to generatean arylcopper(I) species, which opens the vinylaziridine toprovide allylic amines such as 59. The reaction was SN2′ re-

Bpin

Br/OTf

Pd(dba)2 (5 mol%)

toluene 100 °C, 16 h

DPEphos (5 mol%)tBuOK (1.1 equiv) Pd

Pd-bound aryne

R R

R

R

R


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

SiMe3

OTf

(Ph3P)AuCl (10 mol%)

CsF, CH3CNR R

R

R7 examples, 45–88% yield

Scheme 31 Synthesis of nanographene from a polycyclic aryne

TMS OTf

TMSTfO

CsF(4+2)

cycloaddition

OTf

TMS

nano graphene

perylene

CsF, [Pd2(dba)3]

[2+2+2] cycloaddition

22 rings, C78H36

polycyclic aryne

Scheme 32 Conjugated trimeric scaffolds accessible from indolyne

NMe

TfOTMS

CsF, [Pd2(dba)3]

BINAP, CH3CN, 50 °C

MeN

NMe

MeN

MeN

MeN

NMe+

SiMe3

X

Y

I

OTf

1. s-BuLi, THF, –48 °C;CuI, –48 °C to 0 °C, then

X

Y+

SiMe3LiCu

2

1. E+, –48 °C to rt12 h

X

Y

E

SiMe3

E = H, alkyl, allyl, OH, NR2, CO2Et(yields up to 84%)


58


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gioselective in the case of acyclic vinylaziridines. Various vi-nylaziridines reacted with benzyne to give the product al-lylic 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 ringis a challenging and highly desired transformation. The vici-nal difunctionalization of arenes using trifluoromethylatedreagents was first reported by Hu and co-workers in 2013,who ingeniously reacted an aryne with 1-iodophenylacetyl-ene, 2,2,6,6-tetramethylpiperidine (TMP) and AgCF3(Scheme 35).63 The TMP plays an important role in the di-functionalization of the aryne. Mechanistically, intermedi-ate I is formed via the reaction between the aryne andAgCF3·TMP; I further hydrogen bonds with another TMPmolecule to provide II. Abstraction of a proton from II andcoordination with iodophenylacetylene produces III. The‘ate’ complex IV is formed by intramolecular nucleophilicattack, which rearranges to afford the expected product, a1-iodo-2-(trifluoromethyl)benzene. Methyl- and phenyl-substituted aryne precursors gave product mixtures of re-gioisomers in 1:1 ratio. However, excellent regioselectivitywas observed for the methoxy-substituted aryne precursor.

Scheme 35 Ag-mediated trifluoromethylation–iodination of arynes

Isocoumarins are basic key structures found in variousnatural products. Kobayashi and co-workers synthesizedsubstituted isocoumarins 60 in a single-step transformationusing arynes (Scheme 36).64 The in situ generated aryne re-acts with copper acetylide, generated from phenylacetyleneand NHC–copper hydroxide or carbonate. Mechanistically,the intermediate 60a is intercepted by CO2 producing cop-

per carboxylate 60b; the copper heterocycle 60c is formedvia 6-endo-dig cyclization of 60b. Finally, transmetalationwith a cesium salt furnishes 60d, which is then convertedinto the isocoumarin. The substrate scope was demonstrat-ed on substituted aryne precursors as well as on aryl/alkyl-substituted terminal alkynes.

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

Nishihara and co-workers reported the synthesis of cya-no-substituted iminoisobenzofurans by one-pot reaction ofarynes, isocyanides, and cyanoformates in the presence ofcatalytic [Pd(NCPh)2(dppf)](BF4)2 (Scheme 37).65 Along withiminoisobenzofurans 61, minor amount of α-iminonitriles62 were also formed. The iminoisobenzofurans were thenconverted into α-iminonitriles using DIBAL-H or the Lewisacid AlMe3. In these reactions, the formation of three newC–C bonds at the expense of one C–C bond cleavage and mi-gration 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 substitutedpyrazolo[5,1-a]isoquinolines 64 by reaction of 2-alkynyl-benzaldehyde 63, sulfonylhydrazine, and benzyne in thepresence of silver triflate (Scheme 38).66 An intermediateisoquinolium-2-ylamide, generated from the 2-alkynyl-benzaldehyde and sulfonylhydrazine in the presence ofLewis acid, undergoes [3+2] cycloaddition with the aryne togive the pyrazolo[5,1-a]isoquinoline.

OTf

TMS+

NTs

+ R

CuI (10 mol%)PPh3 (10 mol%)

i-Pr2NEt (5 equiv)CsF (3.0 equiv)toluene/CH3CN

55 °C, 18 hNHTs

R


59

RTMS

OTf+ AgCF3 + Ph I

CsF, TMPCH3CN

50 °C, 5 h

RCF3

I10 examples, 35–94% yield

R

AgCF3·TMP

RAgTMP

CF3

NAgArH

NHB

NAgArH

N

NAgArH

NI

I Ph

Ag species

RCF3

I+ Ph Ag

AgCF3TMP

1-iodophenylacetylene

B = TMP, Ag(CF3)2 or F

Ph

CF3

RI

II III

IV

R1 H +

TMS

OTf

R2+ CO2

IPrCuCl

CsF, Cs2CO3

CH3CN/THF (1:1)

OR2

O

R1

15 examples, 33–84% yield 60

R1 H

R2

R1 Cu

R2[Cu]

R1

R2

R1

O

O[Cu]

OR2

O

R1

[Cu]

OR2

O

R1

[Cs]

[Cu]

H2O

[(IPr)CuCl]Cs2CO3

[Cs]

CO2

60a

60b

60c

60d

OTf

TMS

+[Pd(NCPh)2(dppf)](BF4)2 (10 mol%)

KF/18-crown-6 (4 equiv)THF, 50 °C, 18 h

R1 CN-R2

NC

O

R3

R1

O

NR2

CNR3

+

R1

COR3

NR2

CN

DIBAL-H

0 °C to rt16 examples, 40–67% yield

61 62


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2-Vinylcyclopropane-1,1-dicarboxylate was utilized asan electrophile for the first time in a three-component cou-pling reaction with an aryne; a terminal alkyne was em-ployed as the nucleophile (Scheme 39).67 The reaction con-ditions utilized catalytic Pd(dba)2, with dppp as the ligand,and CuI for the synthesis of difunctionalized arenes 65. Theterminal alkyne undergoes addition to the aryne to gener-ate a carbocopper intermediate, which then attacks the cy-clopropanedicarboxylate ring activated by the transitionmetal. Regioisomers were observed in the case of unsym-metrical aryne precursors.

Jiang and co-workers reported the construction of vari-ously substituted phenanthridinones 19a and acridone al-kaloids 66 by Pd-catalyzed and ligand-controlled regiodi-vergent C1 insertion involving an aryne, CO, and a 2-iodo-aniline (Scheme 40).68. Mechanistically, the Pd catalystwithout a bulky ligand undergoes oxidative addition withiodoaniline. The in situ generated aryne co-ordinates withthe complex 19a′ followed by insertion to provide the inter-mediate 19c′. The insertion of CO provides acyl–Pd species19d′, which on reductive elimination delivers the phenan-thridinone product 19a. When the bidentate phosphine li-gand bis(diphenylphosphino)methane (dppm) was em-ployed, complex 66a′ coordinates with CO instead of thearyne due to steric hindrance, giving intermediate 66c′. Fur-ther interception of 66c′ with aryne followed by reductiveelimination of Pd affords the acridone product 66. Optimi-zation showed that for phenanthridinone synthesis theconditions required were Pd(OAc)2 as catalyst and TBAI asthe additive; to avoid the formation of the minor productacridone 10% H2O was added to the acetonitrile solvent. Theoptimized synthesis of acridones also used Pd(OAc)2 as cat-alyst, but the addition of the ligand dppm was crucial; theslow release of aryne was also important, and was achievedby using KF.

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

OTf

TMS

+AgOTf (10 mol%)

CsF, Et3NBCl CH3CN/1,4-dioxane


CHO

R2

R1

TsNHNH2

R1

N

R2

N63

64

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

OTf

TMS

+R1

+ CO2Me

CO2MePd(dba)2, dppp, CuI

KF, 18-crown-6, CH3CN50 °C, 16 h

R1

CO2Me

CO2Me

R R


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

TMS

OTf

I+

NHR1

NOR1

N

O

R1

R2 R3

Pd(OAc)2, K2CO3

CsF, TBAI

CH3CN (10% H2O)CO

R2 R3 Pd(OAc)2, K2CO3

KF, dppm

CH3CN, COR2 R3

33 examples, 45–88% yield19a 66

NPdII

R1

R2

R3

NR1

R2

R3

PdII

O

PdII

NHR1R2

I

Pd

NR1R2

I

R3

N

O

R1

R2

R3

PdP

P

R3

R2 PdP

P

NR1

O

PdP

PR1HN

R2

CO

PdPP

NHR1R2

I

Pd(0)

C O

R3

C O

spacious metal center catalysis

p coordination

slow released aryne precursor

19a66

iodoaniline

66a'

66b'

66c'

66d'

19a'

19b'19c'

19d'


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Jiang and co-workers extended their previous method-ology (Scheme 40) to the synthesis of phenanthridinone19b through C–H activation. The reaction was carried out inthe presence of unactivated anilines, aryne, and CO. The useof CuF2·2H2O for the slow release of aryne was found to becrucial to obtain high yields of products. Diverse phenan-thridinones 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-potdifunctionalization of arynes via C–C and C–S bond forma-tion by reacting terminal alkynes, arynes, and benzenesul-fonothioates in the presence of catalytic CuI to give 1-alkynyl-2-(arylthio)benzenes 67 (Scheme 42).70 Varioussubstituents on the aryne precursors, terminal alkynes, andbenzenesulfonothioates were tolerated.

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

Hu and Zeng extended their previous methodology(Scheme 35) for the one-pot trifluoromethylthiolation–io-dination of arynes with (trifluoromethylthio)silver and 1-iodo-2-phenylacetylene (Scheme 43).71 The in situ generat-ed aryne undergoes insertion in the Ag–S bond to providean o-SCF3-substituted arylsilver intermediate, which is fur-ther trapped by 1-iodo-2-phenylacetylene to afford 1-iodo-2-(trifluoromethylthio)arenes in good yields. These prod-ucts 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 ef-ficient 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 po-lymerization reaction has also been reported.

The ortho-palladated derivatives of α,α-dimethyl-phenethylamine (phentermine) 68 (R = Me, X = H) and ho-moveratrylamine 68 (R = H, X = OMe) were reacted withbenzyne to give eight-membered palladacycles 69. This isthe first report of the isolation of an aryne-inserted pallada-cycle. The palladacycle on reaction with CO in methanolproduced unnatural amino acids 71 (Scheme 44).72

Scheme 44 Synthesis of unnatural amino acids

The 10- and 11-membered palladacycles were also syn-thesized by reacting the ortho-palladated derivative of ho-moveratrylamine 68a with insertion of two molecules ofbenzyne. The palladacycle 72 reacted with CO or RNC to af-ford products 75 and 76, respectively (Scheme 45).73

Scheme 45 Synthesis of 10- and 11-membered palladacycles

Knochel and co-workers utilized 2-iodophenyl arene-sulfonate precursors 77 for the generation of arynes usingiPrMgCl.19 Studer and co-workers used this aryne precursorfor the synthesis of 2,2′-disubstituted biphenyls 78. Li2CuCl4was a suitable catalyst for the homocoupling under an oxy-gen atmosphere. Moderate yields of 2,2′-disubstituted bi-phenyls 78 were obtained (Scheme 46).74

TMS

OTf+

NHR2R1 R3

Pd(OAc)2, Cu(OAc)2

KOAc, KI, CuF2·2H2O

DMF/CH3CN R1

NR2

O

R3


HCO

19b

OTf

TMS

+R1

+CuI (10 mol%), BnBr (2 equiv)

CsF, 18-crown-6, K2CO3

CH3CN, 40 °C

SR2

R R


PhSO2SR2

R167

R

TMS

OTf+

AgSCF3

Ph I

rt, 8–24 hR

I

SCF3


CH3CN

X

X

R

NH2

R

PdY

)2

PdNH2

X

X

RR

Y)2

PdNH2

X

X

RR

YL

CO2MeNH3Y

X

X

RR

L

COMeOH– Pd(0)

X = H, OMeY = Cl, BrR = Me, H

6869

70

71

MeO

MeONH2Pd

Br) 2

L

MeO

MeO

PdNH2

Br)

2

MeO PdNH2

BrL

CO– Pd – HBr

MeO

MeO

NH

O

2XyNC

MeO

MeO

PdNH2 Br

CNXy

NXy

1) TlTfO – TlBr

2) Δ– [Pd]– XyNC

MeO

MeO

NHNHXyTfO-

MeO

- - -

L = 4-pic, tBuNC

68a 72

73

74

75

76


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

7 Total Synthesis of Natural Products Using Arynes

Arynes have been used to generate key synthetic inter-mediates for the synthesis of different bioactive naturalproducts. Various complex natural products have been syn-thesized 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 justici-din B, retrojusticidin B, and the formal synthesis of analo-gous natural products (Scheme 48) by using their well-es-tablished Pd-catalyzed [2+2+2] cocyclization of arynes andunsymmetrical conjugated dienes in the presence of an N-heterocyclic carbene ligand (Scheme 26).57

Jeganmohan and Pimparkar extended their methodolo-gy (Scheme 15) for the synthesis of bioactive natural prod-ucts phenaglydon, 6(5H)-phenanthridin-5(6H)-one, and N-methylcrinasiadine in moderate to good yields (Scheme49).44

Jiang and co-workers extended their well-establishedmethodology (Scheme 40) to the synthesis of the phenan-thridinone alkaloids; N-methylcrinasiadine, N-isopentylcri-nasiadine, and N-benzylcrinasiadine in excellent yield. Theprotocol was also applied to the synthesis of the acridonealkaloid 10-methyl-2,3-(methylenedioxy)acridin-9(10H)-one in moderate yield (Scheme 50).68

Yao and co-workers extended their protocol (Scheme17) to the formal synthesis of the phenanthrene-based nat-ural product (±)-tylophorine. A good yield was observed forthe key step of the synthetic route wherein the Pd-cata-lyzed annulation furnished the desired phenanthrene coreof the natural product (Scheme 51).46

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

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

I

OSO

O

Cl+ R

XX = NHMe, NHEt, SH

1) iPrMgHal, THF –78 °C, then 0 °C

2) Li2CuCl4, O2

XX

R

R


Scheme 47 Synthesis of a poly(o-arylene)

TMS

OTf

CsF18-crown-6

solvent

CuXquench

X

H

]

]

CuX = nBu2CuCNLi2

Scheme 48 Synthesis of justicidin B and retrojusticidin B

+

OTf

TMS

[Pd2(dba)3]

CH3CN, reflux, 24 h

MeO

MeO

O

OMeMeO

O H

Ar

MeO

MeOAr

O

OMe

O

OMeCsF

MeO

MeOO

O

OO

MeO

MeOO

OO

O

justicidin B retrojusticidin B

IMes·HCl

66% yield

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

H

N

OMe

H+

N

OMe

Pd(OAc)2 (5 mol%)pivalic acid (5 equiv)

K2S2O8, CsF, CH3CN100 °C, 12 h

O

O

OTf

TMS

O

O

+ N

O

O

O

Me

N-methylcrinasiadine, 30% 25%

N

OOMe

hvpivalic acid (5 equiv)

MeOH, rt, 4 hNH

O

R1

R1 = MeR1 = H

R1

R1 = Me, 69% phenaglydonR1 = H, 67%, 6(5H)-phenanthridin-5(6H)-one

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

TMS

OTf

I+

NHR

Pd(OAc)2, K2CO3

CsF, TBAI

CH3CN (10% H2O)CO, 100 °C, 12 h

Pd(OAc)2, K2CO3

KF, dppm

CH3CN, CON O

O

OR

O

O

R = Me = N-methylcrinasiadine, 80% yieldR = isopentyl = N-isopentylcrinasiadine, 61% yieldR = benzyl = N-benzylcrinasiadine, 55% yield

R = Me = 10-methyl-2,3-(methylenedioxy)acridin-9(10H)-one, 55% yield

phenanthridinone alkaloids

acridone alkaloid

N

O

R

O

O


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Gogoi and co-workers applied their methodology(Scheme 18) to the total synthesis of the biologically activenatural product flemichapparin C. The developed protocolwas performed using 4-hydroxy-7-methoxycoumarin and4,5-(methylenedioxy)benzyne to afford the desired naturalproduct (Scheme 53).47

Zhang and co-workers utilized their Cu-catalyzed meth-odology (Scheme 19) for the synthesis of phenaglydon andcrinasiadine natural products. The removal of the directinggroup in the presence of BBr3 and PhI(TFA)2 afforded the re-spective natural products (Scheme 54).48

Diversity oriented natural product synthesis is a rapidlydeveloping area of research.5,6 In this context, aryne chem-istry paves a new pathway to achieve this goal through var-ious types of transition-metal-catalyzed reactions.

8 Conclusion

This review highlights the scope and importance of thetransition-metal-catalyzed aryne reactions in synthetic or-ganic chemistry. The highly reactive aryne species in com-bination with a transition metal made it possible to con-struct biaryl motifs, fused polycyclic aromatic compounds,different novel carbocycles, various heterocycles, and com-plex natural products. From a laboratory curiosity to a high-ly explored reactive intermediates; arynes have travelled along path. To cross the barrier from basic to applied re-search, a completely ‘off the shelf’ practical method ofaryne generation is essential. The current rate at which thisarea of research is growing, we have no doubt that arynechemistry might occupy an important position in combina-tion with transition metals as a key step in the synthesis ofdrugs and advanced materials.

Funding Information

R.A.D thanks UGC-SRF research fellowship. S.B.M thanks great fullyacknowledges generous financial support from DST-SERB, New Delhi.DST-SERB(GAP317426)

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

Pd(dba)2 (5 mol%) dppm (10 mol%) CsF (3.5 equiv)

toluene/CH3CN110 °C

OMeMeO

MeOOMe

N

formal synthesis of (±)-tylophorine

I

MeO

MeO

EtO2C

NBoc

+TMS

OTf

MeO

MeO

MeO

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CO2Et

OMeMeO

OMe

46% (73% brsm)

Scheme 52 Synthesis of N-methylcrinasiadine, N-isopentylcrinasia-dine, and N-benzylcrinasiadine

TMS

OTf+

NHR

Pd(OAc)2, Cu(OAc)2

KOAc, KI, CuF2·2H2O

DMF/CH3CN

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O

O N O

O

OR

R = Me = N-methylcrinasiadine, 78% yieldR = isopentyl = N-isopentylcrinasiadine, 61% yieldR = benzyl = N-benzylcrinasiadine, 55% yield

phenanthridinone alkaloids

Scheme 53 Synthesis of flemichapparin C

O O

OH

+

OTf

TMS

Pd(OAc)2 (5 mol%)Cu(OAc)2·H2O (1.2 equiv)

CsF (2 equiv)

Na(OAc)2 (1.2 equiv), CH3CN120 °C

O

O

OMeO

O

O MeO

O

O

67%, flemichapparin C

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

H

N

OQ

H+

N

OQCu(OAc)2

DMF/MeCN, O2 80 °C, 12 h

OTf

TMS

CsF, TBAI

1. BBr3

2. PhI(TFA)2

NH

O

NH

O

O

O

crinasiadine, 55%phenaglydon, 62%

R2 R2

R1 R1

R1 = H, R2 = Me 91%R1–R2 = OCH2O 62%


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Transition-Metal-Catalyzed Reactions Involving Arynes

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