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o‑Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors

Jiarong Shi,† Lianggui Li,† and Yang Li*
Cite This: Chem. Rev. 2021, 121, 3892−4044 Read Online
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ABSTRACT: Arynes are among the most active organic intermediates and have found
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numerous applications in expeditious preparation of substituted arenes. In the past 20 years,

chemists have witnessed a resurgence in aryne chemistry, which is mainly attributed by the
extensive utilization of Kobayashi’s method, a fluoride-induced removal of the TMS group
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with concomitant departure of its ortho OTf group on o-silylaryl triflates. Nowadays, o-silylaryl
triflates are the most frequently employed aryne precursors. This review provides an overview
of the history of Kobayashi’s method, its methodological achievements, and its applications in
the synthesis of natural products, bioactive molecules, and polycyclic aromatic hydrocarbons.
CONTENTS 4.3. [2 + 2] Cycloaddition Reactions 3912

4.4. [n + 2] Cycloaddition Reactions 3913
1. Introduction 3893 4.5. Ene Reactions 3913
2. Preparation Methods and Activation Conditions 3896 5. Nucleophilic Addition Reactions 3914
2.1. Preparation Methods 3896 5.1. N-Arylation Reactions 3915
2.2. Activation Conditions 3898 5.2. O-Arylation Reactions 3917
2.2.1. Solvents 3898 5.3. C-Arylation Reactions 3917
2.2.2. Fluoride Sources 3899 5.4. S-Arylation Reactions 3919
2.2.3. Additives 3899 5.5. P-Arylation Reactions 3920
2.2.4. Temperature 3899 5.6. With B-Nucleophile 3921
2.2.5. Microwave 3899 5.7. With F-Nucleophile 3921
2.2.6. Safety 3899 6. Nucleophilic Annulation Reactions 3921
3. Regioselectivity 3899 6.1. With O-Nucleophiles 3921
3.1. Steric Effect 3899 6.2. With N-Nucleophiles 3922
3.2. Electronic Effect 3900 6.3. With C-Nucleophiles 3924
3.3. Distortion/Interaction Model 3901 6.4. With S- and Se-Nucleophiles 3925
3.4. Effect of a Fused Small Ring 3902 6.5. With P-Nucleophiles 3926
4. Pericyclic Reactions 3903 7. Insertion Reactions 3926
4.1. Diels−Alder Reactions 3903 7.1. Insertion into C−N σ-Bonds 3927
4.1.1. With Furans 3903 7.2. Insertion into C−C σ-Bonds 3928
4.1.2. With 2-Pyranones 3903 7.3. Insertion into C−O σ-Bonds 3930
4.1.3. With Anthracenes 3903 7.4. Insertion into Other σ-Bonds 3930
4.1.4. With Cyclic 1,3-Dienes 3903 7.5. Insertion into π-Bonds 3933
4.1.5. With Acyclic 1,3-Dienes 3904 8. Multicomponent Reactions (MCRs) 3935
4.1.6. Intramolecular Diels−Alder Reactions 3906 8.1. Isocyanide-Triggered MCRs 3935
4.2. 1,3-Dipolar Cycloaddition Reactions 3906 8.2. N-Nucleophile-Triggered MCRs 3937
4.2.1. With 4-Hydroxyisoquinolinium and 3- 8.3. Other Nucleophile-Triggered MCRs 3941
Oxidopyridinium 3907 8.4. DMF-Involved MCRs 3945
4.2.2. With Diazo Compounds 3907
4.2.3. With Azides 3909
4.2.4. With Nitrile Oxides 3909
4.2.5. With Nitrones 3910 Received: September 17, 2020
4.2.6. With Azomethine Imines and Nitrile Published: February 18, 2021
Imines 3910
4.2.7. With N-Heteroaromatic Ring Imides 3910
4.2.8. With Cyclic 1,3-Dipoles 3911
4.2.9. With Other 1,3-Dipoles 3911
© 2021 American Chemical Society https://dx.doi.org/10.1021/acs.chemrev.0c01011

3892 Chem. Rev. 2021, 121, 3892−4044
Chemical Reviews pubs.acs.org/CR Review
8.5. MCRs via Aryne [3 + 2] Cycloaddition 14. Syntheses of Natural Products and Bioactive
Reaction 3947 Molecules 3996
9. Cascade or Tandem Reactions 3948 14.1. Cycloaddition Strategies 3996
9.1. Cycloaddition Reaction-Initiated Cascade 14.2. Nucleophilic Annulation Strategies 3998
Reactions 3948 14.3. Insertion Reaction Strategies 4000
9.1.1. Initiated by Diels−Alder Reaction 3948 14.4. Cascade Reaction and MCR Strategies 4003
9.1.2. Initiated by [3 + 2] Cycloaddition 14.5. Transition-Metal-Catalyzed Strategies 4004
Reaction 3950 14.6. Benzdiyne Strategies 4005
9.1.3. Initiated by [2 + 2] Cycloaddition 15. PAHs, Polymer Chemistry, and Materials Sci-
Reaction 3951 ence 4006
9.1.4. Initiated by Other Cycloaddition Reac- 15.1. Preparation of PAHs 4006
tion 3953 15.1.1. Through Pd-Catalyzed Cyclotrimeriza-
9.2. Nucleophilic Addition-Initiated Rearrange- tion 4006
ments 3953 15.1.2. Through Pd-Catalyzed Cocyclotrimeri-
9.2.1. Claisen Rearrangements 3953 zation 4009
9.2.2. [2,3]/[1,2] Sigmatropic Rearrangements 3954 15.1.3. Through Pd-Catalyzed Annulation Re-
9.2.3. Other Rearrangements 3955 actions 4010
9.3. Nucleophilic Addition-Triggered Other Cas- 15.1.4. Benzdiyne and Naphthodiyne Strat-
cade Reactions 3956 egies 4010
9.4. Nucleophilic Annulation-Induced Cascade 15.1.5. Other Cycloaddition Strategies 4013
Reactions 3958 15.2. Polymer Chemistry 4014
9.5. Insertion Reaction-Triggered Cascade Reac- 15.3. Materials Science 4015
tions 3960 15.3.1. Triptycene-Based Materials 4015
9.5.1. Through C−C Bond Insertion 3960 15.3.2. Nanotube and Graphene 4015
9.5.2. Through Other Insertion Reactions 3961 16. Conclusions 4015
9.6. Other Cascade Reactions 3963 Author Information 4017
10. Transition-Metal-Catalyzed Reactions 3964 Corresponding Author 4017
10.1. Palladium-Catalyzed Reactions 3964 Authors 4017
10.1.1. (Co)cyclotrimerization 3964 Author Contributions 4017
10.1.2. With π-Allylpalladium Species 3966 Notes 4017
10.1.3. With Arylpalladium Species 3968 Biographies 4017
10.1.4. With Alkylpalladium and Vinylpalladi- Acknowledgments 4017
um 3973 Abbreviations 4017
10.1.5. With Azapalladium Species 3974 References 4018
10.1.6. Other Palladium-Catalyzed Reactions 3975
10.1.7. Insertion into Element−Element σ-
Bonds 3975 1. INTRODUCTION
10.2. Nickel-Catalyzed Reactions 3976 Arynes are a family of transient species that are among the
10.3. Copper-Catalyzed/Mediated Reactions 3977 most active organic intermediates. The history of aryne
10.4. Silver-Catalyzed/Mediated Reactions 3981 chemistry can be traced back to 1902 when Stoermer and
10.5. Gold-Catalyzed Reactions 3982 Kahlert first postulated the formation of 2,3-didehydrobenzo-
10.6. Platinum-Catalyzed Reactions 3982 furan from 3-bromobenzofuran with bases in ethanol (Figure
10.7. Cobalt-Catalyzed Reaction 3982 1).1 Based on their experimental observations, Bachmann and
11. Benzdiyne Chemistry 3983 Clarke in 19272 and Wittig et al. in 19423 proposed the
11.1. 1,4-Benzdiyne Chemistry 3983 generation of a benzyne intermediate. In 1953, Roberts
11.2. 1,3-Benzdiyne Chemistry 3984 performed a 14C-labeling experiment on chlorobenzene using
11.3. 1,2-Benzdiyne Chemistry 3985 potassium amide in liquid ammonia as the activating reagent
12. Hetaryne Chemistry 3986 and suggested the formation of a symmetrical benzyne
12.1. Pyridynes and 2,3-Quinolyne 3987 species.4
12.1.1. 2,3-Pyridyne 3987 As short-lived intermediates,5,6 arynes possess some unique
12.1.2. 3,4-Pyridyne 3988 properties. The triple bond on an aryne is somewhere between
12.1.3. 2,3-Quinolyne 3989 a double and a triple bond. One π-bond belongs to the
12.2. Indolynes 3990 aromatic system and the other one is formed by the lateral
12.3. Other Hetarynes 3991 overlap of the two sp2 orbitals in the plane of the benzene ring.
12.3.1. 4,5-Benzofuranyne 3991 Accordingly, these angle-strained cyclic alkynes are signifi-
12.3.2. 6,7-Thienobenzyne 3991 cantly weakened. For instance, the IR stretching frequency for
13. Cyclohexyne, 1,2-Cyclohexadiene, and 1,2,3- the triple bond on benzyne is 1846 cm−1 in a neon matrix,7
Cyclohexatriene 3991 whereas it is 2150 cm−1 for normal alkynes. The bond length
13.1. Preparation Methods 3991 of a benzyne was determined to be 1.24 Å through the
13.2. Cyclohexyne Reactions 3993 simulation of the 13C dipolar NMR spectrum,8 which is in
13.3. 1,2-Cyclohexadiene Reactions 3995 good agreement with theoretical calculations.9 Consequently,
13.4. 1,2,3-Cyclohexatriene Reactions 3995 arynes are typically described as strained alkynes other than
biradicals. Other properties of benzyne, such as microwave,10
3893 https://dx.doi.org/10.1021/acs.chemrev.0c01011
Chem. Rev. 2021, 121, 3892−4044
Figure 1. Timeline for aryne generation methods.
mass spectrometry,11 photoelectron spectroscopy,12 and NMR logenation with lithium amalgam or n-BuLi and (2) by forming
spectroscopy,8,13 have also been measured. Particularly, Grignard reagent with magnesium.17−19 Both strategies,
Warmuth isolated benzyne in a hemicarcerand as a molecular however, fall short of compatibility with functional groups
container.13−15 In addition, the ring strain induced by the and arynophiles that are vulnerable under these harsh
formal triple bond on the six-membered ring results in their conditions. Several generation methods were then developed
low-lying LUMO orbitals with small energy gap between the in the 1960s. In 1960, o-benzenediazonium carboxylate
HOMO and LUMO orbitals,16 making arynes superior (caution: o-benzenediazonium carboxylates are potentially
electrophiles that are amenable to a broad spectrum of explosive), conveniently prepared by diazotization of anthra-
arynophiles as well as transformations. In the past ∼70 years, nilic acid, was reported by Stiles and Miller to be able to
numerous achievements have been realized in the realm of release benzyne through thermal decomposition at 40−60
aryne chemistry. °C.20,21 Later in 1962, diphenyliodonium-2-carboxylate was
Since the early era of aryne chemistry, people have also disclosed to produce benzyne at 160 °C in diglyme.22 In
endeavored to search for “ideal” aryne generation methods. the same year, Wittig and Hoffmann developed 1,2,3-
Why do we need to care much about the constitution of an benzothiadiazole S,S-dioxide as a benzyne precursor, which
aryne precursor and its generation conditions? Because arynes could be activated via thermal decomposition.23 In 1964,
are transient intermediates, they have to be generated in situ. benzyne was found to be formed via the oxidation of 1-
Consequently, even a simple aryne reaction, i.e., nucleophilic aminobenzotriazole with lead tetraacetate (LTA) or nickel
reaction or Diels−Alder reaction, is no longer a single-step peroxide.24,25
operation after counting aryne generation as a step. To this In 1973, a bulky base, lithium 2,2,6,6-tetramethylpiperidide
end, both the constitution and the accompanied generation (LiTMP), was first applied to the dehydrohalogenation
conditions of an aryne precursor are indispensable in any aryne strategy in order to avoid undesired nucleophilic addition by
transformation. In many cases, they are the key factors for the the base,26 the efficiency of which was further enhanced by the
success of an aryne reaction. Therefore, people should be employment of lithium diadamantylamide (LDAM) in 2018.27
aware of the ways on how to generate an aryne species o-Bromoaryl tosylates were first introduced by Tochtermann as
associated with the compatibility considerations with respect aryne precursors in 1974 for the preparation of polycyclic
to functional groups, reactive intermediates, and reaction aromatic hydrocarbons, which could be activated through a
media. sequential metal−halogen exchange with organolithium
The first strategy to generate benzyne was through reagent and an elimination of the sulfonate.28 In 1987,
dehydrohalogenation of halobenzenes, i.e., chlorobenzene Furukawa et al. disclosed that o-haloaryl sulfoxides were able to
and fluorobenzene, along with the early investigations in this serve as aryne precursors by using Grignard reagents as the
field (Figure 1). Strong bases, such as PhLi, NaNH2, and LDA, activating reagents.29 In 1991, Suzuki et al. first demonstrated
were normally utilized. In the 1950s, o-dihalobenzenes started that o-iodophenyl triflate could be facilely converted to
to serve as benzyne precursors, which could be activated benzyne in the presence of n-BuLi, the method of which was
through two means: (1) lithium-halogen exchange-demetalha- then found to have many useful applications.30 Subsequently,
Chem. Rev. 2021, 121, 3892−4044
Figure 2. Structures of Kobayashi aryne precursors.
modifications on this protocol by using trimethylsilylmethyl was then enhanced by employing LiZnEt2(TMP)40 or
Grignard reagent, TMSCH2MgCl,31 and catalytic amounts of Li[Zn(n-Bu)TMP2]41 as the activating reagents.
alkynyllithium32 as activating reagents were realized. In 1997, Since 2000, many new generation protocols have been
Johnson33 and Ueda34 independently reported an unprece- discovered. In 2002, Uchiyama et al. demonstrated that lithium
dented aryne generation protocol via the [4 + 2] cycloaddition dialkyl(2,2,6,6-tetramethylpiperidino)zincate (R2Zn(TMP)Li)
reaction of alkyne and 1,3-diyne, which is now known as could efficiently activate halobenzenes.42,43 In 2004, Knochel
hexadehydro-Diels−Alder (HDDA) reaction and has obtained and co-workers revealed that o-iodoaryl sulfonates were able to
many achievements mainly by Hoye et al. in the past serve as versatile aryne precursors by using isopropylmagne-
decade.35−38 A benzyne generation method between PhOTf sium chloride (i-PrMgCl) as the activating reagent.44−46
and LDA was first disclosed in 1999,39 the efficiency of which Notably, aryne precursors bearing silyl groups as accepting
Chem. Rev. 2021, 121, 3892−4044
groups (AGs) were developed by the groups of Kitamura method has also been expanded to benzdiynes, heterocyclic
(2006),47 Akai (2011),48 Novák (2012),49 Xu/Jiang/Wang arynes (hetarynes), cyclohexynes, and 1,2-cyclohexadienes.
(2015),50 Daugulis (2016),51 and Raminelli (2020),52 all of Along with the advances of Kobayashi’s method, many exciting
which were found to facilely generate benzyne under fluoride- applications have been accomplished in the fields of natural
induced conditions. Meanwhile, precursors containing OTf product synthesis, preparation of polycyclic aromatic hydro-
group as the LG were realized by Hosoya, where the AGs carbons (PAHs), and materials science. In the past 2 decades,
could be boronic ester (2013),53 arylsulfoxide (2014),54 and there are many review articles that have elaborated on various
diarylphosphinyl groups (2018).55 In 2016, Stuart et al. re- aspects of aryne chemistry.38,69,71−102 None of them, however,
examined the early method using diaryliodonium salts as aryne provided a comprehensive survey on o-silylaryl triflates. This
precursors56 and demonstrated that a combination of aryl- review aims to summarize different aspects of Kobayashi’s
(mesityl)iodonium tosylates and LiHMDS could efficiently method from the preparation and activation of aryne
generate arynes.57,58 Since 2006, a series of Pd-catalyzed precursors to diverse types of transformations and to its
generation protocols have been realized by Hu (2006),59 Kim applications.
(2008),60 and Greaney (201061 and 201462). In 2017, Li et al.
reported an aryne generation method via Grob fragmentation 2. PREPARATION METHODS AND ACTIVATION
on the [2 + 2] cycloadducts of 3-triflyloxyarynes.63 Similarly, o- CONDITIONS
bromoacetophenone derivatives were found to serve as aryne 2.1. Preparation Methods
precursors, where t-BuOK was used as the activating reagent.64
Very recently, generation methods based on one-pot protocols In Kobayashi’s seminal report, they depicted the preparation of
were realized.65−67 o-(trimethylsilyl)phenyl triflate (2-1) from 2-chlorophenol. 2-
In 1983, Kobayashi and co-workers published a seminal Chlorophenol was first converted to o-(trimethylsilyl)-
work for the preparation of o-(trimethylsilyl)phenyl triflate as a phenoxytrimethylsilane (2-2) in two steps, which was then
benzyne precursor, the activation of which employed a treated with dropwise addition of excess n-BuLi and a
fluoride-induced removal of the TMS group with concomitant subsequent triflation with triflic anhydride (Tf2O) to afford
departure of its ortho OTf group.68 This aryne generation 2-1 (Scheme 1a).68 Suzuki et al. employed this method to
protocol, however, received almost no attention in a period of
15 years. Until the end of 1990s, o-silylaryl triflates started to Scheme 1. Metal−Halogen Exchange Strategies
be increasingly explored as aryne precursors. Astonishingly, in
the past 2 decades, people have witnessed a blooming advance
in aryne chemistry, which was mainly attributed by the
exponential applications of Kobayashi’s method.
The most distinct advantage of this generation method is
not because it CAN generate aryne but the way how it
maintains a low-level concentration of aryne species under
arynophile-friendly conditions. The combination of CsF and
acetonitrile solvent, sometimes with toluene as cosolvent, is a
magic recipe in Kobayashi’s protocol. An explanation for this is
that CsF has low solubility in acetonitrile, which in turn would
only activate a small portion of o-silylaryl triflate at any reaction
stage.69 In addition, DFT calculations on the fluoride-induced
benzyne generation process of o-silylphenyl triflate revealed
that the removal of the TMS group by fluoride is through a
pseudo-SN2 mechanism with the formation of a pentacoordi-
nated silicon ate complex as the rate-determining step.70
Therefore, this system could provide a constant supply of a
suitably low concentration of aryne intermediate. As a prepare 3-bromo substituted o-silylaryl triflates by using 2,6-
consequence of Kobayashi’s method, the reaction efficiency dibromophenol.103 This preparation procedure was then
can be generally enhanced with high functional group modified by several groups in order to increase the efficiency.
tolerance, which could also accommodate different aryne In 2002, Pérez, Guitián and co-workers developed a facile one-
reaction modes. pot procedure to prepare 2-1 and its analogues (Scheme
Figure 2 lists some of the Kobayashi aryne precursors that 1b).104 Starting from substituted 2-bromophenols, a sequential
have been utilized in the field of aryne chemistry. These O-silylation with hexamethyldisilazane (HMDS), metal−
structures include Kobayashi precursors of various substituted halogen exchange with n-BuLi at low temperature, O- to C-
benzynes, naphthalynes, phenanthrynes, arynes with polycyclic silyl group migration, and triflation could afford functionalized
frameworks, pyridynes, and indolynes. Moreover, Kobayashi Kobayashi aryne precursors 2-1 in good to excellent yields.
precursors of polyarynes are also shown in Figure 2. Moreover, this method has also been employed in the
A significant contribution of Kobayashi’s method to modern preparation of polycyclic aryne precursors. Subsequently,
aryne chemistry is its potential to promote continuous Greaney et al. developed a scalable continuous flow process
discovery of new reaction modes. Some new types of aryne that could readily synthesize functionalized 2-1 in excellent
transformations include transition-metal-catalyzed reactions yields from substituted 2-bromophenols.105 A further mod-
since the end of 1990s, aryne insertion reactions since early ification on Kobayashi’s original procedure was reported by
2000, multicomponent aryne reactions, and aryne-triggered or Brimble and co-workers, the pathway of which avoided the
aryne-involved cascade reactions. Moreover, Kobayashi’s employment of n-BuLi (Scheme 1c).106 After the generation of
Chem. Rev. 2021, 121, 3892−4044
2-2, selective desilylation with TBAF and triflation could afford Scheme 3. Preparation Method by Pérez and Vollhardt
compound 2-1 in 81% overall yield in a four-step procedure.
Another strategy to access o-silylaryl triflates is through
direct metalation on the ortho C−H bond of phenol with
strong base, which is followed by a subsequent incorporation
of a TMS group. In 1984, Snieckus et al. employed an amide
directing group to realize an ortho deprotonation-silyl group
migration (retro-Brook rearrangement) event to obtain
compound 2-3. After triflation, compound 2-4 with an amide
functional group on the C3 position was produced (Scheme
2a).107 In 2005, Danheiser and co-workers reported a one-pot
Scheme 2. ortho-Lithiation Strategies
thoxyborane/acidic workup. Subsequent oxidation and tri-

flation produced o-silylaryl triflates 2-13 in good to excellent
yields.
In 2010, Harrity et al. demonstrated a new approach to
access substituted Kobayashi aryne precursor 2-1. In this
protocol, the benzene ring was constructed through a [4 + 2]
cycloaddition reaction of 2-pyrones and trimethylsilyl
alkynylboronate 2-14. After C−B bond oxidation with H2O2
and triflation, functionalized 2-1 were obtained (Scheme
4a).111 The Diels−Alder reaction step, however, was not
Scheme 4. Arene Ring Formation Strategies
preparation of o-silyl salicylaldehyde 2-6 from the methox-

ymethyl (MOM) either of phenol 2-5 (Scheme 2b).108 An
ortho-lithiation with n-BuLi on 2-5 was followed by silylation
to introduce a TMS group. After another directed metalation
and subsequent quenching with DMF in the same flask, o-silyl
salicylaldehyde 2-6 was obtained upon acid workup, which
could be then converted to o-silylaryl triflates 2-7. In 2009,
Garg et al. developed a facile ortho-lithiation protocol on the
N-monoalkyl carbamate derivative of phenol 2-8 to prepare
compound 2-9 after capturing the phenyllithium intermediate
with TMSCl. After removal of the carbamate group on 2-9 and
triflation with PhNTf2, compound 2-1 could be produced in regioselective. In 2015, in a study carried out by Yoshikai and
good overall yield from phenol (Scheme 2c).109 The 4,5- co-workers on one-pot preparation of the benzo[b]phosphole
indolyne precursor was also efficiently prepared using this derivative, they started with Grignard reagent 2-15 and
protocol. produced compound 2-16 through a sequential transition-
The methods through direct construction of a benzene ring metal-catalyzed arylmagnesiation of diphenylacetylene, reac-
bearing a TMS and/or an OTf group were reported as well. In tion with dichlorophenylphosphine, and an intramolecular
a study carried out by Pérez, Vollhardt and co-workers, they phospha-Friedel−Crafts reaction process. After removal of the
developed a procedure for the preparation of 3-trimethylsilyl-2- benzyl group and triflation, o-silylaryl triflate 2-17 was obtained
biphenylenyl triflates (2-13) from 2-10.110 As shown in (Scheme 4b).112
Scheme 3, a cobalt-catalyzed cycloaddition of 2-10 with In recent years, transition-metal-catalyzed ortho-C−H
bis(trimethylsilyl)acetylene (BTMSA) assembled 2-11, the functionalization strategies were applied in the preparation of
structure of which contains a biphenylene core. Boronic acid 2- o-silylaryl triflates. In 2015, Gevorgyan et al. developed a 2-fold
12 was then obtained via a sequence of selective mono- C−H functionalization protocol on arene 2-18 by using
bromination/metal−halogen exchange/quenching with trime- pyrimidyldiisopropylsilyl (PyrDipSi) as the directing group,
Chem. Rev. 2021, 121, 3892−4044
which could produce compound 2-19 (Scheme 5a).113 In this also prepared Kobayashi aryne precursors of 2,3-carbazolyne
study, they demonstrated the preparation of a substituted and 2,3-fluorenyne.
Postfunctionalization directly on the o-silylaryl triflate
Scheme 5. Transition-Metal-Catalyzed ortho-C−H Bond framework represents a straightforward and economical
Functionalization Strategies approach toward substituted Kobayashi aryne precursors.
Both the TMS and OTf groups, however, are vulnerable to
many arene functionalization conditions. In 2015, Pilarski and
co-workers achieved a distinct Ir-catalyzed C−H borylation
reaction on o-silyl(hetero)aryl triflates 2-28 in chemoselective
manner, furnishing 2-29 by introducing a (pinacolato)boryl
group (B(pin)) directly on the sterically less hindered
positions (Scheme 6a).117,118 Furthermore, the B(pin) group
Scheme 6. Postfunctionalization Strategies
could be converted to a variety of functional groups.

Meanwhile, Hosoya et al. reported an identical transformation
with a different substrate scope from Pilarski’s work.119 In
addition, Yoshida, Hosoya, and co-workers could further
convert B(pin) to sulfide by using their developed Cu-
catalyzed deborylthiolation method.120 In 2017, Raminelli et
al. reported a modular synthesis of functionalized silylbiaryl
triflates 2-31 through a chemoselective Suzuki reaction on
iodinated silylaryl triflates 2-30, which was readily prepared
from phenols through diiodination and a modified Pérez-
Guitián procedure104 (Scheme 6b).121
Kobayashi aryne precursor by converting the acetate group on
2-19 to OTf, giving rise to o-silylaryl triflate 2-20 in 83% yield. 2.2. Activation Conditions
As an application on the methodology developed by Jeon and The key factors for the success of a typical aryne reaction are
co-workers on catalytic reductive C−H silylation of phenols not only the conditions that can generate the corresponding
with traceless acetal directing groups,114 they realized a one- aryne species but also the compatibility of these conditions
pot procedure to directly transform the benzodioxasiline with respect to substrate structures, functional groups, and
products 2-21 to o-silylaryl triflates 2-22 through a reaction modes. Consequently, more needs to be considered
nucleophilic addition by MeLi and triflation procedure beyond the aryne generation method itself. In addition, the
(Scheme 5b).115 This protocol could also be utilized in the highly reactive nature of an aryne species requires a slow-
preparation of sterically encumbered 1,2,3-trisubstituted o- releasing process so that arynophiles could effectively capture
silylaryl triflates. Recently, Pilarski et al. reported a procedure this transient intermediate in the course of an aryne
to reach substituted o-silylaryl triflates 2-27 from arylboronic transformation. However, arynophiles behave quite differently,
acids 2-23.116 As shown in Scheme 5c, the key step in this and many factors, such as reactivity, stability, and competing
procedure involved a Ru-catalyzed ortho-C−H silylation on side reactions, might also affect the overall efficiency.
anthranilamido boronates ArB(aam) 2-24, generated from 2- Therefore, the “conditions” that are chosen to generate arynes
23, to furnish compound 2-25. Upon oxidation on 2-25, ortho- from the corresponding o-silylaryl triflates are crucial for the
silylphenols 2-26 were produced. Finally, protection of 2-26 success of a designated aryne reaction.
using 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride 2.2.1. Solvents. Acetonitrile is the most prevailingly
(NfF) afforded aryne precursors 2-27. In this study, they employed solvent, which usually accommodates well with
Chem. Rev. 2021, 121, 3892−4044
various fluoride sources as well as reaction modes. The CsF/ low temperature might alter the chemoselectivity of an aryne
MeCN system can constantly supply a low concentration of reaction.
fluoride ion. In order to further slow down the aryne 2.2.5. Microwave. Microwave was also employed in aryne
generation rate, toluene can be added as a cosolvent. THF is reactions, which could promote both the generation and the
another commonly employed solvent. Due to the low solubility reaction rate of an aryne transformation.123−126
of inorganic salts in THF, KF/18-c-6 is normally used. Other 2.2.6. Safety. Besides, safety issue upon activation of o-
solvents that have been employed or examined include 1,4- silylaryl triflates have been assessed by Garg et al. through
dioxane, 1,2-dimethoxyethane (DME), 1,2-diethoxyethane calorimetric analysis. They concluded that o-silylaryl triflates
(DEE), triglyme, dichloromethane (DCM), N,N-dimethylfor- may be used under mild conditions with no general concern
mamide (DMF), N,N-dimethylacetamide (DMA), acetone, for a runaway reaction.127
EtOAc, chlorobenzene, methyl tert-butyl ether (MTBE),
butyronitriles (n-PrCN, i-PrCN), and DMSO. 3. REGIOSELECTIVITY
2.2.2. Fluoride Sources. Fluoride salts are indispensable Regioselectivity is a fundamental issue in aryne chemistry.
activating reagents for o-silylaryl triflates. The key factor for the When an unsymmetrically substituted benzyne participates in a
success of an aryne transformation, however, is not how fast a reaction with an unsymmetrical or polar arynophile, two
fluoride species could kick out the TMS group. In contrast, it regioisomeric products will be envisioned. In this context, the
matters on how to manage various factors together in order to diminished reaction efficiency attributed by the formation of
maintain a constant supply of aryne species in manageable rate. an unwanted regioisomer in an aryne transformation will
Among those fluoride salts, CsF, KF, n-Bu4NF (TBAF), and severely damage its synthetic application. Therefore, it is
tetra-n-butylammonium difluorotriphenylsilicate (TBAT) are essential to find ways in order to reach a high level of
normally utilized. Other fluoride salts, such as Me4NF, regioselectivity in an aryne reaction. A further outlook in this
BnMe3NF, and tris(dimethylamino)sulfonium difluorotrime- aspect of aryne chemistry would not only enhance the
thylsilicate (TAS-F), have also been reported. regioselective ratio but also be able to “overturn” the preferred
CsF is the most commonly used fluoride source in site of attack under certain circumstances so as to achieve more
Kobayashi aryne generation conditions. Because CsF is diversified synthesis. So far, certain rules and protocols have
hygroscopic and wet CsF would diminish the reaction been disclosed to manipulate the regioselectivity in inter-
efficiency due to aggregation during the reaction, dry CsF is molecular aryne transformations along with the advances of
recommended in order to ensure reproducible aryne reactions. recent aryne chemistry, those of which are steric effect,
In this context, CsF could be dried at 140 °C under vacuum electronic effect, and ring-strain (Figure 3). Particularly
for hours and should be stored in a vacuum desiccator with
drying agent or within a glovebox. When an aryne reaction is
performed in acetonitrile under a dilute solution, the initial
suspension of CsF in acetonitrile would become a homoge-
neous solution by the end of the reaction (the generated
CsOTf is soluble in acetonitrile).
In recent years, fluoride-free generation of arynes from o-
silylaryl triflates was reported and utilized.88,122 Moreover, with
two vicinal electron-withdrawing groups on domino aryne
precursors, carbonates could replace fluoride as efficient
activating reagents to trigger the generation of the correspond-
ing arynes.102 Figure 3. Effects that tune the regioselectivity.
2.2.3. Additives. In order to fulfill the demands on
different types of aryne reactions, additives are usually added. noteworthy is a recent application of a distortion/interaction
18-Crown-6 (18-c-6) has been commonly employed to model128 by the groups of Houk and Garg, which could explain
enhance the solubility of fluoride salts. In order to remove the electronic factors in the regioselective control of an aryne
the adventitious water from the solvent or reagents, drying reaction. In contrast, intramolecular aryne reactions always
agent, i.e., 4 Å MS, can be added. In an opposite way, certain prefer ortho-selectivity in annulation reactions, which have
amount of water could be intentionally added to the reaction found many applications in natural product synthesis.78,79,92
media to serve as a proton source. Bases are frequently utilized Because intramolecular aryne transformations normally employ
additives in aryne reactions, those of which include K2CO3, the generation methods other than Kobayashi’s, they will not
Cs2CO3, Na2CO3, Li2CO3, KHCO3, NaHCO3, (NH4)HCO3, be covered in this section.
t-BuOK, K3PO4, LiOAc, NaOAc, KOAc, CsOAc, NaOH, 3.1. Steric Effect
CsOPiv, Et 3 N, N,N,N′,N′-tetramethylethylenediamine Presumably, the earliest tuning factor used to differentiate the
(TMEDA), pyridine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]- two aryne triple-bond carbons in intermolecular trans-
undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane formations is through steric repulsion, which requires the
(DABCO), and diisopropylethylamine (DIPEA). In some incorporation of a bulky group on the 3-position of a benzyne
cases, phase transfer catalysts, such as tetra-n-butylammonium intermediate (Scheme 7a). For instance, 3-tert-butylbenzyne is
iodide (TBAI) and bromide (TBAB), can be employed as well. known to favor the less sterically congested meta-position of
2.2.4. Temperature. The normal reaction temperature for the t-Bu group when it reacts with arynophiles. This steric
a standard benzyne reaction ranges from room temperature to effect was demonstrated by Kazmaier et al. in an aryne
100 °C. In some uncommon cases, higher than 100 °C or insertion reaction into the Sn−H bond of Bu3SnH, in which a
lower than 0 °C was reported. Particularly, the employment of single product 3-2a was obtained from aryne precursor 3-1a
Chem. Rev. 2021, 121, 3892−4044
Scheme 7. Steric Repulsion by 3-Alkyl Groups on Arynes tert-butylbenzyne 3-9a resulted in a mixture of regioisomers in
only a 1.7:1 ratio (Scheme 8b).132 Subsequently, this silyl-
based aryne strategy was successfully utilized by the groups of
Akai-Ikawa,48,133 Du Bois,134 and Hosoya.135 Furthermore,
Houk, Garg, and co-workers revealed that the regioselective
preference can be affected by the structure of arynophiles.130
As shown in Scheme 8c, they systematically investigated the
reaction of 3-triethylsilylbenzyne (3-12) with various nucleo-
philes. It was found that only when a nucleophile is bulky
enough will the meta-3-13 product be formed exclusively.
When a nucleophile is less sterically congested, a certain
amount of ortho-3-13 product could be obtained as well.
Other than 3-silyl groups as effective sterically congested
groups, 3-boronic esters could serve as a suitable steric tuning
factor in aryne reactions as well. In 2010, Akai and co-workers
discovered that a 3-borylbenzyne species 3-14, generated from
with no observation of its regioisomer 3-3a (Scheme 7a).129 In
o-iodoaryl triflates, underwent regioselective Diels−Alder
contrast, 3,5-dimethylbenzyne, generated from aryne precursor
reactions with 2-substituted furans, furnishing various cyclo-
3-1b, has a smaller steric effect than that of 3-1a and, hence,
adducts anti-3-15 and syn-3-15 in generally excellent anti-
afforded a mixture of 3-2b and 3-3b in a 68:32 ratio in the
selectivity (Scheme 9).136,137 Their theoretical study revealed
reaction with Bu3SnH. Moreover, in a study carried out by
Houk, Garg, and co-workers, they demonstrated that the
reactions of 3-tert-butylbenzyne 3-4 with various nucleophiles Scheme 9. 3-Boronic Ester as Sterically Congested Groups
always prefer the meta-position to yield 3-5 (Scheme 7b).130
3-Silyl groups were found to be efficient sterically congested
tuning factors in regioselective aryne transformations. In 2005,
Schlosser et al. disclosed that the Diels−Alder reaction of 3-
fluoro-6-(trimethylsilyl)benzyne (3-6) with 2-(trimethylsilyl)-
furan (3-7) furnished a single cycloadduct 3-8 (Scheme 8a).131
In a study carried out by Akai and co-workers, they found that
the benzyne intermediate containing either a 3-TMS group 3-
9b or a 3-tert-butyldimethylsilyl (3-TBS) group 3-9c could
react with 2-tert-butylfuran (3-10) to preferentially afford anti-
cycloadducts 3-11b and 3-11c; whereas, the reaction with 3- that for those furans containing an electron-withdrawing
substituent on the 2-position, such as ester, ketone, nitrile,
Scheme 8. 3-Silyl Groups as Sterically Congested Groups and phenyl group, the regioselectivity was controlled by steric
repulsion.
3.2. Electronic Effect
Electronic effect is the most broadly employed tuning factor in
aryne transformations, which could provide versatile means to
realize high regioselective control. Both inductively electron-
withdrawing (EW) and electron-donating (ED) substituents
have been employed. Because of the nature of inductive effect,
only when these groups are on the 3- or 6-position of a
benzyne ring will they exhibit obvious differentiation ability.
When these substituents are on the 4- or 5-position of a
benzyne, however, the inductive effect will be largely
attenuated.138−140
3-Alkoxy groups and 3-halogens have been traditionally
utilized as effective EW tuning groups in aryne trans-
formations, giving rise to products with preferential meta-
selectivity in the reactions with both nucleophiles and other
polar arynophiles (Figure 3b). Because the EW effect induced
by these groups has been broadly employed in many aryne
transformations and is widely recognized in aryne chem-
istry,74,141 it will not be discussed in this section.
On the other hand, the ED effect was disclosed behind the
EW effect, which could result in opposite regioselective
outcomes in the aryne reactions. In 1993, Suzuki and co-
workers found that a silyl group on the 3-position of benzyne
possesses a remarkable electron-donating inductive ability in
1,3-dipolar reactions with nitrones (Scheme 10a).103 For
instance, the reaction of both 3-16a and 3-16b with nitrones
Chem. Rev. 2021, 121, 3892−4044
Scheme 10. ED-Inductive Effect by 3-Silyl and 3-Boryl study, they proposed that the regioselectivity between the
Groups reaction of 3-14 and 2-substituted furans containing a methyl,
n-butyl, methoxy, or TMS group was controlled by an
electrostatic effect and aryne distortion,136,137 and a more
definite electronic effect was later observed by the same group
on nucleophilic addition reactions with aryne precursor 3-21,
which could generate 3-borylbenzyne 3-22 in a chemoselective
manner in the presence of fluoride (Scheme 10c).143 This 3-
borylbenzyne 3-22 exhibited good to high ortho-selectivity
with respect to amines, affording ortho-3-23 preferentially over
meta-3-23. Among different boryl groups, 1,8-diaminonaph-
thalene (dan) protected 3-borylbenzyne gave the highest ortho
to meta ratio.
3.3. Distortion/Interaction Model
In recent years, Garg, Houk, and co-workers employed a
distortion/interaction model128 in aryne transformations to
explain and predict aryne regioselectivity.144−148 This model
divides the activation energy of a bimolecular process into two
components: a distortion energy that allows the reactants to
reach the transition state geometry and a second energy that
accounts for the interaction between two distorted species.
With the assistance of this aryne distortion/interaction model,
they could also predict the regioselectivity in the reactions with
hetarynes (indolynes, pyridynes, and benzofura-
nyne),144,145,147−153 cyclohexynes,153−155 and 1,2-cyclohexa-
dienes.156,157 Intriguingly, their experimental results are highly
consistent with this model. Besides, the groups of Suzuki,158
Buszek,159 and Akawa/Akai137,143 have also tried to explain the
regioselective issue in their studies. Recently, Mirzaei and
afforded the [3 + 2] cycloadducts 3-18a and 3-18b as the Khosravi employed frontier molecular orbital contribution
major regioisomers. In comparison, the reaction of aryne 3-16c analysis160 and orbital electronegativity161 to predict the aryne
with a 3-methoxymethoxy (3-MOMO) group as the EW group regioselectivity. More theoretical studies on the structure of
produced cycloadduct 3-17c exclusively. In 2011, Akai et al. substituted benzynes were reported by Schaefer et al.162
found that the nucleophilic addition reaction of primary Figure 4 lists the geometry optimized structures of some
amines with 3-trimethylsilylbenzyne precursor 3-19 preferred commonly substituted benzynes, 1 3 0 , 1 4 3 , 1 4 6 hetar-
the ortho-position of the TMS group, furnishing ortho-3-20 as ynes,145,149,152,153 cyclohexynes,153−155 and 1,2-cyclohexa-
the major products (Scheme 10b).142 Although in Akai’s 2010 dienes156,157 using DFT methods. Based on the aryne
Figure 4. Geometry optimized substituted benzynes, hetarynes, and angle-strained cyclic alkynes/allenes.
Chem. Rev. 2021, 121, 3892−4044
distortion/interaction model, when a triple-bond carbon on Scheme 12. Manipulating Regioselectivity on 3,4-Pyridyne
aryne has a larger internal angle over the other one, this site is
more electrophilic. This model also reveals that the internal
angle difference is closely related to regioselectivity. As long as
the internal angle difference is larger than 4°, a distinct
regioselectivity will be realized.145,146,148
With the assistance of the aryne distortion/interaction
model, Garg and co-workers could readily predict the
regioselective preference with respect to different substituents
on the benzyne ring. Distinctively, they could also overturn the
regioisomeric ratios by positioning a designated EW group on
the proximal position of an aryne triple bond. As shown in
Scheme 11, they demonstrated that by employing 3-24b with a
Scheme 11. Reversing the Regioselectivity on 4,5-Indolynes
3.4. Effect of a Fused Small Ring

Another factor that could tune aryne regioselectivity is through
ring-strain on small ring-fused arynes, which is uncommon in
aryne chemistry. This tuning factor was accidentally discovered
by Suzuki and co-workers, when they studied the [2 + 2]
cycloaddition reaction of a four-membered ring-fused aryne
precursor 3-31 (Scheme 13a).158 Two regioisomers 3-32a and
bromo group on the C6-position of 4,5-indolyne, the original Scheme 13. Study on Small Ring-Fused Arynes
geometry of 4,5-indolyne (3-24a) changed and the C4-
position of 3-24b became more electrophilic, which could
produce 3-25 preferentially.151 In the absence of the 6-bromo
group, a typical 4,5-indolyne (3-24a) favors the C5-position in
nucleophilic addition reactions and afforded 3-26 as the major
products.
In 2013, Garg and Goetz demonstrated another excellent
example by using the inductively EW tuning factor to
manipulate the regioselectivity on 3,4-pyridyne.152 As shown
in Scheme 12a, their DFT calculations indicated similar
internal angles (125.3° and 124.7°) on the triple bond of a
typical 3,4-pyridyne, suggesting a lack of regioselective control
with respect to 3,4-pyridyne. Notably, both C2- and C5-
substituted 3,4-pyridynes with various EWGs could change the
internal angles on the triple-bond carbons. In addition, these 3-32b were obtained in a 31:1 ratio. Although they first
changes are in opposite trends, depending on the location of speculated that steric repulsion might be responsible for the
the EWG, on either the 2- or 5-position. Under the guidance of regioselective control, this possibility was then ruled out by
these theoretical insights, they examined the regioselective employing different ring-fused aryne precursors. In a study
outcomes of these substituted 3,4-pyridynes with various carried out by Houk, Garg, and co-workers on indolyne
arynophiles. As shown in Scheme 12b, the reaction of 3-27a− precursors, they calculated a four-membered ring-fused
3-27c with N-methylaniline afforded the corresponding benzyne 3-33 (Scheme 13b).150 Because the internal angle
products 3-28, 3-29, and 3-30, respectively. Although the difference for two triple-bond carbons is 8°, it could easily
reaction with simple 3,4-pyridyne (3-27a) showed almost no recognize that the position with a larger internal angle is the
selectivity, both 5-bromo-3,4-pyridyne (3-27b) and 2-sub- preferred site of attack. By taking advantage of this tuning
stituted 3,4-pyridyne 3-27c exhibited noticeably enhanced factor, Suzuki et al. accomplished the syntheses of a series of
meta-selectivity with respect to the EWGs, affording 3-29b and hexasubstituted benzenes, those of which were otherwise
3-30a, respectively, as the major products. difficult to access via other methods.163−165 It should be
Chem. Rev. 2021, 121, 3892−4044
mentioned that in an early study on cyclopropabenzyne 3-34 scaffolds from anthracenes and o-silylaryl triflates.190−197
carried out by Apeloig, Halton and co-workers in 1986, they Because of the rigidity of a triptycene framework, it has
proposed that the regioselectivity in the reaction of 3-34 found useful applications in materials science, which will be
should be significant (Scheme 13c).166 However, there was no covered in section 15.
follow-up study on this intermediate. 4.1.4. With Cyclic 1,3-Dienes. Cyclic 1,3-diene aryno-
Although this tuning factor has been reported with only philes other than furan and 2-pyranone were studied. In 2012,
limited examples, it does not mean that this effect is rare. In Biju and co-workers reported a highly efficient [4 + 2]
contrast, it might have already existed in aryne chemistry. For cycloaddition reaction of both 6-substituted and 6,6-disub-
instance, both the 4,5-indolyne and 4,5-benzofuranyne have an stituted pentafulvenes 4-1 with arynes, affording benzonorbor-
internal angle difference equal or larger than 4° (Figure 4). nadiene derivatives 4-2 in good to excellent yields (Scheme
Accompanied with the recent rapid advance in hexadehydro- 16a).198 This type of transformation was also utilized by Ho
Diels−Alder (HDDA) aryne chemistry, the ring strain induced
by the fused small rings on those aryne intermediates might, at Scheme 16. Aryne Diels−Alder Reactions with
least in part, attribute to their excellent regioselectivity.35,38,167 Pentafulvenes, 1,2-Benzoquinones, and Tropones
4. PERICYCLIC REACTIONS
4.1. Diels−Alder Reactions
Pericyclic reactions are the earliest as well as the most well-
investigated reaction modes in aryne chemistry. Among them,
aryne Diels−Alder reactions with various dienes as arynophiles
have been extensively studied (Scheme 14). With the recent
Scheme 14. General Scheme for Aryne Diels−Alder

Reactions
intensive exploration on o-silylaryl triflates, not only conven-

tional dienes but also new types of diene arynophiles were
developed in aryne Diels−Alder reactions.
4.1.1. With Furans. Furans are fundamental arynophiles in
aryne Diels−Alder reactions, which have been utilized since and Huang.199 Meanwhile, Biju and co-workers studied the
the early era of aryne chemistry (Scheme 15a). With the reaction between 1,2-benzoquinones (4-3) and arynes, which
employment of Kobayashi’s method, many applications on this could construct dioxobenzobicyclooctadienes 4-4 (Scheme
reaction mode were realized,134,168−182 which will not be 16b).200 Further derivatization on the products gave rise to
discussed in this section. both benzoquinoxalinobarrelene and naphthalene derivatives.
This protocol was also employed by Liu and co-workers in
Scheme 15. Aryne Diels−Alder Reactions with Furan, 2- their syntheses of diterpenoid derivatives.201,202 Subsequently,
Pyranone, and Anthracene Biju et al. applied tropones (4-5) in the Diels−Alder reaction
with arynes, affording functionalized benzobicyclo[3.2.2]-
nonatrienone derivatives 4-6 in modest to high yields (Scheme
16c).203 Moreover, this type of [4 + 2] cycloaddition was also
utilized by Hoye et al.167
In a study carried out by Cheng, Zhai, and co-workers on N-
arylation of 2-aminopyridine with o-silylaryl triflates, they
disclosed that the N-arylated products, 1-arylpyridin-2(1H)-
imine derivatives 4-7, could further participate in an aryne
Diels−Alder reaction to produce benzoisoquinuclidines 4-8
(Scheme 17a).204 In 2018, Tejedor, Garcı ́a-Tellado, and co-
workers demonstrated that 2,2-dimethyl-2H-pyrans 4-9 could
serve as efficient electron-rich diene arynophiles to react with
4.1.2. With 2-Pyranones. Another type of common diene arynes.205 As shown in Scheme 17b, a sequential Diels−Alder/
arynophile is 2-pyranone, the [4 + 2] cycloadduct of which retro-Diels−Alder reaction process with the extrusion of
could then undergo an extrusion of CO2 to form a naphthalene acetone occurred, furnishing polysubstituted methyl 2-
framework (Scheme 15b).183−189 naphthoates 4-10 in good to excellent yields. This protocol
4.1.3. With Anthracenes. The central ring of an was recently employed by Garcı ́a-Tellado et al.206 Besides,
anthracene could serve as a 1,3-diene moiety, which has both isoindoles207 and cyclohexadienes208,209 have been shown
been traditionally utilized in an efficient preparation of to serve as efficient dienes in aryne Diels−Alder reactions as
triptycene framework with arynes generated through the well. Intriguingly, Wang and co-workers demonstrated that η5-
methods other than Kobayashi’s (Scheme 15c). Hence, there indenyl complexes 4-11 of both iron210 and ruthenium211 as
are limited recent examples in the preparation of triptycene well as the η5-fluorenyl ruthenium complex211 could participate
Chem. Rev. 2021, 121, 3892−4044
Scheme 17. Aryne Diels−Alder Reactions with Other Cyclic Scheme 18. Aryne Diels−Alder Reactions with Linear 1,3-
1,3-Dienes Dienes
Scheme 19. Aryne Diels−Alder Reaction/Eliminative

Aromatization Processes
in the aryne Diels−Alder reaction to afford the corresponding

cycloadducts 4-12 (Scheme 17c).
4.1.5. With Acyclic 1,3-Dienes. Although cyclic 1,3-
dienes have been broadly employed as efficient arynophiles in
aryne Diels−Alder reactions, acyclic 1,3-dienes received much
less attention with respect to the aryne generation methods
other than Kobayashi’s. In 2005, Lautens and co-workers
demonstrated that ethyl sorbate and its analogues 4-13 could
participate in the Diels−Alder reactions with benzyne,
generated from benzenediazonium-2-carboxylate. In this
study, they also revealed that substrate 4-13 bearing
Oppolzer’s sultam as the chiral auxiliary could react with o-
silylaryl triflates to yield cycloadducts 4-14 in excellent and co-workers disclosed that in the presence of TFA ortho-
diastereoselectivities (Scheme 18a).212 Subsequently, the hydroxybenzophenones 4-20 were obtained in moderate to
same group applied Oppolzer’s sultam as the chiral auxiliary excellent yields from 3-vinylchromones 4-19 and o-silylaryl
in diastereoselective Diels−Alder reactions between either the triflates (Scheme 19b).227 In 2018, Mukherjee and co-workers
pyrrole or furan moiety and o-silylaryl triflates, affording developed a unique protocol to prepare a series of meta-
enantiomerically pure benzofused [2.2.1] heterobicycles.213 disubstituted fused aromatic systems 4-22 with chiral side
Moreover, aryne Diels−Alder reactions with linear dienes were chains through a successive aryne Diels−Alder reaction with
then utilized by various groups.214−223 It is worth mentioning glycal-based dienes 4-21 and eliminative aromatization
that Vankar and co-workers applied this strategy in the (Scheme 19c).228
preparation of 1,2-annulated-C-aryl glycosides 4-16 from 1,3- 1,3-Dienes containing heteroatoms are useful arynophiles in
diene 4-15, the products of which could be further converted aryne hetero-Diels−Alder reactions. In 2006, Piers and co-
to sugar-fused and sugar-branched naphthalenes as well workers examined benzyne Diels−Alder reaction with
(Scheme 18b).224 borabenzenes 4-23, which produced highly Lewis acidic 1-
In some cases, the cycloadducts could undergo eliminative borabenzobarrelene derivatives 4-24 (Scheme 20).229 The
aromatization to assemble naphthalene rings. In 2003, Comins products in this transformation exhibited high stability.
et al. demonstrated that a tandem [4 + 2] cycloaddition In 2014, Romero-Ortega and co-workers employed 2-
reaction between arynes and 5-vinyl-2,3-dihydro-4-pyridones (trichloromethyl)-1,3-diazabutadienes (4-25) as 1,3-dienes to
(4-17) with a following eliminative aromatization could afford react with benzyne and harvested 4-susbstituted 2-
β-amino-ketones 4-18 (Scheme 19a).225,226 Similarly, Wu, Sha, (trichloromethyl)quinazolines 4-26 in good to excellent yields
Chem. Rev. 2021, 121, 3892−4044
Scheme 20. Aryne Diels−Alder Reactions with Scheme 22. Other Aryne Aza-Diels−Alder Reactions
Borabenzenes
after the elimination of a secondary amine moiety (Scheme

21a).230 In 2016, He et al. reported an inverse electron-
Scheme 21. Aryne Diels−Alder Reactions with Aza-1,3-

dienes
sequential aza-Diels−Alder reaction/N-arylation pathway

(Scheme 22b).237 Stable o-quinone methides 4-34 could also
participate in hetero-Diels−Alder reaction with arynes, giving
rise to both 9-aryl and 9-cinnamyl substituted xanthenes 4-35
in moderate to high yields (Scheme 23).238 The same
transformation was also realized by Panda et al.239
Scheme 23. Aryne Diels−Alder Reaction with o-Quinone

Methides
Styrenes are good Diels−Alder partners with arynes. In

2012, Wu et al. first reported a sequential aryne Diels−Alder/
dehydrogenation reaction with α,β-unsaturated compounds
demand aza-Diels−Alder reaction of arynes with 2-aza-dienes, containing styrene moiety. Various acyl-/ethoxycarbonyl-/
generated in situ from anilines and ethylglyoxylate, the cyano-substituted styrenes 4-36 could be used in the reaction
cycloadduct of which underwent a further N-arylation to to furnish the corresponding 9-functionalized phenanthrenes
afford N-aryl dihydrophenanthridine derivatives 4-27 (Scheme 4-37 (Scheme 24a).240 In 2014, Biju and co-workers disclosed
21b).231 In 2018, Zhang and co-workers developed a tandem that unactivated styrenes 4-38 participated in the aryne Diels−
transformation that involved a Rh(I)-catalyzed coupling Alder reaction to produce cycloadducts 4-39 (Scheme 24b).241
reaction of vinyl azides with isonitriles to form vinyl Particularly, when styrenes bearing an electron-withdrawing
carbodiimide intermediates 4-28, which then proceeded group (EWG) on the 4-position of the benzene ring, a proton
through an aryne Diels−Alder reaction to furnish isoquinoline transfer/aromatization process readily took place to afford 4-
derivatives 4-29 (Scheme 21c).232 In addition, other examples 39. Recently, Tiwari et al. employed β-bromovinylarenes 4-40
on this type of transformations have also been reported.233−235 as 1,3-dienes in the aryne Diels−Alder reaction, furnishing
In 2015, Rodriguez, Coquerel and co-workers reported two phenanthrenes, chrysenes, and tetraphenes 4-41 (Scheme
aryne aza-Diels−Alder reactions using electron-rich 2-aza- 24c).242 The presence of the β-bromo group on 4-40 allowed a
dienes 4-30 as 1,3-dienes (Scheme 22a).236 The first facile eliminative aromatization after the [4 + 2] cycloaddition
transformation involved an in situ oxidation of the cyclo- reaction. In 2015, Wu, Shi and co-workers found that the aryne
adducts with MnO2 to produce isoquinolines 4-31, while the Diels−Alder reaction with γ-arylallenylcarboxyamides 4-42
second approach directly afforded isoquinolines 4-32 by occurred in a highly chemoselective manner to afford 4-43,
employing formimidamides as 1,3-dienes, the structure of whereas the amide moiety did not involve in this trans-
which equips with a sacrificial dimethylamino group that could formation (Scheme 24d).243 Notably, this transformation
promote a following eliminative aromatization reaction. required the presence of an allene moiety.
Moreover, this study also led to a total synthesis of In 2012, Li, Jia, and co-workers realized an aryne Diels−
benzo[c]phenanthridine alkaloid nornitidine, which will be Alder reaction with methyleneindolinones 4-44, which allowed
covered in section 14. Subsequently, the same group employed a quick construction of structurally unprecedented naphtho-
an excess amount of aryne to obtain compounds 4-33 via a fused oxindoles 4-46 in modest to high yields (Scheme
Chem. Rev. 2021, 121, 3892−4044
Scheme 24. Aryne Diels−Alder Reactions with Styrenes Scheme 25. Aryne Diels−Alder Reactions with
Methylene(iso)indolinones and Fluorene-Derived Alkenes
25a).244 In this study, they proposed a fluoride-assisted

deprotonation on the cycloadduct 4-45 with departure of
hydride to account for the formation of 4-46. However, there
might be other possibilities to reach this dehydrative
aromatization step. In 2017, Jeganmohan et al. developed a
unique transformation between o-silylaryl triflates and 3-
methyleneisoindolin-1-ones 4-47, furnishing the skeleton of
aristolactam alkaloids 4-49 (Scheme 25b).245 This reaction
involves a [4 + 2] cycloaddition reaction and a fluoride-
moderate to high yields (Scheme 26c).251 Notably, they
mediated desulfonylation of the cycloadduct 4-48. Recently,
found that a N-benzhydryl (CHPh2) protecting group was
He and co-workers demonstrated that the Diels−Alder
crucial to prevent a possible competing [4 + 2] cycloaddition
reactions between arynes and fluorene-derived alkenes 4-50
reaction on the pyrrole ring.
could produce benzo[b]fluoranthenes (4-51) after in situ
4.1.6. Intramolecular Diels−Alder Reactions. In 2005,
dehydrogenative oxidation with MnO2 (Scheme 25c).246
Danheiser and co-workers reported an intramolecular aryne
Both alkenylindoles and alkenylpyrroles were utilized in
Diels−Alder reaction with conjugated enynes and arenynes 4-
aryne Diels−Alder reactions, allowing the rapid construction of
60, giving rise to highly condensed polycyclic aromatic
polycyclic heterocycles. In 2014, Wu, Sha, and co-workers
compounds 4-61 (Scheme 27a).108 Recently, Ohmori, Suzuki,
employed 3-alkenylindoles 4-52 as 1,3-dienes in the aryne
and co-workers demonstrated an intramolecular [4 + 2]
Diels−Alder reaction, affording benzo[a]carbazole-5-carbox-
cycloaddition of aryne and phenolate by employing o-
ylates 4-53 after an in situ oxidation with molecular oxygen
bromoaryl tosylates as the aryne precursors.252 In this study,
(Scheme 26a).247 Subsequently, the same protocol was utilized
they showed one example with o-silylaryl triflate 4-62 as the
by Liang, Pi, and co-workers.248 In addition, 2-alkenylindoles
precursor and obtained cycloadduct 4-63 in 89% yield
4-54 were also employed in the aryne Diels−Alder reaction
(Scheme 27b).
(Scheme 26b).249,250 Depending on the stoichiometry of o-
silylaryl triflates, both 6,7-dihydrobenzo[c]carbazoles 4-55 and 4.2. 1,3-Dipolar Cycloaddition Reactions
aryl substituted 7,11b-dihydrobenzo[c]carbazoles 4-56 were Along with the study on Kobayashi’s method, a family of 1,3-
obtained in good to excellent yields. In the presence of dipolar cycloaddition reactions were explored and utilized. The
molecular oxygen, benzo[c]carbazole derivatives 4-57 were mild generation conditions with respect to o-silylaryl triflates
produced. In 2016, Wu, Sha, and co-workers demonstrated an allow the compatibility of this method with not only diverse
interesting chemoselective aryne Diels−Alder reaction with 2- functional groups but also a variety of 1,3-dipoles, some of
vinylpyrroles 4-58, furnishing benzo[e]indoles 4-59 in which might be otherwise unstable under harsh reaction/
Chem. Rev. 2021, 121, 3892−4044
Scheme 26. Aryne Reactions with Alkenylindoles and Scheme 28. General Scheme for Aryne 1,3-Dipolar
Alkenylpyrroles Cycloaddition Reactions
4.2.1. With 4-Hydroxyisoquinolinium and 3-Oxido-

pyridinium. The earliest study on the 1,3-dipolar cyclo-
addition reaction with o-silylaryl triflates was carried out by
Carroll and co-workers. In 1996, they reported a convenient
strategy toward the synthesis of MK801, which is known to
inhibit opioid tolerance and dependence (Scheme 29a).253 In
Scheme 29. Aryne 1,3-Dipolar Cycloaddition Reactions with

4-Hydroxyisoquinolinium and 3-Oxidopyridinium Species
Scheme 27. Intramolecular Aryne Diels−Alder Reactions
this work, N-alkyl-4-hydroxy-1-methylisoquinolinium betaines

4-64 participated in the aryne 1,3-dipolar cycloaddition
reaction and afforded N-alkyl-5-methyl-1l-oxo-5H-dibenzo-
[a,d]cyclohepten-5,l0-imines 4-65 in high efficiency, which
was then converted to MK801. They also examined the
reactivity of 4-64 with two other benzyne precursors, namely,
1-aminobenzotriazole (4-66) (generated via oxidation with
lead tetraacetate) and anthranilic acid (4-67) (generated via
diazotization), both of which gave either low yield or no
desired product at all (Scheme 29a). In 2012, Shi and co-
workers further expanded the scope of this protocol to 3-
oxidopyridinium species 4-68, giving rise to bicyclo[3.2.1]
generation conditions. Scheme 28a summarizes a general skeleton 4-69 under mild conditions (Scheme 29b).254
equation for the aryne 1,3-dipolar reaction, which can also be 4.2.2. With Diazo Compounds. Diazo compounds are
seen as a formal [3 + 2] cycloaddition reaction. Benzofused prevalently utilized in 1,3-dipolar cycloaddition reactions with
heterocyclic rings can be facilely prepared, those of which have o-silylaryl triflates. In 2007, Yamamoto and Jin first
found useful synthetic applications. Among 1,3-dipoles, azides, demonstrated that 1H-indazoles 4-70 and 1-arylated indazoles
diazo compounds, nitrones, and nitrile oxides are commonly 4-71 could be readily synthesized in good to high yields from
utilized in aryne cycloaddition reactions (Scheme 28b). diazo compounds by simply varying the reaction conditions
Chem. Rev. 2021, 121, 3892−4044
and the stoichiometry of o-silylaryl triflates (Scheme 30a).255 to fused-2H-indazoles via an acid- or heat-mediated rearrange-
Later in 2008, in a study carried out by Larock and co-workers, ment (Scheme 31c).261
Diazo compounds with electron-withdrawing activating
Scheme 30. Aryne 1,3-Dipolar Cycloadditions with Diazo groups other than carbonyl were also examined. In 2015, Ma
Compounds and co-workers achieved a 1,3-dipolar cycloaddition reaction of
o-silylaryl triflates with 2,2,2-trifluorodiazoethane (CF3CHN2),
affording potentially bioactive 3-trifluoromethyl-1H-indazoles
4-80 in good to high yields with moderate regioselectivities
(Scheme 32a).262 In 2018, Peng and co-workers disclosed that

CF3CHN2 and α-Diazomethylphosphonates
they disclosed that dicarbonyl-containing diazo compounds 4-

72 could enforce carbonyl migration to produce 1-acyl- or 1-
alkoxycarbonyl indazoles 4-73 in high to excellent yields
(Scheme 30b).256
In 2009, Hari, Aoyama, and co-workers developed a one-pot,
two step procedure for the preparation of 3-substituted
indazoles 4-75 from arynes and 2-diazo-(2-trimethylsilyl)-
ethanols 4-74, which could be readily synthesized from two types of [3 + 2] cycloadducts, namely, 3-alkyl/aryl-1H-
diazo(trimethylsilyl)methylmagnesium bromide with various indazoles 4-82 and 3-alkyl/aryl-3H-indazole-3-phosphonates
ketones and aldehydes (Scheme 31a).257 Recently, the groups 4-83, could be prepared from α-substituted α-diazomethyl-
phosphonates 4-81 (Scheme 32b).263 By simply varying the
Scheme 31. Aryne 1,3-Dipolar Cycloaddition Reactions with phosphoryl group, 3-alkyl/aryl-1H-indazoles 4-82 could be
Other Diazo Compounds obtained from dimethyl α-diazoalkylphosphonates (R2 = Me),
whereas 3-alkyl/aryl-3H-indazole-3-phosphonates 4-83 were
achieved from diisopropyl α-diazoalkylphosphonates (R2 = i-
Pr).
N-Substituted hydrazones were employed as stable and
readily accessible precursors of diazo compounds. In 2011, Shi
and co-workers demonstrated that under fluoride-induced
activation conditions, N-tosylhydrazones 4-84 could generate
the corresponding diazo compounds, which then underwent
1,3-dipolar cycloaddition reaction with arynes (Scheme
33a).264 Notably, TEBAC (Et3NBn+Cl−) served as a phase
transfer catalyst to effectively enhance the reaction yields. Later
in 2012, the same group reported an aryne 1,3-dipolar reaction
with N-aryl/alkylhydrazones 4-85, affording 1,3-disubstituted

N-Substituted Hydrazones
of Zhai258,259 and Reddy260 independently developed an aryne

1,3-dipolar cycloaddition reaction with 3-diazoindolin-2-ones
4-76, furnishing spiro[indazole-3,3′-indolin]-2′-ones 4-77 in
good to excellent yields (Scheme 31b). Subsequently, Cheng,
Zhai, and co-workers utilized 6-diazocyclohex-2-en-1-one
derivatives 4-78 as 1,3-dipoles to react with arynes, giving
rise to spiro-3H-indazoles 4-79 that could be further converted
Chem. Rev. 2021, 121, 3892−4044
indazoles 4-86 through an annulation/oxidation process Scheme 35. Aryne 1,3-Dipolar Cycloaddition Reactions with
(Scheme 33b).265 Other Azides
4.2.3. With Azides. Azides are very efficient 1,3-dipoles
and have been extensively utilized in alkyne click chemistry.
Not surprisingly, they could be employed in aryne [3 + 2]
cycloaddition reactions as well to build a benzotriazole
framework. Distinctively, these aryne-azide [3 + 2] cyclo-
addition reactions are under copper-free conditions. The
preparation of benzotriazoles 4-87 via the aryne 1,3-dipolar
reaction with azides was realized in 2008 independently by the
groups of Larock,266 Chandrasekhar,267 and Feringa268
(Scheme 34a). In 2009, Biehl and Ankati reported a

Azides
zoles could find more useful applications. In this context, Zajc

and co-workers developed a sequential aryne-azide 1,3-dipolar
annulation/Julia−Kocienski reaction process to synthesize N1-
vinyl benzotriazoles 4-92 from azidomethyl phenyl-1H-
tetrazol-5-yl sulfide (4-91) (Scheme 35c).271 This strategy
smartly avoided the N1/N2 regioselective problem in conven-
tional alkylation reaction of benzotriazoles. Beside the
microwave-assisted aryne click protocol using either aryl/ aforementioned examples, this transition-metal-free aryne-
alkyl azides or those in situ generated from alkyl halides and azide [3 + 2] cycloaddition protocol turned out to be quite
sodium azide (Scheme 34b).123 Notably, they found that the general and has found a broad spectrum of synthetic
departure rate of the OTf group from o-silylaryl triflates could applications.272−292
be significantly promoted under microwave irradiation 4.2.4. With Nitrile Oxides. In 2010, the groups of
conditions. Recently, Biju and co-workers studied the reaction Larock293 and Browne294 independently reported aryne 1,3-
between NaN3 and o-silylaryl triflates. They found that N-H dipolar cycloaddition reactions with nitrile oxides, in situ
benzotriazoles could be obtained by using CsF/18-c-6 in generated from N-hydroxybenzimidoyl chloride analogues 4-
acetonitrile; whereas N-aryl benzotriazoles were formed when 93 via fluoride-induced deprotonation reaction, furnishing
the reaction employed KF/18-c-6 in THF in an open-flask substituted benzisoxazoles 4-94 in moderate to excellent yields
(Scheme 34c).269 with high functional group tolerance (Scheme 36). Dis-
In 2009, Moses and Zhang demonstrated that aromatic tinctively, this protocol allowed a simultaneous generation of
azides 4-88, generated in situ from anilines, t-BuONO, and two highly active species, namely, an aryne and a nitrile oxide,
TMSN3, could react with arynes to give benzotriazoles in good in the same reaction media. Subsequently, Larock and co-
to high yields (Scheme 35a).124 Both anthranilic acids and o- workers further expanded the synthetic application of this
silylaryl triflates could serve as efficient aryne precursors in this
transformation. They also noticed that microwave irradiation Scheme 36. Aryne 1,3-Dipolar Cycloaddition Reactions with
dramatically shortened the reaction time of this one-pot Nitrile Oxides
protocol. An advantage for this protocol is to avoid the
handling of potentially explosive aliphatic/aromatic azides. In
2011, Reddy et al. employed glycosyl azides 4-89 with the
azide group on different positions of the glycosyl ring to
prepare benzotriazole-linked glycoconjugates 4-90, those of
which might be applied in nucleoside synthesis (Scheme
35b).270 The selective formation of 1-substituted benzotria-
Chem. Rev. 2021, 121, 3892−4044
protocol and prepared a library of building blocks containing 3- Scheme 38. Aryne 1,3-Dipolar Cycloaddition Reactions with
substituted benzisoxazoles, those of which possess potential Azomethine Imines and Nitrile Imines
biological activity.295
4.2.5. With Nitrones. In 2012, Larock et al. demonstrated
that nitrones could participate in aryne 1,3-dipolar cyclo-
addition reactions to furnish substituted benzisoxazolines 4-95
with high functional group tolerance (Scheme 37a).296

Nitrones

N-Heteroaromatic Ring Imides
Meanwhile, Kaliappan and Khangarot developed a highly

diastereoselective aryne 1,3-dipolar cycloaddition protocol
with sugar-derived chiral cyclic nitrone 4-96 (Scheme
37b).297 The resulting sugar-based benzo[d]isoxazoline
products 4-97 could be further converted to aza-C-aryl
glycosides via a selective N−O bond cleavage. In 2017, Yao
and co-workers realized an in situ generation of nitrone species
from ketoximes 4-98 and a subsequent aryne 1,3-dipolar
cycloaddition reaction (Scheme 37c).298 A ketonitrone
intermediate was first generated between ketoxime and
aryne, which then participated in a [3 + 2] cycloaddition
reaction with another aryne to furnish benzisoxazolines 4-99.
In this study, they also disclosed that under high reaction
temperature benzisoxazolines 4-99 could isomerize to
dihydrobenzo[d]oxazoles 4-100. Moreover, this aryne-nitrone
cycloaddition protocol was utilized in many synthetic
applications as well.299−304
4.2.6. With Azomethine Imines and Nitrile Imines. In
2009, Larock and co-workers demonstrated that stable The [3 + 2] cycloaddition reaction breaks the aromaticity of
azomethine imines 4-101 could participate in aryne 1,3-dipolar pyridine ring and generates intermediate 4-109, which could
cycloaddition reaction, giving rise to tricyclic pyrazoloindazo- then transform to pyrido[1,2-b]indazoles 4-110 after elimi-
lones 4-102 (Scheme 38a).305 Recently, Sha, Wu, and co- native aromatization.308 Furthermore, a one-pot process was
workers reported a [3 + 2] cycloaddition reaction of C,N-cyclic also developed by the same group through a sequential AgOTf-
azomethine imines 4-103 with o-silylaryl triflates, furnishing N- catalyzed cyclization of N′-(2-alkynylbenzylidene)-tosylhydra-
substituted indazolo[3,2-a]isoquinolines 4-104 (Scheme zides 4-111 to generate N-tosylisoquinolinium imides 4-112
38b).306 Similarly, nitrile imines 4-106, generated in situ and an aryne 1,3-dipolar cycloaddition reaction, affording
from aryl/heterocyclic substituted hydrozonyl chlorides 4-105, indazolo[3,2-a]-isoquinolines 4-113 in modest to high yields
could react with arynes to afford 1-substitued-1H-indazoles 4- (Scheme 39b).309 In 2018, Sharma and co-workers reported an
107 in modest to excellent yields (Scheme 38c).307 aryne [3 + 2] cycloaddition reaction with N-benzoyl protected
4.2.7. With N-Heteroaromatic Ring Imides. N-Tosyl- quinolinium imides 4-114, giving rise to four-ring-fused N,N′-
pyridinium imides 4-108 were utilized by Wu, Shi and co- heterocyclic compounds 4-115 in moderate to high yields
workers as 1,3-dipoles in aryne reactions (Scheme 39a).308,309 (Scheme 39c).310 Different from the reaction with N-
Chem. Rev. 2021, 121, 3892−4044
tosylpyridinium imides 4-108, the benzoyl-protecting group on Scheme 41. Aryne 1,3-Dipolar Cycloaddition Reactions with
the products 4-115 did not eliminate after the [3 + 2] DTOs and Thiadiazoles
cycloaddition reaction.
4.2.8. With Cyclic 1,3-Dipoles. Cyclic 1,3-dipoles could
also be employed in aryne [3 + 2] cycloaddition reactions.
Several mesoionic dipoles, such as sydnones, münchnones, and
1,3-dithiolium-4-olates (DTOs), were investigated in aryne
cycloaddition reactions. In 2010, Larock, Shi, and co-workers
first utilized sydnones 4-116 as 1,3-dipoles to react with arynes.
2H-Indazoles 4-118 were obtained in good to excellent yields
(Scheme 40a).311,312 After the aryne 1,3-dipolar cycloaddition

Sydnones and Münchnone
(Scheme 42a).321 In 2014, Hu and co-workers developed an

unprecedented strategy toward enantiopure cyclic sulfoxi-
Scheme 42. Reactions with Other 1,3-Dipoles
reaction, extrusion of CO2 occurred on the cycloadducts 4-117

to afford 2H-indazole derivatives 4-118. Synthetic applications
based on this protocol were then explored by different research
groups.153,313−316 Münchnones are isoelectronic with sydnones
and have been utilized as cyclic 1,3-dipoles as well. In 2014, the
groups of Larock and Shi317 and Gribble318 independently
demonstrated an aryne [3 + 2] cycloaddition reaction with
münchnones 4-119, producing isoindoles 4-121318 after
extrusion of CO2 from the cycloadducts 4-120 (Scheme 40b).
Recently, Audisio, Taran, and co-workers prepared a series
of 1,3-dithiolium-4-olates (DTOs) 4-122 and studied their
reactivity with strained alkynes.319 As shown in Scheme 41a,
various benzo[c]thiophenes 4-124 were facilely prepared
through an aryne [3 + 2] cycloaddition/extrusion of carbonyl
sulfide (COS) sequence via intermediate 4-123. Another type mines, in which N-tert-butanesulfinyl imines 4-132 as quasi-
of cyclic 1,3-dipole is thiadiazole. In 2015, Willis and Chen 1,3-dipoles could participate in aryne 1,3-dipolar cycloaddition
disclosed that both 3,4-dichloro-1,2,5-thiadiazole and unsym- reaction to produce cycloadducts 4-133 in good to high yields
metrical thiadiazoles 4-125, such as 3-hydroxy-4-amino- (Scheme 42b).322 In this study, the presence of the PhSO2CF2
thiadiazoles, could react with o-silylaryl triflates to furnish group was the key for the success of this transformation,
benzo[d]isothiazoles 4-127 in modest to excellent yields allowing both high efficiency and excellent stereoselectivity in
(Scheme 41b).320 Cyanic acid can be then extruded from the the [3 + 2] cycloaddition reaction.
cycloadduct 4-126 after the 1,3-dipolar cycloaddition reaction. In 2018, Singh and Garg demonstrated that 2,3-disubstuted
4.2.9. With Other 1,3-Dipoles. Other 1,3-dipoles as aryne benzo[b]thiophenes 4-136 could be obtained in the aryne 1,3-
[3 + 2] cycloaddition partners have been investigated. In 2007, dipolar cycloaddition reaction with acyl ketene dithioacetals 4-
Huang et al. reported a 1,3-dipolar cycloaddition of Kobayashi 134 (Scheme 43a).323 Notably, this study unraveled the dipole
benzyne precursor with 1,3-bis(2,4,6-trimethylphenyl)-2-N- character of acyl ketene dithioacetals 4-134 conveyed by their
phenylthiocarbamoyl imidazolinium inner salt (4-130), pre- resonance structure 4-135, furnishing 4-136 through a
pared from the reaction between N-heterocyclic carbene 4-128 sequential [3 + 2] cycloaddition reaction and extrusion of an
and 2-tolyl isothiocyanate (4-129), resulting in the formation ethylene moiety via either path a or path b. In the same year,
of spiro(imidazolidine-2,3′-benzo[b]thiophene) (4-131) Ko and co-workers utilized azomethine ylides 4-137 as 1,3-
Chem. Rev. 2021, 121, 3892−4044
Scheme 43. Aryne 1,3-Dipolar Cycloaddition Reactions with Scheme 44. Aryne [2 + 2] Cycloaddition Reactions with
Acyl Ketene Dithioacetals, Azomethine Ylides, and α- CS and CSe Bonds
Haloamides
structure of which was otherwise hard to be accessed (Scheme

44c).328
In 2009, Hsung and co-workers demonstrated a [2 + 2]
cycloaddition reaction between enamides 4-148 and benzyne,
furnishing cycloadducts 4-149 in moderate to excellent yields
(Scheme 45a).329 A similar aryne [2 + 2] cycloaddition
Scheme 45. Aryne [2 + 2] Cycloaddition Reactions with

Enamides
dipoles to react with arynes and obtained spirooxindole-3,2′-

pyrrolidine derivatives 4-138 in moderate to excellent yields
(Scheme 43b).324 Fluoride ion in this transformation served as
both the activating reagent for o-silylaryl triflates and the base
to deprotonate ketimine species. Meanwhile, Singh et al.
revealed that N-alkoxy oxindoles 4-141 could be readily
reaction with N,N-bis(Boc)-protected dehydroalanine 4-150
prepared via a formal [3 + 2] cycloaddition reaction between
was recently reported by Ramtohul et al., in which α,α-
arynes and α-haloamides 4-139, which can be seen as putative
disubstituted benzocyclobutene amino acids 4-151 were
aza-oxyallyl cation synthons 4-140 (Scheme 43c).325 Notably,
readily prepared (Scheme 45b).330 Notably, a simple
N-alkoxy substituents on α-haloamides were necessary for the
modification on the N-protecting group of the substrates
success of this transformation, which was reasoned by their
could result in the formation of either indoline or isoquinoline
stabilizing ability to the aza-oxyallyl cation 4-140.
products (see section 6).331,332
4.3. [2 + 2] Cycloaddition Reactions In 2014, Yu, Liu, and co-workers examined aryne [2 + 2]
In comparison with intensively investigated as well as broadly cycloaddition reactions with a series of olefins (Scheme
utilized [4 + 2] and 1,3-dipolar cycloaddition reactions, formal 46a).333 Among them, norbornadiene, norbornene, vinyl
[2 + 2] cycloaddition with o-silylaryl triflates received much butyl ether, and alkyl acrylate could all afford benzocyclobu-
less attention. In 1998, Okuma and co-workers first employed tenes 4-152 in high yields. Subsequently, Lakshman and co-
Kobayashi benzyne precursor in the benzyne [2 + 2] workers systematically investigated the reaction between o-
cycloaddition reaction with thiopivalophenone 4-142, giving silylaryl triflates and cyclic enol ethers 4-153, such as analogues
rise to 2-tert-butyl-2-p-tolyl-2H-benzo[b]thiete (4-143), albeit of 2,3-dihydrofuran, 2,3-dihydro-3H-pyran, and 1,4-dioxene.
in low yield (Scheme 44a).326 By using thiofenchone (4-144) All of them could produce the corresponding benzocyclobu-
as the substrate, a mixture of [2 + 2] cycloadducts 4-145 was tenes 4-154 in moderate to high yields with excellent
obtained (Scheme 44b).327 In 2001, the same group stereoselective control (Scheme 46b).334
demonstrated that benzoselenete 4-147 could be efficiently Similar to 2,3-dihydro-3H-pyran, tetrahydropyridines were
prepared through a benzyne [2 + 2] cycloaddition reaction reported as well. In 2017, Wang, Lu, and co-workers
with 1,1,3,3-tetramethylindane-2-selone (4-146), the product demonstrated that the [4 + 2] cycloadducts 4-155 between
Chem. Rev. 2021, 121, 3892−4044
Scheme 46. Aryne [2 + 2] Cycloaddition Reactions with Scheme 48. Aryne [n + 2] Cycloaddition Reactions
Olefins
allene ketones and 1-azadienes could participate in a further

aryne [2 + 2] cycloaddition reaction to yield 4-156 (Scheme
47a).335 Later in 2018, another [4 + 2]/[2 + 2] cycloaddition
Scheme 47. Other Aryne [2 + 2] Cycloaddition Reactions
In 2010, Cossı ́o et al. carried out both computational and

experimental studies on the reaction between imidazo[1,2-
a]pyridines/pyrimidines 4-166 and arynes, which led to the
formation of benzo[a]imidazo-[5,1,2-cd]indolizines (X = CH)
and 2,3,9c-triazocyclopenta[j,k]fluorenes (X = N) 4-167 via a
reaction process was reported by Wang and co-workers, in [8 + 2] cycloaddition reaction/dehydrogenative aromatization
which the generated [4 + 2] cycloadducts 4-159 from process (Scheme 48c).126 Microwave irradiation was found to
compounds 4-157 could react with arynes to afford 4-158 promote the reaction, whereas classical heating only produced
via the [2 + 2] cycloaddition reaction (Scheme 47b).336 Other trace amounts of the products. Their computational study
[2 + 2] cycloaddition reactions between o-silylaryl triflates and revealed that both the [8 + 2] cycloaddition step and the
simple olefins were also explored.337,338 aromatization step were concerted. In addition, the nonlinear
4.4. [n + 2] Cycloaddition Reactions optical properties of coumarin derivatives340 and the excited
state intramolecular proton transfer property of this class of
Along with Shi’s study on aryne 1,3-dipolar cycloaddition with
molecules341 were investigated. Recently, Cheng, Zhai, and co-
3-oxidopyridinium species (X = O) 4-160, they observed the
workers demonstrated that pyridinium 1,4-zwitterionic thio-
formation of benzofuran derivatives 4-161, the generation of
lates 4-168 could serve as 1,5-dipoles and reacted with o-
which was through a sequential aryne [7 + 2] cycloaddition
silylaryl triflates to produce 12aH-benzo[f ]pyrido[1,2-d][1,4]-
reaction/pyridine ring-opening process (Scheme 48a).254 By
thiazepines 4-169 (Scheme 48d).342 Meanwhile, benzo[b]-
employing 3-amidopyridinium species (X = NR2) 4-162 as the
thiophenes were also obtained as side products, the formation
substrates, indole scaffold 4-163 could be obtained via the
of which was through a [3 + 2] cycloaddition/elimination of
same process. In 2007, Xu and co-workers reported an aryne
the pyridine process.
[8 + 2] cycloaddition reaction with indolizines and annulated
indolizines 4-164, affording indolizino[3,4,5-ab]isoindoles and 4.5. Ene Reactions
benzo[6,7]pyrrolizino[3,4,5-ab]isoquinolines 4-165 after rear- The employment of Kobayashi’s method provides mild
omatization (Scheme 48b).339 Both the fluorescence and conditions for aryne ene reactions. The first aryne ene reaction
electrochemical properties of these compounds were then with o-silylaryl triflates was reported by Cheng and co-workers.
investigated. In 2006, they found that alkynes could participate in the ene
Chem. Rev. 2021, 121, 3892−4044
reaction with arynes under mild conditions, affording arylallene reaction, they identified that the trityl group (Tr) could serve
derivatives 4-170 in moderate to good yields (Scheme 49a).343 as an ideal protecting group on various anilines 4-178 (Scheme
51a). Consequently, the aryne heteroene reaction proceeded
Scheme 49. Aryne Ene Reactions with Alkynes
Scheme 51. Other Aryne Ene Reactions
In 2014, Ma and Yuan observed an intramolecular aryne ene

reaction as the first step in a Pd-catalyzed cascade trans- smoothly to yield 2-arylanilines 4-179 in moderate to excellent
formation (Scheme 49b).344 In this transformation, the
yields with high functional group tolerance. Based on the fact
generated aryne 4-172 from o-silylaryl triflates 4-171 proceeds
through an intramolecular ene reaction to generate allene that only ortho-arylated products were obtained and with their
intermediate 4-173, which then reacts with arylpalladium deuterium-labeling experiment, a concerted aryne ene reaction
species to afford benzofurans 4-174. mechanism was proposed. Recently, Jones and co-workers
Olefins could also serve as ene arynophiles. Several applied an aryne ene reaction on Hantzsch esters 4-180 to
intermolecular aryne ene reactions with olefins have been realize either C2 or C3 arylated products 4-181 and 4-182,
recently elaborated, whereas with aryne precursors other than respectively, in regioselective manner (Scheme 51b).353,354
Kobayashi’s.345−347 Although the aryne ene reaction of o- They reasoned that the formation of C3 arylated products 4-
silylaryl triflates with alkenes was accidentally discovered by 182 was the result of steric repulsion by the bulky group on the
Okuma and co-workers in their aryne three-component C4-position of Hantzsch esters 4-180b. Both the experimental
coupling reactions,348 Yin, Liu, and co-workers systematically studies and the DFT calculations suggested a concerted aryne
investigated this transformation with respect to various olefins, ene process. Moreover, examples of aryne ene reactions
producing allyl arenes 4-175 in good to high yields (Scheme involved in cascade transformations were reported.241,355,356
50a).349 In 2016, He et al. also reported an aryne ene reaction
Scheme 50. Aryne Ene Reactions with Olefins 5. NUCLEOPHILIC ADDITION REACTIONS
The electrophilic nature of aryne species makes them excellent
reaction partners with respect to a variety of nucleophiles. In a
study carried out by Garg et al., they quantitatively determined
the electrophilicity of benzyne by using the diffusion-clock
method.357 This study revealed that benzyne is only 1 order of
magnitude less electrophilic than bis(4-methoxyphenyl)-
methylium ion. More importantly, nucleophiles could trigger
or initiate different modes of aryne transformations, such as
nucleophilic addition/annulation reactions, insertion reactions,
and multicomponent reactions. Among them, the primary
reaction mode is nucleophilic addition to arynes, which
includes a protonation on the vicinal position of the arene
with an α,β-unsaturated cyclic ketone 4-176, affording ring. In this transformation, arynes serve as efficient arylation
compounds 4-177 in good to excellent yields (Scheme synthons under transition-metal-free conditions. Therefore, it
50b).350 Moreover, an example of the aryne ene reaction can be seen as an alternate to the prevailingly investigated
with allene species was exhibited by Lee et al.351 transition-metal-catalyzed arylation strategies. Particularly,
In 2012, a distinct aryne heteroene reaction of N-substituted various nucleophiles, especially those with heteroatom and/
anilines was disclosed by Greaney and co-workers.352 After or inert ones, have been found to be efficient arynophiles,
searching for solutions to prevent the competing N-arylation further underlining the merit of aryne arylation strategy.
Chem. Rev. 2021, 121, 3892−4044
5.1. N-Arylation Reactions conditions. Unsubstituted primary or N-alkyl amides, however,

Nitrogen is an efficient nucleophilic element in aryne were inert under arylation conditions, which was reasoned by
chemistry, which is also one of the most investigated their weak nucleophilicity. In 2011, Lynch and co-workers
arynophiles with o-silylaryl triflates. In 2002, Yoshida, Kunai, reported an efficient N-arylation reaction on acetanilides 5-5
and co-worker first demonstrated a N-arylation reaction of N- with o-silylaryl triflates (Scheme 53b).362 The reaction
alkyl substituted imidazoles 5-1 with o-silylaryl triflates, employed TBAT as the fluoride source, producing N-arylated
affording N-alkyl-N′-arylimidazolium salts 5-2 in modest to products 5-6 in good to high yields. Furthermore, Jin et al.
good yields (Scheme 52).358 could solve the inactivity problem of N-alkyl amides by using
N-alkoxy amides 5-7 as the substrates, which allowed a smooth
formation of N-arylated products 5-8 with high functional
Scheme 52. N-Arylation Reactions with N-Alkyl Substituted
group tolerance (Scheme 53c).363 Particularly, this arylation
Imidazoles
transformation exhibited a distinct chemoselectivity on N-
alkoxy amides over other functionalized N−H bonds, such as
N-Ac, N-Cbz, N-Boc, and even N-Ts moieties, when
hydroxamic acids derived from N-protecting amino acids and
peptides were utilized. It was reasoned that the presence of the
N-alkoxy group results in a decreased pKa value on the amide
N−H bond.
In 2017, Shen, Xu, and co-workers reported that N-arylation
of cyclic 2-benzoxazolinones (X = O) and 2-benzimidazoli-
Subsequently, Larock et al. systematically investigated the nones (X = NMe) 5-9 with arynes proceeded smoothly with
arylation reactions of o-silylaryl triflates with amines (R2 = aryl, no observation of aryne insertion into the N−CO bond on the
alkyl), sulfonamides (R2 = R′SO2), carbamates (R2 = CO2Et), substrates (Scheme 54a).364 Subsequently, Li, Wang, and co-
and benzamides (R2 = ArCO) (Scheme 53a).359,360 Depending
Scheme 54. N-Arylation Reactions with 2-Benzoxazolinone
Scheme 53. N-Arylation Reactions with Amides and Oxadiazolones
workers showed that 3-aryl-1,2,4-oxadiazolones 5-11 under-

went a facile N-arylation reaction with arynes, furnishing
compounds 5-12 in good to excellent yields (Scheme 54b).365
In 2019, Shanmugam et al. investigated the reaction between
(het)aryl amino amides 5-13 and o-silylaryl triflates and
observed the chemoselective formation of N-monoarylated
products 5-14 and N,N-diarylated products 5-15 on amine
nitrogen with no observation of N-arylated products on amide
nitrogen (Scheme 55a).366 They also applied this protocol in
the preparation of triaryl amine derivatives, which are blue and
red emissive with high quantum yields. In 2018, Nilsson and
co-workers developed a unique N-arylation protocol on amino
on the stoichiometry of aryne precursors, either monoarylated sugars 5-16 (Scheme 55b).367 In this study, both N-mono- and
products 5-3 or diarylated products 5-4 could be obtained in N,N-diarylated products 5-17 could be achieved by varying the
moderate to excellent yields. Moreover, Jung and co-workers stoichiometry of o-silylaryl triflates. Notably, unprotected
found that the N-arylation reaction of aromatic amines with carbohydrate amines showed excellent chemoselectivity,
benzyne proceeded smoothly in the presence of either 2,5- furnishing N-arylated products with no observation of the O-
dimethoxytetrahydrofuran or 1,3-diacetone dicarboxylic arylation reaction. In the presence of carbohydrate diamines, a
acid.361 Different from the copper-mediated Ullmann reaction selective N-monoarylation reaction could be manipulated.
and the palladium-catalyzed Buchwald−Hartwig C−N cou- Tertiary amines can serve as efficient nucleophiles in
pling reaction, this method is under transition-metal-free arylation reactions. In 2013, Biju and co-workers demonstrated
Chem. Rev. 2021, 121, 3892−4044
Scheme 55. N-Arylation Reactions with Primary Amines Isocyanates could serve as N-nucleophiles to react with
arynes as well. In 2012, Hsieh and co-workers reported a
double arylation protocol of isocyanates 5-22 with arynes. As
shown in Scheme 57a, they found that both water and a
Scheme 57. N-Arylation Reactions with Isocyanates
a monoselective N-arylation reaction of aromatic tertiary

amines, leading to the formation of diaryl amines 5-18 after
demethylation (Scheme 56a).368 Ammonium bicarbonate was
Scheme 56. N-Arylation Reactions with Tertiary Amines
catalytic amount of pyridine derivatives were needed in order

to reach high yields.371 Mechanistically, they proposed that
pyridine could attack isocyanate 5-22 to generate zwitterion 5-
24 first, which is followed by a nucleophilic addition to aryne
to produce unstable carbamic acid 5-25 in the presence of
water. Decarboxylation on intermediate 5-25 would occur to
afford amine 5-26, which then undergoes the N-arylation
reaction with a second aryne to give products 5-23. Similarly,
Ko and co-workers developed both monoarylation372 and
diarylation reactions373 on tosyl and aryl isocyanates (Scheme
57b). In these studies, they proposed that isocyanate hydrolysis
takes place first to release primary amines before N-arylation.
The N-arylation reaction with arynes turns out to be a
general scenario with respect to various N-nucleophiles. In
2015, Yao reported an efficient N-arylation reaction with
amidines 5-27 and N,N-disubstituted amidines 5-29, affording
the corresponding N-arylated products 5-28 and 5-30,
found to be the key additive for the success of this respectively (Scheme 58a).374 In the same year, Singh et al.
transformation. Moreover, no diarylation product was detected revealed a N-arylation reaction by using NH-sulfoximines 5-31
even in the presence of an excess amount of o-silylaryl triflates, as the substrates (Scheme 58b).375 There are two features for
which was reasoned by the delocalization of the lone pair this transformation: (1) no aryne insertion into either the S
electrons on nitrogen between two benzene rings after the first O or SN bond was reported; (2) substrates with chiral
N-arylation reaction. Similar transformation was also realized centers could be tolerated under the reaction conditions. In
by Ko et al. using N-methyl morpholine (5-19) as the 2017, Cheng, Zhai, and co-workers demonstrated a chemo-
nucleophile and obtained tertiary anilines 5-20 after selective N-arylation reaction of 2-aminopyridine derivatives 5-
demethylation (Scheme 56b).369 In 2016, Diesendruck and 33 to produce compound 5-34, in which the pyridine nitrogen
co-workers reported a straightforward N-arylation protocol served as the sole nucleophile (Scheme 58c).204
with tertiary amines, affording various quaternary ammonium In 2016, Mhaske et al. found that, in the presence of a
salts 5-21, such as trialkylaryl, dialkyldiaryl, triarylalkyl, and N- catalytic amount of water, sodium nitrite could attack arynes
chiral ammonium salts (Scheme 56c).370 In this study, and produce nitrobenzenes 5-35 (Scheme 59a).376 Sub-
methanol was added as both the cosolvent and proton source sequently, Cheng, Zhai, and co-workers employed Mitsunobu
to prevent Hoffman elimination. Although this transformation reagent 5-36 as the N-nucleophile to realize a N-arylation
had a broad substrate scope, it was not applicable to reaction with arynes, giving rise to arylhydrazides 5-37 in
triarylamines. modest to high yields (Scheme 59b).377 Furthermore, diverse
Chem. Rev. 2021, 121, 3892−4044
Scheme 58. N-Arylation Reactions with Other N- 5.2. O-Arylation Reactions

Nucleophiles In comparison with N-nucleophiles, there are limited examples
of O-arylation transformations. Almost at the same moment
with their N-arylation study, the Larock group investigated O-
arylation reactions as well.360,378,396 In 2004, they reported
facile O-arylation reactions on both phenols and aromatic
carboxylic acids with arynes, affording the corresponding O-
arylated products 5-40 and 5-41 in good to excellent yields
with high functional group tolerance (Scheme 60a).396
Scheme 60. O-Arylation Reactions with Phenols and

Carboxylic Acids
Raminelli et al. applied this method in the O-arylation of

sterically hindered 2,6-dihalophenols.397 In addition, O-
arylation of phenols was also reported by other groups.398,399
Scheme 59. N-Arylation Reactions with Sodium Nitrite and Unfortunately, the Larock’s method was not applicable to both
Mitsunobu Reagents alcohols and aliphatic carboxylic acids at the moment. Until
2015, Chen, Zhang, and co-workers could solve this inactivity
problem on aliphatic carboxylic acids. As shown in Scheme
60b, they noticed that sodium carboxylates, generated from
NaOH and aliphatic carboxylic acids, have enhanced
nucleophilicity over their acid form.400 Consequently, a
combination of aliphatic carboxylic acid and its sodium salt
in the reaction with arynes could furnish the corresponding
products 5-42 along with a small amount of C−OH bond
insertion products.
The inactivity problem with alcohols was then solved by Biju
and co-workers. In 2016, they found that under low reaction
temperature (−20 °C), a number of linear, O-tethered, and
branched aliphatic alcohols could all react with arynes to
exclusively produce the corresponding O-arylated products 5-
43 (Scheme 61a).401 In the presence of both tertiary and
primary alcohols on the same substrate, selective arylation on
the primary alcohol occurred. In this study, they also observed
a temperature dependent reaction behavior, the details of
which will be discussed in Scheme 140c. Recently, Mukherjee
and co-workers demonstrated an intriguing O-arylation
protocol of carbohydrates 5-44, which could furnish O-arylated
products 5-45 selectively (Scheme 61b).402 Notably, this
nitrogen-containing heterocycles could be prepared through
transformation prefers not only primary over secondary
one-pot processes under either Fisher indole synthesis
alcohols but also equatorial over axial ones. Besides, an
conditions or through condensation with 1,3-diones. They
uncommon O-nucleophile was also examined. In 2008,
proposed that 1,3-zwitterion 5-38 should be first formed from
Kolomeitsev et al. applied trifluoromethanolate salt 5-46,
Mitsunobu reagent 5-36 and PPh3, which then attacks aryne to
readily prepared from trifluoromethyl triflate and 5-47, as a
produce 1,5-zwitterion 5-39. Upon protonation and removal of
trifluoromethoxy group carrier in the reaction with Kobayashi
triphenylphosphine oxide, arylhydrazides 5-37 could be
benzyne precursor, affording both phenyl trifluoromethyl ether
obtained. An alternative mechanistic pathway would be the
(5-48) and fluorobenzene (Scheme 61c).403
generation of hydrazide first from 5-38 and water, which in
turn attacks aryne to give 5-37. Moreover, these N-arylation 5.3. C-Arylation Reactions
protocols have become general methods with many synthetic Carbon nucleophiles are quite different from heteroatom
applications.378−395 nucleophiles in arylation reactions with arynes, because aryne
Chem. Rev. 2021, 121, 3892−4044
Scheme 61. O-Arylation with Other O-Nucleophiles Scheme 63. Asymmetric C-Arylation Reaction of β-Enamino
Esters
unprecedented study, C-arylated products 5-54 with stereo-

defined quaternary centers were obtained in up to 96%
enantiomeric excess (ee) after hydrolytic workup. In addition,
a one-pot transformation of a β-ketoester substrate to the
corresponding arylated product was demonstrated. Chirality
transfer from the N-bound chiral auxiliary to the final product
was studied by their computations as well. Recently, another
distinct asymmetric C-arylation reaction was achieved by Luo
et al. by using electrochemical method to generate arynes from
1-aminobenzotriazoles, which will not be discussed here.408
insertion into various carbon-based bonds, i.e., C−C and C− This C-arylation strategy was further expanded to β-
heteroatom bonds, has been well-known as the following step dicarbonyl compounds, such as malonamide esters409 and
after nucleophilic addition of carbanions to arynes (see section secondary β-keto amides.410 In 2012, Mhaske and co-workers
7). In order to prevent insertion reactions, a quick protonation demonstrated that α-arylation of α-substituted/unsubstituted
operation is normally necessary, and the structure of the N-arylmalonamide esters 5-55 with o-silylaryl triflates could
substrate plays an essential role for the selection of this produce compounds 5-56 and 5-57 containing benzylic
reaction mode. quaternary stereocenters (Scheme 64a).409 In particular, by
In 2007, Ramtohul and co-worker disclosed that β-enamino using N-aryl-N-methyl malonamide ester as the substrate, only
esters/ketones 5-49 could readily participate in C-arylation
reaction with arynes, affording a variety of substituted aromatic Scheme 64. C-Arylation Reactions with β-Dicarbonyl
β-enamino compounds 5-50 in moderate to excellent yields Compounds
(Scheme 62a).404 Particularly, there was no observation of
Scheme 62. C-Arylation with β-Enamino Compounds
both N-arylation and C−C bond insertion products on 5-49.

Their deuterium-labeling experiments suggested that an
intramolecular proton transfer is responsible for quenching
the generated aryl anion after nucleophilic addition. Recently,
Gogoi el al. applied this method in the C-arylation reaction of
4-aminocoumarins 5-51 and furnished 4-amino-3-arylcoumarin
derivatives 5-52 (Scheme 62b).405 This protocol was also
utilized by Cheng et al.406
Of particular interest was a recent achievement on
asymmetric C-arylation of β-enamino esters 5-53 developed
by Houk, Garg, and co-workers (Scheme 63).407 In this
Chem. Rev. 2021, 121, 3892−4044
monoarylated products were observed. Meanwhile, Coquerel, Based on a previous observation by Hu and co-workers, the
Rodriguez, and co-worker reported a C-arylation reaction of introduction of phenylsulfonyl group on fluorinated carbanions
secondary β-keto amides 5-58 with arynes, furnishing products could make them better nucleophiles. Consequently, they
5-59 in good to excellent yields (Scheme 64b).410 The realized a nucleophilic fluoroalkylation of arynes with
preferential formation of C-arylated products in this trans- fluorobis(phenylsulfonyl)methane (5-68) furnished fluorobis-
formation was reasoned by the proper acidity of the N−H (phenylsulfonyl)methylated arenes 5-69 in good to high yields
bond on secondary β-keto amides, which could interrupt the (Scheme 65b).416 In 2018, Burtoloso and co-workers revealed
undesired C−C bond insertion reaction. In 2017, Mohanan et that the C-arylation reaction of readily accessible β-
al. realized a decarboxylative C-arylation reaction of ketosulfoxonium ylides 5-70 with arynes furnished α-aryl-β-
fluoromalonamates 5-60 (R1 ≠ t-Bu) with arynes, affording ketosulfoxonium ylides 5-71, which could be further converted
α-aryl-α-fluoroamides 5-61 in good to excellent yields to α-aryl ketones after desulfurization (Scheme 65c).417
(Scheme 64c).411 The employment of tert-butyl ester of 5.4. S-Arylation Reactions
fluoromalonamate 5-60 (R1 = t-Bu) could prevent the
In their study on both N- and O-arylation reactions with o-
decarboxylation reaction and produced the arylated fluoroma-
silylaryl triflates, Larock and co-worker also demonstrated two
lonamates 5-62 instead. They reasoned that the decarbox-
S-arylation examples by using arenethiols 5-72 as nucleophiles,
ylation step could be promoted by the increased electro-
furnishing diaryl sulfides 5-73 in good yields (Scheme 66a).360
philicity of the α-carbon after arylation reaction.
Other than β-keto amides, Chen, Du, and co-workers
revealed that malonates 5-63 could also undergo a mono C- Scheme 66. S-Arylation Reactions with Thiolates
arylation reaction with arynes to afford compounds 5-64,
whereas other 1,3-diketone compounds preferred the C−C σ-
bond insertion pathway (Scheme 64d).412 Although in
Yoshida’s previous study, malonates were found to proceed
through the C−C σ-bond insertion pathway with arynes,413
this different reactivity was reasoned by the employment of
more acidic acetonitrile as the solvent, which could facilitate
the protonation of aryl anion and yields the C-arylated
products 5-64.
Oxindoles were found to be suitable substrates for C-
arylation reactions. In 2016, Srihari, Mehta, and co-workers
disclosed that 3,3-disubstituted oxindoles 5-66 and 5-67 could In addition, Kolomeitsev et al. showed that trifluoromethane-
be obtained through C-arylation of oxindoles 5-65 with arynes thiolate salt, the TDAE2+2CF3S− (or Me4N+CF3S−)/CsF
at room temperature (Scheme 65a).414 It was also found that system, could serve as an S-nucleophile to attack benzyne
and afforded phenyl(trifluoromethyl)sulfane (5-74) in 83%
Scheme 65. Other C-Arylation Reactions yield (Scheme 66b).403
In 2014, the groups of Mhaske418 and Singh419 independ-
ently reported a highly efficient S-arylation protocol of alkyl/
aryl sodium sulfinates with o-silylaryl triflates. In Mhaske’s
study, they employed aryl/alkyl/heteroaryl sodium sulfinates
5-75 as the S-nucleophiles to react with arynes, furnishing
diaryl sulfones, aryl alkyl sulfones, and aryl heteroaryl sulfones
5-76, respectively (Scheme 67a).418 Similar results were
Scheme 67. S-Arylation Reactions with Sodium Sulfinates
under elevated temperature (90 °C), a C−C bond insertion

reaction occurred, which will be discussed in Scheme 100b. In obtained by Singh et al., where unsymmetrical biaryl sulfones,
a study carried out by Shanmugam et al. on the reactivity of aryl vinyl sulfones, and aryl alkyl sulfones could be
isatin-based Morita−Baylis−Hillman (MBH) adducts, they conveniently prepared (Scheme 67a).419 One difference
reported a similar C-arylation reaction with arynes, which between these two systems is the utilization of different
contained a small amount of [3 + 2] spiroannulation products fluoride sources. In 2018, Shibata and co-workers prepared
as well.415 trifluoromethanesulfonyl arenes 5-77, namely, aryl triflones,
Chem. Rev. 2021, 121, 3892−4044
through a trifluoromethanesulfonylation of arynes with sodium Scheme 69. P-Arylation Reactions with Phosphines
trifluoromethanesulfinate (NaSO2CF3) (Scheme 67b).420 In
this study, 15-c-5 was employed in order to increase the
solubility of the sodium salts.
In 2017, Peng et al. reported a mild protocol toward the
preparation of triarylsulfonium salts 5-79 via an S-arylation
reaction of diarylsulfides 5-78 with o-silylaryl triflates (Scheme
68a).421 This transformation furnished triarylsulfonium salts 5-
Scheme 68. S-Arylation Reactions with Other S-

Nucleophiles
Scheme 70. P-Arylation Reactions with Alkoxyphosphines
79 with high functional group tolerance. Meanwhile, Shen, Xu affording aromatic oxophosphorus compounds 5-88 in good to
and co-workers demonstrated that the S-arylation reaction excellent yields.135 Notably, steric repulsion played a
proceeded selectively and smoothly on cyclic 2-oxazolidine- determining role in terms of regioselective control in this
thiones 5-80 with arynes to afford S-arylated dihydrooxazoles study. Moreover, the deuterium labeling experiment suggested
5-81 (Scheme 68b).364 Both the N-arylation reaction and that the hydrated TBAF served as the proton source. In
aryne insertion into the thiocarbonyl group were not detected Mhaske’s study, they could readily prepare aryl phosphonates,
with these substrates. Recently, Yao, Tan, and co-workers aryl phosphinates, and aryl phosphine oxides from trialkyl
revealed a chemoselective S-arylation reaction of thio- phosphites, diethyl phenylphosphonite, and diphenylphosphin-
oxindoles 5-82, affording 2-(arylthio)indolenines 5-83 in ite, respectively (Scheme 70).426 In this work, the proton
good to excellent yields (Scheme 68c).422 source was acetonitrile.
In 2016, the P-arylation reactions of both dialkylphosphites
5.5. P-Arylation Reactions
and secondary phosphine oxides with arynes were realized
P-Nucleophiles were studied behind other nucleophiles with o- independently by the groups of Chen427 and Zhang428
silylaryl triflates. In 2010, Jugé et al. first realized a P-arylation (Scheme 71). In Chen’s study, they could obtain dialkyl
reaction of phosphines with arynes, giving rise to both achiral arylphosphonates and tertiary phosphine oxides 5-90 from
and chiral quaternary phosphonium salts 5-84 (Scheme
69a).423 Particularly, when chiral phosphines were employed Scheme 71. P-Arylation with Dialkyl Phosphites and
with either P-chirality or chirality on the carbon backbone, Secondary Phosphine Oxides
phosphonium triflates could be synthesized in an enantio- or
diastereomerically pure form. In order to tune the
physicochemical properties of 1,3-diphosphacyclobutane-2,4-
diyls, Ito and co-workers applied the P-arylation protocol onto
both sterically encumbered 1-tert-butyl-424 and 1-amino-1,3-
diphosphacyclobuten-4-yl anions 5-85,425 which could afford
the corresponding P-arylated products 5-86 (Scheme 69b). It
was found that the incorporated aromatic substituent could
influence the open-shell character of 5-86. Moreover, the
potential of 5-86 as the HF detector was investigated.
In 2013, the groups of Hosoya135 and Mhaske 426
independently reported a P-arylation reaction of various
alkoxyphosphines 5-87 with o-silylaryl triflates (Scheme 70).
In Hosoya’s study, they demonstrated a P-arylation protocol
through the Michaelis−Arbuzov-type reaction with arynes,
Chem. Rev. 2021, 121, 3892−4044
dialkyl phosphites and secondary phosphine oxides 5-89, 6. NUCLEOPHILIC ANNULATION REACTIONS
respectively, in good to excellent yields under mild Along with the studies on arylation reactions with o-silylaryl
conditions.427 The employment of Cs2CO3 was believed to triflates, different types of nucleophile-induced aryne trans-
both enhance the nucleophilicity of the substrate and increase formations have also been developed, affording various 1,2-
the concentration of the P(III) form through tautomerization difunctionalized arenes. A step further from arylation protocols
of the P(V) phosphinylidene (Scheme 71). Moreover, their is to tether an electrophile (E) and a nucleophile (Nu)
deuterium labeling experiments suggested that trace amounts together with a linker, so that the generated aryl anion from
of water in hygroscopic CsF/Cs2CO3 served as the proton nucleophilic addition to the aryne could react with the tethered
source. Meanwhile, Zhang and co-workers demonstrated that electrophilic component intramolecularly (Scheme 73). In this
P-arylation of diarylphosphine oxides and dialkyl phosphites
could furnish various arylphosphorus compounds in good to Scheme 73. General Scheme for Aryne Nucleophilic
excellent yields (Scheme 71).428 Annulation Reactions
5.6. With B-Nucleophile
In a study carried out by Takita, Uchiyama, and co-workers
toward the preparation of borylzincate species 5-91 from
dialkylzinc and diboron, they applied this borylzincate species
5-91 in the reaction with arynes, generated from o-halo-
iodobenzene. Among those substrates, they showed one way, an overall aryne annulation transformation could be
example with Kobayashi benzyne precursor, giving rise to B- realized through this sequential intermolecular nucleophilic
arylated products 5-92 in 66% yield (Scheme 72a).429 addition/intramolecular bond-forming process. This section
will be elaborated on based on the types of nucleophiles as well
Scheme 72. Aryne Reactions with B- and F-Nucleophiles as the types of electrophiles.
6.1. With O-Nucleophiles
The first nucleophilic annulation reaction of this type with o-
silylaryl triflates employed O-nucleophiles. In 2005, Larock and
Zhao demonstrated that salicylates 6-1 (X = O) could
participate in a tandem nucleophilic addition/electrophilic
cyclization process with arynes to afford xanthones 6-2 in
modest to high yields (Scheme 74a).436,437 Notably, the
employment of CsF in THF could promote intramolecular
cyclization over intermolecular proton abstraction. Moreover,
methyl thiosalicylate 6-1 (X = S) could produce the
corresponding thioxanthones as well. This method was
recently utilized by Cichewicz et al.438 In 2009, Okuma and
co-workers revealed that aldehyde could serve as an electro-
phile in this transformation. When salicylaldehydes 6-3 reacted
with benzyne, both xanthenes 6-4 and xanthones 6-5 were
obtained, whereas under basic conditions 9-hydroxyxanthenes
5.7. With F-Nucleophile 6-6 could be achieved in moderate to high yields (Scheme
Although arynes have been utilized as efficient synthons in 74b).439 Mechanistically, xanthenes 6-4 and xanthones 6-5 are
formed through disproportionation of 9-hydroxyxanthenes 6-6.
many types of transformations, nucleophilic fluorination on
To prevent a disproportionation reaction, Yuan, He, and co-
aryne has been rarely reported using either Kobayashi’s
workers employed 2-trifluoroacetylphenols 6-7 as the sub-
method403 or other aryne generation methods.430−432 The
strates and harvested trifluoromethylated xanthenes 6-8 in
reasons are both poor nucleophilicity of a fluoride ion and the moderate to excellent yields with no observation of xanthenes
reversibility of a fluorination reaction.433 In 2014, Ikawa, Akai and xanthones (Scheme 74c).440 N-tosylimines could also
and co-workers first achieved a highly efficient nucleophilic serve as electrophiles in this type of transformations. In this
fluorination reaction using a modified Kobayashi’s method.434 context, the groups of He441 and Lu442 independently reported
In this study, they prepared 2-(trialkylsilyl)phenyl non- an efficient preparation of 9-aminoxanthenes 6-10 from salicyl
afluorobutanesulfonates 5-94 from 2-(trialkylsilyl)phenols 5- N-tosylimines 6-9 and arynes (Scheme 74d). Recently,
93 and nonafluorobutanesulfonyl fluoride (NfF). A strongly Yoshida et al. disclosed that the reaction between S-(2-
nucleophilic fluoride salt, Bu4NF(t-BuOH)4, was then added in hydroxyaryl) 4-toluenethiosulfonates 6-11 (X = O) and o-
one-pot fashion to afford fluoroarenes 5-95 in moderate to silylaryl triflates could furnish phenoxathiins 6-12 (X = O)
good yields (Scheme 72b).434 It was also found that (Scheme 74e).443 Notably, the optimal conditions employed
fluorination with 3-silylbenzyne preferred a meta-selectivity, triglyme as an uncommon solvent, which was found to give
suggesting that solvation with fluoride ion might make it a higher yields than those in THF. In this study, they also
bulkier nucleophile. Subsequently, they further enhanced the demonstrated that phenothiazines could be obtained from S-
reaction efficiency by employing the microflow technique and (2-aminoaryl) 4-toluenethiosulfonates 6-11 (X = NH).
reached higher yields than those under batch conditions.435 Michael acceptors were also employed as the electrophiles in
They reasoned that the highly efficient mixing under microflow this type of transformation. In 2010, Huang and Zhang
conditions allows both quick fluoride addition and immediate demonstrated a nucleophilic addition/Michael addition
protonation, hence, resulting in high reaction yields. process between 4-(2-hydroxyphenyl)but-3-(E)-en-2-one ana-
Chem. Rev. 2021, 121, 3892−4044
Scheme 74. Aryne Nucleophilic Annulation with O- 6.2. With N-Nucleophiles

Nucleophiles Although N-nucleophiles were employed behind O-nucleo-
philes, they have become the most investigated nucleophiles in
this subfield of aryne chemistry. Along with the study on
salicylates and thiosalicylates by Larock et al., they
demonstrated that methyl 2-aminobenzoate derivatives 6-17
could proceed through a nucleophilic annulation reaction with
arynes to afford acridones 6-18 (Scheme 76a).437 In 2009, the
Scheme 76. Aryne Nucleophilic Annulation with N-

Nucleophiles and Esters
logues 6-13 and arynes, which could lead to the preparation of

xanthenes 6-14 in moderate to excellent yields (Scheme
75a).444 Subsequently, Larock and co-workers reported a
similar transformation with an expanded scope of substrates.445
In 2018, Mei, Shi, and co-workers investigated the reactivity of
ortho-hydroxyphenyl-substituted para-quinone methides 6-15
with Kobayashi benzyne precursor, giving rise to xanthene
scaffold 6-16 (Scheme 75b).446 Soon after this work, He et al.
also reported the same transformation.447
groups of Larock448 and Ramtohul449 independently reported
the reaction between indole-2-carboxylate esters 6-19 and
Scheme 75. Aryne Nucleophilic Annulation with O-
arynes, which led to the formation of polycyclic indole-
Nucleophiles and Michael Acceptors
indolone ring systems 6-20 under mild conditions (Scheme
76b). Besides, Ramtohul disclosed that both pyrrole- and
imidazole-2-carboxylate esters 6-21 could afford the corre-
sponding polycyclic products 6-22 as well (Scheme 76c).449 In
2011, Okuma and co-workers revealed the preparation of 2-
phenylindolin-3-ones 6-24 from amino acid methyl esters 6-23
(Scheme 76d).450 Mechanistically, this transformation pro-
ceeds through a nucleophilic annulation reaction with an
additional C-arylation reaction. In 2013, Argade and Vaidya
reported an efficient transformation between substituted 1,3-
quinazolin-4-ones 6-25 and o-silylaryl triflates, furnishing fused
quinazolinone scaffolds 6-26 in moderate to excellent yields
(Scheme 76e).451 Notably, a variety of functional groups, such
as ester, Weinreb amide, ketone, acid chloride, and α,β-
unsaturated ester, worked well as the electrophiles. Moreover,
Chem. Rev. 2021, 121, 3892−4044
they applied this method in the total syntheses of several Scheme 78. Aryne Nucleophilic Annulation with N-
bioactive quinazolinone-based natural products. This nucleo- Nucleophiles and Ketones
philic annulation protocol was also utilized by Chen et al. in
their study.452
In 2011, Larock and Rogness reported that N-arylisatins 6-
28 could be readily prepared from 2-oxo-2-(arylamino)acetates
6-27 and arynes in modest to excellent yields under mild
conditions (Scheme 77).453 In this study, NaHCO3 was found
Scheme 77. Aryne Nucleophilic Annulation with 2-Oxo-2-

(arylamino)acetates
Scheme 79. Formation of Indolines 6-39,

Tetrahydroquinolines 6-41, and Benzimidazoles 6-43
to be necessary and served as the optimal base to promote this

transformation. As shown in Scheme 77, two plausible reaction
pathways were proposed after nucleophilic addition: (1) direct
annulation via intermediate 6-29 (path a); (2) C−N σ-bond
insertion through four-membered ring intermediate 6-30 and
annulation on 6-31 (path b). Singh et al. also reported the
same transformation promoted by heterogeneous catalysts
under microwave irradiation.454
α-Aminoketones and their analogues were utilized in this
type of transformation as well. In 2013, Zhu et al.
demonstrated that N-aryl-α-aminoketones 6-32 could react
with arynes through a successive nucleophilic addition/
annulation/dehydration process, affording N-aryl-2,3-disubsti-
tuted indoles 6-33 in moderate to high yields (Scheme 78a).455
This transformation is regiospecific, which is in contrast with
the classic Bischler−Möhlau reaction that usually gives a
mixture of two regioisomers. Similar transformations were also
studied by other groups.456,457 In 2014, Zhu and co-workers 6-40, N-aryl tetrahydroquinolines 6-41 were achieved with
employed this nucleophilic annulation protocol in an efficient anti-selectivity. In 2018, Song et al. realized a convenient
preparation of 5,6-dihydroindolo[1,2-a]-quinolines 6-35 from preparation of N-heterocyclic benzimidazoles 6-43 from
2-acyl substituted tetrahydroquinolines 6-34 (Scheme 78b).458 benzimidazole derivatives 6-42 via the nucleophilic annulation
These 2-acyl substituted tetrahydroquinolines were readily protocol (Scheme 79b).461 When indole and indazole scaffolds
synthesized through a Lewis acid-catalyzed three-component were used, a strong base Cs2CO3 was employed to replace
Povarov reaction of α-oxo aldehydes, anilines, and dienophiles. K2CO3 in order to ensure the success of the reactions.
Recently, Dai, He and co-workers reported a nucleophilic In 2012, Larock and co-workers reported two aryne
annulation reaction between carbocyclic β-aminoketones 6-36 annulation approaches, both of which combined N-nucleo-
and arynes, furnishing hexahydrophenanthridines 6-37 in philes with accompanying imine electrophiles (Scheme
modest to high yields (Scheme 78c).459 80).462,463 They first employed 2-substituted pyridines to
In 2014, He, Dai and co-workers revealed that the realize a nucleophilic annulation reaction with arynes. When
dehydration step could be prohibited by avoiding acidic imines 6-44 generated from 2-pyridinecarboxaldehyde were
workup in the transformation with α-aminoketones. When α- treated with arynes, N-aryl-2-pyrido[1,2-a]indoles 6-45 were
aminoketones 6-38 were employed to react with arynes, obtained (Scheme 80a).462 Mechanistically, this transforma-
multisubstituted indolines 6-39 could be obtained with syn- tion involves a sequential N-nucleophilic addition, cyclization
selectivity (Scheme 79a).460 In the cases with β-aminoketones with imine, and N-arylation with a second molecule of aryne.
Chem. Rev. 2021, 121, 3892−4044
Scheme 80. Aryne Nucleophilic Annulation with N- unsubstituted indole 6-49 (path a) or to carbon to give
Nucleophiles and Imines intermediate 6-52 (path b). At 60 °C, 1,3-hydrogen shift could
occur on 6-52 to produce 6-49; whereas at −10 °C, an aryne
ene reaction would convert 6-52 to N-arylindole 6-50.
Michael acceptors were employed as annulation partners
associated with N-nucleophilic addition. In 2008, Stoltz and
co-workers first demonstrated a protocol toward convenient
preparation of functionalized indolines 6-54 by using N-Boc-
protected dehydroalanine esters 6-53 (Scheme 82a).331 TBAT
Scheme 82. Aryne Nucleophilic Annulation with N-

Nucleophiles and Michael Acceptors
In this study, they also achieved a one-pot three-component

transformation of 2-pyridinecarboxaldehyde, t-BuNH2, and
Kobayashi benzyne precursor, affording the same product in
good yield. Meanwhile, they demonstrated that 1-methyl-1H-
indazoles 6-47 could be obtained in modest to high yields from
o-silylaryl triflates and 1,1-dimethylhydrazones 6-46 (Scheme
80b).463 Two preparation procedures were employed in order
to reach 6-47: (1) a one-pot NCS-chlorination/aryne
annulation (condition A) and (2) an Ac2O-acylation/
deprotection/aromatization process (condition B).
In 2016, Biju et al. studied the reactions between 2H-azirines
6-48 and arynes and disclosed a temperature-dependent
reaction behavior (Scheme 81). 464 In this study, N-
Scheme 81. Aryne Nucleophilic Annulation with 2H-

Azirines was found to be an ideal fluoride source in this transformation.
Subsequently, Huang and Zhang treated anilines 6-55
containing an α,β-unsaturated ketone moiety on the ortho
position with arynes and obtained 9-functionalized acridines 6-
56 (Scheme 82b).444 Along with the study on the aryne
nucleophilic annulation reaction using N-pyridin-2-yl-meth-
animines as the substrates, Larock et al. also examined the
reaction of 2-(pyridin-2-yl-methylene)malonates 6-57 with
arynes, which could yield pyrido[1,2-a]indole derivatives 6-58
(Scheme 82c).462
In 2017, Sedalia et al. demonstrated a highly diastereose-
lective synthesis of chiral 2,3-disubstituted indolines 6-60 from
γ-amino-α,β-unsaturated esters 6-59, which could be readily
prepared from α-amino acids (Scheme 83a).465 A similar work
was also reported by Ikawa, Akai, and co-workers.466
Meanwhile, She and co-workers accomplished an efficient
synthesis of indole-fused hydrocarbazoles 6-62 through a
formal [3 + 2] annulation reaction of protected p-quinamines
6-61 and o-silylaryl triflates (Scheme 83b).467 Notably, when 4
Å molecular sieves (4 Å MS) were used as the additive, the
reaction could reach the highest yield. In 2018, Mhaske and
Pandya reported a transformation between carbamoylpropio-
lates 6-63 and arynes, which could produce various (E)-
oxindolylidene acetates 6-64 with high functional group
unsubstituted 2,3-diarylindoles 6-49 were preferentially formed
tolerance (Scheme 83c).468
at 60 °C; whereas at −10 °C, the selectivity switched to the
formation of 1,2,3-triarylindoles 6-50. Mechanistically, they 6.3. With C-Nucleophiles
proposed that after a formal [2 + 2] cycloaddition reaction of In Stoltz’s study on the preparation of functionalized indolines
aryne with the CN bond to construct intermediate 6-51, a from N-Boc protected dehydroalanine esters, they disclosed
1,2-hydrogen shift takes place either to nitrogen to produce N- that a simple modification on dehydroalanine esters 6-65 from
Chem. Rev. 2021, 121, 3892−4044
Scheme 83. Other Reactions with N-Nucleophiles and 72 in moderate to good yields (Scheme 85a).470 In addition,
Michael Acceptors Shanmugam et al. also observed the formation of small
Scheme 85. Aryne Nucleophilic Annulation with Other C-

Nucleophiles
N-Boc to the N-acyl group could efficiently furnish

polyfunctionalized isoquinolines 6-66 (Scheme 84a).331
amounts of spiroannulation products along with the C-
Scheme 84. Aryne Nucleophilic Annulation with arylation products when isatin based Morita−Baylis−Hillman
Dehydroalanine Esters and N-(1-Arylvinyl)acetamides (MBH) adducts reacted with arynes.415 In 2016, He and co-
workers disclosed that carbazolequinones 6-74 could be
obtained in moderate to high yields through a nucleophilic
annulation reaction of 2-amino-1,4-naphthoquinones 6-73
with arynes (Scheme 85b).471 Primary amines worked better
than secondary amines, whereas tertiary amine did not react at
all. Mechanistically, this transformation was proposed to
proceed through a sequential C-nucleophilic addition to
generate intermediate 6-75/addition of aryl anion to iminium
nitrogen to produce 6-76/oxidative dehydrogenation process.
They reasoned that the electron-withdrawing ability of
naphthalenedione makes the iminium nitrogen electrophilic,
although there might be other possibilities.
6.4. With S- and Se-Nucleophiles
Sulfur is a less investigated nucleophile in aryne chemistry,
which is usually accompanied by the study on O-nucleophiles.
In Larock’s early study on O-nucleophilic annulation protocol,
they also showed examples with respect to S-nucleophiles
(Scheme 74a).436,437 In 2006, Okuma et al. investigated the
reactivity of 3,3-di-tert-butylthiirane-2-thione (6-77) with
Kobayashi benzyne precursor and obtained an annulation
product 2-(2,2,4,4-tetramethylpentan-3-ylidene)benzo[d]-
Mechanistically, the overall process involves a sequential C- [1,3]dithiole (6-78) in 90% yield via intermediate 6-79
nucleophilic addition of enamine to aryne to produce 6-67/ (Scheme 86a).472 Subsequently, the same group examined
annulation/dehydrative aromatization on intermediate 6-68. the chemical behavior of 5-isopropylidene-4,4-dimehtyl-1,2-
Moreover, they applied this methodology in the total synthesis dithiolane-3-thione (6-80) and found that this compound
of opiate alkaloid papaverine. Similar work was also reported could react with benzyne to generate benzo-1,3-dithiole 6-81
by Ramtohul et al.332 In a study carried out by Guan and co- in 85% yield, the mechanistic pathway of which experiences the
workers on the coupling reaction of N-(1-arylvinyl)acetamides formation and recombination of a betaine intermediate 6-82
6-69 with alkynes and arynes, they reported a facile (Scheme 86b).473
construction of isoquinolines 6-70 as well (Scheme 84b).469 In 2015, Werz and co-workers prepared a series of
In 2017, Srihari, Mehta, and co-workers realized a amphiphilic benzodithioloimines 6-83 containing both pos-
spiroannulation reaction between substituted N-methyl-3- itively and negatively polarized sulfur (Scheme 87).474 When
(carbethoxymethyl)oxindoles 6-71 and arynes, which could these benzodithioloimines 6-83 reacted with arynes, thian-
produce the corresponding indano-spirooxindole scaffolds 6- threne derivatives 6-84 were achieved in modest to excellent
Chem. Rev. 2021, 121, 3892−4044
Scheme 86. Aryne Nucleophilic Annulation with S- Scheme 88. Aryne Nucleophilic Annulation with Se-
Nucleophiles Nucleophiles
the OAc group by the generated aryl anion might be possible

to account for the formation of 6-87.
6.5. With P-Nucleophiles
Recently, Tobisu and co-workers revealed a unique dearylative
annulation process between triarylphosphine 6-90 and
arynes.477 As shown in Scheme 89, a pentacoordinated
Scheme 89. Aryne Nucleophilic Annulation with P-

Scheme 87. Aryne Nucleophilic Annulation with Nucleophiles
Benzodithioloimines
tetraarylfluorophosphorane 6-91 was first produced through

a sequential nucleophilic addition of triarylphosphine 6-90 to
aryne and an intramolecular SNAr reaction on an aryl fluoride
moiety. Subsequent dearylation reaction from fluorophosphor-
yields. Furthermore, benzo[d]pyrrolo[2,1-b]thiazole was ob- ane 6-91 could furnish fluorinated dibenzophosphole deriva-
tained in moderate yield from 2-thiocyanatopyrrole and the tives 6-92 in a convergent manner.
Kobayashi benzyne precursor. Mechanistically, this trans-
formation proceeds through a S-nucleophilic addition to 7. INSERTION REACTIONS
benzyne with concomitant opening of the dithioloimine ring When a nucleophile and an electrophile are covalently bonded
to generate intermediate 6-85, which is followed by cyclization via either single or double bond, aryne insertion into this
on the electrophilic sulfur bearing the newly generated nitrile covalent bond is a natural extension to nucleophilic aryne
group to afford thianthrene 6-84. transformations under transition-metal-free conditions. A wide
In 2002, Biehl et al. investigated the reaction between range of σ- and π-bonds could be “inserted” by arynes, those of
Barton esters and arynes. Following their early study on Barton which include C−C, C−heteroatom, and heteroatom−
esters with arynes generated from anthranilic acids,475 they heteroatom bonds. Normally, this type of transformations
reported a reaction between acetic acid 2-selenoxo-2H-pyridin- proceeds through either a four-membered ring transition state
1-yl esters 6-86, namely, Barton 2-selenoxo esters and arynes or direct 1,3-migration of the covalently bonded electrophile
generated from different precursors (Scheme 88).476 Among after nucleophilic addition on arynes (Scheme 90). With the
them, the reactions with o-silylaryl triflates could afford extensive employment of Kobayashi’s method, since early
benzo[b]seleno[2,3-b]pyridines (6-87) in moderate yields. 2000, aryne insertion reaction has become a convenient means
Based on their study, an unprecedented mechanism involving in preparing a broad spectrum of vicinal difunctionalized
single electron transfer (SET) was proposed: selenium atom arenes.91,478 This section will be divided by the types of
attacks aryne via SET produces radical adduct 6-88, which
would then undergo annulation reaction to generate Scheme 90. General Scheme for Aryne Insertion Reactions
intermediate 6-89. Product 6-87 could be obtained after
aromatization. Despite this mechanistic pathway proposed by
Biehl, an alternative mechanism via a sequential Se-
nucleophilic addition to aryne and SN2′-type displacement of
Chem. Rev. 2021, 121, 3892−4044
chemical bonds that could be “inserted” by aryne inter- Scheme 92. Aryne Insertion into the C−N σ-Bond of
mediates. Amides
7.1. Insertion into C−N σ-Bonds
The first type of σ-bond inserted by arynes, generated from o-
silylaryl triflates, was the N−CO σ-bond of substituted ureas.
In 2002, Shirakawa, Hiyama, and co-workers disclosed that
arynes could insert into the N−CO bond of ureas 7-1 under
transition-metal-free conditions (Scheme 91).479 Various 1,4-
Scheme 91. Aryne Insertion into the C−N σ-Bond of Ureas
benzodiazepines, 1,5-benzodiazocines, and 2-aminobenza-

mides 7-2 were readily achievable in this transformation,
some of which are otherwise hardly accessible through analogues 7-8 and afforded products 7-9, which were capable
conventional methods. Moreover, when substituted arynes, of undergoing further conversion to prepare quinolones,
such as 3-methoxybenzyne, 3-phenylbenzyne, and 1,2-naph- indoles, and ketoanilines (Scheme 93a).484 In an aim to
thalyne, were utilized, excellent regioselective control was
observed. Mechanistically, this transformation involves a first Scheme 93. Aryne Insertion into the C−N σ-Bond of Imides
nucleophilic addition of the urea nitrogen to aryne, which is
followed by an intramolecular aryl anion cyclization to form a
four-membered ring intermediate 7-3. After ring-opening, the
insertion products 7-2 could be obtained. Recently, Ikawa,
Akai, and co-workers also applied this protocol in the reaction
between N-(p-toluenesulfonyl)imidazolidin-2-ones and 3-tri-
flyloxybenzynes, giving rise to the C−N insertion product in a
highly regioselective manner.480
This outstanding discovery by Shirakawa and Hiyama
commenced a new research direction in aryne chemistry,
namely, aryne insertion reactions. In 2005, Larock and Liu
demonstrated that arynes could insert into the C−N bond of
N-aryltrifluoroacetamides 7-4 under transition-metal-free con-
ditions, furnishing vicinal difunctionalized arenes 7-5 in
moderate to high yields (Scheme 92a).481 Two plausible
pathways were proposed and the difference between them readily prepare 3,4-dioxygenated quinolin-2-one natural
resides in the nucleophile, either an anionic nitrogen or a products, Heretsch, Christmann, and co-workers examined
neutral one. This method, however, was restricted by the fact Stoltz’s method by treating arynes with unsymmetrical imides
that only the C−N σ-bond of trifluoacetyl-protected anilines 7-10 (Scheme 93b).485 Conventional methods, however, only
could be inserted. In 2014, Yamazaki and co-workers employed afforded the C−N insertion product 7-11 in low yields. By
this method in a double C−CN bond insertion of p- applying the flow process in this transformation, the reaction
phenylenebis(perfluoroalkanamides) by benzyne, where the yields were significantly enhanced. Consequently, a family of
perfluoroalkyl group can be either CF3 or C2F5.482 The quinolinone alkaloids could be readily prepared (see section
restriction on trifluoacetyl-protected anilines in Larock’s study 14).
was then broken by Greaney et al. in 2010, whereby the N− Beside these previous achievements on aryne insertion into
CO bond of both pivoloyl (piv)- and benzoyl-protected the C(sp2)−N bonds of ureas, amides, and imides, Jones et al.
anilines 7-6 could be inserted by arynes, giving rise to recently accomplished a formal aryne insertion reaction into
aminobenzophenones 7-7 in good to excellent yields (Scheme the C(sp3)−N bond of 1,3-diaza-heterocycles 7-12, which led
92b).483 In this study, biologically active acridones and to the construction of benzofused medium-ring N-heterocycles
acridines were then prepared in a one-pot fashion. 7-13 (Scheme 94).486 This transformation proceeds through a
In 2016, Stoltz and co-workers further expanded the sequential N-arylation with aryne to generate zwitterion 7-14
substrate scope for C−N σ-bond insertion to acetylacetamide that is in equilibrium with a ring-opened form 7-15 and an
Chem. Rev. 2021, 121, 3892−4044
Scheme 94. Aryne Insertion into the C−N σ-Bond of 1,3- reported a similar work on aryne insertion into the C−C σ-
Diaza-heterocycles bond of β-dicarbonyl species 7-18 to produce 7-19 (Scheme
95b).413 Applications on this β-dicarbonyl approach were then
reported.412,490,491
These two early studies stimulated an active field of aryne
insertion reaction with the construction of two C−C bonds.
Langer could utilize this method to prepare various fluorinated
1,5-dicarbonyl compounds from fluorinated 1,3-dicarbonyl
substrates.492 Phthalazines were prepared through a three-step
sequence of aryne C−C bond insertion/diazo transfer
reaction/Diaza−Wittig reaction.493 2,3-Benzodiazepines were
constructed via a one-pot, two-step process, which led to the
syntheses of biologically active molecules, such as tofisopam,
girisopam, and nerisopam.494
Beside β-dicarbonyl species as effective substrates for C−C
intramolecular cyclization to afford benzofused N-heterocycle σ-bond insertion, variations on different substrate frameworks
7-13. were then explored as well. In 2005, Yoshida, Kunai, and co-
7.2. Insertion into C−C σ-Bonds workers revealed an aryne insertion into the C−C σ-bond of α-
cyanocarbonyl compounds 7-20, furnishing compounds 7-21a
Although carbon−carbon σ-bond insertion of dimethylmalo- in moderate to excellent yields along with small amount of
nate by aryne was first achieved by Shair and Danishefsky in further C-arylation products 7-21b (Scheme 96a).495 In 2007,
their total synthesis of dynemicin A,487,488 the harsh aryne
generation conditions by treating aryl bromide with lithium
Scheme 96. Aryne C−C Bond Insertion with Nitrile-
tetramethylpiperidide (LiTMP) restricted the application of
Containing Molecules
this protocol. Since the first employment of o-silylaryl triflates
in C−C σ-bond insertion transformations independently by
the groups of Stoltz489 and Yoshida/Kunai,413 it has become
the most studied as well as broadly applied insertion protocol
in aryne chemistry. In general, a key factor for the success of
this aryne transformation is the effective formation of
carbanion nucleophiles from activated C−H bonds by
electron-withdrawing groups.
In 2005, Stoltz and co-workers first demonstrated that an
acyl-alkylation of aryne occurred on β-ketoesters 7-16 via a σ-
bond insertion event, giving rise to 7-17 in moderate to
excellent yields (Scheme 95a).489 This transformation is mild
and highly efficient with a broad substrate scope, allowing the
concomitant formation of two new C−C bonds in one
operation. Distinctively, benzannulated skeletons were readily
achieved from cyclic β-ketoesters through a ring-expansion
operation. Subsequently, Yoshida, Kunai, and co-workers
Scheme 95. Aryne Insertion into the C−C σ-Bond of β-

Dicarbonyl Compounds
the same group accomplished double aryne insertion cascade

processes from either α-Ts nitrile or dinitrile compounds 7-22,
which led to the formation of diarylmethane skeleton 7-23
through a sequential C−CN bond insertion/C-arylation via
intermediates 7-24 and 7-25, respectively (Scheme 96b).496
Recently, Wang and co-workers demonstrated that aryne
alkylcyanation could take place with N,N-disubstituted amino-
malononitriles 7-26, giving rise to 2-substituted benzonitriles
7-27 in moderate to high yields (Scheme 96c).497
β-Keto sulfones were found to be suitable substrates for this
C−C bond insertion protocol as well. In 2008, the groups of
Huang498 and Hu416 independently demonstrated that β-keto
sulfones 7-28 could participate in aryne insertion reaction to
Chem. Rev. 2021, 121, 3892−4044
afford compounds 7-29 through a preferential C−C bond 39 were obtained by Mhaske et al. from α-SCF3 ketones 7-38
insertion reaction (Scheme 97a). In Hu’s study, 2-fluoro-2- (Scheme 98c).503
Notably, all the aforementioned C−C σ-bond insertion
Scheme 97. Aryne Insertion into the C−C σ-Bond of β-Keto reactions require two strong EWGs in order to enhance the
Sulfones acidity of the target C−H bond and, consequently, permit the
generation of the corresponding carbanion. Beyond these
successes, efforts have also been tried by employing substrates
bearing a less acidic C−H bond for C−C bond insertion
reactions. In this context, Yoshida and co-workers disclosed
that compounds 7-41 could be achieved via acylfluorenylation
of arynes from fluorene derivative 7-40 (Scheme 99a).504 This
Scheme 99. Aryne C−C Bond Insertion with 2-Aryl Ketones
(phenylsulfonyl)acetophenone (7-30) was employed to

produce acyl-fluoroalkylated arenes 7-31 in good to high
yields (Scheme 97a).416 This method was also utilized in a
study by Hammond and Xu.499 Later in 2009, Huang et al.
disclosed an aryne insertion into the C−C σ-bond of α-
sulfonyl cyclic ketones 7-32, delivering medium- and large-
sized benzannulated cyclic ketones 7-33 (Scheme 97b).500
In 2009, Liang, Li and co-workers reported an aryne C−C
bond insertion into β-ketophosphonates 7-34, leading to the
formation of o-acylbenzylphosphonates 7-35 that could be
further elaborated on to afford olefins via the Wittig reaction
(Scheme 98a).501 Recently, aryne insertion into the C−C bond
of α-nitroketones 7-36 was realized by Zheng et al. to afford 2-
nitromethyl aromatic ketones 7-37 (Scheme 98b).502 In 2017,
o-methyl trifluoromethyl sulfide substituted benzophenones 7-
Scheme 98. Aryne C−C Bond Insertion with Substrates

Containing Heteroatom EWGs reaction was made possible by the aromatic stabilization ability
of fluorenyl anion 7-42 after deprotonation. In 2011, the same
group disclosed that benzyl trifluoromethyl ketones 7-43 could
serve as suitable substrates for C−C σ-bond insertion reaction
as well, giving rise to compounds 7-44 (Scheme 99b).505 It was
found that the acidity of the benzylic C−H bond could be
sufficiently enhanced by using the CF3 group. In 2016, Zeng et
al. revealed that 2-benzylphenyl ketones 7-46 could be readily
accessed via aryne C−C bond insertion reaction on 2-
phenylacetophenones 7-45, the transformation of which was
promoted by the electron-deficient aryl group on the substrate
(Scheme 99c).506
In 2016, Zeng and co-workers unraveled a ring expansion
reaction via aryne insertion into the C−C σ-bond of α-aryl
cycloketones 7-47, where products 7-48 containing medium-
sized rings could be readily synthesized (Scheme 100a).507
Two types of product skeletons could be obtained, depending
on the position of the α-aryl group, either imbedded in or
attached outside of the cycloketone ring. Meanwhile, in a study
carried out by Srihari and Mehta on C-arylation of oxindoles
Chem. Rev. 2021, 121, 3892−4044
Scheme 100. Aryne C−C Bond Insertion with α-Aryl Scheme 102. Aryne C−O Bond Insertion with Epoxides and
Cycloketones Oxaziridines
with arynes, they disclosed a temperature-controlled C−C σ-

bond insertion transformation on 7-49, constructing dibenzo-
[b,e]azepin-6-one derivatives 7-50 under elevated temperatures
(Scheme 100b).414 Moreover, they developed a concise
synthesis toward potent antiulcer agent darenzepine.
Although 2-arylacetates are inert due to the reduced acidity
of the benzyl C−H bond, Chandrasekhar and co-workers
revealed that both N-tosylacetimidates (X = O) and N-
tosylacetimidamides (X = NH) 7-51 could serve as effective
substrates for the aryne C−C σ-bond insertion reaction to
produce compounds 7-52 (Scheme 101).508 In addition, the
employment of cyclic 2-sulfonyliminoindolines 7-53 furnished Mechanistically, this transformation proceeds through inter-
either the ring-expansion product 7-54 or the arylation mediates 7-62 and 7-63. Cyclization on 7-63 produces 7-60
product, depending on the solvent.508 (path a); whereas intramolecular 1,4-hydrogen migration
affords 7-61 (path b).
Scheme 101. Aryne C−C Bond Insertion with N- Although carboxylic acid has been known to normally
Tosylacetimidamides and Cyclic 2-Sulfonyliminoindolines participate in the O-arylation reaction with arynes,396 aryne
insertion into the C−O σ-bond of carboxylic acids 7-64 was
realized by Larock et al. to construct o-hydroxyaryl ketones 7-
65 in modest to high yields (Scheme 103).512 Subsequent
Scheme 103. Aryne C−O Bond Insertion with Carboxylic

Acids
7.3. Insertion into C−O σ-Bonds

In comparison with aryne insertion into the C−N and C−C σ-
transformation on in situ generated phenolate anion could give
bonds, there are limited examples on the C−O σ-bond
rise to xanthones, 4-chromanones, and flavones.513 The keys
insertion. In 2007, Peña and co-workers reported a selective
for the success of this transformation reside in high reaction
aryne insertion into the C−O bond of styrene oxide (7-55)
temperature (125 °C), dilute reaction media, and an excess
(Scheme 102a).509 Although this study proved the feasibility of
amount of aryne and CsF.
aryne insertion into the σ-bond of strained epoxides, the low
yield of 7-56 associated with several side-products impeded its 7.4. Insertion into Other σ-Bonds
further application. In 2010, Larock and Kivrak reported an Aryne insertion into other element−element σ-bonds has
aryne insertion into the C−O bond of oxaziridines 7-57, shown to be a convenient and highly diverse approach to
furnishing dihydrobenzisoxazoles 7-58 with high functional incorporate various elements as well as substituents on the
group tolerance (Scheme 102b).510 In this study, they ruled arene ring. In 2005, Yoshida, Kunai, and co-workers reported
out the possibility of aryne 1,3-dipolar cycloaddition reaction an aryne insertion into the C−P bond of cyanomethyldiphe-
with the in situ generated nitrone intermediates via isomer- nylphosphine oxide (7-66a) (R1 = CN) and harvested
ization of oxaziridines. In 2018, Vankar and Dubbu applied compounds 7-67 (Scheme 104a).514 By employing ethyl
aryne insertion reaction on 1,2-anhydrosugars 7-59 and (diphenylphosphinyl)acetate (7-66b) (R1 = CO2Et) as the
achieved both 1,2-dihydrobenzofuran-fused C-aryl glycosides substrate, two products via aryne insertion into either the C−P
7-60 and C2-O-phenolic glycals 7-61 (Scheme 102c).511 bond or the C−C bond of 7-66b were obtained in a 1:1 ratio.
Chem. Rev. 2021, 121, 3892−4044
Scheme 104. Aryne Insertion into Carbon-Based σ-Bonds Scheme 105. NHC-Catalyzed Aryne Insertion into the C−H
Bond of Aldehydes
Subsequently, the same group developed two types of aryne

insertion reactions into carbon−halogen σ-bonds. In 2007,
they disclosed that aryne could insert into the C−X (X = Cl,
Br) bond of acid halides 7-68 to afford compounds 7-69,
where both aryl and aliphatic acyl functional groups were
found to be effective (Scheme 104b).515 Moreover, this Scheme 106. Aryne Insertion into C−S σ-Bonds
transformation was highly regioselective when substituted
aryne precursors were employed. In 2009, they exhibited that
aryne could insert into the C−Cl bond of dichlorotriazines 7-
70 to produce 7-71, albeit in low to moderate yields (Scheme
104c).516
In 2010, a prominent N-heterocyclic carbene (NHC)-
catalyzed formal insertion of aryne into the Cformyl−H bond of
aldehydes was achieved by Glorius and Biju.517 As shown in
Scheme 105, after screening for different NHC precursors,
they identified catalyst 7-72 as an ideal carbene precursor.
Products 7-73, such as benzophenones, α,β-unsaturated
ketones, and other aryl ketones, were readily achievable via
this aryne hydroacylation protocol. Mechanistically, they
proposed that the generated Breslow intermediate 7-74 attacks nucleophiles. In 2005, Yoshida, Kunai, and co-workers
aryne to produce alkoxide intermediate 7-77 through either C- reported a facile insertion reaction of arynes into the N−Si
arylated intermediate 7-75 or a concerted transition state 7-76, bond of aminosilanes 7-81, which could afford 2-silylanilines 7-
which could then realize the formation of products 7-73 along 82 (Scheme 107a).520 Notably, the silyl groups on the 2-
with regeneration of the NHC catalyst 7-72. silylaniline products 7-82 could not be further removed by
In 2017, Xu et al. reported that aryl triflones 7-79 could be fluoride ion in the reaction. In 2013, Wang et al. demonstrated
achieved via an aryne insertion into the C−S bond of CF3SO2- that o-haloaminoarenes 7-84 were obtained through a one-pot
containing carbon nucleophiles 7-78 (Scheme 106a).518 protocol by inserting arynes into the N-halogen bond of the in
Electron-withdrawing substituents on the aryl group of the situ generated N-haloamines 7-83 (Scheme 107b).521 Their
substrates were necessary for this transformation. In addition, mechanistic study revealed that, after nucleophilic addition to
β-triflyl esters could work as well, albeit in low yields. Recently, aryne by 7-83, an aryl radical might partially account for the
Mhaske and co-workers demonstrated that aryne could insert formation of 7-84.522 In 2013, aryne N−P bond insertion was
into the C−S σ-bond of sulfonium ylides to afford o- realized by Zhang and co-workers, in which N-aryl
substituted thioanisole derivatives 7-80 (Scheme 106b).519 diphenylphospinic amides 7-85 served as effective substrates
Although both ketone and nitrile groups were effective and the products 7-86 could be potentially utilized as bidentate
electron-withdrawing groups on sulfonium salts to promote aminophosphine ligands (Scheme 107c).523 Subsequently, this
this reaction, the ester group was found to be inert. protocol was applied in the P−N bond insertion of
Aryne insertion into nitrogen-based σ-bonds has also been enantiopure P-stereogenic diarylphosphinic amides with
intensively investigated, the success of which is mainly retention of the configuration at the P-center.524 In 2014,
attributed to the high nucleophilic character of nitrogen Zeng and Rao realized an aminocyanation reaction through
Chem. Rev. 2021, 121, 3892−4044
Scheme 107. Aryne Insertion into Nitrogen-Based σ-Bonds Notably, trifluoromethyl group was found to be essential for
the efficient construction of products 7-92. Recently, Biju and
co-workers revealed that aryne can insert into the S−N σ-bond
of sulfenamides 7-93, giving rise to 2-sulfanylanilines 7-94
(Scheme 108b).527 Mechanistically, N-nucleophile on 7-93
attacks aryne first, which is followed by a 1,3-migration of S-
moiety to the ortho position of the nitrogen substituent. This
study was also applied in a convenient preparation of
antidepressant drug vortioxetine.
Sulfur can serve as a nucleophile, leading to aryne insertion
reactions into S-based σ-bonds. In 2004, Yoshida, Kunai, and
co-workers demonstrated that aryne insertion into the S−Sn
bonds of stannyl sulfides 7-95 proceeded smoothly to produce
compounds 7-96 (Scheme 109a).528 Moreover, Murafuji and
Scheme 109. Aryne Insertion into Other Sulfur-Based σ-

Bonds
aryne insertion into the N−CN σ-bond of N-aryl cyanamides

7-87, producing 2-aminobenzonitriles 7-88 with broad Chen applied aryne insertion protocol on the S−Bi σ-bond of
substrate scope (Scheme 107d).525 Later, Wang and Chen 7-97, furnishing o-arylthio triarylbismuthanes 7-98 (Scheme
disclosed that aryne could efficiently insert into the N−OH 109b).529 In 2017, 1,2-bis(trifluoromethylthio)arenes 7-100
bond of hydroxyindolinones 7-89 to afford sterically congested were obtained from bis(trifluoromethyl)disulfide 7-99 by
2-aminophenols 7-90 (Scheme 107e).526 They reasoned that Daugulis and Mesgar via an aryne S−S bond insertion pathway
the structural rigidity of the substrates could prohibit a (Scheme 109c).530 Similarly, selenium-based σ-bonds could be
competing [3,3]-sigmatropic rearrangement reaction, the inserted by arynes as well. In 2007, Raminelli et al. reported a
process of which was observed by using N-hydroxyindoles. direct benzyne insertion into the Se−Se bond of 7-101,
Along with the study on aryne insertion into N−COCF3 affording o-bis(organochalcogenide)benzenes 7-102 in modest
bond, Larock et al. also accomplished an insertion reaction into to good yields (Scheme 110a).531 Subsequently, the same
the N−SOCF3 bond of compounds 7-91 (Scheme 108a).481 group achieved an aryne selenostannylation reaction via aryne
insertion into the Se−Sn bond of tributyl(phenylselanyl)-
stannane 7-103, which could give the corresponding products
Scheme 108. Aryne Insertion into N−S σ-Bonds
7-104 (Scheme 110b).532
In 2011, Kazmaier and co-workers demonstrated a catalyst-
free hydrostannation protocol to synthesize compounds 7-105
Scheme 110. Aryne Insertion into Selenium-Based σ-Bonds
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through an aryne insertion into the Sn−H bond of Bu3SnH phosphines 7-112 was realized by Hirano, Miura, and co-
(Scheme 111a).129 Similar results were also reported by Moses workers through an aryne insertion into the P−P bond of 7-
112 (Scheme 112b).536 For ease of handling, the diphosphi-
Scheme 111. Aryne Insertion into the F−Sn Bond of nated products 7-113 were further converted to phosphine
Bu3SnF sulfides 7-114 with S8.
In 2014, Taniguchi and Curran accomplished a first and
distinct hydroboration protocol on arynes (Scheme 113a).537
Scheme 113. Aryne Insertion into Other σ-Bonds
et al.533 A distinct aryne insertion into the F−Sn bond of

Bu3SnF was disclosed by Yoshida and co-workers, affording In this study, they employed stable N-heterocyclic carbene
compounds 7-106 via the simultaneous formation of a C−F boranes (NHC-borane) 7-115 to react with arynes, affording
and a C−Sn bond in highly regioselective manner (Scheme B-aryl NHC-boranes 7-116 in modest to high yields.
111b).534 Their mechanistic investigation revealed that a Furthermore, they could convert the product to the
difluorotributylstannate (Bu3SnF2−) species 7-107 was respon- corresponding pinacol borane or phenylboronic acid.538
sible for the overall conversion. The nucleophilic addition of 7- Besides, aryne insertion into the I−I σ-bond was also realized
107 to aryne would form intermediate 7-108, which then by Pérez, Guitián, and co-workers, and o-diiodoarenes 7-117
converts to 7-109 via a 1,3-migration of Bu3SnF. At last, were obtained in modest to high yields (Scheme 113b).539
fluoride dissociation on 7-109 could produce 7-106. This 7.5. Insertion into π-Bonds
study also led to the preparation of the anti-inflammatory drug
flurbiprofen. Aryne insertion into π-bonds, i.e., CS, CC, PN, PO,
In 2016, Guo, He, and co-workers demonstrated an aryne SO, and SN bonds, has also been achieved. In 2011,
insertion reaction into the P−OH σ-bond of diarylphosphinic Greaney et al. uncovered a distinct aryne insertion protocol
acid 7-110, giving rise to o-hydroxy-substituted arylphosphine into the CS bond of thioureas 7-118, which could afford
oxides 7-111 in modest to high yields (Scheme 112a).535 The functionalized amidines 7-119 in modest to high yields
employment of TBAT as a less basic fluoride source (Scheme 114a).540 In contrast to the aryne reaction with
suppressed the undesired O-arylation side-reaction on the ureas, in which a C−N σ-bond was inserted by arynes,479 the
phenol oxygen of 7-111. Their mechanistic study favored a O- reaction of arynes with thioureas exhibited completely different
nucleophilic attack/Fries rearrangement pathway on the P−
OH bond over a [2 + 2] cycloaddition/ring-opening process Scheme 114. Aryne Insertion into CS and CC Bonds
on the PO bond. Aryne diphosphination with tetraaryldi-
Scheme 112. Aryne Insertion into P-Based σ-Bonds
Chem. Rev. 2021, 121, 3892−4044
chemoselectivity. In 2013, Shi et al. reported a reaction Scheme 116. Aryne Insertion into the SO Bond of DMSO
between o-silylaryl triflates and vinylogous amides 7-120
containing no free N−H bonds, furnishing 2-substituted
benzaldehydes or ketones 7-121 in modest to high yields
(Scheme 114b).541 This overall CC bond insertion
transformation proceeds through a [2 + 2] cycloaddition
reaction and a subsequent ring-opening on intermediate 7-122
to generate an iminium inner salt 7-123, which could then be
trapped by methanol to afford aminal 7-124. Upon hydrolysis,
1,2-difunctionalized arenes 7-121 can be obtained.
In 2014, Lopez-Leonardo, López-Ortiz, Alajarin, and co-
workers disclosed that P-(2-arylamino)phenyl phosphonium
triflates 7-126 could be accessed through the reaction of
iminophosphoranes 7-125 with o-silylaryl triflates (Scheme
115a).542 This transformation proceeds through a [2 + 2]/
Scheme 115. Aryne Insertion into PN and PO Bonds
component to capture the generated phenolate ion and yielded

7-130 (Scheme 116b).545 A similar transformation was
recently achieved by Gogoi et al. by using both allyl bromides
and vinyl bromides as the alkylation components.546
In 2015, Wang and co-workers reported a similar trans-
formation, which could produce compounds 7-131a and 7-
131b (Scheme 117a).547 Their mechanistic study revealed that
Scheme 117. Aryne Insertion into the SO Bond of Diaryl

Sulfoxides
retro [2 + 2] cycloaddition reaction sequence, which was

followed by either N-protonation or N-arylation in the
presence of excess aryne. In this study, P-(2-phenylthio)phenyl
phosphonium triflates were also obtained in good yields from
phosphane sulfides. Recently, Gogoi et al. realized an aryne
insertion into the PO bond of phosphine oxides 7-127,
giving rise to o-aryloxotriphenylphosphonium triflates 7-128 in
moderate to good yields with high functional group tolerance the formation of 7-131a might proceed through a sulfonium
(Scheme 115b).543 A sequential formal aryne [2 + 2] ylide intermediate 7-132; whereas, 7-131b should be realized
cycloaddition and O-arylation with a second molecule of via an intramolecular 1,4-migration of the R2 group. When
aryne was proposed as the reaction mechanism. diaryl sulfoxides 7-133 were employed, a different reaction
In 2014, Chen, Xiao, and co-workers first demonstrated an mode was discovered. Peng et al. found that o-aryloxy
aryne insertion protocol into the SO bond of DMSO with triarylsulfonium salts 7-134 could be obtained from sulfoxides
concomitant formation of C−S and C−O bonds on the vicinal 7-133 at room temperature (Scheme 117b).548
positions of a benzene ring (Scheme 116a).544 Mechanistically, In 2015, Hosoya et al. demonstrated an unprecedented
this transformation includes an aryne insertion into the SO preparation of o-sulfanylanilines 7-136 from arynes and
bond, O-alkylation with α-bromo carbonyl compounds, and sulfilimines 7-135 (Scheme 118a).549 The mechanism for
demethylation of sulfonium ion to produce products 7-129. In this transformation involves a sequential regioselective [2 + 2]
2019, Gogoi et al. employed activated alkynes as the third cycloaddition reaction of aryne with the SN bond to
Chem. Rev. 2021, 121, 3892−4044
Scheme 118. Aryne Insertion into SN Bonds component (E). Meanwhile, the positive charge on Nu can be
captured by a fourth, nucleophilic component (Nu′) or that
from the E end to realize a benzannulated scaffold.
Alternatively, anionic nucleophiles that are compatible with
electrophilic components in the reaction system could also be
employed in this strategy to realize three-component coupling
reactions.
8.1. Isocyanide-Triggered MCRs
Yoshida, Kunai, and co-workers first accomplished a series of
three-component coupling reactions of arynes with isocya-
nides. In 2004, they reported that diverse benzannulated
iminofurans 8-4 could be readily assembled through the MCR
of o-silylaryl triflates, isocyanides 8-1, and aldehydes (Scheme
120a).553 The mechanism for this transformation proceeds
Scheme 120. Aryne Three-Component Coupling Reactions

with Isocyanides
generate intermediate 7-137/S−N bond cleavage on 7-137/

intramolecular ipso-substitution at the more electron-deficient
aryl group on intermediate 7-138. In this study, they also
found that when sulfilimine contains a methyl group, o-arylthio
aniline could be obtained. This transformation was then
applied in the preparation of diaryl sulfides 7-140 by using S-
(o-bromoaryl)-S-methylsulfilimines 7-139 as the substrates
(Scheme 118b).550 A subsequent intramolecular Buchwald−
Hartwig amination operation was able to convert 7-140 to
phenothiazine. Moreover, they disclosed that the SN bond
of sulfoximines 7-141 could be inserted by arynes (Scheme
118c).551 Their computational calculations suggested a similar
mechanistic pathway to that of diarylsulfoxides. In particular,
the reaction modes were highly dependent on the substrates.
When S,S-diarylsulfoximines were employed, o-sulfinylanilines
7-142 could be achieved in a regioselective manner, whereas
N-arylation products 7-143 were obtained from both S-alkyl-S-
aryl- and S, S-dialkylsulfoximines.
8. MULTICOMPONENT REACTIONS (MCRs)

Another aryne reaction mode is multicomponent reaction
through a nucleophilic addition of isocyanide 8-1 to aryne to
(MCR).552 The general scheme for this transformation begins
generate a zwitterion 8-2, which in turn reacts with aldehyde to
with nucleophilic addition of neutral nucleophiles (Nu) to
afford a formal [3 + 2] cycloadduct 8-4 after annulation from
highly electrophilic aryne species to generate a zwitterionic
intermediate 8-3. Subsequently, the same group disclosed that
intermediate (Scheme 119). The strongly nucleophilic aryl
aldehydes could be replaced by imines,554 ketones,555
anion on this zwitterion would then attack a third, electrophilic
benzoquinones,555 or sulfonylimines,555 giving rise to deriva-
tives of iminoisoindolines or iminodihydroisobenzofurans. In
Scheme 119. General Scheme for Multicomponent 2011, Stoltz and co-workers discovered that the combination
Reactions of o-silylaryl triflates, isocyanides, and phenyl esters 8-5 could
deliver iminoisobenzofurans 8-6 as well in good to excellent
yields (Scheme 120b).556 By employing aqueous oxalic acid to
hydrolyze the iminoisobenzofuran products, they developed a
one-pot, two-step transformation to produce o-ketobenzamides
8-7. Further exploration unraveled that electron-deficient
alkynes 8-8 could serve as efficient third components in the
Chem. Rev. 2021, 121, 3892−4044
MCR of arynes and isocyanide, furnishing carbocyclic Scheme 122. Aryne MCRs with Isocyanides and 3-
iminoindenones 8-9 in moderate to high yields (Scheme Substituted Propynes
120c).556
In 2009, Huang and Sha revealed a MCR of arynes,
isocyanides, and terminal alkynes, affording polysubstituted
pyridines 8-10 and isoquinolines 8-11 under mild conditions
in highly chemo- and regioselective manners (Scheme
121).557,558 After nucleophilic addition of isocyanide to
Scheme 121. Aryne MCRs with Isocyanides and Terminal

Alkynes
Scheme 123. Aryne MCRs with Isocyanides and Organic

Bromides
aryne, the generated zwitterionic intermediate 8-12′ can be

trapped by terminal alkyne to produce imide intermediate 8- part from 8-19 could back attack intermediate 8-21 to furnish
13. A 1,5-hydride shift on imide 8-13 then occurs to yield an product 8-20. In 2014, Biju and co-workers reported a three-
allenyl imine species 8-14. Consequently, this allenyl imine component coupling reaction of arynes and isocyanides using
intermediate 8-14 could take part in a further aza-Diels−Alder either CO2 or water as the third component (Scheme 124).561
reaction/aromatization to afford either polysubstituted pyr- When CO2 was utilized, N-substituted phthalimides 8-22 were
idines 8-10 with alkynes or isoquinoline derivatives 8-11 with obtained. The plausible mechanistic pathway for this trans-
arynes. Overall, this protocol allows a ready assembly of four
components through two uniquely ordered sequences. Scheme 124. Aryne MCRs with Isocyanides and CO2/Water
In 2013, Sha, Wu, and co-workers demonstrated an
interesting multicomponent transformation of arynes, iso-
cyanides, and 3-substituted propynes 8-15 (Scheme 122).559
Disubstituted pyridines 8-16 (R2 = H) could be obtained in
moderate to high yields by using 3-bromopropyne (8-15a) as
the third component, whereas the employment of 3-
acetoxypropynes (8-15b) led to the formation of trisubstituted
pyridines (R2 = aryl). Mechanistically, this transformation
involves a 1,3-hydride shift from N-allenyl imine 8-17 to
generate azatriene 8-18, which then participates in an
intramolecular pericyclization and aromatization through the
extrusion of either HBr or HOAc.
In 2011, Yoshida et al. developed a three-component
coupling reaction of arynes, isocyanides, and organic bromides
8-19, leading to the production of bromoarenes 8-20 (Scheme
123).560 In this MCR, either alkynyl bromides or polyfluor-
oaryl bromides served as the sources of electrophilic bromide
to react with zwitterion 8-2. Meanwhile, the departed anionic
Chem. Rev. 2021, 121, 3892−4044
formation might proceed through a fluoride-induced ring (SO2F2) could be efficiently trapped in the MCR of arynes and
opening of iminoisobenzofuranone species 8-23, generated secondary amines to afford various 2-aminoarenesulfonyl
from 8-2 and CO2 via either a concerted or stepwise manner, fluoride derivatives 8-28 in modest to high yields with high
and further cyclization to afford phthalimide derivatives 8-22. functional group tolerance (Scheme 125d).568 Besides, Mhaske
In the presence of water, benzamide derivatives 8-24 could be and Dhokale found that sodium nitrite (NaNO2) could serve
obtained after trapping the zwitterion intermediate 8-2 with as a nucleophile. After trapping the generated aryl anion with
water. Similar work was also reported by the groups of Wang/ aldehyde, (2-nitrophenyl)methanol derivatives 8-29 were
Ji562 and Pirali.563 achieved through a three-component coupling reaction of
8.2. N-Nucleophile-Triggered MCRs arynes, NaNO2, and aldehydes (Scheme 125e).376
In 2019, Tian et al. reported a MCR of o-silylaryl triflates,
Nitrogen nucleophiles are versatile arynophiles in aryne MCRs.
tertiary amines, and organohalides, leading to the formation of
In 2006, Yoshida, Kunai, and co-workers first accomplished a
diverse tertiary 2-haloanilines 8-30 (Scheme 126a).569 Beside
three-component coupling reaction of arynes, imines, and
CO2, furnishing six-membered benzoxazinone derivatives 8-25
in modest to high yields (Scheme 125a).564 Subsequently, they Scheme 126. Tertiary Amine-Triggered Aryne MCRs
Scheme 125. N-Nucleophile-Triggered Aryne MCRs
carbon tetrachloride, carbon tetrabromide, carbon tetraiodide,

hexachloroethane, fluorotribromomethane, NCS, NBS, and
NIS could all serve as effective organohalides. As proposed, the
departed anionic moieties from organohalides served as
nucleophiles in the dealkylation step on ammonium salt
intermediate. Meanwhile, Biju and co-workers also disclosed a
MCR of arynes and tertiary amines with either aryl selenium
bromide or diaryl diselenide as the third component (Scheme
126b).570 2-Selanyl aniline derivatives 8-31 could be facilely
prepared in modest to high yields.
In a study carried out by Biju et al., they revealed an
interesting aryl to aryl amino-group migration event. As shown
in Scheme 127a, this MCR involved o-silylaryl triflates,
aromatic tertiary amines 8-32, and aldehydes, which could
produce 2-functionalized tertiary amines 8-33.571 Distinctively,
reported another MCR of arynes, secondary amines, and CO2, an aryl to aryl tertiary amino group migration via intermediates
where anthranilic acid derivatives 8-26 were readily prepared 8-34 and 8-35 was observed through the SNAr mechanism in
(Scheme 125b).565 Moreover, the same group developed two this transformation. They reasoned that the formation of
types of three-component coupling reactions of arynes and electron-deficient quaternary ammonium intermediate 8-34
aminosilanes with either aldehydes566 or sulfonylimines,567 might be the key for this aryl migration event. Moreover,
giving rise to the corresponding 2-aminobenzhydrols (X = O) activated ketones, such as N-methylisatin, trifluoroacetophe-
and 2-aminobenzhydrylamines (X = NTs) 8-27, respectively none, and benzil, could also serve as effective third
(Scheme 125c). In these studies, a catalytic amount of benzoic components in this reaction. In 2016, the same group reported
acid was found to be essential to promise the high reaction a MCR of arynes, aromatic tertiary amines, and CO2 (Scheme
efficiency. According to their mechanistic investigation, they 127b).572 A switchable selectivity was observed. When
proposed that a secondary amine could be formed in situ from aromatic tertiary amines containing an electron-deficient
aminosilane and benzoic acid, which is the actual active species substituent on the arene ring were utilized, an aryl to aryl
for the following three-component coupling transformations. amino-group migration occurred to afford 2-aminoaryl
Recently, Kim and Kwon demonstrated that sulfuryl fluoride benzoates 8-36. In contrast, in the presence of electron-
Chem. Rev. 2021, 121, 3892−4044
Scheme 127. Tertiary Amine-Triggered Aryne MCRs Scheme 128. N-Heteroaromatic-Triggered Aryne MCRs
Involving Aryl Migration
species 8-42 could abstract a proton from the terminal alkyne

to generate an acetylide anion 8-45, which would then attack
the N-arylated quinolinium/pyridinium cation 8-43 to afford
8-44.
Ketones with no α-hydrogens were employed as the third
component. In 2013, Biju et al. demonstrated a MCR of
arynes, N-heterocycles, and isatins 8-46 (Scheme 129a).576
When isoquinolines were employed, spirooxazino isoquinoline
donating or neutral groups, 2-arylamino benzoates 8-37 were Scheme 129. Quinoline-Triggered Aryne MCRs
obtained via a nitrogen to oxygen alkyl group migration
pathway. Similar aryl to aryl amino-group migration was
reported by Okuma and co-workers in their preparation of
both 9- and 10-membered N,O-containing heterocycles 8-39
via a MCR of arynes, aldehydes, and substituted indolines (n =
1) or tetrahydroquinolines (n = 2) 8-38 (Scheme 127c).573
N-Heteroaromatic compounds were found to be effective
triggers in aryne multicomponent reactions. In 2006, Cheng
and Jeganmohan first demonstrated a three-component
coupling reaction of arynes, N-heteroaromatics 8-40 (e.g.,
pyridines, quinolines, and isoquinolines), and nitriles, affording
the corresponding N-arylated 1,2-dihydro-2-pyridinyl, 1,2-
dihydro-2-quinolinyl, and 1,2-dihydro-1-isoquinolinyl nitriles
8-41, respectively (Scheme 128a).574 A representative
mechanistic pathway was proposed by using pyridine as the
N-heteroaromatic substrate: (1) 1,4-dipole 8-42, generated
from N-nucleophilic addition to aryne, abstracts an α-hydrogen
from nitrile; (2) the nitrile anion would then attack cation 8-43
to realize 8-41. The discovery by using acetonitrile as an
efficient third component is particularly noteworthy because
the reactions with o-silylaryl triflates are normally carried out in
acetonitrile. In 2010, Cheng et al. reported that various N-
heteroaromatics 8-40, such as quinolines, isoquinolines, and
pyridines could participate in the MCRs with arynes and
terminal alkynes to assemble 8-44 in good to high yields
(Scheme 128b).575 Similar to their previous study, zwitterionic
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derivatives 8-47 could be produced in moderate to high yields. Scheme 131. Other N-Heteroaromatic-Triggered Aryne
Subsequently, the groups of Biju577 and Lei/Hu578 independ- MCRs
ently reported a similar MCR of arynes, quinolines, and
aldehydes/ketones, giving rise to products 8-48 (Scheme
129b). When pyridines were utilized as the nucleophilic
triggers, an unexpected reaction pathway involving the
formation of pyridine carbenes 8-49 was disclosed by Biju et
al. through labeling experiments (Scheme 130).576 Mechanis-
Scheme 130. Aryne MCRs with Pyridines and Isatins
tically, pyridine carbene 8-49 can be generated from 8-42,

which then attacks isatin 8-46 to form 8-50. A subsequent
intramolecular aryl transfer through an SNAr pathway with the
formation of a σ-complex intermediate 8-51 would take place
to enable the production of indolin-2-one derivatives 8-52. reaction of arynes, imines, and various carbon nucleophiles,
This mechanistic proposal was later supported by Rodriguez, such as chloroform, acetonitrile, and methyl propiolate, and
Coquerel, and co-workers through their theoretical calcu- obtained products 8-61 (Scheme 132a).584 Meanwhile,
lations.579
Hydrogen abstraction from the third component, i.e., solvent
Scheme 132. Imine-Triggered MCRs
molecules, was found to be a common tactic in N-
heteroaromatic-triggered MCRs. In 2016, Chenoweth and
Suh reported that both DCM and MeCN could participate in
the MCRs with benzyne and phthalazine (8-53), affording the
corresponding products 8-54 and 8-55, respectively, albeit in
low yields (Scheme 131a).580 The dual roles of DCM and
MeCN in these transformations are both the proton sources
and the subsequent nucleophiles. In the same year, Dai, He,
and co-workers disclosed that dialkylphosphites 8-56 could be
utilized as the third component as well to produce 8-57, and
N-heteroaromatics 8-40 were found to be quinolines,
isoquinolines, phenanthrolines, and acridines (Scheme
131b).581 Chloroform could also participate in this type of
transformation to give 8-58 in modest to excellent yields
(Scheme 131c).582 In 2018, Tian, Yu and co-workers disclosed
a MCR of o-silylaryl triflates, electron-deficient N-hetero-
aromatics 8-59, and carbon tetrachloride, furnishing the
corresponding products 8-60 in good to high yields (Scheme
131d).583 In this study, both the control experiment and the
DFT calculations indicated that chlorine transfer from CCl4
was favored over either intramolecular 1,4-proton transfer or
proton abstraction from MeCN.
Like the CN double bonds on N-heteroaromatics, imines
could serve as efficient nucleophilic triggers in aryne
multicomponent reactions as well. In 2017, Tian and co-
workers demonstrated a three-component carboarylation
Chem. Rev. 2021, 121, 3892−4044
Voskressensky et al. synthesized cyanomethyl-substituted Scheme 134. Aziridine/Azetidine-Triggered Aryne MCRs

tetrahydroisoquinolines and tetrahydrothieno[3,2-c]pyridines
8-63 through the MCR of the dihydro analogues of
isoquinoline and pyridine 8-62 with benzyne and acetonitrile
(Scheme 132b).585 A four-component reaction was also
developed through the in situ generation of imines from
primary amines and aldehydes.586 In a study carried out by
Tian, Yu, and co-workers on the MCRs of arynes with
electron-deficient N-heteroaromatics, they also realized similar
transformations with imines using carbon tetrachloride as the
third component, giving rise to products 8-64 (Scheme
132c).583 Recently, Peng et al. disclosed that oxazolines 8-65
could serve as nucleophilic triggers in the aryne three-
component coupling reaction with chloroform, furnishing
products 8-66 in modest to high yields (Scheme 132d).587
Intriguingly, after screening various chiral auxiliaries, isopropyl
group (i-Pr) was found to be the superior auxiliary (Aux) and
trichloromethylated chiral oxazolidines 8-66 could be prepared
in good to excellent diastereoselectivities.
In a rare case, Wu and co-workers reported a preparation of
cinnolines 8-68 through a MCR of arynes, tosylhydrazine
unsuitable. Wu, Sha, and co-workers later developed a MCR of
(TsNHNH2), and α-bromo ketones 8-67 (Scheme 133).588
arynes, aziridines 8-74 with 2-carbonyl substituents, and TBAF
hydrate as a fluorinating reagent, which led to the formation of
Scheme 133. Aryne MCRs with Tosylhydrazine and α- α-fluoro-β-amino acid derivatives 8-75 in moderate to
Bromo Ketones excellent yields (Scheme 134b).591 A small amount of water
was found to be crucial for the success of this transformation,
the role of which was proposed to protonate the aryl anion on
zwitterion intermediate. A similar reaction was recently
observed when Yudin, Studer, and co-workers studied the
reactivity between vinylaziridines and o-silylaryl triflates;
whereas arynes, generated under Knochel’s conditions by
using o-haloaryl sulfonates as the aryne precursors and
Grignard reagent as the activating reagent, proceeded through
a formal [5 + 2] cycloaddition reaction pathway with
vinylaziridines.592
In 2015, Biju et al. noticed that trifluoroacetic acid (TFA)
could promote the MCR of arynes, N-substituted aziridines 8-
Based on their mechanistic investigation, a plausible 70, and water, affording N-aryl β-amino alcohol derivatives 8-
mechanism was proposed: a formal [2 + 2 + 2] cycloaddition 76 in moderate to high yields (Scheme 135a).593 Moreover,
of arynes, α-bromo ketones, and diazene, generated from four-membered azetidines were found to be good substrates
tosylhydrazine and CsF, could furnish intermediate 8-69,
which then converts to cinnolines 8-68 after elimination of Scheme 135. Other Aziridine/Azetidine-Triggered Aryne
water. Because diazene is short-lived and would reduce the MCRs
aryne intermediate, another possible reaction pathway might
involve a direct reaction of tosylhydrazine with aryne.
The reaction of N-substituted aziridines with arynes to
generate zwitterionic species could be traced back to 1972, in
which Giumanini studied their reaction with benzyne by using
fluorobenzene as the precursor.589 This benzyne generation
method, however, only afforded the desired product in low
efficiency. Along with the development of Kobayashi’s method,
N-substituted aziridines were recently employed in aryne
MCRs. In 2013, Larionov and co-workers first demonstrated
that the MCR of arynes, aziridines 8-70, and acetonitrile could
produce N-aryl γ-aminobutyronitriles 8-71 in good to excellent
yields (Scheme 134a).590 Mechanistically, this three-compo-
nent transformation includes (1) N-nucleophilic addition of
aziridine 8-70 to aryne to form zwitterionic species 8-72; (2)
the aryl anion on 8-72 abstracts a proton from acetonitrile; (3)
the deprotonated acetonitrile attacks the three-membered ring
on intermediate 8-73 to furnish 8-71. Although four-
membered azetidine could be utilized in this reaction as well,
both five- and six-membered cyclic amines were found to be
Chem. Rev. 2021, 121, 3892−4044
for this MCR as well to afford the corresponding N-aryl γ- fluoride, and 2,4-pentanedione were all employed as
amino alcohols. Their detailed mechanistic studies clearly nucleophiles in this transformation. Recently, they reported
revealed that water is responsible for the protonation of aryl the same type of MCR by using nitrogen nucleophile as the
anion 8-77 and TFA is the actual nucleophile in the SN2-type third component.596 In 2017, Tian et al. achieved an aryne
ring-opening reaction on 8-78. After hydrolysis of intermediate MCR with enantioenriched tertiary benzylic amines 8-88 and
8-79, N-aryl β-amino alcohols 8-76 could be obtained. various nucleophiles, such as benzenethiol, thiolate, thiocar-
Subsequently, the same group reported a MCR of arynes boxylic acid, sulfinic acid, sodium sulfinate, selenol, malononi-
and carboxylic acids with either aziridines or azetidines, trile, and azidosilane, furnishing structurally diverse benzylic
producing the corresponding N-aryl β-amino alcohols and N- compounds 8-89 in moderate to excellent yields (Scheme
aryl γ-amino alcohols 8-80, respectively (Scheme 135b).594 137b).597 An overall stereospecific nucleophilic substitution
In 2016, a unique aryne MCR was disclosed by Biju and co- with inversion of the configuration and excellent retention of
workers, where N-substituted electron-deficient aziridines 8-81 enantiopurity occurred via an SN2 reaction pathway on the in
were employed and N-aryl α-amino epoxides 8-82 could be situ generated ammonium salt.
obtained in good yields with good diastereoselectivity (Scheme 8.3. Other Nucleophile-Triggered MCRs
136). 595 Both variations on aziridines 8-81 and the
Multicomponent reactions of arynes, activated carbonyl
compounds, and electron-deficient alkenes/alkynes were
Scheme 136. Aryne MCRs with Electron-Deficient developed. In general, these transformations involve a
Aziridines and Aldehydes sequential aryne insertion into a C−C σ-bond, an annulation
reaction with alkene or alkyne, and elimination to afford
polysubstituted naphthalenes. In 2007, Huang and Xue first
demonstrated a MCR of arynes, β-keto sulfones 8-90, and
electron-deficient alkenes to produce polysubstituted naph-
thols 8-91 and naphthalenes 8-92 in moderate to good yields
(Scheme 138a).598 In 2018, Shu, Wu, and co-workers
Scheme 138. MCRs via Aryne C−C σ-Bond Insertion
replacement of aldehydes with N-substituted isatins were

found to be efficient in this transformation. A mechanistic
pathway was proposed: after a sequential aziridine-triggered
formation of zwitterion 8-83 and intramolecular 1,4-proton
abstraction, a strained aziridinium ylide 8-84 can be generated,
which could add to aldehyde to give an alkoxide anion 8-85;
this alkoxide then opens the aziridinium ring to furnish α-
amino epoxides 8-82.
In 2018, Ko and co-workers demonstrated that 1,4-
diazabicyclo[2.2.2]octane (DABCO) (8-86) could serve as a
cyclic amine trigger in aryne MCR in combination with various
nucleophiles, which could yield 2-(4-phenylpiperazin-1-yl)-
ethan-1-amine-containing derivatives 8-87 (Scheme 137a).369
Other than thiols, methyl acrylate, allyl acetate, methyl acetate,
Scheme 137. Other N-Nucleophile-Triggered Aryne MCRs
accomplished two types of three-component σ-bond inser-

tion/benzannulation transformations of arynes and alkynoates
8-93 with either α-cyanoacetophenones (R2 = CN) or 1,3-
diketones (R2 = COAr), affording various polysubstituted
naphthalene derivatives 8-94a and 8-94b, respectively
(Scheme 138b).599 When 1,3-diketones were employed, a
decarbonalytion reaction occurred to produce 8-94b.
Beside the aforementioned mechanism, a combination of
these three components could proceed through different
reaction pathway. In 2016, Shu, Wu, and co-workers reported a
Chem. Rev. 2021, 121, 3892−4044
formal [2 + 2 + 2] cycloaddition reaction involving arynes, 1,3- Scheme 140. O-Nucleophile-Triggered Aryne MCRs
dicarbonyl compounds 8-95, and alkynoates 8-93, affording
naphthalene derivatives 8-96 in moderate to high yields
(Scheme 139).600 Mechanistically, they proposed that
Scheme 139. Formal [2 + 2 + 2] Cycloaddition Reaction of

Arynes, 1,3-Dicarbonyl Compounds, and Alkynoates
deprotonated 8-95 attacks alkynoates 8-93 first to generate

8-97, which in turn reacts with aryne in an annulation fashion
to produce the final product after dehydration on intermediate
8-98.
O-Nucleophiles were also utilized in aryne MCRs with o-
silylaryl triflates, albeit with limited application. Since 2008, the
Okuma group has investigated the MCRs of cyclic ethers and
active methines with different aryne precursors.348,601,602
Among these studies, they demonstrated a MCR of epoxides
8-99, chloroform, and Kobayashi benzyne precursor, furnish-
ing isomeric mixtures of trichloroalkyl phenyl ethers 8-100a
and 8-100b, albeit in low efficiency (Scheme 140a).348 In
Yoshida’s investigation on the MCRs of arynes, isocyanides,
and alkynyl bromides, they noticed that the oxygen atom on
both THF and oxetane could attack aryne to generate the
corresponding 1,3-dipoles 8-101, which then reacted with
either alkynyl bromides or polyfluoroaryl bromides to produce Scheme 141. Aryne MCRs with Trifluoromethoxylation
benzo[b]oxepine derivatives 8-102 in moderate to high yields Reagents
(Scheme 140b).560 In 2016, Biju and co-workers reported a
temperature dependent switchable reactivity of arynes with
aliphatic alcohols. At 60 °C, THF could serve as an efficient
nucleophilic trigger in the MCR with arynes and aliphatic
alcohols to produce ethers 8-103 (Scheme 140c);401 whereas
at low temperature, direct aryne insertion into the O−H bond
of alcohols occurred (see Scheme 61a). Recently, Qi, Jiang,
and co-workers employed precursors of 3-triflyloxybenzyne 8-
104 in a four-component coupling reaction with cyclic ethers,
CO2, and amines, giving rise to functionalized carbamate
derivatives 8-105 in modest to high yields (Scheme 140d).603
Mechanistically, this transformation initiates with a cyclic
ether-triggered formation of zwitterion 8-106, followed by
protonation with in situ generated ammonium cation of
carbamate 8-107 from diethylamine and CO2, which could “Cl”. In this study, they also identified that a thermally stable
then furnish products 8-105 after ring opening reaction. trifluoromethoxide salt [K(cis-dicyclohexano-18-c-6)]+CF3O−
In 2018, Hu and co-workers prepared trifluoromethyl was responsible for the success of this transformation.
benzoate (TFBz) (8-108) as an unprecedented trifluorome- Recently, Lei, Zhu, and co-workers reported a new class of
thoxylation reagent and employed this reagent in a three- trifluoromethoxylation reagent, trifluoromethyl aryl sulfonates
component reaction with arynes and various halogen sources, (TFMS) 8-110, and applied them in the trifluoromethox-
furnishing o-haloaryl trifluoromethyl ethers 8-109 in modest to ylation-iodination of arynes, yielding products 8-111 (Scheme
high yields (Scheme 141a).604 Those halogen sources were 141b).605 In this study, they systematically screened the crown
phenylethynyl bromide for “Br”, C6F5I for “I”, and CCl4 for ether, fluoride salts, solvent effect, and “I” sources.
Chem. Rev. 2021, 121, 3892−4044
Sulfonium ylides could be generated from the reaction of Scheme 143. Cyclic Thioether-Triggered Aryne MCRs
certain S-containing molecules with o-silylaryl triflates, which
would then participate in the subsequent transformations. In
2014, Xu, Shen, and co-workers demonstrated a MCR of
thioethers, arynes, and isatins, furnishing various spiroepoxy
oxindoles 8-112, albeit with no diastereoselectivity (Scheme
142a).606 In this study, sulfonium ylide 8-114 could be
Scheme 142. MCRs via Benzyne-Induced Sulfonium Ylides
could protonate the sulfonium ylide intermediate. Meanwhile,

He et al. disclosed a similar MCR by employing both inorganic
salts, i.e., KF, KCl, KBr, and KSCN, and silylated reagents, i.e.,
TMSCN, TMSN3, and TMSCl, as nucleophiles (Scheme
143c).610
Phosphines were examined in aryne MCRs as well. In this
context, Biju et al. reported several MCRs of arynes,
phosphines, and carbonyl compounds.611,612 In 2014, they
first exhibited that stable pentacovalent phosphoranes 8-121
based on the benzooxaphosphole scaffold could be obtained in
good to high yields from the MCR of arynes, phosphines, and
aldehydes (Scheme 144a).611 Two plausible mechanistic
pathways were proposed to capture aldehydes after the initial
formation of 1,3-phosphonium zwitterion intermediate 8-122
through either a stepwise manner (path a) or a formal [3 + 2]
cycloaddition reaction (path b). Subsequently, they demon-
generated through a sequential nucleophilic addition of
thioether to aryne and an immediate intramolecular 1,4-proton Scheme 144. Phosphine-Triggered Aryne MCRs
shift on 8-113. Subsequently, the reaction of 8-114 with isatin
produces product 8-112 via intermediate 8-115. In 2016,
Zhang, Wang, and co-workers discovered that sulfonium ylide
8-116 could be generated via a successive benzyne insertion
into the SO bond of sulfoxides/O-arylation/proton
abstraction pathway (Scheme 142b).607 Consequently, they
developed a MCR of sulfoxides, benzyne, and carbonyl
electrophiles, such as N-methyl isatins and activated aromatic
aldehydes, giving rise to the corresponding epoxide products 8-
117a and 8-117b, respectively.
Recently, saturated sulfur heterocycles were employed to
serve as nucleophilic triggers in aryne three-component
coupling reactions in combination of various nucleophiles as
the third components. In 2018, Tan, Xu, and co-workers
systematically investigated the reactivity of saturated sulfur
heterocycles 8-118 in the MCRs with arynes and different
nucleophiles, which led to the preparation of products 8-119
(Scheme 143a).608,609 They found that four- to six-membered
cyclic thioethers could all participate in ring-opening reactions
upon activation with arynes, and the nucleophilic components
could be C-, O-, S-, and N-based nucleophiles.608 Moreover,
they disclosed that this protocol could be applied in a ring-
opening fluorination reaction by using KF as the fluorine
source, affording products 8-120 in modest to high yields
(Scheme 143b).609 In this transformation, 2,3-dimethylindole
was found to serve as a non-nucleophilic proton mediator that
Chem. Rev. 2021, 121, 3892−4044
strated that different kinds of acyclic and cyclic activated iodine ate complex 8-131, which then converts to the ortho-
carbonyl compounds 8-123 could participate in the same kind iodinated aryl fluoride 8-132 upon proton abstraction. This
of transformation through a formal [3 + 2] cycloaddition work not only provides a facile aryne fluorination maneuver
fashion, leading to the formation of substituted (spiro)- but also represents an unprecedented example in catalytic
benzoxaphosphole derivatives 8-124 in moderate to high yields aryne transformations under transition metal-free condi-
(Scheme 144b).612 Recently, the groups of Biju613 and Cai/ tions.517
He614 independently employed CO2 as the third component In addition, inorganic salts were developed to serve as active
and prepared zwitterionic phosphonium benzoates 8-125 nucleophiles to attack arynes. In 2019, Jiang and co-workers
(Scheme 144c). No annulated benzooxaphosphol-3(1H)- reported a three-phase, four-component coupling reaction of
ones were formed in this reaction system. In 2018, Biju et al. arynes, KCl, CO2, and chloroalkanes 8-133 (Scheme 147a).616
discovered that a combination of phosphines and base, such as
Cs2CO3, could convert arynes into aryl anion equivalents Scheme 147. Inorganic Salts-Triggered Aryne MCRs
(Scheme 145).615 Both aldehydes and isatins were used to
Scheme 145. Formation of Benzyl Alcohols via Phosphine-

Triggered Aryne MCR
capture the aryl anions and afforded the corresponding benzyl

alcohols 8-126. They proposed that after the nucleophilic In this study, KCl was utilized as a chloride source to attack
addition of phosphine to aryne and protonation, the generated arynes in the presence of 18-c-6, resulting in 2-chloroaryl anion
tetraaryl phosphonium salt 8-127 could be attacked by a base, species 8-134 that was trapped by CO2. The generated 2-
either Cs2CO3 or CsOH, to produce a pentavalent phosphorus chlorobenzoate 8-135 could then react with chloroalkanes to
intermediate 8-128. Consequently, aryl anion would be afford 2-chlorobenzoates 8-136. Recently, Biju et al. revealed
released from 8-128, which then attacks either aldehyde or that KI could serve as an efficient nucleophile in aryne MCR
isatin to afford 8-126. with aldehydes (Scheme 147b).617 2-Iodobenzyl alcohols 8-
Along with their study on fluorination/trifluoroalkylation of 137 were facilely obtained with good functional group
arynes, Hu and co-workers achieved a distinct diphenyliodo- tolerance. In this study, they also disclosed that both KBr
nium-catalyzed vicinal fluorination-iodination of arynes by and KCl could be employed and the electrophiles were
using CsF as the fluorine source and C4F9I (RfI) as the replaceable by N-methylisatin and CO2.
electrophile (Scheme 146).433 Based on their experimental Moreover, Jiang and co-workers discovered an aryne MCR
studies, they proposed the formation of an adduct 8-129 from with allyl bromides 8-138 and CO2 and obtained ortho-
Ph2I+OTf− and fluoride ion, which possesses higher reactivity brominated aryl esters 8-139 in moderate to high yields
toward arynes than the classical fluoride ion. The generated o- (Scheme 148).618 Depending on the electronic nature of the
fluoroaryl anion 8-130 could be captured by RfI to generate an
Scheme 148. Aryne MCRs with Allyl Bromides and CO2
Scheme 146. Diphenyliodonium-Catalyzed Fluorination-
Iodination of Arynes
Chem. Rev. 2021, 121, 3892−4044
allyl bromides, they proposed two possible mechanisms. For Scheme 150. Aryne MCRs with DMF
those substrates containing electron-rich or electron-neutral
groups (path a), an allylic cation 8-140 and bromide anion
might be generated, the latter of which undergoes a sequential
nucleophilic addition to aryne and then to CO2 by the
generated aryl anion. The resulting 2-bromobenzoate inter-
mediate 8-141 could then combine with allylic cation 8-140 to
yield product 8-139. For those electron-deficient substrates
(path b), allyl bromide could serve as a nucleophile to generate
a 1,3-zwitterion 8-142, which was followed by the formation of
1,5-zwitterion 8-143 by capturing CO2 and a subsequent
intramolecular allyl group shift to furnish allyl 2-bromoben-
zoates 8-139.
8.4. DMF-Involved MCRs
Those aforementioned MCRs are normally triggered by certain
nucleophiles to generate zwitterionic intermediates or aryl
anions, which could in turn react with various electrophilic
components. Beside these typical approaches, MCRs involving
an aryne insertion into the CO bond represent a unique
tactic. Although aryne insertion into the CO bond of
aldehydes was first discovered by Yoshida, Kunai, and co-
workers in 2004,619 DMF was then found to be a more
amenable and versatile reagent. As shown in Scheme 149, a
Scheme 149. General Scheme for Aryne Insertion into the

CO Bond of DMF
high yields by trapping o-quinone methide 8-145 with zinc

enolates of α-chlorinated methines 8-150 (Scheme 151).626,627
formal [2 + 2] cycloaddition of aryne with the CO bond of
DMF could produce a benzoxetene intermediate 8-144, the Scheme 151. Trapping o-Quinone Methide with Zinc
ring strain of which would then allow a selective ring-opening Enolates of α-Chlorinated Methines
to afford an ortho-quinone methide intermediate 8-145.
Subsequent Michael addition on 8-145 with a nucleophilic
substrate as the third component occurs to regenerate the
benzene ring.
In 2010, Miyabe and co-workers first discovered that o-
quinone methide 8-145 could be trapped by organozinc
reagents (Scheme 150a).620,621 Subsequently, the same group
developed an unprecedented MCR of arynes, DMF, and active
methylenes from 1,3-diketones or β-keto esters (Scheme
150b).622 This transformation involves the generation of o-
quinone methide 8-145 and a subsequent annulation with
active methylene species to form cyclic products 2H-
chromenes 8-146 from 1,3-diketones and coumarins 8-147
from β-keto esters. In marked contrast, direct aryne insertion
into the C−C σ-bond of those active methylenes as a plausible
competing reaction was prohibited. Meanwhile, Yoshida et al.
reported a similar MCR of arynes, DMF, and active methylene
compounds, i.e., arylacetic acids or arylacetonitriles, furnishing
coumarin scaffolds in moderate to excellent yields.623 By
employing N,S-keteneacetals as the third component, 2-
aryliminochromene derivatives were also achieved in good
yields.624 Furthermore, Miyabe et al. developed a one-pot,
four-component coupling reaction by trapping the coupling
product 8-149 with thiols through an SN2′ pathway, producing Mechanistically, Michael addition on 8-145 with zinc enolate
xanthene derivatives 8-148 in moderate to high yields (Scheme 8-153 would generate intermediate 8-154, which could cyclize
150c).625 to produce dihydrobenzofurans 8-151. Additional diethyl zinc
In 2013, Miyabe and co-workers demonstrated that (Et2Zn) was found to promote the decarboxylation of 8-151
dihydrobenzofurans 8-151 could be obtained in modest to and resulted in the formation of benzofurans 8-152.627
Chem. Rev. 2021, 121, 3892−4044
In 2018, Chandrasekhar and co-workers reported an efficient reaction. In addition, Jiang et al. noticed that diaryliodonium
synthesis of 2-aroyl benzofurans 8-155 from 8-145 and salts 8-163 could serve as electrophiles to react with o-quinone
sulfonium ylides 8-156 through a [4 + 1] annulation pathway methide 8-145, furnishing ortho-formyl diaryl ethers 8-164 in
(Scheme 152a).628 The sulfonium ylide 8-156 served as both a good to excellent yields (Scheme 153b).631 Similar to this
work, Gogoi and Sharma revealed that aryl sulfonyl chlorides
Scheme 152. Trapping o-Quinone Methide with Sulfonium 8-165 were able to capture the oxygen on 8-145 and produced
Ylides and Diesters of Acetylenedicarboxylic Acid 2-formylarylsulfonates 8-166 in high efficiency with high
functional group tolerance (Scheme 153c).632
Moreover, Gogoi and co-workers developed two protocols
using either 2-bromoacetophenones633 or activated alkenes634
as the electrophilic components in the reactions with o-
quinone methide. When 2-bromoacetophenones 8-167 were
employed, 2-aroyl benzofurans 8-155 were achieved in good to
high yields via an O-alkylation on 8-145 to form 8-168/
annulation/aromatization process (Scheme 154a).633 This
Scheme 154. Trapping o-Quinone Methide with Alkyl/Allyl

Bromides and Allenes
nucleophile and an electrophile in the annulation step via

intermediate 8-157. In 2014, Miyabe and co-workers revealed
that o-quinone methide 8-145 could be efficiently trapped by
diesters of acetylenedicarboxylic acid 8-158, producing the [4
+ 2] cycloadducts 8-159 (Scheme 152b).629
In addition, the nucleophilic feature of o-quinone methide 8-
145 was disclosed by several groups. In 2014, Lu, Wang, and
co-workers realized a preparation of α-amino-α-aryl carbon-
itriles 8-161 via the MCR of arynes, DMF, and aroyl cyanides
8-160 (Scheme 153a).630 In this study, they employed aroyl
cyanides 8-160 as nontoxic cyanide sources, which could
slowly release cyanide anion from intermediate 8-162 in the
Scheme 153. Nucleophilic Feature of o-Quinone Methide
transformation is mechanistically different from those

previously reported benzofuran formation strategies.626−628
Subsequently, they also demonstrated that allyl bromides were
able to capture o-quinone methide 8-145 and produced 2-
formyl substituted allyl aryl ethers 8-169; whereas 2-methyl-3-
(arylsulfonyl)-2H-chromen-2-ol scaffolds 8-171 were obtained
from 2-bromoallylsulfones 8-170. The mechanistic pathway for
the formation of 8-171 was proposed to proceed through the
addition of 8-145 to the in situ generated sulfonyl allene 8-172
and a subsequent annulation on intermediate 8-173 (Scheme
154b).634
In a rare case, Zhang et al. discovered a MCR of arynes,
carbodiimides 8-174, and terminal alkynes or haloalkynes,
furnishing 2-aminoaryl alkynyl imines 8-175 in good to
excellent yields (Scheme 155).635 Mechanistically, carbodii-
mides participates in an aryne [2 + 2] cycloaddition reaction to
Chem. Rev. 2021, 121, 3892−4044
Scheme 155. Carbodiimide-Involved Aryne MCRs tion, which in turn participates in aryne [3 + 2] cycloaddition
reactions. In 2013, Shi and co-workers disclosed an in situ
production of nitrones 8-181 from hydroxylamines and
acetylenedicarboxylates, which could then undergo aryne [3
+ 2] cycloaddition reaction to afford functionalized dihy-
drobenzisoxazoles 8-182 (Scheme 156b).638 This three-
component reaction took advantage of the in situ generation
of nitrones with pot efficiency.
In 2014, Wu et al. demonstrated a silver triflate (AgOTf)-
catalyzed MCR of arynes, tosylhydrazine, and 2-alkynylben-
zaldehyde 8-183 for the efficient production of H-pyrazolo-
[5,1-a]isoquinolines 8-184 (Scheme 157a).639 As proposed,
Scheme 157. Other MCRs via Aryne [3 + 2] Cycloaddition

Reaction
produce an azetine species 8-176, the high ring strain of which

then leads to a selective ring-opening to generate intermediate
8-177. At this stage, a terminal alkyne or a haloalkyne then
adds to 8-177 through a six-membered ring transition state to
assemble 8-178. After N-arylation or C−Z bond insertion with
the second aryne species, products 8-175 could be obtained.
Particularly, this study revealed an unusual reconnection
pattern on one of the CN bonds of carbodiimides.
8.5. MCRs via Aryne [3 + 2] Cycloaddition Reaction
Several studies were reported involving the in situ assembly of
active 1,3-dipoles for aryne [3 + 2] cycloaddition reactions.
The groups of Zhang636 and Huang637 independently reported
a MCR of arynes, pyridines, and 2-bromoacetophenones,
furnishing pyrido[2,1-a]isoindoles 8-179 (Scheme 156a).
Mechanistically, 1,3-dipolar species 8-180 can be generated
through a sequential N-alkylation of pyridine and deprotona-
Scheme 156. MCRs via Aryne [3 + 2] Cycloaddition

Reaction
this transformation involves a facile formation of isoquinoli-

nium-2-yl amide 8-185 via a AgOTf-catalyzed 6-endo
cyclization of N′-(2-alkynylbenzylidene)hydrazide intermedi-
ate, which was generated from 8-183 and tosylhydrazine. The
following aryne [3 + 2] cycloaddition reaction could yield H-
pyrazolo[5,1-a]isoquinolines 8-184 in a one-pot fashion.
Chem. Rev. 2021, 121, 3892−4044
Recently, Chandaluri, Kumar, Singh, Sawant, and co-workers Scheme 158. Aryne [4 + 2] Cycloaddition-Initiated Cascade
revealed that azomethine imines 8-186 could be generated via Reactions
a Pd-catalyzed MCR with azidobenzaldehyde, isocyanide, and
4-chlorophenylsulfonyl hydrazide, which were then captured in
situ by arynes to afford fluorescent indazolo[2,3-c]quinazolines
8-187 in good to high yields (Scheme 157b).640 In a study
carried out by Ramana et al. on the chemical behavior of the
Ohira−Bestmann reagent (dimethyl diazo-2-oxopropylphosph-
onate, OBR) (8-188), they discovered a fluoride-mediated
dephosphonylation of OBR to furnish α-diazocarbonyl
intermediate 8-189. Consequently, 8-189 could participate in
a sequential aryne [3 + 2] cycloaddition reaction and Michael
addition with either acrylate or acrylonitrile, giving rise to
products 8-190 (Scheme 157c).641
9. CASCADE OR TANDEM REACTIONS

Beyond those aforementioned typical aryne reaction modes,
aryne-involved cascade/tandem reactions have also shown
significant potential along with the advances of Kobayashi’s
method. On one hand, reactive intermediates could be
generated in an aryne-involved reaction step, such as through
a pericyclic reaction or by activating an inert functional group,
to ensure the following cascade steps. On the other hand,
tandem processes could also be achieved by properly
incorporating different types of aryne transformations in
consecutive manners. These cascade processes not only
possess the atom- and step-economy advantages but also
could rapidly build-up complexity for the construction of
challenging structural motifs.
9.1. Cycloaddition Reaction-Initiated Cascade Reactions
9.1.1. Initiated by Diels−Alder Reaction. In 2007,
Zhang and Xie disclosed that N-substituted imidazoles 9-1 Scheme 159. Cascade Furan Cycloaddition Reactions
could undergo tandem reaction with benzyne to afford aryl
amines 9-2 containing the anthracene scaffold (Scheme
158a).642 Although Yoshida and Kunai previously demon-
strated that N-arylation occurred preferentially in the presence
of excess amount of N-substituted imidazoles,358 this study
revealed that by increasing the stoichiometry of the Kobayashi
benzyne precursor, the anthracene framework could be
obtained. Mechanistically, this tandem transformation pro-
ceeds through a benzyne Diels−Alder reaction with substituted
imidazole, followed by the extrusion of nitrile on intermediate
9-3 via a retro Diels−Alder reaction, to afford intermediate 9-
4. After a sequential Diels−Alder reaction with the second
benzyne to produce 9-5/N-arylation with the third benzyne/
rearrangement, aryl amines 9-2 could be realized. In 2015,
Chenoweth and co-workers reported a tandem triple aryne-
tetrazine reaction, giving rise to a class of dibenzo[de,g]-
cinnolines 9-7 (Scheme 158b).643,644 The overall process
includes (1) [4 + 2] cycloaddition reaction of aryne with
tetrazine 9-6 and subsequent extrusion of nitrogen gas to
afford phthalazine heterocycle 9-8; (2) N-arylation-proton
transfer to generate s-cis diene intermediate 9-9; (3) formation formation of six adjacent stereocenters.645,646 Extended
of 9-10 via either Diels−Alder reaction with the second PAHs could then be obtained by treating 9-12 with HCl in
molecule of aryne or through a nonconcerted pathway; and (4) EtOH. Moreover, trisfuran 9-13 was found to participate in a
dehydrogenative aromatization to yield 9-7. cascade [4 + 2]/[4 + 2]/[4 + 2] cycloaddition process with
Accompanied with the research on the preparation of benzyne to construct exo,exo,exo,exo-9-14 with a concomitant
polycyclic aromatic hydrocarbons (PAHs), Peña, Guitián, and formation of 10 adjacent stereocenters.646
co-workers demonstrated a cascade furan cycloaddition In 1997, Guitián and co-workers examined the reaction
transformation. As shown in Scheme 159, a tandem [4 + 2]/ between 1,8-diethynylnaphthalene (9-15) and benzyne
[4 + 2] cycloaddition process occurred between bisfurans 9-11 (Scheme 160).647 Unexpectedly, they observed the formation
and arynes, affording exo,exo-9-12 with a stereoselective of benzo[a]pyrene (9-16) among other possibilities. Based on
Chem. Rev. 2021, 121, 3892−4044
Scheme 160. Cascade Diels−Alder Reaction with 1,8- More Diels−Alder reaction-triggered cascade processes were
Diethynylnaphthalene reported as well. In 2014, Biju and co-workers demonstrated a
cascade [4 + 2] cycloaddition/ene reaction process between
styrenes and arynes (Scheme 162a).241 9-Aryl-9,10-dihydro-
Scheme 162. Aryne [4 + 2] Cycloaddition/C-Arylation

Cascades
their experimental result, they proposed that this trans-

formation proceeds through a benzyne Diels−Alder reaction
with arylacetylene to afford a cyclic allene species 9-17, a
further cyclization with the other alkyne group to generate a
σ,π-diradical intermediate 9-18, and the formation of benzo-
[a]pyrene (9-16) after hydrogen migration.
In a study carried out by Biju et al. on the reaction between
indene/benzofuran 9-19 and arynes, a tandem [4 + 2]/[2 + 2]
cycloaddition process was discovered, which led to the
formation of dihydrobenzocyclobutaphenanthrene derivatives
9-20 in excellent diastereoselectivity (Scheme 161a).337 In
Scheme 161. Aryne [4 + 2]/[2 + 2] Cycloaddition Cascade

Reactions
phenanthrene derivatives 9-24 were readily achievable. In the

same year, Liu et al. employed functionalized benzylideneph-
thalans 9-25 as the substrates to react with arynes and obtained
phenanthro[10,1-bc]furans 9-26 in moderate to high yields
(Scheme 162b).648 They proposed that after aryne Diels−
Alder reaction with 9-25, a fluoride-induced deprotonation on
the cycloadduct occurs to generate anion 9-27, which then
undergoes a C-arylation reaction with another molecule of
aryne. Based on Biju’s study in Scheme 162a, a concerted ene
reaction pathway might also account for the formation of the
above products. Meanwhile, Jia, Li, and co-workers reported
2017, Wang, He, and co-workers disclosed a new [4 + 2]/[2 + the synthesis of compounds 9-29 from arylidenoxindoles 9-28,
2] cycloaddition process between N-sulfonyl ketimines 9-21 in which a tandem [4 + 2] cycloaddition/C-arylation reaction
and arynes, furnishing dihydrocyclobutaquinoline derivatives took place (Scheme 162c).649
9-23 in moderate to high yields with high functional group Recently, Yennam and co-workers reported an unusual
tolerance (Scheme 161b).233 The overall transformation cascade process by treating 2-arylidene-1,3-indandiones 9-30
proceeds through an inverse electron-demand aza Diels− bearing electron-rich functional groups with arynes, affording
Alder reaction and a [2 + 2] cycloaddition on intermediate 9- dibenz[a,c]anthracene-9,14-dione derivatives 9-31 through a
22. Diels−Alder reaction/ring expansion process (Scheme
Chem. Rev. 2021, 121, 3892−4044
Scheme 163. Cascade Reactions of Arynes with 2-Arylidene-1,3-indandiones
163).650 Mechanistically, after the Diels−Alder reaction to Scheme 164. Aryne Cascade Reactions with Pyridine N-
generate cycloadduct 9-32, alcohol intermediate 9-33 could be Oxides
formed via an intramolecular nucleophilic addition on 9-32,
which then experiences a retro-aldol reaction to furnish
product 9-31. Interestingly, when R1 is an electron-poor
substituent on 9-30, a C−C bond insertion/ring expansion
transformation occurred, affording dibenzo[a,d]-
cycloheptanoid analogues 9-34 in moderate to high yields.
The mechanism for this transformation involves (1) Michael
addition of fluoride ion to 9-30 to form intermediate 9-35, (2)
[2 + 2] cycloaddition reaction of 9-35 with aryne to generate
intermediate 9-36, and (3) ring expansion to produce 9-34
(Scheme 163).
9.1.2. Initiated by [3 + 2] Cycloaddition Reaction. In
1974, Abramovitch et al. first explored the reactions of pyridine
N-oxides 9-37 with benzyne, generated via various methods
other than Kobayashi’s, which led to the formation of a
mixture of 3- and 2-(2-hydroxyphenyl)pyridines in low
yields.651 In 2006, Larock and co-workers revisited this
reaction by using o-silylaryl triflates and discovered a
regioselective coupling reaction, furnishing substituted 3-(2-
hydroxyphenyl)pyridines 9-38 (Scheme 164a).139 Mechanisti-
cally, after aryne [3 + 2] cycloaddition reaction with pyridine
N-oxide 9-37 to generate cycloadduct 9-39, intermediate 9-40
could be formed via a further rearrangement. It was
rationalized that hydrogen Ha on intermediate 9-40 is more
acidic than Hb. Hence, 3-(2-hydroxyphenyl)pyridines 9-38
could be obtained upon preferential deprotonation of hydro-
gen Ha. This transformation was also employed on 3-
siylbenzynes with a detailed mechanistic study.130,652 In
2012, Liu et al. disclosed a different regioselective outcome
from Larock’s system by simply modifying the reaction
conditions. 6 5 3 As shown in Scheme 164b, 2-(2-
hydroxyphenyl)pyridines 9-41 were obtained from pyridine
N-oxides and arynes in a highly regioselective manner. They In 2011, Wu and co-workers reported an unprecedented
reasoned that an excess amount of N-oxides and fluoride could cascade process by using 2-alkynylbenzaldoximes 9-44, arynes,
promote a deprotonation on intermediate 9-39, giving rise to and a catalytic amount of silver triflate, giving rise to 2-oxa-6-
2-substituted pyridines 9-41 exclusively. In addition, they azabicyclo[3.2.2]nona-6,8-diene derivatives 9-45 in modest to
noticed that the presence of propiolates switches the high yields (Scheme 165).656 Based on their mechanistic study,
regioselectivity to deliver 3-substituted pyridines 9-43 via the they proposed that silver triflate catalyzes the formation of
interception of cyclopropyl ketone intermediate 9-42. Sub- isoquinoline-N-oxides 9-46 from 2-alkynylbenzaldoximes 9-44,
sequently, this transformation was extended to quinoline N- which then undergoes a [3 + 2] cycloaddition reaction with
oxides654,655 and acridine N-oxides.655 aryne to afford fused 1,2-dihydroisoquinolines 9-47. A
Chem. Rev. 2021, 121, 3892−4044
Scheme 165. Silver-Catalyzed, Aryne [3 + 2] Cycloaddition- In 2016, Studer et al. investigated the reaction behavior of
Involved Cascade Reaction vinyl sulfides 9-56 with arynes and achieved highly substituted
alkenes 9-57 and 9-58 in high stereoselectivity.659 As shown in
Scheme 167a, benzannulated sulfonium ylides 9-59 could be
Scheme 167. Aryne Cascade Processes with Vinyl Sulfides
subsequent rearrangement involving a N−O bond cleavage on

9-47 and an intramolecular radical addition on 9-48 could
result in the formation of 9-45.
In the same year, Hwu et al. demonstrated a benzyne-
induced conversion of β-amino alcohols to olefins in a
stereospecific manner.657 As shown in Scheme 166a, 1,3-
Scheme 166. Other Aryne [3 + 2] Cycloaddition-Initiated

Cascade Reactions
generated after aryne [3 + 2] cycloaddition reaction with vinyl

sulfides. Consequently, a proton transfer with a following β-
elimination could furnish products 9-57; whereas, in the cases
of α-ester- and α-acyl-substituted vinyl sulfides (R1 = COR′)
9-56, a successive C-arylation/1,4-proton transfer/β-elimina-
tion process occurred to yield products 9-58. A similar
transformation was then independently reported by the groups
of Yu/Zhang/Meng660 and Li/Chen,661 in which 2-methyl-
enebenzothiophene-3-ones 9-60 reacted with arynes to furnish
eight-membered cyclic sulfides 9-61 (Scheme 167b). The
mechanism for this transformation involves a tandem [3 + 2]
cycloaddition reaction/1,2-proton transfer/C−S bond cleavage
process.
In 2018, Mo et al. reported a formal [7 + 2] cycloaddition
reaction between N-vinyl-α,β-unsaturated nitrones 9-62 and
arynes, giving rise to 9-membered benzoxazonines 9-64
(Scheme 168a).662 A cascade [3 + 2] cycloaddition reaction/
[3,3] sigmatropic rearrangement via intermediate 9-63
accounted for the formation of 9-64. Recently, Anderson and
co-workers demonstrated a distinct cascade process between
N-alkenylnitrones 9-65 and o-silylaryl triflates, furnishing
spirocyclic pyrroline cyclohexadienones 9-67 in moderate to
thiazolidine-2-thiones 9-50, readily prepared from β-amino excellent yields (Scheme 168b).663 Mechanistically, this
alcohols 9-49 with DBU and carbon disulfide, underwent a [3 transformation commences with a 1,3-dipolar cycloaddition
+ 2] cycloaddition reaction with benzyne to give intermediate reaction to produce cycloadduct 9-66, which then undergoes a
9-51, which then released olefin 9-52 and byproduct 9-53 via a dearomative [3,3]-sigmatropic rearrangement to afford spi-
retro [3 + 2] cycloaddition reaction. This protocol also led to rocyclic pyrrolines 9-67.
the syntheses of (−)-1-deoxy-D-fructose,657 and iminosu- 9.1.3. Initiated by [2 + 2] Cycloaddition Reaction. In
gars.658 In 2014, Larock, Shi, and co-worker reported a 2004, Yoshida, Kunai, and co-workers revealed a unique
tandem [3 + 2]/retro [4 + 2]/[4 + 2] cycloaddition process tandem process between aldehydes and arynes. Diverse 9-
between stable münchnones 9-54 and arynes, affording 9,10- arylxanthene derivatives 9-69 were synthesized through a
dihydro-9,10-epiminoanthracenes 9-55 in good to excellent sequential formal [2 + 2] cycloaddition reaction/isomerization
yields (Scheme 166b).317 to o-quinone methide 9-68/Diels−Alder reaction with another
Chem. Rev. 2021, 121, 3892−4044
Scheme 168. Aryne [3 + 2] Cycloaddition-Initiated further developed a tandem [2 + 2] cycloaddition reaction/

Rearrangement Reactions pericyclic ring-opening/intramolecular [4 + 2] cycloaddition
process to produce nitrogen heterocycles 9-75 in a highly
stereoselective manner (Scheme 170).329 This work also led to
the total syntheses of chelidonine and norchelidonine, which
will be elaborated on in section 15.665
Scheme 170. Cascade Reactions Triggered by Aryne [2 + 2]

Cycloaddition with Enamides
In 2013, Studer and co-workers demonstrated a facile

preparation of carbazole scaffolds 9-77 in the reaction between
nitrosoarenes 9-76 and arynes.666 As depicted in Scheme 171a,
Scheme 171. Other [2 + 2] Cycloaddition-Initiated Cascade

molecule of aryne (Scheme 169a).619 This protocol was also Reactions
employed by Werz et al. on cyclopropenones, furnishing
Scheme 169. Cascade Reaction-Triggered by Aryne [2 + 2]

Cycloaddition with Aldehydes
either NH-carbazoles or N-arylated carbazoles 9-77 were

spirocyclic xanthene-cyclopropenes.664 In 2012, Wu and co- achievable by varying the fluoride source and the solvent.
workers disclosed a tandem reaction between enals 9-70 and Mechanistically, after the aryne [2 + 2] cycloaddition reaction
arynes, in which 2H-chromenes 9-73 were readily achieved with nitrosoarenes 9-76 and a cycloreversion, o-quinone
through a successive [2 + 2] cycloaddition reaction/thermal derivative 9-78 was generated, which then undergoes an
electrocyclic ring-opening on cycloadduct 9-71/6e-electro- intramolecular electrophilic aromatic substitution and a C−
cyclization of 9-72 process (Scheme 169b).240 OH bond cleavage by a nucleophile or other pathway on the
In a study carried out by Hsung and co-workers on the aryne resulting intermediate 9-79 to afford 9-80. Either protonation
[2 + 2] cycloaddition reaction with enamides 9-74, they or N-arylation on 9-80 could yield the corresponding products
Chem. Rev. 2021, 121, 3892−4044
9-77. Recently, He et al. reported that the reaction between Scheme 173. Aryne [8 + 2] Cycloaddition-Initiated Cascade
fluorene-derived N-arylimines 9-81 and arynes could construct Reactions
spiroacridines 9-82 in modest to good yields, the mechanistic
pathway of which includes a successive [2 + 2] cycloaddition
reaction/ring-opening/electrocyclization reaction sequence
(Scheme 171b).246
9.1.4. Initiated by Other Cycloaddition Reaction. In
2017, Yoo and co-workers disclosed that pyridinium
zwitterions 9-83 could serve as unprecedented 1,5-dipoles,
which reacted with arynes to yield polycyclic 1,4-benzodiaze-
pines 9-85 (Scheme 172).667 This transformation proceeds
Scheme 172. Aryne [5 + 2] Cycloaddition-Initiated Cascade

Reactions
through a cascade [5 + 2]/[2 + 2] cycloaddition process Scheme 174. Aryne-Induced Claisen Rearrangements
involving two molecules of arynes. Their mechanistic studies
revealed that the [5 + 2] cycloadduct 9-84 would undergo an
immediate [2 + 2] cycloaddition reaction with another
molecule of aryne.
In 2018, Wang, He, and co-worker undertook a systematic
study on the reaction between azaheptafulvenes 9-86 and o-
silylaryl triflates (Scheme 173a).355 Both cyclohepta[b]indoles
9-87 and polycyclic oxacyclohepta[b]indoles 9-88 were
obtained, depending on the stoichiometry of arynes.
Mechanistically, cyclohepta[b]indoles 9-87 could be produced
through a tandem [8 + 2] cycloaddition/ene reaction
sequence; whereas oxacyclohepta[b]indoles 9-88 are as-
sembled via a further [6 + 2] cycloaddition reaction with a
third molecule of aryne. Meanwhile, they found that when
heteroazulenes 9-89 were employed, a mixture of 9-90a and 9-
90b were obtained, the formation of which followed a similar
pathway to that of 9-87 (Scheme 173b).355
9.2. Nucleophilic Addition-Initiated Rearrangements
9.2.1. Claisen Rearrangements. Another cascade/
tandem reaction mode is aryne-induced rearrangement trans-
formations.93 In 2009, Greaney and co-workers discovered an
aryne aza-Claisen rearrangement of tertiary allylamines 9-91 to
yield products 9-92, the mechanistic pathway of which involves
a tandem N-arylation of allylamines 9-91/protonation of
zwitterion intermediate 9-93 with solvent/aza-Claisen rear-
rangement on 9-94 (Scheme 174a).668 An alternative pathway
including the 6-endo SN2′ reaction of zwitterion intermediate
9-93 was ruled out by using unsymmetrically substituted aryne
precursors. This protocol was also applied to cyclic tertiary
allylamines, affording benzannulated medium-ring amines co-workers applied this ring-expansion protocol on 2-vinyl-
through a ring-expansion operation. Subsequently, Saito and azetidines 9-95 and furnished benzazocine derivatives 9-96 in
Chem. Rev. 2021, 121, 3892−4044
modest to high yields (Scheme 174b).669 In 2018, Karunakar Scheme 176. Other Aryne Reaction-Induced [2,3] Stevens
et al. reported that secondary allylamines 9-97 could react with Rearrangements
arynes to afford ortho-allyl-substituted N-arylanilines 9-98,
those of which were further converted to aryl-fused medium-
sized heterocyclic molecules via a ring-closing metathesis
operation (Scheme 174c).670
9.2.2. [2,3]/[1,2] Sigmatropic Rearrangements. Recent
studies revealed that arynes can promote the formation of both
quaternary ammonium and sulfonium ylides from tertiary
amines and thioethers, respectively, which could in turn induce
the following sigmatropic rearrangements. One of the
advantages for this strategy on aryne-promoted formation of
onium ylides over traditional approaches is its strong-base-free
conditions.
In 2016, the groups of Gu/Tian671 and Biju672 independ-
ently demonstrated an aryne-induced [2,3] Stevens rearrange-
ment transformation on tertiary allylamines 9-99 bearing
electron-withdrawing groups, which led to the formation of
homoallylic amines 9-100 and 9-101 in modest to high yields
with high functional group tolerance (Scheme 175). No aza-
Scheme 175. Aryne Reaction-Induced [2,3] Stevens

Rearrangement
terminal or internal ones, the corresponding conjugated dienes

9-109 or amino-substituted allenes 9-110 were obtained,
respectively.
Recently, Biju and co-workers demonstrated an aryne-
induced Sommelet−Hauser rearrangement of tertiary benzyl-
amines 9-111, producing α-aryl amino acid derivatives 9-112
(Scheme 177).676 After the formation of ammonium ylide 9-
Scheme 177. Aryne Reaction-Induced Sommelet−Hauser

Rearrangement
Claisen rearrangement was observed in both studies. This

transformation follows a sequential nucleophilic addition of
tertiary amine to aryne, a proton transfer on intermediate 9-
102 to furnish a quaternary ammonium ylide 9-103, and a
[2,3] Stevens rearrangement. Moreover, both groups examined
this protocol on optically active tertiary allylamines and
obtained quaternary stereocenters with a retention of
enantiopurity and an inversion of configuration.
In 2017, Sweeney and co-workers applied this aryne-induced
[2,3] Stevens rearrangement protocol on N-(2-malonyl) 113, a [2,3] sigmatropic rearrangement occurred to furnish a
tetrahydropyridines 9-104 and furnished 3-substituted N- dearomatized intermediate 9-114. Upon a 1,3-protron shift, α-
aryl-2-acylpyrrolidines 9-105 in modest to excellent yields aryl amino acid 9-112 was generated. This transformation was
(Scheme 176a).673 Moreover, Liu et al. employed 1,2,3,4- found to be temperature dependent, preferring the Sommelet−
tetrahydroisoquinolines 9-106 as the substrates to readily Hauser rearrangement at low temperature, whereas a [1,2]
prepare (E)-3-aryl-2,3,4,5-tetrahydro-1H-3-benzazonines 9- Stevens rearrangement took place at 70 °C.
107 in highly stereospecific manner (Scheme 176b).674 In Beside ammonium ylides, sulfonium ylides could also be
2018, Tian and co-workers reported an aryne-induced [2,3] facilely generated from arynes and thioethers upon S-arylation
Stevens rearrangement with tertiary propargylic amines 9-108 and deprotonation. In 2017, the groups of Biju677 and Tan/
bearing electron-withdrawing groups (Scheme 176c).675 Xu678 independently reported an aryne-induced [2,3] Stevens
Depending on the structure of the propargyl groups, either rearrangement with allylthioethers 9-115, affording function-
Chem. Rev. 2021, 121, 3892−4044
alized β-keto arylthioethers 9-116 and 9-117 in modest to high obtained, albeit in low yields. Notably, their mechanistic
yields with high functional group tolerance (Scheme 178). In studies revealed that both 3-aryl-3-benzazepine 9-122 and the
the study carried out by Tan, Xu, and co-workers, propargyl C-arylated product could be formed from a common
thioethers were also examined.678 ammonium ylide intermediate 9-123. Similar transformations
were also reported by Voskressensky686 and Guranova.687
Scheme 178. Aryne Reaction-Induced [2,3] Stevens 9.2.3. Other Rearrangements. In 2011, Greaney et al.
Rearrangement with Allylthioethers realized an aryne Fischer-indole synthesis by using N-tosyl
hydrazones 9-124 and o-silylaryl triflates, furnishing N-
tosylindoles 9-125 in moderate to high yields (Scheme
180a).688 After N-arylation on 9-124, a one-pot addition of
Scheme 180. Other Aryne Reaction-Induced Rearrangement

Reactions
Aryne-induced [1,2] Stevens rearrangement was reported by

Boekelheide and Otsubo in 1975 using anthranilic acid as a
benzyne precursor.679 In 2017, Guo, He, and co-workers
disclosed a convenient preparation of multisubstituted β-keto
thioethers 9-119 from arynes and benzyl thioethers 9-118
bearing β-keto groups (Scheme 179a).680 Upon generation of
Scheme 179. Aryne Reaction-Induced [1,2] Sigmatropic

Rearrangements
BF3·OEt2 promoted the Fischer cyclization reaction. In 2016,

the same group demonstrated a unique aryne Truce−Smiles
rearrangement, which was triggered by the nucleophilic
addition of aryl sulfonamides 9-126 to arynes and afforded
biaryls 9-127 under transition-metal-free conditions (Scheme
180b).689 Sterically hindered tri- and tetra-ortho-substituted
biaryls could be achieved. Mechanistically, a Smiles-type ipso
substitution on intermediate 9-128 occurs to produce
Meisenheimer complex 9-129, which in turn undergoes an
extrusion of SO2 to produce biaryls 9-127. In 2017, a
nucleophilic addition-triggered Fries rearrangement on o-
silylaryl triflates 9-130 was revealed by Bronner et al., giving
sulfonium ylide 9-120, a [1,2] sigmatropic rearrangement rise to 2,3-disubstituted phenols 9-131 in moderate to high
occurred to produce the product 9-119. Inspired by yields (Scheme 180c).690
Boekelheide’s early study,679 o-silylaryl triflates were recently In 2018, Palakodety and co-workers demonstrated a base-
utilized in ring-contraction transformations with thioethers via mediated cyclization of propargylic alcohols 9-132 with arynes,
the [1,2] Stevens rearrangement pathway.681−684 In 2018, Liu affording 3-benzofuranyl-2-oxindoles 9-133 along with the
and Pan reported that substituted 1,2,3,4-tetrahydroisoquino- formation of 3-spirooxindole benzofurans 9-134 as minor
lines 9-121 could participate in the aryne-induced [1,2] products (Scheme 181).691 It was found that the nature of the
Stevens rearrangement, affording 3-aryl-3-benzazepines 9-122 R2 group on 9-132 could influence the reaction outcome.
in moderate to high yields (Scheme 179b).685 In addition, Mechanistically, O-arylated intermediate 9-135 undergoes a
under reduced temperature, α-arylated products were propargyl Claisen rearrangement to generate an allene species
Chem. Rev. 2021, 121, 3892−4044
Scheme 181. Aryne Cascade Reactions with Propargylic enantioenriched α-chiral alkanoyl hydrazides were used,
Alcohols complete retention of the configuration was observed. Besides,
water, amines, alkoxyamine, and thiophenol could all serve as
efficient nucleophiles in this transformation.
9.3. Nucleophilic Addition-Triggered Other Cascade
Reactions
Aryne arylation reaction could trigger subsequent cascade/
tandem reactions as well. In 2015, Hwu and co-workers
accomplished an unprecedented aryne-induced tandem N-
arylation/[3 + 2] cycloaddition process using 2 equiv of Schiff
bases 9-141, furnishing imidazolidines 9-142 in good to high
yields (Scheme 183).693 Mechanistically, after an aryne-
Scheme 183. Tandem N-Arylation/[3 + 2] Cycloaddition

Reaction
induced formation of ylide species 9-143 from the Schiff

base, a subsequent [3 + 2] cycloaddition reaction with another
molecule of the Schiff base takes place to construct 9-142 in
high diastereoselectivity. In addition, electron-deficient alkenes
were also utilized as the third component in this trans-
formation, giving rise to highly substituted pyrrolidines.
Meanwhile, Voskressensky et al. investigated aryne-induced
9-136, which is followed by a 5-exo-dig cyclization to give arylation−Hoffman cleavage processes.694,695 In 2014, they
intermediate 9-137. Upon protonation, product 9-133 could studied the reaction between arynes and 10-carbamoyl-
be obtained. Meanwhile, a small portion of intermediate 9-135 substituted benzo[b][1,6]naphthyridines 9-144 and obtained
participates in an intramolecular nucleophilic addition on 2-vinylquinolines 9-146, albeit in low to moderate yields
alkyne, producing 3-spirooxindole benzofurans 9-134 after (Scheme 184a).694 After nucleophilic addition to aryne, a
protonation. Hoffman-type fragmentation occurred on intermediate 9-145.
In 2018, Tian et al. accomplished a benzyne-induced In 2018, the same group realized a similar cascade process by
Curtius-type rearrangement with N′-methyl-N′-phenyl acyl using tetrahydropyrido[4,3-d]pyrimidin-4-ones 9-147 con-
hydrazides 9-138 in the presence of various nucleophiles densed with isoxazole, thiazole, thiadiazole, or triazole rings
(Scheme 182).692 An isocyanate intermediate 9-140 was as the substrates, furnishing 6-vinyl-substituted pyrimidones 9-
proposed from the reaction of benzyne and acyl hydrazide 9- 148 fused with the corresponding azole rings via a Hofmann
138, which could then react with alcohols to yield carbamates cleavage of the tetrahydropyridine moiety (Scheme 184b).695
9-139 (NuH = ROH) in modest to excellent yields. When In a study carried out by Hoye et al. on the reaction of
hexadehydro-Diels−Alder (HDDA) aryne with natural prod-
Scheme 182. Benzyne-Induced Curtius-Type ucts, they showed one example between tropinone (9-149)
Rearrangement and Kobayashi benzyne precursor, leading to the formation of
product 9-150 in 66% yield (Scheme 184c).167
In 2015, Voskressensky and co-workers studied the reaction
between 4-hydroxymethylisoindolines 9-151 and o-silylaryl
triflates and obtained 4-aminomethyl-substituted dihydroiso-
benzofuran derivatives 9-152 in good to high yields. This
transformation involves a nucleophilic addition to aryne by the
tertiary amine and a subsequent intramolecular recyclization
via intermediate 9-153 (Scheme 185a).696 In 2018, in a
derivatization study on the natural product lycorine,
Hergenrother et al. observed an unusual reaction behavior of
9-154 with benzyne, which involves a benzyne-induced N-
Chem. Rev. 2021, 121, 3892−4044
Scheme 184. N-Arylation−Hoffman Cleavage Cascades In 2018, Guranova and co-workers reported their study on
thieno[2,3-c]pyrrolines 9-156 bearing a branched substituent
on the nitrogen atom and discovered the formation of
thienylaziridines 9-157 (Scheme 186).687 Mechanistically, the
Scheme 186. Aryne Cascade Reaction with Thieno[2,3-

c]pyrrolines
generated ammonium ylide 9-158 participates in a 6π-

electrocyclic opening to give intermediate 9-159, which then
Scheme 185. N-Arylation-Triggered Cascade Reactions undergoes an intramolecular 1,6-hydrogen shift to produce the
resonance-stabilized azomethine ylide 9-160. A subsequent 4π-
electrocyclization would yield thienylaziridines 9-157.
Recently, Almqvist and co-workers reported an aryne-
induced cascade formation of 6-arylthio-substituted-N-alkenyl
2-pyridones 9-162 from bicyclic thiazolino-2-pyridones 9-161
(Scheme 187).698 Although the classical Kobayashi benzyne
Scheme 187. S-Arylation-Triggered Cascade Reactions
precursor only gave the corresponding products in low to

moderate yields, the employment of the 3-methoxybenzyne
precursor could significantly enhance the reaction efficiency
with distinct regioselective control. Notably, this process
preferred a thioether ring-opening pathway over a potentially
competing [4 + 2] cycloaddition reaction.
Tandem reactions involving C-arylation with arynes were
reported. In 2011, Peña, Guitián, and co-workers revealed a
formal aryne insertion into the C(sp)−O σ-bond of
ethoxyacetylene (9-163), giving rise to 2-ethoxyethynylaryl
derivatives 9-164 (Scheme 188).699 Both the experimental
observation with 3-methoxybenzyne and computational studies
suggested that, instead of a nucleophilic addition of the oxygen
atom to aryne, this transformation initiates with a nucleophilic
arylation of 9-154 and a ring rearrangement process to yield 9- addition by the triple bond carbon to generate zwitterionic
155 in 41% yield (Scheme 185b).697 structure 9-165, which could cyclize to produce intermediate
Chem. Rev. 2021, 121, 3892−4044
Scheme 188. Aryne Reaction with Ethoxyacetylene cleavage/cyclization process, although other mechanistic
pathways might not be excluded.
In 2017, Gogoi et al. accomplished an aryne-induced
isomerization from coumarin to isocoumarin (Scheme
190a).702 3-Substituted isocoumarins 9-177 were readily
Scheme 190. C-Nucleophile-Triggered Aryne Cascade

Reactions
9-166. Consequently, 9-166 would convert to products 9-164

via a concomitant 1,2-hydrogen migration and ring-opening.
Despite this proposed mechanistic pathway, there might be
other possibilities.
In 2016, Pirali and co-workers revealed that the reaction of
secondary α,α′-disubstituted α-isocyanoacetamides 9-167 with
arynes could afford 2-arylimidazolones 9-168, whereas those of
α-nonsubstituted and α-monosubstituted isocyanoacetamides
only yielded complex mixtures (Scheme 189a).700 Mechanis-
Scheme 189. Isocyano Group-Triggered Aryne Cascade

Reactions
prepared from 4-hydroxycoumarins 9-173 and o-silylaryl

triflates with high functional group tolerance. Mechanistically,
a four-membered ring intermediate 9-175 could be first
generated from anion 9-174, which then undergoes a ring-
opening to form ketene intermediate 9-176. Upon ring closure,
isocoumarin product 9-177 could be obtained. Recently, John,
Hopf, and co-workers reported another C-arylation/cyclization
process between 4-haloacetoacetates 9-178 and arynes,
affording 4-aryl-3-(2H)-furanones 9-179 in moderate to good
yields (Scheme 190b).703
9.4. Nucleophilic Annulation-Induced Cascade Reactions
Cascade processes involving nucleophilic annulation with o-
silylaryl triflates were reported. In 2008, Liang, Li, and co-
workers demonstrated a facile preparation of benzofurans 9-
181 from arynes and iodonium ylides 9-180 (Scheme
191a).704 They proposed that this cascade process occurs
through a nucleophilic addition of zwitterion intermediate 9-
182 to benzyne to generate intermediate 9-183, which
undergoes an intramolecular cycloaddition to give either
intermediate 9-184 or 9-185. A subsequent reductive
tically, a 1,4-zwitterion 9-169 is first proposed after elimination could construct benzofurans 9-181. In 2010, Lin,
nucleophilic addition. After intramolecular proton abstraction Wang, and co-workers disclosed an efficient synthesis of indole
from amide, the generated intermediate 9-170 could then scaffolds 9-187 from 2-azidoacrylates 9-186 and o-silylaryl
cyclize to yield 2-arylimidazolone 9-168. In 2018, Chen, Li, triflates in the presence of PPh 3 (Scheme 191b). 705
and co-workers reported a domino reaction between 2- Mechanistically, this transformation commences with a
isocyanophenyloxyacrylates 9-171 and arynes, furnishing nucleophilic double cyclization of iminophosphoranes 9-188,
compounds 9-172 by installing an olefin and a benzoxazole generated from 2-azidoacrylates 9-186 and PPh3, with benzyne
on the vicinal positions of a benzene ring (Scheme 189b).701 to produce 9-189. Hydrolysis on intermediate 9-189 will give
They proposed that this cascade process proceeds through a intermediate 9-190, which could then be converted to indole
successive nucleophilic addition/Michael addition/C−O bond product 9-187 after dehydrogenative oxidation.
Chem. Rev. 2021, 121, 3892−4044
Scheme 191. Aryne Nucleophilic Annulation-Induced Scheme 192. Aryne Cascade Reactions with Hydrazones and
Cascade Reactions Hydrazides
Scheme 193. Aryne Cascade Reactions with Aziridines and

3,4-Dihydroisoquinolines
Hydrazones and hydrazides were also employed in cascade

aryne transformations. In 2011, Larock et al. revealed that o-
(dimethylamino)aryl ketones 9-192 could be achieved in
moderate to excellent yields from the reaction of 1,1-
dimethylhydrazones of aldehydes 9-191 with arynes, the
mechanism of which involves a nucleophilic annulation to
afford dihydroindazole intermediate 9-193 and a subsequent
ring opening pathway (Scheme 192a).706 Moreover, acridones
were obtained from o-halobenzaldehyde hydrazones, the
formation of which included an additional intramolecular
SNAr reaction and demethylation. Recently, Chudasama and
co-workers reported a preparation of 2-hydrazobenzophenones
9-195 from arynes and readily achievable acyl hydrazides 9-
194 (Scheme 192b).707,708 Three plausible pathways were
proposed for this transformation, all of which could lead to the
formation of 9-195. The 2-hydrazobenzophenone products 9-
195 could be further converted to 1H-/2H-indazoles707 and 2-
aminobenzophenones.708
In a study carried out by Wu, Sha, and co-workers on the
reaction between 2-carboxylic acid ester substituted aziridines
9-196 and arynes, they found that indole spiro-derivatives 9-
197 were obtained under anhydrous conditions (Scheme
193a).591 Mechanistically, ammonium salt 9-198 could be
formed via an aryne nucleophilic annulation reaction, which is
then converted to 1-benzyl-2-methyleneindolin-3-ones 9-199
through ring-opening. Next, dimerization via the Diels−Alder
reaction occurs on 9-199 to yield products 9-197. In 2016,
Voskressensky et al. revealed a unique aryne-induced aryl
anion migration event in the reaction of arynes with 1-aroyl- carbonyl group on oxy-anion 9-202 with a concomitant aryl
3,4-dihydroisoquinolines 9-200 (Scheme 193b).709 The group migration.
formation of 12a-aryl substituted indoxylisoquinolines 9-201 In 2016, He and co-workers realized a cascade process
was proposed to proceed through the reformation of the between aza-Morita−Baylis−Hillman (AMBH) adducts 9-203
Chem. Rev. 2021, 121, 3892−4044
and o-silylaryl triflates, furnishing 4-quinolone derivatives 9- Scheme 195. Aryne C−C Bond Insertion-Initiated Cascade/
204 in moderate to high yields with a broad substrate scope One-Pot Reactions
(Scheme 194a).350 This transformation involves an aryne
Scheme 194. Aryne Cascade Reactions with Allyl Amines

and Carbamoylpropiolates
195b).712 Moreover, 4-aryl-2-naphthols 9-212a prepared

through this protocol were utilized in the synthesis of
binaphtols.712−715
In order to solve the lack of regioselectivity problem in
Okuma’s study,712 Suzuki and co-workers proposed to use
ketodioxinones 9-213 as the substrate in a tandem aryne acyl-
alkylation/intramolecular aldol condensation process, which
could yield functionalized β-hydroxynaphthoate derivatives 9-
214 in a highly regioselective manner (Scheme 196a).716
Mechanistically, after nucleophilic addition to form inter-
mediate 9-215, the generated aryl anion preferentially attacks
the more electrophilic ketone carbonyl group, hence,
exclusively affording intermediate 9-216. In 2019, Muthuk-
rishnan et al. accomplished a benzannulation reaction of 1,3-
nucleophilic annulation reaction to generate intermediate 9-
oxopentanedioates 9-217 with o-silylaryl triflates, giving rise to
205 and a subsequent ene reaction with another molecule of
highly functionalized naphthalene derivatives 9-218 in
aryne. Similarly, in a study carried out by Mhaske et al. on the
moderate to high yields (Scheme 196b).717 Furthermore,
aryne nucleophilic annulation reaction with carbamoylpropio-
they converted the naphthalene derivatives into a series of
lates 9-206, they observed the formation of spirooxindolo-
rhodamine dye analogues. Meanwhile, Pabbaraja, Mehta, and
pyrrolidones 9-207, which was realized through a Michael
co-workers disclosed a cascade process to produce 9-220a and
addition/annulation event on oxindolylidene acetate 9-208
9-220b, when unsubstituted dimethylacetonedicarboxylates
with another molecule of carbamoylpropiolate 9-206 (Scheme
(9-219) (R1 = H) reacted with arynes (Scheme 196c).718
194b).468
Interestingly, when C2-substituted dimethylacetonedicarbox-
9.5. Insertion Reaction-Triggered Cascade Reactions ylates 9-221 (R1 ≠ H) were employed, the aldol condensation
9.5.1. Through C−C Bond Insertion. The uniqueness of step became highly selective, leading to the formation of
carbon−carbon σ-bond insertion by arynes is its ready compounds 9-222 in good to high yields. This preferred
assembly of two new C−C bonds on the arene ring, which cyclization pathway was attributed by the stereoelectronic
could then be converted to different useful frameworks, such as factors with respect to the R1 group.
natural products bearing polycyclic ring systems. Along with In addition, Okuma et al. examined the reaction of
the study carried out by Stoltz and co-workers on aryne trifluoromethylated β-diketones 9-223 with arynes.719,720 As
insertion into the C−C σ-bonds of β-ketoesters, they shown in Scheme 197, polysubstituted isocoumarins 9-224
developed two one-pot procedures for aryne acyl-alkylation/ were obtained in moderate to good yields, the formation of
condensation, which could further convert the aryne insertion which proceeds through an extrusion of CF3 anion after a C−C
products to either 3-hydroxyisoquinolines 9-209 or 2-hydroxy- bond insertion/cyclization process. This study also led to the
1,4-naphthoquinones 9-210 (Scheme 195a).710 This protocol preparation of natural products thunberginol A and xyridine
was also applied in the total syntheses of (−)-jorunnamycin A A.719
and (−)-jorumycin,711 unraveling its great potential toward Other interesting cascade processes initiated by aryne acyl-
polycyclic ring systems. Subsequently, Okuma et al. employed alkylation were recently reported. Huang, Fu, Huang, and co-
aroylacetones 9-211 as the substrates and realized a tandem workers discovered an unusual cascade process between arynes
aryne insertion/intramolecular aldol reaction/dehydration and α,γ-diketo esters 9-225, which led to the formation of
process, furnishing 4-aryl-2-naphthols 9-212a and 3-aryl-1- highly functionalized indanes 9-226 in modest to high yields
naphthols 9-212b, albeit in poor regioselectivity (Scheme (Scheme 198a).721 Based on their theoretical study, a
Chem. Rev. 2021, 121, 3892−4044
Scheme 196. Aryne Cascade Reactions with Analogues of Scheme 198. Other Aryne C−C Bond Insertion-Initiated
Acetonedicarboxylate Cascade Reactions
produced, respectively (Scheme 199a).512 The mechanism for

this reaction includes an aryne insertion into the C−O σ-bond
Scheme 197. Preparation of Isocoumarins from of carboxylic acids and an intramolecular Michael addition on
Trifluoromethylated β-Diketones 9-235 to furnish the annulated products 9-234. Subsequently,
Ma and co-workers demonstrated that 2,3-allenoic acids 9-236
could react with arynes through a sequential C−O σ-bond
insertion and intramolecular Michael addition on intermediate
9-238, which could afford chromone derivatives 9-237 in
moderate to excellent yields (Scheme 199b).723 In 2017,
Mhaske et al. reported a sequential aryne insertion into the C−
O bond of silyl-protected acid 9-239 and the intramolecular
Michael addition reaction, giving cyclohexenone-fused spi-
robenzofuran-3-one analogues 9-240 that share the same core
structure with natural product leptosphaerin C (Scheme
199c).724
In 2012, the groups of Larock and Shi725 and Stoltz726
mechanism was suggested: after nucleophilic addition of 9-225 independently reported the reaction between β-lactams and
to aryne, aryl anion 9-227 could be converted to 9-229 via the arynes (Scheme 200). N-Unsubstituted β-lactams 9-241 (R1 =
ring-opening of benzocyclobutene intermediate 9-228; sub- H) were found to react with arynes to afford acridones 9-242.
sequent cyclization on 9-229 would then furnish product 9- Mechanistically, this cascade transformation involves (1) aryne
226. Another example was reported by Ramachary et al., in insertion into the strained C−N σ-bond of β-lactams to form
which benzannulated bicyclo[3.3.0]octanes 9-231 were readily 2,3-dihydroquinolin-4-ones 9-243; (2) nucleophilic annulation
achieved from lawsones 9-230 and o-silylaryl triflates in a reaction with another molecule of aryne to generate 9-244; (3)
highly selective manner (Scheme 198b).722 It was reasoned extrusion of ethylene; (4) N-arylation with another molecule
that, after the formation of tertiary alkoxide 9-232, an alkoxide- of aryne to give acridones 9-242 (R′ = Ar). Moreover, Larock,
induced C−C bond rearrangement could happen to produce Shi, and co-workers found that N-alkyl dihydroquinolinone 9-
9-231. 241 (R1 = alkyl) could furnish acridones 9-242 (R′ = alkyl)
9.5.2. Through Other Insertion Reactions. Along with with arynes; whereas N-phenyl dihydroquinolinone gave only a
the study carried out by Larock on aryne insertion into the C− trace amount of the desired product.725
OH σ-bond of carboxylic acids, they disclosed that when both In 2011, Alajarin, Lopez-Leonardo, and co-workers revealed
acrylic and propiolic acids 9-233 were utilized, the an aryne insertion into the PN bond of both P-alkynyl-λ5-
corresponding 4-chromanones and flavones 9-234 could be phosphazenes 9-245 and P-alkenyl-λ5-phosphazenes 9-247,
Chem. Rev. 2021, 121, 3892−4044
Scheme 199. Cascade Reactions via Aryne C−O Bond Scheme 201. Cascade Reaction Initiated by Aryne Insertion
Insertion/Michael Addition Pathway into PN Bond
Scheme 202. Aryne Cascade Reaction with Allyl Sulfoxides
Scheme 200. Aryne Cascade Reaction with β-Lactam
1,2,3-trisubstituted arenes 9-253 in a highly selective manner.

Three chemical bonds, namely, C−S, C−O, and C−C bonds,
were assembled on the consecutive positions of a benzene ring.
By using substituted aryne precursors, up to pentasubstituted
arenes could be conveniently prepared.
In 2017, Yoshida, Hosoya, and co-workers disclosed that o-
arylthio-substituted diaryl ethers 9-256 could be obtained from
arynes and diaryl sulfoxides by conducting the reaction at high
temperature, the mechanism of which involves an intra-
leading to the formation of the corresponding 1,4-benzaza- molecular migratory O-arylation via intermediates 9-254 and
phosphorinium triflates 9-246 and 9-248, respectively, in good 9-255 (Scheme 203a).729 In 2017, Studer and Li reported an
to excellent yields (Scheme 201).727 Mechanistically, the unprecedented transformation between arynes and vinyl
overall transformation involves a successive formal [2 + 2] sulfoxides 9-257, affording o-sulfinylaryl vinyl ethers 9-258
cycloaddition reaction to generate 9-249/retro [2 + 2] (Scheme 203b).730 It was proposed that after the formation of
cycloaddition reaction to produce 9-250/6π-electrocyclization 9-259, a stereospecific S to O vinyl group migration occurred
to afford 9-251/protonation process. to produce products 9-258. They also observed that water was
In 2016, Li and co-workers realized a cascade three- an essential additive to suppress fluoride-mediated dispropor-
component coupling reaction of arynes, aryl allyl sulfoxides tionation of sulfoxide. Recently, Peng and co-workers revealed
9-252, and an electrophile (Scheme 202).728 This trans- two desulfurization reactions between benzyne and diaryl/
formation proceeds through a unique combination of aryne heteroaryl sulfoxides, producing biaryls 9-260 and desulfurized
insertion into the SO bond of sulfoxides with a subsequent heteroarenes 9-261, respectively (Scheme 203c).731 Both their
C−H bond functionalization via rearrangement, furnishing mechanistic study and theoretical calculations suggested the
Chem. Rev. 2021, 121, 3892−4044
Scheme 203. Other Cascade Reactions via Aryne Insertion dented radical mechanism was proposed: a biradical
into SO Bonds intermediate 9-265 can be first generated from the reaction
between thioaldehyde 9-263 and benzyne, which is followed
by a proton abstraction to form intermediate 9-266 and an
internal combination to afford 9-264.
In 2013, Hwu et al. demonstrated a unique and efficient
transition-metal-free preparation of phenanthrenes 9-268 from
allenylsilanes 9-267 and o-silylaryl triflates (Scheme 205).733
Scheme 205. Aryne Cascade Reactions with Allenylsilanes
Notably, the stabilizing ability of the β-silyl group through the

hyperconjugation was proposed to promote the formation of
zwitterionic adducts 9-269. Annulation of 9-269 with another
molecule of aryne could produce intermediate 9-270, which
then undergoes oxidation to give products 9-268. In 2018,
Jones et al. revealed a transition-metal-free cross-dehydrogen-
ative coupling reaction on o-silylaryl triflates 9-271, furnishing
α-functionalized heterocyclic and aliphatic tertiary amines 9-
272 (Scheme 206).734 Their deuterium labeling studies
generation of a common tetraaryl(heteroaryl) sulfurane species Scheme 206. Aryne Cascade Reactions via Intramolecular
9-262 that could proceed through two disassembly pathways 1,5-Hydride Transfer
to give either 9-260 or 9-261, the formation of which was
determined by the electronic property of the substrates.
9.6. Other Cascade Reactions
In a study carried out by Okuma and co-workers on the
reaction between benzyne, generated from different precursors,
and a sterically congested thione 2,4,6-tri-tert-butylthiobenzal-
dehyde (9-263), they obtained 5,7-di-tert-butyl-3,3-dimethy-
lindan-1-yl phenyl sulfide (9-264) in 86% yield with the
Kobayashi benzyne precursor (Scheme 204).732 An unprece-
Scheme 204. Aryne Cascade Reaction with Sterically

Congested Thione
suggested that the cleavage of the α-C−H bond of amine via

an intramolecular 1,5-hydride transfer on aryne 9-273 accounts
for the formation of aryl anion 9-274, which could then
deprotonate a range of “pronucleophiles”, such as acetonitrile,
chloroform, nitromethane, and phenylacetylene. Consequently,
those nucleophiles would in turn attack the iminium ion and
yield products 9-272.
In a study carried out by Li, Lai, Kira, and co-workers on the
reaction of stable monomeric dialkylstannylene 9-275 with
benzyne, they observed the formation of 9-276 in 75% yield
(Scheme 207).735 A plausible mechanism was proposed: (1)
Chem. Rev. 2021, 121, 3892−4044
Scheme 207. Aryne Cascade Reaction with Scheme 208. Pd-Catalyzed [2+ 2 + 2] Cyclotrimerization of
Dialkylstannylene Arynes
initially formed stannacyclopropene 9-277 transforms to combination of Pd(PPh3)4 and o-silylaryl triflates worked well.
zwitterion 9-278; (2) one of the silyl groups on 9-278 then In contrast, the employment of 1,2-dibromobenzene as the
migrates to aryl anion to generate stannene 9-279; (3) benzyne precursor and n-BuLi as the activating reagent
insertion of the CSn bond into a C−H bond of the migrated afforded triphenylene only in low yield. Notably, symmetrically
TMS group could afford product 9-276. substituted aryne gave symmetric triphenylene derivative,
whereas 3-methoxybenzyne afforded a mixture of isomers
10. TRANSITION-METAL-CATALYZED REACTIONS 10-2a and 10-2b in a 93:7 ratio. Based on these observations,
they proposed a preferential formation of complex 10-3. Since
Transition metal π-complexes with arynes have long been
then, they employed the Pd-catalyzed [2 + 2 + 2]
studied since several decades ago. During the early era of this
cyclotrimerization strategy in the preparation of a variety of
field, both early transition metals (Ti, Zr, Nb, Mo, W, Re, V,
polycyclic aromatic hydrocarbons, which will be discussed in
etc.) and late transition metals (Ni, Pt, Ru, and Pd) were
section 15.110,744−746 In addition, Don et al. disclosed that a
investigated.736−742 One property of the transition metal π-
Pd(II)−Pb(II) bimetallic metal−organic framework (MOF)
complexes with arynes is that this coordination mode can
using N-heterocyclic dicarbene ligand could serve as an
release part of the ring strain on those angle-strained arynes,
efficient heterogeneous catalyst in aryne cyclotrimerization.747
leading to the formation of stable complexes. These early
As shown in Scheme 209, a general mechanism for this
studies, however, mainly focused on the coordination of
cyclotrimerization was proposed. Sequential complexation of
transition metal with arynes using stoichiometric amounts of
metal reagents, whereas only limited synthetic applications
with zirconium-aryne complexes were reported.736,739,740 Not Scheme 209. Proposed Mechanism for Pd-Catalyzed [2+ 2
until the end of 1990s were transition-metal-catalyzed aryne + 2] Cyclotrimerization
transformations commenced. Because of the mild generation
conditions with respect to Kobayashi’s method and its tunable
aryne generation rate, this method was found to be well suited
for transition metal catalysis. Consequently, there has been a
rapid development in this field of aryne chemistry in the past 2
decades.73,77,90,98 Here in this section, transition metal-
catalyzed aryne transformations will be classified by metals.
10.1. Palladium-Catalyzed Reactions
Palladium is the earliest as well as the most investigated
transition metal compatible with o-silylaryl triflates in catalytic
aryne chemistry. Since the first discovery by Guitián, Pérez,
and co-workers in 1998,743 Pd-catalyzed aryne transformations
have been broadly explored. Based on the type of active
palladium intermediates involved in catalytic cycles, these Pd-
catalyzed aryne transformations could be classified into [2 + 2
+ 2] cyclotrimerization, π-allylpalladium-involved reactions,
arylpalladium-involved reactions, alkyl/vinylpalladium-involved
reactions, azapalladium-involved reactions, and Pd-catalyzed Pd(0) catalyst with two benzynes furnishes complex 10-4,
aryne insertion into element−element σ-bonds. which then leads to the formation of a five-membered
10.1.1. (Co)cyclotrimerization. The earliest investigated palladacycle 10-5. After binding with benzyne intermediate,
reaction mode was Pd-catalyzed aryne [2 + 2 + 2] triphenylene can be produced from 10-6 along with the
cyclotrimerization. In 1998, Pérez, Guitián, and co-workers regeneration of Pd(0) catalyst.
reported the first Pd-catalyzed [2 + 2 + 2] cyclotrimerization of It can be envisioned that the replacement of one or two
arynes that could readily prepare triphenylene derivatives 10-1 arynes with other unsaturated bonds, such as alkynes, alkenes,
(Scheme 208).743 In this study, they examined various Pd- and allenes, in this [2 + 2 + 2] cycloaddition strategy would
catalysts as well as aryne precursors and found that the construct more versatile and useful frameworks other than
Chem. Rev. 2021, 121, 3892−4044
triphenylene scaffolds. The efficiency of this strategy, however, threne derivatives 10-13 in moderate to excellent yields
would be affected by the production of complex mixtures due (Scheme 212a).752 Similar type of reaction was later reported
to a lack of chemoselectivity. Pleasingly, by carefully varying
the reaction conditions, this problem could be solved. In 1999, Scheme 212. Pd-Catalyzed Aryne Cocyclotrimerization of
Pérez, Guitián and co-workers found that dimethyl acetylene- Arynes with Olefins
dicarboxylate (DMAD) could participate in a chemoselective
cocyclotrimerization with arynes in the presence of palladium
catalysts (Scheme 210).748−750 By simply switching the choice
Scheme 210. Aryne Cocyclotrimerization with DMAD
of appropriate Pd-catalyst, two types of products, phenan-

threnes 10-7 via aryne−aryne−alkyne cyclization and naph-
thalenes 10-8 via aryne−alkyne−alkyne cyclization, were
obtained in this reaction. The employment of Pd(PPh3)4
afforded substituted phenanthrenes 10-7 as the major
products; whereas Pd2(dba)3 led to the preferential formation
of naphthalenes 10-8. In this study, an experimental evidence
suggested complex 10-9 from Pd(PPh3)4 and DMAD; while
Pd2(dba)3 was expected to form palladacycle 10-10 with
DMAD. Polycyclic aryne precursors were also examined, which
showed the same reaction behavior.750
One drawback on Pérez and Guitián’s system is that
electron-rich alkynes normally give phenanthrenes in low
yields.748 Right after this early investigation, Yamamoto and
co-workers reported an alternative Pd(OAc)2/(o-tol)3P system by Lee et al. by using oxadisilole fused oxabicyclic alkenes 10-
for an efficient cocyclotrimerization of alkynes with benzyne to 14 to obtain exo-adducts 10-15 (Scheme 212b).753 In 2006,
exclusively produce phenanthrenes 10-11 (Scheme 211).751 Peña, Pérez, and co-workers revealed that electron-deficient
Various electron-rich alkynes could be employed to efficiently alkenes could participate in this Pd-catalyzed cocyclotrimeriza-
furnish phenanthrene skeletons in good yields. tion reaction, which led to the production of dihydrophenan-
threnes 10-16 by using PPh3 as the ligand or ortho-olefinated
Scheme 211. Pd-Catalyzed Cocyclotrimerization of Arynes biaryls 10-17 in the presence of P(o-tol)3 ligand (Scheme
with Electron-Rich Alkynes 212c).754 In 2018, Peña et al. employed diiodo compound 10-
18 as the precursor of pyramidalized alkene and achieved
cyclotrimerized products 10-19 with arynes (Scheme 212d).755
Allenes have also been utilized as the third component in
aryne cocyclotrimerization reactions. In 2009, Liang, Li, and
co-workers first applied allenes 10-20 in a Pd-catalyzed
cocyclotrimerization reaction with arynes, affording phenan-
threne analogues 10-21 in modest to good yields (Scheme
213a).756 In 2013, Ma et al. reported a Pd-catalyzed
Along with the study on alkyne-aryne cocyclotrimerization, preparation of phenanthrene derivatives 10-23 from prop-
people also revealed that olefins could serve as efficient argylic carbonates 10-22 and Kobayashi benzyne precursor
partners with a broad spectrum of applications. One (Scheme 213b).757 In this study, an allenylic palladium species
prevailingly investigated approach was to assemble two arynes 10-24 was proposed to be first generated from 10-22, which
and one olefin together to a central 6-membered ring under could then react with two molecules of benzyne to produce
Pd-catalyzed conditions, which can be seen as an aryne−aryne- phenanthrene derivatives 10-23 after annulation.
alkene cocyclotrimerization reaction mode. In 2004, Cheng Another type of Pd-catalyzed [2 + 2 + 2] cocyclotrimeriza-
and co-workers demonstrated a Pd-catalyzed cocyclotrimerization employs only one aryne, and the other two components
tion of bicyclic alkenes 10-12 and o-silylaryl triflates, furnishing can be either alkenes or alkynes. In 2003, Pérez, Guitián, and
the corresponding norbornane anellated 9,10-dihydrophenan- co-workers demonstrated a Pd-catalyzed [2 + 2 + 2]
Chem. Rev. 2021, 121, 3892−4044
Scheme 213. Pd-Catalyzed Cocyclotrimerization of Arynes Scheme 215. Pd-Catalyzed Aryne Reaction with Conjugated
with Allenes Dienes
cocyclotrimerization of arynes with benzodiynes 10-25, which

could achieve benzo[b]fluorenones 10-26 (Scheme 214a).758
Scheme 214. Pd-Catalyzed Aryne-Alkyne-Alkyne

Cocyclotrimerization
intermediate 10-31. Upon reductive elimination and oxidative

aromatization, naphthalene derivatives 10-30 could be
obtained (Scheme 215).
10.1.2. With π-Allylpalladium Species. The aforemen-
tioned Pd-catalyzed cyclotrimerization strategies normally
employ three π-bond-containing components, those of which
include either three arynes or arynes with various stoichio-
metric amounts of alkynes/alkenes. Other than those π-bond-
containing species, π-allylpalladium as a relatively stable species
was found to be an efficient intermediate in Pd-catalyzed aryne
transformations. In 2000, Yamamoto and co-workers first
revealed a Pd-catalyzed annulation reaction between o-silylaryl
triflates and allyl chlorides 10-32 via a controlled sequential
incorporation of two arynes onto π-allylpalladium species
(Scheme 216).762,763 In the presence of [Pd2(dba)3]·CHCl3 as
In this study, they noticed that both the steric and electronic the catalyst, a combination of Kobayashi benzyne precursor
properties of a diyne species could significantly affect the with allyl chloride could construct phenanthrene derivatives
reaction outcome. This reaction mode was further examined 10-37 along with 10-37′ as the minor products. As shown in
by Sato, Mori, and co-workers in their preparation of Scheme 216, a proposed mechanism involves the insertion of
arylnaphthalene derivatives 10-28 from diynes 10-27 (Scheme benzyne into π-allylpalladium species 10-33 to give 10-34.
214b).759,760 Notably, those diynes containing a Weinreb After another benzyne insertion, intermediate 10-35 could be
amide moiety could deliver 10-28 in the highest yields. This generated. Subsequent intramolecular carbopalladation on 10-
method was also used in the total syntheses of taiwanins C & 35 produces intermediate 10-36, which then undergoes β-
E759 and dehydrodesoxypodophyllotoxin,760 which will be hydride elimination and alkene isomerization to afford
elaborated on in section 14. phenanthrene products 10-37. Recently, Dong et al. also
One interesting discovery was reported by Argade et al. in revealed that a Pd(II)−Pb(II) bimetallic metal−organic
2013, where they employed an unsymmetrically conjugated framework (MOF) using N-heterocyclic dicarbene ligand
dienes 10-29 to react with arynes in the presence of Pd-catalyst could catalyze the coupling reaction of aryne with various
(Scheme 215).761 Naphthalene derivatives 10-30 were allyl halides, giving rise to phenanthrene products.764
obtained. Control experiments revealed that this reaction Since Yamamoto’s initial success on the π-allylpalladium-
cannot proceed through a straightforward Diels−Alder involved aryne annulation reaction, this protocol has received
reaction pathway due to the steric repulsion of the aryl much attention. In the same year, Yamamoto et al. reported a
group on diene. Instead, Pd-catalyzed cyclopalladation of aryne 1,2-diallylation of benzyne through bis-π-allylpalladium com-
with the first alkene, followed by an intramolecular insertion of plex 10-38, which was generated from allyl chloride and
the second alkene, could afford seven-membered palladacycle allyltributylstannane (Scheme 217a).765 This in situ generated
Chem. Rev. 2021, 121, 3892−4044
Scheme 216. π-Allylpalladium-Involved Aryne Scheme 217. π-Allylpalladium-Involved Aryne Three-

Carbocyclization Reactions Component Coupling Reactions
bis-π-allylpalladium species 10-38 is amphiphilic, permitting an

ortho double allylation on benzyne to produce 10-39.
Subsequently, Cheng and co-workers utilized this protocol to
develop several unique transformations. They first demon-
strated two similar transformations using either alkynylstan-
nanes766 or allenylstannanes767 as the third components to
couple with π-allylpalladium species, furnishing the corre- Scheme 218. Other π-Allylpalladium-Involved Aryne
sponding products 10-40 (Scheme 217b) and 10-41 (Scheme Reactions with Alkynes
217c), respectively. In 2005, they realized a Pd-catalyzed three-
component coupling reaction of allyl halides, arynes, and
arylboronic acids, leading to the formation of o-allylbiaryl
derivatives 10-42 in good to high yields (Scheme 217d).768 In
2008, the same group reported a Pd-catalyzed MCR of o-
silylaryl triflates, allylic acetates/halides, and terminal alkynes
in the presence of catalytic amount of CuI, which could
produce 1-allyl-2-alkynylbenzene derivatives 10-43 in good to
excellent yields (Scheme 217e).769
Variations of this reaction mode were reported as well. In
2009, Li, Liang, and co-workers realized a Pd-catalyzed aryne
coupling reaction using allylic alkynoates 10-44 as the source
of both allyl and alkynyl moieties, which yielded 1-allyl-2-
ethynylbenzenes 10-45 (Scheme 218a).770 This transformation
was enabled by a Pd-catalyzed decarboxylative activation of 10-
44. In 2015, Werz et al. demonstrated a Pd-catalyzed three-
component coupling reaction of arynes, terminal alkynes, and
vinyl cyclopropane dicarboxylate (10-46), furnishing 1-allyl-2-
alkynylbenzenes 10-47 in moderate to good yields (Scheme
218b).771 In this study, a π-allylpalladium species 10-48 was In 2001, Chatani, Murai, and co-workers disclosed that π-
proposed to be generated from vinyl cyclopropane dicarbox- allylpalladium species could participate in a MCR of benzyne,
ylate 10-46 through the ring opening of vinyl cyclopropane allyl acetates, and CO, and the generated 2-methyleneindanone
with Pd(0). derivatives 10-49 could be reached via a carbopalladation of
Chem. Rev. 2021, 121, 3892−4044
the benzyne/CO insertion/intramolecular Heck reaction reactions through either oxidative addition of Pd(0) to aryl
sequence (Scheme 219a).772 In 2010, Liang, Li, and co- halides or directing-group assisted C−H bond activation. One
challenge for the success of this strategy is how to manipulate
Scheme 219. Aryne Annulation Reactions via π- the reaction of highly reactive arylpalladium species with
Allylpalladium Species transient aryne intermediates in a tunable manner.
10.1.3.1. Six-Membered Carbocycles. In 2005, Larock et al.
demonstrated the first Pd-catalyzed annulation reaction of
arynes with 2-halobiaryls 10-54, giving rise to fused polycyclic
aromatics 10-55 (Scheme 220a).775,776 It was found that the
Scheme 220. Pd-Catalyzed Aryne Annulation Reactions

with 2-Halobiaryls and 1-(2-Bromophenyl)-1H-indoles
key factor for the success of this transformation was to control

a slow aryne generation rate. A number of heterocycles, such as
benzofuran, indole, and chromone, could furnish the
corresponding products. In 2007, Zhang and co-workers
reported a Pd-catalyzed annulation protocol between arynes
and heterocyclic halobiaryls, 1-(2-bromophenyl)-1H-indoles
10-56, leading to the formation of indolo[1,2-f ]-
phenanthridines 10-57 in moderate to excellent yields
(Scheme 220b).777 This protocol was then applied by Kang,
Ko, and co-workers in the preparation of indolo[1,2-
f ]phenanthridine-based organic sensitizers.778
In 2006, Cheng and co-workers reported a Pd-catalyzed
carbocyclization reaction using 2-fold arynes and one aryl
halides 10-58, furnishing triphenylene derivatives 10-59 in
good to high yields (Scheme 221).779 In this study, thallium
Scheme 221. Pd-Catalyzed Aryne Carbocyclization Reaction

workers developed a Pd-catalyzed cyclocarbonylation reaction with Aryl Halides
of arynes with allyl carbonates and CO, furnishing 2-
benzylidene-2,3-dihydro-1H-inden-1-ones 10-49 and 2-meth-
ylene-3-substituted-2,3-dihydro-1H-inden-1-ones 10-50
(Scheme 219b).773 Notably, the formation of the preferred
products depended on the choice of ligands. In 2018, Cheng,
Zhai, and co-workers revealed an unprecedented decarbox-
ylative approach from vinyl benzoxazinanones 10-51 and
constructed cis-5,5a,6,10b-tetrahydroindeno[2,1-b]indoles 10-
52 in modest to high yields (Scheme 219c).774 Mechanisti- acetate Tl(OAc) was found to be necessary for the success of
cally, after the generation of a π-allylpalladium species from 10- this transformation. Alternatively, either in the absence of
51, a further conversion occurs to generate a four-membered Tl(OAc) or by using various silver salts as additives only
palladacycle intermediate 10-53, which could then capture yielded product 10-59 in low efficiency. They hypothesized
arynes to assemble 10-52. that thallium salt could assist the removal of halide on
10.1.3. With Arylpalladium Species. Arylpalladium palladium intermediate. Similar transformation was also
species are the most investigated in Pd-catalyzed aryne achieved in Larock’s study, in which Pd(OAc)2/dppf complex
transformations. These species could be obtained in the was found to be the ideal catalyst.776 In comparison with
Chem. Rev. 2021, 121, 3892−4044
Cheng’s work,779 this catalytic system did not need thallium Scheme 223. Pd-Catalyzed Aryne Annulation Reactions
salt, albeit with slightly lower yields. Involving Intramolecular Heck Reactions
In 2006, Cheng et al. accomplished another Pd-catalyzed
aryne carboannulation reaction of bicyclic alkenes 10-60, aryl
iodides 10-61, and o-silylaryl triflates, furnishing 9,10-
dihydrophenanthrene derivatives 10-62 in moderate to
excellent yields (Scheme 222a).780 When oxabenzonorborna-
Scheme 222. Arylpalladium-Involved Aryne

Carbocyclization Reactions with Bicyclic Alkenes and
Alkynes
construct complex molecular frameworks.785−788 In 2012,

Cheng and co-workers first demonstrated a Pd-catalyzed
cascade annulation reaction of arynes with alkyne-tethered aryl
dienes were utilized as the coupling partners, the products halides 10-70 and 10-72, furnishing isochromen-6-ones 10-71
could be further converted to polyaromatic hydrocarbons. In and phenanthro[1,10-bc]oxepines 10-73, respectively, in good
this study, Pd(dba)2/P(2-furyl)3 complex was found to be the to high yields through a Pd-catalyzed biscarbocyclization
best catalyst of the choice. The high regio- and stereoselectivity cascade process (Scheme 224).785 A mechanism was proposed
in this transformation was reasoned by (1) insertion of bicyclic for these transformations: (1) insertion of alkyne into the Pd−
alkene into arylpalladium species is favored over that of aryne; C bond of palladium π-complex 10-74 generates vinyl-
(2) C−H activation on the arene ring of aryl iodide palladium 10-75; (2) cyclopalladation on 10-75 through
preferentially proceeds on the less hindered site. Moreover, intramolecular C−H bond activation affords five-membered
Larock and co-workers disclosed a similar Pd-catalyzed three- palladacycle 10-76; (3) aryne cyclopalladation could produce
component coupling transformation of arynes, aryl halides, and seven-membered palladacycle 10-77; and (4) reductive
alkynes to yield substituted phenanthrenes 10-63, the elimination furnishes the polycyclic product 10-71.
mechanistic pathway of which also follows a sequential In 2016, Garcıá -López and co-workers achieved an
insertion of alkyne and then aryne into arylpalladium unprecedented Pd-catalyzed cascade reaction of o-silylaryl
intermediate (Scheme 222b).781 In this study, they found triflates with 10-78, giving rise to heterospirocyclic compounds
that Tl(OAc) was crucial for the success of this reaction. This 10-79 in moderate to excellent yields (Scheme 225).786 Similar
transformation could readily assemble polycyclic aromatic to the mechanism in Cheng’s study,785 this cascade process
compounds in a highly regioselective manner. includes an intramolecular Heck arylation via 5-exo-trig
In 2009, Larock et al. disclosed that o-halo allylic benzenes cyclization to generate alkylpalladium species 10-80, which is
10-64 could undergo Pd-catalyzed annulation reaction with followed by intermolecular aryne carbopalladation and C−H
arynes to afford 9,10-phenanthrenes 10-65 (Scheme 223a).782 activation (or vice versa) to produce seven-membered
In 2016, Yao, Zhang, and co-workers developed another palladacycles 10-81 or 10-82. Reductive elimination on either
annulation reaction of arynes with 2-halostyrenes 10-66, 10-81 or 10-82 could afford product 10-79.
producing phenanthrene derivatives 10-67 in modest to Meanwhile, Lautens and co-workers independently discov-
excellent yields with broad functional group tolerance (Scheme ered a similar Pd-catalyzed cascade spirocyclization process
223b).783 The mechanism of this transformation includes a (Scheme 226a).787 Two types of frameworks, namely,
sequential oxidative addition of Pd(0) to aryl iodide/aryne spirooxindole and spirodihydrobenzofuran 10-84, could be
insertion/intramolecular endo-Heck reaction. In a recent study readily accessed from 10-83 in moderate to excellent yields.
carried out by Sridharan et al., they reported one example on Although it is generally difficult to determine whether the C−
Pd-catalyzed annulation reaction of benzyne with compound H activation step to form five-membered or seven-membered
10-68, giving rise to product 10-69 in 55% yield (Scheme palladacycle occurs first on alkylpalladium species after Heck
223c).784 arylation, their mechanistic study clearly indicated that the
In addition to Pd-catalyzed carbocyclization among arynes, reaction through a seven-membered palladacycle is unfavor-
arylhalides, and alkynes/alkenes to build six-membered rings, able. In 2017, Yao et al. reported a Pd-catalyzed cascade
distinct cascade processes were also developed by using process that proceeds through the same mechanistic pathway,
alkyne/alkene-tethered arylhalides as the substrates to which could produce heterocycle-fused 9,10-dihydrophenan-
Chem. Rev. 2021, 121, 3892−4044
Scheme 224. Pd-Catalyzed Aryne Annulation Reactions Scheme 226. Other Pd-Catalyzed Aryne Annulation
with Alkyne-Tethered Aryl Halides Reactions with Alkene-Tethered Aryl Iodides
Scheme 227. Pd-Catalyzed Aryne Annulation Reaction with

Ketone-Tethered Aryl Iodides
Later in 2012, Larock et al. disclosed that 2-halobenzamides

Scheme 225. Pd-Catalyzed Aryne Annulation Reaction with 10-89 were able to serve as efficient annulation partners with
Alkene-Tethered Aryl Bromides arynes (Scheme 228a).790 The employment of this approach
readily accessed N-substituted phenanthridinone derivatives
10-90 with a concomitant formation of C−C and C−N bonds.
It was noticed that mono N-substituted amide is essential for
Scheme 228. Pd-Catalyzed Formation of Phenanthridinone

Derivatives
threnes 10-86 from 10-85 (Scheme 226b).788 Depending on

the length of the linker, products via both 5-exo-trig or 6-exo-
trig Heck cyclization could be obtained.
10.1.3.2. Six-Membered Heterocycles. Beside the formation
of all carbon six-membered rings via arylpalladium-involved
aryne annulation processes, six-membered heterocyclic rings
could also be constructed. In 2010, Liang, Li, and co-workers
employed substrates 10-87 bearing a tethered aryl iodide and
ketone to achieve a Pd-catalyzed annulation reaction with
arynes, affording 6H-benzo[c]-chromenes 10-88 with good
functional group tolerance (Scheme 227).789 Mechanistically,
this transformation involves an α-arylation of ketones, which
was the first example of this kind in aryne chemistry.
Chem. Rev. 2021, 121, 3892−4044
the success of the reaction. In contrast, the employment of 2- efficient with respect to various substituents, including electron
halobenzamides containing either the absence of N-substituent deficient N-methoxybenzamides (condition B).794 Moreover,
or N,N-dimethyl group did not observe any desired products. DMSO was found to be crucial for this transformation and a
In a study carried out by Harmata et al. on the preparation of KIE value of 4.7 suggested that the key step in this catalytic
benzofused benzothiazines from o-halo sulfoximines, they also cycle should be the C−H activation step. In 2019, Li, Wang,
reported Pd-catalyzed annulation examples, albeit in low and co-workers combined photoredox catalysis with palladium
yields.791 Recently, Meng, Xu, and co-workers achieved a Pd- catalyst in an annulation reaction of N-methoxybenzamides
catalyzed decarbonylative annulation of phthalimides 10-91 with arynes by using molecular oxygen as a terminal oxidant in
with o-silylaryl triflates, affording phenanthridinones 10-92 replacement of K2S2O8 or Cu(OAc)2 (Scheme 229b).795
with good functional group tolerance (Scheme 228b).792 Phenanthridinone derivatives 10-98 were facilely prepared
Mechanistically, the catalytic cycle involves (1) oxidative under mild conditions.
addition of Pd(0) into an imide N−CO bond to generate This Pd-catalyzed C−H activation strategy was then
intermediate 10-93; (2) decarbonylation to give a five- expanded to other directing groups. In 2014, Sha et al.
membered palladacycle 10-94; (3) aryne insertion to form a discovered that aryl ketone O-acetyloximes 10-99 could serve
seven-membered palladacycle 10-95; and (4) reductive as effective substrates in Pd-catalyzed annulation reaction with
elimination to yield 10-92 along with the regeneration of arynes, affording phenanthridine derivatives 10-100 (Scheme
Pd(0) species. 230a).796 Their mechanistic study suggested that the reaction
An alternative strategy to generate arylpalladium species is
through direct C−H bond activation. This protocol, however, Scheme 230. Pd-Catalyzed C−H Bond Activation Protocols
encountered difficulty when efforts were tried to combine C− with Other Directing Groups
H bond activation with aryne transformations. A plausible
reason to account for this problem can be a mismatch between
harsh C−H activation conditions and highly active, unstable
aryne intermediates. Until 2014, two distinct Pd-catalyzed
annulation reactions of arynes with N-methoxybenzamides 10-
96 were independently reported by the groups of Jeganmo-
han793 and Xu,794 which could construct tricyclic phenan-
thridinone derivatives 10-97 (Scheme 229a). Although both
Scheme 229. Formation of Phenanthridinones via Pd-

Catalyzed C−H Bond Activation Protocol
initiates with an ortho C−H activation directed by the oxime

group. Besides, Li, Wei, and co-workers employed N-alkoxy
benzsulfonamides 10-101 as the substrates in a Pd-catalyzed
C−H activation/aryne insertion/annulation process, giving rise
to various dibenzosultams 10-102 in good to excellent yields
(Scheme 230b).797 An excess amount of Cu(OAc)2 was
studies employed an amide-directed ortho-activation of the needed for this transformation, so it was reasoned that the
C(sp2)−H bond to generate the desired five-membered copper salt might be responsible for the removal of the R2
palladacycle intermediate, their reaction conditions were group in the reaction. Recently, Chikhalia et al. revealed a Pd-
quite different. In Jeganmohan’s study, they found that both catalyzed annulation reaction of N-methyl-benzylamines 10-
1-adamantanecarboxylic acid (Adm-1-CO2H) and K2S2O8 103 with arynes, which led to the construction of various 5,6-
were crucial for the success of this transformation (condition dihydrophenanthridine derivatives 10-104 in moderate to high
A).793 In addition, N-methybenzamides worked as well. N- yields (Scheme 230c).798 Moreover, benzyne insertion into the
Methoxybenzamides 10-96 bearing halogens and EWGs on the six-membered palladacycles was also investigated by Saura-
benzene ring, however, only furnished N-arylated products, Llamas, Vicente, and co-workers.799−801
suggesting that the C−H activation step is the rate-limiting Others have attempted to construct six-membered hetero-
step. Notably, Xu et al. revealed another catalytic system by cyclic rings via the arylpalladium-aryne annulation protocol. In
using Pd(OAc)2, Cu(OAc)2, TBAB, and CsF in a binary 2014, Liang and co-workers reported an efficient Pd-catalyzed
solvent of DMSO and dioxane, which was found to be highly annulation of arynes and N-substituted-N-(2-iodophenyl)-
Chem. Rev. 2021, 121, 3892−4044
formamides 10-105 (Scheme 231).802 This transformation aryne generation conditions, phenanthridinones 10-108 were
could furnish phenanthridinone derivatives 10-106 in moder- obtained exclusively by using CsF/TBAI/MeCN with 10%
H2O; (b) using dppm as the ligand and under slow aryne
Scheme 231. Pd-Catalyzed Aryne Annulation Reactions releasing conditions, acridones 10-109 could be achieved
with N-(2-Iodophenyl)formamides preferentially. It was reasoned that both the steric and electron-
donating effects of the dppm ligand could prevent the
coordination of aryne with palladium, hence, allowing a
preferential CO binding event. Subsequently, a modification
was realized by the same group by using anilines 10-110 to
replace 2-iodoanilines, which required an ortho C−H activation
step to generate an arylpalladium intermediate (Scheme
232b).804 Phenanthridinone derivatives 10-111 were achieved
with no formation of acridone alkaloid scaffold. In this study,
they found that CuF2 was crucial for the success of this three-
component annulation reaction. Based on their experimental
study, the mechanism involves a dimeric palladium inter-
mediate from palladation of aniline under a CO atmosphere.
ate to excellent yields via an arylation-annulation process. Two 10.1.3.3. Five-Membered Rings. Other than the formation
possible pathways might be involved on arylpalladium of six-membered rings, methods toward the construction of
intermediate 10-107 after the insertion of aryne to five-membered rings via an arylpalladium species have also
arylpalladium species: (a) insertion of carbonyl group to been achieved by Larock and others. In 2005, Larock and co-
Pd−C bond and a β-hydride elimination and (b) oxidative workers demonstrated that fluoren-9-one scaffold 10-113
addition of palladium to the amide C−H bond and reductive could be readily constructed from o-halobenzaldehydes 10-
elimination. There was no clear evidence, however, on which 112 via a Pd-catalyzed annulation reaction with arynes
pathway is the real one. (Scheme 233).805,806 This transformation provided an efficient
A distinct Pd-catalyzed three-component annulation reac-
tion of arynes, CO, and anilines was realized by Jiang et al. Scheme 233. Pd-Catalyzed Aryne Annulation Reactions
(Scheme 232).803,804 In 2015, they first reported a ligand with o-Halobenzaldehydes
controlled regiodivergent preparation of both phenanthridi-
nones 10-108 and acridone alkaloids 10-109 through Pd-
catalyzed coupling of arynes, CO, and 2-iodoanilines (Scheme
232a).803 In particular, the regioselective control could be
realized by simply altering both the ligand and aryne
generation rate: (a) in the absence of ligand and under fast
Scheme 232. Pd-Catalyzed Aryne Annulation Reactions

with Anilines and CO
solution for the expeditious preparation of fluoren-9-one

derivatives from readily available starting materials. After
aryne insertion into the Pd−C bond of arylpalladium species,
there are two plausible mechanistic pathways to account for
the formation of final products from intermediate 10-114: (1)
addition to the carbonyl group with following a β-hydride
elimination on intermediate 10-115 (path a); (2) oxidative C−
H insertion to form a Pd(IV) intermediate 10-116 and a
reductive elimination (path b).
Later in 2009, Larock et al. also disclosed that o-halostyrenes
10-117 could undergo Pd-catalyzed annulation reactions with
arynes to produce 9-fluorenylidenes 10-118 in good to
excellent yields (Scheme 234).782,807 This synthetic protocol
involves the generation of two new C−C bonds under mild
conditions with broad functional group compatibility. The
formation of 9-fluorenylidene scaffold from o-halostyrenes 10-
117 was distinctly different from the work carried out by Yao
and Zhang, where phenanthrenes were obtained.783 It was
noticed that the substrates in the study by Yao, Zhang, and co-
workers would prohibit β-hydride elimination after 5-exo-trig
Chem. Rev. 2021, 121, 3892−4044
Scheme 234. Pd-Catalyzed Aryne Annulation with o- Scheme 236. Other Pd-Catalyzed Aryne Annulation
Halostyrenes Reactions
Heck cyclization with an arylpalladium intermediate. Con-

sequently, the phenanthrene framework was formed then.783
Arynes can be also utilized in Pd-catalyzed annulation
reactions with anilines, furnishing carbazole frameworks. In a
study carried out by Jiao and co-workers on Pd-catalyzed
annulation of anilines and electron-deficient alkynes, they
exhibited one example by using the Kobayashi benzyne
precursor to reach carbazole (10-119) in 60% yield (Scheme
10.1.3.4. Other Arylpalladium-Involved Reaction. In 2007,
235a).808 Their mechanistic study suggested a sequential
Greaney and co-workers realized a three-component Heck
coupling reaction of aryl iodides, arynes, and electron-deficient
Scheme 235. Pd-Catalyzed Aryne Reactions to Construct olefins, furnishing highly functionalized biaryls 10-126 in
Carbazole Frameworks modest to high yields (Scheme 237).812
Scheme 237. Pd-Catalyzed Aryne Reaction with Aryl

Iodides and Electron-Deficient Olefins
10.1.4. With Alkylpalladium and Vinylpalladium. In

addition to π-allylpalladium and arylpalladium species, both
alkylpalladium and vinylpalladium have been investigated in
aminopalladation of aryne, arene C−H bond activation, and aryne transformations. In 2006, Greaney et al. reported an
reductive elimination, although it could not exclude a possible unprecedented Pd-catalyzed three-component coupling reac-
direct ortho C−H activation on anilines with Pd(0) to form tion of aryne, methyl bromoacetate/benzyl bromides, and
dimeric arylpalladium intermediate as postulated by Jiang.804 acrylates, furnishing products 10-127 in moderate to excellent
In 2012, Larock and co-workers reported a similar annulation yields (Scheme 238).813 The mechanistic pathway of this
reaction between arynes and 2-haloacetanilides 10-120,
affording N-acylcarbazoles 10-121 (Scheme 235b).809 It was Scheme 238. Alkylpalladium-Involved Aryne Reaction
found that strong electron-withdrawing groups on these
substrates disfavor the nucleophilic addition of nitrogen to
arylpalladium intermediate in the ring-closing step.
Recently, Luan and co-workers discovered a Pd-catalyzed
cascade process between arynes and naphthalene-based biaryls
10-122, furnishing spirofluorene scaffold 10-123 (Scheme
236a).810 This unprecedented dearomatization/[3 + 2]
spiroannulation process includes a successive aryne insertion
into the arylpalladium species/Heck-type dearomative 5-exo- transformation involves an aryne carbopalladation on the
trig cyclization/hydride elimination sequence. Notably, this alkylpalladium intermediate followed by an intermolecular
process is distinctively different from the prior Larock’s report, Heck reaction. Notably, it was found that the replacement of
which resulted in an exclusive formation of triphenylene allyl chloride with methyl bromoacetate could prohibit the
framework by using 2-halobiaryls.775,776 Phosphine as a aryne−aryne−alkene [2 + 2 + 2] cocyclotrimerization reaction
cyclization acceptor was also reported by Tobisu, Chatani, mode.
and co-workers (Scheme 236b).811 In their study on Pd- Efforts have been make to realize alkenylpalladium-involved
catalyzed intramolecular formation of dibenzofused six- aryne transformations. Along with Larock’s study on 2-
membered phosphacycles from triphenylphosphine derivatives, halobiaryls, they also reported the Pd-catalyzed annulation
they exhibited one example for the construction of 10-125 reactions of arynes with vinylic halides/triflates 10-128, which
between bromide 10-124 and Kobayashi benzyne precursor in could yield phenanthrenes 10-129 (Scheme 239a).775,776 In
24% yield. 2010, Huang and co-workers demonstrated a Pd-catalyzed
Chem. Rev. 2021, 121, 3892−4044
Scheme 239. Vinylpalladium-Involved Aryne Reactions transformation involves an oxidative insertion of Pd(0) to
C−S bond, aryne insertion, and a subsequent reductive
elimination on intermediate 10-136 to produce 10-135. It
was noticed that the formation of methanethiol or ethanethiol
byproduct in the catalytic cycle required an equivalent of
sacrificing aryne. Subsequently, Gogoi et al. reported a Pd-
catalyzed aryne annulation reaction with 4-hydroxycoumarins
10-137, which could furnish coumestans 10-138 in moderate
to high yields (Scheme 240b).816 It was proposed that the
reaction first generates an anion species 10-139, which could
then transform to intermediate 10-140. After aryne insertion,
the generated intermediate 10-141 would undergo a reductive
elimination to produce coumestans 10-138 in the presence of a
base. Moreover, this methodology was applied to the synthesis
of natural product flemichapparin C, which will be discussed in
section 14.
In 2018, Chen, Xiao, and co-workers reported a Pd-catalyzed
formal [2 + 2 + 2] annulation reaction of arynes and various
vinyl triflates 10-142, producing phenanthrene scaffolds 10-
143 in moderate to excellent yields with a broad substrate
scope (Scheme 241).817 The catalytic cycle of this trans-
Scheme 241. Pd-Catalyzed Formation of Phenanthrenes

carboannulation reaction of arynes with either allyl-substituted from Arynes and Vinyl Triflates
iodocycloenones 10-130 or iodofuranones 10-132, leading to
the formation of substituted naphthalene derivatives 10-131
and 10-133, respectively, in moderate to good yields (Scheme
239b).814
In 2014, a distinct Pd-catalyzed annulation reaction of
arynes with α-carbamoyl ketene dithioacetals 10-134 was
realized by Liu, Wang, and co-workers, giving rise to 2-
quinolinones 10-135 in modest to excellent yields with broad
substrate scope (Scheme 240a).815 Mechanistically, this formation involves a 2-fold aryne insertion into the vinyl-
palladium species, a 6-endo-Heck cyclization, and a 1,3-hydride
Scheme 240. Other Vinylpalladium-Involved Aryne migration. Particularly, the addition of LiOPiv was found to be
Reactions crucial for the success of this transformation, which could
prefer a 6-endo-Heck reaction mode over a competing 5-exo-
Heck cyclization.
10.1.5. With Azapalladium Species. Azapalladium was
also employed in aryne transformations. In 2009, Neuville,
Zhu, and co-workers demonstrated the first annulation
transformation of arynes with azapalladium intermediate,
generated from acyloximes 10-144 via an oxidative addition
of Pd(0) complex, which led to the generation of
phenanthridines scaffold 10-145 (Scheme 242).818 Butyroni-
trile with a high boiling point was the optimal solvent for this
transformation. They proposed that the reaction mechanism
includes (1) oxidative insertion of Pd(0) into an acyloxime N−
O bond to generate azapalladium 10-146; (2) aryne insertion
to produce 10-147; (3) intramolecular C−H activation to
form a seven-membered palladacycle 10-148; (4) reductive
elimination to produce 10-145 along with the regeneration of
Pd(0) species. Alternatively, cyclopalladation to generate five-
membered palladacycle from azapalladium 10-146, followed by
aryne insertion and reductive elimination, would be another
plausible pathway.
In 2015, Ma, Xu, and co-workers reported a Pd-catalyzed
annulation reaction of arynes with acrylamides 10-149 and
harvested quinolinone derivatives 10-150 (Scheme 243).819 In
this work, they conducted an intermolecular KIE experiment
and obtained a KIE value of 1.7, suggesting that the C−H
bond cleavage on acrylamide is not the rate-determining step.
With the perception that C−H activation on electron-deficient
Chem. Rev. 2021, 121, 3892−4044
Scheme 242. Pd-Catalyzed Formation of Phenanthridines not be directly inserted by arynes in the absence of palladium
from Arynes and Acyloximes catalyst. A general mechanistic scheme includes the oxidative
addition of a Pd(0) species to those σ-bonds to generate the
Pd(II) intermediate, which then gives rise to vicinal
difunctionalized arenes after aryne insertion and reductive
elimination.
In 2001, Shirakawa, Hiyama and co-workers reported the
first example of this kind by activating either alkynyl- or
vinylstannane with Pd-catalyst, giving rise to 10-154 (Scheme
245a).822 The generated C−Sn bond on 10-154 could be
Scheme 245. Pd-Catalyzed Aryne Insertion into C−Sn and

Sn−Sn σ-Bonds
Scheme 243. Pd-Catalyzed Formation of Quinolinones from

Arynes and Acrylamides
further converted to a variety of a C−C bond through cross-

acrylamide is difficult, they proposed that aryne insertion into
coupling manipulation. In 2004, Yoshida, Kunai, and co-
the acyclic azapalladium species was the favorable pathway
workers accomplished a Pd-catalyzed distannylation of arynes
over that of the five-membered palladacycle.
to give 10-155 in modest to good yields (Scheme 245b).823
10.1.6. Other Palladium-Catalyzed Reactions. Nishi-
Subsequently, the same group revealed a Pd-catalyzed
hara and co-workers reported a Pd(II)-catalyzed three-
distannylation of arynes, which could furnish a mixture of
component coupling reaction of aryne, isocyanides 10-151,
10-156 and 10-157 (Scheme 245c).824 These divergent
and cyanoformates 10-152, furnishing iminoisobenzofuran
transformations were realized by switching the ligands and
derivatives 10-153 (Scheme 244).820,821 It was found that
varying the reaction stoichiometry.
cationic palladium catalyst played an essential role in this
In 2005, Yoshida, Kunai, and co-workers discovered an
three-component coupling transformation.
unprecedented catalytic transformation, where bissilylation of
10.1.7. Insertion into Element−Element σ-Bonds.
aryne could be reached from cyclic disilanes 10-158 to form
Aryne insertion into element−element σ-bonds could be
10-159 (Scheme 246a).825−827 Both five- and six-membered
enabled by palladium complexes, those of which will otherwise
cyclic disilanes 10-158 worked well in this reaction. In 2015,
Werz and co-workers found that palladium could efficiently
Scheme 244. Pd-Catalyzed Formation of activate aryl thiocyanates 10-160 and furnished 1,2-thiobenzo-
Iminoisobenzofurans nitriles 10-161 (Scheme 246b).828 In particular, molecular
oxygen was found to be necessary for the success of this
process, the role of which was assumed to stabilize an
intermediate in the catalytic cycle. Moreover, C−C bond
insertion on the three-membered ring of 10-162 by Pd(0)
species was also reported by Wu and co-workers, which could
proceed through a further [3 + 2] cycloaddition reaction with
arynes to afford products 10-163 in good to excellent yields
(Scheme 246c).829
Chem. Rev. 2021, 121, 3892−4044
Scheme 246. Pd-Catalyzed Aryne Insertion into Other σ- ones. Besides, Sato et al. also reported nickel-catalyzed [2 + 2 +
Bonds 2] cocyclotrimerization reactions of 3,4-pyridyne with either
diynes832 or alkynes,833 which will be discussed in section 12.
In 2009, Sato and co-workers investigated a Ni-catalyzed
cocyclotrimerization of 1,6-dienes 10-168 with arynes
(Scheme 248).834 Unexpectedly, they did not obtain products
Scheme 248. Ni-Catalyzed [2 + 2 + 2] Cocyclotrimerization

of Arynes with 1,6-Dienes
10.2. Nickel-Catalyzed Reactions

In comparison with Pd-catalyzed aryne transformations, nickel
catalysis has received much less attention. In the past 2
decades, there are only a few reports on Ni-catalyzed aryne
transformations.
In 2004, Cheng and co-workers revealed the first nickel-
catalyzed chemoselective [2 + 2 + 2] cocyclotrimerization of
arynes with allenes 10-164 (Scheme 247a).830 This trans-
Scheme 247. Ni-Catalyzed [2 + 2 + 2] Cocyclotrimerization

of Arynes with Allenes and Diynes
via the aryne-alkene-alkene cyclization reaction mode. Instead,

an aryne−aryne−alkene cyclization reaction was observed to
afford 9,10-dihydrophenanthrenes 10-169. NHC ligand
SIMes·HBF4 10-170 was found to be the ideal ligand for
this transformation. In this study, the employment of diene
moiety was crucial for the success of this reaction, so it was
reasoned that both double bonds are needed in order to form a
sufficiently stable nickel-diene complex. Mechanistically, there
are two plausible pathways that could account for the
formation of a seven-membered nickelacycle 10-173: (1)
formation of five-membered nickelacycle 10-171 with one
aryne and an olefin, followed by insertion of a second aryne
formation belongs to an aryne−aryne−allene cyclization mode, (path a) and (2) formation of five-membered nickelacycle 10-
which furnished 10-methylene-9,10-dihydrophenanthrenes 10- 172 with two aryne species, followed by insertion of an olefin.
165 in a highly chemoselective manner. The internal double Upon reductive elimination on intermediate 10-173, 9,10-
bond of allenes participated in the reaction, and the resulting dihydrophenanthrenes 10-169 were generated.
exocyclic double bond on the product did not isomerize to In 2011, Lautens and co-workers developed a Ni-catalyzed
form a phenanthrene skeleton. The proposed mechanistic cocyclotrimerization of enynes 10-174 and o-silylaryl triflates,
pathway is close to that in palladium catalyzed transformations. furnishing compounds 10-175 in modest to excellent yields
In 2005, the same group demonstrated another Ni-catalyzed (Scheme 249a).835 This transformation was under ligand-free
aryne cocyclotrimerization transformation (Scheme 247b).831 conditions. In particular, when the olefin contains an adjacent
Naphthalene derivatives 10-167 containing 5- to 7-membered substituent (R4 ≠ H), products 10-175 with excellent trans-
fused-ring were achieved between arynes and diynes 10-166. It stereoselectivity were obtained. In 2009, Xie and Qiu also
was noticed that this transformation is sensitive to the revealed a Ni-catalyzed three-component [2 + 2 + 2]
structure of diynes with terminal diynes the most reactive cocyclotrimerization reaction of arynes, alkynes, and alkenes,
Chem. Rev. 2021, 121, 3892−4044
Scheme 249. Other Ni-Catalyzed Aryne Reactions Scheme 250. Ni-Catalyzed Aryne [4 + 2] Cycloaddition
Reaction with Styrenes
undergoes a ring-expansion to give nickelacycle 10-183 (path

b). Rearomatization on 10-183 could yield intermediate 10-
affording dihydronaphthalene derivatives 10-176 (Scheme
185, which then undergoes a reductive elimination to afford
249b).836 In order to avoid the aryne−aryne−alkyne cyclo-
10-182.
addition side reaction, activated alkenes, i.e., methyl acrylate,
were necessary. Excellent regioselectivity was observed when 10.3. Copper-Catalyzed/Mediated Reactions
unsymmetrical alkynes were utilized in this reaction. Cu-catalyzed aryne transformations were studied behind that
Other than cocyclotrimerization, more reaction modes were of palladium and nickel. Moreover, the reaction modes
also developed. In 2007, Cheng et al. reported an efficient Ni- involved in Cu-catalyzed aryne reactions are quite different
catalyzed three-component coupling reaction of arynes, from those in palladium catalysis. For instance, there was only
boronic acids 10-177, and alkenes 10-178, affording the one example on Cu-catalyzed [2 + 2 + 2] cyclotrimerization of
coupling products 10-179 in moderate to excellent yields benzyne to produce triphenylene product in Zhang’s study;840
(Scheme 249c).837 It was noticed that organoboronic acids whereas copper acetylide species have been broadly employed
played a dual role in this reaction, serving as both the proton as the key intermediates in aryne transformations.
sources and the C-nucleophiles. In 2018, Cheng and co- Copper acetylide intermediates can be facilely generated
workers discovered a new Ni-catalyzed aryne reaction mode. from terminal alkynes, which then undergo efficient
Phenanthridinone derivatives 10-181 could be achieved from nucleophilic addition to arynes. Consequently, the generated
1,2,3-benzotriazin-4-(3H)-ones 10-180 and arynes in good to arylcopper species could couple with various third compo-
excellent yields via a Ni(0)/dppm-catalyzed denitrogenative nents. In 2008, Zhang and co-workers reported the first Cu-
annulation process (Scheme 249d).838 This transformation has catalyzed coupling reactions between terminal alkynes and
a broad substrate scope with high functional group tolerance. arynes.840 As shown in Scheme 251, in the absence of ligand,
Recently, Ichikawa et al. revealed a Ni-catalyzed formal [4 + the coupling product 10-186 was produced in good to high
2] cycloaddition reaction between styrenes and arynes, yields. Meanwhile, a three-component coupling reaction was
producing 9,10-dihydrophenanthrenes 10-182 in good to achieved by using allyl chlorides as the third component and
excellent yields with broad substrate scope (Scheme 250).839 CuI/dppe as the catalyst, giving rise to 1,6-enyne products 10-
This transformation was distinctly different from Biju’s 187. In the latter transformation, K2CO3 was found to suppress
previous study on cycloaddition reaction of styrenes with the protonation step. Mechanistically, the generated copper
arynes,241 in which a successive ene reaction with a second acetylide species 10-188 attacks aryne to form a carbocopper
molecule of aryne occurred on the [4 + 2] cycloadduct, except intermediate 10-189, which could undergo protonation to
for those styrenes bearing a strong electron-withdrawing produce 10-186 (path a). In the presence of allyl chloride, a
substituent on the 4-position. Mechanistically, after the subsequent oxidative addition on 10-189 occurs, furnishing the
coordination of styrene and benzyne with nickel, seven- 1,6-enyne products 10-187 after reductive elimination (path
membered nickelacycle 10-183 was generated via an oxidative b). Alternatively, a direct nucleophilic addition of carbocopper
cyclization pathway (path a). Alternatively, five-membered 10-189 to allyl chloride might take place to directly furnish 10-
nickelacycle 10-184 might be formed as well, which then 187. Subsequently, Biehl et al. applied microwave conditions in
Chem. Rev. 2021, 121, 3892−4044
Scheme 251. Cu-Catalyzed Aryne Reactions with Terminal Alkynes
Zhang’s Cu-catalyzed alkyne-aryne coupling reaction, yielding arynes before protonation (Scheme 252b).842 Diverse 2-
both symmetrical and unsymmetrical diaryl alkynes in much alkynylbiaryls 10-191 were readily prepared. In 2012, Pineschi
shorter reaction time.125 et al. employed alkenyl aziridines 10-192 in a Cu-catalyzed
At almost the same time with Zhang’s discovery on Cu- three-component coupling reaction of alkynes and arynes,
catalyzed aryne transformations, Cheng et al. demonstrated a affording products 10-193 in moderate to high yields (Scheme
three-component coupling reaction of arynes, terminal alkynes, 252c).843 In this study, CuI/PPh3 was utilized as the catalyst
and activated alkenes (Scheme 252a).841 In this study, CuI/ and both cyclic and acyclic alkenyl aziridines could serve as
PCy3 in binary solvents was found to be the optimal efficient third components.
conditions, which could furnish 1-alkyl-2-alkynylbenzenes 10- In 2009, Cheng and co-workers accomplished a highly regio-
190 in moderate to high yields. In 2009, Yoshida and co- and chemoselective three-component coupling reaction of
workers revealed a Cu-catalyzed 2:1 coupling reaction of arynes, allylic epoxides 10-194, and terminal alkynes to
arynes with terminal alkynes, in which copper acetylide
assemble compounds 10-195, where copper and palladium
participated in a sequential nucleophilic addition to two
served as cooperative catalysts in this transformation (Scheme
253).844 Mechanistically, an oxidative addition of Pd(0) with
Scheme 252. Cu-Catalyzed Coupling Reactions with Arynes
and Terminal Alkynes
Scheme 253. Cooperative Cu- and Pd-Catalyzed Reactions
of Arynes, Terminal Alkynes, and Allylic Epoxides
Chem. Rev. 2021, 121, 3892−4044
allylic epoxide could generate a π-allylpalladium complex 10- Scheme 255. Aryne Coupling Reactions Involving Cu(III)
196, which is then attacked by carbocopper species 10-189 to Intermediates
produce product 10-195 with regeneration of both Cu- and
Pd-catalysts.
In 2014, Kobayashi and co-workers employed carbon
dioxide to capture carbocopper intermediate 10-189, which
led to the formation of isocoumarins 10-197 via a Cu-catalyzed
three-component coupling reaction of arynes, terminal alkynes,
and CO2 (Scheme 254a).845 The employment of [(IPr)CuCl]
Scheme 254. Cu-Catalyzed Coupling Reactions of Arynes,

Terminal Alkynes, and CO2
oxazoles, and O-benzoylhydroxylamines was achieved, afford-

(IPr = 1,3-bis(diisopropyl)-phenylimidazol-2-ylidene) (10- ing o-(benz)oxazolyl anilines 10-207. The success of the latter
198) as the NHC-copper catalyst was the key for the success transformation was based on the fact that the active hydrogen
of this transformation. Mechanistically, the generated carbo- on (benz)oxazoles is sufficiently acidic to be removed by a
copper intermediate 10-189 attacks CO2 to produce a copper base. Subsequently, Xiao et al. realized a Cu-catalyzed three-
carboxylate 10-199, which then undergoes a 6-endo-dig component iodoalkynylation reaction of arynes, terminal
cyclization to furnish endocyclic copper heterocycle 10-200. alkynes, and NIS, giving rise to o-alkynyl aryl iodides 10-208
After protonation, isocoumarin 10-197 was obtained. In 2016, in moderate to high yields (Scheme 255b).848 Based on their
Xu and co-workers developed a Cu-catalyzed three-component mechanistic study, they proposed that copper is involved in
coupling reaction of arynes, terminal alkynes, and benzene- two key steps in this transformation: (1) formation of 1-iodo-
sulfonothioates 10-201, giving rise to o-alkynyl arylsulfides 10- 2-arylacetylene (10-209) via an alkynylcopper(III) intermedi-
202 in moderate to high yields (Scheme 254b). 846 ate from copper acetylide 10-188 and NIS; (2) insertion of
Benzenesulfonothioates 10-201 were found to be efficient aryne into the C(sp)−I bond of 10-209. The exact reaction
electrophiles to capture the carbocopper intermediate 10-189 pathway, however, was not addressed. Very recently, Xie and
in this transformation. co-workers reported a Cu-catalyzed oxidative 1:2 coupling
In 2019, Chen, Xiao, and co-workers found that O- reaction of arynes with terminal alkynes under aerobic
benzoylhydroxylamines 10-203 could serve as the third conditions, which led to the formation of arenediynes 10-
component as well, furnishing o-alkynyl anilines 10-204 in 210 in modest to excellent yields (Scheme 255c).849 Their
modest to high yields (Scheme 255a).847 The role of O- mechanistic study suggested the formation of an aryl-Cu(III)
benzoylhydroxylamines 10-203 was proposed to react with intermediate 10-211 via the oxidation of carbocopper 10-189,
carbocopper 10-189 to generated an aryl-Cu(III) intermediate which could be attacked by another copper acetylide 10-188 to
10-205, which could then convert to 10-204 along with the furnish arenediynes 10-210 and regenerate Cu(I) species.
regeneration of Cu(I) species. Furthermore, by altering Inspired by the work on Pd-catalyzed ortho-C−H activation/
terminal alkynes to (benz)oxazoles 10-206, a Cu-catalyzed aryne insertion annulation strategy,793,794 Zhang and co-
three-component carboamination reaction of arynes, (benz)- workers reported a series of Cu-catalyzed transforma-
Chem. Rev. 2021, 121, 3892−4044
tions.850−852 In 2017, they first realized a Cu-catalyzed direct Scheme 257. Other Cu-Catalyzed ortho-C−H/N−H
ortho-C−H/N−H annulation of N-quinolylbenzamides 10- Annulation Transformations
212 with arynes, furnishing phenanthridinones 10-213 in
modest to excellent yields with broad substrate scope (Scheme
256).850 Mechanistically, after ligation with N,N-bidentate
Scheme 256. Cu-Catalyzed Formation of

Phenanthridinones via ortho-C−H/N−H Annulation
Process
Scheme 258. Cu-Catalyzed Formal Aryne Insertion into σ-

Bonds
directing group, an intramolecular C−H activation occurs to

give a five-membered complex 10-214. Upon carbocupration
with aryne to afford 10-215 and a subsequent reductive
elimination, phenanthridinones 10-213 could be produced.
Moreover, their KIE study suggested that Cu-catalyzed C−H
activation is the rate-limiting step. Later in 2018, they applied
this Cu-catalyzed ortho-C−H/N−H annulation strategy in the
reaction of arynes with indolocarboxamides 10-216 and 10-
218, furnishing the corresponding polyheterocyclic indolo-
[3,2-c]/[2,3-c]quinolines 10-217 and 10-219, respectively
(Scheme 257a).851 In addition, 2-quinolinones 10-221 were
obtained in modest to excellent yields from electron-deficient
acrylamides 10-220 through this protocol (Scheme 257b).852
Cu-catalyzed aryne insertion reactions into σ-bonds were
also explored. In 2010, Yoshida et al. first disclosed that aryne
could insert into the C(sp)−Br σ-bond of bromoalkynes 10-
222 in the presence of CuBr2 (Scheme 258a).853 A mixture of
2-bromo-2′-(phenylethynyl)biphenyls 10-223 and 1-bromo-2-
(phenylethynyl)benzenes 10-224 were obtained under the
same conditions. Mechanistically, this transformation involves
the insertion of one or two arynes into a Cu−Br bond of CuBr2
first and a subsequent nucleophilic coupling of arylcopper
species with bromoalkyne. Subsequently, the same group
demonstrated that diborylation of both alkynes and o-silylaryl metathesis of 10-227 with another diboron substrate could
triflates could be realized by using (PPh3)3CuOAc as an afford diboralated products 10-225 in moderate to good yields.
efficient catalyst (Scheme 258b).854 In this transformation, a In 2016, Chen and co-workers revealed a Cu-catalyzed P-
borylcopper species 10-226 was proposed to be first generated, arylation of secondary phosphine oxides 10-228 with arynes,
which was followed by an aryne insertion into the Cu−B bond giving rise to phosphine oxides 10-229 in good to excellent
to produce arylcopper intermediate 10-227. A σ-bond yields (Scheme 258c).855 This reaction proceeds through a
Chem. Rev. 2021, 121, 3892−4044
sequential formation of R12P(O)Cu species 10-230/aryne single or double insertion of arynes into arylstannanes,
insertion/protonation to yield 10-229 along with the respectively.
regeneration of copper catalyst. In recent years, Tsui and co-workers developed several Cu-
In 2017, Yoshida and co-workers reported two types of Cu- mediated trifluoromethylation reactions of arynes. In 2018,
catalyzed aryne σ-bond insertion reactions with tributyltin they demonstrated a Cu-mediated vicinal trifluoromethylation-
cyanide (10-231) and alkynyl tributylstannanes 10-233 allylation of arynes by using Grushin’s fluoroform-derived
(Scheme 259a).856 These C−Sn bonds could be readily [CuCF3] reagent (generated from CuCl/t-BuOK/CF3H) and
allyl bromides, furnishing trifluoromethylated allylarenes 10-
Scheme 259. Cu-Catalyzed Aryne Insertion into C−Sn σ- 242 (Scheme 260a).859 Mechanistically, aryne insertion into
Bonds
Scheme 260. Cu-Mediated Vicinal Trifluoromethylation-
Allylation of Arynes
Cu−CF3 bond, followed by an oxidative addition to allyl

bromide, will produce a π-allylcopper species 10-243. Upon
reductive elimination, trifluoromethylated allylarenes 10-242
could be obtained. Moreover, they applied this method in the
synthesis of CF3-containing analogue of the antispasmodic
drug papaverine. The same group then realized a Cu-mediated
1,2-bis(trifluoromethylation) of arynes with Grushin’s fluoro-
form-derived [CuCF 3 ] as well, furnishing 1,2-bis-
(trifluoromethyl)arenes 10-244 (Scheme 260b).860 2,3-Di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) was found to be
an efficient oxidant for this transformation. Their mechanistic
studies suggested that the formation of an o-trifluoromethyl
aryl radical 10-245 is through a CF3 group transfer from
[CuCF3] to aryne. In addition, a Cu-catalyzed aryne
inserted by arynes, furnishing ortho-cyanoarylstannanes 10-232
polymerization was realized by Mikami, Uchiyama, and co-
and alkynylstannylated arenes 10-234, respectively. In these
worker, which will be discussed in section 15.861
transformations, CuCN was used as the catalyst with no need
for ligand. It was proposed that the cyano- or alkynyl- 10.4. Silver-Catalyzed/Mediated Reactions
stannylation initiates with the formation of potassium In 2013, Hu and co-workers revealed an unprecedented Ag-
cyanocuprate(I) 10-235 and tributyltin fluoride (10-236) mediated vicinal trifluoromethylation-iodination of arynes
from fluoride ion and an organostannane. Compound 10-235 using AgCF3, facilely prepared from TMSCF3 and AgF, and
then adds to arynes to generate an arylcuprate(I) 10-237. After 1-iodophenylacetylene (10-246), affording substituted o-
nucleophilic addition to tributyltin fluoride (10-236), the trifluoromethylated iodoarenes 10-247 in modest to high
corresponding products could be produced. Recently, yields (Scheme 261a). 862 2,2,6,6-Tetramethylpiperidine
Tsuchimoto et al. combined this Cu-catalyzed alkynylstanny- (TMP) was found to play an essential role in this
lation protocol with a Zn-catalyzed stannylation of terminal transformation. With their in-depth mechanistic study, they
alkynes.857 In 2019, Yoshida et al. revealed a Cu-catalyzed proposed a plausible mechanism: (1) AgCF3·TMP complex
arylstannylation of arynes with electron-deficient arylstannanes attacks aryne to generate intermediate 10-248 first; (2) after
10-238 (Scheme 259b).858 By using copper(I) 2-thiophene- binding with another molecule of TMP to produce 10-249,
carboxylate (CuTC) (10-239) as the catalyst, both substituted deprotonation will happen to furnish anionic intermediate 10-
ortho-stannylbiaryls 10-240 and teraryls 10-241 could be 250; (3) 10-250 coordinates with iodophenylacetylene via
prepared, the mechanistic pathway of which involves either a halogen bonding to give 10-251; (4) ate complex 10-252 is
Chem. Rev. 2021, 121, 3892−4044
Scheme 261. Ag-Catalyzed/Mediated Aryne Reactions Scheme 262. Au-Catalyzed Aryne Reactions
Karunakar et al., where gold did not directly interact with

aryne in the reaction.869
10.6. Platinum-Catalyzed Reactions
formed through intramolecular nucleophilic addition, which is
then converted to product 10-247. Subsequently, the same In 2010, Yoshida and co-workers accomplished a platinum-
group demonstrated a Ag-mediated trifluoromethylthiolation- catalyzed diborylation reaction of arynes, affording 1,2-
iodination of arynes with trifluoromethylthiosilver (AgSCF3) diborylarenes 10-225 in modest to high yields (Scheme
and 1-iodophenylacetylene (10-246), which led to the 263).870 A Pt-isocyanide catalyst was found to be ideal for the
formation of o-trifluoromethylthiolated arenes 10-253
(Scheme 261b).863 Moreover, they realized a Ag-catalyzed Scheme 263. Pt-Catalyzed Diborylation Reaction of Arynes
formal insertion of arynes into the Rf−I bond of 10-254 (Rf =
CF3 , C 2 F5 ) via an ionic atom-/group-transfer of R fI
compounds to yield o-perfluoroalkyl iodoarenes 10-255
(Scheme 261c).864 In this work, 1,10-phenanthroline (phen)
served as an efficient ligand. Some other Ag-catalyzed aryne-
involved transformations were also reported, where silver
catalysts did not directly interact with arynes.365,656,865,866
10.5. Gold-Catalyzed Reactions
success of this transformation. The 1,2-diborylarene products
In 2015, a gold-catalyzed [2 + 2 + 2] cyclotrimerization of o-
could be converted to ortho-terphenyls via a further Suzuki-
silylaryl triflates was realized by Zhang, Chen and co-workers,
Miyaura coupling reaction. This protocol was also applied on
furnishing triphenylenes in moderate to high yields (Scheme
indolynes, which will be discussed in section 12.871
262a).867 Ph3PAuCl was used as the catalyst and the reaction
Besides, Gagné and co-workers employed Kobayashi
mechanism was proposed to be the same with that in Pd-
benzyne precursor in the reaction with (triphos)Pt-CH3+ 10-
catalyzed cyclotrimerization reactions. In 2008, Zhang et al.
259 to synthesize a π-complex 10-260 (Scheme 264).872
reported a gold- and copper-catalyzed tandem reaction
Thermolysis of complex 10-260 furnished (triphos)Pt(o-
between terminal alkynes and arynes, giving rise to alkynylated
tolyl)+ 10-261, while protonolysis of this complex gave rise
biphenyl derivatives 10-256 (Scheme 262b).868 A cooperative
to toluene.
Au- and Cu-catalyzed process was proposed: complex 10-257
can be first formed between gold catalyst and aryne; next, 10.7. Cobalt-Catalyzed Reaction
carbocopper intermediate 10-189 reacts with complex 10-257 In 2001, in an early study carried out by Chatani, Murai, and
to afford organogold intermediate 10-258. Upon protodeme- co-workers, they examined various transition metal catalysts in
talation, alkynylated biphenyl derivatives 10-256 were carbonylation reactions with o-silylaryl triflates. By using
generated. In addition, a Au-catalyzed cyclization of N- Co2(CO)8 as the catalyst, anthraquinones 10-262 were
propargylic β-enaminones with arynes was reported by obtained in good yields (Scheme 265).772 In this study, they
Chem. Rev. 2021, 121, 3892−4044
Scheme 264. Transformations of Pt-Benzyne π-Complex
Scheme 265. Cobalt-Catalyzed Formation of

Anthraquinones with Arynes
Figure 5. 1,4-Benzdiyne, 1,3-benzdiyne, and 1,2-benzdiyne.
2) as the 1,4-benzdiyne equivalent via triflation of hydro-

quinone 11-1 in pyridine (Scheme 266).873 In the presence of
Scheme 266. Heptacene 11-4 from 1,4-Benzdiyne
proposed that the insertion of a CO molecule on intermediate

10-263 could produce 10-264, which then undergoes a
sequential incorporation of another molecule of aryne and
reductive elimination to furnish the anthraquinone products
10-262.
11. BENZDIYNE CHEMISTRY

TBAF, “twistacene” 11-4 with a seven linear polyacene core
The extensive exploration on o-silylaryl triflates not only was obtained in 22% yield via a double [4 + 2] cycloaddition
significantly expanded the realm for the preparation of 1,2- reaction/extrusion of CO process between 11-2 and pyrano-
disubstituted benzenes as well as benzannulated scaffolds but diphenylcyclopentadienone (11-3). This heptacene 11-4
also has been applied in the facile preparation of polysub- possesses a stable nonpropeller twist topology, causing only
stituted arenes and polycyclic aromatic hydrocarbons (PAHs) marginal changes in electronic properties and reversible redox
via equivalents of polyarynes.89 Those polyarynes can be character.
classified into benzdiynes (i.e., 1,4-benzdiyne, 1,3-benzdiyne, In 2015, Pavliček, Peña, and co-workers treated 1,4-
and 1,2-benzdiyne), naphthodiynes, and other diynes with benzdiyne equivalent 11-2 with iodine and perylene (11-5)
larger aromatic systems. Although these polyarynes started to in a two-step transformation, which could afford diiodoarene
be used as early as in the 1980s,89 the introduction of 11-6 as a new aryne precursor (Scheme 267).874 By using low-
Kobayashi’s method significantly stimulated the recent temperature scanning tunneling microscopy and atomic force
advances in this subfield of aryne chemistry. In this section, microscopy techniques, they observed the generation of
we will focus on the methodology development on the
equivalents of 1,4-benzdiyne, 1,3-benzdiyne, and 1,2-benz- Scheme 267. Preparation of Diiodoarene 11-6 and the
diyne, which could sequentially generate two triple bonds on a Observation of Individual Polycyclic Aryne 11-7
benzene ring in the course of polyaryne transformations
(Figure 5). Because naphthodiynes have shown distinct
applications in the preparation of PAHs, they will be discussed
in section 15. Moreover, Suzuki et al. employed 1,3,5-
benztriyne strategy to prepare a series of hexasubstituted
benzenes.163−165 Because o-haloaryl triflates were utilized as
the aryne precursors in their studies, these works will not be
covered here.
11.1. 1,4-Benzdiyne Chemistry
The earliest and most widely investigated polyaryne is 1,4-
benzdiyne, which has found useful applications in the
preparation of PAHs. In 2003, Wudl and co-workers first
synthesized 1,4-bis(trimethylsilyl)phenyl-2,5-bis(triflate) (11-
Chem. Rev. 2021, 121, 3892−4044
individual polycyclic aryne intermediate 11-7 from 11-6 products 11-15 was developed through the differential
through a tip-induced dissociation of iodine on an ultrathin generation of 1,2-aryne 11-13 at 0 °C and then 4,5-aryne
insulating film. Based on bond-order analysis, the dominant 11-15 at 45 °C.
constitution of 11-7 was suggested to be a cumulene resonance 11.2. 1,3-Benzdiyne Chemistry
structure.
In comparison with 1,4-benzdiyne, the study of 1,3-benzdiyne
Meanwhile, the same group reported an efficient preparation
equivalents has received much less attention, especially those
of polyphenyl aryne precursors through a controlled reaction
with Kobayashi’s generation method. An interesting aspect for
of 1,4-benzdiyne equivalent 11-2 with cyclopentadienones 11-
1,3-benzdiyne transformations is its potential to construct
8, giving rise to new set of aryne precursors 11-9 (Scheme
angularly fused acenes. In order to rapidly prepare unsym-
268a).875 Both the proportion of solvent and the stoichiometry
metrical and multiring fused heterocyclic compounds, Ikawa,
Akai, and co-workers designed two Kobayashi equivalents of
Scheme 268. Double Annulation Strategies with Equivalents 1,3-benzdiyne 11-16 and 11-17 (Scheme 269).877 When
of 1,4-Benzdiyne
Scheme 269. Study on 1,3-Benzdiyne by Ikawa and Akai
compound 11-16 was treated with fluoride, only aryne 11-18

was generated. This result was attributed to the fact that the
TMS group between the two electron-withdrawing OTf groups
of fluoride salts were the key factors that could avoid the is more vulnerable to the activating reagent. In contrast, two
generation of the second aryne. These polyphenyl aryne aryne intermediates, namely, 1,2-aryne 11-19 and 3,4-aryne
precursors have potential for the use in the synthesis of various 11-20, could be released chemoselectively in a stepwise
acene, phene, and starphene derivatives. Meanwhile, Seliver- manner from aryne precursor 11-17, which was explained by
stov et al. demonstrated a method to prepare ring-fused aryne the higher stability of the TBS group. Through the employ-
precursors 11-10, which could be further utilized in the ment of different arynophiles, unsymmetrical, multisubstituted
synthesis of unsymmetrical adducts 11-11 (Scheme 268b).876 aromatic compounds 11-21 were readily achieved.
In 2016, Ikawa, Akai, and co-workers discovered that 1,4- Along with the study on 1,4-benzdiyne precursors, Kitamura
benzdiyne equivalent 11-2 could release two aryne species, et al. also prepared a new type of 1,3-benzdiyne equivalent
namely, 1,2-benzyne and 4,5-benzyne, at different time. [3,6-bis(trimethylsilyl)-2-(triflyloxy)phenyl](phenyl)iodonium
Various arynophiles were then employed in a one-pot fashion triflate (11-24) (Scheme 270).878 The preparation of 11-24
at two aryne stages, leading to a convenient assembly of a set of commenced with the reaction of sodium 2,3,6-trichlorophen-
unsymmetrical multiannulated products 11-11 (Scheme oxide (11-22) with TMSCl, Mg, CuCl, and LiCl in DMI at 55
268c).877 In 2017, Kitamura and co-workers further modified °C and afforded compound 11-23 in 98% yield. After a
the structure of 1,4-benzdiyne equivalent 11-2 and prepared successive iodination/hydrolysis/triflation/oxidation, 1,3-benz-
[2,5-bis(trimethylsilyl)-4-(triflyloxy)phenyl](phenyl)iodonium diyne equivalent 11-24 could be produced in overall moderate
triflate (11-12) (Scheme 268d).878 It was found that the yield. By treating 11-24 with fluoride ion, they observed a
phenyliodonio/TMS part on 11-12 exhibits high reactivity chemoselective generation of 1,2-aryne intermediate 11-25
toward fluoride ion, which allows a chemoselective generation from the phenyliodonio/TMS part. Bis-cycloadducts 11-27
of 1,2-benzyne intermediate 11-13. Consequently, a one-pot could then be obtained by trapping 1,2-aryne 11-25 and 3,4-
procedure for the preparation of various doubly cyclized aryne 11-26 with different arynophiles.
Chem. Rev. 2021, 121, 3892−4044
Scheme 270. Study on 1,3-Benzdiyne by Kitamura position. When TPBT reagent 11-28 was treated with
protected benzothioamides, both 2,4-disubstituted benzothia-
zoles 11-32a and 2-substituted benzothiazoles 11-32b could be
obtained, the selectivity of which was determined by the
structure of the protecting groups. Mechanistically, after the
formation of 2,3-aryne 11-30, an intramolecular cyclization
generates zwitterion 11-31. Depending on whether the R2
group contains an α-hydrogen or not, either 1,3-carbonyl
migration on 11-31a or 1,5-hydrogen shift on 11-31b occurred
to produce the corresponding products 11-32a and 11-32b,
respectively.
Later in 2016, Li and co-workers realized two diamination
reactions with TPBT 11-28 (Scheme 272). When N-aromatic
Scheme 272. Domino Aryne Diamination Reactions
11.3. 1,2-Benzdiyne Chemistry

There is a common feature for the above 1,4-benzdiyne and
1,3-benzdiyne transformations: two sets of formal triple bonds
occupy four positions on the same benzene ring. In contrast,
two aryne intermediates, namely, 1,2-aryne and 2,3-aryne,
share a common C2 position in a 1,2-benzdiyne process
(Figure 5). Therefore, a maximum of trisubstituted benzenes
should be realized. Although seemingly disadvantageous for
forming less substituted benzenes comparing with 1,4- and 1,3-
benzdiyne processes, the chemistry of 1,2-benzdiyne has a
distinctive feature in terms of regioselective control. Because
or N-aliphatic sulfamides 11-33 reacted with TPBT 11-28,
the 2,3-aryne intermediate can only be generated after the
vicinal diamination occurred to furnish 1,2-diaminobenzenes
consumption of 1,2-aryne in a 1,2-benzdiyne process, this strict
11-34 (Scheme 272a).880 The SO2 group on the substrates
mechanistic requirement offers a unique platform for chemo-
serves as both the linker and the electron-tuning factor. When
and regioselective 1,2-benzdiyne transformations.
Tf-protected anilines reacted with TPBT 11-28, 1,3-
In 2015, Li and co-workers synthesized a Kobayashi 1,2-
diaminobenzenes 11-35 were obtained (Scheme 272b).881
benzdiyne precursor, 2-(trimethylsilyl)-1,3-phenylene bis-
Due to the electron-withdrawing inductive effect of the
(trifluoromethanesulfonate) (TPBT) (11-28), which is now
nitrogen substituent at the 2,3-aryne stage, a high level of
known as the domino aryne reagent (Scheme 271).879 Upon
regioselective control was observed in this transformation.
activation, this TPBT reagent could generate 3-triflyloxyben-
Moreover, by using toluene as the solvent and K2CO3 as the
zyne (11-29), which allows the nucleophile to attack its C1
activating reagent, an intramolecular thia-Fries rearrangement
of a Tf group from NTf took place, furnishing 1,2,3-
Scheme 271. Reaction of Domino Aryne Precursor 11-28 trisubstituted 1,3-diaminobenzenes 11-36.
with Protected Benzothioamides Because two aryne species are generated in consecutive
manner in a domino 1,2-benzdiyne process, combinations of
different types of arynophiles might be plausible beyond two
nucleophiles. To this end, Li et al. realized a domino aryne
nucleophilic-ene process, affording benzo-fused N-heterocyclic
compounds 11-39 from 11-38 (Scheme 273a).882 Notably,
distinct chemoselectivity was observed at two aryne stages: an
intermolecular nucleophilic addition proceeds faster than the
ene reaction on 1,2-aryne 11-40; whereas the intramolecular
ene reaction takes place exclusively on 2,3-aryne 11-41. In
addition, a new domino aryne precursor TTPM 11-37 with an
OTs group to replace one of the two OTf groups was found to
be the key for the success of this transformation. It was
explained that the retarded departure tendency of the OTs
Chem. Rev. 2021, 121, 3892−4044
Scheme 273. Domino Aryne Annulation Reactions Scheme 274. 3-Silylbenzyne as Equivalent of 1,2-Benzdiyne
activation, aryne precursors 11-51 could generate the

corresponding 2,3-aryne species, which was then trapped by
various arynophiles and furnished polysubstituted arenes
containing pyridine substituent in good yields and excellent
regioselectivity.
In addition to the above transformations, 1,3-bis(triflyloxy)-
2-iodoarenes 11-54 was also employed as a 1,2-benzdiyne
precursor by Yoshida, Hosoya, and co-workers (Scheme
275).884,885 In the presence of trimethylsilylmethyl Grignard
Scheme 275. 1,2-Benzdiyne Processes with N-Silyl Amines

and N-Silyl Sulfides
group would defer the generation of 2,3-aryne 11-41, hence,

favoring an intramolecular ene reaction.
Moreover, domino aryne nucleophilic/Diels−Alder reaction
processes were independently realized by the groups of
Hoye883 and Li.356 As shown in Scheme 273b, Hoye et al.
demonstrated that substrate 11-42 could participate in domino
aryne nucleophilic addition, intramolecular hexadehydro-
Diels−Alder (HDDA) reaction with either TPBT 11-28 or
TTPM 11-37 to generate a naphthalyne intermediate 11-43,
which was then trapped by various arynophiles to afford
polysubstituted naphthalenes 11-44.883 On the other hand, Li
and co-workers disclosed that cinnamyl sulfonamides 11-46
could also realize a nucleophilic, Diels−Alder reaction cascade reagent, the generated 3-triflyloxybenzynes 11-29 could insert
process, furnishing a variety of [6,n,6,6]-tetracyclic and into the N−Si bond of N-silylamines884 (Scheme 275a) and
[6,5,6,6,6]-pentacyclic ring structures 11-47 in a highly the S−Si bond of silyl sulfides885 (Scheme 275b) regiose-
efficient manner (Scheme 273c).356 In this study, a series of lectively to afford the corresponding o-silylaryl triflates 11-55
domino aryne precursors 11-45 were systematically inves- and 11-57, respectively, as 2,3-aryne precursors. Upon
tigated, and 11-45 with a 2,6-difluorophenylsulfonate (Ar = activation and trapping with various arynophiles, polysub-
2,6-difluorophenyl) as the second LG was identified to serve as stituted arenes 11-56 and 11-58 could be obtained from these
an ideal domino aryne precursor. A synthetic effort toward the 2,3-aryne precursors.
construction of ergot alkaloid framework was reported, which
will be discussed in section 14. 12. HETARYNE CHEMISTRY
In 2018, Li and co-workers developed an aryne 1,2,3- When a formal C−C triple bond is positioned within a
trifunctionalization protocol from 2,6-bis(silyl)aryl triflates 11- heterocyclic aromatic framework, the structure can be seen as a
48, where the generated 3-silylaryne intermediate 11-49 could heterocyclic aryne or hetaryne. Akin to the history of benzyne
react with pyridine N-oxides 11-50 or N-hydroxylamides 11- chemistry, the early precursors of hetarynes also required harsh
52 in a highly regioselective manner to afford the generation conditions, which restricted their synthetic
corresponding o-silylaryl triflates/tosylates 11-51 and 11-53, application. Along with the widespread application of
respectively, in one-pot fashion (Scheme 274).652 Upon Kobayashi’s method in benzyne chemistry, this generation
Chem. Rev. 2021, 121, 3892−4044
method has been extended to hetaryne chemistry as well.83,100 Scheme 276. Preparation of 2,3-Pyridyne Precursors
In this section, we wish to summarize the preparation and the
reactivity study on Kobayashi precursors of various hetarynes,
those of which include pyridynes (2,3-pyridyne, 3,4-pyridine),
2,3-quinolyne, indolynes (4,5-indolyne, 5,6-indolyne, 6,7-
indolyne), 4,5-benzofuranyne, and 6,7-thienobenzyne (Figure
6).
with furan; whereas a mixture of 12-11a and 12-11b were

Figure 6. Hetarynes with preferred site of attack. obtained in a 3:1 ratio with 2-methylfuran (Scheme 277a).889
Scheme 277. Cycloaddition Reactions with 2,3-Pyridynes

12.1. Pyridynes and 2,3-Quinolyne
Pyridynes are the most widely studied hetarynes. According to
the location of the formal triple bond on a pyridine ring,
pyridynes can be classified into 2,3-pyridyne and 3,4-pyridyne.
DFT studies on both pyridynes indicated that although the
structure of 3,4-pyridyne is consistent with a formal triple bond
moiety, the cumulenic structure of 2,3-pyridyne seems to be
more favorable (Figure 6).886,887 This cumulenic resonance
structure not only confers greater electrophilic character at the
C2 position but also makes 2,3-pyridyne extreme reactive,
resulting in low reaction efficiency due to the unexpected side
reactions. In addition, while the reaction of 2,3-pyridyne can
normally yield the corresponding products in satisfactory
regioselectivity, those with unsubstituted 3,4-pyridyne lack
regioselective control.
12.1.1. 2,3-Pyridyne. In 1991, Effenberger and Daub
prepared two Kobayashi precursors of 2,3-pyridyne with the
TMS and OTf groups on the opposite positions of the pyridine
ring. They first treated pyridin-2(1H)-one (12-1) with LDA
and TMSCl to prepare 3-(trimethylsilyl)-2-((trimethylsilyl)-
oxy)pyridine (12-2), which could then be converted to 2,3-
pyridyne precursor 12-3 (Scheme 276a).888 The same protocol
was also employed to synthesize 2,3-pyridyne precursor 12-5
from pyridin-3-ol (12-4). This study was the first preparation Subsequently, they examined the Diels−Alder reaction of 2,3-
of Kobayashi precursors of 2,3-pyridyne. Their further pyridyne precursor 12-3 with furans by using anhydrous CsF
investigation on the [4 + 2] cycloaddition reaction of both as the activating reagent (Scheme 277b).890 Unfortunately,
12-3 and 12-5 with furan, however, failed to produce the these reactions only furnished the cycloadducts 12-12 in low
desired cycloadducts. In 1995, Walters and Shay demonstrated yields. In addition, [4 + 2] cycloaddition reactions of 2,3-
a five-step preparation of 5-methoxy-2,3-pyridyne precursor pridynes have also been used by Lautens.891 In 2014, Saito,
12-9.889 As shown in Scheme 276b, this synthetic route Sato, and co-workers reported a [3 + 2] cycloaddition reaction
commenced with the replacement of the nitro group on 4- between organic azides and 2,3-pyridyne precursors 12-3 and
nitropyridine 1-oxide (12-6) with sodium methoxide via SNAr 12-9, affording cycloadducts 12-13 as the only regioisomer
mechanism and a subsequent production of pyridone 12-7 in (Scheme 277c).892 Although 4-methoxy-2,3-pyridyne exhibits
refluxing acetic anhydride. Pyridone 12-8 was then prepared the same regioselective preference with that of simple 2,3-
through silylation of 12-7, which was converted to the 2,3- pyridyne, the reactions with 12-9 normally give higher yields.
pyridyne precursor 12-9 after triflation. Other types of [3 + 2] cycloaddition reactions with 2,3-
With compound 12-9 in hand, Walters and Shay examined pyridyne have also been reported by Gribble.318
its [4 + 2] cycloaddition reaction with furans through dropwise In addition to pericyclic reactions, nucleophiles were also
addition of compound 12-9 into the reaction media. examined. In 2012, Larock studied the reactions of 2,3-
Cycloadduct 12-10 (R = H) was produced in 41% yield pyridyne with organic amines and o-aminobenzoates (Scheme
Chem. Rev. 2021, 121, 3892−4044
278a).893 2-Aminopyridines 12-14 were obtained from primary 12-22 was obtained through Fries rearrangement on 12-20b by
and secondary amines, while benzonaphthyridinones 12-16 treating it with LDA and a subsequent triflation.
In 2013, Garg et al. reported the preparation of three
Scheme 278. Reactions of 2,3-Pyridynes with Nucleophilic Kobayashi precursors of 3,4-pyridyne (Scheme 280).152
Arynophiles
Scheme 280. Preparation of 3,4-Pyridyne Precursors by
Garg
could be achieved from secondary and tertiary o-amino-

benzoates 12-15. Both transformations were realized in
excellent regioselectivity. In this study, slow addition of
pyridyne precursor was found to prevent unwanted side
reactions. Later in 2013, Saito, Minami, Sato, and co-workers Starting from 3-hydroxypyridine (12-23), silylcarbamates 12-
investigated the reaction of 2,3-pyridyne precursors with 24 could be obtained through carbamoylation and a C4-
compounds 12-17, such as N,N-dimethylimidazolidone selective silylation procedure (Scheme 280a). 3,4-Pyridyne
(DMI) (X = NMe, n = 1), DMPU (X = NMe, n = 2), and precursor 12-25 was prepared from 12-24a via a one-pot
1-methyl-2-oxazolidone (X = O, n = 1), affording the deprotection of the R1 group and triflation. Alternatively,
corresponding C−N σ-bond insertion products 12-18 in compound 12-24b could be converted to 12-26 in two steps in
moderate to excellent yields (Scheme 278b).894 In 2016, Garg 53% yield. As shown in Scheme 280b, compound 12-28 was
et al. examined the reactivity of 2,3-pyridyne with N- prepared from benzyl ether 12-27 through sulfamoylation and
nucleophiles, 1,3-dipoles, and DMI as well.895 In addition, C4 silylation, which was then readily converted to 3,4-pyridyne
Kobayashi precursors of 2,3-pyridyne have also been utilized as precursor 12-29 after deprotection and triflation. Gram
hetaryne substrates in benzyne transformations.318,417,536,668 quantities of these three 3,4-pyridyne precursors were prepared
12.1.2. 3,4-Pyridyne. In 1992, Snieckus and Tsukazaki by using the protocols in Scheme 280.
first employed the directed ortho metalation strategy to prepare After the preparation of Kobayashi precursors of 3,4-
Kobayashi precursors of 3,4-pyridyne.896 As shown in Scheme pyridyne 12-21 and 12-22, Snieckus and Tsukazaki examined
279, starting from 3-pyridyl carbamate (12-19), silylation with their reactivity with furan and 1,3-diphenylisobenzofuran,
trialkylsilyl chloride could yield compounds 12-20 in good to which led to the formation of the corresponding cycloadducts
excellent yields. After reductive removal of the carbamate 12-30 and 12-31, respectively, in low to moderate yields
group and triflation, 3,4-pyridyne precursor 12-21 could be (Scheme 281).896 Tetracyclone could also serve as diene
produced from 12-20a. Alternatively, 3,4-pyridyne precursor arynophile. Notably, when benzenethiol was used as the
nucleophile, a 1:1 mixture of 12-32a and 12-32b was obtained
Scheme 279. Preparation of 3,4-Pyridyne Precursors by from the reaction with 12-21; whereas the reaction with 12-22
Snieckus gave rise to 12-33 in 55% yield as the only isomer. A distinct
regioselectivity study on the reaction of different 3,4-pyridyne
precursors was carried out by Garg and co-workers.147,152 Both
the 5-bromo group on 12-26 and the sulfamate group on 12-
29 could serve as effective EW inductive substituents, leading
to regioselective transformations with respect to both 3,4-
pyridyne precursors 12-26 and 12-29. The details on this study
have been discussed in Scheme 12. More [4 + 2] cycloaddition
reactions with the Kobayashi precursor of 3,4-pyridyne were
also reported by the groups of Coudert897 and Carroll.898
In 2009, Sato and Iwayama demonstrated a Ni(0)-catalyzed
[2 + 2 + 2] cocyclotrimerization of diynes and 3,4-pyridynes,
furnishing isoquinoline derivatives 12-35 (Scheme 282).832 In
this study, intramolecular [2 + 2 + 2] cocyclotrimerization of
Chem. Rev. 2021, 121, 3892−4044
Scheme 281. Reactivity Study on 3,4-Pyridynes by Snieckus Scheme 283. Ni-Catalyzed Cocyclotrimerization of 3,4-
Pyridyne with Alkynes
Scheme 284. Silver-Catalyzed Tandem Reaction with 3,4-

Scheme 282. Ni-Catalyzed [2 + 2 + 2] Cocyclotrimerization Pyridynes
of Diynes and 3,4-Pyridines
12-34 with tethered diyne and pyridyne moiety was also

achieved. Mechanistically, they proposed that oxidative
addition of diyne to nickel(0) complex could afford nickel-
acyclopentadiene intermediate 12-36 (Scheme 282). Insertion native aromatization on the [3 + 2] cycloadducts. By
of 3,4-pyridyne to 12-36 generates seven-membered nickela- employing 2-chloro-3,4-pyridyne (12-46) in this transforma-
cycle 12-37a or 12-37b, which then undergoes reductive tion, products 12-49 were obtained, the formation of which
elimination to produce isoquinoline 12-35. was proposed to proceed through a sequential N−N bond
Subsequently, the same group realized a Ni(0)-catalyzed [2 cleavage on cycloadduct 12-47 and an intramolecular
+ 2 + 2] cocyclotrimerization of 3,4-pyridyne with two recombination on radical intermediate 12-48.
molecules of 2-butyn-1,4-diol derivatives 12-38 and 1,3-diynes Along with their study on the C−N bond insertion reactions
12-40, affording isoquinoline derivatives 12-39 and 12-41, with 2,3-pyridyne, Saito, Minami, Sato, and co-workers also
respectively (Scheme 283).833 They reasoned that the investigated the reactivity of 3,4-pyridyne with DMI, DMPU,
reactivity and selectivity in this transformation originates and 1-methyl-2-oxazolidone, which led to the formation of 12-
from the coordination of the oxygen at the propargylic position 50a and 12-50b as mixtures of regioisomers (Scheme 285a).894
in nickel complex 12-42. In addition, the same group examined the [3 + 2]
In 2012, Fang, Wu, and co-workers reported a silver triflate- cycloaddition reactions of 3,4-pyridyne with organic azides,
catalyzed tandem reaction of N′-(2-alkynylbenzylidene)- furnishing the corresponding cycloadducts 12-51a and 12-51b
hydrazide 12-43 with 3,4-pyridyne precursor 12-21 (Scheme as well (Scheme 285b).892 Moreover, Kobayashi precursors of
284).899 As previously demonstrated with arynes by the same 3,4-pyridyne have also been utilized as hetaryne substrates in
group,656 this transformation was proposed to proceed through benzyne transformations.369,474,537,783,788,835
a [3 + 2] cycloaddition reaction between 3,4-pyridyne and 12.1.3. 2,3-Quinolyne. 2,3-Quinolyne was normally seen
isoquinolinium-2-yl amide 12-44, furnishing pyridinyl-fused H- as the analogue of 2,3-pyridyne and has been only employed
pyrazolo[5,1-a]isoquinolines 12-45a and 12-45b after elimi- along with the study on 2,3-pyridyne.892−894
Chem. Rev. 2021, 121, 3892−4044
Scheme 285. Other 3,4-Pyridyne Transformations Scheme 287. Preparation of Indolyne Precursors by Garg
12.2. Indolynes
In 2009, Buszek and co-workers developed a Fischer indole
synthesis strategy to prepare Kobayashi precursors of 4,5-, 5,6-,
and 6,7-indolynes.900 As shown in Scheme 286, hydrazine
indolyne precursor 12-64. The same protocol was also applied
Scheme 286. Preparation of Indolyne Precursors by Buszek in the preparation of 6,7-indolyne precursor 12-66 from
carbamate 12-65 (Scheme 287). In this study, both N-
unprotected and N-Boc-protected analogues of these three
types of indolynes as well as 3-substituted 4,5-indolyne
precursors were also prepared.150 Moreover, direct function-
alization on the framework of indolyne precursors was
demonstrated by the groups of Pilarski117,118 and Yoshida.902
As has been discussed in Figure 4, Houk, Garg, and co-
workers employed a distortion/interaction model to rationalize
the selectivity issue in either nucleophilic addition reactions or
other transformations with polar arynophiles with respect to
4,5-, 5,6-, and 6,7-indolynes.144,145,148−150 This model suggests
that whenever the internal angle difference between triple
bond carbons is larger than 4°, a substantial degree of
regioselectivity could be envisioned. As depicted in Figure 6,
6,7-indolyne prefers its C6-position and 4,5-indolyne prefers its
C5-position. 5,6-Indolyne, however, does not show an obvious
preference on which site is more electrophilic. These
theoretical studies were then examined with polar arynophiles,
hydrochloride salt 12-53 could be prepared in 51% overall the regioselectivity of which was highly consistent with their
yield from 4-nitro-2-(trimethylsilyl)phenol (12-52), which was prediction.150
then subjected to Fischer’s cyclization conditions with In 2015, Oestreich and co-workers reported a platinum(0)-
phenylacetaldehyde to afford indole products 12-54 and 12- catalyzed insertion reaction of indolynes into the B−B bond of
55 in a 1:5 ratio. After methylation, Kobayashi precursors of bis(pinacolato)diboron (pinB)2, furnishing products 12-67,
4,5-indolyne 12-56 and 5,6-indolyne 12-57 were prepared. 12-68, and 12-69 in moderate yields (Scheme 288).871 Among
Meanwhile, starting from 2-nitro-6-(trimethylsilyl)phenol (12- those products, 6,7-bis[(pinacolato)boryl]indole 12-67 could
58), the corresponding 6,7-indolyne precursor 12-59 was undergo C7-selective Suzuki−Miyaura cross coupling reactions
synthesized by employing the same preparation procedure. In to afford 12-70. Moreover, Kobayashi precursors of indolynes
addition, [4 + 2] cycloaddition reactions of 12-56, 12-57, and
12-59 with 2-tert-butylfuran were examined, all of which Scheme 288. Pt-Catalyzed Insertion of Boron−Boron Bond
afforded the corresponding cycloadducts in high yields.
In the same year, Garg et al. provided an efficient protocol
toward Kobayashi precursor of 4,5-indolyne,901 which was
then expanded to the preparation of both 5,6-indolyne and 6,7-
indolyne precursors (Scheme 287).150 Carbamate 12-60 was
synthesized from commercially available 5-benzyloxyindole,
which was then converted to silyl carbamate 12-61 in 84%
yield via a selective silylation operation. Meanwhile, carbamate
12-62 was obtained in 10% yield along with the formation of
12-61. Next, a one-pot deprotection/triflation on both
carbamates gave 4,5-indolyne precursor 12-63 and 5,6-
Chem. Rev. 2021, 121, 3892−4044
have been extensively utilized as hetaryne substrates along with

benzyne transforma-
tions.135,236,365,407,415,424,433,471,521,522,526,549,550,604,864,903,904
12.3. Other Hetarynes
12.3.1. 4,5-Benzofuranyne. In 2016, Garg and co-
workers prepared the Kobayashi precursor of 4,5-benzofur-
anyne 12-71 from 5-hydroxybenzofuran (Scheme 289a).153
Figure 7. Structures of cyclohexynes, 1,2-cyclohexadienes, and 1,2,3-
Scheme 289. 4,5-Benzofuranyne and 6,7-Thienobenzyne cyclohexatriene.
13.1. Preparation Methods

Because the preparation for Kobayashi precursors of cyclo-
hexyne, 1,2-cyclohexadiene, and 1,2,3-cyclohexatriene mainly
follow similar synthetic protocols or from the same key
intermediates, these procedures will be discussed together. In
1990, Johnson and Shakespeare reported a preparation of the
Kobayashi precursor of 1,2,3-cyclohexatriene 13-3.908 As
shown in Scheme 290a, starting from 2-bromocyclohexenone
Scheme 290. Preparation Procedures via 2-

(Trimethylsilyl)cyclohexenone (13-2)
Upon activation with CsF, the generated 4,5-benzofuranyne

intermediate 12-72 were then trapped by various arynophiles
to afford the corresponding products 12-73 in good to
excellent yields. Based on their distortion/interaction model,
the C5-position of 4,5-benzofuranyne is the more electrophilic
site in the reactions with polar arynophiles. Moreover, this
model also suggested that the regioselectivity in the reaction
with 4,5-benzofuranyne (7° internal angel difference) should
be higher than those with 4,5-indolyne (4° internal angle
difference).
12.3.2. 6,7-Thienobenzyne. In 2018, Yoshida, Hosoya,
and co-workers reported the preparation of a series of 2,3-
disubstituted 6,7-thienobenzyne precursors 12-74 (Scheme
289b).905 The corresponding 6,7-thienobenzynes 12-75 could
be trapped by arynophiles, furnishing the desired products 12- (13-1), 2-(trimethylsilyl)cyclohexenone (13-2) could be
76 in modest C6 regioselectivity. prepared in three steps. Enolization of compound 13-2 with
In addition, Kobayashi precursors of 3,4-furanyne906 and LDA, followed by triflation with PhNTf2 afforded 1,2,3-
4,5-pyrimidyne895 were also synthesized. Unfortunately, efforts cyclohexatriene precursor 13-3 in 50% yield.
to capture the desired hetaryne intermediates from these Enone 13-2 was then employed as a common building block
precursors with various arynophiles were found to be for the preparation of both cyclohexyne and 1,2-cyclo-
unfruitful. hexadiene precursors. In 1998, Guitián et al. reported a facile
preparation of cyclohexyne precursor 13-5 from compound
13. CYCLOHEXYNE, 1,2-CYCLOHEXADIENE, AND 13-2 (Scheme 290b).909 A two-step one-pot operation was
1,2,3-CYCLOHEXATRIENE successfully developed, which includes a hydride conjugate
addition to enone 13-2 with L-Selectride and a subsequent
Beside arynes and hetarynes, six-membered angle-strained triflation on intermediate 13-4, furnishing cyclohexyne
cyclic alkynes/allenes have also been studied along with the precursor 13-5 in 78% yield. In 2009, the same group
advances of aryne chemistry.78,141,907 There are three aliphatic employed enone 13-2 to prepare Kobayashi precursors of 1,2-
active species bearing a parent six-membered ring, namely, cyclohexadiene 13-7.910 As shown in Scheme 290c, Michael
cyclohexyne, 1,2-cyclohexadiene, and 1,2,3-cyclohexatriene, addition on enone 13-2 with L-Selectride afforded either
which also include heteroatom-imbedded analogues (Figure compound 13-6a after aqueous workup or compound 13-6b
7). Although owning great synthetic potential, these transient by trapping with iodomethane. Further enolization and
intermediates remain largely unexplored.78 Along with the triflation on 13-6 could produce the corresponding 1,2-
employment of Kobayashi’s method as the generation cyclohexadiene precursors 13-7a and 13-7b.
conditions for these species, more and more applications In 2016, West and co-workers reported an efficient and
were reported in the past decade. scalable synthesis of 1,2-cyclohexadiene precursors.911 As
Chem. Rev. 2021, 121, 3892−4044
shown in Scheme 291, a copper-mediated conjugate addition Scheme 293. Preparation Methods Developed by Garg
of dimethylphenylsilyllithium to enol triflate derivative 13-8,
Scheme 291. Preparation of 1,2-Cyclohexadiene Precursors

by West
protocol was also employed by the same group in the

readily prepared from cyclohexane-1,2-dione, could generate preparation of 3,4-oxacyclohexyne precursor.153
intermediate 13-9, which was then trapped by acetic anhydride In 2018, Kwon et al. reported an unusual preparation of
to furnish an acetoxy-substituted 1,2-cyclohexadiene precursor substituted cyclohexyne precursors 13-28 via alkenyl cation
13-10. Alternatively, tosylate 13-11 could be prepared from intermediate 13-27 (Scheme 294).915 Mechanistically, cation
enone 13-8 via 1,2-reduction and protection with tosyl
chloride, which was then subjected to a copper-mediated Scheme 294. Preparation Method Developed by Kwon
allylic substitution with dimethylphenylsilyllithium to afford
1,2-cyclohexadiene precursor 13-12.
In 2018, Okano and co-workers developed a method to
reach both Kobayashi precursors of cyclohexynes and 1,2-
cyclohexadienes in a regiocontrolled manner.912,913 As shown
in Scheme 292, the treatment of silyl enol ether 13-13 with a
Scheme 292. Preparation Methods Developed by Okano
13-26 could be generated by treating silylalkynols 13-25 with

triflic acid, which then cyclizes to produce alkenyl cation 13-
27. Subsequently, triflate anion combines with 13-27 to afford
Kobayashi precursors of either cyclohexyne or 1,4-dihydrona-
phalyne 13-28. A unique property of this method is its ease to
introduce various substituents at the C3-position of the
cyclohexyne scaffold.
In 2014, Danheiser and Tlais reported a preparation of N-
tosyl-3-azacyclohexyne precursor 13-32 (Scheme 295).916 In
combination of LDA and t-BuOK resulted in a silyl group this study, they started with α-bromination of lactam 13-29 to
migration (retro-Brook rearrangement) to generate α-silyl afford dibromide 13-30, which was then converted to α-silyl
enolate 13-14, which was then trapped by Comins’ reagent 13- lactam 13-31 by using an excess amount of n-BuLi and
15 to produce 1,2-cyclohexadiene precursors 13-16. Moreover, TMSCl. Furthermore, α-deprotonation on 13-31 and triflation
α-silyl enolate 13-14 could isomerize to intermediate 13-17 in
the presence of a stoichiometric amount of water, yielding Scheme 295. Preparation Method Developed by Danheiser
cyclohexyne precursors 13-18 upon triflation. In this study,
various silyl groups, such as TES, TBS, TIPS, and TBDPS,
were found to be effective.
In 2019, Garg et al. demonstrated a concise protocol to
prepare both cyclohexyne and 1,2-cyclohexadiene precursors
(Scheme 293).914 Starting from α-bromocyclohexanone (13-
19), silyl enol ether 13-20 was readily prepared using DABCO
and triethylchlorosilane (TESCl). Upon treatment of 13-20
with sec-BuLi, a metal−halogen exchange and retro-Brook
rearrangement occurred to generate intermediate 13-21. One-
pot triflation of 13-21 with PhNTf2 furnished cyclohexyne
precursor 13-22; while quenching 13-21 with aqueous sodium
bicarbonate produced α-silyl ketone 13-23, which was then
converted to 1,2-cyclohexadiene precursor 13-24. This
Chem. Rev. 2021, 121, 3892−4044
could readily prepare N-tosyl-3-azacyclohexyne precursor 13- Scheme 297. Reactions on Cyclohexyne by Pérez and
32. Guitián
In 2015, Houk, Garg, and co-workers demonstrated an
efficient preparation of 3,4-piperidyne precursor 13-36
(Scheme 296a).155 The synthesis commenced with ortho
Scheme 296. Preparation of 3,4-Piperidyne and Aza-1,2-

cyclohexadiene Precursors
In 2014, Houk, Garg, and co-workers systematically

investigated the reaction between cyclohexynes and various
1,3-dipoles, furnishing 5-membered heterocycles 13-46
(Scheme 298).154 A variety of trapping agents, i.e., azide,
Scheme 298. Reactions on Cyclohexyne by Houk and Garg
silylation of 4-methoxypyridine (13-33) to afford silylpyridine

13-34 in 77% yield. Next, one-pot reductive carbamoylation
and hydrolysis yielded vinylogous amide 13-35 in high yield.
At last, a conjugate reduction/triflation operation on 13-35
furnished a protected 3,4-piperidyne precursor 13-36. With
this protocol in hand, they accomplished the synthesis of a
series of aza-1,2-cyclohexadiene precursors.157 As shown in
Scheme 296b, vinylogous amide 13-37, prepared from 4-
methoxypyridine (13-33) through a similar preparation
procedure to that in Scheme 296a, was converted to either
ketone 13-38a or 13-38b after 1,4-reduction with L-Selectride
and followed with protonation or methylation, respectively.
diazo compound, N-phenylpyrazole, nitrone, and nitrile oxide,
After triflation, o-silyl triflates 13-39 were obtained. Alter-
were effective with respect to cyclohexyne. In addition, they
natively, ketones 13-38 could be transformed to enols 13-40,
employed 3-benzyloxycyclohexyne (13-47) in the reactions
which then underwent triflation to yield o-silyl triflates 13-41.
with both imidazole and benzyl azide, which could afford the
13.2. Cyclohexyne Reactions corresponding products in good to high regioselectivity. These
In 2002, Pérez, Guitián, and co-workers reported a transition- regioselectivities were predicted by their distortion/interaction
metal-catalyzed cyclotrimerization of cyclohexyne, affording model as well.
dodecahydrotriphenylene (13-42) in moderate yield (Scheme In 2014, Danheiser et al. examined the reactivity of N-tosyl-
297a).917 Both Pd(PPh3)4 and Pt(PPh3)4 were found to be 3-azacyclohexyne (13-32) in the presence of various
active catalysts in this transformation. Later in 2006, Peña arynophiles, i.e., tetracyclone, benzyl azide, and Bu3SnH, all
examined a Pd-catalyzed [2 + 2 + 2] cocyclotrimerization of of which could afford the corresponding products 13-48 in
cyclohexynes with alkynes, which could furnish octahydrophe- moderate to high yields with excellent regioselectivity (Scheme
nanthrenes 13-43 in moderate yields (Scheme 297b).918 In 299a).916 Subsequently, Bräse and co-workers reported the
addition, they also studied the reactivity of cyclohexyne cycloaddition reactions of compound 13-32 with sydnones 13-
precursor in the presence of catalytic amount of Ni(COD)2 49, furnishing fused amino-substituted pyrazole scaffolds 13-
and obtained 13-45 in 27% yield, along with 10% of 13-42 50a and 13-50b (Scheme 299b).919 In 2015, Houk, Garg, and
(Scheme 297c).918 It was proposed that the formation of 13- co-workers studied the reactivity of 3,4-piperidyne precursor
45 was from the Diels−Alder reaction of two molecules of 13-36 with different arynophiles (Scheme 299c).155 Based on
dimer 13-44. their distortion/interaction model calculations, they predicted
Chem. Rev. 2021, 121, 3892−4044
Scheme 299. Reactions on Aza/Oxo-Cyclohexynes Scheme 300. Preparation of Heteroatom-Containing PAHs

by Garg
than that of oxadiazinone 13-53. Meanwhile, Yoshida, Hosoya,

and co-workers reported a chemoselective preparation of
similar compounds from the reaction of oxadiazinone 13-53
with precursors of cyclohexyne and arynes.189 Besides, those
Kobayashi precursors of cyclohexynes have also been utilized
along with the studies on arynes, such as distannylation,823
acyl-alkylation/condensation,710 cycloaddition,134 the reaction
with sulfoxonium ylides,417 and asymmetric C-arylation of
chiral enamines.407
In 2018, Li and co-workers developed a facile preparation
toward cyclohexenynone precursors as equivalents of poly-
substituted cyclohexynes.920 As shown in Scheme 301a,
that the C4 position is more electrophilic in the reactions with oxidative dearomatization of o-silylaryl triflates 13-57 and
nucleophiles and unsymmetrical cycloaddition partners. In
2016, the same group also investigated the reactivity of 3,4- Scheme 301. Cyclohexenynone Precursors
oxacyclohexyne precursor 13-51 with various arynophiles.153
As shown in Scheme 299d, their distortion/interaction model
calculation indicated that the C4 position of 3,4-oxacyclohex-
yne (13-52) is more electrophilic, which was then confirmed
by their experimental results.
Recently, Garg and co-workers applied 3,4-piperidyne
precursor 13-36 in the preparation of heteroatom-containing
PAHs (Scheme 300).903 In this study, oxadiazinone 13-53 was
utilized to trap 3,4-piperidyne intermediate, affording pyrones
13-54a and 13-54b as a mixture of regioisomers. The isolated
13-54a was then subjected to a second Diels−Alder reaction
with various arynes and cyclic alkynes, resulting in the modular
syntheses of PAHs 13-55a and 13-55b (Scheme 300a). In this
study, a three-component coupling reaction was also realized
by using equal molar concentrations of 3,4-piperidyne
precursor 13-36, Kobayashi benzyne precursor, and oxadiazi-
none 13-53, giving rise to 13-56 as the only product (Scheme
300b). They reasoned that 3,4-piperidyne is more readily
generated from its precursor 13-36 than that of benzyne. In
contrast, the reaction of oxadiazinone 13-53 with benzyne only
obtained double cycloaddition product, which could be
explained by the higher reactivity of the benzopyrone
intermediate generated after the first Diels−Alder reaction
Chem. Rev. 2021, 121, 3892−4044
13-59 containing a phenol moiety was utilized to access two Scheme 303. Reactions on 1,2-Cyclohexadiene and
types of cyclohexenynone precursors 13-58 and 13-60, Azacyclic Allenes by Houk and Garg
respectively. Moreover, both 13-58 and 13-60 could be
converted to a variety of densely functionalized cyclohexyne
precursors by further manipulating the carbonyl, olefin, and
methoxy groups. A study on these cyclohexenynone precursors
with different arynophiles revealed that they could readily
participate in cycloaddition reactions and nucleophilic
additions to produce the corresponding products in moderate
to high yields. In this study, they also demonstrated that the
reaction of these densely substituted cyclohexyne precursors
with aryl allyl sulfoxides 13-61 could afford 2,2-disubstituted
1,3-cyclohexadiones 13-63, which was formed via a [2,3]
sigmatropic rearrangement on an allyl sulfonium ylide
intermediate 13-62 (Scheme 301b).
13.3. 1,2-Cyclohexadiene Reactions preferential formation of the endo products. In addition, their
In 2009, Peña, Guitián, and co-workers investigated the DFT calculations explained that the regioselective control is
reactivity of 1,2-cyclohexadiene in both the [4 + 2] through either the stepwise or concerted reaction pathway.
cycloaddition reaction and Pd-catalyzed [2 + 2 + 2] Meanwhile, West et al. examined the reaction of 1,2-
cocyclotrimerization with alkyne.910 As shown in Scheme cyclohexadiene with various 1,3-dipoles, such as nitrones,
302a, the [4 + 2] cycloaddition reaction of 13-7a with both nitrile oxides, and azomethine imines, all of which could
furnish the corresponding products in high regio- and
Scheme 302. Reactions on 1,2-Cyclohexadiene stereoselectivity.911 In 2018, the same group reported an in-
depth study on azacyclic allenes.157 As shown in Scheme 303b,
azacyclic allene precursors 13-39 (R = H) and 13-41 (R =
CO2Me) were subjected to the Diels−Alder reactions with
furans and N-phenylpyrrole, affording cycloadducts 13-72 in
moderate to excellent yields. It was observed that the site of
cycloaddition was distal to the methyl group and proximal to
the ester group on 13-39 and 13-41. Their DFT calculations
suggested a concerted asynchronous endo transition state.
Moreover, they exhibited that the stereochemical information
could be transferred from enantioenriched precursor 13-39
and 13-41 to the cycloadducts 13-72.
13.4. 1,2,3-Cyclohexatriene Reactions
In comparison with the study on cyclohexynes and 1,2-
cyclohexadienes, there are only a few reports on 1,2,3-
cyclohexatriene with respect to the Kobayashi-type precursor.
In 1990, Johnson et al. treated 1,2,3-cyclohexatriene precursor
13-3 with CsF in the presence of diphenylisobenzofuran and
obtained cycloadduct 13-73, albeit in 24% yield (Scheme
304a).908 In 1994, Paquette and Hickey carried out the
Scheme 304. Reactions on 1,2,3-Cyclohexatriene
furan and tropone (13-64) afforded mixtures of endo- and exo-

cycloadducts 13-65 and 13-66, respectively, with excellent
endo-selectivity. Moreover, Pd-catalyzed [2 + 2 + 2]
cocyclotrimerization of 1,2-cyclohexadiene with DMAD
yielded compounds 13-67 and 13-68, albeit in low yields
(Scheme 302b). Mechanistically, after Pd-catalyzed trimeriza-
tion of 13-69, a fluoride-induced deprotonation/rearomatiza-
tion could generate anion 13-70. Consequently, both
protonation and nucleophilic addition to DMAD would
happen to yield 13-67 and 13-68, respectively.
In 2016, Houk, Garg, and co-workers systematically
investigated the reaction behavior of 1,2-cyclohexadiene with reaction of compound 13-3 with cyclopentadiene and achieved
nitrones.156 As shown in Scheme 303a, the reaction between
cycloadduct 13-74 in 74% yield, which was converted to
1,2-cyclohexadiene precursor 13-7a and nitrones occurred in
regioselective manner to afford isoxazolidines 13-71 with compound 13-75 for further study (Scheme 304b).921,922
Chem. Rev. 2021, 121, 3892−4044
14. SYNTHESES OF NATURAL PRODUCTS AND of tert-butyl 6-(furan-3-yl)-2,3-dimethoxybenzoate (14-8) and

BIOACTIVE MOLECULES aryne precursor 14-7, furnishing cycloadduct 14-9. After an
Along with the advances of Kobayashi’s method, it has also acid-promoted regiospecific lactonization and dehydration,
been applied in the preparation of natural products as well as arnottin I 14-10 was obtained. Further saponification on
bioactive molecules. There are several previous reviews on arnottin I, followed by a hypervalent iodide-mediated
aryne-involved synthesis of natural products, which include not spirocyclization, achieved the synthesis of racemic arnottin II
only Kobayashi’s method but also those from different 14-11.
precursors.78,79,92 This section will focus on the examples In the same year, Raminelli et al. accomplished the syntheses
related to o-silylaryl triflates. of a series of aporphine alkaloids (Scheme 307).926,927 The key
14.1. Cycloaddition Strategies
Scheme 307. Total Syntheses of Aporphine Alkaloids
In 1998, Guitián and co-workers accomplished a concise total
synthesis of ellipticine (14-6) by employing a regioselective [4
+ 2] cycloaddition reaction between 1,3-dimethyl-4-(phenyl-
sulfonyl)-4H-furo[3,4-b]indole (14-1) and 2-chloro-3,4-pyr-
idyne (14-3), generated from pyridyne precursor 14-2, as the
key step (Scheme 305).923 This transformation gave a mixture
Scheme 305. Concise Total Synthesis of Ellipticine
step for the construction of the aporphine core 14-13 is an

aryne [4 + 2] cycloaddition reaction with 1-methyleneisoqui-
nolines 14-12, which is followed by rearomatization via a
hydrogen migration event. Upon further modifications, (R)-
of regioisomers 14-4 and 14-5 in a 1:2.4 ratio. The isolated aporphine 14-14, lysicamine 14-15, (±)-nuciferine 14-16,
cycloadduct 14-5 then proceeded through a reductive cleavage (±)-nornuciferine 14-17, (±)-zanthoxyphylline iodide 14-18,
of the ether bridge with a following hydrogenolysis to produce (±)-O-methylisothebaine 14-19, and (±)-trimethoxynorapor-
ellipticine 14-6. Subsequently, they further investigated the [4 phine 14-20 were successfully prepared. Particularly, the
+ 2] cycloaddition reaction of 14-1 with a series of halo- preparation of (±)-zanthoxyphylline iodide 14-18, (±)-O-
substituted 3,4-pyridyne precursors and revealed that both 2- methylisothebaine 14-19, and (±)-trimethoxynoraporphine
bromo- and 2-fluoro-3,4-pyridynes yielded the corresponding 14-20 proceeded through a highly regioselective aryne
regioisomers in an ∼1:1 ratio.924 In addition, the reaction with Diels−Alder reaction by using 3-methoxybenzyne.927
5-chloro-3,4-pyridyne gave no regioselective control as well. In 2015, Rodriguez, Coquerel, and co-workers developed an
In 2015, Lewis and co-workers reported the concise total aryne aza-Diels−Alder reaction, which was applied in the total
syntheses of arnottin I 14-10 and arnottin II 14-11 (Scheme synthesis of benzo[c]phenanthridine alkaloid nornitidine 14-
306).925 The synthetic route involves a Diels−Alder reaction 25 (Scheme 308).236 This synthetic route contains two aryne
[4 + 2] cycloaddition reactions. First, Diels−Alder reaction of
Scheme 306. Total Syntheses of Arnottin I and II N-Boc-pyrrole 14-21 with aryne precursor 14-7 afforded
cycloadduct 14-22 in 88% yield. A sequential rhodium-
catalyzed ring opening on 14-22, deprotection of the Boc
group, and dehydration with DMF could readily prepare 2-aza-
diene 14-23. An aryne aza-Diels−Alder reaction with aryne
precursor 14-24 then occurred with a concomitant extrusion of
dimethylamine to realize the synthesis of nornitidine (14-25).
Nornitidine (14-25) was achieved in five steps with an overall
yield of 22%.
In 2017, Jeganmohan and Reddy developed a two-step
procedure to construct aristolactam alkaloid skeleton and
employed this strategy to realize the facile total syntheses of
caldensine (14-30), sauristolactam (14-31), N-methyl piper-
olactam A (14-32), aristolactam FI (14-33), cepharanone B
(14-34), norcepharanone (14-35), and piperolactam C (14-
Chem. Rev. 2021, 121, 3892−4044
Scheme 308. Total Synthesis of Nornitidine Scheme 310. Total Synthesis of Clausenawalline D
resulting N-arylbenzotriazole 14-40 was subjected to photol-

36) (Scheme 309).245 In this study, a ruthenium-catalyzed ysis conditions to furnish clausenawalline D (14-41) in 22%
oxidative cyclization of benzamides 14-26 with vinyl sulfone yield along with the formation of its regioisomer in the same
amount.
Scheme 309. Total Syntheses of Aristolactam Alkaloids Aryne [2 + 2] cycloaddition reaction was also employed in
natural product synthesis. In 2012, Hsung et al. developed a
unique tandem process involving a successive aryne [2 + 2]
cycloaddition reaction with enamide 14-42/pericyclic ring-
opening/intramolecular Diels−Alder reaction process (Scheme
311).665 Starting from aryne precursor 14-7 and enamide 14-
42, compound 14-43 was obtained in 65% overall yield
through this tandem transformation. Upon hydroboration-
oxidation on compound 14-43, a 1:1 mixture of 14-44-cis and
14-44-trans could be obtained in 70% yield. The isolated 14-
Scheme 311. Total Syntheses of (±)-Chelidonine and

(±)-Norchelidonine
14-27 afforded 3-methyleneisoindolin-1-ones 14-28, which

then participated in an aryne [4 + 2] cycloaddition-
desulfonylation transformation to furnish the aristolactam
core 14-29.
In the same year, Bochet and co-workers achieved a total
synthesis of an antimalarial alkaloid clausenawalline D (14-
41).928 As shown in Scheme 310, the [3 + 2] cycloaddition
reaction of aryne precursor 14-37 with aromatic azide 14-38
gave a 1:1 mixture of regioisomers 14-39a and 14-39b in 82%
yield. Upon deprotection of the benzyl group on 14-39b, the
Chem. Rev. 2021, 121, 3892−4044
44-cis was then converted to (±)-chelidonine (14-45) and Scheme 313. Total Syntheses of Indolactam Alkaloids
(±)-norchelidonine (14-46).
14.2. Nucleophilic Annulation Strategies
In 2008, along with the study on the preparation of
isoquinolines through aryne nucleophilic annulation protocol,
Stoltz and co-workers demonstrated its application in an
expeditious total synthesis of papaverine (14-49).331 As shown
in Scheme 312a, starting from enamine 14-47, a dehydrative
Scheme 312. Total Syntheses of Papaverine and

(−)-Quinocarcin
aryne annulation reaction with 14-24 took place to afford

isoquinoline 14-48. After saponification and decarboxylation
on compound 14-48, papaverine (14-49) was obtained. This
strategy was also utilized by Stoltz et al. in the asymmetric total
synthesis of (−)-quinocarcin (14-54) (Scheme 312b).929 The
reaction between aryne precursor 14-50 and enamine 14-51
could produce isoquinoline 14-52 in 60% yield, which was peptide 14-58 to the C4 position of 6-bromo-4,5-indolyne
then converted to compound 14-53 in four steps. After (14-57) could afford compound 14-59 in 62% yield with high
saponification on the methyl ester, oxazolidine ring could be regioselectivity. Consequently, unsaturated ester 14-60 was
constructed via partial reduction of the lactam with lithium in obtained after debromination and dehydration. An annulation
liquid ammonia and an acid promoted cyclization, leading to approach with ZrCl 4 in DCM, followed by further
the formation of (−)-quinocarcin (14-54). modification, achieved the synthesis of indolactam V (14-
In 2011, Garg and co-workers accomplished a concise total 61). In 2014, the same group optimized several key steps and
synthesis of indolactam V 14-61 via indolyne intermediate.151 achieved the total synthesis of (−)-indolactam V. 930
As shown in Scheme 313a, they proposed to use Kobayashi Furthermore, they developed a late-stage functionalization on
precursor of 6-bromo-4,5-indolyne 14-55, because the the C7 position of indolactam V (14-61) via a Pd-catalyzed
generated 6-bromo-4,5-indolyne (14-57) exhibited preferential cross-coupling reaction, allowing the assembly of a quaternary
C4 regioselectivity in nucleophilic reactions. In comparison, a carbon center on this site.930 As shown in Scheme 313b,
typical 4,5-indolyne (14-56) prefers C5 regioselectivity. With compound 14-62 was obtained from indolactam V (14-61) in
this understanding in mind, they commenced a total synthesis two steps, which could then be transformed to 14-63 in 61%
toward indolactam V (14-61). Nucleophilic addition of yield through an alkylative coupling strategy. After three-step
Chem. Rev. 2021, 121, 3892−4044
modification, (−)-pendolmycin (14-64) was prepared. Sim- be prepared, which was then subjected to Claisen rearrange-
ilarly, both (−)-lyngbyatoxin A (14-65) and (−)-teleocidin A- ment conditions with a subsequent universal removal of benzyl
2 (14-66) were synthesized using this strategy as well. protecting groups, giving rise to toxyloxanthone B (14-76) in
In 2013, Argade and Vaidya developed a nucleophilic 64% yield.
annulation reaction between arynes and substituted 1,3- In 2016, He et al. developed a formal [3 + 2] cycloaddition
quinazolin-4-ones 14-67 and applied this protocol in the facile strategy between arynes and 2-aminoquinones to afford the
syntheses of tryptanthrin, phaitanthrins, and cruciferane calothrixin framework, the mechanistic pathway of which
(Scheme 314).451 The reaction of compound 14-67 with proceeds through a C-nucleophilic addition to aryne and
cyclization to form a C−N bond.471 Subsequently, they
Scheme 314. Total Syntheses of Tryptanthrin, employed 2-aminophenanthridinedione (14-77) as the sub-
Phaitanthrins, and Cruciferane strate to react with benzyne and obtained an indolo[3,2-
j]phenanthridine alkaloid calothrixin B (14-79) in 26% yield
via intermediate 14-78, although there might be other
mechanistic possibilities (Scheme 316a).932 Further oxidation
of 14-79 with m-CPBA furnished calothrixin A (14-80) in 71%
yield. In 2017, Guo, He, and co-workers accomplished the
modular syntheses of dictyodendrins F, G, H, and I by using
the same protocol.933 As shown in Scheme 316b, pyrrolinone
14-82 was prepared in six steps from aminoquinone 14-81,
Scheme 316. Total Syntheses of Calothrixins and

Dictyodendrins
benzyne afforded tryptanthrin (14-68) in excellent yield. Next,

K2CO3-induced aldol condensation of 14-68 with acetone gave
phaitanthrin A (14-69) in 79% yield. Alternatively, phaitan-
thrin B (14-70) was prepared by treating 14-68 with methyl
acetate and LDA. Subsequent borohydride-induced induced
reductive intramolecular cyclization on 14-70 constructed
(±)-cruciferane (14-71) in 82% yield.
In 2014, Moody and co-workers accomplished a total
synthesis of toxyloxanthone B (14-76).931 As shown in Scheme
315, this synthesis involves an aryne nucleophilic annulation
reaction between methyl salicylate 14-72 and o-silylaryl triflate
14-73, furnishing the xanthone framework 14-74 in
regioselective manner. Consequently, compound 14-75 could
Scheme 315. Total Synthesis of Toxyloxanthone B
Chem. Rev. 2021, 121, 3892−4044
which was then subjected to the reaction with o-silylaryl triflate Scheme 318. Enantioselective Total Synthesis of
14-50 to afford annulated product 14-83 in 40% yield. (+)-Amurensinine
Universal removal of the methyl groups on 14-83 with BBr3
completed the synthesis of dictyodendrin F (14-84) in 54%
yield. Similar synthetic procedure on modified substrates led to
the preparation of dictyodendrins G, H, and I.
In 2018, Zhu and co-workers demonstrated an aryne
annulation protocol with α-amino imides, furnishing 2,2-
disubstituted indolin-3-ones with direct incorporation of 2-
aminoethyl or 2-aminopropyl substituents. By employing this
methodology, they realized an enantioselective total synthesis
of marine alkaloid (+)-hinckdentine A (14-91) (Scheme
317). 934 This synthesis commenced with a catalytic
Scheme 317. Enantioselective Total Synthesis of

(+)-Hinckdentine A
produced (−)-14-95 in 90% ee (path a, Scheme 318). This

(−)-14-95 was then converted to (+)-amurensinine (14-96) in
four steps. Alternatively, they transformed (±)-14-95 to
hydroxysilane (±)-14-97 first and subjected it to oxidative
kinetic resolution conditions to produce (−)-14-97 in 47%
yield and higher than 99% ee (path b, Scheme 318). After a
few steps, (+)-amurensinine (14-96) was achieved in 99% ee
from hydroxysilane (−)-14-97.
In 2010, Stoltz et al. reported a concise enantioselective total
synthesis of benzannulated macrolactone natural product
(−)-curvularin using this aryne C−C σ-bond insertion
protocol as the key step.937 As shown in Scheme 319, the
synthesis started with acetate 14-98, which could be converted
to β-ketolactone 14-99 in four steps. The insertion reaction of
enantioselective Michael addition of methyl α-(2-nitrophen- 14-99 with aryne precursor 14-73 furnished benzannulated
yl)-α-isocyanoacetate (14-85) to phenyl vinyl selenone (14- macrolactone 14-100 in 30% yield. After deprotection of the
86), affording (S)-14-87 in moderate ee. After four-step benzyl groups, (−)-curvularin (14-101) was obtained in 8%
manipulation, imide 14-88 was prepared, which then overall yield from acetate 14-98. Moreover, this aryne insertion
participated in a nucleophilic annulation reaction with benzyne
to produce indolin-3-one 14-89. Further five-step modification Scheme 319. Enantioselective Total Synthesis of
furnished compound 14-90. After selective bromination and (−)-Curvularin
oxidation with NMO, (+)-hinckdentine A (14-91) was
afforded.
14.3. Insertion Reaction Strategies
Accompanied with the discovery on aryne insertion into the
C−C bond of β-ketoester,489 Stoltz and co-workers employed
this methodology to realize a convergent and enantioselective
total synthesis of (+)-amurensinine (14-96).935,936 As shown
in Scheme 318, β-ketoester 14-93 was readily prepared in six
steps from (3,4-dimethoxyphenyl)acetic acid (14-92), which
then participated in a C−C σ-bond insertion reaction with
aryne precursor 14-7 to afford ketoester (±)-14-94 in 57%
yield. The reduced hydroxyester (±)-14-95 was subjected to
oxidative kinetic resolution using Pd(sparteine)Cl2 and O2 and
Chem. Rev. 2021, 121, 3892−4044
strategy has also been employed in the facile preparation of Scheme 321. Syntheses of Radermachol and Darenzepine
cytosporone B and phomopsin C,938 isocoumarins thunbergi-
nol A and xyridine A,719 tofisopam,939 and turkiyenine940 by
other groups.
In 2016, Chandrasekhar and co-workers employed aryne
insertion strategy as the key step to achieve a formal total
synthesis of pentacyclic alkaloid (±)-cephalotaxine (14-107)
(Scheme 320).941 Starting from β-ketoester 14-102, a C−C σ-
Scheme 320. Total Synthesis of (±)-Cephalotaxine
Scheme 322. Total Synthesis of Cossonidine
bond insertion with aryne precursor 14-7 yielded 14-103 in

72% yield. The Wacker oxidation of 14-103 afforded 14-104 in
70% yield, which was converted to spiro pyrrolidine 14-105 as
a crude intermediate. Upon removal of the Boc group and
lactam formation, pentacyclic compound 14-106 could be
assembled. After five-step modification from 14-106,
(±)-cephalotaxine (14-107) was achieved.
In the same year, Srihari, Mehta and co-workers employed
aryne insertion protocol to construct benzannulated medium-
rings, which was used in the preparation of pentacyclic natural
product radermachol (14-111)942 and potent antiulcer agent
darenzepine (14-114).414 As shown in Scheme 321a, the
reaction between aryne precursor 14-108 and indan-1,3-dione
(14-109) could readily access benzannulated cycloheptane-
dione 14-110 in 78% yield. Subsequent three-step trans-
formations realized the synthesis of radermachol (14-111).942 of the nitrile group with cobalt boride and borane t-butylamine
Meanwhile, darenzepine (14-114) was readily prepared complex on 14-118 was the next key step to reach tertiary
through a benzyne insertion into the C−C σ-bond of amine 14-119 after a further LiAlH4 reduction and photo-
compound 14-112 to furnish N-Boc-dibenzoazepinenone 14- chemical hydroamination. A sequential Birch reduction/
113 and a following three-step manipulation (Scheme intramolecular Diels−Alder reaction could set up the [2.2.2]
321b).414 bicycle on heptacyclic compound 14-120, which was trans-
In 2018, Kisunzu, Sarpong and co-workers demonstrated a formed to the target natural product cossonidine (14-121) in
total synthesis of hetisine-type natural product cossonidine six steps.
(14-121) by using the aryne insertion reaction as one of the In 2019, Slamon, Stoltz, and co-workers accomplished the
key steps (Scheme 322).943 The reaction between β-ketoester total syntheses of (−)-jorunnamycin A (14-130) and
14-116 and aryne precursor 14-115 assembled tricyclic (−)-jorumycin (14-131).711 As shown in Scheme 323, by
compound 14-117 in 38−45% yield, which was then converted employing their previously developed one-pot aryne acyl-
to compound 14-118 in five steps. Chemoselective reduction alkylation/condensation protocol,710 3-hydroxy-isoquinoline
Chem. Rev. 2021, 121, 3892−4044
Scheme 323. Total Syntheses of (−)-Jorunnamycin A and Scheme 324. Total Synthesis of (±)-Galanthamine
(−)-Jorumycin
(±)-galanthamine (14-137) was synthesized in seven steps

from compound 14-136.
Recently, Dai and co-workers reported their efforts toward
the synthesis of hamigeran natural products, the structures of
which contain a common 6−7−5 tricyclic carbon skeleton
(Scheme 325).945 This synthesis commenced with the reaction
Scheme 325. Synthesis toward the 6−7−5 Tricyclic Core of

Hamigerans
14-123 was obtained in 45% yield from aryne precursor 14-

122 and methyl acetoacetate through an in situ condensation
procedure. After triflation, the generated compound 14-124
was then coupled with isoquinoline N-oxide 14-125 using
modified Fagnou’s method, furnishing bis-isoquinoline 14-126
in 93% yield. After further transformations, compound 14-127
was prepared, which was subjected to the key asymmetric
hydrogenation reaction. After optimization, they found that
pentacycle 14-128 could be obtained in 83% yield with >20:1
dr and 88% ee by using [Ir(cod)Cl]2 and (S,RP)-BTFM-
Xyliphos (14-129) as the chiral ligand, leading to the
formation of four new stereocenters and a central C-ring
lactam. After five-step modification, (−)-jorunnamycin A (14- of β-ketoester 14-139 with aryne precursor 14-138 and
130) was achieved. In addition, (−)-jorunnamycin A (14-130) furnished C−C σ-bond insertion product 14-140 in 60%
could be readily transformed to (−)-jorumycin (14-131) in a yield. A six-step manipulation on bicyclic compound 14-140
single operation. could prepare dienone 14-141, which was subjected to
In the same year, Chandrasekhar et al. reported a total Nazarov cyclization conditions to construct tricyclic com-
synthesis of (±)-galanthamine (14-137) employing aryne pound 14-142. Next, they could introduce an all-carbon
insertion into the C−C σ-bond of γ-amino butyric acid as the quaternary center via either a Ni-catalyzed conjugate methyl
key step.944 As shown in Scheme 324, the reaction of β-formyl addition (path a) or a Corey−Chaykovsky reaction (path b),
ester 14-133 with aryne precursor 14-132 produced leading to the formation of the corresponding compounds 14-
compound 14-134 in a regioselective manner. Benzofuranone 143 and 14-144, respectively. Both 14-143 and 14-144 were
14-135 was then prepared from 14-134 in three steps, which converted to an advanced intermediate 14-145, which was
was further converted to tetracyclic lactol 14-136. Finally, expected to be transformed to hamigeran natural products.
Chem. Rev. 2021, 121, 3892−4044
In 2018, Heretsch, Christmann, and co-workers realized the were prepared from the corresponding precursors 14-153 and
syntheses of a series of 3,4-dioxygenated quinolin-2-one natural 14-154, respectively, via a successive Claisen rearrangement
products, including (±)-peniprequinolone, (±)-aflaquinolones and Grubbs’ olefin cross metathesis (Scheme 326b).485 Very
E and F, (±)-quinolinones A and B, and (±)-aniduquinolone recently, the same group realized the concise syntheses of
C (Scheme 326a).485 In this study, the key step was a yaequinolones J1 (14-157) and J2 (14-158) through a similar
synthetic procedure (Scheme 326c).946
Scheme 326. Syntheses of 3,4-Dioxygenated Quinolin-2-one 14.4. Cascade Reaction and MCR Strategies
Natural Products In 2011, Hwu and Hsu accomplished a total synthesis of
bioactive (−)-1-deoxy-D-fructose (14-163) via a benzyne-
induced olefination of β-amino alcohol (Scheme 327).657 In
Scheme 327. Total Synthesis of (−)-1-Deoxy-D-fructose
this study, they started with D-(+)-glucose (14-159) and

converted it to compound 14-160 in three steps. By treating
compound 14-160 with benzyne, a cascade process took place
to afford enol acetate 14-162 in 75% yield, the mechanistic
pathway of which includes a benzyne [3 + 2] cycloaddition
reaction to generate a tricyclic intermediate 14-161 and a retro
[3 + 2] cycloaddition process. After saponification and in situ
cyclization, the synthesis of (−)-1-deoxy-D-fructose (14-163)
was realized. Moreover, this benzyne-induced olefination
methodology was also applied in the preparation of various
deoxy and iminosugars.658
In 2019, Chudasama et al. disclosed a synthesis of
neurological medicine phenazepam (14-167).708 As shown in
Scheme 328, the reaction of acyl hydrazide 14-164, generated
from 2-chlorobenzaldehyde and diisopropyl azodicarboxylate
(DIAD), with benzyne produced 2-hydrazobenzophenone 14-
165 in 67% yield through a benzyne-based molecular
Scheme 328. Synthesis of Phenazepam
regioselective aryne insertion into the C−N σ-bond of

unsymmetrical imides 14-146, which could afford N-glycolated
2-aminobenzophenones 14-147 under continuous flow con-
ditions. An intramolecular aldol reaction would then assemble
3,4-dioxygenated quinoline-2-ones 14-148. This procedure was
applied to the syntheses of (±)-aflaquinolone E (14-149),
(±)-aflaquinolone F (14-150), (±)-quinolinone A (14-151),
and (±)-quinolinone B (14-152). Furthermore, (±)-anidu-
quinolone C (14-155) and (±)-peniprequinolone (14-156)
Chem. Rev. 2021, 121, 3892−4044
transformation process. Compound 14-166 was then obtained Wilkinson’s catalyst, which could furnish taiwanin C (14-176)
from 14-165. Subsequent bromination and alkylation-cycliza- in 64% yield. Alternatively, taiwanin E (14-177) was obtained
tion on compound 14-166 afforded phenazepam (14-167) in through Baeyer−Villiger oxidation of 14-175 and subsequent
77% yield. hydrolysis. This strategy was also applied in the total synthesis
Along with the study carried out by Yoshida et al. on three- of dehydrodesoxypodophyllotoxin by the same group.760
component coupling reaction of arynes, cyclic ethers, and In 2013, Argade and Patel developed a Pd-catalyzed [2 + 2 +
organic halides, they also applied this protocol in the synthesis 2] cocyclotrimerization of unsymmetrical conjugated dienes
of a benzo[b]oxepine-based nonsteroidal estrogen (Scheme and arynes, which could be applied in the concise syntheses of
329).560 The reaction of oxetane, aryne precursor 14-168, and justicidin B (14-181) and retrojusticidin B (14-182).761 As
shown in Scheme 331, arylnaphthalene 14-179 was prepared
Scheme 329. Total Synthesis of Benzoxepine
Scheme 331. Syntheses of Justicidin B and Tetrojusticidin B
(4-benzyloxyphenyl)ethynyl bromide (14-169) afforded 14-

170 in a regioselective manner. A platinum-catalyzed
diborylation reaction on the triple bond of 14-170 produced
vicinal diborylalkene 14-171, which was then converted to
benzoxepine (14-172) via a Suzuki−Miyaura coupling/base-
induced proto-deborylation/dechlorination pathway.
14.5. Transition-Metal-Catalyzed Strategies
In 2004, Sato, Mori, and co-worker applied a Pd-catalyzed [2 +
2 + 2] cocyclotrimerization of diynes and arynes in the total
syntheses of taiwanins C and E.759 As shown in Scheme 330,
Pd-catalyzed reaction of aryne precursor 14-7 with diyne 14-
in 66% yield from aryne precursor 14-24 and 14-178 by using
173 facilely assembled arylnaphthalene 14-174 in 61% yield.
this protocol, which was then converted to acid 14-180 via a
After four-step manipulation, compound 14-175 was obtained.
selective saponification on the less-hindered ester group.
Decarbonylation of 14-175 was realized by treating it with
Chemoselective reduction reactions on 14-180 were realized,
affording justicidin B (14-181) by using borane dimethyl
Scheme 330. Total Syntheses of Taiwanins C and E sulfide complex as the reductant as well as retrojusticidin B
(14-182) through the reduction with lithium borohydride.
In 2015, Jiang and co-workers employed their regiodivergent
approach on the Pd-catalyzed three-component coupling
reaction of arynes, 2-iodoanilines, and CO to synthesize both
phenanthridinone and acridone alkaloids (Scheme 332a).803
When aryne precursor 14-7 and N-methyl-2-iodoaniline (14-
183) (R = Me) were subjected to a Pd(OAc)2/dppm catalytic
system, acridone alkaloid 2,3-methylenedioxy-10-methyl-9-
acridanone (14-184) was achieved in 55% yield. Alternatively,
several phenanthridinone alkaloids 14-185 could be obtained
under ligand-free conditions. In 2016, Gogoi et al. accom-
plished a Pd-catalyzed cascade reaction of 4-hydroxycoumarins
14-186 with 14-7, which led to a facile synthesis of
flemichapparin C (14-187) (Scheme 332b).816
In 2016, a total synthesis of biologically active alkaloid
(±)-tylophorine was reported by Yao, Zhang, and co-
worker.783 As shown in Scheme 333a, α,β-unsaturated ester
14-189 was prepared in four steps from amine 14-188, which
Chem. Rev. 2021, 121, 3892−4044
Scheme 332. Syntheses of Acridone Alkaloid, Scheme 334, the generated 1,2-aryne intermediate 14-195
Phenanthridinone Alkaloids, and Flemichapparin C from 1,3-benzdiyne equivalent 14-194 reacted with chloro-
Scheme 334. Synthesis of Risperidone
Scheme 333. Syntheses of (±)-Tylophorine and Callosumin
oxime 14-196 to produce cycloadduct 14-197 in 52% yield as

a single regioisomer. Next, 3,4-aryne intermediate 14-198
could be generated from 14-197 and captured by fluoride ion,
giving rise to compound 14-199. Upon deprotection of the
Boc group and alkylation, risperidone (14-200) was success-
fully prepared.
In 2018, Li et al. applied their domino aryne nucleophilic-
ene cascade protocol in the preparation of ibutamoren
mesylate (14-206), which is used for the treatment of growth
hormone deficiency.882 As shown Scheme 335a, the reaction of
domino aryne precursor 14-201 with compound 14-202
constructed indoline 14-203 in 56% yield. Upon hydro-
genation, compound 14-204 was obtained. Selective amide
hydrolysis on compound 14-204 produced 14-205, which was
then converted to ibutamoren mesylate (14-206). In 2019, the
same group developed a domino aryne nucleophilic, [4 + 2]
cycloaddition reaction strategy and employed it to the
construction of an ergot alkaloid skeleton.356 As shown in
Scheme 335b, the synthesis commenced with the reaction of
14-201 with 3-(pyridin-2-yl)allyl sulfonamide 14-207, furnish-
ing tetracyclic compound 14-208 in 40% yield. Piperidine 14-
209 could be achieved in 91% yield via a one-pot, two-step
was then subjected to a Pd-catalyzed annulation reaction with
operation from 14-208. After deprotection of the Ts group and
aryne precursor 14-24 to construct phenanthrene 14-190 in
oxidative dehydration on 14-209, compound 14-210 was
46% yield. Subsequently, a three-step operation including
obtained in 81% yield, the structure of which shares an
deprotection of the Boc group/intramolecular cyclization/
identical core skeleton with that of lysergine.
lactam reduction could afford (±)-tylophorine (14-191).
In 2019, Ohmori, Suzuki, and co-workers accomplished an
Along with a study carried out by Ichikawa et al. on Ni-
enantioselective total synthesis of actinorhodin (14-218) by
catalyzed [4 + 2] cycloaddition reaction of styrenes with o-
employing 1,4-benzdiyne chemistry.947 As shown in Scheme
silylaryl triflates, they exhibited a concise preparation of a
336, 1,4-benzdiyne equivalent 14-211 was employed, the
naturally occurring stilbenoid callosumin (14-193) between
structure of which contains a Suzuki precursor with a I/OTs
3,5-dimethoxystyrene (14-192) and aryne precursor 14-24
pair and a Kobayashi precursor with a TMS/OTf pair. Upon
(Scheme 333b).839
activation with n-BuLi at low temperature (Suzuki’s activation
14.6. Benzdiyne Strategies conditions), 1,2-aryne 14-212 was selectively generated and
Along with the study on 1,3-benzdiyne equivalent 14-194, captured by furan to afford cycloadduct 14-213 in excellent
Ikawa, Akai, and co-workers reported a convergent synthesis of yield. Next, 4,5-aryne 14-214 was released under Kobayashi’s
antipsychotic drug risperidone (14-200).877 As shown in conditions, which then participated in a regioselective alkyl-
Chem. Rev. 2021, 121, 3892−4044
Scheme 335. Syntheses of Ibutamoren Mesylate and Ergot Scheme 336. Total Synthesis of Actinorhodin
Alkaloid Skeleton
Scheme 337. General Scheme for Pd-Catalyzed [2 + 2 + 2]

acylation reaction with methyl acetoacetate to produce ketone Cyclotrimerization
14-215. With ketone 14-215 in hand, further manipulation
afforded naphthol 14-216 in four steps. Dimerization of 14-
216 under Laatsch conditions (Ag2O, Et3N), followed by
reduction and protection of phenol, could furnish compound
14-217 in excellent yield. Finally, actinorhodin (14-218) was
synthesized in seven steps from compound 14-217.
15. PAHs, POLYMER CHEMISTRY, AND MATERIALS

SCIENCE fruitful achievements in the past 2 decades. Particularly, some
of those PAHs are otherwise inaccessible through traditional
Along with the blooming advances of Kobayashi’s method in
methods, further underlining the power and essential role of
the past 2 decades, people sought for its interdisciplinary
aryne chemistry in the field of PAHs.
applications, whereby exciting progress was achieved in the
In 1999, Pérez, Guitián, and co-workers reported Pd-
fields of polycyclic aromatic hydrocarbons (PAHs),81,99,948−951
catalyzed cyclotrimerization of 1,2-naphthalyne and 9,10-
polymer chemistry, and materials science. Particularly, as one
phenanthryne (Scheme 338).744 In this study, the reaction of
of the classical aryne reaction modes, [4 + 2] cycloaddition
unsymmetrical 1,2-naphthalyne yielded a mixture of trimers
reaction has been extensively utilized in this field.
15-1a and 15-1b in a 2.7:1 ratio. In addition, cyclo-
15.1. Preparation of PAHs trimerization of symmetrical 9,10-phenanthryne built com-
15.1.1. Through Pd-Catalyzed Cyclotrimerization. Pd- pound 15-2, a highly twisted molecular propeller, which was
catalyzed [2 + 2 + 2] (co)cyclotrimerization of arynes has later proven to be C2-symmetric.745 Subsequently, Cobas,
shown to be a powerful and convenient strategy to construct Pérez, Guitián, and co-workers further investigated the
structurally complex PAHs from relatively simple and readily reactivity of unsymmetrical arynes. They found that both
achievable o-silylaryl triflates. As shown in Scheme 337, various 3,4-phenanthryne and 1,2-triphenylyne could yield unsym-
PAHs bearing a common triphenylene core could be metrical products as well. With the employment of the
assembled through Pd-catalyzed [2 + 2 + 2] cyclotrimerization Kobayashi precursor of 3,4-phenanthryne, a double helicene
of arynes. Soon after the first discovery of this methodology, 15-3 constituted by a [5]helicene and a [7]helicene unit with
the groups of Pérez, Peña, and Guitián commenced their two rings in common was obtained, the relative configuration
exploration toward the preparation of PAHs and accomplished of which was established by their 1H NMR data and
Chem. Rev. 2021, 121, 3892−4044
Scheme 338. PAHs via Pd-Catalyzed Cyclotrimerization
Scheme 339. More Cyclotrimerized PAHs
calculations.746 In 2008, Pd-catalyzed cyclotrimerization of 1,2- twist.953 In 2009, Chi, Wu, and co-workers first prepared
triphenylyne was also examined, giving rise to nonplanar hexamethyltriphenylene 15-6 from 4,5-dimethylbenzyne,
polycyclic arene 15-4 in 10% yield.952 which was then converted to electron-deficient trinaphthylene
Cyclotrimerization of both 3,6-dimethylbenzyne and 4,5- carboximides 15-7.954 Moreover, they observed a long-range
dimethylbenzyne were studied. In 2007, Mount, Galow et al. columnar stacking on 15-7, which might be used as n-type
prepared 1,4,5,8,9,12-hexamethyltriphenylene 15-5 from 3,6- semiconductors in electronic devices.
dimethylbenzyne, the crystal structure of which is C2- More exciting applications on this Pd-catalyzed cyclo-
symmetric and highly distorted with a 53° end-to-end trimerization protocol were reported by different research
Chem. Rev. 2021, 121, 3892−4044
Scheme 340. Cyclotrimerization of Indolynes
Scheme 341. PAHs via On-Surface Cyclodehydrogenation Reactions
groups, and the structural complexity of the corresponding which prefers a highly nonplanar “twist” conformation of C1
triphenylene-based products has been significantly enhanced symmetry.958 Since 2012, Peña and co-workers have system-
(Scheme 339). In 2004, Pérez, Vollhardt, and co-workers atically synthesized a series of nanographene structures by
employed biphenylynes to assemble C3-symmetric trimers 15- employing this cyclotrimerization protocol. They first demon-
8,110 which was later found to reversibly and selectively add strated that hexaphenyl-substituted [16]cloverphene 15-12
onto a semiconductor surface via Diels−Alder reaction.955 could be prepared in 22% yield, which is a cata-condensed
Both substituted 2,3-triphenylynes956 and 2,3-naphthalynes957 PAH with a C3-symmetric conformation.959 The presence of
were able to trimerize to furnish the corresponding 15-9 and six phenyl groups could induce distortion from planarity and,
15-10, respectively. In 2011, Sygula et al. examined a Pd- hence, enhance the solubility. Subsequently, they synthesized
catalyzed cyclotrimerization of corannulyne and obtained a two new types of nanographenes: a 3-fold symmetric molecule
crowded PAH 15-11 with a formula of C60H24, the structure of 15-13 with 22 fused benzene rings960 and 15-14 with a 19
Chem. Rev. 2021, 121, 3892−4044
Scheme 342. Study on Isobenzofuran Trimer 15-29
cata-fused benzene rings distributed within six branches.961 15.1.2. Through Pd-Catalyzed Cocyclotrimerization.
Due to the extreme insolubility of the products, however, As has been discussed in section 10, alkynes are efficient
conventional characterization methods were not applicable. In components in Pd-catalyzed cocyclotrimerization reactions.
this context, they employed scanning probe microscopy There are two types of reaction modes: aryne−aryne−alkyne
techniques, both noncontact atomic force microscopy (nc- cyclotrimerization mode (path a) and aryne−alkyne−alkyne
AFM) and scanning tunneling microscopy (STM), with atomic cyclotrimerization mode (path b) (Scheme 343).
resolution to characterize these PAHs.
In 2017, Garg, Houk, and co-workers demonstrated a Pd- Scheme 343. General Scheme for Pd-Catalyzed
catalyzed cyclotrimerization of indolynes (Scheme 340).962 Cocyclotrimerization of Arynes with Alkynes
Kobayashi precursors of 4,5-indolyne 15-15, 5,6-indolyne 15-
17, and 6,7-indolyne 15-19 were examined, each of which
produced a pair of indole-based conjugated trimers. Their
computational study also described the structural and photo-
physical properties of these compounds.
In the same year, Tsurusaki, Kamikawa, and co-workers
subjected aryne precursor 15-21 to Pd-catalyzed cyclo-
trimerization conditions and obtained hexapole helicenes 15-
22 with six [5]helicene subunits (Scheme 341a).963,964 Both
their experimental study963 and theoretical examination964
suggested a first formation of saddle-like C2-symmetic 15-22a
in the Pd-catalyzed cycloaddition step, which could be In an early study carried out by Pérez, Guitián, and co-
quantitatively converted to more stable propeller-like D3- workers, they found that the employment of Pd(PPh3)4 as the
symmetic structure 15-22b under thermal conditions. In 2019, catalyst normally results in the phenanthrene framework;
Godlewski, Peña, and co-workers further subjected 15-22b to whereas in the presence of Pd2(dba)3, the reaction favors
on-surface Au-promoted cyclodehydrogenation conditions, naphthalene derivatives (Scheme 210).749 In 2004, they
reported the preparation of both 15-32a and 15-32b using
furnishing nanographene 15-23 with 3-fold symmetry.965
this protocol (Scheme 344).110 Subsequently, they examined
This PAH was characterized by scanning probe microscopy
cocyclotrimerization of 7-methoxy-1,2-didehydronaphthalene
with atomic resolution. Recently, Godlewski, Peña, and co-
with DMAD and obtained compounds 15-33a, 15-33b, and
workers were able to further convert PAH 15-25, prepared
15-33c in a 5.9:8.6:1 ratio.968 Furthermore, an asymmetric
from aryne precursor 15-24, to trigonal porous nanographene version was examined, which could reach pentahelicene 15-33a
on the gold surface in two on-surface cyclodehydrogenation with up to 76% ee. Although the enantioselectivity in this
reactions (Scheme 341b).966 At 300 °C on the gold surface, reaction was not high, it was claimed to be the first transition-
compound 15-26 was first formed; while heating at 370 °C, metal-catalyzed enantioselective cycloaddition reaction with
triporous nanographene 15-27 could be produced, the arynes. When cycloaddition of 2,3-triphenylynes with DMAD
structure of which contains 102 sp2 carbon atoms. In addition, was examined, compounds 15-34a and 15-34b were
nc-AFM and STM techniques were utilized to analyze these obtained.956 Further study on 15-34b analogues revealed
structures. that they could self-assemble and form ordered mesophases.969
Besides, Hamura et al. demonstrated that the cyclo- In 2008, both 3,4-phenanthryne and 1,2-triphenylyne were
trimerized product 15-28 from the corresponding o-silylaryl studied, affording the corresponding sterically congested PAHs
triflates could serve as an equivalent of isobenzofuran trimer 15-35 and 15-36, respectively.952 Similarly, PAHs 15-37959
15-29. Under thermal conditions, a retro Diels−Alder reaction and 15-38961 were also prepared from more complex aryne
occurred to extrude three tetraphenylcyclopentadienone precursors along with the study on aryne cyclotrimerization
molecules and generate intermediate 15-29. Subsequent (Scheme 344).
cycloaddition of 15-29 with naphthoquinone 15-30 afforded Recently, Tsurusaki, Kamikawa, and co-workers demon-
the Y-shaped polycyclic aromatic ketone 15-31 (Scheme strated a distinct Pd-catalyzed enantioselective cross-cyclo-
342).967 trimerization of two helicenyl arynes with dialkyl acetylenedi-
Chem. Rev. 2021, 121, 3892−4044
Scheme 344. PAHs from Pd-Catalyzed Cocyclotrimerization with Alkynes
carboxylate, yielding optically active triple helicenes 15-39 with 15.1.4. Benzdiyne and Naphthodiyne Strategies. A
an enantiomeric ratio of up to 98:2 by using (S)-QUINAP as common strategy is to perform 2-fold Diels−Alder reactions
the ligand (Scheme 344).970 Their DFT calculations indicated between equivalents of benzdiyne/naphthodiyne and dienes
that the enantioselectivity originates from the dynamic kinetic containing polycyclic aromatic rings. This strategy has the
resolution of a five-membered palladacycle intermediate. In advantage that those polyaryne precursors can quickly expand
2011, Kitamura et al. reported the preparation of tetracene the aromatic system through simple operations.
octaesters 15-40 via a Pd-catalyzed 2-fold [2 + 2 + 2] 15.1.4.1. 1,4-Benzdiyne Strategies. As shown in Scheme
cocyclotrimerization with dialkyl acetylenedicarboxylates.971 346a, 1,4-benzdiyne equivalent 15-47 has been extensively
15.1.3. Through Pd-Catalyzed Annulation Reactions. utilized as a unique building block to reach linear PAHs 15-48
Since the first report by Larock et al. on Pd-catalyzed via a 2-fold Diels−Alder reaction process. After Wudl’s first
annulation reaction of arynes with 2-halobiaryls 15-41 to example on preparing heptacene from pyrano-diphenylcyclo-
pentadienone and 15-47 (Scheme 266),873 Sygula et al.
produce fused polycyclic aromatics 15-42,775,776 this protocol
accomplished the synthesis of bis-corannulenoanthracene 15-
has been employed by Mü llen and co-workers in the
50 from isocorannulenofuran 15-49 and 15-47 (Scheme
preparation of core-expanded rylenebis(dicarboximide) dyes 346b).975 Further Diels−Alder reaction of 15-50 with maleic
(Scheme 345). In 2007, Müllen et al. revealed the synthesis of anhydride harnessed compound 15-51, the angularly fused
dibenzocoronene bis(dicarboximide) 15-43 and core-modified structure of which could allow two benzocorannulene pincers
quaterrylenebis(dicarboximide) (QDI) 15-44, both of which to capture C60 with strong affinity.
possess significant hypsochromic shifts of absorption, excellent In 2017, Itami, Yamaguchi, and co-worker demonstrated a
photostabilities, and high fluorescence quantum yields.972 concise preparation of multiply arylated anthracenes 15-56a
Subsequently, the same group achieved core-expanded and 15-56b.976 As shown in Scheme 347, aryne [4 + 2]
perylene tetracarboxdiimide 15-45973 and terrylene tetracar- cycloaddition reaction of 15-52 as a precursor of 15-47 with
boxdiimide 15-46974 as well and investigated their optical tetraarylthiophene S-oxide 15-53 yielded tetraarylnaphthalyne
properties (Scheme 345). precursor 15-54 as a mixture of regioisomers after triflation.
Chem. Rev. 2021, 121, 3892−4044
Scheme 345. PAHs via Pd-Catalyzed Annulation Reactions
Scheme 346. PAHs via 1,4-Benzdiyne Chemistry
Consequently, a second [4 + 2] cycloaddition reaction of 15- supported the resonance structure predicted by the Clar
54 with tetraarylthiophene S-oxide 15-55 took place to afford model.
octaarylanthracenes 15-56a and 15-56b in 46% overall yield. 15.1.4.2. 2,6-Naphthodiyne Strategies. 2,6-Naphthodiyne
In a study carried out by Peña, Pascual, and co-workers on equivalent 15-63 received more attention than 1,4-benzdiyne
on-surface production of planar nanographenes, they prepared 15-47, which could afford various polycyclic aromatic
12-ring dibromo polycyclic aromatic compound 15-60 from frameworks 15-64 after double Diels−Alder reactions (Scheme
15-47 (Scheme 348a).977 The first Diels−Alder reaction of 15- 349a). Since 2007, Kitamura and co-workers prepared a series
47 with compound 15-57 assembled aryne precursor 15-58 in of 1,4,7,10-tetraalkyltetracenes 15-65 from the reaction of 15-
63 with 2,5-disubstituted furans and a subsequent deoxy-
37% yield, which then underwent a second Diels−Alder
genative aromatization, those of which exhibited different
reaction with tetraphenylcyclopentadienone (15-59) to solid-state optical properties (Scheme 349b).979−982 In 2016,
produce 15-60 in 61% yield. Recently, Peña, Pérez, and co- Moresco, Peña and co-workers reported that the double
workers reported a modified synthesis of kekulene (15-62) cycloadduct of 15-63 with furan could be converted to
from the key intermediate 5,6,8,9-tetrahydrobenzo[m]- tetracene (15-66) via on-surface reduction.983,984 This 2,6-
tetraphene (15-61), readily prepared from 15-47 and styrene naphthodiyne equivalent 15-63 was also employed in the
(Scheme 348b).978 The structure of individual kekulene (15- preparation of various PAHs via double [4 + 2] cycloaddition
62) was resolved by ultrahigh-resolution AFM and was reactions with cyclopentadienones, giving rise to 6,9,16,19-
simulated by their computational study. These studies tetraphenyl-1.20,4.5,10.11,14.15-tetrabenzooctatwistacene
Chem. Rev. 2021, 121, 3892−4044
Scheme 347. Preparation of PAHs 15-56 via 1,4-Benzdiyne Chemistry
Scheme 348. Other PAHs via 1,4-Benzdiyne Chemistry
(15-67)985 and other large acenes 15-68 to 15-71 (Scheme 15.1.4.3. 1,7-Naphthodiyne Strategy. In 2016, Pérez et al.
349b).986 employed compound 15-81 as 1,7-naphthodiyne equivalent to
A unique procedure was developed to prepare hexacene (15- readily prepare angularly fused acene derivatives 15-82, those
77) from 2,6-naphthodiyne equivalent 15-63. Inspired by the of which include benzo[c]phenanthrene (15-83), sterically
method developed by Hamura et al. toward the isobenzofuran congested polyarenes octaphenyl-benzo[c]-phenanthrene (15-
scaffold from the cycloadduct of benzyne with furan,987 Peña, 84), and 5,10,15,16-tetraphenylnaphtho[2,3-a]tetraphene (15-
Moresco, and co-workers first synthesized cycloadduct 15-72 85) (Scheme 351a).992
from 15-47 (Scheme 350a). Upon treatment of 15-72 with 15.1.4.4. 1,5-Naphthodiyne Strategy. In 2019, Uno et al.
3,6-di(2-pyridyl)-1,2,4,5-tetrazine (15-73), isobenzofuran 15- prepared 1,5-naphthodiyne equivalent 15-86 and subjected it
74 was generated and reacted in situ with 15-63 to afford a to the Diels−Alder reactions with cyclopentadiene and 1,3-
mixture of regioisomers 15-75. Further Diels−Alder reaction cyclohexadiene, obtaining cycloadducts 15-87 and 15-88,
of 15-75 with furan produced 15-76 as a mixture of four respectively (Scheme 351b).993 Both reactions resulted in
diastereomers, which was subjected to the surface-assisted 1:1 mixtures of syn- and anti-isomers. Furthermore, cyclo-
deoxygenation reaction on Au(111) to yield hexacene (15- adduct 15-87 could be converted to PAH 15-90; while syn-
77).988 Subsequently, this on-surface strategy was also applied oriented diethanochrysene-connected bisporphyrin syn-15-89
to the preparation of decacene (15-78),989 dodecacene (15- was prepared from 15-88. The 1:1 complex of syn-15-89 with
79),990 and tetraepoxy[10]cyclacene 15-80 (Scheme 350b).991 C60 or C70 was determined by X-ray diffraction analysis.
Chem. Rev. 2021, 121, 3892−4044
Scheme 349. PAHs via 2,6-Naphthodiyne Chemistry
Scheme 350. Other PAHs via 2,6-Naphthodiyne Protocols
15.1.5. Other Cycloaddition Strategies. The Diels− precursor 15-93 as well. In a study carried out by Itami,
Alder cycloaddition reaction has also been extensively utilized Yamaguchi, and co-workers toward hexaarylbenzenes of
in the preparation of other PAHs. In 2005, Kunai et al. different substituents, they accomplished the preparation of
prepared a trisaryne equivalent 15-91 containing a 1,3,5-triaryl tetraarylnaphthalene 15-99 via Diels−Alder reaction of
benzene core, which was then subjected to triple aryne tetraarylthiophene S-oxide with benzyne.998 In 2016, Mastalerz
transformation to afford 1,3,5-tris(9,10-diphenyl-2-anthryl)- and co-workers demonstrated a synthesis of conformationally
benzene (15-92) and other related compounds (Scheme highly stable contorted hexabenzoovalene 15-101 containing
352). 994 In 2008, Sygula and co-workers synthesized two peripheral triptycene units and six tert-butyl substituents
corannulyne precursor 15-93 and obtained cycloadducts 15- with improved solubility.999,1000 In this structure, two phenyl-
94, 15-95, and 15-96 in the reactions with various diene ene blades of the peripheral triptycene units are almost
arynophiles.995 Subsequently, they reported the preparation of coplanar. A double [4 + 2] cycloaddition reaction with
corannulene-based molecular clip 15-97996 and a highly triptycene-based aryne precursor 15-100 was involved in the
nonplanar hydrocarbon C80H32 15-98997 from corannulyne synthetic procedure. In 2018, Peña, Wornat, Gross, and co-
Chem. Rev. 2021, 121, 3892−4044
Scheme 351. PAHs from 1,7- and 1,5-Naphthodiyne
workers developed a method that can integrate AFM with 15.2. Polymer Chemistry
other analytical tools to identify PAHs from complex molecular o-Silylaryl triflates have also been employed in polymer
mixtures, which led to the detection of a seven-ring PAH chemistry, which could be divided to aryne (co)polymerization
benz[l]indeno[1,2,3-cd]pyrene (15-103).1001 Consequently, and modification on polymers. In 2005, Ihara, Inoue, and co-
PAH 15-103 was synthesized from 9,10-phenanthryne workers reported a polymerization of o-silylaryl triflates,
precursor 15-102. In addition, PAHs 15-1041002 and 15- affording polymer 15-116 via an alternating copolymerization
105904,1003 were readily prepared via a sequential [4 + 2] of aryne with pyridine (Scheme 354a).1007 However, there was
cycloaddition reaction with various o-silylaryl triflates and no observation of direct polymerization of arynes in this study.
oxidative aromatization. In 2004, Katz et al. prepared In 2015, Mikami, Uchiyama, and co-worker accomplished the
Kobayashi precursors bearing [6]- and [7]-helicene skel- first Cu-catalyzed direct polymerization of o-silylaryl triflates,
etons.1004 Upon activation with fluoride, the generated aryne furnishing poly(ortho-phenylene)s 15-117 of up to ∼100-mer
species underwent an intramolecular Diels−Alder reaction to size in a straightforward manner (Scheme 354b).861 In this
the other ring on the frameworks, giving rise to bridged transformation, Lipshutz-type cuprate, nBu2Cu(CN)Li2, and a
derivatives 15-106, 15-107, and their analogues. broad range of monovalent copper salts were found to be
Recently, Jancarik, Gourdon and co-workers developed a essential for the success of this polymerization. Moreover, both
facile strategy to prepare various long acenes by using tetraene radical species and light were not able to initiate or promote
7,7-dimethoxy-2,3,5,6-tetramethylenebicyclo[2.2.1]heptane this polymerization.
(15-108) as the key synthon.1005,1006 As shown in Scheme In 2015, Craig et al. demonstrated their single-molecule
353a, double [4 + 2] cycloaddition reaction of 15-108 with force spectroscopy (SMFS) studies on the forbidden ring-
opening reactions of a series of polymers containing either
various o-silylaryl triflates could afford the desired acenes after
benzocyclobutene or cyclopropane units.1008 Among those
a few step manipulations. Consequently, heptacene (15-109),
polymers, polymer 15-121 was prepared via copolymerization
benzo[a]hexacene (15-110), cis-dibenzopentacene (15-111), of benzocyclobutene 15-119 with monoepoxidized cyclo-
and trans-dibenzopentacene (15-112) were readily prepared octadiene 15-120 (Scheme 355a). Benzocyclobutene 15-119
through this protocol. In 2019, Audisio et al. demonstrated the was obtained from [2 + 2] cycloaddition reaction of (E, Z)-1,5-
first approach to [4]-, [5]-, [6]-, and [7]-helicenes 15-115 cyclooctadiene 15-118 with benzyne. Subsequently, polymer
containing pyrazole moiety through regioselective 1,3-dipolar 15-124 was prepared by the same group starting from
cycloaddition reaction of o-silylaryl triflates 15-113 and benzocyclobutene 15-123 that was synthesized from 1,3-
sydnones 15-114 (Scheme 353b).315 This transformation cyclooctadiene (15-122) and benzyne (Scheme 355a).1009 In
was regioselective with preferential formation of more sterically 2017, Maynard, Garg, and co-workers reported a concise and
constrained heterohelicenes. Their DFT calculations indicated practical synthesis of air-stable benzonorbornadiene polymers
that the origin of selectivity was controlled by primary orbital 15-126, which was realized through the ring opening
interactions and C−H···π dispersive interactions. metathesis polymerization (ROMP) of the [4 + 2] cyclo-
Chem. Rev. 2021, 121, 3892−4044
Scheme 352. PAHs via Other Aryne [4 + 2] Cycloaddition Reactions
adducts 15-125 of benzyne with either cyclopentadiene or (Scheme 356).1022 In addition, modifications on carbon
furans (Scheme 355b). 1010 Meanwhile, Gidron et al. nanotubes, 1023−1025 carbon nanohorn, 1026 and gra-
demonstrated an efficient protocol to transform long phene1027−1029 with o-silylaryl triflates have also been reported.
oligofurans 15-127 to oligoarenes in a highly selective
manner.1011,1012 As shown in Scheme 355c, [4 + 2] 16. CONCLUSIONS
cycloaddition reaction of benzyne with oligofurans 15-127 In this review, we describe the history and development of
containing up to six units afforded the corresponding Kobayashi aryne precursors over the past 2 decades. As arynes
cycloadducts 15-128, which could be converted to the desired have to be released in situ from their precursors in any aryne
oligonaphthalenes 15-129 through a subsequent deoxygena- transformation, chemists have endeavored to search for “ideal”
tion operation. Besides, triptycene moieties, generated from aryne generation methods since the early era of aryne
the Diels−Alder reaction of anthracene with o-silylaryl triflates, chemistry. Among them, Kobayashi’s method has been
have also been utilized in polymer chemistry.1013,1014 recognized as one of the best protocols in modern aryne
15.3. Materials Science chemistry, primarily due to its mild generation conditions that
well accommodate a broad spectrum of functional groups as
15.3.1. Triptycene-Based Materials. Triptycenes gen- well as different types of aryne reactions. In this context, this
erated via the [4 + 2] cycloaddition reaction of anthracenes protocol not only significantly enhanced the efficiency of
with o-silylaryl triflates have been found useful in materials traditional aryne transformations, i.e., pericyclic reactions and
science. Some of those applications include triptycene-based nucleophilic reactions, but also provided a platform for
self-assembled thin films1015−1017 and the preparation of continuing discovery toward new synthetic strategies. For
supramolecular scaffolds.1018−1021 instance, insertion reactions and multicomponent reactions
15.3.2. Nanotube and Graphene. In 2016, Pérez, emerged along with the study on o-silylaryl triflates. Because of
Martin,́ and co-workers found that 1,4-benzdiyne equivalent the supreme compatibility advantage of this mild generation
15-47 could add to C60 to prepare a C60-aryne precursor 15- protocol, it has also been applied in a variety of distinct cascade
130, which could in turn connect with a second C60 or the or tandem reactions, some of which are otherwise hard to be
fewlayered graphene (FLG) unit to assemble compound 15- reached through other aryne generation methods. Particularly,
131 and FLG−C60 nanoconjugate 15-132, respectively the employment of o-silylaryl triflates commenced a new
Chem. Rev. 2021, 121, 3892−4044
Scheme 353. Other PAHs via Aryne Cycloaddition Scheme 355. Aryne-Involved Polymer Chemistry
Protocols
Scheme 354. Aryne (Co)polymerization
Scheme 356. 1,4-Benzdiyne as the Linker for C60 and

Fewlayered Graphene
research field on transition-metal-catalyzed aryne transforma-

tions, which also shows a great potential to incorporate
uncommon substituents or functional groups via transition
metal catalysis. Besides, Kobayashi precursors of polyarynes
have been extensively utilized to access various polysubstituted
arenes, especially in the expeditious construction of PAHs.
With the recent resurgence in aryne chemistry, there is no
doubt that more and more synthetic strategies as well as
applications will be developed in the future to further expand
the boundary of aryne chemistry. Meanwhile, some new
research fields might be unraveled with the discovery of a yet
unexplored reactivity/property of arynes, especially by
incorporating transition metals in aryne reactions. Although
it is traditionally difficult to imagine how to reach asymmetric reactions, such as through the preparation of chiral nonplanar
aryne transformations, a few recent examples suggested PAHs and in asymmetric arylation reactions. In addition, the
possible solutions on how to realize asymmetric aryne chemistry of hetarynes has not been sufficiently explored yet,
Chem. Rev. 2021, 121, 3892−4044
the success of which could assemble useful heterocyclic ACKNOWLEDGMENTS

aromatic compounds. Another exciting subfield would be the
The authors gratefully acknowledge research support of this
application of this generation protocol in angle-strained
work by the Basic and Frontier Research Project of Chongqing
aliphatic cyclic alkynes/allenes. Beyond traditional aryne
(Grants cstc2018jcyjAX0357 and cstc2019jcyj-bshX0021),
transformations, unprecedented reaction modes as well as
Fundamental Research Funds for the Central Universities
asymmetric transformations should be developed associated
with Kobayashi precursors of cyclohexynes and 1,2-cyclo- (Grant 2018CDXZ0003), and NSFC (Grants 21971028,
hexadienes. For instance, an excellent work on nickel-catalyzed 21772017, and 21901025). J.S. was funded by the China
asymmetric reaction of 1,2-cyclohexadiene was reported by Postdoctoral Science Foundation (Grant 2018M640897).
Houk, Garg, and co-workers after we finished this review.1030
In view of the substantial body of evidence represented by ABBREVIATIONS
the myriad successes captured in this review, it is certain that Ac acetyl
with the assistance of Kobayashi’s mild generation method, acac acetylacetonate
both the intrinsic properties and synthetic potentials of aryne BHT 2,6-di-tert-butyl-4-methylphenol
as highly reactive, while synthetically important building Bn benzyl
blocks, will be further explored and exploited. There is an B2(pin)2 bis(pinacolato)diboron
undoubtedly bright future for this protocol. Boc tert-butyloxycarbonyl
2,2′-bpy 2,2′-bipyridine
AUTHOR INFORMATION Cp cyclopentadienyl
Corresponding Author Cy cyclohexyl
Yang Li − School of Chemistry and Chemical Engineering, cod 1,5-cyclooctadiene
Chongqing University, Chongqing, P. R. China 400030; coe cyclooctene
orcid.org/0000-0002-0090-2894; Email: y.li@ 18-c-6 18-crown-6
cqu.edu.cn DABCO 1,4-diazabicyclo[2.2.2]octane
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
Authors DCB 1,2-dichlorobenzene
Jiarong Shi − School of Chemistry and Chemical Engineering, DCE 1,2-dichloroethane
Chongqing University, Chongqing, P. R. China 400030; DCM dichloromethane
orcid.org/0000-0001-5723-6514 DDQ 2,3-dichloro-5,6-dicyanobenzoquinone
Lianggui Li − School of Chemistry and Chemical Engineering, DIPEA N, N-diisopropylethylamine
Chongqing University, Chongqing, P. R. China 400030 DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
Complete contact information is available at:
DMF N,N-dimethylformamide
https://pubs.acs.org/10.1021/acs.chemrev.0c01011
DMSO dimethyl sulfoxide
dba dibenzylideneacetone
Author Contributions
†
dppb 1,4-bis(diphenylphosphino)butane
J. Shi and L. Li contributed equally to this work. dppe 1,2-bis(diphenylphosphino)ethane
Notes dppf 1,1′-bis(diphenylphosphino)ferrocene
The authors declare no competing financial interest. dppm 1,1-bis(diphenylphosphino)methane
dppp 1,3-bis(diphenylphosphino)propane
Biographies dr diastereomeric ratio
Jiarong Shi was born in Jiangsu Province, China, in 1991. He received dtbpy 4,4′-di-tert-butyl-2,2′-dipyridyl
his B.Sc. (2013) and Ph.D. (2018) degrees from Chongqing EDC N-(3-(dimethylamino)propyl)-N′-ethylcarbodii-
University under the guidance of Professor Yang Li. As a student, mide
his research interests were on multiaryne chemistry. He is now an ETPO 4-ethyl-2,6,7-trioxa-1-phosphabicyclo-[2.2.2]-
Assistant Research Fellow at Chongqing University and is working on octane
the development of new aryne transformations. ee enantiomeric excess
Het heteroaryl
Lianggui Li was born in Guangxi Province, China, in 1993. He HFIP hexafluoroisopropanol
received his B.Sc. degree in Chemistry from Guangxi Normal HMDS hexamethyldisilazane
University in 2017. He joined Professor Yang Li’s group in 2017 as HMPA hexamethylphosphoramide
a Ph.D. student. His research interest is the study on new reaction HOBt 1-hydroxybenzotriazole
modes in aryne chemistry. IMes 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
Yang Li was born in Jilin Province, China, in 1978. In 2000, he IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene
received his B.Sc. degree from Jilin University, China, with Professor i-Pr isopropyl
Ruren Xu and Professor Jihong Yu. In 2006, he obtained his Ph.D. KHMDS potassium bis(trimethylsilyl)amide
degree from the University of Georgia under the guidance of LDA lithium diisopropylamide
Professor George Majetich. From 2006 to 2009, he was a Postdoctoral L-Selectride lithium tri-sec-butylborohydride
Fellow with Professor Vy M. Dong and Professor Datong Song at the Me methyl
University of Toronto. From 2009 to 2012, he was a Postdoctoral Mes 2,4,6-trimethylphenyl
Fellow with Professor Stephen J. Lippard at Massachusetts Institute of Mes* 2,4,6-tri-tert-butylphenyl
Technology. In 2012, he joined Chongqing University, China. His MOM methoxymethyl
research interests are benzyne chemistry and bioinorganic chemistry. Ms methanesulfonyl
Chem. Rev. 2021, 121, 3892−4044
MW microwave (8) Orendt, A. M.; Facelli, J. C.; Radziszewski, J. G.; Horton, W. J.;
m-CPBA m-chloroperoxybenzoic acid Grant, D. M.; Michl, J. 13C Dipolar NMR Spectrum of Matrix-Isolated
NBE norbornene o-Benzyne-1,2-13C2. J. Am. Chem. Soc. 1996, 118, 846−852.
NBS N-bromosuccinimide (9) Scheiner, A. C.; Schaefer, H. F., III; Liu, B. The X̃ 1A1 and ã3B2
NCS N-chlorosuccinimide States of o-Benzyne: A Theoretical Characterization of Equilibrium
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o‑Silylaryl Triﬂates: A Journey of Kobayashi Aryne Precursors

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numerous applications in expeditious preparation of substituted arenes. In the past 20 years,

CONTENTS 4.3. [2 + 2] Cycloaddition Reactions 3912

© 2021 American Chemical Society https://dx.doi.org/10.1021/acs.chemrev.0c01011

Figure 1. Timeline for aryne generation methods.

Figure 2. Structures of Kobayashi aryne precursors.

Scheme 2. ortho-Lithiation Strategies

thoxyborane/acidic workup. Subsequent oxidation and tri-

Scheme 4. Arene Ring Formation Strategies

preparation of o-silyl salicylaldehyde 2-6 from the methox-

Scheme 6. Postfunctionalization Strategies

could be converted to a variety of functional groups.

Scheme 11. Reversing the Regioselectivity on 4,5-Indolynes

3.4. Eﬀect of a Fused Small Ring

Scheme 14. General Scheme for Aryne Diels−Alder

intensive exploration on o-silylaryl triﬂates, not only conven-

Scheme 19. Aryne Diels−Alder Reaction/Eliminative

in the aryne Diels−Alder reaction to aﬀord the corresponding

after the elimination of a secondary amine moiety (Scheme

Scheme 21. Aryne Diels−Alder Reactions with Aza-1,3-

sequential aza-Diels−Alder reaction/N-arylation pathway

Scheme 23. Aryne Diels−Alder Reaction with o-Quinone

Styrenes are good Diels−Alder partners with arynes. In

25a).244 In this study, they proposed a ﬂuoride-assisted

4.2.1. With 4-Hydroxyisoquinolinium and 3-Oxido-

Scheme 29. Aryne 1,3-Dipolar Cycloaddition Reactions with

Scheme 27. Intramolecular Aryne Diels−Alder Reactions

this work, N-alkyl-4-hydroxy-1-methylisoquinolinium betaines

Scheme 32. Aryne 1,3-Dipolar Cycloaddition Reactions with

they disclosed that dicarbonyl-containing diazo compounds 4-

Scheme 33. Aryne 1,3-Dipolar Cycloaddition Reactions with

of Zhai258,259 and Reddy260 independently developed an aryne

Scheme 34. Aryne 1,3-Dipolar Cycloaddition Reactions with

zoles could ﬁnd more useful applications. In this context, Zajc

Scheme 37. Aryne 1,3-Dipolar Cycloaddition Reactions with

Scheme 39. Aryne 1,3-Dipolar Cycloaddition Reactions with

Meanwhile, Kaliappan and Khangarot developed a highly

Scheme 40. Aryne 1,3-Dipolar Cycloaddition Reactions with

(Scheme 42a).321 In 2014, Hu and co-workers developed an

Scheme 42. Reactions with Other 1,3-Dipoles

reaction, extrusion of CO2 occurred on the cycloadducts 4-117

structure of which was otherwise hard to be accessed (Scheme

Scheme 45. Aryne [2 + 2] Cycloaddition Reactions with

dipoles to react with arynes and obtained spirooxindole-3,2′-

allene ketones and 1-azadienes could participate in a further

Scheme 47. Other Aryne [2 + 2] Cycloaddition Reactions

In 2010, Cossı ́o et al. carried out both computational and

In 2014, Ma and Yuan observed an intramolecular aryne ene

5.1. N-Arylation Reactions conditions. Unsubstituted primary or N-alkyl amides, however,

workers showed that 3-aryl-1,2,4-oxadiazolones 5-11 under-

Scheme 57. N-Arylation Reactions with Isocyanates

a monoselective N-arylation reaction of aromatic tertiary

Scheme 56. N-Arylation Reactions with Tertiary Amines

catalytic amount of pyridine derivatives were needed in order

Scheme 58. N-Arylation Reactions with Other N- 5.2. O-Arylation Reactions

Scheme 60. O-Arylation Reactions with Phenols and

Raminelli et al. applied this method in the O-arylation of

unprecedented study, C-arylated products 5-54 with stereo-

Scheme 62. C-Arylation with β-Enamino Compounds

both N-arylation and C−C bond insertion products on 5-49.