Fully Substituted Conjugate Benzofuran Core: Multiyne Cascade Coupling and Oxidation of Cyclopropenone

Article abstract of DOI:10.1021/acs.orglett.1c01304

An unprecedented C═C double bond cleavage of cyclopropenone and dioxygen activation by multiyne cascade coupling has been developed. This chemistry provides a novel, simple, and efficient approach to synthesize fully substituted conjugate benzofuran derivatives from simple substrates under mild conditions. The density functional theory (DFT) calculations reveal that the unique homolytic cleavages of cyclopropenone and molecular oxygen are crucial to the success of this reaction.

Full text of DOI:10.1021/acs.orglett.1c01304

pubs.acs.org/OrgLett
Letter
Fully Substituted Conjugate Benzofuran Core: Multiyne Cascade
Coupling and Oxidation of Cyclopropenone
Liangliang Yao, Qiong Hu,* Li Bao, Wenjing Zhu, and Yimin Hu*
Cite This: Org. Lett. 2021, 23, 4971−4975
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An unprecedented CC double bond cleavage of
cyclopropenone and dioxygen activation by multiyne cascade coupling
has been developed. This chemistry provides a novel, simple, and efficient
approach to synthesize fully substituted conjugate benzofuran derivatives
from simple substrates under mild conditions. The density functional
theory (DFT) calculations reveal that the unique homolytic cleavages of
cyclopropenone and molecular oxygen are crucial to the success of this
reaction.
Scheme 1. Different Strategies in Attaining Benzofuran with
Pattern-Tunable Substituents and Our Work
enzofuran-based motifs are widely found in natural
products and biologically active compounds.1 In partic-
B
ular, fully substituted conjugate benzofuran cores are
ubiquitous structures in many leading drug candidates and
serve as precursors for the construction of related molecules.2
For example, rifampicin has a significant antitubercular
activity.3 Usnic acid, which is isolated from Usnea longissima,
has selective antioxidant action in reducing oxidative damage
(Figure 1).4 Given their widespread applications, several
efficient methodologies have been developed for the
construction of functionalized benzofurans.5
To data, there are two general strategies to assemble a fully
substituted conjugate benzofuran core in the literature. The
first strategy is based on transition metal-catalyzed C−H
functionalization, which can directly introduce the desired
functional groups to the substituted patterns (Scheme 1a).6
The second strategy proceeds via annulation, which capitalizes
on individual construction of the benzene or five-membered
heteroarenes (Scheme 1b).7 Although these transformations
are efficient and general, harsh reaction conditions, expensive
catalyst systems, and prefunctionalized substrates are the
unavoidable issues associated with them. Therefore, the
development of mild and metal-free strategies toward fully
substituted conjugate benzofuran is highly desirable.
Arynes are the most reactive organic species and have been
broadly employed in numerous organic syntheses.8 In
particular, the thermal cycloisomerization of tethered multi-
ynes to give benzyne intermediates has led to aryne chemistry
becoming a blossoming area in recent years.9 This so-called
hexadehydro-Diels−Alder (HDDA) reaction, demonstrated by
Received: April 18, 2021
Published: June 11, 2021
Figure 1. Fully substituted conjugate benzofuran-containing natural
products and drug candidates.
https://doi.org/10.1021/acs.orglett.1c01304
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4971−4975
4971

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
Scheme 2. Substrate Scope of Tetraynes
Scheme 4. Control Experiments
a
Reaction conditions: tetraynes 1 (1.0 mmol), 2,3-diphenylcycloprop-
2-enone 2a (1.2 equiv), H2O (1.0 equiv), acetonitrile (2 mL), stirred
b
at 95 °C under O2 for 12 h. Isolated yield.
a b
,
Scheme 3. Substrate Scope of Cyclopropenones
a
obtained. It seems that molecular oxygen is essential for this
transformation. After a brief screening of different reaction
parameters, including solvent, temperature, and molar ratio of
reactants, the optimal reaction conditions were identified as
follows: 1.0 equiv of tetraynes under O2 atmosphere reacted
with 1.2 equiv of cyclopropenes and 1.0 equiv of H2O in
acetonitrile (2 mL) at 95 °C for 12 h. Further investigation of
the catalysts indicated that the copper catalyst was an effective
system in oxygenation with molecular oxygen,14 but the
reaction proceeded well without metal catalysts or other
additives.
The scope of tetrayne substrates was investigated under the
optimized conditions. As depicted in Scheme 2, various
tetraynes containing different functional groups worked well
leading to the desired benzofurans (3a−3t) in moderate to
good yields (ranging from 63% to 85%). When tolerated,
tetrayne substrates bearing different esters (OMe, OEt, and
OiPr) gradually decreased in yields (3a (80%), 3b (75%), and
3c (73%)). By contrast, the substituted groups in the aryl ring
of tetraynes bearing electron-withdrawing groups, including
Reaction conditions: dimethyl 2,2-bis(5-phenylpenta-2,4-diyn-1-yl)-
malonate 1a (1.0 mmol), cyclopropenones 2 (1.2 equiv), H2O (1.0
equiv), acetonitrile (2 mL), stirred at 95 °C under O2 for 12 h.
b
Isolated yield.
Hoye’s group in 2012,10 can prepared polysubstituted arenes in
“one-pot” process.11 As a part of our research on the efficient
construction of polysubstituted arenes via HDDA-derived
benzyne chemistry,12 herein we report an unexpected metal-
free CC double bond cleavage of cyclopropenone, dioxygen
activation by multiyne cascade coupling, and reassembed into
fully substituted conjugate benzofuran derivatives (Scheme
1c).
When tetrayne 1p and 2,3-diphenylcycloprop-2-enone 2a
were initially investigated in our multicomponent coupling of
tetrayne for the corresponding C−O/C−S difunctionalized
benzene derivative synthesis,13 to our delight, an unexpected
fully substituted conjugate benzofuran 3p was obtained in 12%
yield in DMSO under air. In contrast, when the reaction was
performed under an Ar atmosphere, no product 3p was
4972
https://doi.org/10.1021/acs.orglett.1c01304
Org. Lett. 2021, 23, 4971−4975

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 5. Relative Free-Energy Profiles for the Reaction of 1b and 2a in CH3CN
para-Cl and para-F (3o and 3r), exhibited higher yields than
the electron-donating groups, such as para-Me, meta-Me, para-
Et, and para-nPr (3k−3n), likely because the electron-
withdrawing groups increased the reactivity. Compound 3o
was isolated with the highest yield (85%) among the examined
substrates. Notably, the N-tetrayne substrate that contained
alkyl groups instead of phenyl or substituted phenyl groups
also generated products with good regioselectivity (3d (78%)).
Moreover, the structures of 3o, 3p, and 3q were confirmed by
X-ray diffraction (CCDC 2044192 (3o), 2044191 (3p), and
2044195 (3q)).
Encouraged by the above results, the scope of cyclo-
propenones was then examined, and the results are shown in
Scheme 3. Electron-donating para-Me substituted 2,3-diary-
lcycloprop-2-enone 2b showed a slightly higher reactivity and
furnished 3u in 82% yields. Furthermore, 2,3-diphenylcyclo-
prop-2-enones with halogens (F, Cl) at the para-position of
the phenyl ring reacted smoothly with 1a, providing the
desired products (3v and 3w) in 69% and 78% yields,
respectively. Unfortunately, the more challenging substrates 2-
methyl-3-phenylcycloprop-2-enone 2e and 2,3-diethylcyclo-
prop-2-enone 2f failed to undergo this process, and no desired
products were detected. It is noteworthy that these reactions
showed high regioselectivity with only one isomer detected.
These results indicated the potential of the HDDA-derived
benzynes of current multiyne cascade coupling with cyclo-
propenones for the synthesis of fully substituted conjugate
benzofuran derivatives.
Several control experiments were performed to elaborate the
reaction mechanism clearly (Scheme 4). When tetrayne
substrate 1b was employed to react with 2a under Ar in the
absence of O2 and H2O (see the SI), a spiro-cyclic compound
4a was obtained in 16% yield instead of 3b (Scheme 4a), and
the configuration of 4a was further confirmed by X-ray
diffraction (CCDC 2044193). Similarly, the model reactions
also cannot occur when only 1.0 equiv of H2O or O2 was
involved in these reactions (Scheme 4b and c), which
highlighted the essential roles of molecular oxygen and H2O
in this transformation. Meanwhile, 18O-labeling experiments
were carried out to elucidate the origin of the oxygen atom of
the ketonic carbonyl group. When the reaction was carried out
in the presence of 1.0 equiv of H218O, no 18O-labeled product
was detected (Scheme 4d). In contrast, 18O-product was
detected by HRMS in the final product (see the SI) when 18O-
labeled cyclopropenone 2a′ was used in the reaction system
(Scheme 4e). These results demonstrated that the oxygen
atom of the ketonic carbonyl group in the product was
originated from molecular oxygen. In addition, 3b was not
observed in the presence of 5,5-dimethyl-1-pyrroline-N-oxide
(DMPO) under the optimized conditions, which revealed that
the reaction might occur through a radical process (Scheme
4f).
On the basis of the above control experiments, a plausible
mechanism was proposed and further elucidated by density
functional theory (DFT) calculations at the B3LYP+D3(BJ)/
6-311+G(2d,p) level of theory (see also the SI) to gain further
insight into the reaction mechanism (Scheme 5). Initially, we
4973
https://doi.org/10.1021/acs.orglett.1c01304
Org. Lett. 2021, 23, 4971−4975

Organic Letters
pubs.acs.org/OrgLett
Letter
expect an attack by the strongly nucleophilic oxygen of the
cyclopropenone 2a at the HDDA-derived benzyne intermedi-
ate IN1, formed zwitterionic intermediate IN2 via TS1. This
species can underwent a ring closure to the spirocyclic
benzoxete intermediate IN3 via TS2.15 Because of the ring
strain, the intermediate IN3 exhibited ring opening to afford an
o-quinone intermediate IN4 via TS3. On the basis of previous
reports,13 the zwitterion intermediate IN4 could be formed by
a resonance structure of o-quinone intermediate IN4. In the
next step, the formation of a five-membered furan ring
intermediate IN5 (unstable) was anticipated because of the
participation of IN4 in the nucleophilic attack process via TS4.
Followed by homolytic cleavage of the CC bond, the tertiary
carbon radical to be trapped by O2 to generate the key
intermediate IN6 via TS5.16 Then, the peroxide radical
intermediate IN6 underwent an intramolecular radical
coupling to provide a more stable intermediate IN7 via TS6.
Zwitterionic intermediate IN8, a polarization form of IN7, also
experienced nucleophilic attack in the presence of residual
water to form hydroxy hydroperoxide intermediate IN9 via
TS7.17 Finally, hydroxy hydroperoxide intermediate IN9
underwent homolytic O−O bond scission, followed by C−O
bond fragmentation, and then removal of a molecule of
hydrogen peroxide to afford the desired product 3b.18
Compared with previous work,19 this transformation provided
an example where the CC double bond cleavage of the
cyclopropenone, probably because the highly substituted arene
species IN4 were not allowed to react with another aryne. The
computed free-energy variations validated the rationality of the
proposed reaction mechanism. All of these processes were
feasible at 95 °C.
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Qiong Hu − Key Laboratory of Functional Molecular Solids,
Ministry of Education; Anhui Laboratory of Molecule-Based
Materials, State Laboratory Cultivation Base, College of
Chemistry and Materials Science, Anhui Normal University,
Wuhu, Anhui 241002, China; Email: huqiong@
ahnu.edu.cn
Yimin Hu − Key Laboratory of Functional Molecular Solids,
Ministry of Education; Anhui Laboratory of Molecule-Based
Materials, State Laboratory Cultivation Base, College of
Chemistry and Materials Science, Anhui Normal University,
Wuhu, Anhui 241002, China; orcid.org/0000-0002-
1638-5393; Email: yiminhu@ahnu.edu.cn
Authors
Liangliang Yao − Key Laboratory of Functional Molecular
Solids, Ministry of Education; Anhui Laboratory of
Molecule-Based Materials, State Laboratory Cultivation
Base, College of Chemistry and Materials Science, Anhui
Normal University, Wuhu, Anhui 241002, China
Li Bao − Key Laboratory of Functional Molecular Solids,
Ministry of Education; Anhui Laboratory of Molecule-Based
Materials, State Laboratory Cultivation Base, College of
Chemistry and Materials Science, Anhui Normal University,
Wuhu, Anhui 241002, China
In summary, we have demonstrated a novel approach to
synthesize fully substituted conjugate benzofuran derivatives
through a chemical bond cleavage and reassembly strategy. In
this reaction, both the benzene and furan rings were
simultaneously constructed, whereas the multiyne cascade
coupling was performed to produce HDDA-derived benzyne
intermediate and trapped by the cyclopropenone. Following
this strategy, there might be more possibilities for the
incorporation of functional groups in the ring-forming process,
which could obviate aforementioned challenges of C−H
functionalization and the dependence of arenes. DFT
calculations showed that the unexpected homolytic cleavage
of cyclopropenone and dioxygen activation were crucial to the
success of this reaction. Because of its metal-free nature, this
reaction satisfied the particular purity requirements of
biological and medicinal chemistry. Further work on the
applications and scope extension of this protocol is ongoing in
our laboratory.
Wenjing Zhu − Key Laboratory of Functional Molecular
Solids, Ministry of Education; Anhui Laboratory of
Molecule-Based Materials, State Laboratory Cultivation
Base, College of Chemistry and Materials Science, Anhui
Normal University, Wuhu, Anhui 241002, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01304
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (22071001, 21572002) and the
Department of Human Resources of Anhui Province.
REFERENCES
■
(1) (a) Khanam, H.; Shamsuzzaman. Bioactive Benzofuran
Derivatives: A Review. Eur. J. Med. Chem. 2015, 97, 483−504.
(b) Radadiya, A.; Shah, A. Bioactive Benzofuran Derivatives: An
Insight on Lead Developments, Radioligands and Advances of the
Last Decade. Eur. J. Med. Chem. 2015, 97, 356−376.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01304.
(2) (a) Nevagi, R. J.; Dighe, S. N.; Dighe, S. N. Biological and
Medicinal Significance of Benzofuran. Eur. J. Med. Chem. 2015, 97,
561−581. (b) Hiremathad, A.; Patil, M. R.; Chethana, K. R.; Chand,
K.; Santos, M. A.; Keri, R. S. Benzofuran: An Emerging Scaffold for
Antimicrobial Agents. RSC Adv. 2015, 5, 96809−96828.
(3) (a) Telenti, A.; Imboden, P.; Marchesi, F.; Lowrie, D.; Cole, S.;
Colston, M. J.; Matter, L.; Schopfer, K.; Bodmer, T. Detection of
Rifampicin-Resistance Mutations in Mycobacterium Tuberculosis.
Lancet 1993, 341, 647−650. (b) Campbell, E. A.; Korzheva, N.;
Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A.
Experimental procedures for all reactions, spectroscopic
characterization data for all new compounds, details of
computational methods, and copies of 1H and 13C NMR
spectra (PDF)
Accession Codes
CCDC 2044191−2044193 and 2044195 contain the supple-
mentary crystallographic data for this paper. These data can be
4974
https://doi.org/10.1021/acs.orglett.1c01304
Org. Lett. 2021, 23, 4971−4975

Organic Letters
pubs.acs.org/OrgLett
Letter
Structural Mechanism for Rifampicin Inhibition of Bacterial RNA
Polymerase. Cell 2001, 104, 901−912.
Hexadehydro-Diels−Alder Reaction. J. Org. Chem. 2015, 80, 11744−
11754. (d) Wang, T.; Niu, D.; Hoye, T. R. The Hexadehydro-Diels−
Alder Cycloisomerization Reaction Proceeds by a Stepwise Mecha-
nism. J. Am. Chem. Soc. 2016, 138, 7832−7835.
(4) (a) Odabasoglu, F.; Cakir, A.; Suleyman, H.; Aslan, A.; Bayir, Y.;
Halici, M.; Kazaz, C. Gastroprotective and Antioxidant Effects of
Usnic Acid on Indomethacin-Induced Gastric Ulcer in Rats. J.
Ethnopharmacol. 2006, 103, 59−65. (b) White, P. A. S.; Oliveira, R.
(11) (a) Xiao, X.; Hoye, T. R. The Domino Hexadehydro-Diels−
Alder Reaction Transforms Polyynes to Benzynes to Naphthynes to
Anthracynes to Tetracynes (and Beyond?). Nat. Chem. 2018, 10,
838−844. (b) Arora, S.; Zhang, J.; Pogula, V.; Hoye, T. R. Reactions
of Thermally Generated Benzynes with Six-membered N-Hetero-
aromatics: Pathway and Product Diversity. Chem. Sci. 2019, 10,
9069−9076. (c) Ghorai, S.; Lin, Y.; Xia, Y.; Wink, D. J.; Lee, D.
Silver-Catalyzed Annulation of Arynes with Nitriles for Synthesis of
Structurally Diverse Quinazolines. Org. Lett. 2020, 22, 626−630.
(12) (a) Zheng, X.; Liu, B.; Yang, F.; Hu, Q.; Yao, L.; Hu, Y. Access
to Benzoxazepines and Fully Substituted Indoles via HDDA
Coupling. Org. Lett. 2020, 22, 956−959. (b) Yao, L.; Fang, B.; Hu,
Q.; Lei, Y.; Bao, L.; Hu, Y. Phenanthrenes/Dihydrophenanthrenes:
The Selectivity Controlled by Different Benzynes and Allenes. Chem.
Commun. 2020, 56, 15185−15188.
(13) Yao, L.; Hu, Q.; Lei, Y.; Bao, L.; Hu, Y. C−O/C−S
Difunctionalized Benzene Derivatives via Multicomponent Coupling
of Tetraynes. Org. Chem. Front. 2020, 7, 3633−3637.
(14) Li, J.; Wei, J.; Zhu, B.; Wang, T.; Jiao, N. Cu-Catalyzed
Oxygenation of Alkene-Tethered Amides with O2 via Unactivated
CC Bond Cleavage: A Direct Approach to Cyclic Imides. Chem. Sci.
2019, 10, 9099−9103.
(15) Wallbaum, J.; Jones, P. G.; Werz, D. B. Reacting Cyclo-
propenones with Arynes: Access to Spirocyclic Xanthene-Cyclo-
propene Motifs. J. Org. Chem. 2015, 80, 3730−3734.
(16) Liang, Y.-F.; Jiao, N. Oxygenation via C−H/C−C Bond
Activation with Molecular Oxygen. Acc. Chem. Res. 2017, 50, 1640−
1653.
(17) Hirashima, S.-i.; Nobuta, T.; Tada, N.; Itoh, A. Acceleration of
Norrish Type I Reaction with Molecular Oxygen and Catalytic CBr4.
Synlett 2009, 2009, 2017−2019.
(18) (a) Tada, N.; Cui, L.; Okubo, H.; Miura, T.; Itoh, A. An
Efficient Synthesis of gem-Dihydroperoxides with Molecular Oxygen
and Anthracene under Light Irradiation. Adv. Synth. Catal. 2010, 352,
2383−2386. (b) Cui, L.; Tada, N.; Okubo, H.; Miura, T.; Itoh, A.
Efficient Synthesis of gem-Dihydroperoxides with Molecular Oxygen
and Anthraquinone under Visible Light Irradiation with Fluorescent
Lamp. Green Chem. 2011, 13, 2347−2350.
(19) (a) Schuster-Haberhauer, A.; Gleiter, R.; Körner, O.; Leskovar,
A.; Werz, D. B.; Fischer, F. R.; Rominger, F. CpCo-Mediated
Reactions of Cyclopropenones: Access to CpCo-Capped Benzoqui-
none Complexes. Organometallics 2008, 27, 1361−1366. (b) Werz, D.
B.; Klatt, G.; Raskatov, J. A.; Köppel, H.; Gleiter, R. CpCo-Mediated
Reactions of Cyclopropenones: A DFT Study. Organometallics 2009,
28, 1675−1682. (c) Augustin, A. U.; Werz, D. B. Exploiting Heavier
Organochalcogen Compounds in Donor−Acceptor Cyclopropane
Chemistry. Acc. Chem. Res. 2021, 54, 1528−1541.
́
C. M.; Oliveira, A. P.; Serafini, M. R.; Araujo, A. A. S.; Gelain, D. P.;
Moreira, J. C. F.; Almeida, J. R. G. S.; Quintans, J. S. S.; Quintans-
Junior, L. J.; Santos, M. R. V. Antioxidant Activity and Mechanisms of
Action of Natural Compounds Isolated from Lichens: A Systematic
Review. Molecules 2014, 19, 14496−14527.
(5) (a) Hosseinian, A.; Babazadeh, M.; Edjlali, L.; Rahmani, Z.;
Vessally, E. Intramolecular Cyclization of Aryl Propargyl Ethers: A
Straightforward and Convenient Approach to Benzofuran Derivatives.
Curr. Org. Synth. 2018, 15, 972−981. (b) Heravi, M. M.; Zadsirjan,
V.; Hamidi, H.; Tabar Amiri, P. H. Total Synthesis of Natural
Products Containing Benzofuran Rings. RSC Adv. 2017, 7, 24470−
24521.
(6) (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. C−C Bond Formation via Double C−H Functionalization: Aerobic
Oxidative Coupling as a Method for Synthesizing Heterocoupled
Biaryls. Org. Lett. 2007, 9, 3137−3139. (b) Li, Y.; Waser, J. Zinc−
Gold Cooperative Catalysis for the Direct Alkynylation of
Benzofurans. Beilstein J. Org. Chem. 2013, 9, 1763−1767.
(c) Huang, Q.; Ke, S.; Qiu, L.; Zhang, X.; Lin, S. Palladium(II)/
Polyoxometalate-Catalyzed Direct Alkenylation of Benzofurans under
Atmospheric Dioxygen. ChemCatChem 2014, 6, 1531−1534.
(7) (a) Barluenga, J.; Gómez, A.; Santamaría, J.; Tomás, M.
Regioselective Synthesis of 4,6,7-Trisubstituted Benzofurans from
Furfural Imines and Nonheteroatom Stabilized Alkynylcarbene
Complexes. J. Am. Chem. Soc. 2009, 131, 14628−14629. (b) Mur-
akami, K.; Yorimitsu, H.; Osuka, A. Practical, Modular, and General
Synthesis of Benzofurans through Extended Pummerer Annulation/
Cross-Coupling Strategy. Angew. Chem., Int. Ed. 2014, 53, 7510−
7513. (c) Pan, J.-L.; Liu, C.; Chen, C.; Liu, T.-Q.; Wang, M.; Sun, Z.;
Zhang, S.-Y. Dual Directing-Groups-Assisted Redox-Neutral Annula-
tion and Ring Opening of N-Aryloxyacetamides with 1-Alkynylcyclo-
butanols via Rhodium(III)-Catalyzed C−H/C−C Activations. Org.
Lett. 2019, 21, 2823−2827. (d) Deng, G.; Li, M.; Yu, K.; Liu, C.; Liu,
Z.; Duan, S.; Chen, W.; Yang, X.; Zhang, H.; Walsh, P. J. Synthesis of
Benzofuran Derivatives through Cascade Radical Cyclization/
Intermolecular Coupling of 2-Azaallyls. Angew. Chem., Int. Ed. 2019,
58, 2826−2830.
(8) (a) Bhojgude, S. S.; Bhunia, A.; Biju, A. T. Employing Arynes in
Diels−Alder Reactions and Transition-Metal-Free Multicomponent
Coupling and Arylation Reactions. Acc. Chem. Res. 2016, 49, 1658−
1670. (b) Shi, J.; Li, Y.; Li, Y. Aryne Multifunctionalization with
Benzdiyne and Benztriyne Equivalents. Chem. Soc. Rev. 2017, 46,
1707−1719. (c) Werz, D. B.; Biju, A. T. Uncovering the Neglected
Similarities of Arynes and Donor−Acceptor Cyclopropanes. Angew.
Chem., Int. Ed. 2020, 59, 3385−3398. (d) He, J.; Qiu, D.; Li, Y.
Strategies toward Aryne Multifunctionalization via 1,2-Benzdiyne and
Benzyne. Acc. Chem. Res. 2020, 53, 508−519. (e) Scherubl, M.;
̈
Daniliuc, C. G.; Studer, A. Arynes as Radical Acceptors: TEMPO-
Mediated Cascades Comprising Addition, Cyclization, and Trapping.
Angew. Chem., Int. Ed. 2021, 60, 711−715.
(9) (a) Karmakar, R.; Lee, D. Reactions of Arynes Promoted by
Silver Ions. Chem. Soc. Rev. 2016, 45, 4459−4470. (b) Ghorai, S.; Lee,
D. Aryne-Based Multicomponent Coupling Reactions. Synlett 2020,
31, 750−771. (c) Fluegel, L. L.; Hoye, T. R. Hexadehydro-Diels−
Alder Reaction: Benzyne Generation via Cycloisomerization of
Tethered Triynes. Chem. Rev. 2021, 121, 2413−2444.
(10) (a) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods,
B. P. The Hexadehydro-Diels−Alder Reaction. Nature 2012, 490,
208−212. (b) Woods, B. P.; Baire, B.; Hoye, T. R. Rates of
Hexadehydro-Diels−Alder (HDDA) Cyclizations: Impact of the
Linker Structure. Org. Lett. 2014, 16, 4578−4581. (c) Marell, D. J.;
Furan, L. R.; Woods, B. P.; Lei, X.; Bendelsmith, A. J.; Cramer, C. J.;
Hoye, T. R.; Kuwata, K. T. Mechanism of the Intramolecular
4975
https://doi.org/10.1021/acs.orglett.1c01304
Org. Lett. 2021, 23, 4971−4975