Benzyne 1,2,4-Trisubstitution and Dearomative 1,2,4-Trifunctionalization

Article abstract of DOI:10.1021/jacs.1c04389

Both 1,2,4-trisubstitution and dearomative 1,2,4-trifunctionalization of benzyne have been accomplished from sulfoxides bearing a penta-2,4-dien-1-yl moiety. These cascade transformations proceed through a benzyne insertion into the S═O bond and an uncommon regiospecific anionic [4,5]-sigmatropic rearrangement, furnishing a C-O, C-S, and C-C bond on the C1-, C2-, and C4-position of a benzene ring, respectively. This study showcases new cascade benzyne reaction modes involving both distal C-H bond functionalization and dearomatization.

Full text of DOI:10.1021/jacs.1c04389

pubs.acs.org/JACS
Communication
Benzyne 1,2,4-Trisubstitution and Dearomative 1,2,4-
Trifunctionalization
Jiarong Shi,# Lianggui Li,# Chunhui Shan,# Zhonghong Chen, Liang Dai, Min Tan, Yu Lan,*
and Yang Li*
Cite This: J. Am. Chem. Soc. 2021, 143, 10530−10536
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Both 1,2,4-trisubstitution and dearomative 1,2,4-trifunctionalization of benzyne have been accomplished from
sulfoxides bearing a penta-2,4-dien-1-yl moiety. These cascade transformations proceed through a benzyne insertion into the SO
bond and an uncommon regiospecific anionic [4,5]-sigmatropic rearrangement, furnishing a C−O, C−S, and C−C bond on the C1-,
C2-, and C4-position of a benzene ring, respectively. This study showcases new cascade benzyne reaction modes involving both
distal C−H bond functionalization and dearomatization.
Table 1. Reaction Optimization between Aryne Precursor
1a and Sulfoxide 2a
enzyne is a highly reactive species that can expeditiously
a
1
Bassemble numerous vicinal difunctionalized benzenes.
Scheme 1. Background and Our Work
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), “F” (0.8 mmol), and
BrCH2CO2Et (0.4 mmol) in solvent overnight.
benzyne-triggered/induced cascade transformation has become
one of the most powerful strategies in benzyne chemistry,
which not only possesses atom-/step-economy advantages6 but
also could rapidly build-up complexity for challenging
frameworks.7 The benzyne intermediate in these cascade
processes, however, exclusively serves as a benzene-based
building block, whereas almost no further elaboration occurs
on the generated mono-/disubstituted benzene ring after
typical benzyne transformations, i.e., nucleophilic addition or
cycloaddition. It can be envisioned that new cascade protocols
The low-lying LUMO orbital of a benzyne and the small
energy gap between its HOMO and LUMO orbitals make it an
excellent synthon, which is amenable to diverse arynophiles.2
Along with the employment of mild generation methods, i.e.,
from o-silylaryl triflates (Kobayashi’s protocol)3 and via
hexadehydro-Diels−Alder (HDDA) reactions developed by
Hoye et al.,1n,s benzyne chemistry experienced a resurgence in
the past two decades.1b,t New benzyne reaction modes, such as
insertion reactions,4 transition-metal-catalyzed reactions,5 and
cascade/tandem reactions,1t emerged associated with the
intensive exploration on Kobayashi’s method. Particularly,
Received: April 27, 2021
Published: July 8, 2021
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536
© 2021 American Chemical Society
10530

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scheme 2. Substrate Scope for Compound 3
a
Condition A: a mixture of 1 (0.2 mmol), 2 (0.4 mmol), CsF (0.8 mmol), BrCH2CO2Et/Boc2O (0.4 mmol), and MeCN (0.2 mL) was stirred at
b
room temperature overnight. Condition B: a mixture of 1 (0.4 mmol), 2 (0.2 mmol), CsF (0.8 mmol), BrCH2CO2Et/Boc2O (0.4 mmol), and
MeCN (0.2 mL) was stirred at room temperature overnight.
that could either further functionalize the sites other than the
formal triple bond on a benzyne ring, namely benzyne
polysubstitution,1m or unfold the latent structural characters
of the generated benzene ring via dearomatization means8
would significantly expand the realm of benzyne chemistry.
To our knowledge, only two approaches were reported with
respect to the above consideration. Along with our study on
aryne chemistry,9 we disclosed a new cascade strategy by
treating benzyne with aryl allyl sulfoxides to achieve 1,2,3-
trisubstituted9b (Scheme 1a) and 1,2,3,5-tetrasubstituted
benzenes.9c Both transformations share a common successive
benzyne insertion into the SO bond of sulfoxide and an
anionic [3,6]-sigmatropic rearrangement via transition state i.9c
On the other hand, Anderson and co-workers recently
accomplished a distinct cascade process between N-alkenylni-
trones and o-silylaryl triflates, furnishing spirocyclic pyrroline
10531
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Figure 1. DFT Calculations for Plausible Mechanistic Pathways between 1a and 2a. The free energy values are calculated at the M06-2X/6-
31+G(d) level of theory in acetonitrile with the SMD model using the Gaussian 09 series of programs.
cyclohexadienones via a 1,3-dipolar cycloaddition reaction and
a dearomative [3,3]-sigmatropic rearrangement on cycloadduct
ii (Scheme 1b).7u Considering almost endless topological
combination of substituents on the six functionalizable
positions of a benzene ring10 and rich functionalities to be
generated upon dearomatization,8 it remains a potentially
fruitful yet highly unexplored field in benzyne chemistry.
Herein, we wish to report our discovery on direct benzyne
1,2,4-trisubstitution with sulfoxides containing penta-2,4-dien-
1-yl moiety, the mechanism of which involves a regiospecific
anionic [4,5]-sigmatropic rearrangement via transition state iii
with an activation energy of 15.8 kcal/mol under mild
conditions (Scheme 1c). Moreover, this protocol is not limited
to 1,2,4-trisubstitution, but could furnish a dearomatized
cyclohexa-2,5-dien-1-one framework when the target C4-
position contains no hydrogen.
We postulated that an extension of the π system on allyl
sulfoxide with a unit of two electrons, e.g. an olefin, might shift
the bond-forming site accordingly with two atoms aside on the
benzene ring in the rearrangement step. Consequently, an
anionic [4,5]-sigmatropic rearrangement via transition state iii
could be conceived (Scheme 1c). Although this 10-electron
rearrangement pathway is thermally allowed by the Wood-
ward−Hoffmann rules, it might be scrambled by several
competing reactions, such as Claisen rearrangement, anionic
[3,6]-sigmatropic rearrangement, and/or an allyl S → O shift.
In order to examine our hypothesis, sulfoxide 2a was prepared
and subjected to the reaction with aryne precursor 1a. As
shown in Table 1, product 3a was obtained in 33% yield (entry
1). In this reaction, the pentadienyl moiety was directly
delivered to the meta-position of the sulfur atom with no
observation of a 1,3-silyl group migration product.9c Although
anionic [4,5]-sigmatropic rearrangement was discovered by
Ollis et al. in 1973 on either allyl(pentadienyl)ammonium
ylides11 or N-pentadienyl-2-oxyanilinium ylides,12 there was no
further practical synthetic application associated with this type
of rearrangement reaction. It is noteworthy that [5,5]-
sigmatropic rearrangements could occur on aryl pentadienyl
ethers under either thermal13 or Lewis acid mediated
conditions.14 In contrast, our system prefers an anionic
[4,5]-sigmatropic rearrangement pathway, which should be
attributed to the presence of an ortho-oxo anion.
Further investigation revealed that this transformation is
sensitive to the reaction concentration. By gradually increasing
the concentration of 1a from 0.1 to 1.0 M, the yield of 3a was
significantly improved (entries 2−4). Since aryne precursor 1a
was completely consumed in all of these conditions, this
phenomenon could be reasoned by the fact that a high
concentration will promote aryne insertion reaction into the
SO bond of sulfoxide. Raising the reaction temperature
resulted in diminished yields (entries 5 and 6). It was found
that the addition of a stronger base Cs2CO3 did not enhance
the yield (entry 7). The employment of 18-c-6 with either CsF
or KF gave lower yields as well (entries 8 and 9). In addition,
other solvents were examined and none of them could produce
3a in higher yield than that in acetonitrile (entries 10−12).
Consequently, the optimal conditions for this transformation
10532
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scheme 3. Study on Dearomatization
Scheme 4. Synthetic Applications
Further study revealed that the reaction with 3,6-
disubstituted aryne precursors led to the formation of
pentasubstituted products 3i−3l (Scheme 2b). When 3-
EWG-substituted benzynes containing a substituent on its
C5-position were examined, pentasubstituted arenes 3m−3q
could be readily achieved in good to high yields and in a
regiospecific manner, where the pentadienyl moiety migrated
to the sterically congested C4-position. In these examples,
those EWGs on the C3-position of a benzyne play a
determining role for the exceptional regioselectivity. Partic-
ularly, hexasubstituted benzenes 3r and 3s were readily
achievable with respect to those benzynes containing properly
positioned substituents (Scheme 2b). Next, sulfoxides 2b−2f
with substituted penta-2,4-dien-1-yl groups were examined, all
of which could afford the corresponding products 3t−3aa in
moderate to good yields (Scheme 2c).
To shed light on the mechanism of this transformation, DFT
calculations were performed at the M06-2X/6-31+G(d) level
of theory. As shown in Figure 1, the corresponding zwitterionic
phenolate-sulfonium intermediate IM2 can be generated
through a metathesis between aryne precursor 1a and sulfoxide
2a. A [4,5]-sigmatropic rearrangement then occurs via
transition state TS3 with an energy barrier of only 15.8 kcal/
a
A mixture of 1 (0.4 mmol), 2a (0.2 mmol), CsF (0.8 mmol), and
b
MeCN (0.2 mL) was stirred at room temperature overnight. Isolated
yield.
employ 2 equiv of sulfoxide 2a with 1.0 M solution of 1a in
acetonitrile at room temperature (condition A, entry 4).
We then explored the substrate scope for this trans-
formation. When aryne precursors bearing either a 3-TMS or
a 3-TES group as the σ-electron-donating group (EDG) were
employed, products 3b and 3c could be obtained, respectively
(Scheme 2a). Notably, plausible products through either
desilylation or 1,3-silyl migration9c were not detected under
the reaction conditions, suggesting that anionic [4,5]-
sigmatropic rearrangement via transition state iii is a
predominant pathway (Scheme 1c). Furthermore, σ-electron-
withdrawing groups (EWGs), such as methoxy, acetoxy, fluoro,
chloro, and bromo groups, were found to be favorable 3-
substituents on benzyne, leading to the regiospecific
construction of 1,2,3,4-tetrasubstituted arenes 3d−3h in
good to excellent yields (Scheme 2a). Although these groups
are on the ortho-position of the generated sulfonium ion, no
obvious steric repulsion was observed in the rearrangement
step. In the cases of 3-EWG-substituted benzynes, an excess
amount of benzyne precursors was utilized, which could afford
the corresponding products in higher yields (condition B,
Scheme 2a). In contrast to the success of those 3-EDG- and 3-
EWG-sustituted benzynes, unsubstituted o-benzyne afforded a
1,2,4-trisubstituted product in only 26% isolated yield.15 This
observation suggested that the polarized formal triple bond on
arynes could facilitate the insertion step into the SO bond of
sulfoxide.
mol, supportive of a concerted 10-electron Huckel type
̈
aromatic process. After this step, charge neutralization takes
place through the formation of cyclohexadienone intermediate
IM4 with exergonic 84.0 kcal/mol, which can further isomerize
to a phenol derivative. Alternatively, either [2,3]- or [3,6]-
sigmatropic rearrangements would occur on IM2 via transition
state TS5 or TS7, respectively. The calculated activation free
energies for both processes, however, are slightly higher than
that for [4,5]-sigmatropic rearrangement. It can be explained
by the second order orbital interaction between two
10533
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
conjugative π-electron fragments in transition state TS3. The
noncovalent interaction (NCI) plots of TS3 also illustrate a
strong interaction between two π-systems (Figure 1). In
comparison, the calculated free energy barriers for [3,3]- and
[5,6]-sigmatropic rearrangements are 28.6 and 25.6 kcal/mol,
respectively, via transition states TS9 and TS11. Furthermore,
nucleophilic substitution processes involving a 1,4-allyl shift
and phenolate alkylation could be ruled out as well because of
the relatively high activation free energies of transition states
TS13 and TS15 (please see Supporting Information (SI) for
more details).
sulfoxides containing a penta-2,4-dien-1-yl moiety. For the first
time, direct functionalization on the distal C4/C5-position of a
benzyne triple bond was accomplished via an anionic [4,5]-
sigmatropic rearrangement in these cascade processes. Up to
hexasubstituted benzenes and fully functionalized cyclohexa-
2,5-dien-1-ones could be obtained in a highly regioselective
manner. Notably, all three new chemical bonds, namely C−O,
C−S, and C−C bonds, come from the same sulfoxide
substrate, demonstrating a highly economical cascade process.
Future work includes the exploration of other benzyne
multifunctionalization maneuvers as well as the synthetic
applications of these protocols.
Those examples in Scheme 2 contain either a C5-hydrogen
with respect to a 3-EDG or a C4-hydrogen in the presence of a
3-EWG on the benzyne ring, so that the penta-2,4-dien-1-yl
moiety could displace these hydrogens after rearrangement. As
this [4,5]-sigmatropic rearrangement reaction was found to be
such a preferred pathway among other possibilities, we were
curious to explore its potential in dearomative 1,2,4-
trisubstitution when the above C4/C5-positions are occupied
by substituents other than hydrogen. As shown in Scheme 3,
4,4-disubstituted cyclohexa-2,5-dien-1-one 4a was achieved in
63% yield, when the precursor of 3-methoxy-4-methylbenzyne
was treated with 2a. Similarly, 4b−4d were obtained in
moderate to good yields. Moreover, the formation of 4e in
good yield suggests that the methoxy group can serve as an
effective C4-substitutent. 3-Halo-substituted aryne intermedi-
ates were found to provide the corresponding products 4f−4k
as well. Particularly noteworthy was the feasible dearomatiza-
tion on those fully functionalized aryne precursors, giving rise
to products 4g−4k in good to high yields. When the aryne
precursor containing a fused cyclohexane ring was employed,
dearomatized compound 4l was obtained, albeit in moderate
yield. As for the aryne precursor bearing a 3-TBS group,
product 4m was obtained in only 30% yield. The facile
formation of cyclohexa-2,5-dien-1-ones in Scheme 3 reiterates
the merit of this aryne insertion/[4,5]-sigmatropic rearrange-
ment protocol in breaking the boundary of traditional benzyne
chemistry. To our knowledge, only the Anderson group
recently realized a cascade benzyne dearomatization process
(Scheme 1b).7u Our work demonstrates a completely different
yet highly regioselective cascade maneuver along with the
formation of a potentially useful cyclohexa-2,5-dien-1-one
scaffold.8a,16
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04389.
■
sı
Experimental details for all chemical reactions and
measurements and X-ray single crystallographic data
(PDF)
Accession Codes
CCDC 2070200 and 2070202 contain the supplementary
crystallographic data for this paper. These data can be 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
■
Yang Li − College of Chemistry, Jilin University, Changchun, P.
R. China 130012; School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing, P. R. China
400030; orcid.org/0000-0002-0090-2894; Email: y.li@
cqu.edu.cn
Yu Lan − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030;
Green Catalysis Center and College of Chemistry, Zhengzhou
University, Zhengzhou, Henan, P. R. China 450001;
orcid.org/0000-0002-2328-0020; Email: lanyu@
cqu.edu.cn
Authors
We then investigated further manipulation on the products.
It was found that Pd-catalyzed annulation of compound 3v
could directly afford naphthalene derivative 5a in 65% yield
(Scheme 4a). Similarly, naphthalenes 5b−5d were readily
prepared using this protocol. Notably, polysubstituted
naphthalenes can be readily obtained in two steps from 3-
bromobenzynes and sulfoxides (Scheme 4a). Alternatively,
oxidative cleavage by ozonolysis on compound 3w, followed by
a CuI-catalyzed ring closure reaction,17 furnished benzofuran
6a in 58% overall yield (Scheme 4b). Meanwhile, the
employment of 3v and 3m through the same reaction
sequence featured substituted benzofurans 6b and 6c,
respectively. Next, elaboration on dearomatized compound
4a was examined. A sequential ozonolysis/reduction/treatment
with p-TsOH on compound 4a was able to assemble bicyclic
compound 7 (Scheme 4c). The above derivatization examples
indicate that our products could be conveniently converted to
diverse bicyclic ring systems.
Jiarong Shi − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030;
orcid.org/0000-0001-5723-6514
Lianggui Li − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030
Chunhui Shan − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing, P. R. China
400030; College of Chemistry, Chongqing Normal
University, Chongqing, P. R. China 401331; orcid.org/
0000-0002-6175-1743
Zhonghong Chen − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing, P. R. China
400030
Liang Dai − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030
Min Tan − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030
In summary, both 1,2,4-trisubstitution and dearomative
1,2,4-trifunctionalization of benzyne have been realized with
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04389
10534
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(3) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-Induced 1,2-
Elimination of o-Trimethylsilylphenyl Triflate to Benzyne under Mild
Conditions. Chem. Lett. 1983, 12, 1211−1214.
Author Contributions
#J.S., L.L., and C.S. contributed equally to this work.
Notes
(4) (a) Pena, D.; Pérez, D.; Guitián, E. Insertion of Arynes into σ
̃
The authors declare no competing financial interest.
Bonds. Angew. Chem., Int. Ed. 2006, 45, 3579−3581. (b) Asamdi, M.;
Chikhalia, K. H. Aryne Insertion into σ Bonds. Asian J. Org. Chem.
2017, 6, 1331−1348.
ACKNOWLEDGMENTS
■
(5) (a) Guitián, E.; Pérez, D.; Pena, D. Palladium-Catalyzed
̃
Cycloaddition Reactions of Arynes. In Palladium in Organic Synthesis;
Tsuji, J., Ed.; Springer: Berlin Heidelberg, 2005; Vol. 14, pp 109−146.
(b) Worlikar, S. A.; Larock, R. C. Pd-Catalyzed Reactions Involving
Arynes. Curr. Org. Chem. 2011, 15, 3214−3232. (c) Feng, M.; Jiang,
X. Reactions of Arynes Involving Transition-Metal Catalysis. Synthesis
2017, 49, 4414−4433. (d) Dhokale, R. A.; Mhaske, S. B. Transition-
Metal-Catalyzed Reactions Involving Arynes. Synthesis 2018, 50, 1−
16.
The authors gratefully acknowledge research support of this
work by Basic and Frontier Research Project of Chongqing
(cstc2018jcyjAX0357), Fundamental Research Funds for the
Central Universities (2018CDXZ0003), and NSFC
(21901025, 21971028, 21772017, 21822303). S. J. was funded
by China Postdoctoral Science Foundation (2018M640897).
(6) (a) Trost, B. M. The Atom Economy-A Search for Synthetic
Efficiency. Science 1991, 254, 1471−1477. (b) Newhouse, T.; Baran,
P. S.; Hoffmann, R. W. The Economies of Synthesis. Chem. Soc. Rev.
2009, 38, 3010−3021.
REFERENCES
■
(1) For reviews, see: (a) Hoffmann, R. W. Dehydrobenzene and
Cycloalkynes; Academic Press: New York, 1967. (b) Wenk, H. H.;
Winkler, M.; Sander, W. One Century of Aryne Chemistry. Angew.
Chem., Int. Ed. 2003, 42, 502−528. (c) Sanz, R. Recent Applications
of Aryne Chemistry to Organic Synthesis. A Review. Org. Prep. Proced.
Int. 2008, 40, 215−291. (d) Gampe, C. M.; Carreira, E. M. Arynes
and Cyclohexyne in Natural Product Synthesis. Angew. Chem., Int. Ed.
2012, 51, 3766−3778. (e) Tadross, P. M.; Stoltz, B. M. A
Comprehensive History of Arynes in Natural Product Total Synthesis.
Chem. Rev. 2012, 112, 3550−3577. (f) Bhunia, A.; Yetra, S. R.; Biju,
A. T. Recent Advances in Transition-Metal-Free Carbon-Carbon and
Carbon-Heteroatom Bond-Forming Reactions Using Arynes. Chem.
Soc. Rev. 2012, 41, 3140−3152. (g) Dubrovskiy, A. V.; Markina, N.
A.; Larock, R. C. Use of Benzynes for the Synthesis of Heterocycles.
(7) For selected examples on benzyne-triggered/induced cascade
transformations, see: (a) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.;
Wang, F.; Li, J.-H. Cycloaddition of Arynes with Iodonium Ylides: A
Mild and General Route for the Synthesis of Benzofuran Derivatives.
Org. Lett. 2008, 10, 1525−1528. (b) Cant, A. A.; Bertrand, G. H. V.;
Henderson, J. L.; Roberts, L.; Greaney, M. F. The Benzyne Aza-
Claisen Reaction. Angew. Chem., Int. Ed. 2009, 48, 5199−5202.
(c) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung,
R. P. Enamide-Benzyne-[2 + 2] Cycloaddition: Stereoselective
Tandem [2 + 2]-Pericyclic Ring-Opening-Intramolecular N-Tethered
[4 + 2] Cycloadditions. Org. Lett. 2009, 11, 3666−3669. (d) Hong,
D.; Chen, Z.; Lin, X.; Wang, Y. Synthesis of Substituted Indoles from
2-Azidoacrylates and ortho-Silyl Aryltriflates. Org. Lett. 2010, 12,
4608−4611. (e) Chai, G.; Qiu, Y.; Fu, C.; Ma, S. Efficient Assembly
of Chromone Skeleton from 2,3-Allenoic Acids and Benzynes. Org.
Lett. 2011, 13, 5196−5199. (f) Ren, H.; Luo, Y.; Ye, S.; Wu, J. Silver
Triflate Catalyzed Reaction of 2-Alkynylbenzaldoxime with Aryne.
Org. Lett. 2011, 13, 2552−2555. (g) Ma, Z.-X.; Feltenberger, J. B.;
Hsung, R. P. Total Syntheses of Chelidonine and Norchelidonine via
an Enamide-Benzyne-[2 + 2] Cycloaddition Cascade. Org. Lett. 2012,
14, 2742−2745. (h) Chakrabarty, S.; Chatterjee, I.; Tebben, L.;
Studer, A. Reactions of Arynes with Nitrosoarenes-An Approach to
Substituted Carbazoles. Angew. Chem., Int. Ed. 2013, 52, 2968−2971.
(i) Bhojgude, S. S.; Thangaraj, M.; Suresh, E.; Biju, A. T. Tandem [4
+ 2]/[2 + 2] Cycloaddition Reactions Involving Indene or
Benzofurans and Arynes. Org. Lett. 2014, 16, 3576−3579.
(j) Swain, S. P.; Shih, Y.-C.; Tsay, S.-C.; Jacob, J.; Lin, C.-C.;
Hwang, K. C.; Horng, J.-C.; Hwu, J. R. Aryne-Induced Novel Tandem
1,2-Addition/(3 + 2) Cycloaddition to Generate Imidazolidines and
Pyrrolidines. Angew. Chem., Int. Ed. 2015, 54, 9926−9930. (k) Holden,
C. M.; Sohel, S. M. A.; Greaney, M. F. Metal Free Bi(hetero)aryl
Synthesis: A Benzyne Truce-Smiles Rearrangement. Angew. Chem.,
Int. Ed. 2016, 55, 2450−2453. (l) Zhang, J.; Chen, Z.-X.; Du, T.; Li,
B.; Gu, Y.; Tian, S.-K. Aryne-Mediated [2,3]-Sigmatropic Rearrange-
ment of Tertiary Allylic Amines. Org. Lett. 2016, 18, 4872−4875.
(m) Roy, T.; Thangaraj, M.; Kaicharla, T.; Kamath, R. V.; Gonnade,
R. G.; Biju, A. T. The Aryne [2,3] Stevens Rearrangement. Org. Lett.
Org. Biomol. Chem. 2013, 11, 191−218. (h) Pérez, D.; Pena, D.;
̃
Guitián, E. Aryne Cycloaddition Reactions in the Synthesis of Large
Polycyclic Aromatic Compounds. Eur. J. Org. Chem. 2013, 2013,
5981−6013. (i) Goetz, A. E.; Shah, T. K.; Garg, N. K. Pyridynes and
Indolynes as Building Blocks for Functionalized Heterocycles and
Natural Products. Chem. Commun. 2015, 51, 34−45. (j) García-
López, J.-A.; Greaney, M. F. Synthesis of Biaryls Using Aryne
Intermediates. Chem. Soc. Rev. 2016, 45, 6766−6798. (k) 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. (l) Karmakar, R.;
Lee, D. Reactions of Arynes Promoted by Silver Ions. Chem. Soc. Rev.
2016, 45, 4459−4470. (m) Shi, J.; Li, Y.; Li, Y. Aryne Multi-
functionalization with Benzdiyne and Benztriyne Equivalents. Chem.
Soc. Rev. 2017, 46, 1707−1719. (n) Diamond, O. J.; Marder, T. B.
Methodology and Applications of the Hexadehydro-Diels-Alder
(HDDA) Reaction. Org. Chem. Front. 2017, 4, 891−910. (o) Roy,
T.; Biju, A. T. Recent Advances in Molecular Rearrangements
Involving Aryne Intermediates. Chem. Commun. 2018, 54, 2580−
2594. (p) Takikawa, H.; Nishii, A.; Sakai, T.; Suzuki, K. Aryne-Based
Strategy in the Total Synthesis of Naturally Occurring Polycyclic
Compounds. Chem. Soc. Rev. 2018, 47, 8030−8056. (q) Pozo, I.;
Guitián, E.; Pérez, D.; Pena, D. Synthesis of Nanographenes,
̃
Starphenes, and Sterically Congested Polyarenes by Aryne Cyclo-
trimerization. Acc. Chem. Res. 2019, 52, 2472−2481. (r) Werz, D. B.;
Biju, A. T. Uncovering the Neglected Similarities of Arynes and
Donor-Acceptor Cyclopropanes. Angew. Chem., Int. Ed. 2020, 59,
3385−3398. (s) Fluegel, L. L.; Hoye, T. R. Hexadehydro-Diels-Alder
Reaction: Benzyne Generation via Cycloisomerization of Tethered
Triynes. Chem. Rev. 2021, 121, 2413−2444. (t) Shi, J.; Li, L.; Li, Y. o-
Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors. Chem.
Rev. 2021, 121, 3892−4044.
2016, 18, 5428−5431. (n) Li, Y.; Muck-Lichtenfeld, C.; Studer, A.
̈
Sulfonium Ylides by (3 + 2) Cycloaddition of Arynes with Vinyl
Sulfides: Stereoselective Synthesis of Highly Substituted Alkenes.
Angew. Chem., Int. Ed. 2016, 55, 14435−14438. (o) Ma, X.-P.; Li, L.-
G.; Zhao, H.-P.; Du, M.; Liang, C.; Mo, D.-L. Formal [7 + 2]
Cycloaddition of Arynes with N-Vinyl-α,β-Unsaturated Nitrones:
Synthesis of Benzoxazonines and Their N-O Bond Cleavage. Org. Lett.
2018, 20, 4571−4574. (p) Pandya, V. G.; Mhaske, S. B. Divergent
Synthesis of Oxindolylidene Acetates and Spirooxindolopyrrolidones
from Arynes. Org. Lett. 2018, 20, 1483−1486. (q) Idiris, F. I. M.;
Majesté, C. E.; Craven, G. B.; Jones, C. R. Intramolecular Hydride
Transfer onto Arynes: Redox-Neutral and Transition Metal-Free
(2) Rondan, N. G.; Domelsmith, L. N.; Houk, K. N.; Bowne, A. T.;
Levin, R. H. The Relative Rates of Electron-Rich and Electron-
Deficient Alkene Cycloadditions to Benzyne. Enhanced Electro-
philicity as a Consequence of Alkyne Bending Distortions.
Tetrahedron Lett. 1979, 20, 3237−3240.
10535
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
C(sp3)-H Functionalization of Amines. Chem. Sci. 2018, 9, 2873−
2878. (r) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.;
Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C.
D.; Tadross, P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.;
(17) Chen, C.-Y.; Dormer, P. G. Synthesis of Benzo[b]furans via
CuI-Catalyzed Ring Closure. J. Org. Chem. 2005, 70, 6964−6967.
Grunanger, C. U.; Allan, K. M.; Virgil, S. C.; Slamon, D. J.; Stoltz, B.
̈
M. Concise Total Syntheses of (−)-Jorunnamycin A and (−)-Jor-
umycin Enabled by Asymmetric Catalysis. Science 2019, 363, 270−
275. (s) Hu, W.; Zhang, C.; Huang, J.; Guo, Y.; Fu, Z.; Huang, W.
Access to Highly Functionalized Indanes from Arynes and α,γ-Diketo
Esters. Org. Lett. 2019, 21, 941−945. (t) Roy, T.; Gaykar, R. N.;
Bhattacharjee, S.; Biju, A. T. The Aryne Sommelet-Hauser Rearrange-
ment. Chem. Commun. 2019, 55, 3004−3007. (u) Alshreimi, A. S.;
Zhang, G.; Reidl, T. W.; Pena, R. L.; Koto, N.-G.; Islam, S. M.; Wink,
̃
D. J.; Anderson, L. L. Synthesis of Spirocyclic 1-Pyrrolines from
Nitrones and Arynes through a Dearomative [3,3′]-Sigmatropic
Rearrangement. Angew. Chem., Int. Ed. 2020, 59, 15244−15248.
(8) For selected reviews, see: (a) Roche, S. P.; Porco, J. A., Jr.
Dearomatization Strategies in the Synthesis of Complex Natural
Products. Angew. Chem., Int. Ed. 2011, 50, 4068−4093. (b) Wu, W.-
T.; Zhang, L.; You, S.-L. Catalytic Asymmetric Dearomatization
(CADA) Reactions of Phenol and Aniline Derivatives. Chem. Soc. Rev.
2016, 45, 1570−1580. (c) Wertjes, W. C.; Southgate, E. H.; Sarlah, D.
Recent Advances in Chemical Dearomatization of Nonactivated
Arenes. Chem. Soc. Rev. 2018, 47, 7996−8017.
(9) (a) He, J.; Qiu, D.; Li, Y. Strategies toward Aryne Multi-
functionalization via 1,2-Benzdiyne and Benzyne. Acc. Chem. Res.
2020, 53, 508−519. (b) Li, Y.; Qiu, D.; Gu, R.; Wang, J.; Shi, J.; Li, Y.
Aryne 1,2,3-Trifunctionalization with Aryl Allyl Sulfoxides. J. Am.
Chem. Soc. 2016, 138, 10814−10817. (c) Shi, J.; Li, L.; Shan, C.;
Wang, J.; Chen, Z.; Gu, R.; He, J.; Tan, M.; Lan, Y.; Li, Y. Aryne
1,2,3,5-Tetrasubstitution Enabled by 3-Silylaryne and Allyl Sulfoxide
via an Aromatic 1,3-Silyl Migration. J. Am. Chem. Soc. 2021, 143,
2178−2184.
(10) Suzuki, S.; Segawa, Y.; Itami, K.; Yamaguchi, J. Synthesis and
Characterization of Hexaarylbenzenes with Five or Six Different
Substituents Enabled by Programmed Synthesis. Nat. Chem. 2015, 7,
227−233.
(11) (a) Laird, T.; Ollis, W. D. [4,5] Anionic Sigmatropic
Rearrangements. J. Chem. Soc., Chem. Commun. 1973, 658−660.
(b) Laird, T.; Ollis, W. D.; Sutherland, I. O. Base Catalyzed
Rearrangements Involving Ylide Intermediates. Part 7. The Re-
arrangements of Allyl(pentadienyl)- and Propynyl(pentadienyl)-
ammonium Cations. The [5,4] Sigmatropic Rearrangement. J.
Chem. Soc., Perkin Trans. 1 1980, 2033−2048.
(12) Ollis, W. D.; Somanathan, R.; Sutherland, I. O. More [4,5]
Sigmatropic Rearrangements. J. Chem. Soc., Chem. Commun. 1973,
661−661.
(13) Fráter, G.; Schmid, H. Thermische Umwandlung von Penta-
̈
2,4-dienyl-phenylathern in 4-(Penta-2,4-dienyl)-phenole; [5s,5s]-
Sigmatropische Umlagerungen. Helv. Chim. Acta 1970, 53, 269−290.
(14) (a) Maruyama, K.; Nagai, N.; Naruta, Y. Lewis Acid Mediated
Claisen-Type Rearrangement of Aryl Dienyl Ethers. Tetrahedron Lett.
1985, 26, 5149−5152. (b) Maruyama, K.; Nagai, N.; Naruta, Y. Lewis
Acid Mediated Claisen-Type Rearrangement of Aryl Dienyl Ethers. J.
Org. Chem. 1986, 51, 5083−5092.
(15) It was found that only 0.31 equiv of sulfoxide 2a was consumed
in the reaction with the parent o-benzyne, which means that 84% of
the reacted sulfoxide 2a has been converted to the desired product.
(16) (a) Ding, Q.; Ye, Y.; Fan, R. Recent Advances in Phenol
Dearomatization and Its Application in Complex Syntheses. Synthesis
2013, 45, 1−16. (b) Sun, W.; Li, G.; Hong, L.; Wang, R. Asymmetric
Dearomatization of Phenols. Org. Biomol. Chem. 2016, 14, 2164−
2176.
10536
https://doi.org/10.1021/jacs.1c04389
J. Am. Chem. Soc. 2021, 143, 10530−10536