Aryne 1,2,3,5-Tetrasubstitution Enabled by 3-Silylaryne and Allyl Sulfoxide via an Aromatic 1,3-Silyl Migration

Article abstract of DOI:10.1021/jacs.0c11119

Although benzyne has been well-known to serve as a synthon that can conveniently prepare various 1,2-difunctionalized benzenes, the sites other than its formal triple bond remain silent in typical benzyne transformations. An unprecedented aryne 1,2,3,5-tetrasubstitution was realized from 3-silylbenzyne and aryl allyl sulfoxide, the mechanistic pathway of which includes a regioselective aryne insertion into the SO bond, a [3,6]-sigmatropic rearrangement, and a thermal aromatic 1,3-silyl migration cascade.

Full text of DOI:10.1021/jacs.0c11119

pubs.acs.org/JACS
Communication
Aryne 1,2,3,5-Tetrasubstitution Enabled by 3‑Silylaryne and Allyl
Sulfoxide via an Aromatic 1,3-Silyl Migration
Jiarong Shi,§ Lianggui Li,§ Chunhui Shan,§ Junli Wang, Zhonghong Chen, Rongrong Gu, Jia He,
Min Tan, Yu Lan,* and Yang Li*
Cite This: J. Am. Chem. Soc. 2021, 143, 2178−2184
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Although benzyne has been well-known to serve as a synthon that can conveniently prepare various 1,2-
difunctionalized benzenes, the sites other than its formal triple bond remain silent in typical benzyne transformations. An
unprecedented aryne 1,2,3,5-tetrasubstitution was realized from 3-silylbenzyne and aryl allyl sulfoxide, the mechanistic pathway of
which includes a regioselective aryne insertion into the SO bond, a [3,6]-sigmatropic rearrangement, and a thermal aromatic 1,3-
silyl migration cascade.
simple benzyne to realize polysubstitution tasks, which will
s one of the most active organic intermediates, benzyne
Aand its analogs have long been recognized as versatile require a selective C−H bond functionalization on the benzyne
ring in a properly designed tandem or cascade process.
Notably, the success of this strategy would not only break the
restriction of benzyne 1,2-difunctionalization but also provide
highly efficient and economical maneuvers toward polysub-
stituted benzenes.
benzene-based building blocks, which could expeditiously
assemble numerous vicinal difunctionalized benzenes as well as
benzofused compounds.1 The formal triple bond character of
benzyne, however, mechanistically prohibits the introduction
of more than two substituents on the benzyne ring using
conventional methods. This intrinsic restriction of benzyne has
largely impeded its application in the preparation of
polysubstituted benzenes. Although equivalents of benzdiy-
ne1o,2 and benztriyne3 could be utilized, only limited reaction
modes were reported along with lack of regioselective control
in the cases of 1,4-benzdiyne i and 1,3-benzdiyne ii (Scheme
1a). Moreover, multistep preparation procedures for these
“polyaryne” precursors also diminish the atom/step economy
evaluation on this approach. An intriguing proposal is to utilize
Along with our study on aryne chemistry,2a,c,e,g,h,k,4 we
previously achieved a benzyne 1,2,3-trisubstitution protocol.4b
Prompted by this work, we then aimed to reach the less
accessible distal C−H bond of benzyne iii, where benzyne
1,2,4-trifunctionalization or more substitution could be
conceived (Scheme 1b). To the best of our knowledge,
however, there was no precedent on this type of trans-
formation. In this context, the groups of Pilarski5 and Hosoya6
independently reported a Ir-catalyzed chemoselective C−H
borylation reaction on o-silyl (hetero)aryl triflates, whereas the
corresponding arynes were generated in a separate step
(Scheme 1c). It can be envisioned that cascade benzyne
polysubstitution processes containing a selective distal C−H
bond functionalization would be more challenging. Herein, we
wish to present our discovery on an unprecedented aromatic
1,3-silyl migration event via intermediate v, which was
generated between 3-silylbenzyne iv and allyl sulfoxide
(Scheme 1d). As a consequence of this thermal 1,3-silyl
shift, a cascade process toward the expeditious construction of
1,2,3,5-tetrasubstitued arenes from single arynes was accom-
plished.
Scheme 1. Background and Our Work
After searching for plausible solutions for benzyne 1,2,4-
trisubstitution, we decided to use 3-silylbenzyne iv and allyl
Received: October 22, 2020
Published: January 28, 2021
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184
© 2021 American Chemical Society
2178

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
sulfoxide4b to examine this hypothesis (Scheme 1d). This
design was based on the following considerations: (1) the 3-
silyl group on benzyne is known to serve as an inductively
electron-donating group (EDG)7 that could direct the
incoming sulfoxide oxygen to attack its ortho-position; (2) it
might then act as a “blocking group” after the allyl group
migrates to the C3-position and trigger a subsequent
rearrangement, presumably a Cope rearrangement, on
intermediate v.
a
Table 1. Reaction Optimization of 1,3-Silyl Migration
entry “F” (equiv) additive (equiv) solvent temp (°C) yield (%)
1
2
3
4
5
6
7
8
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (2.0)
CsF (4.0)
CsF (4.0)
KF (4.0)
TBAF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
no
no
no
no
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
dioxane
THF
rt
49
83
80
50
78
29
41
10
nr
50
80
50
50
50
50
50
100
80
50
50
As shown in Scheme 2, a series of 3-silylbenzyne precursors
1a−1f were prepared, which could generate the corresponding
Cs2CO3 (2.0)
18-c-6 (2.0)
18-c-6 (2.0)
no
no
no
no
no
Scheme 2. Reactions of 3-Silylbenzynes with Allyl Sulfoxide
9
10
11
12
trace
64
68
DME
a
Conditions: 1e (0.2 mmol), 2a (0.4 mmol), “F”, and BrCH2CO2Et
(0.4 mmol) in solvent (2 mL) overnight.
yield (entries 5 and 6). Other fluoride salts could not enhance
the yield as well (entries 7 and 8). At last, different solvents
were tested and all of them gave lower yields than that with
MeCN (entries 9−12). Finally, the optimal conditions for this
transformation were determined to be CsF in MeCN at 50 °C,
furnishing 3a in 83% yield with complete suppression of the
desilylation pathway (entry 2).
arynes upon activation with CsF in acetonitrile. These
precursors were then subjected to the reaction with p-tolyl
allyl sulfoxide (2a) and ethyl bromoacetate at room temper-
ature. When 1a with a 3-trimethylsilyl (3-TMS) group was
used, the reaction only afforded a desilylation product 4 in 54%
yield. By altering aryne precursors to 1b with a 3-triethylsilyl
(3-TES) group, 1c with a 3-tri(n-butyl)silyl (3-n-Bu3Si) group,
or 1d with a 3-triphenylsilyl (3-TPS) group, compound 4
remained the only obtained product. Intriguingly, when aryne
precursors containing a 3-tert-butyldimethylsilyl (3-TBS)
group (1e) and 3-tris(isopropyl)silyl (3-TIPS) group (1f)
were examined, the main reaction path changed dramatically,
affording 3a and 3b in 49% and 36% yields, respectively, along
with certain amount of the desilylation product 4. Notably, no
product via Cope rearrangement was detected. Alternatively,
the formation of 3a and 3b should proceed through a net 1,3-
silyl migration on the benzene ring. In the presence of a
fluoride ion, those silyl groups with less sterically hindered
substituents are vulnerable, whereas both TBS and TIPS
groups could sustain. Although the thermal 1,3-silyl shift of
allylsilanes has been studied by Kwart8 and Kira9 and has
attracted some theoretical attention,10 harsh reaction con-
ditions (>350 °C) for this transformation prohibited its
synthetic application. Besides the much milder reaction
temperature, our serendipitous discovery is of great interest,
because, to the best of our knowledge, there was no precedent
of thermal 1,3-silyl migration on aromatic systems. Moreover,
this type of transformation provides a convenient means to
deliver an aromatic silyl group to its meta-position specifically
under certain circumstances.
We then explored the substrate scope for this trans-
formation. As shown in Scheme 3, this reaction can be also
scaled up to gram-scale, giving rise to 3a in 79% yield. When 3-
TIPS-substituted benzyne precursor 1f was examined under
the optimal conditions, 3b was obtained in 60% yield. By
altering ethyl bromoacetate to allyl bromide, cinnamyl
bromide, and di-tert-butyl dicarbonate (Boc2O), the corre-
sponding products 3c−3e were obtained as well. The
employment of different aryl groups on sulfoxide afforded
the desired products 3f−3j in moderate to good yields.
Sulfoxides with substituted allyl groups were tested, and
products 3k−3p were readily achieved. Among them, the X-ray
crystallographic structure of 3k unequivocally confirmed this
1,3-silyl migration event. Notably, desilylation reactions were
suppressed, despite the fact that silyl groups are naturally
vulnerable to the fluoride ion. We reasoned that the presence
of either the tert-butyl group or triple isopropyl groups on
silicon would kinetically disfavor the desilylation reaction.
Consequently, the 1,3-silyl shift turned out to be the dominant
path under the reaction conditions.
Distinctively, this cascade process still obeys the regiose-
lective regulation when additional substituents are properly
positioned on the benzyne ring, furnishing arenes with up to
five substituents. For instance, when Kobayashi precursor 1g
was employed, pentasubstituted benzene 3q was harvested in
56% yield (Scheme 4). Similarly, pentasubstituted benzenes 3r
and 3s could be obtained in good yields as well from the
corresponding aryne precursors 1h and 1i. The examples in
Schemes 3 and 4 demonstrate that aromatic 1,3-silyl migration
is a general scenario in this transformation, leading to an
unprecedented tandem maneuver toward polysubstituted
benzenes with substituents of different types.
With the above observation in hand, we decided to optimize
the reaction conditions. As shown in Table 1, in the presence
of ethyl bromoacetate, p-tolyl allyl sulfoxide (2a) could react
with benzyne precursor 1e to afford 3a. By screening the
reaction temperature (entries 1−3, Table 1), it was found that
50 °C was the best one. Altering the stoichiometry of CsF to
2.0 equiv gave only 50% of 3a (entry 4). Additives, such as
Cs2CO3 and 18-crown-6, were used but did not improve the
2179
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Scheme 3. Substrate Scope
Scheme 4. Pentasubstituted Benzenes
Scheme 5. Further Investigations
a
Conditions: a mixture of 1 (0.2 mmol), 2 (0.4 mmol), RX (0.4
mmol), and CsF (0.8 mmol) in MeCN (2 mL) was heated at 50 °C
overnight.
Further studies were carried out in order to explore the
scope and the mechanism of this transformation. When aryne
precursor 1j was employed, only desilylation product 5 was
obtained in 60% yield, indicating that the 1,3-silyl shift can be
prohibited by the presence of the C5-methyl group. To test the
generality of aromatic silyl migration, 6-substituted 2-(tert-
butyldimethylsilyl)phenols 6 were prepared (Scheme 5a).
Under ortho bromination conditions (Br2/t-BuNH2 in toluene
at −30 °C), the 1,3-silyl shift did happen after bromide adds to
the C2-position, giving rise to products 7 (Scheme 5b). The X-
ray crystallographic structure of 7b was also determined. This
observation suggests that aromatic 1,3-silyl migration could
serve as a potentially useful tool under certain circumstances.
To further understand the mechanistic aspect of this system, a
crossover experiment was performed. When 1f and 1i were
treated with 2a under standard conditions, only 3b and 3s
were obtained in 60% and 61% yields, respectively, supporting
an intramolecular silyl migration pathway (Scheme 5c).
Another experiment was then tested by using aryl crotyl
sulfoxide 2b and allyl bromide, which only afforded 8 in 53%
yield (Scheme 5d). This result suggests a direct migration of
the crotyl group to the ortho position of oxygen and phenolate
allylation with allyl bromide should occur after crotyl
migration.
Density functional theory calculations at the M06-2X level of
theory were then performed. As shown in Scheme 6a, in situ
generated 3-TBS-benzyne vi was chosen as the relative zero in
calculated free energy profiles, which can react with aryl crotyl
2180
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Scheme 6. DFT Predicted Pathway between 3-TBS-benzyne vi and Crotyl Sulfoxide 2b
a
The free energy values are calculated at the M06-2X level of theory in acetonitrile solvent.
sulfoxide 2b via a four-membered metathesis-type transition
state TS1 to afford a zwitterionic sulfonium intermediate IM1.
The calculated activation free energy for this step is only 10.9
kcal/mol, indicative of an easily reachable process. Inter-
mediate IM1 possesses a sulfonium ylide resonance structure
as well. Consequently, a [3,6]-sigmatropic rearrangement can
occur via transition state TS2 with an energy barrier of 22.2
kcal/mol. The generated cyclohexadienone intermediate IM2
is 6.3 kcal/mol more stable than IM1, which can be attributed
by the cancelation of zwitterionic character on IM1. The
geometry information on transition state TS2 shows that the
lengths of the forming C3−C(allyl) bond and the breaking S−
C(allyl) bond are 2.84 and 3.00 Å, respectively, supportive of a
concerted 10-electron sigmatropic rearrangement (Scheme
6a). In our theoretical study, several competitive pathways had
also been examined at the IM1 stage, such as [3,3]-sigmatropic
rearrangement, [3,4]-sigmatropic rearrangement, allyl S → O
shift, and phenolate alkylation (Scheme 6b). Those possibil-
ities were excluded by their higher activation free energies via
the corresponding transition states TS3−TS6. Although in our
previous study an alternative pathway was proposed to account
for the mechanism between benzyne and allyl sulfoxide,4b
[3,6]-sigmatropic rearrangement turned out to be more likely
to occur based on our calculations and experimental evidence
in Scheme 5d.
After the formation of IM2, the silyl group was found to
undergo a facile 1,3-migration via a four-membered ring
transition state TS7, leading to the formation of a more stable
intermediate IM3. In contrast, a plausible Cope rearrangement
pathway at the IM2 stage was precluded by its high activation
energy of 23.0 kcal/mol (see the Supporting Information (SI)
for details). After deprotonative aromatization on IM3 and a
subsequent alkylation on the generated phenolate IM4 with
ethyl bromoacetate via transition state TS8, product 3k could
be achieved. In this system, the electrostatic potential (ESP)
surface of transition state TS7 shows that the structure is
highly charge-separated, where the positive charge (cool tones)
is located on the silicon group and the center of the negative
charge (warm tones) is on the oxygen atom (Scheme 6a). This
charge-separation mechanism could be considered as a quasi-
concerted process (see Figure S5 in the SI for detailed
discussion), which is distinctly different from the previous
theoretical studies on the 1,3-silyl shift of allylsilanes.10 We
speculated that the cationic silicon can be stabilized by one
2181
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
tert-butyl and two methyl groups and the anionic side forms an
aromatic phenolate structure, which can be confirmed by a
nucleus independent chemical shift (NICS) calculation (see
Figure S6 in the SI).
We then investigated further manipulation on the products.
As shown in Scheme 7, compound 3o was chosen as an
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11119.
■
sı
Experimental details for all chemical reactions and
measurements and X-ray single crystallographic data
(PDF)
Scheme 7. Synthetic Applications of 3o
Accession Codes
CCDC 1923158 and 2033152 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
■
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 450001, P. R. China;
orcid.org/0000-0002-2328-0020; Email: lanyu@
cqu.edu.cn
Yang Li − 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
Authors
Jiarong Shi − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030
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; orcid.org/0000-0002-6175-1743
Junli Wang − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing, P. R. China 400030
Zhonghong Chen − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing, P. R. China
400030
Rongrong Gu − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing, P. R. China
400030
Jia He − 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
example. After deprotection and annulation, tricyclic com-
pound 9 was obtained in three steps. The TBS group on
compound 9 could then be converted to a variety of functional
groups, such as iodo, bromo, chloro, and acetyl groups, to
furnish 10a−10d. Although a TBS group on benzene is
normally difficult to replace, the electron-rich nature of the
benzene ring on compound 9 accounts for its facile
replacement by electrophilic species. Alternatively, the C−S
bond on compound 9 was transformed to biphenyl 11 via a
sequential oxidation and nickel-catalyzed cross-coupling
reaction.11 Moreover, the C−S bond on compound 10c
could be converted to benzaldehyde in two steps, giving rise to
compound 12. Notably, racemic compound 12 contains an
identical core structure with that of bioactive molecule RG
12915, a potent antagonist of 5-hydroxytryptamine3 (5-HT3)
receptor.12
In summary, we accomplished an unprecedented aryne
1,2,3,5-tetrasubstitution transformation between 3-silylaryne
and allyl sulfoxides. This is the first example of single benzyne
multifunctionalization involving a distal C−H bond function-
alization cascade. In this study, a thermal aromatic 1,3-silyl
migration was discovered, which possesses potential synthetic
application under mild conditions. Moreover, our theoretical
calculation clearly addressed the mechanistic aspects of this
cascade transformation.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11119
Author Contributions
§J.S., L.L., and C.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge research support of this
work by the Basic and Frontier Research Project of Chongqing
(cstc2018jcyjAX0357, cstc2019jcyj-bshX0021), Fundamental
Research Funds for the Central Universities
2182
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Shi, J.; Tan, L.; Qiu, D.; Luo, X.; Li, Y. Domino Aryne Annulation via
a Nucleophilic-Ene Process. J. Am. Chem. Soc. 2018, 140, 3555−3559.
(h) Lv, C.; Wan, C.; Liu, S.; Lan, Y.; Li, Y. Aryne Trifunctionalization
Enabled by 3-Silylaryne as a 1,2-Benzdiyne Equivalent. Org. Lett.
2018, 20, 1919−1923. (i) Nakamura, Y.; Miyata, Y.; Uchida, K.;
Yoshida, S.; Hosoya, T. 3-Thioaryne Intermediates for the Synthesis
of Diverse Thioarenes. Org. Lett. 2019, 21, 5252−5258. (j) Xiao, X.;
Hoye, T. R. One-Pot, Three-Aryne Cascade Strategy for Naphthalene
Formation from 1,3-Diynes and 1,2-Benzdiyne Equivalents. J. Am.
Chem. Soc. 2019, 141, 9813−9818. (k) He, J.; Jia, Z.; Tan, H.; Luo,
X.; Qiu, D.; Shi, J.; Xu, H.; Li, Y. Arene Trifunctionalization with
Highly Fused Ring Systems through a Domino Aryne Nucleophilic
and Diels-Alder Cascade. Angew. Chem., Int. Ed. 2019, 58, 18513−
18518. (l) Ikawa, T.; Masuda, S.; Takagi, A.; Akai, S. 1,3- and 1,4-
Benzdiyne Equivalents for Regioselective Synthesis of Polycyclic
Heterocycles. Chem. Sci. 2016, 7, 5206−5211. For recent examples
on 1,3-benzdiyne chemistry, see: (m) Kitamura, T.; Gondo, K.;
Oyamada, J. Hypervalent Iodine/Triflate Hybrid Benzdiyne Equiv-
alents: Access to Controlled Synthesis of Polycyclic Aromatic
Compounds. J. Am. Chem. Soc. 2017, 139, 8416−8419. (n) Duong,
H. M.; Bendikov, M.; Steiger, D.; Zhang, Q.; Sonmez, G.; Yamada, J.;
Wudl, F. Efficient Synthesis of a Novel, Twisted and Stable,
Electroluminescent “Twistacene. Org. Lett. 2003, 5, 4433−4436.
For recent examples on 1,4-benzdiyne chemistry, see: (o) Hamura,
T.; Arisawa, T.; Matsumoto, T.; Suzuki, K. Two-Directional
Annelation: Dual Benzyne Cycloadditions Starting from Bis-
(sulfonyloxy)diiodobenzene. Angew. Chem., Int. Ed. 2006, 45,
6842−6844. (p) Chen, C.-L.; Sparks, S. M.; Martin, S. F. C-Aryl
Glycosides via Tandem Intramolecular Benzyne-Furan Cycloaddi-
tions. Total Synthesis of Vineomycinone B2 Methyl Ester. J. Am.
Chem. Soc. 2006, 128, 13696−13697. (q) Hamura, T.; Chuda, Y.;
Nakatsuji, Y.; Suzuki, K. Catalytic Generation of Arynes and Trapping
by Nucleophilic Addition and Iodination. Angew. Chem., Int. Ed. 2012,
(2018CDXZ0003), and NSFC (21901025, 21971028,
21772017, 21822303). S.J. was funded by the China
Postdoctoral Science Foundation (2018M640897).
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.
Org. Biomol. Chem. 2013, 11, 191−218. (h) Pérez, D.; Pena, D.;
̃
́
Guitian, 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) Feng, M.; Jiang, X. Reactions of Arynes
Involving Transition-Metal Catalysis. Synthesis 2017, 28, 4414−4433.
(n) Asamdi, M.; Chikhalia, K. H. Aryne Insertion into σ Bonds. Asian
J. Org. Chem. 2017, 6, 1331−1348. (o) Shi, J.; Li, Y.; Li, Y. Aryne
Multifunctionalization with Benzdiyne and Benztriyne Equivalents.
Chem. Soc. Rev. 2017, 46, 1707−1719. (p) Diamond, O. J.; Marder, T.
B. Methodology and Applications of the Hexadehydro-Diels-Alder
(HDDA) Reaction. Org. Chem. Front. 2017, 4, 891−910. (q) Roy, T.;
Biju, A. T. Recent Advances in Molecular Rearrangements Involving
Aryne Intermediates. Chem. Commun. 2018, 54, 2580−2594.
(r) 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. (s) Pozo, I.;
́
51, 3368−3372. (r) Alonso, J. M.; Díaz-Alvarez, A. E.; Criado, A.;
́
Pérez, D.; Pena, D.; Guitian, E. [16]Cloverphene: A Clover-Shaped
̃
cata-Condensed Nanographene with Sixteen Fused Benzene Rings.
Angew. Chem., Int. Ed. 2012, 51, 173−177. (s) Schuler, B.; Collazos,
́
S.; Gross, L.; Meyer, G.; Pérez, D.; Guitian, E.; Pena, D. From
̃
Perylene to a 22-Ring Aromatic Hydrocarbon in One-Pot. Angew.
Chem., Int. Ed. 2014, 53, 9004−9006. (t) Kumarasinghe, K. G. U. R.;
Fronczek, F. R.; Valle, H. U.; Sygula, A. Bis-Corannulenoanthracene:
An Angularly Fused Pentacene as a Precursor for Barrelene-Tethered
Receptors for Fullerenes. Org. Lett. 2016, 18, 3054−3057. (u) García,
́
D.; Rodríguez-Pérez, L.; Herranz, M. A.; Pena, D.; Guitian, E.; Bailey,
̃
S.; Al-Galiby, Q.; Noori, M.; Lambert, C. J.; Pérez, D.; Martín, N. A
C60-Aryne Building Block: Synthesis of a Hybrid All-Carbon
Nanostructure. Chem. Commun. 2016, 52, 6677−6680. (v) Ninomiya,
M.; Ando, Y.; Kudo, F.; Ohmori, K.; Suzuki, K. Total Synthesis of
Actinorhodin. Angew. Chem., Int. Ed. 2019, 58, 4264−4270.
(3) (a) Hamura, T.; Ibusuki, Y.; Uekusa, H.; Matsumoto, T.; Suzuki,
K. Poly-Oxygenated Tricyclobutabenzenes via Repeated [2 + 2]
Cycloaddition of Benzyne and Ketene Silyl Acetal. J. Am. Chem. Soc.
2006, 128, 3534−3535. (b) Hamura, T.; Ibusuki, Y.; Uekusa, H.;
Matsumoto, T.; Siegel, J. S.; Baldridge, K. K.; Suzuki, K.
Dodecamethoxy- and Hexaoxotricyclobutabenzene: Synthesis and
Characterization. J. Am. Chem. Soc. 2006, 128, 10032−10033.
(c) Shinozaki, S.; Hamura, T.; Ibusuki, Y.; Fujii, K.; Uekusa, H.;
Suzuki, K. Hexaradialenes by Successive Ring Openings of Tris-
(alkoxy-tricyclobutabenzenes): Synthesis and Characterization.
Angew. Chem., Int. Ed. 2010, 49, 3026−3029.
́
Guitian, E.; Pérez, D.; Pena, D. Synthesis of Nanographenes,
̃
Starphenes, and Sterically Congested Polyarenes by Aryne Cyclo-
trimerization. Acc. Chem. Res. 2019, 52, 2472−2481. (t) Werz, D. B.;
Biju, A. T. Uncovering the Neglected Similarities of Arynes and
Donor-Acceptor Cyclopropanes. Angew. Chem., Int. Ed. 2020, 59,
3385−3398.
(2) For recent examples on 1,2-benzdiyne chemistry, see: (a) Shi, J.;
Qiu, D.; Wang, J.; Xu, H.; Li, Y. Domino Aryne Precursor: Efficient
Construction of 2,4-Disubstituted Benzothiazoles. J. Am. Chem. Soc.
2015, 137, 5670−5673. (b) Qiu, D.; He, J.; Yue, X.; Shi, J.; Li, Y.
Diamination of Domino Aryne Precursor with Sulfonamides. Org.
Lett. 2016, 18, 3130−3133. (c) Li, L.; Qiu, D.; Shi, J.; Li, Y. Vicinal
Diamination of Arenes with Domino Aryne Precursors. Org. Lett.
2016, 18, 3726−3729. (d) Yoshida, S.; Nakamura, Y.; Uchida, K.;
Hazama, Y.; Hosoya, T. Aryne Relay Chemistry en Route to
Aminoarenes: Synthesis of 3-Aminoaryne Precursors via Regioselec-
tive Silylamination of 3-(Triflyloxy)arynes. Org. Lett. 2016, 18, 6212−
6215. (e) Shi, J.; Xu, H.; Qiu, D.; He, J.; Li, Y. Selective Aryne
Formation via Grob Fragmentation from the [2 + 2] Cycloadducts of
3-Triflyloxyarynes. J. Am. Chem. Soc. 2017, 139, 623−626. (f) Uchida,
K.; Yoshida, S.; Hosoya, T. Three-Component Coupling of Triflyloxy-
Substituted Benzocyclobutenones, Organolithium Reagents, and
Arynophiles Promoted by Generation of Aryne via Carbon-Carbon
Bond Cleavage. Org. Lett. 2017, 19, 1184−1187. (g) Xu, H.; He, J.;
(4) (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) Qiu, D.; Shi, J.; Guo, Q.;
Xu, Q.; Li, B.; Li, Y. Cyclohexenynone Precursors: Preparation via
Oxidative Dearomatization Strategy and Reactivity. J. Am. Chem. Soc.
2018, 140, 13214−13218.
2183
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(5) (a) Demory, E.; Devaraj, K.; Orthaber, A.; Gates, P. J.; Pilarski,
L. T. Boryl (Hetero)aryne Precursors as Versatile Arylation Reagents:
Synthesis through C-H Activation and Orthogonal Reactivity. Angew.
Chem., Int. Ed. 2015, 54, 11765−11769. (b) Larsson, J.; Demory, E.;
Devaraj, K.; Sollert, C.; Pilarski, L. T. Selective Activation of
Arylboronate or Aryne Reactivity as a Versatile Postfunctionalization
Strategy. Synlett 2016, 27, 969−976.
(6) Yoshida, S.; Shimomori, K.; Nonaka, T.; Hosoya, T. Facile
Synthesis of Diverse Multisubstituted ortho-Silylaryl Triflates via C-H
Borylation. Chem. Lett. 2015, 44, 1324−1326.
(7) (a) Matsumoto, T.; Sohma, T.; Hatazaki, S.; Suzuki, K. On the
Regiochemistry of Cycloaddition of Unsymmetrical Aryne with
Nitrone Remarkable Effect of Trialkylsilyl Substituent. Synlett 1993,
1993, 843−846. (b) Ikawa, T.; Nishiyama, T.; Shigeta, T.; Mohri, S.;
Morita, S.; Takayanagi, S.-I.; Terauchi, Y.; Morikawa, Y.; Takagi, A.;
Ishikawa, Y.; Fujii, S.; Kita, Y.; Akai, S. ortho-Selective Nucleophilic
Addition of Primary Amines to Silylbenzynes: Synthesis of 2-
Silylanilines. Angew. Chem., Int. Ed. 2011, 50, 5674−5677.
(c) Bronner, S. M.; Mackey, J. L.; Houk, K. N.; Garg, N. K. Steric
Effects Compete with Aryne Distortion to Control Regioselectivities
of Nucleophilic Additions to 3-Silylarynes. J. Am. Chem. Soc. 2012,
134, 13966−13969.
(8) (a) Kwart, H.; Slutsky, J. Unimolecular Thermal Rearrangement
of Allylsilanes. A Sigmatropic 1,3 Migration of Silicon. J. Am. Chem.
Soc. 1972, 94, 2515−2516. (b) Slutsky, J.; Kwart, H. The Kinetics,
Stereochemistry, and Mechanisms of the Silaallylic and Silapropynylic
Rearrangements. J. Am. Chem. Soc. 1973, 95, 8678−8685.
(9) Zhang, L. C.; Kabuto, C.; Kira, M. Retention Stereochemistry of
Thermal 1,3-Silyl Migration in Allylsilanes. J. Am. Chem. Soc. 1999,
121, 2925−2926.
(10) (a) Yamabe, T.; Nakamura, K.; Shiota, Y.; Yoshizawa, K.;
Kawauchi, S.; Ishikawa, M. Novel Aspects of the [1,3] Sigmatropic
Silyl Shift in Allylsilane. J. Am. Chem. Soc. 1997, 119, 807−815.
(b) Takahashi, M.; Kira, M. A Theoretical Study of Stereochemistry
of 1,3-Migration in Allylsilane and Related Allylmetallic Compounds.
J. Am. Chem. Soc. 1997, 119, 1948−1953. (c) Takahashi, M.; Kira, M.
A Theoretical Study of Mechanisms of 1,3-Silyl Migration in
Formylmethylsilane and Related Migrations. Comparison with
Allylsilane. J. Am. Chem. Soc. 1999, 121, 8597−8603.
(11) Someya, C. I.; Weidauer, M.; Enthaler, S. Nickel-Catalyzed
C(sp2)-C(sp2) Cross Coupling Reactions of Sulfur-Functionalities
and Grignard Reagents. Catal. Lett. 2013, 143, 424−431.
(12) (a) Youssefyeh, R. D.; Campbell, H. F.; Airey, J. E.; Klein, S.;
Schnapper, M.; Powers, M.; Woodward, R.; Rodriguez, W.; Golec, S.;
Studt, W.; Dodson, S. A.; Fitzpatrick, L. R.; Pendley, C. E.; Martin, G.
E. Development of High-Affinity 5-HT3 Receptor Antagonists. 2. Two
Novel Tricyclic Benzamides. J. Med. Chem. 1992, 35, 903−911.
(b) Martin, G. E.; Chase, B. J.; Davis, M. A.; Pendley, C. E. Potent 5-
Hydroxytryptamine3 Receptor Antagonist Activity of RG 12915. Drug
Dev. Res. 1993, 28, 38−46.
2184
https://dx.doi.org/10.1021/jacs.0c11119
J. Am. Chem. Soc. 2021, 143, 2178−2184