Reactivity of Arynes for Arene Dearomatization

Article abstract of DOI:10.1021/acs.orglett.8b01466

An unprecedented aryne-mediated dearomatization reaction is described. An aryne intermediate generated from arenesulfonyl ynamide-tethered triynes and tetraynes reacts with both the π-systems of a tethered alkene and the arenesulfonyl group to generate cy

Full text of DOI:10.1021/acs.orglett.8b01466

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reactivity of Arynes for Arene Dearomatization
Rajdip Karmakar,† Anh Le,† Peipei Xie,‡ Yuanzhi Xia,*,‡ and Daesung Lee*,†
†Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, People’s Republic of
China
S
* Supporting Information
ABSTRACT: An unprecedented aryne-mediated dearomatization
reaction is described. An aryne intermediate generated from
arenesulfonyl ynamide-tethered triynes and tetraynes reacts with
both the π-systems of a tethered alkene and the arenesulfonyl group
to generate cyclohexa-1,3-diene-containing pentacyclic and hexacy-
clic frameworks. Density functional theory (DFT) calculations show
a nucleophilic dearomatization mechanism involving a zwitterionic
intermediate derived from an aryne. A novel halogen effect on the
efficiency of the dearomatization and deterrence of aromatization of the cyclohexa-1,3-diene moiety was also observed.
Scheme 1. Discovery of Aryne-Mediated Dearomatization
he reactivity of arynes is generally manifested as a
Tstrained alkyne, 1,2-diradical, or 1,2-zwitterion, depend-
ing on the reacting counterpart.1 In the presence of π-philic
transition metals, arynes participate in C−H insertion, which is
evidence for the involvement of the 1,2-dicarbenoid.2 Although
arynes can potentially behave as a 1,2-dicarbene, this reactivity
has never been revealed in any aryne-mediate transformations.
The arene-dearomatization reaction described herein is the
first evidence that the aryne species can interact with two π-
systems through free 1,2-dicarbene reactivity.3
Dearomatization of arenes to cyclohexa-1,3- or cyclohexa-
1,4-dienes could be achieved under a variety of conditions.4
Among these, breaking aromaticity by adding a nucleophile
onto arenes is limited to only a small range of arene
structures.4p−r Different from polycyclic arenes,5 monocyclic
arenes react only under harsh conditions, resulting in low
yield,4r,6 unless complexed with certain transition metals.4q,s,7
In this regard, the facile dearomatization of benzene via Diels−
Alder reaction with aryne is unique,8 wherein the relief of
strain energy of arynes9 should play a crucial role.
In light of the previously reported Ag(I)-catalyzed C−H
insertion reaction,2 we surmised that, in an appropriate
environment, the 1,2-dicarbenoid can participate in two
independent C(sp2)−H insertion events (see Scheme 1).
When 1a was subjected to typical conditions (10 mol %
AgOTf, toluene, 90 °C),10 two products 2a and 3a were
obtained.11 While 2a is the result of a mono C−H insertion,
followed by the elimination of AcOH, the product 3a can be
considered as the result of an unprecedented 1,2-dicarbene
mechanism.
most favorable solvent (entry 1). The substituent on the alkene
tether, for example, p-nitrophenylcarboxy and pivaloxy group
at the allylic position has almost no effect on yields (entry 2 vs
entry 3). Relocating the oxygen substituent from the allylic to
the propargylic position did not affect the yield (entry 4 vs
entry 5). Free hydroxyl group such as in 1f did not interfere
with the reaction,12 affording 3e in comparable yield (entry 6).
Substrate 1g, containing a styryl moiety, produced hexacyclic
product 3g (entry 7), whereas a similar substrate 1h afforded
product 4h and 2h in 40% and 18% yields, respectively (entry
8).
At this juncture, we surmised that the yield of the reaction
could be improved by circumventing the elimination process,
thus, we explored the reactivity of tetraynes devoid of an
oxygen substituent (see Table 2). Tetrayne 1i containing a
carboxylate in the tether afforded 4i with a 1.3:1 diastereo-
meric ratio (entry 1). Tetrayne 1j containing an allyldime-
thylsilyl group afforded silacyclic product 4j in 35% yield
(entry 2). Although not involving the elimination step, the
yield of 4i and 4j still remained in a marginal range. A
Based on the formation of novel multicyclic framework
involving arene dearomatization, we further explored the scope
of this transformation. First, we tried to optimize the reaction
conditions, along with the variation in the structure of the
tethered alkene (see Table 1). It was found that AgOTf did not
have a noticeable effect on the reaction, and PhCF3 was the
Received: May 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01466
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
halogen substituents on the efficiency of the reaction was
examined. From tetraynes 1l−1o, which differ only by the
halogen substituent on the alkene moiety, pentacyclic products
4l−4o were obtained in good yields (entries 4−7). One
noteworthy observation is that the elimination of AcOH is
shunted in these products containing a haloalkene moiety. The
highest yield with 1l bearing a fluoride-substituent might be
the consequence of the carbocation-stabilizing effect of the
fluoride with an intermediate along the reaction path.13
Next, we explored the impact of electron-donating and
electron-withdrawing substituents on the arenesulfonamide
(see Table 3). The reaction of 1p containing a 4-MeOPh
Table 1. Optimization and the Effect of an Alkene Tether
Table 3. Effect of the Substituents on the Arenesulfonamide
a
Conditions: A = AgOTf (10 mol %), PhCH3, 90 °C; B = PhCH3, 90
b
c
d
°C; C = PhCF3, 90 °C. Isolated yield. Yield from 1a. Yield from
1b. In PhCl and 1,2-dichloroethane, 3d was obtained in 34% and
e
40% yields, respectively.
Table 2. Effect of the Substituents on the Alkene
a
b
c
PhCF3, 90 °C. Isolated yield. In a 1.0 g-scale reaction, 4y was
d
isolated in 67% yield. PhCF3, 120 °C.
afforded only 37% yield of 3p (entry 1), whereas 1q with a
phenyl group provided 3q in 48% yield (entry 2). Substrate 1r
with a phenyl instead of a methyl group on the alkene afforded
3r in 46% yield (entry 3). The 4-fluoro and 4-trifluoromethyl
groups in 1s and 1t slightly improved the yield, providing 3s
and 3t in 53% and 59% yields, respectively (entries 4 and 5).
These examples clearly suggest that more electron-deficient
arenesulfonyl groups can improve the yield. Substrate 1u with
3-CF3 afforded 3u in 51% yield (entry 6), while 1o with a 3,5-
difluophenyl group provided 3v in 35% yield (entry 7).
Naphthalene-2-sulfonyl substrate 1w furnished a 1:2.3 mixture
of 3w′ and 3w in 53% yield (entry 8).
a
b
Conditions: B = PhCH3, 90 °C; C = PhCF3, 90 °C. Isolated yield.
c
d
Mixture of diastereomers. Slightly higher 43% yield was obtained
with a phenyl instead of a tolyl group.
significant increase in yield was achieved by installing a vinyl
bromide moiety in tetrayne 1k, which yielded 4k in 67% yield
(entry 3). Encouraged by this result, the impact of different
B
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Comparison of 1x and 1y containing a vinyl bromide clearly
shows the beneficial effect of an electron-withdrawing 4-CF3
on the arenesulfonyl moiety, providing 61% and 76% yield of
4x and 4y, respectively (entries 9 and 10). The dearomatiza-
tion occurred with the aryne intermediate generated from
ketone-containing triyne 1z providing 4z at slightly higher
temperature, where the silyl ether remained unreacted.10e
The mechanism of this unprecedented aryne-mediated
dearomatization process was explored by DFT calculation,14
employing a structurally simplified aryne IN1 (see Scheme 2).
Scheme 3. Substrates with an Unsuitable Alkene Moiety
a
Scheme 2. DFT-Based Mechanistic Study
generating 8 (see eq 1 in Scheme 3). The electron-rich
aromatic π-system in 1bb led to only Diels−Alder reaction,15
forming benzobarrelene 9 after hydrolysis (see eq 2 in Scheme
3), whereas allyl ether-tethered tetrayne 1cc just decomposed
(see eq 3 in Scheme 3). These results indicate that a terminal
alkene tethered with a two-atom tether to the aryne moiety is
required for dearomatization reaction.
The reactivity of a representative dearomatized compound
4z was explored (see Scheme 4). Treatment of 4z with p-
Scheme 4. Chemical Reactivity of Dearomatized Products
a
ΔGsol and ΔG298 are relative free energies (kcal/mol) calculated in
solution and in the gas phase, respectively.
The calculated lowest energy pathway reveals a 1,2-dicarbene
character of IN2 through aryne, which promotes the concerted
formation of a cyclopropyl carbene via a relatively low-energy
transition state TS1. Carbene IN2 behaves similar to a
zwitterion, such that it undergoes nucleophilic addition (Path
I) onto an electron-deficient arenesulfonyl group via TS2 to
generate 1,3-zwitterion IN3. The ring expansion of the
cyclopropyl moiety of IN3 generates isomeric 1,6-zwitterion
IN4, which leads to the final product P via TS4 for
intramolecular proton transfer. The change of ΔG going
from aryne IN1 to product P is −58.7 kcal/mol, and the
highest barrier involved in the dearomatization is only 14.8
kcal/mol; thus, this overall process should be kinetically and
thermodynamically favorable. On the other hand, the energy of
TS6 leading to product P-2 (Path II) is 10.9 kcal/mol higher
than that of TS2 leading to product P-3/4. Also, the unusual
stability of the vinyl halide-containing products such as 4l−4o
toward aromatization was computationally studied. The DFT
calculations with Model-4 show that a fluoro-substituent raises
the activation barrier for the AcOH elimination. Even though
the calculations corroborate experimental observations, the
reason for this unusual phenomenon is yet to be identified.
A limitation was noticed regarding the alkene structure on
tetrayne substrates (see Scheme 3). A nonterminal alkene in
1aa favorably participates in a type-I Alder-ene reaction,
TsOH·H2O (10 mol %) at 90 °C induced aromatization via
elimination of AcOH, affording compound 7. The sulfonamide
of 7 could be removed easily by treating 7 in Et3N at 55 °C,
providing compound 8, which is the consequence of a base-
mediated alkene isomerization and an E2-type elimination.
The indoline moiety in 8 was oxidized by MnO2 to generate a
unique 1H-benzo[f ]indole containing biaryl structure 9. In
contrast, oxidation of 3q with DDQ afforded 10 with intact
indoline moiety in low yield.
In conclusion, we discovered a novel dearomatization
reaction mediated by the 1,2-dicarbene reactivity of arynes.
In this process, one aromatic system is generated via HDDA
reaction as a form of an aryne, the high reactivity of which then
ensues the dearomatization of the tethered aryl group
connected through a sulfonamide linkage. The efficiency of
this transformation is profoundly affected by substrate
C
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tethered alkene and electron-withdrawing substituents on the
arenesulfonyl group increased the efficiency of the reaction.
DFT calculations revealed that the 1,2-dicarbene character of
an aryne promoted cyclopropanation with the nearby alkene,
followed by a nucleophilic attack of the remaining carbene as a
form of zwitterion onto the electron-deficient arenesulfonyl
group, leading to dearomatization after proton shift in the final
step. The relatively strained pentacyclic framework can be
readily converted to useful building blocks, including 1H-
benzo[f ]indole that contains a CF3 group.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01466.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1574874 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
R.; Kaliappan, K. P.; Ku
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Gomez, G. Chem. Rev. 2007, 107, 1580. (s) Liebov, B. K.; Harman,
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AUTHOR INFORMATION
Corresponding Authors
■
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*E-mail: dsunglee@uic.edu.
*E-mail: xyz@wzu.edu.cn.
ORCID
Yuanzhi Xia: 0000-0003-2459-3296
Daesung Lee: 0000-0003-3958-5475
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful to NSF (No. CHE 1361620, to D.L.) and the
NSFC (Nos. 21372178 and 21572163, to Y.X.) for financial
support. The Mass Spectrometry Laboratory at UIUC is
greatly acknowledged.
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data and by analogy to the X-ray structure of 4j.
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See the Supporting Information for details.
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E
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