Palladium-Catalyzed [4 + 3] or [2 + 2 + 3] Annulation via C-H Activation and Subsequent Decarboxylation: Access to Heptagon-Embedded Polycyclic Aromatic Hydrocarbons

Article abstract of DOI:10.1021/acs.orglett.1c00520

The construction of a seven-membered ring in the polycyclic aromatic hydrocarbon skeleton remains a notoriously difficult but attractive challenge. Herein a novel palladium-catalyzed [4 + 3] decarboxylative annulation of 2-iodobiphenyls with 2-(2-halophenyl)acrylic acids is reported, which provides an efficient approach for assembling various tribenzo[7]annulenes via a C-H activation and decarboxylation process. Moreover, tribenzo[7]annulenes can be also synthesized via a [2 + 2 + 3] decarboxylative annulation strategy by employing readily available 1,2-halobenzenes, phenylboronic acids, and 2-(2-halophenyl)acrylic acids.

Full text of DOI:10.1021/acs.orglett.1c00520

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Letter
Palladium-Catalyzed [4 + 3] or [2 + 2 + 3] Annulation via C−H
Activation and Subsequent Decarboxylation: Access to Heptagon-
Embedded Polycyclic Aromatic Hydrocarbons
Xiumei Yang, Xiahong Chen, Yankun Xu, Minghao Zhang, Guobo Deng, Yuan Yang,* and Yun Liang*
Cite This: Org. Lett. 2021, 23, 2610−2615
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ABSTRACT: The construction of a seven-membered ring in the polycyclic aromatic hydrocarbon skeleton remains a notoriously
difficult but attractive challenge. Herein a novel palladium-catalyzed [4 + 3] decarboxylative annulation of 2-iodobiphenyls with 2-
(2-halophenyl)acrylic acids is reported, which provides an efficient approach for assembling various tribenzo[7]annulenes via a C−H
activation and decarboxylation process. Moreover, tribenzo[7]annulenes can be also synthesized via a [2 + 2 + 3] decarboxylative
annulation strategy by employing readily available 1,2-halobenzenes, phenylboronic acids, and 2-(2-halophenyl)acrylic acids.
eptagon-embedded polycyclic aromatic hydrocarbons
(PAHs) have provoked considerable attention due to
2-Iodobiphenyl has become among the most important
building blocks for assembling diverse cyclic compounds in the
field of transition-metal-catalyzed C−H annulations.8−11
Among them, palladium-catalyzed annulation reactions of 2-
iodobiphenyls have attracted increasing interest owing to the
excellent catalytic activity of palladium catalysts in both C−H
activation and cross-coupling reactions.9−11 So far, the vast
majority of reported methods have focused on [4 + 1] or [4 +
2] annulations of 2-iodobiphenyls with coupling partners to
form five- and six-membered rings (Scheme 1A).9,10 Great
efforts in this field have been made by the groups of Zhang,
Larock, and others. However, methods to build a larger ring,
such as a seven- or eight-membered ring, are still extremely
rare.11,12 Only two examples reported by Zhang11a and Shi11b
realized a [4 + 4] annulation for the synthesis of
tetraphenylenes by homocoupling of 2-iodobiphenyls (Scheme
1A). To the best of our knowledge, the [4 + 3] annulation of
2-iodobiphenyls has been unreported until now. On the basis
H
their unique electronic properties and molecular geometry
resulting from the existence of a seven-membered ring.1−6
Accordingly, some efficient methods for assembling heptagon-
embedded PAHs have been established, and typical strategies
include intramolecular oxidative cyclization (Scholl reaction)2
and the conversion of aromatic ring-fused cycloheptanones,3−5
which can, in turn, be synthesized by the Friedel−Crafts
reaction,3 ring expansion,4 and cyclotrimerization.5 Recently,
palladium-catalyzed cross-coupling annulation has emerged as
a powerful tool for accessing heptagon-embedded PAHs.6,7
Wong and Leowanawat independently reported a palladium-
catalyzed [4 + 3] annulation for the synthesis of dibenzo-
[4,5:6,7]cyclohepta[1,2,3-de]naphthalenes via a double Suzuki
coupling or a decarbonylation/decarboxylation strategy.6c,d In
particular, elegant palladium-catalyzed intermolecular C−H
annulation tactics have been reported by Kwong and Yoshikai.7
Nevertheless, the development of synthetic strategies for
heptagon-embedded PAHs lags far behind on account of the
synthetic challenge caused by constructing a curved seven-
membered ring composed of all sp2 carbon atoms in the π
systems. Therefore, the development of new methods,
especially palladium-catalyzed intermolecular C−H annula-
tions, for the synthesis of heptagon-embedded PAHs is in
urgent demand.
Received: February 12, 2021
Published: March 17, 2021
https://doi.org/10.1021/acs.orglett.1c00520
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2610−2615
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were pleased to find that the anticipated [4 + 3]
decarboxylative annulation could be efficiently completed
under the optimal catalytic conditions composed of
PdCl2(PPh3)2 and K2CO3 in DMSO at 140 °C, delivering
product 3aa in 85% yield (entry 1). A screening of palladium
catalysts, such as PdCl2(dppf), Pd(OAc)2, PdCl2, and
Pd(dba)2, demonstrated that all of them were inferior to
PdCl2(PPh3)2 in terms of the yield (entries 2−5).
Subsequently, several P ligands, including P(o-tol)3, Pt-Bu3,
PCy3, and dppf, were investigated and were found to have a
negative effect on this [4 + 3] annulation reaction (entries 6−
8). Moreover, attempts to use other bases, namely, Cs2CO3,
K3PO4, NaOAc, and NaHCO3, did not provide a better
outcome (entries 9−11). Notably, we found that the nature of
the solvents was crucial for the reaction: Compared with
DMSO, using DMF as the medium showed similar efficiency
(entry 12), and the substitution of MeCN afforded a lower
yield (entry 13), whereas replacing DMSO with toluene led to
no product formation (entry 14). Finally, the change in
reaction temperature did not improve the yield (entries 15 and
16). Pleasingly, the reaction is applicable to being scaled up to
1 mmol of 1a, affording 78% of 3aa (entry 1).
After identifying the optimal reaction conditions, we set out
to investigate the substrate scope of this transformation
(Scheme 2, top). The reactivity of the halogen atom was
initially checked. Gratifyingly, 2-bromobiphenyl and 2-(2-
chlorophenyl)acrylic underwent [4 + 3] decarboxylative
annulation to afford product 3aa in 50 and 80% yield,
respectively, whereas 2-(2-iodophenyl)acrylic acid was un-
reactive. A wide range of 2-iodobiphenyls 1b−i bearing
symmetrical substituents were then investigated. Delightedly,
this protocol exhibited good functional group tolerance.
Various substituents, such as Me, OMe, F, Cl, CF3, and CN,
could survive under the reaction conditions (3ba−ia). The
regioselective formation of products 3ba−ea revealed that the
C−H activation process was controlled by steric hindrance.
The structure of 3da was unequivocally confirmed by X-ray
crystallography. (See the Supporting Information (SI).)
Several unsymmetrical substrates, such as monosubstituted,
disubstituted, and heterocyclic 2-iodobiaryls, were also ex-
plored to better understand the mechanism. All of them could
proceed smoothly to deliver a mixture of regioisomers 3ja−ma
in good overall yields. These results indicated that intermediate
D/D′ could be generated by the reductive elimination of
intermediate C with poor regioselectivity.
Next, the scope with respect to 2-(2-bromophenyl)acrylic
acids 2 was examined (Scheme 2, bottom). Satisfactorily, a
series of 2-(2-bromophenyl)acrylic acids with different func-
tional groups on the benzene ring were subjected to the
standard conditions, delivering decarboxylative annulation
products 3ab−ag in 55−92% yield. However, substrate 2h
with a phenyl group at the three-position of the acrylic acids
underwent the [4 + 3] annulation to produce product 3ah in
only 15% yield. It is worth noting that 8-bromo-1-naphthoic
acid was also a viable coupling partner, leading to the
formation of product 3ai in a 45% yield.
The Suzuki−Miyaura reaction has become a powerful tool
for the assembly of biphenyl derivatives. We envision that a [2
+ 2 + 3] decarboxylative annulation for the synthesis of
tribenzo[7]annulenes could be realized by the Suzuki coupling
of 1,2-halobenzenes and phenylboronic acids followed by the
reaction with acrylic acids 2. To verify our hypothesis, we
performed the reaction of 1-bromo-2-iodobenzene 4a, phenyl-
Scheme 1. [4 + x] Annulations of 2-Iodobiphenyls
of our ongoing interest in the palladium-catalyzed C−H
functionalization of aryl iodides,13 we herein report a new
palladium-catalyzed [4 + 3] annulation of 2-iodobiphenyls with
2-(2-halophenyl)acrylic acids for assembling tribenzo[7]-
annulenes via C−H activation and subsequent decarboxylation
(Scheme 1B). Moreover, tribenzo[7]annulenes can also be
synthesized via a [2 + 2 + 3] decarboxylative annulation of 1,2-
halobenzenes, phenylboronic acids, and 2-(2-halophenyl)-
acrylic acids. Notably, this unique seven-membered carbon
ring framework has rarely been reported to date.14
We began our studies by investigating the reaction of 2-
iodobiphenyl (1a) with 2-(2-bromophenyl)acrylic acid (2a)
(Table 1). After a general survey of the reaction parameters, we
a
Table 1. Optimization of the Reaction Conditions
b
entry
variation from the standard conditions
yield (%)
c
1
2
3
4
5
6
7
8
none
85 (78)
66
50
47
56
69
83
67
63
76
81
81
60
trace
77
82
PdCl2(dppf) instead of PdCl2(PPh3)2
Pd(OAc)2 instead of PdCl2(PPh3)2
PdCl2 instead of PdCl2(PPh3)2
Pd(dba)2 instead of PdCl2(PPh3)2
P(o-tol)3 (10 mol %) was added
Pt-Bu3 or PCy3 (10 mol %) was added
dppf (5 mol %) was added
Cs2CO3 instead of K2CO3
K3PO4 or NaOAc instead of K2CO3
NaHCO3 instead of K2CO3
DMF instead of DMSO
9
10
11
12
13
14
15
16
MeCN instead of DMSO
toluene instead of DMSO
at 130 °C
at 150 °C
a
Reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv), PdCl2(PPh3)2
(5 mol %), K2CO3 (3 equiv), and DMSO (2 mL) at 140 °C under N2
b
c
for 2 h. Isolated yield. 1a (1 mmol) and DMSO (8 mL) were used.
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a
a
Scheme 2. [4 + 3] Decarboxylative Annulation
Scheme 3. [2 + 2 + 3] Decarboxylative Annulation
a
Reaction conditions: 4 (0.2 mmol), 5 (1.1 equiv), 2 (1.2 equiv)
PdCl2(PPh3)2 (5 mol %), K2CO3 (3 equiv), and DMSO (2 mL) at
b
c
140 °C. 1,2-Diiodobenzene instead of 1-bromo-2-iodobenzene. 2-
(2-Chlorophenyl)acrylic acid instead of 2-(2-bromophenyl)acrylic
acid.
Scheme 4. Control Experiment and Possible Reaction
Mechanism
a
b
c
Reaction conditions: See entry 1, Table 1. 2-Bromobiphenyl. 2-(2-
d
e
Chlorophenyl)acrylic acid. 2-Iodo-4-methylbiphenyl. 2-Iodo-4′-
f
g
methylbiphenyl. 2-Iodo-4′,5-dimethylbiphenyl. 4′-Chloro-2-iodo-4-
h
methylbiphenyl. 2-(2-Iodophenyl)-1-methyl-1H-indole
boronic acid 5a, and 2a (Scheme 3). Gratifyingly, product 3aa
could be afforded in 61% yield. Inspired by this result, we
systematically tested three components of the [2 + 2 + 3]
annulation. Intriguingly, this protocol showed superior
applicability. Both 1,2-diiodobenzene and 2-(2-chlorophenyl)-
acrylic acid were reactive, providing product 3aa in 71 and 74%
yield. Various functional groups on the three coupling partners
were also well tolerated, and moderate to good yields were
isolated.
To gain insights into the reaction mechanism, we prepared
palladacycle B-Int to perform the reaction with 2a, delivering
product 3aa in 40% yield (eq 1 in Scheme 4). The result
demonstrated that palladacycle B was probably generated in
the reaction process. On the basis of the experimental results as
well as previous reports,7a,15 a possible mechanism for this
transformation is illustrated as Scheme 4. Initially, 2-
halobiphenyls, which could be generated from either 1,2-
halobenzenes with arylboronic acids or iodobenzene with (2-
bromophenyl)boronic acid, undergo an oxidative addition to
generate intermediate A under the initiation of Pd(0).
Subsequently, a C−H activation of intermediate A affords
palladacycle(II) B, which forms palladacycle(IV) C via an
oxidative addition to the C−Br bond of acrylic acid 2a. Finally,
the sequential reductive elimination and decarboxylation of
palladacycle(IV) C takes place, delivering intermediate D/D′,
which was further reductively eliminated to furnish product 3
and regenerate Pd(0).
In summary, we have established an efficient palladium-
catalyzed [4 + 3] decarboxylative annulation of 2-iodobiphen-
yls with 2-(2-halophenyl)acrylic acids to assemble interesting
tribenzo[7]annulenes. The approach realizes the construction
of a seven-membered ring via a C−H activation and
decarboxylation in moderate to excellent yields. Importantly,
readily available starting materials, such as 1,2-halobenzenes,
phenylboronic acids, and 2-(2-halophenyl)acrylic acids, are
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also employed to afford various tribenzo[7]annulenes through
a palladium-catalyzed [2 + 2 + 3] decarboxylative annulation.
It is particularly noteworthy that six reaction sites were orderly
activated in this [2 + 2 + 3] annulation protocol.
of Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China
Minghao Zhang − National & Local Joint Engineering
Laboratory for New Petro-chemical Materials and Fine
Utilization of Resources, Key Laboratory of Chemical Biology
and Traditional Chinese Medicine Research, Ministry of
Education, Key Laboratory of the Assembly and Application
of Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China
Guobo Deng − National & Local Joint Engineering
Laboratory for New Petro-chemical Materials and Fine
Utilization of Resources, Key Laboratory of Chemical Biology
and Traditional Chinese Medicine Research, Ministry of
Education, Key Laboratory of the Assembly and Application
of Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China;
orcid.org/0000-0002-5470-5706
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00520.
Experimental procedures, full characterization of prod-
ucts, and NMR spectra (PDF)
Accession Codes
CCDC 2042467 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, UK; fax: +44 1223 336033.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00520
Notes
AUTHOR INFORMATION
The authors declare no competing financial interest.
■
Corresponding Authors
ACKNOWLEDGMENTS
■
Yuan Yang − National & Local Joint Engineering Laboratory
for New Petro-chemical Materials and Fine Utilization of
Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of
Education, Key Laboratory of the Assembly and Application
of Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China;
orcid.org/0000-0002-9061-1758; Email: yuanyang@
hunnu.edu.cn
Yun Liang − National & Local Joint Engineering Laboratory
for New Petro-chemical Materials and Fine Utilization of
Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of
Education, Key Laboratory of the Assembly and Application
of Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China;
orcid.org/0000-0002-2550-9220; Email: yliang@
hunnu.edu.cn
This work was supported by the National Natural Science
Foundation of China (21901071 and 21971061), the Natural
Science Foundation of Hunan Province (2020JJ5350), the
Scientific Research Fund of Hunan Provincial Education
Department (18A002 and 19B359), and the Science and
Technology Planning Project of Hunan Province
(2018TP1017).
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Xiumei Yang − National & Local Joint Engineering
Laboratory for New Petro-chemical Materials and Fine
Utilization of Resources, Key Laboratory of Chemical Biology
and Traditional Chinese Medicine Research, Ministry of
Education, Key Laboratory of the Assembly and Application
of Organic Functional Molecules of Hunan Province, Hunan
Normal University, Changsha, Hunan 410081, China
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Laboratory for New Petro-chemical Materials and Fine
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and Traditional Chinese Medicine Research, Ministry of
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