Palladium-Catalyzed Regioselective Aromatic Extension of Internal Alkynes through a Norbornene-Controlled Reaction Sequence

Article abstract of DOI:10.1002/anie.201713207

A regioselective aromatic π-extension reaction of internal alkynes is reported. The proposed method employs three easily available components, namely aryl halides, 2-haloarylcarboxylic acids, and disubstituted acetylenes. The transformation is driven by a controlled reaction sequence of C?H activation, decarboxylation, and annulation to give poly(hetero)aromatic compounds in a site-selective fashion. Unlike in previously reported palladium-catalyzed three-component annulations, alkyne carbopalladation is the last step of this tandem reaction.

Full text of DOI:10.1002/anie.201713207

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Accepted Article
Title: Palladium-catalyzed Regioselective Aromatic Extension of
Internal Alkynes Through a Norbornene-controlled Reaction
Sequence
Authors: Qingyang Zhao, Wai Chung Fu, and Fuk Yee Kwong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201713207
Angew. Chem. 10.1002/ange.201713207
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10.1002/anie.201713207
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Palladium-Catalyzed Regioselective Aromatic Extension of
Internal Alkynes through a Norbornene-Controlled Reaction
Sequence**
Qingyang Zhao, Wai Chung Fu* and Fuk Yee Kwong*
Abstract:
A regioselective aromatic π-extension reaction of
internal alkynes is reported. The proposed method employs three
easily available components of aryl halides, 2-haloarylcarboxylic
acids and disubstituted acetylenes. The transformation is driven by
a controlled reaction sequence of C-H activation, decarboxylation
and annulation to give site-selective poly(hetero)aromatic
compounds.
Unlike previously reported Pd-catalyzed three-
component annulative reactions, the carbopalladation of alkynes
proceeds at the last step of this tandem reaction.
Internal alkyne is a functional motif for the construction of
polycyclic aromatic hydrocarbons (PAHs) via transition metal-
catalyzed annulative reactions (Scheme 1a).[1] Very recently, the
group of Itami developed an impressive annulative π-extension
technology[2] and reported the internal π-extension of alkynes
with dibenzosiloles or dibenzogermoles.[3] The biaryl “π-
fragments” need to be pre-activated in order to react with
transition metals and successive carbometalation of alkynes
affords the polycyclic product. In fact, the preparation of these
fragments required multiple synthetic steps such as organic
protocols, Suzuki reaction or C-H arylations.[4] Moreover,
homodimerization of aryl halides and unselective coupling
processes might occur in domino reactions with internal alkynes
(Scheme 1b).[1r-s] Although the biaryl motif could be in-situ
generated in Pd-catalyzed three-component reactions,[5] the
regioselectivity still suffered from 1,4-palladium migration and
uncontrolled carbopalladation of alkynes or ortho-TMS aryl
triflate-generated arynes (Scheme 1c).
Thus, symmetrical
components were often employed in existing methods to avoid
multiple regioisomers being afforded.[1] In addition to the
problematic regioisomeric outcome, the unavailability of
heteroaromatic counterparts of the aforementioned substrates
offset their utility in the synthesis of organic materials as
selective incorporations of heteroatom in an extended π-system
Scheme 1. Aromatic π-extension reactions of internal alkynes.
constitute key optoelectronic properties.[6]
The significant
introduction of NBE in such a system can regulate the site-
selectivity as well as modulate the reaction sequence as in a
recent report of Pd/NBE cascade by Luan.[10] The Pd-
catalyzed/NBE-mediated reaction, which was discovered by
Catellani in the 1990s,[11] is a bisfunctionlization strategy for aryl
halides at both ortho- and ipso-positions.[12] Our proposed
methodology is depicted in Scheme 2, and the major challenges
in the tandem reaction arise from: 1) the homodimerization of
aryl iodides; 2) competitive carbopalladation between NBE and
alkynes; and 3) one-shot control of three regioselective regions
(Scheme 1d). The cascade initiates with the oxidative addition
of Pd(0) to aryl iodides, followed by carbopalladation of
norbornene and concerted metalation–deprotonation (CMD) of
the ortho-C-H bond to form an electron-rich aryl norboryl
palladacycle (ANP). Seminal works by Catellani, Lautens and
others have shown that a variety of aryl halides would react with
the ANP to undergo biaryl coupling.[12,13] However, the homo-
coupling of the initiating aryl halide might be facile at this
point,[1s] and directing groups assisted in the heterobiaryl
formation will be remained in the product scaffold.[13b,13c]
Building upon our experimental studies and computational
results,[9c] our proposal was focused on the use of a carboxyl
group as a traceless directing group which could be removed by
intramolecular decarboxylation during the course of reaction.[14]
We envisioned that carboxyl-directed oxidative addition of o-
demand of nanographenes and PAHs in material sciences[7] as
well as medicinal chemistry;[8] and our experience in developing
catalytic methods have prompted us to consider of using a
norbornene(NBE)-mediated palladium cascade to address these
concerns.[9]
Herein, we disclose the development of a
regioselective aromatic π-extension of internal alkynes with
readily available aryl iodides and o-haloaryl carboxylic acids for
the efficient one-pot assembly of structurally diverse and
heteroatom-embedded PAHs (Scheme 1d).
The facile carbopalladation of alkynes after oxidative addition
has been well documented and we envisioned that the
[*]
Dr. Q. Zhao, Dr. W. C. Fu and Prof. Dr. F. Y. Kwong
Department of Chemistry, The Chinese University of Hong Kong
Shatin, New Territories, Hong Kong (Hong Kong)
E-mail: stephenfwc@gmail.com, fykwong@cuhk.edu.hk
Dr. Q. Zhao
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of the Ministry of Education, College of Chemistry and
Materials Science, Northwest University, Xi’an, 710127 (China)
Supporting information for this article is given via a link at the end
of the document.((Please delete this text if not appropriate))
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bromobenzoic acid to ANP which gives Pd(IV) species A,[15] is
generality and regioselectivity of our reaction. Gratifyingly, o-
bromoarylcarboxylic acids substituted at C4-C6 positions were
suitable coupling partners and were converted to desired
products in 43-89% isolated yields (4l-4v). It is worth to note
that o-chloroaryl carboxylic acids were also applicable
the key factor to the control of regioselective biaryl formation.[13a-
b,16]
The intermolecular decarboxylative cross-coupling was
envisaged to be suppressed due to the harsh reaction
conditions.[16] A following facile C(sp2)-C(sp2) bond formation
generates the biaryl motif and decarboxylation affords
intermediate B. After β-C elimination of NBE from B, we were
interested if the affording palladacycle C could be captured by
an alkyne for a reductive annulation.
substrates to form compound 4v and 4u.
Completely
regioselective biaryl formation was observed for all the cases
and the relative configurations of compounds 4v and 4u (see
Supporting Information) were unambiguously determined by X-
ray crystallographic analyses.[17] In comparison with traditional
electrophilic reactions and existing methods, the herein reported
procedure allowed the installation of functional groups at
designated positions or generally unreactive bay-region (4s) of
an extended π-system.[2a] The tolerated fluorinated groups (CF3,
OCF3, F) have important pharmaceutical implications,[18] while
chloro-groups could be substituted with π-fragments or other
functional groups by means of transition metal catalysis.[4,19]
Table 1: Reaction scope and regioselective synthesis of PAHs.[a]
Scheme 2. A mechanistic proposal for our regioselective π-extension reaction.
Stimulated by the challenges, we first examined the
system using diphenylacetylene, o-iodotoluene and o-
bromobenzoic acid as the model substrates and a number of
reaction parameters such as Pd catalyst, base, solvent, and
reagent stoichiometry were screened. It is to our delight that the
product PAH 4a was obtained in 35% yield in the presence of 10
mol% Pd(OAc)2, 25 mol% PPh3, 2 equiv. alkyne and 3 equiv.
NBE (see Supporting Information for detailed screening tables).
We sought to resolve the competitive carbopalladations by a
meticulous fine-tuning of the stoichiometry among the substrates
and NBE. During the investigation, we found that the model
reaction without alkyne furnished a NBE-embodied biaryl side
product SP1 (Scheme 2) in moderate yield while excluding NBE
only gave a trace amount of the desired product. Reducing the
amount of NBE to 1 equiv (alkyne:NBE = 2:1) dramatically
decreased the yield to 33% and only a trace amount of SP1 was
observed by GC-MS analysis. These results possibly indicated
that the carbopalladation of alkyne proceeded at the last step of
the catalytic cycle and might have a higher carbopalladation rate
than that of NBE. The highest product yield of 81% was
achieved when 1.5 equiv. alkyne and 3 equiv. NBE were used.
X-ray crystallographic analysis revealed the conformation of 4a
(see Table 1 and Supporting Information).[17]
[a] Reaction conditions: Pd(OAc)2 (10 mol%), P(2-MeC6H4)3 (25 mol%), aryl
iodides (0.2 mmol), 2-bromoaryl carboxylic acid (0.4 mmol), diphenylacetylene
(0.3 mmol), norbornene (0.6 mmol), K2CO3 (0.6 mmol), DMF (0.1 M), 130 °C
for 20 h under N2. Isolated yields were reported. [b] Reaction conducted in 1
mmol scale with respect to 2-iodotoluene.
(trifluoromethyl)benzoic acid was used.
[c]
2-Chloro-5-
Encouraged by the effective reaction system in hand, we
first explored the scope of aryl iodides (Table 1). We were
delighted to see that aryl iodides with different electronic
properties and steric profile were successfully transformed to the
corresponding PAH products with mostly good-to-excellent
yields (4a-4k). Aryl iodide 2g bearing a bulky ortho-phenyl ring
and a spirocenter reacted smoothly to give 4g in 88% yield. The
π-extension reaction of diphenylacetylene proceeded efficiently
to form a chrysene structure in compound 4f. A five-fold scale-
up reaction was performed and negligible deviation in the
isolated yield of 4a was observed. Diversely substituted o-
haloarylcarboxylic acids were then tested to demonstrate the
Having established a solid scope of aryl iodides and o-
halocarboxylic acids, we were excited to turn our attention to the
exploration of alkynes in our reaction (Table 2). Diaryl alkynes
substituted with electron-withdrawing groups (CF3, Cl) or
electron-donating groups (Me, OMe) underwent the three-
component reaction to afford 4aa to 4ag in 52-81% yield.
Importantly, unsymmetrical alkyl aryl acetylenes were found to
react and gave the product PAHs 4ah to 4ak in excellent
regioselectivity (91:9 to 95:5) and single regioisomer could be
obtained by chromatographic techniques. To shed light on the
conformation of our regioselective product, NMR experiments
were carried out and the 2D NOESY spectrum of compound 4ak
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10.1002/anie.201713207
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clearly revealed the correlation between the two methyl groups
along with the apparent downfield shift of the marked protons
from 4a, indicating that the acetylenyl methyl group is placed at
the C10 position, which is in complete contrast with a previous
report by Wang and Glorius.[1l]
Table 2: Scope of alkynes and structure elucidation with NMR study.[a]
Scheme 3. Synthetic utilities of our method. See supporting information for
detailed reaction conditions.
[a] Reaction conditions: Pd(OAc)2 (10 mol%), P(2-MeC6H4)3 (25 mol%), aryl
iodides (0.2 mmol), 2-bromoaryl carboxylic acid (0.4 mmol), diarylacetylene or
alkyl aryl acetylene (0.3 mmol), norbornene (0.6 mmol), K2CO3 (0.6 mmol),
DMF (0.1 M), 130 °C for 20 h under N2. Isolated yields were reported. [b] 2-
Chloro-5-(trifluoromethyl)benzoic acid was used.
In conclusion, the regioselective aromatic extension of
internal alkynes was accomplished by using a norbornene-
mediated palladium cascade. A sequence of catalytic events of
C-H activation, decarboxylation and annulation allowed for the
one-pot efficient assembly of PAHs using widely available
alkynes, aryl iodides and o-haloaryl carboxylic acids, while
previous reported pre-functionalized coupling partners required
tedious multistep synthesis. With regard to the cross-assembly
approach, a broad reaction scope with respect to all three
coupling partners was realized and heteroatom-incorporated
polyaromatic compounds were easily accessed from pyridyl,
quinolyl and thienyl fragments.
illustrated the utility of our method in targeting large conjugated
π-system or heteroatom-embedded nanographenes. We
believed this operationally simple protocol will be highly
attractive to the communities in manipulating fused polyarene
structures for material science (nanomaterials, optoelectronics,
thin-film transistors) and organic synthesis.
Selective heteroatom incorporation in large PAH materials
has been reported to be of prominent importance in enhancing
their properties such as solubility, electronic structures,
semiconducting and optoelectronic properties.[6] Herein, we
demonstrate the efficient assembly of heteroatom-containing
PAH products 4ba to 4bh from three different components under
standard reaction conditions (Scheme 3a). The heterocycles in
all the three π-fragments were well tolerated (pyridine, thiophene,
quinoline) in our system and the nitrogen atoms could be
regioselectively manipulated in an extended quinolinyl system
(4bc, 4bd, 4be, 4bf). To demonstrate the utility of our method in
a wider scope, a Suzuki coupling reaction has been adapted to
connect compound 4ag with four p-tolyl groups, illustrating the
opportunities for further functionalization after our protocol
Further transformations
(Scheme 3b).
An oxidative cyclization driven by DDQ
transformed 4ad to a large conjugated π-system 6 (Scheme 3c).
Owing to the steric hindrance of the inner methyl group,
nanographene 6 was expected to be twisted in shape. An
operationally simple protocol would be highly desirable for
chemists working outside of the field of catalysis.[20] To our
delight, the catalyst system was found to be largely compatible
under air and moisture with the synthesis of product 4a under
standard conditions, in which only a slight drop in product yield
was resulted in the presence of 50 equiv. water (69% yield) or
air (70% yield).
Acknowledgements
We thank RGC of Hong Kong (153367/16P and C5023-14G) for
financial support. CUHK direct grant (4053237) and National
Natural Science Foundation of China (21602172) are gratefully
acknowledged. We thank Ms. Bella Chan for X-ray analyses.
Keywords: three-component
•
C-H activation
•
polycyclic aromatic
hydrocarbons • palladium • decarboxylation • annulation
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Qingyang Zhao, Wai Chung Fu* and Fuk
Yee Kwong*
Page No. – Page No.
Text for Table of Contents
Palladium-Catalyzed Regioselective
Aromatic Extension of Internal
Alkynes through a Norbornene-
Controlled Reaction Sequence
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