Carboxylic Acid Directed C-H Arylation of Azulene

Article abstract of DOI:10.1021/acs.orglett.0c01576

The first example of directed C-H activation for azulene is reported. A variety of 2-arylazulenes are obtainable exclusively from 1-azulene carboxylic acids, with yields of up to 82percent. Some heteroaryl groups such as pyridine and thiophene are also tolerated in the reaction. The efficacy of the reaction is found to be highly dependent on the conditions, with a phosphate base and a bulky carboxylic acid being key additives.

Full text of DOI:10.1021/acs.orglett.0c01576

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Letter
Carboxylic Acid Directed C−H Arylation of Azulene
Zhuang Mao Png, Teck Lip Dexter Tam, and Jianwei Xu*
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ABSTRACT: The first example of directed C−H activation for
azulene is reported. A variety of 2-arylazulenes are obtainable
exclusively from 1-azulene carboxylic acids, with yields of up to
82%. Some heteroaryl groups such as pyridine and thiophene are
also tolerated in the reaction. The efficacy of the reaction is found
to be highly dependent on the conditions, with a phosphate base
and a bulky carboxylic acid being key additives.
copper-catalyzed iododeborylation in only 2 steps instead of
zulene (1), discovered in 1863 by Piesse, is a deeply dark
Ablue isomer of naphthalene. Over the years, azulene and the 4 steps required classically.32
Although these methodologies greatly simplified the 2-
its derivatives have attracted the interest of chemists due to its
unique properties. For instance, azulene has an inherent dipole
moment of about 1.08 D, with the seven-membered ring being
slightly electron deficient, while the five-membered ring is
electron rich.1 Azulene is also the first known and probably the
most well-known exception to Kasha’s rule, exhibiting
fluorescence from the S2 → S0 state with a quantum yield of
about 0.2, in contrast with a S1 → S0 quantum yield of about
10−4.2 The HOMO−LUMO gap of azulene, and by extension,
its color, can be tuned by attaching electron-donating or
-withdrawing groups to the appropriate position, resulting in
deeply red, purple, or even green azulene derivatives.3 Azulene
has also been explored in diverse fields, including sensory
materials,4 near-infrared materials,5,6 electrochromic materi-
als,7−9 organic photovoltaics materials,10,11 photocatalysts,12
liquid crystals,13 capacitance,14 and even medicinal purpo-
ses.15−17 Some azulene-containing polymers doped with either
iodine or trifluoroacetic anhydride have also been reported to
exhibit electrical conductivity of about 1 S cm−1.18,19
functionalization of azulene, we envisioned an alternate route
via directed C−H activation. In the past two decades, the field
of directed C−H activation has exploded, with a wide range of
transformations being reported, such as alkoxycarbonyla-
tion,33,34 arylation,35 halogenation,36 oxidation,37 and even
polymerization.38 Control of regioselectivity has also been
achieved in many cases with directing groups such as amides39
and sulfoxides40 enabling selective functionalization.41
Although C−H activation has been applied to azulene for its
functionalization,42 these are unsurprisingly almost exclusively
done at the 1,3- position, making use of their natural
reactivity.43−59 To our knowledge, there has been no attempt
to make use of directed C−H activation to overcome the
natural reactivity, so as to enable functionalization of azulene at
other positions.
We envisioned that a carboxylic acid directing group at the
1-position could direct arylation to the 2-position via a putative
five-membered palladacycle.60 A carboxylic acid group could
easily be installed at the 1-position via established and easily
scalable methodologies.61 The carboxylic acid could then be
removed either post-reaction or in situ if so desired, thus acting
as a traceless directing group. Such a strategy would be
advantageous over the borylation strategy, as it avoids any
regioselectivity and separation issues between the 1- or 2-
position. Furthermore, installation of the carboxylic acid group
is also operationally simple and avoids the use of costly iridium
Apart from the highly reactive 1,3-positions of azulene,20−22
preparation of azulene analogues is synthetically challenging.
For instance, classically, obtaining a relatively simple 2-
iodoazulene, via Nozoe’s methodology, requires at least 4
steps, starting from 2-halo tropone or 2-methoxy tropone with
an overall yield of about 20%.23−26 A significant advancement
in the field was achieved in 2003, where Sugihara’s group
developed the direct borylation of azulene at the 2-position via
the use of an iridum catalyst, with a selectivity of 7:1 over the
1-position.27 The selectivity of the borylation was attributed to
the formation of a π-complex between the five-membered ring
and the iridium center, as well as steric factors. The boronic
ester could then be further reacted via Suzuki coupling to form
other 2-functionalized azulenes.28−31 More recently, the
boronic ester was then converted to an iodo group via
Received: May 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01576
© XXXX American Chemical Society
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catalysts. To our knowledge, directed C−H activation being
applied to the functionalization of azulene is unprecedented.
To begin our investigation, we started with carboxylic
directed arylation conditions developed by Yu’s group and Su’s
group, using either aryl iodides or aryl borates as the coupling
partner (see Supporting Information).62−64 Unfortunately,
none of these conditions gave any discernible product,
although the starting material was completely consumed.
However, an initial hit was obtained when we applied the
conditions developed by Larrosa’s group, where a 3.5% yield of
the arylated product (2a) was obtained (Figure 1).65
Decarboxylation was also observed in situ, with none of the
corresponding 3a found.
activation reactions to improve the yield of the reaction.66
Finally, we also modified the reaction temperature between 90
and 120 °C and found the reaction at 100 °C afforded the
highest yield (entries 8−10), while lowering the temperature
below 90 °C only yielded the starting material. Further control
experiments were carried out, but no discernible improvements
were observed (see Supporting Information). As such, the
conditions in entry 9 were found to be optimal, with the
phosphate base and the bulky acid being key components of
the reaction.
We then proceeded to examine the scope of the reaction.
We started by examining the scope of 4-iodo aryl groups
tolerated (Figure 2a). Unsurprisingly, both the phenyl (2b)
and the tolyl (2c) groups were tolerated in the reaction, giving
yields of 67% and 75% respectively. The reaction with the 4-
trifluoromethyl (2d) group also proceeded, although with a
lower yield of 31%. Halides such as fluorides and chlorides also
did not interfere with the reaction (2e and 2f). Electronically
withdrawing esters (2g) and cyano (2h) groups were also
tolerated, with no decomposition or hydrolysis observed. Even
the boc-protected aniline (2i) could also withstand the reaction
conditions, with a yield of 76%. Next, we examined the
substitution patterns on the iodoarene (Figure 2b). Both the
methoxy and the aceto groups were tolerated on the 3-position
(2j and 2k), as well as having both the 3,5-dimethyl groups
(2l), which could be useful for solubility purposes. Even
introducing a furan ring on the 3,4-position of the ring was also
tolerated (2m), with a yield of 40%. We were also pleased that
a variety of heteroarenes (Figure 2c) were also amendable to
this coupling reaction, including 2- and 3-thiophenes (2n and
2o), as well as 4-iodopyridines with a 2,5-dichloro substituent
(2p). Finally, the reaction also proceeded smoothly when the
6-position of azulene was functionalized by methyl and tert-
butyl groups (4a−b, 5a−b) (Figure 2d). Some substrates
which are unsuccessful are also reported in the Supporting
Information (SI). These were often due to either steric effects
or coordination with the catalyst inhibiting the reaction. We
also attempted the reaction with bromobenzene as the
coupling partner, but only recovered the starting material
after 16 h, while increasing the temperature to 120 °C only led
to starting material decomposition. Finally, the reaction was
also scalable to 5 mmol scale with almost no loss in reaction
efficacy for 2a.
Figure 1. (a) Initial hit for directed C−H arylation at the 2-position
of azulene. (b) Optimized conditions.
We first began our optimization (Table 1) by varying the
solvent used. Pleasingly, an increase in yield to 15% and 20%
Table 1. Selected Optimization Results
Acid
(4.5 equiv)
Base
(1 equiv)
Temp
(°C)
Solvent
(1 mL)
Yield
(%)
Entry
b
1
2
3
4
5
6
AcOH
K2CO3
K2CO3
K2CO3
K2HPO4
K2HPO4
K2HPO4
120
120
120
120
120
120
−
4
15
20
36
0
b
AcOH
AcOH
AcOH
TFA
N-Ac
isoleucine
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
b
As previously discussed by Daugulis’s group67 and Yu’s
group,63 we believe that the reaction likely proceeds through a
carboxylate group directed C−H activation to form a putative
palladacycle dimer intermediate,60 which then undergoes
oxidative addition by the aryl iodide to form a Pd(IV)
intermediate (Figure 3). Subsequent reductive elimination,
followed by decarboxylation yields the 2-aryl azulene product.
In principle, the C−H activation could also take place at the 8-
position of azulene. However, in all our reactions, no 8-
arylazulene product was ever observed.
To rationalize our observations, we utilized Density
Functional Theory (DFT) to understand the reaction
mechanism. From our calculations, the ΔE for the deproto-
nation of azulene at the C2 and C8 positions, as well as the ΔE
of the putative C2 and C8 palladacycle dimer intermediates,
were very small, suggesting that the stability of the palladacycle
intermediate is not the main reason for the exclusive formation
of the 2-aryl azulene product (see SI, Figure S5). However, the
C2 oxidative addition intermediate was found to be 3 kcal/mol
lower than that of C8. This large ΔE arises from steric and
2
7
8
9
10
TRIPS
TRIPS
TRIPS
TRIPS
K2HPO4
K2HPO4
K2HPO4
K2HPO4
120
110
100
90
Dioxane
Dioxane
Dioxane
Dioxane
68
66
72
25
a
Yields were determined by 1H NMR analysis with 1,1,2,2-
b
tetrachloroethane as internal standard. 0.5 equiv of base was used.
was found when toluene (entry 2) or dioxane (entry 3) was
used as the respective solvent. Changing the palladium and
silver source and loading did not improve the reaction yield
(see Supporting Information). However, when the base was
changed to a dipotassium phosphate, the yield increased to
36% (entry 4). Meanwhile, changing the acid source to the
trifluoroacetic acid and N-acetyl isoleucine did not improve the
reaction efficacy (entries 5−6). Surprisingly, when the bulky
carboxylic acid, 2,4,6-triisopropylbenzoic acid (TRIPS), was
used in place of acetic acid, the yield increased drastically to
68% (entry 7). This acid has also been used in previous C−H
B
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Figure 2. Substrate scope for 2-arylation of azulene. (a) Functional group tolerance. (b) Aryl group substitution pattern tolerance. (c) Heteroarene
tolerance. (d) Azulene substitution patterns. All reactions were conducted at 0.5 mmol scale.
large range of functional groups including various heteroarenes.
Substitution patterns on the aryl iodide are also tolerated,
except for the 2,6-positions. We believe that this methodology
will help to enlarge the chemist toolbox in preparing
functionalized azulene to better explore its interesting
properties. Further exploration of directed C−H activation,
such as by installing the carboxylic acid at the 2-position or the
6-position, could also enable the functionalization of other
previously inaccessible positions of azulene.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01576.
Reaction optimization, spectroscopic data, experimental
details, characterization data for all compounds, and
DFT calculations (PDF)
Figure 3. Proposed catalytic cycle for carboxylic acid directed C−H
arylation.
AUTHOR INFORMATION
Corresponding Author
■
electronic repulsion in the C8 oxidative addition intermediate
compared to C2 oxidative addition. However, further
mechanistic studies such as kinetic isotope effect (KIE) studies
would be required to understand the complete selectivity of
the 2-position over the 8-position, as well as the specific role of
each component in the reaction mixture, especially the role of
the phosphate and the bulky acid.
Jianwei Xu − Institute of Materials Research and Engineering, the
Agency for Science, Technology and Research (A*STAR),
Singapore 138634 Singapore; Department of Chemistry,
National University of Singapore, Singapore 117543
Singapore; orcid.org/0000-0003-3945-5443; Email: jw-
xu@imre.a-star.edu.sg
In summary, a convenient methodology of functionalizing
azulene at the 2-position via directed C−H activation of
azulene has been developed. This methodology uses easily
prepared and scalable starting materials to directly access the 2-
position without other regioisomers. The reaction tolerates a
Authors
Zhuang Mao Png − Institute of Materials Research and
Engineering, the Agency for Science, Technology and Research
(A*STAR), Singapore 138634 Singapore
C
https://dx.doi.org/10.1021/acs.orglett.0c01576
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Letter
(24) Nozoe, T.; Seto, S.; Matsumura, S. Bull. Chem. Soc. Jpn. 1962,
35 (12), 1990−1998.
Teck Lip Dexter Tam − Institute of Materials Research and
Engineering, the Agency for Science, Technology and Research
(A*STAR), Singapore 138634 Singapore; orcid.org/0000-
0003-2423-4752
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Journal of Organic Chemistry 2018, 2680−2692.
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Sugihara, Y. Eur. J. Org. Chem. 2003, 2003, 3663−3665.
(28) Xia, J.; Capozzi, B.; Wei, S.; Strange, M.; Batra, A.; Moreno, J.
R.; Amir, R. J.; Amir, E.; Solomon, G. C.; Venkataraman, L.; Campos,
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01576
Notes
The authors declare no competing financial interest.
(29) Koide, T.; Takesue, M.; Murafuji, T.; Satomi, K.; Suzuki, Y.;
Kawamata, J.; Terai, K.; Suzuki, M.; Yamada, H.; Shiota, Y.;
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ACKNOWLEDGMENTS
■
We acknowledge the financial support from Institute of
Materials Research and Engineering and the Agency for
Science, Technology and Research (A*STAR), Science and
Engineering Research Council for this work (Grant Nos.
1527200019 and 1527200021). We thank the A*STAR
Graduate Academy for studentship of Png Zhuang Mao. We
would also like to thank Professor Matthew Gaunt for helpful
and insightful discussions.
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