Oxidant-Induced Azolation of Electron-Rich Phenol Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c01796

Since N-arylazoles are widely present in natural products, pharmaceuticals, and functional materials, it is important to develop a simple and efficient synthetic method for the synthesis of N-arylazoles. Herein, an oxidant-induced intermolecular azolation of phenol derivatives was demonstrated under catalyst-free condition. Both monoazolation and diazolation of phenols can be successfully achieved via this practical and powerful method.

Full text of DOI:10.1021/acs.orglett.0c01796

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Letter
Oxidant-Induced Azolation of Electron-Rich Phenol Derivatives
§
§
Xiaoyu Wang, Shengchun Wang, Yiming Gao, He Sun, Xing’an Liang, Faxiang Bu, Takfaoui Abdelilah,
and Aiwen Lei*
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sı Supporting Information
ABSTRACT: Since N-arylazoles are widely present in natural products,
pharmaceuticals, and functional materials, it is important to develop a
simple and efficient synthetic method for the synthesis of N-arylazoles.
Herein, an oxidant-induced intermolecular azolation of phenol
derivatives was demonstrated under catalyst-free condition. Both
monoazolation and diazolation of phenols can be successfully achieved
via this practical and powerful method.
mination of arenes has been recognized as one of the
Scheme 2. Synthesis of N-Arylazoles from Pyrazoles
A
central issues in synthetic chemistry since the last century
1
due to the unique physiological activity of arylamines. Among
these arylamines, N-arylazole scaffolds are ubiquitous structural
units in biologically active molecules, agrochemicals, and
2
3
drugs such as rimonabant, celecoxib, and so on (Scheme 1),
whose synthesis drew much attention from chemists.
Scheme 1. Some Biologically Active Molecules with N-
Arylazole Skeleton
facilitated by single-electron-transfer progress, where the
radical cations of arene or N-centered radical usually serve as
9
the key reactive intermediates (Scheme 2c). Though there are
several reports to synthesize N-arylazoles, an operationally
simple method is still required. Herein, we present a simple
and efficient synthetic protocol to construct N-arylazoles
without catalyst (Scheme 2d).
The synthesis of N-arylazoles have been successfully realized
by the transition-metal-catalyzed azolation reactions between
azoles and aryl halides or aryl boronic acids (including
4
5
Buchwald−Hartwig amination, Ullmann-type amination, and
6
7
Received: May 28, 2020
Chan−Evans−Lam reaction, etc.) (Scheme 2a). Assisted by
a directing group, transition-metal-catalyzed dehydrogenative
cross coupling has been developed over the past decades,
8
avoiding the prefunctionalization of arenes (Scheme 2b).
Recently, the elegant photochemical and electrochemical
studies have provided a novel strategy for arene azolation
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01796
A
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a
Inspired by oxidative-induced C−H bond activation
Table 1. Optimization of Reaction Conditions
10
strategies with simple synthetic operation, we envisioned
that the azolation of phenols can be realized through oxidant-
induced activation of pyrazole with the corresponding radical
of pyrazole as an intermediate. First, electron paramagnetic
resonance (EPR) was used to gain important mechanistic
information (Figure 1). To find a suitable oxidant that can
b
entry
1
2
3
4
5
6
7
8
9
solvent
oxidant
yield (%)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
EtOH
DCE
HFIP
MeCN
MeCN
MeCN
K S O
75
ND
31
32
30
ND
ND
ND
trace
ND
trace
64
2
2
8
8
c
K S O
2
2
(NH ) S O
4 2 2 8
Selectfluor
DDQ
TBHP
K S O
2
2
8
8
8
8
8
8
8
K S O
2 2
1
1
1
1
1
0
1
2
3
4
K S O
2 2
K S O
2 2
d
e
f
K S O
2 2
K S O
63
67
2
2
K S O
2
2
a
Conditions: the reaction was carried out with 4-methoxyphenol 1a
0.6 mmol), 1H-pyrazole 2a (0.3 mmol), oxidant (0.6 mmol), 5 h, 3
(
Figure 1. EPR experiment of K S O and pyrazoles: (a) pyrazoles,
2
2
8
b
c
mL of solvent, N . ND: not detected. Isolated yield. At room
temperature. 1.5 equiv of oxidant was used. 2.5 equiv of oxidant was
used. The reaction was carried out under air.
2
K S O and DMPO were added at 80 °C; (b) fitting result; (c)
2
2
8
d
e
pyrazoles, 4-methoxyphenol, K S O and DMPO were added at 80
2
2
8
f
°
C; (d) pyrazoles, K S O and DMPO were added at room
temperature.
2 2 8
a
Scheme 3. Scope of the Mono-azolation
oxidize pyrazole to form a corresponding radical, different
combinations of oxidants and pyrazoles were investigated (see
details in Figure S3). When pyrazoles were treated with the
cheap oxidant K S O at 80 °C in MeCN, the N-centered
2
2
8
radical trapped by 3,4-dihydro-2,2-dimethyl-2H-pyrrole 1-
oxide (DMPO) was shown by EPR (Figure 1a, g = 2.0069,
AN1 = 13.5 G, AN2 = 3.8 G, A = 15.5 G). The same radicals
H
can be detected even with the addition of 4-methoxyphenol
(
Figure 1c). On the basis of these discoveries, a practical
azolation of phenols under metal-free and catalyst-free
condition is theoretically feasible.
Therefore, we chose 4-methoxyphenol and pyrazole as
model substrates to investigate the reaction conditions using
different oxidants, solvents, and loading of oxidants (Table 1).
Gratifyingly, the azolation products were obtained in 75% yield
with 2 equiv of K S O at 80 °C in MeCN (entry 1). In
2
2
8
accordance with the result of EPR study, the target product
had not been detected at room temperature, which shows that
the thermal activation of K S O may be a start-up step (entry
2
2
8
2
). In addition, other oxidants such as (NH ) S O , selectfluor,
4 2 2 8
DDQ, and TBHP (entry 3−6) were evidenced not as effective
as K S O . Without oxidant, the azolation reaction cannot be
2
2
8
achieved (entry 7). Subsequently various solvents were
screened. Using DMF or DCE as solvents, no target product
was detected. And trace azolation product was produced when
EtOH or HFIP was selected as solvent (entries 8−11). When
the amount of K S O was increased to 2.5 equiv or decreased
2
2
8
to 1.5 equiv, the reaction gave slightly worse results (entries 12
and 13). When an air atmosphere was used in place of
nitrogen, a similar yield was observed (entry 14).
With the optimized conditions, the scope of the mono-
azolation was explored among different functional groups
substituted pyrazoles and phenols (Scheme 3). Various
pyrazoles were satisfactory azolation reagents, providing the
a
Conditions: the reaction was carried out with phenols 1 (0.6 mmol),
b
pyrazoles 2 (0.3 mmol), 5 h, 3 mL of MeCN, N . Conditions: the
reaction was carried out with phenols 1 (20 mmol), pyrazoles 2 (10
mmol), 5 h, 50 mL of MeCN, N .
2
2
B
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corresponding desired products (3a−3i) in good yields. In
addition, triazole, indazole, and benzotriazole were compatible
with this reaction system in moderate yields (3j−3l). Then
different phenols were tested with the monoazolation reaction.
Replacement of the 4-methoxy group with electron-donating
substituents at the same position, such as ethoxy, benzyloxy,
and (2-methylallyl)oxy, was tolerated in this reaction (3m−
components for the azolation reaction. As depicted in Figure
2a, the initial reaction rate depended on the concentration of
3
o). Moreover, disubstituted phenols were investigated. The
reaction of 2-tert-butyl-4-methoxyphenol reacted smoothly
3p), and 3,4-dimethoxyphenol proceeded in low yield and
(
high site selectivity (3q). Remarkably, a good selective
azolation of 6-methoxypyridin-3-ol 3r was achieved. Besides
phenols, 4-methoxy-1-naphthol was also suitable for achieving
9d
azolation (3s). Different from the previous reports, hydro-
quinone was tolerated in this oxidation-induced azolation
reaction (3t). Furthermore, the gram-scale experiments were
carried out, showing the utility of our protocol.
Interestingly, diazolation products were obtained when
pyrazole was added in excess. However, the yield of diazolation
phenol can only be isolated in 40% in one step (see details in
Figure S4). In order to improve the reaction efficacy, the two-
step synthesis method was used in which monoazolation
products were selected as substrates to afford diazolation
products under the standard reaction conditions (Scheme 4).
With this method, both phenols disubstituted with the same
pyrazole or different pyrazoles can be obtained smoothly (4a−
4
h).
To further explore the mechanism, preliminary kinetic
studies were also carried out to determine the order of reaction
a
Scheme 4. Scope of the Di-azolation
Figure 2. (a) Kinetic behavior of 1a. (b) Kinetic behavior of 2a. (c)
Kinetic behavior of K S O .
2
2
8
the phenol, demonstrating first-order dependencies on phenol.
Conversely, a zero-order reaction on pyrazole and K S O is
2
2
8
proved (Figure 2b,c). This result indicates that the activation
of phenol is also critical to this reaction. In addition, initial
EPR studies show that pyrazole can easily react with K S O to
2
2
8
produce the corresponding N-centered radical.
Based on the above-mentioned results, a possible mecha-
nism of simultaneous activation of pyrazole and phenol is
proposed (Scheme 5). Initially, K S O thermally decomposes
2
2
8
Scheme 5. Proposed Mechanism
a
Conditions: the reaction was carried out with 3 (0.6 mmol), 2 (0.3
mmol), 5 h, 3 mL of MeCN, N2.
C
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1
1
to produce sulfate radical anion. While sulfate radical anion
oxidizes pyrazole to form the corresponding N-centered
radical, it activates phenol to produce the corresponding C-
centered radical. Then the intermediate 5 is obtained via a
radical/radical cross-coupling and is further aromatized to
form the final product.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21562026, 21762025, and 21702027)
and the Natural Science Foundation of Jiangxi Province
(
20192ACBL20026).
In summary, we have developed an intermolecular azolation
of phenol derivatives via oxidant-induced strategy under
catalyst-free conditions. This method realizes mono-/diazo-
lation of phenols, exhibiting a broad substrate scope and high
functional group tolerance. This work provides an operation-
ally simple strategy for achieving azolation reaction via
oxidation-induced pyrazoles activation and shows potential as
an alternative new avenue for further development of azolation
transformations.
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Shengchun Wang − Institute for Advanced Studies (IAS),
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Yiming Gao − Institute for Advanced Studies (IAS), College of
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He Sun − Institute for Advanced Studies (IAS), College of
Chemistry and Molecular Sciences Wuhan University, Wuhan
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(
Xing’an Liang − Institute for Advanced Studies (IAS), College of
Chemistry and Molecular Sciences Wuhan University, Wuhan
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Faxiang Bu − Institute for Advanced Studies (IAS), College of
Chemistry and Molecular Sciences Wuhan University, Wuhan
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§
X.W. and S.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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