Cobalt-Catalyzed C-H Acetoxylation of Phenols with Removable Monodentate Directing Groups: Access to Pyrocatechol Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c00312

An efficient cobalt-catalyzed C-H acetoxylation of phenols has been developed by using PIDA (phenyliodine diacetate) as a sole acetoxy source to synthesize pyrocatechol derivatives for the first time. The key feature of this method is the use of earth-abundant metal cobalt as the green and inexpensive catalyst for the acetoxylation of C(sp²)-H bonds under neutral reaction conditions. Furthermore, the gram-scale reaction and late-stage functionalization demonstrated the usefulness of this method.

Full text of DOI:10.1021/acs.orglett.0c00312

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Letter
Cobalt-Catalyzed C−H Acetoxylation of Phenols with Removable
Monodentate Directing Groups: Access to Pyrocatechol Derivatives
Quan Gou,* Xiaoping Tan, Mingzhong Zhang, Man Ran, Tengrui Yuan, Shuhua He, Linzong Zhou,
Tuanwu Cao,* and Feihua Luo
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ABSTRACT: An efficient cobalt-catalyzed C−H acetoxylation of
phenols has been developed by using PIDA (phenyliodine
diacetate) as a sole acetoxy source to synthesize pyrocatechol
derivatives for the first time. The key feature of this method is the
use of earth-abundant metal cobalt as the green and inexpensive
catalyst for the acetoxylation of C(sp2)−H bonds under neutral
reaction conditions. Furthermore, the gram-scale reaction and late-
stage functionalization demonstrated the usefulness of this method.
s a powerful synthetic weapon, C−H activation plays an
Scheme 1. Synthetic Methods of Cobalt-Catalyzed C(sp2)−
A
essential role in modern organic chemistry and has
H Acetoxylation
aroused considerable attention from synthetic chemists.1
Utilizing C−H activation technologies, the rapid synthesis
and late-stage functionalization of various compounds could be
easily achieved with atom-economical and green character-
istics.2 In the past decades, numerous elegant works on C−O
bond formation, which could conveniently construct the
scaffold of bioactive molecules, natural products, and materials,
have been reported in the field of C−H functionalization.3
Since Sanford first reported C(sp2)−H acetoxylation in 2004,4
related protocols have been further developed by Yu,5 Chen,6
and Dong7 et al. Thereafter, various types of C−H
acetoxylation reactions based on versatile building blocks
were successfully performed by the employment of noble-
metal catalysts, such as Pd,8 Rh,9 Ru,10 and Au.11 However,
these metals always keep the inevitable disadvantages of air-
instability and earth scarcity. By comparison, the use of first-
row transition metals, for example, Co,12a,g Ni,12h,i and Cu12j
complexes, which have been exploited as efficient catalysts to
be conducted in C−H functionalization, easily overcome these
shortcomings. In particular, cobalt-catalyzed acetoxylation was
established by Chatani13a and Deb13b to realize the
diversification of aromatic amides in 2018 (Scheme 1, eqs 1
and 2). More recently, Cai also independently developed a
synthesis protocol for acetoxylation in anilides (Scheme 1, eq
3).13c Compared with other remarkable first-row transition-
metal-catalyzed acetoxylations by directing groups, reactions
using cobalt catalysts remain scarce. Despite these significant
advances in cobalt catalysis by a directing group, the further
acetoxylation of more unique molecular structures with the
important value of biological activities remains undeveloped.
Pyrocatechols as a class of unique structure motifs are
widespread in natural products, agrochemicals, pigments,
biologically active molecules, like echinacoside and fruquinti-
Received: January 22, 2020
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© XXXX American Chemical Society
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nib, and so on. (Figure 1).14 Recently, pyrocatechols have
aroused widespread interest by medicinal and synthetic
Table 1. Optimization of Acetoxylation Reaction
Conditions
a
b
entry
1
2
catalyst
OAc source
solvent
yield (%)
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Cp*Co(CO)I2
CoCO3
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
I(III)-OAc
DMP
A-OAc
B-OAc
PIDA
PIDA
PIDA
PIDA
PIDA
AcOH
AcOH
DCE
DMF
toluene
BTF
BTF
BTF
BTF
BTF
BTF
BTF
BTF
BTF
BTF
BTF
BTF
BTF
21%
nr
trace
nr
14%
40%
nr
nr
nr
nr
trace
38%
22%
28%
nr
c
3
4
5
6
7
8
d
e
f
9
10
11
12
13
14
15
16
17
18
Figure 1. Natural products and drugs containing the structural
scaffold of pyrocatechols.
g
Co(OAc)2
Co(OAc)2
Co(acac)2
56%
nr
h
g
i
79% (72%)
chemists due to their use as a class of efficient synthons for
the synthesis and late-stage functionalization of potential drug
candidates.15 However, the preparation of pyrocatechols by
transition-metal catalysis is limited in the exploration of
palladium.16 Although these methods could have perfectly
proceeded with the assistance of diverse directing groups, the
shortcomings of expensive metal catalysts, weak reactivity, and
a limited substrate scope are exposed. Herein we develop a
more convenient and powerful strategy via cobalt catalysis to
realize the regioselective acetoxylation of phenol derivatives.
We started to investigate our hypothesis using a simple 2-
phenoxypyridine 1a as a model substrate. Our initial trials with
the previously reported Co-catalyzed conditions failed to yield
any of the corresponding 2-(pyridin-2-yloxy) phenyl acetate 2a
(Scheme 1, eq 4).13 On the basis of our previous work on
hypervalent iodine,17 we commenced our attempts via
Co(OAc)2-catalysis using PIDA as the OAc source. For-
tunately, the desired acetoxylation product was detected with
the employment of PIDA in AcOH, albeit affording a
significantly lower yield (21%) (Table 1, entry 1). Then, we
attempted to add Ac2O, which efficiently accelerated the
reactivity of C−H acetoxylation in the literature reports.8c,f To
our great disappointment, the starting substrate 1a was
completely retained (Table 1, entry 2). The solvent effect is
a critical factor in promoting the reaction. Then, various
solvents from commercial vendors were examined closely. We
found that the polar solvents such as 1,2-dichloroethane
(DCE) and dimethylformamide (DMF) were detrimental to
the acetoxylation reaction (Table 1, entries 3 and 4).
Afterward, these aromatic solvents were investigated by the
cobalt catalysis. The toluene was inferior to AcOH (Table 1,
entry 5). To our delight, benzotrifluoride (BTF) was the
optimal solvent, giving the desired product in 40% yield (Table
1, entry 6). Next, we examined different types of inorganic and
organic oxidants, including Ag2CO3 and 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) (Table 1, entries 7 and
8). Adding these oxidants, the reactions were suppressed
entirely, and the starting substrate 1a was observed. Then, we
a
Reaction conditions: 1a (0.2 mmol), catalyst (10 mol %), and OAc
source (3.0 equiv) in solvent (2.0 mL) at 115 °C for 24 h.
b
Determined by 1H NMR analysis of the crude product with CH2Br2
c
d
as the internal standard. Addition of Ac2O (1.0 mL). Addition of
Ag2CO3 (2.0 equiv). Addition of DDQ (2.0 equiv). Addition of
K2CO3 (2.0 equiv). Addition of 1 atm O2. Reaction under N2.
Isolated yields. nr = no reaction. BTF = benzotrifluoride.
e
f
g
h
i
found that a general base, for example, K2CO3, was detrimental
to the reaction (Table 1, entry 9). In the investigation of the
different OAc sources, these hypervalent iodines, including
Dess−Martin periodinane (DMP) and I(III)-OAc, were
inferior to PIDA (Table 1, entries 10 and 11). When
selectively installed by electron-donating or electron-with-
drawing substituents on PIDA, the yields of the reaction were
reduced to 38 and 22%, respectively (Table 1, entries 12 and
13). Changing the Co(OAc)2 to other cobalt catalysts, like
Cp*Co(CO)I2 and CoCO3, dramatically decreased the
reactivity of C−H acetoxylation (Table 1, entries 14 and
15). Finally, the addition of 1.0 atm O2 was crucial for
increasing reaction yields via Co(OAc)2 catalysis, providing the
desired product 2a in 56% yield (Table 1, entry 16).
Incredibly, the reaction was shut down under N2 (Table 1,
entry 17). Then, when Co(acac)2 was used instead of
Co(OAc)2, the acetoxylation product 2a was smoothly
afforded in 72% isolated yield (Table 1, entry 18).
B
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a b
,
Next, we evaluated the efficiency of various directing groups
under the optimal reaction conditions (Scheme 2). First, we
Scheme 3. Scope for the Acetoxylation of Phenols
Scheme 2. Examination of Various Directing Groups
investigated the modified pyridine groups with different
substituents and their influence on the reactivity of C−H
acetoxylation. The pyridine groups bearing electron-with-
drawing or electron-donating substituents such as Cl and Me
were conducted, providing lower yields (Scheme 2, 3a−4a).
Moreover, the coordinating capability of the directing groups
like the reported dimethoxy-1,3,5-triazin-2-yloxy and pyrimi-
dine was significantly diminished under the reaction
conditions,18 giving the products 5a and 6a in 0 and 45%
yield, respectively. Dramatically, the phenol that was assembled
with 2-pyridylmethyl ether shut down the reaction of C−H
acetoxylation, presumably because the length of the tether
hampers the coordinating capability of the directing group
(Scheme 2, 7a).
After the optimal reaction conditions were obtained, we
investigated the scope of the cobalt-catalyzed acetoxylation of
phenols to synthesize multisubstituted pyrocatechol derivatives
(Scheme 3). A variety of para-substituted phenols with
electron-rich groups, even containing sterically hindered
fragments, were well tolerated, affording moderate yields
(Scheme 3, 2b−d). All para-substituted phenols with useful
electron-deficient groups, including F, Cl, Br, CN, CO2Me, and
NO2, also worked smoothly to provide the desired products in
moderate to good yield (Scheme 3, 2e−j). Notably, the phenol
with an unmasked ketone also performed efficiently, albeit
resulting in a slightly lower yield (Scheme 3, 2k). These
phenols with the building blocks of biphenyl, cinnamic acid,
and phenylethyl alcohol performed well under the conditions
to give the corresponding pyrocatechols, which are the key
synthetic intermediates of 2-phenylnaphthalenoids,19a echina-
coside,19b and vernakalant,19c respectively (Scheme 3, 2l−n).
Meta-substituted substrates with either electron-donating or
electron-withdrawing groups still afforded the acetoxylation
products without incident under the reaction conditions
(Scheme 3, 2o−s). Moreover, the sterically hindered substrates
were also tolerated to give the corresponding product in
moderate yield (Scheme 3, 2t−u). Gratifyingly, various
scaffolds of polycyclic aromatic hydrocarbons bearing naph-
thalene, quinoline, benzoquinoline, and pyrene were compat-
ible with the reaction conditions (Scheme 3, 2v−y). It is worth
noting that the strongly coordinating nitrogen atoms in
quinoline and benzoquinoline did not interfere with the
properties of the catalyst.
a
Reaction conditions: 1 (0.2 mmol), Co(acac)2 (10 mol %), and
PIDA (3.0 equiv) in BTF (2.0 mL) under O2 at 115 °C for 24 h.
b
Isolated yields.
Afterward, we further examined the developed synthetic
method and employed it in the late-stage acetoxylation of the
comparatively simple pesticide molecule diflufenican, as shown
in Scheme 4. To our delight, the diflufenican showed better
compatibility under the reaction conditions and was efficiently
Scheme 4. Late-Stage Functionalization of a Pesticide
Molecule
C
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conducted to provide the related late-stage acetoxylation
products 2z in 46% yield. It is worth noting that the modified
pesticide molecule could offer significant potential for
agrochemical applications.
Then, the utility of the reaction conditions of cobalt-
catalyzed acetoxylation was successfully conducted on a gram
scale to provide the title compound 2a in 65% yield (Scheme
5). Both 2-pyridiyloxy and acetyl group on compound 2a could
the CoII catalyst was released, which was further transformed
by ligand exchange.
In summary, we have disclosed the cobalt-catalyzed
regioselective acetoxylation of C(sp2)−H bonds of phenols
by using PIDA as a sole acetoxy source and O2 as a green
oxidant with the removable directing group for the first time.
This C−H acetoxylation protocol could produce a diverse
range of functional pyrocatechols without any additives. This
method is demonstrated with good functional-group compat-
ibility, a wide substrate scope, high regioselectivity, and gram-
scale synthesis. Under the neutral reaction conditions, this
approach is successfully applied in the late-stage acetoxylation
of a pesticide molecule. The detailed mechanism study and the
applications of this methodology to the preparation of other
medicinally important compounds using a cobalt catalyst are
currently being investigated in our laboratory.
Scheme 5. Gram-Scale Synthesis
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00312.
Preparative and analytical details of starting molecules
and title compounds (PDF)
be conveniently removed via a three-step procedure to obtain
the catechol.10a,16c Subsequently, the catechol could be
transferred to other significant molecules.20 Thus this method
may provide an unconventional tool to synthesize diverse
substituted pyrocatechols under neutral reaction conditions.
To explore the reaction mechanism, we studied kinetic
isotope experiments (parallel intermolecular KIE = 2.25; see
the Supporting Information), which indicated that the cleavage
of the C(sp2)−H bond occurred as the rate-limiting step.21 On
the basis of the limited experiment and the literature, a
plausible reaction mechanism for C−H acetoxylation was
tentatively proposed (Scheme 6). Initially, under the assistance
AUTHOR INFORMATION
■
Corresponding Authors
Quan Gou − School of Chemistry and Chemical Engineering,
Laboratory of Natural Medicine Research and Development in
Wuling Mountain, Yangtze Normal University, Chongqing
408100, China; orcid.org/0000-0002-3066-505X;
Email: gouquan@yznu.edu.cn, gouq@outlook.com
Tuanwu Cao − School of Chemistry and Chemical Engineering,
Laboratory of Natural Medicine Research and Development in
Wuling Mountain, Yangtze Normal University, Chongqing
408100, China; Email: caotw2013@163.com
Scheme 6. Proposed Reaction Mechanism
Authors
Xiaoping Tan − School of Chemistry and Chemical Engineering,
Laboratory of Natural Medicine Research and Development in
Wuling Mountain, Yangtze Normal University, Chongqing
408100, China; orcid.org/0000-0001-6531-0251
Mingzhong Zhang − School of Chemistry and Chemical
Engineering, Laboratory of Natural Medicine Research and
Development in Wuling Mountain, Yangtze Normal University,
Chongqing 408100, China; orcid.org/0000-0001-5427-
3168
Man Ran − School of Chemistry and Chemical Engineering,
Laboratory of Natural Medicine Research and Development in
Wuling Mountain, Yangtze Normal University, Chongqing
408100, China
Tengrui Yuan − Department of Organic and Macromolecular
Chemistry, Ghent University, 9000 Gent, Belgium
Shuhua He − School of Chemistry and Chemical Engineering,
Laboratory of Natural Medicine Research and Development in
Wuling Mountain, Yangtze Normal University, Chongqing
408100, China
Linzong Zhou − School of Geographical Science and Tourism
Management, Chuxiong Normal University, Chuxiong 675000,
China
of a 2-pyridiyloxy group, substrate 1 could easily coordinate
the CoII catalyst to form intermediate A. Then, intermediate A
was oxidized by the oxidants of O2/PIDA and transformed to
the CoIII complex, followed by the direct activation of the inert
C(sp2)−H to form intermediate B.13,22 Then, the Co(III)
species was further oxidized to afford a hexacoordinated
Co(IV) intermediate C in the presence of PIDA. Finally,
followed by the reductive elimination of the hypervalent
Co(IV) intermediate, the desired product 2 was generated, and
Feihua Luo − College of Materials Science and Engineering,
Yangtze Normal University, Chongqing 408100, China
D
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Letter
I. J. Org. Chem. 2017, 82, 12406. (c) Chen, C.; Pan, Y.; Zhao, H.; Xu,
X.; Xu, J.; Zhang, Z.; Xi, S.; Xu, L.; Li, H. Org. Chem. Front. 2018, 5,
415.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00312
(10) (a) Raghuvanshi, K.; Rauch, K.; Ackermann, L. Chem. - Eur. J.
2015, 21, 1790. (b) Okada, T.; Nobushige, K.; Satoh, T.; Miura, M.
Org. Lett. 2016, 18, 1150.
Notes
The authors declare no competing financial interest.
(11) (a) Pradal, A.; Toullec, P. Y.; Michelet, V. Org. Lett. 2011, 13,
6086. (b) Qiu, D.; Zheng, Z.; Mo, F.; Xiao, Q.; Tian, Y.; Zhang, Y.;
Wang, J. Org. Lett. 2011, 13, 4988.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Program of Fuling
District Science and Technology (grant no.
FLKJ,2019ABB2038), the Project for Basic Research and
Frontier Exploration of Science and Technology Commission
of Chongqing (grant nos. cstc2019jcyj-msxm1275 and
cstc2018jcyjAX0419), and the Science and Technology
Research Program of Chongqing Municipal Education
Commission (grant nos. KJQN201901422 and KJ1601202).
(12) For selected reports on Co-catalyzed C−H acetoxylation, see:
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