Benzene C-H Etherification via Photocatalytic Hydrogen-Evolution Cross-Coupling Reaction

Article abstract of DOI:10.1021/acs.orglett.7b00463

Aryl ethers can be constructed from the direct coupling between the benzene C-H bond and the alcohol O-H bond with the evolution of hydrogen via the synergistic merger of photocatalysis and cobalt catalysis. Utilizing the dual catalyst system consisting of 3-cyano-1-methylquinolinum photocatalyst and cobaloxime, intermolecular etherification of arenes with various alcohols and intramolecular alkoxylation of 3-phenylpropanols with formation of chromanes are accomplished. These reactions proceed at remarkably mild conditions, and the sole byproduct is equivalent hydrogen gas.

Full text of DOI:10.1021/acs.orglett.7b00463

Letter
pubs.acs.org/OrgLett
Benzene C−H Etherification via Photocatalytic Hydrogen-Evolution
Cross-Coupling Reaction
†
,‡
†
,‡
‡
‡
†
Yi-Wen Zheng, Pan Ye, Bin Chen,* Qing-Yuan Meng, Ke Feng, Wenguang Wang,
‡
,†,‡
Li-Zhu Wu, and Chen-Ho Tung*
†Key Laboratory of Colloid and Interface Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, PR China
‡
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry &
University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100190, PR China
*
S Supporting Information
ABSTRACT: Aryl ethers can be constructed from the direct
coupling between the benzene C−H bond and the alcohol O−H
bond with the evolution of hydrogen via the synergistic merger of
photocatalysis and cobalt catalysis. Utilizing the dual catalyst system
consisting of 3-cyano-1-methylquinolinum photocatalyst and
cobaloxime, intermolecular etherification of arenes with various
alcohols and intramolecular alkoxylation of 3-phenylpropanols with
formation of chromanes are accomplished. These reactions proceed
at remarkably mild conditions, and the sole byproduct is equivalent
hydrogen gas.
ryl ethers are structural constituents of pharmaceuticals
Scheme 1. Aryl Ether Synthesis
1
A
and bioactive natural products, and these ethers represent
one of the most ideal substrates that can be used to replace aryl
halides for catalytic cross-coupling reactions in terms of
2
availability, cost, safety, and atom efficiency. Over the years,
typical methodologies for aryl etherification have been well
3
established, such as the Ullmann ethers synthesis and the
4
Chan−Evans−Lam reaction. The scope of aryl ethers was
largely extended by the Buchwald−Hartwig cross-coupling
approach. This protocol was demonstrated to be efficient for
the coupling of aryl halides with phenols or alcohols
5
(
Buchwald’s group) and aryl halides with alkoxides (Hartwig’s
6
group) in the presence of palladium catalyst and base (Scheme
a). Recently, MacMillan and co-workers developed a highly
1
efficient and general carbon−oxygen formation reaction
employing simple alcohols and aryl halides via the synergistic
merger of photoredox catalysis and nickel catalysis (Scheme
7
1
b). However, in the above methods, the leaving groups in the
desired substituted position of the starting materials have to be
installed in preceding synthetic steps. In addition, by using any
kind of leaving group stoichiometric amounts of unwanted
coproducts or chemical waste will be inevitably produced.
Therefore, cross coupling between aromatic C−H bond and
alcoholic O−H bond will be an ecological and economical
methodology for aryl ether synthesis.
years, a few examples of aryl ether synthesis from the coupling
between simple arenes and alcohols were successfully
demonstrated by the utilization of CDC strategy in the
presence of Pd, Cu/Ag or Co catalysis. However, in these
reactions, stoichiometric oxidants were used, and large amounts
of waste were produced. To date, to the best of our knowledge,
9
Cross-dehydrogenative coupling (CDC) builds C−C bonds
or C−heteroatom bonds through a direct coupling either from
two different C−H bonds or from one C−H bond and one
8
heteroatom−H bond. It eliminates the prefunctionalization of
the starting material, and the overall skeletal structure of the
product resembles that of the starting materials. In the past few
Received: February 15, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00463
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
only one example of direct etherification of benzene was
(5 mol %), and Co(dmgBF ) (CH CN) (3 mol %) in dry and
2
2
3
2
reported by Fukuzumi and co-workers, who used oxygen as the
degassed acetonitrile by mercury lamp (λ > 300 nm) at room
temperature provided the anisole in 95% yield based on the
consumption of benzene. Generally, after 5 h of irradiation, the
1
0
oxidant. However, in the oxidative conditions, the reaction
yield and selectivity were low, and the substrate scope was still
limited (Scheme 1c). Herein, we describe an oxidant-free
hydrogen-evolution cross-coupling approach for photocatalytic
one-step benzene C−H etherification by alcohols with high
selectivity, and an equivalent amount of hydrogen was obtained
as the sole byproduct (Scheme 1d).
conversion of benzene was 80%. A quantitative yield of H was
2
also obtained (Scheme 3 and Table S1). Control experiments
Scheme 3. Photocatalytic Etherification of Benzene with
a
Alcohols
Photocatalytic hydrogen-evolution cross-coupling, which
consists of a photoredox cycle and hydrogen-evolution system,
11
was developed by Wu, Tung, and co-workers. Utilizing this
+
+
strategy, a quinolinum ion photocatalyst (QuH or QuCN )
with a cobalt catalyst [Co(dmgBF ) (CH CN) ] were
2
2
3
2
combined for the successful synthesis of aniline directly from
benzene and ammonia and phenol from benzene and water
with evolution of hydrogen gas under remarkably mild
12
conditions in excellent yields in our preceding work. We
anticipate that it should be possible to utilize the dual catalyst
system to synthesize aryl ethers directly from coupling of the
benzene C−H bond and the alcohol O−H bond with evolution
of hydrogen.
An outline of a possible mechanism for photocatalytic
hydrogen-evolution cross-coupling of benzene with alcohol is
illustrated in Scheme 2. On the basis of the established one-
a
Reaction conditions: benzene (0.2 mmol), ROH (10 equiv).
Scheme 2. Proposed Pathway for Benzene Etherification via
Photocatalytic Hydrogen-Evolution Cross-Coupling
Conversions (based on benzene) were determined by GC and yields
were determined by GC (3a and 3b) or NMR (3c−l) using n-
tetradecane as an internal standard. Isolated yields were given in
parentheses. Selectivity = GC yield or NMR yield/conversion.
demonstrated that photocatalyst, metal cocatalyst, and light
were necessary to achieve C−O bond formation (Table S1). It
should be noted that the produced anisole cannot undergo
further photoreactions to yield dimethoxybenzene even at high
benzene conversion. To verify this observation, anisole instead
benzene was employed as starting material. Though anisole
16
(
Ep/2 = 1.81 V vs SCE) possesses a lower oxidation potential
than benzene, no consumption of anisole occurred under the
+
13
13a,17
electron redox potentials of QuCN * (E = 2.72 V vs SCE)
same conditions. According to the previous research,
the
red
14
and benzene (Eox = 2.48 V vs SCE), we assumed that the
reaction could be initiated via electron transfer from benzene to
the singlet excited state of QuCN upon irradiation. This
crucial electron-transfer step could lead to a benzene radical
cation and a photocatalyst radical anion that would then
resistance of anisole during photocatalytic alkoxylation may
result from the fast back-electron transfer of the generated
charge pair of the photocatalyst anion radical and the anisole
radical cation.
+
Using the optimal conditions, we examined the scope of this
hydrogen-evolution crossing-coupling method for benzene
etherification by various alcohols (Scheme 3). For coupling
of benzene with primary alcohols, good to excellent selectivities
were obtained with a stoichiometric amount of hydrogen gas.
For example, a series of simple alkyl alcohols were effective
coupling partners (3a−d). Moreover, halohydrins were also
found to participate efficiently (3e and 3f) in the reactions.
Importantly the use of glycol ethers as starting materials did not
compromise the efficiency of the cross-coupling (3g−i).
Notably, as an alkyl alcohol bearing two hydroxyl groups
(ethylene glycol) was used, only one of them could be coupled
to benzene with a high level of efficiency to form 2-
II
transfer an electron to the Co (dmgBF ) (CH CN)
2
2
3
2
•
+
13b
[
E (QuCN ) = E (QuCN ) = −0.60 V vs SCE,
ox
red
15
0 II/I I
E (Co ) = −0.55 V vs SCE ] to produce Co complex and
ground-state QuCN , accordingly completing the photo-
catalysis cycle. The resulting benzene radical cation could
react with a nucleophile (ROH) to give a dienyl radical andI
eliminate a proton, which would be captured by the Co
complex to form Co hydride. The intermediate metal hydride
accepts an electron from the dienyl radical and decomposes by
proton attack to return to Co , concluding the cobalt catalysis
cycle and producing H . The generated aryl cation loses a
+
III
II
2
proton to yield aryl ether.
18
We began our direct benzene etherification studies by using
methanol as alkoxylation reagent with the photocatalyst
QuCN and metal cocatalyst Co(dmgBF ) (CH CN) . Upon
phenoxyethanol (3j), which has antimicrobial activity and
acts as a synthetic intermediate in the production of plasticizers,
+
19
pharmaceuticals, and fragrances. Carbonyl and ester groups
2
2
3
2
investigating a range of reaction parameters, irradiation of
benzene (1, 40 mM), methanol (2a, 10 equiv), QuCN ClO4
were also tolerated. Corresponding products 3k and 3l were
obtained in 91% and 93% yield, respectively, based on the
+
−
B
DOI: 10.1021/acs.orglett.7b00463
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
2
consumption of the starting material. However, secondary
alcohols that were readily oxidized into the corresponding
ketones were not suitable for this method.
We next turned our attention to explore the scope of arene
components (Scheme 4). A diverse array of electron-deficient
Montmorillonite K10. Finally, butoxycaine 6 was prepared as
23
the previous literature in 91% yield by coupling 5 with CO
and (diethylamino)ethanol. The buloxycaine was successfully
de novo synthesized from benzene by the application of the
photocatalytic hydrogen-evolution cross-coupling method in
three steps.
2
0
Scheme 4. Photocatalytic Etherification of Arenes with
Methanol
Analogous to the intermolecular direct benzene C−H
etherification, intramolecular C−H alkoxylation of substituted
arenes also performed well using this synergistic protocol
a
(
Scheme 6). 3-Phenyl-1-propanol was preliminarily investigated
Scheme 6. Photocatalytic Intramolecular Etherification of
a
Arenes
a
Reaction conditions: arene (0.2 mmol), CH OH (10 equiv).
3
Conversions (based on arene) and yields were determined by NMR
using n-tetradecane as an internal standard. Isolated yields were given
in parentheses. Selectivity = NMR yield/conversion. The ratio of the
isomer was determined by NMR.
a
Reaction conditions: arene (0.2 mmol). Conversions (based on
arenes with functional groups such as ketones, acid, and ether
were viable substrates, affording a mixture of ortho, meta, and
para isomers (3m−p). Among them, ortho methoxylation
products were substantial for phenyl ketones and benzoic acid,
while similar amounts of ortho and para isomers for benzoate
arene) and yields were determined by NMR using n-tetradecane as an
internal standard. Isolated yields were given in parentheses. Selectivity
=
NMR yield/conversion. The ratio of the isomer was determined by
NMR.
(
3p) were produced. Additionally, a variety of chlorobenzenes
were found to be competent substrates in this transformation
without further optimization, and chromane (8a) was obtained
in 21% yield with >99% selectivity. The unreacted 3-phenyl-1-
propanol was quantitatively recovered. Various functional
groups could be well compatible to produce chromanes in
modest yields with nearly 100% selectivity. Transformation
proceeds smoothly in the presence of electron-withdrawing
substituents (8b, 52% yield). The synthetically useful halogens
were well tolerated, and the influence of regioisomeric
substitution was also explored. The chloro- or bromo-
substituent in the ortho position leads to the single regioisomer
(
3q−s, 69−87% conversion, 89−97% selectivity).
We sought to demonstrate that this methodology is
applicable for the synthesis of practical and high-value building
blocks such as pharmaceuticals. More specifically, we envisaged
butoxycaine that could be de novo synthesized from benzene in
utility of the photocatalytic hydrogen-evolution cross-coupling
C−O bond formation strategy (Scheme 5). In contrast to the
Scheme 5. De novo Synthesis of Buloxycaine from Benzene
5
-chloro- or bromochromane (8c and 8d). However, two
regiosomers, 6- and 8- halogenated chromanes (8e−f′), were
found for meta-halogen-substituted substrates with regioselec-
tivity ratio greater than 4:1.
In summary, the synthesis of aryl ethers through direct
etherification of benzene with alcohols via an external oxidant-
free dual catalytic strategy has been developed. The only
byproduct for this reaction is equivalent hydrogen gas. This
catalytic system also permits the direct intramolecular
alkoxylation of 3-phenyl-1-propanols for chromane construc-
tion. These results demonstrate that hydrogen-evolution cross-
coupling can be a useful strategy to achieve a variety of
challenging bond constructions as long as the redox potentials
of substrate, photocatalyst, and cocatalyst are matched.
2
1
previous report, benzene was used as a starting material for
the synthesized butoxycaine. First, butoxybenzene was
synthesized by hydrogen-evolution cross-coupling of benzene
(
0.2 mmol) with 1-butanol under the optimal conditions as
described above in a yield of 56% with 99% selectivity (33%
yield of 4 was obtained when benzene was scaled up to 4
mmol). Subsequently, regioselective bromination of 4 with
anhydrous sodium bromide gave 90% yield of 5 in the presence
of sodium chlorite and Mn(acac) with the aid of moist
3
C
DOI: 10.1021/acs.orglett.7b00463
Org. Lett. XXXX, XXX, XXX−XXX

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AUTHOR INFORMATION
Corresponding Authors
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H.; Lei, T.; Li, Z.-J.; Feng, K.; Chen, B.; Tung, C.-H.; Wu, L.-Z. J. Am.
Chem. Soc. 2013, 135, 19052−19055. (b) Zhong, J.-J.; Meng, Q.-Y.;
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Wu, L.-Z. Org. Lett. 2014, 16, 1988−1991. (c) Zhong, J.-J.; Wu, C.-J.;
Meng, Q.-Y.; Gao, X.-W.; Lei, T.; Tung, C.-H.; Wu, L.-Z. Adv. Synth.
Catal. 2014, 356, 2846−2852. (d) Gao, X.-W.; Meng, Q.-Y.; Li, J.-X.;
Zhong, J.-J.; Lei, T.; Li, X.-B.; Tung, C.-H.; Wu, L.-Z. ACS Catal. 2015,
*
E-mail: chenbin@mail.ipc.ac.cn.
E-mail: chtung@mail.ipc.ac.cn.
*
ORCID
Bin Chen: 0000-0003-0437-1442
Wenguang Wang: 0000-0002-4108-7865
Li-Zhu Wu: 0000-0002-5561-9922
Chen-Ho Tung: 0000-0001-9999-9755
5
, 2391−2396. (e) Zhang, G.; Liu, C.; Yi, H.; Meng, Q.; Bian, C.;
Chen, H.; Jian, J.-X.; Wu, L.-Z.; Lei, A. J. Am. Chem. Soc. 2015, 137,
273−9280. (f) Xiang, M.; Meng, Q.-Y.; Li, J.-X.; Zheng, Y.-W.; Ye,
C.; Li, Z.-J.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Chem. - Eur. J. 2015, 21,
9
Notes
The authors declare no competing financial interest.
1
8080−18084. (g) Wu, C.-J.; Meng, Q.-Y.; Lei, T.; Zhong, J.-J.; Liu,
W.-Q.; Zhao, L.-M.; Li, Z.-J.; Chen, B.; Tung, C.-H.; Wu, L.-Z. ACS
ACKNOWLEDGMENTS
Catal. 2016, 6, 4635−4639.
■
(12) Zheng, Y.-W.; Chen, B.; Ye, P.; Feng, K.; Wang, W.; Meng, Q.-
This work was financially supported by the Ministry of Science
and Technology of China (2013CB834804, 2013CB834505,
and 2014CB239402), the National Natural Science Foundation
of China (21390404, 91427303, and 21402217), the Strategic
Priority Research Program of Chinese Academy of Sciences
XDB17030400), and the Technical Institute of Physics and
Chemistry, CAS.
Y.; Wu, L.-Z.; Tung, C.-H. J. Am. Chem. Soc. 2016, 138, 10080−10083.
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