X-ray Absorption and Electron Paramagnetic Resonance Guided Discovery of the Cu-Catalyzed Synthesis of Multiaryl-Substituted Furans from Aryl Styrene and Ketones Using DMSO as the Oxidant

Article abstract of DOI:10.1021/acs.orglett.7b00865

The first example of DMSO serving not only as a solvent but also as an oxidant to promote the oxidation of Cu(I) to Cu(II) has been demonstrated. X-ray absorption and electron paramagnetic resonance evidence revealed a single-electron redox process where DMSO could oxidize Cu(I) to Cu(II). The novel discovery guided the rational design of copper-catalyzed oxidative cyclization of aryl ketones with styrenes to furans, providing a new method for the synthesis of multiaryl-substituted furans from cheap and readily available starting materials.

Full text of DOI:10.1021/acs.orglett.7b00865

Letter
pubs.acs.org/OrgLett
X‑ray Absorption and Electron Paramagnetic Resonance Guided
Discovery of the Cu-Catalyzed Synthesis of Multiaryl-Substituted
Furans from Aryl Styrene and Ketones Using DMSO as the Oxidant
Yong Wu,† Zhiyuan Huang,† Yi Luo,† Dong Liu,† Yi Deng,† Hong Yi,† Jyh-Fu Lee,§ Chih-Wen Pao,§
Jeng-Lung Chen,§ and Aiwen Lei*,†,‡
†College of Chemistry and Molecular Sciences, the Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072,
P.R. China
‡State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. China
§National Synchrotron Radiation Research Center, Hsinchu 30076, Taiwan
S
* Supporting Information
ABSTRACT: The first example of DMSO serving not only as
a solvent but also as an oxidant to promote the oxidation of
Cu(I) to Cu(II) has been demonstrated. X-ray absorption and
electron paramagnetic resonance evidence revealed a single-
electron redox process where DMSO could oxidize Cu(I) to
Cu(II). The novel discovery guided the rational design of
copper-catalyzed oxidative cyclization of aryl ketones with styrenes to furans, providing a new method for the synthesis of
multiaryl-substituted furans from cheap and readily available starting materials.
Scheme 1. Alternative Method for Recirculation of Cu(I) to
Cu(II) Utilizing DMSO as the Oxidant
opper-catalyzed coupling reactions have enriched the
Capproaches for the construction of carbon−carbon and
carbon−heteroatom bonds1 in accordance with the demand for
sustainable chemistry and organic synthesis of pharmaceutically
active compounds2 and material molecules.3 Along with the
development of copper-catalyzed reactions, however, the
majority of this research concentrated on synthetic method-
ology prior to the mechanistic understanding. The unidentified
varied redox state, complicated catalyst structure, and unclear
coordination mode in copper-catalyzed reactions are the major
obstacles that hinder the further development of efficient
synthetic processes. In fact, the synthetic methodologies and
fundamental mechanistic studies complement each other.4
Recent research has seen a remarkable increase in the
understanding of the real role of copper species in copper-
catalyzed reactions.5 Generally, oxidation of low-valent copper
species, in particular, oxidation of Cu(I) to Cu(II), employed
various oxidants such as peroxides1h and molecular oxygen,1g
which are well-known and extensively used in organic synthesis.
However, to the best of our knowledge, so far, there has been
no example of the oxidation of Cu(I) to Cu(II) utilizing
DMSO as the oxidant. The novel discovery should provide an
alternative way for recirculation of Cu(I) to Cu(II) (Scheme 1).
We herein communicate the observation of oxidation of
Cu(I) to Cu(II) utilizing DMSO as the oxidant and solvent.
X‑ray absorption (XAS) and electron paramagnetic resonance
(EPR) spectroscopies are utilized to explore this trans-
formation, enabling deep understanding of the single-electron
redox process between DMSO and Cu(I) as well as inspiring us
to apply the above strategy to the synthesis of useful chemicals
such as multisubstituted furans (MSF) from aryl ketone and
styrenes.
In the beginning, we commenced our research by
investigating the interaction between DMSO and Cu(I)
under nitrogen atmosphere by EPR. As shown in Figure 1,
the signal gradually strengthened during the reaction of CuBr
with DMSO at rt from 5 to 120 min, indicating the formation
of Cu(II) species. The novel phenomenon prompted us to
probe more detailed interactions between Cu(I) and DMSO.
To precisely identify the variation of the redox states of
copper in the solution, XAS spectroscopy was utilized to
explore the redox process between Cu(I) and DMSO. As
shown in Figure 2a, initially, when DMSO was mixed with
CuCl rapidly, the X-ray absorption near edge structure
(XANES) spectrum of the solution gave an edge at 8981.4
eV, which is very close to that of CuCl solid (8982.0 eV).
However, mixing DMSO with CuCl at 80 °C for 2 h led to the
formation of Cu(II) species and consumption of Cu(I),
Received: March 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00865
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Letter
to the synthesis of useful chemical materials. The synthesis of
MSF has drawn considerable attention over the past decade6
due to the importance of these compounds in various natural
products, pharmaceuticals, and materials chemistry7 and the
wide application in a variety of functional group trans-
formations as well.8 As far as we know, there has been no
catalytic work for the synthesis of MSF utilizing cheap and
easily available styrenes and aryl ketones as substrates.
Owing to our continuous interest in the understanding of the
mechanism of copper-catalyzed reactions,9 we envisaged that
aryl ketones may serve as the electron donor to transfer one
electron to Cu(II) similar to 1,3-dicarbonyl compounds.9c An
EPR experiment was carried out to corroborate our speculation
(Figure 3). As a result, the decrease of Cu(II) signal over time
Figure 1. EPR spectra of the oxidation process: CuBr (0.5 mmol) in
DMSO (5.0 mL) at rt under N2.
Figure 3. EPR spectra of the reduction process: CuBr2 (0.5 mmol)
and deoxybenzoin (0.6 mmol) in DMF (5.0 mL) at 100 °C under N2.
confirmed our assumption. Then, DMSO was selected as the
oxidant for condition optimization, considering that it can
recirculate Cu(I) to Cu(II) and also retard aryl ketones from
being destroyed by peroxides and oxygen. With this
mechanistic blueprint, we started evaluation of the reaction
between styrene (1a) and deoxybenzion (2a) in the presence of
copper catalyst (see the Supporting Information).
After exploring a wide range of conditions, treatment of 1a
with 1.6 equiv of 2a in the presence of 15 mol % of CuCl2 in
DMSO gave the product 4a in 82% yield. With the optimized
reaction conditions established, we next investigated the
substrate scope and generality for this transformation using a
broad range of substrates. First, different aryl ketones were
tested (Scheme 2). The reactions of styrene with methyl-
substituted aryl ketones showed good reaction efficiency (3a,b).
Electron-rich substituted aryl ketones were well tolerated with
lower catalyst loading (3c,d), while electron-poor aryl ketone
afforded the corresponding product in moderate yield (3e).
The aryl ketones with halide substituents were able to furnish
the desired products in this transformation, thereby facilitating
additional modifications at the halogenated position (3f−i).
Extensive screening revealed that deoxybenzoin with naph-
thalene groups also showed good reactivity toward the
annulation product (3j,k). It should be mentioned that
fluorene, dibenzofuran, dibenzothiophene, and carbazole
groups, which are useful motifs in material chemistry due to
their special properties, were also compatible in the reaction
system, demonstrating great potential for application of this
method in material sciences.
Figure 2. (a) X-ray absorption spectra of various Cu species: black
line, CuBr2 (0.05 mmol) in DMSO (5.0 mL) at rt; red line, CuBr
(0.05 mmol) in DMSO (5.0 mL) at rt; blue line, CuBr (0.05 mmol) in
DMSO (5.0 mL) at 80 °C, 2 h; black dot, CuCl solid; red dot, CuO
line. (b) XANES spectra of the oxidation process: CuBr (0.05 mmol)
in DMSO (5.0 mL) at rt.
indicating that DMSO could oxidize Cu(I) to Cu(II). In situ
XAS experiments were also carried out to monitor the
oxidation process. As shown in Figure 2b, the decrease of
Cu(I) signal was observed while accumulation of Cu(II) was
confirmed. This result provided direct evidence that Cu(I)
could be oxidized to Cu(II) by DMSO.
All of the above results revealed that DMSO could oxidize
Cu(I) to Cu(II). We decided to apply this novel redox system
B
DOI: 10.1021/acs.orglett.7b00865
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Letter
Scheme 2. Substrate Scope for the Copper-Catalyzed
Oxidative Annulation of Styrene (1a) with Aryl Ketones 2
Scheme 3. Substrates Scope for the Copper-Catalyzed
a
Oxidative Annulation of Deoxybenzion (2a) with Styrene
a
Derivatives 1
a
Reaction conditions: styrene (0.25 mmol), deoxybenzoin (0.4
mmol), CuCl2 (15 mol %), DMSO (1 mL), at 120 °C for 40 h.
b
c
CuCl2 (10 mol %). deoxybenzoin (0.5 mmol), 150 °C, 24 h.
butyl-4-methylphenol (BHT), were added into the reaction
system. As a result, only a trace or small amount of the desired
product could be observed (see the Supporting Information),
suggesting a probable radical process of this reaction.
Attempts to further understand the role of DMSO led us to
investigate the reaction with dibenzyl sulfoxide instead of
DMSO. In this case, 58% yield of product was obtained, while a
large amount of dibenzyl sulfide was isolated (see the
Supporting Information). It indicated that DMSO indeed
acted as an oxidant and was finally reduced to dimethyl sulfide.
According to the above results and previous work from our
group and others,9c,10 a proposed mechanism was presented in
Scheme 4. Carbon-centered radical A was generated from aryl
ketone via single-electron transfer. Then radical addition of A
a
Reaction conditions: styrene (0.25 mmol), aryl ketone (0.4 mmol),
CuCl2 (15 mol %), DMSO (1 mL), at 120 °C for 40 h under N2.
b
c
CuCl2 (10 mol %), 40 h. CuCl2 (7.5 mol %), 8 h.
Meanwhile, the reaction was found to be applicable to a wide
range of styrene derivatives, and the steric and electronic
variations in the styrene moieties were tested as well (Scheme
3). A series of styrenes, bearing either electron-donating groups
(R= Me, OMe, tBu) or electron-withdrawing groups (R = Br,
Cl, F, CF3) on the aryl ring, all reacted smoothly with
deoxybenzion, affording the desired products in good to
excellent yields (4a−h). A slightly decreased reactivity was
observed for the reaction of meta- and ortho-substituted
styrenes (4i−k). 2-Vinylnaphthalene and trans-anethole also
showed good efficiency for the generation of the desired
annulation products (4l and 4m). Notably, cyclic alkenes, such
as indene, could also be well tolerated, giving the target MSF
product in moderate yield (4n). Importantly, the target
tetrasubstituted furans could also be obtained from this
oxidative C−H/C−O cyclization process, which was a very
useful moiety widely present in materials science (4o).
Scheme 4. Proposed Mechanism
Furthermore, initial mechanistic studies were carried out to
shed light on the reaction mechanism. To confirm that the
reaction went through a radical addition pathway, the
commonly used radical-trapping/inhibiting reagents, either
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-
C
DOI: 10.1021/acs.orglett.7b00865
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Letter
(2) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
Chem. Rev. 2008, 108, 2796.
to styrene furnished benzyl radical B. Subsequently, inter-
mediate C was formed via further carbon-centered radical B
addition to carbonyl oxygen and hydrogen radical elimination,
which was successfully monitored by 1H NMR (see the
Supporting Information). Final aromatization of C afforded the
final product D.
At last, to demonstrate the practicality of this system, we
carried out the reaction in 10 mmol scale and successfully
prepared 3a in 2.07 g (70% isolated yield). Notably, only small
amounts of DMSO were needed (see the Supporting
Information).
In conclusion, we successfully developed a facile and practical
way for the oxidation of Cu(I) to Cu(II) by DMSO, which was
evidenced by XAS and EPR studies. The novel discovery
guided the rational design of copper-catalyzed oxidative
cyclization of aryl ketones and styrenes to multiaryl-substituted
furans. Notably, the reaction demonstrated a broad substrate
scope, providing an ideal way to multiaryl-substituted furans
from cheap and easily available starting materials. A more
detailed reaction mechanism and its application to the synthesis
of other useful heterocycles are currently underway in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00865.
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Detailed experimental procedures for catalytic studies
and metal complexes syntheses; 1H, 13C spectra;
characterization data of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aiwenlei@whu.edu.cn.
ORCID
Aiwen Lei: 0000-0001-8417-3061
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003), the Ministry
of Science and Technology of China (2012YQ120060), the
Fundamental Research Funds for the Central Universities, and
the Program of Introducing Talents of Discipline to
Universities of China (111 Program).
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