Electrochemical Cross-Dehydrogenative Coupling between Phenols and β-Dicarbonyl Compounds: Facile Construction of Benzofurans

Article abstract of DOI:10.1002/chem.201904750

Preparative electrochemical synthesis is an ideal method for establishing green, sustainable processes. The major benefits of an electro-organic strategy over that of conventional chemical synthesis are the avoidance of reagent waste and mild reaction conditions. Here, an intermolecular cross-dehydrogenative coupling between phenols and β-dicarbonyl compounds has been developed to build various benzofurans under undivided electrolytic conditions. Neither transition metals nor external chemical oxidants are required to facilitate the dehydrogenation and dehydration processes. The key factor in success was the use of nBu₄NBF₄ as the electrolyte and hexafluoroisopropanol as the solvent, which play key roles in the cyclocondensation step. This electrolysis is scalable and can be used as a key step in drug synthesis. On the basis of several experimental results, the mechanism, particularly of the remarkable anodic oxidation and cyclization process, was illustrated.

Full text of DOI:10.1002/chem.201904750

A Journal of
Accepted Article
Title: Electrochemical Cross-Dehydrogenative Coupling between
Phenols and β-Dicarbonyl Compounds: Facile Construction of
Benzofurans
Authors: Zhuangzhi Shi, Yandong Wang, Bailin Tian, and Mengning
Ding
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To be cited as: Chem. Eur. J. 10.1002/chem.201904750
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Electrochemical Cross-Dehydrogenative Coupling between
Phenols and β-Dicarbonyl Compounds: Facile Construction of
Benzofurans
Yandong Wang,[a] Bailin Tian, [b] Mengning Ding,[b] and Zhuangzhi Shi[a]*
Dedication ((optional))
Abstract: Preparative electrochemical synthesis is an ideal method
for establishing green, sustainable processes. The major benefits of
electro-organic strategy over conventional chemical synthesis are
the avoidance of reagent waste and the mild reaction conditions.
Here, an intermolecular cross-dehydrogenative coupling (CDC)
between phenols and β-dicarbonyl compounds to build various
benzofurans under undivided electrolytic conditions has been
developed. Neither transition metals nor external chemical oxidants
are required to facilitate the dehydrogenation and dehydration
processes. The key factor in the success was the use of nBu4NBF4
as the electrolyte and hexafluoroisopropanol (HFIP) as the solvent,
which play key roles in the cyclocondensation step. This electrolysis
is scalable and can be used as a key step in drug synthesis. On the
basis of the several experimental results, the mechanism,
particularly of the remarkable anodic oxidation and cyclization
process, was illustrated.
benzofurans under transition-metal and chemical oxidant-
free conditions is in high demand.
Electrochemical synthesis[6] is
a green and sustainable
method for organic synthesis, which usually does not use metal
catalysts or chemical oxidants.[7] Based on this chemistry,
electrochemical cross-dehydrogenative coupling (CDC) and
cyclization has been an efficient method for the construction of
cyclic compounds.[8] Such a process typically proceeds in an
intramolecular manner.[9] Recently, the intermolecular anodic C-
H
oxidation and functionalization of arenes,[10] especially
treatment of phenols for phenol–arene,[11] phenol–phenol[12] and
phenol–thiophene[13] cross-couplings has been developed
successively (Fig. 1b). Inspired by these precedent results, we
wondered whether β-dicarbonyl compounds could be employed
as sp3 carbon coupling partners with phenols. We
serendipitously found that benzofurans could be formed directly
without addition of any Lewis acid for dehydration. Here, we
report a robust electrochemical synthesis of benzofurans from
phenols and β-dicarbonyl compounds through cascade
intermolecular dehydrogenative C(sp2)-C(sp3) coupling and
cyclization (Fig. 1c). Notably, the electrolyte nBu4NBF4 and the
solvent HFIP were first found to be crucial for the dehydrative
step. The electrooxidation of phenols with β-dicarbonyl
compounds showed excellent chemoselectivity, without
Introduction
The diversity of benzofuran scaffolds found in natural
products and synthetic compounds, as well as their
biological and pharmaceutical relevance, have stimulated
research into the development of new synthetic strategies
for the construction of readily functionalized benzofuran ring
systems (Figure 1a).[1] Although numerous procedures have
been established for this purpose,[2] transition-metal-
catalyzed cyclization reactions are the most common in
such target or diversity-oriented syntheses.[3] Of particular
interest is the iron-catalyzed cascade CDC[4] and cyclization
between phenols and β-dicarbonyl compounds. However,
these methods require using stoichiometric amounts of
peroxides, which can be explosive and environmentally
unfriendly.[5] Undoubtedly, the development of a safe and
low-cost strategy enabling the efficient synthesis of
formation of any homocoupling byproducts.
Mechanistic
experiments and cyclic voltammetry (CV) investigations were
conducted to demonstrate an unusual pathway for this
transformation. Such a strategy for benzofuran synthesis has
exciting possibilities because of its superior practicality,
scalability, safety, and environmental friendliness.
Results and Discussion
To begin our studies, we chose 4-methoxyphenol (1a) and
dibenzoylmethane (2a) as the model substrates (Table 1). The
electrochemical oxidation of 1a (0.60 mmol) and 2a (1.20 mmol)
was carried out in a 0.06 M solution of nBu4NBF4 as the
electrolyte using DCM/HFIP (1/1) as cosolvents in an undivided
cell equipped with platinum plates as the anode and cathode
under a 2.5 V potential for 10 hours, and the desired product
3aa was generated in an 83% yield (Table 1, entry 1). No
products of oxidation of the enol tautomer of dibenzoylacetone
(2a) and of the benzofurans 3aa were detected. This is because
the onset potential of oxidation the enol of 2a and of 3aa is
about 0.4 V and 0.3 V higher respectively than that of phenol 1a
(Table S1, entries 5 and 8). The current efficiency of this
reaction, determined by a constant-current electrolysis at a
[a]
[b]
Y. Wang, and Prof. Dr. Z. Shi
State Key Laboratory of Coordination Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093 (China)
E-mail: shiz@nju.edu.cn
B. Tian, and Prof. Dr. M. Ding
Key Lab of Mesoscopic Chemistry, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093 (China)
Supporting information and the ORCID identification number(s) for
the author(s) for this article can be found under ((Please delete this
text if not appropriate))
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Fig. 1 Construction of benzofurans by electrochemical CDC strategy. (a) Examples of bioactive compounds containing a benzofuran scaffold. (b)
Electrochemical C-H (hetero)arylation of phenols. (c) Electrochemical intermolecular cyclization of phenols and β-dicarbonyl compounds to construct benzofurans.
Table 1 Reaction optimization.
current density of 4 mA cm-2, was very good, 65% for an 81%
yield of 3aa. The reaction failed in the absence of HFIP (entry 2),
and a 78% yield was observed using pure HFIP as the solvent
n
(entry 3). Other supporting electrolytes such as Bu4NPF6 (entry
4) and other electrodes such as a graphite rod cathode (entry 5)
were also effective for this transformation, although with slightly
lower yields. Under the current reaction conditions, lowering the
potential to 2.0 V decreased the yield to 59% (entry 6). In
addition, changing the ratio of substrates 1a and 2a decreased
the yield (entries 7-8). Under an air atmosphere, the reaction
Yield of
Entry
Variation from the standard conditions
3aa (%)b
1
2
none
without HFIP
83
0
maintained
a good reactivity (entry 9). Finally, a control
experiment confirmed that the transformation did not occur
without electricity (entry 10).
3
without DCM
78
80
79
59
68
63
81
0
4
Using nBu4NPF6 instead of nBu4NBF4
Scope of the methodology. With the optimized reaction
conditions in hand, we examined the substrate scope (Fig. 2).
The reactions of β-diketone 2a with a broad range of phenols
were first examined. Commercially available phenols bearing
nBuO (1b), PhO (1c), and allyloxy (1d) substituents at the C4-
position underwent facile cross-coupling and cyclization,
affording the corresponding products 3ba-3da in 75-86% yields.
Substrate 1e containing a dihydrobenzofuran motif led to
product 3ea in an 82% yield, without any overoxidation
byproduct. In addition to ether substituents, para-substituted
phenols with aryl substituents such as 1f-1g were also
5
Using C(+)/Pt(-)
6
2.0 V instead of 2.5 V
1a/2a = 1/1
7
8
1a/2a = 2/1
9
under air
10
without electric current, under air
aReaction conditions: platinum plate anode and cathode (1.0 cm×1.0 cm×0.1
mm) with an oven-dried undivided cell, constant potential = 2.5 V, 1a (0.60
mmol), 2a (1.20 mmol), nBu4NBF4 (0.60 mmol), HFIP/DCM (1/1, 10 mL), 10
hours, room temperature, under N2. bIsolated yield
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Fig. 2 Substrate scope for the construction of benzofurans 3 between phenols 1 and β-dicarbonyl compounds 2. Reaction conditions: platinum plate
anode and cathode (1.0 cm×1.0 cm×0.1 mm) with an oven-dried undivided cell, constant potential = 2.3~2.7 V, 1 (0.60 mmol), 2 (1.20 mmol), nBu4NBF4 (0.60
mmol), HFIP/DCM (1/1, 10 mL), 8~26 hours; room temperature, under N2; Isolated yields. See supporting information for experimental details.
compatible. Phenols bearing Me (1h), tBu (1i), allyl (1j), tBu (1i),
SiMe3 (1k), Ph (1l-1m), F (1n), Cl (1o) and Br (1p-1q) groups at
the C2 or C3 position gave the corresponding benzofurans in
30-90% yields. Among them, the structure of 3pa was further
confirmed by X-ray analysis. Naphthol 1r underwent facile cross-
coupling, affording the product 3ra in modest yield. Next, various
β-diketones (2b-2k) with a wide range of substituents were also
employed for cyclization with phenol 1a. Among them, excellent
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Yoon's conditions[17] could also undergo annulation to form
product 10 in a 46% yield in our reaction conditions (Fig. 4c).
Using a nonsymmetric β-diketone 11 with 4-tBuBz and 4-OMeBz
as a substrate, we got products 12 and 13 in 52% and 20%
yields, respectively, indicating that the less electron-rich benzoyl
carbonyl is the most reactive towards the intramolecular addition
of the phenol hydroxyl followed by dehydration (Fig. 4d). The
known compound 14 was proven to undergo intramolecular
condensation to form benzofuran 15 in the presence of an iron
salt.[5a] In our catalyst-free conditions, such a cyclization could
occur by the combination of HFIP and nBu4NBF4 (Fig. 4e).
regioselectivity was obtained with nonsymmetric benzoyl
acetones 2c-2j with different substituents, as well as furan-
based substrate 1k. Notably, this strategy was not limited to β-
diketones; β-keto amide 2l and β-keto ester 2m were also
tolerable, providing the desired products in 41% and 28% yields.
Synthetic Applications. The drug Dronedarone was developed
by Sanofi Pharm for the treatment of atrial fibrillation and atrial
flutter.[14] The original route was patented by Gubin et al., based
on the construction of a functionalized benzofuran 6 (Fig. 3).[15]
To demonstrate the applicability of our methodology, we
provided an alternative route to obtain the intermediate 6. The
reaction of phenol 1d was scalable to 6.0 mmol with β-diketone
2g, giving 4 in 52% yield on a gram-scale. One-pot deprotection
followed by a reaction with Tf2O afforded compound 5 in 74%
yield. It was then subjected to nitration[16] to provide the desired
product 6 in good yield.
Fig. 3 Synthesis of compound 6 as a key intermediate for Dronedarone.
(a) platinum plate anode and cathode (1.0 cm×1.0 cm×0.1 mm) with an oven-
dried undivided cell, constant potential = 2.7 V, 1d (6.0 mmol), 2g (10.0 mmol),
nBu4NBF4 (3.0 mmol), HFIP/DCM (1/1, 50 mL), room temperature, under N2.
(b) 1 mol% Pd(PPh3)4, 1.0 equiv of 4, 3.0 equiv of K2CO3, MeOH, 10 h; then
Tf2O, pyridine, 0 °C to room temperature, 10 h. (c) 0.5 mol% Pd2(dba)3, 1.2
Fig.
4
Mechanistic experiments. (a) Comparing Fe-catalyzed and
electrochemical system. (b) Radical clock experiment. (c) Oxidative [3+2]
cycloaddition of phenol 1a and olefin 9. (d) The selectivity of nonsymmetrical
β-diketone 11. (e) Investigation of the dehydration step.
t
mol% BuBrettPhos, 5.0 mol% tris(3,5-dioxaheptyl)amine, 1.0 equiv of 5, 2.0
equiv of NaNO2, tBuOH, 130°C, 24 h, under Ar.
To further obtain mechanistic insights into the cationic
oxidation pathway, cyclic voltammetry (CV) investigations were
systematically conducted on the reaction of phenol 1a and β-
diketone 2a, as well as various combinations of the substrates
(Fig. 5). Both phenol 1a and the enol of β-diketone 2a show
electrochemical reactivity at relatively high oxidative potentials,
with onsets of ~1.2 V and ~1.6 V vs Ag/AgCl, respectively (Table
S1, entries 1 and 5). The mixture of 1a and 2a shows an
increased anodic current, consistent with the occurrence of an
electroorganic reaction that involves both reactants. The addition
of HFIP to the system further enhances the anodic current with
an unaltered onset potential (relative to that of 1a). This result
clearly reveals the unique role of HFIP to facilitate the coupling
reaction[19] and supports our assumption that the overall reaction
began with the oxidation of phenols.
Mechanistic Studies. Several experiments were conducted to
elucidate the reaction mechanism (Scheme 2). We first
investigated the reaction of 1a and 2a under reported Fe-
catalyzed systems using (tBuO)2 as the oxidant.[5] Low yields of
the desired product 3aa were observed, demonstrating the
unique reactivity of this electrochemical chemistry (Fig. 4a).
Under standard conditions, a radical clock experiment was
performed on an olefin-containing substrate 7, only yielding the
normal cyclization product 8 in a 52% yield. This result can
exclude the free radical generated at the acidic α methylene
group of β-diketones during the reaction (Fig. 4b). The oxidative
[3+2] cycloaddition of phenols and alkenes via a phenoxonium
cation intermediate has been reported under photo[17] or
electrochemical[18] conditions. Substrates 1a and 9 used in
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protons or HFIP could be reduced at the Pt cathode to generate
hydrogen gas.
Fig. 5 CV investigations of reaction mixtures. CV characteristics of reaction
background (solvent and additives), phenol 1a in DCM, β-diketone 2a in DCM,
mixture of 1a and 2a in DCM, mixture of 1a and 2a in DCM and HFIP (best
mimicking the reaction conditions), 1a in DCM and HFIP, and 2a in DCM and
HFIP.
Next, systematic CV studies of phenols and β-diketones with
different electron densities provide further mechanistic clues. As
shown in the CVs of Fig. 6a, the onset of the oxidation potential
of 1a and 1f (~1.2 V vs Ag/AgCl) is lower than that of 1s (~2.0 V).
Therefore, the oxidation of phenols 1a and 1f should be much
faster than that of the enols of 2a and 2f. As a result,
benzofurans 3aa, 3ca, and 3fa were formed. This is the case, in
Fig. 2, for the phenols 3b-r electro-oxidized in the presence of
diketone 2a and for phenol 1a electro-oxidized in the presence
of diketones 2b-m. In the case of phenol 1s and diketone 2a, the
oxidation of the enol of diketone 2a should be easier than that of
phenol 1a (ΔEonset(
) ~-0.8 V), and, as a result, no benzofuran
2a-1a
was obtained. Similarly, due to the presence of the strongly
electron-attracting CF3 group, the enol of diketone 2n is probably
as easily oxidized as phenol 1a (close onsets of their oxidation
potential as shown in Figs 6a and 6b). Since there was a 100%
mole excess of diketone, the oxidation of the enol of 2n was
faster enough to prevent the formation of the benzofuran. These
results demonstrate the utility of CV in rationalizing the formation
of benzofurans by oxidizing phenols in the presence of β-
diketones: the phenol must be more easily oxidized that the enol
of the diketone.
Fig. 6 CV characteristics of different phenols and β-diketones. (a) CV
characteristics of phenols 1a, 1f and 1s (non-reactive). (b) CV characteristics
of diketones 2a, 2c, and 2n (non-reactive). Different conditions in (a) and (b)
were labeled A-F for better visualization.
Based on the above experimental results, a mechanism has
been proposed in Fig. 7. A successive single-electron-transfer
oxidation of phenol 1 by anodic oxidation (via A) generates a
phenoxonium cation B.[18] This cation species can isomerize to a
highly reactive oxonium ion as a Michael receptor,[20] which then
reacts with nucleophilic β-dicarbonyl compounds 2 to afford
intermediate
D
with excellent site-selectivity. Then, the
tautomerization of D would provide phenol E. Finally, the
cooperation between HFIP and nBu4NBF4 triggers intramolecular
condensation to generate the benzofurans 3. The formed
Fig. 7 Proposed mechanism.
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Conclusions
In summary, we have developed an efficient electrochemical
system that can undergo a CDC reaction and condensation
between phenols and β-dicarbonyl compounds to produce a
series of benzofurans. This strategy avoids the use of transition
metals and external chemical oxidants and provides a simple
and atom-economical way to synthesize benzofurans. Due to
these advantages, this reaction should be of high synthetic value.
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Experimental Section
General procedures for synthesis of 3aa. A solution of phenol
1a (0.6 mmol), β-diketone 2a (1.2 mmol) and nBu4NBF4 (0.6
mmol) in HFIP/DCM = 1/1 (10.0 mL) was stirred at room
temperature under N2 atmosphere in an oven-dried undivided
cell which was equipped with platinum plate electrodes (1.0
cm×1.0 cm×0.1 mm) as both the anode and cathode. A balloon
filled with N2 atmosphere was connected to the electrolytic cell.
The reaction mixture was stirred and electrolyzed at a constant
potential of 2.5 V for 10 hours. The reaction was monitored by
thin layer chromatography(TLC), visualized by fluorescence
quenching under UV light. After the reaction was completed, the
product 3aa (162.9 mg, 83% yield) was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate,
100:1 (v/v)).
CV Experiments. Cyclic voltammetry was performed with a
potentiostat (Corrtest CS3104) in a three-electrode cell at
synthetic conditions. Platinum plates were used as working and
counter electrodes and a leak-free Ag/AgCl (Harvard Apparatus
LF-2) was used as reference electrode. The ranging of scan was
0V to 3.5V with a 0.1 V/s scan rate.
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Data availability. The authors declare that the data supporting
the findings of this study are available within the article and its
Supplementary Information Files.
[7]
Acknowledgements
We thank the “1000-Youth Talents Plan”, and the National
Natural Science Foundation of China (grant 21672097,
21972064) for their financial support and, as well as the
“Innovation
& Entrepreneurship Talents Plan” of Jiangsu
Province.
Keywords:
Electrochemistry
·phenols
·β-
diketones ·CDC ·benzofurans
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Electrochemical
Dehydrogenative Coupling between
Phenols and β-Dicarbonyl
Compounds: Facile Construction of
Benzofurans
Cross-
Electrifying: A mild electrochemical system was developed for the preparation of
benzofurans via cross-dehydrogenative coupling between phenols and β-dicarbonyl
compounds. This method has good functional group compatibility and can serve as
a powerful synthetic tool with high synthetic value.
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