Palladium-catalyzed tandem C-H functionalization/cyclization strategy for the synthesis of 5-hydroxybenzofuran derivatives

Article abstract of DOI:10.1021/acs.orglett.6b03310

A palladium-catalyzed benzoquinone C-H functionalization/ cyclization strategy with terminal alkynes was employed for the synthesis of some biologically relevant 2, 3-disubstituted 5-hydroxybenzofuran derivatives. The benzoquinone acts as a reactant as well as an oxidant. During the process, an additional alkyne functionality can be introduced at the C3 position of the benzofuran. Base, ligand, and external oxidant are not required in this protocol.

Full text of DOI:10.1021/acs.orglett.6b03310

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Tandem C−H Functionalization/Cyclization
Strategy for the Synthesis of 5‑Hydroxybenzofuran Derivatives
Sachin S. Ichake, Ashok Konala, Veerababurao Kavala, Chun-Wei Kuo, and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Ting-Chow Road, Taipei 116, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: A palladium-catalyzed benzoquinone C−H functionaliza-
tion/cyclization strategy with terminal alkynes was employed for the
synthesis of some biologically relevant 2,3-disubstituted 5-hydroxybenzo-
furan derivatives. The benzoquinone acts as a reactant as well as an
oxidant. During the process, an additional alkyne functionality can be
introduced at the C3 position of the benzofuran. Base, ligand, and external
oxidant are not required in this protocol.
enzofuran, an important oxygen-containing heterocycle, has
Bbeen shown to be a potent inhibitor against many diseases,
viruses, microbes, fungi, and enzymes.1 As a result, a wide variety
of benzofuran-containing drugs play an important role in the
treatment of various types of diseases. 5-Hydroxybenzofuran, a
derivative of benzofuran, has attracted considerable interest due
to its presence in an enormous number of natural products that
have a wide range of biological activities. For example, natural
products such as gnetumelin B (anti-inflammatory activity),2
corsifuran C (antibacterial activity),3 moracin U (antioxidant
activity),4 sainfuran (antifungal activity)5 and lespedezavirgatal
(oxygen radical absorbance capacity)6 contain a 5-hydroxyben-
zofuran core (Figure 1). In addition, 5-hydroxybenzofuran
derivatives that contain a 1-oxo/hydroxy-5-methyl-4-hexenyl
substituent at the C-2 position function as insect toxins.7
tion of quinones with terminal alkynes. Previous reports
suggested that 5-hydroxybenzofuran derivatives can be synthe-
sized by the condensation of 4-methoxyphenol with 2-
bromoacetaldehyde diethyl acetal, followed by acid-promoted
intramolecular cyclization12 or by the cyclocondensation of p-
benzoquinone and enaminones either by heating or by
microwave assistance.13 These two strategies involve multistep
processes accompanied by low yields of the final product. 5-
Hydroxybenzofuran derivatives can also be prepared by the
condensation of p-benzoquinone with acetyl acetone or ethyl
acetoacetate in the presence of a Lewis acid catalyst.14 Very
recently, Wu et al. extended the above protocol to ketones for the
synthesis of 5-hydroxybenzofuran derivatives in the presence of
scandium triflate and triethyl orthoformate.15 Kim et al. reported
on the synthesis of 2-substituted 5-hydroxybenzofuran from
alkyne-containing quinols using a Pt-catalyzed domino dien-
one−phenol rearrangement/intramolecular 5-endo-dig cycliza-
tion reaction sequence.16 Although 5-hydroxybenzofuran
derivatives are present in a wide variety of natural products and
have a wide range of biological activities, efficient synthetic routes
for hydroxybenzofuran derivative production are few in number.
As a result, an efficient protocol for the synthesis of 5-
hydroxybenzofurans derivatives starting from readily available
starting materials would be highly desirable.
As a part of our interest in developing efficient methodologies
for the synthesis of active heterocycles,17 our recent studies
dealing with the chemistry of benzoquinones encouraged us to
focus on exploring the multiple roles of benzoquinone18 in the
same reaction. A review of the literature suggested that the C−H
functionalization of quinones with alkynes by palladium catalysis
is an unexplored area. We anticipated that 2-phenyl-5-
hydroxybenzofuran 3aa derivatives could be prepared from
benzoquinone 2 and the terminal alkyne 1 in the presence of a
palladium catalyst via C−H functionalization, followed by the
nucleophilic addition of the phenolic OH to the alkyne19 as
Figure 1. Representative natural products and biologically active
compounds that contain a 5-hydroxybenzofuran core.
The development of palladium-catalyzed C−C bond for-
mation reactions has dramatically changed the fate of organic
synthesis.8 A literature survey indicates that the palladium-
catalyzed direct C−H functionalization of quinones with aryl
boronic acid9 or arenes/aryl chlorides10 can be used for the
synthesis of aryl-substituted quinones. Other metals such as silver
and titanium and rhodium-catalyzed C−H functionalization
reactions of quinones with aryl boronic acid, arenes, and
aryltrifluoroborates, respectively, have also been reported.11 No
reports, however, are available regarding the C−H functionaliza-
Received: November 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03310
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Letter
shown in Scheme 1. Benzoquinone would function as an
oxidant20 as well as a reactant in such a reaction sequence.
paratively less reactive homocoupling product. Interestingly,
when we repeated the reaction in the absence of a base and a
ligand, the product 3a was obtained in 74% yield (Table 1, entry
6). Also, lowering (80 °C) or increasing (120 °C) the reaction
temperature was ineffective in producing the product 3a (Table
1, entries 7 and 8). Notably, by decreasing the catalyst loading to
5 mol % and to 2.5 mol %, the yield of 3a gradually decreased
(Table 1, entries 9 and 10). Further, other palladium salts
including PdCl2 (PPh3)2 and PdCl2 were also found to be
unproductive (Table 1, entries 11 and 12). Finally, the product
was formed in trace amounts when DMF was used as the solvent
(Table 1, entry 13), but other solvents failed to afford product 3a
(Table 1, entries 14 and 15).
Scheme 1. Palladium-Catalyzed C−H Functionalization of
Benzoquinones with Alkynes
In order to validate our hypothesis, we began by examining the
reactivity of phenylacetylene toward benzoquinone in the
presence of a palladium catalyst in various solvents, ligands,
and bases. The reaction was initially carried out at 100 °C in the
presence of 10 mol % of Pd(OAc)2 and 20 mol % of PPh3 ligand.
Surprisingly, the expected 2-phenyl-5-hydroxybenzofuran 3aa
was not detected, and instead, the more interesting 3-
phenylethynyl-substituted 2-phenyl-5-hydroxybenzofuran 3a
was obtained in 50% yield along with 10% of the homocoupling
product 4a (Table 1, entry 1). The structure of 3a was further
Prompted by our initial results and with optimized reaction
conditions in hand, we next focused our attention on substrate
scope to determine the generality of this reaction. As summarized
in Scheme 2, a wide range of electron-donating, electron-
a c
Scheme 2. Scope with Various Terminal Alkynes −
a d
−
Table 1. Optimization Studies
b
solvent
(2 mL)
base/ligand
(equiv)
yield (%)
a
entry catalyst (mol %)
(3a/4a)
1
2
3
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
DMSO
DMSO
DMSO
PPh3 (0.2)
PCy3 (0.2)
50/10
25/26
0/47
1,10-
phenanthroline
(0.2)
4
5
6
7
8
9
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (2.5)
Pd(OAc)2 (5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K2CO3 (2.0)
Cs2CO3 (2.0)
0/80
0/75
74/5
c
58/10
42/28
18/40
40/20
0/0
d
10
11
PdCI2(PPh3)2
(10)
12
13
14
15
PdCI2 (10)
DMSO
DMF
0/0
8/40
0/0
0/0
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
acetonitrile
THF
a
All of the reactions were carried out using 0.5 mmol of 1a and 1.5
b
a
mmol of BQ in 2 mL of solvent at 100 °C for 12 h. Isolated yields.
All of the reactions were carried out using 0.5 mmol of 1, 3 equiv 2,
c
d
b
Reaction carried out at 80 °C. Reaction carried out at 120 °C.
and 10 mol % Pd(OAc)2 in DMSO (2 mL), 100 °C for 12 h. Isolated
yields. In all cases, 5−8% alkyne self-coupled product isolated.
c
confirmed by H, 13C NMR spectroscopy and HRMS data. To
further increase the yield of 3a, ligands such as PCy3 and 1,10-
phenanthroline were employed, but no significant increase in
product yield was observed (Table 1, entries 2 and 3). In the
presence of bases such as K2CO3 and Cs2CO3, the desired
product 3a was not observed, and instead, the self-coupled
product 4a was obtained (Table 1, entries 4 and 5). It is possible
that the presence of base might be impede the anticipated
reaction by rapidly converting phenylacetylene to the com-
1
withdrawing, and halogen substituents at the para position of the
aromatic ring of terminal alkynes were utilized, and all were
converted smoothly into the desired benzofuran derivatives
using our protocol, although a bromo substituent gave a slightly
lower yield of 3f, but the other products 3a−e and 3g were
isolated in good to moderate yields. The structure of 3c was also
confirmed by X-ray crystallography.21 It is also noteworthy that
4-phenyl-substituted phenylacetylene also gave the desired
B
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product 3h in good yield. 2-Ethynylnaphthalene and 3,4-
(methylenedioxy)phenylacetylene were also converted into the
expected benzofuran derivatives 3i and 3j in good yields.
Moreover, the scope of the reaction with respect to meta
substituents on the phenylacetylene was also examined; the 3-
bromo-substituted phenylacetylene derivative gave lower yields
of the expected product 3o, whereas the expected products 3k−n
and 3p were formed in good to moderate yields. The reactions of
phenylacetylenes bearing ortho substituents such as 2-Me and 2-
Cl under optimized conditions failed to afford the desired
products 3q and 3r, and instead, alkyne homocoupling products
were observed. We attribute this to the fact that steric effects
likely have a major effect on this reaction. Heterocycle terminal
alkynes such as 2-ethynylthiophene and 2-ethynylbenzofuran
were also well tolerated and converted to the corresponding
benzofuran derivatives 3s and 3t in slightly lower yields using
current protocol. An inseparable mixture of products was
obtained when the reaction was conducted with two different
alkynes (2b and 2c) under the optimized reaction conditions.
In an attempt to enhance the scope of the reaction further, we
examined the reaction of phenylacetylenes with 2-methylbenzo-
quinone under optimized reaction conditions (Scheme 3). To
To investigate the mechanism for the reaction, some control
experiments were conducted, as shown in Scheme 4. When the
Scheme 4. Control Experiment
alkyne self-coupled product 4a was treated with benzoquinone
under optimized reaction conditions, the desired product 3a was
not produced. This rules out the possibility that the reaction
proceeds via an alkyne self-coupled product. The possibility that
the reaction proceeds through a hydroquinone intermediate was
also eliminated based on the finding that when 1a or 4a were
directly exposed to the hydroquinone under optimized reaction
conditions no reaction occurred.
a c
−
Scheme 3. Scope with Substituted Benzoquinones
On the basis of the results of the above control experiments
and substrate scope, especially when ortho-substituted phenyl-
acetylenes and 2-substituted benzoquinones were used, a
plausible mechanism is depicted as shown in Figure 2. These
a
All of the reactions were carried out using 0.5 mmol of 1, 3 equiv of
2′, and 10 mol % Pd(OAc)2 in DMSO (2 mL), at 100 °C for 12 h.
b
c
Isolated yields. In all cases 5−8% alkyne self-coupled product
isolated.
our delight, the reaction proceeded exclusively at the C5 and C6
positions of benzoquinone, but unfortunately, no product
corresponding to the C3 position was observed. Steric hindrance
by the C2 methyl group might be prohibit the reaction at the C3
position. Both regioisomeric benzofuran derivatives were
separated by column chromatography to afford 5a in 40% yield
and 5a′ in 32% yield, the structures of which were confirmed by
1H and 13C NMR spectroscopy and X-ray crystallography.21
Other substituted phenylacetylenes such as 4-Me and 4-Cl were
also well tolerated in reactions with 2-methylbenzoquinone, and
in both cases, the anticipated isomeric products 5b, 5b′ and 5c,
5c′ were obtained in good yields. However, naphthoquinone
failed to produce the expected product under optimized reaction
conditions.
Figure 2. Plausible reaction pathway.
results suggest that Pd(OAc)2 initially coordinates with
benzoquinone to form complex a. The triple bond of the alkyne
then coordinates to the palladium center of complex a, followed
by a direct deprotonation with the assistance of an acetate ligand
to generate alkynylpalladium complex b.22 The resulting
alkynylpalladium undergoes oxidative insertion followed by
reductive elimination to form a 2-ethynylphenylbenzoquinone
C
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intermediate. This intermediate again coordinates with the Pd
complex to generate complex c followed by aromatization to
form complex d. A second molecule of alkyne then coordinates
to the palladium center of complex d followed by a direct
deprotonation with the assistance of an acetate ligand to generate
complex e. After the formation of complex e, the desired product
3a is then produced, through either path A or path B, along with
the regeneration of the catalyst in the presence of benzoquinone.
In conclusion, a palladium-catalyzed benzoquinone C−H
functionalization/cyclization strategy using terminal alkynes was
employed for the synthesis of 2,3-disubstituted 5-hydroxybenzo-
furan derivatives by taking advantage of the dual role of
benzoquinone. The main challenge associated with the current
protocol, i.e., the tendency for the alkyne to undergo self-
coupling and the selection of an appropriate ligand, was
successfully overcome. Easily available starting materials, ligand
free, and a wide substrate scope makes this protocol potentially
very useful. Control experiments suggest that the benzofuran
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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.orglett.6b03310.
General experimental procedures and spectroscopic data
of all the compounds; 1H and 13C NMR spectral data for
representative compounds; X-ray crystallographic data for
3c, 5a and 5a′ (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cheyaocf@ntnu.edu.tw.
ORCID
Ching-Fa Yao: 0000-0002-8692-5156
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work by the Ministry of Science and
Technology of the Republic of China (MOST 103-2113M-003-
008-MY3) and National Taiwan Normal University (103-07-C).
The Instrumentation Centre at National Taiwan Normal
University is gratefully acknowledged. We are grateful to Mr.
Ting-Shen Kuo (X-ray), Ms. Hsiu-Ni Huan (HRMS), and Ms.
Chiu-Hui He (NMR) for providing the analysis data presented in
this paper.
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