Synthesis of poly-functionalized benzofurans: Via one-pot domino oxidation/[3+2] cyclization reactions of a hydroquinone ester and ynamides

Article abstract of DOI:10.1039/c9ra02144b

Densely substituted amino-functionalized benzofurans were concisely accessed via the first one-pot domino oxidation/[3+2] cyclization of a hydroquinone ester and easily accessible ynamides under mild conditions in a short time. The complex benzofurans wer

Full text of DOI:10.1039/c9ra02144b

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Synthesis of poly-functionalized benzofurans via
one-pot domino oxidation/[3+2] cyclization
reactions of a hydroquinone ester and ynamides†
Cite this: RSC Adv., 2019, 9, 12567
Dongxin Zhang, * Jingjing Man, Yan Chen, Lei Yin, Junchao Zhong
and Qian-Feng Zhang*
Received 20th March 2019
Accepted 15th April 2019
Densely substituted amino-functionalized benzofurans were concisely accessed via the first one-pot
domino oxidation/[3+2] cyclization of a hydroquinone ester and easily accessible ynamides under mild
conditions in a short time. The complex benzofurans were able to be efficiently synthesized all from
simple and inexpensive starting materials in two steps.
DOI: 10.1039/c9ra02144b
rsc.li/rsc-advances
Benzofuran derivatives are valuable structural motifs that are construction of amino-functionalized benzofurans from yna-
oen found in natural products and biologically active mides have not been reported. Therefore, we initiated our
1
compounds. Various methods have been developed for the design to access benzofuran derivatives via the [3+2] cycliza-
2
,3
synthesis of those heterocyclic scaffolds, among which the tions of ynamides with quinones. Quinones can be easily
intramolecular annulation of preformed ortho-alkynylated oxidized from hydroquinones, which provides the possibility for
phenols catalyzed by transition metals is the most general coupling the oxidation and cyclization into a one-pot domino
2
e–o
5,6b
way.
catalyzed tandem oxidative coupling and annulation process chose to optimize the cyclization step.
to access benzofurans from simple phenols and b-keto esters First, we started the investigation with ynamide 1a and
Scheme 1a), and the group of Dominguez disclosed a one- quinone 2a. Lewis acids have been reported as good activators
Recently, Li and coworkers reported a novel iron- process.
Before coupling the two steps together, we rst
3
a
(
pot approach to benzofurans from 2-hydroxybenzophenones
and N,N-dimethylacetamide promoted by copper under
3
b
oxidative conditions (Scheme 1b). Both of the two methods
provided direct access to benzofuran derivatives from simple
easy accessible starting materials under oxidative conditions,
but all the reactions were performed at high temperature and
with relatively high catalyst loading. Fast reactions under mild
conditions are undoubtedly more desirable. In this context,
we report the direct synthesis of densely substituted benzo-
furans from simple and inexpensive starting materials via the

rst one-pot domino oxidation/[3+2] cyclization of a hydro-
quinone derivative and ynamides under mild conditions
(
Scheme 1c).
Over the past decades, ynamides, as powerful synthons, have
been involved in the transition-metal catalyzed cyclization
reactions for the construction of diverse building blocks of
functionalized molecules including important pharmaco-
4
phores. Although various cyclic systems have been achieved via
4a–q
the reactions of ynamides,
to the best of our knowledge,
Institute of Molecular Engineering and Applied Chemistry, Anhui University of
Technology, No. 59 Hudong Road, Ma'anshan 243002, China. E-mail: dxzhang@
ahut.edu.cn; zhangqf@ahut.edu.cn
†
Electronic supplementary information (ESI) available: Experimental details,
characterization data of reactants and products, and copies of NMR
spectroscopy. See DOI: 10.1039/c9ra02144b
Scheme 1 Direct accesses to benzofuran derivatives under oxidative
conditions.
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6
,7a
of quinones.
However, by the use of Lewis acid Sc(OTf)
3
as equiv. to 1.2 equiv. did not affect the reaction efficiency and
the catalyst, there was no desired benzofuran product forma- product 3a was obtained in 90% yield (Table 1, entry 9). As
tion at all while the ynamide hydrolysis byproduct 4a formed expected, when excess amount of 1a was used, product 3a was
exclusively (Table 1, entry 1). Attempts by the addition of 4 A˚ formed along with small amount of 4a (Table 1, entry 10). The
molecular sieves and carrying out the reaction under inert catalyst loading could be reduced to 5 mol%, even 2 mol%
atmosphere suppressed the hydrolysis somehow with still no without signicant negative effect for the efficiency of the [3+2]
product formation (Table 1, entry 2). To overcome the low cyclization (Table 1, entries 11 and 12).
reactivity problem of 2a and the hydrolysis problem of 1a, we
With the best cyclization reaction conditions in hand, next
pursued to improve the reactivity of quinone by installing an we tried to combine the oxidation step with the [3+2] cyclization
5
a
ester group on the quinone ring, which may enhance its into a one-pot domino process. Hydroquinone ester 5 was rst
7
electrophilicity. Quinone ester 2b was easily synthesized via mixed with oxidant Ag O and MgSO in CH Cl and the mixture
2
4
2
2
oxidation of commercially available methyl 2,5-dihydrox- was stirred for 2 h. Then 1a and Sc(OTf) were directly added to
3
8,9
ybenzoate (5). Gratifyingly, the reaction of 1a with quinone the above mixture. To our delight, the one-pot domino
ester 2b catalyzed by Sc(OTf) afforded the desired [3+2] oxidation/[3+2] cyclization occurred efficiently, affording 3a in
3
cyclization product 3a in 89% yield within 5 min with only 91% yield (Table 1, entry 13). The one-pot process provided the
trace amount of hydrolysis product detected (Table 1, entry 3). densely substituted benzofuran (3a) in a step-economy manner.
By the use of Cu(OTf)
a and 2b afforded both 3a and 4a, in 61% and 18% yield process was employed (Scheme 2).
respectively (Table 1, entry 4). Yb(OTf)3 also catalyzed the In general, the reactions of 5 with a series of ynamides in the
reaction efficiently with small amount of 4a (4%) formation one-pot system afforded poly-substituted benzofurans 3 in good
Table 1, entry 5). Other Lewis acids, such as AlCl could to excellent yields (85–96%). Ynamides with both aromatic and
catalyze the reaction to afford 3a with no 4a formation though alkyl groups at the terminal position could be tolerated,
the efficiency is much lower than that of Sc(OTf) (Table 1, furnishing 3-aromatic or 3-alkyl substituted benzofurans with
entry 6). Screening of a small set of solvents indicated that high yields (Scheme 2). The reactions of alkyl-terminated yna-
CH Cl was the most suitable solvent for this [3+2] cyclization mides gave slightly higher yields than that of aromatic-
Table 1, entries 7 and 8). Reducing the amount of 2b from 1.5 terminated ones (3a, 3b vs. 3c; 3e vs. 3f; 3g vs. 3h). For
2
as the catalyst, in 5 min the reaction of Next, for the substrate scope exploration, the one-pot domino
1
(
3
3
2
2
(
a
Table 1 Optimization of the reaction conditions
b
b
Entry
1
Catalyst (10 mol%)
Solvent
R
Time
Yield (3a) [%]
Yield (4a) [%]
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
3
3
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
H
H
5 min
2 h
—
—
89
61
83
33
80
86
90f
88
91
88
91
91
33
c
2
3
4
5
6
7
8
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
2
2
2
2
2
2
2
2
2
2
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
5 min
5 min
5 min
30 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
Trace
18
Cu(OTf)
Yb(OTf)
AlCl
2
3
4
3
Trace
5
Trace
Trace
9
Trace
Trace
Trace
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
THF
PhMe
3
3
3
3
3
3
d
9
CH
CH
CH
CH
CH
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
e
10
11
12
13
d,g
d,h
d,h,i
a
Unless otherwise noted, reactions were carried out using ynamide 1a (0.10 mmol), 2 (0.15 mmol) with catalyst (0.01 mmol) in solvent 2.0 mL at
ꢀ
b
c
˚
d
room temperature (25 C) in air. Isolated yields relative to 1a.f 100 mg 4 A molecular sieves were added and under Ar atmosphere. 2b (0.12
e
g
h
mmol) was used. 1a (0.12 mmol), 2b (0.10 mmol) was used. Yield relative to 2b. Catalyst (0.005 mmol) was used. Catalyst (0.002 mmol)
i
was used. Hydroquinone ester 5 (0.12 mmol), Ag
2
4 2 2
O (0.24 mmol), and MgSO (0.24 mmol) were mixed in CH Cl (2.0 mL) and the mixture was
stirred for 2 h, and then 1a (0.10 mmol) and Sc(OTf)
3
(0.002 mmol) were added.
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Scheme 3 (a) Concise access to complex benzofurans from simple
and inexpensive starting materials. (b) A large scale reaction for the
synthesis of 3h.
quinone ester 2b, which is subsequently activated by Sc(OTf) .
3
4q
According to Johnson et al., ynamides may also be functioned
by the scandium Lewis acid to increase the nucleophilicity. A
undergoes nucleophilic attack by the ynamide to give keteni-
minium ion B. Then, 1,2-proton shi followed by the intra-
molecular cyclization of B furnishes intermediate C. Finally,
3
aer tautomerization and release of Sc(OTf) , desired product 3
is formed.
Scheme 2 Substrate scope of the one-pot domino oxidation/[3+2]
cyclization reaction. Reaction conditions: hydroquinone ester 5 (0.12
In summary, we have developed a fast and step-economical
one-pot domino oxidation/[3+2] cyclization reactions of
a hydroquinone ester and ynamides. A series of densely
functionalized benzofurans were concisely achieved in good to
excellent yields from simple and inexpensive starting mate-
rials under mild conditions. A gram scale reaction proved that
the one-pot reaction was able to be scaled up easily. Further
studies on the expansion of the reaction scope and on the
mmol), Ag
CH Cl (2.0 mL) and the mixture was stirred for 2 h, and then 1 (0.10
mmol) and Sc(OTf) (0.002 mmol) were added.
2 4
O (0.24 mmol), and MgSO (0.24 mmol) were mixed in
2
2
3
ynamides with sulfonyl system, the triisopropylsilyl-terminated
ynamide was successfully applied in the one-pot reaction, and
the desired product 3d was obtained in 85% yield. The reactions
of ynamides with propiolactam system also worked well to give
3e (85%) and 3f (91%). Ynamides derived from indole ester
reacted well with 5 in this one-pot system, giving rise to the
interesting 1-benzofuranyl indole derivatives (3g, 3h) in perfect
yields, 90% and 96% respectively.
It is worth to mention that ynamides (1) used here were all
easily prepared in one step via copper-catalyzed oxidative cross
coupling of corresponding simple amides and terminal
4
q,10
alkynes according to literature procedures,
which indicates
that the complex poly-functionalized benzofurans (3) were
able to be efficiently synthesized all from simple and inex-
pensive staring materials in only two steps (Scheme 3). A large
scale reaction was performed to synthesize 1-benzofuranyl
indole 3h. Starting from simple commercial available 1-hep-
tyne, methyl indole-3-carboxylate, and methyl 2,5-dihydrox-
ybenzoate (5), 1.64 g of 3h was obtained in two steps with high
efficiency (Scheme 3b).
The postulated mechanisms resulting in the formation of
densely substituted benzofurans 3 are proposed as shown in
Scheme 4 Proposed mechanism for the one-pot domino oxidation/
2
Scheme 4. Hydroquinone 5 is rst oxidized by Ag O to give [3+2] cyclization.
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construction of other heterocycles based on the domino
strategy used in this study are ongoing and will be reported in
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Acknowledgements
This study was supported by Anhui Provincial Natural Science
Foundation (No. 1908085MB33) and the Anhui University of
Technology.
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9 MgSO
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was used to absorb water generated from the
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excess amount of MgSO4 may help to attenuate the
hydrolysis of the ynamide.
8
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