Cascade Claisen and Meinwald Rearrangement for One-Pot Divergent Synthesis of Benzofurans and 2 H-Chromenes

Article abstract of DOI:10.1021/acs.orglett.0c00770

A new cascade approach has been developed for the one-pot four-step divergent synthesis of polysubstituted benzofurans and 2H-chromenes, featuring a novel cascade aromatic Claisen rearrangement/Meinwald rearrangement/dehydrative or oxidative cyclization. This new method was demonstrated with 39 examples tolerating different substitutions at an epoxide, allylic ether, and aromatic ring, and we showcased its utility with the first total synthesis of natural product liparacid A in seven steps.

Full text of DOI:10.1021/acs.orglett.0c00770

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Letter
Cascade Claisen and Meinwald Rearrangement for One-Pot
Divergent Synthesis of Benzofurans and 2H‑Chromenes
Liyan Song,* Qian Su, Xi Lin, Zhihui Du, Huiyou Xu, Ming-An Ouyang, Hongliang Yao,
and Rongbiao Tong*
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ABSTRACT: A new cascade approach has been developed for the
one-pot four-step divergent synthesis of polysubstituted benzofur-
ans and 2H-chromenes, featuring a novel cascade aromatic Claisen
rearrangement/Meinwald rearrangement/dehydrative or oxidative
cyclization. This new method was demonstrated with 39 examples
tolerating different substitutions at an epoxide, allylic ether, and
aromatic ring, and we showcased its utility with the first total synthesis of natural product liparacid A in seven steps.
enzofurans and 2H-chromenes (2H-1-benzopyrans) are
two classes of heteroarenes of pharmaceutical importance
and regarded as privileged scaffolds in medicinal chemistry due
to their unique physicochemical properties.1 Selected examples
are presented in Figure 1, which shows that benzofurans and
particular for substitution at the benzene ring. Herein, we
report the development of a new cascade process that allows
for expedite access to not only 7-allyl benzofurans but also 8-
(β-keto)alkyl 2H-chromenes.
B
Recently, we developed a new cascade reaction for the
synthesis of 2H-chromenes.5 The key cascade process was
believed to involve aromatic Claisen rearrangement, in situ
generation of ortho-quinone methides (o-QM) via 1,6-
elimination of HOAc, and 6π-electrocyclization (Scheme 1a).
We hypothesized that if an epoxide group was preinstalled to
the benzylic position (Scheme 1b), a new cascade involving
aromatic Claisen rearrangement6/Meinwald rearrangement7
with R2 migration would deliver the flanked substituted phenol
intermediate that might undergo either dehydrative (Burgess8)
or oxidative (DDQ9) cyclization to 7-allyl benzofurans and 8-
(β-keto)alkyl 2H-chromenes, respectively. Notably, such site
substitution has rarely been addressed by prior synthetic
methodologies.
Our study began with examination of the heating conditions
(Table 1) to initiate the proposed cascade process using
compound 1a as the model substrate (the synthesis of 1a was
provided in the Supporting Information (SI)). A survey of
different solvents was first conducted, and both toluene and
xylene were found to be suitable (entries 2−3) to give the key
intermediate 2a, probably owing to their high boiling points
required for the thermo-promoted Claisen−Meinwald rear-
rangement. Lower temperature cannot initiate the desired
reaction (entry 1), and higher temperature would slightly
Figure 1. Selected examples of benzofurans and 2H-chromenes with
biological activity.
2H-chromenes have a wide range of applications including
insecticides, pesticides, antidiabetics, and antibacterial and
anticancer drugs.2 In addition, 2H-chromenes are a core
structural framework of many bioactive natural products.3 The
medicinal importance of benzofurans and 2H-chromenes has
aroused great interest from the synthetic community in
developing new and improved synthetic methods,4 which
have tremendously advanced the development of benzofuran-
and 2H-chromene-containing drugs. Nevertheless, the efficient
synthesis of polyfunctionalized benzofurans and 2H-chromenes
continues to be important and remains challenging, in
Received: February 28, 2020
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© XXXX American Chemical Society
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A

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involved acid-catalyzed reactions and resulted in a mixture of
unknown products. We then tried to use MsCl/DBU to trap
the cyclic hemiketal that was believed to be in equilibrium with
the keto-ol form (2a). It was very encouraging with 54% yield
of 3a (entry 11). Finally, we found Burgess reagent8 was better
for dehydration (79%yield, entry 12) and could be added
before heating (84%, entry 13). This greatly simplified the
operation (a mixture of epoxide substrate and Burgess reagent
in toluene was heated to reflux for 30 min) and constitutes a
new, unique one-pot four-step reaction.
Scheme 1. Our Previous Synthesis of 2H-Chromenes and
This Work
With the optimized conditions in hand, the substrate scope
was then examined and presented in Scheme 2. A series of
substrates (1a−1z) were prepared by using the modified
literature protocols (see SI for details). As depicted in Scheme
2, C2- (and C5-) substituted benzofurans (3a−3i) could be
efficiently prepared by using the one-pot cascade reaction from
1,2-trans-disubstituted epoxide substrates (1a−1i) bearing
a
Scheme 2. Substrate Scope
Table 1. Selected Conditions for the One-Pot Claisen
Rearrangement/Meinwald Rearrangement/Dehydrative
Cyclization
a
b
entry
solvent
temp (°C, time)
additive
Yield (%, 2a/3a)
1
2
3
4
5
6
7
8
9
10
11
12
13
PhH
80 (30 min)
110 (30 min)
140 (30 min)
180 (30 min)
180 (2 h)
110 (30 min)
110 (30 min)
110 (30 min)
110 (30 min)
110 (30 min)
110 (30 min)
110 (30 min)
110 (30 min)
−
−
−
−
−
H3PO4
HCl
TFA
TsOH
A-15
<5 (1/0)
80 (1/0)
78 (1/0)
71 (1/0)
38 (1/2)
0
PhMe
xylene
DCB
DCB
c
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
c
0
0
c
c
23 (0/1)
32 (0/1)
54 (0/1)
79 (0/1)
84 (0/1)
c
d
MsCl/DBU
Burgess
Burgess
e
f
a
Condition: 1a (0.2 mmol), solvent (4 mL), nitrogen atmosphere,
b
c
reflux, 30 min. Isolated yields. Cooled to rt, 0.2 equiv of acid was
added. Cooled to rt, 1.2 equiv of DBU and 1.1 equiv of MsCl were
added. Cooled to rt, 1.1 equiv of Burgess reagent was added and
heated to reflux for 30 min. Burgess reagent was added prior to the
d
e
f
cascade reaction. DCB: 1,2-dichlorobenzene. DBU: 1,8-diazabicyclo-
[5.4.0]undec-7-ene. A-15: Amberlyst 15 hydrogen form (polystyrene-
based ion-exchange resin with strongly acidic sulfonic group).
erode the yield (entry 4). We found that extended time at
elevated temperature would result in partial dehydration to
benzofuran 3a, though the overall yield was not satisfactory
(entry 5). After the cascade Claisen and Meinwald rearrange-
ment was completed, we attempted to add an acid to activate
the carbonyl group for the well-established ketalization−
dehydration sequence10 (entries 6−10). Unfortunately, no
dehydration was observed at room temperature when 0.2 equiv
of H3PO4, HCl, or CF3CO2H was used (entries 6−8), while p-
toluenesulfonic acid or amberlyst-15 gave only low yields (23−
32%, entries 9−10). This “unexpected” difficulty may be
attributed to the presence of the acid-labile prenyl group that
a
Condition: epoxide (0.2 mmol), Burgess reagent (0.22 mmol),
toluene (4 mL), nitrogen atmosphere, reflux, 30 min. Isolated yields
are shown. 1,2-Dichlorobenzene as the solvent. Remove solvent,
toluene (4 mL), Burgess reagent (0.22 mmol), nitrogen atmosphere,
reflux, 30 min. Isolated yields are shown. Containing inseparable
b
c
impurities.
B
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different substituents (R1) on the epoxide in 46−93% yields.
Alkyl or phenyl substituents (R1) would result in good to
excellent yields (3a−3d), and the electron-rich and electron-
withdrawing substituents (R) on the aromatic ring had little
effect on the reaction yields (3h−3i). However, alkenyl or
benzoyl substituents (R1) would lead to slightly lower yields
(3e−3g). The sharp contrast of yields between 3e and 3f,
whose chemical structures are similar, did exist and might be
due to the increased steric effect on the carbonyl group during
the subsequent cyclization. The cascade reaction of terminal
epoxide substrates (1j−1m) afforded the corresponding
benzofurans (3j−3m) in good to excellent yields. The
electron-rich and electron-withdrawing substituents (R) on
the aromatic ring did not seem to greatly influence the reaction
yields. The 1,1-disubstituted epoxide substrates (1n−1o)
delivered the C3-substituted benzofurans in good to excellent
yields (3n−3o). Then we examined the trisubstituted epoxide
substrates. It was notable that R2 (methyl or phenyl) migrated
to the benzylic position to provide the C2- and C3-
disubstituted benzofurans (3p−3q). Interestingly, the phenyl
group, not the methyl group, was found to involve the
migration in the Meinwald rearrangement. Importantly, these
two examples substantiated the Meinwald rearrangemnt and
excluded the possible 1,5-H/alkyl migration in our system.
When the cyclic epoxides (1r−1t) were used, the cascade one-
pot four-step reaction furnished polycyclic benzofurans (3r−
3t) in excellent yields.
Scheme 3. Cascade Claisen Rearrangement/Cope
Rearrangement/Meinwald Rearrangement/Dehydration to
a
Benzofurans
a
Condition: epoxide (0.2 mmol), 1,2-dichlorobenzene (4.0 mL),
nitrogen atmosphere, reflux, 30 min. Remove solvent, toluene (4.0
mL), Burgess reagent (0.22 mmol), nitrogen atmosphere, reflux, 30
min. Isolated yields are shown.
Scheme 4. Cascade Claisen Rearrangement/Meinwald
Rearrangement/Oxidative Oxa-6π-electrocyclization to 2H-
a
Chromenes
Next, we came to examine the allyl scope of substrates
(Scheme 2). The R4−R7 substitution on the allyl groups did
not significantly erode the yields of cascade reactions (3a, 3u−
3x, 3z). However, a lower yield was observed when R6 was not
hydrogen (3y), which might be due to the negative steric effect
on the Claisen rearrangement. The alkene geometry of 3x was
determined by the large coupling constant of the trans-alkene
protons. Note that ca. 8% unidentified impurities could not be
separated from 3w, although many efforts had been made.
In order to further expand the substrate scope and provide
expedited access to aromatic C5 substituted benzofurans, we
envisioned that if there was a non-hydrogen substituent at C7,
the para Claisen rearrangement (or Claisen−Cope rearrange-
ment11) might occur and the subsequent Meinwald rearrange-
ment would generate the requisite intermediate for the
cyclization−dehyration sequence, providing otherwise poorly
accessible benzofurans with substitutions at both C5 and C7.
To test this idea, we synthesized a small series of substrates
(3aa−3ac) with C7 substitution and examine the cascade
process (Scheme 3). It was found that the nature of the C7
substituent would have a significant influence on the reaction.
For example, the cascade reaction of compound 1aa with
fluoride at C7 gave 3aa in 52% yield, while substrates (1ab−
1ac) with the carbon-based substituents (methyl, prenyl) at C7
smoothly underwent the cascade reaction to furnish benzofur-
ans (3ab−3ac) in excellent yields. Notably, 3ac exhibited
abnormal chemoselectivity, because the allyl group, not the
preinstalled prenyl group at C7, participated in the second
Cope rearrangement. This observation was consistent with our
previous report.5
a
Condition: epoxide (0.2 mmol), DDQ (0.22 mmol), toluene (4
mL), nitrogen atmosphere, reflux, 30 min. Isolated yields are shown.
expand the utility of the newly discovered cascade Claisen−
Meinwald rearrangement to access polyfunctionalized 2H-
chromenes. To our delight, the mixture of substrate 1a and
DDQ9 in toluene under reflux conditions afforded the desired
2H-chromene 4a in excellent yield (Scheme 4a) and DDQ did
not seem to negatively affect the cascade Claisen rearrange-
ment/Meinwald rearrangement. The substrate scope was
examined briefly and presented in Scheme 4b. Alkyl or phenyl
substituents (R1) were well tolerated, and the corresponding
substituted 2H-chromenes were isolated in good to excellent
yield (4a−4b, 4e−4g), while alkenyl substituents (R1) would
erode the reaction yields (4h−4i). The presence of the methyl
group in 4i showed a negative steric effect and lowered the
reaction yield. The electronegativity or the position of
substituents on the aromatic ring had little effect on the
To further exploit highly functionalized intermediate 2a
from the new cascade Claisen and Meinwald rearrangement,
we conceived that 2a might undergo oxidative oxa-6π-
electrocyclization to deliver 2H-chromenes if an appropriate
oxidant could be identified to generate the ortho-quinone
methide (o-QM)12 (Scheme 4). This would considerably
C
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reaction yields (4c−4d, 4j). Notably, CuI-catalyzed Ullmann-
type C−O bond formation13 could be used to elaborate 2H-
chromene 4j to the tricyclic hybrid benzofuran-2H-chromene
4k (Scheme 4c).
Finally, we showcased the utility of this new cascade process
by the first total synthesis of the scarce natural product
liparacid A (11). Liparacid A14 was isolated in 2007 from the
rhizoma of Liparis nakaharai, which has been used in Chinese
folk medicine for the treatment of cancer. As depicted in
Scheme 5, our synthesis commenced with synthesis of aryl
AUTHOR INFORMATION
Corresponding Authors
■
Liyan Song − Key Laboratory of Biopesticide and Chemical
Biology (Ministry of Education), College of Plant Protection,
Fujian Agriculture and Forestry University, Fuzhou, Fujian
350002, China; Email: songliyan@fafu.edu.cn
Rongbiao Tong − Department of Chemistry, The Hong Kong
University of Science and Technology, Kowloon, Hong Kong,
China; orcid.org/0000-0002-2740-5222; Email: rtong@
ust.hk
Scheme 5. Total Synthesis of Liparacid A
Authors
Qian Su − Key Laboratory of Biopesticide and Chemical Biology
(Ministry of Education), College of Plant Protection, Fujian
Agriculture and Forestry University, Fuzhou, Fujian 350002,
China
Xi Lin − Key Laboratory of Biopesticide and Chemical Biology
(Ministry of Education), College of Plant Protection, Fujian
Agriculture and Forestry University, Fuzhou, Fujian 350002,
China
Zhihui Du − Key Laboratory of Biopesticide and Chemical
Biology (Ministry of Education), College of Plant Protection,
Fujian Agriculture and Forestry University, Fuzhou, Fujian
350002, China
Huiyou Xu − Key Laboratory of Biopesticide and Chemical
Biology (Ministry of Education), College of Plant Protection,
Fujian Agriculture and Forestry University, Fuzhou, Fujian
350002, China
Ming-An Ouyang − Key Laboratory of Biopesticide and
Chemical Biology (Ministry of Education), College of Plant
Protection, Fujian Agriculture and Forestry University, Fuzhou,
Fujian 350002, China
Hongliang Yao − Guangdong Key Laboratory of Animal
Conservation and Resource Utilization, Guangdong Public
Laboratory of Wild Animal Conservation and Utilization, Drug
Synthesis and Evaluation Center, Guangdong Institute of
Applied Biological Resources, Guangzhou, Guangdong 510260,
China
propargyl ether 6 by CuI-catalyzed etherification15 of 4-
bromosalicylaldehyde (5) in 88% yield. Lindlar reduction16 of
6 (97% yield) and subsequent Corey−Chaykovsky reaction17
provided the epoxide 8 in 80% yield over two steps. The
desired 2H-chromene core system 9 was obtained from 8 via
our new cascade approach on a 2.0 mmol scale with a 45%
overall yield. A conventional three-step sequence involving
Luche reduction18 of ketone 9 (96%), formylation (79%), and
Kraus−Pinnick oxidation (87%)19 furnished Liparacid A (11).
All spectroscopic data for our synthetic sample were well in
agreement with those reported for the natural Liparacid A.
In summary, we have developed a new cascade strategy for
the one-pot four-step divergent syntheses of otherwise more
difficult to access substituted benzofurans and 2H-chromenes
with high efficiency. The new cascade processes involved either
aromatic Claisen rearrangement−Meinwald rearrangement−
cycloketalization−dehydration or aromatic Claisen rearrange-
ment−Meinwald rearrangement−o-quinone methide forma-
tion−oxa-6π-electrocyclization. The new cascades were illus-
trated with 39 examples and employed as the key strategy for
the first total synthesis of natural product liparacid A (seven
steps). We believe that this new synthetic approach is
complementary to the prior synthetic methods and will find
wide application for the synthesis of polysubstituted
benzofurans and 2H-chromenes, in particular with substituents
at C7 or C8.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00770
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by National Natural
Science Foundation of China (NSFC 21502018), Fujian
Agriculture and Forestry University Foundation for Distin-
guished Young Scholars (XJQ201623), the Foundation of Key
Laboratory of Biopesticide and Chemical Biology (Key-
lab2019-03), Guangdong Academic of Sciences Special Project
of Science and Technology Development (2016GDASRC-
0104), and Research Grant Council of Hong Kong (GRF
16311716, 16303617, and 16304618).
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00770.
■
■
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