Diphenyl-Diselenide-Mediated Domino Claisen-Type Rearrangement/Cyclization of Propargylic Aryl Ethers: Synthesis of Naphthofuran-2-carboxaldehyde Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b02942

A diphenyl-diselenide-mediated Claisen-type rearrangement/cyclization of propargylic aryl ethers under metal-free conditions is developed, affording various naphthofuran-2-carboxaldehydes in moderate to excellent yield. The broad substrate scope and excel

Full text of DOI:10.1021/acs.orglett.9b02942

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diphenyl-Diselenide-Mediated Domino Claisen-Type
Rearrangement/Cyclization of Propargylic Aryl Ethers: Synthesis of
Naphthofuran-2-carboxaldehyde Derivatives
Jun-Dan Fang,†,§ Xiao-Biao Yan,‡,§ Wu-Jie Lin,† Yi-Chuan Zhao,† and Xue-Yuan Liu*,†
†State Key Laboratory of Applied Organic Chemistry (SKLAOC), College of Chemistry and Chemical Engineering, Lanzhou
University, 222 South Tianshui Road, Lanzhou 730000, China
‡School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China
S
* Supporting Information
ABSTRACT: A diphenyl-diselenide-mediated Claisen-type
rearrangement/cyclization of propargylic aryl ethers under
metal-free conditions is developed, affording various naph-
thofuran-2-carboxaldehydes in moderate to excellent yield.
The broad substrate scope and excellent functional group
compatibility suggest that it can be a straightforward and
powerful method to access naphthofuran-2-carboxaldehydes in
a highly regioselective manner. Moreover, this reaction can be
scaled up to the gram scale.
enzofuran scaffolds are a basic and valuable structural
Scheme 1. Strategies for the Construction of Naphthofuran
Skeleton
B
skeleton in natural products.1 Among them, naphthofuran
and its derivatives, such as ( )-laevigatin, (+)-heritol, and
furomollugin, represent an important class of biological active
compounds due to their significant pharmacological properties
(Figure 1).2 Accordingly, it is of urgent desire to develop a new
Figure 1. Naphthofuran-containing biologically active compounds.
strategy to synthesize naphthofurans. In general, the intra-
molecular cyclization of 2-alkenylphenols catalyzed by
transition metals (e.g., Pd, Cu, Co)3a−d or promoted by
stoichiometric amounts of I2,3e PhI(OAc)2,3f and Ag2O3g is a
commonly used method to construct the benzo(naphtho)furan
cores. In 2016, an elegant work was developed through an
intermolecular reaction of naphthols with terminal alkynes in
the presence of a catalytic amount of BF3·Et2O (Scheme 1a).4
Additionally, the Claisen-type rearrangement of naphthyl-
substituted propargylic ethers has been a straightforward
method to build naphthofurans, but it usually requires a high
temperature or the assistance of microwave irradiation
(Scheme 1b).5 Very recently, a FeCl3-catalyzed Claisen
rearrangement/aerobic dehydrogenative cyclization of allenyl-
Received: August 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02942
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
methyl ether has been reported by Jiang and coworkers
(Scheme 1c).6 Despite these formidable advances, the
development of an efficient method to access functionalized
benzo(naphtho)furans under mild conditions is still in highly
demand but remains a challenge.
Table 1. Optimization of Reaction Conditions
Over the past decade, the domino or cascade reaction has
become a powerful and ingenious strategy for the synthesis of
natural products or complex compounds.7 It has shown
undeniable advantages, including extensive functional group
compatibility and the economies of labor and cost. As part of
our ongoing interest in the transformation of propargylic aryl
ethers,8 we anticipated that the construction of naphthofuran-
2-carboxaldehydes would be realized by the following domino
process: propargylic C−H selenylation, Claisen-type rearrange-
ment, cyclization reaction, and the formation of aldehyde.
Although the organic diselenide has been extensively used in
the synthesis of organoselenium compounds,9 it has rarely
been reported as a reaction promoter for the construction of an
aldehyde or other functional groups. Herein we report a
diphenyl-diselenide-mediated Claisen-type rearrangement/cyc-
lization cascade strategy for the synthesis of naphthofuran-2-
carboxaldehyde derivatives (Scheme 1d). To the best of our
knowledge, this reaction represents the first highly regiose-
lective domino procedure to construct naphthofuran-2-
carboxaldehydes.
We started our investigation by using 2-((3-phenylprop-2-
yn-1-yl)oxy)naphthalene (1a) as the model substrate and
performing the reactions in CH3CN at 80 °C under an argon
atmosphere. To our delight, the desired product (2a) was
obtained in 83% yield when diphenyl diselenide and TBHP
(tert-butyl hydroperoxide, 5.0 to 6.0 M in decane) were used
(Table 1, entry 1). No desired product was observed in the
absence of diphenyl diselenide or TBHP. These results
indicated that diphenyl diselenide and oxidant were crucial
for this reaction. Screening of the solvents revealed that
CH3NO2 was the optimal solvent (Table 1, entries 2−8). The
effects of different oxidants were also tested (Table 1, entries
9−14). A slightly better yield (92%) was achieved when H2O2
(30% in water, w/w) was used (Table 1, entry 14). Further
optimization of reaction temperature has shown that the
reaction at 80 or 100 °C gave the best results (Table 1, entries
15−17). Changing the loading of H2O2 or diphenyl diselenide
has failed to increase the yield efficiently (Table 1, entries 18−
21). Therefore, the reaction conditions of entry 14 in Table 1
were used as the standard conditions of this transformation.
With the optimized reaction conditions in hand, we then
studied the reactions with respect to the scope of propargylic
aryl ethers derived from β-naphthol (Scheme 2). The steric
hindrance and electronic effect did not affect the efficiency of
this transformation, and a variety of naphthofuran-2-carbox-
aldehyde derivatives were obtained in good to excellent yield
(2a−v).10 Notably, a gamut of functionalities such as halogen
(−F, Cl, Br), methoxyl, aldehyde, ester (−CO2Me, CO2Et),
and strong electron-withdrawing groups (−CF3, CN, NO2)
were well-tolerated. For disubstituted aryl groups attached to
the triple bond, the diphenyl-diselenide-promoted reaction
system was also efficient, affording the desired products with
good yields (2w−ab). In addition, substrates containing the
naphthalene, thiophene, and pyridine groups (1ac−ae) could
also smoothly transform into the naphthofuran-2-carboxalde-
hydes (2ac−ae) in moderate to excellent yield. The reaction
could be scaled up to the gram scale and produced 2a in 87%
yield under the optimal conditions.
b
entry
oxidant
TBHP
solvent
T (°C)
yield (%)
c
d
1
2
3
4
5
6
7
8
CH3CN
DCE
toluene
THF
CH3OH
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
40
60
100
80
80
80
80
83, 0, 0
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
K2S2O8
DCP
BPO
PhI(OAc)2
H2O2
H2O2
H2O2
9
23
11
0
0
DMSO
trace
87
0
0
0
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
9
10
11
12
13
14
15
16
17
18
19
20
21
72
48
92
e
74
e
81
H2O2
H2O2
H2O2
H2O2
92
f
85
g
89
68
h
i
H2O2
93
a
Reaction conditions: 1a (0.2 mmol scale), diphenyl diselenide, and
oxidant (4.0 equiv) in solvent (2.0 mL) were stirred at 80 °C for 1 h
under an argon atmosphere. Isolated yields. In the absence of
diphenyl diselenide. In the absence of TBHP. Reaction time: 8 h.
H2O2 (2.0 equiv) was used. H2O2 (3.0 equiv) was used. Diphenyl
diselenide (0.6 equiv) was used. Diphenyl diselenide (1.2 equiv) was
used.
b
c
d
e
f
g
h
i
Next, we explored the compatibility of propargylic aryl
ethers derived from various naphthols (Scheme 3). Propargylic
ethers derived from β-naphthols tethered with functional
groups, including bromide (2af, 2ak), alkoxyl (2ai, 2aj),
aldehyde (2ag), and ester (2ah), furnished the corresponding
products in good yield. α-Naphthyl-substituted propargylic
ethers were also the efficient substrates whereby the
corresponding naphthofuran-2-carboxaldehydes could be iso-
lated in good yield (2al−an).10 The propargylic phenyl ether
(1ao) was less effective than naphthyl ones, and benzofuran-2-
carboxaldehyde (2ao) was obtained in 32% yield.11 One
possible reason is that unlike the naphthyl-based substrates
with the π-extended system, the intermediate from the phenyl
substrate might be unstable because the dearomatization of
phenyl might have occurred in the process of the Claisen-type
rearrangement.5,6
To illuminate the reaction mechanism of this trans-
formation, several control experiments were carried out
(Scheme 4). The reaction was inhibited in the presence of a
radical inhibitor such as TEMPO, BHT, or 1,1-diphenyl-
ethylene (Scheme 4a). The radical trapping product 3 was
obtained in 47% isolated yield. These results indicated that a
radical process might be involved in this transformation.
Furthermore, we tried to track the reaction process. It is worth
pointing out that compound 4 was isolated when the reaction
was stirred for 6 min under standard conditions (Scheme 4b).
B
DOI: 10.1021/acs.orglett.9b02942
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Organic Letters
Letter
Scheme 2. Scope of β-Naphthyl-Substituted Propargylic
Ethers
Scheme 4. Mechanism Studies
a
intermediate 4 is formed from C or C′ through hydrogen
abstraction and intramolecular cyclization. Finally, the desired
product is obtained under oxidative conditions.
In conclusion, we have developed a diphenyl-diselenide-
promoted Claisen-type rearrangement/cyclization domino
reaction, which affords various naphthofuran-2-carboxaldehyde
derivatives in moderate to excellent yield from propargylic aryl
ethers under metal-free conditions. The broad substrate scope
and excellent functional group compatibility of this method
suggest that it can be a straightforward and powerful alternative
to the established methodologies for the synthesis of
benzo(naphtho)furan-2-carboxaldehydes.
a
b
Reaction conditions: See Table 1, entry 14. Isolated yields. 4.0
mmol scale.
Scheme 3. Scope of Propargylic Aryl Ethers Derived from
Various Naphthols
a
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.9b02942.
Experimental procedures, characterization data, and
NMR spectra (PDF)
Accession Codes
CCDC 1943585 and 1943766 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
Reaction conditions: See Table 1, entry 14. Isolated yields.
Additionally, when the reaction finished, compound 4 had
disappeared and 2a was obtained in excellent yield. According
to this result, we suggest that compound 4 might be the
possible intermediate of this reaction.
On the basis of the above control experiments and previous
reports,5,9f,l,n−q a plausible mechanism was proposed (Scheme
4c). Initially, intermediate B might be formed through
propargylic C−H selenylation.8b Subsequently, intermediate
B undergoes the Claisen-type rearrangement to give C, which
can be isomerized to naphthol derivatives C′. Then,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuxuey@lzu.edu.cn
ORCID
Xue-Yuan Liu: 0000-0002-8862-9924
Author Contributions
§J.-D.F. and X.-B.Y. contributed equally.
C
DOI: 10.1021/acs.orglett.9b02942
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Financial support from the Natural Science Foundation of
China (21871115) is gratefully acknowledged.
■
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DOI: 10.1021/acs.orglett.9b02942
Org. Lett. XXXX, XXX, XXX−XXX