Acid-Catalyzed Ring-Opening Cyclization of Spirocyclopropanes for the Construction of a 2-Arylbenzofuran Skeleton: Total Synthesis of Cuspidan B

Article abstract of DOI:10.1055/s-0035-1561590

Acid-catalyzed ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes under metal-free conditions proceeded smoothly at room temperature to provide 2-aryl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-ones in excellent yields without the formation

Full text of DOI:10.1055/s-0035-1561590

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
A
special topic
H. Nambu et al.
Special Topic
Synthesis
Acid-Catalyzed Ring-Opening Cyclization of Spirocyclopropanes
for the Construction of a 2-Arylbenzofuran Skeleton: Total Syn-
thesis of Cuspidan B
Hisanori Nambu*
Naoki Ono
O
O
OH
cat. TsOH
CH2Cl2
2
Ar
Ar
Ar
Takayuki Yakura*
[R = H]
O
O
O
oxidation
ring-opening
cyclization
R
R
R
Graduate School of Medicine and Pharmaceutical Sciences,
University of Toyama, Sugitani, Toyama 930-0194, Japan
nambu@pha.u-toyama.ac.jp, yakura@pha.u-toyama.ac.jp
8 examples
2-arylbenzofuran
OH
OH
Efficient synthetic method
· excellent yields: 93–98%
· an easily handled and cheap catalyst: TsOH
· mild conditions: at room temperature
· short reaction times: 1–2.5 h
O
cuspidan B
OH
Received: 30.01.2016
Accepted after revision: 01.03.2016
Published online: 05.04.2016
OH
OH
OH
H3C
OH
CH3
OCH3
DOI: 10.1055/s-0035-1561590; Art ID: ss-2016-c0077-op
O
O
OH
cuspidan B (1)
Abstract Acid-catalyzed ring-opening cyclization of cyclohexane-1,3-
dione-2-spirocyclopropanes under metal-free conditions proceeded
smoothly at room temperature to provide 2-aryl-3,5,6,7-tetrahydro-1-
benzofuran-4(2H)-ones in excellent yields without the formation of 3-
substituted isomers. The obtained product was converted into a 2-aryl-
benzofuran derivative via a synthetically useful 2-aryl-2,3-dihydroben-
zofuran intermediate. Furthermore, the first total synthesis of cuspidan
B was achieved by using the present method.
stemofuran E
OH
OH
OCH3
OH
O
HO
O
HO
OH
regiafuran A
cathafuran B
Key words cyclopropanes, benzofurans, natural products, ring open-
H3CO
ing, cyclization, total synthesis
OH
O
HO
The 2-arylbenzofuran skeleton is present in a wide
range of biologically active natural products, including cus-
pidan B (1),1 stemofuran E,2 regiafuran A,3 cathafuran B4
and addisofuran B5 (Figure 1), and in pharmaceutically ac-
tive compounds.6 Consequently, much effort has been de-
voted to the synthesis of 2-arylbenzofuran derivatives.7,8
However, a general and practical method has not yet been
established. Many of the reported approaches are based on
transition-metal-catalyzed reactions.7 However, because
such reactions often suffer from drawbacks such as the ne-
cessity to use harsh conditions and the generation of toxic
heavy metal waste that is expensive to remove during the
production of pharmaceutically active ingredients, the de-
velopment of a simple, flexible and non-metal method for
the synthesis of 2-arylbenzofurans is highly desirable.8
Cyclopropanes represent versatile synthetic intermedi-
ates because of their high reactivity arising from their
strong ring strain.9 Doubly activated cyclopropanes have
been extensively investigated for their use in the synthesis
of a variety of carbo- and heterocyclic compounds.10 On the
other hand, spirocyclopropanes have rarely been synthe-
sized and utilized in synthetic organic chemistry despite
addisofuran B
Figure 1 Structures of cuspidan B (1), stemofuran E, regiafuran A,
cathafuran B, and addisofuran B
their high potential for the construction of bicyclic com-
pounds. We recently reported a simple preparation of cy-
clohexane-1,3-dione-2-spirocyclopropanes 4 from 1,3-cy-
clohexanediones 2 with (1-aryl-2-bromoethyl)dimethylsul-
fonium bromides 3 in the presence of powdered potassium
carbonate11 and a novel ring-opening cyclization with pri-
mary amines to generate tetrahydroindol-4-ones 5, one of
which was easily converted into 4-hydroxyindole 6 by a
stepwise oxidation via 4-hydroxyindoline (Scheme 1, A).12
This sequential protocol provides a new method for the
synthesis of 4-hydroxyindoles and is the first example of
the construction of an indole skeleton using spirocyclopro-
pane 4. The reaction of 4 with a primary amine proceeded
at room temperature without any additives, in contrast to
similar reactions of non-spirocyclopropanes. In other
words, the spirocyclopropanes 4 show a higher reactivity
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
H. Nambu et al.
Special Topic
Synthesis
than the non-spiro compounds. This high reactivity of spi-
rocyclopropanes stimulated us to investigate further devel-
opment of the reaction using spirocyclopropanes 4. Herein,
we report a new ring-opening cyclization of 1-aryl-
spiro[2.5]octane-4,8-diones 4 with an acid to form 2-aryl-
3,5,6,7-tetrahydro-1-benzofuran-4(2H)-ones 7,13–15 which
lytic amount of trifluoroacetic acid (TFA) did not reach
completion even after 24 h and gave 7a in 53% yield along
with the recovered starting material 4a in 21% yield
(entry 6). Although the Lewis acid catalysts BF3·OEt2,
TMSOTf, Sc(OTf)3, and MgI2 were effective for the present
reaction (entries 1–4), our efforts focused on the use of
conveniently handled and inexpensive TsOH·H2O.
can be converted into 2-aryl-4-hydroxybenzofuran
8
(Scheme 1, B). The first total synthesis of cuspidan B (1) was
achieved by using this procedure.
Table 1 Ring-Opening Cyclization of Spirocyclopropane 4a with a Cat-
alytic Amount of Activator
A. Previous work: Preparation and ring-opening cyclization of
spirocyclopropanes 4 to construct an indole skeleton
O
O
activator
(0.1 equiv)
O
Br
Br
O
S
powdered
K2CO3
2
Ph
Ph
CH2Cl2
r.t.
+
O
Ar
O
EtOAc
4a
O
O
7a
R2
R1
R1
74–94%
2
3
4
R2
Yield (%)a
Ar =
Entry
Activator
Time (h)
1
2
3
4
5
6
BF3·OEt2
TMSOTf
Sc(OTf)3
MgI2
1
1.2
1.5
1
98
98
98
95
98
53b
O
OTBS
4
oxidation
R3NH2
2
Ar
Ph
THF, r.t.
R1 = H
R2 = H
R3 = Bn
N
N
Bn
R1
R3
5
6
TsOH·H2O
TFA
1
up to 98% yield
24
B. This work: Ring-opening cyclization of spirocyclopropanes 4
to construct a benzofuran skeleton
a Isolated yield.
b The starting material 4a was recovered in 21% yield.
OR4
O
O
oxidation
R1 = H
activator
By using TsOH as an acid catalyst, we investigated the
reactions of a range of spirocyclopropanes 4 (Table 2). The
reaction of 4b and 4c, bearing a p-methyl or p-bromo sub-
stituent on the benzene ring, provided the corresponding
tetrahydrobenzofuran-4-ones 7b and 7c in 96 and 97%
yield, respectively (entries 2 and 3). High yields of 7d–f
(96–98%) were consistently obtained in the reaction of di-
medone-derived spirocyclopropanes 4d–f11 (entries 4–6).
The reaction of spirocyclopropane 4g, derived from 5-
methyl-1,3-cyclohexanedione, afforded 7g in 93% yield
(entry 7). Aside from high product yields, the introduction
of an electron-withdrawing substituent, a bromo group, on
the benzene ring required longer reaction times to reach
completion [cf. entries 3 and 6 (2.5 h) vs entries 1, 2, and 4–
7 (1 h)]. We next examined the reaction of alkyl-substituted
spirocyclopropane. Treatment of n-butyl-substituted spiro-
cyclopropane 4h under the same conditions (0.1 equiv
TsOH in CH2Cl2 at room temperature) for 24 h gave the cor-
responding product 7h in 72% yield and recovered starting
material 4h in 3% yield (entry 8). Both cyclopropanes, de-
rived from five-membered ring diketone and acyclic dike-
tones, formed the products with low yields.18
2
2
Ar
Ar
Ar
O
O
O
R1
R1
4
7
8
2-arylbenzofuran
Scheme 1 Construction of indole and benzofuran skeletons from 1,3-
cyclohexanedione 2
At the outset of this work, we explored a ring-opening
cyclization of 1-phenylspiro[2.5]octane-4,8-dione (4a),
which was prepared from 1,3-cyclohexanedione (2a) with
(1-phenyl-2-bromoethyl)dimethylsulfonium bromides (3a)
according to our previously reported method (Scheme 1, A;
R1 = R2 = H).11 We first chose the use of catalytic amounts of
Lewis acids including BF3·OEt2, TMSOTf, and Sc(OTf)3. It is
well known that push-pull activated cyclopropanes are
generally activated by a Lewis acid to generate 1,3-dipole
intermediates.16 The reaction with 0.1 equivalents of these
Lewis acids in CH2Cl2 proceeded at room temperature to
completion within 1 to 1.5 h, giving 2-phenyl-substituted
tetrahydrobenzofuran-4-one 7a14 in 98% yield with no evi-
dence of the formation of a 3-phenyl-substituted product
(Table 1, entries 1–3). We then examined the use of magne-
sium iodide.17 MgI2 catalyzed the reaction of 4a in 1 h to af-
ford 7a in 95% yield (entry 4). We then tested a Brønsted
acid as an activator; thus, p-toluenesulfonic acid monohy-
drate (TsOH·H2O) displayed catalytic activity similar to that
of the above Lewis acids and provided 7a in 98% yield
(entry 5). However, the reaction in the presence of a cata-
A plausible mechanism for the ring-opening cyclization
of spirocyclopropane 4 with an acid catalyst is shown in
Scheme 2. Spirocyclopropane 4 is activated by coordination
of the carbonyl group in 4 with an acid catalyst, resulting in
regioselective cleavage of the cyclopropane to provide a rel-
atively stable benzylic carbocation. This carbocation is rap-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
H. Nambu et al.
Special Topic
Synthesis
idly trapped by the enol oxygen atom to form 2-aryl-substi-
tuted tetrahydrobenzofuran-4-one 7.19 Since the benzylic
carbocation intermediates derived from spirocyclopro-
panes 4c and 4f, bearing a p-bromo substituent on the ben-
zene ring, are less stable than those obtained from the oth-
er spirocyclopropanes 4a,b,d,e, and 4g, the reactions of 4c
and 4f required longer reaction times to reach completion.
Table 2 TsOH-Catalyzed Ring-Opening Cyclization of Spirocyclopropanes 4
O
O
TsOH⋅H2O
(0.1 equiv)
R2
R2
CH2Cl2
r.t.
O
O
R1
R1
4
7
Entry
1
Substrate
Time (h)
Product
Yield (%)a
O
O
1
98
O
O
O
O
O
O
7a
4a
O
O
2
3
4
5
6
2.5
96
97
96
96
98
7b
4b
O
O
1
Br
Br
7c
4c
O
O
1
O
O
O
O
7d
7e
4d
O
O
O
2.5
O
O
4e
O
1
Br
Br
7f
4f
O
O
7b
1
93
O
O
7g
4g
O
O
nBu
8
24
72c
nBu
O
O
7h
4h
a Isolated yield.
b The starting material 4g and the product 7g were diastereomeric mixtures (ca. 1:1).
c Starting material 4h was recovered in 3% yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
H. Nambu et al.
Special Topic
Synthesis
oxidation of the resulting 2,3-dihydrobenzofuran with DDQ
furnished 4-hydroxybenzofuran derivative 8a in 98% yield
from 10a. This synthetic route offers a distinct advantage
because 2-aryl-2,3-dihydrobenzofuran is a ubiquitous scaf-
fold that is found in many biologically active molecules and
natural products.22,23
O
O
H+ or LA
Ar
Ar
H or LA-
O
O
R
R
4
O
Finally, we applied the present synthetic method to the
total synthesis of cuspidan B (1), isolated from the bark of
Gnetum cuspidatum1 (Scheme 4). Cuspidan B exhibits
growth inhibitory activities against human promyelocytin
leukemia (HL-60) cells. Spirocyclopropane 4i was prepared
according to our previous method.11 The reaction of the
known styrene derivative 1124 with bromodimethylsulfo-
nium bromide25 and dimethysulfide in acetonitrile, gave
sulfonium salt 3b in 66% yield.26 The reaction of 1,3-cyclo-
hexanedione (2a) with 3b in the presence of powdered
K2CO3 furnished 4i in 96% yield. TsOH-catalyzed ring-open-
ing cyclization of 4i proceeded smoothly at room tempera-
ture to give the corresponding tetrahydrobenzofuran-4-one
7i in 97% yield. Pd(OAc)2-catalyzed aerobic dehydrogena-
tion of 7i under acidic conditions provided TBS-deprotected
2,3-dihydrobenzofuran 10b in 51% yield along with TBS-
deprotected substrate 7j in 32% yield. Conversion of 7j into
10b was also achieved by aerobic dehydrogenation under
O
Ar
2
Ar
O
O
H or LA-
R
R
7
Scheme 2 Plausible mechanism
We then synthesized 2-phenylbenzofuran 8a from tet-
rahydrobenzofuran-4-one 7a (Scheme 3). We initially ex-
amined the conversion of 7a into 2,3-dihydrobenzofuran
10a via bromoketone intermediate 9. Bromination of 7a
with lithium diisopropylamide (LDA) and N-bromosuccin-
imide (NBS) in tetrahydrofuran (THF) afforded bromoke-
tone 9 in only 33% yield as well as some by-products. Aro-
matization by using a combination of LiBr and Li2CO3 fur-
nished 2-phenyl-4-hydroxy-2,3-dihydrobenzofuran (10a)
in 83% yield. Since the bromination yield was very low, we
next examined the direct conversion from 7a into 10a em-
ploying a palladium-catalyzed aerobic dehydrogenation.20
The reaction of 7a in the presence of catalytic amounts of
Pd(OAc)2,21 ortho-dimethylaminopyridine ligand (2NMe2py)
and TsOH with continuous bubbling of oxygen in dimethyl
sulfoxide (DMSO) at 80 °C for 24 h proceeded successfully
to give the product 10a in 59% yield and recovered starting
material 7a in 23% yield. Dehydrogenation of 10a, bearing a
free phenolic hydroxyl group at the C4 position, with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave a com-
plex mixture of products. Conversion of phenol 10a into
tert-butyldimethylsilyl (TBS) ether with TBSCl followed by
Br
Me
Me
Br
S
Br
Me
S
OTBS
Br
OTBS
Me
Me2S, MeCN
66%
OTBS
OTBS
11
3b
O
O
3b (1.5 equiv)
OTBS
powdered K2CO3
cat. TsOH
EtOAc
96%
CH2Cl2
97%
O
O
OTBS
2a
4i
O
O
LDA, NBS
Pd(OAc)2
2NMe2py
TsOH·H2O
Br
OH
O
OH
OTBS
Ph
Ph
THF
33%
O
O
O2, DMSO
80 °C
7a
9
Pd(OAc)2, 2NMe2py
TsOH·H2O, O2
DMSO
O
O
10b
51%
OH
OH
OTBS
7i
LiBr, Li2CO3
DMF, reflux
Pd(OAc)2, 2NMe2py
TsOH·H2O, O2
DMSO, 80 °C
59%
(7a: 23%)
80 °C
+
O
83%
OH
OTBS
1) TBSCl, imidazole
CH2Cl2
O
7j
OH
Ph
O
Ph
32%
2) DDQ, 1,4-dioxane
reflux
O
OH
OH
OH
98%
1) TBSCl
Et3N, DMAP
8a
10a
10b
2) DDQ, 1,4-dioxane
reflux
3) TBAF, THF
O
2NMe2py:
cuspidan B (1)
67%
N
NMe2
Scheme 4 Total synthesis of cuspidan B (1)
Scheme 3 Synthesis of 4-hydroxy-2-phenylbenzofuran 8a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
H. Nambu et al.
Special Topic
Synthesis
the same conditions as those for 7i to 10b. Finally, protec-
tion of three phenolic hydroxyl groups in 10b with TBSCl
followed by dehydrogenation of the resulting bis-silyl ether
with DDQ and then deprotection of these TBS groups with
tetrabutylammonium fluoride (TBAF) produced cuspidan B
(1) in 67% yield. The synthetic material 1 showed spectro-
scopic data (1H and 13C NMR, and IR spectra) consistent
with those reported for the natural product 1.1
In summary, we have developed a regioselective ring-
opening cyclization of cyclohexane-1,3-dione-2-spirocyclo-
propanes with an acid catalyst. The metal-free reaction
proceeded smoothly at room temperature to provide 2-
aryl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-ones in excel-
lent yields. The present protocol is applicable to the synthe-
sis of 2-phenyl-4-hydroxybenzofuran via a synthetically
useful 2,3-dihydrobenzofuran intermediate. To our knowl-
edge, this is the first example of the construction of a 2-ar-
ylbenzofuran ring system by using a ring-opening reaction
of activated cyclopropanes. In addition, the first total syn-
thesis of cuspidan B was achieved by employing the present
protocol. Further application of this method to the synthe-
sis of a variety of benzofuran and 2,3-dihydrobenzofuran
natural products is in progress.
1-Butylspiro[2.5]octane-4,8-dione (4h)
Rh2(OAc)4 (8.8 mg, 0.020 mmol, 1 mol %) was added to a solution of 2-
diazocyclohexane-1,3-dione (276 mg, 2.0 mmol) and 1-hexene (2.5
mL, 20 mmol). After stirring at r.t. for 1 h, the reaction mixture was
purified by column chromatography (silica gel; EtOAc–hexane, 30%)
to provide 4h.
Yield: 78 mg (20%); colorless oil.
IR (film): 2957, 2863, 1679, 1324, 1184, 1024 cm–1
1H NMR (400 MHz, CDCl3): δ = 2.72–2.54 (m, 4 H), 2.12–2.01 (m, 4 H),
1.88 (d, J = 8.0 Hz, 1 H), 1.58 (m, 1 H), 1.47 (m, 1 H), 1.28 (t, J = 6.4 Hz,
3 H), 1.16 (m, 1 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 206.9, 204.9, 47.6, 46.9, 40.2, 39.3,
31.5, 26.6, 26.2, 22.1, 18.2, 13.9.
HRMS (EI): m/z [M+] calcd for C12H18O2: 194.1307; found: 194.1278.
.
Ring-Opening Cyclization of Spirocyclopropanes 4; Typical Proce-
dure
2-Phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (7a)13a,g,i–k,14
TsOH·H2O (4 mg, 0.020 mmol) was added to a solution of 1-phenyl-
spiro[2.5]octane-4,8-dione (4a; 43 mg, 0.20 mmol) in CH2Cl2 (1 mL).
After stirring at r.t. for 1 h, the reaction was quenched by addition of
H2O (3 mL), and the resulting mixture was extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with brine (10
mL) and dried over anhydrous MgSO4. The filtrate was concentrated
in vacuo, and the residue was purified by column chromatography
(silica gel; EtOAc–hexane, 60%) to provide 7a.
Melting points are uncorrected. IR spectra were recorded with a JAS-
CO FT/IR-460 Plus spectrophotometer and absorbance bands are re-
ported in wavenumbers (cm−1). All NMR spectra were recorded with a
JEOL JNM-ECX400P spectrometer. 1H NMR spectra were recorded at
400 MHz. Chemical shifts are reported relative to internal standard
(tetramethylsilane at δH = 0.00 ppm, CD3OD at δH = 3.30 ppm or CDCl3
at δH = 7.26 ppm). Data are presented as follows: chemical shift (δ,
ppm), multiplicity (s = singlet, d = doublet, t = triplet, quint = quintet,
m = multiplet, br = broad), coupling constant, and integration. 13C
NMR spectra were recorded at 100 MHz. Chemical shifts are reported
relative to internal reference (CD3OD at δC = 49.0 ppm or CDCl3 at δC =
77.0 ppm). All 13C NMR spectra were determined with complete pro-
ton decoupling. High-resolution mass spectra were determined with
JEOL JMS-GCmate II and JEOL JMS-AX505HD instruments. Column
chromatography was performed on Silica Gel 60 PF254 (Nacalai
Tesque) and Kanto silica gel 60 N (63–210 mesh) under pressure. Ana-
lytical thin-layer chromatography (TLC) was carried out on Merck
Kieselgel 60 F254 plates. Visualization was accomplished with UV light
and phosphomolybdic acid stain solution followed by heating.
Yield: 42 mg (98%); colorless oil.
IR (film): 2945, 1633, 1401, 1228, 1180, 1060, 760, 770 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.41–7.31 (m, 5 H), 5.75 (dd, J = 10.4,
7.6 Hz, 1 H), 3.29 (ddt, J = 14.4, 10.4, 2.0 Hz, 1 H), 2.88 (ddt, J = 14.4,
7.6, 2.0 Hz, 1 H), 2.51 (tt, J = 6.4, 2.0 Hz, 2 H), 2.39 (dd, J = 7.6, 6.4 Hz,
2 H), 2.09 (quint, J = 6.4 Hz, 2 H).
.
13C NMR (100 MHz, CDCl3): δ = 195.4, 177.0, 140.6, 128.7, 128.4,
125.8, 112.9, 86.3, 36.4, 33.9, 23.9, 21.7.
2-(4-Methylphenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
(7b)13k,14
According to the typical procedure for ring-opening cyclization of
spirocyclopropanes, 7b was synthesized from 1-(4-methylphe-
nyl)spiro[2.5]octane-4,8-dione (4b; 46 mg, 0.20 mmol) and TsOH·H2O
(4 mg, 0.020 mmol) for 1 h. The crude product was purified by col-
umn chromatography (silica gel; EtOAc–hexane, 80%) to provide 7b.
Yield: 44 mg (97%); white solid; mp 99.5–100.5 °C.
All reagents such as BF3·OEt2, TMSOTf, Sc(OTf)3, MgI2, TsOH·H2O, TFA,
1,3-cyclohexanedione (2a), bromodimethylsulfonium bromide,
Pd(OAc)2, 2NMe2py, NBS, DDQ, K2CO3, and TBAF were purchased from
suppliers such as Sigma–Aldrich Co.; Wako Pure Chemical Industries,
Ltd.; Tokyo Chemical Industry Co., Ltd.; Nacalai Tesque, INC. Dehy-
drated CH2Cl2, THF, DMSO, DMF, CH3CN and EtOAc were purchased
from Wako Pure Chemical Industries, Ltd. Spirocyclopropanes 4a–g
were prepared according to our reported procedures.11 (5-Vinyl-1,3-
phenylene)bis(oxy)bis(tert-butyldimethylsilane) (11) was prepared
according to a reported procedure.24
IR (KBr): 2946, 1631, 1403, 1229, 1181, 919, 816 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.18 (m, 4 H), 5.72 (dd, J = 10.4,
8.0 Hz, 1 H), 3.26 (ddt, J = 14.4, 10.4, 2.0 Hz, 1 H), 2.88 (ddt, J = 14.4,
8.0, 2.0 Hz, 1 H), 2.50 (tt, J = 6.4, 2.0 Hz, 2 H), 2.39 (dd, J = 8.0, 6.4 Hz,
2 H), 2.36 (s, 3 H), 2.08 (quint, J = 6.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 195.4, 177.0, 138.4, 137.5, 129.4,
126.0, 113.0, 86.4, 36.5, 33.8, 24.0, 21.7, 21.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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H. Nambu et al.
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Synthesis
2-(4-Bromophenyl)-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
Yield: 63 mg (98%); colorless oil.
IR (film): 2956, 1636, 1399, 1218, 827, 772 cm–1
(7c)13k
.
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7c was synthesized from 1-(4-bromophe-
nyl)spiro[2.5]octane-4,8-dione (4c; 59 mg, 0.20 mmol) and TsOH·H2O
(4 mg, 0.020 mmol) for 2.5 h. The crude product was purified by col-
umn chromatography (silica gel; EtOAc–hexane, 60%) to provide 7c.
1H NMR (400 MHz, CDCl3): δ = 7.52 (dt, J = 8.4, 2.4 Hz, 2 H), 7.19 (dt,
J = 8.4, 2.4 Hz, 2 H), 5.72 (dd, J = 10.4, 7.6 Hz, 1 H), 3.29 (ddt, J = 14.4,
10.4, 2.0 Hz, 1 H), 2.82 (ddt, J = 14.4, 7.6, 2.0 Hz, 1 H), 2.37 (t, J =
2.0 Hz, 2 H), 2.27 (d, J = 2.0 Hz, 2 H), 1.15 (s, 3 H), 1.14 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.6, 175.8, 139.8, 131.9, 127.4,
122.4, 111.3, 85.6, 51.0, 37.8, 34.2, 33.9, 28.8, 28.6.
Yield: 57 mg (97%); white solid; mp 109–110 °C.
IR (KBr): 2948, 1624, 1486, 1399, 1229, 1184, 908, 826 cm–1
.
HRMS (EI): m/z [M+] calcd for C16H17O2Br: 320.0412; found: 320.0417.
1H NMR (400 MHz, CDCl3): δ = 7.52 (dt, J = 8.4, 2.0 Hz, 2 H), 7.20 (dt,
J = 8.4, 2.0 Hz, 2 H), 5.70 (dd, J = 10.4, 7.6 Hz, 1 H), 3.29 (ddt, J = 14.4,
10.4, 2.0 Hz, 1 H), 2.82 (ddt, J = 14.4, 7.6, 2.0 Hz, 1 H), 2.51 (tt, J = 6.4,
2.0 Hz, 2 H), 2.39 (dd, J = 7.6, 6.4 Hz, 2 H), 2.09 (quint, J = 6.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 195.3, 176.8, 139.7, 131.9, 127.5,
122.4, 112.9, 85.4, 36.5, 34.0, 23.9, 21.7.
6-Methyl-2-phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
(7g)13a,g,i,j
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7g was synthesized from 6-methyl-1-phenyl-
spiro[2.5]octane-4,8-dione (4g; 46 mg, 0.20 mmol) and TsOH·H2O (4
mg, 0.020 mmol) for 1 h. The crude product was purified by column
chromatography (silica gel; EtOAc–hexane, 60%) to provide a diaste-
reomeric mixture (ca. 1:1) of 7g.
6,6-Dimethyl-2-phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-
one (7d)13a,d,e,13i–k
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7d was synthesized from 6,6-dimethyl-1-phenyl-
spiro[2.5]octane-4,8-dione (4d; 48 mg, 0.20 mmol) and TsOH·H2O (4
mg, 0.020 mmol) for 1 h. The crude product was purified by column
chromatography (silica gel; EtOAc–hexane, 60%) to provide 7d.
Yield: 43 mg (93%); colorless oil.
IR (KBr): 2926, 1638, 1402, 1224, 1100, 921, 820 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.26 (m, 5 H), 5.79–5.73 (m, 1 H),
3.32–3.24 (m, 1 H), 2.90–2.84 (m, 1 H), 2.36 (s, 3 H), 2.60–2.54 (m,
1 H), 2.48–2.42 (m, 1 H), 2.39–2.32 (m, 1 H), 2.26–2.10 (m, 2 H), 1.15
(s, 1.5 H), 1.14 (s, 1.5 H).
13C NMR (100 MHz, CDCl3): δ = 195.02, 194.98, 176.7, 140.7, 140.6,
128.8, 128.48, 128.46, 125.9, 125.8, 112.7, 112.5, 86.6, 86.4, 45.1, 45.0,
33.9, 31.94, 31.92, 30.0, 29.8, 21.04, 21.01.
Yield: 46 mg (96%); colorless oil.
IR (film): 2957, 1636, 1401, 1219, 1042, 758, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.31 (m, 5 H), 5.77 (dd, J = 10.4,
8.0 Hz, 1 H), 3.30 (ddt, J = 14.4, 10.4, 2.0 Hz, 1 H), 2.88 (ddt, J = 14.4,
8.0, 2.0 Hz, 1 H), 2.38 (t, J = 2.0 Hz, 2 H), 2.28 (d, J = 2.0 Hz, 2 H), 1.15
(s, 3 H), 1.14 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.7, 176.0, 140.7, 128.8, 128.5,
125.8, 111.4, 86.5, 51.0, 37.8, 34.2, 33.9, 28.8, 28.6.
2-Butyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (7h)
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7h was synthesized from 4h (39 mg, 0.20 mmol)
and TsOH·H2O (4 mg, 0.020 mmol) for 1 h. The crude product was pu-
rified by column chromatography (silica gel; EtOAc–hexane, 40%) to
provide 7h (28 mg, 72%) as a colorless oil and starting material 4h
(1.3 mg, 3%) was recovered.
6,6-Dimethyl-2-(4-methylphenyl)-3,5,6,7-tetrahydro-1-benzofu-
ran-4(2H)-one (7e)13a
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7e was synthesized from 6,6-dimethyl-1-(4-meth-
ylphenyl)spiro[2.5]octane-4,8-dione (4e; 51 mg, 0.20 mmol) and
TsOH·H2O (4 mg, 0.020 mmol) for 1 h. The crude product was purified
by column chromatography (silica gel; EtOAc–hexane, 60%) to provide
7e.
IR (film): 2934, 2864, 1631, 1404, 1379, 1233, 1181 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.80 (m, 1 H), 2.90 (dd, J = 13.6, 9.6 Hz,
1 H), 2.46 (dd, J = 13.6, 7.2 Hz, 1 H), 2.42 (t, J = 6.4 Hz, 2 H), 2.35 (t, J =
6.4 Hz, 2 H), 2.03 (quint, J = 6.4 Hz, 2 H), 1.76 (m, 1 H), 1.63 (m, 1 H),
1.39 (m, 4 H), 0.92 (t, J = 6.4 Hz, 3 H).
Yield: 49 mg (96%); white solid; mp 55.5–56.5 °C.
IR (KBr): 2954, 1633, 1401, 1210, 1051, 759, 699 cm–1
13C NMR (100 MHz, CDCl3): δ = 195.8, 177.7, 112.9, 86.3, 36.3, 35.8,
31.3, 27.1, 24.0, 22.4, 21.7, 13.9.
.
1H NMR (400 MHz, CDCl3): δ = 7.23–7.18 (m, 4 H), 5.73 (dd, J = 10.4,
8.0 Hz, 1 H), 3.26 (ddt, J = 14.4, 10.4, 2.0 Hz, 1 H), 2.88 (ddt, J = 14.4,
8.0, 2.0 Hz, 1 H), 2.36 (s, 3 H), 2.36 (d, J = 2.4 Hz, 2 H), 2.27 (d, J =
2.4 Hz, 2 H), 1.143 (s, 3 H), 1.135 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.7, 176.0, 138.4, 137.7, 129.5,
125.9, 111.5, 86.6, 51.0, 37.8, 34.1, 33.7, 28.8, 28.6, 21.2.
HRMS (EI): m/z [M+] calcd for C12H18O2: 194.1307; found: 194.1304.
5-Bromo-2-phenyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one
(9)
A solution of LDA (1.0 M in THF, 0.35 mL, 0.35 mmol), prepared from
diisopropylamine and butyllithium in n-hexane, was added to a solu-
tion of 7a (64 mg, 0.32 mmol) in THF (2 mL) at –78 °C. After stirring at
–78 °C for 1 h, a solution of NBS (113 mg, 0.64 mmol) in THF (1 mL)
was added to the reaction mixture at –78 °C. After stirring at –78 °C
for 2 h, at –40 °C for 2 h, and at r.t. for 2 h, the reaction was quenched
by addition of sat. aq NH4Cl (5 mL), and the resulting mixture was ex-
tracted with Et2O (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL) and brine (10 mL), and dried over anhy-
drous MgSO4. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (silica gel; EtOAc–hexane,
40%) to provide a diastereomeric mixture (ca. 1:1) of 9.
6,6-Dimethyl-2-(4-bromophenyl)-3,5,6,7-tetrahydro-1-benzofu-
ran-4(2H)-one (7f)
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7f was synthesized from 1-(4-bromolphenyl)-6,6-
dimethylspiro[2.5]octane-4,8-dione (4f; 64 mg, 0.20 mmol) and
TsOH·H2O (4 mg, 0.020 mmol) for 2.5 h. The crude product was puri-
fied by column chromatography (silica gel; EtOAc–hexane, 50%) to
provide 7f.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
H. Nambu et al.
Special Topic
Synthesis
Yield: 31 mg (33%); yellow oil.
IR (film): 2927, 2360, 1656, 1626, 1407, 1237, 1117, 762, 699 cm–1
ganic layers were washed with H2O (5 mL) and brine (5 mL), and dried
over anhydrous MgSO4. The filtrate was concentrated in vacuo to pro-
vide the crude product (74 mg), which was used in the next step
without further purification.
.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.31 (m, 6 H), 5.85–5.77 (m, 1 H),
4.50–4.47 (m, 1 H), 3.35–3.27 (m, 1 H), 2.95–2.78 (m, 2 H), 2.54–2.40
(m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 188.2, 188.1, 176.6, 140.1, 128.9,
128.85, 128.78, 128.73, 125.94, 125.87, 110.9, 110.7, 87.1, 87.0, 48.6,
48.4, 33.92, 33.88, 30.9, 30.8, 21.4, 21.3.
DDQ (58 mg, 0.32 mmol) was added to a solution of the crude prod-
uct in 1,4-dioxane (1 mL). After stirring and heating to reflux for 4 h,
the reaction mixture was allowed to cool to r.t. and diluted with Et2O
(10 mL). The whole was washed with sat. aq NaHCO3 (3 × 5 mL), H2O
(5 mL) and brine (5 mL), and dried over anhydrous MgSO4. The filtrate
was concentrated in vacuo, and the residue was purified by column
chromatography (silica gel; EtOAc–hexane, 5%) to provide 8a.
HRMS (EI): m/z [M+] calcd for C14H13O2Br: 292.0099; found: 292.0124.
4-Hydroxy-2-phenyl-2,3-dihydrobenzofuran (10a)
Yield: 42 mg (98%); colorless oil.
LiBr (10 mg, 0.12 mmol) and Li2CO3 (8.6 mg, 0.12 mmol) were added
to a solution of 9 (31 mg, 0.11 mmol) in DMF (1 mL). After stirring and
heating to reflux for 2 h, the reaction was quenched by addition of sat.
aq NH4Cl (5 mL), and the resulting mixture was extracted with 20%
EtOAc in hexane (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL) and brine (10 mL), and dried over anhy-
drous MgSO4. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (silica gel; EtOAc–hexane,
40%) to provide 10a.
IR (film): 2360, 2341, 1484, 1264, 1067, 837, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.86 (dd, J = 8.0, 1.6 Hz, 2 H), 7.43 (dd,
J = 8.0, 1.6 Hz, 2 H), 7.33 (tt, J = 7.2, 1.6 Hz, 1 H), 7.17–7.10 (m, 2 H),
7.01 (s, 1 H), 6.65 (dd, J = 7.2, 1.6 Hz, 1 H), 1.07 (s, 9 H), 0.26 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 156.4, 154.6, 149.2, 130.5, 128.7,
128.3, 124.8, 124.7, 122.5, 112.4, 104.8, 99.0, 25.8, 18.3, –4.3.
HRMS (EI): m/z [M+] calcd for C20H24O2Si: 324.1546; found: 324.1499.
Yield: 19 mg (83%); pale-yellow solid; mp 78–79 °C.
{2-Bromo-1-[3,5-bis(tert-butyldimethylsilyloxy)phenyl]ethyl}di-
methylsulfonium Bromide (3b)
IR (KBr): 3391, 1661, 1498, 1459, 1289, 1227, 1029, 1003, 773,
700 cm–1
.
(5-Vinyl-1,3-phenylene)bis(oxy)bis(tert-butyldimethylsilane)22 (11;
729 mg, 2.0 mmol) was added to a solution of bromodimethylsulfo-
nium bromide (444 mg, 2.0 mmol) and dimethyl sulfide (1.5 mL, 20
mmol) in MeCN (4 mL) at 0 °C. After stirring at 0 °C for 1 h, Et2O (10
mL) was added to the reaction mixture and the resulting precipitate
was collected by filtration. The precipitate was washed with Et2O (10
mL), and dried in vacuo to provide sulfonium salt 3b.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.29 (m, 5 H), 7.04 (t, J = 8.4 Hz,
1 H), 6.50 (d, J = 8.4 Hz, 1 H), 6.34 (d, J = 8.4 Hz, 1 H), 5.80 (dd, J = 9.6,
8.0 Hz, 1 H), 4.72 (s, 1 H), 3.60 (dd, J = 15.2, 9.6 Hz, 1 H), 3.15 (dd, J =
15.2, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.4, 152.3, 141.8, 129.3, 128.6,
128.1, 125.8, 112.0, 107.9, 102.4, 84.5, 35.3.
Yield: 778 mg (66%); white solid; mp 138.5–139.5 °C.
IR (KBr): 2928, 2360, 2330, 1593, 1455, 1174, 1033, 784, 828 cm–1
HRMS (EI): m/z [M+] calcd for C14H12O2: 212.0837; found: 212.0848.
.
1H NMR (400 MHz, CDCl3): δ = 6.71 (d, J = 2.4 Hz, 2 H), 6.44 (t, J =
2.4 Hz, 1 H), 6.35 (br s, 1 H), 4.19–4.09 (m, 2 H), 3.63 (s, 3 H), 3.11 (s,
3 H), 0.98 (s, 18 H), 0.23 (s, 12 H).
Palladium-Catalyzed Aerobic Dehydrogenation of Tetrahydroben-
zofuran-4-ones 7; Typical Procedure
13C NMR (100 MHz, CDCl3): δ = 157.7, 131.9, 114.5, 113.9, 58.7, 30.7,
4-Hydroxy-2-phenyl-2,3-dihydrobenzofuran (10a)
25.6, 24.9, 23.4, 18.2, –4.3.
HRMS (FAB): m/z [M + H]+ calcd for C22H43O2Si2S79Br81Br: 587.0869;
found: 587.0870.
Pd(OAc)2 (67 mg, 0.30 mmol), 2-(dimethylamino)pyridine (2NMe2py;
0.07 mL, 0.60 mmol) and TsOH·H2O (228 mg, 1.20 mmol) were added
to a solution of spirocyclopropane 7a (643 mg, 3.00 mmol) in DMSO
(6 mL). After continuous bubbling of oxygen through the reaction
mixture at 80 °C for 12 h, Pd(OAc)2 (67 mg, 0.30 mmol), 2NMe2py (0.07
mL, 0.60 mmol) and TsOH·H2O (228 mg, 1.20 mmol) were added to
the reaction mixture. After continuous bubbling of oxygen through
the reaction mixture at 80 °C for 12 h, the reaction was quenched by
addition of sat. aq NH4Cl (20 mL), and the resulting mixture was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with H2O (2 × 20 mL) and brine (20 mL), and dried over anhy-
drous MgSO4. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (silica gel; EtOAc–hexane,
60%) to provide 10a (378 mg, 59%) as a pale-yellow solid and recov-
ered 7a (147 mg, 23%) as a colorless oil.
1-[3,5-Bis(tert-butyldimethylsilyloxy)phenyl]spiro[2.5]octane-
4,8-dione (4i)
Powdered K2CO3 (81 mg, 0.60 mmol) was added to a suspension of
sulfonium salt 3b (173 mg, 0.30 mmol) in EtOAc (2 mL). After stirring
at r.t. for 10 min, 1,3-cyclohexanedione (2a; 22 mg, 0.20 mmol) was
added to the reaction mixture at 0 °C. After stirring at 0 °C for 1 h, the
reaction mixture was warmed to r.t. over 4 h and stirred at r.t. for 1 h.
The reaction was quenched by addition of sat. aq Na2S2O3 (5 mL), and
the resulting mixture was extracted with EtOAc (2 × 10 mL). The com-
bined organic layer was washed with brine (5 mL) and dried over an-
hydrous MgSO4. The filtrate was concentrated in vacuo, and the resi-
due was purified by column chromatography (silica gel; EtOAc–hex-
ane, 20%) to provide 4i.
4-tert-Butyldimethylsilyloxy-2-phenylbenzofuran (8a)
tert-Butyldimethylchlorosilane (70 mg, 0.46 mmol) was added to a
solution of 10a (28 mg, 0.13 mmol) and imidazole (25 mg, 0.37
mmol) in CH2Cl2 (1 mL) at 0 °C. After stirring at r.t. for 1.5 h, the reac-
tion was quenched by addition of sat. aq NH4Cl (5 mL), and the result-
ing mixture was extracted with CH2Cl2 (2 × 10 mL). The combined or-
Yield: 89 mg (96%); white solid; mp 61–62 °C.
IR (KBr): 2931, 2859, 1686, 1591, 1449, 1378, 1327, 1254, 1168, 1033,
832, 782 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
H. Nambu et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 6.29 (d, J = 2.4 Hz, 2 H), 6.22 (t, J =
2.4 Hz, 1 H), 3.12 (t, J = 8.4 Hz, 1 H), 2.75 (dddd, J = 17.2, 8.4, 4.8,
1.2 Hz, 1 H), 2.61 (ddd, J = 17.2, 8.4, 4.8 Hz, 1 H), 2.51–2.40 (m, 2 H),
2.34–2.23 (m, 2 H), 2.14–2.01 (m, 2 H), 0.97 (s, 18 H), 0.19 (s, 6 H),
0.17 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 206.0, 201.2, 156.2, 135.2, 114.8,
112.0, 50.1, 48.5, 39.8, 39.4, 25.7, 20.8, 18.2, 17.9, –4.5.
IR (KBr): 3367, 2359, 1607, 1361, 1235, 1156, 1008, 845 cm–1
.
1H NMR (400 MHz, acetone-d6): δ = 8.37 (br s, 2 H), 6.35 (d, J = 2.0 Hz,
1 H), 6.32 (t, J = 2.0 Hz, 2 H), 5.67 (dd, J = 10.4, 7.6 Hz, 1 H), 3.18 (ddt,
J = 14.8, 10.4, 2.0 Hz, 1 H), 2.63 (ddt, J = 14.4, 7.6, 2.0 Hz, 1 H), 2.55–
2.50 (m, 2 H), 2.30–2.26 (m, 2 H), 2.09–2.03 (m, 2 H).
13C NMR (100 MHz, acetone-d6): δ = 194.8, 177.6, 159.7, 144.9, 113.1,
104.8, 103.1, 86.5, 37.1, 35.1, 24.4, 22.5.
HRMS (EI): m/z [M+] calcd for C26H42O4Si2: 474.2622; found:
474.2632.
HRMS (EI): m/z [M+] calcd for C14H14O4: 246.0892; found: 246.0855.
Cuspidan B (1)1
6,6-Dimethyl-2-[3,5-bis(tert-butyldimethylsilyloxy)phenyl]-
3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one (7i)
tert-Butyldimethylchlorosilane (167 mg, 1.1 mmol) and 4-(dimethyl-
amino)pyridine (DMAP; 7 mg, 0.055 mmol) were added to a solution
of 10b (45 mg, 0.18 mmol) and triethylamine (0.18 mL, 1.3 mmol) in
CH2Cl2 (2 mL) at 0 °C. After stirring at r.t. for 0.5 h, the reaction was
quenched by addition of sat. aq NH4Cl (5 mL), and the resulting mix-
ture was extracted with EtOAc (2 × 10 mL). The combined organic lay-
ers were washed with H2O (5 mL) and brine (5 mL), and dried over
anhydrous MgSO4. The filtrate was concentrated in vacuo to provide
crude product (129 mg), which was used in the next step without fur-
ther purification.
According to the typical procedure for ring-opening cyclization of spi-
rocyclopropanes, 7i was synthesized from 4i (789 mg, 1.70 mmol)
and TsOH·H2O (32 mg, 0.17 mmol) in CH2Cl2 (9 mL) for 1 h. The crude
product was purified by column chromatography (silica gel; EtOAc–
hexane, 40%) to provide 7i.
Yield: 767 mg (97%); colorless oil.
IR (film): 2931, 2859, 1686, 1591, 1449, 1378, 1327, 1254, 1168,
1033, 832, 782 cm–1
.
DDQ (125 mg, 0.55 mmol) was added to a solution of the crude prod-
uct in 1,4-dioxane (4 mL). After stirring and heating at reflux for 3.5 h,
the reaction mixture was allowed to cool to r.t. and diluted with Et2O
(10 mL). The whole was washed with sat. aq NaHCO3 (3 × 5 mL), H2O
(5 mL) and brine (5 mL), and dried over anhydrous MgSO4. The filtrate
was concentrated in vacuo to provide the crude product (88 mg),
which was used in the next step without further purification.
1H NMR (400 MHz, CDCl3): δ = 6.40 (d, J = 2.0 Hz, 2 H), 6.28 (t, J =
2.0 Hz, 1 H), 5.62 (dd, J = 10.4, 8.0 Hz, 1 H), 3.24 (ddt, J = 14.4, 10.4,
2.0 Hz, 1 H), 2.81 (ddt, J = 14.4, 8.0, 2.0 Hz, 1 H), 2.51 (tt, J = 6.4, 2.0 Hz,
2 H), 2.39 (dd, J = 8.0, 6.4 Hz, 2 H), 2.09 (quint, J = 6.4 Hz, 2 H), 0.97 (s,
18 H), 0.19 (s, 12 H).
13C NMR (100 MHz, CDCl3): δ = 195.4, 177.1, 156.9, 142.8, 113.0,
111.8, 110.6, 85.9, 36.5, 34.0, 25.7, 23.9, 21.7, 18.2, –4.4.
TBAF (0.75 mL, 1.0 M in THF, 0.75 mmol) was added to a solution of
the crude product in THF (3 mL) at 0 °C. After stirring at 0 °C for 10
min, the reaction was quenched with H2O (5 mL) and the whole mix-
ture was extracted with EtOAc (3 × 5 mL). The combined organic lay-
ers were washed with brine (5 mL) and dried over anhydrous MgSO4.
The filtrate was concentrated in vacuo, and the residue was purified
by column chromatography (silica gel; EtOAc–hexane, 60%) to provide
cuspidan B (1).
HRMS (EI): m/z [M+] calcd for C26H42O4Si2: 474.2622; found:
474.2593.
4-Hydroxy-2-(3,5-dihydroxyphenyl)-2,3-dihydrobenzofuran (10b)
and 2-(3,5-Dihydroxyphenyl)-6,6-dimethyl-3,5,6,7-tetrahydro-1-
benzofuran-4(2H)-one (7j)
According to the typical procedure for palladium-catalyzed aerobic
dehydrogenation of tetrahydrobenzofuran-4-ones, 10b was synthe-
sized from 7i (565 mg, 1.20 mmol), Pd(OAc)2 (2 × 27 mg, 2 × 0.12
mmol), 2NMe2py (2 × 0.03 mL, 2 × 0.24 mmol) and TsOH·H2O (2 × 91
mg, 2 × 0.48 mmol) in DMSO (3 mL) for 2 × 12 h (continuous bubbling
of oxygen). The crude product was purified by column chromatogra-
phy (silica gel; EtOAc–hexane, 60%) to provide 10b and 7j.
Yield: 30 mg (67%); pale-yellow solid; mp 245 °C (decomposition).
IR (KBr): 3332, 1618, 1496, 1441, 1348, 1226, 1149, 1032, 957,
767 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.07 (s, 1 H), 7.07 (t, J = 8.0 Hz, 1 H),
6.98 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 2.4 Hz, 2 H), 6.58 (d, J = 8.0 Hz,
1 H), 6.27 (t, J = 2.4 Hz, 1 H), 4.87 (s, 3 H).
Compound 10b
13C NMR (100 MHz, CD3OD): δ = 160.0, 157.7, 155.6, 152.2, 133.6,
126.2, 119.7, 108.7, 104.2, 103.8, 103.6, 99.5.
Yield: 148 mg (51%); pale-yellow solid; mp 82–83 °C.
IR (KBr): 3357, 3280, 1605, 1468, 1354, 1166, 1018, 841, 768 cm–1
.
1H NMR (400 MHz, acetone-d6): δ = 8.30 (br s, 2 H), 6.97 (t, J = 8.0 Hz,
1 H), 6.39–6.28 (m, 5 H), 5.64 (dd, J = 9.6, 7.2 Hz, 1 H), 3.57 (dd, J =
15.6, 9.6 Hz, 1 H), 3.00 (dd, J = 15.6, 7.2 Hz, 1 H).
13C NMR (100 MHz, acetone-d6): δ = 162.4, 159.6, 155.1, 146.3, 129.7,
112.8, 108.8, 104.7, 102.7, 101.6, 84.6, 36.4.
Acknowledgment
This research was supported, in part, by a Grant-in-Aid for Scientific
Research (C) (Grant No. 15K07853) from the Japan Society for the Pro-
motion of Science (JSPS).
HRMS (EI): m/z [M+] calcd for C14H12O4: 244.0736; found: 244.0752.
Supporting Information
Compound 7j
Yield: 93 mg (32%); brown solid; mp 57.5–58.5 °C.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561590.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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H. Nambu et al.
Special Topic
Synthesis
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