Ring-opening cyclization of spirocyclopropanes using sulfoxonium ylides

Article abstract of DOI:10.1248/CPB.C20-00132

Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes using dimethylsulfoxonium methylide proceeded regioselectively to produce 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones in good to high yields. The reactions of cycloheptane- and cyclopentane-1,3-dione-2-spirocyclopropanes could construct [7.6]- and [5.6]-fused ring systems. This reaction was also carried out using sulfoxonium ethylide, butylide, and benzylide, resulting in the formation of the corresponding 2,3-trans-disubstituted products in good to high yields, and it was shown that the dimethyl group can act as a dummy substituent. It was found that the 2- and 3-phenyhexahydrobenzopyran-5-ones can be readily converted into 5-hydroxyflavan and 5-hydroxy-isoflavan, respectively.

Full text of DOI:10.1248/CPB.C20-00132

Vol. 68, No. 5
Chem. Pharm. Bull. 68, 479–486 (2020)
479
Regular Article
Ring-Opening Cyclization of Spirocyclopropanes Using Sulfoxonium Ylides
Yuta Onuki, Hisanori Nambu,* and Takayuki Yakura*
Faculty of Pharmaceutical Sciences, University of Toyama; Sugitani, Toyama 930–0194, Japan.
Received February 13, 2020; accepted March 2, 2020
Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes using dimethylsulfoxonium
methylide proceeded regioselectively to produce 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones in good to
high yields. The reactions of cycloheptane- and cyclopentane-1,3-dione-2-spirocyclopropanes could construct
[7.6]- and [5.6]-fused ring systems. This reaction was also carried out using sulfoxonium ethylide, butylide,
and benzylide, resulting in the formation of the corresponding 2,3-trans-disubstituted products in good to
high yields, and it was shown that the dimethyl group can act as a dummy substituent. It was found that the
2- and 3-phenyhexahydrobenzopyran-5-ones can be readily converted into 5-hydroxyflavan and 5-hydroxy-
isoflavan, respectively.
Key words sulfoxonium ylide; spirocyclopropane; ring-opening cyclization; flavan; isoflavan
non-, alkyl-, and phenyl-substituted sulfoxonium ylides 2 as a
Introduction
In the 1960s, Corey and Chaykovsky developed the reaction carbon nucleophile is reported (Chart 2B).
of sulfur ylides, such as sulfonium ylide 1 and sulfoxonium
ylide 2, with carbonyl compounds, which became known as
Results and Discussion
Initially, the reaction was carried out using highly reactive
the Corey–Chaykovsky reaction.1,2) Both 1 and 2 react with
either aldehydes or ketones in the same way to give the corre- dimethylsulfonium methylide (1a), which was prepared in situ
sponding epoxides. However, when reacted with enones, they from trimethylsulfonium iodide (6) (Chart 3). After treatment
behave differently. For example, dimethylsulfonium methyl- of sulfonium salt 6 using sodium hydride in dimethylsulfoxide
ide (1a) reacts with calcone to afford epoxide in 87% yield, (DMSO) at room temperature for 0.5h,3) the produced sulfo-
whereas dimethylsulfoxonium methylide (2a) produces cy- nium ylide 1a was reacted with 2′-phenylspirocyclopropane
clopropane in 95% yield3) (Chart 1). Using density functional 3a.20) Unfortunately, reaction at room temperature for 24h
theory calculations, Yu and colleagues recently reported that gave only decomposition products, indicating that the reac-
these different reaction outcomes can be attributed to thermo- tivity of 1a is too high to induce a ring-opening cyclization
dynamics, as sulfonium ylide 1a is less stable, and therefore reaction.
more highly reactive, than sulfoxonium ylide 2a.4) To date,
Next, the reaction of the lower reactive sulfoxonium ylide
sulfur ylides 1a and 2a have been widely used in the synthe- 2a with 3a was examined (Table 1). When the dimethylsulf-
sis of various epoxides,5,6) cyclopropanes,7,8) and heterocyclic oxonium methylide (2a), which was prepared in situ from
compounds.9–11)
2.1eq of trimethylsulfoxonium iodide (7a) using 2.0eq of
Doubly-activated cyclopropanes are versatile intermedi- sodium hydride in DMSO at room temperature for 0.5h,3) re-
ates for the synthesis of a wide range of carbocycles12) and acted with 3a, the desired ring-opening cyclization proceeded
heterocycles.13) With this in mind, regioselective ring-opening regioselectively at room temperature within 8h to afford
cyclizations of cyclohexane-1,3-dione-2-spirocyclopropanes 3-phenyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one
(5a)
3 have been developed for the synthesis of indole14–16) and in 68% yield (entry 1). Trimethylsulfoxonium chloride (7b)
benzofuran.17,18) Furthermore, we recently reported that the proved to be a more suitable sulfoxonium ylide precursor than
regio- and diastereoselective ring-opening cyclization of spi- 7a, leading to a higher yield of 5a (76%, entry 2), presumably
rocyclopropanes 3 with electron-withdrawing group (EWG)- because side reactions caused by the presence of the highly
substituted sulfonium ylides 1b affords 2,3-trans-disubstituted nucleophilic iodide ion are prevented when switching to the
2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones
4
in high lower nucleophilic chloride ion.18) Changing the solvent from
yields19) (Chart 2A). The reaction proceeds through nucleo- DMSO to N,N-dimethylformamide (DMF) led to a decrease
philic attack of the carbanion in 1b to the electrophilic cyclo- in the product yield to 71% (entry 3). However, neither CH2Cl2
propane carbon possessing an R1 substituent in 3. Subsequent- nor toluene21) were found to be suitable solvents, leading to
ly, an SN2-type cyclization occurs to afford the product 4 with the recovery of 3a (entries 4 and 5). In contrast, when tetra-
the concomitant release of dimethyl sulfide. This was the first
example of the ring opening of cyclopropanes using a sulfoni-
um ylide as a carbon nucleophile. However, sulfonium ylides
used in this reaction were limited to EWG-stabilized ones 1b.
Since sulfur ylides with various reactivities have been used in
organic synthesis,5–11) this study focused on the reaction be-
tween different sulfur ylides and spirocyclopropanes. Herein,
the ring-opening cyclization of spirocyclopropanes 3 using
Chart 1. The Corey–Chaykovsky Reaction
*To whom correspondence should be addressed. e-mail: nambu@pha.u-toyama.ac.jp; yakura@pha.u-toyama.ac.jp
© 2020 The Pharmaceutical Society of Japan

480
Chem. Pharm. Bull.
Vol. 68, No. 5 (2020)
hydrofuran (THF) was used as a solvent (at reflux for 3h), the
reaction with 3a gave the product 5a in 75% yield (entry 6).
Changing the base from sodium hydride to potassium tert-
butoxide22) (tBuOK in THF at reflux for 3h) led to a similar
product yield of 5a in both cases (74%, entry 7). For ylide
preparation in THF, the reaction required 3h at reflux, where-
as in DMSO it required only 0.5h at room temperature. For
this reason, DMSO was chosen as a solvent. Next, an attempt
was made to reduce the amount of 7b and base used (entries
8–10), where 1.5eq of 7b and 1.2eq of sodium hydride were
found to give the best result. Moreover, increasing the reac-
tion temperature to 50°C led to a lower product yield (72%,
entry 11). Finally, 1.5eq of 7b and 1.2eq of sodium hydride
in DMSO at room temperature were chosen as the optimized
conditions.
Next, the reactions of a range of spirocyclopropanes 3b–i,
8, and 10 with sulfoxonium salt 7b were investigated (Table
2). Under the previously stated optimized conditions, dime-
done-derived spirocyclopropane 3b gave the corresponding
hexahydrobenzopyran-5-one 5b in 83% yield (entry 1). The
reaction of aryl-substituted spirocyclopropanes 3c and 3d
bearing p-methyl or p-bromo substituents on their benzene
rings afforded products 5c and 5d in 82 and 71% yields,
respectively (entries 2 and 3). It was also possible to use
2′,3′-nonsubstituted spirocyclopropanes 3e–h23) in this reac-
tion, furnishing the corresponding products 5e–h in 71–78%
yields (entries 4–7). The reaction of n-butyl-substituted spi-
rocyclopropane 3i was then investigated (entry 8). Unexpect-
edly, the 4-butyl-substituted product 5i′ was obtained together
with 3-butyl-substituted 5i, where the combined yield of these
products was 83% and the ratio of 5i to 5i′ was determined to
Chart 2. Ring-Opening Cyclization of Spirocyclopropanes 3 with Sul-
fur Ylides 1 and 2
1
be 76:24 from H-NMR analysis of the crude product. Since
the butyl-substituted carbocation, formally formed by the
cleavage of cyclopropane, is less stable than phenyl-substituted
one, it is speculated that the sulfoxonium ylide 2a would par-
tially attack to the less hindered carbon atom on cyclopropane
in 3i to produce the regioisomer 5i′ as a minor product. Next,
the reactions of spirocyclopropanes 8 and 10 derived from
cycloheptane- and cyclopentane-1,3-diones were investigated
(entries 9 and 10). Although the yields of the corresponding
products 9 and 11 decreased to 64 and 41%, respectively, it
was discovered that the present reaction can also be used to
construct [7.6]- and [5.6]-fused ring systems.
Chart 3. The Reaction of Spirocyclopropane 3a with Sulfonium Ylide
1a Prepared from Sulfonium Salt 6
Table 1. The Reaction of Spirocyclopropane 3a with Sulfoxonium Ylide
2a Prepared from Sulfoxonium Salts 7a and 7ba)
In addition, the reaction of non-spirocyclopropane was ex-
amined under the optimized conditions (Chart 4). The reaction
of 1,1-diacetyl-2-phenylcyclopropane (12) with sulfoxonium
salt 7b in the presence of sodium hydride in DMSO at room
temperature for 12h resulted in the formation of only decom-
position products, suggesting that a spiro-type structure is
crucial for successful ring-opening cyclization to occur. It is
clear that the spirocyclopropane is more reactive than non-
spiro one, probably due to its higher ring strain energy.
As an extension of the present method, the reaction was car-
ried out using sulfoxonium ethylide, butylide, and benzylide.
Initially, the corresponding sulfoxonium salts were prepared
as sulfoxonium ylide precursors (Chart 5). Since the Shea
group has already proven that triethylsulfoxonium chloride
(14) is a precursor of sulfoxonium ethylide 2b,24) salt 14 was
prepared from diethyl sulfide (13) according to their reported
procedure. Ethylation of 13 with iodoethane and iodine, anion
exchange with benzyltributylammonium chloride, and oxida-
Entry
7 (eq)
Base (eq)
Solvent
Time (h) Yield (%)
1
2
7a (2.1)
7b (2.1)
7b (2.1)
7b (2.1)
7b (2.1)
7b (2.1)
7b (2.1)
7b (2.1)
7b (1.5)
7b (1.2)
7b (1.5)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
tBuOK (2.0)
NaH (1.5)
NaH (1.2)
NaH (1.1)
NaH (1.2)
DMSO
DMSO
DMF
8
8
68
76
71
NR
NR
75
74
79
82
68
72
3
8
4b)
5b)
6b)
7b)
8
CH2Cl2
Toluene
THF
24
24
8
THF
8
DMSO
DMSO
DMSO
DMSO
12
12
12
12
9
10
11c)
a) All reactions were performed on a 0.3mmol scale. b) Sulfoxonium ylide 2a was
prepared by heating at reflux for 3h. c) The reaction was carried out at 50°C.

Vol. 68, No. 5 (2020)
Chem. Pharm. Bull.
481
Table 2. The Reaction of Spirocyclopropanes 3, 8 and 10 with Sulfoxo-
nium Salt 7ba)
Chart 4. The Reaction of Cyclopropane 12 with Sulfoxonium Salts 7b
Chart 5. Preparation of the Sulfoxonim Salts 14, 17 and 20
anion exchange reaction gave tributylsulfonium chloride (16).
However, the oxidation of 16 with mCPBA was not successful.
As a result of the testing of different oxidation conditions, it
was found that the Sharpless oxidation (cat. RuCl3, NaIO4)25)
could be applied to this step, resulting in the formation of
sulfoxonium salt 17 in 16% yield from 15 (Chart 5b). Because
of the difficulty in synthesizing the tribenzylsulfoxonium salt,
benzyldimethylsulfoxonium chloride (20) was successfully
prepared as an alternative. Although the sulfoxonium ylide
precursor 20 has the potential to form methylide in addition
to benzylide, it was expected that the deprotonation of 20
would proceed at the most basic benzylic position. Alkylation
of dimethyl sulfide (18) with benzyl bromide and a subsequent
anion exchange reaction gave benzyldimethylsulfonium chlo-
ride (19). Finally, the Sharpless oxidation of 19 provided the
corresponding sulfoxonium salt 20 in 44% yield from benzyl
bromide (Chart 5c).
Using these sulfoxonium ylide precursors, the reactions of
spirocyclopropanes with sulfoxonium ethylide 2b, butylide 2c,
and benzylide 2d were investigated (Chart 6). After treatment
of triethylsulfoxonium chloride (14) under the aforementioned
optimized conditions, spirocyclopropane 3a was added. The
reaction proceeded at room temperature within 12h, af-
fording 2-methyl-3-phenylhexahydrobenzopyran-5-one (5j)
in 73% yield (Chart 6a). From this result, it was found that
sulfoxonium ethylide 2b was generated from 14 under these
conditions.26) The stereochemistry of 5j was determined from
1H nuclear Overhauser effect experiments to be 2,3-trans
a) All reactions were performed on a 0.3mmol scale. After preparation of sulf- (see Supplementary materials), as in previous results.19) Tri-
oxonium ylide 2a from 1.5eq of sulfoxonium salt 7b with 1.2eq of sodium hydride
butylsulfoxonium chloride (17) was determined to be a very
in DMSO for 0.5h in situ, spirocyclopropane 3, 8 or 10 was added to the reaction
mixture. b) The ratio of 5i to 5i′ was determined from 1H-NMR analysis of the crude
good precursor in the formation of sulfoxonium butylide 2c
to furnish the final trans-3-phenyl-2-propyl-substituted prod-
uct 5k in 72% yield (Chart 6b). Next, the reaction of 3a with
product.
tion using m-chloroperoxybenzoic acid (mCPBA) resulted in benzyldimethylsulfoxonium chloride (20) was examined under
the formation of sulfoxonium salt 14 (Chart 5a). Next, tributyl- the same conditions, which was found to proceed smoothly
sulfoxonium chloride (17) was prepared according to the same to afford trans-2,3-diphenyl-substituted 5l as the sole prod-
procedure. Alkylation of dibutyl sulfide (15) followed by an uct in 90% yield (Chart 6c). This result clearly implies that

482
Chem. Pharm. Bull.
Vol. 68, No. 5 (2020)
application of the present method in the synthesis of a variety
of flavan- and isoflavan-based natural products is currently in
progress.
Experimental
General Melting points are uncorrected. IR spectra were
recorded on a JASCO FT/IR-460 Plus spectrophotometer and
absorbance bands are reported in wavenumber (cm−1). All
NMR spectra were recorded using a JEOL JNM-ECX400P
spectrometer. 1H-NMR spectra were recorded at 400 or
500MHz. Chemical shifts are reported relative to internal
standard (tetramethylsilane at δH 0.00, CDCl3 at δH 7.26, or
(CD3)2SO at δH 2.50). Data are presented as follows: chemical
shift (δ, ppm), multiplicity (s=singlet, d=doublet, t=triplet,
q=quartet, quint=quintet, sext=sextet, m=multiplet), cou-
pling constant and integration. 13C-NMR spectra were record-
ed at 100 or 126MHz. The following internal reference was
used (CDCl3 at δC 77.0 or (CD3)2SO at δC 39.5). All 13C-NMR
spectra were determined with complete proton decoupling.
High-resolution mass spectra (HR-MS) were determined with
JEOL JMS-GCmate II instrument [electron ionization (EI)]
and Thermo Scientific LTQ Orbitrap XL ETD [electrospray
ionization (ESI)]. Column chromatography was performed on
Silica Gel 60 PF254 (Nacalai Tesque, Kyoto, Japan) and Kanto
silica gel 60N (63–210 mesh) under pressure. Analytical TLC
was carried out on Merck Kieselgel 60F254 plates. Visualiza-
tion was accomplished with UV light and phosphomolybdic
acid stain solution followed by heating.
Chart 6. Reaction of Spirocyclopropanes 3a and 3e with Sulfoxonium
Ylides 2b–d Prepared from Sulfoxonim Salts 14, 17 and 20
Chart 7. Conversion of Hexahydrobenzopyran-5-ones 5a and 5m into
5-Hydroxyisoflavan (21) and 5-Hydroxyflavan (22)
Reagents were used as received unless otherwise noted.
Sodium hydride (60% dispersion in mineral oil) was washed
with three portions of dry hexane to remove the mineral oil and
the corresponding sulfoxonium benzylide 2d was formed as the remaining sodium hydride was dried in vacuo. Dehydrated
expected. The reaction of 2′,3′-nonsubstituted spirocyclopro- DMSO, DMF, CH2Cl2, toluene, THF, acetonitrile, and metha-
pane 3e with 20 proceeded at 50°C, providing the 2-phenyl- nol were purchased from Kanto Chemical Co., Inc. (Tokyo,
substituted product 5k27,28) in 84% yield (Chart 6c). In the Japan) and Wako Pure Chemical Corporation (Osaka, Japan).
case of the reactions of 14 and 17, either diethyl sulfoxide or 1-Phenylspiro[2.5]octane-4,8-dione (3a),20) 6,6-dimethyl-1-
dibutyl sulfoxide are expelled as by-products in the cyclization phenylspiro[2.5]octane-4,8-dione (3b),20) 1-(4-methylphenyl)-
step. However, the reaction of 20 produces dimethyl sulfoxide spiro[2.5]octane-4,8-dione
as a leaving group. It is very interesting and useful in terms spiro[2.5]octane-4,8-dione (3d),20) spiro[2.5]octane-4,8-dione
of atom economy that the dimethyl group in 20 can act as a (3e),23) (3f),23)
6,6-dimethylspiro[2.5]octane-4,8-dione
dummy substituent.
6-methylspiro[2.5]octane-4,8-dione (3g),23) 6-phenylspiro[2.5]-
(3c),20)
1-(4-bromophenyl)-
To demonstrate the utility of this reaction, the conversions octane-4,8-dione (3h),23) 1-butylspiro[2.5]octane-4,8-dione
of hexahydrobenzopyran-5-ones 5a and 5m into isoflavan (3i),17) 1-phenylspiro[2.4]heptane-4,7-dione (10),20) 1,1-diacetyl-
and flavan derivatives 21 and 22 were carried out (Chart 7), 2-phenylcyclopropane (12),23) and triethylsulfoxonium chloride
because isoflavan and flavan are structural motifs found in a (14)24) were prepared according to literature procedures.
number of biologically active natural products.29–32) On the
Typical Procedure for the Ring-Opening Cyclization of
basis of a reported procedure for the aromatization of cyclo- Spirocyclopropane 3 with Sulfoxonium Salt 7: 3-Phenyl-
hexenone,33) reaction of 5a and 5m with iodine in methanol 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one (5a) (Table
followed by aromatization using a combination of LiI and 1, Entry 9) Trimethylsulfoxonium chloride (7b) (58mg,
Li2CO3 afforded 5-hydroxyisoflavan (21) and 5-hydroxyflavan 0.45mmol) was added to a suspension of sodium hydride
(22) in 68 and 61% yields, respectively.
(8.6mg, 0.36mmol) in DMSO (1.5mL) at room temperature.
In conclusion, a regioselective ring-opening cyclization of After stirring for 30min, 1-phenylspiro[2.5]octane-4,8-dione
spirocyclopropanes with dimethylsulfoxonium methylide has (3a) (64mg, 0.30mmol) was added to the mixture. After stir-
been developed, which affords 2-nonsubstituted hexahydro- ring at room temperature for 12h, the reaction was quenched
benzopyran-5-ones in up to 83% yields. Spirocyclopropanes with water (3mL) and the whole mixture was extracted with
derived from cycloheptane- and cyclopentane-1,3-diones could EtOAc (3×10mL). The combined organic layer was washed
be applied to this reaction. It was also found that sulfoxonium with brine (10mL) and dried over anhydrous MgSO4. The fil-
ethylide, butylide, and benzylide can be used in the present trate was concentrated in vacuo, and the residue was purified
protocol. Moreover, it was shown that the dimethyl group can by column chromatography (silica gel, 30% EtOAc in hexane)
act as a dummy substituent. The obtained products were read- to provide 5a (56mg, 82%) as a white solid: mp 117.0–117.5°C;
ily converted into flavan and isoflavan derivatives. Further IR (KBr, cm−1) 2949, 1640, 1617, 1398, 1379, 1215, 1188, 1129,

Vol. 68, No. 5 (2020)
Chem. Pharm. Bull.
483
1
1008, 981, 764, 702; H-NMR (400MHz, CDCl3) δ: 7.34 (t, crude product was purified by column chromatography (silica
J=7.2Hz, 2H), 7.26 (t, J=7.2Hz, 1H), 7.21 (d, J=7.2Hz, gel, 40% EtOAc in hexane) to provide 5e (35mg, 78%) as a
2H), 4.32 (ddd, J=10.8, 4.0, 2.0Hz, 1H), 3.90 (td, J=10.8, white solid: mp 41.5–42.0°C; IR (KBr, cm−1) ν 2941, 1644,
1
2.8Hz, 1H), 3.04 (tt, J=10.8, 4.0Hz, 1H), 2.73 (ddd, J=16.4, 1617, 1399, 1275, 1228, 1178, 1131, 1092, 964, 859; H-NMR
4.0, 2.0Hz, 1H), 2.46–2.29 (m, 5H), 2.04–1.92 (m, 2H); (400MHz, CDCl3) δ: 4.10 (t, J=5.2Hz, 2H), 2.39–2.35 (m,
13C-NMR (100MHz, CDCl3) δ: 198.1, 171.0, 140.6 128.7, 4H), 2.24 (t, J=6.4Hz, 2H), 1.95 (quint, J=6.4Hz, 2H),
127.3, 127.1, 111.6, 71.4, 37.8, 36.6, 28.4, 24.9, 20.8; HR-MS 1.90–1.84 (m, 2H); 13C-NMR (100MHz, CDCl3) δ: 198.2,
(EI) m/z Calcd for C15H16O2 (M+) 228.1150. Found 228.1142.
171.5, 111.6, 67.3, 36.6, 28.6, 21.4, 20.8, 17.5; HR-MS (EI) m/z
7,7-Dimethyl-3-phenyl-2,3,4,6,7,8-hexahydro-5H-1-ben- Calcd for C9H12O2 (M+) 152.0837. Found 152.0801.
zopyran-5-one (5b) (Table 2, Entry 1) According to the 7,7-Dimethyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-
typical procedure for the ring-opening cyclization of 3a with 5-one (5f) (Table 2, Entry 5) According to the typical
7b, 5b was prepared from 3b (73mg, 0.30mmol) with 7b procedure for the ring-opening cyclization of 3a with 7b, 5f
(58mg, 0.45mmol). The crude product was purified by col- was prepared from 3f (50mg, 0.30mmol) with 7b (58mg,
umn chromatography (silica gel, 25% EtOAc in hexane) to 0.45mmol). The crude product was purified by column chro-
provide 5b (64mg, 83%) as a white solid: mp 92.0–92.5°C; IR matography (silica gel, 25% EtOAc in hexane) to provide 5f
(KBr, cm−1) ν 2952, 1651, 1624, 1455, 1395, 1377, 1215, 1168, (40mg, 74%) as a colorless oil: IR (film, cm−1) ν 2955, 1654,
1
1125, 1026, 765, 702; H-NMR (400MHz, CDCl3) δ: 7.34 (t, 1626, 1397, 1372, 1270, 1232, 1200, 1165, 1125, 1089, 1065,
1
J=7.6Hz, 2H), 7.26 (t, J=7.6Hz, 1H), 7.21 (d, J=7.6Hz, 960; H-NMR (500MHz, CDCl3) δ: 4.10 (t, J=5.0Hz, 2H),
2H), 4.31 (ddd, J=10.4, 4.0, 2.4Hz, 1H), 3.92 (t, J=10.4Hz, 2.26–2.23 (m, 6H), 1.87 (quint, J=5.0Hz, 2H), 1.06 (s, 6H);
1H), 3.04 (tt, J=10.4, 4.0Hz, 1H), 2.74 (m, 1H), 2.38–2.22 (m, 13C-NMR (126MHz, CDCl3) δ: 197.9, 169.7, 110.2, 67.4, 50.5,
5H), 1.09 (s, 3H), 1.08 (s, 3H); 13C-NMR (100MHz, CDCl3) δ: 42.4, 31.9, 28.5, 28.3, 21.4, 17.2; HR-MS (EI) m/z Calcd for
197.7, 169.2, 140.6, 128.7, 127.3, 127.1, 110.2, 71.4, 50.5, 42.1, C11H16O2 (M+) 180.1150. Found 180.1146.
37.7, 32.1, 29.0, 27.7, 24.5; HR-MS (EI) m/z Calcd for C17H20O2
7-Methyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one
(5g) (Table 2, Entry 6) According to the typical procedure
(M+) 256.1463. Found 256.1450.
3-(4-Methylphenyl)-2,3,4,6,7,8-hexahydro-5H-1-benzopy- for the ring-opening cyclization of 3a with 7b, 5g was pre-
ran-5-one (5c) (Table 2, Entry 2) According to the typical pared from 3g (46mg, 0.30mmol) with 7b (58mg, 0.45mmol).
procedure for the ring-opening cyclization of 3a with 7b, 5c The crude product was purified by column chromatography
was prepared from 3c (68mg, 0.30mmol) with 7b (58mg, (silica gel, 40% EtOAc in hexane) to provide 5g (37mg, 74%)
0.45mmol). The crude product was purified by column chro- as a white solid: mp 76.0–76.5°C; IR (KBr, cm−1) ν 2948,
1
matography (silica gel, 30% EtOAc in hexane) to provide 1644, 1615, 1396, 1298, 1225, 1134, 1066, 964, 916; H-NMR
5c (60mg, 82%) as a white solid: mp 72.5–73.0°C; IR (KBr, (400MHz, CDCl3) δ: 4.17 (dt, J=10.8, 6.4Hz, 1H), 4.02 (ddd,
cm−1) ν 2940, 1645, 1620, 1518, 1463, 1395, 1213, 1186, 1128, J=10.8, 7.6, 4.0Hz, 1H), 2.44 (m, 1H), 2.36 (dd, J=15.6,
1
1080, 1009, 980, 817; H-NMR (400MHz, CDCl3) δ: 7.14 (d, 2.4Hz, 1H), 2.31–2.01 (m, 5H), 1.93–1.81 (m, 2H), 1.06 (d,
J=8.0Hz, 2H), 7.10 (d, J=8.0Hz, 2H), 4.29 (ddd, J=10.8, J=5.6Hz, 3H); 13C-NMR (100MHz, CDCl3) δ: 198.2, 170.9,
4.0, 2.4Hz, 1H), 3.86 (t, J=10.8Hz, 1H), 3.00 (tt, J=10.8, 111.1, 67.4, 45.0, 36.7, 28.4, 21.4, 21.0, 17.4; HR-MS (EI) m/z
4.0Hz, 1H), 2.71 (ddq, J=16.4, 5.6, 1.6Hz, 1H), 2.45–2.38 (m, Calcd for C10H14O2 (M+) 166.0994. Found 166.0998.
4H), 2.33 (s, 3H), 2.31 (m, 1H), 2.05–1.91 (m, 2H); 13C-NMR
7-Phenyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one
(100MHz, CDCl3) δ: 198.0, 170.9, 137.4, 136.7, 129.4, 127.1, (5h) (Table 2, Entry 7) According to the typical procedure
111.6, 71.4, 37.3, 36.6, 28.3, 24.8, 21.0, 20.8; HR-MS (EI) m/z for the ring-opening cyclization of 3a with 7b, 5h was pre-
Calcd for C16H18O2 (M+) 242.1307. Found 242.1340.
pared from 3h (64mg, 0.30mmol) with 7b (58mg, 0.45mmol).
3-(4-Bromophenyl)-2,3,4,6,7,8-hexahydro-5H-1-benzo- The crude product was purified by column chromatogra-
pyran-5-one (5d) (Table 2, Entry 3) According to the phy (silica gel, 30% EtOAc in hexane) to provide 5h (48mg,
typical procedure for the ring-opening cyclization of 3a with 71%) as a white solid: mp 78.0–78.5°C; IR (KBr, cm−1) ν
7b, 5d was prepared from 3d (88mg, 0.30mmol) with 7b 2944, 1647, 1613, 1398, 1276, 1182, 1128, 1091, 1062, 964,
1
(58mg, 0.45mmol). The crude product was purified by col- 763, 704; H-NMR (400MHz, CDCl3) δ: 7.34 (t, J=7.2Hz,
umn chromatography (silica gel, 40% EtOAc in hexane) to 2H), 7.25–7.23 (m, 3H), 4.22 (m, 1H), 4.05 (td, J=10.4,
provide 5d (65mg, 71%) as a white solid: mp 125.0–125.5°C; 3.6Hz, 1H), 3.34 (tt, J=11.6, 4.4Hz, 1H), 2.71–2.54 (m, 4H),
IR (KBr, cm−1) ν 2939, 1645, 1619, 1489, 1462, 1395, 1214, 2.36–2.21 (m, 2H), 1.91–1.90 (m, 2H); 13C-NMR (100MHz,
1
1187, 1130, 1106, 1072, 1008, 978, 825; H-NMR (400MHz, CDCl3) δ: 197.2, 170.6, 143.0, 128.7, 126.9, 126.6, 111.4, 67.6,
CDCl3) δ: 7.46 (d, J=8.0Hz, 2H), 7.08 (d, J=8.0Hz, 2H), 43.7, 38.9, 36.1, 21.4, 17.5; HR-MS (EI) m/z Calcd for C15H16O2
4.28 (ddd, J=10.4, 3.2, 2.4Hz, 1H), 3.87 (t, J=10.4Hz, 1H), (M+) 228.1150. Found 228.1147.
3.01 (tt, J=10.4, 3.2Hz, 1H), 2.71 (dd, J=16.4, 3.2Hz, 1H),
3-Butyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one
2.45–2.35 (m, 4H), 2.29 (dd, J=16.4, 10.4Hz, 1H), 2.04–1.93 (5i) and 4-Butyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-
(m, 2H); 13C-NMR (100MHz, CDCl3) δ: 197.9, 170.9, 139.5, 5-one (5i′) (Table 2, Entry 8) According to the typical
131.8, 129.0, 120.9, 111.3, 71.0, 37.2, 36.6, 28.3, 24.7, 20.8; procedure for the ring-opening cyclization of 3a with 7b, 5i
HR-MS (EI) m/z Calcd for C15H15BrO2 (M+) 306.0255. Found and 5i′ were prepared from 3i (58mg, 0.30mmol) with 7b
306.0235.
2,3,4,6,7,8-Hexahydro-5H-1-benzopyran-5-one
(58mg, 0.45mmol). The crude product was purified by column
(5e) chromatography (silica gel, 15% EtOAc in hexane) to provide
(Table 2, Entry 4) According to the typical procedure for 5i (38mg, 62%) as a colorless oil and 5i′ (13mg, 21%) as a
the ring-opening cyclization of 3a with 7b, 5e was prepared colorless oil. 5i: IR (neat, cm−1) ν 2929, 1655, 1625, 1395,
1
from 3e (41mg, 0.30mmol) with 7b (58mg, 0.45mmol). The 1377, 1215, 1188, 1132, 1006, 754; H-NMR (400MHz, CDCl3)

484
Chem. Pharm. Bull.
Vol. 68, No. 5 (2020)
δ: 4.15 (ddd, J=10.4, 3.6, 2.4Hz, 1H), 3.59 (t, J=10.4Hz, HR-MS (EI) m/z Calcd for C16H18O2 (M+) 242.1307. Found
1H), 2.49 (ddd, J=15.2, 4.4, 2.0Hz, 1H), 2.42–2.30 (m, 242.1320.
4H), 2.01–1.89 (m, 2H), 1.87–1.70 (m, 2H), 1.46–1.19 (m,
3-Phenyl-3,4,6,7-tetrahydrocyclopenta[b]pyran-5(2H)-
6H), 0.90 (t, J=7.2Hz, 3H); 13C-NMR (100MHz, CDCl3) one (11) (Table 2, Entry 10) According to the typical
δ: 198.3, 171.3, 111.1, 71.5, 36.6, 31.5, 31.4, 28.7, 28.4, 24.1, procedure for the ring-opening cyclization of 3a with 7b, 11
22.7, 20.8, 13.9; HR-MS (EI) m/z Calcd for C13H20O2 (M+) was prepared from 10 (60mg, 0.30mmol) with 7b (58mg,
208.1463. Found 208.1445. 5i′: IR (neat, cm−1) ν 2952, 1653, 0.45mmol). The crude product was purified by column chro-
1615, 1396, 1372, 1277, 1182, 1124, 1083, 1022; 1H-NMR matography (silica gel, 40% EtOAc in hexane) to provide 11
(400MHz, CDCl3) δ: 4.18 (dtd, J=10.8, 4.0, 1.2Hz, 1H), 4.03 (26mg, 41%) as a white solid: mp 107.5–108.0°C; IR (KBr,
(td, J=10.8, 4.0Hz, 1H), 2.61 (m, 1H), 2.43–2.27 (m, 4H), cm−1) ν 2932, 1681, 1625, 1460, 1402, 1237, 1116, 956, 768,
1
1.92 (quint, J=6.4Hz, 2H), 1.81–1.70 (m, 2H), 1.61 (m, 1H), 708; H-NMR (400MHz, CDCl3) δ: 7.36 (t, J=7.2Hz, 2H),
1.38–1.23 (m, 4H), 1.11 (tdd, J=9.2, 8.4, 5.2Hz, 1H), 0.89 (t, 7.28 (t, J=7.2Hz, 1H), 7.21 (d, J=7.2Hz, 2H), 4.44 (ddd,
J=6.4Hz, 3H); 13C-NMR (100MHz, CDCl3) δ: 197.7, 170.7, J=10.8, 4.0, 2.0Hz, 1H), 4.09 (t, J=10.8Hz, 1H), 3.06 (tt,
116.1, 63.5, 37.2, 33.5, 29.4, 28.8, 26.7, 24.7, 22.7, 20.9, 14.1; J=10.8, 4.4Hz, 1H), 2.63–2.55 (m, 3H), 2.51–2.48 (m, 2H),
HR-MS (EI) m/z Calcd for C13H20O2 (M+) 208.1463. Found 2.36 (m, 1H); 13C-NMR (100MHz, CDCl3) δ: 203.5, 183.9,
208.1483.
Preparation of 1-Phenylspiro[2.6]nonane-4,9-dione (8) (EI) m/z Calcd for C14H14O2 (M+) 214.0994. Found 214.1007.
(Table 2, Entry 9) According to our reported proce- Preparation of Tributylsulfoxonium Chloride (17) (Chart
139.8, 128.9, 127.4, 115.3, 73.3, 37.5, 33.7, 26.2, 23.4; HR-MS
dure for the synthesis of spirocyclopropanes from cycloal- 5) Dibutyl sulfide (15) (920mg, 5.00mmol), butyl iodide
kane-1,3-diones with sulfonium salt,20) 8 was prepared (805mg, 5.50mmol) and iodine (635mg, 2.50mmol) were
from cycloheptane-1,3-dione with (2-bromo-1-phenylethyl)- heated at 70°C and stirred in the dark for 24h. The result-
dimethylsulfonium bromide. Powdered K2CO3 (726mg, ing mixture was then transferred to a flask containing water
3.00mmol) and cycloheptane-1,3-dione (221mg, 1.75mmol) (15mL) and CH2Cl2 (10mL). After the addition of benzyl-
were added to a suspension of the sulfonium salt (857mg, tributylammonium chloride (1.56g, 5.00mmol), the reaction
2.63mmol) in EtOAc (17.5mL). After stirring at room tem- mixture was stirred at room temperature for 24h. The aque-
perature for 8h, the sulfonium salt (286mg, 0.87mmol) and ous layer was separated from the reaction mixture and washed
powdered K2CO3 (242mg, 1.75mmol) were further added to with CH2Cl2 (5 ×10mL). Evaporation of water in vacuo fur-
the reaction mixture. After stirring at room temperature for nished the crude product 16 (1.05g, approx. 4.40mmol) as a
2h, the reaction mixture was filtered through a Celite pad and colorless oil, which was used in the next step without further
the filter cake was rinsed with EtOAc (100mL). Combined purification.
filtrates were washed with water (30mL) and the aqueous
RuCl3 (46mg, 0.22mmol) was added to a biphasic solu-
layer was extracted with EtOAc (2×15mL). The combined tion of crude product 16 in acetonitrile (6.3mL), CH2Cl2
organic layer was washed with brine (30mL) and dried over (6.3mL), and water (9.4mL). The mixture was stirred vigor-
anhydrous MgSO4. The filtrate was concentrated in vacuo, ously at room temperature for 10min and then NaIO4 (3.77g,
and the residue was purified by column chromatography 17.6mmol) was added in 5 portions over 10min to the brown
(silica gel, 1:1 Et2O/hexane) to provide 8 (332mg, 83%) as colored solution. After stirring at room temperature for 12h,
a white solid: mp 76.5–77.0°C; IR (KBr, cm−1) ν 2945, 1701, the reaction was quenched with MeOH (20mL) and the re-
1677, 1496, 1457, 1333, 1221, 1205, 1127, 1110, 966, 948, 897, sulting suspension was filtered through a Celite pad, and
1
782, 754; H-NMR (400MHz, CDCl3) δ: 7.28–7.19 (m, 3H), the filter cake was rinsed with MeOH (20mL). The filtrate
7.12–7.09 (m, 2H), 3.37 (t, J=8.0Hz, 1H), 2.73 (m, 1H), 2.64 was concentrated in vacuo, and the residue was purified by
(dt, J=12.8, 4.4Hz, 1H), 2.39 (dd, J=8.0, 4.0Hz, 1H), 2.32 column chromatography (silica gel, 4:4:1 CH2Cl2/hexane/
(m, 1H), 2.03–1.86 (m, 4H), 1.81 (m, 1H), 1.71 (dd, J=8.8, MeOH) to provide 17 (206mg, 18% from 15) as a white solid:
4.4Hz, 1H); 13C-NMR (100MHz, CDCl3) δ: 206.0, 205.3, mp 99.0–99.5°C; IR (KBr, cm−1) ν 2960, 2872, 1469, 1385,
133.9, 128.3, 128.2, 127.4, 52.4, 41.9, 41.8, 38.7, 24.0, 22.3, 1183, 1091, 936, 750; 1H-NMR (400MHz, CDCl3) δ: 4.39
20.8; HR-MS (EI) m/z Calcd for C15H16O2 (M+) 228.1150. (t, J=7.6Hz, 6H), 1.93 (quint, J=7.6Hz, 6H), 1.60 (sext,
Found 228.1163.
J=7.6Hz, 6H), 1.03 (t, J=7.6Hz, 9H); 13C-NMR (100MHz,
3-Phenyl-3,4,6,7,8,9-hexahydrocyclohepta[b]pyran- CDCl3) δ: 49.6, 22.0, 21.6, 13.5; HR-MS (ESI+) m/z Calcd for
5(2H)-one (9) (Table 2, Entry 9) According to the typical C24H54ClO2S2 [2(nBu3SO)+Cl−]+ 473.3248. Found 473.3261.
procedure for the ring-opening cyclization of 3a with 7b,
Preparation of Benzyldimethylsulfoxonium Chloride
9 was prepared from 8 (68mg, 0.30mmol) with 7b (58mg, (20) (Chart 5) Dimethyl sulfide (18) (1.86g, 30.0mmol)
0.45mmol). The crude product was purified by column chro- and benzyl bromide (855mg, 5.00mmol) were stirred at room
matography (silica gel, 20% EtOAc in hexane) to provide 9 temperature for 24h. The resulting white precipitate was col-
(47mg, 64%) as a colorless oil: IR (film, cm−1) ν 2939, 1639, lected by suction, washed with Et2O (10mL), dried in vacuo,
1611, 1455, 1375, 1349, 1235, 1195, 1182, 1152, 1107, 1029, and then dissolved in water (15mL) and CH2Cl2 (10mL). After
1
995, 956, 757, 700; H-NMR (400MHz, CDCl3) δ: 7.33 (t, the addition of benzyltributylammonium chloride (1.56g,
J=7.2Hz, 2H), 7.27–7.19 (m, 3H), 4.28 (dt, J=10.4, 4.0Hz, 5.00mmol), the reaction mixture was stirred at room tempera-
1H), 3.84 (t, J=10.4Hz, 1H), 2.96 (tt, J=10.4, 4.0Hz, 1H), ture for 24h. The aqueous layer was separated from the reac-
2.81 (dd, J=16.4, 4.0Hz, 1H), 1.80 (m, 1H), 2.63–2.59 (m, tion mixture and washed with CH2Cl2 (5 ×10mL). Evapora-
3H), 2.32 (dd, J=16.8, 10.4Hz, 1H), 1.92–1.75 (m, 4H); tion of water in vacuo furnished the crude product 19 (630mg,
13C-NMR (100MHz, CDCl3) δ: 201.3, 171.4, 140.9, 128.7, approx. 3.34mmol) as a colorless oil, which was used in the
127.3, 127.0, 114.0, 71.3, 41.2, 37.7, 32.1, 27.5, 23.5, 21.1; next step without further purification.

Vol. 68, No. 5 (2020)
Chem. Pharm. Bull.
485
RuCl3 (35mg, 0.17mmol) was added to a biphasic solu- 2.59–2.38 (m, 5H), 2.04 (quint, J=6.0Hz, 2H); 13C-NMR
tion of crude product 19 in acetonitrile (4.8mL), CH2Cl2 (100MHz, CDCl3) δ: 198.0, 171.0, 140.4, 138.3, 128.3, 128.1,
(4.8mL), and water (7.1mL). The mixture was stirred vigor- 128.0, 127.9, 127.0, 126.7, 112.0, 83.8, 45.2, 36.6, 28.5, 26.3,
ously at room temperature for 10min and then NaIO4 (2.86g, 20.9; HR-MS (EI) m/z Calcd for C21H20O2 (M+) 304.1463.
13.4mmol) was added in 5 portions over 10min to the brown Found 304.1488.
colored solution. After stirring at room temperature for 12h,
2-Phenyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one
the reaction was quenched with MeOH (20mL) and the result- (5m)27,28) (Chart 6) According to the typical procedure for
ing suspension was filtered through a Celite pad, and the filter the ring-opening cyclization of 3a with 7b, 5m was prepared
cake was rinsed with MeOH (20mL). The filtrate was concen- from 3e (41mg, 0.30mmol) with 20 (92mg, 0.45mmol) at
trated in vacuo and the crude solid was purified by recrystal- 50°C. The crude product was purified by column chroma-
lization from MeOH/CHCl3 to provide 20 (446mg, 44% from tography (silica gel, 8:1.5:0.5 CH2Cl2/hexane/EtOAc) to
benzyl bromide) as a white solid: mp 162.5–163.0°C; IR (KBr, provide 5m (57mg, 84%) as a colorless oil: IR (neat, cm−1) ν
1
1
cm−1) ν 2962, 2878, 1496, 1236, 1050, 958, 776, 700; H-NMR 2943, 1651, 1622, 1394, 1293, 1181, 1073, 759, 700; H-NMR
(400MHz, (CD3)2SO) δ: 7.56–7.50 (m, 5H), 5.76 (s, 2H), 3.91 (400MHz, CDCl3) δ: 7.41–7.32 (m, 5H), 4.94 (dd, J=10.4,
(s, 6H); 13C-NMR (100MHz, (CD3)2SO) δ: 131.8, 130.3, 129.4, 2.4Hz, 1H), 2.52–2.35 (m, 5H), 2.28 (m, 1H), 2.17 (m, 1H),
123.8, 56.5, 36.4; HR-MS (EI) m/z Calcd for C9H13ClOS (M+) 2.05–1.97 (m, 2H) 1.90 (m, 1H); 13C-NMR (100MHz, CDCl3)
204.0376. Found 204.0390.
δ: 198.2, 171.5, 140.3, 128.6, 128.2, 125.9, 111.6, 79.1, 36.7,
rel-(2R,3S)-2-Methyl-3-phenyl-2,3,4,6,7,8-hexahydro-5H- 29.1, 28.7, 20.9, 18.1.
1-benzopyran-5-one (5j) (Chart 6) According to the typical
Typical Procedure for the Synthesis of Isoflavan and
procedure for the ring-opening cyclization of 3a with 7b, 5j Flavan Derivatives: 5-Hydroxy-3-phenyl-3,4-dihydro-2H-
was prepared from 3a (64mg, 0.30mmol) with 1424) (77mg, 1-benzopyran (21) (Chart 7) Iodine (228mg, 0.90mmol,)
0.45mmol). The crude product was purified by column chro- was added to a solution of 5a (68mg, 0.30mmol) in MeOH
matography (silica gel, 40% EtOAc in hexane) to provide 5j (1.5mL) at room temperature. After stirring for 3h, the reac-
(53mg, 73%) as a white solid: mp 131.5–132.0°C; IR (KBr, tion mixture was quenched by addition of saturated aqueous
cm−1) ν 2930, 1646, 1616, 1455, 1392, 1378, 1244, 1227, 1188, Na2S2O3 (3mL), and the resulting mixture was extracted with
1
1100, 1030, 987, 865, 758, 702; H-NMR (400MHz, CDCl3) EtOAc (3×10mL). The combined organic layers were washed
δ: 7.31 (t, J=7.2Hz, 2H), 7.24 (t, J=7.2Hz, 1H), 7.13 (d, with water (10mL) and brine (10mL), and dried over anhy-
J=7.2Hz, 2H), 4.12 (dq, J=10.0, 6.4Hz, 1H), 2.68 (dd, drous MgSO4. Filtration and evaporation in vacuo furnished
J=16.0, 5.2Hz, 1H), 2.60 (td, J=10.0, 5.2Hz, 1H), 2.45–2.37 the crude product (152mg), which was used in the next step
(m, 4H), 2.31 (dd, J=16.0, 11.2Hz, 1H), 2.06–1.92 (m, 2H), without further purification.
1.14 (d, J=6.4Hz, 3H); 13C-NMR (100MHz, CDCl3) δ: 198.0,
LiI (24mg, 0.33mmol) and Li2CO3 (44mg, 0.33mmol) were
171.0, 141.7, 128.7, 127.7, 127.0, 111.9, 77.7, 45.2, 36.6, 28.5, added to a solution of crude product in DMF (3.0mL). After
26.8, 20.9, 19.2; HR-MS (EI) m/z Calcd for C16H18O2 (M+) stirring at reflux for 2.0h, the reaction was cooled to room
242.1307. Found 242.1303.
temperature and diluted with 20% EtOAc in hexane (3mL).
rel-(2R,3S)-2-Propyl-3-phenyl-2,3,4,6,7,8-hexahydro-5H- The reaction mixture was quenched by addition of saturated
1-benzopyran-5-one (5k) (Chart 6) According to the typi- aqueous NH4Cl (3mL), and the resulting mixture was ex-
cal procedure for the ring-opening cyclization of 3a with 7b, tracted with 20% EtOAc in hexane (3×10mL). The combined
5k was prepared from 3a (64mg, 0.30mmol) with 17 (115mg, organic layers were washed with water (10mL) and brine
0.45mmol). The crude product was purified by column chro- (10mL), and dried over anhydrous MgSO4. Filtration was
matography (silica gel, 30% EtOAc in hexane) to provide concentrated in vacuo, and the residue was purified by column
5k (58mg, 74%) as a colorless oil: IR (neat, cm−1) ν 2957, chromatography (silica gel, 40% EtOAc in hexane) to provide
1
1652, 1624, 1392, 1223, 1187, 1112, 959, 760, 702; H-NMR 21 (46mg, 68%) as a pale yellow solid: mp 79.5–80.0°C;
(400MHz, CDCl3) δ: 7.31 (t, J=7.2Hz, 2H), 7.24 (tt, J=7.2, IR (KBr, cm−1) ν 3400, 2925, 1707, 1616, 1595, 1496, 1470,
1.6Hz, 1H), 7.12 (dd, J=7.2, 1.6Hz, 2H), 4.03 (ddd, J=8.8, 1460, 1329, 1276, 1234, 1091, 1073, 1029, 980, 774, 757,
1
7.6, 4.0Hz, 1H), 2.72–2.65 (m, 2H), 2.45–2.37 (m, 4H), 2.30 700; H-NMR (400MHz, CDCl3) δ: 7.36 (t, J=7.6Hz, 2H),
(ddt, J=17.2, 12.0, 2.0Hz, 1H), 2.04–1.93 (m, 2H), 1.51 (m, 7.29–7.24 (m, 3H), 6.99 (t, J=8.4Hz, 1H), 6.51 (d, J=8.4Hz,
1H), 1.41–1.26 (m, 3H), 0.82 (t, J=7.2Hz, 3H); 13C-NMR 1H), 6.37 (d, J=8.4Hz, 1H), 4.87 (s, 1H), 4.35 (dq, J=10.4,
(100MHz, CDCl3) δ: 198.0, 171.1, 142.0, 128.7, 127.7, 126.8, 1.6Hz, 1H), 4.00 (t, J=10.4, 1H), 3.22 (tt, J=10.8, 4.0Hz,
111.7, 80.9, 43.3, 36.6, 34.8, 28.5, 27.0, 20.9, 18.1, 13.8; HR-MS 1H), 3.07 (ddd, J=16.4, 5.6, 1.6Hz, 1H), 2.80 (dd, J=16.4,
(EI) m/z Calcd for C18H22O2 (M+) 270.1620. Found 270.1620.
12.4Hz, 1H); 13C-NMR (100MHz, CDCl3) δ: 155.5, 154.0,
rel-(2R,3S)-2,3-Diphenyl-2,3,4,6,7,8-hexahydro-5H- 141.3, 128.8, 127.4, 127.2, 127.1, 109.7, 109.1, 106.7, 70.4, 38.1,
1-benzopyran-5-one (5l) (Chart 6) According to the typi- 26.6; HR-MS (EI) m/z Calcd for C15H14O2 (M+) 226.0994.
cal procedure for the ring-opening cyclization of 3a with 7b, Found 226.0999.
5l was prepared from 3a (43mg, 0.20mmol) with 20 (61mg,
5-Hydroxy-2-phenyl-3,4-dihydro-2H-1-benzopyran (22)
0.30mmol). The crude product was purified by column chro- (Chart 7) According to the typical procedure for the synthe-
matography (silica gel, 40% EtOAc in hexane) to provide 5l sis of 21, 22 was prepared from 5m (57mg, 0.25mmol). The
(55mg, 90%) as a white solid: mp 127.0–127.5°C; IR (KBr, crude product was purified by column chromatography (silica
cm−1) ν 2931, 1645, 1617, 1455, 1391, 1340, 1227, 1189, 1128, gel, 20% EtOAc in hexane) to provide 22 (34mg, 61%) as a
1
1092, 1008, 982, 764; H-NMR (400MHz, CDCl3) δ: 7.19–7.07 pale yellow solid: mp 103.5–104.0°C; IR (KBr, cm−1) ν 3404,
(m, 8H), 6.95 (d, J=6.8Hz, 2H), 4.94 (d, J=10.0Hz, 1H), 2925, 1704, 1616, 1592, 1496, 1465, 1339, 1278, 1201, 1055,
1
3.05 (dt, J=10.0, 5.2Hz, 1H), 2.79 (dd, J=16.8, 5.2Hz, 1H), 1017, 774, 758, 700; H-NMR (400MHz, CDCl3) δ: 7.44–7.37

486
Chem. Pharm. Bull.
Vol. 68, No. 5 (2020)
14) Nambu H., Fukumoto M., Hirota W., Yakura T., Org. Lett., 16,
4012–4015 (2014).
15) Nambu H., Hirota W., Fukumoto M., Tamura T., Yakura T., Chem.
Eur. J., 23, 16799–16805 (2017).
16) Nambu H., Tamura T., Yakura T., J. Org. Chem., 84, 15990–15996
(2019).
17) Nambu H., Ono N., Yakura T., Synthesis, 48, 1892–1901 (2016).
18) Nambu H., Onuki Y., Ono N., Yakura T., Adv. Synth. Catal., 2018,
2938–2944 (2018).
(m, 4H), 7.32 (t, J=7.2Hz, 1H), 6.99 (t, J=8.0Hz, 1H), 6.55
(d, J=8.0Hz, 1H), 6.37 (d, J=8.0Hz, 1H), 5.01 (dd, J=10.4,
2.4Hz, 1H), 4.77 (s, 1H), 2.86–2.72 (m, 2H), 2.25 (m, 1H),
2.07 (m, 1H); 13C-NMR (100MHz, CDCl3) δ: 156.3, 153.9,
141.5, 128.5, 127.9, 127.2, 126.0, 109.6, 109.4, 106.6, 77.4, 29.3,
19.4; HR-MS (EI) m/z Calcd for C15H14O2 (M+) 226.0994.
Found 226.1004.
Conflict of Interest The authors declare no conflict of
interest.
19) Nambu H., Onuki Y., Ono N., Tsuge K., Yakura T., Chem. Com-
mun., 55, 6539–6542 (2019).
20) Nambu H., Fukumoto M., Hirota W., Ono N., Yakura T., Tetrahe-
dron Lett., 56, 4312–4315 (2015).
21) Wagner C. E., Kim J.-S., Shea K. J., J. Am. Chem. Soc., 125, 12179–
12195 (2003).
Supplementary Materials The online version of this ar-
ticle contains supplementary materials.
22) Wang D., Schwinden M. D., Radesca L., Patel B., Kronenthal D.,
Huang M.-H., Nugent W. A., J. Org. Chem., 69, 1629–1633 (2004).
23) Nambu H., Ono N., Hirota W., Fukumoto M., Yakura T., Chem.
Pharm. Bull., 64, 1763–1768 (2016).
24) Zhao R., Shea K. J., ACS Macro Lett., 4, 584–587 (2015).
25) Edwards M. G., Paxton R. J., Pugh D. S., Whitwood A. C., Taylor
R. J. K., Synthesis, 3279–3288 (2008).
26) Shea and Zhao reported the preparation of sulfoxonium ethylide 2b
from triethylsulfoxonium chloride (14) using lithium diisopropyl-
amide as a base. See ref. 24.
27) Li M., Chen C., He F., Gu Y., Adv. Synth. Catal., 352, 519–530
(2010).
28) Kotha S., Ali R., Saifuddin M., Tetrahedron, 71, 9003–9011 (2015).
29) Belinky P. A., Aviram M., Fuhrman B., Rosenblat M., Vaya J., Ath-
erosclerosis, 137, 49–61 (1998).
30) Morito K., Hirose T., Kinjo J., Hirakawa T., Okawa M., Nohara T.,
Ogawa S., Inoue S., Muramatsu M., Masamune Y., Biol. Pharm.
Bull., 24, 351–356 (2001).
31) Maloney D. J., Deng J.-Z., Starck S. R., Gao Z., Hecht S. M., J. Am.
Chem. Soc., 127, 4140–4141 (2005).
32) Lee D. Y., Kim D. H., Lee H. J., Lee Y., Ryu K. H., Jung B.-I., Song
Y. S., Ryu J.-H., Bioorg. Med. Chem. Lett., 20, 3764–3767 (2010).
33) Mphahlele M. J., Moekwa T. B., Org. Biomol. Chem., 3, 2469–2475
(2005).
References and Notes
1) Corey E. J., Chaykovsky M., J. Am. Chem. Soc., 84, 867–868
(1962).
2) Corey E. J., Chaykovsky M., J. Am. Chem. Soc., 84, 3782–3783
(1962).
3) Corey E. J., Chaykovsky M., J. Am. Chem. Soc., 87, 1353–1364
(1965).
4) Xiang Y., Fan X., Cai P.-J., Yu Z.-X., Eur. J. Org. Chem., 2019,
582–590 (2019).
5) Schmid M., Grossmann A. S., Wurst K., Magauer T., J. Am. Chem.
Soc., 140, 8444–8447 (2018).
6) Ahmad A., Burtoloso A. C. B., Org. Lett., 21, 6079–6083 (2019).
7) Hajra S., Roy S., Saleh S. A., Org. Lett., 20, 4540–4544 (2018).
8) Patel K., Mishra U. K., Mukhopadhyay D., Ramasastry S. S. V.,
Chem. Asian J., 14, 4568–4571 (2019).
9) Chagarovsky A. O., Budynina E. M., Ivanova O. A., Villemson E.
V., Rybakov V. B., Trushkov I. V., Melnikov M. Y., Org. Lett., 16,
2830–2833 (2014).
10) Aher R. D., Kumar B. S., Sudalai A., J. Org. Chem., 80, 2024–2031
(2015).
11) Triandafillidi I., Savvidou A., Kokotos C. G., Org. Lett., 21, 5533–
5537 (2019).
12) Ivanova O. A., Trushkov I. V., Chem. Rec., 19, 2189–2208 (2019).
13) Budynina E. M., Ivanov K. L., Sorokin I. D., Melnikov M. Y., Syn-
thesis, 49, 3035–3068 (2017).