Multisubstituted furan formation from (Z)- or (E)-enynyl acetates: Tandem reactions accelerated by electron-donating groups on aromatic rings

Article abstract of DOI:10.1021/jo300251c

Multisubstituted furans were readily prepared from (Z)- or (E)-conjugated enynyl acetates with NXS under metal-free conditions at room temperature via the same haloallenyl ketone intermediates. This tandem haloallenyl ketone formation-furan formation reaction sequence was accelerated by electron-donating groups on the aromatic rings.

Full text of DOI:10.1021/jo300251c

Article
pubs.acs.org/joc
Multisubstituted Furan Formation from (Z)- or (E)-Enynyl Acetates:
Tandem Reactions Accelerated by Electron-Donating Groups on
Aromatic Rings
Noriko Okamoto and Reiko Yanada*
Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
S
* Supporting Information
ABSTRACT: Multisubstituted furans were readily prepared
from (Z)- or (E)-conjugated enynyl acetates with NXS under
metal-free conditions at room temperature via the same
haloallenyl ketone intermediates. This tandem haloallenyl
ketone formation−furan formation reaction sequence was
accelerated by electron-donating groups on the aromatic rings.
have reported the tandem synthesis of indoles and isoquino-
lines through a similar reaction pathway catalyzed by In(OTf)3
or PtCl2 as a π-electron coordination metal catalyst.6 On the
other hand, the same cyclization reaction from (E)-enyne
stereoisomers has not been reported because of their steric
factors (path B). Recently, we have communicated a regio- and
stereoselective (Z)- or (E)-haloenol ester synthesis.7 Various
(Z)- and (E)-enynyl acetates could be obtained by Sonogashira
coupling reaction of (Z)- or (E)-haloenol esters and alkynes.
Here, we report the synthesis of multisubstituted furans from
these (Z)- or (E)-enynyl acetates. Without requiring a metal
catalyst, these tandem reactions were accelerated by electron-
donating groups on the aromatic rings.
INTRODUCTION
■
Among heterocycles, five- and six-membered heterocycles are
the most common structural motifs appearting in natural
products and are found in industrial intermediates and
pharmaceuticals. Of the various synthetic methodologies,
cyclization reactions of simple acyclic compounds are attractive
ways to construct these heterocycles.1 Electrophilic cyclizations
have been achieved as an efficient method in the synthesis of
indoles, pyrroles, furans, and thiophenes employing electro-
philes such as transition metals2 and/or halogenation reagents.3
The typical course of these cyclization reactions involves (i)
coordination of the electrophilic source to the unsaturated
carbon−carbon bond of the (Z)-enyne to generate A; (ii)
nucleophilic attack of the heteroatom on the activated
intermediate to produce B; and (iii) facile removal4 or
rearrangement5 of the group G bonded to the heteroatom to
generate the heterocyclic products C (Scheme 1, path A). We
RESULTS AND DISCUSSION
■
The starting materials, (Z)- or (E)-enynyl acetates 1 or 2, were
readily synthesized regio- and stereoselectively from consec-
utive Sonogashira coupling reaction of (Z)- or (E)-iodoenyl
acetates F or G, obtained from the reaction of alkyne E with
NIS and acetic acid according to our method.7 The results are
summarized in Table 1.
Scheme 1. Synthesis of Heteroaromatics C from (Z)- or (E)-
Enyne Stereoisomers
Our initial investigation focused on the optimization of
electrophilic source to unsaturated carbon−carbon bond. We
hypothesized that PtCl2-catalyzed cyclization reaction might
provide a convenient access to furans.6c Contrary to our
expectations, the reaction did not occur at all (Table 2, entry
1). Recently, Jiang and co-workers reported the iodocyclization
reaction of (Z)-enynyl acetate 1 (R1 = R2 = H) with iodine to
produce 2,5-substituted 3-iodofurans under basic conditions.8
We examined the same reaction with 1a and iodine, but furan
3a was obtained in low yield (Table 2, entry 2). Next we
treated 1a with NXS as the electrophilic source directed against
the triple bond of 1a. Most substrates 1 could afford the
corresponding 2,4,5-trisubstituted 3-halofurans 3a−3k′ with
Received: February 14, 2012
Published: March 22, 2012
© 2012 American Chemical Society
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Table 1. Stereoselective Synthesis of (Z)- and (E)-Enynyl Acetates
entry
R1
OMe
R2
R3
1 or 2
yield (%) (Z:E)
1
Ph
Ph
Ph
Ph
p-MeC6H4
Ph
1a
1b
1c
1d
1e
1f
95 (Z)
2
OMe
quant (20:1)
86 (14:1)
90 (25:1)
99 (10:1)
81 (11:1)
88 (9:1)
97 (25:1)
quant (14:1)
96 (E)
3
OMe
cyclohexyl
nBu
4
OMe
5
OMe
p-MeOC6H4
p-MeC6H4
p-FC6H4
Ph
Ph
6
OMe
Ph
7
OMe
Ph
1g
1h
1i
8
NHCO2Et
NHAc
OMe
p-MeC6H4
p-MeC6H4
Ph
9
Ph
nBu
nBu
nBu
nBu
nBu
10
11
12
13
14
15
16
17
18
19
2a
2b
2c
2d
2e
2f
OMe
p-MeOC6H4
p-MeC6H4
p-FC6H4
nBu
87 (E)
OMe
86 (E)
OMe
96 (E)
OMe
81 (E)
OMe
cyclohexyl
Ph
p-MeC6H4
nBu
72 (E)
OMe
2g
2h
2i
76 (E)
NHCO2Et
NHAc
Me
nBu
nBu
nBu
p-MeC6H4
p-MeC6H4
p-MeC6H4
93 (E)
69 (E)
2j
82 (E)
Table 2. Multisubstituted Furan 3 Synthesis with (Z)-Enynyl acetate 1
entry
(Z)-enynyl acetate 1
E
time (h)
furan 3
yield (%)
a
1
1a (R1 = OMe, R2 = Ph, R3 = p-MeC6H4)
PtCl2
I2
24.00
6.00
2.00
0.25
1.00
4.50
6.00
0.25
1.00
0.50
1.50
0.25
6.00
recovery of 1a
b
c
2
1a
3a (R1 = OMe, R2 = Ph, R3 = p-MeC6H4, X = I)
3b (R1 = OMe, R2 = Ph, R3 = p-MeC6H4, X = Br)
3a (R1 = OMe, R2 = Ph, R3 = p-MeC6H4, X = I)
3c (R1 = OMe, R2 = Ph, R3 = Ph, X = I)
(12)
d
3
1a
NBS
NIS
NIS
NIS
NIS
NIS
NBS
NIS
NIS
NIS
NIS
90
71
61
61
67
56
d
4
1a
d
5
1b (R1 = OMe, R2 = Ph, R3 = Ph)
d
6
1c (R1 = OMe, R2 = Ph, R3 = cyclohexyl)
3d (R1 = OMe, R2 = Ph, R3 = cyclohexyl, X = I)
d
n
n
7
1d (R1 = OMe, R2 = Ph, R3 = Bu)
3e (R1 = OMe, R2 = Ph, R3 = Bu, X = I)
d
8
1e (R1 = OMe, R2 = p-MeOC6H4, R3 = Ph)
1f (R1 = OMe, R2 = p-MeC6H4, R3 = Ph)
1f
3f (R1 = OMe, R2 = p-MeOC6H4, R3 = Ph, X = I)
3g (R1 = OMe, R2 = p-MeC6H4, R3 = Ph, X = Br)
3h (R1 = OMe, R2 = p-MeC6H4, R3 = Ph, X = I)
3i (R1 = OMe, R2 = p-FC6H4, R3 = Ph, X = I)
3j (R1 = NHCO2Et, R2 = Ph, R3 = p-MeC6H4, X = I)
3k (R1 = NHAc, R2 = Ph, R3 = p-MeC6H4, X = I)
3k′ (R1 = NAc2, R2 = Ph, R3 = p-MeC6H4, X = I)
d
c
9
(81)
d
10
50
59
57
21
23
d
11
1g (R1 = OMe, R2 = p-FC6H4, R3 = Ph)
1h (R1 = NHCO2Et, R2 = Ph, R3 = p-MeC6H4)
1i (R1 = NHAc, R2 = Ph, R3 = p-MeC6H4)
d
12
d
13
a
b
Compound 1a (1 equiv) and PtCl2 (0.1 equiv) in toluene at 70 °C. Compound 1a (1 equiv), I2 (1.5 equiv), and NaHCO3 (1.5 equiv) in CH2Cl2
at room temp.8 The yield was obtained from H NMR, because 3a or 3g was obtained as inseparable mixture with another structurally unknown
compound. Compound 1 (1 equiv) and NXS (1.2 equiv) in DCE/MeCN = 1/1 at room temp.
c
1
d
NXS (Table 2, entries 3−13). Unfortunately, the reactions were
accompanied by some structurally unknown byproduct.
Therefore, we obtained moderate yields of the iodofurans 3
(Table 2, entries 4−8, 10−13). NBS gave higher product yields
than the yields obtained with NIS, although longer reaction
times were needed (Table 2, entries 3, 4, 9 and 10). The
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Table 3. Multisubstituted Furan 3 Synthesis with (E)-Enynyl Acetate 2
entry
(E)-enynyl acetate 2
E
time (h)
furan 3
yield (%)
a
n
1
2a (R1 = OMe, R2 = Bu, R3 = Ph)
PtCl2
I2
24.0
20.0
1.0
24.0
2.0
0.5
1.0
2.0
4.0
4.5
5.0
1.0
8.0
recovery of 2a
b
n
2
2a
2a
2a
2a
3l (R1 = OMe, R2 = Bu, R3 = Ph, X = I)
51
c
n
3
NBS
NCS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
3m (R1 = OMe, R2 = Bu, R3 = Ph, X = Br)
91
c
4
recovery of 2a
c
n
5
3l (R1 = OMe, R2 = Bu, R3 = Ph, X = I)
92
82
95
93
77
67
69
78
36
44
84
c
n
n
6
2b (R1 = OMe, R2 = Bu, R3 = p-MeOC6H4)
3n (R1 = OMe, R2 = Bu, R3 = p-MeOC6H4, X = I)
c
n
n
7
2c (R1 = OMe, R2 = Bu, R3 = p-MeC6H4)
3o (R1 = OMe, R2 = Bu, R3 = p-MeC6H4, X = I)
c
n
n
8
2d (R1 = OMe, R2 = Bu, R3 = p-FC6H4)
3p (R1 = OMe, R2 = Bu, R3 = p-FC6H4, X = I)
c
n
n
n
n
9
2e (R1 = OMe, R2 = Bu, R3 = Bu)
3q (R1 = OMe, R2 = Bu, R3 = Bu, X = I)
c
10
2f (R1 = OMe, R2 = cyclohexyl, R3 = p-MeC6H4)
3r (R1 = OMe, R2 = cyclohexyl, R3 = p-MeC6H4, X = I)
c
n
n
11
2g (R1 = OMe, R2 = Ph, R3 = Bu)
3e (R1 = OMe, R2 = Ph, R3 = Bu, X = I)
c
n
n
12
2h (R1 = NHCO2Et, R2 = Bu, R3 = p-MeC6H4)
3s (R1 = NHCO2Et, R2 = Bu, R3 = p-MeC6H4, X = I)
c
n
n
13
2i (R1 = NHAc, R2 = Bu, R3 = p-MeC6H4)
3t (R1 = NHAc, R2 = Bu, R3 = p-MeC6H4, X = I)
n
3t′ (R1 = NAc2, R2 = Bu, R3 = p-MeC6H4, X = I)
c
n
n
14
2j (R1 = Me, R2 = Bu, R3 = p-MeC6H4)
NIS
5.0
3u (R1 = Me, R2 = Bu, R3 = p-MeC6H4, X = I)
a
b
Compound 2a (1 equiv) and PtCl2 (0.1 equiv) in toluene at 70 °C. (E)-Enynyl acetate 2a (1 equiv), I2 (1.5 equiv), and NaHCO3 (1.5 equiv) in
CH2Cl2 at room temp.8 Compound 2 (1 equiv) and NXS (1.2 equiv) in DCE/MeCN = 1/1 at room temp. Compound 2j (1 equiv), NIS (1.2
c
d
equiv), Pd(OAc)2 (a little), and CuI (a little) in DCE/MeCN = 1/1 at room temp.
reaction rate seemed to depend on the substituent R3: the
reaction was faster when R3 was an aromatic substituent rather
than an aliphatic substituent (Table 2, entries 4−7). The nature
of the R2 group on the double bond had a slight effect on the
reaction rate (Table 2, entries 5, 8, 10 and 11). Interestingly,
intermediates were observed on TLC in the case of slow
reactions (≥1 h) (vide infra). The reaction of the compound 1i
having the N-acetyl electron-donating substituent as R1
afforded the corresponding furan 3k together with N-
diacetylated product 3k′, probably arising from N-acetylation
of 3k by transfer from O-acetyl group of starting compound 1i.
Next, we examined the reaction of various (E)-enynyl acetate
2 with some electrophiles, applying the standard conditions
used for the formation of 3 from (Z)-enynyl acetate 1. As
expected from the structural factors, the PtCl2-catalyzed
cyclization reaction did not proceed (Table 3, entry 1).
According to the mechanism proposed by Jiang and co-
workers,8 we assumed that (E)-enynyl acetate 2 also would not
react with I2. Contrary to our expectations, furan 3l could be
formed in 51% yield (Table 3, entry 2). Bromofuran 3m was
obtained from 2a by using NBS (Table 3, entry 3). The use of
NCS resulted in recovery of starting material 2a (Table 3, entry
4). Surprisingly, most of the substrates 2 could be converted
into multisubstituted furans 3 in higher yields than the yields of
the reaction with (Z)-enynyl acetate 1 and NIS (Table 3,
entries 5−14). With respect to the reactivity, similar tendencies
with the results obtained from (Z)-enynyl acetate 1 were
observed: (i) aromatic substituent R3 underwent a facile furan
formation (Table 3, entries 5−9) and (ii) the reaction
proceeded via the intermediate (vide infra). The furan
formation reaction mentioned here can proceed under mild
and metal-free conditions and can provide a powerful
methodology toward the synthesis of diversely substituted
furans.
1). When either (Z)- or (E)-enynyl acetates 1d or 2g was
stirred with NIS at room temperature for only 10 min, the same
allenylketone 4a was obtained. Compound 4b was also
obtained from 2e. Because allenylketone 4 was relatively
unstable, 4a or 4b was gradually isomerized in low yield under
neutral conditions into the corresponding furan 3e or 3q after
storage at room temperature (eq 2).
On the basis of the results obtained above, we propose a
plausible reaction mechanism (Scheme 2). Initially, electro-
philic addition of NXS to the triple bond of (Z)- or (E)-enynyl
acetates 1 or 2 was assisted by an electron-donating group
(EDG) at the para-position on the aromatic ring of 1 or 2 to
afford haloallenyl ketone intermediate 4 through ionic
intermediate H. EDG of haloallenyl ketone 4 also assisted in
the formation of intermediate I. Intramolecular Michael-type
migration of X to the conjugated polyene moiety, leading to
haloirenium zwitterion J, which subsequently underwent 1,2-
halogen migration and nucleophilic attack of oxygen anion,
furnished 3-halofuran 3. Gevorgyan and co-workers reported
furan 3 formation from iodoallenylketone 4 (EDG = H, R2 =
Ph, R3 = nBu, X = I) via 1,2-iodomigration with Au(III)-catalyst
at room temperature for 3 days.9 In our experiment, enynyl
In an effort to understand the reaction mechanism, we
attempted to isolate and identify the reaction intermediate (eq
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Data are reported as follows: chemical shifts, relative integration value,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br =
broad, m = multiplet), coupling constants (Hz). Infrared spectra were
obtained using an FT spectrometer. Analytical thin layer chromatog-
raphy was performed on Merck silica gel 60 F254 TLC plates.
General Procedure for the Preparation of (Z)- and (E)-Enynyl
Acetates 1 and 2. To a solution of (Z)- or (E)-iodoenol acetate (0.5
mmol) in Et3N (3 mL) were added Pd(OAc)2 (5.6 mg, 0.025 mmol),
PPh3 (13 mg, 0.05 mmol), CuI (4.7 mg, 0.025 mmol), and alkyne
(0.75 mmol), and the mixture was stirred at 50 °C under nitrogen.
The reaction was monitored by TLC to establish completion.
Saturated aqueous NH4Cl solution was added to the reaction mixture
and extracted with AcOEt (three times). The combined organic
solution was washed with brine, dried over anhydrous MgSO4, and
concentrated at the reduced pressure. Column chromatography on
silica gel using hexanes/ethyl acetate as an eluent afforded 1 or 2.
(Z)-1-(4-Methoxyphenyl)-2-phenyl-4-(p-tolyl)but-1-en-3-yn-1-yl
Acetate (1a). White solid: 1H NMR (CDCl3) δ 7.38 (2H, dd, J = 7.6,
2.1 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.25−7.23 (3H, m), 7.16 (2H, d, J =
8.9 Hz), 7.12 (2H, d, J = 7.6 Hz), 6.71 (2H, dd, J = 6.9, 2.1 Hz), 3.75
(3H, s), 2.35 (3H, s), 2.31 (3H, s); 13C NMR (CDCl3) δ 168.6, 159.9,
151.6, 138.5, 136.1, 130.2, 129.6, 129.1, 128.3, 127.6, 126.6, 120.2,
113.7, 113.5, 95.7, 86.8, 55.2, 21.5, 21.0; IR (CHCl3, cm−1) 1763,
1606, 1507, 1464, 1445, 1370, 1300, 1253, 1195, 1174, 1094, 1033,
1016; MS (EI) m/z = 382 (M+); HRMS (EI) m/z calcd for C26H22O3
382.1569, found 382.1568.
Scheme 2. Plausible Reaction Mechanism for the Synthesis
of Furans
acetate 1d or 2g (EDG = OMe, R2 = Ph, R3 = nBu) gave furan
3e at room temperature after 5−6 h under metal-free
conditions (Table 2, entry 7, and Table 3, entry 11). These
results suggest that the EDG on the aromatic ring assisted in
the formation of furan 3.
Halofurans are attractive and important building blocks that
provide sites for further functionalization, for example, C−C,
C−N, or C−S bond formation.10 To further explore the utility
of our methodology, we studied the Sonogashira coupling
reaction of 3-iodofuran 3l with terminal alkynes. The
corresponding 2,3,4,5-tetrasubstituted furans 5a and 5b were
obtained in high yields (eq 3).
(Z)-1-(4-Methoxyphenyl)-2,4-diphenylbut-1-en-3-yn-1-yl Acetate
(1b). Yellow solid: 1H NMR (CDCl3) δ 7.44 (2H, dd, J = 3.2, 1.6 Hz),
7.38 (2H, dd, J = 7.9, 1.7 Hz), 7.32−7.31 (3H, m), 7.27−7.23 (3H,
m), 7.16 (2H, d, J = 8.9 Hz), 6.72 (2H, d, J = 8.9 Hz), 3.76 (3H, s),
2.32 (3H, s); 13C NMR (CDCl3) δ 168.5, 160.0, 151.9, 136.0, 131.4,
130.3, 129.6, 128.3, 128.3, 127.7, 126.5, 123.3, 113.6, 95.4, 87.4, 55.2,
21.0; IR (CHCl3, cm−1) 1759, 1606, 1511, 1489, 1443, 1370, 1254,
1174, 1095, 1032, 1027; MS (EI) m/z = 368 (M+); HRMS (EI) m/z
calcd for C25H20O3 368.1412, found 368.1412.
(Z)-4-Cyclohexyl-1-(4-methoxyphenyl)-2-phenylbut-1-en-3-yn-1-
1
yl Acetate (1c). Orange solid: H NMR (CDCl3) δ 7.30 (2H, dd, J =
7.6, 2.1 Hz), 7.22−7.18 (3H, m), 7.11 (2H, d, J = 8.9 Hz), 6.69 (2H, d,
J = 8.9 Hz), 3.75 (3H, s), 2.60 (1H, s), 2.27 (3H, s), 1.84−1.72 (4H,
m), 1.51 (3H, br s), 1.34 (3H, br s); 13C NMR (CDCl3) δ 168.5,
159.7, 150.9, 136.7, 130.2, 129.6, 128.1, 127.4, 126.9, 114.1, 113.5,
101.0, 78.4, 55.2, 32.7, 29.9, 25.9, 24.8, 21.0; IR (CHCl3, cm−1) 2935,
2856, 1757, 1607, 1510, 1445, 1369, 1298, 1251, 1236, 1196, 1176,
1153, 1060, 1032, 837; MS (EI) m/z = 374 (M+); HRMS (EI) m/z
calcd for C25H26O3 374.1882, found 374.1887.
(Z)-1-(4-Methoxyphenyl)-2-phenyloct-1-en-3-yn-1-yl Acetate
1
(1d). Pale yellow solid: H NMR (CDCl3) δ 7.30 (2H, dd, J = 7.6,
2.1 Hz), 7.21−7.19 (3H, m), 7.10 (2H, d, J = 8.9 Hz), 6.69 (2H, d, J =
8.9 Hz), 3.74 (3H, s), 2.41 (2H, t, J = 7.2 Hz), 2.26 (3H, s), 1.56−1.53
(2H, m), 1.47−1.45 (2H, m), 0.93 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 168.6, 159.7, 151.0, 136.7, 130.2, 129.6, 128.2, 127.4, 126.8,
114.1, 113.5, 97.0, 78.4, 55.2, 30.9, 22.0, 21.0, 19.5, 13.6; IR (CHCl3,
cm−1) 2961, 2936, 1757, 1606, 1510, 1465, 1444, 1370, 1296, 1252,
1176, 1151, 1029; MS (EI) m/z = 348 (M+); HRMS (EI) m/z calcd
for C23H24O3 348.1725, found 348.1724.
CONCLUSION
■
In summary, we have demonstrated a highly efficient
multisubstituted furan synthesis under metal-free conditions
from (Z)- or (E)-enynyl acetates with NXS via the same
haloallenyl ketone intermediates. This tandem allenyl ketone
formation−furan formation reaction sequence was accelerated
by electron-donating groups on the aromatic rings. Our
approach allows for excellent regioselective synthesis of 2,4,5-
trisubstituted 3-halofurans. The 3-iodofuran was also utilized
for the transformation to a tetrasubstituted furan by Pd-
catalyzed coupling reaction.
(Z)-1,2-Bis(4-methoxyphenyl)-4-phenylbut-1-en-3-yn-1-yl Ace-
1
tate (1e). Orange solid: H NMR (CDCl3) δ 7.44−7.43 (2H, m),
7.32−7.30 (5H, m), 7.19 (2H, dd, J = 6.9, 2.1 Hz), 6.79 (2H, dd, J =
6.9, 2.1 Hz), 6.73 (2H, dd, J = 6.9, 2.1 Hz), 3.79 (3H, s), 3.77 (3H, s),
2.31 (3H, s); 13C NMR (CDCl3) δ 168.6, 159.9, 159.1, 151.1, 131.4,
130.8, 130.2, 129.7, 129.3, 128.3, 128.2, 126.8, 123.4, 113.8, 113.6,
113.1, 95.3, 87.6, 55.2, 21.0; IR (CHCl3, cm−1) 2961, 2937, 1757,
1607, 1577, 1512, 1490, 1464, 1443, 1370, 1299, 1293, 1256, 1243,
1193, 1174, 1115, 1090, 1029, 1020, 836; MS (EI) m/z = 398 (M+);
HRMS (EI) m/z calcd for C26H22O4 398.1518, found 398.1518.
(Z)-1-(4-Methoxyphenyl)-4-phenyl-2-(p-tolyl)but-1-en-3-yn-1-yl
Acetate (1f). Orange solid: 1H NMR (CDCl3) δ 7.43 (2H, dd, J = 3.2,
1.6 Hz), 7.31−7.26 (5H, m), 7.18 (2H, d, J = 8.9 Hz), 7.05 (2H, d, J =
8.2 Hz), 6.72 (2H, d, J = 8.9 Hz), 3.75 (3H, s), 2.31 (3H, s), 2.31 (3H,
s); 13C NMR (CDCl3) δ 168.6, 159.9, 151.5, 137.5, 133.0, 131.4,
130.2, 129.5, 129.1, 128.3, 128.2, 126.7, 123.4, 113.6, 95.3, 87.6, 55.2,
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR and 13C NMR
spectra were recorded on 600 MHz spectrometer. Chemical shifts are
reported in δ (ppm) from tetramethylsilane as an internal standard.
3947
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The Journal of Organic Chemistry
Article
21.2, 21.0; IR (CHCl3, cm−1) 1757, 1606, 1508, 1490, 1464, 1443,
1370, 1300, 1254, 1193, 1174, 1091, 1029, 1016, 989, 837; MS (EI)
m/z = 382 (M+); HRMS (EI) m/z calcd for C26H22O3 382.1569,
found 382.1565.
(CDCl3) δ 168.6, 163.2, 161.5, 159.8, 150.5, 133.1, 133.1, 129.0, 127.6,
119.7, 119.7, 115.6, 115.5, 113.3, 112.0, 92.7, 88.1, 55.3, 30.9, 30.1,
22.3, 20.8, 13.9; IR (CHCl3, cm−1) 2961, 2934, 1755, 1608, 1506,
1465, 1442, 1370, 1299, 1251, 1238, 1196, 1177, 1155, 1098, 1094,
1056, 1033, 893, 837; MS (EI) m/z = 366 (M+); HRMS (EI) m/z
calcd for C23H23FO3 366.1631, found 366.1632.
(Z)-2-(4-Fluorophenyl)-1-(4-methoxyphenyl)-4-phenylbut-1-en-
1
3-yn-1-yl Acetate (1g). Yellow solid: H NMR (CDCl3) δ 7.44 (2H,
dd, J = 3.2, 1.6 Hz), 7.36−7.31 (5H, m), 7.16 (2H, d, J = 8.2 Hz), 6.94
(2H, t, J = 8.6 Hz), 6.73 (2H, d, J = 8.2 Hz), 3.77 (3H, s), 2.31 (3H,
s); 13C NMR (CDCl3) δ 168.5, 163.0, 161.4, 160.1, 152.1, 132.1,
132.1, 131.5, 131.4, 131.4, 130.3, 129.4, 128.5, 128.4, 126.4, 123.2,
115.5, 115.3, 113.7, 113.5, 112.6, 95.7, 87.2, 55.2, 21.0; IR (CHCl3,
cm−1) 2937, 2840, 1762, 1605, 1507, 1490, 1465, 1443, 1370, 1301,
1254, 1238, 1194, 1174, 1158, 1101, 1088, 1029, 1014, 840; MS (EI)
m/z = 386 (M+); HRMS (EI) m/z calcd for C25H19FO3 386.1318,
found 386.1315.
(E)-2-Butyl-1-(4-methoxyphenyl)oct-1-en-3-yn-1-yl Acetate (2e).
Yellow oil: 1H NMR (CDCl3) δ 7.70 (2H, d, J = 8.9 Hz), 6.84 (2H, d,
J = 8.9 Hz), 3.81 (3H, s), 2.33 (2H, t, J = 6.9 Hz), 2.21 (3H, s), 2.17
(2H, dd, J = 8.2, 6.9 Hz), 1.58−1.48 (4H, m), 1.42−1.34 (4H, m),
0.93−0.90 (6H, m); 13C NMR (CDCl3) δ 168.8, 159.4, 149.1, 128.8,
127.7, 113.2, 112.7, 95.5, 78.8, 55.2, 31.4, 30.6, 30.0, 22.4, 22.0, 20.8,
19.4, 14.0, 13.6; IR (CHCl3, cm−1) 2960, 2934, 2874, 2862, 1753,
1608, 1511, 1466, 1442, 1370, 1297, 1252, 1239, 1195, 1177, 1085,
1035, 836; MS (EI) m/z = 328 (M+); HRMS (EI) m/z calcd for
C21H28O3 328.2038, found 328.2035.
(E)-2-Cyclohexyl-1-(4-methoxyphenyl)-4-(p-tolyl)but-1-en-3-yn-
1-yl Acetate (2f). Orange oil: 1H NMR (CDCl3) δ 7.76 (2H, d, J = 8.9
Hz), 7.27 (2H, d, J = 7.6 Hz), 7.11 (2H, d, J = 8.2 Hz), 6.87 (2H, d, J
= 8.9 Hz), 3.81 (3H, s), 2.47−2.43 (1H, m), 2.34 (3H, s), 2.25 (3H,
s), 1.82−1.69 (4H, m), 1.61−1.55 (3H, m), 1.32−1.24 (3H, m); 13C
NMR (CDCl3) δ 168.9, 159.7, 148.9, 138.1, 131.1, 129.1, 129.0, 127.8,
120.6, 117.6, 113.2, 95.1, 86.3, 55.2, 39.2, 31.2, 26.4, 25.9, 21.5, 20.8;
IR (CHCl3, cm−1) 2934, 1755, 1607, 1512, 1451, 1370, 1251, 1196,
1177, 1062, 1034, 837; MS (EI) m/z = 388 (M+); HRMS (EI) m/z
calcd for C26H28O3 388.2038, found 388.2037.
(Z)-1-(4-((Ethoxycarbonyl)amino)phenyl)-2-phenyl-4-(p-tolyl)-
1
but-1-en-3-yn-1-yl Acetate (1h). Orange solid: H NMR (CDCl3) δ
7.38−7.36 (2H, m), 7.33 (2H, d, J = 8.2 Hz), 7.24−7.22 (5H, m), 7.15
(2H, d, J = 8.2 Hz), 7.12 (2H, d, J = 8.2 Hz), 6.58 (1H, br s), 4.20
(2H, q, J = 7.1 Hz), 2.35 (3H, s), 2.32 (3H, s), 1.29 (3H, t, J = 7.2
Hz); 13C NMR (CDCl3) δ 168.7, 153.3, 151.3, 138.6, 138.6, 136.0,
131.4, 129.7, 129.7, 129.1, 129.0, 128.4, 127.8, 120.2, 117.8, 114.4,
96.2, 86.7, 61.4, 21.5, 21.0, 14.5; IR (CHCl3, cm−1) 3433, 2985, 1762,
1734, 1609, 1586, 1522, 1509, 1445, 1411, 1370, 1316, 1238, 1194,
1180, 1015, 843, 818; MS (EI) m/z = 439 (M+); HRMS (EI) m/z
calcd for C28H25NO4 439.1784, found 439.1783.
(Z)-1-(4-Acetamidophenyl)-2-phenyl-4-(p-tolyl)but-1-en-3-yn-1-
yl Acetate (1i). Brown solid: 1H NMR (CDCl3) δ 7.58 (1H, s), 7.35−
7.32 (4H, m), 7.27−7.24 (5H, m), 7.12 (4H, t, J = 8.9 Hz), 2.35 (3H,
s), 2.33 (3H, s), 2.12 (3H, s); 13C NMR (CDCl3) δ 168.9, 168.5,
151.1, 138.7, 138.5, 135.9, 131.4, 129.6, 129.5, 129.1, 128.5, 127.9,
120.1, 118.9, 114.6, 96.3, 86.6, 24.6, 21.5, 21.0; IR (CHCl3, cm−1)
3434, 1762, 1693, 1603, 1589, 1516, 1508, 1445, 1405, 1370, 1314,
1248, 1196, 1179, 1095, 1015, 846; MS (EI) m/z = 409 (M+); HRMS
(EI) m/z calcd for C27H23NO3 409.1678, found 409.1681.
(E)-1-(4-Methoxyphenyl)-2-(phenylethynyl)hex-1-en-1-yl Acetate
(2a). Orange oil: 1H NMR (CDCl3) δ 7.77 (2H, d, J = 8.9 Hz), 7.37−
7.37 (2H, m), 7.31−7.29 (3H, m), 6.89 (2H, d, J = 8.9 Hz), 3.82 (3H,
s), 2.29 (2H, t, J = 7.9 Hz), 2.25 (3H, s), 1.67−1.63 (2H, m), 1.42−
1.41 (2H, m), 0.96 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 168.7,
159.8, 150.4, 131.3, 129.0, 128.3, 128.0, 127.6, 123.6, 113.3, 112.1,
94.0, 88.4, 55.3, 31.0, 30.1, 22.4, 20.8, 14.0; IR (CHCl3, cm−1) 2961,
2933, 1751, 1608, 1512, 1490, 1465, 1443, 1370, 1299, 1251, 1176,
1098, 1058; MS (EI) m/z = 348 (M+); HRMS (EI) m/z calcd for
C23H24O3 348.1725, found 348.1732.
(E)-1-(4-Methoxyphenyl)-2-((4-methoxyphenyl)ethynyl)hex-1-en-
1-yl Acetate (2b). Yellow oil: 1H NMR (CDCl3) δ 7.77 (2H, d, J = 8.9
Hz), 7.31 (2H, d, J = 8.9 Hz), 6.88 (2H, d, J = 8.9 Hz), 6.83 (2H, d, J
= 8.2 Hz), 3.81 (3H, s), 3.80 (3H, s), 2.28 (2H, t, J = 7.6 Hz), 2.24
(3H, s), 1.64−1.63 (2H, m), 1.42−1.40 (2H, m), 0.95 (3H, t, J = 7.2
Hz); 13C NMR (CDCl3) δ 168.7, 159.7, 159.5, 149.7, 132.7, 128.9,
127.7, 115.8, 114.0, 113.3, 112.3, 94.0, 87.0, 55.3, 55.2, 31.0, 30.1, 22.3,
20.8, 13.9; IR (CHCl3, cm−1) 2961, 2935, 2839, 1751, 1607, 1570,
1507, 1465, 1442, 1370, 1289, 1248, 1196, 1176, 1099, 1056, 1033,
834; MS (EI) m/z = 378 (M+); HRMS (EI) m/z calcd for C24H26O4
378.1831, found 378.1830.
(E)-1-(4-Methoxyphenyl)-2-phenyloct-1-en-3-yn-1-yl Acetate
1
(2g). Orange oil: H NMR (CDCl3) δ 7.83 (2H, d, J = 8.9 Hz),
7.48 (2H, d, J = 8.2 Hz), 7.34 (2H, t, J = 7.6 Hz), 7.28−7.25 (1H, m),
6.89 (2H, d, J = 8.9 Hz), 3.84 (3H, s), 2.34 (2H, t, J = 6.9 Hz), 1.98
(3H, s), 1.51−1.50 (2H, m), 1.41−1.37 (2H, m), 0.90 (3H, t, J = 7.6
Hz); 13C NMR (CDCl3) δ 168.9, 160.0, 150.0, 137.6, 129.2, 128.4,
128.1, 127.5, 127.4, 113.3, 112.7, 95.9, 79.4, 55.3, 30.5, 22.0, 20.8, 19.5,
13.6; IR (CHCl3, cm−1) 2961, 1936, 1757, 1608, 1511, 1465, 1444,
1370, 1306, 1294, 1252, 1237, 1195, 1178, 1150, 1062, 1033, 1011,
834, 809; MS (EI) m/z = 348 (M+); HRMS (EI) m/z calcd for
C23H24O3 348.1725, found 348.1725.
(E)-1-(4-((Ethoxycarbonyl)amino)phenyl)-2-(p-tolylethynyl)hex-
1-en-1-yl Acetate (2h). Orange oil: 1H NMR (CDCl3) δ 7.78 (2H, d,
J = 8.9 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 7.6 Hz), 7.11
(2H, d, J = 7.6 Hz), 6.65 (1H, br s), 4.23 (2H, q, J = 7.1 Hz), 2.34
(3H, s), 2.29 (2H, t, J = 7.9 Hz), 2.24 (3H, s), 1.65−1.61 (2H, m),
1.41−1.40 (2H, m), 1.31 (3H, t, J = 6.9 Hz), 0.95 (3H, t, J = 7.2 Hz);
13C NMR (CDCl3) δ 168.7, 153.3, 149.7, 138.2, 138.2, 131.1, 129.9,
129.0, 128.3, 120.4, 117.6, 113.0, 94.6, 87.5, 61.3, 31.1, 30.0, 22.3, 21.4,
20.7, 14.5, 13.9; IR (CHCl3, cm−1) 2961, 2932, 1734, 1611, 1586,
1521, 1508, 1410, 1370, 1256, 1237, 1195, 1183, 1097, 1066, 1016,
892, 818; MS (EI) m/z = 419 (M+); HRMS (EI) m/z calcd for
C26H29NO4 419.2097, found 419.2106.
(E)-1-(4-Acetamidophenyl)-2-(p-tolylethynyl)hex-1-en-1-yl Ace-
1
tate (2i). Orange solid: H NMR (CDCl3) δ 7.77 (2H, d, J = 8.2
Hz), 7.47−7.45 (3H, m), 7.26 (2H, d, J = 7.6 Hz), 7.10 (2H, d, J = 8.2
Hz), 2.34 (3H, s), 2.29 (2H, t, J = 7.6 Hz), 2.25 (3H, s), 2.15 (3H, s),
1.64−1.63 (2H, m), 1.41−1.40 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C
NMR (CDCl3) δ 168.9, 168.3, 149.6, 138.4, 138.1, 131.2, 130.7, 129.1,
128.2, 120.3, 118.8, 113.2, 94.7, 87.4, 31.1, 30.1, 24.6, 22.4, 21.5, 20.8,
14.0; IR (CHCl3, cm−1) 3435, 2961, 2931, 2862, 1755, 1691, 1608,
1588, 1518, 1515, 1507, 1405, 1370, 1315, 1299, 1239, 1194, 1182,
1099, 1055, 1017, 1003, 893; MS (EI) m/z = 389 (M+); HRMS (EI)
m/z calcd for C25H27NO3 389.1991, found 389.1997.
(E)-1-(p-Tolyl)-2-(p-tolylethynyl)hex-1-en-1-yl Acetate (2j). Yellow
oil: 1H NMR (CDCl3) δ 7.72 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 7.6
Hz), 7.17 (2H, d, J = 8.2 Hz), 7.11 (2H, d, J = 7.6 Hz), 2.35 (3H, s),
2.34 (3H, s), 2.30 (2H, t, J = 7.6 Hz), 2.24 (3H, s), 1.65−1.63 (2H,
m), 1.42−1.40 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ
168.7, 150.3, 138.6, 138.2, 132.2, 131.2, 129.1, 128.6, 127.4, 120.5,
113.1, 94.4, 87.6, 31.1, 30.1, 22.4, 21.5, 21.4, 20.8, 14.0; IR (CHCl3,
cm−1) 2961, 2929, 2863, 1757, 1539, 1507, 1370, 1236, 1195, 1184,
1099, 1055, 893, 810; MS (EI) m/z = 346 (M+); HRMS (EI) m/z
calcd for C24H26O2 346.1933, found 346.1940.
(E)-1-(4-Methoxyphenyl)-2-(p-tolylethynyl)hex-1-en-1-yl Acetate
1
(2c). Yellow oil: H NMR (CDCl3) δ 7.77 (2H, d, J = 8.9 Hz), 7.27
(2H, d, J = 7.6 Hz), 7.11 (2H, d, J = 7.6 Hz), 6.88 (2H, d, J = 8.9 Hz),
3.82 (3H, s), 2.35 (3H, s), 2.28 (2H, t, J = 7.9 Hz), 2.25 (3H, s), 1.66−
1.61 (2H, m), 1.42−1.40 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 168.7, 159.7, 150.0, 138.2, 131.1, 129.0, 128.9, 127.6, 120.5,
113.3, 112.2, 94.2, 87.7, 55.2, 31.0, 30.1, 22.3, 21.5, 20.8, 14.0; IR
(CHCl3, cm−1) 2959, 2932, 2862, 1753, 1607, 1508, 1464, 1441, 1369,
1298, 1250, 1196, 1177, 1098, 1055, 1034, 837; MS (EI) m/z = 362
(M+); HRMS (EI) m/z calcd for C24H26O3 362.1882, found 362.1882.
(E)-2-((4-Fluorophenyl)ethynyl)-1-(4-methoxyphenyl)hex-1-en-1-
yl Acetate (2d). Orange oil: 1H NMR (CDCl3) δ 7.74 (2H, d, J = 8.9
Hz), 7.34−7.33 (2H, m), 6.99 (2H, t, J = 8.6 Hz), 6.89 (2H, d, J = 8.2
Hz), 3.82 (3H, s), 2.28 (2H, t, J = 7.6 Hz), 2.24 (3H, s), 1.64−1.62
(2H, m), 1.42−1.41 (2H, m), 0.96 (3H, t, J = 7.6 Hz); 13C NMR
3948
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Article
General Procedure of the Synthesis of Multisubstituted
Furans from (Z)- or (E)-Enynyl Acetates. To a solution of (Z)-
enynyl acetates 1 or (E)-enynyl acetates 2 (0.1 mmol) in 1,2-
dichloroethane (0.25 mL) and MeCN (0.25 mL) was added NXS
(0.12 mmol), and the mixture was stirred at room temperature. After
the completion of the reaction was confirmed by TLC, 10% Na2S2O3
aqueous solution was added for quenching. The aqueous layer was
extracted with AcOEt (two times). The combined organic layers were
dried over Na2SO4 and concentrated. The crude product was purified
by column chromatography to give 3.
2935, 2839, 1608, 1520, 1499, 1465, 1379, 1301, 1254, 1238, 1197,
1179, 1114, 1068, 1032, 942; MS (EI) m/z = 418 (M+); HRMS (EI)
m/z calcd for C24H19BrO2 418.0568, found 418.0559.
3-Iodo-5-(4-methoxyphenyl)-2-phenyl-4-(p-tolyl)furan (3h).
1
White needle: mp 117−119 °C; H NMR (CDCl3) δ 8.11 (2H, d, J
= 8.2 Hz), 7.45 (2H, t, J = 7.6 Hz), 7.40−7.34 (3H, m), 7.26−7.25
(4H, m), 6.79 (2H, t, J = 5.8 Hz), 3.77 (3H, s), 2.43 (3H, s); 13C
NMR (CDCl3) δ 159.1, 149.8, 148.6, 137.8, 131.0, 130.5, 129.5, 128.4,
128.1, 127.0, 126.4, 126.4, 123.1, 113.9, 71.4, 55.2, 21.4; IR (CHCl3,
cm−1) 1613, 1604, 1519, 1499, 1482, 1301, 1253, 1179, 1032, 941,
835; MS (EI) m/z = 466 (M+); HRMS (EI) m/z calcd for C24H19IO2
466.0430, found 466.0429.
3-Iodo-5-(4-methoxyphenyl)-4-phenyl-2-(p-tolyl)furan (3a).
1
White needle: mp 99−100 °C; H NMR (CDCl3) δ 7.99 (2H, d, J
= 8.2 Hz), 7.46−7.43 (3H, m), 7.36−7.35 (4H, m), 7.27 (2H, d, J =
8.2 Hz), 6.78 (2H, d, J = 8.9 Hz), 3.76 (3H, s), 2.40 (3H, s); 13C NMR
(CDCl3) δ 159.1, 150.2, 148.3, 138.1, 134.2, 130.6, 129.1, 128.6, 128.0,
127.6, 127.0, 126.4, 126.2, 123.0, 113.8, 70.3, 55.2, 21.4; IR (CHCl3,
cm−1) 2937, 1612, 1571, 1513, 1497, 1487, 1464, 1444, 1375, 1301,
1252, 1179, 1106, 1068, 1034, 942, 835; MS (EI) m/z = 466 (M+);
HRMS (EI) m/z calcd for C24H19IO2 466.0430, found 466.0432.
3-Bromo-5-(4-methoxyphenyl)-4-phenyl-2-(p-tolyl)furan (3b).
3-(4-Fluorophenyl)-4-iodo-2-(4-methoxyphenyl)-5-phenylfuran
(3i). White solid: mp 137−139 °C; 1H NMR (CDCl3) δ 8.10 (2H, d, J
= 7.6 Hz), 7.47 (2H, t, J = 7.9 Hz), 7.38−7.32 (5H, m), 7.16 (2H, t, J
= 8.6 Hz), 6.80 (2H, d, J = 8.9 Hz), 3.79 (3H, s); 13C NMR (CDCl3) δ
163.4, 161.8, 159.3, 150.1, 148.8, 132.5, 132.4, 130.3, 130.0, 130.0,
128.4, 128.2, 127.1, 126.4, 125.4, 122.7, 115.9, 115.7, 114.0, 71.0, 55.3;
IR (CHCl3, cm−1) 1606, 1517, 1498, 1301, 1254, 1236, 1197, 1179,
1157, 1065, 1031, 943, 841, 810; MS (EI) m/z = 470 (M+); HRMS
(EI) m/z calcd for C23H16FIO2 470.0179, found 470.0183.
1
Colorless oil: H NMR (CDCl3) δ 7.97 (2H, d, J = 8.2 Hz), 7.44−
7.40 (7H, m), 7.27 (2H, d, J = 8.2 Hz), 6.79 (2H, d, J = 8.9 Hz), 3.78
(3H, s), 2.40 (3H, s); 13C NMR (CDCl3) δ 159.2, 147.8, 147.3, 137.9,
132.4, 130.5, 129.2, 128.7, 127.9, 127.1, 127.1, 125.6, 123.4, 123.0,
113.9, 100.3, 55.2, 21.4; IR (CHCl3, cm−1) 2938, 2839, 1611, 1513,
1501, 1488, 1464, 1444, 1420, 1379, 1301, 1254, 1178, 1110, 1073,
1034, 969, 943, 835, 809; MS (EI) m/z = 418 (M+); HRMS (EI) m/z
calcd for C24H19BrO2 418.0568, found 418.0562.
Ethyl (4-(4-Iodo-3-phenyl-5-(p-tolyl)furan-2-yl)phenyl)carbamate
1
(3j). Pale yellow solid: mp 180−181 °C; H NMR (CDCl3) δ 8.00
(2H, d, J = 8.2 Hz), 7.46−7.44 (3H, m), 7.36 (4H, t, J = 7.9 Hz),
7.28−7.26 (4H, m), 6.54 (1H, br s), 4.21 (2H, q, J = 7.1 Hz), 2.41
(3H, s), 1.30 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 153.4, 150.5,
148.0, 138.3, 137.3, 134.0, 130.6, 129.1, 128.7, 128.1, 127.6, 127.0,
126.5, 126.3, 125.3, 118.3, 70.4, 61.3, 21.4, 14.5; IR (CHCl3, cm−1)
3434, 1733, 1614, 1593, 1584, 1518, 1498, 1413, 1236, 1197, 1098,
1061, 942, 821; MS (EI) m/z = 523 (M+); HRMS (EI) m/z calcd for
C26H22INO3 523.0644, found 523.0647.
3-Iodo-5-(4-methoxyphenyl)-2,4-diphenylfuran (3c). White nee-
1
dle: mp 127−128 °C; H NMR (CDCl3) δ 8.11 (2H, d, J = 7.6 Hz),
7.47−7.43 (5H, m), 7.37−7.35 (5H, m), 6.78 (2H, d, J = 8.9 Hz), 3.77
(3H, s); 13C NMR (CDCl3) δ 159.2, 149.9, 148.6, 134.1, 130.7, 130.4,
128.7, 128.4, 128.1, 128.0, 127.1, 126.4, 126.4, 122.9, 113.9, 71.0, 55.2;
IR (CHCl3, cm−1) 1611, 1570, 1512, 1489, 1464, 1445, 1376, 1301,
1253, 1179, 1112, 1065, 1030, 963, 942, 835; MS (EI) m/z = 452
(M+); HRMS (EI) m/z calcd for C23H17IO2 452.0273, found
452.0272.
N-(4-(4-Iodo-3-phenyl-5-(p-tolyl)furan-2-yl)phenyl)acetamide
1
(3k). Colorless needle: mp 236−239 °C; H NMR (CDCl3) δ 8.00
(2H, d, J = 8.2 Hz), 7.48−7.34 (9H, m), 7.28 (2H, d, J = 8.2 Hz), 7.18
(1H, br s), 2.41 (3H, s), 2.16 (3H, s); 13C NMR (CDCl3) δ 168.2,
150.6, 147.8, 138.3, 137.2, 134.0, 130.6, 129.1, 128.8, 128.1, 127.5,
127.3, 126.5, 126.2, 119.5, 70.5, 24.7, 21.4; IR (CHCl3, cm−1) 3435,
2926, 1691, 1603, 1517, 1497, 1407, 1370, 1315, 942, 822, 812; MS
(EI) m/z = 493 (M+); HRMS (EI) m/z calcd for C25H20INO2
493.0539, found 493.0538.
2-Cyclohexyl-3-iodo-5-(4-methoxyphenyl)-4-phenylfuran (3d).
White needle: mp 122−124 °C; 1H NMR (CDCl3) δ 7.43−7.26
(7H, m), 6.76 (2H, d, J = 8.9 Hz), 3.77 (3H, s), 2.88−2.84 (1H, m),
1.90 (4H, dt, J = 36.7, 6.9 Hz), 1.76−1.65 (3H, m), 1.44−1.30 (3H,
m); 13C NMR (CDCl3) δ 158.7, 158.2, 147.4, 134.1, 130.4, 128.5,
127.6, 126.8, 123.5, 123.5, 113.7, 69.5, 55.2, 37.8, 31.1, 26.2, 25.9; IR
(CHCl3, cm−1) 2935, 2856, 1616, 1512, 1489, 1451, 1444, 1300, 1252,
1236, 1198, 1179, 1034, 988, 953, 835; MS (EI) m/z = 458 (M+);
HRMS (EI) m/z calcd for C23H23IO2 458.0743, found 458.0748.
2-Butyl-3-iodo-5-(4-methoxyphenyl)-4-phenylfuran (3e). Color-
less oil: 1H NMR (CDCl3) δ 7.42−7.35 (3H, m), 7.31−7.29 (4H, m),
6.76 (2H, d, J = 8.9 Hz), 3.76 (3H, s), 2.79 (2H, t, J = 7.6 Hz), 1.74−
1.71 (2H, m), 1.46−1.44 (2H, m), 0.98 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 158.8, 155.1, 147.8, 134.2, 130.4, 128.5, 127.6, 126.8, 123.7,
123.5, 113.8, 71.2, 55.2, 30.3, 27.7, 22.3, 13.9; IR (CHCl3, cm−1) 2960,
2934, 1610, 1512, 1488, 1466, 1443, 1299, 1252, 1179, 1034, 835; MS
(EI) m/z = 432 (M+); HRMS (EI) m/z calcd for C21H21IO2 432.0586,
found 432.0583.
N-Acetyl-N-(4-(4-iodo-3-phenyl-5-(p-tolyl)furan-2-yl)phenyl)-
acetamide (3k′). Pale yellow oil: 1H NMR (CDCl3) δ 8.01 (2H, d, J =
8.2 Hz), 7.54−7.47 (5H, m), 7.37 (2H, d, J = 6.2 Hz), 7.29 (2H, d, J =
8.2 Hz), 7.01 (2H, d, J = 8.9 Hz), 2.42 (3H, s), 2.27 (6H, s); 13C NMR
(CDCl3) δ 172.9, 151.3, 146.9, 138.7, 138.2, 133.8, 130.7, 130.4, 129.2,
129.1, 128.9, 128.8, 128.4, 127.3, 126.6, 126.4, 70.9, 26.9, 21.4; IR
(CHCl3, cm−1) 2925, 1712, 1607, 1511, 1497, 1445, 1417, 1370, 1293,
1245, 1108, 1068, 1028, 1015, 942, 822; MS (EI) m/z = 535 (M+);
HRMS (EI) m/z calcd for C27H22INO3 535.0644, found 535.0641.
3-Butyl-4-iodo-2-(4-methoxyphenyl)-5-phenylfuran (3l). White
1
needle: mp 36−38 °C; H NMR (CDCl3) δ 8.05 (2H, d, J = 6.9
Hz), 7.59 (2H, d, J = 8.9 Hz), 7.43 (2H, t, J = 7.6 Hz), 7.32 (1H, t, J =
7.2 Hz), 6.97 (2H, d, J = 8.9 Hz), 3.84 (3H, s), 2.62 (2H, t, J = 8.2
Hz), 1.63−1.60 (2H, m), 1.50−1.45 (2H, m), 0.98 (3H, t, J = 7.2 Hz);
13C NMR (CDCl3) δ 159.0, 149.5, 148.2, 130.5, 128.3, 127.8, 127.1,
126.2, 124.6, 123.8, 114.1, 71.3, 55.3, 31.8, 26.8, 22.8, 13.9; IR (CHCl3,
cm−1) 2960, 2934, 1615, 1605, 1506, 1483, 1465, 1292, 1253, 1236,
1198, 1178, 1040, 946, 834; MS (EI) m/z = 432 (M+); HRMS (EI)
m/z calcd for C21H21IO2 432.0586, found 432.0585.
3-Iodo-4,5-bis(4-methoxyphenyl)-2-phenylfuran (3f). White nee-
1
dle: mp 99−100 °C; H NMR (CDCl3) δ 8.11 (2H, d, J = 7.6 Hz),
7.46 (2H, t, J = 7.9 Hz), 7.38−7.36 (3H, m), 7.27 (2H, d, J = 8.9 Hz),
6.99 (2H, d, J = 8.9 Hz), 6.79 (2H, d, J = 8.9 Hz), 3.88 (3H, s), 3.77
(3H, s); 13C NMR (CDCl3) δ 159.4, 159.1, 149.7, 148.6, 131.8, 130.5,
128.4, 128.1, 127.0, 126.4, 126.2, 126.1, 123.1, 114.2, 113.9, 71.8, 55.2;
IR (CHCl3, cm−1) 2961, 2839, 1612, 1518, 1499, 1465, 1443, 1300,
1289, 1251, 1178, 1032, 942, 835; MS (EI) m/z = 482 (M+); HRMS
(EI) m/z calcd for C24H19IO3 482.0379, found 482.0386.
3-Bromo-4-butyl-5-(4-methoxyphenyl)-2-phenylfuran (3m). Pale
1
yellow needle: mp 36 °C; H NMR (CDCl3) δ 8.04 (2H, d, J = 8.2
Hz), 7.61 (2H, d, J = 8.9 Hz), 7.43 (2H, t, J = 7.9 Hz), 7.31 (1H, t, J =
7.6 Hz), 6.98 (2H, d, J = 8.9 Hz), 3.86 (3H, s), 2.66 (2H, t, J = 7.9
Hz), 1.65−1.61 (2H, m), 1.47−1.46 (2H, m), 0.98 (3H, t, J = 7.2 Hz);
13C NMR (CDCl3) δ 159.1, 147.7, 146.4, 130.1, 128.4, 127.6, 127.0,
125.4, 123.8, 122.4, 114.1, 101.8, 55.3, 31.6, 24.7, 22.8, 13.9; IR
(CHCl3, cm−1) 2961, 2933, 2862, 1604, 1506, 1486, 1465, 1457, 1443,
1293, 1252, 1237, 1178, 1045, 1027, 950, 834; MS (EI) m/z = 384
(M+); HRMS (EI) m/z calcd for C21H21BrO2 384.0725, found
384.0717.
3-Bromo-5-(4-methoxyphenyl)-2-phenyl-4-(p-tolyl)furan (3g).
1
White solid: H NMR (CDCl3) δ 8.09 (2H, d, J = 6.9 Hz), 7.46−
7.41 (4H, m), 7.33 (1H, t, J = 7.2 Hz), 7.29−7.25 (4H, m), 6.80 (2H,
d, J = 8.9 Hz), 3.77 (3H, s), 2.42 (3H, s); 13C NMR (CDCl3) δ 159.2,
148.0, 146.8, 137.7, 131.6, 130.3, 129.5, 129.5, 129.2, 128.5, 127.8,
127.1, 125.6, 123.0, 113.9, 101.2, 55.2, 21.4; IR (CHCl3, cm−1) 2961,
3949
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Article
3-Butyl-4-iodo-2,5-bis(4-methoxyphenyl)furan (3n). White nee-
dle: mp 64−66 °C; 1H NMR (CDCl3) δ 7.97 (2H, d, J = 8.9 Hz), 7.58
(2H, d, J = 8.9 Hz), 6.97 (4H, dd, J = 8.6, 1.7 Hz), 3.85 (6H, s), 2.61
(2H, t, J = 8.2 Hz), 1.62−1.61 (2H, m), 1.48−1.46 (2H, m), 0.98 (3H,
t, J = 7.2 Hz); 13C NMR (CDCl3) δ 159.3, 158.9, 149.7, 147.6, 127.8,
127.0, 124.3, 123.9, 123.4, 114.1, 113.7, 69.8, 55.3, 31.8, 26.8, 22.8,
13.9; IR (CHCl3, cm−1) 2960, 2935, 1615, 1507, 1495, 1465, 1442,
1305, 1294, 1251, 1178, 1099, 1038, 946, 834; MS (EI) m/z = 462
(M+); HRMS (EI) m/z calcd for C22H23IO3 462.0692, found
462.0687.
3-Butyl-4-iodo-2-(4-methoxyphenyl)-5-(p-tolyl)furan (3o). White
needle: mp 49−50 °C; 1H NMR (CDCl3) δ 7.93 (2H, d, J = 8.2 Hz),
7.58 (2H, d, J = 8.9 Hz), 7.23 (2H, d, J = 8.9 Hz), 6.96 (2H, d, J = 8.9
Hz), 3.84 (3H, s), 2.61 (2H, dd, J = 9.3, 7.2 Hz), 2.38 (3H, s), 1.63−
1.60 (2H, m), 1.48−1.46 (2H, m), 0.98 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 159.0, 149.8, 147.8, 137.8, 129.0, 127.8, 127.0, 126.2, 124.4,
123.9, 114.1, 70.6, 55.3, 31.8, 26.8, 22.8, 21.3, 13.9; IR (CHCl3, cm−1)
2960, 2934, 1616, 1507, 1494, 1465, 1457, 1443, 1292, 1252, 1237,
1197, 1178, 1098, 1040, 946, 834, 821; MS (EI) m/z = 446 (M+);
HRMS (EI) m/z calcd for C22H23IO2 446.0743, found 446.0743.
3-Butyl-5-(4-fluorophenyl)-4-iodo-2-(4-methoxyphenyl)furan
(3p). Colorless needle: mp 51−52 °C; 1H NMR (CDCl3) δ 8.02 (2H,
dd, J = 4.8, 2.4 Hz), 7.58 (2H, d, J = 8.9 Hz), 7.12 (2H, t, J = 8.6 Hz),
6.98 (2H, d, J = 8.2 Hz), 3.86 (3H, s), 2.61 (2H, t, J = 8.2 Hz), 1.62−
1.60 (2H, m), 1.50−1.45 (2H, m), 0.98 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 163.1, 161.5, 159.1, 148.8, 148.2, 128.2, 128.1, 127.1, 126.9,
126.8, 124.5, 123.7, 115.4, 115.3, 114.1, 71.1, 55.3, 31.8, 26.8, 22.8,
13.9; IR (CHCl3, cm−1) 2960, 1615, 1597, 1506, 1493, 1466, 1291,
1253, 1238, 1178, 1159, 1094, 1040, 946, 838; MS (EI) m/z = 450
(M+); HRMS (EI) m/z calcd for C21H20FIO2 450.0492, found
450.0494.
1517, 1509, 1405, 1370, 1314, 1237, 1197, 946 809; MS (EI) m/z =
473 (M+); HRMS (EI) m/z calcd for C23H24INO2 473.0852, found
473.0855.
N-Acetyl-N-(4-(3-butyl-4-iodo-5-(p-tolyl)furan-2-yl)phenyl)-
1
acetamide (3t′). White solid: mp 104−106 °C; H NMR (CDCl3) δ
7.95 (2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.9 Hz), 7.26 (2H, d, J = 8.2
Hz), 7.21 (2H, d, J = 8.2 Hz), 2.68 (2H, t, J = 8.2 Hz), 2.40 (3H, s),
2.33 (6H, s), 1.66−1.63 (2H, m), 1.51−1.50 (2H, m), 1.01 (3H, t, J =
7.2 Hz); 13C NMR (CDCl3) δ 173.0, 151.0, 146.5, 138.4, 138.0, 131.5,
129.1, 129.0, 127.4, 127.2, 126.5, 126.4, 71.0, 31.6, 27.0, 22.8, 21.4,
13.9; IR (CHCl3, cm−1) 2961, 2933, 1713, 1506, 1370, 1292, 1238,
1197, 1035, 1014, 946, 821; MS (EI) m/z = 515 (M+); HRMS (EI)
m/z calcd for C25H26INO3 515.0957, found 515.0956.
3-Butyl-4-iodo-2,5-di-p-tolylfuran (3u). White needle: mp 49−50
°C; 1H NMR (CDCl3) δ 7.94 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2
Hz), 7.24 (4H, d, J = 7.6 Hz), 2.64 (2H, t, J = 8.2 Hz), 2.39 (6H, s),
1.63−1.61 (2H, m), 1.48−1.47 (2H, m), 0.99 (3H, t, J = 7.2 Hz); 13C
NMR (CDCl3) δ 150.0, 147.9, 137.9, 137.3, 129.3, 129.0, 128.3, 127.8,
126.3, 125.5, 125.2, 70.8, 31.7, 26.9, 22.8, 21.4, 21.3, 13.9; IR (CHCl3,
cm−1) 2960, 2928, 2862, 1507, 1493, 1467, 1457, 1100, 946, 822; MS
(EI) m/z = 430 (M+); HRMS (EI) m/z calcd for C22H23IO 430.0794,
found 430.0791.
Allenylketone 4a. Orange oil: 1H NMR (CDCl3) δ 8.01 (2H, d, J =
8.9 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.38 (2H, t, J = 7.6 Hz), 7.32 (1H, d,
J = 7.6 Hz), 6.97 (2H, d, J = 8.9 Hz), 3.90 (3H, s), 2.47−2.43 (2H, m),
1.46−1.45 (2H, m), 1.23−1.21 (2H, m), 0.83 (3H, t, J = 7.6 Hz); 13C
NMR (CDCl3) δ 202.2, 190.4, 163.9, 132.1, 132.0, 130.5, 128.8, 128.3,
128.0, 113.8, 108.0, 68.8, 55.5, 40.0, 31.1, 21.4, 13.6; IR (CHCl3,
cm−1) 2961, 2935, 2874, 2862, 1652, 1601, 1575, 1509, 1465, 1314,
1260, 1167, 1031, 857, 842; MS (EI) m/z = 432 (M+); HRMS (EI)
m/z calcd for C21H21IO2 432.0586, found 432.0587.
Allenylketone 4b. Orange oil: 1H NMR (CDCl3) δ 7.86 (2H, d, J =
8.2 Hz), 6.93 (2H, d, J = 8.9 Hz), 3.88 (3H, s), 2.46−2.43 (2H, m),
2.30 (2H, t, J = 7.2 Hz), 1.53−1.33 (6H, m), 1.12−1.10 (2H, m), 0.95
(3H, t, J = 7.2 Hz), 0.77 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ
206.3, 192.2, 163.0, 131.2, 130.9, 113.4, 107.5, 66.9, 55.4, 39.5, 31.0,
29.6, 28.1, 22.4, 21.1, 13.9, 13.6; IR (CHCl3, cm−1) 2961, 2933, 2874,
1643, 1602, 1509, 1466, 1312, 1257, 1032, 843; MS (EI) m/z = (M+);
HRMS (EI) m/z calcd for C19H25IO2 412.0899, found 412.0899.
Sonogashira Coupling Reaction of 3-Iodofuran 3 with
Terminal Alkynes. To a solution of 3-iodofuran 3 (0.1 mmol) in
Et3N (1 mL) were added PdCl2(PPh3)2 (7 mg, 0.01 mmol), CuI (1.9
mg, 0.01 mmol), and alkyne (0.3 mmol), and the mixture was stirred
at 50 °C under nitrogen. The reaction was monitored by TLC to
establish completion. Saturated aqueous NH4Cl solution was added to
the reaction mixture and extracted with AcOEt (three times). The
combined organic solution was washed with brine, dried over
anhydrous MgSO4, and concentrated at the reduced pressure. Column
chromatography on silica gel using hexane/ethyl acetate as an eluent
afforded 5.
2,4-Dibutyl-3-iodo-5-(4-methoxyphenyl)furan (3q). Colorless oil:
1H NMR (CDCl3) δ 7.48 (2H, d, J = 8.9 Hz), 6.94 (2H, d, J = 8.9 Hz),
3.83 (3H, s), 2.70 (2H, t, J = 7.6 Hz), 2.52 (2H, t, J = 8.2 Hz), 1.67−
1.64 (2H, m), 1.57−1.55 (2H, m), 1.43−1.39 (4H, m), 0.96 (3H, t, J =
7.6 Hz), 0.94 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ 158.6, 154.6,
147.2, 126.7, 124.3, 122.2, 114.0, 71.7, 55.3, 31.9, 30.2, 27.6, 26.6, 22.7,
22.2, 13.9, 13.8; IR (CHCl3, cm−1) 2960, 2933, 2874, 2862, 1616,
1601, 1576, 1559, 1506, 1466, 1457, 1443, 1292, 1250, 1178, 1041,
1017, 834; MS (EI) m/z = 412 (M+); HRMS (EI) m/z calcd for
C19H25IO2 412.0899, found 412.0894.
3-Cyclohexyl-4-iodo-2-(4-methoxyphenyl)-5-(p-tolyl)furan (3r).
1
White viscous oil: H NMR (CDCl3) δ 7.86 (2H, d, J = 8.2 Hz),
7.45 (2H, d, J = 8.9 Hz), 7.21 (2H, d, J = 8.2 Hz), 6.96 (2H, d, J = 8.9
Hz), 3.85 (3H, s), 2.80−2.78 (1H, m), 2.37 (3H, s), 1.95−1.75 (7H,
m), 1.37−1.24 (3H, m); 13C NMR (CDCl3) δ 159.53, 150.90, 148.91,
137.89, 129.83, 128.89, 127.89, 127.49, 126.93, 124.09, 113.77, 66.54,
55.31, 37.30, 31.34, 26.92, 25.97, 21.33; IR (CHCl3, cm−1) 2931, 1615,
1506, 1494, 1465, 1450, 1294, 1251, 1176, 1045, 1029, 939, 836; MS
(EI) m/z = 472 (M+); HRMS (EI) m/z calcd for C24H25IO2 472.0899,
found 472.0901.
Ethyl (4-(3-Butyl-4-iodo-5-(p-tolyl)furan-2-yl)phenyl)carbamate
(3s). White needle: mp 135−137 °C; 1H NMR (CDCl3) δ 7.93
(2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.9 Hz), 7.45 (2H, d, J = 8.2 Hz),
7.24 (2H, d, J = 8.2 Hz), 6.63 (1H, br s), 4.25 (2H, q, J = 7.1 Hz),
2.64−2.63 (2H, m), 2.39 (3H, s), 1.63−1.60 (2H, m), 1.48−1.47 (2H,
m), 1.33 (3H, t, J = 7.2 Hz), 0.98 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 153.5, 150.1, 147.5, 138.0, 137.2, 129.0, 127.7, 126.3, 126.3,
125.3, 118.7, 70.8, 61.4, 31.7, 26.9, 22.8, 21.4, 14.6, 13.9; IR (CHCl3,
cm−1) 3435, 2961, 2933, 1733, 1585, 1522, 1411, 1316, 1258, 1185,
1098, 1066, 946, 839; MS (EI) m/z = 503 (M+); HRMS (EI) m/z
calcd for C24H26INO3 503.0957, found 503.0950.
3-Butyl-4-(hex-1-yn-1-yl)-2-(4-methoxyphenyl)-5-phenylfuran
1
(5a). Pale yellow oil: H NMR (CDCl3) δ 8.13 (2H, d, J = 7.6 Hz),
7.62 (2H, d, J = 8.2 Hz), 7.40 (2H, t, J = 7.9 Hz), 7.27 (1H, t, J = 6.9
Hz), 6.97 (2H, d, J = 8.2 Hz), 3.85 (3H, s), 2.69 (2H, t, J = 7.9 Hz),
2.55 (2H, t, J = 6.9 Hz), 1.67−1.66 (4H, m), 1.56−1.55 (2H, m),
1.46−1.44 (2H, m), 0.98 (3H, t, J = 7.2 Hz), 0.97 (3H, t, J = 7.6 Hz);
13C NMR (CDCl3) δ 158.8, 151.4, 147.1, 130.8, 128.4, 127.3, 127.0,
124.3, 124.1, 124.0, 114.1, 107.4, 97.3, 73.1, 55.3, 31.8, 30.9, 24.5, 22.8,
22.0, 19.5, 14.0, 13.6; IR (CHCl3, cm−1) 2960, 2934, 2873, 2862, 1605,
1572, 1507, 1465, 1443, 1294, 1250, 1177, 1035, 834; MS (EI) m/z =
386 (M+); HRMS (EI) m/z calcd for C27H30O2 386.2246, found
386.2252.
N-(4-(3-Butyl-4-iodo-5-(p-tolyl)furan-2-yl)phenyl)acetamide (3t).
Pale yellow solid: mp 168−170 °C; 1H NMR (CDCl3) δ 7.93 (2H, d, J
= 8.2 Hz), 7.61 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J = 8.9 Hz), 7.37 (1H,
br s), 7.25 (2H, t, J = 7.6 Hz), 2.63 (2H, t, J = 8.2 Hz), 2.39 (3H, s),
2.20 (3H, s), 1.64−1.58 (2H, m), 1.50−1.45 (2H, m), 0.98 (3H, t, J =
7.2 Hz); 13C NMR (CDCl3) δ 168.3, 150.2, 147.3, 138.0, 137.0, 129.0,
127.6, 127.1, 126.3, 126.1, 125.5, 119.8, 70.9, 31.7, 26.9, 24.7, 22.8,
21.4, 13.9; IR (CHCl3, cm−1) 3435, 2961, 2932, 1690, 1599, 1586,
3-Butyl-2-(4-methoxyphenyl)-5-phenyl-4-(phenylethynyl)furan
1
(5b). Pale yellow needle: mp 63−65 °C; H NMR (CDCl3) δ 8.18
(2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 7.6 Hz), 7.56 (2H, d, J = 6.9 Hz),
7.44 (2H, t, J = 7.2 Hz), 7.40−7.36 (3H, m), 7.30 (1H, t, J = 6.9 Hz),
6.99 (2H, d, J = 8.9 Hz), 3.86 (3H, s), 2.78 (2H, t, J = 7.6 Hz), 1.76−
1.74 (2H, m), 1.50−1.49 (2H, m), 0.98 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 158.9, 152.2, 147.5, 131.3, 130.6, 128.5, 128.4, 128.1, 127.7,
127.1, 124.6, 123.9, 123.7, 123.7, 114.1, 106.7, 96.0, 82.5, 55.3, 31.8,
3950
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The Journal of Organic Chemistry
Article
24.5, 22.8, 14.0; IR (CHCl3, cm−1) 2960, 2934, 2862, 1607, 1598,
1572, 1507, 1484, 1464, 1443, 1295, 1250, 1178, 1136, 1028, 967, 834;
MS (EI) m/z = 406 (M+); HRMS (EI) m/z calcd for C29H26O2
406.1933, found 406.1924.
(6) (a) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem.,
Int. Ed. 2006, 45, 3822−3825. (b) Obika, S.; Kono, H.; Yasui, Y.;
Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462−4468.
(c) Okamoto, N.; Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R.
Angew. Chem., Int. Ed. 2009, 48, 9693−9696. (d) Okamoto, N.;
Takeda, K.; Yanada, R. J. Org. Chem. 2010, 75, 7615−7625.
(7) Okamoto, N.; Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R. J.
Org. Chem. 2011, 76, 9133−9138.
ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(8) Chen, Z.; Huang, G.; Jiang, H.; Huang, H.; Pan, X. J. Org. Chem.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: ryanada@ps.hirokoku-u.ac.jp.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by a Grant-in-Aid for Scientific
Research from JSPS KAKENHI (23590032). N.O. is grateful to
the Research Foundation by Hiroshima International Uni-
versity.
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