Synthesis of propargylic ethers by gold-mediated reaction of terminal alkynes with acetals

Article abstract of DOI:10.1248/cpb.c19-00322

A gold-catalyzed introduction of various terminal alkynes to acetals was investigated. Extensive optimization of the reaction conditions revealed that thermally stable cationic gold catalysts bearing bulky ligands such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate (IPrAu(BTZ-H)OTf) were particularly suitable for the reaction. Additionally, significant solvent effects were observed. Ether solvents such as tetrahydrofuran (THF), cyclo pentyl methyl ether (CPME), and 1,4-dioxane were effective for the reaction. Studies on the scope of substrates and alkynes indicated that various alkynes and acetals were feasible to provide a wide range of propargylic ethers.

Full text of DOI:10.1248/cpb.c19-00322

872
Chem. Pharm. Bull. 67, 872–876 (2019)
Vol. 67, No. 8
Regular Article
Highlighted Paper selected by Editor-in-Chief
Synthesis of Propargylic Ethers by Gold-Mediated Reaction of Terminal
Alkynes with Acetals
Miyu Furuta, Kyoko Sugiyama, Minami Yamaguchi, Hirofumi Ueda, and Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University; 6–3 Aoba, Aramaki, Aoba-ku, Sendai 980–8578, Japan.
Received April 12, 2019; accepted May 8, 2019
A gold-catalyzed introduction of various terminal alkynes to acetals was investigated. Extensive optimi-
zation of the reaction conditions revealed that thermally stable cationic gold catalysts bearing bulky ligands
such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethane-
sulfonate (IPrAu(BTZ-H)OTf) were particularly suitable for the reaction. Additionally, significant solvent
effects were observed. Ether solvents such as tetrahydrofuran (THF), cyclo pentyl methyl ether (CPME),
and 1,4-dioxane were effective for the reaction. Studies on the scope of substrates and alkynes indicated that
various alkynes and acetals were feasible to provide a wide range of propargylic ethers.
Key words gold catalysis; acetal; terminal alkyne; propargylic ether
2, which adds to the oxonium ion 5 to form 6. Next, the
Introduction
Alkyne is one of the most useful functional groups in gold catalyst works as a π-Lewis acid, activating the al-
synthetic organic chemistry and can be transformed into kyne moiety to promote 5-endo-dig cyclization to furnish
corresponding alkane, alkene, allene, and carbonyl groups.1) pyrrole 3. During the course of the investigation, we ob-
Furthermore, they work as a 1,3-dipolarophile. For example, served that the choice of the appropriate ligand such as
Huisgen-type 1,3-dipolar cycloaddition with azides, known 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos)
as click reaction, is a widely used method in chemical biol- or 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) on
ogy.2) Moreover, medicinal products comprising alkynes are the gold catalyst was crucial for achieving a smooth reaction.
frequently used for the treatment of diseases such as cranial Therefore, we conducted fundamental studies on the first step
nerve disease and gynecological disease. Due to the prevalent of the above cascade reaction using various gold catalysts and
application of alkynes in organic synthesis, chemical biology, acetals to clarify the scope and limitation of the initial reac-
and medicinal chemistry, the development of a methodology tion of gold acetylides with acetals.
to incorporate alkyne moiety in organic compounds is an im-
portant research topic.
Results and Discussion
The most fundamental means to introduce alkyne moiety
First, we explored the optimal reaction conditions for ob-
to an organic molecule is a reaction of metal acetylides with taining propargylic ether 10a by using acetal 8a and phen-
electrophiles.3–20) For example, metal acetylides prepared by ylacetylene 2a as model substrates. Reactions using π-philic
reacting terminal acetylenes with lithium,3) magnesium,4) catalysts such as AuCl, AuCl3, CuI, and PtCl2 in toluene did
zinc,5) tin,6) boron,7) aluminum,8) and titanium9) reagents react not produce the desired 10a even after heating at 50°C for
with carbonyl compounds or acetals to produce propargylic 12h (Table 1, entries 1–4). The use of cationic gold cata-
alcohol or ether, respectively. However, these methods re- lyst generated in situ from a combination of AuPPh3Cl and
quire a strong base or a stoichiometric amount of metal to AgOTf gave 10a in a modest yield (Table 1, entry 5). Reac-
generate metal acetylides. On the other hand, the addition of tion conditions established in our pyrrole synthesis24) using
terminal acetylene to acetals proceeds in the presence of a
catalytic amount of zinc,10,11) copper,12) and tin13) reagents to
afford propargylic ether, although these reactions often require
heating conditions and would not be applied to acid-sensitive
substrates. Based on the high functional group compatibil-
ity,14–17) gold catalyzed synthesis of propargylic alcohol18) or
ether19) from terminal alkyne has recently been developed.
However, in these reactions, electrophiles are only limited to
aryl aldehydes. Additionally, Dalla and colleagues reported
a gold-mediated introduction of alkyne moieties to cyclic
acetals,20) whose limitation was the necessity to use trimeth-
ylsilyl alkynes.
Recently, we developed a modular synthesis of substituted
pyrroles from aminoacetals and alkynes via gold-mediated
tandem catalysis21–24) (Chart 1). The cascade reaction is
initiated by the formation of gold acetylide 4 from alkyne
Chart 1. Gold-Catalyzed Substituted Pyrrole Synthesis
*To whom correspondence should be addressed. e-mail: tokuyama@m.tohoku.ac.jp
© 2019 The Pharmaceutical Society of Japan

Vol. 67, No. 8 (2019)
Chem. Pharm. Bull.
873
Table 1. Optimization of Gold-Catalyzed Propargylic Ether Synthesis
Table 2. Substrate Scope of Alkynes
Time
(min)
Yield
(%)
Entry
Catalyst (mol%)
AuCl (10)
Solvent
1
2
3
4
5
6
7
8
9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
720
720
720
720
45
5
ND
ND
ND
ND
67
52
71
80
67
71
42
77
67
57
74
82
87
72
AuCl3 (10)
CuI (10)
PtCl2 (10)
AuPPh3Cl (10), AgOTf (10)
RuPhosAuCl (10), AgOTf (10)
IPrAuCl (10), AgOTf (10)
IPrAu(BTZ-H)(OTf) (10)
IPrAu(BTZ-H)(OTf) (5)
5
5
5
10 IPrAu(BTZ-H)(OTf) (2)
11 IPrAu(BTZ-H)(OTf) (1)
12 IPrAu(BTZ-H)(OTf) (2)
13 IPrAu(BTZ-H)(OTf) (2)
14 IPrAu(BTZ-H)(OTf) (2)
15 IPrAu(BTZ-H)(OTf) (2)
16 IPrAu(BTZ-H)(OTf) (2)
17 IPrAu(BTZ-H)(OTf) (2)
18a) IPrAu(BTZ-H)(OTf) (2)
30
30
30
45
180
20
10
20
20
1,2-DCE
Acetonitrile
1,4-Dioxane
CPME
THF
THF
a) 2eq of 2a was used.
a) 7mol% catalyst was used in toluene solvent.
RuPhosAuCl22) that has a biphenylphosphine ligand and IP-
rAuCl possessing a bulky carbene ligand were quite efficient or methoxy group at the para position, provided the corre-
in providing 10a in good yields (Table 1, entries 6 and 7). sponding alkynes 10b and 10c in good yield (Table 2, entries
We reasoned that the superiority of the bulky gold catalyst 1 and 2). Alkynes bearing meta- or ortho-methoxy substituent
would be due to the suppression of product decomposition on the benzene ring gave alkynes 10d and 10e in moderate
by gold catalyzed methanolysis. Furthermore, thermally sta- yield, respectively (Table 2, entries 3 and 4). Notably, aryl
ble catalyst, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene iodide was tolerant under standard conditions (Table 2, entry
3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate 5). Conversely, when the substrate contained an electron with-
(IPrAu(BTZ-H)OTf),25,26) which itself works as a cationic gold drawing group such as a nitro group on the benzene ring, 10g
catalyst, improved the yield of 10a up to 80% (Table 1, entry was afforded in low yield because of the suppressed nucleo-
8). Next, we selected IPrAu(BTZ-H)OTf as the best catalyst philicity of the corresponding acetylide (Table 2, entry 6). In
and conducted extensive optimization experiments regarding the reaction using alkyl alkynes, 10h and 10i were produced
catalyst loading and the solvent (Table 1, entries 9–18). The in moderate yields (Table 2, entries 7 and 8).
loading of catalyst was reduced to 2mol% without substantial
Further, various types of acetals were reacted with ethynyl
loss of the yield, although the reaction time was prolonged benzene (2a). Diethyl and diisopropyl acetals were suitable
(Table 1, entry 10). Non-polar solvents such as toluene and substrates for generating the propargylic ethers 10j and 10k
xylene together with ether solvents were found to be suitable in excellent yields (Table 3, entries 1 and 2), respectively.
(Table 1, entries 12–17). Especially, the reaction using tetra- Substrates possessing dimethyl acetal at the benzyl or the neo-
hydrofuran (THF) provided 10a in highest yield (Table 1, pentyl positions gave the corresponding products 10l or 10 m
entry 17). Even in the case of reaction using reduced amount (Table 3, entries 3 and 4). The reaction was feasible to instal-
of alkyne 2a to 2eq, 10a was obtained with a slight loss of the lation of alkyne moiety to a cyclic acetal. A tetrahydropyranyl
yield (Table 1, entry 18).
(THP) derivative 8f gave 10n (Chart 2) albeit with a low yield.
After establishing the optimal conditions, we shifted our at-
In conclusion, we conducted detailed studies on the gold-
tention to the substrate scope. Various terminal alkynes 2a–i catalyzed introduction of various terminal alkynes to acetals.
were exposed to acetals 8a–e in the presence of 2mol% of the During the optimization process, we found that thermally
gold catalyst in THF at 100°C (Table 2). Arylalkynes bearing stable cationic gold catalysts bearing bulky ligands were par-
electron donating groups on the benzene ring, such as methyl ticularly suitable for the reaction. Because it was feasible to

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Chem. Pharm. Bull.
Vol. 67, No. 8 (2019)
Table 3. Substrate Scope of Acetals
(5mol%), thiourea (2mol%), and alcohol (0.2M). To the solu-
tion was added cinnamaldehyde at room temperature. The
mixture was stirred until TLC (hexanes/AcOEt=3:1) indi-
cated a complete consumption of cinnamaldehyde. The reac-
tion mixture was concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (hexanes/AcOEt=10:1) to afford acetal.
(3,3-Dimethoxypropyl)benzene (8a)
According to the general procedure A, dimethylacetal 8a
was obtained from cinnamaldehyde with MeOH in 15mmol
scale (2.30g, 12.7mmol, 85%) as a colorless liquid; Its
1H-NMR spectra data was completely identical with that
reported27); IR (neat, cm−1) 3027, 2952, 2829, 1603, 1025,
1
1054, 747; H-NMR (400MHz, CDCl3) δ: 7.30–7.25 (2H, m),
7.20 (3H, d, J=7.2Hz), 4.37 (1H, t, J=6.0Hz), 3.33 (6H,
s), 2.68 (2H, t, J=8.0Hz), 1.95–1.90 (2H, m); 13C-NMR
(100MHz, CDCl3) δ: 141.5, 128.2, 125.7, 103.5, 52.5, 33.9, 30.7
(one peak is missing due to overlapped); high resolution (HR)-
MS EI Calcd for C11H16O2[M]+ 180.1150. Found 180.1165.
(3,3-Diethoxypropyl)benzene (8b)
According to the general procedure A, diethylacetal 8b was
obtained from cinnamaldehyde with EtOH in 0.75mmol scale
(136mg, 0.653mmol, 87%) as a colorless liquid; 1H-NMR
spectra data was completely identical with that reported27)
;
Chart 2. Application to Cyclic Acetal
IR (neat, cm−1) 3027, 2975, 2928, 2876, 1604, 1129, 1063, 747;
use this reaction to synthesize a broad range of propargylic 1H-NMR (400MHz, CDCl3) δ: 7.29–7.25 (2Η, m), 7.21–7.16
ethers by mild gold catalysis, we expect this protocol to find (3H, m), 4.49 (1H, t, J=6.0Hz), 3.87 (2H, dq, J=7.2, 9.2Hz),
widespread use in the synthesis of various propargylic ethers 3.49 (2H, dq, J=7.6, 9.2Hz), 2.71–2.67 (2H, m), 1.97–1.92
in chemical biology and medicinal chemistry.
(2H, m), 1.21 (6H, t, J=7.2Hz.); 13C-NMR (100MHz,
CDCl3) δ: 141.7, 128.3, 128.3, 125.7, 102.1, 60.9, 35.0, 30.9,
15.3; HR-MS (EI) Calcd for C13H20O2[M]+ 208.1463. Found
Experimental
Materials were obtained from commercial suppliers and 208.1508.
used without further purification unless otherwise mentioned.
All reactions were carried out in oven-dried glassware under
(3,3-Diisopropoxypropyl)benzene (8c)
According to the general procedure A, diisopropylac-
a slight positive pressure of argon unless otherwise noted. etal 8c was obtained from cinnamaldehyde with i-PrOH in
Anhydrous Et2O, THF, MeCN, and CH2Cl2 were purchased 2.0mmol scale (200mg, 0.846mmol, 42%) as a colorless
1
from Kanto Chemical Co., Inc. Anhydrous toluene, AcOEt liquid; H-NMR spectra data was completely identical with
and N,N-dimethylformamide (DMF) were purchased from that reported27); IR (neat, cm−1) 3027, 2971, 2930, 1604, 1128,
1
Wako Pure Chemical Industries, Ltd.. Anhydrous toluene, 1034, 699; H-NMR (400MHz, CDCl3) δ: 7.29–7.15 (5Η, m),
xylene, 1,2-dichloroethane, 1,4-dioxane, methoxycyclopentane, 4.56 (1H, t, J=5.2Hz), 3.85 (2H, sept, J=6.4Hz), 2.71–2.67
MeOH, EtOH, i-PrOH, and Et3N were dried and distilled ac- (2H, m), 1.94–1.89 (2H, m), 1.20 (6H, d, J=6.4Hz), 1.14 (6H,
cording to the standard protocols. Flash column chromatogra- d, J=6.0Hz); 13C-NMR (100MHz, CDCl3) δ: 142.0, 128.4,
phy was performed on Silica Gel 60N (Kanto, spherical neu- 128.3, 125.7, 99.7, 67.7, 36.9, 31.1, 23.4, 22.6; HR-MS (EI)
tral, 40–50µm) using the indicated eluent. Preparative TLC Calcd for C15H24O2[M]+, 236.1776. Found 236.1814.
was performed on Merck 60F254 glass plates precoated with
General Procedure for Gold-Catalyzed Nucleophilic
a 0.50mm and a 0.25mm thickness of silica gel. Analytical Addition of Acetylenes to Acetals
TLC was performed on Merck 60F254 glass plates precoated
with a 0.25mm thickness of silica gel. IR spectra were mea-
(3-Methoxypent-1-yne-1,5-diyl)dibenzene (10a)
A 10mL test tube equipped with a magnetic stirring bar
sured on a JASCO FT/IR-4100 spectrometer. NMR spectra was charged with IPrAu(BTZ-H)OTf (1.7mg, 1.99µmol,
were recorded on a JNM-AL400 spectrometer with tetra- 2mol%) and THF (200µL, 0.5M). To the solution were
methylsilane (0ppm) and chloroform (7.26ppm) as an internal added acetal 8a (18.0mg, 0.100mmol) and alkyne 2a (55.0 µL,
standard. Chemical shifts were expressed in δ (ppm) values, 0.500mmol, 5.0eq) at room temperature. The mixture was
and coupling constants were expressed in hertz (Hz). The fol- heated at 100°C and the solution was stirred until TLC
lowing abbreviations are used for spin multiplicity: s=singlet, (hexanes–Et2O=10:1) indicated a complete consumption of
d=doublet, t=triplet, q=quartet, sept=septet, m=multi- acetal 8a. The reaction was quenched with saturated aqueous
plet, and br=broad. Mass spectra were recorded on a Brucker NaHCO3 and the mixture was extracted with AcOEt three
micrOTOF II (electrospray ionization (ESI)) and JEOL JMS-T times. The combined organic extracts were washed with brine,
100GC (electron ionization (EI)).
dried over Na2SO4, and concentrated under reduced pressure.
General Procedure A for Preparation of Acetals
A
The residue was purified by flash column chromatography
300mL two-necked round-bottomed flask equipped with a on silica gel (hexanes–Et2O=60:1) to afford propargyl ether
magnetic stirring bar was charged with N-chlorosuccinimide 10a (21.9mg, 87.5µmol, 87%) as a yellow oil; IR (neat, cm−1)

Vol. 67, No. 8 (2019)
Chem. Pharm. Bull.
875
1
3026, 2927, 2820, 1601, 756, 691; H-NMR (400MHz, CDCl3) propargyl ether 10f was obtained from acetal 8a with alkyne
δ: 7.46–7.44 (2H, m), 7.31–7.17 (8H, m), 4.14 (1H, t, J=6.4Hz), 2f in 0.50mmol scale (151mg, 0.402mmol, 80%) as a yel-
3.47 (3H, s), 2.87–2.83 (2H, m), 2.20–2.03 (2H, m); 13C-NMR low oil; IR (neat, cm−1) 3061, 3025, 2819, 1601, 1577, 1030,
1
(100MHz, CDCl3) δ: 141.4, 131.7, 128.5, 128.4, 128.3, 128.3, 715; H-NMR (400MHz, CDCl3) δ: 7.65 (2H, d, J=8.4Hz),
125.9, 122.7, 87.8, 86.2, 70.8, 56.5, 37.2, 31.5; HR-MS (ESI) 7.31–7.15 (7H, m), 4.11 (1H, t, J=6.8Hz), 3.46 (3H, s),
Calcd for C17H15 [M−OMe]+, 219.1168. Found 219.1178.
2.83 (2H, dt, J=8.0, 1.2Hz), 2.19–2.05 (2H, m); 13C-NMR
1-(3-Methoxy-5-phenylpent-1-yn-1-yl)-4-methylbenzene (100MHz, CDCl3) δ: 141.2, 137.4, 133.2, 128.5, 128.4, 125.9,
(10b)
122.2, 94.2, 89.3, 85.2, 70.7, 56.5, 37.0, 31.4; HR-MS (EI)
According to the general procedure described for 10a, Calcd for C18H17IO [M]+, 376.0324. Found 376.0323.
propargyl ether 10b was obtained from acetal 8a with alkyne
2b in 0.50mmol scale (106mg, 0.402mmol, 80%) as a yel-
1-(3-Methoxy-5-phenylpent-1-yn-1-yl)-4-nitrobenzene (10g)
According to the general procedure described for 10a,
low oil; IR (neat, cm−1) 3085, 3065, 3027, 2853, 1601, 817, propargyl ether 10g was obtained from acetal 8a with alkyne
1
746; H-NMR (400MHz, CDCl3) δ: 7.35 (2H, d, J=8.4Hz), 2g in 0.50mmol scale (21.6mg, 73.1µmol, 15%) as a yel-
7.31–7.18 (5H, m), 7.12 (2H, d, J=8.4Hz), 4.14 (1H, t, low oil; IR (neat, cm−1) 3104, 3081, 3058, 1594, 1454, 749;
J=6.4Hz), 3.47 (3H, s), 2.85 (2H, dt, J=6.4, 2.4Hz), 2.35 1H-NMR (400MHz, CDCl3) δ: 8.19 (2H, d, J=8.4Hz), 7.58
(3H, s), 2.19–2.04 (2H, m); 13C-NMR (100MHz, CDCl3) δ: (2H, d, J=8.0Hz), 7.31 (2H, J=7.2Hz), 7.25–7.19 (3H, m),
141.5, 138.4, 131.6, 129.0, 128.5, 128.4, 125.9, 119.6, 87.0, 86.3, 4.16 (1H, t, J=6.4Hz), 3.48 (3H, s), 2.85 (2H, t, J=7.6Hz)
70.8, 56.4, 37.3, 31.5, 21.4; HR-MS (ESI) Calcd for C18H17 2.22–2.04 (2H, m); 13C-NMR (100MHz, CDCl3) δ: 147.2,
[M−OMe]+, 233.1325. Found 233.1322.
141.1, 132.5, 129.6, 128.5, 128.5, 126.1, 123.5, 93.5, 84.3, 70.7,
1-Methoxy-4-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene 56.8, 36.9, 31.4; HR-MS (ESI) Calcd for C17H14NO2 [M−
(10c)
OMe]+, 264.1019. Found 264.1023.
According to the general procedure described for 10a,
propargyl ether 10c was obtained from acetal 8a with alkyne
(3-Methoxynon-4-yn-1-yl)benzene (10h)
According to the general procedure described for 10a,
2c in 0.50mmol scale (103mg, 0.366mmol, 73%) as a yel- propargyl ether 10h was obtained from acetal 8a with alkyne
low oil; IR (neat, cm−1) 2932, 2837, 2817, 1605, 1062, 832, 2h in 0.50mmol scale (79.7mg, 0.346mmol, 69%) as a yellow
699; 1H-NMR (400MHz, CDCl3) δ: 7.39 (2H, dt, J=8.8, oil; IR (neat, cm−1) 3061, 3027, 2861, 1604, 1081, 748, 699;
2.8Hz), 7.31–7.12 (5H, m), 6.83 (2H, dt, J=8.8, 2.8Hz), 4.12 1H-NMR (400MHz, CDCl3) δ: 7.29–7.15 (5H, m), 3.90 (1H,
(1H, t, J=6.4Hz), 3.81 (3H, s), 3.47 (3H, s), 2.87–2.82 (2H, tt, J=6.4, 2.0Hz), 3.38 (3H, s), 2.77 (2H, t, J=7.6Hz), 2.24
m), 2.17–2.04 (2H, m); 13C-NMR (100MHz, CDCl3) δ: 159.6, (2H, dt, J=6.8, 2.0Hz), 2.05–1.93 (2H, m), 1.55–1.40 (4H, m),
141.5, 133.1, 128.5, 128.3, 125.8, 114.8, 113.9, 86.3, 86.1, 70.8, 0.92 (3H, t, J=7.2Hz); 13C-NMR (100MHz, CDCl3) δ: 141.7,
56.4, 55.2, 37.3, 31.5; HR-MS (ESI) Calcd for C18H17O [M− 128.5, 128.3, 125.8, 86.7, 78.6, 70.6, 56.1, 37.5, 31.5, 30.8,
OMe]+, 249.1274. Found 249.1271.
1-Methoxy-3-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene 199.1481. Found 199.1460.
(10d) (5-Cyclohexyl-3-methoxypent-4-yn-1-yl)benzene (10i)
According to the general procedure described for 10a, According to the general procedure described for 10a,
21.9, 18.3, 13.5; HR-MS (ESI) Calcd for C15H19 [M−OMe]+,
propargyl ether 10d was obtained from acetal 8a with alkyne propargyl ether 10i was obtained from acetal 8a with alkyne
2d in 0.50mmol scale (77.0mg, 0.275mmol, 55%) as a yel- 2i in 0.50mmol scale (75.9mg, 0.296mmol, 59%) as a yel-
low oil; IR (neat, cm−1) 3085, 3058, 3023, 2992, 2821, 1602, low oil; IR (neat, cm−1) 3012, 2853, 2817, 1496, 1105, 749;
1
1163, 786, 746; H-NMR (400MHz, CDCl3) δ: 7.31–7.17 (6H, 1H-NMR (400MHz, CDCl3) δ: 7.30–7.16 (5H, m), 4.56 (1H,
m), 7.05 (1H, dt, J=8.0Hz, 1.2Hz), 6.98 (1H, t, J=2.4Hz), dt, J=7.2, 2.0Hz), 3.39 (3H, s), 2.78 (2H, dt, J=7.2, 0.8Hz),
6.87 (1H, dd, J=8.4, 1.6Hz), 4.14 (1H, t, J=6.4Hz), 3.80 2.44 (1H, quin, J=1.6Hz), 2.80–1.94 (2H, m), 1.82–1.72 (2H,
(3H, s), 3.47 (3H, s), 2.85 (2H, t, J=8.4Hz), 2.16–2.08 (2H, m), 1.71–1.69 (2H, m), 1.51–1.45 (3H, m), 1.34–1.29 (3H, m);
m); 13C-NMR (100MHz, CDCl3) δ: 159.3, 141.4, 129.3, 128.5, 13C-NMR (100MHz, CDCl3) δ: 141.7, 128.5, 128.3, 125.8, 90.9,
128.4, 125.9, 124.2, 123.7, 116.6, 114.9, 87.6, 86.1, 70.8, 56.4, 78.6, 70.6, 56.6, 37.6, 32.7, 31.5, 29.0, 25.9, 24.7; HR-MS (ESI)
55.2, 37.2, 31.4; HR-MS (ESI) Calcd for C18H17O [M−OMe]+, Calcd for C17H21 [M−OMe]+, 225.1638. Found 225.1646.
249.1274. Found 249.1264.
(3-Ethoxypent-1-yne-1,5-diyl)dibenzene (10j)
1-Methoxy-2-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene
(10e)
According to the general procedure described for 10a,
propargyl ether 10j was obtained from acetal 8b with phen-
According to the general procedure described for 10a, ylacetylene (2a) in 0.10mmol scale (21.8mg, 82.5µmol, 82%)
propargyl ether 10e was obtained from acetal 8a with alkyne as a yellow oil; IR (neat, cm−1) 3061, 3027, 2974, 2927, 2864,
1
2e in 0.50mmol scale (103mg, 0.368mmol, 74%) as a yellow 1600, 1092, 756, 698; H-NMR (400MHz, CDCl3) δ: 7.45–7.43
oil; IR (neat, cm−1) 3061, 3027, 2833, 1596, 1292, 751, 700; (2H, m), 7.32–7.16 (8H, m), 4.22 (1H, t, J=6.4Hz), 3.87 (1H,
1H-NMR (400MHz, CDCl3) δ: 7.42 (1H, dd, J=7.2, 7.2Hz), dq, J=9.2, 6.8Hz), 3.49 (1H, dq, J=9.2, 6.8Hz), 2.86 (2H,
7.31–7.17 (6H, m), 6.92–6.86 (2H, m), 4.20 (1H, t, J=6.4Hz), t, J=7.6Hz), 2.19–2.08 (2H, m), 1.26 (3H, t, J=7.6Hz);
3.87 (3H, s), 3.50 (3H, s), 2.95–2.82 (2H, m), 2.20–2.04 (2H, 13C-NMR (100MHz, CDCl3) δ: 141.5, 131.7, 128.5, 128.4,
m); 13C-NMR (100MHz, CDCl3) δ: 160.1, 141.6, 133.5, 129.7, 128.2, 125.9, 122.9, 88.5, 85.7, 69.0, 64.4, 37.4, 31.6, 15.2 (one
128.5, 128.3, 125.8, 120.3, 111.9, 110.5, 91.3, 82.5, 70.9, 56.4, peak is missing due to overlapped); HR-MS (ESI) Calcd for
55.6, 37.2, 31.4; HR-MS (ESI) Calcd for C18H17O [M−OMe]+, C17H15 [M−OEt]+, 219.1168. Found 219.1129.
249.1274. Found 249.1265.
(3-Isopropoxypent-1-yne-1,5-diyl)dibenzene (10k)
1-Iodo-4-(3-methoxy-5-phenylpent-1-yn-1-yl)benzene (10f)
According to the general procedure described for 10a,
According to the general procedure described for 10a, propargyl ether 10k was obtained from acetal 8c with phen-

876
Chem. Pharm. Bull.
Vol. 67, No. 8 (2019)
ylacetylene (2a) in 0.10mmol scale (23.6mg, 84.8µmol, 84%)
Conflict of Interest The authors declare no conflict of
as a yellow oil; IR (neat, cm−1) 3085, 3065, 3027, 2971, 1600, interest.
1
756, 698; H-NMR (400MHz, CDCl3) δ: 7.44–7.42 (2H, m),
7.30–7.16 (8H, m), 4.30 (1H, t, J=6.4Hz), 3.98 (1H, sept,
J=6.4Hz), 2.89–2.78 (2H, m), 2.17–2.06 (2H, m), 1.27 (3H,
d, J=6.4Hz), 1.16 (3H, d, J=6.4Hz); 13C-NMR (100MHz,
CDCl3) δ: 141.8, 131.7, 128.5, 128.3, 128.2, 128.2, 125.8, 123.0,
89.2, 85.0, 69.9, 66.5, 37.8, 31.6, 23.3, 21.4; HR-MS (ESI)
Calcd for C17H15 [M−Oi-Pr]+, 219.1168. Found 219.1177.
(3-Methoxyprop-1-yne-1,3-diyl)dibenzene (10l)
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According to the general procedure described for 10a,
propargyl ether 10l was obtained from acetal 8d with phenyl-
acetylene (2a) in 0.50mmol scale (82.7mg, 0.372mmol, 74%)
1
as a yellow oil; Its H-NMR spectra data was completely iden-
tical with that reported28); IR (neat, cm−1) 3058, 3023, 2917,
1
2848, 1598, 734, 696; H-NMR (400MHz, CDCl3) δ: 7.58 (1H,
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(3-Methoxy-4-methylpent-1-yne-1,4-diyl)dibenzene (10m)
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1
2819, 1599, 1490, 1094, 757, 697; H-NMR (400MHz, CDCl3)
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2-(Phenylethynyl)tetrahydro-2H-pyran (10n)
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ylacetylene (2a) in 0.50mmol scale (33.7mg, 0.181mmol, 36%)
as a pale yellow oil; Its 1H-NMR spectra data was identi-
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Acknowledgments This work was supported by the Drug
Discovery and Life Science Research (BINDS) from AMED
(Grant Number JP18am0101100) and JSPS KAKENHI Grant
Numbers JP18H04379, JP18H04231, JP18H04642, 18H02549,
17K08204 and 18H06100.
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