Synthesis of substituted styrenes and 3-vinylphenols using ruthenium-catalyzed ring-closing enyne metathesis

Article abstract of DOI:10.1021/jo500561z

The synthesis of substituted styrenes 3 and 3-vinylphenols 9 was achieved by ring-closing enyne metathesis (RCEM)/dehydration of 7 and RCEM/tautomerization of 8, respectively. Those methods provide selective access to unique aromatic compounds and solve the problem of regioisomer formation.

Full text of DOI:10.1021/jo500561z

Note
pubs.acs.org/joc
Synthesis of Substituted Styrenes and 3‑Vinylphenols Using
Ruthenium-Catalyzed Ring-Closing Enyne Metathesis
Kazuhiro Yoshida,* Kana Nishii, Yuto Kano, Shiro Wada, and Akira Yanagisawa*
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: The synthesis of substituted styrenes 3 and 3-
vinylphenols 9 was achieved by ring-closing enyne metathesis
(RCEM)/dehydration of 7 and RCEM/tautomerization of 8,
respectively. Those methods provide selective access to unique
aromatic compounds and solve the problem of regioisomer
formation.
transformations. In fact, a wide variety of aromatic compounds
s the demand for substituted aromatic compounds
Acontinues to increase, the development of new synthetic can be synthesized by those methods.
The purpose of this study was to extend the application of
methods for such compounds remains an important subject in
organic synthesis. Recently, much attention is being devoted to
aromatic ring construction using ruthenium-catalyzed ring-
closing metathesis (RCM),1,2 a new method that selectively
produces unique aromatic compounds.3,4 As our contribution
to this field,5 in 2009, we developed the ring-closing enyne
metathesis (RCEM)/dehydration of 2 to produce styrenes 3
and the RCEM/tautomerization of 4 to generate 4-vinyl-
phenols 5 (Scheme 1).5j Those methods have great generality
because acyclic precursors 2 and 4 can be readily prepared from
well-known building blocks 1 using only highly reliable
the previous methods from two points of view. First, we
expected to increase the variety of obtainable styrenes 3 by the
RCEM/dehydration of new enyne substrates 7, which were
anticipated to be prepared through the C1-homologation of 1
followed by vinyl addition to resulting aldehydes 6 (Scheme 1).
Second, we expected to synthesize 3-vinylphenols 9, which are
new target molecules and the regioisomers of 5, by the RCEM/
tautomerization of 8, which were expected to be prepared from
7. We report herein the results in detail.
The acyclic precursors for the ring-closing process are enynes
7 and 8. To show how these compounds were prepared, a
typical example is presented in Scheme 2 where 7a and 8a were
synthesized. Ynal 1a was prepared from commercially available
2-bromobenzaldehyde6 and phenylacetylene by means of the
Sonogashira coupling. Our choice of reaction for the
subsequent C1-homologation from 1a to 6a was the Wittig
olefination with (methoxymethyl)triphenylphosphonium chlor-
ide and hydrolysis sequence. Resulting aldehyde 6a was reacted
Scheme 1. Strategy for Synthesizing Styrenes 3, 4-
Vinylphenols 5, and 3-Vinylphenols 9
Scheme 2. Representative Example of the Preparation of 7
and 8
Received: March 10, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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a
Table 1. Synthesis of Substituted Styrenes 3 by RCEM/Dehydration of 7
a
Ring-closing enyne metathesis was carried out with 7 and ruthenium catalyst (10a, 7.5 mol %) in toluene under ethylene atmosphere (1 atm) at 80
b
c
°C for 2 h. The reaction mixture was treated with p-toluenesulfonic acid (10 mol %) at rt for 1 h. Isolated yield by silica gel chromatography. The
reaction was performed under nitrogen atmosphere. Dehydration with p-toluenesulfonic acid was accomplished at 50 °C. RCEM was conducted
with 15 mol % of 10a at 100 °C for 24 h. RCEM was executed with 15 mol % of 10a. RCEM was realized with 30 mol % of 10a.
d
e
f
g
with vinyl Grignard reagent to produce desired enyne 7a.
Finally, we converted 7a into the other desired enyne substrate
8a by simple oxidation with Dess−Martin periodinane.7
which have a methyl group at R4 position and an ethyl group at
R3 position, respectively, were also converted into correspond-
ing products 3f and 3g, respectively (entries 7 and 8). However,
the conversion of 7h having a methyl group at R2 position into
3h met with failure (entries 9 and 10).9 On the other hand,
regardless of the presence of a methyl group at R2 position, the
reaction of 7i having a terminal alkyne part proceeded to give 3i
in 92% yield (entry 11). Finally, the construction of two rings
simultaneously gave 3j in moderate yield from 7j (entries 12
and 13).
Table 2 shows the results of the RCEM/tautomerization of
810 to produce 3-vinylphenols 9. From these, it is proved that
this procedure can provide unique aromatic compounds.
Analogously to the case of 7, the reaction of 8 under ethylene
atmosphere proceeded more smoothly than that under nitrogen
The results of the synthesis of substituted styrenes 3 from
various enynes 7 are shown in Table 1. When RCEM of 7a with
Grubbs second-generation catalyst 10a8 at 80 °C under
nitrogen atmosphere followed by dehydration with a catalytic
amount of p-toluenesulfonic acid was carried out, desired
styrene 3a was obtained in 58% yield (entry 1). As we have
experienced in the past that ethylene gas accelerated the RCEM
process,5j we next conducted the reaction under ethylene
atmosphere. As a result, the product was obtained in an almost
quantitative yield (entry 2). Using those conditions, we
obtained several styrenes 3b−e having various substituents
from 7b−e in good yields (entries 3−6). Substrates 7f and 7g,
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a
Table 2. Synthesis of Substituted 3-Vinylphenols 9 by RCEM/Tautomerization of 8
a
Ring-closing enyne metathesis was carried out with 8 and ruthenium catalyst (10a, 7.5 mol %) in toluene under ethylene atmosphere (1 atm) at 80
b
c
d
°C for 2 h. Isolated yield by silica gel chromatography. The reaction was performed under nitrogen atmosphere. The reaction was conducted with
7.5 mol % of 10b. The reaction was executed with 10 mol % of 10b for 12 h. The reaction was accomplished with 15 mol % of 10a at 100 °C for 24
e
f
h.
distilled from CaH2 under nitrogen and stored in a glass flask with a
Teflon stopcock under nitrogen. Toluene was distilled from sodium
benzophenone-ketyl under nitrogen and stored in a glass flask with a
Teflon stopcock under nitrogen. Grubbs second-generation catalyst
10a11a,12 and Hoveyda−Grubbs second-generation catalyst 10b11b
were prepared according to the reported procedures. β-Bromo-α,β-
unsaturated aldehydes 11c and 11e were prepared according to the
reported procedures.13 Dess−Martin periodinane was prepared
according to the reported procedure.14 MnO2 was prepared according
to the reported procedure.15 β-Bromo-α,β-unsaturated ketone 11f was
prepared from the corresponding alcohol by oxidation with Dess−
Martin periodinane. Isopropenylmagnesium bromide solution (16c)
was prepared by a general method from propenyl bromide and
magnesium in THF. Aromatic aldehydes 11a, 11b, 11d, and 11g,
dichlorobis(triphenylphosphine)palladium, copper iodide, all terminal
acetylenes 15a−f, (methoxymethyl)triphenylphosphonium chloride,
potassium hexamethyldisilazide, hydrochloric acid, vinylmagnesium
bromide solution (16a), pyridine, methyltriphenylphosphonium
bromide, potassium tert-butoxide, n-butyllithium solution, 9-
borabicyclo[3.3.1]nonane (9-BBN) solution, sodium peroxoborate
tetrahydrate, palladium acetate, triphenylphosphine, ethylmagnesium
bromide solution (16b), potassium carbonate, and p-toluenesulfonic
acid monohydrate were used as received.
atmosphere. In fact, the reaction of 8a under ethylene
atmosphere doubled the isolated yield of 9a (entry 1 vs 2).
The reactivity of 8 was lower than that of 7 in general, but use
of Hoveyda−Grubbs second-generation catalyst 10b11 im-
proved the reactivity to a certain extent (entries 4 vs 5, 7 vs 8,
and 9 vs 10). Once again, the reaction of the substrate having a
methyl group at R2 position failed (entries 12 and 13), but the
reaction of 8i having a terminal alkyne part proceeded well to
give the corresponding product in good yield (entry 14).
In conclusion, on the basis of our previous work, we have
developed new synthetic methods for styrenes 3 and 3-
vinylphenols 9. Easy access to the products and no formation of
undesirable regioisomers are proof of the generality of the
methods for producing unique aromatic compounds.
EXPERIMENTAL SECTION
■
All anaerobic and moisture-sensitive manipulations were carried out
with standard Schlenk techniques under predried nitrogen or glovebox
techniques under prepurified argon. NMR spectra were recorded at
400 or 500 MHz for 1H and 100 or 125 MHz for 13C. Chemical shifts
are reported in δ ppm referenced to an internal SiMe4 standard for 1H
NMR and chloroform-d (δ 77.0) for 13C NMR. High-resolution mass
spectra were recorded on Orbitrap mass spectrometers. Tetrahy-
drofuran was distilled from sodium benzophenone-ketyl under
nitrogen prior to use. Triethylamine and dichloromethane were
Preparation of Acyclic Precursors 7 and 8. General
Procedure A: Sonogashira Coupling. To a mixture of dichlorobis-
(triphenylphosphine)palladium (5 mol %) and bromoarene or
bromoalkene (1 equiv) in THF (0.13−0.15 M) was added triethyl
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Note
amine (3 equiv). After being stirred for 10 min at room temperature,
terminal acetylene (1.5 equiv) and copper iodide (5 mol %) were
added to the mixture. The resulting mixture was stirred at room
temperature for 24 h. The reaction mixture was quenched with
saturated aq. NH4Cl, extracted with EtOAc three times, and washed
with brine. The organic layers were dried over Na2SO4 and
concentrated under reduced pressure after filtration. The crude
mixture was purified by silica-gel column chromatography.
General Procedure B: C1-Homologation by Wittig Reaction/
Hydrolysis. To a suspension of (methoxymethyl)triphenylphos-
phonium chloride (2 equiv) in anhydrous THF was added 0.5 M
solution of KHMDS in toluene (2 equiv) at −78 °C. The mixture was
stirred at the same temperature for 1 h, and then a solution of
aldehyde or ketone (1 equiv) in anhydrous THF (0.13 M) was added
to the mixture. The resulting mixture was allowed to warm up to 0 °C
over 3 h and then diluted with hexane and passed through Celite. The
residual solid was washed with hexane thoroughly. The filtrate was
concentrated under reduced pressure. The crude mixture was taken up
in THF (0.69 M) and treated with 3 M HCl (0.46 M). The mixture
was stirred at a refluxing temperature (65 °C) overnight. Then, the
reaction mixture was quenched with saturated aq. Na2CO3, extracted
with EtOAc three times, and washed with brine. The organic layers
were dried over Na2SO4 and concentrated under reduced pressure
after filtration. The crude mixture was purified by silica-gel column
chromatography.
2-(Phenylethynyl)benzaldehyde (1a). Following the General
Procedure A; purified by silica-gel column chromatography (hexane/
EtOAc = 10/1) (3.53 g, 99% yield). This product was characterized by
comparison of the spectroscopic data with those reported previously.16
2-(2-(Phenylethynyl)phenyl)acetaldehyde (6a). Following the
General Procedure B; purified by silica-gel column chromatography
(hexane/EtOAc = 10/1) (1.66 g, 62% yield). This product was
characterized by comparison of the spectroscopic data with those
reported previously.17
1-(2-(Phenylethynyl)phenyl)but-3-en-2-ol (7a). Following the
General Procedure C; purified by silica-gel column chromatography
(hexane/EtOAc = 4/1) (388.3 mg, 83% yield, white solid): mp 35−40
1
°C; H NMR (400 MHz, CDCl3) δ 1.50−1.90 (br s, 1H), 2.98−3.03
(m, 1H), 3.20 (dd, J = 13.5, 5.0 Hz, 1H), 4.54−4.59 (m, 1H), 5.14 (dt,
J = 10.5, 1.2 Hz, 1H), 5.26 (dt, J = 17.4, 1.4 Hz, 1H), 5.97−6.05 (m,
1H), 7.22−7.39 (m, 6H), 7.50−7.56 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 42.6, 73.1, 88.0, 93.5, 114.84, 114.89, 123.2, 126.6, 128.35,
128.40, 130.3, 131.5, 132.3, 139.9, 140.3, 140.4; HRMS (ESI) calcd for
C18H16OK (M+ + K) 287.0833, found 287.0824.
1-(2-(Phenylethynyl)phenyl)but-3-en-2-one (8a). Following the
General Procedure D; The reaction was carried out at room
temperature for 1 h. Pyridine was not used; purified by silica-gel
column chromatography (hexane/EtOAc = 5/1) (77.7 mg, 98% yield,
1
white solid): mp 55−60 °C; H NMR (400 MHz, CDCl3) δ 4.15 (s,
2H), 5.82 (dd, J = 10.3, 1.4 Hz, 1H), 6.37 (dd, J = 17.8, 1.4 Hz, 1H),
6.48 (dd, J = 17.9, 10.3 Hz, 1H), 7.25−7.36 (m, 6H), 7.47−7.52 (m,
2H), 7.55−7.57 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 45.9, 87.7,
93.8, 123.0, 123.5, 127.1, 128.4, 128.5, 128.7, 128.9, 130.0, 131.5,
132.3, 135.7, 136.4, 197.4; HRMS (ESI) calcd for C18H15O (M+ + H)
247.1117, found 247.1117.
General Procedure C: Grignard Reaction. To a stirred solution
of aldehyde 6 or enone 8g (1 equiv) in THF (0.18 M) was added
Grignard reagent 16 (1.0 M solution in THF, 2 equiv) at 0 °C. The
mixture was stirred at the same temperature for 30 min and then
quenched by addition of saturated aq. NH4Cl, extracted with EtOAc
three times, and washed with brine. The organic layers were dried over
Na2SO4 and concentrated under reduced pressure after filtration. The
crude mixture was purified by silica-gel column chromatography to
afford 7.
6-(Phenylethynyl)benzo[d][1,3]dioxole-5-carbaldehyde (1b). Fol-
lowing the General Procedure A; purified by silica-gel column
chromatography (hexane/EtOAc = 10/1) (2.66 g, >99% yield). This
product was characterized by comparison of the spectroscopic data
with those reported previously.16
General Procedure D: Oxidation with Dess−Martin Period-
inane. To a stirred suspension of Dess−Martin periodinane (2 equiv)
and pyridine (4 equiv) in CH2Cl2 (0.15 M) was added a solution of
alcohol 7 or 14 (1 equiv) at 0 °C. The reaction mixture was warmed
up to room temperature and stirred for 30 min. The mixture was then
diluted with Et2O and passed through Celite. The residual solid was
washed with Et2O thoroughly. The filtrate was concentrated under
reduced pressure and purified by silica-gel column chromatography.
General Procedure E: Wittig Reaction. A suspension of t-BuOK
(0.96 M suspension in THF, 1.5 equiv) or a solution of n-BuLi (1.6 M
solution in THF, 1.5 equiv) was added to a suspension of
methyltriphenylphosphonium bromide (1.5 equiv) in anhydrous
THF (0.34 M) at 0 °C. The mixture was stirred at the same
temperature for 30 min, and then a solution of aldehyde 11 (1 equiv)
in anhydrous THF (2.56 M) was added to the mixture. After being
stirred at 0 °C for 2 h, the reaction mixture was diluted with saturated
aqueous NH4Cl, extracted with Et2O, washed with brine, dried over
MgSO4, and evaporated. The crude mixture was purified by silica-gel
column chromatography or vacuum distillation to afford 12.
General Procedure F: Hydroboration/Oxidation. A solution of
9-BBN (0.5 M solution in THF, 3 equiv) was added to 12 (1 equiv) at
room temperature, and the mixture was stirred at refluxing
temperature for 24 h. After H2O (0.30 M) and NaBO3·4H2O (15
equiv) were added at room temperature, the reaction mixture was
stirred for 70 min. Then, the reaction mixture was diluted with
saturated aqueous NH4Cl, extracted with Et2O, washed with brine,
dried over Na2SO4, and evaporated. The crude mixture was purified by
silica-gel column chromatography to afford 13.
2-(6-(Phenylethynyl)benzo[d][1,3]dioxol-5-yl)acetaldehyde (6b).
Following the General Procedure B; purified by silica-gel column
chromatography (hexane/EtOAc = 10/1) (1.14 g, 54% yield, yellow
solid): mp 74−77 °C; 1H NMR (400 MHz, CDCl3) δ 3.85 (d, J = 2.0
Hz, 2H), 6.01 (s, 2H), 6.73 (s, 1H), 7.03 (s, 1H), 7.31−7.37 (m, 3H),
7.46−7.50 (m, 2H), 9.76−9.77 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 49.2, 87.5, 92.9, 101.6, 110.4, 111.7, 116.8, 122.9, 128.4,
129.0, 131.3, 147.0, 148.4, 199.3; HRMS (APCI) calcd for C17H13O3
(M+ + H) 265.0859, found 265.0855.
1-(6-(Phenylethynyl)benzo[d][1,3]dioxol-5-yl)but-3-en-2-ol (7b).
Following the General Procedure C; purified by silica-gel column
chromatography (hexane/EtOAc = 8/1) (650.1 mg, 98% yield, yellow
solid): mp 68−72 °C; 1H NMR (400 MHz, CDCl3) δ 1.65−1.80 (br s,
1H), 2.93 (dd, J = 13.8, 8.2 Hz, 1H), 3.12 (dd, J = 13.5, 4.8 Hz, 1H),
4.48−4.52 (m, 1H), 5.14 (dt, J = 10.5, 1.4 Hz, 1H), 5.26 (dt, J = 17.2,
1.4 Hz, 1H), 5.95−6.03 (m, 3H), 6.77 (s, 1H), 6.98 (s, 1H), 7.32−7.37
(m, 3H), 7.48−7.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 42.5,
73.3, 88.2, 92.2, 101.4, 110.6, 111.6, 114.9, 116.0, 123.3, 128.1, 128.4,
131.3, 135.0, 140.3, 146.2, 148.0; HRMS (ESI) calcd for C19H16O3Na
(M+ + Na) 315.0992, found 315.0981.
1-(6-(Phenylethynyl)benzo[d][1,3]dioxol-5-yl)but-3-en-2-one
(8b). Following the General Procedure D; The reaction was carried
out at room temperature for 1 h. Pyridine was not used; purified by
silica-gel column chromatography (hexane/EtOAc = 5/1) (57.2 mg,
98% yield, yellow solid): mp 60−63 °C; 1H NMR (400 MHz, CDCl3)
δ 4.07 (s, 2H), 5.82 (dd, J = 10.4, 1.5 Hz, 1H), 5.99 (s, 2H), 6.38 (dd,
J = 17.8, 1.5 Hz, 1H), 6.47 (dd, J = 17.5, 10.3 Hz, 1H), 6.73 (s, 1H),
6.99 (s, 1H), 7.29−7.36 (m, 3H), 7.44−7.50 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 45.6, 87.8, 92.4, 101.5, 110.2, 111.6, 116.3, 123.1,
128.2, 128.4, 129.0, 131.1, 131.3, 135.6, 146.6, 148.2, 197.4; HRMS
(ESI) calcd for C19H15O3 (M+ + H) 291.1016, found 291.1013.
2-(2-((4-Methoxyphenyl)ethynyl)cyclopent-1-en-1-yl)ethanol
(14c). Following the General Procedure E−F−A; General Procedure
E/n-BuLi was used. The crude mixture was purified by vacuum
distillation; General Procedure A/After stirring a mixture of Pd(OAc)2
General Procedure G: Oxidation with MnO2. MnO2 (20 equiv)
was added to a solution of 7 (1 equiv) in CH2Cl2 (0.02 M). After
being stirred at a refluxing temperature overnight (ca. 17 h), the
reaction mixture was passed through Celite. The residual solid was
washed with CH2Cl2 thoroughly. The filtrate was concentrated under
reduced pressure and purified by silica-gel column chromatography to
afford 8.
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(10 mol %) and PPh3 (40 mol %) in NEt3 at room temperature for 10
min, alcohol 13c was added to the mixture. 1-Ethynyl-4-
methoxybenzene (15b) (3 equiv) and CuI (10 mol %) were used.
The reaction was carried out at 90 °C for 24 h; purified by recycling
gel permeation chromatography (CHCl3) (652.9 mg, 5% yield for 3
steps, colorless oil): Because of the difficulty of separation of
intermediates from impurities, the yield was calculated through 3
1H); 13C NMR (100 MHz, CDCl3) δ 16.9, 31.3, 42.3, 43.7, 72.9, 79.3,
91.8, 113.7 (d, J = 22.0 Hz), 115.1, 117.1 (d, J = 22.0 Hz), 119.5, 134.0
(d, J = 8.6 Hz), 140.1, 142.4 (d, J = 7.7 Hz), 161.9 (d, J = 250.0 Hz);
HRMS (ESI) calcd for C15H17ClFO (M+ + H) 267.0946, found
267.0949.
1-(2-(5-Chloropent-1-yn-1-yl)-5-fluorophenyl)but-3-en-2-one
(8d). Following the General Procedure G; purified by silica-gel column
chromatography (hexane/EtOAc = 4/1) (95.6 mg, 37% yield, yellow
oil): 1H NMR (400 MHz, CDCl3) δ 2.02 (quint, J = 6.4 Hz, 2H), 2.60
(t, J = 7.1 Hz, 2H), 3.67 (t, J = 6.4 Hz, 2H), 4.03 (s, 2H), 5.87 (dd, J =
10.3, 1.8 Hz, 1H), 6.36 (dd, J = 17.9, 1.6 Hz, 1H), 6.44 (dd, J = 17.9,
10.1 Hz, 1H), 6.90−6.95 (m, 2H), 7.37−7.43 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 16.8, 31.2, 43.6, 45.5, 79.0, 92.3, 114.3 (d, J =
22.9 Hz), 117.1 (d, J = 21.9 Hz), 119.9, 129.1, 133.9 (d, J = 8.6 Hz),
135.6, 138.7 (d, J = 8.6 Hz), 162.0 (d, J = 252.7 Hz), 196.6; HRMS
(ESI) calcd for C15H15ClFO (M+ + H) 265.0790, found 265.0789.
2-(2-((4-Methoxyphenyl)ethynyl)-3,4-dihydronaphthalen-1-yl)-
ethanol (14e). Following the General Procedure E−F−A; General
Procedure E/t-BuOK was used. The crude mixture was purified by
silica-gel column chromatography (hexane only); General Procedure
A/After stirring a mixture of Pd(OAc)2 (10 mol %) and PPh3 (40 mol
%) in NEt3 was stirred at room temperature for 10 min, alcohol 13e
was added to the mixture. 1-Ethynyl-4-methoxybenzene (15b) (3
equiv) and CuI (10 mol %) were used. The reaction was carried out at
90 °C for 24 h; purified by silica-gel column chromatography (hexane/
EtOAc = 2/1) (994.9 mg, 13% yield for 3 steps, orange gum): Because
of the difficulty of separation of intermediates from impurities, the
1
steps; H NMR (400 MHz, CDCl3) δ 1.61−1.75 (br s, 1H), 1.91
(quint, J = 7.8 Hz, 2H), 2.42−2.49 (m, 2H), 2.54−2.62 (m, 2H),
2.60−2.66 (m, 2H), 3.78 (s, 3H), 3.78−3.83 (m, 2H), 6.81−6.86 (m,
2H), 7.35−7.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.5, 34.0,
35.9, 36.8, 55.2, 60.9, 84.7, 93.1, 113.9, 115.7, 120.3, 132.8, 147.4,
159.3; HRMS (ESI) calcd for C16H19O2 (M+ + H) 243.1380, found
243.1378.
1-(2-((4-Methoxyphenyl)ethynyl)cyclopent-1-en-1-yl)but-3-en-2-
ol (7c). Following the General Procedure D−C; General Procedure
D/Pyridine was not used. The reaction mixture was stirred for 1 h;
purified by silica-gel column chromatography (hexane/EtOAc = 2/1)
1
(25.6 mg, 41% yield for 2 steps, colorless oil): H NMR (400 MHz,
CDCl3) δ 1.75 (br d, J = 3.9 Hz, 1H), 1.91 (quint, J = 7.6 Hz, 2H),
2.40−2.70 (m, 6H), 3.81 (s, 3H), 4.37 (unresolved q, J = 4.1 Hz, 1H),
5.12 (dt, J = 10.5, 1.4 Hz, 1H), 5.39 (dt, J = 17.4, 1.4 Hz, 1H), 5.94
(ddd, J = 16.5, 10.5, 6.0 Hz, 1H), 6.82−6.86 (m, 2H), 7.35−7.40 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 22.6, 36.4, 36.7, 38.5, 55.3, 71.6,
84.7, 93.5, 113.9, 114.7, 115.7, 121.1, 132.8, 140.7, 147.0, 159.4;
HRMS (ESI) calcd for C18H21O2 (M+ + H) 269.1536, found
269.1534.
1
1-(2-((4-Methoxyphenyl)ethynyl)cyclopent-1-en-1-yl)but-3-en-2-
one (8c). Following the General Procedure D; Pyridine was not used.
The reaction mixture was stirred for 1 h; purified by silica-gel column
chromatography (hexane/EtOAc = 2/1) (63.7 mg, 61% yield, cream
yield was calculated through 3 steps; H NMR (400 MHz, CDCl3) δ
1.64−1.75 (br s, 1H), 2.52 (t, J = 8.0 Hz, 2H), 2.80 (t, J = 8.0 Hz, 2H),
3.16 (t, J = 6.8 Hz, 2H), 3.61−3.92 (m, 2H), 3.81 (s, 3H), 6.83−6.90
(m, 2H), 7.12−7.27 (m, 3H), 7.35 (d, J = 7.8 Hz, 1H), 7.39−7.45 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 28.2, 28.5, 34.3, 55.3, 62.0, 88.8,
96.0, 114.0, 115.6, 120.1, 123.4, 126.6, 127.3, 127.7, 132.8, 134.3,
136.3, 137.7, 159.6; HRMS (ESI) calcd for C21H21O2 (M+ + H)
305.1536, found 305.1535.
2-(2-((4-Methoxyphenyl)ethynyl)-3,4-dihydronaphthalen-1-yl)-
acetaldehyde (6e). Following the General Procedure D; The reaction
mixture was stirred for 1 h; purified by silica-gel column
chromatography (hexane/EtOAc = 4/1) (24.4 mg, 62% yield, yellow
oil): 1H NMR (400 MHz, CDCl3) δ 2.61 (t, J = 8.5 Hz, 2H), 2.88 (t, J
= 7.5 Hz, 2H), 3.83 (s, 3H), 3.90 (s, 2H), 6.84−6.91 (m, 2H), 7.14−
7.26 (m, 4H), 7.38−7.44 (m, 2H), 9.69 (t, J = 2.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 27.9, 28.5, 46.3, 55.3, 88.2, 97.6, 114.1, 115.1,
122.6, 123.4, 126.9, 127.7, 127.8, 132.2, 132.9, 134.3, 135.9, 159.9,
200.2; HRMS (ESI) calcd for C21H17O2 (M− − H) 301.1234, found
301.1245.
1
yellow solid): mp 38−44 °C; H NMR (400 MHz, CDCl3) δ 1.92
(quint, J = 7.8 Hz, 2H), 2.39−2.46 (m, 2H), 2.56−2.64 (m, 2H), 3.62
(s, 2H), 3.82 (s, 3H), 5.93−5.87 (m, 1H), 6.36−6.47 (m, 2H), 6.83−
6.88 (m, 2H), 7.36−7.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
22.6, 35.8, 36.7, 42.6, 55.4, 84.5, 94.3, 114.1, 115.6, 122.4, 129.2, 132.9,
135.9, 143.2, 159.6, 197.7; HRMS (ESI) calcd for C18H19O2 (M+ + H)
267.1380, found 267.1380.
2-(5-Chloropent-1-yn-1-yl)-5-fluorobenzaldehyde (1d). Following
the General Procedure A; purified by silica-gel column chromatog-
raphy (hexane/EtOAc = 10/1) (1.85 g, 82% yield, red orange oil): 1H
NMR (400 MHz, CDCl3) δ 2.10 (quint, J = 6.4 Hz, 2H), 2.70 (t, J =
6.8 Hz, 2H), 3.72 (t, J = 6.4 Hz, 2H), 7.22−7.29 (m, 1H), 7.51 (dd, J =
8.7, 5.3 Hz, 1H), 7.56 (dd, J = 8.7, 3.0 Hz, 1H), 10.46 (d, J = 3.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 16.9, 31.0, 43.5, 76.2, 95.4, 113.5
(d, J = 23.0 Hz), 121.2 (d, J = 23.0 Hz), 123.3 (d, J = 2.9 Hz), 135.3
(d, J = 7.7 Hz), 137.8 (d, J = 6.7 Hz) 162.0 (d, J = 253.9 Hz), 190.5;
HRMS (APCI) calcd for C12H11ClFO (M+ + H) 225.0477, found
225.0479.
2-(2-(5-Chloropent-1-yn-1-yl)-5-fluorophenyl)acetaldehyde (6d).
Following the General Procedure B; The crude mixture was taken up
in THF (2.76 M) and then treated with 3 M HCl (1.84 M); purified
by silica-gel column chromatography (hexane/EtOAc = 10/1) (156.7
mg, 53% yield, yellow oil): 1H NMR (400 MHz, CDCl3) δ 2.04
(quint, J = 6.4 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 3.69 (t, J = 6.4 Hz,
2H), 3.83 (d, J = 2.0 Hz, 2H), 6.91−6.96 (m, 2H), 7.44 (dd, J = 8.5,
5.7 Hz, 1H), 9.73 (t, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
16.8, 31.1, 43.6, 49.1, 78.7, 92.9, 114.7 (d, J = 21.9 Hz), 117.2 (d, J =
22.9 Hz), 120.1, 134.1 (d, J = 8.6 Hz), 136.6 (d, J = 7.6 Hz), 162.0 (d,
J = 253.7 Hz), 198.4; HRMS (ESI) calcd for C13H11ClFO (M− − H)
237.0488, found 237.0496.
1-(2-((4-Methoxyphenyl)ethynyl)-3,4-dihydronaphthalen-1-yl)-
but-3-en-2-ol (7e). Following the General Procedure C; purified by
silica-gel column chromatography (hexane/EtOAc = 2/1) (266.8 mg,
1
62% yield, yellow oil): H NMR (400 MHz, CDCl3) δ 1.83−1.89 (br
s, 1H), 2.53 (t, J = 8.4 Hz, 2H), 2.78−2.84 (m, 2H), 3.10 (dd, J = 14.0,
6.0 Hz, 1H), 3.16 (dd, J = 14.0, 7.8 Hz, 1H), 3.82 (s, 3H), 4.45
(unresolved q, J = 6.2 Hz, 1H), 5.11 (dt, J = 10.3, 1.4 Hz, 1H), 5.26
(dt, J = 17.0, 1.4 Hz, 1H), 6.03 (ddd, J = 19.7, 15.3, 9.2 Hz, 1H),
6.84−6.89 (m, 2H), 7.14−7.25 (m, 3H), 7.38−7.43 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 28.2, 28.5, 38.6, 55.3, 72.7, 89.1, 96.4,
114.0, 114.5, 115.6, 120.5, 123.7, 126.6, 127.3, 127.7, 132.8, 134.4,
136.4, 137.8, 140.7, 159.6; HRMS (ESI) calcd for C23H23O2 (M+ + H)
331.1693, found 331.1690.
1-(2-((4-Methoxyphenyl)ethynyl)-3,4-dihydronaphthalen-1-yl)-
but-3-en-2-one (8e). Following the General Procedure G; purified by
silica-gel column chromatography (hexane/EtOAc = 2/1) (21.1 mg,
1-(2-(5-Chloropent-1-yn-1-yl)-5-fluorophenyl)but-3-en-2-ol (7d).
Following the General Procedure C; purified by recycling gel
permeation chromatography (CHCl3) (165.8 mg, 62% yield, colorless
oil): 1H NMR (400 MHz, CDCl3) δ 1.57−1.82 (br s, 1H), 2.06
(quint, J = 6.5 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.92 (dd, J = 13.5, 8.0
Hz, 1H), 3.03 (dd, J = 13.8, 5.3 Hz, 1H), 3.72 (t, J = 6.4 Hz, 2H),
4.42−4.48 (m, 1H), 5.14 (dt, J = 10.6, 1.4 Hz, 1H), 5.25 (dt, J = 17.4,
1.4 Hz, 1H), 5.94 (ddd, J = 17.4, 10.8, 6.2 Hz, 1H), 6.88 (td, J = 8.5,
2.8 Hz, 1H), 6.96 (dd, J = 9.6, 2.8 Hz, 1H), 7.37 (dd, J = 8.7, 6.0 Hz,
1
89% yield, brown gum): H NMR (400 MHz, CDCl3) δ 2.60 (t, J =
8.5 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H), 3.83 (s, 3H), 4.09 (s, 2H), 5.75
(dd, J = 10.5, 1.4 Hz, 1H), 6.38 (dd, J = 17.6, 1.4 Hz, 1H), 5.68 (dd, J
= 17.6, 10.5 Hz, 1H), 6.84−6.90 (m, 2H), 7.13−7.22 (m, 4H), 7.37−
7.43 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 28.0, 28.5, 44.4, 55.3,
88.6, 97.2, 114.1, 115.3, 121.7, 123.9, 126.8, 127.5, 127.6, 128.6, 132.9,
134.3, 134.7, 134.8, 135.9, 159.8, 197.9; HRMS (ESI) calcd for
C23H21O2 (M+ + H) 329.1536, found 329.1534.
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Note
1-(2-(Phenylethynyl)phenyl)ethanone (1f). Following the General
Procedure A; purified by silica-gel column chromatography (hexane/
EtOAc = 10/1) (1.45 g, 91% yield). This product was characterized by
comparison of the spectroscopic data with those reported previously.18
2-(2-(Phenylethynyl)phenyl)propanal (6f). Following the General
Procedure B; purified by silica-gel column chromatography (hexane/
131.0, 134.1, 147.2, 149.1, 151.4; HRMS (ESI) calcd for C24H31O3
(M+ + H) 367.2268, found 367.2262.
1-(2-((4-tert-Butylphenyl)ethynyl)-4,5-dimethoxyphenyl)butan-2-
one (18). Following the General Procedure D; Dess−Martin
periodinane (2.5 equiv) was used; purified by silica-gel column
chromatography (hexane/EtOAc = 4/1) (331.0 mg, 93% yield, white
solid): mp 72−77 °C; 1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.3
Hz, 3H), 1.33 (s, 9H), 2.53 (q, J = 7.6 Hz, 2H), 3.89 (s, 2H), 3.89 (s,
3H), 3.90 (s, 3H), 6.74 (s, 1H), 7.03 (s, 1H), 7.36−7.39 (m, 2H),
7.43−7.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 7.8, 31.1, 34.7,
35.2, 48.0, 55.9, 55.9, 87.2, 92.3, 112.6, 114.3, 115.4, 120.1, 125.3,
130.0, 131.0, 147.7, 149.3, 151.5, 209.0; HRMS (ESI) calcd for
C24H28NaO3 (M+ + Na) 387.1931, found 387.1920.
1
EtOAc = 10/1) (647.0 mg, 51% yield, brown oil): H NMR (400
MHz, CDCl3) δ 1.50 (d, J = 7.2 Hz, 3H), 4.19 (q, J = 7.2 Hz, 1H),
7.18 (d, J = 7.7 Hz, 1H), 7.30 (td, J = 7.5, 1.5 Hz, 1H), 7.34−7.38 (m,
4H), 7.50−7.54 (m, 2H), 7.61 (dd, J = 7.5, 1.6 Hz, 1H), 9.82 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 14.1, 51.2, 87.2, 94.1, 122.8, 123.4,
127.4, 127.9, 128.4, 128.6, 129.0, 131.4, 132.8, 140.0, 201.2; HRMS
(ESI) calcd for C18H18NaO2 (M+ + Na+MeOH) 289.1199, found
289.1186.
3-(2-((4-tert-Butylphenyl)ethynyl)-4,5-dimethoxybenzyl)pent-1-
en-3-ol (7g). Following the General Procedure C; purified by silica-gel
column chromatography (hexane/EtOAc = 3/1) (138.6 mg, 90%
4-(2-(Phenylethynyl)phenyl)pent-1-en-3-ol (7f). Following the
General Procedure C; purified by silica-gel column chromatography
(hexane/EtOAc = 5/1) (28.0 mg, 75% yield, yellow oil): The
1
yield, white solid): mp 93−97 °C; H NMR (400 MHz, CDCl3) δ
0.92 (t, J = 7.3 Hz, 3H), 1.33 (s, 9H), 1.67 (q, J = 7.6 Hz, 2H), 1.75−
1.84 (br s, 1H), 3.09 (s, 2H), 3.88 (s, 3H), 3.88 (s, 3H), 5.09 (dd, J =
11.0, 1.4 Hz, 1H), 5.13 (dd, J = 17.4, 1.4 Hz, 1H), 5.99 (dd, J = 17.4,
10.7 Hz, 1H), 6.81 (s, 1H), 7.01 (s, 1H), 7.37−7.39 (m, 2H), 7.43−
7.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 7.9, 31.1, 33.2, 34.7,
44.8, 55.9, 88.6, 91.6, 112.9, 113.8, 114.3, 116.1, 120.4, 125.4, 131.0,
132.4, 143.2, 147.3, 148.7, 151.3; HRMS (ESI) calcd for C26H33O3
(M+ + H) 393.2424, found 393.2412.
1
following data are for a mixture of two diastereomers (0.84/0.16); H
NMR (400 MHz, CDCl3) δ 1.31 (d, J = 7.1 Hz, 0.48H), 1.36 (d, J =
7.1 Hz, 2.52H), 1.55−1.75 (br s, 1H), 3.58−3.65 (m, 1H), 4.40 (t, J =
6.8 Hz, 0.16H), 4.44 (tt, J = 5.7, 4.1 Hz, 0.84H), 5.12 (dt, J = 10.5, 1.6
Hz, 0.84H), 5.18 (dt, J = 10.5, 1.4 Hz, 0.16H), 5.24 (dt, J = 17.4, 1.4
Hz, 0.84H), 5.26 (dt, J = 17.4, 1.4 Hz, 0.16H), 5.88−5.97 (m, 1H),
7.19−7.24 (m, 1H), 7.32−7.38 (m, 5H), 7.50−7.55 (m, 3H); The
following data are for a major diastereomer; 13C NMR (100 MHz,
CDCl3) δ 14.1, 42.6, 76.2, 88.1, 93.7, 115.3, 122.8, 123.2, 126.2, 127.1,
128.3, 128.4, 128.5, 131.4, 132.5, 139.4, 145.5; HRMS (ESI) calcd for
C19H18NaO (M+ + Na) 285.1250, found 285.1245.
3-Methyl-1-(2-(phenylethynyl)phenyl)but-3-en-2-ol (7h). Follow-
ing the General Procedure C; Isopropenyl Grignard reagent (16c)
(0.51 M solution in THF) and THF (0.08 M) were used; purified by
silica-gel column chromatography (hexane/EtOAc = 2/1) (151.9 mg,
73% yield, yellow solid): mp 54−60 °C; 1H NMR (400 MHz, CDCl3)
δ 1.68 (d, J = 3.4 Hz, 1H), 1.86 (s, 3H), 2.93 (dd, J = 13.8, 9.4 Hz,
1H), 3.28 (dd, J = 13.7, 4.1 Hz, 1H), 4.49 (dt, J = 8.2, 3.6 Hz, 1H),
4.87 (t, J = 1.4 Hz, 1H), 5.00 (t, J = 0.9 Hz, 1H), 7.22−7.28 (m, 1H),
7.28−7.32 (m, 2H), 7.33−7.39 (m, 3H), 7.50−7.57 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 18.1, 41.3, 75.7, 88.1, 93.5, 111.0, 123.0,
123.2, 126.6, 128.3, 128.4, 130.2, 131.5, 132.4, 140.5, 147.1; HRMS
(ESI) calcd for C19H18NaO (M+ + Na) 285.1250, found 285.1248.
3-Methyl-1-(2-(phenylethynyl)phenyl)but-3-en-2-one (8h). Fol-
lowing the General Procedure D; purified by silica-gel column
chromatography (hexane/EtOAc =7/1) (24.3 mg, 84% yield, yellow
4-(2-(Phenylethynyl)phenyl)pent-1-en-3-one (8f). Following the
General Procedure D; The crude mixture was purified by silica-gel
column chromatography (hexane/EtOAc = 10/1) (46.3 mg, 78%
1
yield, yellow solid): mp 30−34 °C; H NMR (400 MHz, CDCl3) δ
1.48 (d, J = 6.8 Hz, 3H), 4.66 (q, J = 6.8 Hz, 1H), 5.65 (dd, J = 9.4, 2.5
Hz, 1H), 6.32 (dd, J = 17.6, 2.5 Hz, 1H), 6.34 (dd, J = 17.4, 9.4 Hz,
1H), 7.16 (dd, J = 7.8, 1.4 Hz, 1H), 7.24 (td, J = 7.6, 1.4 Hz, 1H), 7.30
(td, J = 7.6, 1.6 Hz, 1H), 7.34−7.40 (m, 3H), 7.52−7.59 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 17.0, 48.3, 87.5, 93.9, 122.8, 122.9, 127.0,
127.3, 128.4, 128.4, 128.6, 129.0, 131.5, 132.7, 135.1, 142.3, 199.8;
HRMS (ESI) calcd for C19H16NaO (M+ + Na) 283.1093, found
283.1090.
1
solid): mp 64−69 °C; H NMR (400 MHz, CDCl3) δ 1.90 (dd, J =
2-((4-tert-Butylphenyl)ethynyl)-4,5-dimethoxybenzaldehyde (1g).
Following the General Procedure A; purified by silica-gel column
chromatography (hexane/EtOAc = 7/1) (2.56 g, 97% yield, beige
solid): mp 120−125 °C; 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 9H),
3.96 (s, 3H), 4.00 (s, 3H), 7.06 (s, 1H), 7.39−7.43 (m, 3H), 7.48−
7.50 (m, 2H), 10.50 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 31.1,
34.9, 56.1, 56.3, 84.2, 95.2, 108.1, 114.2, 119.4, 121.9, 125.5, 130.0,
131.3, 149.6, 152.3, 153.6, 190.6; HRMS (ESI) calcd for C21H22NaO3
(M+ + Na) 345.1461, found 345.1461.
2-(2-((4-tert-Butylphenyl)ethynyl)-4,5-dimethoxyphenyl)-
acetaldehyde (6g). Following the General Procedure B; purified by
silica-gel column chromatography (hexane/EtOAc = 4/1) (1.08 g,
48% yield, yellow solid): mp 79−84 °C; 1H NMR (400 MHz, CDCl3)
δ 1.33 (s, 9H), 3.86 (d, J = 2.0 Hz, 2H), 3.90 (s, 3H), 3.92 (s, 3H),
6.72 (s, 1H), 7.08 (s, 1H), 7.35−7.39 (m, 2H), 7.42−7.45 (m, 2H),
9.78 (t, J = 2.3 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 31.1, 34.8,
49.0, 55.96, 56.01, 86.9, 92.9, 112.8, 114.5, 115.9, 119.9, 125.4, 127.3,
131.1, 148.1, 149.5, 151.7, 199.6; HRMS (ESI) calcd for C22H25O3
(M+ + H) 337.1798, found 337.1796.
1-(2-((4-tert-Butylphenyl)ethynyl)-4,5-dimethoxyphenyl)butan-2-
ol (17). Following the General Procedure C; Ethyl Grignard reagent
(16b) (1.0 M solution in THF) was used; purified by silica-gel column
chromatography (hexane/EtOAc = 2/1) (599.2 mg, 82% yield, yellow
gum): 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J = 7.5 Hz, 3H), 1.33 (s,
9H), 1.52−1.60 (br s, 1H), 1.56−1.69 (m, 2H), 2.78 (dd, J = 13.5, 8.5
Hz, 1H), 3.13 (dd, J = 13.7, 4.1 Hz, 1H), 3.90 (s, 3H), 3.90 (s, 3H),
3.87−3.96 (m, 1H), 6.78 (s, 1H), 7.03 (s, 1H), 7.36−7.39 (m, 2H),
7.42−7.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 10.1, 30.0, 31.2,
34.8, 42.0, 55.9, 56.0, 73.7, 87.6, 92.0, 113.0, 114.6, 115.0, 120.4, 125.4,
1.6, 0.9 Hz, 3H), 4.29 (s, 2H), 5.83−5.85 (m, 1H), 6.19 (s, 1H), 7.22−
7.38 (m, 6H), 7.44−7.50 (m, 2H), 7.53−7.57 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.8, 43.3, 87.9, 93.5, 123.1, 123.2, 125.3, 126.9,
128.4, 128.5, 129.8, 131.4, 132.3, 137.4, 144.4, 199.0; HRMS (ESI)
calcd for C19H16ONa (M+ + Na) 283.1093, found 283.1083.
2-((Trimethylsilyl)ethynyl)benzaldehyde (1i). Following the Gen-
eral Procedure A; purified by silica-gel column chromatography
(hexane/EtOAc = 9/1) (4.41 g, >99% yield). This product was
characterized by comparison of the spectroscopic data with those
reported previously.16
2-(2-Ethynylphenyl)acetaldehyde (6i). Following the General
Procedure B; After the Wittig reaction, the crude mixture was taken
up in MeOH (0.44 M) and treated with K2CO3 (0.1 equiv). The
mixture was stirred at room temperature for 2 h, and then quenched
by addition of saturated aq. NH4Cl, extracted with EtOAc three times,
and washed with brine. The organic layers were dried over Na2SO4
and concentrated under reduced pressure after filtration. Then, the
crude mixture was used for hydrolysis; purified by silica-gel column
chromatography (hexane/EtOAc = 20/1) (1.32 g, 46% yield). This
product was characterized by comparison of the spectroscopic data
with those reported previously.19
1-(2-Ethynylphenyl)-3-methylbut-3-en-2-ol (7i). Following the
General Procedure C; Isopropenyl Grignard reagent (16c) (0.51 M
solution in THF) was used; purified by silica-gel column
chromatography (hexane/EtOAc = 4/1) (178.2 mg, 49% yield,
1
colorless oil): H NMR (400 MHz, CDCl3) δ 1.58−1.72 (br s, 1H),
1.84 (t, J = 1.2 Hz, 3H), 2.87 (dd, J = 13.7, 9.2 Hz, 1H), 3.19 (dd, J =
13.8, 4.1 Hz, 1H), 3.29 (s, 1H), 4.39−4.43 (m, 1H), 4.84−4.88 (m,
1H), 4.98−4.99 (m, 1H), 7.21 (td, J = 7.6, 1.8 Hz, 1H), 7.28−7.33 (m,
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Note
2H), 7.51 (dd, J = 7.6, 0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
18.1, 40.9, 75.6, 81.2, 82.4, 110.9, 121.9, 126.4, 128.9, 130.1, 133.0,
141.1, 147.1; HRMS (ESI) calcd for C13H14NaO (M+ + Na) 209.0937,
found 209.0937.
2H), 3.80 (s, 3H), 5.15 (d, J = 1.6 Hz, 1H), 5.55 (d, J = 1.6 Hz, 1H),
6.80−6.85 (m, 2H), 7.08 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H),
7.19−7.24 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 25.2, 32.4, 33.0,
55.2, 113.2, 113.5, 123.6, 126.1, 127.0, 128.3, 133.6, 138.5, 142.6,
144.4, 148.8, 159.1; HRMS (ESI) calcd for C18H19O (M+ + H)
251.1430, found 251.1432.
1-(5-Chloropent-1-en-2-yl)-6-fluoronaphthalene (3d). Following
the General Procedure H; The reaction mixture was treated with p-
toluenesulfonic acid monohydrate at room temperature for 1 h, then
stirred at 50 °C for 1 h; purified by silica-gel column chromatography
(hexane/EtOAc = 10/1) (30.5 mg, 89% yield, colorless oil): 1H NMR
(400 MHz, CDCl3) δ 1.84−1.92 (m, 2H), 2.67 (t, J = 5.7 Hz, 2H),
3.55 (t, J = 5.3 Hz, 2H), 5.12−5.16 (m, 1H), 5.45 (q, J = 1.4 Hz, 1H),
7.20−7.25 (m, 1H), 7.23−7.28 (m, 1H), 7.43−7.48 (m, 2H), 7.70 (d, J
= 6.6 Hz, 1H), 8.01 (dd, J = 7.6, 4.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 30.8, 35.6, 44.4, 111.2 (d, J = 16.2 Hz), 116.1 (d, J = 20.0
Hz) 116.6, 124.3, 126.4, 126.7, 126.7, 128.2 (d, J = 6.7 Hz), 134.6 (d, J
= 6.7 Hz), 140.8, 146.9, 160.5 (d, J = 196.5 Hz); HRMS (APCI) calcd
for C15H15ClF (M+ + H) 249.0841, found 249.0840.
1-(2-Ethynylphenyl)-3-methylbut-3-en-2-one (8i). Following the
General Procedure D; The crude mixture was purified by silica-gel
column chromatography (hexane/EtOAc = 4/1) (47.2 mg, >99%
yield, colorless oil): 1H NMR (400 MHz, CDCl3) δ 1.90 (t, J = 0.9 Hz,
3H), 3.23 (s, 1H), 4.23 (s, 2H), 5.82−5.86 (m, 1H), 6.15 (s, 1H),
7.18−7.26 (m, 2H), 7.31 (td, J = 7.6, 1.4 Hz, 1H), 7.51 (dd, J = 7.8,
1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17.7, 42.9, 81.2, 82.1,
122.1, 125.4, 126.8, 129.0, 129.8, 132.9, 137.8, 144.2, 198.8; HRMS
(ESI) calcd for C13H12NaO (M+ + Na) 207.0780, found 207.0776.
2,2′-(1,4-Phenylenebis(ethyne-2,1-diyl))dibenzaldehyde (1j). Fol-
lowing the General Procedure A; The crude mixture was purified by
silica-gel column chromatography (2.56 g, 97% yield). This product
was characterized by comparison of the spectroscopic data with those
reported previously.20
2,2′-((1,4-Phenylenebis(ethyne-2,1-diyl))bis(2,1-phenylene))-
diacetaldehyde (6j). Following the General Procedure B; purified by
silica-gel column chromatography (hexane/EtOAc = 2/1) (842.7 mg,
1-(1-(4-Methoxyphenyl)vinyl)-9,10-dihydrophenanthrene (3e).
Following the General Procedure H; The reaction mixture was treated
with p-toluenesulfonic acid monohydrate at 50 °C overnight; purified
by silica-gel column chromatography (hexane/EtOAc = 4/1) (31.3
1
38% yield, yellowish solid): mp 119−125 °C; H NMR (400 MHz,
CDCl3) δ 3.92 (d, J = 2.1 Hz, 4H), 7.23−7.38 (m, 6H), 7.49 (s, 4H),
7.58−7.62 (m, 2H), 9.80 (t, J = 2.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 49.3, 89.3, 93.8, 122.9, 123.4, 127.6, 129.1, 130.2, 131.4,
132.4, 134.3, 199.2; HRMS (APCI) calcd for C26H19O2 (M+ + H)
363.1380, found 363.1376.
1
mg, >99% yield, cream yellow solid): mp 80−86 °C; H NMR (400
MHz, CDCl3) δ 2.54−2.60 (m, 2H), 2.66−2.72 (m, 2H), 3.79 (s, 3H),
5.15 (d, J = 1.4 Hz, 1H), 5.73 (d, J = 1.4 Hz, 1H), 6.78−6.83 (m, 2H),
7.15−7.35 (m, 7H), 7.75−7.79 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 26.2, 28.9, 55.2, 113.0, 113.7, 123.3, 124.0, 126.4, 126.9,
127.3, 127.6, 127.8, 129.3, 133.2, 134.73, 134.79, 135.7, 137.4, 141.0,
148.3, 159.2; HRMS (ESI) calcd for C23H21O (M+ + H) 313.1587,
found 313.1587.
1,1′-((1,4-Phenylenebis(ethyne-2,1-diyl))bis(2,1-phenylene))bis-
(but-3-en-2-ol) (7j). Following the General Procedure C; purified by
silica-gel column chromatography (CH2Cl2/EtOAc = 4/1) (71.0 mg,
67% yield, white solid): The following data are for a mixture of two
1
diastereomers; H NMR (400 MHz, CDCl3) δ 1.69−1.76 (br s, 2H),
1-Methyl-4-(1-phenylvinyl)naphthalene (3f). Following the Gen-
eral Procedure H; The reaction mixture was treated with p-
toluenesulfonic acid monohydrate at 50 °C overnight; purified by
silica-gel column chromatography (hexane/EtOAc = 5/1) (28.8 mg,
84% yield, white solid): mp 46−51 °C; 1H NMR (400 MHz, CDCl3)
δ 2.73 (s, 3H), 5.37 (d, J = 1.4 Hz, 1H), 5.96 (d, J = 1.4 Hz, 1H),
7.22−7.28 (m, 3H), 7.28−7.37 (m, 5H), 7.47 (ddd, J = 8.4, 6.9, 1.4
Hz, 1H), 7.78 (m, 1H), 8.01 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
19.5, 116.1, 124.3, 125.5, 126.2, 126.6, 126.9, 127.1, 127.6, 128.3,
131.9, 132.7, 134.2, 138.1, 141.2, 148.4; HRMS (APCI) calcd for
C19H17 (M+ + H) 245.1325, found 245.1327.
1-(1-(4-tert-Butylphenyl)vinyl)-3-ethyl-6,7-dimethoxynaphtha-
lene (3g). Following the General Procedure H; purified by silica-gel
column chromatography (hexane/EtOAc = 3/1) (15.4 mg, 77% yield,
colorless gum): 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 1.33 (t, J
= 7.8 Hz, 3H), 2.79 (q, J = 7.8 Hz, 2H), 3.62 (s, 3H), 3.97 (s, 3H),
5.38 (d, J = 1.4 Hz, 1H), 5.88 (d, J = 1.4 Hz, 1H), 6.95 (s, 1H), 7.08
(s, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.24−7.29 (m, 4H), 7.49 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 15.6, 28.8, 31.3, 34.5, 55.4, 55.7,
3.01 (dd, J = 13.5, 8.2 Hz, 2H), 3,19 (dd, J = 13.5, 5.0 Hz, 2H), 4.55
(q, J = 6.2 Hz, 2H), 5.14 (dt, J = 10.5, 1.2 Hz, 2H), 5.26 (dt, J = 17.4,
1.4 Hz, 2H), 6.00 (ddd, J = 21.7, 10.5, 6.2 Hz, 2H), 7.22−7.34 (m,
6H), 7.49 (s, 4H), 7.55 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 42.6, 73.2, 90.0, 93.2, 114.9, 122.9, 123.1, 126.7, 128.6,
130.4, 131.4, 132.4, 140.0, 140.3; HRMS (APCI) calcd for C30H27O2
(M+ + H) 419.2006, found 419.1999.
Synthesis of Substituted Styrenes 3 by RCEM/Dehydration
of 7. General Procedure H: RCEM/Dehydration. To a solution of
1,5-octadiene-7-yn-3-ols 7 (1 equiv) in toluene (0.01 M) was added
catalyst 10a (7.5 mol %) under nitrogen, and then the system was
evacuated carefully and filled with ethylene gas (1 atm) in three cycles.
The reaction mixture was heated to 80 °C and stirred for 2 h. After
cooling to room temperature, the reaction mixture was treated with p-
toluenesulfonic acid monohydrate (10 mol %) and stirred for 1 h at
room temperature. The mixture was concentrated under reduced
pressure and purified by silica-gel column chromatography to afford 3.
1-(1-Phenylvinyl)naphthalene (3a). Following the General Proce-
dure H; The reaction mixture was treated with p-toluenesulfonic acid
monohydrate at 50 °C overnight; purified by silica-gel column
chromatography (hexane/EtOAc = 10/1) (30 mg, 99% yield). This
product was characterized by comparison of the spectroscopic data
with those reported previously.21
5-(1-Phenylvinyl)naphtho[2,3-d][1,3]dioxole (3b). Following the
General Procedure H; purified by silica-gel column chromatography
(hexane/EtOAc = 5/1) (31.9 mg, 93% yield, white solid): mp 79−83
°C; 1H NMR (400 MHz, CDCl3) δ 5.35 (d, J = 1.4 Hz, 1H), 5.94 (d, J
= 1.6 Hz, 1H), 5.96 (s, 2H), 7.05 (s, 1H), 7.13 (s, 1H), 7.23−7.37 (m,
7H), 7.66 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 100.9,
102.8, 104.0, 116.0, 124.0, 125.9, 126.5, 126.9, 127.7, 128.4, 128.8,
130.8, 139.0, 140.8, 147.3, 147.5, 148.5; HRMS (APCI) calcd for
C19H15O2 (M+ + H) 275.1067, found 275.1061.
105.5, 106.1, 115.2, 124.2, 125.2, 125.7, 126.5, 126.6, 129.8, 138.5,
139.7, 148.3, 148.7, 149.1, 150.6; HRMS (ESI) calcd for C26H31O2
(M+ + H) 375.2319, found 375.2311.
2-Methyl-1-vinylnaphthalene (3i). Following the General Proce-
dure H; The reaction mixture was treated with p-toluenesulfonic acid
monohydrate at 50 °C overnight; purified by silica-gel column
chromatography (hexane/EtOAc = 10/1) (33.8 mg, 92% yield,
colorless oil): 1H NMR (400 MHz, CDCl3) δ 2.48 (s, 3H), 5.43 (dd, J
= 18.1, 2.0 Hz, 1H), 5.76 (dd, J = 11.7, 2.0 Hz, 1H), 7.03 (dd, J = 18.1,
11.4 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.38−7.47 (m, 2H), 7.67 (d, J
= 8.5 Hz, 1H), 7.78−7.80 (m, 1H), 8.11 (d, J = 8.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.8, 121.0, 124.7, 125.2, 125.8, 126.9,
128.0, 128.8, 131.8, 132.1, 132.6, 134.2, 134.5; HRMS (ESI) calcd for
C13H13 (M+ + H) 169.1012, found 169.1013.
4-(1-(4-Methoxyphenyl)vinyl)-2,3-dihydro-1H-indene (3c). Fol-
lowing the General Procedure H; The reaction mixture was treated
with p-toluenesulfonic acid monohydrate at 50 °C overnight; purified
by silica-gel column chromatography (hexane/EtOAc = 2/1) (19.3
mg, 77% yield, yellow oil): 1H NMR (400 MHz, CDCl3) δ 1.93
(quint, J = 7.6 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H), 2.90 (t, J = 7.6 Hz,
1-(1-(4-(1-(3-Methyl-2-vinylphenyl)vinyl)phenyl)vinyl)-
naphthalene (3j). Following the General Procedure H; 10a (30 mol
%) was used. The reaction mixture was treated with p-toluenesulfonic
acid monohydrate at 50 °C for 4 h; purified by silica-gel column
chromatography (hexane/EtOAc = 10/1) (23.5 mg, 60% yield,
colorless gum): 1H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 5.95 (s,
4237
dx.doi.org/10.1021/jo500561z | J. Org. Chem. 2014, 79, 4231−4239

The Journal of Organic Chemistry
Note
2H), 7.16−7.22 (m, 4H), 7.28−7.36 (m, 2H), 7.34−7.54 (m, 6H),
7.74 (d, J = 8.7 Hz, 2H), 7.82 (t, J = 7.3 Hz, 4H); 13C NMR (100
MHz, CDCl3) δ 116.1, 125.4, 125.7, 125.8, 126.4, 126.6, 127.1, 127.9,
128.1, 131.8, 133.6, 139.6, 140.2, 147,7; HRMS (APCI) calcd for
C30H23 (M+ + H) 383.1794, found 383.1789.
Synthesis of Substituted 3-Vinylphenols 9 by RCEM/
Tautometization of 8. General Procedure I: RCEM/Tautomeri-
zation. To a solution of 1,5-octadiene-7-yn-3-ones 8 (1 equiv) in
toluene (0.01 M) was added catalyst 10a (7.5 mol %) under nitrogen,
and then the system was evacuated carefully and filled with ethylene
gas (1 atm) in three cycles. The reaction mixture was heated to 80 °C
and stirred for 2 h. After cooling to room temperature, the mixture was
concentrated under reduced pressure and purified by silica-gel column
chromatography to afford 9.
1-Methyl-4-(1-phenylvinyl)naphthalen-2-ol (9f). Following the
General Procedure I; purified by silica-gel column chromatography
(hexane/EtOAc = 4/1) (16.5 mg, 67% yield, colorless oil): H NMR
1
(400 MHz, CDCl3) δ 2.58 (s, 3H), 4.94 (s, 1H), 5.37 (d, J = 1.4 Hz,
1H), 5.96 (d, J = 1.4 Hz, 1H), 7.04 (s, 1H), 7.20 (ddd, J = 8.2, 6.9, 1.2
Hz, 1H), 7.22−7.34 (m, 5H), 7.45 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.70
(d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 10.6, 115.1, 116.3, 118.9, 123.1, 123.3, 126.2, 126.6, 126.9,
127.6, 127.7, 128.4, 134.1, 139.3, 140.8, 147.7, 149.8; HRMS (ESI)
calcd for C19H15O (M− − H) 259.1128, found 259.1131.
3-Methyl-4-vinylnaphthalen-2-ol (9i). Following the General
Procedure I; purified by silica-gel column chromatography (hexane/
1
EtOAc = 4/1) (13.5 mg, 86% yield, white solid): mp 56−59 °C; H
NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 5.03 (d, J = 2.1 Hz, 1H),
5.40 (dd, J = 18.1, 2.1 Hz, 1H), 5.79 (dd, J = 11.7, 2.1 Hz, 1H), 7.01
(dd, J = 18.3, 11.7 Hz, 1H), 7.05 (s, 1H), 7.30 (ddd, J = 8.4, 6.9, 1.4
Hz, 1H), 7.37 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H), 7.60−7.65 (m, 1H),
7.96−8.02 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 13.5, 108.3,
121.5, 123.4, 123.7, 125.4, 125.5, 126.2, 127.5, 133.0, 134.1, 136.9,
152.2; HRMS (ESI) calcd for C13H11O (M− − H) 183.0815, found
183.0808.
4-(1-Phenylvinyl)naphthalen-2-ol (9a). Following the General
Procedure I; purified by silica-gel column chromatography (hexane/
1
EtOAc = 5/1) (6.60 mg, 92% yield, colorless oil): H NMR (400
MHz, CDCl3) δ 5.00−5.03 (br m, 1H), 5.39 (d, J = 1.2 Hz, 1H), 5.97
(d, J = 1.2 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 7.15−7.19 (m, 2H),
7.25−7.34 (m, 5H), 7.38 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.68 (dd, J =
14.1, 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 109.4, 116.4, 119.0,
123.6, 126.4, 126.6, 126.7, 127.4, 127.8, 128.4, 135.0, 140.6, 142.0,
147.6, 152.7; HRMS (ESI) calcd for C18H13O (M− − H) 245.0972,
found 245.0974.
ASSOCIATED CONTENT
■
S
* Supporting Information
8-(1-Phenylvinyl)naphtho[2,3-d][1,3]dioxol-6-ol (9b). Following
the General Procedure I; purified by silica-gel column chromatography
(hexane/EtOAc = 5/1) (11.3 mg, 84% yield, brown solid): mp 107−
Summary of synthetic schemes for all compounds and 1H NMR
and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
114 °C; H NMR (400 MHz, CDCl3) δ 4.93−4.99 (br m, 1H) 5.34
(d, J = 1.4 Hz, 1H), 5.92 (s, 2H), 5.92 (d, J = 1.4 Hz, 1H), 6.90 (d, J =
2.5 Hz, 1H), 6.97 (m, 2H), 7.03 (d, J = 2.8 Hz, 1H), 7.22−7.32 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 100.9, 102.9, 109.7, 116.1,
116.9, 123.8, 126.5, 127.8, 128.4, 132.1, 140.4, 140.8, 146.0, 147.9,
151.9; HRMS (ESI) calcd for C19H13O3 (M− − H) 289.0870, found
289.0875.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: kyoshida@faculty.chiba-u.jp.
*E-mail: ayanagi@faculty.chiba-u.jp.
■
7-(1-(4-Methoxyphenyl)vinyl)-2,3-dihydro-1H-inden-5-ol (9c).
Following the General Procedure I; 10b (10 mol %) was used and
the reaction mixture was stirred for 12 h; purified by silica-gel column
chromatography (hexane/EtOAc = 2/1) (16.2 mg, 87% yield, cream
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
■
yellow solid): mp 84−87 °C; H NMR (400 MHz, CDCl3) δ 1.93
We appreciate the financial support in the form of a Grant-in-
Aid for Scientific Research (WAKATE B-25810058) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. We also gratefully acknowledge financial support
from the next generation training program in Chiba University,
the Naito Foundation, and the Iodine Research Project in
Chiba University headed by Professor Hideo Togo.
(quint, J = 7.6 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 2.85 (t, J = 7.6 Hz,
2H), 3.81 (s, 3H), 4.60 (s, 1H), 5.15 (d, J = 1.4 Hz, 1H), 5.53 (d, J =
1.6 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.81−
6.85 (m, 2H), 7.20−7.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
25.5, 31.6, 33.1, 55.3, 110.6, 113.3, 113.6, 114.0, 128.3, 133.4, 134.9,
139.2, 146.3, 148.5, 154.2, 159.2; HRMS (APCI) calcd for C18H19O2
(M+ + H) 267.1380, found 267.1383.
4-(5-Chloropent-1-en-2-yl)-7-fluoronaphthalen-2-ol (9d). Follow-
ing the General Procedure I; 10b (7.5 mol %) was used; purified by
silica-gel column chromatography (hexane/EtOAc = 4/1) (11.3 mg,
61% yield, brown solid): mp 107−114 °C; 1H NMR (400 MHz,
CDCl3) δ 1.83−1.92 (m, 2H), 2.65 (t, J = 8.2 Hz, 2H), 3.55 (t, J = 6.6
Hz, 2H), 5.02−5.05 (br s, 1H), 5.13 (d, J = 1.6 Hz, 1H), 5.45 (q, J =
1.4 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 7.08
(ddd, J = 9.4, 8.5, 2.8 Hz, 1H), 7.28 (dd, J = 10.1, 2.5 Hz, 1H), 7.89
(dd, J = 9.4, 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 30.8, 35.4,
44.4, 108.4 (d, J = 4.8 Hz), 109.9 (d, J = 21.1 Hz), 113.7 (d, J = 24.9
Hz), 116.1, 116.8, 123.8, 128.1 (d, J = 9.6 Hz), 136.2 (d, J = 9.6 Hz),
143.1, 146.3, 153.6, 161.2 (d, J = 247.2 Hz); HRMS (ESI) calcd for
C15H13ClFO (M− − H) 263.0644, found 263.0652.
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1
(5.4 mg, 55% yield, brown gum): H NMR (400 MHz, CDCl3) δ
2.43−2.51 (m, 2H), 2.62−2.70 (m, 2H), 3.79 (s, 3H), 4.67−4.76 (br s,
1H), 5.15 (d, J = 1.4 Hz, 1H), 5.71 (d, J = 1.4 Hz, 1H), 6.70 (d, J = 2.5
Hz, 1H), 6.79−6.84 (m, 2H), 7.15−7.33 (m, 6H), 7.70 (d, J = 7.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 25.4, 29.1, 55.3, 110.1, 113.0,
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136.2, 137.67, 142.3, 148.0, 153.9, 159.3; HRMS (APCI) calcd for
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4238
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The Journal of Organic Chemistry
Note
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