Preparation of 1,4-bis(2-ethynyl-3-thienyl) benzene derivatives linked by oligo(ethyleneglycol) chain

Article abstract of DOI:10.1002/hc.20718

1-(2-Phenylethynyl-3-thienyl)-4-[2-(triisopropylsilyl)ethynyl-3-thienyl] benzene derivative, bearing both a polar oligo(ethyleneglycol) chain and hydrophobic alkyl chains, was prepared. The triisopropylsilyl group was then removed by tetrabutylammonium fl

Full text of DOI:10.1002/hc.20718

Heteroatom Chemistry
Volume 22, Number 3/4, 2011
Preparation of 1,4-Bis(2-ethynyl-3-thienyl)
benzene Derivatives Linked by
Oligo(Ethyleneglycol) Chain
Kozo Toyota, Hiroshi Katsuta, Takeaki Iwamoto, and Noboru Morita
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai
980-8578, Japan
Received 1 October 2010; revised 18 January 2011
In both biological and artificially (biomimetic)
ABSTRACT:
1-(2-Phenylethynyl-3-thienyl)-4-[2-
(triisopropylsilyl)ethynyl-3-thienyl]benzene
large systems, heteroatoms play important and
versatile roles in coordination, hydrogen bonding,
and redox reaction. Moreover, heteroatoms (main
group elements as well as transition metals) are very
important in organic syntheses of large molecular
systems at various synthetic stages such as protec-
tion, deprotection, and coupling reaction: cooper-
ation of heteroatoms (boron, silicon, phosphorus,
sulfur, halogens, palladium, and so on) will create a
fascinating world of artificially large molecules.
By utilizing heteroatoms, we have developed
peptide-inspired bis(ethynylthienyl)arene spacers
(abbreviated as ETB or ETAr spacers, Fig. 1): we
have prepared several ETB/ETAr-related derivatives
such as 1–6 [8]. The spacers provide promising po-
tential building blocks for the construction of larger
systems such as linked ETB/ETAr system (Fig. 2).
Our linked ETB/ETAr system concept shown
in the previous paper [8d,e] is very much bioin-
spired. Proteins, especially membrane binding
proteins (transmembrane proteins and monotopic
membrane proteins), normally contain both a
hydrophobic and hydrophilic domain, and exhibit
special functionality such as catalytic (or enzymatic)
activity. Our synthetic strategy involves connecting
the ETB or the related units to hydrophobic or hy-
drophilic chains to enable the preparation of large
assembled molecules in water (in the presence or ab-
sence of surfactant or lipid bilayer). As a part of the
fundamental research, we report here the prepara-
tion of novel ETB derivatives (structure A in Fig. 2)
deriva-
tive, bearing both a polar oligo(ethyleneglycol) chain
and hydrophobic alkyl chains, was prepared. The
triisopropylsilyl group was then removed by tetrabutyl-
ammonium fluoride and the diphenylphosphinyl
group was introduced by successive treatment
with EtMgBr, chlorodiphenylphosphine, and aerial
ꢀ
C
dioxygen.
2011 Wiley Periodicals, Inc. Heteroatom
Chem 22:531–537, 2011; View this article online at
wileyonlinelibrary.com. DOI 10.1002/hc.20718
INTRODUCTION
Artificially large and sophisticated molecular sys-
tems, such as artificial enzymes and artificial molec-
ular architectures, are of current interest [1–4]. This
category may also include the so-called biomimetic
or bioinspired molecules [5–7], whose structures or
functions are not always very similar to the biopoly-
mers (such as peptides and proteins), but the design
of which is inspired by them.
Dedicated to Professor Kin-ya Akiba on the occasion of his 75th
birthday.
A part of this work was presented at the 90th National Meeting
of the Chemical Society of Japan, Higashi-osaka, Japan, March
2010.
Correspondence to: Kozo Toyota; e-mail: toyota@m.tohoku
.ac.jp.
c
ꢀ
2011 Wiley Periodicals, Inc.
531

532 Toyota et al.
Side chain
S
S
A
Hydrophilic loop
R
S
S
R3
R2
S
n
R4
R1
S
R
S
n = 1, ETB spacer
n = 2, ETAr spacer
S
4: R = SiMe3
S
S
B
R
A
A
S
Hydrophilic loop
R
S
R
R5
R4
S
S
R
R6
R3
S
1: A = H, R = Si(i-Pr)3
2: A = H, R = SiMe3
3: A = F, R = SiMe 3
S
R7
R2
5: R = Si(i-Pr)3
Me
R8
R1
S
S
S
n-Bu
Hydrophilic
group
Hydrophilic
group
n-Hex
FIGURE 2 Concept of peptide-inspired “linked ETB/ETAr
system.” Above, monotopic membrane-peptide-inspired
structure. Below, transmembrane-peptide-inspired structure.
S
6
RESULTS AND DISCUSSION
FIGURE 1 ETB spacer, ETAr spacer, and related com-
In the first place, we prepared the polar moiety of A
(Fig. 2) as compound 12 in Scheme 1: commercially
available 4-bromo-2-thiophenecarbaldehyde (7) was
reduced by NaBH4 to give 8 in 82% isolated yield
(route a in the literature [11], 99% yield without
pounds.
bearing a polar oligo(ethyleneglycol) chain and
hydrophobic alkyl chains [9]. A very recent report of
Kinbara et al. also shows a protein-mimicking
concept similar to the linked ETB/ETAr system
[10]. Compound A can be regarded as the simplest
form of linked ETB system, containing both a polar
domain and a hydrophobic domain.
purification).
Iodination
of
8
with
N-
iodosuccinimide (NIS) afforded 10 in 90% yield.
Compound 10 was obtained via route b: 4-Bromo-
5-iodothiophene-2-carbaldehyde (9) was prepared
by reaction of 7 with NIS, in 77% yield. Reduction
Heteroatom Chemistry DOI 10.1002/hc

Preparation of 1,4-Bis(2-ethynyl-3-thienyl)benzene Derivatives 533
In the second place, preparation of model com-
pound 14 (Scheme 2), whose triple bonds are pro-
tected by trialkylsilyl group, was studied. Synthetic
procedure was based on the previously reported
preparative method of unsymmetrical ETB deriva-
tives [8c]: Suzuki-Miyaura cross coupling of the po-
lar bromide 12 with borolane 13a [9] afforded 14 in
36% yield.
HO
Route a
(i)
CHO
S
S
Br
Br
7
8
Route b
We then planned to prepare analogous com-
pounds bearing different side chains. Phenylethynyl
side chain was chosen for a side chain of the
hydrophobic domain and polar phosphynylethynyl
group was chosen for the polar domain: Re-
action of 12 and the phenylethynyl substituted
(thienylphenyl)bolorane 13b [9] gave compound 15
(49% yield). The silyl-protected ethynyl side chains
of 15 are changeable to various side chains by de-
protection and successive reactions such as meta-
lation, cross coupling, or catalytic azide-alkyne cy-
cloaddition. Actually, the silyl group was removed
by addition of tetrabutylammonium fluoride to give
16 in 77% yield. Reaction of 16 with EtMgBr and
chlorodiphenylphosphine, followed by oxidation by
air, afforded 17, bearing a hydrophobic group and a
polar group, in 49% yield.
Figure 3 depicts ultraviolet–visible (UV–vis)
spectra of 1 [8e], 14, and 17 in CH2Cl2. Comparison
of the UV spectra of 14 and 17 with that of 1 shows
an apparent increase of the molar absorption coeffi-
cients, because compounds 14 and 17 have two ETB
moieties in a molecule. The shape of the spectrum
of 14 is not a simple multiplication of the spectrum
of 1; a significant change in shape was observed in
300–400 nm region. This fact suggests a change in
(iii)
(ii)
HO
CHO
S
S
(iv)
I
I
Br
Br
(v)
9
10
HO
S
R
Br
11
O
O
(vi)
O
O
R = i-Pr3Si
O
O
S
S
R
R
Br
Br
100000
12
1
14
17
80000
60000
40000
20000
0
SCHEME 1 Reagents and conditions: (i) NaBH4, (82%);
(ii) N-iodosuccinimide (NIS), acetic acid, THF, r.t., 5 h (90%);
(iii) NIS, acetic acid, CHCl3, r.t., 3 d (77%); (iv) NaBH4,
i-PrOH, r.t., 100 min (52%); (v) ethynyltriisopropylsilane,
PdCl2(PPh3)2, CuI, i-Pr2NH, THF, 50◦C, 17 h (76%); (vi) NaH,
THF, then TsO(CH2CH2O)5Ts, 60◦C, 30 min (33%).
of 9 with NaBH4 afforded the alcohol 10 in 52%
yield. Probably, compound 9 is not so stable under
the reduction conditions, resulting in the low
yield of 10. Thus, route a is superior to route b.
Sonogashira coupling reaction of 10 with ethynyl-
triisopropylsilane afforded 11 in 76% yield, which
was converted to 12 in 33% yield by successive
treatment of 11 with NaH and penta(ethylene
glycol)di-p-toluenesulfonate.
250
300
350
400
450
500
Wavelength/nm
FIGURE 3 UV–vis spectra of 1, 14, and 17 in CH2Cl2. Data
for 1 was taken from [8d].
Heteroatom Chemistry DOI 10.1002/hc

534 Toyota et al.
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
R1
R1
R1
R2
R1
R2
Br
Br
12: R1 = i-Pr3Si
(i)
+
S
S
O
O
B
13a: R2 = i-Pr3Si
b: R2 = Ph
R2
14: R1 = R2 = i-Pr3Si
S
15: R1 = i-Pr3Si, R2 = Ph
16: R1 = H, R2 = Ph
(ii)
n-Hex
(iii)
17: R1 = P(O)Ph2, R2 = Ph
SCHEME 2 Reagents and conditions: (i) For 14, Pd(PPh3)4, K2CO3, Toluene, THF, H2O, 85◦C, 17 h, 36%; for 15, Pd(PPh3)4,
K2CO3, 1,4-dioxane, H2O, 80◦C, 16 h, 49%; (ii) TBAF, THF, r.t., 1 h (77%); (iii) EtMgBr, THF, 0◦C, 40 min, then Ph2PCl, 0◦C to
r.t., 2 h, work up in the air (49%).
π conjugation in the linked compound 14 compared
with 1. One possible reason is a change in copla-
narity of the dithienylbenzene moieties, caused by
intramolecular interaction of the two ETB moieties,
although a contribution of electronic effect of the
alkyl chain and the ethyleneglycol chain cannot be
neglected at all. On the other hand, little change was
a polar oligo(ethyleneglycol) chain and hydrophobic
alkyl chains. These derivatives may find practical ap-
plication as functional units in future, particularly in
the context of catalysis. Further studies on the appli-
cation of the products and construction of linked
ETAr systems with extended axis are in progress.
1
observed between the H and 13C nuclear magnetic
resonance (NMR) chemical shifts of the central ben-
zene rings of 1 and 14, except for the fact that two dif-
ferent thienyl groups are substituted in the case of 14
and the benzene-ring signals become nonequivalent
in 14. Thus, intramolecular interactions between the
ETB moieties, such as stacking of the aromatic rings,
seem to be small.
Compounds 14–17 themselves are hardly sol-
uble in water. However, investigation of behavior
of 17 as a peptide-inspired compound was tried in
aqueous media. Figure 4 shows the UV–vis spectrum
of 17 in aqueous sodium dodecyl sulphate solution
(ca. 0.01 mol/L). A significant change in the shape
was observed in the 330–370 nm region. This may
suggest conformational change of the dithienylben-
zene moiety. As the concentration of 17 is low, due
to poor solubility, 31P NMR could not be measured.
In summary, we have prepared some 1,4-bis(2-
ethynyl-3-thienyl)benzene derivatives, bearing both
EXPERIMENTAL
Melting points were measured on a Yanagimoto
MP-J3 micro melting point apparatus (Yanagi-
moto Seisakusyo Co., Ltd., Kyoto, Japan) and are
uncorrected. NMR spectra were recorded on a
Bruker Avance-400 or AM-600 spectrometer (Bruker
Japan Co., Ltd., Tsukuba, Japan). UV–vis spectra
were measured on a Hitachi U-3210 spectrometer
(Hitachi, Ltd., Tokyo, Japan) whereas a Horiba FT-
300 (Horiba, Ltd., Kyoto, Japan) or a Shimadzu
FTIR-8100M spectrometer (Shimadzu Corporation,
Kyoto, Japan) was used to obtain the infrared (IR)
spectra. A Hitachi M-2500S spectrometer was used
to obtain MS data. FT-ICR-MS spectra were mea-
sured on a Bruker APEX III spectrometer.
4-Bromo-5-iodothiophene-2-carbaldehyde 9.
mixture of 4-bromothiophene-2-carbaldehyde (7,
A
Heteroatom Chemistry DOI 10.1002/hc

Preparation of 1,4-Bis(2-ethynyl-3-thienyl)benzene Derivatives 535
2
1. 5
1
tion. The organic phase was separated, dried over
MgSO4, and the solvent was removed under reduced
pressure. The residue was treated with an alumina
column (eluent = CHCl3) to give 7.44 g (23.3 mmol,
90% yield) of 10.
Route b. A mixture of 9 (97.4 mg, 0.307 mmol)
and NaBH4 (19.0 mg, 0.502 mmol) in 2-propanol
(5 mL) was stirred at room temperature for 100
min. Water and hexane were added to the reaction
mixture, the organic phase was separated, washed
with brine, dried over MgSO4, and the solvent was
removed under reduced pressure. The residue was
treated with a silica-gel column (eluent = CHCl3) to
give 51.0 mg (0.160 mmol, 52% yield) of 10.
0. 5
10: Colorless solid, mp 56–58◦C; R = 0.31 (Al2O3-
0
250
f
1
300
350
400
450
500
CHCl3); H NMR (400 MHz, CDCl3) δ = 1.89 (1H, t,
J = 6.0 Hz, OH), 4.78 (2H, d, J = 6.0 Hz, CH2),
Wavelength/nm
and 6.81 (1H, s, 3-thienyl); 13C{ H} NMR (150 MHz,
1
FIGURE 4 UV–vis spectrum of 17 (in ca. 0.01 mol/L aque-
ous sodium dodecyl sulfate solution). Concentration of 17 is
ambiguous.
CDCl3) δ = 59.6 (CH2), 76.5 (5-thienyl), 119.6 (4-
thienyl), 127.7 (3-thienyl), and 150.3 (2-thienyl); IR
(KBr) 3350 (OH), 3081, 2928, 2869, 2637, 1725, 1671,
1530, 1455, 1422, 1401, 1369, 1302, 1238, 1165, 1121,
1000, 955, 837, 824, 681, 646, 581, 517, and 426 cm−1;
MS (70 eV) m/z (rel intensity) 320 (M+ +2; 100), 318
(M+; 97), 303 (M+ − OH+2; 12), 301 (M+ − OH; 12),
193 (M+ − I + 2; 30), and 191 (M+ − I; 29). Calcd for
C5H4BrIOS: m/z 317.8211. Found: m/z 317.8208.
2.00 g, 10.5 mmol), NIS (2.82 g, 12.5 mmol), acetic
acid (60 mL), and CHCl3 (35 mL) was stirred at room
temperature for 3 days. The reaction mixture was
treated with saturated aqueous NaHCO3 and then
saturated aqueous Na2S2O3 solution. The organic
phase was separated, dried over MgSO4, and the
solvent was removed under reduced pressure. The
residue was treated with a silica-gel column (eluent
= hexane-EtOAc 1:1) to give 2.55 g (8.05 mmol, 77%
[3-Bromo-2-{2’-(triisopropylsilyl)ethynyl}-5-thieyl]
methanol 11. A mixture of 10 (7.44 g, 23.3 mmol),
ethynyltriisopropylsilane (5.20 mL, 23.4 mmol),
PdCl2(PPh3)2 (325 mg, 0.463 mmol), CuI (87.2 mg,
0.458 mmol), and N,N-diisopropylamine (20 mL)
in THF (100 mL) was stirred at 50◦C for 17 h. After
cooling to room temperature, CHCl3 and water were
added to the reaction mixture. The organic phase
was separated, dried over MgSO4, and the solvent
was evaporated under reduced pressure. The residue
was treated with a silica-gel column (eluent =
hexane-EtOAc 5:1) to give 6.62 g (17.7 mmol, 76%
yield) of 9: colorless solid, mp 96–97◦C; R = 0.12
f
1
(SiO2-CCl4); H NMR (400 MHz, CDCl3) δ = 7.50
(1H, s, 3-thienyl) and 9.75 (1H, s, CHO); 13C{ H}
1
NMR (150 MHz, CDCl3) δ = 91.1 (5-thienyl), 121.8
(4-thienyl), 137.3 (3-thienyl), 148.5 (2-thienyl), and
180.3 (CHO); IR (KBr) 3073, 2845, 1871, 1775, 1721,
1670 (C=O), 1507, 1397, 1358, 1298, 1218, 1167,
1117, 968, 839, 830, 712, 662, 583, 509, and 480 cm−1;
MS (70 eV) m/z (rel intensity) 318 (M+ + 2; 100) and
316 (M+; 98). Calcd for C5H2BrIOS: m/z 315.8054.
Found: m/z 315.8052. Calcd for C5H2BrIOS: C, 18.95,
H, 0.64%. Found: C, 19.20; H, 0.65%.
yield) of 11: pale yellow oil; R = 0.34 (SiO2-CH2Cl2);
f
1H NMR (400 MHz, CDCl3) δ = 1.09–1.19 (21H, br
s, isopropyl), 1.84 (1H, t, J = 6.0 Hz, OH), 4.76 (2H,
d, J = 6.0 Hz, CH2), and 6.85 (1H, s, 3-thienyl);
1
13C{ H} NMR (150 MHz, CDCl3) δ = 11.2 (CHMe2),
≡
≡
(3-Bromo-2-iodo-5-thienyl)methanol 10 Route
a. 4-Bromo-2-hydroxymethylthiophene (8) was pre-
pared according to the literature [10]. A mixture of 8
(5.00 g, 25.9 mmol), NIS (6.38 g, 28.3 mmol), acetic
acid (30 mL), and tetrahydrofuran (THF, 40 mL)
was stirred at room temperature for 5 h. CHCl3 and
water were added to the reaction mixture. The re-
sulting mixture was treated with saturated aqueous
NaHCO3 and then saturated aqueous Na2S2O3 solu-
18.6 (Me), 60.0 (CH2), 97.3 (C C), 100.4 (C C),
116.1 (4-thienyl), 120.8 (5-thienyl), 127.4 (3-thienyl),
and 145.1 (2-thienyl); IR (neat) 3350 (OH), 2945,
≡
2867, 2147 (C C), 1526, 1464, 1383, 1366, 1235,
1107, 1073, 1017, 997, 920, 884, 833, 764, 677, 583,
and 504 cm−1; MS (70 eV) m/z (rel intensity) 374
(M+ + 2; 25), 372 (M+; 24), 331 (M+ − i-Pr+2; 100),
329 (M+ − i-Pr; 94), 303 (M+ − i-Pr − Si + 2; 20),
301 (M+ − i-Pr − Si; 19), 289 (M+ − 2i-Pr + 3; 20),
Heteroatom Chemistry DOI 10.1002/hc

536 Toyota et al.
287 (M+ − 2i-Pr + 1; 19), 275 (M+ − i-Pr − 2MeCH
+ 2; 18), 273 (M+ − i-Pr − 2MeCH; 16), 261 (M+ −
2i-Pr − Si + 3; 26), and 259 (M+ − 2i-Pr − Si + 1;
25). Calcd for C16H25BrOSSi: M, 372.0579. Found:
m/z 372.0574.
s, thienyl), 7.81 (4H, d, 3 J = 8.8 Hz, phenyl), and
1
7.84 (4H, d, 3 J = 8.8 Hz, phenyl); 13C{ H} NMR (150
MHz, CDCl3) δ = 11.3 (CHMe2), 11.4 (CHMe2), 14.1
(MeCH2), 18.7 (CHMe2), 18.7 (CHMe2), 22.5 (CH2),
28.7 (CH2), 30.3 (CH2), 31.4 (CH2), 31.5 (CH2), 67.8
(CH2O), 69.4 (CH2O), 70.6 (CH2O), 70.7 (CH2O),
≡
≡
≡
≡
1,18-Bis[4-bromo-5-{2’-(triisopropylsilyl)ethynyl}
thiophen-2-yl]-2,5,8,11,14,17-hexaoxaoctadecane 12.
Sodium hydride (dispersion in oil, 43.6 mg, ca. 1
mmol) was washed with dry hexane (8 mL) under
nitrogen. To a mixture of the sodium hydride
and 11 (191 mg, 0.510 mmol) in THF (10 mL),
a THF (4 mL) solution of pentaethylene glycol
di-p-toluenesulfonate (147 mg, 0.268 mmol) was
added and the resulting mixture was stirred at 60◦C
for 30 min. The reaction mixture was cooled to room
temperature and treated with 0.1 M hydrochloric
acid. CHCl3 and water were added to the mixture,
the organic phase was separated, dried over MgSO4,
and the solvents were removed under reduced
pressure. The crude products were treated with
recycle gel permeation chromatography (eluent =
97.7 (C C), 98.8 (C C), 99.8 (C C), 100.2 (C C),
115.8 (thienyl), 118.4 (thienyl), 124.7 (thienyl),
126.5 (thienyl), 127.6 (phenyl), 127.7 (phenyl),
134.1 (phenyl), 134.7 (phenyl), 141.8 (thienyl), 144.0
(thienyl), 144.1 (thienyl), and 146.9 (thienyl); UV–
vis (CH2Cl2) 266 (log ε, 4.75), 289 (4.73), and 335 nm
≡
(sh, 4.53); IR (neat) 2865, 2137 (C C), 1717, 1559,
1541, 1516, 1509, 1262, 1098, 1019, 997, 920, 884,
828, 803, 772, 677, and 459 cm−1. FT-ICR-MS Calcd
for C96H146NaO6S4Si4: (M + Na)+, 1657.8972. Found:
m/z 1657.8961.
Compound 15. A mixture of 12 (209 mg, 0.221
mmol), 13b (203 mg, 0.432 mmol), Pd(PPh3)4 (9.8
mg, 0.084 mmol), K2CO3 (302 mg, 2.18 mmol), 1,4-
dioxane (4 mL), and water (4 mL) was heated under
nitrogen atmosphere at 80◦C for 16 h. After cooling
to room temperature, Et2O and water were added
to the reaction mixture. The organic phase was sep-
arated, washed with brine, and dried over MgSO4.
The solvent was removed under reduced pressure
and the residue was treated with a silica-gel col-
umn chromatography (eluent = hexane-EtOAc, 1:1)
to give 154.7 mg (0.105 mmol, 49% yield) of 15: yel-
CH2Cl2) to give 83.7 mg (0.0881 mmol, 33% yield)
1
of 12: yellow oil; R = 0.69 (SiO2-EtOAc); H NMR
f
(400 MHz, CDCl3) δ = 1.13 (42H, br s, isopropyl),
3.63–3.65 (20H, m, CH2), 4.63 (4H, s, CH2), and 6.84
(2H, s, 3-thienyl); 13C{ H} NMR (100 MHz, CDCl3)
1
δ = 11.1 (CHMe2), 18.5 (Me), 67.4 (CH2), 69.3 (CH2),
≡
70.4 (CH2), 70.5 (CH2), 70.6 (CH2), 97.3 (C C),
≡
100.2 (C C), 115.8 (4-thienyl), 120.8 (5-thienyl),
128.2 (3-thienyl), and 142.5 (2-thienyl); IR (neat)
low oil; R = 0.29 (SiO2-hexane-EtOAc 1:1); 1H NMR
f
≡
2944, 2865, 2147 (C C), 1559, 1507, 1352, 1246,
(400 MHz, CDCl3) δ = 0.90 (6H, m, Me), 1.13 (42H,
1173, 1115, 997, 920, 884, 835, 764, 677, and 662
cm−1. FT-ICR-MS Calcd for C42H68Br2NaO6S2Si2:
(M + Na)+, 969.2260. Found: m/z 969.2252.
br s, i-Pr), 1.32–1.40 (12H, m, CH2), 1.67–1.75 (4H,
3
m, CH2), 2.82 (4H, t, J = 7.6 Hz, CH2), 3.64–3.66
(20H, m, OCH2CH2O), 4.68 (4H, s, thienylCH2O),
6.93 (2H, s, thienyl), 7.13 (2H, s, thienyl), 7.30–
7.32 (6H, m, Ph), 7.44–7.47 (4H, m, Ph), 7.85 (4H,
d, 3 J = 8.4 Hz, phenyl), and 7.92 (4H, d, 3 J =
Compound 14. A mixture of 12 (30.6 mg, 0.0322
mmol), 13a (105 mg, 0.190 mmol), Pd(PPh3)4 (13.2
mg, 0.0114 mmol), K2CO3 (124 mg, 0.894 mmol),
THF (5 mL), toluene (3 mL), and water (2 mL)
was heated at 85◦C for 17 h. After cooling to
room temperature, CHCl3 and water were added
to the reaction mixture. The organic phase was
separated, washed with brine, dried over MgSO4,
and the solvent was removed under reduced pres-
sure. Treatment of the residue with a silica-gel col-
umn chromatography (eluent = EtOAc) followed by
gel-permeation column chromatography (eluent =
CH2Cl2) afforded 19.0 mg of 14 (0.0116 mmol, 36%
yield based on the starting 12).
8.4 Hz, phenyl); 13C{ H} NMR (100 MHz, CDCl3)
1
δ = 11.2 (CHMe2), 14.0 (MeCH2), 18.6 (CHMe2),
22.5 (CH2), 28.7 (CH2), 30.2 (CH2), 31.3 (CH2), 31.5
(CH2), 67.7 (CH2O), 69.2 (CH2O), 70.5 (CH2O), 70.5
≡
≡
(CH2O), 70.6 (CH2O), 83.7 (C C), 94.7 (C C), 99.0
≡
≡
(C C), 99.8 (C C), 115.3, 118.3, 123.2, 124.9, 126.3,
127.6, 127.6, 128.1, 128.2, 131.1, 134.0, 134.7, 141.8,
143.6, 143.8, and 147.1; IR (neat) 2940, 2865, 2137
≡
(C C), 1597, 1516, 1458, 1381, 1348, 1291, 1244,
1096, 995, 918, 884, 830, 772, 754, 679, 592, and
525 cm−1. FT-ICR-MS Calcd for C90H114NaO6S4Si2:
(M + Na)+, 1497.6929. Found: 1497.6922. Calcd for
C90H114O6S4Si2·(H2O)1/2: C, 72.78; H, 7.80%. Found:
C, 72.58; H, 7.75%.
14: Yellow oil; R = 0.37 (SiO2-hexane-EtOAc
f
1:1); 1H NMR (600 MHz, CDCl3) δ = 0.87–1.71
(106H, m, Me(CH2)4 and isopropyl), 2.78 (4H, t,
3 J = 7.6 Hz, CH2), 3.64–3.67 (20H, m, CH2CH2O),
4.68 (4H, s, CH2O), 6.89 (2H, s, thienyl), 7.09 (2H,
Compound 16. To a solution of 15 (93.4 mg,
0.0633 mmol) in THF (1.4 mL), 0.140 mmol of
Heteroatom Chemistry DOI 10.1002/hc

Preparation of 1,4-Bis(2-ethynyl-3-thienyl)benzene Derivatives 537
1.69–1.76 (4H, m, CH2), 2.83 (4H, t, 3 J =7.5 Hz,
thienyl-CH2), 3.64–3.67 (20H, m, OCH2CH2O), 4.71
(4H, s, thienylCH2O), 6.91 (2H, s, thienyl), 7.15 (2H,
s, thienyl), 7.27–7.29 (6H, m, Ph), 7.39–7.44 (4H, m,
tetrabutylammonium fluoride (1.0 M solution in
THF, 0.140 mL) was added at room temperature and
the resulting mixture was stirred for 1 h. Et2O and
water were added to the reaction mixture. The or-
ganic phase was separated, washed with brine, and
dried over MgSO4. The solvent was removed under
reduced pressure and the residue was treated with a
silica-gel column chromatography (eluent = hexane
to EtOAc) to give 57.0 mg (0.0490 mmol, 77% yield)
1
Ph), and 7.68–7.82 (8H, m, phenyl); 13C{ H} NMR
(100 MHz, CDCl3) δ = 14.1 (MeCH2), 22.5 (CH2),
28.7 (CH2), 30.3 (CH2), 31.3 (CH2), 31.5 (CH2), 67.7
(CH2O), 69.8 (CH2O), 70.5 (CH2O), 70.6 (CH2O), 83.6
1
≡
≡
≡
(C C), 89.0 (d, JPC = 168.4 Hz, C C), 95.0 (C C),
99.5 (d, 2 JPC = 30.1 Hz, C C), 114.0 (d, JPC = 4.4 Hz,
2
≡
of 16: yellow oil; R = 0.13 (SiO2-hexane-EtOAc 1:1);
f
1H NMR (400 MHz, CDCl3) δ = 0.90 (6H, t, 3 J = 7.0
Hz, Me), 1.32–1.40 (12H, m, CH2), 1.67–1.75 (4H, m,
CH2), 2.81 (4H, t, 3 J = 7.6 Hz, CH2), 3.44 (2H, s,
o-Ph), 115.7, 123–136 (m, arom), 143.4, 146.4, 147.4,
and 148.8; 31P{ H} NMR (162 MHz, CDCl3) δ = 9.5;
1
UV–vis (CH2Cl2) 268 (log ε, 4.73), 302 (4.78), and
≡
≡
C CH), 3.65–3.67 (20H, m, OCH2CH2O), 4.69 (4H,
353 nm (sh, 4.55); IR (neat) 2926, 2854, 2150 (C C),
s, thienylCH2O), 6.94 (2H, s, thienyl), 7.11 (2H, s,
thienyl), 7.30–7.32 (6H, m, Ph), 7.44–7.47 (4H, m,
Ph), 7.79 (4H, d, 3 J = 8.6 Hz, phenyl), and 7.88 (4H,
1717, 1438, 1205, 1120, 831, 795, 754, 725, and 692
cm−1. FT-ICR-MS Calcd for C96H92NaO8P2S4: (M +
Na)+, 1585.5042. Found: 1585.5047.
1
d, 3 J = 8.6 Hz, phenyl); 13C{ H} NMR (100 MHz,
CDCl3) δ = 14.0 (MeCH2), 22.5 (CH2), 28.7 (CH2),
REFERENCES
30.2 (CH2), 31.3 (CH2), 31.5 (CH2), 67.7 (CH2O),
≡
69.4 (CH2O), 70.5 (CH2O), 70.6 (CH2O), 77.4 (C C),
[1] Venkataraman, D.; Yurt, S.; Venkataraman, B. H.;
Gavvalapalli, N. J Phys Chem Lett 2010, 1, 947.
[2] Reed, C. A. Acc Chem Res 2005, 38, 215.
[3] Ryu, J. -H.; Hong, D. -J.; Lee, M. Chem Commun
2008, 1043.
[4] Sue, D.; Takaishi, K.; Harada, T.; Kuroda, R.;
Kawabata, T.; Tsubaki, K. J Org Chem 2009, 74, 3940.
[5] Davis, J. M.; Tsou, L. K.; Hamilton, A. D. Chem Soc
Rev 2007, 36, 326.
≡
≡
≡
83.8 (C C), 83.8 (C C), 94.7 (C C), 115.4, 116.6,
123.2, 124.9, 126.6, 127.7, 127.8, 128.1, 128.3, 131.1,
133.9, 135.0, 142.5, 144.0, 145.1, and 147.2. FT-ICR-
MS Calcd for C72H74NaO6S4: (M + Na)+, 1185.4280.
Found: 1185.4253.
Compound 17. To a solution of 16 (57.0 mg,
0.0490 mmol) in THF (2 mL), 0.11 mmol of Et-
MgBr (0.98 M solution in Et2O, 0.11 mL) was added
at 0◦C and the resulting mixture was stirred for
40 min. To the solution, chlorodiphenylphosphine
(0.030 mL, 0.16 mmol) was added at 0◦C. The reac-
tion mixture was allowed to warm to room tempera-
ture and stirred for 2 h. Et2O and water were added
to the resulting solution, the organic phase was sep-
arated, washed with brine, and dried over MgSO4.
The solvent was removed under reduced pressure
and the residue was treated with an alumina col-
umn chromatography (eluent = EtOAc to EtOH).
A crude product thus obtained was further purified
by gel permeation chromatography to give 36.6 mg
[6] Biros, S. M.; Moisan, L.; Mann, E.; Carella, A.; Zhai,
D.; Reed, J. C.; Rebek, J., Jr. Bioorg Med Chem Lett
2007, 17, 4641.
[7] Cummings, C. G.; Ross, N. T.; Katt, W. P.; Hamilton,
A. D. Org Lett 2009, 11, 25.
[8] (a) Toyota, K.; Goto, Y.; Okada, K.; Morita, N.
Heterocycles 2007, 71, 2227; (b) Toyota, K.; Okada,
K.; Katsuta, H.; Morita, N. Tetrahedron 2009, 65, 145;
(c) Toyota, K.; Tsuji, Y.; Okada, K.; Morita, N. Hetero-
cycles 2009, 78,127; (d) Toyota, K.; Tsuji, Y.; Morita,
N. J Sulf Chem 2009, 30, 351; (e) Toyota, K.; Katsuta,
H.; Tsuji, Y.; Iwamoto, T.; Morita, N. Heterocycles
2009, 78, 3037.
[9] Katsuta, H.; Tsuji, Y.; Yamamoto, T.; Toyota, K.;
Iwamoto, T.; Morita, N. 90th National Meeting of
Chem. Soc. Jpn. abstr. 2G3-45.
[10] Muraoka, T.; Shima, T.; Hamada, T.; Morita, M.;
Takagi, M.; Kinbara, K. Chem Commun 2011, 47,
194.
(0.0239 mmol, 49% yield) of 17: yellow oil; R = 0.27
f
1
(Al2O3-EtOAc); H NMR (400 MHz, CDCl3) δ = 0.91
[11] Dowle, M. D.; Hayes, R.; Judd, D. B.; Williams, C. N.
Synthesis 1983, 73.
(6H, t, 3 J = 6.8 Hz, Me), 1.33–1.42 (12H, m,CH2),
Heteroatom Chemistry DOI 10.1002/hc