Bithiophene with winding vine-shaped molecular asymmetry. Preparation, structural characterization, and enantioselective synthesis

Article abstract of DOI:10.1246/bcsj.20160265

Preparation of 2,2-bithiophene derivatives bearing ?-alkenyl groups at the 3,3-positions and ring-closing metathesis reactions of the obtained compound were performed. The reaction of bithiophene bearing 3-butenyl substituents 1 with 5mol% Grubbs 1st generation catalyst underwent ring-closing metathesis (RCM) to afford the cyclized product 7 showing winding vine-shaped molecular asymmetry in up to 88% yield. Enantioselective RCM was also achieved by the use of chiral SchrockHoveyda molybdenum-alkylidene catalyst in up to 87% ee.

Full text of DOI:10.1246/bcsj.20160265

Advance Publication Cover Page
Bithiophene with Winding Vine-Shaped Molecular Asymmetry. Preparation,
Structural Characterization, and Enantioselective Synthesis
Yuka Toyomori, Satoru Tsuji, Shinobu Mitsuda, Yoichi Okayama, Shiomi Ashida, Atsunori Mori,*
Toru Kobayashi, Yuji Miyazaki, Tsuyoshi Yaita, Sachie Arae, Tamotsu Takahashi,
and Masamichi Ogasawara*
Advance Publication on the web September 16, 2016
doi:10.1246/bcsj.20160265
©
2016 The Chemical Society of Japan

Bithiophene with Winding Vine-shaped Molecular Asymmetry. Preparation,
Structural Characterization, and Enantioselective Synthesis
1
1
1
1
1
1
2
Yuka Toyomori, Satoru Tsuji, Shinobu Mitsuda, Yoichi Okayama, Shiomi Ashida, Atsunori Mori *, Toru Kobayashi, Yuji
Miyazaki, Tsuyoshi Yaita, Sachie Arae, Tamotsu Takahashi, and Masamichi Ogasawara3,4*
2
2
3
3
1
2
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Quantum Beam
3
Science Directorate Japan Atomic Energy Agency, 1-1-1 Koto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Institute for Catalysis,
4
Hokkaido University, Kita21, Nishi10, Kita-ku, Sapporo 001-0021, Present address: Graduate School of Science and Technology,
Tokushima University, 2-1 Minamijyousanjima-cho, Tokushima 770-8506
E-mail: amori@kobe-u.ac.jp; ogasawar@tokushima-u.ac.jp
Abstract
Preparation of 2,2'-bithiophene derivatives bearing -
the presence of a rhodium catalyst afforded aldehyde 3.9
Following bromination at the 2-position of thiophene and Wittig
methylenation lead to 2-bromo-3-(3-buten-1-yl)thiophene 4
(Scheme 1a). Bromothiophene 4 was also obtained from 3-
methylthiophene (5) by sequential cationic and radical
bromination reactions of 5 both with NBS to afford 2-bromo-3-
bromomethylthiophene (6) in 95% and 70% yields, respectively.
Treatment of 6 with allyl Grignard reagent leads to 4 (85%),
whose protocol has also been applied to the monomer synthesis
of polythiophene with extremely high solubility in hydrocarbons
(Scheme 1b). Obtained 3-substituted bromothiophene 1 was
subjected to dimerization of the thienylmagnesium species
formed by halogen-metal exchange with a half equivalent of
EtMgCl followed by palladium-catalyzed cross coupling with
the remaining 4, to afford 1 in 63% yield. (Scheme 1c)
Preparation of 1 was alternatively carried out by oxidative
alkenyl groups at the 3,3'-positions and ring-closing metathesis
reactions of the obtained compound were performed. The
reaction of bithiophene bearing 3-butenyl substituents 1 with 5
mol% Grubbs 1st generation catalyst underwent ring-closing
metathesis (RCM) to afford the cyclized product 7 showing
winding vine-shaped molecular asymmetry in up to 88% yield.
Enantioselective RCM was also achieved by the use of chiral
Schrock-Hoveyda molybdenum-alkylidene catalyst in up to 87%
ee.
1
0
1
. Introduction
Design of novel organic compounds showing molecular
1
asymmetry attracts much attention in topochemical interest as
well as application of such compounds as functional organic
homocoupling, which was performed by the reaction of the
2
11
molecules particularly as asymmetric catalysts. We have
metalated thiophene with CuCl
2
(70%).
3
recently reported that ring-closing metathesis (RCM) of a
(a)
CHO
bisimidazole derivative bearing N-butenyl substituents leads to
macrocyclic E-olefin and the thus cyclized product shows a
Bpin
CHO
Rh cat.
NBS
Ph3P=CH2
60%
4
novel class of molecular asymmetry. The chirality in this unique
S
Br
S
S
90%
molecule could be viewed in multiple ways as axial, planar, or
helical chirality, and we proposed a term "winding vine-shaped
molecular asymmetry" for this molecular asymmetry. We have
also been successful in enantioselective preparation of such
compounds of the molecular asymmetry using a chiral
85%
4
2
3
(
b)
Br
Br
NBS/
AIBN
MgCl
NBS
4
S
S
THF
95%
CCl4
70%
THF
85%
5
6
molybdenum-alkylidene catalyst. Our further concern turned to
5
the design of other heterobiaryls showing the related molecular
asymmetry. Since we have been interested in developing C-H
functionalization reactions of five-membered heteroaromatic
(c)
NiCl2(PPh3)IPr
(1.0 mol %)
0
.5 EtMgCl
rt, 2 h
S
4
1
/2
S
6
7
compounds representative as thiophene derivatives directed to
advanced organic materials, it is intriguing to study if
preparation of such vine-shaped compounds are available in
60 °C, 20 h
1
(63%)
1
thiophene derivatives. Herein, we report concise preparation of
Scheme 1. Preparation of bithiophene RCM precursor
2
,2'-bithiophene derivatives bearing -alkenyl substituents at
the 3- and 3'-positions in the thiophene rings and ring-closing
metathesis of the thus obtained compounds leading to
bithiophenes with winding vine-shaped molecular asymmetry.
Transformation of the cylclized bithiophene and their
enantioselective preparation by the molybdenum-catalyzed
The obtained bithiophene 1 was subjected to the ring-closing
metathesis (RCM) with a ruthenium catalyst as shown in Scheme
4
2. In RCM of bisimidazole derivatives the reaction using
1
2
Grubbs 2nd generation catalyst in the presence of a Lewis acid
Ti(OiPr)
as an additive has been effective,13 however, the
4
8
asymmertric ring-closing metathesis are also studied.
reaction of bithiophene derivative 1 proceeded smoothly without
Lewis acid to give the cyclized product 7 in 67% yield. The
absence of imino nitrogen may have avoided poisoning of the
ruthenium catalyst facilitating the smooth reaction of the
ruthenium complex with a terminal olefin leading to alkylidene
ruthenium complex A. Thus, rotation of thiophene-thiophene
2
. Results and Discussion
Thiophene derivative 1 bearing -olefinic substituents at
the 3- and 3'-positions was synthesized as shown in the following
pathways: the reaction of (3-thienyl)boronate 2 with acrolein in

bond would lead to the favorable intramolecular metathesis
reaction. Lowering the reaction to room temperature with
Grubbs 2nd generation catalyst resulted in no reaction, while the
reaction was found to proceed at room temperature with Grubbs
resulted in the smaller angle.
(a)
(b)
1
2b,14
1
7
st generation catalyst
7%) suggesting that bithiophene 1 was much reactive compared
within a shorter reaction period (1 h,
with the case of the bisimidazole analog. The reaction of 1 under
much higher dilution (0.05 M to 0.025 M) improved the yield to
8
8%. The results are summarized in Table 1.
Ru cat.
S
S
S
S
1,2-dichloroethane
Figure 1. (a) HPLC profile of 7 with chiral column (DAICEL
Chiralpak IF) and (b) X-ray crystal structure of the cyclized
product 7
7
1
S
A
S
[
Ru]
We next envisaged unsymmetrical (hetero)biaryl derivatives.
Metathesis precursor of bithiophene bearing a different
substituent in the side chain was synthesized as shown in
Scheme 3 (1). The reaction of bromomethyl-bromothiophene 6
with methallyl Grignard reagent afforded 8 in 85% yield.
Following halogen metal exchange with EtMgCl and the
reaction of bromothiophene bearing a 3-butenyl substituent
furnished the corresponding unsymmetrical bithiophene 9 in
67% yield. Although RCM of bithiophene with unsymmetrical
substituent leading to trisubstituted olefin 11 was found
unsuccessful at all with a ruthenium catalyst, the reaction was
found to proceed using Schrock's molybdenum-alkylidene
catalyst 10 to afford the cyclized bithiphene 11 (60%
conversion). The metathesis precursor bearing thiophene and
benzene rings was also synthesized as shown Scheme 3 (2) by
the reaction of bromothiophene 4 with EtMgCl followed by
treatment with bromobenzene 12, which was prepared by the
reaction of 2-bromomethyl-bromobenzene with methallyl
Grignard reagent, in the presence of Pd-PEPPSI-SIPr as a
catalyst to afford 13 in 74% yield. RCM of 13 was found to
proceed successfully with Grubbs 2nd generation catalyst (5
mol%) in 77% yield.
Scheme 2. Ring-closing metathesis of bithiophene 1 leading to
macrocyclic olefin with winding vine-shaped molecular
asymmetry
Table 1. Ring-closing metathesis of bithiophene 1.a)
Catalystb)
mol%)
Grubbs 2nd (5)
Grubbs 2nd (5)
Grubbs 1st (5)
Time
(h)
24
Temp (ºC)
Yield of 7 (%)
(
1
6
80
rt
80
rt
67
0
70
77
24
24
1
c)
Grubbs 1st (5)
Grubbs 1st
rt
5
88
d)
(10)
a) Unless noted, the reaction was carried out with 1 in 1,2-
dichloroethane (0.05 M) under a nitrogen atmosphere. b) Grubbs
2
nd:
RuCl
2
(═CHPh)(PCy
3
)SIMes;
Grubbs
1st:
RuCl
2
(═CHPh)(PCy )
3 2
. c) The reaction was carried out with
dichloromethane (0.05 M) as a solvent. d) The reaction with
dichloromethane (0.025 M)
H3C
1
) EtMgCl
CH3
Measurement of a mass spectrum of the metathesis product
2) 4,NiCl (PPh )IPr
2
3
S
6
+
MgCl
supported formation of the cyclized product 7 with liberation of
S
Br
S
THF
6
7%
1
ethylene from 1. The H NMR spectrum of 7 also supports
8
, 85%
formation of macrocyclic E-olefin structure to bring about
remarkable shift of vinylic proton signal (5.8 ppm) to lower
frequency induced by the placement of the corresponding
hydrogen atom to deshielded region of the ring current of
thiophene. Measurement of UV-vis spectra of 7 and the
metathesis precursor 1 suggested less -conjugation between the
thiophenes in 7 after the ring closure to result in twisting of the
dihedral angle of the two thiophene rings by the formation of the
olefinic 10-membered ring. HPLC analysis of 7 was carried out
with chiral column DAICEL Chiralpak IF to observe separation
of the enantiomers with hexane as an eluent (Figure 1a).
9
10 (5 mol %)
iPr
S
(
1)
S
iPr
Me
N
benzene
40 °C, 4 h
OC(CF3)2Me
OC(CF3)2Me
Mo
Ph
Me
1
1, 60% conv.
10
Br
Grubbs 2nd
(5 mol %)
EtMgCl
THF
12
S
(2)
S
4
Pd-PEPPSI
SIPr 74%
ClCH2CH2Cl
rt, 18 h, 77%
-
1
3
1
4
Figure 1b shows an ORTEP diagram of X-ray structure analysis
of rac-7 showing the 10-membered macrocyclic E-olefin
Scheme 3. Preparation of metathesis precursor and ring-closing
metathesis of unsymmetrical (hetero)biaryls
1
5
involving bithiophene. Similar to the case of bisimidazole the
crystal structure was composed of an enantiopair of (R) and (S)
isomers. It was found that dihedral angle between the thiophene
Transformation reactions of the E-olefin in the macrocyclic
4
a
rings was 74.0°. Comparing with that of imidazole (47.8°)
bithiophene were examined. As revealed in our previous studies
4
b
bithiophene exhibited a more twisted structure because the
on the transformation of vine-shaped bisimidazoles, several
reactions shown to proceed in a cis-addition manner were found
to take place smoothly. Epoxidation proceeded with mCPBA to
2
carbon atom bearing a substituent was sp -hybridized whereas
3
4
nitrogen of imidazole, showing slightly sp -like characteristics,

afford the corresponding epoxide 15 in a quantitative yield. The
reaction of 7 with catalytic osmium/NMO also afforded the
dihydroxylation product 16 (90%). The obtained epoxide and
diol involve formation of diastereomers, however, HPLC and
NMR analyses of 15 and 16 only observed the single isomers
suggesting that the reactions proceeded in diastereoselective
manners. (Scheme 4)
Table 2. Ring-closing metathesis of bithiophene 1.a)
R
R
Mo cat./L*
benzene
Substrate
Ligand
L1
L2
L3
L1
L3
L4
L3
L4
Product Conv. (%)[b]
%ee[c]
0
0
OH
1
7
81
86
86
14
78
77
71
67
cat. K2OsO4•10H2O
(
R=H)
NMO
OH
S
S
S
S
0
90%
7
9
11
14
82
42
61
67
87
16
(
R=CH
3
)
)
1
3
O
mCPBA
99%
(R=CH
3
S
S
>
a) The reaction of substrate (0.1 mmol) was carried out for 12 h
in anhydrous benzene (2 mL) in the presence of 10 mol %
molybdenum complex 17 and 10 mol % chiral ligand. b) The
15
Scheme 4. Transformation of the olefin moiety of bithiophene 7
1
conversion was determined by H NMR analysis of the crude
Enantioselective RCM of bithiophene derivative was studied
with a molybdenum-alkylidene complex in the presence of a
chiral ligand composed of axially chiral biphenol or binaphthol
mixture. c) Enantiomeric excess was determined by HPLC
bearing a chiral stationary phase column Daicel Chiralpak IC.
5
, 17
derivatives.
The reaction was carried out with bithiophene 1
3. Conclusion
with 10 mol % Mo precursor 17 and 10 mol % chiral ligand L
In summary, we have shown that bithiophene derivatives
with winding vine-shaped molecular asymmetry are synthesized
by ring-closing metathesis catalyzed by ruthenium or
molybdenum complex. The obtained bithiophene was confirmed
to be separated by HPLC with chiral column and X-ray crystal
structure analysis of 7 revealed the selective formation of E-
alkene and the dihedral angle between thiophene-thiophene bond
was 74°, which was larger than that of the related bisimidazole
(48°). Asymmetric metathesis (ARCM) was found to proceed in
the reaction of unsymmetrical substrate, which lead to
trisubstituted olefin, with chiral molybdenum catalyst in
moderate to good enantioselectivities albeit the determination of
(
Chart 1), which were mixed to generate the chiral complex in
1
8, 19
situ, in a benzene solution.
Several chiral ligands were
examined, however, asymmetric induction was not observed in
the RCM reaction with L1-L3 as a ligand whereas the reaction
proceeded smoothly. When 9 with unsymmetrical-structure-
forming trisubstituted olefin 11 was employed as a metathesis
precursor, a good enantioselectivity was observed albeit with
much lower conversion with Mo/L1 catalyst (82% ee, 14%
conv.). The yield of the RCM product was improved with chiral
ligand L3 or L4 (78% and 77% yields, respectively) with slightly
inferior selectivities (42% ee and 61% ee). It is interesting to
compare the observed selectivity in ARCM with asymmetric
synthesis of planer-chiral cyclic amide by palladium-catalyzed
2
1
the absolute configuration has not been successful yet.
2
0
allylic substitution shown by Tomooka and co-workers, in
which the presence of a substituent at the olefinic moiety plays
a significant role to show excellent asymmetric induction. It was
also found that biaryl composed of thiophene and benzene 13
effected the reaction to afford the metathesis product 14 in an
excellent enantioselectivity with L3 (67% ee) and L4 (87% ee).
These results are summarized in Table 2.
4. Experimental
General. All the reactions were carried out with standard
Schlenk technique under nitrogen atmosphere unless otherwise
noted. Asymmetric ring-closing metathesis (ARCM) was carried
out in the glove box and anhydrous benzene employed for the
reaction was freshly distilled prior to use. X-ray structure
analysis was performed by Rigaku Saturn CCD area detector
with graphite monochromated Mo- radiation at Japan Atomic
Energy Agency. High resolution mass spectra (HRMS) were
measured by JEOL JMS-T100LP AccuTOF LC-Plus (ESI) with
a JEOL MS-5414DART attachment. HPLC analyses with a
chiral column was carried out with JASCO LC-2000 Plus with
chiral column Daicel Chiralpak IF or IC (0.46 cm I.D. x 25 cm,
flow rate: 1.0 mL/min) using UV (297 nm) detector. Benzene
was distilled from sodium benzophenone ketyl prior to use.
Unless otherwise specified, other chemicals were purchased and
used as such.
tBu
tBu
Ar
iPr
OH
OH
OH
OH
OH
OH
iPr
Me
N
N
N
Mo
Ph
Me
tBu
tBu
Ar
1
7
L1
L2
Ar = C H -3,5-(CF )
3 2
6
3
(L3)
Ar = C6F (L4)
5
3
-(3-Oxo-propan-1-yl)thiophene (3): A solution of thiophene-
3-boronic acid pinacol ester (2, 6.0 g, 29 mmol), acrolein (1.23
g, 22 mmol) , [Rh(OH)cod] (200 mg, 0.6 mmol), xantphos (380
Chart 1. Molybdenum-alkylidene precursor 17 and chiral
ligands L
2
mg, 0.9 mmol). The mixture was dissolved in methanol (5.5 mL),
water (5.5 mL), and toluene (110 mL) was stirred at 50 °C under
nitrogen atmosphere. After cooling to room temperature, the
reaction mixture was poured into water and the organic phase
was separated. Aqueous was extracted with diethyl ether. The
combined organic layer was washed with water twice and dried
over anhydrous sodium sulfate. The solvent was removed under
reduced pressure to leave a crude oil, which was subjected to

1
silica-gel chromatography to afford 3 (2.8 g, 91%), which was
3
(88% yield). H NMR (300 MHz, CDCl ) δ 1.62-1.74 (m, 2H),
identical with the authentic sample and employed directly for the
2.27-2.35 (m, 2H), 2.50 (td, J = 13.1, 2.8 Hz, 2H), 2.75 (ddd, J
= 13.1, 4.6, 2.8 Hz, 2H), 4.37-4.52 (m, 2H), 6.89 (d, J = 5.2 Hz,
2H), 7.26 (d, J = 5.2 Hz, 2H); C NMR δ 28.50, 34.23, 124.90,
9
a
next reaction without further purification.
-Bromo-3-(3-buten-1-yl)thiophene (4): To a solution of 3 (1.0
g, 7.2 mmol) in 30 mL THF were added N-bromosuccinimide
1.28 g, 7.2 mmol) in five portions with 1 h interval at 0 °C under
1
3
2
129.48, 129.83, 131.54, 140.92; IR (ATR) 2925, 2854, 1457,
-
1
(
1439, 1227, 1185, 1053, 969, 877, 827, 726, 657 cm ; HRMS
+
nitrogen atmosphere. After completion of the reaction was
confirmed, the resulting mixture was poured into water to result
in phase separation. The aqueous layer was extracted with
diethyl ether twice and the combined organic layer was dried
over anhydrous sodium sulfate. After removal of the solvent, the
obtained crude oil was passed through a silica-gel column using
hexane/ethyl acetate as an eluent to afford 1.41 g of the
corresponding bromide (90%), which was employed for the
following reaction. Asolution of methyl(triphenyl)phosphonium
iodide (3.1 g, 7.8 mmol) in THF (70 mL) was cooled to -78 °C
under nitrogen atmosphere. An equimolar amount of nBuLi (1.6
M hexane solution) was added to the solution dropwise and
further stirring was continued for 3 h. To the resulting mixture
was added the obtained bromothiophene (1.4 g, 6.5 mmol) at -
(DART-ESI+) Calcd for C14
m/z 247.0610.
H
15
S
2
[M+H] : 247.0615; found:
Preparation of 1 by oxidative homocoupling with CuCl
2
: To
a solution of 4 (130 mg, 0.6 mmol) was added EtMgCl (0.93 M
THF solution, 0.77 mL, 0.72 mmol) dropwise and the resulting
solution was stirred at 60 °C for 3 h. CuCl ･2H O (102 mg, 0.6
2 2
mmol), THF (2 mL) and TMEDA (0.09 mL, 0.6 mmol) were
then added to the mixture and further stirring was continued at
60 °C for 20 h. After cooling to room temperature, the mixture
was passed through a Celite pad, which was washed with
chloroform repeatedly. The filtrate was poured into water and the
aqueous layer was extracted with diethyl ether. The combined
organic layer was washed with water twice and dried over
anhydrous sodium sulfate. Removal of the solvent left a crude
oil, which was purified by column chromatography on silica gel
using hexanes as an eluent to afford 50 mg of 1 (70%).
7
8 °C. The mixture was gradually raised to room temperature
and stirring was further continued for 20 h. The mixture was
poured into water to result in phase separation. The aqueous
layer was extracted with diethyl ether twice and the combined
organic layer was dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure to leave a crude oil,
which was purified by column chromatography on silica gel
using hexanes as an eluent to afford 0.77 g of 4, which was
3-(3-Buten-1-yl)-3’-(3-methyl-3-buten-1-yl)-2,2'-bithiophene
(9): Preparation of 9 was carried out with 4 and 8 (0.67 g, 1.7
mmol), which was prepared by the reaction of 6 and
methallymagnesium chloride, in a similar manner to that of 4 to
1
afford 0.33 g of 9 as a colorless liquid (67% yield). H NMR
3
(500 MHz, CDCl ) δ 1.70 (s, 3H), 2.25-2.38 (m, 4H), 2.63-2.73
1
0
identical with the authentic sample (55%).
(m, 4H), 4.70 (d, J = 22.7 Hz, 2H), 4.96 (d, J = 10.3 Hz, 1H),
5.02 (d, J = 17.1 Hz, 1H), 5.81 (ddt, J = 17.1, 10.3, 6.5 Hz, 1H),
Preparation of 2-bromo-3-(3-buten-1-yl)thiophene (4) was also
carried out with 3-methylthiophene (5) by sequential ionic and
radical bromination with NBS and NBS/AIBN to give 2-bromo-
1
3
7.00 (d, J = 5.2 Hz, 2H), 7.29 (d, J = 5.2 Hz, 2H); C NMR δ
22.53, 27.30, 28.34, 34.79, 38.77, 110.43, 115.07, 125.54,
125.55, 128.55, 128.56, 128.89, 129.02, 137.99, 141.34, 141.63,
145.13; IR (ATR) 3073, 2925, 2853, 1649, 1448, 1374, 1231,
3
-bromomethyl-thiophene
(6)
and
treatment
with
allymagnesium chloride to give 4 was performed in a manner
1
0
-1
reported previously.
-[(3-Buten-1-yl)thiophene-2-yl]-3-(3-buten-1-yl)thiophene
1): To a 50 mL Schlenk tube equipped with a magnetic stirring
1091, 995, 912, 829, 723, 647 cm ; HRMS (DART-ESI+) Calcd
+
2
(
for C17
H
21
S
2
[M+H] : 289.1085; found: m/z 289.1086.
2-[3-(3-Buten-1-yl)thiophene-2-yl)]-1-(3-methyl-3-buten-1-
yl)benzene (13): Preparation of 13 with 4 (0.43 g, 2 mmol) and
2-bromo-1-(3-methyl-3-buten-1-yl)benzene (12, 0.50 g, 2.2
mmol), which was prepared by the reaction of 1-bromo-2-
(bromomethyl)benzene and methallymagnesium chloride, was
bar was dissolved 2-bromo-3-(3-buten-1-yl)-thiophene (4) (2.16
g, 10.0 mmol) in 15 mLTHF under N2, Ethylmagnesium chloride
(
0.95 M THF solution: 5.26 mL, 5.0 mmol) was added dropwise
and stirring was continued at room temperature for 2 h.
NiCl (PPh )IPr (78 mg, 0.1 mmol) was added to the resulting
2
3
carried out in a similar manner to that of 4 to afford 0.41 g of 13
1
mixture, which was stirred at 60 ºC for 20 h. After cooling to
room temperature, the mixture was poured into water to separate
into two phases. The aqueous layer was extracted with diethyl
ether. The combined organic layer was washed with water twice
and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure to leave a crude oil, which was
purified by chromatography on silica gel using hexane as an
(74%). H NMR (300 MHz, CDCl
3
) δ 1.62 (s, 3H), 2.13-2.31 (m,
4H), 2.47 (dd, J = 9.5, 8.5 Hz, 2H), 2.60-2.70 (m, 2H), 4.62 (d,
J =17.1, 2H), 4.90 (d, 10.2 Hz, 1H), 4.94 (d, 16.2 Hz, 1H), 5.74
(ddt, J = 17.1, 10.2, 6.6 Hz, 1H), 6.98 (d, J = 5.13 Hz, 1H), 7.26
(d, J = 5.2 Hz, 1H), 7.20-7.24 (m, 1H), 7..26 (d, J = 5.2 Hz, 1H),
1
3
7.28-7.33 (m, 2H) ; C NMR δ 22.44, 28.22, 32.03, 34.72, 39.46,
110.27, 115.03, 123.94, 125.68, 128.07, 128.46, 129.16, 132.02,
133.39, 126.68, 138.13, 138.65, 142.29, 145.49; IR (ATR) 3071,
1
eluent to afford 0.85 g of 1 as a colorless liquid (63% yield). H
-
NMR (300 MHz, CDCl
t, J = 8.7 Hz, 4H), 4.93 (d, J = 11.5 Hz, 2H), 4.98 (d, J = 17.1
Hz, 2H), 5.71-5.85 (m, 2H), 6.98 (d, J = 5.2 Hz, 2H), 7.29 (d, J
3
) δ 2.29 (dt, J = 2.3, 7.2 Hz, 4H), 2.61
2967, 2933, 2852, 1948, 1450, 912, 889, 835, 756, 723, 647 cm
1
+
(
23 1
; HRMS (DART-ESI+) Calcd for C19H S [M+H] : 283.1521;
found: m/z 283.1514. The product contains a trace amount of
inseparable impurities despite attempted purifications. Thus,
crude 13 was employed for the metathesis reaction.
Ring-closing-metathesis reactions with a ruthenium catalyst
were carried out in a similar to that forming 7. The reaction with
a molybdenum catalyst was carried out in a glove box with the
1
3
=
5.2 Hz, 2H); C NMR δ 28.34, 34.76, 115.08, 125.55, 128.56,
1
1
29.02, 137.96, 141.38; IR (ATR) 3076, 2922, 2851, 1640, 1448,
-
1
412, 1232, 1089, 994, 912, 831, 724 cm ; HRMS (DART-
+
ESI+) Calcd for C16
75.0939.
19 2
H S [M+H] : 275.0928; found: m/z
2
Cyclodeca[2,1-b:3,4-b’]dithieno-7-(E)-ene (7): To a solution
of 3,3'-bis(3-buten-1-yl)-2,2'-bithiophene (4) (1.01 g, 3.7 mmol)
in 150 mL of dichloromethane was added Grubbs 1st generation
catalyst (0.30 g, 0.37 mmol) under nitrogen atmosphere and
stirring was continued at room temperature for 5 h. The solvent
was removed under reduced pressure to leave a crude solid,
which was purified by chromatography on silica gel using
hexanes as an eluent to afford 0.80 g of 7 as a colorless solid.
metathesis
precursor
(0.1
)[OC(CF
mmol)
2
Me] ,
and
2
(2,6-iPr -
C
6
H
3
)N=Mo(=CHCPhMe
2
3
)
2
(10 mol%) in
anhydrous benzene (2 mL). The conversion was monitored by
1
measurement of
characterization and analytical data were shown below.
7-Methyl-cyclodeca[2,1-b:3,4-b’]dithieno-7-(E)-ene (11): H
NMR (500 MHz, CDCl ) δ 0.87 (s, 3H), 1.84 (td, J = 11.9, 3.7
Hz, 1H), 2.00-2.15 (m, 2H), 2.21 (ddd, J = 12.1, 3.6 Hz, 1H),
H
NMR spectrum. Spectroscopic
1
3

2
1
5
7
2
1
2
8
.54 (td, J = 12.8, 3.9 Hz, 1H), 2.67-2.78 (m, 2H), 2.81 (dt, J =
3.0, 3.6 Hz, 1H), 4.23 (dd, J = 10.7, 4.7 Hz, 1H), 6.90 (d, J =
.1 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 7.23 (d, J= 5.1 Hz, 1H),
box. To the resulting solution was added chiral ligand L1 (2.4
mg, 0.0058 mmol) and further stirring was continued at room
temperature for 0.5 h followed by addition of metathesis
precursor (0.1 mmol). The reaction mixture was stirred at room
temperature for 12 h. The test tube was taken out of the glove
box and acetone (2.0 mL) was added to quench the reaction. The
mixture was passed through a short path silica gel column. The
solution was concentrated under reduced pressure to leave a oil,
1
3
3
.27 (d, J = 5.1 Hz, 1H); C NMR (125 MHz, CDCl ) δ 14.18,
7.12, 28.42, 29.51, 41.84, 123.63, 124.95, 125.14, 129.84
30.00, 131.19, 131.48, 134.01, 141.36, 141.83; IR (ATR) 2924,
857, 1444, 1408, 1383, 1233, 1193, 1088, 1067, 1016, 998, 878,
-
1
34, 817, 772, 725, 691, 675, 656, 645 cm ; HRMS (DART-
+
1
ESI+) Calcd for C15
H
17
S
2
[M+H] : 261.0784; found: m/z
which was subjected to measurement of H NMR spectrum to
2
7
61.0772.
-Methyl-cyclodeca[2,1-b]thieno-[3,4]benzo-7-(E)-ene (14):
estimate conversion . The enantioselectivity was measured by
HPLC analysis with a chiral column (Daicel Chiralpak IC or IF)
using hexane as an eluent.
1
H NMR (300 MHz, CDCl
3
) δ 0.85 (s, 3H), 1.88 (td, J = 12.3,
2
.4 Hz, 1H), 2.01-2.10 (m, 2H), 2.25-2.38 (m, 2H), 2.64 (ddd, J
=
12.6, 5.3, 2.3 Hz, 1H), 2.76 (dt, J = 12.9, 3.5 Hz, 1H), 3.07 (td,
Acknowledgement
J = 128, 2.2 Hz, 1H), 4.09-4.19 (m, 1H), 6.92 (d, J = 5.1, 1H),
.07 (dd, J = 7.5,1.3, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.18 -7.33
This work was supported by KAKENHI by JSPS
(Exploratory Research no. 24655083), Cooperative Research
Program from Catalysis Research Center, Hokkaido University
(Grant no. 13A1001), and Special Coordination Funds for
Promoting Science and Technology, Creation of Innovation
Centers for Advanced Interdisciplinary Research Areas
(Innovative Bioproduction Kobe). We thank Dr. Yuji Suzaki of
Tokyo Institute of Technology for valuable discussion on X-ray
crystal structure analysis and Kei Miyamura for the illustration
of morning glory in toc.
7
1
3
(m, 4H); C NMR (500 MHz, CDCl
3
) δ 14.63, 28.38, 29.52,
3
1
2
8
2.03, 43.04, 122.44, 123.46, 125.97, 128.37, 129.97, 131.11,
31.75, 134.65, 136.28, 138.14, 139.82, 142.93. IR (ATR) 3060,
925, 2859, 1483, 1447, 1382, 1233, 1106, 1016, 1016, 967, 878,
-
1
38, 754, 721, 660, 646, 589 cm ; HRMS (DART-ESI+) Calcd
+
for C17
H
19S [M+H] : 255.1208; found: m/z 255.1211.
Epoxidation of macrocyclic alkene 7: To a solution of 7 (24.6
mg, 0.1 mmol) in 1 mL of CHCl and 1 mL of saturated NaHCO
3
3
aq. was added m-chloroperbenzoic acid (51.7 mg, 0.3 mmol) at
room temperature. The resulting mixture was allowed to stir at
References
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CHCl and the combined organic layer was dried over anhydrous
1.
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3
sodium sulfate. The organic layer was washed with water twice
and dried over anhydrous sodium sulfate. Removal of the solvent
under reduced pressure left a crude solid, which was purified by
column chromatography on silica gel using hexane/isopropyl
acetate (10:1) as an eluent to afford 27.4 mg of epoxide 15 as a
colorless solid (>99% yield). H NMR (300 MHz, CDCl
2.
3.
1
3
) δ
0
2
.88-1.02 (m, 2H), 2.00 (dt, J = 11.6, 2.2 Hz, 2H), 2.26-2.36 (m,
H), 2.69-2.87 (m, 4H), 6.91 (d, J = 5.2 Hz, 2H), 7.31 (d, J = 5.2
1
3
Hz, 2H). C NMR δ 24.16, 33.94, 57.94, 126.04, 129.33, 129.63,
1
1
6
42.35; IR (ATR) 2963, 2923, 2856, 1469, 1444, 1413, 1236,
215, 1093, 1042, 1023, 984, 906, 863, 854, 822, 797, 782, 732,
-
1
15 2
91, 677, 660 cm ; HRMS (DART-ESI+) Calcd for C14H S O
+
[
M+H] : 263.0564; found: m/z 263.0572.
Dihydroxylation of macrocyclic alkene 7: To a solution of 7
24.6 mg, 0.1 mmol) in 1 mL of acetone and 0.5 mL of water was
added OsO (1.6 mg, 0.005 mmol) and N-methylmorpholine-N-
(
4.
4
oxide (20 µL, 0.12 mmol) at room temperature. The resulting
mixture was allowed to stir at room temperature for 1 week. The
reaction mixture was poured into water and two phases were
separated. Aqueous was extracted twice with CHCl3. The organic
layer was washed with water twice and dried over anhydrous
sodium sulfate. Removal of the solvent under reduced pressure
5.
6.
left
chromatography on silica gel using hexane/isopropyl acetate
50:50-0:100) as an eluent to afford 31 mg of diol 16 as a
a
crude solid, which was purified by column
(
1
colorless solid (90% yield). H NMR (300 MHz, CDCl
1
1
3
) δ 1.70-
.82 (m, 4H), 1.95 (brs, 2H), 2.33-2.44 (m, 2H), 2.68 (dt, J =
4.3, 4.2 Hz, 2H), 3.39 (brs, 2H), 6.95 (d, J = 5.2 Hz, 2H), 7.36
1
3
(d, J = 5.2 Hz, 2H); C NMR δ 24.31, 33.43, 66.47, 127.14,
1
9
27.87, 129.10, 142.39; IR (ATR) 3384, 2923, 1445, 1157, 1069,
-
1
99, 979, 886, 833, 729, 679, 647 cm ; HRMS (DART-ESI+)
+
17 2 2
Calcd for C14H S O [M+H] : 281.0670; found: m/z 281.0666.
Typical procedure for enantioselective RCM catalyzed by
chiral molybdenum carbene complex 17 representative as
the case of L1: Molybdenum complex 17 (3.1mg, 0.0058 mmol)
was dissolved in 1.0 mL anhydrous benzene in a 10 mL screw-
capped test tube equiped with a magnetic stirring bar in a glove
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2
528.

Graphical Abstract
Title>
<
Bithiophene with Winding Vine-shaped Molecular Asymmetry. Preparation, Structural Characterization, and Enantioselective
Synthesis
<
Authors' names>
1
1
1
1
1
1
2
Yuka Toyomori, Satoru Tsuji, Shinobu Mitsuda, Yoichi Okayama, Shiomi Ashida, Atsunori Mori *, Toru Kobayashi, Yuji
Miyazaki, Tsuyoshi Yaita, Sachie Arae, Tamotsu Takahashi, and Masamichi Ogasawara
2
2
3
3
3,4
*
<Summary>
The reaction of bithiophene bearing 3-butenyl substituents 1 with 5 mol % Grubbs 1st generation catalyst underwent ring-closing
metathesis (RCM) to afford the cyclized product 7 showing winding vine-shaped molecular asymmetry in up to 88% yield.
Enantioselective RCM was also achieved by the use of chiral Schrock-Hoveyda molybdenum-alkylidene catalyst in up to 87% ee.
<Diagram>