Synthesis of 3,4-Ethylenedioxythiophene (EDOT) from (Z)-but-2-ene-1,4-diol or but-2-yne-1,4-diol

Article abstract of DOI:10.3987/COM-10-S(E)16

3,4-Ethylenedioxythiophene (EDOT) was synthesized from commercially available (Z)-but-2-ene-1,4-diol or but-2-yne-1,4-diol using epoxidation, etherification, and thiophene formation. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)16

HETEROCYCLES, Vol. 82, No. 1, 2010
449
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 449 - 460. © The Japan Institute of Heterocyclic Chemistry
Received, 1st April, 2010, Accepted, 14th May, 2010, Published online, 17th May, 2010
DOI: 10.3987/COM-10-S(E)16
SYNTHESIS OF 3,4-ETHYLENEDIOXYTHIOPHENE (EDOT) FROM
(Z)-BUT-2-ENE-1,4-DIOL OR BUT-2-YNE-1,4-DIOL
Iwao Hachiya,a Tomohiro Matsumoto,a Tatsuhiko Inagaki,a Atsushi
Takahashi, a,b and Makoto Shimizua,*
a Department of Chemistry for Materials, Graduate School of Engineering, Mie
University, Tsu, Mie 514-8507, Japan. E-mail: mshimizu@chem.mie-u.ac.jp.
b Takemoto Oil & Fat Co., Ltd., Gamagori, Aichi 443-0036, Japan
Abstract – 3,4-Ethylenedioxythiophene (EDOT) was synthesized from
commercially available (Z)-but-2-ene-1,4-diol or but-2-yne-1,4-diol using
epoxidation, etherification, and thiophene formation.
INTRODUCTION
Poly(3,4-ethylenedioxythiophene) (PEDOT) prepared by polymerization of 3,4-ethylenedioxythiophene
(EDOT (1)) and its derivatives are one of the most successful conducting polymers and widely used as
antistatic treatment of plastics and electrode materials for solid state electrolyte capacitors because they
have properties such as high conductivity with excellent stability, relatively high transparency to visible
light, and aqueous processability of the poly(styrene sulfonic acid)-doped form.1 The most general
synthetic route toward EDOT (1) is the double Williamson etherification of
3,4-dihydroxy-2,5-thiophenedicarboxylic acid esters, which are prepared from thiodiglycolic acid
(Scheme 1).2 The method has some drawbacks such as use of a carcinogenic reagent (1,2-dihaloethane),
use of heavy metals (copper chromite), and high temperature (in quinoline at 180 oC). On the other hand,
Reynolds et al. and Bäuerle et al. respectively reported efficient syntheses of EDOT (1) and substituted
EDOTs by Mitsunobu reaction of 3,4-dihydroxy-2,5-thiophenedicarboxylic acid ethyl ester with several
diols as a key step.3 However, the latter methods also used heavy metals (copper chromite or
CuCO3/Cu(OH)2) in decarboxylation step. Therefore, the development of alternative methods for the
synthesis of EDOT (1) is highly desirable.4 Herein, we report new synthetic routes to EDOT (1) starting
from (Z)-but-2-ene-1,4-diol or but-2-yne-1,4-diol.
-----------------------------------
This paper is dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 1, 2010
(CO2Et)2
NaOMe
NaO
ONa
H2SO4, MeOH
reflux,16 h
HO2C
S
CO2H
MeO2C
S
CO2Me
MeOH, reflux, 1 h
MeO2C
CO2Me
S
O
O
O
O
copper chromite
quinoline, 180 oC
ClCH2CH2Cl
reflux, 2 days
1) 10% NaOH
2) 1 M HCl
MeO2C
HO2C
CO2Me
CO2H
S
S
O
O
O
O
Electropolymerization or
FeCl3 polymerization
O
O
S
S
n
S
S
S
O
O
O
O
1: EDOT
PEDOT
Scheme 1. Synthesis of EDOT (1) and PEDOT
RESULTS AND DISCUSSION
Scheme 2 shows our synthetic plan for EDOT (1): EDOT (1) could be obtained by dehydrogenation of
tetrahydrothiophene (2), tetrahydrothiophene (2) from 1,4-diol (3), 1,4-dioxane ring by ring-opening of
oxirane (6) with 2-bromoethanol (7) followed by intramolecular etherification, and the oxirane (6) from
commercially available (Z)-but-2-ene-1,4-diol (8).
O
O
O
O
O
O
O
O
HO
OH
BnO
HO
OBn
OH
S
1: EDOT
S
2
3
4
8
Br
O
HO
BnO
O
BnO
OBn
OBn
6
5
+
Br
HO
7
Scheme 2. Retro-synthetic Analysis of EDOT (1)
First, benzylation of (Z)-but-2-ene-1,4-diol (8) was carried out with benzyl bromide under the reaction
conditions shown in entry 1 (Table 1) to give (Z)-1,4-dibenzyloxybut-2-ene (9) in 50% yield.5 In order to

HETEROCYCLES, Vol. 82, No. 1, 2010
451
improve the yield, the reaction time A and B were investigated in detail. When disodium salt of
(Z)-but-2-ene-1,4-diol (8) was prepared for 6 h followed by benzylation with benzyl bromide for 13 h,
dibenzyl ether (9) was obtained in 95% yield (entry 4).
Table 1. Synthesis of (Z)-1,4-Dibenzyloxybut-2-ene (9)
1) NaH (2.4 equiv)
THF, reflux, time A
HO
OH
BnO
OBn
2) BnBr (2.4 equiv)
THF, reflux, time B
8
9
Entry
Time A (h)
Time B (h)
Yield (%)a
1
1
2
8
6
16
15
6
50
62
74
95
2
3
4
13
a Isolated yield.
We next examined the epoxidation of the (Z)-1,4-dibenzyloxybut-2-ene (9) with m-CPBA.6 Table 2
summarizes the results. The epoxidation reaction of (Z)-1,4-dibenzyloxybut-2-ene (9) with m-CPBA (1.1
equiv) for 17 h gave (2R*,3S*)-2,3-bis((benzyloxy)methyl)oxirane (6) in 86% yield (entry 1). When the
epoxidation reaction with m-CPBA (1.2 equiv) was carried out for 24 h, the oxirane (6) was obtained in
91% yield (entry 2). Increasing the amounts of m-CPBA decreased the yields of oxirane (6) (entries 3 and
4).
Table 2. Synthesis of (2R*,3S*)-2,3-Bis((benzyloxy)methyl)oxirane (6)
O
m-CPBA
BnO
OBn
BnO
OBn
CH2Cl2, 0 oC ~ rt, time
9
6
Entry
m-CPBA (equiv)
Time (h)
Yield (%)a
1
1.1
1.2
1.5
2.3
17
24
24
24
86
91
67
56
2
3
4
a Isolated yield.

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HETEROCYCLES, Vol. 82, No. 1, 2010
Br
(1.1 equiv)
7
BF3·OEt2 (10 mol%)
HO
Br
O
KOH (1.0 equiv)
O
O
HO
BnO
O
CH2Cl2, rt, 16 h
EtOH, reflux, 6 h
67% (2 steps)
BnO
OBn
BnO
OBn
OBn
6
5
4
10% Pd/C (0.2 equiv)
H2 (1 atm)
0.1 M HCl aq (0.1 equiv)
MsCl (4.0 equiv)
Et3N (4.0 equiv)
Na2S·9H2O (3.0 equiv)
O
O
O
O
O
CH2Cl2, 0 oC, 5.5 h
92%
DMF, 50 oC, 17 h
78%
MeOH, rt, 4 h
96%
HO
OH
MsO
OMs
3
10
O
O
O
O
O
DDQ (2.0 equiv)
chlorobenzene, 80 oC, 6.0 h
21%
S
2
S
S
11
1: EDOT
Scheme 3. Synthesis of EDOT (1) via the trans-Tetrahydrothiophene Derivative (2)
BF3·OEt2 catalyzed ring-opening reaction of oxirane (6) with 2-bromoethanol (7) proceeded to give crude
(2R*,3R*)-3-(2-chloroethoxy)-1,4-bis(benzyloxy)butan-2-ol (5),7 and subsequent intramolecular
etherification of the crude alcohol (5) using KOH as a base in EtOH under reflux gave
2,3-bis(benzyloxymethyl)-1,4-dioxane (4) in 67% yield. Debenzylation of 4 by hydrogenation gave
(2R*,3R*)-2,3-bis(hydroxymethyl)-1,4-dioxane (3) in 96% yield,8 which in turn was mesylated to give
(2R*,3R*)-2,3-bis(methanesulfonyloxymethyl)-1,4-dioxane (10) in 92% yield. The reaction of the
bismesylate (10) with sodium sulfide nonahydrate (Na2S·9H2O) gave (3S*,4S*)-tetrahydro-
3,4-ethylenedioxythiophene (2) in 78% yield.9 Finally, dehydrogenation of the tetrahydrothiophene
derivative (2) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave EDOT (1) in 21% yield
(Scheme 3). However, the yield was not satisfied in the last dehydrogenation step. We next examined an
alternative synthesis from cis-tetrahydrothiophene derivative (11). The cis-tetrahydrothiophene derivative
(11) could be synthesized from (E)-but-2-ene-1,4-diol (13) instead of (Z)-but-2-ene-1,4-diol (8). Scheme
4 shows the synthetic route to the cis-derivative (11). Reduction of commercially available
but-2-yne-1,4-diol (12) by LiAlH4 gave (E)-but-2-ene-1,4-diol (13) in 79% yield.10 The
cis-tetrahydrothiophene derivative (11) was synthesized from (E)-but-2-ene-1,4-diol (13) in a similar
manner to the trans-derivative (2). Dehydrogenation of the cis-derivative (11) using DDQ gave EDOT (1)
in 40% yield (53% conversion yield) along with the recovered 11 in 23 % yield.

HETEROCYCLES, Vol. 82, No. 1, 2010
453
1) NaH (2.4 equiv)
THF, reflux, 3.5 h
LiAlH4 (1.3 equiv)
OH
OH
HO
HO
THF, reflux, 2.0 h
79%
2) BnBr (2.4 equiv)
THF, reflux, 3.5 h
12
13
91%
Br
(1.1 equiv)
HO
7
O
m-CPBA (1.2 equiv)
BF3·OEt2 (10 mol%)
OBn
BnO
CH2Cl2, 0 oC ~ rt, 15 h
92%
CH2Cl2, rt, 10 h
BnO
OBn
14
15
10% Pd/C (0.2 equiv)
H2 (1 atm)
Br
KOH (5.2 equiv)
aq HCl (0.1 equiv)
O
O
HO
O
EtOH, reflux, 12 h
49% (2 steps)
MeOH, rt, 24 h
quant
BnO
MsO
OBn
OMs
BnO
OBn
16
18
17
19
MsCl (4.0 equiv)
Et3N (4.0 equiv)
Na2S·9H2O (2.5 equiv)
O
O
O
O
O
O
O
O
CH2Cl2, 0 oC to rt, 27 h
75%
EtOH, reflux, 12 h
46%
HO
OH
DDQ (2.0 equiv)
chlorobenzene, reflux, 9 h
40% (53% conversion yield)
S
S
11
1: EDOT
Scheme 4. Synthesis of EDOT (1) via the cis-Tetrahydrothiophene Derivative (11)
CONCLUSIONS
In conclusion, we have found a new synthetic route to 3,4-ethylenedioxythiophene (EDOT) via
ring-opening of oxiranes (6) or (15) with 2-bromoethanol (7) followed by intramolecular etherification of
bromo alcohols (5) or (16). The present method is an attractive synthetic route because several EDOT
derivatives11 can be synthesized using 2-bromo alcohol derivatives instead of 2-bromoethanol (7) in
ring-opening of oxirane (6) or (15).
EXPERIMENTAL
General: Infrared spectra were recorded on a JASCO FT/IR-460 Plus spectrometer. 1H NMR spectra were
recorded on a JEOL ECX-400 spectrometer (400 MHz) or a JEOL JNM !-500 spectrometer (500 MHz)
13
with tetramethylsilane as an internal standard. C NMR spectra were recorded on a JEOL ECX-400
spectrometer (100 MHz) or a JEOL JNM !-500 spectrometer (126 MHz). Chemical shifts are reported in

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HETEROCYCLES, Vol. 82, No. 1, 2010
! units, parts per million from the central peak of CDCl3 (! 77.0) as an internal reference. High resolution
mass spectra (EI) were recorded on a JEOL JMS-700D mass spectrometer. Purification of products was
performed by column chromatography on silica gel (Kanto Chemical Co. Inc., Silica Gel 60 N (spherical,
neutral)) and/or preparative TLC on silica gel (Merck Kiesel Gel GF254). All reactions were carried out
under an argon atmosphere except for debenzylation of (2R*,3R*)-2,3-bis(benzyloxymethyl)-1,4-dioxane
(4) by hydrogenation.
(Z)-1,4-Dibenzyloxybut-2-ene (9)5
Sodium hydride (11.0 g as a 60% dispersion in mineral oil, 272 mmol) was placed in a round-bottomed
flask and the mineral oil was removed by washing with hexane (30 mL, 20 mL and 30 mL). A solution of
(Z)-but-2-ene-1,4-diol (8) (10.0 g, 113 mmol) in THF (70 mL) was added to the flask at 0 oC. The mixture
was stirred under reflux for 6 h. Benzyl bromide (47.0 g, 272 mmol) was added to the mixture. The
reaction mixture was stirred under reflux for 13 h and then cooled to room temperature. Water (200 mL)
was added to quench the reaction. The phases were separated and the aqueous phase was extracted with
Et2O (100 mL x 2). The combined organic extracts were washed with sat. aqueous NH4Cl (100 mL),
water (100 mL), and brine (100 mL), dried over sodium sulfate, and filtered. The solvents were
evaporated in vacuo and then the residue was purified by chromatography on silica gel (n-Hex/EtOAc =
8/1, as an eluent) to give (Z)-1,4-dibenzyloxybut-2-ene (9) (8.75 g, 95%) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 7.25-7.39 (m, 10H), 5.87-5.89 (m, 2H), 4.52 (s, 4H), 4.05 (dd, J = 1.4,
13
2.8 Hz, 4H). C NMR (100 MHz, CDCl3): ! = 138.1, 129.5, 128.4, 127.8, 127.6, 72.2, 65.8. IR (neat):
3087, 3063, 3028, 2855, 1496, 1454, 1383, 1361, 1329, 1247, 1203, 1090, 1028, 738, 670, 606 cm-1.
HRMS (EI): calcd. for C18H20O2 268.1463; [M+]; found for 268. 1455.
(2R*,3S*)-2,3-Bis((benzyloxy)methyl)oxirane (6)6
m-CPBA (8.29 g as a 77% wt% solid, 37.0 mmol) in CH2Cl2 (70 ml) was added to a solution of
o
(Z)-1,4-dibenzyloxybut-2-ene (8) (8.00 g, 29.8 mmol) in CH2Cl2 (30 mL) at 0 C. The reaction mixture
o
was warmed to room temperature, stirred for 24 h, and then cooled to 0 C. The reaction mixture was
filtered through a Celite pad to remove the precipitated m-chlorobenzoic acid and washed with sat.
aqueous NaHCO3 (100 mL), sat. aqueous Na2S2O3 (100 mL), and brine (100 mL), dried over sodium
sulfate, and filtered. The solvents were evaporated in vacuo and then the residue was purified by
chromatography on silica gel (n-Hex/EtOAc = 4/1, as an eluent) to give (2R*,3S*)-2,3-
bis((benzyloxy)methyl)oxirane (6) (7.72 g, 91%) as a colorless oil.
1H NMR (500 MHz, CDCl3): ! = 7.27-7.36 (m, 10H), 4.61 (d, J = 11.9 Hz, 2H), 4.51 (d, J = 11.9 Hz, 2H),
3.66-3.70 (m 2H), 3.50-3.55 (m, 2H), 3.24-3.27 (m, 2H). 13C NMR (ꢀꢁꢂ MHz, CDCl3): ! = 137.7, 128.4,

HETEROCYCLES, Vol. 82, No. 1, 2010
455
127.7, 73.2, 68.0, 54.4. IR (neat): 3087, 3063, 3030, 2998, 2998, 2860, 1496, 1454, 1368, 1325, 1254,
1205, 1096, 1028, 991, 948, 907, 853, 820, 768, 737, 698, 607 cm-1. HRMS (EI): calcd. for C18H20O3
284.1412; [M+]; found for 284. 1410.
(2R*,3R*)-2,3-Bis(benzyloxymethyl)-1,4-dioxane (4)
BF3·OEt2 (0.02 mL,
1
M
in CH2Cl2, 0.02 mmol) was added to
a
mixture of
(2R*,3S*)-2,3-bis((benzyloxy)methyl)oxirane (6) (60 mg, 0.21 mmol) and 2-bromoethanol (7) (30 mg,
0.23 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and then
concentrated in vacuo. To the residue including crude (2R*,3R*)-3-(2-bromoethoxy)-1,4-
bis(benzyloxy)butan-2-ol (5) in EtOH (5 mL) was added a solution of KOH (12 mg, 0.21 mmol) in EtOH
(5 mL) at room temperature. The reaction mixture was stirred under reflux for 6 h and then cooled to
room temperature. The reaction mixture was filtered through a Celite pad. The Celite pad and the
round-bottomed flask were rinsed with EtOAc. The solvents were evaporated in vacuo and then the
residue was purified by preparative TLC on silica gel (n-Hex/EtOAc = 4/1, as an eluent) to give
(2R*,3R*)-2,3-bis(benzyloxymethyl)-1,4-dioxane (4) (46.3 mg, 67%) as a pale yellow oil.1H NMR (500
MHz, CDCl3): ! = 7.22-7.34 (m, 10H), 4.54 (d, J = 12.2 Hz, 2H), 4.42 (d, J = 12.2 Hz, 2H), 3.62-3.80 (m,
6H), 3.50-3.55 (m 2H), 3.41-3.47 (m, 2H). 13C NMR (126 MHz, CDCl3): ! = 137.7, 128.2, 127.7, 127.5,
76.0, 73.4, 69.6, 66.7. IR (neat): 3064, 3029, 2997, 2859, 1496, 1454, 1367, 1326, 1253, 1204, 1096,
1028, 991, 948, 908, 849, 738, 698, 608 cm-1. HRMS (EI): calcd. for C20H24O4 328.1675 [M+]; found for
328.1672.
(2R*,3R*)-2,3-Bis(hydroxymethyl)-1,4-dioxane (3)
To 10% Pd/C (100 mg, 0.0940 mmol) was added a solution of (2R*,3R*)-2,3-bis(benzyloxymethyl)-
1,4-dioxane (4) (1.55 g, 4.72 mmol) in MeOH (30 mL) and 0.1 M HCl (4.7 mL, 0.47 mmol). The mixture
was stirred under H2 (1 atm) at room temperature for 4 h. The reaction mixture was filtered through a
Celite pad. The Celite pad and the round-bottomed flask were rinsed with MeOH. The solvents were
evaporated in vacuo and then the residue was purified by chromatography on silica gel (EtOAc, as an
eluent) to give (2R*,3R*)-2,3-bis(hydroxymethyl)-1,4-dioxane (3) (0.67 g, 96%) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 3.51-3.90 (m, 10H), 3.15 (brs, 2H). C NMR (100 MHz, CDCl3): ! =
13
76.8, 66.6, 62.5. IR (neat): 3416, 2961, 2919, 2861, 1449, 1371, 1267, 1120, 1078, 1009, 968, 908, 844,
790, 734, 650 cm-1. HRMS (EI): calcd. for C6H12O4 148.0736 [M+]; found for 148.0737.
(2R*,3R*)-2,3-Bis(methanesulfonyloxymethyl)-1,4-dioxane (10)
To a solution of (2R*,3R*)-2,3-bis(hydroxymethyl)-1,4-dioxane (3) (148 mg, 1.00 mmol) and Et3N (399

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HETEROCYCLES, Vol. 82, No. 1, 2010
o
mg, 3.94 mmol) in CH2Cl2 (5 mL) was added MsCl (459 mg, 4.01 mmol) at 0 C. The reaction mixture
was stirred at 0 oC for 5.5 h. Water (10 mL) was added to quench the reaction. The mixture was extracted
with CH2Cl2 (10 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30
mL), dried over sodium sulfate, and filtered. The solvents were evaporated in vacuo and then the residue
was purified by chromatography on silica gel (n-Hex/EtOAc = 2/1, as an eluent) to give
(2R*,3R*)-2,3-bis(methanesulfonyloxymethyl)-1,4-dioxane (10) (280 mg, 92%) as a white crystal.
Mp 103-104 oC. 1H NMR (400 MHz, CDCl3): ! = 4.33-4.39 (m, 4H), 3.71-3.91 (m, 6H), 3.08 (s, 6H). 13C
NMR (100 MHz, CDCl3): ! = 73.7, 68.2, 66.7, 37.6. IR (KBr): 3025, 3014, 2965, 2953, 2935, 2875, 1452,
1350, 1289, 1249, 1173, 1126, 1088, 1043, 985, 920, 849, 816, 754, 743, 640 cm-1. HRMS (EI): calcd. for
C8H16O8S2 304.0287 [M+]; found for 304.0280.
(3S*,4S*)- Tetrahydro-3,4-ethylenedioxythiophene (2)
To (2R*,3R*)-2,3-bis(methanesulfonyloxymethyl)-1,4-dioxane (10) (36 mg, 0.12 mmol) was added DMF
(3 mL) and sodium sulfide nonahydrate (Na2S·9H2O) (87 mg, 0.36 mmol) at room temperature. The
o
reaction mixture was stirred at 50 C for 17 h. H2O (10 mL) was added to quench the reaction. The
reaction mixture was filtered through a Celite pad. The Celite pad and the round-bottomed flask were
rinsed with EtOAc. The mixture was extracted with EtOAc (30 mL). The organic layers were washed
with brine (30 mL), dried over sodium sulfate, and filtered. The solvents were evaporated in vacuo and
then the residue was purified by chromatography on silica gel (n-Hex/EtOAc = 2/1, as an eluent) to give
(3S*,4S*)-tetrahydro-3,4-ethylenedioxythiophene (2) (13.5 mg, 78%) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 3.66-3.85 (m, 4H), 3.51-3.59 (m, 2H), 2.84-2.91 (m, 2H), 2.67-2.75 (m,
13
2H). C NMR (100 MHz, CDCl3): ! = 79.8, 66.4, 27.7. IR (neat): 2956, 2914, 2855, 1456, 1357, 1277,
1251, 1118, 1088, 985, 907, 875, 730, 629 cm-1. HRMS (EI): calcd. for C6H10O2S 146.0402 [M+]; found
for 146. 0403.
EDOT (1)12
To DDQ (45 mg, 0.20 mmol) was added a solution of (3S*,4S*)-tetrahydro-3,4-ethylenedioxythiophene
o
(2) (15 mg, 0.10 mmol) in chlorobenzene (5 mL) at room temperature. The mixture was stirred at 80 C
for 6 h and then cooled to room temperature. 10% Aqueous sodium hydrogen sulfite (10 mL) was added
to quench the reaction. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers
were washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL), dried over sodium sulfate, and
filtered. The solvents were evaporated in vacuo and then the residue was purified by chromatography on
silica gel (n-Hex/EtOAc = 1/1, as an eluent) to give EDOT (1) (3.0 mg, 21%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): ! = 6.32 (s, 2H), 4.19 (s, 4H). 13C NMR (100 MHz, CDCl3): ! = 141.6, 99.5,

HETEROCYCLES, Vol. 82, No. 1, 2010
457
64.5. IR (neat): 3111, 2983, 2924, 2872, 1484, 1446, 1421, 1367, 1272, 1247, 1186, 1136, 1057, 1022,
934, 891, 860, 833, 765 cm-1.
(E)-But-2-ene-1,4-diol (13)10
To a solution of LiAlH4 (0.59 g, 15.5 mmol) in THF (50 mL) was added a solution of but-2-yne-1,4-diol
o
(12) (1.02 g, 11.9 mmol) in THF (50 mL) at 0 C. The reaction mixture was stirred under reflux for 2 h
o
and cooled to 0 C. 3 M NaOH was added slowly to the reaction mixture until no gas evolution was
observed. The reaction mixture was then adjusted to a pH of 8; silica gel was added, and the solvent was
removed in vacuo. The free-flowing product/silica gel mixture was loaded on the top of a prepacked silica
gel column and flashed (n-Hex/EtOAc = 1/1, as an eluent) to give (E)-but-2-ene-1,4-diol (13) (0.83 g,
79%) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 5.89-5.91 (m, 2H), 4.17-4.19 (m, 4H), 1.63 (brs, 2H). C NMR (100
13
MHz, CDCl3): ! = 130.5, 62.9. IR (neat): 3338, 2924, 2870, 1709, 1658, 1451, 1420, 1370, 1279, 1222,
1085, 991, 889, 769, 663 cm-1. HRMS (EI): calcd. for C4H8O2 88.0524 [M+]; found for 88.0525.
(E)-1,4-Dibenzyloxybut-2-ene (14)
Sodium hydride (2.01 g as a 60% dispersion in mineral oil, 50.2 mmol) was placed in a round-bottomed
flask and the mineral oil was removed by washing with hexane (30 mL, 20 mL and 30 mL). A solution of
o
(E)-2-butene-1,4-diol (13) (1.84 g, 20.9 mmol) in THF (30 mL) was added to the flask at 0 C. The
mixture was stirred under reflux for 3.5 h. Benzyl bromide (8.59 g, 50.2 mmol) was added to the mixture.
The reaction mixture was stirred under reflux for 3.5 h and then cooled to room temperature. Water (100
mL) was added to quench the reaction. The phases were separated and the aqueous phase was extracted
with Et2O (100 mL x 2). The combined organic extracts were washed with sat. aqueous NH4Cl (100 mL),
water (100 mL), and brine (100 mL), dried over sodium sulfate, and filtered. The solvents were
evaporated in vacuo and then the residue was purified by chromatography on silica gel (n-Hex/EtOAc =
8/1, as an eluent) to give (E)-1,4-dibenzyloxybut-2-ene (14) (5.09 g, 91%) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 7.25-7.36 (m, 10H), 5.78-5.80 (m, 2H), 4.49 (s, 4H), 4.06 (dd, J = 0.9,
13
2.8 Hz, 4H). C NMR (100 MHz, CDCl3): ! = 138.2, 129.5, 128.4, 127.7, 127.6, 72.2, 70.1. IR (neat):
3087, 3063, 3029, 2923, 2852, 1496, 1454, 1387, 1362, 1310, 1250, 1204, 1109, 1072, 1028, 970, 736,
697, 607 cm-1. HRMS (EI): calcd. for C18H20O2 268.1463 [M+]; found for 268.1474.
(2R*,3R*)-2,3-Bis((benzyloxy)methyl)oxirane (15)
m-CPBA (4.87 g as a 77% wt% solid, 21.7 mmol) in CH2Cl2 (50 mL) was added to a solution of
o
(E)-1,4-dibenzyloxybut-2-ene (14) (5.05 g, 18.8 mmol) in CH2Cl2 (50 mL) at 0 C. The reaction mixture

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HETEROCYCLES, Vol. 82, No. 1, 2010
o
was warmed to room temperature, stirred at room temperature for 15 h, and then cooled to 0 C. The
reaction mixture was filtered through a Celite pad to remove the precipitated m-chlorobenzoic acid and
washed with sat. aqueous NaHCO3 (100 mL), sat. aqueous Na2S2O3 (100 mL), and brine (100 mL), dried
over sodium sulfate, and filtered. The solvents were evaporated in vacuo and then the residue was
purified by chromatography on silica gel (n-Hex/EtOAc = 4/1, as an eluent) to give (2R*,3R*)-2,3-
bis((benzyloxy)methyl)oxirane (15) (4.94 g, 92%) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 7.25-7.39 (m, 10H), 4.61 (d, J = 11.9 Hz, 2H), 4.55 (d, J = 11.9 Hz, 2H),
3.76 (dd, J = 2.8, 11.5 Hz, 2H), 3.51 (dd, J = 5.5, 11.5 Hz, 2H), 3.11-3.14 (m, 2H). 13C NMR (ꢀꢃꢃ MHz,
CDCl3): ! = 137.8, 128.4, 128.2, 127.7, 73.3, 69.8, 54.4. IR (neat): 3087, 3063, 3030, 2998, 2858, 1496,
1454, 1366, 1315, 1241, 1207, 1107, 1028, 937, 906, 874, 737, 698, 608 cm-1. C18H20O3 284.1412 [M+];
found for 284.1405.
(2R*,3S*)-2,3-Bis(benzyloxymethyl)-1,4-dioxane (17)
BF3·OEt2 (0.02 mL,
1
M
in CH2Cl2, 0.02 mmol) was added to
a
mixture of
(2R*,3R*)-2,3-bis((benzyloxy)methyl)oxirane (15) (60 mg, 0.21 mmol) and 2-bromoethanol (7) (30 mg,
0.23 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 h and then
concentrated in vacuo. To the residue including crude (2R*,3S*)-3-(2-bromoethoxy)-1,4-
bis(benzyloxy)butan-2-ol (16) in EtOH (5 mL) was added a solution of KOH (60 mg, 1.1 mmol) in EtOH
(5 mL) at room temperature. The reaction mixture was stirred under reflux for 12 h and then cooled to
room temperature. The reaction mixture was filtered through a Celite pad. The Celite pad and the
round-bottomed flask were rinsed with EtOAc. The solvents were evaporated in vacuo and then the
residue was purified by preparative TLC on silica gel (n-Hex/EtOAc = 4/1, as an eluent) to give
(2R*,3S*)-2,3-bis(benzyloxymethyl)-1,4-dioxane (17) (33.8 mg, 49%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): ! = 7.24-7.35 (m, 10H), 4.54 (d, J = 12.4 Hz, 2H), 4.50 (d, J = 12.4 Hz, 2H),
13
3.91-4.00 (m, 2H), 3.76-3.82 (m, 4H), 3.61-3.67 (m, 2H), 3.46-3.50 (m, 2H). C NMR (100 MHz,
CDCl3): ! = 137.8, 128.4, 127,7, 127.7, 74.0, 73.3, 67.2, 63.7. IR (neat): 3088, 3063, 3029, 2952, 2910,
2863, 1496, 1453, 1367, 1272, 1207, 1103, 1028, 909, 890, 737, 698, 610 cm-1. HRMS (EI): calcd. for
C20H24O4 328.1675 [M+]; found for 328.1691.
(2R*,3S*)-2,3-Bis(hydroxymethyl)-1,4-dioxane (18)
To 10% Pd/C (194 mg, 0.182 mmol) was added a solution of (2R*,3S*)-2,3-bis(benzyloxymethyl)-1,4-
dioxane (17) (2.99 g, 9.10 mmol) in MeOH (30 mL) and 0.1 M HCl (0.9 mL, 0.9 mmol). The mixture
was stirred under H2 (1 atm) at room temperature for 24 h. The reaction mixture was filtered through a
Celite pad. The Celite pad and the round-bottomed flask were rinsed with MeOH. The solvents were

HETEROCYCLES, Vol. 82, No. 1, 2010
459
evaporated in vacuo and then the residue was purified by chromatography on silica gel (EtOAc, as an
eluent) to give (2R*,3S*)-2,3-bis(hydroxymethyl)-1,4-dioxane (18) (1.35 g, quant) as a colorless oil.
1H NMR (400 MHz, CDCl3): ! = 3.63-3.88 (m, 10H), 2.43 (brs, 2H). C NMR (100 MHz, CDCl3): ! =
13
75.2, 63.7, 59.9. IR (neat): 3394, 2931, 2873, 1452, 1416, 1358, 1281, 1231, 1106, 1048, 1001, 953, 890,
862, 831, 795, 724, 675 cm-1. HRMS (EI): calcd. for C6H12O4 148.0736 [M+]; found for 148.0737.
(2R*,3S*)-2,3-Bis(methanesulfonyloxymethyl)-1,4-dioxane (19)
To a solution of (2R*,3S*)-2,3-bis(hydroxymethyl)-1,4-dioxane (18) (1.35g, 9.11 mmol) and Et3N (3.70 g,
o
36.6 mmol) in CH2Cl2 (30 mL) was added MsCl (4.20 g, 36.7 mmol) at 0 C. The reaction mixture was
warmed up to room temperature and then stirred at room temperature for 27 h. Water (100 mL) was
added to quench the reaction. The mixture was extracted with CH2Cl2 (50 mL x 3). The combined organic
layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and filtered. The
solvents were evaporated in vacuo and then the residue was purified by chromatography on silica gel
(n-Hex/EtOAc = 2/1, as an eluent) to give (2R*,3S*)-2,3-bis(methanesulfonyloxymethyl)-1,4-dioxane
(19) (2.08 g, 75%) as a white crystal.
Mp 109-112 oC. 1H NMR (400 MHz, CDCl3): ! = 4.45 (dd, J = 7.3, 11.0 Hz, 2H), 4.29 (dd, J = 4.6, 11.0
13
Hz, 2H), 4.07-4.13 (m, 2H), 3.86-3.92 (m, 2H), 3.68-3.74 (m, 2H), 3.08 (s, 6H). C NMR (126 MHz,
CDCl3): ! = 72.2, 65.4, 63.6, 37.8.ꢀIR (KBr): 3029, 2999, 2964, 2939, 2923, 2891, 2868, 1481, 1453,
1419, 1355, 1298, 1288, 1261, 1166, 1147, 1131, 1111, 1098, 1068, 1009, 987, 969, 912, 893, 874, 833,
811, 799, 766, 725 cm-1. HRMS (EI): calcd. for C8H16O8S2 304.0287 [M+]; found for 304.0287.
(3S*,4R*)-Tetrahydro-3,4-ethylenedioxythiophene (11)
To (2R*,3S*)-2,3-bis(methanesulfonyloxymethyl)-1,4-dioxane (19) (2.08 g, 6.83 mmol) was added EtOH
(40 mL) and sodium sulfide nonahydrate (Na2S·9H2O) (4.13 g, 17.1 mmol) at room temperature. The
reaction mixture was stirred under reflux for 12 h and then cooled to room temperature. The reaction
mixture was filtered through a Celite pad. The Celite pad and the round-bottomed flask were rinsed with
EtOAc. The mixture was extracted with EtOAc (50 mL). The solvents were evaporated in vacuo and then
the residue was purified by chromatography on silica gel (n-Hex/EtOAc = 2/1, as an eluent) to give
(3S*,4R*)-tetrahydro-3,4-ethylenedioxythiophene (11) (0.46 g, 46%) as a yellow oil.
1H NMR (400 MHz, CDCl3): ! = 4.16-4.20 (m, 2H), 3.82-3.88 (m 2H), 3.55-3.62 (m, 2H), 3.04-3.08 (m,
2H), 2.84-2.88 (m, 2H). 13C NMR (100 MHz, CDCl3): ! = 77.4, 62.8, 29.2. IR (neat): 2944, 2865, 1441,
1347, 1291, 1274, 1252, 1215, 1181, 1105, 1087, 1058, 1033, 1006, 925, 904, 870, 819, 754, 675, 629
cm-1. HRMS (EI): calcd. for C6H10O2S 146.0402 [M+]; found for 146. 0402.

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HETEROCYCLES, Vol. 82, No. 1, 2010
EDOT (1)
To DDQ (123 mg, 0.54 mmol) was added a solution of (3S*,4R*)-tetrahydro-3,4-ethylenedioxythiophene
(11) (40.0 mg, 0.27 mmol) in chlorobenzene (5 mL) at room temperature. The mixture was stirred under
reflux for 9 h and then cooled to room temperature. 10% Aqueous sodium hydrogen sulfite (10 mL) was
added to quench the reaction. The mixture was extracted with EtOAc (10 mL x 3). The combined organic
layers were washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL), dried over sodium sulfate,
and filtered. The solvents were evaporated in vacuo and then the residue was purified by chromatography
on silica gel (n-Hex/EtOAc = 9/1, as an eluent) to give EDOT (1) (15.3 mg, 40% (53% conversion yield))
as a pale yellow oil and the recovered (11) (9.1 mg, 23 %) as a yellow oil.
REFERENCES AND NOTES
1. For a review, see: L. Groenendaal, F. Jonas, D. Freitag, H. Pielartzik, and J. R. Reynolds, Adv.
Mater., 2000, 12, 481 and references therein.
2. Q. Pei, G. Zuccarello, M. Ahlskog, and O. Inganäs, Polymer, 1994, 35, 1347.
3. (a) K. Zong, L. Madrigal, L. Groenendaal, and J. R. Reynolds, Chem. Commun., 2002, 2498. (b) D.
Caras-Quintero, and P. Bäuerle, Chem. Commun., 2002, 2690.
4. Short step synthesis of EDOT via p-TsOH catalyzed transetherification of 3,4-dimethoxythiophene
with ethylene glycol, see: F. von Kieseritzky, F. Allared, E. Dahlstedt, and J. Hellberg, Tetrahedron
Lett., 2004, 45, 6049.
5. C.-Y. Chuang, V. C. Vassar, Z. Ma, R. Geney, and I. Ojima, Chirality, 2002, 14, 151.
6. A. Thurner, F. Faigl, L. Tóke, A. Mordini, M. Valacchi, G. Reginato, and G. Czira, Tetrahedron,
2001, 57, 8173.
7. G. Prestat, C. Baylon, M.-P. Heck, and C. Mioskowski, Tetrahedron Lett., 2000, 41, 3829.
8. J.-E. Goujon, D. Gueyrard, P. Compain, O. R. Martin, K. Ikeda, A. Kato, and N. Asano, Bioorg.
Med. Chem., 2005, 13, 2313.
9. J. Shiina, R. Obata, H. Tomoda, and S. Nishiyama, Eur. J. Org. Chem., 2006, 2362.
10. M. G. Organ, J. T. Cooper, L. R. Rogers, F. Soleymanzadeh, and T. Paul, J. Org. Chem., 2000, 65,
7959.
11. J. L. Segura, R. Gómez, E. Reinold, and P. Bäuerle, Org. Lett., 2005, 7, 2345.
1
12. H NMR, 13C NMR, and IR spectra of the synthetic and the commercially available EDOT (1) were
identical.