Efficient synthesis of 3,4-ethylenedioxythiophenes (EDOT) by Mitsunobu reaction

Article abstract of DOI:10.1039/b207640c

Using the Mitsunobu reaction as a key step, a general and efficient method for the synthesis of EDOT monomers has been developed. Novel substituted EDOTs and the first chiral derivatives were generated in high yields.

Full text of DOI:10.1039/b207640c

Efficient synthesis of 3,4-ethylenedioxythiophenes (EDOT) by Mitsunobu
reaction
Dolores Caras-Quintero and Peter Bäuerle*
Department Organic Chemistry II (Organic Materials and Combinatorial Chemistry), University of Ulm,
Albert-Einstein-Allee 11, D-89081, Ulm, Germany. E-mail: peter.baeuerle@chemie.uni-ulm.de;
Fax: +49-731-50-22840; Tel: +49-731-50-22250
Received (in Cambridge, UK) 6th August 2002, Accepted 30th September 2002
First published as an Advance Article on the web 16th October 2002
Using the Mitsunobu reaction as a key step, a general and
efficient method for the synthesis of EDOT monomers has
been developed. Novel substituted EDOTs and the first
chiral derivatives were generated in high yields.
anions can only be processed from aqueous suspensions
(BAYTRON P®).2 Therefore, we explore the development of
novel EDOT derivatives as a basis for soluble and self-
organizing PEDOTs as well as of structurally defined model
oligomers.
Due to its unique combination of high environmental stability,
high conductivity and transparency in the oxidized state,
poly(3,4-ethylenedioxythiophene) (PEDOT) is widely used as
antistatic coatings in photographic films, as electrode materials
for solid electrolyte capacitors, and in several other applica-
tions.1 Oxidative polymerization of monomeric 3,4-ethylene-
dioxythiophene (EDOT) results in an insoluble and structurally
undefined polymer which in the presence of polyelectrolyte
The most common and industrially applied route for the
synthesis of EDOTs is the double Williamson etherification of
3,4-dihydroxy-2,5-thiophenedicarboxylic acid diethyl ester 1,
which is readily available by Hinsberg reaction of thiodiacetic
acid diethyl ester and glyoxal,3 with 1,2-dihaloethanes under
basic conditions as the key step.1,4 EDOT is formed efficiently,
whereas monosubstituted EDOTs are typically obtained in
medium to moderate yields. The ring closure reaction, however,
completely fails when either sterically hindered or higher
substituted dihaloethanes are used. Recently, acid-catalyzed
transetherification of 3,4-dialkoxythiophenes with 1,3-propane-
diols using widely available reagents was successfully em-
ployed for the synthesis of some 3,4-propylenedioxythiophene
(ProDOT) derivatives.1,5 Herein, we report a novel and general
procedure for the synthesis of EDOT derivatives. In particular,
a number of these are not accessible by the Williamson ether
synthesis and, for the first time, chiral EDOTs become
available.
Table 1 Mitsunobu reaction of thiophene 1 and 1,n-alkanediols 2,4 to
EDOTs 3 and ProDOTs 5
Entry Diol
Product
3a
Yield (%)a
1
2
2ab
2bb
80
74
3b
The key step of our synthesis is the Mitsunobu reaction
between 3,4-dihydroxy-2,5-thiophenedicarboxylic acid diethyl
ester 1 and 1,n-alkanediols by means of dialkylazodicarbox-
ylates and trialkylphosphines. This condensation reaction
occurs under mild and neutral reaction conditions and tolerates
a variety of functional groups. The general synthetic applicabil-
ity of this method is demonstrated by reacting thiophene 1 with
a number of differently substituted glycols 2aUi resulting in
EDOTs 3aUi (Table 1). Derivatives 3aUd which also have
previously been prepared by Williamson ether synthesis are
obtained in higher yields (entries 1, 2, 5, 6) throughout. In
particular, novel mono and disubstituted derivatives 3eUi which
were not available with the traditional syntheses are formed in
good yields (entries 7U11). From these derivatives, chlor-
omethylated EDOTs 3e can be used as precursors for higher
functionalized EDOTs due to the versatility of the halide
functionality. Furthermore, the first disubstituted EDOTs 3gUi
represent promising precursors for soluble PEDOTs. The
reaction is not operative when sterically demanding diols, such
as 3-methylbutane-1,2-diol, 3,3-dimethylbutane-1,2-diol,
1,2-diphenylethane-1,2-diol and tertiary alcohols, such as
2,3-dimethylbutane-2,3-diol are used. Sterically crowded re-
actants represent a rather general problem in Mitsunobu
reactions.6,7
3
4
5
6
7
8
9
(R)2bc
(S)2bc
2cb
(S)3bf
(R)3bf
3c
74
70
70
47
65
70
67
2db
3d
2eb
3eh
2fd
3fi
2gbe
3gh
10
2hdf
3hh
40
11
12
13
2ibg
4ab
4bb
3ih
5a
5b
20
60
40
a Isolated yields. b Commercially available diol. c (R)-(2)-1,2-propanediol
(R)2b (ee > 97%) and (S)-(+)-1,2-propanediol (S)2b (ee > 99%) were
purchased from Aldrich. d Diols 2f and 2h are new and were prepared
following literature procedures (3-butoxypropane-1,2-diol 2f in 65% yield
according to ref. 11 and 7,8-tetradecanediol 2h in 72% yield according to
ref. 12). e Meso/trans-mixture, 93/7. f Meso/trans-mixture, 87/13. g Meso/
trans-mixture, 30/70. h New EDOT derivative. i Analogous derivatives
have been synthesized using Chevrot’s method.13
In order to widen the scope of the new method, we reacted
1,3-propanediols 4a,b with thiophene 1 under Mitsunobu
conditions. ProDOTs 5a,b were efficiently obtained in good to
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medium yields (entries 12, 13).† Due to the need to form an
unfavorable 8-membered ring, the next higher homologue
1,4-butanediol, however, showed no reaction.
Reuter (Bayer AG, Krefeld). The work was financially
supported by the Fond der Chemischen Industrie.
Notes and references
†
General procedure for the Mitsunobu reaction of thiophene 1 and 1,n-
alkanediols 2, 4: Under argon and exclusion of light, to a solution of
3,4-dihydroxy-2,5-thiophenedicarboxylic acid diethyl ester 1 (1.72 g, 6.6
mmol), diol 2, 4 (6.6 mmol) and tributylphosphine (TBP) (4.3 mL, 16.5
mmol) in THF (abs., 12 mL) at 20 °C, was slowly added diisopropylazodi-
carboxylate (DIAD) (3.4 mL, 16.5 mmol) via cannula and without dilution
over 20 minutes. After the addition, the reaction mixture was warmed to 40
°C for 48 h. The solvent was then removed under reduced pressure. The
resulting yellowUred oil was diluted in hexane (15 mL) and stirred
vigorously to produce a precipitation of the product and hydrazine
dicarboxylic acid. Final purification by flash chromatography (SiO2Udi-
chloromethane) yielded the pure compounds 3,5 as white solids.
In recent years, the scope of the Mitsunobu reaction in natural
products syntheses has been extensively discussed and re-
viewed. Since a clean SN2 process is generally observed, this
reaction is found to be particularly effective at inverting the
configuration of chiral secondary alcohols.7 If no racemisation
occurs, the use of chiral glycols in the reaction with thiophene
1 could lead to chiral EDOT derivatives. In this respect, we
reacted 1 with (R)-(+)-1,2-propanediol (R)2b and (S)-
(2)-1,2-propanediol (S)2b, respectively, under Mitsunobu
conditions (entries 3, 4). The resulting chiral 5-methyl-EDOTs
(S)3b and (R)3b were obtained in good yields comparable to
that of racemic 5-methyl-EDOT 3b (entry 2). The enantiomeric
purity of the chiral compounds (S)3b and (R)3b was determined
Representative data: Disubstituted EDOT 3g: mp 132U133 °C; 1H NMR
3
(400 MHz, CDCl3, 25 °C): d = 4.45 (m, 2H), 4.33 (q, J = 7.1 Hz, 4H),
1.37 (dd, 3J = 6.7 Hz, 4J = 2.4 Hz, 6 H), 1.36 (t, 3J = 7.1 Hz, 6 H); 13
C
NMR (100 MHz, CDCl3, 25 °C): d = 160.78, 144.68, 111.17, 73.24, 61.03,
14.26, 14.18; Anal. calc. for C14H18O6S: C 53.49, H 5.77, S 10.20; found:
C 53.20, H 5.74, S 10.08%.
Representative data: Chiral EDOT (R)-(+)-3b: mp 126U128 °C; 1H NMR
(400 MHz, CDCl3, 25 °C): d = 4.46U4.30 (m, 6H), 3.99 (dd, 3J = 11.6 Hz,
4J = 7.9 Hz 1H), 1.46 (d, 3H), 1.36 (t, 6H); 13C NMR (100 MHz, CDCl3,
25 °C): d = 160.84, 145.46, 144.77, 111.52, 111.46, 70.58, 69.32, 61.24,
1
to be > 97% by H-NMR in the presence of chiral europium
20
61.18, 16.17, 14.28, 14.26; [a]D +51 (c1.0, CHCl3); Anal. calc. for
complex [Eu(tfc)3].8
C13H16O6S: C 51.99, H 5.37, S 10.68; found: C 51.96, H 5.28, S
10.71%.
Representative data: Chiral EDOT (R)-(+)-7b: bp 90U100 °C/1 3 1022
mbar; 1H NMR (500 MHz, CDCl3): d = 6.30 (AB system, JAB = 3.74 Hz,
2H), 4.29U3.79 (m, 3H), 1.33 (d, 3H); 13C NMR (126 MHz, CDCl3, 25 °C):
20
d = 142.22, 141.48, 99.32, 70.03, 69.47, 16.25; [a]D + 34.3 (c1.0,
CHCl3); Anal. calc. for C7H8O2S: C 53.83, H 5.16, S 20.53; found: C 53.65,
H 5.37, S 20.66%.
These results clearly confirm that the Mitsunobu reaction of
thiophene 1 with chiral diols takes place without any racemisa-
tion resulting in enantiomers of high optical purity. The absolute
configuration at C-5 of EDOTs (S)3b and (R)3b can not be
established by this method.
Polymerizable EDOT monomers are typically obtained by
saponification9 and decarboxylation10 of the diesters. As an
example, chiral derivative (R)3b was transformed to the
corresponding diacid (R)6b and subsequently to the 5-methyl-
EDOT (R)7b in yields of 92 and 64%, respectively. Since the
reactions do not break any of the four bonds to the chiral center
of the starting diester (R)3b, it is obvious that the relative
positions of the groups bonded to the chiral center will not
change.
1 L. Groenendaal, F. Jonas, D. Freitag, H. Pielartzik and J. R. Reynolds,
Adv. Mater., 2000, 12, 481–494.
2 (a) F. Jonas and R. Dhein, Bayer AG, German Patent DE 4229 192,
1994; (b) K. Lerch, U. Guntermann and F. Jonas, Bayer AG, Eur. Patent
825 219, 1998; (c) D. M. de Leeuw, P. A. Kraakman, P. F. G. Bongaerts,
C. M. J. Mutsaers and D. B. M. Klaassen, Synth. Met., 1994, 66,
263–273.
3 F. Dallacker and V. Mues, Chem. Ber., 1975, 108, 569–575; F.
Dallacker and V. Mues, Chem. Ber., 1975, 108, 576–581.
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8, 882–889; (b) S. A. Sapp, G. A. Sotzing and J. R. Reynolds, Chem.
Mater., 1998, 10, 2101–2108; (c) B. C. Thompson, P. Schottland, K.
Zong and J. R. Reynolds, Chem. Mater., 2000, 12, 1563–1571.
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1999, 11, 1379–1382.
6 D. L. Hughes, Org. React., 1992, 42, 335–656.
7 (a) O. Mitsunobu, Synthesis, 1981, 1–28; (b) B. R. Castro, Org. React.,
1983, 29, 1–162.
8 The enantiomeric purity of the EDOT derivatives 3b was determined by
using Eu(tfc)3 as a chiral shift reagent. A reasonable separation of the
signals (triplet) of the ester methyl groups (d = 1.36 ppm) is observed
when 10 mg of the shift reagent was added to a CDCl3 solution of the
EDOT giving a final concentration of 0.13 mM. The signals are shifted
downfield and separated into four triplets. The signals at 1.425 and
1.355 ppm correspond to (R)-(+)-3b, the signals at 1.415 and 1.365 ppm
to the (S)-(2)-enantiomer.
In summary, we have demonstrated that the Mitsunobu
reaction is a useful and efficient method for the synthesis of
mono- and disubstituted EDOT and ProDOT derivatives.
Moreover, this method allows, for the first time, the preparation
of chiral EDOT monomers in high enantiomeric excess. Studies
to further examine the scope and limitations of this novel
method are now in progress as well as the polymerization of the
various monomers to the corresponding substituted PEDOTs. In
particular, polymerization of enantiomerically pure EDOT 7b
should lead to the corresponding chiral polymer.
9 V. N. Gogte, L. G. Shah, B. D. Tilak, K. N. Gadekar and M. B.
Sahasrabudhe, Tetrahedron, 1967, 23, 2437–2441.
10 (a) I. Winter, C. Reese, J. Hormes and G. Heywang, Chem. Phys., 1995,
194, 207–213 (with copper) (b) F. Jonas and G. Rauchschwalbe, Bayer
AG, Eur. Patent 1142888, 2001 (with CuCO3/Cu(OH)2).
11 W. P. Weber and J. P. Shepherd, Tetrahedron Lett., 1972,
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12 T. Morimoto and M. Hirano, J. Chem. Soc., Perkin Trans. 2, 1982,
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We gratefully acknowledge helpful discussions with Dr S.
Kirchmeyer (H.C.Starck/Bayer AG, Leverkusen) and Dr K.
13 P. Schottland, O. Stephan, P.-Y. Le Gall and C. Chevrot, J. Chim. Phys.
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