3-Alkoxy-4-bromothiophenes: General synthesis of monomers and regio-selective preparation of two dimers

Article abstract of DOI:10.1016/j.tetlet.2011.01.050

3-Alkoxy-4-bromothiophenes were synthesized in three steps from the readily available methyl 2-carboxylate-3-hydroxythiophene and two isomers of bithiophenes based on the 3-bromo-4-methoxythiophene moiety were regio-selectively prepared.

Full text of DOI:10.1016/j.tetlet.2011.01.050

Tetrahedron Letters 52 (2011) 1288–1291
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
3-Alkoxy-4-bromothiophenes: general synthesis of monomers
and regio-selective preparation of two dimers
⇑
Gurunathan Savitha, Noémie Hergué, Erwan Guilmet, Magali Allain, Pierre Frère
University of Angers, MOLTECH-Anjou, UMR CNRS 6200, Group Linear Conjugated Systems, 2 Bd Lavoisier, 49045 Angers, France
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Alkoxy-4-bromothiophenes were synthesized in three steps from the readily available methyl 2-car-
boxylate-3-hydroxythiophene and two isomers of bithiophenes based on the 3-bromo-4-methoxythi-
ophene moiety were regio-selectively prepared.
Received 13 October 2010
Revised 4 January 2011
Accepted 12 January 2011
Available online 18 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkoxythiophene
Bromothiophene
Bithiophenes
Sꢀ ꢀ ꢀO interactions
Functionalized thiophenes on the 3 and 4 positions are attrac-
tive building blocks for the development of materials based on
conjugated systems usable as organic semiconductors in electronic
method is not adapted for grafting longer or branched alkoxy
chains. Thus attempts with alcoholate anion of hexan-1-ol or 2-
ethylhexan-1-ol gave yields inferior to 5%.
As part of our research aimed in the development of new
synthetic routes to substituted thiophenes, we have been develop-
ing the access to alkoxythiophene derivatives from easily avail-
p
-
1
–7
or optoelectronic devices or as electrode materials for sensors.
In this field, the attachment of alkoxy groups to b-positions of thi-
ophene rings has emerged as a solution for developing polymers
with moderate bandgap, low oxidation potential, and good stabil-
ity of the conducting oxidized state.8 3-Alkoxythiophene deriva-
tives are usually prepared from 3-bromothiophene by the
aromatic nucleophilic substitution with alcoholate anion catalyzed
able starting materials. We recently reported the synthesis of
16
3,4-dialkoxythieno[2,3-b]thiophenes,
3,6-dialkoxythieno[3,2-
1
7
18
b]thiophenes, and 3-substituted thieno[3,2-b]furanes from b-
hydroxythiophene derivatives. As continuation in this approach,
we herein report a straightforward and general procedure for the
synthesis of 3-alkoxy-4-bromothiophene derivatives from the
readily accessible methyl 2-carboxylate-3-hydroxythiophene. The
selective synthesis of two regioisomers of dimers, namely 3,3 -di-
bromo-4,4 -dimethoxy-2,2 -bithiophene and 4,4 -dibromo-3,3 -
dimethoxy-2,2 -bithiophene is also described.
9
by Cu (I) halide. More recently a transetherification reaction from
3
-methoxythiophene has allowed the preparation of various
3,5
alkoxythiophene derivatives. Efficient synthesis of 3,4-dialkoxy-
thiophenes was also described from ethyl 3,4-dihydroxy-2,5-thio-
phene-dicarboxylate obtained in one step by the condensation
between diethyl malonate and diethylthiodiglycolate, or from
0
0
0
0
0
0
1
0,11
3
,4-dimethoxythiophene by the transetherification reaction.
Cihaner and Onal reported the synthesis of 3-bromo-4-meth-
oxythiophene in 70% yield by the reaction of methanolate anion
Br
OR
1
2
on 3,4-dibromothiophene in the presence of CuO and KI.
However, this protocol suffers from various drawbacks. Firstly
S
3
-alkoxy-4-bromothiophene
3
,4-dibromothiophene is an expensive starting material, which is
13,14
synthesized in two steps from thiophene.
Secondly the proce-
MeO
Br
Br
dure requires a long reaction time of about 3 days. We recently
reported that the reaction time can be effectively reduced to
Br
OMe
S
S
0 min by carrying out the reaction in microwave.15 Although con-
S
3
S
venient for the preparation of 3-bromo-4-methoxythiophene, this
OMe
MeO
Br
⇑
Corresponding author.
E-mail address: pierre.frere@univ-angers.fr (P. Frère).
4,4'-dibromo-3,3'-dimethoxy-
3,3'-dibromo-4,4'-dimethoxy-
2,2'-bithiophene
2,2'-bithiophene
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.050

G. Savitha et al. / Tetrahedron Letters 52 (2011) 1288–1291
1289
CO
2
Me
CO
Cl
2
Me
MeONa
MeOH
Br
OR
+
Br
OH
Br
OR
SH
OH
K
2
CO
3
1) NaOH, EtOH
Me 2) Cr Cu , quinoline
microwave
Br
2
CO
2
2
2 5
O
AcOH
CO
2
Me
S
S
CO
2
Me
S
RX DMF
S
4
CO
SH
2
Me
3
CO
Cl
2
Me
2
MeOH
1
+
NaHCO
3
Cl
3a and 4a R = CH
3
3
3
b and 4b R = C
c and 4c R = CH
6
H
13
2
2 5 4 9
CH(C H )C H
Scheme 1.
Br
OMe
Br
OMe
Br
OMe
1
) LDA
+
Me
3
Si
Me
3
Si
SiMe
3
S
2) SiMe
3
Cl
S
S
5
6
4a
MeO
Br
Br
OMe
MeO
Br
1
) LDA
4
tBu NF
S
S
3
Me Si
SiMe
3
THF
Me
3
Si
S
S
2)CuCl
2
S
Br
OMe
Br
OMe
5
8
7
Scheme 2.
The 3-alkoxy-4-bromothiophene derivatives were prepared in
four steps from 2-carboxylate-3-hydroxythiophene 1 according
to Scheme 1. The last can be easily obtained by the action of thio-
late anion of methyl thioglycolate on the methyl chloroacrylate as
described by Huddleston and Barker.19 Interestingly the commer-
cially available economically viable 2,3-dichloro propionate, which
generates in situ methyl chloroacrylate by using an excess of so-
dium hydrogenocarbonate20 can be also used in a simple protocol
in methanol. The regioselective bromination of compound 1 was
carried out by treating with 1 equiv of bromine in acetic acid to
give compound 2 in 76% yield.21 The O-alkylation of compound 2
was carried out with alkylating reagents, such as methyl iodide,
under microwave irradiation in the presence of copper chromite
gave the target molecule 4 in 70–75% yields for the two steps.22
We next focused our attention toward the synthesis of two
regioisomers of bithiophene derivative from 3-bromo-4-methoxy-
thiophene. Firstly lithiation of compound 4a was carried out by
treating with 1.0–1.2 equiv of lithium diisopropylamide (LDA) fol-
lowed by the treatment with chlorotrimethylsilane (Scheme 2).
The reaction led to a mixture of mono 5 and di-silylated 6 deriva-
1
tives in 60% and 22% yields, respectively. As revealed by H NMR of
compound 4a, the difference between the chemical shifts of the
two aromatic protons is an indication of their highly different acid-
ity. The deshielding of proton adjacent to bromine atom
(7.18 ppm) is associated with a stronger acidity and the reaction
with LDA allowed the deprotonation at 2-position. A second lithi-
1
-bromohexane, or 1-bromo-2-ethylhexane in the presence of
CO as base in DMF to give corresponding alkoxy derivatives 3
K
2
3
in 70–80% yields. Finally, decarboxylation of the acid resulting
from the saponification of compounds 3 at 200 °C in quinoline
Br
Br
OMe
Br
OMe
1
) LDA
S
2
MeO C
2
CO Me
2
2
CO Me
) CuCl
2
S
S
9
3
a
MeO
1) NaOH, EtOH
2
) Cr Cu , quinoline
2
2 5
O
microwave
Br
Br
OMe
S
S
MeO
10
Scheme 3.
2 2
Figure 1. UV–vis. spectra of compounds 8 and 10 in CH Cl .

1
290
G. Savitha et al. / Tetrahedron Letters 52 (2011) 1288–1291
Figure 2. Ortep view of compound 7, ellipsoids drawn at 50% probability level.
ation of 5 with LDA followed by the treatment with a slight excess
of CuCl afforded bithiophene derivative 7 in 25% yield. Finally the
treatment of 7 with fluorine anion led to the formation of one of
4-methoxythiophene moiety by playing on the regio selective syn-
thesis of monosilylated derivative, was presented. The role of the
relative position of the substituents on the thiophene moieties
and its impact in the UV absorption spectra were also demon-
strated. Further utilization of the synthesized 3-alkoxy-4-bromo
thiophene in the synthesis of low band gap polymers is under pro-
gress in our laboratory.
2
23
the regioisomers of bithiophene 8 in 70% yield.
The synthesis of another regioisomer of bithiophene 10 with
methoxy groups in the external positions was attempted by the di-
rect copper catalyzed coupling reaction of the 2-lithio derivative of
4
a, which afforded the target molecule only in 5% yield. However,
an alternate procedure for the synthesis of bithiophene 10 from
compound 3a is depicted in Scheme 3. The treatment of 3a with
Acknowledgment
1
equiv of LDA and CuCl
on further saponification and the decarboxylation reaction in quin-
oline in the presence of Cr Cu upon microwave irradiation gave
0 in 30% yield. Compound 10 was found to be very sensitive to
2
afforded bithiophene 9 in 55%, which
We thank Région des Pays de la Loire for the financial support to
G. Savitha for a postdoc position.
2
2 5
O
2
4
1
Supplementary data
light and temperature and its stability was very low, which turned
slowly to a dark brown solid in 1 h at room temperature after puri-
fication. However, we found that the solid was stable for several
days when stored at ꢁ20 °C in dark.
1
Supplementary data (experimental data and copies of H NMR
and 1 C NMR of the new compounds) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
3
The comparison of the UV–vis absorption spectra of compounds
2
011.01.050.
8
and 10 revealed the predominant role of the relative position of
the methoxy groups and bromine atoms on the conformation
adopted by the two bithiophene isomers (Fig. 1). For compound
References and notes
1
0 a structureless absorption band with a kmax at 270 nm was ob-
1. Barbarella, G.; Melucci, M.; Sotgiu, G. Adv. Mater. 2005, 17, 1581–1593.
2
3
.
.
Roncali, J. Macromol. Rapid. Commun. 2007, 28, 1761–1775.
served whereas for isomer 8 a red shifted well resolved absorption
band with a kmax at 328 nm was observed. These marked differ-
ences indicate that derivative 8 with the methoxy groups in the
internal position allows the conjugated systems to adopt more ri-
gid and more planar structure.25 As already demonstrated for bithi-
ophene derivatives substituted with alkoxy groups, the planar
For updated reviews on advanced functional polythiophenes based on tailored
precursors, see: (a) Blanchard, P.; Leriche, P.; Frère, P.; Roncali, J. In Handbook of
Conducting Polymers; Skotheim, T. A., Reynolds, J. R., Eds.; CRC Press: Boca
Raton, 2007; Vol. 3, (b) Mishra, M.; Ma, C. Q.; Bäuerle, P. Chem. Rev. 2009, 109,
1141–1276.
4.
Ho, H. A.; Najari, A.; Leclerc, M. Acc. Chem. Res. 2008, 41, 168–178.
5. Ho, H. A.; Bera Aberem, M.; Leclerc, M. Chem. Eur. J. 2005, 11, 1718–1724.
6. Schulz, E.; Fahmi, K.; Lemaire, M. Acros Chim. Acta 1994, 1, 1–16.
8
conformation is stabilized by Sꢀ ꢀ ꢀO intramolecular interactions.
7.
Blanchard, P.; Jousselme, B.; Frère, P.; Roncali, J. J. Org. Chem. 2002, 67, 3961–
964.
In contrast the structures of bithiophenes substituted by bromine
atoms at the 3 and 3 -positions are known to present a large tor-
3
0
8. Roncali, J.; Blanchard, P.; Frère, P. J. Mater. Chem. 2005, 15, 1589–1610.
9. Keegstra, M. A.; Peters, T. H.; Brandsma, L. Tetrahedron 1992, 48, 3633–3652.
sion between the two thiophene rings.26
1
1
0. Frontana-Uribe, B. A.; Heinze, J. Tetrahedron Lett. 2006, 47, 4635–4640.
1. von Kieseritzky, F.; Allared, F.; Dahstedt, E.; Hellberg, J. Tetrahedron Lett. 2004,
45, 6049–6050.
This was later supported by the results of X-ray diffraction stud-
ies of the single crystals of 7 obtained by slow evaporation from
2
7
12. Cihaner, A.; Önal, A. M. J. Electroanal. Chem. 2007, 601, 68.
13. Zhang, Q. T.; Tour, J. M. J. Am. Chem. Soc. 1998, 120, 5355–5362.
14. Tour, J. M.; Wu, R. Macromolecules 1992, 25, 1901–1907.
3
CHCl solution. As shown in Figure 2 the two thiophene cycles
adopt a planar anti conformation with a dihedral angle inferior
to 1°. The interatomic S–O distances of 2.92 Å was found to be con-
siderably shorter than the sum of the Van der Waals radii of sulfur
and oxygen (3.35 Å), thus conforming the occurrence of non cova-
lent Sꢀ ꢀ ꢀO intramolecular interactions, which stabilize the planar
conformation.
In conclusion, we have described a convenient and effective
synthesis of 3-alkoxy-4-bromothiophene derivatives. Additionally
the synthesis of two isomers of bithiophene, based on 3-bromo-
15. Hergué, N.; Mallet, C.; Frère, P.; Allain, M.; Roncali, J. Macromolecules 2009, 42,
5593–5599.
16. Hergué, N.; Frère, P. Org. Biomol. Chem. 2007, 5, 3442–3449.
17. Hergué, N.; Frère, P.; Roncali, J. Org. Biomol. Chem. 2011, 9, 588–595.
18. Hergué, N.; Mallet, C.; Touvron, J.; Allain, M.; Leriche, P.; Frère, P. Tetrahedron
Lett. 2008, 49, 2425–2428.
1
2
9. Huddleston, P. R.; Barker, J. M. Synth. Commun. 1979, 9, 731–734.
0. Hagiwari, H.; Komatsubara, N.; Hoshi, T.; Suzuki, T.; Ando, M. Tetrahedron Lett.
1999, 40, 1523–1526.
21. Corral, C.; Lissavetzky, J. Synthesis 1984, 847–850.

G. Savitha et al. / Tetrahedron Letters 52 (2011) 1288–1291
1291
2
2
2
2. Compound 4a see Refs. 12 and 15.
Compound 10: Beige solid, dec. from 150 °C, 1H NMR (CDCl
3
) d (ppm) 3.91 (s,
Compound 4b: Colorless oil, 1H NMR (CDCl
) d (ppm) 0.91 (t, 3H, 3J = 7.1 Hz),
6H), 6.40 (s, 2H); C NMR (CDCl
(Maldi-Tof): C10 Br calcd 383.8, 385.8, 381.8; found 383.3, 385.3, 381.3.
13
3
3
) d (ppm) 57.7, 98.2, 105.3, 128.5, 154.4; MS
3
1
.34 (m, 4H), 1.44 (m, 2H), 1.82 (m, 2H), 3.98 (t, 2H, J = 6.4 Hz), 6.21 (d, 1H,
H
8
2 2 2
O S
4
4
13
J = 3.5 Hz), 7.18 (d,1H, J = 3.5 Hz); C NMR (CDCl
3
) d (ppm) 14.1, 22.6, 25.7,
25. Leriche, P.; Frère, P.; Roncali, J. J. Mater. Chem. 2005, 15, 3473–3478.
26. Antolini, L.; Folli, U.; Goldoni, F.; Iarossi, D.; Mucci, A.; Schenetti, L. Acta
Polymer. 1998, 49, 248–251.
27. X-ray single-crystal diffraction data were collected at 293 K on a BRUKER-
NONIUS KappaCCD diffractometer, equipped with a graphite monochromator
+Å
2
9.0, 31.6, 71.0, 97.1, 103.5, 121.9, 153.9; m/z (M ) = 262; Elemental Anal.
Calcd for C10 15OBrS: C, 45.63; H, 5.74. Found: C, 45.37; H, 5.68.
Compound 4c: Colorless oil, H NMR (CDCl
H
1
3
) d (ppm) 0.99 (m, 6H), 1.35–1.62
3
4
(
m, 8H), 1.82 (m, 1H), 3.90 (d, 2H, J = 5.7 Hz), 6.22 (d, 1H, J = 3.6 Hz), 7.18 (d,
4 13
1
7
C
H, J = 3.6 Hz); C NMR (CDCl
3.4, 96.9, 103.7, 121.8, 154.1; m/z (M ) = 291. Elemental Anal. Calcd for
19OBrS: C, 49.49; H, 6.58. Found: C, 49.75; H, 6.35.
3
) d (ppm) 11.2, 14.1, 23.0, 23.9, 29.1, 30.5, 39.3,
utilizing MoKa radiation (k = 0.71073 Å). The structure was solved by direct
+
Å
2
methods using SIR92 (Altomare et al., 1993) and refined on F by full matrix
least-squares techniques using SHELXL97 (G.M. Sheldrick, 1998). All non-H
atoms were refined anisotropically and absorption was corrected by SADABS
12
H
1
3. Compound 5: Colorless oil, H NMR (CDCl
3
) d (ppm) 0.38 (s, 9H), 3.88 (s, 3H),
+Å
6
.47 (s, 1H); m/z (M ) = 261.
program (Sheldrick, Bruker, 2000). The
calculation without refinement.
H atoms were included in the
Compound 7: Beige solid, mp 140 °C, 1H NMR (CDCl
3
) d (ppm) 0.41 (s, 18H),
3
.90 (s, 6H); 13C NMR (CDCl
) d (ppm) ꢁ1.08, 60.9, 113.6, 123.2, 132.1, 151.9;
MS (Maldi-Tof): C16 24Br Si calcd 527.9, 529.9, 525.9; found 527.4, 529.4,
25.4.
Compound 8: Yellow pale solid, mp 142 °C, 1H NMR (CDCl
H), 7.15 (s, 2H); 13C NMR (CDCl
) d (ppm) 61.0, 106.3, 119.3, 120.8, 150.2; MS
Maldi-Tof): C10 Br calcd 383.8, 385.8, 381.8; found 383.2, 385.2, 381.2.
Elemental Anal. Calcd for C10 Br : C, 31.27; H, 6.10. Found: C, 31.31; H,
.32.
4. Compound 9: Yellow solid, mp 210–212 °C (dec.); 1H NMR (CDCl
3
Crystallographic data for 7: C16
H
24Br
0.30 ꢂ 0.18 ꢂ 0.05 mm , monoclinic, space group P2
b = 10.3625(5) Å, c = 11.2464(6) Å, b = 96.069(5)°, V = 1160.3(1) Å , Z = 2,
2
O
2
S
2
Si
2
,
M = 528.47, colorless plate,
3
H
2
O
S
2 2
2
1
/n, a = 10.0120(7) Å,
3
5
3
ꢁ1
3
) d (ppm) 3.91 (s,
q
calc = 1.513 g/cm ,
l(Mo
Ka
) = 3.783 mm
,
F(0 0 0) = 532,
hmin = 3.25°,
6
3
h
max = 30.00°, 20,108 reflections collected, 3369 unique (Rint = 0.08), 113
1
2
(
H
8
2
O
S
2 2
parameters,
I > 2
R
= 0.0390 and wR = 0.0649 using 1904 reflections with
1
2
H
8
O
2
S
2 2
r(I),
R
= 0.1075 and wR = 0.0785 using all data, GOF = 0.990,
ꢁ
3
6
ꢁ0.464 < Dq < 0.453 eÅ .
3
) d (ppm)
) d (ppm) 52.5, 62.7, 110.9, 117.9,
12Br M–Br calcd 420.9, 418.9,
Crystallographic data excluding structure factors have been deposited with the
Cambridge Crystallographic Data under reference CCDC 781722.
1
3
3
1
.91 (s, 3H), 4.06 (s, 3H); C NMR (CDCl
31.8, 158.5, 160.4; MS (Maldi-Tof): C14
3
H
2 6 2
O S
found 420.4, 418.4.