Facile synthesis of 3-alkoxy-4-cyanothiophenes as new building blocks for donor-acceptor conjugated systems

Article abstract of DOI:10.1021/ol200296j

3-Alkoxy-4-cyanothiophenes are efficiently synthesized in two steps from the readily available 4-cyano-3-oxotetrahydrothiophene. Regioisomers of bithiophene derivatives are easily synthesized by playing on the strong electronic dissymmetry of the thiophene ring induced by the alkoxy and cyano groups.

Full text of DOI:10.1021/ol200296j

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1762–1765
Facile Synthesis of
3-Alkoxy-4-cyanothiophenes As New
Building Blocks for Donor-Acceptor
Conjugated Systems
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ꢀ
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Noemie Hergue, Charlotte Mallet, Gurunathan Savitha, Magali Allain, Pierre Frere,*
and Jean Roncali*
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LUNAM Universite, MOLTECH-Anjou UMR CNRS 6200, Group Linear Conjugated
Systems, 2 Boulevard Lavoisier, 49045 Angers, France
Pierre.frere@univ-angers.fr; Jean.roncali@univ-angers.fr
Received January 30, 2011
ABSTRACT
3-Alkoxy-4-cyanothiophenes are efficiently synthesized in two steps from the readily available 4-cyano-3-oxotetrahydrothiophene. Regioisomers
of bithiophene derivatives are easily synthesized by playing on the strong electronic dissymmetry of the thiophene ring induced by the alkoxy and
cyano groups.
Low band gap conjugated systems have been a focus of
sustained interest for many years.1,2 Initially motivated by
fundamental problems related to the posssibility of synthe-
sizing a true organic metal by progressive closure of the
energy gap,1 the topic has received renewed interest in the
context of organic solar cells.2 The synthesis of new
materials with low band gap (Eg) values and also broad
absorption bands represents one of the most efficient
strategies to develop organic solar cells with higher
efficiencies.2 The synthetic principles for band gap control
of conjugated systems resort roughly to three main
approaches:1 (i) rigidification of the conjugated system,3,4
(ii) increase of the quinoid character of the aromatic basic
units,5 and (iii) introduction ofalternant electron-donating
(D) and electron acceptor (A) groups on the conjugated
backbone.6 A major advantage of the D/A approach lies in
the possibility of finely tuning the band gap of the polymer
by modifying the spatial extension, ratio, and sequential
(4) For examples of rigidification by nonbonded intramolecular
ꢁ
interactions, see: (a) Turbiez, M.; Frere, P.; Roncali, J. J. Org. Chem.
ꢁ
2003, 68, 5367. (b) Turbiez, M.; Frere, P.; Allain, M.; Videlot, C.;
Ackermann, J.; Roncali, J. Chem.;Eur. J. 2005, 11, 3742. (c) Spencer,
H. J.; Skabara, P. J.; Giles, M.; McCullough, I.; Coles, S. J.; Hursthouse,
ꢀ
(1) (a) Roncali, J. Chem. Rev. 1997, 97, 730.
M. B. J. Mater. Chem. 2005, 15, 4783. (d) Turbiez, M.; Hergue, N.;
Leriche, P.; Frere, P. Tetrahedron Lett. 2009, 50, 7148.
ꢁ
(2) (a) Chen, Y.-J.; Yang, S.-H.; Hsu, C.-S. Chem. Rev. 2009, 109,
5868. (b) Chen, J.; Cao, Y. Acc. Chem. Res. 2009, 42, 1709. (c) Roncali, J.
Macromol. Rapid Commun. 2007, 28, 1761. (d) Po, R.; Maggini, M.;
Camaioni, N. J. Phys. Chem. C 2010, 114, 695.
(5) (a) Wudl, F.; Kobayashi, M.; Heeger, J. A. J. Org. Chem. 1984, 49,
3382. (b) Bredas, J. L. J. Chem. Phys. 1985, 82, 3808. (b) Karsten, B. P.;
ꢀ
Janssen, R. A. J. Org. Lett. 2008, 10, 3513.
(3) For examples of rigidification by a covalent bridge, see: (a)
Roncali, J.; Thobie-Gautier, C. Adv. Mater. 1994, 6, 846. (b) Blanchard,
P.; Brisset, H.; Riou, A.; Roncali, J. J. Org. Chem. 1997, 62, 2401. (c)
Blanchard, P.; Verlhac, P.; Michaux, L.; Frere, P.; Roncali, J. Chem.;
Eur. J. 2006, 12, 1244.
(6) (a) Havinga, E. E.; ten Hoeve, W.; Wynberg, H. Polym. Bull.
1992, 29, 119. (b) Karikomi, M.; Kitamura, C.; Tanaka, S.; Yamashita,
Y. J. Am. Chem. Soc. 1995, 117, 6791. (c) Zoombelt, A. P.; Fonrodona,
M.; Turbiez, M. G. R.; Wienk, M. M.; Janssen, R. A. J. J. Mater. Chem.
2009, 19, 5336.
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r
10.1021/ol200296j
Published on Web 03/10/2011
2011 American Chemical Society

arrangement of the donor and acceptor blocks in the
conjugated chain. However, combining donor and accep-
tor blocks with multiple possible variations poses the
question what are the structural limits of this approach.
Whereas an extended push-pull molecule with D and A
groups connected by a conjugating linker represents one
limiting case, the other limit would involve a system in
which D and A groups alternate on every carbon of the
conjugated chain. Taking polythiophene as a model, the
realization of this maximum possible D-A alternation
imposes that the D and A groups must be introduced on
the same thiophene unit. In this context, 3-alkoxy-4-cya-
nothiophenes 1 represent interesting building blocks since
both substituents combine strong donor or acceptor
strength with low steric demand (Figure 1).7
Scheme 1. Synthetic Pathway for the Synthesis of 1
diazomethane12 or with an ethoxycarbonylmethoxy group
by a Mitsunobu reaction,13 no simple and efficient general
method has been reported so far.
Figure 1. Limit structures in D-A approach.
We have recently described the synthesis of 3-methoxy-
4-cyanothiophene in two steps from 3,4-dibromothio-
phene.8 After substitution of the first bromo atom by the
methoxy group, the introduction of the cyano group was
performed with an excess of cyanide anion under micro-
wave irradiation. However, extension of this method to
longer alkoxy chains was limited by the difficulty in
synthesizing the intermediate 3-alkoxy-4-bromothiophene
derivatives.9 As a further step, we report here a new rapid
and efficient synthetic approach for the preparation
of 3-alkoxy-4-cyanothiophene derivatives 1 based on O-
alkylation of the readily accessible 4-cyano-3-oxotetrahy-
drothiophene 210 followed by oxidative aromatization
(Scheme 1).
The main difficulty resides in the selective O-alkylation
reaction of the enolate anion A for obtaining dihydrothio-
phene derivatives 3 in good yields. Baraldi et al. mainly
obtained C-alkylated derivatives 4 by treatment of 1 in dry
acetone with alkyl halides in the presence of anhydrous
potassium carbonate while the O-alkylated product was
formed only in 5-10% yield.11 Although O-alkylation of 2
by a methoxy group has been achieved by reaction with
The orientation to O-alkylation largely depends on the
nature of the base and of the alkylating agent used for the
nucleophilic substitution. The various conditions used for
the synthesis of compounds 3 are gathered in Table 1.
As expected, the use of methyl iodide in the presence of
K2CO3 as base gives 3a in a very low yield (entry 1). The
reactivity of the enolate anion can be improved to reach
yields of ca. 35% by the addition of crown ether to the
reactionmedium (entry 2) or inthe presence of a softcation
such as Csþ (entry 3).
The use of a stronger alkylating agent such as trifluor-
omethanesulfonate increases the yield of 3a up to 55%. With
a long-chain haloalkane in the presence of Cs2CO3 as a base,
the reaction proceeds in a moderate yield of 40-45% for
compound 3b after 2 h at room temperature or 15 min at
80 °C but the yield decreases to 22% for the compounds
containing branched alkyl chains (3c) (entries 4-7).
Application of microwave irradiation for enhancing
nucleophilic substitutions has been demonstrated,14 and
herein we have examined if this method could increase the
yield of O-alkylated compounds 3b and 3c.
Reactions were carried out by mixing compound 2 and an
alkylating agent in DMF in the presence of Cs2CO3 as the
base, and then the mixture was irradiated in an open vessel in a
CME microwave oven. TLC showed the complete consump-
tion of 2after 2 min of irradiation. With hexyl iodide (entry 8),
compound 3c was isolated in 53% yield while a small amount
(<10%) of C-alkylated compound 4c was also formed. A
large increase of the O-alkylation yield was observed when a
mesylate derivative was used as an alkylating agent. Thus,
(7) (a) Demanze, F.; Yassar, A.; Garnier, F. Adv. Mater. 1995, 7, 907.
(b) Ho, H. A.; Brisset, H.; Elandaloussi, E.; Frere, P.; Roncali, J. Adv.
Mater. 1996, 8, 990. (c) Berson, S.; Cecioni, S.; Billon, M.; Kervella, Y.;
de Bettignies, R.; Bailly, S.; Guillerez, S. Solar Energy Mater. Solar Cells
2010, 94, 699.
ꢁ
ꢀ
ꢁ
(8) Hergue, N.; Mallet, C.; Frere, P.; Allain, M.; Roncali, J. Macro-
molecules 2009, 42, 5593.
(9) Savitha, G.; Hergue, N.; Guilmet, E.; Allain, M.; Frere, P.
ꢀ
ꢁ
Tetrahedron Lett. 2011, 52, 1288.
(10) Compound 2 is easily prepared by condensation of acrylonitrile
on methylthioglycolate; see ref 11.
(11) Baraldi, P. G.; Pollini, G. P.; Zanirato, V. Synthesis 1985, 969.
(12) Chou, T.-S.; Chang, C.-Y.; Wu, M.-C.; Hung, S.-H.; Liu, H.-M.;
Yeh, W.-Y. J. Chem. Soc., Chem. Commun. 1992, 1643.
(13) Redman, A. M.; Dumas, J.; Scott, W. J. Org. Lett. 2000, 2, 2061.
(14) Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem. 2006, 71, 6697.
Org. Lett., Vol. 13, No. 7, 2011
1763

Table 1. Optimization for the Synthese of O-Alkylated Compounds 3
a Procedure A: 1 g of 2 þ 1.2 equiv of base þ1.2 equiv of RX in 10 mL of DMF strirred a rt for 2 h. b Procedure B: 1 g of 2 þ 1.2 equiv of base þ1.2 equiv
of RX in 10 mL of DMF irradied for 2 mn (P = 70-100 W, T = 80 °C). c Isolated yield.
compounds 3c and 3d were isolated in 95% and 71% yields
respectively (entry 9 and 10).
n-BuLi19 or LDA leads to selective deprotonation at the
5-position. Subsequent treatment of the lithiated derivative
with tributylstannyl chloride gave stannic derivatives 6 in
90% yield.
Unsymmetrical bithiophenes 7a,b have been prepared
by Stille coupling of bromo and stannic compounds 5
and 6. The reaction was carried out in toluene at 110 °C
with Pd(PPh3)4 as a catalyst (10 mol %), and com-
pounds 7a and 7b have been obtained in 55% yield.
Small amounts of the symmetrical bithiophene 8 were
also formed due to the homocoupling of the stannic
compound.
Aromatization of 3,4-disubstituted-2,5-dihydrothio-
phenes to the corresponding thiophene derivatives has
been achieved with oxidants such as hydrogen peroxide,15
sulfuryl chloride,16 bromine,17 and recently copper
dibromide.18 While oxidation of compounds 3 with sulfur-
yl chloride and hydrogen peroxide gives compounds 1 in
less than 20% yield, the use of 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ) gives the target compounds in
90-95% yield.
Thus, from the readily available compound 2, the com-
bination of microwave irradiation, a mesylate reagent, and
oxidation with DDQ affords the target molecules in a
65-86% overall yield.
We next focused our attention on the different reactiv-
ities of the 2- and 5-positions of 3-alkoxy-4-cyanothio-
phenes 1. The combined effects of the mesomeric electron
donor effect of the methoxy group and the electron-with-
drawing character of the cyano group create a large
dissymmetry in the electron density of the thiophene ring
at the 2- and 5-positions (Figure S1). Of course, such a
situation is propitious to highly regioselective reactions
(Scheme 2). Treatment of compounds 1 with 1 equiv of
NBS leads to exclusive bromination at the 2-position
which presents the highest electron density, leading to
Scheme 2. Synthesis of Bithiophenes 7 and 8
1
compound 5 in 80-85% yield. As revealed by H NMR
of compounds 1, the strong difference between the chemi-
cal shifts of the two aromatic protons is an indication of
their highly different acidity. The large deshielding of the
proton adjacent to the cyano group (7.8 ppm) is associated
with a stronger acidity, and reaction with a base such as
(15) Takaya, T.; Kosaka, S.; Otsuji, Y.; Imoto, E. Bull. Chem. Soc.
Jpn. 1968, 41, 2086.
(16) (a) Press, J. B.; Hofmann, C. M.; Safir, S. R. J. Org. Chem. 1979,
€
44, 3292. (b) Rossy, P. A.; Hoffmann, W.; Muller, N. J. Org. Chem. 1980,
45, 617. (c) Banks, M. R. J. Chem. Soc., Perkin Trans. 1 1986, 507.
(17) Dang, Y.; Chen, Y. J. Org. Chem. 2007, 72, 6901.
(18) Dang, Y.; Chen, Y. Eur. J. Org. Chem. 2007, 2007, 5661.
(19) It can be noted that the nucleophilic addition of n-BuLi on a
cyano group has never been observed.
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Org. Lett., Vol. 13, No. 7, 2011

The symmetrical derivatives 8b,c have been synthesized
in 35% yield by favoring the homocoupling reaction of the
stannic derivatives 6b,c using a catalytic amount of CuCl2
(10 mol %) and 0.5 equiv of I2.20
The distances between the planes of two molecules of 8c1 is
˚
d1 = 3.63 A while the distances between the cores of two
˚
molecules of 8c2 is d2 = 3.63 A.
Figure 3. X-ray structure of compound 8c. Ellipsoids are drawn
at 50% probability level.
Figure 2. X-ray structure of compound 7a. Ellipsoids are drawn
at 50% probability level. The S---O intramolecular interaction is
indicated by a dotted line.
To summarize, we have developed a facile and
efficient general method for the synthesis of 3-alkoxy-
4-cyanothiophenes in two steps from the easily avail-
able 4-cyano-3-tetrahydrothiophene. The large dis-
symmetry introduced in the electron density of the
thiophene ring allows straightforward regioselective
substitution of the 2- or 5-position and thus makes it
possible to use 3-alkoxy-4-cyanothiophenes as build-
ing blocks of new alternant donor-acceptor conju-
gated systems. The chain length dependence of the
electronic properties of oligomers based on these new
building blocks is under investigation and will be
reported in future publications.
The crystallographic structures of single crystals of 7a
and 8c obtained by slow evaporation of chloroform-
ethanol solutions have been analyzed by X-ray diffraction.
Compound 7a crystallizes in the monoclinic P21/c space
group. As shown in Figure 2 the two thiophene rings adopt
a planar anti-conformation with a dihedral angle close to
˚
1°. The S---O distance of 2.783(3) A is considerably shorter
than the sum of the van der Waals radii of sulfur and
˚
˚
˚
oxygen (1.85 A þ 1.40 A = 3.25 A) which is characteristic
for noncovalent S---O intramolecular interactions leading
to the self-planarization and rigidification of the π-con-
jugated system.5 The molecules stack along the a-axis with
cyano groups superimposed to methoxy ones (Figure S2).
The distance between the planes of overlapping molecules
ꢀ
Acknowledgment. We thank Regiondes Pays dela Loire
for the postdoc grant for G. Savitha.
˚
is 3.51 A.
Compound 8c crystallizes in the triclinic P1 space group.
The structure is defined by two independent half molecules
named 8c1 and 8c2. The molecule 8c2 presents a more
important thermal agitation than 8c1 for the atoms at the
extremity of the branched alkyl chains. Both molecules
adopt a planar anti-conformation (Figure 3). The molecules
8c1 and 8c2 stack in two different directions (Figure S3).
Supporting Information Available. Experimental pro-
cedures and characterization data of compounds. Copies
of 1H and 13C NMR of compounds 1, 3, 7, and 8.
Theoretical calculation for compound 1a and Figure S1.
X-ray structures data and figures (pp S3 and S4) for
compounds 7a and 8c. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) Kang, S.-K.; Baik, T.-G.; Jiao, X. H.; Lee, Y.-T. Tetrahedron
Lett. 1999, 40, 2383.
Org. Lett., Vol. 13, No. 7, 2011
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