Facile and scalable synthesis of the fused-ring heterocycles thieno[3,2-b]thiophene and thieno[3,2-b]furan

Article abstract of DOI:10.1021/ol9010745

An optimized synthetic methodology which allows for efficient and scalable access to the important fused-ring heterocycle thieno[3,2-b]thiophene and the first reported isolation of thieno[3,2-b]furan is presented. The properties of thieno[3,2-b]furan were

Full text of DOI:10.1021/ol9010745

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3144-3147
Facile and Scalable Synthesis of the
Fused-Ring Heterocycles Thieno[3,2-b]-
thiophene and Thieno[3,2-b]furan
John T. Henssler and Adam J. Matzger*
Department of Chemistry and the Macromolecular Science and Engineering Program,
UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
matzger@umich.edu
Received May 15, 2009
ABSTRACT
An optimized synthetic methodology which allows for efficient and scalable access to the important fused-ring heterocycle thieno[3,2-b]thiophene
and the first reported isolation of thieno[3,2-b]furan is presented. The properties of thieno[3,2-b]furan were assessed through a detailed analysis
of the NMR data and an investigation of the chemical reactivity. Thieno[3,2-b]furan is chemically robust and offers good selectivity toward
functionalization at the 2-position via bromination and the 5-position via deprotonation.
Incorporation of fused-ring five-membered heterocycles
in place of traditionally R-linked segments has increasingly
been utilized as a powerful means of tuning properties of
conjugated oligomers and polymers.1,2 Thieno[3,2-b]-
thiophene, a structure with two fused thiophene rings, a
heterocyclic analog of naphthalene, has been employed as a
key component in a wide range of molecular architectures
including high performance materials such as porous hy-
drogen storage hosts3 and conjugated oligomers and poly-
mers.2 The established utility of this fused-ring moiety and
its potential for incorporation into the design of novel
materials makes the route to produce thieno[3,2-b]thiophene
an important target for synthetic optimization.
The fusion of a thiophene ring with a different five-
membered heterocycle has also been an area of synthetic
(1) Selected examples include:(a) Fong, H. H.; Pozdin, V. A.; Amassian,
A.; Malliaras, G. G.; Smilgies, D. M.; He, M. Q.; Gasper, S.; Zhang, F.;
Sorensen, M. J. Am. Chem. Soc. 2008, 130, 13202–13203. (b) Okamoto,
T.; Kudoh, K.; Wakamiya, A.; Yamaguchi, S. Chem.sEur. J. 2007, 13,
548–556. (c) Miguel, L. S.; Matzger, A. J. Macromolecules 2007, 40, 9233–
9237. (d) He, M. Q.; Zhang, F. X. J. Org. Chem. 2007, 72, 442–451. (e)
Zhang, X. N.; Johnson, J. P.; Kampf, J. W.; Matzger, A. J. Chem. Mater.
2006, 18, 3470–3476. (f) Zhang, X. N.; Cote, A. P.; Matzger, A. J. J. Am.
Chem. Soc. 2005, 127, 10502–10503. (g) Lim, E.; Jung, B. J.; Lee, J.; Shim,
H. K.; Lee, J. I.; Yang, Y. S.; Do, L. M. Macromolecules 2005, 38, 4531–
4535. (h) Zhang, X. N.; Kohler, M.; Matzger, A. J. Macromolecules 2004,
37, 6306–6315. (i) Zhang, X. N.; Matzger, A. J. J. Org. Chem. 2003, 68,
9813–9815. (j) Yamamoto, T.; Takimiya, K. J. Am. Chem. Soc. 2007, 129,
2224–2225. (k) Okamoto, T.; Kudoh, K.; Wakamiya, A.; Yamaguchi, S.
Org. Lett. 2005, 7, 5301–5304. (l) Nakayama, J.; Dong, H. B.; Sawada,
K.; Ishii, A.; Kumakura, S. Tetrahedron 1996, 52, 471–488. (m) Liu, J. Y.;
Zhang, R.; Sauve, G.; Kowalewski, T.; McCullough, R. D. J. Am. Chem.
Soc. 2008, 130, 13167–13176. (n) Ogawa, K.; Rasmussen, S. C. Macro-
molecules 2006, 39, 1771–1778. (o) Radke, K. R.; Ogawa, K.; Rasmussen,
S. C. Org. Lett. 2005, 7, 5253–5256. (p) Murphy, A. R.; Frechet, J. M. J.
Chem. ReV. 2007, 107, 1066–1096. (q) Litvinov, V. P. Usp. Khim. 2005,
74, 235–267.
(2) Selected examples include: (a) McCulloch, I.; Heeney, M.; Chabinyc,
M. L.; DeLongchamp, D.; Kline, R. J.; Coelle, M.; Duffy, W.; Fischer, D.;
Cundloch, D.; Hamadani, B.; Hamilton, R.; Richter, L.; Salleo, A.; Shkunov,
M.; Sporrowe, D.; Tierney, S.; Zhong, W. AdV. Mater. 2009, 21, 1091–
1109. (b) Liu, Y.; Wang, Y.; Wu, W. P.; Liu, Y. Q.; Xi, H. X.; Wang,
L. M.; Qiu, W. F.; Lu, K.; Du, C. Y.; Yu, G. AdV. Funct. Mater. 2009, 19,
772–778. (c) Parmer, J. E.; Mayer, A. C.; Hardin, B. E.; Scully, S. R.;
McGehee, M. D.; Heeney, M.; McCulloch, I. Appl. Phys. Lett. 2008, 92,
1133090–1133093. (d) Tang, W. H.; Ke, L.; Tan, L. W.; Lin, T. T.; Kietzke,
T.; Chen, Z. K. Macromolecules 2007, 40, 6164–6171. (e) Li, Y. N.; Wu,
Y. L.; Liu, P.; Birau, M.; Pan, H. L.; Ong, B. S. AdV. Mater. 2006, 18,
3029–3032. (f) Xiao, K.; Liu, Y. Q.; Qi, T.; Zhang, W.; Wang, F.; Gao,
J. H.; Qiu, W. F.; Ma, Y. Q.; Cui, G. L.; Chen, S. Y.; Zhan, X. W.; Yu, G.;
Qin, J. G.; Hu, W. P.; Zhu, D. B. J. Am. Chem. Soc. 2005, 127, 13281–
13286.
(3) (a) Koh, K.; Wong-Foy, A. G.; Matzger, A. J. J. Am. Chem. Soc.
2009, 131, 4184–4185. (b) Wong-Foy, A. G.; Matzger, A. J.; Yaghi, O. M.
J. Am. Chem. Soc. 2006, 128, 3494–3495.
10.1021/ol9010745 CCC: $40.75
Published on Web 06/23/2009
 2009 American Chemical Society

Scheme 1
.
Synthetic Route to Thieno[3,2-b]thiophene (2) and
Thieno[3,2-b]furan (4)
Figure 1. Selected π-conjugated fused-ring molecules.
interest for decades. For example, 4H-thieno[3,2-b]pyrrole,4
selenopheno[3,2-b]thiophene,5 and telluropheno[3,2-b]-
thiophene6 have all been synthesized and their properties
have been studied through experimental and computational
methods.7 However, one combination that has presented a
particular challenge for synthetic chemists is that of a
thiophene and a furan ring, as in thieno[3,2-b]furan.8 Two
effective methods of altering the physical and electronic
properties, as well as the solid-state packing of conjugated
molecules, include (1) substituting furan rings in place of
thiophene rings9 and (2) introducing ring fusion to R-linked
heterocyclic oligomers.1,2 Thieno[3,2-b]furan has the poten-
tial to leverage both of these strategies. Although data from
due to the low yield, the route has not been widely employed.
With optimization of the acid source, solvent, temperature,
reaction time, and isolation method, we have achieved
significant improvement in the yield of this step. Altering
the cyclization conditions by exposing 1 to a sulfonic acid
resin in refluxing ether produces the desired thieno[3,2-b]-
thiophene product, 2, in 71% yield (Scheme 1), on greater
than 10 g scale. Ghaisas and Tilak prepared the cyclization
precursor, 1, in 66% yield from thiophene-3-thiol, sodium,
and 2-bromo-1,1-diethoxyethane in ethanol.12 Our strategy
begins with Li-Br exchange of 3-bromothiophene with
t-BuLi followed by quenching with 1,2-bis(2,2-diethoxyeth-
yl)disulfide13 to afford 1 in 94% yield (Scheme 1) which is
carried on to the final ring closing step described above. This
scalable approach to high purity thieno[3,2-b]thiophene offers
improved overall yield in fewer synthetic steps as compared
to all published methods to date.14
Thieno[3,2-b]furan, 4, is generated in 32% yield on greater
than 5 g scale (Scheme 1) utilizing the general method
presented for the synthesis of 2. The modest yield of 4
relative to 2 may be ascribed to a greater instability of 4 in
the presence of strong acid; yield further decreases upon
extended exposure to the sulfonic acid resin and therefore
the reaction time was chosen to balance starting material
conversion with product decomposition. Although ether is
used as the reaction solvent to produce 2, the yield of 4 is
significantly higher when the reaction is carried out in THF.
Recovery of compounds 2 and 4 from the reaction mixture
poses a significant challenge due to their high volatility. This
is especially true for 4 which is more volatile than 2 and is
prepared with a higher boiling point reaction solvent. To
address this issue, the crude reaction mixture is diluted with
petroleum ether and washed with water. Careful evaporation
of solvent is then critical for recovery of 4 (see Supporting
Information for details).15
1
a crude H NMR spectrum of thieno[3,2-b]furan has been
reported, isolation of the parent compound has not been
demonstrated.10 Here we disclose an optimized synthetic
methodology that allows for efficient access to the important
heterocycle thieno[3,2-b]thiophene and the first reported
isolation of thieno[3,2-b]furan. The reactivity of thieno[3,2-b]-
furan was also investigated to shed light on the properties of
this new building block.
At present, thieno[3,2-b]thiophene is most commonly
accessed using a literature procedure that involves a four-
step route with a total linear yield of 51%.11 To improve
synthetic efficiency, a more direct approach developed by
Ghaisas and Tilak was revisited.12 In this route, a key step
is the treatment of 3-(2,2-diethoxy-ethylsulfanyl)thiophene,
1, with phosphorus pentoxide in refluxing benzene. This step
generates thieno[3,2-b]thiophene in 18% yield, but perhaps
(4) First report see: Snyder, H. R.; Carpino, L. A.; Zack, J. F.; Mills,
J. F. J. Am. Chem. Soc. 1957, 79, 2556–2559.
(5) First report see: Gol’dfarb, Y. L.; Litvinov, V. P.; Ozolin′, S. A.
IzVestiya Akademii Nauk. USSR 1968, 6, 1419.
(6) First report see: Yasuike, S.; Kurita, J.; Tsuchiya, T. Heterocycles
1997, 45, 1891–1894.
(7) (a) Alkorta, I.; Blanco, F.; Elguero, J. THEOCHEM 2008, 851, 75–
83. (b) Zhang, Y. X.; Cai, X.; Bian, Y. Z.; Li, X. Y.; Jiang, J. Z. J. Phys.
Chem. C 2008, 112, 5148–5159. (c) Lazzaroni, R.; Boutique, J. P.; Riga,
J.; Verbist, J. J.; Fripiat, J. G.; Delhalle, J. J. Chem. Soc., Perkin Trans. 2
1985, 1, 97–102. (d) Gleiter, R.; Kobayashi, M.; Spangetlarsen, J.;
Gronowitz, S.; Konar, A.; Farnier, M. J. Org. Chem. 1977, 42, 2230–2237.
(8) Perhaps even more surprisingly, furano[3,2-b]furan is unknown.
(9) (a) Kagan, J.; Arora, S. K. Heterocycles 1983, 20, 1941–1943. (b)
Miyata, Y.; Nishinaga, T.; Komatsu, K. J. Org. Chem. 2005, 70, 1147–
1153. (c) Parakka, J. P.; Cava, M. P. Synth. Met. 1995, 68, 275–279. (d)
Chen, L. H.; Wang, C. Y.; Luo, T. M. H. Heterocycles 1994, 38, 1393–
1398. (e) Hucke, A.; Cava, M. P. J. Org. Chem. 1998, 63, 7413–7417. (f)
Miyata, Y.; Terayama, M.; Minari, T.; Nishinaga, T.; Nemoto, T.; Isoda,
S.; Komatsu, K. Chem. Asian J. 2007, 2, 1492–1504.
A detailed analysis of the NMR data and an investigation
of chemical reactivity were performed for 4. The optimized
geometry of 4 was determined using density functional theory
(DFT) at the B3LYP/6-31G* level and predictions of the
1H and 13C NMR chemical shifts were calculated by the
gauge included atomic orbitals (GIAO) method within the
(13) Although 1,2-bis(2,2-diethoxyethyl)disulfide is commercially avail-
able, we have adapted a literature procedure to generate the disulfide
(Supporting Information): Parham, W. E.; Wynberg, H. Org. Syn. 1955,
35, 51–52.
(10) Paulmier, C.; Morel, J.; D., S.; Pastour, P. Bull. Soc. Chim. Fr.
1973, 243, 4–2441.
(11) Fuller, L. S.; Iddon, B.; Smith, K. A. J. Chem. Soc., Perkin Trans.
1 1997, 22, 3465–3470.
(14) The general method used to generate 2 can also be used to make
other derivatives and we demonstrate this utility with the production of
3-bromothieno[3,2-b]thiophene in fewer steps and higher yield than the best
literature procedure (Supporting Information).
(12) Ghaisas, V. V.; Tilak, B. D. Proc. Ind. Acad. Sci. 1954, 39A, 14–
19. This method utilizes thiophene-3-thiol, which is not commercially
available.
Org. Lett., Vol. 11, No. 14, 2009
3145

1
Table 1. Peak Assignments and Chemical Shifts (ppm) in H
Scheme 3. Bromination of Thieno[3,2-b]furan in THF with NBS
and 13C NMR Spectra of 4 Based on Experimental and
Computational Data (GIAO/DFT B3LYP/6-31++G** level)
from the B3LYP/6-31G* Optimized Structure
atom
experimental
calculated
∆
Scheme 4. Synthetic Route to
2-(Thiophen-2-yl)thieno[3,2-b]furan (9) and
5-(Thiophen-2-yl)thieno[3,2-b]furan (11)
C8
C2
C5
C7
C6
C3
H2
H5
H6
H3
158
146
126
123
111
106
7.56
7.21
7.07
6.74
160
151
132
131
115
110
7.76
7.24
7.11
6.89
2
5
6
8
4
4
0.20
0.03
0.04
0.15
experimental coupling constants:
J2-3 ) 2.1 Hz
J2-5 ) 1.4 Hz
J5-6 ) 5.3 Hz
J3-6 ) 0.6 Hz
product. The most selective bromination toward a single
position is achieved in THF at 0 °C (Scheme 3). The reaction
yields 67% of monobrominated 4 with substitution at the 2
vs 5-position in a ratio of 96:4 (NMR spectroscopy). To
unambiguously assign the position of bromination in the
major product, the mixture of isomers 7 and 8 was deriva-
tized in order to generate a crystalline material for structure
determination by X-ray crystallography. Under Stille cou-
pling conditions the isomer mixture was coupled to tribu-
tyl(thiophen-2-yl)stannane in 72% yield to provide 9 as the
major product (Scheme 4). The crystal structure of 9 confirms
the assignment of bromination at the R-position on the furan
ring of 4. This change in substitution position in comparison
to the isotopic exchange experiment strongly suggests that
EAS is not the dominant mechanistic pathway for the
monobromination of 4. The result can be explained by
considering 4 to be analogous to 3-vinylthiophene where the
2-3 bond in the furan ring is subject to electrophilic
substitution via an addition-elimination mechanism. Similar
observations have been reported for benzo[b]furan17 and
benzothieno[3,2-b]furan.18
Scheme 2
.
Hydrogen-Deuterium Isotopic Exchange in
Thieno[3,2-b]furan
DFT approach at the B3LYP/6-31++G** level of theory
(Table 1). A one-bond proton-carbon correlation experiment
(HMQC) was used to verify the accuracy of the computa-
tionally predicted direct proton-carbon connectivity.
Hydrogen-deuterium isotopic exchange was carried out
in order to investigate electrophilic aromatic substitution
(EAS)16 on 4, as well as the relative reactivity compared to
structurally similar furan, thiophene, and thieno[3,2-b]-
thiophene. Each compound was diluted in a 3:1 v/v mixture
of acetic acid-d4 (AcOH-d4)/trifluoroacetic acid-d1 (TFA-d1)
1
at 25 °C (Scheme 2) and conversion was monitored by H
NMR spectroscopy. Exchange is most rapid on the thiophene
ring at the 5-position of 4 (>95% after 24 h). Under these
conditions the relative reactivity at each position for this set
of molecules is: 4 (5-position) . 4 (2-position) . 2 (R) >
furan (R) > thiophene (R).
Experimental assignment of the H2 peak location in the
1H NMR spectrum of 4 was made by Li-Br exchange of 7
1
and quenching the resulting anion with D2O. The H NMR
spectrum of the deuterated product does not contain a peak
at 7.56 ppm, which matches the computed peak assignment
for the R-position on the furan ring. Further, the 1.4 and 2.1
Hz splitting are absent from the peaks at 7.21 and 6.74 ppm,
respectively.
To determine the position of deprotonation in 4, one
equivalent of BuLi was added to a solution of 4 in THF at
0 °C and the resulting anion was quenched with Bu3SnCl to
form 10 in 95% crude yield (Scheme 4). Stannyl compound
Treatment of 4 with one equivalent of NBS in either AcOH
or THF results in bromination at the 2-position as the major
(15) Slight modifications to the conditions used to obtain 4 were
empolyed to generate an isomer, thieno[2,3-b]furan, which has not been
previously reported (Supporting Information). Thieno[2,3-b]furan is an
analog of cross conjugated thieno[2,3-b]thiophene, which has been utilized
in band gap controlled conjugated copolymers that display among the highest
charge carrier mobilities to date for polymer organic thin film transistors:
Heeney, M.; Bailey, C.; Genevicius, K.; Shkunov, M.; Sparrowe, D.;
Tierney, S.; McCulloch, I. J. Am. Chem. Soc. 2005, 127, 1078–1079.
(16) (a) Salomaa, P.; Kankaanp, A.; Nikander, E.; Kaipaine, K; Aaltonen,
R. Acta Chem. Scand. 1973, 27, 153–163. (b) Butler, A. R.; Hendry, J. B.
J. Chem. Soc. B 1970, 5, 852–854.
(17) (a) Okuyama, T.; Kunugiza, K.; Fueno, T. Bull. Chem. Soc. Jpn.
1974, 47, 1267–1270. (b) Baciocchi, E.; Clementi, S.; Sebastiani, G. V.
J. Heterocycl. Chem. 1977, 14, 359–360.
3146
Org. Lett., Vol. 11, No. 14, 2009

constant is 0.6 Hz. As a means of comparison, the long-
range coupling constants were measured between the R-R
protons and ꢀ-ꢀ protons in 2. Because each of these two
sets of protons are chemically equivalent, the coupling
constants can not be measured from the major peaks directly.
Instead a concentrated NMR sample was analyzed so that
measurements could be made from the 13C satellites. The
coupling constants in 4 between the R-R protons (1.4 Hz)
and the ꢀ-ꢀ protons (0.6 Hz) are quite similar to those
observed for 2 (1.5 and 0.7 Hz, respectively).
Scheme 5
.
Deprotonation of Thieno[3,2-b]furan and Substitution
with TMS
To quantify the efficiency of bis-substitution via metala-
tion, the dianion was generated with BuLi and quenched with
TMS-Cl under lithiation conditions analogous to those
previously described, producing 14 in 97% yield (Scheme
6). Dibromination is also easily achieved at the R-positions
upon addition of two equivalents of NBS to a solution of 4
in THF, yielding 15 in 92% yield.
Scheme 6. Synthesis of 2,5-Dideuterothieno[3,2-b]furan (6),
2,5-Bis(trimethylsilanyl)thieno[3,2-b]furan (14), and
2,5-Dibromothieno[3,2-b]furan (15)
Replacement of a thiophene ring with furan in 2 results
in markedly different spectroscopic and physical properties.
For example, the absorption profile of 4 is blue-shifted as
compared to 2, reflected in a 22 nm shift in the longest
wavelength absorption maximum from 269 to 247 nm. As
evidenced by the boiling and melting points, the intermo-
lecular interactions are weaker for 4 than for 2. Boiling points
of 177 and 228 °C were measured for 4 and 2, respectively.
Furthermore, a 90 °C depression in the melting point was
observed when comparing 4 (-35 °C) to 2 (55 °C). With
regards to general stability, like 2, compound 4 and all
derivatives presented in this report are stable for more than
a month upon storage in neat form (-10 °C) under air and
show no signs of degradation upon general handling in
ambient conditions over several hours.
In summary, we report an optimized synthetic route to
thieno[3,2-b]thiophene and the first route which allows for the
isolation of thieno[3,2-b]furan. This general approach is also
useful in producing other derivatives of these fused-ring
heterocycles.14 The fundamental reactivity of thieno[3,2-b]-
furan with regards to selectivity involving EAS, addition-
elimination, deprotonation, and Stille coupling were evalu-
ated. Thieno[3,2-b]furan is chemically robust and offers good
selectivity toward functionalization at either the 2 or 5-posi-
tion under appropriate reaction conditions. Substitution of
thieno[3,2-b]thiophene with thieno[3,2-b]furan will serve as
an additional means of tailoring the molecular and bulk
properties of conjugated oligomers and polymers. Incorpora-
tion of thieno[3,2-b]furan into conjugated materials is
currently being investigated in our laboratory.
10 was then coupled to 2-bromothiophene under Stille
conditions in 64% yield to give 11 as the major product
(Scheme 4). As evidenced by NMR data (Supporting
Information), oligomer 11 is the regioisomer of 9 where the
thiophene ring is coupled to 4 at the 5-position. Therefore,
the 5-position was the site of deprotonation and subsequent
stannylation to form the precursor 10.
To quantify the selectivity of deprotonation, 4 was treated
with one equivalent of BuLi as previously described and
quenched with TMS-Cl (Scheme 5). The ratio of substitution
at the 2 vs 5-positions is 4:96 (NMR spectroscopy). This result
is well correlated with data from similar studies on the R-linked
2-(thiophen-2-yl)furan19 and from competition studies between
thiophene and furan.20
The H5 peak in the 1H NMR spectrum was experimentally
identified by quenching the anion of 4 with D2O. The resulting
1H NMR spectrum does not contain a peak at 7.21 ppm and
the 1.4 and 5.3 Hz splitting are absent from the peaks at 7.56
and 7.07 ppm, respectively, thus confirming the computationally
determined peak assignment of H5 as the R-position on the
thiophene ring. It is worth pointing out that upon deuteration
of 4 by EAS, this is the same peak that most rapidly decreased
1
in the H NMR spectrum, experimentally reaffirming the
aforementioned substitution assignment.
Acknowledgment. This work was supported by the
National Science Foundation (CHE 0616487). We thank Dr.
William W. Porter III for X-ray structure determination and
Amelia A. Fuller and Carolin Heggemann (University of
Michigan) for preliminary studies.
The dianion of 4 can be generated at the 2 and 5-positions
by treatment with two equivalents of BuLi in THF at 0 °C.
Quenching the dianion with D2O (Scheme 6) leaves only
the peaks at 6.74 and 7.07 ppm in the H NMR spectrum,
corresponding to the H3 and H6 protons. The coupling
1
Supporting Information Available: Experimental pro-
cedures, UV-vis spectra for 2 and 4, NMR spectra, compu-
tational details and a CIF file for 9. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Svoboda, J.; Pihera, P.; Sedmera, P.; Palecek, J. Collect. Czech.
Chem. Commun. 1996, 61, 888–900.
(19) Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919–
1929.
(20) Gol’dfarb, Y. L.; Danyushevskii, Y. L. J. Gen. Chem. 1961, 31,
3410.
OL9010745
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3147