An iterative approach to the synthesis of thiophene-based organic dyes

Article abstract of DOI:10.1016/j.tetlet.2012.04.059

We developed an iterative synthetic method for oligo-aryl compounds using an organosilicon-based palladium-catalyzed cross-coupling reaction. Aryl compounds containing a benzyloxy(diisopropyl)silyl group (masked Si group) had sufficient chemical stability, and the unmasking step proceeded in a high yield under mild conditions. Both of the key unmasking/coupling steps required no strict anhydrous or degassed conditions. The developed procedure was used for the synthesis of thiophene-based organic dyes for dye-sensitized solar cells.

Full text of DOI:10.1016/j.tetlet.2012.04.059

Tetrahedron Letters 53 (2012) 3288–3291
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An iterative approach to the synthesis of thiophene-based organic dyes
⇑
Shinichiro Fuse, Hayato Yoshida, Takashi Takahashi
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed an iterative synthetic method for oligo-aryl compounds using an organosilicon-based pal-
ladium-catalyzed cross-coupling reaction. Aryl compounds containing a benzyloxy(diisopropyl)silyl
group (masked Si group) had sufficient chemical stability, and the unmasking step proceeded in a high
yield under mild conditions. Both of the key unmasking/coupling steps required no strict anhydrous or
degassed conditions. The developed procedure was used for the synthesis of thiophene-based organic
dyes for dye-sensitized solar cells.
Received 7 March 2012
Revised 6 April 2012
Accepted 16 April 2012
Available online 21 April 2012
Keywords:
Iterative
Ó 2012 Elsevier Ltd. All rights reserved.
Silicon
Palladium-catalyzed cross-coupling
Dye-sensitized solar cell
Thiophene-based dye
Thiophene-based organic dyes make up a very important class
of compounds because they show promise as sensitizers for dye
sensitized solar cells (DSSCs)1–5 and as donor materials for small-
molecule organic solar cells.6,7 Palladium-catalyzed cross-coupling
reactions (i.e., Suzuki–Miyaura,8,9 Migita–Kosugi–Stille,10–13
Kumada–Tamao,14 Negishi,15 Hiyama16 coupling and so on17) are
a particularly powerful tool for the preparation of thiophene-based
dyes. Iterative palladium-catalyzed cross-coupling approaches18–24
have garnered much attention because they can produce structur-
ally diverse compounds from a somewhat-limited number of syn-
thetic operations (activation/unmasking of unreactive groups and
coupling), thus, this approach is suitable for laboratory automa-
tion.24–29 It would be desirable for the development of an iterative
approach to meet the following criteria: (1) that a readily available,
non toxic, and environmentally benign substrate be employed with
the generation of no toxic compound; (2) both the activation/
unmasking and the coupling steps should have good yields and
not require strict anhydrous and/or degassed conditions; and, (3)
a substrate with an unreactive group should have enough stability
so that the compound can be readily isolated and stored with the
activation/unmasking step carried out under mild reaction condi-
tions in one step. Hiyama, Nakao et al. reported an elegant sili-
the development of an iterative synthetic method for oligo-aro-
matic ring compounds using a silicon-based palladium-catalyzed
cross-coupling reaction and its application to the synthesis of thi-
ophene-based organic dyes for DSSC.
Denmark et al. reported a silicon-based cross-coupling reaction
using dimethylsilanol33 as an activating group. In the course of the
solid-phase synthetic study using a silyl linker,31,34–36 Showalter
and co-workers ascertained that the benzyloxy(diisopropyl)silyl
group can be converted into the corresponding diisopropylsilanol
con-based
iterative
palladium-catalyzed
cross-coupling
approach.21 Organosilicon compounds are readily available, non
toxic, and environmentally benign.
We have reported the combinatorial synthesis of aryl
compounds based on palladium-catalyzed cross-coupling reac-
tions in solution and in a solid phase.30–32 Here, we wish to report
⇑
Corresponding author. Tel.: +81 3 5734 2120; fax: +81 3 5734 2884.
E-mail address: ttak@apc.titech.ac.jp (T. Takahashi).
Scheme 1. An iterative approach for the synthesis of oligo-aromatic ring
compounds.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.059

S. Fuse et al. / Tetrahedron Letters 53 (2012) 3288–3291
3289
Table 1
Table 2
Examination of the unmasking step to afford 2a from 1a
Examination of the coupling step to afford 8 from 2a
Entry
[Pd]
[AllylPdCl]2
[Ligand]
PPh3
Yielda (%)
Entry
Reagent
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
12
25
29
13
34
11
28
37
19
19
25
65
6
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
[AllylPdCl]2
Pd(OAc)2
PCy3
1
2
3
4
5
6
7
8
TBAF
TBAF
TBAF
CsF
TFA
PPTS
THF
THF/H2O
0%
58%
72%
No reaction
0%
39%
37%
94%
P(2-furyl)3
P(o-tolyl)3
P(tBu)3
dppe
dppp
dppb
1,4-Dioxane/H2O
1,4-Dioxane/H2O
1,4-Dioxane/H2O
MeOH/H2O
Acetone
p-TsOHÁH2O
dppf
p-TsOHÁH2O
Acetone/H2O
Xantphos
Xphos
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
a
Isolated yield.
under mild reaction conditions (TBAF in THF).37 According to sug-
gestions in these reports, we developed the synthetic plan shown
in Scheme 1. We anticipated that aromatic ring 1 with a benzyl-
oxy(diisopropyl)silyl (masked Si) group would be sufficiently
stable, in addition, it could be readily unmasked under mild
reaction conditions in one step to afford compound 2 with a
diisopropylsilanol (activated Si) group. We planned to couple com-
pound 2 with aromatic ring 3 retaining both halogen and masked
Si groups to afford the desired coupling product 4. By repeating
the unmasking and the coupling steps, the aimed oligo-aromatic
ring compound 5 would be synthesized.
PdCl2
21
8
11
12
9
PdCl2(MeCN)2
PdCl2(PPh3)2
PdCl2(dppf)
Pd(PPh3)4
Pd2(dba)3ÁCHCl3
8
a
Isolated yield.
Table 3
Influence of H2O amount on the coupling of silanol 2a and 4-iodoanisole (7)
The unmasking step (1a–2a) was initially examined (Table 1). A
one-pot, three-component coupling of 2-bromothiophene (6) and
dichlorodiisopropylsilane with benzyl alcohol afforded 2-benzyl-
oxy(diisopropyl)silyl-thiophene (1a) in a high yield.38 The previ-
ously reported combination of TBAF in THF37 did not afford the
desired silanol 2a and only the cleavage of the thiophene-Si bond
was observed (entry 1). Interestingly, the addition of H2O was
effective in this reaction (entries 2 and 3). An excellent yield
(94%) was observed from the combination of p-TsOHÁH2O in ace-
tone/H2O (entry 8). Again, the addition of H2O was crucial to a high
yield under these acidic conditions (entries 7 and 8).
We examined the key cross-coupling reaction of 2a with
4-iodoanisole (7),39 as shown in Table 2. According to a previous
report,33 combinations of [allylPdCl]2 and ligands with Cs2CO3 in
1,4-dioxane/H2O were examined (entries 1–12). Only the combina-
tion of 10 mol % [allylPdCl]2 and AsPh3 gave a satisfactory yield
(entry 12). Various palladium reagents were examined in the
presence of the AsPh3 ligand (entries 12–19). However, an
improvement in yield was not observed.40
Entry
H2O
Yielda (%)
Entry
H2O
Yielda (%)
1
2
3
4
None
30
33
41
55
5
6
7
8
10 equiv
20 equiv
40 equiv
80 equiv
54
65
62
26
1 equiv
3 equiv
5 equiv
a
Isolated yield.
cell shown in Scheme 2. Both building block 2a with an activated
Si group and building block 3a with masked Si- and bromo-groups
were prepared from the common starting material, 2-benzyl-
oxy(diisopropyl)silyl-thiophene (1a) in good yields. The palla-
dium-catalyzed cross-coupling of 2a with 3a afforded the desired
product 4a in a 53% yield. A subsequent unmasking of benzyl silyl
ether 4a produced bithiophene 2c in a 91% yield. Prepared mono-
thiophene 2a and bithiophene 2c were coupled with 4-bromo
triphenylamine (10) to afford the desired coupling products 11
and 12 in moderate yields. Formylation of compounds 11 and 12
by hexamethylenetetramine under microwave irradiation,49 and
the subsequent Knoevenagel condensation with tert-butyl cya-
noacetate, all were carried out in one-pot reactions. Finally, the
acid-mediated removal of tert-butyl groups proceeded smoothly
to afford the desired thiophene-based dyes 15 and 16 in excellent
yields. The developed synthetic scheme does not require strict
anhydrous nor degassed conditions.
The amount of H2O influenced the results of the reaction
(Table 3). A low yield was observed without the addition of H2O
(entry 1). The yield was improved by increasing the amount
(1 equiv to 20 equiv) of H2O (entries 1–6). However, the addition
of a larger amount (80 equiv) of H2O degraded the yield (entry
8). Thus, the optimal amount of H2O was determined to be
20 equiv It should be noted that both the unmasking/coupling
steps afforded reproducible results, and can be performed in the
presence of H2O, and neither required strict anhydrous nor de-
gassed conditions.
The coupling reaction between 3a, 3b,41 and 2a–2c was exam-
ined based on our developed procedure (Table 4). All the coupling
products, 4a–4d and 9, were obtained in moderate to satisfactory
yields.
In conclusion, we have developed an iterative synthetic method
for oligo-aryl compounds using an organosilicon-based palladium-
catalyzed cross-coupling reaction. Aryl compounds containing a
benzyloxy(diisopropyl)silyl group (masked Si group) have
The developed method was applied to the synthesis of thio-
phene-based dyes 1542–44 and 1645–48 for the dye-sensitized solar

3290
S. Fuse et al. / Tetrahedron Letters 53 (2012) 3288–3291
Table 4
Palladium-catalyzed cross-coupling between 3a,b and 2a–2c
Entry
Sub
Sub
Pro
Yieldb (%)
1
2
3
4
5
3a
3a
3a
3b
3b
2a
2b
2c
2a
2b
4a
4b
9
4c
4d
53
48
40c (67)d
47
50
Reagents and condition: 10 mol % [allylPdCl]2, AsPh3, Cs2CO3, 1,4-dioxane/H2O, 90–100 °C, 12–24 h.
b
Isolated yield.
Overall yield from 2c.
Yield based on recovered 2c.
c
d
Scheme 2. Synthesis of thiophene-based organic dyes 15 and 16 for DSSC based on our developed iterative synthetic approach. Reagents and conditions: (a) p-TsOHÁH2O,
acetone/H2O, rt, 8 h, 94% (b) NBS, K2CO3, CH2Cl2, rt, 4 h, 85% (c) 10 mol % [allylPdCl]2, AsPh3, Cs2CO3, 1,4-dioxane/H2O, 90 °C, 12 h, 53% (d) p-TsOHÁH2O, acetone/H2O, rt, 8 h,
91% (e) 10 mol % [allylPdCl]2, AsPh3, Cs2CO3, 1,4-dioxane/H2O, 90 °C, 12 h (11: 49%, 12: 38%) (f) hexamethylenetetramine, AcOH/H2O, microwave irradiation, 150 °C, 1 h then
tert-butyl cyanoacetate, NH4OAc, 70 °C, 12 h {13: 67% (83% based on recovered 11), 14: 38% (81% based on recovered 12)} (g) TFA, CH2Cl2, rt, 2 h, (15: 98%, 16: 95%).
sufficient chemical stability, and the unmasking step proceeded in
a high yield under mild acidic conditions. Both the key unmasking/
coupling steps require no strict anhydrous and/or degassed condi-
tions. The developed procedure was used for the synthesis of thio-
phene-based dyes 15 and 16. Mono- and bi-thiophene compounds
2a and 2c were prepared in satisfactory yields. The coupling of
thiophenes 2a and 2c with a triphenylamine moiety and our orig-
inally developed one-pot formylation/Knoevenagel condensation
afforded the desired thiophene-based dyes. We want to again
emphasize that this developed procedure requires no strict anhy-
drous or degassed conditions.
Acknowledgment
We thank the Kanto Natural Gas Development Co. Ltd., for
financial support.

S. Fuse et al. / Tetrahedron Letters 53 (2012) 3288–3291
3291
27. Doi, T.; Fuse, S.; Miyamoto, S.; Nakai, K.; Sasuga, D.; Takahashi, T. Chem. Asian J.
2006, 1, 370–383.
Supplementary data
28. Fuse, S.; Okada, K.; Iijima, Y.; Munakata, A.; Machida, K.; Takahashi, T.; Takagi,
M.; Shin-ya, K.; Doi, T. Org. Biomol. Chem. 2011, 9, 3825–3833.
29. (a) Machida, K.; Hirose, Y.; Fuse, S.; Sugawara, T.; Takahashi, T. Chem. Pharm.
Bull. 2010, 58, 87–93; (b) Fuse, S.; Machida, K.; Takahashi, T. In New Strategies in
Chemical Synthesis and Catalysis; Pignataro, B., Ed.; WILEY-VCH: Weinheim,
2012, pp 33–56.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
059. These data include MOL files and InChiKeys of the most
important compounds described in this article.
30. Doi, T.; Inoue, H.; Tokita, M.; Watanabe, J.; Takahashi, T. J. Comb. Chem. 2008,
10, 135–141.
31. Yoshida, M.; Doi, T.; Kang, S. M.; Watanabe, J.; Takahashi, T. Chem. Commun.
2009, 2756–2758.
32. Fuse, S.; Sugiyama, S.; Takahashi, T. Chem. Asian J. 2010, 5, 2459–2462.
33. Denmark, S. E. J. Org. Chem. 2009, 74, 2915–2927.
34. Matsuda, A.; Doi, T.; Tanaka, H.; Takahashi, T. Synlett 2001, 1101–1104.
35. Fuse, S.; Hanochi, M.; Doi, T.; Takahashi, T. Tetrahedron Lett. 2004, 45, 1961–
1963.
36. Doi, T.; Yoshida, M.; Hijikuro, I.; Takahashi, T. Tetrahedron Lett. 2004, 45, 5727–
5729.
37. Harikrishnan, L. S.; Showalter, H. D. H. Tetrahedron 2000, 56, 515–519.
38. Bauerle, P.; Cremer, J. Chem. Mater. 2008, 20, 2696–2703.
39. We confirmed that the key coupling reaction of 2a with 4-bromoanisole also
gave the desired coupling product in comparable yield.
40. The coupling reactions between 7 and 2-benzyloxy(diethyl)silyl-thiophene or
2-benzyloxy(dimethyl)silyl-thiophene were examined. However, yields were
reduced in both cases.
41. Aromatic compounds 3a and 3b, retaining bromo-group were employed as
substrate due to their ease of preparation and sufficient chemical stability.
42. Hagberg, D. P.; Marinado, T.; Karlsson, K. M.; Nonomura, K.; Qin, P.; Boschloo,
G.; Brinck, T.; Hagfeldt, A.; Sun, L. J. Org. Chem. 2007, 72, 9550–9556.
43. Shen, P.; Liu, Y. J.; Huang, X. W.; Zhao, B.; Xiang, N.; Fei, J. J.; Liu, L. M.; Wang, X.
Y.; Huang, H.; Tan, S. T. Dyes Pigm. 2009, 83, 187–197.
44. Tang, J.; Hua, J. L.; Wu, W. J.; Li, J.; Jin, Z. G.; Long, Y. T.; Tian, H. Energy Environ.
Sci. 2010, 3, 1736–1745.
45. Thomas, K. R. J.; Hsu, Y. C.; Lin, J. T.; Lee, K. M.; Ho, K. C.; Lai, C. H.; Cheng, Y. M.;
Chou, P. T. Chem. Mater. 2008, 20, 1830–1840.
46. Yen, Y. S.; Hsu, Y. C.; Lin, J. T.; Chang, C. W.; Hsu, C. P.; Yin, D. J. J. Phys. Chem. C
2008, 112, 12557–12567.
47. Chang, Y. J.; Chow, T. J. Tetrahedron 2009, 65, 4726–4734.
48. Moon, S. J.; Yum, J. H.; Humphry-Baker, R.; Karlsson, K. M.; Hagberg, D. P.;
Marinado, T.; Hagfeldt, A.; Sun, L. C.; Gratzel, M.; Nazeeruddin, M. K. J. Phys.
Chem. C 2009, 113, 16816–16820.
References and notes
1. Oregan, B.; Gratzel, M. Nature 1991, 353, 737–740.
2. Koumura, N.; Wang, Z. S.; Mori, S.; Miyashita, M.; Suzuki, E.; Hara, K. J. Am.
Chem. Soc. 2006, 128, 14256–14257.
3. Ooyama, Y.; Harima, Y. Eur. J. Org. Chem. 2009, 2903–2934.
4. Mishra, A.; Fischer, M. K. R.; Bauerle, P. Angew. Chem., Int. Ed. 2009, 48, 2474–
2499.
5. Hagfeldt, A.; Boschloo, G.; Sun, L. C.; Kloo, L.; Pettersson, H. Chem. Rev. 2010,
110, 6595–6663.
6. Yu, G.; Gao, J.; Hummelen, J. C.; Wudl, F.; Heeger, A. J. Science 1995, 270, 1789–
1791.
7. Walker, B.; Kim, C.; Nguyen, T. Q. Chem. Mater. 2011, 23, 470–482.
8. Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866–867.
9. Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 3437–3440.
10. Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 301–302.
11. Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 1423–1424.
12. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636–3638.
13. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992–4998.
14. Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374–4376.
15. Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821–1823.
16. Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918–920.
17. Masuda, N.; Tanba, S.; Sugie, A.; Monguchi, D.; Koumura, N.; Hara, K.; Mori, A.
Org. Lett. 2009, 11, 2297–2300.
18. Sharp, M. J.; Cheng, W.; Snieckus, V. Tetrahedron Lett. 1987, 28, 5093–5096.
19. Spivey, A. C.; Turner, D. J.; Turner, M. L.; Yeates, S. Org. Lett. 2002, 4, 1899–1902.
20. Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007, 129, 758–759.
21. Nakao, Y.; Chen, J. S.; Tanaka, M.; Hiyama, T. J. Am. Chem. Soc. 2007, 129,
11694–11695.
22. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716–6717.
23. Araki, H.; Katoh, T.; Inoue, M. Tetrahedron Lett. 2007, 48, 3713–3717.
24. Wang, C. Y.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 5240–5244.
25. Tanaka, Y.; Fuse, S.; Tanaka, H.; Doi, T.; Takahashi, T. Org. Process Res. Dev. 2009,
13, 1111–1121.
49. Duff, J. C.; Bills, E. J. J. Chem. Soc. 1932, 1987–1988.
26. Fuse, S.; Masui, H.; Tannna, A.; Shimizu, F.; Takahashi, T. ACS Combi. Sci. 2012,
14, 17–24.