Synthesis of thiophene-based building blocks via facile α-monoiodination

Article abstract of DOI:10.1055/s-2001-13361

A new procedure to selectively α-monoiodinate symmetrical thiophene-capped segments is described. The monoiodinated derivatives are further modified, giving access to a variety of thiophene-based building blocks, which are useful for e.g. oligomer synthesis via segmental coupling.

Full text of DOI:10.1055/s-2001-13361

634
LETTER
Synthesis of Thiophene-Based Building Blocks via Facile -Monoiodination
Ulrik Boas, Anantharaman Dhanabalan, Daniel R. Greve, E. W. Meijer*
Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box. 513, 5600 MB Eindhoven,
The Netherlands
E-mail: e.w.meijer@tue.nl
Received 18 January 2001
Abstract: A new procedure to selectively -monoiodinate symmet-
rical thiophene-capped segments is described. The monoiodinated
derivatives are further modified, giving access to a variety of
thiophene-based building blocks, which are useful for e.g. oligomer
synthesis via segmental coupling.
Key words: monoiodination, N-iodosuccinimide, oligothiophenes,
thiophene-based segments
Monoiodinated oligothiophene segments have received
attention in recent years as useful intermediates in the syn-
thesis of conjugated materials,1,2 self-assembled
monolayers3 and as bioactive reagents in e.g. anti-tumor
therapy.4,5 Despite this, only few methods to selectively -
monoiodinate symmetrical thiophene-based segments are
known.4-10 Monoiodination of symmetrical bi- and ter-
thiophenes utilises mostly either mercurioxide, or mercu-
richloride followed by subsequent reaction of the
Scheme 1
oligothienylmercuri compound with elemental iodine.6,7
An alternative route via the monobromo compound and
cuprous iodide gives -monoiodinated bithiophene in low
yield.8 Since the method employing mercuri compounds
biphenyl unit between the terminal thiophenes, attempts
is both toxic, cumbersome, and, in the case of ter-
to synthesise the monoiodinated compound failed, due to
low solubility of the starting material. In the case of 3a,13
1.3 equivalents of NIS were needed in order to minimise
the amount of starting material in the crude mixture, and,
also here, the bisiodinated compound could easily be re-
moved by a column filtration; the monoiodinated segment
3a was obtained in good yield and 95% purity (GC-MS).
thiophene, only gives a moderate yield7, we searched for
a simpler procedure. Wu et al.11 used N-bromosuccinim-
ide (NBS) in combination with acetic acid, in an attempt
to synthesise 5-bromo-[2,2’]bithiophene; however, the
product contained starting material and bisbromo com-
pound even after purification. By applying N-iodosuccin-
imide (NIS) and acetic acid in a procedure analogous to
the bromination described by Wu, we found that
bithiophene 4 could be monoiodinated with excellent se-
lectivity. Small amounts of bisiodo-bithiophene formed
could easily be removed by a filtration of the crude reac-
tion mixture giving 5-iodo-[2,2’]bithiophene 4a in 92-
97% purity. Monoiodination of terthiophene 1 showed an
even higher selectivity, and monoiodinated terthiophene
1a was obtained in 76% yield, after simple workup.12 Our
findings prompted us to apply this procedure to various
thiophene containing segments 1-4, as shown in Scheme
1.
The monoiodo ter- and bithiophene compounds 1a, 4a
were subsequently modified by bromination to yield new
mixed halogenated ter- and bithiophene 1b, 4b in good
yields (70% and 92%, respectively).14 Negishi coupling
under mild conditions gave chemoselective derivatisation
of the iodo position on 4b, obtaining 5-bromo-5’’methyl-
terthiophene 4c in 77% yield (Scheme 2).15 Nickel-catal-
ysed coupling between monoiodo bithiophene 4a and
4-tert-butylphenyl-magnesiumbromide gave 5-tert-butyl
phenyl-[2,2’]bithiophene 4d in acceptable yield.16
In summary, some useful building blocks for e.g. segment
coupling have been synthesised using an easy monoiodi-
nation procedure. The introduced monoiodination proce-
dure has shown to be a useful alternative to previous
described methods. The monoiodinated building blocks
have been further derivatised in good yields, giving access
to a variety of asymmetrical thiophene segments.
Monoiodo-terthiophene 1a and monoiodo-bithiophene
4a13 segments are easily made by this procedure, howev-
er, in the case of compound 2a13 a lower selectivity was
observed under the reaction conditions employed, creat-
ing a larger amount of bisiodo compound (27% by GC-
MS). The latter could, however, be removed by filtration
through a short silicagel column. Upon introduction of a
Synlett 2001, No. 5, 634–636 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Thiophene-Based Building Blocks via Facile -Monoiodination
635
evaporation using an oil pump. Residual succinimide and
bisiodo terthiophene were removed on a short silicagel
column (Et2O-hexane 1:1). Yield: 2.6 g (76%); mp: 142-
143 °C (lit. 138-139 °C);7 1H NMR (300 MHz, d6-acetone):
7.06 (d, J 3.8 Hz, 1H), 7.12 (dd, 3J 4.9 Hz, 4J 1.4 Hz, 1H), 7.24
(d+d, J 3.8 Hz, J 3.8 Hz, 2H), 7.34 (d+dd, J 3.6 Hz, 3J 3.6 Hz,
4J 1.1 Hz, 2H), 7.48 (dd, 3J 4.9 Hz, 4J 1.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3): 72.0, 124.0, 124.4, 124.8, 125.1, 128.0,
135.0, 136.8, 136.9, 137.8, 143.1; LRMS, calcd. (C12H7IS3):
374.27. Found: 374.0; GC: 99% purity
(13) 2-(4-(thiophen-2’-yl)-phenyl)-5-iodo-thiophene (2a): 217
(0.50 g, 2.10 mmol) and NIS (0.54 g, 2.40 mmol) in CHCl3 (12
ml) and AcOH (7 ml) was treated as above. Purification on
short silicagel column, (1. hexane, 2. EtOAc-hexane 1:1).
Yield: 0.32 g (42%); mp: 198 °C (dec); 1H NMR (300 MHz,
CDCl3): 7.02 (d, J 3.9 Hz, 1H), 7.12 (dd, 3J 5.2 Hz, 4J 1.6
Hz, 1H), 7.25 (d, J 3.9 Hz, 1H), 7.33 (dd, 3J 4.9 Hz, 4J 1.1 Hz,
1H), 7.36 (dd, 3J 3.6 Hz, 4J 1.1 Hz, 1H), 7.53-7.56 (m, 2H),
7.63-7.65 (m, 2H); 13C NMR (75 MHz, CDCl3): 72.5, 123.3,
124.6, 125.2, 126.2-126.4, 128.2, 132.6, 134.0, 138.1, 143.8,
150.0; LRMS calcd. (C14 H9 I S2): 368.25. Found: 368.0; GC:
97% purity; 4-(5-iodo-thiophen-2-yl)-7-(thiophen-2’-yl)-
benzo[2.1.3]thiadiazole (3a):
317(0.50 g, 1.70 mmol) and NIS (0.50 g, 2.2 mmol) in CHCl3
(10 ml) and AcOH (5 ml) was treated as above. Purification on
short silicagel column (Et2O-hexane 1:1). Yield: 0.67 g
(92%); mp: 124-126 °C; 1H NMR (300 MHz, CDCl3): 7.24
(dd, 3J 3.6 Hz, 4J 1.4 Hz, 1H), 7.37 (d, J 4.1 Hz, 1H), 7.49 (dd,
3J 5.2 Hz, 4J 1.1 Hz, 1H), 7.73 (d, J 3.8 Hz, 1H), 7.83 (d, J 8.0
Hz, 1H), 7.89 (d, J 7.7 Hz, 1H), 8.15 (dd, 3J 3.9 Hz, 4J 1.1 Hz,
1H); 13C NMR (75 MHz, d8-THF): 82.7, 130.4, 130.7, 130.8,
131.0, 131.9, 132.8, 133.4, 133.9, 143.3, 144.9, 150.9, 157.9,
158.0; MS (MALDI-TOF), calcd. (C14H7IN2S3): 426.31
Found: 426.62; 5-Iodo-[2,2']bithiophene (4a): 4 (2.0 g, 12.0
mmol) and NIS (3.2 g, 14.4 mmol) in CHCl3 (24 ml) and
AcOH (24 ml), was stirred overnight and the reaction mixture
was filtered to remove bisiodinated bithiophene. Solvents
were removed by evaporation on oil pump. The residue was
filtered through a short silicagel column (hexane). Yield: 2.1
g (60%); 1H NMR (300 MHz, d6-acetone): 7.00 (dd, 3J 3.9
Hz, 4J 0.8 Hz, 1H), 7.09 (m, 1H), 7.26 (d, J 3.6 Hz, 1H), 7.29
(dd, 3J 3.6 Hz, 4J 0.8 Hz, 1H), 7.44 (d, J 5.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3): 72.2, 124.4, 124.6, 125.0, 128.1, 136.4,
137.8, 143.5; LRMS calcd.(C8 H5 I S2): 292.15. Found: 291.9;
GC: 95% purity
Scheme 2
Acknowledgement
The University of Copenhagen is gratefully thanked for financial
support. The Authors gratefully thank Xianwen Lou for performing
MALDI-TOF analysis.
References and Notes
(1) Zhu,Y.; Millet, D. B.; Wolf, M. O.; Rettig, S. J.
Organometallics 1999, 18, 1930
(2) Higgins, S. J.; Jones, C. L.; Francis, S. M. Synth. Met. 1999,
98, 211.
(14) 5-Bromo-5’’-iodo[2.2’.5’.2’’]terthiophene (1b): 1a (0.374 g,
1.00 mmol) was dissolved in dry THF (5ml), and the mixture
cooled in an ice bath and NBS (0.178 g, 1.00 mmol) was
added in the cold. The ice bath was removed, the mixture was
shielded from light and stirred overnight at r.t. The solvent
was removed by evaporation and the residue was filtered
through a short silicagel coloumn (Et2O). Yield: 0.320 g
(70%); mp: 175-177 °C (dec); 1H NMR (500 MHz, CDCl3):
6.84 (d, J 3.4 Hz, 1H), 6.91 (d, J 3.4 Hz, 1H), 6.98-7.00 (d+br
s, J 3.9 Hz, 3H), 7.17 (d, J 3.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3): 72.3, 111.4, 124.0, 124.6, 124.8, 125.3, 130.8,
135.5, 135.7, 137.8, 138.4, 142.8.; LRMS calcd.
(3) Choi, N.; Ishida, T.; Inoue, A.; Mizutani, W.; Tokumoto, H.
Appl. Surf. Sci. 1999, 144, 445.
(4) Chang, C. T.; Chang, C.; Lee, C.; Lin, F.; Tsai, J.; Ashendel,
C. L.; Thomas,T. C. K.; Geahlen, R. L.; Waters, D. J. Patent:
US 5578636 A26 1996, 30 pp.
(5) Chang, C. T.; Chen, K. M.; Liu, W. H.; Lin, F. L.; Wu, R. T.
Patent: US 5747525 A5 1998, 34 pp.
(6) Rossi, R.; Carpita, A.; Lezzi, A. Tetrahedron 1984, 40, 2773
(7) MacEachern, A.; Soucy, C.; Leitch, L. C.; Arnason, J. T.;
Morand, P. Tetrahedron 1988, 44, 2403.
(8) Curtis, R. F.; Phillips, G. T. J. Chem. Soc. 1965, 5134.
(9) Steinkopf, W. Liebigs Ann. 1923, 430, 99.
(10) For an alternative approach to monoiodinated
oligothiophenes, see: Sévignon, M.; Papillon, J.; Schulz, E.;
Lemaire, M. Tetrahedron Lett. 1999, 40, 5873.
(11) Wu, R.; Schumm, J. S.; Pearson, D. L.; Tour, J. M. J. Org.
Chem 1996, 61, 6906.
(12) Monoiodination, typical procedure, 5-iodo-[2, 2’, 5’,
2’’]terthiophene (1a): 1 (2.0 g, 8.1 mmol) and NIS (2.1 g, 9.26
mmol) were dissolved in a mixture of dry CHCl3 (30 ml) and
glacial AcOH (20 ml). The mixture was shielded from light
and stirred overnight at r.t. Solvents were removed by
(C12H6BrIS3): 453.3. Found: 453.8; GC: 96% purity; 5-
Bromo-5’-iodo-[2.2’]bithiophene (4b): 4a (1.85 g, 6.34
mmol) was reacted with NBS (1.13 g, 6.34 mmol) in dry THF
(30ml) as above. Filtration through a short silicagel coloumn
(Et2O-hexane 1:1). Yield: 2.17 g (92%); mp: 148-150 °C; 1H
NMR (500 MHz, CDCl3): 6.78 (d, J 3.9 Hz, 1H), 6.86 (d, J
3.9 Hz, 1H), 6.96 (d, J 3.9 Hz, 1H), 7.15 (d, J 3.4 Hz, 1H); 13
C
NMR (75 MHz, CDCl3): 72.5, 111.7, 124.2, 124.4, 125.5,
130.7, 137.8, 142.3; LRMS calcd. (C8 H4 Br I S2): 371.14.
Found: 371.6; GC: 98% purity
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636
U. Boas et al.
LETTER
of this solution was added to a mixture of 4a (0.29 g, 1.00
(15) 5’’-Bromo-5-methyl[2.2’.5’.2’’]terthiophene (4c): A solution
of 2-methyl-thiophene (0.10 g, 1.00 mmol) in dry THF (5ml)
was cooled on an ice bath. A 1.6 M solution of n-BuLi (0.70
ml, 1.10 mmol) was added in the cold and the mixture was
stirred 30 min. on ice bath. ZnCl2 (0.21 g, 1.50 mmol) was
added and the mixture stirred for 1 h at r.t. This solution was
added dropwise to 4b (0.37 g, 1.00 mmol) and Pd (dppf)Cl2
(cat.) in dry THF (5 ml). The mixture was stirred overnight at
r.t. and was poured into water (50 ml). The aqueous layer was
extracted with hexane (2 20 ml), the combined organic
fractions were washed with brine, dried (Na2SO4) and
evaporated in vacuo. Purification by chromatography
(hexane). Yield: 0.264 g (77%); mp: 135-139 °C; 1H NMR
(500 MHz, CDCl3): 2.49 (s, 3H), 6.67 (br s, 1H), 6.89 (d, J
3.9 Hz, 1H), 6.97 (m, 4H); 13C NMR (75 MHz, CDCl3):
15.5, 110.9, 123.6, 123.9, 124.2, 124.6, 126.1, 130.7, 134.5,
134.6, 137.3, 138.8, 139.7; LRMS calcd. (C13H9Br3): 341.4.
Found: 342.0; GC: 96% purity
mmol) and Ni(dppp)Cl2 (5.4 mg, 0.01 mmol) in dry Et2O
(5ml). The mixture was stirred for 2 h at r.t. and refluxed for
30 min. The solvent was removed in vacuo and the residue
was purified by chromatography (Et2O-hexane 1:1). Yield:
0.145 g (43%); mp: 95 °C (dec); 1H NMR (300 MHz, d6-
acetone): 1.33 (s, 9H), 7.1 (t, J 4.0 Hz, 1H), 7.26 (d, J 3.7 Hz,
1H), 7.31 (d, J 2.9 Hz, 1H), 7.38 (d, J 3.7 Hz, 1H), 7.43 (d, J
5.1 Hz, 1H), 7.47 (d, J 8.4 Hz, 2H), 7.61 (d, J 8.4 Hz, 2H) 13
C
NMR (75 MHz, CDCl3): 31.4, 34.7, 114.8, 123.4, 123.6,
124.3, 124.7, 125.5, 126.0, 126.5, 127.9, 131.4, 136.3, 137.7,
143.4, 150.9; LRMS calcd. (C18H18S2): 298.5. Found: 298.0;
GC: 97% purity
(17) Compounds 2 and 3 were prepared by Stille reaction between
2-(tributyl-stannyl)-thiophene and 1.4-dibromo-benzene or
4.7-dibromo-benzo[2.1.3]thiadiazole, respectively, according
to: Dhanabalan, A.; Boas, U.; van Duren, J. K. J.; Janssen,
R. A. J.: To be published.
(16) 5-(4-tert-butyl phenyl)-[2,2’]bithiophene (4d): 1-Bromo-4-
tert-butyl-benzene (2.3 ml, 13.3 mmol) was added to
magnesium turnings (0.5 g, 20.0 mmol) in dry Et2O (13 ml).
The reaction was initiated by shortly heating in an oil bath.
The mixture was refluxed for 30 min, and 1.1 ml (1.1 mmol)
Article Identifier:
1437-2096,E;2001,0,05,0634,0636,ftx,en;G01001ST.pdf
Synlett 2001, No. 5, 634–636 ISSN 0936-5214 © Thieme Stuttgart · New York