Site-selective suzuki-miyaura reactions of 2,3,5-tribromothiophene

Article abstract of DOI:10.1055/s-0029-1218355

The first Suzuki-Miyaura reactions of 2,3,5-tribromothiophene are reported. These reactions provide a convenient and site-selective approach to 5-aryl-2,3-dibromothiophenes, 2,5-diaryl-3-bromothiophenes, and 2,3,5-triarylthiophenes. Georg Thieme Verlag St

Full text of DOI:10.1055/s-0029-1218355

LETTER
3311
Site-Selective Suzuki–Miyaura Reactions of 2,3,5-Tribromothiophene
Site-Selective
e
Suzuki–Mi
r
yaura Re
g
actions of 2,
e
3,5-Tribrom
-
othioph
M
ene ithérand Tengho Toguem,a Alexander Villinger,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
Received 18 September 2009
The Suzuki–Miyaura reaction of commercially available
2,3,5-tribromothiophene (1) with various arylboronic ac-
ids (1.1 equiv) afforded the 5-aryl-2,3-dibromothiophenes
2a–d in 40–53% yield (Scheme 1, Table 1).18
Abstract: The first Suzuki–Miyaura reactions of 2,3,5-tribro-
mothiophene are reported. These reactions provide a convenient
and site-selective approach to 5-aryl-2,3-dibromothiophenes, 2,5-
diaryl-3-bromothiophenes, and 2,3,5-triarylthiophenes.
Key words: catalysis, palladium, Suzuki–Miyaura reaction, site se-
lectivity, thiophene
S
Ar
Br
Br
2a–d
i
Polyhalogenated heterocycles are of considerable current
interest as substrates in site-selective palladium(0)-cata-
lyzed cross-coupling reactions.1 The site selectivity often
relies on the different rates of oxidative additions of palla-
dium(0) species to carbon–halide bonds and on steric pa-
rameters. Electron-poor carbon atoms are usually more
reactive than their electron-rich counterparts.
S
Ar
S
Ar
Br
Br
Br
Br
ii
3a–d
iii
1
S
+
Ar
Ar
Ar
ArB(OH)2
4a–d
Thiophene derivatives are of special interest in this con-
text. Aryl-substituted thiophenes are of significant rele-
vance in medicinal chemistry.2 Functionalized thiophenes
also occur in a number of natural products.3 Due to their
electronic properties, such as luminescence, redox activi-
ty, nonlinear optical chromism, and electron transport,
thiophenes are also important in the field of material sci-
ences.4 This includes, for example, dibenzothiophenes,5
terthiophenes,6 and thienyl-diynes.7
Scheme 1 Synthesis of 2a–d, 3a–d, and 4a–d. Reagents and condi-
tions: (i) 1 (1.0 equiv), ArB(OH)2 (1.1 equiv), Pd(PPh3)4 (5 mol%),
K2CO3 (2 M), 1,4-dioxane–toluene (1:1), 100 °C, 8 h (see Table 1);
(ii) 1 (1.0 equiv), ArB(OH)2 (2.2 equiv), Pd(PPh3)4 (5 mol%), K3PO4
(4.0 equiv), 1,4-dioxane–toluene (1:1), 100 °C, 12 h (see Table 2);
(iii) 1 (1.0 equiv), ArB(OH)2 (4.0 equiv), Pd(PPh3)4 (10 mol%),
K2CO3 (2 M), 1,4-dioxane, 90 °C, 8 h (see Table 3).
Table 1 Synthesis of 5-Aryl-2,3-dibromothiophene 2a–d
Site-selective Sonogashira and Kumada reactions of the
2-position of 2,3- and 2,4-dibromothiophene have been
studied.8,9 Metal–halide exchange reactions10 and Kuma-
da cross-coupling reactions11 of 2,3,5-tribromothiophene
have been reported. In addition, an isolated example of a
Stille coupling12 and of a polymer synthesis have been re-
ported.13 2,5-Disubstituted thiophenes were prepared by
regioselective Sonogashira coupling reactions of 2,3,4,5-
2
Ar
Yield of 2 (%)a
2a
2b
2c
2d
4-MeC6H4
4-EtC6H4
3-FC6H4
2,6-(MeO)C6H3
47
53
40
44
tetraiodothiophene14 and 2,3,4,5-tetrabromothiophene.15 a Yields of isolated products.
Recently, we have reported the synthesis of aryl-substitut-
ed thiophenes and selenophenes by regioselective Suzuki
The Suzuki–Miyaura reaction of 1 with 2.2 equivalents of
arylboronic acids afforded the 2,5-diaryl-3-bro-
mothiophenes 3a–d in 50–67% yield (Scheme 1,
Table 2). The reactions again proceeded with very good
site selectivity. The employment of 4.0 equivalents of
arylboronic acids resulted in the formation of 2,3,5-tri-
arylthiophenes 4a–d in very good yields (Scheme 1,
Table 3).
reactions of tetrabromothiophene and -selenophene, re-
spectively.16,17 Herein, we report what are, to the best of
our knowledge, the first Suzuki–Miyaura reactions of
2,3,5-tribromothiophene.13 The reaction of the latter with
one, two, and three equivalents of arylboronic acids af-
forded 5-aryl-2,3-dibromothiophenes, 2,5-diaryl-3-bro-
mothiophenes, and 2,3,5-triarylthiophenes with very good
site selectivity, respectively.
The Suzuki–Miyaura reaction of 2,5-diaryl-3-bro-
mothiophenes 3a,b with 2.0 equivalents of arylboronic
acids afforded the 2,3,5-triarylthiophenes 5a–c containing
two different aryl groups (Scheme 2, Table 4). Prelimi-
SYNLETT 2009, No. 20, pp 3311–3314
Advanced online publication: 11.11.2009
DOI: 10.1055/s-0029-1218355; Art ID: G32609ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3312
S.-M. T. Toguem et al.
LETTER
only moderate yields, the site selectivities of all reactions
were very good. In fact, inspection of selected crude spec-
tra of 2 and 3 showed that significant amounts of other
heterocyclic products were not formed. The moderate
yields of the isolated products can be explained by practi-
cal problems during the chromatographic purification.
Table 2 Synthesis of 2,5-Diaryl-3-bromothiophene 3a–d
3
Ar
Yield of 3 (%)a
3a
3b
3c
3d
4-MeC6H4
4-EtC6H4
2-ClC6H4
3-ClC6H4
55
67
51
50
The structures of all products were established by spectro-
scopic methods. The structures of 2a, 3a, and 4d were in-
dependently confirmed by X-ray crystal structure
analyses (Figure 1 and Figure 2).19
a Yields of isolated products.
Table 3 Synthesis of 2,3,5-Triarylthiophenes 4a–d
4
Ar
Yield of 4 (%)a
4a
4b
4c
4d
4-MeC6H4
4-t-BuC6H4
3,5-Me2C6H3
4-F3CC6H3
92
87
78
83
Figure 1 Crystal structure of 3a
a Yields of isolated products.
Ar1
Ar1
S
S
Ar1
Br
Ar1
Ar2B(OH)2
i
Ar2
3a,b
5a–c
Scheme 2 Synthesis of 5a-c. Reagents and conditions: (i) 3a,b (1.0
equiv), Ar2B(OH)2 (2.0 equiv), Pd(PPh3)4 (10 mol%), K3PO4 (4.0
equiv), 1,4-dioxane–toluene (1:1), 100 °C, 12 h.
Table 4 Synthesis of 2,3,5-Triarylthiophenes 5a–c
5
Ar1
Ar2
Yield of 5 (%)a
5a
5b
5d
4-MeC6H4
4-EtC6H4
4-EtC6H4
4-EtC6H4
4-MeC6H4
2-(EtO)C6H3
92
87
83
Figure 2 Crystal structure of 4d
a Yields of isolated products.
The regioselectivites reported herein can be explained
based on the different electronic and steric properties of
the three different C–Br bonds of 1. Carbon atom C-5 is
the most reactive position because of its electron-deficient
character and because it is easily sterically accessible
(Figure 3). From the electronic viewpoint, carbon C-2 is
similar to C-5, but it is more sterically hindered because
of the neighborhood of the bromine atom attached to car-
nary results show that the reaction of 5-aryl-2,3-dibro-
mothiophenes 2 with one equivalent of boronic acids
allows a site-selective synthesis of 2,5-diaryl-3-bro-
mothiophenes containing two different aryl groups.
In all reactions, the best yields were obtained when
Pd(PPh3)4 was used as the catalyst. The use of other cata-
lysts, such as Pd(OAc)2/X-Phos, proved to be less suc-
cessful in terms of yield. All reactions were carried out at
90–100 °C. For the synthesis of compounds 2a–d and 4a–
d K2CO3 and for the synthesis of compounds 3a–d and
5a–c K3PO4 was used as the base. 1,4-Dioxane or a 1:1
mixture of 1,4-dioxane and toluene was used as the sol-
vent. The yields of products derived from arylboronic
acids containing electron-donating and electron-with-
drawing substituents lie in a similar range. The yields of
products 4a–d and 5a–c, where no issue of site selectivity
was present, were generally higher than those of 2a–d and
3a–d. Although products 2a–d and 3a–d were isolated in
electron-deficient
sterically hindered
2
S
Br
Br
Br
1
electron-deficient
not sterically hindered
less electron-deficient
not sterically hindered
3
Figure 3 Possible explanation for the site-selectivity of the reac-
tions of 1
Synlett 2009, No. 20, 3311–3314 © Thieme Stuttgart · New York

LETTER
Site-Selective Suzuki–Miyaura Reactions of 2,3,5-Tribromothiophene
3313
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In conclusion, we have reported the first Suzuki–Miyaura
reactions of 2,3,5-tribromothiophene. The reaction with
one, two, and three equivalents of arylboronic acids re-
sulted in formation of 5-aryl-2,3-dibromothiophenes, 2,5-
diaryl-3-bromothiophenes, and 2,3,5-triarylthiophenes
with very good site selectivity, respectively.
Acknowledgment
Financial support by the DAAD (scholarship for S.-M.T.T.) and by
the State of Mecklenburg-Vorpommern is gratefully acknowled-
ged.
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(18) General Procedure for the Synthesis of 2,3-Dibromo-5-
arylthiophene 2
To a mixture of 1 (0.159 g, 0.5 mmol), arylboronic acid (0.55
mmol), Pd(PPh3)4 (5 mol%) were added a mixture of 1,4-
dioxane and toluene (1:1, 5 mL) and an aq solution of K2CO3
(2 mL, 2 M) under argon atmosphere. The reaction mixture
was stirred at 100 °C for 8 h and was subsequently allowed
to cool to 20 °C. The solution was poured into H2O and
CH2Cl2 (25 mL each) and the organic and the aqueous layer
were separated. The latter was extracted with CH2Cl2 (3 × 25
mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography
(flash silica gel, n-heptane).
Synthesis of 2,3-Dibromo-5-p-tolylthiophene (2a)
Starting with 1 (0.320 g, 1.0 mmol) and 4-tolylboronic acid
(0.149 g, 1.1 mmol), 2a was isolated (0.150 g, 47%) as a
colorless solid, mp 83–85 °C. 1H NMR (300 MHz, CDCl3):
d = 2.26 (s, 3 H, CH3), 6.94 (s, 1 H, Ar), 7.08 (d, 3J = 8.0 Hz,
2 H, Ar), 7.26 (d, 3J = 8.2 Hz, 2 H, Ar). 13C NMR (62 MHz,
CDCl3): d = 21.3 (CH3), 109.4, 114.5 (CBr), 125.0, 125.3,
128.7, 129.4, 129.8 (CH, Ar), 130.0, 138.6, 145.6 (C). IR
(KBr): n = 3091 (w), 3019 (w), 2918 (w), 2852 (w), 1498
(m), 1433 (w), 1118 (w), 997 (w), 821 (w), 801 (m), 550 (w)
cm–1. GC-MS (EI, 70 eV): m/z (%) = 334 [M+, 81Br, 81Br],
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(4) For oligothiophenes with low-lying triplet states, see:
(a) Garnier, F. Angew. Chem., Int. Ed. Engl. 1989, 28, 513.
(b) Garnier, F.; Yassar, A.; Hajlaoui, R.; Horowitz, G.;
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1993, 115, 8716. (c) Garnier, F.; Hajlaoui, R.; Yassar, A.;
Srivastava, P. Science 1994, 265, 1684. (d) Dodabalapur,
A.; Torsi, L.; Katz, H. E. Science 1995, 268, 270.
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Synlett 2009, No. 20, 3311–3314 © Thieme Stuttgart · New York

3314
S.-M. T. Toguem et al.
LETTER
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
332 (100) [M+, 81Br, 79Br], 331 (16) [M+], 330 (49) [M+, 79Br,
79Br], 172 (35), 171 (30), 86 (11). HRMS (EI, 70 eV): m/z
calcd for C11H8Br2S [M+, 81Br, 79Br]: 331.86875; found:
331.86882.
(19) CCDC-749926 and 749927 contain all crystallographic
details of this publication and is available free of charge at
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