First site-selective suzuki-miyaura reactions of 2,3,4-tribromothiophene

Article abstract of DOI:10.1055/s-0029-1219380

The first Suzuki-Miyaura reactions of 2,3,4-tribromothiophene are reported. These reactions provide a convenient and site-selective approach to 2-aryl-3,4-dibromothiophenes, 2,4-diaryl-3-bromothiophenes, and 2,3,4-triarylthiophenes. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219380

LETTER
909
First Site-Selective Suzuki–Miyaura Reactions of 2,3,4-Tribromothiophene
Site-Selective
e
Suzuki–Mi
r
yaura Re
g
actions of 2,
e
3,4-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
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax +1(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Received 5 December 2009
The Suzuki–Miyaura reaction of commercially available
2,3,4-tribromothiophene (1) with various arylboronic ac-
ids (1.1 equiv) afforded the 2-aryl-3,4-dibromothiophenes
2a–d in 85–94% yield (Scheme 1, Table 1).10 The Suzu-
ki–Miyaura reaction of 1 with 2.1 equivalents of arylbo-
ronic acids afforded the 2,4-diaryl-3-bromothiophenes
3a–d in 46–55% yield (Scheme 1, Table 2). The employ-
ment of 4.0 equivalents of arylboronic acids resulted in
the formation of 2,3,4-triarylthiophenes 4a–d in very
good yields (Scheme 1, Table 3).
Abstract: The first Suzuki–Miyaura reactions of 2,3,4-tribro-
mothiophene are reported. These reactions provide a convenient
and site-selective approach to 2-aryl-3,4-dibromothiophenes, 2,4-
diaryl-3-bromothiophenes, and 2,3,4-triarylthiophenes.
Key words: catalysis, palladium, Suzuki–Miyaura reaction, site
selectivity, thiophene
Aryl-substituted thiophenes are of considerable pharma-
cological relevance.1 Thiophenes have also been isolated
as natural products.2 Thiophenes are of great importance
in the field of material science, because of their electronic
properties (e.g., redox activity, luminescence, nonlinear
optical chromism, and electron transport).3 In this context,
the synthesis of terthiophenes and thienyldiynes play an
important role.4
S
Ar
Br
Br
2a–d
i
S
Br
S
Ar
Site-selective palladium(0)-catalyzed cross-coupling re-
actions of polyhalogenated heterocycles constitute a pow-
erful tool in organic synthesis.5 The site selectivity often
relies on electronic parameters [oxidative additions of pal-
ladium(0) species to carbon–halogen bonds are usually
more rapid for electron-poor than for electron-rich carbon
atoms]. In addition, steric parameters play an important
role. It has been reported that Sonogashira and Kumada
reactions of 2,3- and 2,4-dibromothiophene proceed with
very good site selectivity (the first attack occurs at carbon
ii
Br
Br
1
Ar
Br
Ar
+
3a–d
iii
ArB(OH)2
S
Ar
4a–d
Ar
Scheme 1 Synthesis of 2a–d, 3a–d, and 4a–d. Reagents and condi-
atom C-2).6 2,3,5-Tribromothiophene undergoes site-se- 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, 5 h (see Table 1); ii,
lective metal–halide exchange, Kumada, and Suzuki
cross-coupling reactions.7 Sonogashira reactions of
1 (1.0 equiv), ArB(OH)2 (2.1 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (4.0
equiv), 1,4-dioxane–toluene (1:1), H2O (1 mL), 100 °C, 12 h, (see Ta-
ble 2); iii, 1 (1.0 equiv), ArB(OH)2 (4.0 equiv), Pd(PPh3)4 (6 mol%),
K2CO3 (2 M, H2O), 1,4-dioxane, 90 °C, 12 h (see Table 3).
2,3,4,5-tetraiodothiophene and 2,3,4,5-tetrabromothio-
phene have been reported to proceed selectively at posi-
tions 2 and 5.8 Aryl-substituted thiophenes and
selenophenes have been prepared by site-selective Suzuki
The Suzuki–Miyaura reaction of 2-aryl-3,4-dibro-
reactions of 2,3,4,5-tetrabromothiophene and 2,3,4,5-tet-
mothiophenes 3a,b with 1.1 equivalents of arylboronic
rabromoselenophene, respectively.9 Herein, we report
acids resulted in site-selective formation of the 2,4-di-
what are, to the best of our knowledge, the first Suzuki–
arylthiophenes 5a–c containing two different aryl groups
Miyaura reactions of 2,3,4-tribromothiophene. This sub-
(Scheme 2, Table 4). Preliminary results show that the
strate is of special synthetic and mechanistic interest since
it contains three positions with different reactivity (com-
pared to only two positions in case of 2,3,4,5-tetrabro-
mothiophene). The reactions reported herein provide a
convenient site-selective approach to 2-aryl-3,4-dibro-
mothiophenes, 2,4-diaryl-3-bromothiophenes, and 2,3,4-
triarylthiophenes which are not readily available.
Table 1 Synthesis of 2-Aryl-3,4-dibromothiophenes 2a–d
2
Ar
Yield of 2 (%)a
2a
2b
2c
2d
4-MeC6H4
4-EtC6H4
4-t-BuC6H4
2-MeOC6H4
89
87
94
85
SYNLETT 2010, No. 6, pp 0909–0912
x
x.
x
x.
2
0
1
0
Advanced online publication: 08.02.2010
DOI: 10.1055/s-0029-1219380; Art ID: G40509ST
© Georg Thieme Verlag Stuttgart · New York
a Yields of isolated products.

910
S.-M. T. Toguem et al.
LETTER
S
Ar1
S
Ar1
Ar2B(OH)2
i
Ar2
Br
Br
Br
5a–c
2a,b
Scheme 2 Synthesis of 5a–c. Reagents and conditions: i, 2a,b (1.0
equiv), Ar2B(OH)2 (1.1 equiv), Pd(PPh3)4 (6 mol%), K3PO4 (4.0
equiv), 1,4-dioxane–toluene (1:1), H2O (1 mL), 100 °C, 12 h.
Table 2 Synthesis of 3-Bromo-2,4-diarylthiophenes 3a–d
3
Ar
Yield of 3 (%)a
3a
3b
3c
3d
4-MeC6H4
4-EtC6H4
3,5-Me2C6H3
4-t-BuC6H4
55
51
46
49
a Yields of isolated products.
Table 3 Synthesis of 2,3,4-Triarylthiophenes 4a–d
Figure 1 Crystal structure of 3a
4
Ar
Yield of 4 (%)a
4a
4b
4c
4d
4-MeC6H4
3,5-Me2C6H3
4-t-BuC6H4
4-MeOC6H4
93
86
94
96
a Yields of isolated products.
Table 4 Synthesis of 3-Bromo-2,4-diarylthiophenes 5a–c
5
Ar1
Ar2
Yield of 5 (%)a
5a
5b
5c
4-MeC6H4
4-EtC6H4
4-EtC6H4
2-MeOC6H4
2-MeOC6H4
87
81
2,6-(MeO)2C6H3 53
a Yields of isolated products.
reaction of these products with 2.0 equivalents of boronic
acids allows the synthesis of 2,3,4-triarylthiophenes con-
taining three different aryl groups.
Figure 2 Crystal structure of 4c
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 2a–d and 4a–d K2CO3
and for the synthesis of 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 solvent.
The yields of 2-aryl-3,4-dibromothiophenes 2a–d and of
2,3,4-triarylthiophenes 4a–d were significantly higher
than those of 2,4-diaryl-3-bromothiophenes 3a–d. The
high yields of 4a–d can be explained by the fact that no is-
sue of site selectivity exists. The high yields show that the
last step, the reaction of carbon atom C-3, must also pro-
ceed in good yields. The high yields of 2a–d suggest that
the rate of the reaction of carbon C-2 is considerably high-
er than that of carbon C-4. This can be explained by elec-
tronic reasons (Scheme 3). Inspection of selected crude
spectra of 2 and 3 showed that no significant amounts of
other heterocyclic products were formed. The moderate
yields of products 3 can be explained by practical prob-
The structures of all products were established by spectro-
scopic methods (NOESY, HMBC). The structures of 3a
and 4c were independently confirmed by X-ray crystal-
structure analyses (Figure 1 and Figure 2).11
Synlett 2010, No. 6, 909–912 © Thieme Stuttgart · New York

LETTER
Site-Selective Suzuki–Miyaura Reactions of 2,3,4-Tribromothiophene
G. L.; Koehane, C. A.; Hajdu, R.; Milligan, J. A.;
911
lems during the chromatographic purification. In fact, the
transformation of thiophenes 2 into 5 proceeded in very
good yields (except for 5c which is derived from sterically
hindered 2,6-dimethoxyphenylboronic acid). These re-
sults suggest that the rate of the reaction of carbon C-4 is
considerably higher than that of carbon C-3.
Rosenbach, M. J.; Mandela, S. Bioorg. Med. Chem. Lett.
2006, 16, 3684. (i) Gonzalez, J. L.; Stephens, C. E.;
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Food Chem. 2006, 54, 1651.
most electron-deficient
1
less sterically hindered
S
less electron-deficient
less sterically hindered
Br
Br
2
Br
less electron-deficient
most sterically hindered
3
(3) 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.;
Deloffre, F.; Servet, B.; Ries, S.; Alnot, P. J. Am. Chem. Soc.
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.
(e) Dodabalapur, A.; Rothberg, L. J.; Fung, A. W. P.; Katz,
H. E. Science 1996, 272, 1462. (f) Noda, T.; Ogawa, H.;
Noma, N.; Shirota, Y. Appl. Phys. Lett. 1997, 70, 699.
(g) Noda, T.; Imae, I.; Noma, N.; Shirota, Y. Adv. Mater.
1997, 9, 239. (h) Cui, Y.; Zhang, X.; Jenekhe, S. A.
Marcomolecules 1999, 32, 3824. (i) Thayumanavan, S.;
Mendez, J.; Marder, S. R. J. Org. Chem. 1999, 64, 4289.
(4) (a) Mori, Y.; Taneda, S.; Hayashi, H.; Sakushima, A.;
Kamata, K.; Suzuki, A. K.; Yoshino, S.; Sakata, M.; Sagai,
M.; Seki, K.-i. Biol. Pharm. Bull. 2002, 25, 145. (b) Liu, P.;
Zhang, Y.; Feng, G.; Hu, J.; Zhou, X.; Zhao, Q.; Xu, Y.;
Tong, Z.; Deng, W. Tetrahedron 2004, 60, 5259. (c) Huss,
U.; Ringbom, T.; Perera, P.; Bohlin, L.; Vasaenge, M. J. Nat.
Prod. 2002, 65, 1517. (d) Albano, V. G.; Bandini, M.;
Melucci, M.; Monari, M.; Piccinelli, F.; Tommasi, S.;
Umani-Ronchi, A. Adv. Synth. Catal. 2005, 11, 1507.
(e) Melucci, M.; Barbarella, G.; Zambianchi, M.; Pietro,
P. D.; Bongini, A. J. Org. Chem. 2004, 69, 4821.
(f) Ciofalo, M.; Petruso, S.; Schillaci, D. Planta Med. 1996,
62, 374. (g) Guillet, G.; Philogene, B. J. R.; O’Meara, J.;
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Figure 3 Possible explanation for the site selectivity of the reac-
tions of 1
As discussed above, 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-2 is the most reactive position because of
its electron-deficient character and because it is easily
sterically accessible (Scheme 3). From the electronic
viewpoint, carbon C-3 is similar to C-4, but C-3 is more
sterically hindered than C-4 because of the neighborhood
of two bromine atoms.
In conclusion, we have reported the first Suzuki–Miyaura
reactions of 2,3,4-tribromothiophene. The reaction with
one, two, and three equivalents of arylboronic acids re-
sulted in formation of 2-aryl-3,4-dibromothiophenes, 2,4-
diaryl-3-bromothiophenes, and 2,3,4-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 acknowl-
edged.
References and Notes
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P. J. J. Chem. Soc., Perkin Trans. 1 1994, 2735. (b)Carpita,
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(d) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun,
J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
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Antimicrob. Agents Chemother. 2002, 46, 797. (h) Vachal,
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53, 2489. (b) Eichhorn, S. H.; Paraskos, A. J.; Kishikawa,
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912
S.-M. T. Toguem et al.
LETTER
(10) General Procedure for the Synthesis of 2-Aryl-3,4-
dibromothiophenes 2
3J = 8.3 Hz, 2 H, Ar). 13C NMR (62 MHz, CDCl3): d = 15.4
(CH3), 28.7 (CH2), 111.0, 114.7 (CBr), 122.0 (CH,
thiophene), 128.2 (2 CH, Ar), 128.9 (2 CH, Ar), 130.3,
139.7, 145.7 (C). IR (KBr): n = 3107 (w), 3020 (w), 2961
(m), 2927 (m), 2630 (w), 2306 (w), 1903 (w), 1524 (w),
1484 (m), 1308 (w), 1126 (w), 963 (w), 877 (s), 828 (s), 785
(m), 722 (s), 645 (w), 585 (m), 539 (m) cm–1. GC-MS (EI, 70
eV): m/z (%) = 348 (44) [M+, 81Br, 81Br], 346 (83) [M+, 81Br,
79Br], 344 (41) [M+, 79Br, 79Br], 333 (54), 331 (100) [M+],
329 (50), 186 (11), 171 (38), 139 (11). HRMS (EI, 70 eV):
m/z calcd for C12H10Br2S [M+, Br, 81Br]: 345.88440; found:
345.88457.
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 5 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, heptanes).
Synthesis of 3,4-Dibromo-2-(4-ethylphenyl)thio-
phene (2b)
Starting with 1 (0.320 g, 1.0 mmol) and 4-ethylphenyl-
boronic acid (0.165 g, 1.1 mmol), 2b was isolated (0.298 g,
87%) as a colorless oil. 1H NMR (300 Hz, CDCl3): d = 1.32
(t, 3J = 7.6 Hz, 3 H, CH3), 2.75 (q, 3J = 7.6 Hz, 2 H, CH2),
7.32 (d, 3J = 8.4 Hz, 2 H, Ar), 7.38 (s, 1 H, Ar), 7.58 (d,
(11) CCDC 760153 and 760154 contain all crystallographic
details of this publication and is available free of charge at
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; Fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
Synlett 2010, No. 6, 909–912 © Thieme Stuttgart · New York