One-Pot Halogen Dance/Negishi Coupling of Dibromothiophenes for Regiocontrolled Synthesis of Multiply Arylated Thiophenes

Article abstract of DOI:10.1002/chem.201604293

One-pot halogen dance/Negishi cross-coupling of readily available 2,5-dibromothiophenes is described. A lithium diisopropylamide (LDA)-mediated halogen dance reaction resulted in the formation of thermodynamically stable α-lithiodibromothiophenes, which w

Full text of DOI:10.1002/chem.201604293

A Journal of
Accepted Article
Title: One-pot Halogen Dance/Negishi Coupling of Dibromothiophenes for Regio-
controlled Synthesis of Multiply Arylated Thiophenes
Authors: Kentaro Okano; Kazuhiro Sunahara; Yoshiki Yamane; Yuki Hayashi; Ats-
unori Mori
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201604293
Link to VoR: http://dx.doi.org/10.1002/chem.201604293
Supported by

Chemistry - A European Journal
10.1002/chem.201604293
COMMUNICATION
One-Pot Halogen Dance/Negishi Coupling of Dibromothiophenes
for Regiocontrolled Synthesis of Multiply Arylated Thiophenes
Kentaro Okano,* Kazuhiro Sunahara, Yoshiki Yamane, Yuki Hayashi, and Atsunori Mori
Abstract: One-pot halogen dance/Negishi cross coupling of readily
available 2,5-dibromothiophenes is described. An LDA-mediated
halogen dance reaction resulted in the formation of
thermodynamically stable -lithiodibromothiophenes, which were
transmetalated with ZnCl2 and subjected to Negishi cross coupling to
provide the corresponding arylated dibromothiophenes in one pot.
The resultant -bromo group was much less reactive than the
remaining-bromo group, which was used in a one-pot double
Suzuki–Miyaura cross coupling, enabling facile synthesis of multiply
arylated thiophenes.
bromine atoms in the product have different reactivities in further
transition metal-catalyzed reactions.[8] However, the scope of the
electrophiles that have been trapped by the lithiated thiophenes
is limited, although numerous halogen dance reactions of
thiophenes have been performed.[7] To the best of our
knowledge, the transient thienyl lithium species generated by the
halogen dance reaction has not been used for cross-coupling
reactions. Here, we report a one-pot halogen dance/Negishi
coupling of bromothiophenes [Scheme 1, Eq. (3)] for
regiocontrolled synthesis of multiply arylated thiophenes.
Arylated thiophenes are structural constituents of drug
candidates and pharmaceuticals,[1] biologically active natural
products,[2] and functional organic materials[3] (Figure 1). Despite
Figure 1. Multiply arylated thiophenes.
Scheme 1. Examples of functional group introduction into thiophene ring.
their potential utilities, general and practical synthetic methods
for multiply arylated thiophenes have not yet been fully
established. Unlike the cases of mono-/di-arylated thiophenes,
regiochemical problems often arise in the synthesis of tri-/tetra-
arylated thiophenes. Achieving sufficient regioselectivity using
conventional cross coupling of brominated thiophenes is
therefore challenging.[1f,4] Stepwise introduction of aryl groups
requires a number of reaction steps; for example, Itami and co-
workers reported the stepwise synthesis of multiply arylated
thiophenes using palladium-catalyzed C–H arylations[5] [Scheme
1, Eq. (1)]. Knochel and co-workers also reported the synthesis
of tetra-substituted thiophenes by deprotonation/functionalization
with Mg(TMP)Cl·LiCl as a base.[6] The generated thienyl
magnesium species can be used for cross-coupling reactions
[Scheme 1, Eq. (2)]. Halogen dance of 2,5-dibromothiophene,[7]
which is a halogen migration reaction, also holds the potential
for pot-economical transformations because the - and -
First we attempted Murahashi coupling[9] to introduce a 4-
anisyl group directly into lithiated dibromothiophene 1, which
was generated by treatment of 2,5-dibromothiophene (2) with
LDA[10] at –78 °C using previously reported conditions[7]
(Scheme 2). The halogen dance was completed at –78 °C within
5 min, and the resultant lithiothiophene 1 was immediately
treated with p-iodoanisole in the presence of various palladium
catalysts to provide the desired arylated compound 3 in up to
20% yield with concomitant generation of unidentified
byproducts, probably through undesired iodine–lithium
exchange.[11] We also attempted slow or inverse addition of
lithiothiophene 1 using Feringa’s method,[12] but the yields were
low.
[a]
Prof. Dr. K. Okano,* K. Sunahara, Y. Yamane, Y. Hayashi, and Prof.
Dr. A. Mori
Department of Chemical Science and Engineering, Kobe University,
1-1 Rokkodai, Nada, Kobe 657-8501 (Japan)
E-mail: okano@harbor.kobe-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Initial attempts to introduce anisyl group by Murahashi coupling.
This article is protected by copyright. All rights reserved

Chemistry - A European Journal
10.1002/chem.201604293
COMMUNICATION
To prevent undesired scrambling of the halogen atoms by
halogen–lithium exchange and improve the operational
processes, we next examined transmetalation of the transient
lithiated dibromothiophene 1 and found that transmetalation with
ZnCl2·TMEDA[13] facilitated Negishi cross coupling[14] to give the
desired arylated dibromothiophene (Table 1). The transient
lithiated dibromothiophene 1 from 2,5-dibromothiophene (2) was
treated with ZnCl2·TMEDA followed by p-iodoanisole,
Pd2(dba)3·CHCl3, and a phosphorus ligand. Among the bidentate
ligands tested, DPEPhos provided the desired compound 3 in
44% yield with 20% recovery of 5 (Table 1, entries 1–3).
Monodentate PPh3 also gave a comparable yield; however, the
The use of Pd(PPh3)4 significantly improved the product yield,
but Pd(tBu3P)2 gave unsatisfactory results (Table 1, entries 7
and 8). The recently reported Pd-PEPPSI-IPr and Pd-PEPPSI-
SIPr[15] provided no product, although recovery of 5 was low
(Table 1, entries 9 and 10). A lower catalyst loading (2.0 mol%)
still gave moderate yield (Table 1, entries 11 and 12).
The established halogen dance/Negishi cross coupling
enabled efficient synthesis of an intermediate of a triarylated
thiophene, human 17-HSD1 inhibitor[1f] (Scheme 3). Hartmann
and co-workers synthesized arylated dibromothiophene 6 from
tribromothiophene 7 in 23% yield by Suzuki–Miyaura cross
coupling, which indicates that it is difficult to control the
regioselectivity of the three bromo groups in the cross coupling.
The halogen dance/Negishi cross coupling of 2,5-
dibromothiophene (2) provided 6 in 73% yield.
desired product
3 was not generated with P(o-tolyl)3 or
JohnPhos (Table 1, entries 4–6).
Table 1. Optimization of palladium catalyst for Negishi coupling[a]
Scheme 3. Regiocontrolled synthesis of aryldibromothiophene via one-pot
halogen dance/Negishi coupling.
Entry
Catalyst
3 [%]
5 [%]
1
Pd2(dba)3·CHCl3 (2.5 mol%), DPPP (10 mol%)
Pd2(dba)3·CHCl3 (2.5 mol%), DPPF (10 mol%)
Pd2(dba)3·CHCl3 (2.5 mol%), DPEPhos (10 mol%)
Pd2(dba)3·CHCl3 (2.5 mol%), PPh3 (20 mol%)
Pd2(dba)3·CHCl3 (2.5 mol%), P(o-tolyl)3 (20 mol%)
Pd2(dba)3·CHCl3 (2.5 mol%), JohnPhos (20 mol%)
Pd(PPh3)4 (5.0 mol%)
6[b]
33[b]
44[b]
45[b]
70[b]
23[b]
20[b]
15[b]
57[b]
63[b]
11[b]
39[b]
12[b]
8[b]
2
These results are complementary to those reported by
Knochel (Scheme 4).[16] They achieved regioselective
magnesiation of tribromothiophene 8 using a combination of
hindered Grignard reagent 9 and diamino ether 10. The resultant
thienyl Grignard was subjected to Negishi cross coupling to give
arylated dibromothiophene 11, which was also obtained from
2,5-dibromo-3-methylthiophene (12) using the halogen
dance/Negishi coupling sequence, in 79% yield.
3
4
[c]
5
–
[c]
6
–
7
77[b]
18[b]
8
Pd(tBu3P)2 (5.0 mol%)
[c]
9
Pd-PEPPSI-IPr (5.0 mol%)
–
[c]
10
11
12
Pd-PEPPSI-SIPr (5.0 mol%)
–
Pd(PPh3)4 (2.0 mol%)
42[b]
29[b]
22[b]
42[b]
Pd(PPh3)4 (1.0 mol%)
[a] Reaction conditions: 2,5-dibromothiophene (2) (1 equiv, 0.30 mmol), LDA
(1.1 equiv, 0.33 mmol), THF, –78 to 0 °C, 5 min; ZnCl2·TMEDA (1.2 equiv, 0.36
mmol), RT, 15 min; catalyst, p-iodoanisole (1.2 equiv, 0.36 mmol), 60 °C, 24 h.
[b] The yield was determined from the 1H NMR spectrum of the crude material
using 1,1,2,2-tetrachloroethane as an internal standard. [c] Not detected in the
crude 1H NMR spectrum. LDA = lithium diisopropylamide. TMEDA = N,N,N’,N’-
tetramethylethylenediamine. DBA = dibenzylidene acetone. DPPP = 1,3-bis(di
phenylphosphino)propane. DPPF
DPEPhos = bis[(2-diphenylphosphino)phenyl] ether. JohnPhos = 2-(di-tert-
butylphosphino)biphenyl. PEPPSI-IPr [1,3-bis(2,6-diisopropylphenyl)imida-
=
1,1′-bis(diphenylphosphino)ferrocene.
=
zolylidene](3-chloropyridyl)palladium(II) dichloride. PEPPSI-SIPr = [1,3-bis(2,6-
diisopropylphenyl)imidazolidene](3-chloropyridyl)palladium(II) dichloride.
Scheme 4. Complementary results to those reported by Knochel.
This article is protected by copyright. All rights reserved

Chemistry - A European Journal
10.1002/chem.201604293
COMMUNICATION
Having identified the optimum reaction conditions, we
investigated the scope of the coupling partner with 2,5-
dibromothiophene (2) (Table 2).[17] In addition to the p-anisyl
group, phenyl and 4-tolyl groups were successfully introduced to
provide the corresponding products 13 and 14 in 59% and 62%
yields, respectively. It is worth noting that the base-labile ester
moiety survived under the reaction conditions to give the desired
product 15 in excellent yield. In addition to para-substituted
iodobenzenes, meta- and ortho-substituted substrates were
investigated. Electron-donating/-withdrawing groups were both
compatible and gave the desired products 6 and 16–18 in good
to excellent yields. When m-bromoiodobenzene was used as the
coupling partner, cross coupling took place selectively at the
iodo group. The pyridine-conjugated thiophene 19 was obtained
in 51% yield from 2-iodopyridine as the coupling partner.
Table 3. Substrate scope for halogen dance–Negishi coupling
R
Yield [%][a]
Product
H
53 21
63 22
70 23
CF3
CO2Et
H
53 24
57 25
CF3
NO2
Table 2. Scope of aryl group in one-pot halogen dance/Negishi coupling[a]
67 26
83[c]
Product
R
Yield [%][b]
OMe
H
68
3
[a] Isolated yield. [b] Reaction conditions: 3-aryl-2,5-dibromothiophene (20)
(1.4 equiv, 0.42 mmol), LDA (1.3 equiv, 0.39 mmol), THF, –78 to 0 °C, 5 min;
ZnCl2·TMEDA (1.4 equiv, 0.42 mmol), RT, 15 min; Pd(PPh3)4 (5 mol%), aryl
iodide (1.0 equiv, 0.30 mmol), 60 °C, 24 h. [c] Aryl iodide (10 mmol) was used.
59 13
62 14
58 15
Me
The resultant diarylated thiophenes had - and -bromo
groups with distinct reactivities in transition metal-catalyzed
transformations;[8] this enabled facile and regiocontrolled
synthesis of tetraarylated thiophenes. We chose Suzuki–Miyaura
cross coupling to perform mono-arylation at the -position of the
thiophene ring (Scheme 5). First, diaryldibromothiophene 22
was treated with a slight excess (1.1 equiv) of arylboronic acid in
the presence of a palladium catalyst and base under the
conventional conditions to give the triarylated thiophene 27 in
50% yield. The product was then subjected to a second cross-
coupling reaction to provide the tetraarylated thiophene 28 in
CO2Et
OMe
Br
51[c]
6
73[c,d]
68 16
OMe
NO2
60 17
71 18
1
47% yield; its H and 13C NMR spectra were identical to those
previously reported.[5b]
51 19
[a] Reaction conditions: 2,5-dibromothiophene (2) (1.4 equiv, 0.42 mmol), LDA
(1.3 equiv, 0.39 mmol), THF, –78 to 0 °C, 5 min; ZnCl2·TMEDA (1.4 equiv,
0.42 mmol), RT, 15 min; Pd(PPh3)4 (5 mol%), aryl iodide (1.0 equiv, 0.30
mmol), 60 °C, 24 h. [b] Isolated yield. [c] Aryl iodide (2.0 mmol) was used. [d]
ZnCl2 (1 M in diethyl ether) was used instead of ZnCl2·TMEDA.
We then investigated the scope of this one-pot reaction of
readily available 3-aryl-2,5-dibromothiophenes[18] (Table 3). First,
the scope of the coupling partner was examined using 3-(4-
anisyl)-2,5-dibromothiophene (20a) as the substrate. Phenyl,
,,-trifluorotolyl, and ethoxycarbonylphenyl groups were
introduced, providing the diarylated dibromothiophenes 21–23 in
satisfactory yields. The same transformation of 3-(4-chloro)-2,5-
dibromothiophene (20b) also took place smoothly to give the
corresponding products 24–26.
Scheme 5. Regioselective stepwise Suzuki–Miyaura cross coupling.
This article is protected by copyright. All rights reserved

Chemistry - A European Journal
10.1002/chem.201604293
COMMUNICATION
The optimal conditions were used for one-pot double
Suzuki–Miyaura cross coupling, which gave rapid access to a
series of multiply arylated thiophenes (Table 4). Two different
tetraarylated thiophenes 28 and 29 were synthesized simply by
changing the order in which the boronic acids were added. The
established protocol was also applied for gram-scale synthesis
of tetraarylated thiophene 33. Similarly, triarylated thiophenes 34
and 35 were synthesized from the corresponding
dibromoarylthiophene.
In conclusion, we have developed
mediated halogen dance/Negishi cross
a
one-pot LDA-
coupling of
dibromothiophenes. This synthetic method provides a wide
range of multiply arylated thiophenes based on one-pot
migration of the bromo group and control of the reactivity of the
transient anion species. The two bromo groups were
regioselectively converted to aryl groups, enabling rapid access
to multiply arylated thiophenes. The synthetic potential of this
method was demonstrated by a concise and regioselective
synthesis of tetraarylated thiophenes.
Table 4. One-pot double Suzuki–Miyaura cross coupling[a]
Product
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP26253001, JP16K05774, and JP16H01153 in the Middle
Molecular Strategy, Creation of Innovation Centers for Advanced
Interdisciplinary Research Areas (Innovative Bioproduction
Kobe) by MEXT, and Kawanishi Memorial ShinMaywa
Education Foundation.
48%[b] 28 (Ref. 5b)
44%[b] 29
Keywords: halogen dance • cross-coupling • one-pot reaction •
thiophene • palladium
[1]
a) C. D. Jones, M. G. Jevnikar, A. J. Pike, M. K. Peters, L. J. Black, A.
R. Thompson, J. F. Falcone, J. A. Clemens, J. Med. Chem. 1984, 27,
1057–1066; b) K. R. Gans, W. Galbraith, R. J. Roman, S. B. Haber, J.
S. Kerr, W. K. Schmidt, C. Smith, W. E. Hewes, N. R. Ackerman, J.
Pharmacol. Exp. Ther. 1990, 254, 180–187; c) K. G. Pinney, A. D.
Bounds, K. M. Dingeman, V. P. Mocharla, G. R. Pettit, R. Bai, E. Hamel,
Bioorg. Med. Chem. Lett. 1999, 9, 1081–1086; d) S. Sasaki, N. Cho, Y.
Nara, M. Harada, S. Endo, N. Suzuki, S. Furuya, M. Fujino, J. Med.
Chem. 2003, 46, 113–124; Drug candidates: see, e) W. F. Fobare, W.
R. Solvibile, A. J. Robichaud, M. S. Malamas, E. Manas, J. Turner, Y.
Hu, E. Wagner, R. Chopra, R. Cowling, G. Jin, J. Bard, Bioorg. Med.
Chem. Lett. 2007, 17, 5353–5356; f) E. Bey, S. Marchais-Oberwinkler,
M. Negri, P. Kruchten, A. Oster, T. Klein, A. Spadaro, R. Werth, M.
Frotscher, B. Birk, R. W. Hartmann, J. Med. Chem. 2009, 52, 6724–
6743; g) S. Theeramunkong, A. Caldarelli, A. Massarotti, S. Aprile, D.
Caprioglio, R. Zaninetti, A. Teruggi, T. Pirali, G. Grosa, G. C. Tron, A. A.
Genazzani, J. Med. Chem. 2011, 54, 4977–4986; h) S. R. Patpi, L.
Pulipati, P. Yogeeswari, D. Sriram, N. Jain, B. Sridhar, R. Murthy, A. D.
T, S. V. Kalivendi, S. Kantevari, J. Med. Chem. 2012, 55, 3911–3922.
a) S. Nakajima, K. Kawazu, Agric. Biol. Chem. 1980, 44, 1529–1533; b)
J. Kagan, G. Chan, S. N. Dhawan, S. K. Arora, I. Prakash, J. Nat. Prod.
1983, 46, 646–650; c) S. R. M. Ibrahim, H. M. Abdallah, A. M. El-
Halawany, G. A. Mohamed, Phytochem. Rev. 2016, 15, 197–220.
a) C. A. Briehn, T. Kirschbaum, P. Bäuerle, J. Org. Chem. 2000, 65,
352–359; b) M.-H. Yoon, A. Facchetti, C. E. Stern, T. J. Marks, J. Am.
Chem. Soc. 2006, 128, 5792–5801; c) C. B. Nielsen, A. Angerhofer, K.
A. Abboud, J. R. Reynolds, J. Am. Chem. Soc. 2008, 130, 9734–9746;
d) A. R. Murphy, J. M. J. Fréchet, Chem. Rev. 2007, 107, 1066–1096.
a) D. T. Tung, D. T. Tuan, N. Rasool, A. Villinger, H. Reinke, C. Fischer,
P. Langer, Adv. Synth. Catal. 2009, 351, 1595–1609; b) S.-M. T.
Toguem, A. Villinger, P. Langer, Synlett 2010, 909–912; c) J. Wang, M.
A. Seefeld, J. Luengo, Tetrahedron Lett. 2011, 52, 6346–6348; d); A.
Rahimi, J. C. Namyslo, M. H. H. Drafz, J. Halm, E. Hübner, M. Nieger,
N. Rautzenberg, A. Schmidt, J. Org. Chem. 2011, 76, 7316–7325;
Palladium-catalyzed multiple arylation of 3-thiophenecarboxylic acids
51%[b] 30 (Ref. 5a)
45%[b] 31
47%[b] 32 (Ref. 5a)
67%[b] (73%[b,c]
)
33
[2]
[3]
61%[b,d] 34 (Ref. 1f)
54%[b,d] 35
[a] Reaction conditions: dibromothiophene (1 equiv, 0.15 mmol), Ar3B(OH)2
(1.1 equiv), [PdCl2(dppf)]·CH2Cl2 (5 mol%), K3PO4 (2.0 equiv), 1,4-dioxane,
80 °C, 24 h; Ar4B(OH)2 (1.1 equiv), K3PO4 (2.0 equiv), 80 °C, 24 h. [b] Isolated
yield. [c] The one-pot double Suzuki–Miyaura reaction of dibromothiophene 26
(5.0 mmol) provided 1.86 g of tetraarylated thiophene 33. The first Suzuki–
Miyaura coupling was performed with 0.90 equiv (4.5 mmol) of Ar3B(OH)2. [d]
[4]
Dibromothiophene
6 (0.30 mmol) was used. The first Suzuki–Miyaura
coupling was performed with 1.0 equiv (0.30 mmol) of Ar3B(OH)2.
This article is protected by copyright. All rights reserved

Chemistry - A European Journal
10.1002/chem.201604293
COMMUNICATION
through C–H bond cleavage, see: e) M. Nakano, H. Tsurugi, T. Satoh,
M. Miura, Org. Lett. 2008, 10, 1851–1854; f) C. M. Amb, S. C.
Rasmussen, Eur. J. Org. Chem. 2008, 801–804; Synthesis of
multisubstituted thiophenes utilizing ynolate, see: g) M. Shindo, Y.
Yoshimura, M. Hayashi, H. Soejima, T. Yoshikawa, K. Matsumoto, K.
Shishido, Org. Lett. 2007, 9, 1963–1966.
[10] a) M. Hamell, R. Levine, J. Org. Chem. 1950, 15, 162–168; b) R.
Levine, W. C. Fernelius, Chem. Rev. 1954, 54, 449–573.
[11] P. Beak, D. J. Allen, J. Am. Chem. Soc. 1992, 114, 3420–3425.
[12] a) M. Giannerini, M. Fananas-Mastral, B. L. Feringa, Nat. Chem. 2013,
5, 667–672; b) M. Giannerini, V. Hornillos, C. Vila, M. Fananas-Mastral,
B. L. Feringa, Angew. Chem. 2013, 125, 13571–13575; Angew. Chem.
Int. Ed. 2013, 52, 13329–13333; c) V. Hornillos, M. Giannerini, C. Vila,
M. Fananas-Mastral, B. L. Feringa, Org. Lett. 2013, 15, 5114–5117; d)
C. Vila, M. Giannerini, V. Hornillos, M. Fananas-Mastral, B. L. Feringa,
Chem. Sci. 2014, 5, 1361–1367; e) C. Vila, V. Hornillos, M. Giannerini,
M. Fañanás-Mastral, B. L. Feringa, Chem. Eur. J. 2014, 20, 13078–
13083; f) . Hornillos, M. Giannerini, C. Vila, M. Fananas-Mastral, B. L.
Feringa, Chem. Sci. 2015, 6, 1394–1398.
[5]
a) S. Yanagisawa, K. Ueda, H. Sekizawa, K. Itami, J. Am. Chem. Soc.
2009, 131, 14622–14623; b) S. Suzuki, Y. Segawa, K. Itami, J.
Yamaguchi, Nat. Chem. 2015, 7, 227–233; c) J. Yamaguchi, A. D.
Yamaguchi, K. Itami, Angew. Chem. 2012, 124, 9092–9142; Angew.
Chem. Int. Ed. 2012, 51, 8960–9009.
[6]
[7]
a) F. M. Piller, P. Knochel, Org. Lett. 2009, 11, 445–448; b) F. M. Piller,
P. Appukkuttan, A. Gavryushin, M. Helm, P. Knochel, Angew. Chem.
2008, 120, 6907–6911; Angew. Chem. Int. Ed. 2008, 47, 6802–6806.
a) A. Vaitiekunas, F. F. Nord, Nature 1951, 168, 875–876; b) S. Kano,
Y. Yuasa, T. Yokomatsu, S. Shibuya, Heterocycles 1983, 20, 2035–
2037; c) Y. A. Getmanenko, P. Tongwa, T. V. Timofeeva, S. R. Marder,
Org. Lett. 2010, 12, 2136–2139; d) K. Shono, Y. Sumino, S. Tanaka, S.
Tamba, A. Mori, Org. Chem. Front. 2014, 1, 678–682; e) S. Gronowitz,
Recent advances in the chemistry of thiophenes, Vol. 1, Academic
Press, Cambridge, England, 1963; f) J. Fröhlich, in Prog. Heterocycl.
Chem., Vol. 6 (Ed.: A. Padwa), Pergamon Press, 1994, pp. 1–35; g) X.-
F. Duan, Z.-B. Zhang, Heterocycles 2005, 65, 2005–2012; For a recent
review, see: h) M. Schnurch, M. Spina, A. F. Khan, M. D. Mihovilovic,
P. Stanetty, Chem. Soc. Rev. 2007, 36, 1046–1057.
[13] a) M. Isobe, S. Kondo, N. Nagasawa, T. Goto, Chem. Lett. 1977, 6,
679–682; b) K. Snégaroff, S. Komagawa, F. Chevallier, P. C. Gros, S.
Golhen, T. Roisnel, M. Uchiyama, F. Mongin, Chem. Eur. J. 2010, 16,
8191–8201.
[14] a) E.-I. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42,
1821–1823; b) E.-I. Negishi, Acc. Chem. Res. 1982, 15, 340–348; c) E.
I. Negishi, Angew. Chem. 2011, 123, 6870–6897; Angew. Chem. Int.
Ed. 2011, 50, 6738–6764.
[15] A recent review on Negishi cross coupling with PEPPSI, see: C.
Valente, M. E. Belowich, N. Hadei, M. G. Organ, Eur. J. Org. Chem.
2010, 4343–4354.
[16] C. Sämann, B. Haag, P. Knochel, Chem. Eur. J. 2012, 18, 16145–
16152.
[8]
[9]
a) T. Kodani, K. Matsuda, T. Yamada, S. Kobatake, M. Irie, J. Am.
Chem. Soc. 2000, 122, 9631–9637; b) H.-J. Son, W.-S. Han, J.-Y.
Chun, S.-N. Kwon, J. Ko, S. O. Kang, Organometallics 2008, 27, 2464–
2473; c) F. Proutiere, M. Aufiero, F. Schoenebeck, J. Am. Chem. Soc.
2012, 134, 606–612; d) S.-M. Tengho Toguem, I. Malik, M. Hussain, J.
Iqbal, A. Villinger, P. Langer, Tetrahedron 2013, 69, 160–173.
[17] The heating conditions were necessary for satisfactory yields in the
cross coupling reaction. When we performed the coupling reaction at
room temperature with p-iodoanisole or o-iodoanisole as a coupling
partner, the corresponding products 3 and 17 were obtained in 35%
and 14% yields, respectively.
a) M. Yamamura, I. Moritani, S.-I. Murahashi, J. Organomet. Chem.
1975, 91, C39–C42; b) S. Murahashi, M. Yamamura, K. Yanagisawa, N.
Mita, K. Kondo, J. Org. Chem. 1979, 44, 2408–2417; c) S. Murahashi, J.
Organomet. Chem. 2002, 653, 27–33.
[18] For the preparation of 3-aryl-2,5-dibromothiophenes, see Supporting
Information.
This article is protected by copyright. All rights reserved

Chemistry - A European Journal
10.1002/chem.201604293
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Kentaro Okano,* Kazuhiro Sunahara,
Yoshiki Yamane, Yuki Hayashi, and
Atsunori Mori
Page No. – Page No.
One-Pot Halogen Dance/Negishi
Coupling of Dibromothiophenes for
Regiocontrolled Synthesis of Multiply
Arylated Thiophenes
A one-pot LDA-mediated halogen dance/Negishi cross coupling of readily prepared
2,5-dibromothiophenes is described. The one-pot reaction involves -bromo group
migration to the  position and then -arylation. The resultant - and -bromo
groups were regioselectively converted to aryl groups by one-pot Suzuki–Miyaura
coupling. The synthetic potential of this method was shown by regiocontrolled
gram-scale synthesis of tetraarylated thiophene.
This article is protected by copyright. All rights reserved