Direct 2-arylation of thiophene using low loading of a phosphine-free palladium catalyst

Article abstract of DOI:10.1080/00397911.2010.518781

The direct coupling of aryl halides with thiophene would be a considerable advantage for sustainable development because of only HBr associated with a base as by-product is formed and the number of steps to prepare these compounds is less than in more cla

Full text of DOI:10.1080/00397911.2010.518781

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Direct 2-Arylation of Thiophene Using
Low Loading of a Phosphine-Free
Palladium Catalyst
Souhila Bensaid a , Julien Roger a , Kassem Beydoun a , David Roy a &
Henri Doucet a
a Institut Sciences Chimiques de Rennes, CNRS-Université de Rennes
“Catalyse et Organometalliques,”, Rennes, France
Accepted author version posted online: 05 Jul 2011.Version of
record first published: 01 Jun 2011.
To cite this article: Souhila Bensaid , Julien Roger , Kassem Beydoun , David Roy & Henri Doucet
(2011): Direct 2-Arylation of Thiophene Using Low Loading of a Phosphine-Free Palladium Catalyst,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:23, 3524-3531
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Synthetic Communications1, 41: 3524–3531, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518781
DIRECT 2-ARYLATION OF THIOPHENE USING LOW
LOADING OF A PHOSPHINE-FREE PALLADIUM
CATALYST
Souhila Bensaid, Julien Roger, Kassem Beydoun, David Roy,
and Henri Doucet
´
Institut Sciences Chimiques de Rennes, CNRS-Universite de Rennes
‘‘Catalyse et Organometalliques,’’ Rennes, France
GRAPHICAL ABSTRACT
Abstract The direct coupling of aryl halides with thiophene would be a considerable advan-
tage for sustainable development because of only HBr associated with a base as by-product
is formed and the number of steps to prepare these compounds is less than in more classical
coupling reactions. We observed that through the use of only 0.2 mol% Pd(OAc)2 as
the catalyst, a range of aryl bromides undergoes coupling via a C-H bond activation/
functionalization reaction with thiophene to give 2-arylated thiophenes in good yields. In
most cases, only traces of polyarylated thiophenes were detected when a large excess of
thiophene was employed. This air-stable catalyst can be used with a wide variety of aryl
bromides.
Keywords Aryl bromides; catalysis; C-H activation; palladium; thiophene
INTRODUCTION
The palladium-catalyzed cross-coupling reactions between aryl halides and
heteroarenes such as thiophene derivatives give powerful access to arylated hetero-
cycles.[1] Negishi, Stille, and Suzuki cross-coupling reactions have been largely
employed for the preparation of such compounds.[2–4] However, these methods are
not very convenient as their organometallic derivatives have to be prepared. More-
over, these reactions are not environmentally attractive as they provide an organo-
metallic or salt (MX) as by-product. In recent years, very interesting results
for the coupling of aryl halides with heteroaromatic derivatives by C-H bond acti-
vation have been reported, and they provide an economically and environmentally
Received June 14, 2010.
Address correspondence to Henri Doucet, Institut Sciences Chimiques de Rennes, UMR 6226
´
CNRS-Universite de Rennes ‘‘Catalyse et Organometalliques,’’ Campus de Beaulieu, Rennes 35042,
France. E-mail: henri.doucet@univ-rennes1.fr
3524

DIRECT ARYLATION OF THIOPHENE
3525
attractive procedure for the preparation of such compounds.[5–10] However, so far
most of the results were obtained using substituted thiophenes. The use of thiophene
itself for such coupling reactions would be a considerable advantage for sustainable
development. These coupling reactions provide only HBr associated with a base as a
by-product and therefore are very interesting both in terms of atom-economy and
inert waste. So far, most of the coupling reactions of thiophene with aryl halides
via
a
C-H bond activation require relatively high catalyst loadings
(3–20 mol%).[11–16] The first example was reported by Ohta and coworkers. In the
presence of 5 mol% Pd(PPh3)4, the 2-arylated thiophenes were obtained in moderate
to good yields.[11] A slightly modified procedure was employed to prepare bioactive
compounds.[13] For these reactions, 20 mol% Pd(PPh3)4 was used. Mori and cowor-
kers also employed this reaction to prepare photoluminescent materials. The coup-
ling of 4-iodoanisole with thiophene in the presence of 3 mol% PdCl2(dppb) and a
stoichiometric amount of AgF as the base provides 2-arylated thiophene in 43%
yield.[14] Finally, Chiong and Daugulis reported in 2007 that the use of 5 mol%
Pd(OAc)2 associated with 10 mol% BuAd2P promotes the coupling of N-(3-chloro-
phenyl)-acetamide with thiophene to give the 2-arylated thiophene in 54% yield.[15]
As the arylation of thiophene would be one of the first steps for the preparation
of complex molecules in many cases, the discovery of an effective procedure,
especially employing lower catalyst loadings, would be a considerable advantage
for industrial applications.
Here, we report on the use of low loading of a phosphine-free palladium cata-
lyst for the direct arylation of thiophene using a variety of aryl bromides. Based on
previous results,[17] for this study, DMAc was chosen as the solvent and KOAc as the
base. The reactions were performed under argon in the presence of 0.2 mol% of
Pd(OAc)2 as the catalyst at 130 ꢀC. Because the formation of polyarylated thiophene
derivatives is possible in the course of this reaction,[18] we initially examined the
influence of various equivalents of thiophene on the ratio of monoarylated product
1a and diarylated product 1b (Scheme 1, Table 1). When only 2 equiv. of thiophene
were employed, the formation of 22% of diarylated thiophene was observed (Table 1,
entry 1), whereas in the presence of 8 or 10 equiv. of thiophene, only 6% or 4% of
diarylated product was detected by gas chromatographic (GC) analysis (Table 1,
entries 4 and 5). As thiophene is a very cheap reagent, and as it is certainly possible
to recycle it when working on a large scale, we decided to employ 8 equiv. of this
reactant for the screening of the scope and limitations of this procedure.
Scheme 1. Direct arylation of thiophene with 4-bromobenzonitrile.

3526
S. BENSAID ET AL.
Table 1. Influence of the reaction conditions for phosphine-free palladium-catalyzed
direct arylation of thiophene using 4-bromobenzonitrile (Scheme 1)
Conversion of
4-bromobenzonitrile (%)a
Entry
Thiophene
Ratio 1a=1b
1
2
3
4
5
2 equiv.
4 equiv.
6 equiv.
8 equiv.
10 equiv.
78:22
89:11
92:8
100
100
100
100
100
94:6
96:4
aConditions: catalyst Pd(OAc)2 (0.002 mmol), 4-bromobenzonitrile (1 mmol),
thiophene (2–10 mmol), KOAc (2 mmol), DMAc (5 mL), 20 h, 130 ꢀC.
Using these conditions, the reactivity of para-, meta-, or ortho-substituted aryl
bromides and also heteroaryl bromides was examined (Scheme 2, Table 2). As
expected, other electron-deficient para-substituted aryl bromides such as 4-bromoa-
cetophenone, 4-bromobenzaldehyde, or 4-bromonitrobenzene gave the desired
2-arylated thiophenes 2–7 in good yields (Table 2, entries 2–7). In the presence of
2-bromonaphthalene, the formation of 8 was also obtained in good yield (Table 2,
entry 8). As expected, a similar reactivity was observed in the presence of the
meta-substituted aryl bromides, 3-bromoacetophenone or 3-bromobenzaldehyde
(Table 2, entries 9 and 10). ortho-Substituents on the aryl bromides generally have
a more important effect on the reaction rates of palladium-catalyzed reactions
because of their steric or coordination properties.[19] Good yields were obtained in
the presence of some more congested aryl bromides such as 2-bromobenzonitrile,
2-bromobenzaldehyde, or 1-bromonaphthalene (Table 2, entries 11, 13, and 15).
On the other hand, 2-bromoacetophenone or 2-bromonitrobenzene were recovered
unreacted (Table 2, entries 12 and 14). This is probably a result of the coordination
of the acetyl or nitro functions to palladium. A similar result was observed in the
course of the direct arylation of thiazole derivatives.[20] With these two substrates,
even the use of 1 mol% PdCl(C3H5)(dppb) as the catalyst was ineffective. Finally,
4-bromoisoquinoline also gave the desired coupling product 16 in 78% yield
(Table 2, entry 16).
Then, we examined the reactivity of more challenging substrates such as the
electron-rich aryl bromides 4-tert-butylbromobenzene or congested 9-bromoantra-
cene (Table 3). This phosphine-free low loading palladium procedure was found
to be ineffective to promote the coupling of such substrates with thiophene. Two
substrate=catalyst ratios (100 and 500), using Pd(OAc)2 as the catalyst, have been
Scheme 2. Direct arylation of thiophene with various aryl bromides.

DIRECT ARYLATION OF THIOPHENE
3527
Table 2. Palladium-catalyzed arylation of thiophene (Scheme 2)
Entry
Aryl bromide
Product
Yield (%)a
1
2
80
82
3
4
5
76
78
72
6
7
75
71
8
9
74
77
10
11
75
74
0
12
13
79
(Continued )

3528
S. BENSAID ET AL.
Table 2. Continued
Entry
14
Aryl bromide
Product
Yield (%)a
0
15
16
73
78
aConditions: catalyst Pd(OAc)2 (0.002 mmol), aryl bromide (1 mmol), thiophene (8 mmol), KOAc
(2 mmol), DMAc (5 mL), 20 h, 130 ꢀC, isolated yields.
employed (0.2 and 1 mol% catalyst), but no formation of the desired products 17 or
20 was detected using this procedure. On the other hand, in the presence of 1 mol%
of thermally more stable catalyst PdCl(C3H5)(dppb), the desired coupling products
17, 18 and 20 were obtained in moderate to good yields (Table 3, entries 1, 2 and 4).
In summary, the use of only 0.2 mol% of the phosphine-free complex Pd(OAc)2
provides an efficient catalyst for the direct coupling of several electron-deficient aryl
bromides with thiophene. A wide variety of functional groups of the aryl bromide
Table 3. Palladium-catalyzed arylation of thiophene using PdCl(C3H5)(dppb) as the catalyst (Scheme 2)
Entry
Aryl bromide
Product
Yield (%)a
1
2
3
38
62
0
4
68
aConditions: catalyst PdCl(C3H5)(dppb) (0.01 mmol), aryl bromide (1 mmol), thiophene (8 mmol),
KOAc (2 mmol), DMAc (5 mL), 20 h, 140 ꢀC, isolated yields.

DIRECT ARYLATION OF THIOPHENE
3529
are tolerated. To minimize the formation of diarylated thiophene, a large excess of
thiophene was employed. However, the recycling of thiophene is certainly possible
for large-scale reactions. This procedure is very simple, is economically attractive,
and uses a commercially available catalyst precursor. To the best of our knowledge,
this work represents the most wide-ranging study reported so far for the preparation
of 2-arylthiophenes from thiophene via a C-H bond activation=functionalization.
The only by-product is HCl associated with AcOK instead of metallic salts with
classical cross-coupling procedures. Moreover, no preparation of an organometallic
derivative is required, reducing the number of steps to prepare these compounds.
EXPERIMENTAL
All reactions were run under argon in Schlenk tubes using vacuum lines.
DMAc analytical grade was not distilled before use. Potassium acetate (99þ) was
1
used. Commercial aryl bromides and thiophene were used without purification. H
and 13C spectra were recorded with a Bruker 200-MHz spectrometer in CDCl3 solu-
tions. Chemical shifts are reported in parts per million (ppm) relative to CDCl3 (7.25
1
for H NMR and 77.0 for 13C NMR). Flash chromatography were performed on
silica gel (230–400 mesh).
Preparation of the PdCl(dppb)(C3H5) Catalyst
An oven-dried 40-mL Schlenk tube equipped with a magnetic stirring bar
under argon atmosphere was charged with [Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and
dppb (426 mg, 1 mmol). Anhydrous dichloromethane (10 mL) was added, and then
the solution was stirred at room temperature for 20 min. The solvent was removed
in a vacuum. The yellow powder was used without purification. 31P NMR
(81 MHz, CDCl3) d ¼ 19.3 (s).
General Procedure for Coupling Reactions
In a typical experiment, the aryl bromide (1 mmol), thiophene (8 mmol), KOAc
(0.118 g, 1.2 mmol), and Pd(OAc)2 or PdCl(C3H5)(dppb) were dissolved in DMAc
(5 mL) under an argon atmosphere. The reaction mixture was stirred at 130 or
140 ꢀC for 20 h. The solvent was removed in vacuo, and then the crude mixture
was purified by silica-gel column chromatography.
4-Thiophen-2-ylbenzonitrile (1a). 4-Bromobenzonitrile (0.182 g, 1 mmol)
and thiophene (0.672 g, 8 mmol) afford 1a in 80% (0.148 g) yield.
4-Thiophen-2-ylacetophenone (2). 4-Bromoacetophenone
1 mmol) and thiophene (0.672 g, 8 mmol) afford 2 in 82% (0.166 g) yield.
(0.199 g,
4-Thiophen-2-ylpropiophenone (3). 4-Bromopropiophenone (0.213 g,
1 mmol) and thiophene (0.672 g, 8 mmol) afford 3 in 76% (0.164 g) yield.
1H NMR (200 MHz, CDCl3) d, 7.96 (d, J ¼ 8.3 Hz, 2H), 7.72 (d, J ¼ 8.3 Hz,
2H), 7.45 (d, J ¼ 3.6 Hz, 1H), 7.38 (d, J ¼ 5.0 Hz, 1H), 7.14 (dd, J ¼ 5.0 and
3.6 Hz, 1H), 2.97 (q, J ¼ 7.5 Hz, 2H), 1.20 (t, J ¼ 7.5 Hz, 3H). 13C NMR (50 MHz,

3530
S. BENSAID ET AL.
CDCl3) d 200.0, 143.0, 138.6, 135.5, 128.8, 128.4, 126.4, 125.7, 124.5, 31.8, 8.3. Anal.
calcd. for C13H12OS: C, 72.19; H, 5.59. Found: C, 72.14; H, 5.64.
4-Thiophen-2-ylbenzophenone (4). 4-Bromobenzophenone
1 mmol) and thiophene (0.672 g, 8 mmol) afford 4 in 78% (0.206 g) yield.
(0.261 g,
4-Thiophen-2-ylbenzaldehyde (5). 4-Bromobenzaldehyde (0.185 g, 1 mmol)
and thiophene (0.672 g, 8 mmol) afford 5 in 72% (0.136 g) yield.
Methyl 4-thiophen-2-ylbenzoate (6). Methyl 4-bromobenzoate (0.215 g,
1 mmol) and thiophene (0.672 g, 8 mmol) afford 6 in 75% (0.164 g) yield.
4-Thiophen-2-ylnitrobenzene(7). 4-Bromonitrobenzene (0.202 g, 1 mmol)
and thiophene (0.672 g, 8 mmol) afford 7 in 71% (0.146 g) yield.
2-Naphthalen-2-ylthiophene (8). 2-Bromonaphthalene (0.207 g, 1 mmol)
and thiophene (0.672 g, 8 mmol) afford 8 in 74% (0.156 g) yield.
3-Thiophen-2-ylacetophenone (9). 3-Bromoacetophenone
1 mmol) and thiophene (0.672 g, 8 mmol) afford 9 in 77% (0.156 g) yield.
(0.199 g,
(0.185 g,
(0.185 g,
3-Thiophen-2-ylbenzaldehyde (10). 3-Bromobenzaldehyde
1 mmol) and thiophene (0.672 g, 8 mmol) afford 10 in 75% (0.141 g) yield.
2-Thiophen-2-ylbenzaldehyde (11). 2-Bromobenzaldehyde
1 mmol) and thiophene (0.672 g, 8 mmol) afford 11 in 74% (0.139 g) yield.
2-Thiophen-2-ylbenzonitrile (13). 2-Bromobenzonitrile (0.182 g, 1 mmol)
and thiophene (0.420 g, 5 mmol) afford 13 in 79% (0.146 g) yield.
2-Naphthalen-1-ylthiophene (15). 1-Bromonaphthalene (0.207 g, 1 mmol)
and thiophene (0.672 g, 8 mmol) afford 15 in 73% (0.154 g) yield.
3-Thiophen-2-ylquinoline (16). 4-Bromoisoquinoline (0.208 g, 1 mmol) and
thiophene (0.672 g, 8 mmol) afford 16 in 78% (0.165 g) yield.
2-(4-tert-Butylphenyl)-thiophene (17). 4-tert-Butylbromobenzene (0.213 g,
1 mmol) and thiophene (0.672 g, 8 mmol) afford 17 in 38% (0.082 g) yield.
(4-Thiophen-2-ylphenyl)-acetonitrile (18). (4-Bromophenyl)-acetonitrile
(0.195, 1 mmol) and thiophene (0.672 g, 8 mmol) afford 18 in 62% (0.123 g) yield.
2-Anthracen-9-yl-thiophene (20). 9-Bromoanthracene (0.256 g, 1 mmol)
and thiophene (0.672 g, 8 mmol) afford 20 in 68% (0.177 g) yield.
REFERENCES
1. For examples of palladium coupling reactions with heteroaromatic substrates, see Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: Amsterdam, 2000.
2. Wang, L.; Wang, Z.-X. Efficient cross-coupling of aryl chlorides with arylzinc reagents
catalyzed by amido pincer complexes of nickel. Org. Lett. 2007, 9, 4335–4338.
3. Liu, W.; Pink, M.; Lee, D. Conjugated polymer sensors built on p-extended borasiloxane
cages. J. Am. Chem. Soc. 2009, 131, 8703–8707.

DIRECT ARYLATION OF THIOPHENE
3531
4. Kondolff, I.; Doucet, H.; Santelli, M. Suzuki coupling reactions of heteroarylboronic
acids with aryl halides and arylboronic acids with heteroaryl bromides using a
tetraphosphine=palladium catalyst. Synlett 2005, 2057–2061.
5. Alberico, D.; Scott, M. E.; Lautens, M. Aryl-aryl bond formation by transition-metal-cat-
alyzed direct arylation. Chem. Rev. 2007, 107, 174–238.
6. Satoh, T.; Miura, M. Catalytic direct arylation of heteroaromatic compounds. Chem.
Lett. 2007, 36, 200–205.
7. Doucet, H.; Hierso, J.-C. Palladium coupling catalysts for pharmaceutical applications.
Curr. Opin. Drug Discover. Devel. 2007, 10, 672–690.
8. Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Recent advances in direct arylation via palladium-
catalyzed aromatic C–H activation. Synlett 2008, 949–957.
9. Bellina, F.; Rossi, R. Recent advances in the synthesis of (hetero)aryl-substituted hetero-
arenes via transition-metal-catalysed direct (hetero)arylation of heteroarene C–H bonds
with aryl halides or pseudohalides, diaryliodonium salts, and potassium aryltrifluorobo-
rates. Tetrahedron 2009, 65, 10269–10310.
10. Roger, J.; Gottumukkala, A. L.; Doucet, H. Palladium-catalysed C3 or C4 direct aryla-
tion of heteroaromatics via a C-H bond activation using aryl halides. Chem. Cat. Chem.
2010, 2, 20–40.
11. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.;
Tani, N.; Aoyagi, Y. Palladium-catalyzed arylation of furan, thiophene, benzo[b]furan
and benzo[b]thiophene. Heterocycles 1990, 31, 1951–1958.
12. Hark, R. R.; Hauze, D. B.; Petrovskaia, O.; Joullie, M. M. Synthetic studies of novel
ninhydrin analogs. Can. J. Chem. 2001, 79, 1632–1654.
13. Dahlgren, A.; Kvarnstrom, I.; Vrang, L.; Hamelink, E.; Hallberg, A.; Rosenquist, A.;
Samuelsson, B. Solid-phase library synthesis of reversed-statine type inhibitors of the
malarial aspartyl proteases plasmepsin I and II. Bioorg. Med. Chem. 2003, 11, 827–841.
14. Masui, K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.; Ikeda, T. Syntheses and
properties of donor-acceptor-type 2,5-diarylthiophene and 2,5-diarylthiazole. Org. Lett.
2004, 6, 2011–2014.
15. Chiong, H. A.; Daugulis, O. Palladium-catalyzed arylation of electron-rich heterocycles
with aryl chlorides. Org. Lett. 2007, 9, 1449–1951.
16. Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. Direct coupling of arenes and iodoarenes
catalyzed by a rhodium complex with a strongly p-accepting phosphite ligand.
Tetrahedron 2008, 64, 6073–6081.
17. Roger, J.; Pozgan, F.; Doucet, H. Ligand-less palladium-catalyzed direct 5-arylation of
thiophenes at low catalyst loadings. Green. Chem. 2009, 11, 425–432.
18. Nakano, M.; Tsurugi, H.; Satoh, T.; Miura, M. Palladium-catalyzed perarylation of
3-thiophene- and 3-furancarboxylic acids accompanied by C-H bond cleavage and
decarboxylation. Org. Lett. 2008, 10, 1851–1854.
19. Feuerstein, M.; Doucet, H.; Santelli, M. Palladium=Tetraphosphine catalysed heck
reaction with ortho-substituted aryl bromides. Synlett 2001, 1980–1982.
20. Roger, J.; Pozˇgan, F.; Doucet, H. Ligand-free palladium-catalyzed direct arylation of
thiazoles at low catalyst loadings. J. Org. Chem. 2009, 74, 1179–1186.