Direct arylation of thiophenes via palladium-catalysed C-H functionalisation at low catalyst loadings

Article abstract of DOI:10.1002/adsc.200700142

Palladium associated with cis,cis,cis-1,2,3,4- tetrakis(diphenylphosphinomethyl)cyclopentane (Tedicyp) was found to promote the direct 2-arylation of a variety of thiophene derivatives via C-H functionalisation in good yields using very low catalyst loadings. Electron-deficient, electron-excessive or sterically-congested aryl bromides are tolerated. Moreover, several substituents on the aryl bromide or thiophene derivatives such as acetyl, formyl, nitrile, nitro, ester, methoxy, fluoro or trifluoromethyl are tolerated. The most reactive aryl bromides were coupled with thiophenes derivatives using as little as 0.1-0.01 mol% catalyst.

Full text of DOI:10.1002/adsc.200700142

FULL PAPERS
DOI: 10.1002/adsc.200700142
À
Direct Arylation of Thiophenes via Palladium-Catalysed C H
Functionalisation at Low Catalyst Loadings
Ahmed Battace,a Mhamed Lemhadri,a Touriya Zair,b Henri Doucet,c,*
and Maurice Santellia,*
a
Laboratoire de Synth›se Organique associØau CNRS, FacultØdes Sciences de Saint JØrôme, UniversitØd ’Aix-Marseille,
Avenue Escadrille Normandie-Niemen, 13397 Marseille, France
Phone: (+33)-(0)4-9128-8825; fax: (+33)-(0)4-9198-9112; e-mail: m.santelli@univ-cezanne.fr
Laboratoire de Chimie Organique AppliquØe, FacultØ des Sciences, UniversitØ Moulay Is, BP 4010, Beni M’mhammed,
b
50000 Meknes, Morocco
c
Institut Sciences Chimiques de Rennes,UMR 6226 CNRS-UniversitØde Rennes “Catalyse et Organometalliques”,
Campus de Beaulieu, 35042 Rennes, France
Phone: (+33)-(0)2-2323-6280; fax: (+33)-(0)2-2323-6939; e-mail: henri.doucet@univ-rennes1.fr
Received: March 19, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Palladium associated with cis,cis,cis-1,2,3,4- or thiophene derivatives such as acetyl, formyl, ni-
tetrakis(diphenylphosphinomethyl)cyclopentane (Te- trile, nitro, ester, methoxy, fluoro or trifluoromethyl
dicyp) was found to promote the direct 2-arylation are tolerated. The most reactive aryl bromides were
À
of a variety of thiophene derivatives via C H func- coupled with thiophenes derivatives using as little as
tionalisation in good yields using very low catalyst 0.1–0.01 mol% catalyst.
loadings. Electron-deficient, electron-excessive or
sterically-congested aryl bromides are tolerated. Keywords: aryl halides; atom economy; C H activa-
À
Moreover, several substituents on the aryl bromide tion; palladium; thiophenes
Introduction
provides either an organometallic or a salt (MX) as
by-product.
A great deal of attention has been given to the syn-
In 1990, Ohta et al. reported the direct arylation of
thesis of arylthiophenes, mainly due to the biological- thiophenes, furans or thiazoles with aryl halides via
À
ly or physical properties demonstrated by this class of C H activation of thiophene in medium to good
compounds.[1] The cross-coupling reaction of thio- yields using 5 mol% Pd
A
phenes with aryl derivatives provides an efficient these exciting results, the direct arylation of heteroar-
method for the synthesis of a wide variety of arylthio- yl derivatives with aryl halides has proved to be a
phenes. These cross-coupling reactions were generally powerful method for the synthesis of heterobiaryls
performed using an organometallic derivative of the (Scheme 2). Recent results such as those reported by
thiophene with an aryl halide or using an organome- Miura, Sanford, Fagnou, Lemaire, or Lautens have
tallic derivative of an aryl with an halothiophene definitively demonstrated that the direct palladium-
8metal=MgX,[2] ZnX,[2] SnR3[3] B(OR)2[4]] using a pal- catalysed arylation of pyridines, furans, thiophenes,
ladium or a nickel catalyst (Scheme 1). The major thiazoles, oxazoles or indoles is a very simple, effi-
drawbacks of these reactions is that they requires the cient and environmentally friendly procedure for the
preparation of organometallic derivatives and also preparation of heterobiaryls.[6]
Scheme 1.
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Results and Discussion
In order to obtain more efficient palladium catalysts
we have prepared the tetrapodal phosphine ligand,
cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cy-
clopentane or Tedicyp (Scheme 3)[11] in which the four
diphenylphosphino groups are stereospecifically
Scheme 2.
The direct coupling of thiophenes with aryl halides bound to the same face of the cyclopentane ring.
À
via C H activation/functionalisation at low catalyst Using this ligand, very high turnover numbers
loadings would provide a cost-effective and environ- (TONs) have been obtained for Suzuki, Heck, Sono-
mentally attractive procedure for the preparation of gashira or Negishi cross-coupling reactions.[12,13] Re-
such compounds. A few results have already been re- cently, we also described the direct coupling of furan
ported for this coupling. In most cases, simple palladi- derivatives with a wide variety of aryl halides.[14] The
um salts or Pd associated with monodentate ligands palladium is shown by NMR to circulate around the 4
were employed, and, relatively high catalysts loadings phosphorus atoms under the “pressure to coordinate”
were generally employed. For example, the direct ary- of the 4 phosphino groups maintained in a half-space.
lation of thiophene-2-carbonitrile, 2-formylthiophene This “pressure to coordinate” is certainly responsible
or a thienothiophene with aryl iodides using 5 mol% for the high TONs obtained with this catalyst both by
Pd(OAc)2 as catalyst and n-Bu4NBr as additive led to an increase of the stability of the catalyst and by an
G
the biaryl products in moderate to good yields.[7a,b,e] easier reductive elimination step for several cross-
The coupling of thiophene derivatives with aryl io- coupling reactions. In this paper, we report on the ef-
dides has also been described using 3 mol% PdCl2 ficiency of this catalytic system for the challenging
A
G
À
AHCTREUNG
ACHTREUNG
AHCTREUNG
AHCTREUNG
thiophene in 67% yield using an electron-deficient also obtained. On the other hand with AcONa as
aryl bromide. On the other hand, bromobenzene led base and DMAc as solvent, a complete conversion of
to a lower yield of 52%.[8b] Finally, the regioselective 4-bromoacetophenone and an high yield of product 1
2-arylation of 3-methoxythiophene has been reported was obtained using 0.1 mol% catalyst and 65% using
recently.[8e] The reaction was performed in DMF in as little as 0.01% catalyst (Table 1, Scheme 3, en-
the presence of KOAc, n-Bu4NBr, and 10 mol% of tries 1 and 2). It should be noted that this reaction is
Pd
derivatives.
If monophosphine ligands such as PPh3 or P(o- NMR analysis of the crude mixtures.
biphenyl)(t-Bu)2 and the bidentate ligand dppb have Using these reaction conditions, we tried to deter-
ACHTREUNG
ACHTREUNG
been successfully used for the coupling of thiophene mine the scope and limitations of the Tedicyp-palladi-
À
derivatives with aryl halides via C H activation, to um catalytic system for the arylation of 2-n-butylthio-
the best of our knowledge, the efficiency of polyden- phene (Table 1). Several functionalised electron-rich,
tate ligands for such couplings has not been demon- electron-poor para- or ortho-substituted aryl bromides
strated. It should be noted that the reported reactions have been employed. Very impressive TONs of 680–
were generally performed using quite high catalyst 7100 were obtained using para-substituted electron-
loadings (3–10 mol%). Moreover, the presence of ad-
ditives such as n-Bu4NBr or expensive reagents such
as AgF or AgNO3 was necessary in several cases.
Therefore, an effective and selective procedure, which
does not require the presence of additives, allowing
high substrate/catalyst ratios for the coupling of these
challenging substrates with both electron-rich, elec-
tron-poor or sterically congested aryl bromides and
using non-expensive bases needs to be found to pro-
vide an industrially viable process.
Scheme 3.
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Arylation of Thiophenes via Palladium-Catalysed C H Functionalisation
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Table 1. Palladium-catalysed reaction of aryl halides with 2-n-butylthiophene (Scheme 3).[a]
Entry
Aryl bromide
Ratio substrate/catalyst
Product
Yield [%]
1
2
3
4
5
6
7
8
4-Bromoacetophenone
4-Bromoacetophenone
4-Bromobenzaldehyde
4-Bromobenzaldehyde
4-Bromobenzophenone
4-Bromobenzophenone
Methyl 4-bromobenzoate
Methyl 4-bromobenzoate
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromonitrobenzene
4-Bromonitrobenzene
Iodobenzene
1000
10000
1000
10000
250
1000
1000
10000
1000
10000
1000
10000
100
1000
100
1000
250
1000
100
250
100
1000
100
1000
100
1000
100
1000
250
50
250
1000
250
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
100 (81)
65
100 (87)
71
94 (79)
68
100 (83)
24
100 (81)
60
100 (80)
50
100 (86)
89
100 (80)
43
100 (83)
51
100 (79)
64
100 (84)
88
100 (87)
95
100 (79)
82
100 (81)
48
54 (49)
39 (37)
100 (81)
91
100 (79)
55
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Iodobenzene
4-tert-Butylbromobenzene
4-tert-Butylbromobenzene
4-Bromoanisole
9
9
10
10
11
11
12
12
13
13
14
14
15
16
17
17
18
18
19
19
4-Bromoanisole
2-Trifluoromethylbromobenzene
2-Trifluoromethylbromobenzene
2-Fluorobromobenzene
2-Fluorobromobenzene
2-Bromotoluene
2-Bromotoluene
1-Bromonaphthalene
1-Bromonaphthalene
2,4,6-Trimethylbromobenzene
2,4,6-Triisopropylbromobenzene
3-Bromopyridine
3-Bromopyridine
3-Bromoquinoline
3-Bromoquinoline
4-Bromoisoquinoline
4-Bromoisoquinoline
1000
100
250
100 (87)
60
[a]
Conditions: catalyst: [Pd
(C3H5)Cl]2/Tedicyp: 1/2 see ref.[11], aryl halide: 1 mmol., 2-n-butylthiophene: 2 mmol., AcONa:
A
2 mmol., DMAc, 20 h, 1508C, yield determined by GC and NMR, yields in parenthesis are isolated.
deficient bromoarenes such as 4-bromobenzophe- tries 21–28). With the Tedicyp/palladium catalyst pre-
none, 4-bromobenzaldehyde, 4-trifluoromethylbromo- cursor, even the sterically challenging very congested
benzene or 4-bromobenzonitrile (Table 1, entries 3– di-ortho-substituted 2,4,6-trimethylbromobenzene or
14). On the other hand, the electron-rich 4-bromoani- 2,4,6-triisopropylbromobenzene led to the expected
sole or 4-tert-butylbromobenzene gave the 5-arylation coupling products 15 and 16, however, in lower TONs
products 9 and 10 in good yields but in lower TONs of 135 and 19 (Table 1, entries 29 and 30). The func-
of 160 and 510, respectively (Table 1, entries 17–20). tional group tolerance of this reaction is worthy of
With our catalyst, for the arylation of 2-n-butylthio- note. Substituents such as acetyl, formyl, benzoyl,
phene with aryl bromides the rate-limiting step seems ester, nitrile, nitro, trifluoromethyl, fluoro or methoxy
to be the oxidative addition of the aryl bromide to have been used successfully. The reactivity of three
palladium. Iodobenzene was found to be quite reac- heteroaryl bromides using our catalyst was also exam-
tive with a TON of 430 (Table 1, entries 15 and 16). ined. 3-Bromopyridine or 3-bromoquinoline led to
The coupling of 2-n-butylthiophene with ortho-substi- the 5-arylated 2-n-butylthiophenes 17 and 18 in good
tuted aryl bromides also proceeds nicely. 4-Trifluoro- yields and TONs using as little as 0.4–0.1 mol% cata-
methylbromobenzene, 2-fluorobromobenzene, 2-bro- lyst (Table 1, entries 31–34). A slightly slower reaction
motoluene or 1-bromonaphthalene gave the arylated was observed with 4-bromoisoquinoline, probably for
thiophene 11–14 in 480–950 TONs (Table 1, en- steric reasons (Table 1, entries 35 and 36).
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Table 2. Tedicyp-Pd-catalysed reaction of aryl halides with thiophene-2-carbonitrile (Scheme 4).[a]
Entry
Aryl halide
Ratio substrate/catalyst
Product
Yield [%]
100 (83)
1
2
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
250
1000
93
20
21
22
23
24
3
4
4-Fluorobromobenzene
4-Fluorobromobenzene
250
1000
100 (81)
96
5
4-tert-Butylbromobenzene
100
72 (67)
6
7
Iodobenzene
Iodobenzene
250
1000
100 (86)
63
8
4-Bromoanisole
100
68 (61)
9
10
2-Trifluoromethylbromobenzene
2-Trifluoromethylbromobenzene
1000
10000
100 (82)
17
25
26
11
12
1-Bromonaphthalene
1-Bromonaphthalene
250
1000
100 (84)
61
[a]
Conditions: catalyst: [Pd
(C3H5)Cl]2/Tedicyp: 1/2 see ref.[11], aryl halide: 1 mmol, thiophene-2-carbonitrile: 2 mmol,
A
AcONa: 2 mmol, DMAc, 20 h, 1508C, yield determined by GC and NMR, yields in parenthesis are isolated.
Then, the reactivity of five other thiophene deriva- itrile was also found to be a suitable substrate for
tives has been examined (Table 2, Table 3, Table 4, low-catalyst loading coupling reactions (Table 2,
Scheme 4, Scheme 5, Scheme 6). Thiophene-2-carbon- Scheme 4). However, the presence of the electron-
Table 3. Tedicyp-Pd-catalysed reaction of aryl halides with 2-acetylthiophene (Scheme 4).[a]
Entry
Aryl halide
Ratio substrate/catalyst
Product
Yield [%]
1
2
4-Bromobenzonitrile
4-Bromobenzonitrile
100
1000
100 (81)
80
27
28
29
30
31
3
4
5
4-Trifluoromethylbromobenzene
4-Fluorobromobenzene
100
100
100
100
100 (76)
100 (75)
70 (66)
4-tert-Butylbromobenzene
1-Bromonaphthalene
6
100 (77)
[a]
Conditions: catalyst: [Pd
A
2 mmol, DMAc, 20 h, 1508C, yield determined by GC and NMR, yields in parenthesis are isolated.
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Table 4. Tedicyp-Pd-catalysed reaction of aryl halides with 2-acetyl-3-methylthiophene (Scheme 4).[a]
Entry
Aryl halide
Ratio substrate/catalyst
Product
Yield [%]
100 (71)
1
2
4-Bromobenzonitrile
4-Bromobenzonitrile
100
1000
80
32
3
4
4-Trifluoromethylbromobenzene
4-Trifluoromethylbromobenzene
100
1000
100 (74)
95
33
5
6
4-Fluorobromobenzene
4-Fluorobromobenzene
100
1000
100 (80)
93
34
7
8
Iodobenzene
Iodobenzene
100
1000
100 (77)
78
35
9
4-tert-Butylbromobenzene
4-Bromoanisole
100
100
100
36
37
38
70 (54)
10
11
100 (70)
100 (68)
3-Bromoacetophenone
12
1-Bromonaphthalene
100
39
60 (44)
[a]
Conditions: catalyst: [Pd
(C3H5)Cl]2/Tedicyp: 1/2 see ref.[11], aryl halide: 1 mmol, 2-acetyl-3-methylthiophene: 2 mmol,
A
AcONa: 2 mmol, DMAc, 20 h, 1508C, yield determined by GC and NMR, yields in parenthesis are isolated.
lower TONs of 72 and 68, respectively (Table 2, en-
tries 5 and 8). Using iodobenzene a higher TON of
630 was obtained (Table 2, entries 6 and 7). The reac-
tivity of the two ortho-substituted aryl bromides, 2-tri-
fluoromethylbromobenzene and 1-bromonaphthalene
was also examined, and, in both cases, good results in
terms of yields of products 25 and 26, and TONs were
Scheme 4.
obtained (Table 2, entries 9–12). These observations
seems to confirm that the oxidative addition of the
withdrawing substituent nitrile on the thiophene ap- aryl bromide to palladium is the rate-limiting step of
pears to slow down the reaction. For example, with the catalytic cycle.
electron-deficient aryl bromides such as 4-trifluoro-
The electron-deficient 2-acetylthiophene reacted
methylbromobenzene or 4-fluorobromobenzene the with activated aryl bromides such as 4-bromobenzoni-
presence of 0.1 mol% catalyst gave high yields of the trile or 4-trifluoromethylbromobenzene to give the
corresponding 5-arylated thiophene-2-carbonitrile coupling products 27 and 28 in high yields and TONs
(Table 2, entries 1–4). The electron-rich bromoarenes of 800 and 100, respectively (Table 3, entries 1–3).
4-tert-butylbromobenzene and 4-bromoanisole also With this thiophene derivative, the electron-rich aryl
led selectively to the 5-arylated products, however in bromide 4-tert-butylbromobenzene or sterically hin-
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Scheme 5.
Scheme 6.
dered 1-bromonaphthalene led to 30 and 31 in TONs 5-arylated compounds in high TONs and good yields
of 70 and 100, respectively (Table 3, entries 5 and 6). using electron-deficient aryl bromides and in 75 TON
Quite similar results were obtained with 2-acetyl-3- with an electron-excessive aryl bromide. In short, the
methylthiophene (Table 4). The 5-arylated thiophenes reactivity of furans and thiophenes for this reaction is
were obtained selectively using 4-bromobenzonitrile, quite similar, and lead to the coupling products in
4-trifluoromethylbromobenzene or 4-fluorobromo- high yields and TONs in several cases. However,
benzene in high TONs of 800, 950 and 930, respec- there is some difference of reactivity between these
tively (Table 4, entries 1–6). The electron-rich or con- heteroaromatics. Although 2-n-butylthiophene ap-
gested aryl bromides 4-tert-butylbromobenzene, 4- pears to be more reactive than 2-n-butylfuran in most
bromoanisole or 1-bromonaphthalene led to lower cases, on the other hand, the arylation of protected
TONs of 70, 100 and 60, respectively (Table 4, en- furfuryl alcohol gave better results than using protect-
tries 9, 10 and 12). In summary, the presence of the ed thiophene-2-methanol. Both with furans and thio-
electron-withdrawing goups nitrile of acetyl in 2 posi- phene derivatives, the presence of electron-withdraw-
tion on the thiophene led in most cases to slower re- ing substituents on the heteroaromatic is tolerated.
À
actions than the couplings preformed with 2-n-bu-
tylthiophene.
Several mechanism have been suggested for the C
H activation/functionalisation of heteroarenes.[6c] With
Thiophenes bearing functionalised alkyl side chains our catalyst we believe that reaction might proceed
are also tolerated by this reaction. For example, 2-(2- via a classical oxidative addition of the aryl bromide
thienyl)ethanol reacted with 4-bromoacetophenone to to a palladium(0) complex followed by a Heck type
give the 5-arylated thiophene in 58% yield insertion of the thiophene to give the intermediate C
(Scheme 5).
(Scheme 7). On this intermediate the Pd on carbon 4
The protected thiophene-2-methanol led to the 5- and the H on carbon 5 are in an anti orientation. As
arylated thiophene derivative in moderate yield using anti b-eliminations are quite difficult, we assume that
the electron-deficient aryl bromides, 4-bromobenzoni- a base-assisted elimination of the proton on carbon 5
trile (Scheme 6). However, the formation of a few un- followed by an aromatisation and elimination of Pd
identified side-products was also observed.
occurs. A migration of the palladium to the 2-position
We had previously reported that Tedicyp and [Pd- of the 2-n-butylthiophene followed by a b-elimination
ACHTREUNG
À
of furans via C H functionalisation in good yields supported by an experiment performed with D2O (no
using very low catalyst loadings.[14] For example, 2-n- incorporation of deuterium on the benzylic CH2 of 2-
butylfuran reacts with a variety of aryl bromides in n-butylthiophene). The b-eliminations using other
good yields and high turnover numbers (TONs) (up thiophene derivatives can be expained with the same
to 1000) in most cases. The reactivity of a few other mechanism. Then, with all these substrates, a reduc-
furan derivatives had also been examined. For exam- tive elimination assisted by the base regenerates the
ple, 2-methylfuran-3-carboxylic acid ethyl ester react- Pd(0) (Scheme 7). However, an electrophilic aromatic
ed with activated aryl bromides such as 4-bromoace- substitution type mechanism is also possible for this
tophenone or 4-bromobenzonitrile to give the cou- reaction.
pling products in very high TONs of 5100 and 9800,
The high TONs obtained with the Tedicyp/palladi-
respectively. Protected furfuryl alcohol also led to the um probably mainly come from a high thermal stabili-
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Arylation of Thiophenes via Palladium-Catalysed C H Functionalisation
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Scheme 7.
ty of the catalyst. However, the structure of this cata- comes from the presence of the four diphenylphosphi-
lyst has certainly also some influence on some steps noalkyl groups stereospecifically bound to the same
of the catalytic cycle. For steric reasons, the oxidative face of the cyclopentane ring which probably increas-
addition of the aryl bromide and the coordination of es the coordination of the ligand to the metal, pre-
the thiophene derivatives to palladium are probably vents the precipitation of the catalyst and could also
not accelerated by presence of a tetraphosphine accelerate the insertion, the b-elimination or the re-
ligand. On the other hand, the insertion of the thio- ductive elimination steps in the catalytic cycle. More-
À
phene derivatives in the Ar Pd bond, and especially over, these thiophenes are commercially available.
the b-elimination and/or the reductive elimination of This is a practical advantage of this reaction.
HBr to regenerate the Pd(0) complex might be accel-
erated by the steric factors and recoordination pres-
sure of the phosphines.
Experimental Section
General Remarks
Conclusions
DMAc analytical grade (99%) was not distilled before use.
AcONa (99+ %) was used. All reactions were run under
argon using vacuum lines in Schlenk tubes in oven-dried
In summary, the coupling of aryl bromides with a va-
riety of thiophene derivatives proceeds nicely using
the tetradentate ligand Tedicyp associated to a palla-
dium complex. The reaction can be performed with as
little as 0.01 mol% catalyst with the most reactive
substrates instead of 3–10 mol% with the reported
procedures. The electron-deficient thiophenes, thio-
phene-2-carbonitrile or 2-acetylthiophenes are slightly
less reactive than the electron-neutral 2-n-butylthio-
phene. Electron-poor, electron-rich or sterically con-
gested aryl bromides have been used successfully.
Even the sterically very congested 2,4,6-triisopropyl-
bromobenzene gave the coupling product. Moreover,
a wide range of functions such as methoxy, fluoro, tri-
fluoromethyl, acetyl, formyl, benzoyl, carboxylate,
nitro or nitrile on the aryl bromide are tolerated. We
believe that this system compares favourably with
other catalyst systems that have been reported for
1
glassware. H (300 MHz) and 13C (75 MHz) spectra were re-
corded in CDCl3 solutions. Chemical shift (d) are reported
in ppm relative to CDCl3. Flash chromatographies were per-
formed on silica gel (230–400 mesh).
Preparation of the Pd-Tedicyp Catalyst[11]
An over-dried 40-mL Schlenk tube equipped with a magnet-
ic stirring bar, under argon atmosphere, was charged with
[Pd(C3H5)Cl]5 (4.2 mg, 11.6 mmol) and Tedicyp (20 mg, 23.2
E
mmol). 2.5 mL of anhydrous DMAc were added, then the so-
lution was stirred at room temperature for 10 min. This cata-
lyst solution was used directly for the catalysed reactions.
General Procedure
In a typical experiment, the aryl halide (1 mmol), thiophene
derivative (2 mmol) and AcONa (2 mmol) were dissolved in
DMAc (3 mL) under an argon atmosphere. The prepared
this process. The efficiency of this catalyst probably Pd-Tedicyp catalyst complex was then transferred to the re-
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action flask via cannula. The reaction mixture was stirred at
1508C for 20 h. The solution was diluted with H2O (5 mL),
then the product was extracted with CH2Cl2. The combined
organic layer was dried over MgSO4 and the solvent was re-
moved under vacuum. The crude product was purified by
silica gel column chromatography.
1-[4-(5-Butylthiophen-2-yl)phenyl]ethanone (1): The reac-
tion of 4-bromoacetophenone (0.199 g, 1 mmol), 2-n-butyl-
thiophene (0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol)
with the palladium complex (0.001 mmol) affords the corre-
sponding product 1 in 81% (0.209 g) isolated yield.
4-(5-Butylthiophen-2-yl)benzaldehyde (2): The reaction of
4-bromobenzaldehyde (0.185 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.001 mmol) affords the corresponding
product 2 in 87% (0.212 g) isolated yield.
2-Butyl-5-(2-fluorophenyl)thiophene (12): The reaction of
2-fluorobromobenzene (0.175 g, 1 mmol), 2-n-butylthio-
phene (0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with
the palladium complex (0.01 mmol) affords the correspond-
ing product 12 in 87% (0.204 g) isolated yield.
2-Butyl-5-(o-tolyl)thiophene (13): The reaction of 2-bro-
motoluene (0.171 g, 1 mmol), 2-n-butylthiophene (0.280 g,
2 mmol) and AcONa (0.164 g, 2 mmol) with the palladium
complex (0.01 mmol) affords the corresponding product 13
in 79% (0.182 g) isolated yield.
2-Butyl-5-(naphthalen-1-yl)-thiophene (14): The reaction
of 1-bromonaphthalene (0.207 g, 1 mmol), 2-n-butylthio-
phene (0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with
the palladium complex (0.01 mmol) affords the correspond-
ing product 14 in 81% (0.215 g) isolated yield.
2-Butyl-5-(2,4,6-trimethylphenyl)thiophene (15): The reac-
tion of 2,4,6-trimethylbromobenzene (0.195 g, 1 mmol), 2-n-
butylthiophene (0.280 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.004 mmol) affords
the corresponding product 15 in 49% (0.127 g) isolated
yield.
[4-(5-Butylthiophen-2-yl)-phenyl]phenylmethanone
(3):
The reaction of 4-bromobenzophenone (0.261 g, 1 mmol), 2-
n-butylthiophene (0.280 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.004 mmol) affords
the corresponding product 3 in 79% (0.253 g) isolated yield.
4-(5-Butylthiophen-2-yl)benzoic acid methyl ester (4):
The reaction of methyl 4-bromobenzoate (0.215 g, 1 mmol),
2-n-butylthiophene (0.280 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.001 mmol) affords
the corresponding product 4 in 83% (0.228 g) isolated yield.
2-Butyl-5-(4-trifluoromethylphenyl)thiophene (5): The re-
action of 4-trifluoromethylbromobenzene (0.225 g, 1 mmol),
2-n-butylthiophene (0.280 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.001 mmol) affords
the corresponding product 5 in 81% (0.230 g) isolated yield.
4-(5-Butylthiophen-2-yl)benzonitrile (6): The reaction of
4-bromobenzonitrile (0.182 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.001 mmol) affords the corresponding
product 6 in 80% (0.193 g) isolated yield.
2-Butyl-5-(4-nitrophenyl)thiophene (7): The reaction of 4-
bromonitrobenzene (0.202 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.01 mmol) affords the corresponding
product 7 in 86% (0.225 g) isolated yield.
2-Butyl-5-phenylthiophene (8): The reaction of iodoben-
zene (0.204 g, 1 mmol), 2-n-butylthiophene (0.280 g,
2 mmol) and AcONa (0.164 g, 2 mmol) with the palladium
complex (0.01 mmol) affords the corresponding product 8 in
80% (0.173 g) isolated yield.
2-Butyl-5-(2,4,6-triisopropylphenyl)thiophene (16): The
reaction
of
2,4,6-triisopropylbromobenzene
(0.283 g,
1 mmol), 2-n-butylthiophene (0.280 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.02 mmol)
affords the corresponding product 16 in 37% (0.127 g) iso-
lated yield.
3-(5-Butylthiophen-2-yl)pyridine (17): The reaction of 3-
bromopyridine (0.158 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.004 mmol) affords the corresponding
product 17 in 81% (0.176 g) isolated yield.
3-(5-Butylthiophen-2-yl)quinoline (18): The reaction of 3-
bromoquinoline (0.208 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.004 mmol) affords the corresponding
product 18 in 79% (0.211 g) isolated yield.
4-(5-Butylthiophen-2-yl)isoquinoline (19): The reaction of
4-bromoisoquinoline (0.208 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.01 mmol) affords the corresponding
product 19 in 87% (0.232 g) isolated yield.
5-(4-Trifluoromethylphenyl)thiophene-2-carbonitrile (20):
The reaction of thiophene-2-carbonitrile (0.218 g, 1 mmol),
4-trifluoromethylbromobenzene (0.225 g, 2 mmol) and
AcONa (0.164 g, 2 mmol) with the palladium complex
(0.004 mmol) affords the corresponding product 20 in 83%
(0.210 g) isolated yield.
5-(4-Fluorophenyl)thiophene-2-carbonitrile (21): The re-
action of 4-fluorobromobenzene (0.175 g, 1 mmol), thio-
phene-2-carbonitrile (0.218 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.004 mmol) affords
the corresponding product 21 in 81% (0.165 g) isolated
yield.
5-(4-tert-Butylphenyl)thiophene-2-carbonitrile (22): The
reaction of 4-tert-butylbromobenzene (0.213 g, 1 mmol),
thiophene-2-carbonitrile (0.218 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.01 mmol)
affords the corresponding product 22 in 67% (0.162 g) iso-
lated yield.
2-Butyl-5-(4-tert-butylphenyl)thiophene (9): The reaction
of 4-tert-butylbromobenzene (0.213 g, 1 mmol), 2-n-butyl-
thiophene (0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol)
with the palladium complex (0.004 mmol) affords the corre-
sponding product 9 in 83% (0.226 g) isolated yield.
2-Butyl-5-(4-methoxyphenyl)thiophene (10): The reaction
of 4-bromoanisole (0.187 g, 1 mmol), 2-n-butylthiophene
(0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.01 mmol) affords the corresponding
product 10 in 79% (0.194 g) isolated yield.
2-Butyl-5-(2-trifluoromethylphenyl)thiophene (11): The
reaction
of
2-trifluoromethylbromobenzene
(0.225 g,
1 mmol), 2-n-butylthiophene (0.280 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.01 mmol)
affords the corresponding product 11 in 84% (0.239 g) iso-
lated yield.
5-Phenylthiophene-2-carbonitrile (23): The reaction of io-
dobenzene (0.204 g, 1 mmol), thiophene-2-carbonitrile
2514
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Adv. Synth. Catal. 2007, 349, 2507 – 2516

À
Arylation of Thiophenes via Palladium-Catalysed C H Functionalisation
FULL PAPERS
(0.218 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.004 mmol) affords the corresponding
product 23 in 86% (0.159 g) isolated yield.
1-[5-(4-Fluorophenyl)-3-methylthiophen-2-yl]ethanone
(34): The reaction of 4-fluorobromobenzene (0.175 g,
1 mmol), 2-acetyl-3-methylthiophene (0.280 g, 2 mmol) and
AcONa (0.164 g, 2 mmol) with the palladium complex
(0.01 mmol) affords the corresponding product 34 in 80%
(0.187 g) isolated yield.
1-(3-Methyl-5-phenylthiophen-2-yl)ethanone (35): The re-
action of iodobenzene (0.204 g, 1 mmol), 2-acetyl-3-methyl-
thiophene (0.280 g, 2 mmol) and AcONa (0.164 g, 2 mmol)
with the palladium complex (0.01 mmol) affords the corre-
sponding product 35 in 77% (0.166 g) isolated yield.
1-[5-(4-tert-Butylphenyl)-3-methylthiophen-2-yl]ethanone
(36): The reaction of 4-tert-butylbromobenzene (0.213 g,
1 mmol), 2-acetyl-3-methylthiophene (0.280 g, 2 mmol) and
AcONa (0.164 g, 2 mmol) with the palladium complex
(0.01 mmol) affords the corresponding product 36 in 54%
(0.147 g) isolated yield.
1-[5-(4-Methoxyphenyl)-3-methylthiophen-2-yl]ethanone
(37): The reaction of 4-bromoanisole (0.187 g, 1 mmol), 2-
acetyl-3-methylthiophene (0.280 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.01 mmol)
affords the corresponding product 37 in 70% (0.172 g) iso-
lated yield.
1-[5-(3-Acetylphenyl)-3-methylthiophen-2-yl]ethanone
(38): The reaction of 3-bromoacetophenone (0.199 g,
1 mmol), 2-acetyl-3-methylthiophene (0.280 g, 2 mmol) and
AcONa (0.164 g, 2 mmol) with the palladium complex
(0.01 mmol) affords the corresponding product 38 in 68%
(0.175 g) isolated yield.
1-[3-Methyl-5-(naphthalen-1-yl)thiophen-2-yl]ethanone
(39): The reaction of 1-bromonaphthalene (0.207 g, 1 mmol),
2-acetyl-3-methylthiophene (0.280 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.01 mmol)
affords the corresponding product 39 in 44% (0.117 g) iso-
lated yield.
1-[4-(5-Hydroxyethylthiophen-2-yl)phenyl]ethanone (40):
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol), 2-
thiophen-2-yl-ethanol (0.256 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.01 mmol)
affords the corresponding product 40 in 58% (0.143 g) iso-
lated yield.
Acetic acid 5-[(4-cyanophenyl)thiophen-2-yl]methyl ester
(41): The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol),
methyl thiophene-2-acetate (0.312 g, 2 mmol) and AcONa
(0.164 g, 2 mmol) with the palladium complex (0.01 mmol)
affords the corresponding product 41 in 52% (0.134 g) iso-
lated yield.
5-(4-Methoxyphenyl)thiophene-2-carbonitrile (24): The
reaction of 4-bromoanisole (0.187 g, 1 mmol), thiophene-2-
carbonitrile (0.218 g, 2 mmol) and AcONa (0.164 g, 2 mmol)
with the palladium complex (0.01 mmol) affords the corre-
sponding product 24 in 61% (0.131 g) isolated yield.
5-(2-Trifluoromethylphenyl)thiophene-2-carbonitrile (25):
The reaction of 2-trifluoromethylbromobenzene (0.225 g,
1 mmol), thiophene-2-carbonitrile (0.218 g, 2 mmol) and
AcONa (0.164 g, 2 mmol) with the palladium complex
(0.001 mmol) affords the corresponding product 25 in 82%
(0.208 g) isolated yield.
5-(Naphthalen-1-yl)thiophene-2-carbonitrile (26): The re-
action of 1-bromonaphthalene (0.207 g, 1 mmol), thiophene-
2-carbonitrile (0.218 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.004 mmol) affords
the corresponding product 26 in 84% (0.197 g) isolated
yield.
4-(5-Acetylthiophen-2-yl)benzonitrile (27): The reaction
of 4-bromobenzonitrile (0.182 g, 1 mmol), 2-acetylthiophene
(0.252 g, 2 mmol) and AcONa (0.164 g, 2 mmol) with the
palladium complex (0.01 mmol) affords the corresponding
product 27 in 81% (0.184 g) isolated yield.
1-[5-(4-Trifluoromethylphenyl)thiophen-2-yl]-ethanone
(28): The reaction of 4-trifluoromethylbromobenzene
(0.225 g, 1 mmol), 2-acetylthiophene (0.252 g, 2 mmol) and
AcONa (0.164 g, 2 mmol) with the palladium complex
(0.01 mmol) affords the corresponding product 28 in 76%
(0.205 g) isolated yield.
1-[5-(4-Fluorophenyl)thiophen-2-yl]ethanone (29): The
reaction of 4-fluorobromobenzene (0.175 g, 1 mmol), 2-ace-
tylthiophene (0.252 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.01 mmol) affords
the corresponding product 29 in 75% (0.165 g) isolated
yield.
1-[5-(4-tert-Butylphenyl)thiophen-2-yl]ethanone (30): The
reaction of 4-tert-butylbromobenzene (0.213 g, 1 mmol), 2-
acetylthiophene (0.252 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.01 mmol) affords
the corresponding product 30 in 66% (0.170 g) isolated
yield.
1-[(5-Naphthalen-1-yl)-thiophen-2-yl]ethanone (31): The
reaction of 1-bromonaphthalene (0.207 g, 1 mmol), 2-ace-
tylthiophene (0.252 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.01 mmol) affords
the corresponding product 31 in 77% (0.194 g) isolated
yield.
4-(5-Acetyl-4-methylthiophen-2-yl)benzonitrile (32): The
reaction of 4-bromobenzonitrile (0.182 g, 1 mmol), 2-acetyl-
3-methylthiophene (0.280 g, 2 mmol) and AcONa (0.164 g,
2 mmol) with the palladium complex (0.01 mmol) affords
the corresponding product 32 in 71% (0.171 g) isolated
yield.
Supporting Information Available
Characterization data for compounds 1–40.
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Adv. Synth. Catal. 2007, 349, 2507 – 2516
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2515

Ahmed Battace et al.
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Adv. Synth. Catal. 2007, 349, 2507 – 2516