Solvent-free palladium-catalyzed direct arylation of heteroaromatics with aryl bromides

Article abstract of DOI:10.1002/cssc.201100771

Solvent is one of the major sources of waste in the course of catalyzed direct arylations. Some palladium-catalyzed direct arylations of heteroaromatics can be advantageously performed without any solvent. In the presence of palladium catalysts (1 mol%) and potassium acetate as the base, the direct 5-arylation of some thiazoles, thiophenes, furans, or pyrroles with aryl bromides as coupling partners proceeds highly regioselectively and in moderate to high yields. However, the use of these solvent-free conditions is limited to electron-deficient aryl bromides. Copyright

Full text of DOI:10.1002/cssc.201100771

DOI: 10.1002/cssc.201100771
Solvent-Free Palladium-Catalyzed Direct Arylation of
Heteroaromatics with Aryl Bromides
Souhila Bensaid and Henri Doucet*[a]
Solvent is one of the major sources of waste in the course of
catalyzed direct arylations. Some palladium-catalyzed direct ar-
ylations of heteroaromatics can be advantageously performed
without any solvent. In the presence of palladium catalysts
(1 mol%) and potassium acetate as the base, the direct 5-aryla-
tion of some thiazoles, thiophenes, furans, or pyrroles with aryl
bromides as coupling partners proceeds highly regioselectively
and in moderate to high yields. However, the use of these
solvent-free conditions is limited to electron-deficient aryl
bromides.
Introduction
The direct arylation of heteroaromatics is an important field for
research in organic synthesis due to the biological or physical
properties of aryl/heteroaryl derivatives. Ohta et al. have re-
ported that the direct 2- or 5-arylation of several heteroaro-
matics with aryl halides proceed in moderate to good yields
using Pd(PPh3)4 as the catalyst and N,N-dimethylacetamide
(DMAc) as the solvent.[1] Since these innovative results, the pal-
ladium-catalyzed direct arylation of heteroaryl derivatives with
aryl halides has proved to be a powerful method for the cost-
effective and environment-friendly synthesis of a wide variety
of arylated heterocycles.[2] Indeed, the major byproducts of the
reaction are a base associated to HX (X=Cl, Br, I), instead of
metallic salts produced under classical procedures (Suzuki, Ne-
gishi, or Stille cross-coupling).[3] Moreover, the method avoids
the preliminary preparation of a requisite organometallic com-
pound thus reducing the number of steps to prepare these
compounds. However, the majority of these reactions are cur-
rently performed in relatively toxic solvents, such as DMF,
DMAc, N-methylpyrrolidone (NMP), dioxane, or xylene.[4–10]
Recently, a few solvents, which can be considered as “green-
er”[11] according to principles by Anastas et al., have been em-
ployed for direct arylations.[12] For example, the direct arylation
of oxazoles, thiazoles, indazoles, or indoles using water as the
solvent was reported by the research groups of Greaney and
Djakovitch.[13] Renꢀ et al. developed biphasic conditions using
water and EtOAc for the direct arylation of thiophenes.[14a]
Polyethylene glycol (PEG 20000) has been found to be a useful
solvent for the direct arylation of triazoles.[14b] Carbonates,
ethers, or alcohols have also been used successfully for the
direct arylation of heteroaromatics (thiazole, thiophene, or oxa-
zole derivatives).[15] Finally, the ruthenium-catalyzed direct ary-
lation of 2-arylpyridines in carbonates or water has been re-
cently reported by Dixneuf et al.[16]
vent waste, hazards, and toxicity. Therefore, the use of solvent-
free conditions for palladium-catalyzed direct arylations would
provide an environmentally attractive procedure for the prepa-
ration of arylated heteroarenes.[12a]
To our knowledge, only one example of direct arylation
using solvent-free conditions has been reported. Bedford et al.
described the reaction of aryl N,N-diethyl carbamates with di-
aryliodonium salts, [ArI(mes)][OTf] (OTf=CF3SO3, mes=2,4,6-
Me3C6H2), using 5 mol% Pd(OAc)2 as the catalyst to selectively
give monoarylated free phenol products in the absence of sol-
vent.[18] Notably, phenols were isolated in yields that were
higher than those achieved previously in acetic acid. On the
other hand, to our knowledge, solvent-free conditions have
not been employed for the direct arylation of heteroaromatics.
Herein, we report the use of such conditions for palladium-cat-
alyzed direct arylations of a range of heteroaromatic deriva-
tives with aryl bromides.
Results and discussion
To determine the suitability of these conditions for palladium-
catalyzed direct arylations, a first set of reactions using benzox-
azole and 4-bromobenzonitrile as the coupling partners was
carried out under previously reported conditions, but without
solvent (Scheme 1). In the presence of polar solvents such as
DMF, NMP, dioxane, or diethylcarbonate, high yields of cou-
pling product (1) were obtained.[9b,14b] However, in the absence
of a solvent, 1 was not obtained, and several unidentified
products were formed. The direct arylation of oxazoles at C2
[a] S. Bensaid, Dr. H. Doucet
Institut Sciences Chimiques de Rennes
UMR 6226 CNRS-Universitꢀ de Rennes 1
“Catalyse et Organometalliques”
Campus de Beaulieu, 35042 Rennes (France)
Fax: +(33)0223236939
Waste prevention is a major requirement in organic synthe-
ses. One of the most promising approaches to reduce waste is
solvent-free reactions.[17] Solvent-free organic reactions make
syntheses easier due to the reduction in reactor size and sim-
pler workup. Such conditions also save energy, and reduce sol-
E-mail: henri.doucet@univ-rennes1.fr
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100771.
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H. Doucet and S. Bensaid
Table 1. Palladium-catalyzed coupling of thiazole derivatives with aryl
bromides.
Scheme 1. Attempts at coupling benzoxazole with 4-bromobenzonitrile.
Entry
1
Aryl bromide
Product
Yield[a] [%]
90
2
seemed to proceed through a simple deprotonation of the ox-
azole by the base.[19] Such deprotonated oxazoles were proba-
bly less stable in the absence of solvents than in DMF or in
carbonates.
2
3
4
89[b]
78[c]
35[d]
Then, we examined the reactivity of 2-i-butylthiazole with
a set of aryl bromides without solvent. Because 5-arylation of
thiazoles proceeded through a different mechanism than 2-ar-
ylation (concerted metallation–deprotonation mechanism)[2i,j,8b]
we could expect a different reactivity of these two heteroar-
enes.[15d] Moreover, such couplings have already been per-
formed by Greaney et al. using water as the solvent.[13a]
Employing 2-i-butylthiazole and 4-bromobenzonitrile as the
coupling partners at 1508C during 24 h with KOAc as the base
and 1 mol% [PdCl(C3H5)(dppb)] (dppb=1,4-bis(diphenylphos-
phino)butane) as the catalyst without solvent, the desired 5-ar-
ylation product (2) was obtained in 90% yield (Table 1,
entry 1). No formation of 4-arylated or 4,5-diarylated thiazoles
was detected. A slightly lower yield in 2 was obtained when
the reaction was performed at 1208C; whereas at 808C the
conversion of 4-bromobenzonitrile was poor (Table 1, entries 3
and 4).
5
3
4
73
6
7
8
78
70[b,e]
86
5
6
7
8
9
88
92
10
11
12
79
62[b,f]
13
14
9
77
79
10
The reaction of other para-substituted electron-deficient aryl
bromides such as 4-bromoacetophenone, 4-bromobenzalde-
hyde, methyl 4-bromobenzoate, 4-trifluoromethylbromoben-
zene, or 4-bromonitrobenzene with 2-alkylthiazoles also gave
the desired products (3—7) in 73–92% yields (Table 1, en-
tries 5, 6, and 8–10). 4-Fluorobromobenzene gave the expected
coupling product (8) in 79% yield (Table 1, entry 11). As ex-
pected, the reactivity of meta-substituted aryl bromides was
found to be similar to para-substituted aryl bromides (Table 1
entries 13 and 14). Next, the reactivity of two ortho-substituted
aryl bromides was examined. Due to their steric or coordina-
tion properties, ortho-substituents on aryl halides generally
have a more important influence on the yields of palladium-
catalyzed reactions.[20] However, both methyl 2-bromobenzoate
and 2-bromobenzonitrile were successfully coupled with 2-i-
butylthiazole to give 11 and 12 in good yields (Table 1, en-
tries 15 and 16). We also explored the reactivity of 2-alkylthia-
zoles with some heteroaryl bromides (Table 1, entries 17–20).
Good performance of this novel friendly protocol in direct cou-
plings with 5-bromopyrimidine, 3-bromopyridine, or 3-bromo-
quinoline was observed. With these substrates, target products
13–15 were obtained in 85–87% yield.
15
11
12
69
16
17
62
87
13
14
18
19
85
81[b]
20
15
86
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), thiazole derivative
(2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h. [b] Pd(OAc)2
(0.01 equiv). [c] Reaction temperature: 1208C. [d] Reaction temperature:
808C. [e] The formation of biphenyl-4,4’-dicarbaldehyde (12%) was also
detected. [f] The formation of a diarylated thiazole was also detected.
We have recently reported that the phosphine-free Pd(OAc)2
catalyst promotes the direct arylation of some heteroaroma-
tics.[4f,8c] This procedure was also examined for the coupling of
four aryl bromides in absence of solvent. Surprisingly, high
yields of 2 and 14 were obtained in the presence of 4-bromo-
benzonitrile or 3-bromopyridine (Table 1, entries 2 and 17).
On the other hand, in the presence of 4-bromobenzaldehyde,
4 was only obtained in 70% due to the formation of biphenyl-
4,4’-dicarbaldehyde as side-product in 12% yield. With 4-bro-
mofluorobenzene another side-product was detected by GC-
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Solvent-Free Direct Arylation of Heteroaromatics
MS analysis due to diarylation of thiazole (Table 1, entries 5
and 10). In the absence of solvent, the aggregation of palladi-
um species to form microparticles seemed faster. Such aggre-
gates are known to promote side-reactions, such as the homo-
coupling of aryl bromides. Therefore, even if it is possible for
the phosphine-free procedure to be employed with some aryl
bromides, the use of [PdCl(C3H5)(dppb)] as the catalyst appears
to be more reliable for such solvent-free reactions.
Table 3. Palladium-catalyzed coupling of thiophene 2-carbonitrile with
aryl bromides (Scheme 2).
Entry
1
Aryl bromide
Product
Yield[a] [%]
74
22
23
2
73
Then, we studied the reactivity of several other heteroaro-
matics in absence of solvent. High yields were generally ob-
tained for the coupling of thiophene derivatives with aryl bro-
mides (Table 2–6). 5-Arylation of 2-methylthiophene was found
to proceed nicely with electron-deficient aryl bromides
(Table 2, entries 1–4); whereas the coupling of 1-bromonaph-
thalene gave 20 in only 20% yield due to a partial conversion
of this aryl bromide (Scheme 2 and Table 2, entry 5).
3
4
24
25
71
73
5
6
26
27
61
64
Table 2. Palladium-catalyzed coupling of 2-methylthiophene with aryl
bromides (Scheme 2).
7
8
28
29
73
75
Entry
Aryl bromide
Product
Yield[a] [%]
1
2
16
17
84
80
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), thiophene 2-carbonitrile
(2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h.
3
4
18
19
77
74
The acetyl function appeared to be quite stable under these
conditions.
5
6
20
21
20
71
A highly functionalized reagent (2-acetyl-4-chlorothiophene)
reacted with aryl bromides (e.g., 4-bromoacetophenone, 4-tri-
fluoromethylbromobenzene, 2-bromobenzonitrile, or bromo-
pyridines) and gave 42–46 in 75–79% yield (Table 5). Notably,
in the course of these reactions no cleavage of the CÀCl bond
of the chlorothiophene derivative was detected, thus allowing
further transformations.
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), 2-methylthiophene
(2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h.
Then, a thiophene substituted by an ester function at the C2
position was employed (Table 6). The target compounds (47—
51) were obtained in 71–80% yield. Decarboxylation of some
thiophene derivatives has been previously observed in DMAc
at elevated temperatures.[4i] However, in the course of these
reactions only traces of decarboxylated thiophenes were
detected.
Scheme 2. Coupling of thiophene derivatives with aryl bromides.
Several aryl bromides were also coupled with furan deriva-
tives (Table 7). These reactions had been previously observed
to proceed nicely in DMAc or diethylcarbonate.[5d,15b] Again, for
these reactions, [PdCl(C3H5)(dppb)] was employed as the cata-
lyst. A poor reactivity of 2-n-butylfuran was observed (Table 7,
entries 1 and 2). Due to its poor coordination properties, this
furan derivative is probably not as good a stabilizing agent for
palladium species as thiophenes or thiazoles; whereas furan-2-
ylmethyl acetate and methyl 2-methylfuran-3-carboxylate were
found to be more reactive under these solvent-free conditions,
and produced 54–57 in 61–74% yield. These two substrates
gave rise to similar results in diethylcarbonate.[15b]
Thiophene 2-carbonitrile has also been coupled successfully
to several electron-deficient aryl bromides (Table 3). Similar
yields to those previously obtained in cyclopentyl methyl
ether[15d] were obtained.
Then, both protected and nonprotected 2-acetylthiopenes
were employed (Table 4). In most cases, similar yields of cou-
pling products were obtained using these two reagents. For
example, in the presence of 4-bromobenzonitrile, 30 and 35
were obtained in 74 and 72% yield (Table 4, entries 1 and 6).
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H. Doucet and S. Bensaid
Table 4. Palladium-catalyzed coupling of 2-acetylthiophenes with aryl
Table 5. Palladium-catalyzed coupling of 2-acetyl-4-chlorothiophene with
bromides (Scheme 2).
aryl bromides (Scheme 2).
Entry
1
Aryl bromide
Product
Yield[a] [%]
74
Entry
1
Aryl bromide
Product
Yield[a] [%]
30
31
32
33
42
43
44
45
46
79
2
3
4
71
70
78
2
3
4
5
78
75
76
78
5
34
35
36
37
38
39
40
41
32
72
70
74
71
75
82
77
6
7
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), 2-acetyl-4-chlorothiophene
(2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h, yield in iso-
lated product.
8
Table 6. Palladium-catalyzed coupling of ethyl thiophene-2-carboxylate
with aryl bromides (Scheme 2).
9
Entry
1
Aryl bromide
Product
Yield[a] [%]
78
10
11
12
47
48
2
3
71
80
49
50
51
4
5
77
75
[a] Conditions:
[PdCl(C3H5)(dppb)]
(0.01 equiv),
2-acetylthiophene
(2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h.
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), ethyl thiophene-2-carbox-
ylate (2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h.
We previously observed that 1-methyl-2-formylpyrrole had
a poor reactivity in direct arylations in diethylcarbonate.[15b]
In absence of solvent, the coupling of this heteroaromatic with
4-bromobenzonitrile led to 58 in only 41% yield (Table 8,
entry 1). Better results were obtained for the coupling of
1-methylpyrrole with 4-bromobenzonitrile, 4-bromonitroben-
zene, or methyl 4-bromobenzoate (Table 8, entries 2–4).
Finally, three aryl bromides were coupled with 2,5-dimethyl-
isoxazole (Table 9). Yields of 75–86% in 62–64 were obtained
using 1 mol% catalyst at 1508C. Notably, lower yields in 62 (47
and 40%) were obtained for the coupling of 4-bromobenzoni-
trile with this isoxazole derivative in diethylcarbonate or cyclo-
pentyl methyl ether; whereas the use of di-n-butyl ether pro-
duced 62 in 89% yield.[15b,d]
Conclusions
These results demonstrated that, in several cases, the direct ar-
ylation of heteroaromatics could be performed without sol-
vent. In the presence of palladium catalyst (1 mol%) at 1508C,
the direct 5-arylation of some thiazoles, thiophenes, furans,
pyrroles, or isoxazoles using aryl bromides as coupling partners
proceeded highly regioselectively and in moderate to high
yields. Under these solvent-free conditions, palladium catalysts
associated to a phosphine ligand should be preferred, even if
a phosphine-free catalyst could be employed in some cases.
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Solvent-Free Direct Arylation of Heteroaromatics
Table 7. Palladium-catalyzed coupling of furan derivatives with aryl
Table 9. Palladium-catalyzed coupling of 3,5-dimethylisoxazole with aryl
bromides.
bromides.
Entry
1
Aryl bromide
Product
Yield[a] [%]
75
Entry Aryl bromide
1
Product
Yield[a] [%]
15
52
53
62
63
64
2
17
2
3
81
86
3
4
54
55
61
71
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), 3,5-dimethylisoxazole
(2 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h.
5
6
56
57
65
74
the use of solvents, reduce waste costs, and simplify separation
procedures at the end of the reaction. For these reasons, this
novel process should give an economically viable and environ-
mentally attractive access to several arylated heteroaromatics.
Moreover, these results indicated that most of these couplings
should also proceed using highly concentrated reaction mix-
tures, thus allowing industrially viable processes.
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), furan derivative (2 equiv),
aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h.
Table 8. Palladium-catalyzed coupling of pyrrole derivatives with aryl
bromides.
Experimental Section
Pd(OAc)2, [Pd(C3H5)Cl]2, dppb, heteroarenes, KOAc (99%), and
Cs2CO3 (99%) were purchased from Alfa Aesar and were not puri-
fied before use.
Preparation of the [PdCl(C3H5)(dppb)] catalyst[21]
Entry
1
Aryl bromide
Product
Yield[a] [%]
41[b]
An oven-dried Schlenk tube (40 mL) equipped with a magnetic stir-
ring bar under argon atmosphere was charged with [Pd(C3H5)Cl]2
(182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol). Then, anhydrous
dichloromethane (10 mL) was added and the solution was stirred
at room temperature for 20 min. The solvent was removed in
vacuum. The yellow powder was used without purification.
31P NMR (81 MHz, CDCl3): d=19.3 ppm (s).
58
59
60
61
2
3
4
74
68
77
Typical experiment for coupling reactions
The reaction of aryl bromide (1 mmol), heteroaromatic (2 mmol),
and KOAc (0.196, 2 mmol) at 1508C in the presence of Pd(OAc)2 or
[PdCl(C3H5)(dppb)] under argon afforded the corresponding prod-
uct after filtration on silica gel (pentane/ether).
[a] Conditions: [PdCl(C3H5)(dppb)] (0.01 equiv), pyrrole derivative
(4 equiv), aryl bromide (1 equiv), KOAc (2 equiv), 1508C, 24 h. [b] 1-
methyl-2-formylpyrrole (2 equiv).
4-(2-Isobutylthiazol-5-yl)benzonitrile (2)
4-Bromobenzonitrile (0.182 g, 1 mmol) and 2-i-butylthiazole
(0.282 g, 2 mmol) afforded 2 (0.218 g, 90%). 1H NMR (200 MHz,
CDCl3): d=7.97 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz,
2H), 2.95 (d, J=7.5 Hz, 2H), 2.18 (m, 1H), 1.08 ppm (d, J=7.5 Hz,
6H); 13C NMR (75 MHz, CDCl3): d=171.7, 139.5, 136.5, 136.2, 132.8,
126.8, 118.5, 111.2, 42.6, 29.8, 22.2 ppm; elemental analysis calcd
(%) for C14H14N2S (242.34): C 69.39, H 5.82; found: C 69.31, H 5.68.
Notably, only electron-deficient aryl bromides were reactive
under these conditions. However, a wide range of functions
such as acetyl, propionyl, formyl, ester, nitro, nitrile, trifluoro-
methyl, or fluoro on the aryl bromide was tolerated. The major
byproduct of these couplings was KBr and AcOH instead of
metallic salts in more classical coupling procedures. Solvent-
free reactions avoid the hazards and toxicity associated with
4-(2-Isobutylthiazol-5-yl)acetophenone (3)[14a]
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and 2-i-
butylthiazole (0.282 g, 2 mmol) afforded 3 (0.189 g, 73%).
4-(2-Isobutylthiazol-5-yl)benzaldehyde (4)
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H. Doucet and S. Bensaid
The reaction of 4-bromobenzaldehyde (0.184 g, 1 mmol) and 2-i-
butylthiazole (0.282 g, 2 mmol) afforded 4 (0.191 g, 78%). H NMR
The reaction of 3-bromoquinoline (0.208 g, 1 mmol) and 2-i-bu-
tylthiazole (0.282 g, 2 mmol) afforded 15 (0.230 g, 86%). 1H NMR
(200 MHz, CDCl3): d=9.08 (s, 1H), 8.12 (s, 1H), 8.01 (d, J=8.5 Hz,
1H), 7.97 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H),
7.48 (t, J=8.0 Hz, 1H), 2.91 (d, J=7.5 Hz, 2H), 2.18 (m, 1H),
1.04 ppm (d, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=170.8,
148.5, 147.4, 138.8, 135.0, 132.3, 129.6, 129.3, 127.7, 127.4, 125.0,
42.6, 29.8, 22.3 ppm; elemental analysis calcd (%) for C16H16N2S
(268.38): C 71.60, H 6.01; found: C 71.84, H 5.92.
1
(200 MHz, CDCl3): d=10.00 (s, 1H), 7.97 (s, 1H), 7.88 (d, J=8.5 Hz,
2H), 7.65 (d, J=8.5 Hz, 2H), 2.95 (d, J=7.5 Hz, 2H), 2.18 (m, 1H),
1.08 ppm (d, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=191.2,
171.4, 139.4, 137.5, 137.0, 135.5, 130.4, 126.7, 42.6, 29.8, 22.3 ppm;
elemental analysis calcd (%) for C14H15NOS (245.34): C 68.54, H
6.16; found: C 68.41, H 6.28.
Methyl 4-(2-propylthiazol-5-yl)benzoate (5)[8c]
4-(5-Methylthiophen-2-yl)-benzonitrile (16)[4f]
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and 2-
i-butylthiazole (0.264 g, 2 mmol) affords 5 (0.225 g, 86%).
5-[4-(Trifluoromethyl)phenyl]-2-isobutylthiazole (6)[8f]
The reaction of 4-trifluoromethylbromobenzene (0.225 g, 1 mmol)
and 2-i-butylthiazole (0.282 g, 2 mmol) afforded 6 (0.251 g, 88%).
5-(4-Nitrophenyl)-2-isobutylthiazole (7)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 2-i-bu-
tylthiazole (0.282 g, 2 mmol) afforded 7 (0.241 g, 92%). 1H NMR
(200 MHz, CDCl3): d=8.27 (d, J=8.5 Hz, 2H), 7.99 (s, 1H), 7.70 (d,
J=8.5 Hz, 2H), 2.95 (d, J=7.5 Hz, 2H), 2.18 (m, 1H), 1.08 ppm (d,
J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=172.1, 146.9, 140.0,
138.1, 136.0, 126.8, 124.4, 42.6, 29.8, 22.2 ppm; elemental analysis
calcd (%) for C13H14N2O2S (262.33): C 59.52, H 5.38; found: C 59.38,
H 5.20.
5-(4-Fluorophenyl)-2-propylthiazole (8)[8c]
The reaction of 4-fluorobromobenzene (0.175 g, 1 mmol), and 2-
propylthiazole (0.264 g, 2 mmol) afforded 8 (0.175 g, 79%).
3-(2-Isobutylthiazol-5-yl)benzonitrile (9)
The reaction of 3-bromobenzonitrile (0.182 g, 1 mmol) and 2-i-bu-
tylthiazole (0.282 g, 2 mmol) afforded 9 (0.186 g, 77%). 1H NMR
(200 MHz, CDCl3): d=7.90 (s, 1H), 7.87–7.75 (m, 2H), 7.59 (d, J=
8.5 Hz, 1H), 7.38 (t, J=8.5 Hz, 1H), 2.95 (d, J=7.5 Hz, 2H), 2.18 (m,
1H), 1.08 ppm (d, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=
171.2, 138.9, 136.0, 133.1, 131.1, 130.6, 129.9, 129.8, 118.2, 113.4,
42.6, 29.8, 22.2 ppm; elemental analysis calcd (%) for C14H14N2S
(242.34): C 69.39, H 5.82; found: C 69.24, H 6.02.
2-Propyl-5-(3-trifluoromethylphenyl)thiazole (10)[8c]
The reaction of 3-(trifluoromethyl)bromobenzene (0.225 g, 1 mmol)
and 2-propylthiazole (0.264 g, 2 mmol) afforded 10 (0.214 g, 79%).
Methyl 4-(2-isobutylthiazol-5-yl)benzoate (11)
The reaction of methyl 2-bromobenzoate (0.205 g, 1 mmol) and 2-
i-butylthiazole (0.282 g, 2 mmol) afforded 11 (0.190 g, 69%).
1H NMR (300 MHz, CDCl3): d=7.77 (d, J=8.5 Hz, 1H), 7.54 (s, 1H),
7.52–7.36 (m, 3H), 3.21 (s, 3H), 2.91 (d, J=7.5 Hz, 2H), 2.18 (m,
1H), 1.04 ppm (d, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=
170.6, 168.3, 140.2, 135.8, 131.7, 131.6, 131.3, 131.0, 129.9, 128.3,
52.1, 42.3, 29.8, 22.3 ppm; elemental analysis calcd (%) for
C15H17NO2S (275.37): C 65.43, H 6.22; found: C 65.24, H 6.10.
2-(2-Isobutylthiazol-5-yl)benzonitrile (12)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 2-meth-
ylthiophene (0.196 g, 2 mmol) afforded 16 (0.167 g, 84%).
2-Methyl-5-(4-nitrophenyl)thiophene (17)[22]
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 2-
methylthiophene (0.196 g, 2 mmol) afforded 17 (0.175 g, 80%).
4-(5-Methylthiophen-2-yl)-acetophenone (18)[22]
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and 2-
methylthiophene (0.196 g, 2 mmol) afforded 18 (0.166 g, 77%).
2-Methyl-5-(4-trifluoromethylphenyl)thiophene (19)[22]
The reaction of 4-trifluoromethylbromobenzene (0.225 g, 1 mmol)
and 2-methylthiophene (0.196 g, 2 mmol) afforded 19 (0.179 g,
74%).
2-Methyl-5-naphthalen-1-ylthiophene (20)[23]
The reaction of 1-bromonaphthalene (0.207 g, 1 mmol) and 2-
methylthiophene (0.196 g, 2 mmol) afforded 20 (0.045 g, 20%).
3-(5-Methylthiophen-2-yl)pyridine (21)[24]
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 2-methyl-
thiophene (0.196 g, 2 mmol) afforded 21 (0.124 g, 71%).
5-(4-Acetylphenyl)thiophene-2-carbonitrile (22)[4f]
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and thio-
phene 2-carbonitrile (0.218 g, 2 mmol) afforded 22 (0.168 g, 74%).
5-(4-Formylphenyl)thiophene-2-carbonitrile (23)[4f]
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol) and thio-
phene 2-carbonitrile (0.218 g, 2 mmol) afforded 23 (0.156 g, 73%).
Methyl 4-(5-cyanothiophen-2-yl)benzoate (24)[4f]
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and
thiophene 2-carbonitrile (0.218 g, 2 mmol) afforded 24 (0.173 g,
71%).
5-(4-Nitrophenyl)thiophene-2-carbonitrile (25)[17]
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and thio-
phene 2-carbonitrile (0.218 g, 2 mmol) afforded 25 (0.168 g, 73%).
5-(3-Acetylphenyl)thiophene-2-carbonitrile (26)[15d]
The reaction of 3-bromoacetophenone (0.199 g, 1 mmol) and thio-
phene 2-carbonitrile (0.218 g, 2 mmol) afforded 26 (0.139 g, 61%).
5-(3-Formylphenyl)thiophene-2-carbonitrile (27)[15d]
The reaction of 3-bromobenzaldehyde (0.185 g, 1 mmol) and thio-
phene 2-carbonitrile (0.218 g, 2 mmol) afforded 27 (0.136 g, 64%).
5-[3-(trifluoromethyl)phenyl]thiophene-2-carbonitrile (28)[15d]
The reaction of 3-(trifluoromethyl)bromobenzene (0.225 g, 1 mmol)
and thiophene 2-carbonitrile (0.218 g, 2 mmol) afforded 28
(0.185 g, 73%).
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and 2-i-bu-
tylthiazole (0.282 g, 2 mmol) afforded 12 (0.150 g, 62%). 1H NMR
(200 MHz, CDCl3): d=8.05 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.70–
7.52 (m, 2H), 7.43 (t, J=8.5 Hz, 1H), 2.91 (d, J=7.5 Hz, 2H), 2.18
(m, 1H), 1.04 ppm (d, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=
172.1, 141.6, 134.9 134.3, 133.6, 133.1, 130.0, 128.1, 118.3, 110.6,
42.5, 29.8, 22.3 ppm; elemental analysis calcd (%) for C14H14N2S
(242.34): C 69.39, H 5.82; found: C 69.58, H 6.00.
5-(2-Cyanophenyl)thiophene-2-carbonitrile (29)[4f]
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and thio-
phene 2-carbonitrile (0.218 g, 2 mmol) afforded 29 (0.157 g, 75%).
4-(5-Acetylthiophen-2-yl)benzonitrile (30)[4f]
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 2-ace-
tylthiophene (0.252 g, 2 mmol) afforded 30 (0.168 g, 74%).
Methyl 4-(5-acetylthiophen-2-yl)benzoate (31)[4f]
5-(2-Propylthiazol-5-yl)pyrimidine (13)[8c]
The reaction of 5-bromopyrimidine (0.159 g, 1 mmol) and 2-pro-
pylthiazole (0.264 g, 2 mmol) afforded 13 (0.178 g, 87%).
3-(2-Propylthiazol-5-yl)pyridine (14)[8c]
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 2-propyl-
thiazole (0.264 g, 2 mmol) afforded 14 (0.173 g, 85%).
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and 2-
acetylthiophene (0.252 g, 2 mmol) afforded 31 (0.185 g, 71%).
1-[5-(4-Trifluoromethylphenyl)-thiophen-2-yl]-ethanone (32)[4f]
The reaction of 4-(trifluoromethyl)bromobenzene (0.225 g, 1 mmol)
and 2-acetylthiophene (0.252 g, 2 mmol) afforded 32 (0.189 g,
70%).
3-(2-Isobutylthiazol-5-yl)quinoline (15)
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ChemSusChem 0000, 00, 1 – 10
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Solvent-Free Direct Arylation of Heteroaromatics
1-(5-Pyridin-3-ylthiophen-2-yl)-ethanone (33)[25]
1-(4-Chloro-5-pyridin-4-yl-thiophen-2-yl)-ethanone (45)[15d]
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 2-acetyl-
thiophene (0.252 g, 2 mmol) afforded 33 (0.158 g, 78%).
1-(5-Isoquinolin-4-ylthiophen-2-yl)-ethanone (34)
The reaction of 4-bromopyridine hydrochloride (0.195 g, 1 mmol)
and 2-acetyl-4-chlorothiophene (0.321 g, 2 mmol) afforded 45
(0.180 g, 76%).
1-(4-Chloro-5-pyridin-3-ylthiophen-2-yl)-ethanone (46)[4h]
The reaction of 4-bromoisoquinoline (0.208 g, 1 mmol) and 2-ace-
tylthiophene (0.252 g, 2 mmol) afforded 34 (0.081 g, 32%). H NMR
1
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 2-acetyl-4-
(400 MHz, CDCl3): d=9.20 (s, 1H), 8.51 (s, 1H), 8.12 (d, J=8.1 Hz,
1H), 7.94 (d, J=8.1 Hz, 1H), 7.72 (d, J=3.8 Hz, 1H), 7.69 (t, J=
7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.26 (d, J=3.8 Hz, 1H),
2.55 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=190.6, 153.4,
146.5, 145.2, 143.4, 133.7, 132.7, 131.5, 129.0, 182.3, 128.2, 127.8,
125.4, 124.1, 26.8 ppm; elemental analysis calcd (%) for C15H11NOS
(253.32): C 71.12, H 4.38; found: C 71.20, H 4.51.
4-[5-(2-Methyl-1,3-dioxolan-2-yl)thiophen-2-yl]benzonitrile
(35)[15d]
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 2-ace-
tylthiophene ethylene acetal (0.340 g, 2 mmol) afforded 35
(0.195 g, 72%).
4-[5-(2-Methyl-1,3-dioxolan-2-yl)-thiophen-2-yl]-benzaldehyde
(36)[4f]
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol) and 2-ace-
tylthiophene ethylene acetal (0.340 g, 2 mmol) afforded 36
(0.192 g, 70%).
2-Methyl-2-[5-(4-nitrophenyl)-thiophen-2-yl]-[1,3]dioxolane (37)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 2-ace-
tylthiophene ethylene acetal (0.340 g, 2 mmol) afforded 37
(0.215 g, 74%).
chlorothiophene (0.321 g, 2 mmol) afforded 46 (0.185 g, 78%).
Ethyl 5-(4-cyanophenyl)thiophene-2-carboxylate (47)[5c]
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and ethyl
thiophene-2-carboxylate (0.312 g, 2 mmol) afforded 47 (0.201 g,
78%).
Ethyl 5-(4-trifluoromethylphenyl)thiophene-2-carboxylate (48)[4f]
The reaction of 4-trifluoromethylbromobenzene (0.225 g, 1 mmol)
and methyl thiophene-2-carboxylate (0.312 g, 2 mmol) afforded 48
(0.213 g, 71%).
Ethyl 5-(4-methoxycarbonylphenyl)thiophene-2-carboxylate (49)
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and
ethyl thiophene-2-carboxylate (0.312 g, 2 mmol) afforded 49
(0.232 g, 80%). 1H NMR (300 MHz, CDCl3): d=8.06 (d, J=8.5 Hz,
2H), 7.78 (d, J=4.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.38 (d, J=
4.0 Hz, 1H), 4.37 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 1.40 ppm (t, J=
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.4, 162.0, 149.3,
137.5, 134.1, 133.8, 130.3, 129.9, 125.8, 124.7, 61.3, 52.2, 14.3 ppm;
elemental analysis: calcd (%) for C15H14O4S (290.34): C 62.05, H
4.86; found: C 62.14, H 4.99.
Ethyl 5-(2-cyanophenyl)thiophene-2-carboxylate (50)
2-Methyl-2-[5-(4-trifluoromethylphenyl)-thiophen-2-yl]-[1,3]di-
oxolane (38)[4f]
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and ethyl
thiophene-2-carboxylate (0.312 g, 2 mmol) afforded 50 (0.201 g,
78%). 1H NMR (300 MHz, CDCl3): d=7.81 (d, J=4.0 Hz, 1H), 7.77
(d, J=8.5 Hz, 1H), 7.67–7.63 (m, 2H), 7.59 (d, J=4.0 Hz, 1H), 7.50–
7.45 (m, 1H), 4.37 (q, J=7.5 Hz, 2H), 1.40 ppm (t, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=161.8, 145.6, 136.6, 135.2, 134.4,
133.9, 133.2, 129.9, 128.7, 128.0, 118.3, 110.5, 61.4, 14.3 ppm; ele-
mental analysis: calcd (%) for C14H11NO2S (257.31): C 65.35, H 4.31;
found: C 65.20, H 4.47.
The reaction of 4-(trifluoromethyl)bromobenzene (0.225 g, 1 mmol)
and 2-acetylthiophene ethylene acetal (0.340 g, 2 mmol) afforded
1
38 (0.223 g, 71%). H NMR (400 MHz, CDCl3): d=8.25 (d, J=8.5 Hz,
2H), 7.71 (d, J=8.5 Hz, 2H), 7.34 (d, J=3.8 Hz, 1H), 7.09 (d, J=
3.8 Hz, 1H), 4.15–4.00 (m, 4H), 1.82 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=150.1, 146.6, 140.9, 140.6, 125.8, 125.6, 125.4,
124.4, 107.0, 65.1, 30.9, 27.4 ppm; elemental analysis calcd (%) for
C14H13NO4S (291.32): C 57.72, H 4.50; found: C 57.60, H 4.37.
2-[5-(2-Methyl-1,3-dioxolan-2-yl)thiophen-2-yl]benzonitrile
(39)[4f]
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and 2-ace-
tylthiophene ethylene acetal (0.340 g, 2 mmol) afforded 39
(0.203 g, 75%).
3-[5-(2-Methyl-1,3-dioxolan-2-yl)-thiophen-2-yl]-pyridine (40)[4f]
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and 2-acetyl-
thiophene ethylene acetal (0.340 g, 2 mmol) afforded 40 (0.203 g,
82%).
Ethyl 5-pyridin-3-ylthiophene-2-carboxylate (51)[4f]
The reaction of 3-bromopyridine (0.158 g, 1 mmol) and ethyl thio-
phene-2-carboxylate (0.312 g, 2 mmol) afforded 51 (0.175 g, 75%).
2-n-Butyl-5-(4-cyanophenyl)furan (52)[5d]
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 2-n-bu-
tylfuran (0.248 g, 2 mmol) afforded 52 (0.034 g, 15%).
3-(5-n-Butylfuran-2-yl)quinoline (53)[15b]
The reaction of 3-bromoquinoline (0.208 g, 1 mmol) and 2-n-butyl-
furan (0.248 g, 2 mmol) afforded 53 (0.043 g, 17%).
4-[5-(2-Methyl-1,3-dioxolan-2-yl)-thiophen-2-yl]-isoquinoline
(41)[4f]
The reaction of 4-bromoisoquinoline (0.208 g, 1 mmol) and 2-ace-
tylthiophene ethylene acetal (0.340 g, 2 mmol) afforded 41
(0.229 g, 77%).
1-[4-(5-Acetyl-3-chlorothiophen-2-yl)-phenyl]-ethanone (42)[15d]
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol) and
2-acetyl-4-chlorothiophene (0.321 g, 2 mmol) afforded 42 (0.220 g,
79%).
1-[4-Chloro-5-(4-trifluoromethylphenyl)-thiophen-2-yl]-ethanone
(43)[15d]
Methyl 4-(5-acetoxymethylfuran-2-yl)benzoate (54)
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and
acetic acid furan-2-ylmethyl ester (0.280 g, 2 mmol) afforded 54
(0.167 g, 61%). 1H NMR (400 MHz, CDCl3): d=8.03 (d, J=8.5 Hz,
2H), 7.71 (d, J=8.5 Hz, 2H), 6.72 (d, J=3.5 Hz, 1H), 6.50 (d, J=
3.5 Hz, 1H), 5.10 (s, 2H), 3.90 (s, 3H), 2.09 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=170.2, 166.3, 153.1, 149.7, 134.0, 129.7, 128.5,
123.2, 112.6, 107.6, 57.7, 51.7, 20.5 ppm; elemental analysis calcd
(%) for C15H14O5 (274.27): C 65.69, H 5.15; found: C 65.87, H 5.04.
Acetic acid 5-(2-cyanophenyl)furan-2-ylmethyl ester (55)[15b]
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and acetic
acid furan-2-ylmethyl ester (0.280 g, 2 mmol) afforded 55 (0.171 g,
71%).
Methyl 2-methyl-5-(4-nitrophenyl)furan-3-carboxylate (56)[5d]
The reaction of 4-trifluoromethylbromobenzene (0.225 g, 1 mmol)
and 2-acetyl-4-chlorothiophene (0.321 g, 2 mmol) afforded 43
(0.237 g, 78%).
2-(5-Acetyl-3-chlorothiophen-2-yl)-benzonitrile (44)[4h]
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol) and
2-acetyl-4-chlorothiophene (0.321 g, 2 mmol) afforded 44 (0.196 g,
75%).
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and
methyl 2-methylfuran-3-carboxylate (0.280 g, 2 mmol) afforded 56
(0.170 g, 65%).
ChemSusChem 0000, 00, 1 – 10
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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ÞÞ
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H. Doucet and S. Bensaid
ni, M. Martinelli, S. Sottocornola, Synthesis 2008, 136; c) B. Liꢀgaut, D.
Lapointe, L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826;
Methyl 5-(4-methoxycarbonylphenyl)-2-methylfuran-3-carboxyl-
ate (57)[5d]
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and
methyl 2-methylfuran-3-carboxylate (0.280 g, 2 mmol) afforded 57
(0.203 g, 74%).
4-(5-Formyl-1-methylpyrrol-2-yl)benzonitrile (58)[6e]
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 1-
methyl-2-formylpyrrole (0.219 g, 2 mmol) afforded 58 (0.086 g,
41%).
4-(1-Methylpyrrol-2-yl)benzonitrile (59)[6e]
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 1-meth-
ylpyrrole (0.324 g, 4 mmol) afforded 59 (0.135 g, 74%).
1-Methyl-2-(4-nitrophenyl)pyrrole (60)[26]
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 1-
methylpyrrole (0.324 g, 4 mmol) afforded 60 (0.137 g, 68%).
Methyl 4-(1-Methylpyrrol-2-yl)benzoate (61)[27]
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and
1-methylpyrrole (0.324 g, 4 mmol) afforded 61 (0.166 g, 77%).
4-(3,5-Dimethylisoxazol-4-yl)benzonitrile (62)[10]
ˇ
d) J. J. Dong, J. Roger, F. Pozgan, H. Doucet, Green Chem. 2009, 11,
1832; e) M. Ionita, J. Roger, H. Doucet, ChemSusChem 2010, 3, 367.
[6] For recent examples of direct arylations of pyrroles or indoles: a) F. Belli-
na, S. Cauteruccio, R. Rossi, Eur. J. Org. Chem. 2006, 1379; b) X. Wang,
D. V. Gribkov, D. Sames, J. Org. Chem. 2007, 72, 1476; c) N. Lebrasseur, I.
Larrosa, J. Am. Chem. Soc. 2008, 130, 2926; d) Y. Fall, H. Doucet, M. San-
telli, ChemSusChem 2009, 2, 153; e) J. Roger, H. Doucet, Adv. Synth.
Catal. 2009, 351, 1977.
[7] For recent examples of direct arylations of imidazoles: a) F. Bellina, S.
Cauteruccio, L. Mannina, R. Rossi, S. Viel, Eur. J. Org. Chem. 2006, 693;
b) I. Cerna, R. Pohl, B. Klepetarova, M. Hocek, Org. Lett. 2006, 8, 5389;
c) F. Bellina, C. Calandri, S. Cauteruccio, R. Rossi, Tetrahedron 2007, 63,
1970; d) F. Bellina, S. Cauteruccio, A. Di Flore, R. Rossi, Eur. J. Org. Chem.
2008, 5436; e) F. Bellina, S. Cauteruccio, A. Di Flore, C. Marchietti, R.
Rossi, Tetrahedron 2008, 64, 6060; f) J. Roger, H. Doucet, Tetrahedron
2009, 65, 9772.
[8] For recent examples of direct 2- or 5-arylations of thiazoles: a) A. L. Got-
tumukkala, H. Doucet, Eur. J. Inorg. Chem. 2007, 3629; b) L.-C. Campeau,
M. Bertrand-Laperle, J.-P. Leclerc, E. Villemure, S. Gorelsky, K. Fagnou, J.
Am. Chem. Soc. 2008, 130, 3276; c) J. Roger, F. Pozˇgan, H. Doucet, J.
Org. Chem. 2009, 74, 1179; d) F. Derridj, J. Roger, F. Geneste, S. Djebbar,
H. Doucet, J. Organomet. Chem. 2009, 694, 455; e) D. Lapointe, T. Mar-
kiewicz, C. J. Whipp, A. Toderian, K. Fagnou, J. Org. Chem. 2011, 76, 749.
[9] For recent examples of direct 2-arylations or vinylations of oxazoles:
a) C. Hoarau, A. Du Fou de Kerdaniel, N. Bracq, P. Grandclaudon, A. Cou-
ture, F. Marsais, Tetrahedron Lett. 2005, 46, 8573; b) R. S. Sꢂnchez, F. A.
Zhuravlev, J. Am. Chem. Soc. 2007, 129, 5824; c) F. Besseliꢃvre, F. Mahu-
teau-Betzer, D. S. Grierson, S. Piguel, J. Org. Chem. 2008, 73, 3278; d) F.
Derridj, S. Djebbar, O. Benali-Baitich, H. Doucet, J. Organomet. Chem.
2008, 693, 135; e) T. Yoshizumi, T. Satoh, K. Hirano, D. Matsuo, A. Orita,
J. Otera, M. Miura, Tetrahedron Lett. 2009, 50, 3273; f) C. Verrier, C.
Hoarau, F. Marsais, Org. Biomol. Chem. 2009, 7, 647.
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol) and 3,5-di-
methylisoxazole (0.192 g, 2 mmol) afforded 62 (0.148 g, 75%).
Methyl 4-(3,5-dimethylisoxazol-4-yl)benzoate (63)[10]
The reaction of methyl 4-bromobenzoate (0.205 g, 1 mmol) and
3,5-dimethylisoxazole (0.192 g, 2 mmol) afforded 63 (0.187 g, 81%).
3,5-Dimethyl-4-(4-nitrophenyl)isoxazole (64)[10]
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol) and 3,5-di-
methylisoxazole (0.192 g, 2 mmol) afforded 64 (0.188 g, 86%).
Acknowledgements
[10] For recent examples of direct arylations of isoxazoles: Y. Fall, C. Rey-
naud, H. Doucet, M. Santelli, Eur. J. Org. Chem. 2009, 4041.
[11] a) P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, New York, 1998, p. 30; b) T. Welton, Chem. Rev.
1999, 99, 2071; c) P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002, 35,
686.
We wish to thank the CNRS and “Rennes Metropole” for financial
support.
Keywords: catalysis
·
cross-coupling
·
heterocycles
·
palladium · synthetic methods
[12] C. Fischmeister, H. Doucet, Green Chem. 2011, 13, 741.
[13] a) G. L. Turner, J. A. Morris, M. F. Greaney, Angew. Chem. 2007, 119, 8142;
Angew. Chem. Int. Ed. 2007, 46, 7996; b) S. A. Ohnmacht, P. Mamone,
A. J. Culshaw, M. F. Greaney, Chem. Commun. 2008, 1241; c) E. Ferrer Fle-
geau, M. E. Popkin, M. F. Greaney, Org. Lett. 2008, 10, 2717; d) S. A. Ohn-
macht, A. J. Culshaw, M. F. Greaney, Org. Lett. 2010, 12, 224; e) L. Joucla,
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Solvent-Free Direct Arylation of Heteroaromatics
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Received: November 28, 2011
Revised: January 5, 2012
Published online on && &&, 0000
ChemSusChem 0000, 00, 1 – 10
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
&
9
&
ÞÞ
These are not the final page numbers!

FULL PAPERS
S. Bensaid, H. Doucet*
&& – &&
Solvent-Free Palladium-Catalyzed
Direct Arylation of Heteroaromatics
with Aryl Bromides
Dry, with some palladium overcast:
Several palladium-catalyzed direct aryla-
tions of heteroaromatics, performed
without solvent, proceeded nicely (see
scheme). The yield in coupling products
strongly depended on the nature of
heteroaromatics and aryl bromide
substituents.
&10
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 0000, 00, 1 – 10
ÝÝ
These are not the final page numbers!