Eco-friendly solvents for palladium-catalyzed desulfitative C-H bond arylation of heteroarenes

Article abstract of DOI:10.1002/cssc.201403429

Herein, we report the Pd-catalyzed regioselective direct arylation of heteroarenes in which benzenesulfonyl chlorides are used as coupling partners through a desulfitative cross-coupling that can be performed in diethyl carbonate (DEC) or cyclopentyl methyl ether (CPME) as green and renewable solvents or even in neat conditions instead of dioxane or dimethylacetamide (DMA). Under these solvent conditions, the reaction proceeds with a wide range of heteroarenes. C2- or C5-arylated products were obtained with furan and pyrrole derivatives. Benzofuran was also arylated regioselectively at the C2-position, whereas the reaction proceeds selectively at the C3- or C4-positions if thiophenes and benzothiophenes are used. Moreover, in some cases, especially with 1-methylindole, solvent-free conditions afforded better regioselectivities and/or yields than the reaction performed in the presence of solvents.

Full text of DOI:10.1002/cssc.201403429

DOI: 10.1002/cssc.201403429
Full Papers
Eco-Friendly Solvents for Palladium-Catalyzed
Desulfitative CÀH Bond Arylation of Heteroarenes
[
a, b]
[a]
[b]
[b]
Anoir Hfaiedh,
Kedong Yuan, Hamed Ben Ammar,* Bechir Ben Hassine, Jean-
[a]
[a]
FranÅois SoulØ, and Henri Doucet*
Herein, we report the Pd-catalyzed regioselective direct aryla-
tion of heteroarenes in which benzenesulfonyl chlorides are
used as coupling partners through a desulfitative cross-cou-
pling that can be performed in diethyl carbonate (DEC) or cy-
clopentyl methyl ether (CPME) as green and renewable sol-
vents or even in neat conditions instead of dioxane or dime-
thylacetamide (DMA). Under these solvent conditions, the reac-
tion proceeds with a wide range of heteroarenes. C2- or C5-
arylated products were obtained with furan and pyrrole deriva-
tives. Benzofuran was also arylated regioselectively at the C2-
position, whereas the reaction proceeds selectively at the C3-
or C4-positions if thiophenes and benzothiophenes are used.
Moreover, in some cases, especially with 1-methylindole, sol-
vent-free conditions afforded better regioselectivities and/or
yields than the reaction performed in the presence of solvents.
Introduction
The discovery of green chemistry processes is a great chal-
lenge and hot topic from both academic and industrial points
ported by Dong and co-workers in 2009, who arylated benzo-
quinoline in high yield using a Pd catalyst in the presence of
[
1]
[7]
of views. Indeed, the simplification of chemical processes
along with the decrease of waste and cost is an important
ideal for human development. In this line, the catalytic direct
functionalization of CÀH bonds has emerged recently as one
of the most promising and powerful methods for the construc-
tion of CÀC bonds because of the generation of lower
amounts of waste compared to that of traditional useful cross-
Ag and Cu salts in dioxane (Figure 1A). The arylation of ben-
zoxazole was performed by Cheng et al. who used similar reac-
tion conditions in dioxane, although they used K CO instead
2
3
[8]
of Ag CO (Figure 1B). Then, Jafarpour and co-workers de-
2
3
scribed the Pd-catalyzed direct desulfitative arylation of cou-
marins in the presence of Cu salts in dioxane and the direct
desulfitative arylation of pyrrole in dimethylacetamide (DMA;
[
2]
[9]
couplings. Among diverse protocols for CÀH bond cross-cou-
Figure 1C). Recently, we described the direct arylation of sev-
[
10]
pling, the Pd-catalyzed direct arylation of (hetero)arenes
eral heteroarenes, such as (benzo)furans,
(benzo)thio-
2
[11]
[12]
through C(sp )ÀH bond activation is under constant investiga-
phenes, and pyrroles,
through a desulfitative cross-cou-
tion. Since the discovery of Ohta and co-workers in 1985–1992
of the direct C2- or C5-arylation of several heteroaromatics
with aryl halides in which Pd(PPh ) was used as the catalyst
pling reaction (Figure 1D). Sodium sulfinates have been also
used in desulfitative direct arylations for the arylation of vari-
[13]
ous heteroarenes The reaction proceeded in high yields if
5 mol% PdCl (CH CN) was used in the presence of lithium car-
3
4
[
3,4]
and dimethylacetamide (DMA) as the solvent, the direct ary-
lation of heteroaromatics has promoted a large effort from
chemists because of the biological and physical properties of
2
3
2
bonate (Li CO ), sometimes with unexpected regioselectivi-
2
3
[11]
ties. The advantages of RSO Cl derivatives over arene sulfi-
2
[
5]
such aryl-heteroaryl derivatives.
nates, arylsulfonyl hydrazides, diaryliodonium salts, or boronic
acids are that many of them are commercially available and
easy to handle. They can be prepared easily from sulfonic
Recently, our group and others disclosed that benzenesul-
fonyl chlorides can be used as suitable and original coupling
[6]
[14]
partners in the Pd-catalyzed direct arylation of heteroarenes.
The first example of such a direct desulfitative-coupling was re-
acids or sulfur substrates by chlorination. Moreover, the gen-
eration of SO is not an important issue for industrial processes
2
as SO2 is added in small amounts to some beverages and
foods as a preservative.
[a] A. Hfaiedh, K. Yuan, Dr. J.-F. SoulØ, Dr. H. Doucet
Institut des Sciences Chimiques de Rennes
The major drawback of such reactions in terms of green
chemistry is that the solvents employed are toxic or not eco-
friendly (e.g., dioxane or DMA) according to solvent selection
“
OrganomØtalliques, MatØriaux et Catalyse”
UMR 6226 CNRS-UniversitØ de Rennes 1
Campus de Beaulieu, 35042 Rennes (France)
E-mail: henri.doucet@univ-rennes1.fr
[15]
guides described by chemical companies. In organic reac-
tions, the solvent is generally the chemical used in the largest
excess, which consequently generates the largest amount of
waste. To develop greener processes, specific attention should
be paid to the choice and amount of the solvent and its com-
patibilities with the catalyst.
[
b] A. Hfaiedh, Prof. H. Ben Ammar, Prof. B. Ben Hassine
Laboratoire de Synth›se Organique AsymØtrique et
Catalyse Homog›ne (UR 11ES56)
UniversitØ de Monastir
FacultØ des Sciences de Monastir
Avenue de l’environnement, Monastir 5000 (Tunisie)
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ardous chemicals such as a reduction of waste, a reduction in
[28]
reactor size, and simpler workup. However, to the best of
our knowledge, carbonates, CPME, or solvent-free conditions
have not been yet employed for Pd-catalyzed direct arylations
through desulfitative cross-coupling in which benzenesulfonyl
chlorides are used as arylating agents. The use of these condi-
tions would provide a cost-effective and environmentally at-
tractive procedure for the preparation of arylated heteroar-
enes.
Herein, we report the influence of DEC or CPME for the Pd-
catalyzed direct desulfitative arylation of a wide range of heter-
oaromatic derivatives. Reactions under neat conditions were
also performed (Figure 1E).
Results and Discussion
Firstly, we selected commercially available 2-n-butylfuran and
4
-nitrobenzenesulfonyl chloride as model substrates and ap-
[10b]
plied our previous best conditions,
that is, 5 mol%
PdCl (CH CN) in the presence of 3 equivalents of Li CO in di-
2
3
2
2
3
oxane at 1408C for 40 h. Under these conditions the C2-aryla-
tion product 1 was obtained in 88% yield (Table 1, entry 1).
Table 1. Solvent screening for the Pd-catalyzed direct desulfitative aryla-
tion of 2-n-butylfuran with 4-nitrobenzenesulfonyl chloride.
Figure 1. Previous examples of Pd-catalyzed desulfitative CÀH bond aryla-
[a,b]
[a]
Entry
Solvent
conc. [molL ])
t
[h]
Conversion
[%]
Yield of 1
[%]
tions in which benzenesulfonyl chlorides are used as coupling partners.
À1
(
1
2
3
4
5
6
7
8
9
dioxane (0.33)
ethylene glycol (0.33)
pentan-1-ol (0.33)
water (0.33)
CPME (0.5)
DMC (0.5)
DEC (0.5)
DEC (1)
DEC (1)
40
40
40
40
40
40
40
40
15
40
40
40
15
100
100
100
100
100
100
65
100
100
100
100
100
100
88
0
0
0
64
trace
58
90
95 (88)
0
0
0
Carbonates, such as diethyl carbonate (DEC) are polar, aprot-
[
16]
ic, nontoxic, and biodegradable solvents.
Based on these
properties, carbonates should offer an environmentally friendly
alternative to standard polar solvents. Carbonates have been
employed successfully for some classical metal-catalyzed reac-
[c]
[
17]
tions such as enantioselective hydrogenation, alkene meta-
[
18]
[19]
[20]
[21]
10
PC (0.5)
thesis, carbonylation, oxidation, hydroxylation, Sono-
1
1
DEC/water (5:1; 0.5)
DEC/pentanol (5:1; 0.5)
neat
[
22]
[23]
gashira coupling, Heck vinylation or allylic alkylation, and
12
[
24]
CÀH bond activation/functionalization.
Cyclopentyl methyl
13
95 (85)
ether (CPME) is a suitable alternative solvent to other ethers
such as THF or dioxane because of its high hydrophobicity—
its limited miscibility in water allows easy separation and re-
covery from water and reduces the waste stream—low forma-
tion of peroxides (compared with THF and diisopropyl ether),
relative stability under acidic and basic conditions, and narrow
explosion range. CPME can be manufactured by the addition
of MeOH to cyclopentene, which produces no apparent
1
[
a] Determined by H NMR spectroscopy. The number in parentheses
shows the isolated yield. [b] Based on 4-nitrobenzenesulfonyl chloride.
[c] Reaction performed at 1008C. PC=propylene carbonate.
Then, we screened greener solvents using these conditions. No
formation of the desired product 1 was observed in protic
polar solvents such as ethylene glycol, pentan-1-ol, or water;
and only the degradation of the benzenesulfonyl chloride de-
rivative was observed (Table 1, entries 2–4). CPME affords the
desired C5-arylation product 1 in 64% yield (Table 1, entry 5).
[
25]
waste.
been performed in CPME, which include CÀH bond aryla-
tion. Reactions performed under solvent-free conditions
have several advantages compared to the use of toxic and haz-
Moreover, metal-catalyzed reactions have already
[
26]
[
27]
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The reaction conducted in dimethylcarbonate (DMC) at
008C—because of the low boiling point of this solvent
908C)—gave only a trace amount of the desired compound
(Table 1, entry 6). Next, we decided to switch to DEC, which
Table 2. Scope of benzenesulfonyl chlorides in the Pd-catalyzed desulfita-
tive arylation of furan derivatives.
1
(
1
has a higher boiling point (126–1288C) than DMC, and per-
formed the reaction at 1408C in 0.5m. Under these conditions,
1
was obtained in 58% yield after 40 h without the full con-
Product
Yield
t
Product
Yield
[%]
t
[h]
sumption of benzenesulfonyl chloride (Table 1, entry 7). A
[
%] [h]
À1
higher concentration of 1 molL allowed the full conversion
of benzenesulfonyl chloride and gave 1 in 90% yield (Table 1,
entry 8). If we used DEC at 1 molL , the reaction time was de-
À1
91
15
15
90
15
creased to 15 h without an effect on the yield (Table 1,
entry 9). Propylene carbonate was also tested, however, the
desired product 1 was not detected (Table 1, entry 10). A mix-
ture of DEC with a protic solvent such as water or pentan-1-ol
to favor the solubilization of the inorganic base only gave the
degradation of the benzenesulfonyl chloride (Table 1, entries 11
and 12). Finally, neat conditions also provide the desired prod-
uct 1 in a high isolated yield of 85% (Table 1, entry 13).
After we had determined that DEC is the best green solvent
for such desulfitative cross-coupling reactions, we next focused
on the scope and limitation for the direct C5-arylation of furan
derivatives (Table 2). Firstly, the influence of the substituents
on the benzenesulfonyl chloride partners for the coupling with
[
a]
8
9
9 (64 ,
2
64
15
15
15
[
b]
)
trace 40
48
46
8
5
1
5
15
40
82
67
15
2
-n-butylfuran was examined using 5 mol% Pd(MeCN) Cl cata-
2 2
lyst and Li CO as base in DEC at 1408C for 15 h. The reaction
2
3
proceeded smoothly with a wide range of benzenesulfonyl
chlorides that bear electron-withdrawing groups such as ÀNO ,
[c]
2
65
15
40
40
40
ÀCN, ÀCF , ÀCl, and ÀBr at the para position, and the C5-aryla-
3
tion products 1–5 were isolated in good to excellent yields.
Moreover, the synthesis of 5 was also conducted with a moder-
ate 64% yield in CPME and with a high yield of 92% using sol-
vent-free conditions. Notably, under all these reaction condi-
tions, the CÀBr bond was not involved in the arylation reac-
tion, which allowed further transformations. However, with an
electron-donating substituent at the para position, such as À
OMe, only trace amounts of 6 were observed, even using a re-
action time longer than 40 h. A meta-substituted benzenesul-
fonyl chloride was also tolerated and gave the desired product
[a]
7
8
6 (78 ,
4
[
c]
48
[b]
)
[
a] Reaction performed in CPME. [b] Reaction performed in neat condi-
tions. [c] ArSO
an autoclave.
2
Cl (1 equiv.), HetArH (2 equiv.); reaction performed using
namely, CPME and neat conditions, displayed a similar activity
for the C5-arylation of 1-(furan-2-yl)propan-2-one, as 15 was
isolated in 78 and 84% yield, respectively.
7
in 48% yield. The reaction was not affected by steric hin-
drance, as 8 with a NO substituent at the ortho position was
2
isolated in 81% yield. However, the presence of two NO sub-
Then, the C2 direct arylation of benzofuran in DEC was in-
vestigated. The reaction proceeded smoothly, but a longer re-
action time of 40 h was required to reach the full consumption
of the benzenesulfonyl chloride (Table 3). From benzofuran, 16
was obtained in a high yield with 4-nitrobenzenesulfonyl chlo-
ride. If we used the less reactive 4-methoxybenzenesulfonyl
chloride, which is not reactive with 2-n-butylfuran (Table 2), the
desulfitative cross-coupling product 17 was isolated in 38%
yield. Interestingly, the reaction gave a higher yield if CPME
was used as the solvent instead of DEC, whereas only trace
amounts of 17 were obtained under neat conditions. Again,
the reaction conditions were found to tolerate the bromo
functional group. For example, 18 was isolated in 78% yield
from 4-bromobenzenesulfonyl chloride. Other solvent condi-
tions, namely, CPME or neat conditions, also allowed the for-
mation of 18 in 83 and 57% yield, respectively. The reaction is
2
stituents on the benzenesulfonyl chloride partner afforded the
desired C5-arylated product 9 in a lower yield. The less reactive
naphthalene-1-sulfonyl chloride reacted over a longer time
(40 h) to provide the desired C5-arylation product 10 in 55%
yield. Next, the reactivity of other furan derivatives was exam-
ined. Menthofuran showed high reactivity with activated ben-
zenesulfonyl chloride to give the desired desulfitative cross-
coupling products 11 and 12 in 82 and 65% yield, respectively.
The reaction was also performed using 2-methylfuran as the
substrate. This was undertaken in an autoclave because of the
low boiling point of this furan (63–668C). The C5-arylated 2-
methylfurans 13 and 14 were isolated in 67 and 48% yield, re-
spectively. A furan that bears a ketone function at the C2-posi-
tion, 1-(furan-2-yl)propan-2-one, also reacted well to afford the
C5-arylated product 15 in 76% yield. Other solvent conditions,
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C2-arylated pyrroles 21 and 22 were isolated in high yields
after only 15 h. In contrast to the reaction with (benzo)furans,
Table 3. Scope of benzenesulfonyl chlorides in the Pd-catalyzed desulfita-
tive arylation of benzofuran.
1-methylpyrrole was arylated using 4-methoxybenzenesulfonyl
chloride in good yield. However, in the crude mixture, we also
observed the formation of a large amount of the C2,C5-diaryla-
tion product. If the reaction was performed in CPME, the ary-
lated product 23 was isolated in a slightly higher yield because
of the decreased amount of the C2,C5-diarylation product. In
contrast, under neat conditions, the desulfitative-coupling
product 23 was obtained in a low yield because of the forma-
tion of a larger amount of C2,C5-diarylation product. Again,
the reaction proceeded well with 4-bromobenzenesulfonyl
chloride to allow the formation of 24 in 75% yield. Other sol-
vents displayed a similar reactivity; for example, 24 was isolat-
ed in 77% yield in CPME and 80% under neat conditions. As in
the case of the arylation of benzofuran, the arylation of pyr-
roles tolerated an ortho substituent on the benzene sulfonyl
chloride reagent. The reaction of 1-methylpyrrole with 2-nitro-
benzenesulfonyl chloride provided aryl pyrrole 25 in 86%
yield. Other substituents on the nitrogen atom, such as benzyl
or phenyl, gave the corresponding coupling products 26, 27,
and 28 in 87, 73, and 73% yield, respectively.
Product
Yield
Product
Yield
[%]
[%]
3
8
8
3
[
a]
[b]
(
58 , trace )
7
9
8
4
[
a]
[b]
(
83 , 57
)
5
2
[
a] Reaction performed in CPME. [b] Reaction performed in neat condi-
tions.
slightly sensitive to steric hindrance. For example, the reaction
of 2-fluorobenzenesulfonyl chloride or 2-nitrobenzenesulfonyl
chloride gave the desired arylated products 19 and 20 in 84
and 52% yield, respectively.
Next, we investigated the direct desulfitative arylation of 1-
[13f,29]
methylindole.
The use of 4-bromobenzenesulfonyl chlo-
ride in dioxane gives a mixture of arylation products at the 2-
or 3-position (29a/29b) in a 51:49 ratio, albeit with a moderate
conversion (Table 5, entry 1). Interestingly, we found that the
solvent has a huge effect on the regioselectivity of this reac-
tion. Indeed, if the reaction was performed in DEC instead of
dioxane, the regioisomer 29b was obtained as the major prod-
uct (Table 5, entry 2), whereas the reaction in CPME gave
almost an equimolar mixture of the two regioisomers. Finally,
using solvent-free conditions, the regioisomer 29a, in which
the arylation took place at the C2-position, was obtained in an
excellent ratio of 85:15 and was isolated in 62% yield (Table 5,
entry 4).
Pyrroles were arylated regio- and chemoselectively at the
C2-position using benzenesulfonyl chloride derivatives in DEC
(
Table 4), but 2 equivalents of pyrrole derivatives were used to
prevent the formation of diarylation products. From 1-methyl-
pyrrole and 4-nitro- or 4-cyanobenzenesulfonyl chlorides, the
Table 4. Scope of benzenesulfonyl chlorides in the Pd-catalyzed desulfita-
tive arylation of pyrrole derivatives.
Product
Yield
%]
Product
Yield
[%]
Table 5. Pd-catalyzed desulfitative direct arylation of 1-methylindole with
[
4-bromobenzenesulfonyl chloride: effect of the solvent on the regioselec-
tivity.
9
4
2
89
[
a]
[a,b]
[a,c]
[b,d]
[c,d]
8
(55 , 23
)
75 (71 , 65
)
8
7
6
3
87
[
a]
[a]
Entry
Solvent
Conversion
%]
29a/29b
[
1
2
3
4
dioxane
DEC
CPME
neat
49
44
46
73
51:49
73
[
[
b]
c]
34:66 (29%
49:51
85:15 (62% )
)
[
a] Presence of 2,5-bis(4-methoxyphenyl)-1-methylpyrrole in the crude
mixture: [b] Reaction performed in CPME. [c] Reaction performed in neat
conditions. [d] Trace of 2,5-bis(4-bromophenyl)-1-methylpyrrole.
1
[a] Determined from the H NMR spectrum of the crude product. [b] Iso-
lated yield of 29b. [c] Isolated yield of 29a.
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Previously, we found that the reaction with 1-methylindole
in dioxane is very sensitive to the steric hindrance of the ben-
Table 7. Scope of benzenesulfonyl chlorides in the Pd-catalyzed desulfita-
tive arylation of thiophene derivatives.
[
12]
zenesulfonyl chloride partner, so we decided to investigate
the regioselectivity of this reaction with 2-bromobenzenesul-
fonyl chloride under different solvent conditions. Again, the
solvent was critical for both regioselectivity and conversion
(
Table 6, entries 1–4). Quasi-equimolar ratios between the two
Product
Yield
[%]
Product
Yield
[%]
regioisomers 30a and 30b were obtained in CPME and DEC,
albeit in a poor conversion of 26 and 41%, respectively
(Table 6, entries 2 and 3). The reaction performed in dioxane
[a]
[b]
5
0 (43 , trace
)
84
Table 6. Pd-catalyzed desulfitative direct arylation of 1-methylindole with
3-bromobenzenesulfonyl chloride: effect of the solvent and steric hin-
drance on the regioselectivity.
74
76
trace
89
4
6
0
6
73
[
a]
[a]
Entry
Solvent
Conversion
%]
30a/30b
[
[a]
1
2
3
4
dioxane
DEC
CPME
neat
31
26
41
95
77:23
55:45
52:48
35 (trace ,
trace
[b]
)
[b]
80:20 (71%
)
1
[
a] Determined from the H NMR spectrum of the crude product. [b] Iso-
[
a]
[b]
7
4
9 (64 , trace )
56
lated yield of 30a.
showed a slightly higher regioselectivity in favor of 30a but
with a low conversion of 31% (Table 6, entry 1). Finally, under
solvent-free conditions, the reaction was complete with a high
regioselectivity in favor of 30a, which was isolated in 71%
yield (Table 6, entry 4).
[c]
[c]
1 (85 )
88
[c]
8
5
Then, we turned our attention to thiophene derivatives. We
found previously that in dioxane the arylation occurs at the
unexpected C3-position in the presence of 5 mol%
[
a] Reaction performed in CPME. [b] Reaction performed in neat condi-
tions. [c] Reaction performed during 72 h.
[
11]
PdCl (CH CN) as catalyst and Li CO3 as base.
In DEC
2
3
2
2
medium, the reaction proceeded similarly, and the C3-arylated
thiophenes were obtained after 40 h (Table 7). Firstly, the influ-
ence of the substituents at the para position on the benzene-
sulfonyl chlorides for the coupling with 2-n-pentylthiophene
was examined. Again, benzenesulfonyl chlorides that bear elec-
veyed. 2-Methylthiophene was arylated to provide the desired
products 36–38 in moderate to high yields. From 2,2’-bithio-
phene and 4-nitrobenzenesulfonyl chloride, the mono-C3-ary-
lated product 39 was obtained selectively in a good yield of
66%. This family of bithiophenes could allow simple access to
tron-withdrawing groups such as ÀNO , ÀCN, ÀBr, and ÀCl dis-
2
played high reactivities, and the C3-arylated products 31–34
were isolated in 74–84% yield. If 4-nitrobenzenesulfonyl chlo-
ride and 2-n-pentylthiophene were used as substrates, the re-
action proceed in a lower yield of 43% in CPME, whereas
almost no reaction occurred under neat conditions. Similar to
the reaction with (benzo)furans, an electron-donating substitu-
ent on the benzenesulfonyl chloride partner, such as 4-me-
thoxybenzenesulfonyl chloride, inhibited the reaction, and only
a trace amount of the arylated product 35 was observed. Next,
the reactivity of other thiophene derivatives in DEC was sur-
[30]
electronic devices or materials.
The C4-arylation of thio-
phenes substituted in the 3-position was also investigated. 3-
Chlorothiophene reacted poorly with 4-nitrobenzenesulfonyl
chloride to give the arylated product 40 in a low yield of 35%.
Notably, with this thiophene derivative, no reaction occurred
in CPME or if solvent-free conditions were used. Interestingly,
the C4-arylated product of 3-methylthiophene was obtained in
a better yield of 79%. With the use of this thiophene, the reac-
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tion occurred smoothly in CPME, whereas under neat condi-
tions only a trace amount of the arylated product 41 was ob-
tained. A bromo substituent at the 2-position of thiophene
was also tolerated, and the 4-arylated 2-halothiophene 42 was
obtained in 56% yield.
To a 5 mL oven-dried Schlenk tube, arylsulfonyl chloride (1–
1
.5 mmol), heteroarene derivatives (1–2 mmol), Li CO3 (0.222 g,
2
3
mmol), DEC (1 mL), CPME (1 mL), or no solvent (see tables and
schemes), and bis(acetonitrile)dichloropalladium(II) (12.9 mg,
.05 mmol) were added successively. The reaction mixture was
evacuated by vacuum–argon cycles (five times) and stirred at
408C (oil bath temperature) for 15–72 h (see tables and schemes).
0
Finally, the arylation of benzothiophene was investigated,
and the reaction proceeds very slowly in DEC. After 40 h, only
1
After cooling the reaction to RT and concentration, the crude mix-
ture was purified by silica column chromatography to afford the
desired arylated products.
4
1% yield of the coupling product 43 was obtained, because
of the partial consumption of 4-nitrobenzenesulfonylchloride.
-Nitrobenzenesulfonylchloride was consumed fully after 72 h,
4
and the aryl thiophene 43 was isolated in 85% yield. Other
benzenesulfonyl chlorides such as 4-bromobenzenesulfonyl
chloride and 2-nitrobenzenesulfonyl chloride also allowed the
formation of C3-arylated benzothiophenes 44 and 45 in high
yields.
[
5b]
2
-n-Butyl-5-(4-nitrophenyl)furan (1)
2-n-Butylfuran (0.124 g, 1 mmol) and 4-nitrobenzenesulfonyl chlo-
ride (0.332 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
0:20) to afford the desired compound 1 in 88% (0.216 g) yield.
H NMR (400 MHz, CDCl ): d=8.10 (d, J=8.6 Hz, 2H), 7.61 (d, J=
8
1
3
8
.6 Hz, 2H), 6.68 (d, J=3.2 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H), 2.61 (t,
Conclusions
J=7.4 Hz, 2H), 1.58 (quint., J=7.4 Hz, 2H), 1.34 (sext., J=7.4 Hz,
2
H), 0.87 ppm (t, J=7.4 Hz, 3H).
We have shown that diethyl carbonate (DEC) and in some
cases cyclopentyl methyl ether (CPME), which are both consid-
ered as “green solvents”, can be employed advantageously as
an alternative to common solvents in the Pd-catalyzed desulfi-
tative direct arylation of several heteroaromatic derivatives in
which benzenesulfonyl chlorides are used as coupling partners.
In the presence of DEC or CPME and 5 mol% PdCl (CH CN) as
[
5b]
2-n-Butyl-5-(4-cyanophenyl)furan (2)
2
-n-Butylfuran (0.124 g, 1 mmol) and 4-cyanobenzenesulfonyl chlo-
ride (0.303 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
2
3
2
85:15) to afford the desired compound 2 in 91% (0.205 g) yield.
1
the catalyst precursor at 1408C, the direct C5-arylation of
furans, the C2-arylation of benzofuran, the C2-arylation of pyr-
roles, and the C3-arylation of (benzo)thiophenes proceed in
moderate to high yields. Notably, the reaction is chemoselec-
tive, as CÀX (X=Cl, Br) bonds are not involved in the arylation
process. In some cases, solvent-free conditions, which are ben-
eficial for the reduction of waste, showed high reactivity, espe-
cially for 1-methylindole with which the arylation took place
more selectively at the C2 position. The major byproducts of
H NMR (400 MHz, CDCl
.6 Hz, 2H), 6.61 (d, J=3.2 Hz, 1H), 6.02 (d, J=3.2 Hz, 1H), 2.60 (t,
J=7.4 Hz, 2H), 1.59 (quint., J=7.4 Hz, 2H), 1.33 (sext., J=7.4 Hz,
H), 0.87 ppm (t, J=7.4 Hz, 3H).
3
): d=7.58 (d, J=8.6 Hz, 2H), 7.51 (d, J=
8
2
[5b]
2-n-Butyl-5-(4-(trifluoromethyl)phenyl)furan (3)
2
-n-Butylfuran (0.124 g, 1 mmol) and 4-trifluoromethylbenzenesul-
fonyl chloride (0.367 g, 1.5 mmol) were used, and the residue was
purified by flash chromatography on silica gel (heptane/ethyl ace-
tate, 95:5) to afford the desired compound 3 in 90% (0.242 g)
yield. H NMR (400 MHz, CDCl ): d=7.71 (d, J=8.6 Hz, 2H), 7.59 (d,
these couplings are LiCl and SO instead of metal salts that
2
1
result from more classical coupling procedures. Moreover, this
method does not require an external toxic oxidant such as Ag
or Cu salts. For these reasons, this new process offers economi-
cally viable and environmentally attractive access to arylated
heteroaromatics. 45 examples are reported, which demon-
strates the wide scope of DEC, CPME, or solvent-free condi-
tions for the desulfitative direct arylation reaction.
3
J=8.6 Hz, 2H), 6.67 (d, J=3.2 Hz, 1H), 6.10 (d, J=3.2 Hz, 1H), 2.70
t, J=7.4 Hz, 2H), 1.69 (quint., J=7.4 Hz, 2H), 1.45 (sext., J=7.4 Hz,
(
2
H), 0.96 ppm (t, J=7.4 Hz, 3H).
[10b]
2
-n-Butyl-5-(4-chlorophenyl)furan (4)
2
-n-Butylfuran (0.124 g, 1 mmol) and 4-chlorobenzenesulfonyl chlo-
ride (0.317 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
Experimental Section
9
0:10) to afford the desired compound 4 in 64% (0.150 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.45 (d, J=8.6 Hz, 2H), 7.20 (d, J=
3
All reactions were performed under argon atmosphere using stan-
dard Schlenk techniques. DEC and CPME were purchased from
Acros Organics and were not purified before use. H NMR spectra
8
.6 Hz, 2H), 6.42 (d, J=3.2 Hz, 1H), 5.95 (d, J=3.2 Hz, 1H), 2.58 (t,
1
J=7.4 Hz, 2H), 1.56 (quint., J=7.4 Hz, 2H), 1.33 (sext., J=7.4 Hz,
2
H), 0.86 ppm (t, J=7.4 Hz, 3H).
were recorded by using Bruker GPX (400 MHz or 300 MHz) spec-
trometers. Chemical shifts (d) were reported in ppm relative to re-
1
13
sidual chloroform (d=7.26 ppm for H; d=77.0 ppm for C), and
[10b]
2-(4-Bromophenyl)-5-n-butylfuran (5)
1
coupling constants were reported in Hertz. H NMR assignment ab-
breviations are singlet (s), doublet (d), triplet (t), quartet (q), dou-
blet of doublets (dd), doublet of triplets (dt), and multiplet (m).
C NMR spectra were recorded at 100 MHz or 75 MHz on the same
2-n-Butylfuran (0.124 g, 1 mmol) and 4-bromobenzenesulfonyl
chloride (0.383 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
1
3
spectrometers and reported in ppm. All reagents were weighed
and handled in air.
90:10) to afford the desired compound 5 in 89% (0.249 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.39 (d, J=8.6 Hz, 2H), 7.36 (d, J=
3
ChemSusChem 2015, 8, 1794 – 1804
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Full Papers
8
.6 Hz, 2H), 6.44 (d, J=3.2 Hz, 1H), 5.95 (d, J=3.2 Hz, 1H), 2.57 (t,
85:15) to afford the desired compound 11 in 82% (0.205 g).
1
J=7.4 Hz, 2H), 1.56 (quint., J=7.4 Hz, 2H), 1.32 (sext., J=7.4 Hz,
H NMR (400 MHz, CDCl ): d=7.57 (d, J=8.6 Hz, 2H), 7.52(d, J=
3
2
H), 0.86 ppm (t, J=7.4 Hz, 3H).
8.6 Hz, 2H), 2.70–2.60 (m, 1H), 2.40–2.10 (m, 3H), 2.10 (s, 3H),
1
.90–1.70 (m, 2H), 1.40–1.10 (m, 1H), 1.02 ppm (d, J=7.5 Hz, 3H).
[10b]
2-n-Butyl-5-(3-(trifluoromethyl)phenyl)furan (7)
3
,6-Dimethyl-2-(2-nitrophenyl)-4,5,6,7-tetrahydrobenzofuran
2
-n-Butylfuran (0.124 g, 1 mmol) and 3-trifluoromethylbenzenesul-
(
12)
fonyl chloride (0.367 g, 1.5 mmol) were used, and the residue was
purified by flash chromatography on silica gel (heptane/ethyl ace-
tate, 98:2) to afford the desired compound 7 in 48% (0.129 g)
Menthofuran (0.150 g, 1 mmol) and 2-nitrobenzenesulfonyl chlo-
ride (0.332 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
1
yield. H NMR (400 MHz, CDCl ): d=7.77 (s, 1H), 7.69 (m, 1H), 7.40–
3
7
.33 (m, 2H), 6.54 (d, J=3.2 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H), 2.61 (t,
75:25 to afford the desired compound 12 in 65% yield (0.176 g).
1
J=7.4 Hz, 2H), 1.60 (quint., J=7.4 Hz, 2H), 1.35 (sext., J=7.4 Hz,
H NMR (400 MHz, CDCl ): d=7.73 (d, J=8.1 Hz, 1H), 7.50 (t, J=
3
2
H), 0.88 ppm (t, J=7.4 Hz, 3H).
7.3 Hz, 1H), 7.44 (dd, J=1.8 and 7.7 Hz, 1H), 7.31 (dt, J=1.6 and
7
.7 Hz, 1H), 2.60 (ddd, J=1.5 and 5.1 and 16.5 Hz, 1H), 2.36–2.28
(
m, 2H), 2,16–2.12 (m, 1H), 1.84 (s, 3H), 1.90–1.83 (m, 1H), 1.81–
2
-n-Butyl-5-(2-nitrophenyl)furan (8)
1
.75 (m, 1H), 1.37–1.27 (m, 1H), 1.01 ppm (d, J=6.7 Hz, 3H);
1
3
C NMR (100 MHz, CDCl ): d=151.7, 148.1, 142.2, 132.0, 130.3,
2
-n-Butylfuran (0.124 g, 1 mmol) and 2-nitrobenzenesulfonyl chlo-
3
1
9
7
27.5, 125.9, 124.5, 119.5, 119.2, 31.3, 31.1, 29.6, 21.5, 20.1,
ride (0.332 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
.2 ppm; elemental analysis calcd (%) for C H NO (271.32): C
16 17
3
0.83, H 6.32; found: C 70.75, H 6.21.
8
0:20) to afford the desired compound 8 in 81% (0.199 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.62 (d, J=8.0 Hz, 1H), 7.56 (d, J=
3
8
.0 Hz, 1H), 7.46 (dt, J=1.4, 7.7 Hz, 1H), 7.27 (ddd, J=1.4 and 7.4
[32]
2-Methyl-5-(4-nitrophenyl)furan (13)
and 8.0 Hz, 1H), 6.51 (d, J=3.3 Hz, 1H), 6.02 (d, J=3.2 Hz, 1H),
2
7
.58 (t, J=7.5 Hz, 2H), 1.57 (quint., J=7.5 Hz, 2H), 1.32 (sext., J=
.5 Hz, 2H), 0.87 ppm (t, J=7.5 Hz, 3H); C NMR (100 MHz, CDCl3):
2-Methylfuran (177 mL, 2 mmol) and 4-nitrobenzenesulfonyl chlo-
ride (0.221 g, 1 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 75:25)
13
d=158.5, 147.2, 146.4, 131.7, 128.3, 127.5, 124.4, 123.8, 110.6,
07.3, 30.1, 27.8, 22.2, 13.8 ppm; elemental analysis calcd (%) for
C H NO (245.28): C 68.56, H 6.16; found: C 68.22, H 6.29.
1
1
to afford the desired compound 13 in 67% (0.136 g) yield. H NMR
1
4
15
3
(400 MHz, CDCl ): d=8.22 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz,
3
2
3
H), 6.78 (d, J=3.0 Hz, 1H), 6.14 (d, J=3.0 Hz, 1H), 2.41 ppm (s,
H).
2
-n-Butyl-5-(2,4-dinitrophenyl)furan (9)
2
-n-Butylfuran (0.124 g, 1 mmol) and 2,4-dinitrobenzenesulfonyl
[
33]
2
-(4-Cyanophenyl)-5-methylfuran (14)
chloride (0.398 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
2-Methylfuran (177 mL, 2 mmol) and 4-cyanobenzenesulfonyl chlo-
ride (0.201 g, 1 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 85:15)
to afford the desired compound 14 in 48% (0.088 g) yield. H NMR
(400 MHz, CDCl ): d=7.61 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz,
6
5:35) to afford the desired compound 9 in 46% (0.133 g) yield.
1
H NMR (400 MHz, CDCl ): d=8.38 (d, J=2.3 Hz, 1H), 8.28 (dd, J=
3
1
2
6
1
.3 and 8.8 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H),
.12 (d, J=3.2 Hz, 1H), 2.62 (t, J=7.5 Hz, 2H), 1.60–1.54 (m, 2H),
3
13
.39–1.26 (m, 2H), 0.88 ppm (t, J=7.4 Hz, 3H); C NMR (75 MHz,
2H), 6.63 (d, J=3.3 Hz, 1H), 6.08–6.02 (m, 1H), 2.32 ppm (s, 3H).
CDCl ): d=161.2, 145.7, 145.2, 144.3, 128.9, 128.0, 126.0, 119.7,
3
114.8, 108.7, 29.9, 27.7, 22.2, 13.6 ppm; elemental analysis calcd (%)
for C H N O (290.28): C 57.93, H 4.86; found: C 58.11, H 4.75.
1-(5-(2-Nitrophenyl)furan-2-yl)propan-2-one (15)
1
4
14
2
5
1
-(Furan-2-yl)propan-2-one (248 mg, 2 mmol) 2-nitrobenzenesul-
[31]
fonyl chloride (0.221 g, 1 mmol) were used, and the residue was
purified by flash chromatography on silica gel (heptane/ethyl ace-
2
-n-Butyl-5-naphthalen-1-ylfuran (10)
2
-n-Butylfuran (0.124 g, 1 mmol) and 1-naphthalenesulfonyl chlo-
tate, 80:20) to afford the desired compound 15 in 76% (0.186 g)
1
ride (0.340 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
yield. H NMR (400 MHz, CDCl ): d=7.70 (ddd, J=1.4 and 2.1 and
3
8.0 Hz, 2H), 7.59 (t, J=7.7 Hz, 1H), 7.42 (dd, J=7.4 and 8.1 Hz, 1H),
9
0:10) to afford the desired compound 10 in 55% (0.138 g) yield.
6.66 (d, J=3.4 Hz, 1H), 6.35 (d, J=3.3 Hz, 1H), 3.76 (s, 2H),
1
13
H NMR (400 MHz, CDCl ): d=8.46 (d, J=8.2 Hz, 1H), 7.88 (d, J=
2.24 ppm (s, 3H); C NMR (100 MHz, CDCl ): d=203.5, 150.0, 148.1,
3
3
8
.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.55–
147.4, 131.9, 128.8, 128.3, 124.0, 123.9, 110.9, 110.7, 43.3, 29.3 ppm;
elemental analysis calcd (%) for C H NO (245.23): C 63.67, H 4.52;
7
.45 (m, 3H), 6.63 (d, J=3.2 Hz, 1H), 6.18 (d, J=3.2 Hz, 1H), 2.77 (t,
13
11
4
J=7.4 Hz, 3H), 1.76 (quint., J=7.4 Hz, 2H), 1.48 (sext., J=7.4 Hz,
found: C 63.95, H 4.21.
2
H), 0.98 ppm (t, J=7.4 Hz, 3H).
[34]
2-(4-Nitrophenyl)benzofuran (16)
2
-(4-Cyanophenyl)-3,6-dimethyl-4,5,6,7-tetrahydrobenzo-
[
5b]
Benzofuran (0.118 g, 1 mmol) and 4-nitrobenzenesulfonyl chloride
furan (11)
(0.331 g, 1.5 mmol) were used, and the residue was purified by
Menthofuran (0.150 g, 1 mmol) and 4-cyanobenzenesulfonyl chlo-
ride (0.303 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
flash chromatography on silica gel (heptane/ethyl acetate, 80:20)
to afford the desired compound 16 in 83% (0.198 g) yield. H NMR
1
(400 MHz, CDCl ): d=8.32 (d, J=7.8 Hz, 2H), 8.10 (d, J=7.8 Hz,
3
ChemSusChem 2015, 8, 1794 – 1804
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1800
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
1
2
7
H), 7.64 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.37 (t, J=
.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.26 ppm (s, 1H).
H NMR (400 MHz, CDCl ): d=7.60 (d, J=8.6 Hz, 2H), 7.43 (d, J=
3
8.6 Hz, 2H), 6.71 (m, 1H), 6.28 (dd, J=3.4, 1.7 Hz, 1H), 6.16 (t, J=
.4 Hz, 1H), 3.64 ppm (s, 3H).
3
[34]
2-(4-Methoxyphenyl)benzofuran (17)
[12]
1-Methyl-2-(4-methoxyphenyl)pyrrole (23)
Benzofuran (0.118 g, 1 mmol) and 4-methoxybenzenesulfonyl chlo-
ride (0.310 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
1-Methylpyrrole (0.162 g, 2 mmol) and 4-methoxybenzenesulfonyl
chloride (0.207 g, 1 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
7
0:30) to afford the desired compound 17 in 38% (0.085 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.82 (d, J=7.8 Hz, 2H), 7.58 (d, J=
85:15) to afford the desired compound 23 in 48% (0.090 g) yield.
3
1
8
.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.25 (t,
H NMR (400 MHz, CDCl ): d=7.24 (d, J=8.6 Hz, 2H), 6.85 (d, J=
3
J=7.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 2H), 6.90 (s, 1H), 3.87 ppm (s,
8.6 Hz, 2H), 6.61 (m, 1H), 6.10 (t, J=3.4 Hz, 1H), 6.07 (dd, J=3.4,
3
H).
1.7 Hz, 1H), 3.76 (s, 3H), 3.54 ppm (s, 3H).
[35]
[38]
2-(4-Bromophenyl)benzofuran (18)
2-(4-Bromophenyl)-1-methylpyrrole (24)
Benzofuran (0.118 g, 1 mmol) and 4-bromobenzenesulfonyl chlo-
ride (0.384 g, 1.5 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
1-Methylpyrrole (0.162 g, 2 mmol) and 4-bromobenzenesulfonyl
chloride (0.255 g, 1 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
8
5:15) to afford the desired compound 18 in 79% (0.215 g) yield.
80:20) to afford the desired compound 24 in 75% (0.177 g) yield.
1
1
H NMR (400 MHz, CDCl ): d=7.73 (d, J=7.8 Hz, 2H), 7.57 (d, J=
H NMR (300 MHz, CDCl ): d=7.51 (d, J=6.8 Hz, 2H), 7.26 (d, J=
3
3
8
.0 Hz, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.31 (t,
6.4 Hz, 2H), 6.73–6.71 (m, 1H), 6.24–6.21 (dd, J=1.8 and 3.4 Hz,
1H), 6.20 (t, J=3.4 Hz, 1H), 3.66 ppm (s, 3H).
J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.02 ppm (s, 1H).
[36]
[5e]
2-(2-Fluorophenyl)benzofuran (19)
1-Methyl-2-(2-nitrophenyl)pyrrole (25)
Benzofuran (0.118 g, 1 mmol) and 2-fluorobenzenesulfonyl chloride
1-Methylpyrrole (0.162 g, 2 mmol) and 2-nitrobenzenesulfonyl chlo-
ride (0.222 g, 1 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 70:30)
(
0.291 g, 1.5 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 95:5) to
1
1
afford the desired compound 19 in 84% (0.178 g) yield. H NMR
to afford the desired compound 25 in 86% (0.173 g) yield. H NMR
(
400 MHz, CDCl ): d=8.07 (t, J=7.7 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H),
(400 MHz, CDCl ): d=7.85 (d, J=8.6 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H),
3
3
7
.57 (d, J=8.0 Hz, 1H), 7.68–7.24 (m, 5H), 7.19 ppm (dd, J=8.6
7.42 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 6.67 (m, 1H), 6.12 (t,
J=3.4 Hz, 1H), 6.06 (dd, J=1.7 and 3.4 Hz, 1H), 3.36 ppm (s, 3H).
and 8.0 Hz, 1H).
[37]
[12]
2-(2-Nitrophenyl)benzofuran (20)
1-Benzyl-2-(4-nitrophenyl)pyrrole (26)
Benzofuran (0.118 g, 1 mmol) and 2-nitrobenzenesulfonyl chloride
1-Benzylepyrrole (0.314 g, 2 mmol) and 4-nitrobenzenesulfonyl
chloride (0.222 g, 1 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
(
0.332 g, 1.5 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 70:30)
1
to afford the desired compound 20 in 52% (0.124 g) yield. H NMR
70:30) to afford the desired compound 26 in 87% (0.242 g) yield.
1
(
400 MHz, CDCl ): d=7.79 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.4 Hz,
H NMR (400 MHz, CDCl ): d=d 8.07 (d, J=8.7 Hz, 2H), 7.36 (d, J=
3
3
1
1
1
H), 7.61 (d, J=8.0 Hz, 1H), 7.58–7.47 (m, 2H), 7.42 (t, J=7.6 Hz,
H), 7.34 (t, J=7.6 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.01 ppm (s,
H).
8.7 Hz, 2H), 7.25–7.15 (m, 3H), 6.92 (dd, J=1.6 and 7.4 Hz, 2H),
6.78 (dd, J=1.8 and 2.7 Hz, 1H), 6.37 (dd, J=1.7 and 3.6 Hz, 1H),
6.24 (dd, J=2.7 and 3.7 Hz, 1H), 5.12 ppm (s, 2H).
[12]
[5e]
1-Methyl-2-(4-nitrophenyl)pyrrole (21)
2-(4-Nitrophenyl)-1-phenylpyrrole (27)
1
-Methylpyrrole (0.162 g, 2 mmol) and 4-nitrobenzenesulfonyl chlo-
1-Phenylpyrrole (0.286 g, 2 mmol) and 4-nitrobenzenesulfonyl chlo-
ride (0.222 g, 1 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 70:30)
ride (0.222 g, 1 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 70:30)
to afford the desired compound 21 in 92% (0.186 g) yield. H NMR
1
1
to afford the desired compound 27 in 63% (0.166 g) yield. H NMR
(
400 MHz, CDCl ): d=8.18 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz,
(400 MHz, CDCl ): d=7.98 (d, J=8.6 Hz, 2H), 7.32–7.25 (m, 3H),
3
3
2
3
H), 6.74 (m, 1H), 6.34 (dd, J=1.7 and 3.4 Hz, 1H), 6.18 (t, J=
.4 Hz, 1H), 3.68 ppm (s, 3H).
7.16 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 6.95 (s, 1H), 6.56
(dd, J=1.7 and 3.4 Hz, 1H), 6.34 ppm (t, J=3.4 Hz, 1H).
[12]
1-Methyl-2-(4-cyanophenyl)pyrrole (22)
2-(2-Nitrophenyl)-1-phenylpyrrole (28)
1
-Methylpyrrole (0.162 g, 2 mmol) and 4-cyanobenzenesulfonyl
1-Phenylpyrrole (0.286 g, 2 mmol) and 2-nitrobenzenesulfonyl chlo-
ride (0.222 g, 1 mmol) were used, and the residue was purified by
flash chromatography on silica gel (heptane/ethyl acetate, 70:30)
chloride (0.202 g, 1 mmol) were used, and the residue was purified
by flash chromatography on silica gel (heptane/ethyl acetate,
1
7
0:30) to afford the desired compound 22 in 89% (0.162 g).
to afford the desired compound 28 in 73% (0.192 g) yield. H NMR
ChemSusChem 2015, 8, 1794 – 1804
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
(
400 MHz, CDCl ): d=7.63 (dd, J=1.5 and 8.5 Hz, 1H), 7.41 (dt, J=
analysis calcd (%) for C H NS (255.38): C 75.25, H 6.71; found:
3
16 17
1
.4 and 7.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.21–7.14 (m, 3H), 7.00
C 75.41, H 7.02.
(
2
dd, J=2.0 and 8.3 Hz, 2H), 6.94 (t, J=2.3 Hz, 1H), 6.32 ppm (d, J=
1
3
.3 Hz, 2H); C NMR (100 MHz, CDCl ): d=149.2, 139.5, 133.0,
3
1
1
32.3, 129.3, 128.2, 128.1, 128.0, 126.9, 125.3, 124.5, 124.2, 111.9,
09.8 ppm; elemental analysis calcd (%) for C H N O (264.28):
4-(4-Bromophenyl)-2-n-pentylthiophene (33)
16
12
2
2
C 72.72, H 4.58; found: C 72.91, H 4.37.
2
-n-Pentylthiophene (163 mL, 1 mmol) and 4-bromobenzenesulfon-
yl chloride (0.255 g, 1.5 mmol) were used, and the residue was pu-
rified by flash chromatography on silica gel (heptane/ethyl acetate,
[
39]
2
-(4-Bromophenyl)-1-methylindole (29a)
8
5:15) to afford the desired compound 33 in 74% (0.229 g) yield.
1
1
-Methylindole (0.196 g, 1.5 mmol) and 4-bromobenzenesulfonyl
H NMR (400 MHz, CDCl ): d=7.52 (d, J=8.0 Hz, 2H), 7.46 (d, J=
3
chloride (0.255 g, 1 mmol) without solvent, the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
8.0 Hz, 2H), 7.24 (d, J=1.7 Hz, 1H), 7.06 (brs, 1H), 2.86 (t, J=
7.5 Hz, 2H), 1.79–1.69 (m, 2H), 1.45–1.36 (m, 4H), 0.96 ppm (t, J=
13
8
0:20) to afford the desired compound 29a in 62% (0.177 g) yield.
7.0 Hz, 3H); C NMR (100 MHz, CDCl ): d=147.2, 140.6, 135.2,
3
1
H NMR (400 MHz, CDCl ): d=7.73 (d, J=7.8 Hz, 1H), 7.70–7.65 (m,
131.8, 127.8, 123.1, 120.8, 118.2, 31.4, 30.3, 30.2, 22.5, 14.1 ppm; el-
emental analysis calcd (%) for C H BrS (309.27): C 58.26, H 5.54;
3
2
H), 7.48–7.42 (m, 3H), 7.38–7.32 (m, 1H), 7.27–7.21 (m, 1H), 6.64
15
17
(
d, J=0.7 Hz, 1H), 3.81 ppm (s, 3H).
found: C 58.45, H 5.21.
[40]
3-(4-Bromophenyl)-1-methylindole (29b)
4
-(4-chlorophenyl)-2-n-pentylthiophene (34)
Methylindole (0.196 g, 1.5 mmol) and 4-bromobenzenesulfonyl
chloride (0.255 g, 1 mmol) in DEC, the residue was purified by flash
chromatography on silica gel (heptane/ethyl acetate, 80:20) to
2-n-Pentylthiophene (163 mL, 1 mmol) and 4-chlorobenzenesulfonyl
chloride (0.316 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
1
afford the desired compound 29b in 29% (0.083 g) yield. H NMR
(
7
1
400 MHz, CDCl ): d=7.89 (d, J=8.0 Hz, 1H), 7.50–7.57 (m, 4H),
.37 (d, J=8.2 Hz, 1H), 7.30 (dt, J=1.0 and 7.6 Hz, 1H), 7.22 (s,
H), 7.21 (dt, J=1.0 and 7.5 Hz, 1H), 3.83 ppm (s, 3H).
85:15) to afford the desired compound 34 in 76% (0.201 g) yield.
3
1
H NMR (400 MHz, CDCl ): d=7.51 (d, J=8.5 Hz, 2H), 7.35 (d, J=
3
8.5 Hz, 2H), 7.22 (d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 2.85 (t,
J=7.6 Hz, 2H), 1.79–1.67 (m, 2H), 1.43–1.35 (m, 2H), 0.93 ppm (t,
13
J=6.1 Hz, 3H); C NMR (100 MHz, CDCl ): d=147.4, 140.8, 135.0,
3
[41]
2
-(2-Bromophenyl)-1-methylindole (30a)
1
32.9, 129.1, 127.7, 123.4, 118.3, 31.5, 30.4, 29.9, 22.6, 14.2 ppm; el-
emental analysis calcd (%) for C H ClS (264.81): C 68.04, H 6.47;
found: C 68.31, H 6.68.
15
17
Methylindole (0.196 g, 1.5 mmol) and 2-bromobenzenesulfonyl
chloride (0.255 g, 1 mmol) without solvent, the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
8
0:20) to afford the desired compound 30a in 71% (0.203 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.70–7.75 (m, 2H), 7.20–7.45 (m, 6H),
[11]
3
2-Methyl-4-(4-nitrophenyl)thiophene (36)
6
.56 (s, 1H), 3.61 ppm (s, 3H).
2
-Methylthiophene (97 mL, 1 mmol) and 4-nitrobenzenesulfonyl
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
4-(4-Nitrophenyl)-2-n-pentylthiophene (31)
7
0:30) to afford the desired compound 36 in 89% (0.195 g) yield.
2
-n-Pentylthiophene (163 mL, 1 mmol) and 4-nitrobenzenesulfonyl
1
H NMR (400 MHz, CDCl ): d=8.22 (d, J=8.8 Hz, 2H), 7.68 (d, J=
8
3
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
.8 Hz, 2H), 7.38 (s, 1H), 7.10 (s, 1H), 2.55 ppm (s, 3H).
7
0:30) to afford the desired compound 31 in 80% (0.220 g) yield.
1
H NMR (400 MHz, CDCl ): d=8.26 (d, J=8.7 Hz, 2H), 7.72 (d, J=
3
8
.7 Hz, 2H), 7.44 (d, J=1.8 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 2.88 (t,
[11]
4
-(4-Bromophenyl)-2-methylthiophene (37)
J=7.6 Hz, 2H), 1.78–1.70 (m, 2H), 1.42–1.38 (m, 4H), 0.94 ppm (t,
J=6.86 Hz, 3H); C NMR (100 MHz, CDCl ): d=148.0, 146.5, 142.3,
1
3
2-Methylthiophene (97 mL, 1 mmol) and 4-bromobenzenesulfonyl
chloride (0.383 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
3
1
39.4, 126.6, 124.3, 122.9, 120.8, 31.3, 30.2, 27.0, 22.4, 14.0 ppm; el-
emental analysis calcd (%) for C H NO S (275.37): C 65.43, H 6.22;
1
5
17
2
found: C 65.21, H 6.59.
85:15) to afford the desired compound 37 in 40% (0.101 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.49 (d, J=8.2 Hz, 2H), 7.41 (d, J=
3
8
.2 Hz, 2H), 7.18 (s, 1H), 7.02 (s, 1H), 2.53 ppm (s, 3H).
4
-(4-Cyanophenyl)-2-n-pentylthiophene (32)
2
-n-Pentylthiophene (163 mL, 1 mmol) and 4-cyanobenzenesulfonyl
chloride (0.302 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
[11]
4-(4-Chlorophenyl)-2-methylthiophene (38)
7
5:25) to afford the desired compound 32 in 84% (0.215 g) yield.
2-Methylthiophene (97 mL, 1 mmol) and 4-chlorobenzenesulfonyl
chloride (0.316 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
1
H NMR (400 MHz, CDCl ): d=7.65 (brs, 4H), 7.35 (d, J=1.5 Hz, 1H),
7
3
.08 (d, J=1.5 Hz, 1H), 2.84 (t, J=7.5 Hz, 2H), 1.72 (quint, J=
.1 Hz, 2H), 1.41–1.33 (m, 4H), 0.92 ppm (t, J=6.8 Hz, 3H);
7
80:20) to afford the desired compound 38 in 73% (0.152 g) yield.
1
3
1
C NMR (100 MHz, CDCl ): d=147.9, 140.6, 140.0, 132.9, 126.9,
H NMR (400 MHz, CDCl ): d=7.48 (d, J=8.0 Hz, 2H), 7.34 (d, J=
3
3
1
23.1, 120.5, 119.3, 110.4, 77.5, 31.5, 30.4, 22.7, 14.3 ppm; elemental
8.0 Hz, 2H), 7.18 (s, 1H), 7.02 (s, 1H), 2.53 ppm (s, 3H).
ChemSusChem 2015, 8, 1794 – 1804
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
[11]
4-(4-Nitrophenyl)-2,2’-bithiophene (39)
3-(4-Bromophenyl)benzothiophene (44)
2
,2’-Bithiophene (0.166 g, 1 mmol) and 4-nitrobenzenesulfonyl
Benzothiophene (0.134 g, 1 mmol) and 4-bromobenzenesulfonyl
chloride (0.383 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
7
0:30) to afford the desired compound 39 in 66% (0.190 g).
85:15) to afford the desired compound 44 in 88% (0.253 g) yield.
1
1
H NMR (400 MHz, CDCl ): d=8.21 (d, J=9.0 Hz, 2H), 7.68 (d, J=
H NMR (400 MHz, CDCl ): d=7.96–7.84 (m, 2H), 7.62 (d, J=8.0 Hz,
3
3
8
6
.8 Hz, 2H), 7.42 (dd, J=1.6 and 8.2 Hz, 2H), 7.23–7.17 (m, 2H),
.99 ppm (dd, J=3.6 and 5.1 Hz, 1H); C NMR (100 MHz, CDCl3):
2H), 7.46 (d, J=8.0 Hz, 2H), 7.42–7.39 ppm (m, 3H).
13
d=140.5, 136.5, 141.6, 139.3, 127.9, 126.7, 125.1, 124.3, 122.3,
1
21.8 ppm; elemental analysis calcd (%) for C H NO S (287.35):
3-(2-Nitrophenyl)benzothiophene (45)
14
9
2 2
C 58.52, H 3.16; found: C 58.88, H 3.31.
Benzothiophene (0.134 g, 1 mmol) and 2-nitrobenzenesulfonyl
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
3
-Chloro-4-(4-nitrophenyl)thiophene (40)
7
0:30) to afford the desired compound 45 in 85% (0.217 g) yield.
1
H NMR (400 MHz, CDCl ): d=7.79–7.74 (m, 2H), 7.73–7.70 (m, 1H),
3
3
-Methylthiophene (0.119 g, 1 mmol) and 4-nitrobenzenesulfonyl
7
.59–7.54 (m, 2H), 7.48–7.43 (m, 1H), 7.32–7.28 (m, 2H), 7.19 ppm
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
13
(s, 1H); C NMR (100 MHz, CDCl ): d=140.4, 139.9, 139.3, 137.4,
3
1
32.5, 132.1, 129.2, 128.6, 124.9, 124.7, 124.1, 124.0, 123.8,
7
0:30) to afford the desired compound 40 in 35% (0.084 g).
1
122.2 ppm; elemental analysis calcd (%) for C14H NO S (255.29):
9 2
H NMR (400 MHz, CDCl ): d=8.31 (d, J=8.7 Hz, 2H), 7.73 (d, J=
3
C 65.87, H 3.55; found: C 65.98, H 3.41.
8
.7 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.35 ppm (d, J=3.6 Hz, 1H);
1
3
C NMR (100 MHz, CDCl ): d=147.6, 141.0, 138.3, 129.7, 125.4,
3
1
24.7, 123.9, 122.6 ppm; elemental analysis calcd (%) for
Acknowledgements
C H ClNO S (264.81): C 50.11, H 2.52; found: C 50.41, H 2.36.
1
0
6
2
A. H. is grateful to “UTIQUE” for a grant. We thank the CNRS,
Rennes Metropole”, and the Scientific Ministry of Higher Educa-
tion and Research of Tunisia for providing financial support.
“
3
-Methyl-4-(4-nitrophenyl)thiophene (41)
3
-Methylthiophene (0.098 g, 1 mmol) and 4-nitrobenzenesulfonyl
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
Keywords: arenes
palladium · solvent effects
·
cÀh activation
·
cross-coupling
·
7
0:30) to afford the desired compound 41 in 79% (0.173 g).
1
H NMR (400 MHz, CDCl ): d=8.28 (d, J=8.9 Hz, 2H), 7.58 (d, J=
3
8
.7 Hz, 2H), 7.35 (d, J=3.4 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H),
[1] a) P. T. Anastas, J. C. Warner, Green Chemistry Theory and Practice,
Oxford University Press, New York, 1998; b) T. Welton, Chem. Rev. 1999,
1
3
2
1
.32 ppm (s, 3H); C NMR (100 MHz, CDCl ): d=146.8, 143.7, 140.8,
3
9
3
9, 2071–2084; c) P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002,
5, 686–694; d) P. Dixneuf, V. Cadierno, Metal-Catalyzed Reactions in
35.7, 129.2, 124.9, 123.7, 123.3, 15.6 ppm; elemental analysis calcd
(
%) for C H NO S (219.26): C 60.26, H 4.14; found: C 60.56, H 4.33.
11 9 2
Water, Wiley, Weinheim, 2013.
[
2] a) J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry, Pergamon,
Amsterdam, 2000; b) E.-I. Negishi, Handbook of Organopalladium
Chemistry for Organic Synthesis, Wiley, New York, 2002; c) L. Ackermann,
Modern Arylation Methods, Wiley, Weinheim 2009.
2
-Bromo-4-(4-nitrophenyl)-3-methylthiophene (42)
2
-Bromo-3-methylthiophene (0.177 g, 1 mmol) and 4-nitrobenzene-
[
3] a) Y. Akita, A. Inoue, K. Yamamoto, A. Ohta, T. Kurihara, M. Shimizu, Het-
erocycles 1985, 23, 2327–2333; b) A. Ohta, Y. Akita, T. Ohkuwa, M.
Chiba, R. Fukunaga, A. Miyafuji, T. Nakata, N. Tani, Y. Aoyagi, Heterocycles
1990, 31, 1951–1958; c) Y. Aoyagi, A. Inoue, I. Koizumi, R. Hashimoto, K.
Tokunaga, K. Gohma, J. Komatsu, K. Sekine, A. Miyafuji, J. Kunoh, Hetero-
cycles 1992, 33, 257–272.
sulfonyl chloride (0.332 g, 1.5 mmol) were used, and the residue
was purified by flash chromatography on silica gel (heptane/ethyl
acetate, 70:30) to afford the desired compound 42 in 56%
1
(
(
(
0.177 g). H NMR (400 MHz, CDCl ): d=8.20 (d, J=8.6 Hz, 2H), 7.43
d, J=8.6 Hz, 2H), 7.19 (s, 1H), 2.12 ppm (s, 3H); C NMR
100 MHz, CDCl ): d=147.1, 143.3, 140.8, 135.2, 129.3, 124.1, 123.8,
3
13
[
4] a) For selected examples of metal-catalyzed direct arylation green sol-
vents see: G. L. Turner, J. A. Morris, M. F. Greaney, Angew. Chem. Int. Ed.
3
111.9, 14.9 ppm; elemental analysis calcd (%) for C H BrNO S
11 8 2
2
007, 46, 7996–8000; Angew. Chem. 2007, 119, 8142–8146; b) L. Acker-
(
298.15): C 44.31, H 2.70; found: C 44.76, H 3.01.
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L. Djakovitch, Adv. Synth. Catal. 2010, 352, 2929–2936; d) P. B. Arockiam,
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4
9, 6629–6632; Angew. Chem. 2010, 122, 6779–6782; e) O. RenØ, K.
3
-(4-Nitrophenyl)benzothiophene (43)
Fagnou, Org. Lett. 2010, 12, 2116–2119; f) Y.-X. Su, Y.-H. Deng, T.-T. Ma,
Y.-Y. Li, L.-P. Sun, Green Chem. 2012, 14, 1979–1981; g) G. Park, S. Lee,
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Benzothiophene (0.134 g, 1 mmol) and 4-nitrobenzenesulfonyl
chloride (0.332 g, 1.5 mmol) were used, and the residue was puri-
fied by flash chromatography on silica gel (heptane/ethyl acetate,
7
0:30) to afford the desired compound 43 in 85% (0.217 g) yield.
1
H NMR (400 MHz, CDCl ): d=8.26 (d, J=8.7 Hz, 2H), 7.88–7.84 (m,
3
[
1
7
H), 7.81–7.77 (m, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.46 (s, 1H), 7.38–
1
3
.33 ppm (m, 2H); C NMR (100 MHz, CDCl ): d=147.1, 142.6,
3
1
1
40.8, 137.0, 135.8, 129.3, 125.8, 125.0, 125.0, 124.1, 123.2,
22.4 ppm; elemental analysis calcd (%) for C H NO S (255.29):
2
009, 74, 1826–1834; d) J. Roger, F. Pozgan, H. Doucet, Green Chem.
1
4
9
2
2009, 11, 425–432; e) D. T. Gryko, O. Vakuliuk, D. Gryko, B. Koszarna, J.
Org. Chem. 2009, 74, 9517–9520; f) J. Roger, A. L. Gottumukkala, H.
C 65.87, H 3.55; found: C 66.09, H 3.28.
ChemSusChem 2015, 8, 1794 – 1804
www.chemsuschem.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
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Received: December 17, 2014
Published online on April 16, 2015
ChemSusChem 2015, 8, 1794 – 1804
www.chemsuschem.org
1804
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim