Pd-Catalysed Direct Arylation of Heteroaromatics Using (Poly)halobenzenesulfonyl Chlorides as Coupling Partners: One Step Access to (Poly)halo-Substituted Bi(hetero)aryls

Article abstract of DOI:10.1002/ejoc.201500354

The reactivity of (poly)halo-substituted benzenesulfonyl chlorides for Pd-catalysed desulfitative arylation was investigated. 2-, 3- and 4-bromobenzenesulfonyl chlorides react nicely to afford arylated heteroarenes in moderate to high yields without cleav

Full text of DOI:10.1002/ejoc.201500354

FULL PAPER
DOI: 10.1002/ejoc.201500354
Pd-Catalysed Direct Arylation of Heteroaromatics Using
(Poly)halobenzenesulfonyl Chlorides as Coupling Partners: One Step Access to
(Poly)halo-Substituted Bi(hetero)aryls
Aymen Skhiri,[a,b] Anissa Beladhria,[a,b] Kedong Yuan,[a] Jean-Francois Soulé,[a]
Ridha Ben Salem,*[b] and Henri Doucet*[a]
Keywords: Homogeneous catalysis / Palladium / Cross-coupling / C–H bond activation / Arylation / Heteroarenes
The reactivity of (poly)halo-substituted benzenesulfonyl
chlorides for Pd-catalysed desulfitative arylation was investi-
gated. 2-, 3- and 4-bromobenzenesulfonyl chlorides react
nicely to afford arylated heteroarenes in moderate to high
yields without cleavage of the C–Br bonds, allowing further
transformations. A minor influence upon reaction yeilds was
found to be exerted by the bromo substituent on the benzene
ring. Even 4-iodobenzenesulfonyl chloride, di- and tri-
bromobenzenesulfonyl chlorides were successfully coupled
with a range of heteroarenes without cleavage of the C–Br
or C–I bonds and very regioselective arylations were ob-
served in all cases. The reaction was also found to tolerate
bromo substituents on the heteroarene.
Introduction
Several aryl-substituted heteroarenes display important
biological properties. For example, Dantrolene is a muscle
relaxant, Atliprofen is an anti-inflammatory drug, Saprisar-
tan is an AT1 receptor antagonist and Tanaproget is a non-
steroidal progestin (Figure 1). The ability to readily gener-
ate halo-substituted arylated heteroarenes is important in
organic chemistry since these species are important building
blocks for biochemists.
In 1990, Ohta et al. reported arylation of a variety of
heteroaromatics with aryl halides as coupling partners, via
C–H bond activation.[1] Since this report , several groups
have developed more effective conditions for generating ar-
ylated heteroarenes by application of such couplings in high
yields.[2–5] We also reported a few years ago the coupling of
2-isobutylthiazole with 1,4-dibromobenzene (Scheme 1).[6]
For this reaction, with a 3:1 ratio of 2-isobutylthiazole and
1,4-dibromobenzene, no coupling product a was detected,
and only b arising from 1,4-diheteroarylation was pro-
duced. Even in the presence of a huge excess of 1,4-di-
bromobenzene (20 equiv.), a was formed in only 60% selec-
tively. These results demonstrate the limitations of di-
Figure 1. Examples of bioactive arylated heteroarenes.
bromobenzenes as reactants for the synthesis of bromo-sub-
stituted heteroarylated benzenes.
Aryl halides have been largely employed in Pd-catalysed
direct arylation, yet relatively little effort has gone into de-
veloping alternative coupling partners to aryl halides for
direct arylations of heteroarenes.[2] In 2009 Dong and co-
[a] Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS – workers reported the synthesis of sulfones via Pd-catalysed
Université de Rennes 1 “Organométalliques, Matériaux et
coupling of 2-phenylpyridine with benzenesulfonyl chlor-
Catalyse”,
ides.[7] These investigators also observed, in one case, a de-
Campus de Beaulieu, 35042 Rennes, France
E-mail: henri.doucet@univ-rennes1.fr
sulfitative direct arylation of a quinoline derivative. Two
years later, Cheng et al. extended the use of benzenesulfonyl
chlorides[8–11] as coupling partners for desulfitative Pd-cata-
lysed direct 2-arylation of benzoxazole derivatives.[12a] We
have also recently reported the first palladium-catalysed de-
sulfitative β-arylation of thiophenes and α-arylation of
http://scienceschimiques.univ-rennes1.fr/catalyse/personnels/
interface/HD.htm
[b] Laboratoire de Chimie Organique Physique (UR 11ES74),
Université de Sfax, Faculté des Sciences de Sfax,
Route de la Soukra km 4, 3038 Sfax, Tunisia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500354.
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New Pd-Catalysed Direct Arylation of Heteroaromatics
gave regioselectively the C5 arylation product 1 in 79%
yield. No formation of 1,4-bis(5-methylfuran-2-yl)benzene
from both C–SO2Cl and C–Br bond activations could be
detected by GC/MS analysis of the crude mixture. A
shorter reaction time of 20 h only afforded 1 in 56% yield
due to partial conversion of 4-bromobenzenesulfonyl chlor-
ide. Subsequently, five thiophene derivatives were employed;
3-methyl-, 2-chloro- and 3-chlorothiophenes were success-
fully coupled with 4-bromobenzenesulfonyl chloride. Aryl-
ated thiophenes 2–4 were obtained in yields ranging from
Scheme 1. Reactivity of 1,4-dibromobenzene in Pd-catalysed direct 55–89%. The reactivity of both 2-bromo- and 3-bromothio-
arylation.
phene was then investigated. Target compounds 5 and 6
were isolated in yields of 83% and 46% without cleavage of
benzofurans.[13] It should be noted that Deng, Luo and co-
workers recently reported that benzenesulfinic acid sodium
salts can also be employed for Pd-catalysed direct arylation
of azoles and indoles under oxidative conditions.[12b,12c] On
the other hand, to the best of our knowledge, the desulfit-
ative direct arylation of heteroarenes with 2-bromo-,
3-bromo- or polybromo-benzenesulfonyl chlorides has not
yet been described. As the use of benzenesulfonyl chlorides
as coupling partners in Pd-catalysed direct arylations ap-
pears to tolerate both 4-bromo and 4-iodo substituents
(Scheme 2, top),[13] the behaviour of (poly)halobenzene-
sulfonyl chlorides warrants more detailed investigation
(Scheme 2, bottom).
both C–Br bonds. It should be noted that with the less reac-
tive heteroarenes, a partial conversion of 4-bromobenz-
enesulfonyl chloride was observed. In all cases, although
an excess of heteroarene was employed (1.5 equiv.), no 1,4-
diheteroarylation of 4-bromobenzenesulfonyl chloride was
detected by GC/MC analysis of the crude mixtures, reveal-
ing that such reaction conditions are not appropriate to
promote direct arylation with aryl bromides. Even the use
of 4 equiv. of 1-benzylpyrrole afforded only desired product
7 in 76% yield; no 1,4-diheteroarylation of 4-bromobenz-
enesulfonyl chloride via C–Br bond activation could be de-
tected.
Scheme 2. Pd-catalysed desulfitative couplings using bromo- or
iodo-substituted benzenesulfonyl chlorides.
Herein, we detail how the position of the halo substitu-
ent on the benzenesulfonyl chlorides modulates Pd-cata-
lysed desulfitative arylation of furans, thiophenes and
pyrroles. The influence of other additional substituents and
the reactivity of some di- and tri-bromobenzenesulfonyl
chlorides has also been investigated.
Scheme 3. Pd-catalysed desulfitative couplings using 4-bromobenz-
enesulfonyl chloride.
The reactivity of 3-bromobenzenesulfonyl chloride was
then examined (Scheme 4). 2-n-Butylfuran and mentho-
furan, naturally present in mint oil, were both found to be
Results and Discussion
We first examined the influence of the bromo substituent amenable to direct arylation with this benzenesulfonyl
position on the benzenesulfonyl chlorides on their reactivity chloride; 8 and 9 were isolated in 70% and 92% yields,
for Pd-catalysed desulfitative coupling with a set of het- respectively. Coupling of 3-bromothiophene with 3-bromo-
eroarenes (Schemes 3, 4, and 5). The reaction of 1.5 equiv. benzenesulfonyl chloride proceeded with significantly re-
of 2-methylfuran and 1 equiv. of 4-bromobenzenesulfonyl duced efficiency; 10 was only obtained in 28% yield. How-
chloride in the presence of 5 mol-% PdCl2(MeCN)2 catalyst ever, both C–Br bonds remained untouched. A mixture of
and Li2CO3 as the base at 140 °C during 40 h in dioxane 1 equiv. of 3-bromobenzenesulfonyl chloride and 4 equiv. of
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Although C–I bonds on benzene rings are known to be
very reactive in the presence of palladium catalysts, we ex-
amined the reactivity of 4-iodobenzenesulfonyl chloride for
such couplings (Scheme 6). The reaction proceeds nicely
with 2-methylfuran and 3-methylthiophene without cleav-
age of the C–I bond to afford 17 and 18 in 72% and 68%
yields, respectively; retention of the C–I bond enables fur-
ther transformations. Lower yields were obtained for the
reaction of 3-chloro- or 3-bromothiophenes with 4-iodo-
benzenesulfonyl chloride as 19 and 20 were formed in 48%
and 66% yields, respectively. Again, C–Br and C–I bonds
remained untouched. The use of 4-iodobenzenesulfonyl
chloride in the presence of an excess of 1-benzylpyrrole af-
fords mono-arylated pyrrole 21 in 67% yield without de-
benzylation or C–I bond cleavage.
Scheme 4. Pd-catalysed desulfitative couplings using 3-bromobenz-
enesulfonyl chloride.
Scheme 6. Pd-catalysed desulfitative couplings using 4-iodo-
benzenesulfonyl chloride.
The presence of a 2-fluoro substituent on 4-bromobenz-
enesulfonyl chloride was expected to promote the reaction
due to its electronic effect. Indeed, high yields of desired
products 22–24 were obtained using a variety of hetero-
arenes as coupling partners (Scheme 7). To gain more in-
sight into the steric effects of a bromobenzenesulfonyl
chloride substituent, the reactivity of 2-alkyl-4-bromobenz-
ene-1-sulfonyl chlorides was also investigated. A detri-
Scheme 5. Pd-catalysed desulfitative couplings using 2-bromobenz-
enesulfonyl chloride.
1-methylpyrrole afforded mono-arylated pyrrole 11 in 81% mental effect of an ortho-methyl substituent on benzenesulf-
yield whereas the use of an excess of 3-bromobenzenesulf- onyl chloride for Pd-catalysed desulfitative coupling had
onyl chloride (2.5 equiv.) led to production of 2,5-diarylated been previously observed for the reaction of benzofuran
pyrrole 12 in 57% yield.
with 2-methylbenzenesulfonyl chloride.[13b] Unexpectedly,
ortho-Substituents often exhibit an important influence 4-bromo-2-ethylbenzene-1-sulfonyl chloride was found to
on Pd-catalysed reactions due to coordination and/or steric react nicely with a variety of heteroarenes. The presence of
properties. However, in the presence of 2-bromobenz- a 4-bromo substituent appears to enhance the reactivity of
enesulfonyl chloride and 2-n-butylfuran or menthofuran, 2-alkylbenzene-1-sulfonyl chlorides. From 2-n-butylfuran
high yields of target products 13 and 14 were obtained and menthofuran, C5-arylated products 25 and 26 were ob-
(Scheme 5). Again too, a moderate yield of 41% for 15 was tained in 63% and 94% yields. The reaction with 2-methyl-
obtained in the presence of 3-methylthiophene. On the thiophene afforded 27 in 60% yield. From 4 equiv. of 1-
other hand, the coupling with 1-methylpyrrole afforded 16 methylpyrrole and 1 equiv. of 4-bromo-2-ethylbenzene-1-
in 79% yield.
sulfonyl chloride or 4-bromo-2-methoxybenzene-1-sulfonyl
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New Pd-Catalysed Direct Arylation of Heteroaromatics
chloride, mono-arylated pyrroles 28 and 29 were obtained
in 76% and 38% yields, respectively. A good yield of 69%
for 30 was also obtained from the reaction with 4-bromo-
2-trifluoromethylbenzene-1-sulfonyl chloride. These results
reveal a limited influence of the electronic properties of sub-
stituents at C2 on the reactivity of 4-bromobenzenesulfonyl
chlorides.
Scheme 8. Pd-catalysed desulfitative couplings using 2,5-dibromo-
benzene-1-sulfonyl chloride.
Scheme 9.[14] A good yield of 36 was obtained in the pres-
ence of 1-methylpyrrole. Again, no cleavage of the two C–
Br bonds was observed.
Scheme 9. Pd-catalysed desulfitative coupling using 3,4-dibromo-
benzene-1-sulfonyl chloride.
Scheme 7. Pd-catalysed desulfitative couplings using substituted 4-
bromobenzenesulfonyl chlorides.
Even 2,4,6-tribromobenzene-1-sulfonyl chloride was suc-
cessfully employed to afford 37 and 38 in moderate to high
As the preparation of 2,5-dibromobenzene-1-sulfonyl yields in the presence of 2-n-butylfuran or 1-methylpyrrole
chloride from 1,4-dibromobenzene proceeds nicely by reac- as reaction partners (Scheme 10). Again, the three C–Br
tion with chlorosulfonic acid,[14] its amenability to desulfit- bonds remained untouched.
ative direct arylation was also evaluated (Scheme 8). Again,
Although the mechanism is not yet elucidated, since cou-
in the presence of 2-n-butylfuran, menthofuran or 2-methyl- pling reactions with halobenzenesulfonyl chlorides proceed
thiophene, expected dibromobenzene derivatives 31–33 without cleavage of the C–Br or C–I bonds, we postulate
were obtained in high yields without cleavage of the C–Br that the first step of the catalytic cycle entails oxidative ad-
bonds. The use of a 1:4 ratio of 2,5-dibromobenzene-1-sulf- dition of the halo-benzenesulfonyl chloride to PdII to afford
onyl chloride and 1-methylpyrrole provided C2-arylated an ArSO2-PdIVCl intermediate. Oxidative addition of benz-
pyrrole 34 in 73% yield whereas an excess of 2,5-dibromo- enesulfonyl chloride on PdII species is known to proceed at
benzene-1-sulfonyl chloride led to tetrabromo-substituted room temperature.[7b] Subsequently, after elimination of
compound 35 in 35% yield.
SO2 and coordination of the heteroarene to Pd, migration
The reactivity of 3,4-dibromobenzene-1-sulfonyl chlor- of the aryl group to the heteroarene followed by a base-
ide, which is also easily obtained by reaction of 1,2-di- assisted proton abstraction likely affords the arylated het-
bromobenzene with chlorosulfonic acid, is described in eroarene and regenerates a PdII species.
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R. Ben Salem, H. Doucet et al.
FULL PAPER
successively added. The reaction mixture was treated by vacuum–
argon cycles (5 times) and stirred at 140 °C (oil bath temperature)
for 40 h. After cooling the reaction at room temperature and con-
centration, the crude mixture was purified by silica column
chromatography to afford the relevant arylated heteroarenes.
2-(4-Bromophenyl)-5-methylfuran (1): 2-Methylfuran (0.123 g,
1.5 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g, 1 mmol)
affords 1 in 79% (0.187 g) yield as a yellow solid; m.p. 58–61 °C.
Due to the low boiling point of 2-methylfuran, this reaction was
performed in an autoclave reactor. 1H NMR (400 MHz, CDCl3): δ
= 7.49 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.6 Hz, 2 H), 6.53 (d, J =
3.2 Hz, 1 H), 6.06 (d, J = 3.2 Hz, 1 H), 2.36 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 152.8, 151.6, 132.1, 130.5, 125.2,
120.8, 108.3, 106.9, 14.2 ppm. C11H9BrO (237.09): calcd. C 55.72,
H 3.83; found C 55.58, H 3.80.
3-(4-Bromophenyl)-4-methylthiophene
(2):
3-Methylthiophene
(0.147 g, 1.5 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 2 in 89% (0.225 g) yield as a colourless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 8.6 Hz, 2 H), 7.14 (d,
J = 8.6 Hz, 2 H), 7.06 (d, J = 3.3 Hz, 1 H), 6.90 (d, J = 3.3 Hz, 1
H), 2.14 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.0,
136.1, 136.0, 131.6, 130.3, 123.3, 122.5, 121.2, 15.5 ppm. C11H9BrS
(253.16): calcd. C 52.19, H 3.58; found C 52.33, H 3.39.
Scheme 10. Pd-catalysed desulfitative couplings using 2,4,6-tri-
bromobenzene-1-sulfonyl chloride.
Conclusions
In summary, we report here the influence of halo substit-
uents on benzenesulfonyl chlorides upon palladium-cata-
lysed desulfitative arylations with a range of heteroarenes.
The reaction proceeds with 2-, 3- or 4-bromobenzenesulf-
onyl chlorides and also 4-iodobenzenesulfonyl chloride
using easily accessible ligand-free Pd(MeCN)2Cl2 catalyst
and Li2CO3 as base. In all cases, the coupling products re-
tained the relevant C–Br or C–I bonds allowing for further
functionalization. This procedure also tolerates a variety of
substituents on the benzenesulfonyl chloride; these include
methoxy, ethyl, fluoro or trifluoromethyl moieties. Poly-
bromobenzenesulfonyl chlorides were also successfully em-
ployed. As several halobenzenesulfonyl chlorides with di-
verse functionalities are readily available and affordable,
such simple reaction conditions (no expensive base and li-
gand) should be very attractive to synthetic chemists look-
ing to expeditiously access (poly)halo-substituted arylated
heteroarenes.
3-(4-Bromophenyl)-4-chlorothiophene
(3):
3-Chlorothiophene
(0.177 g, 1.5 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 3 in 55% (0.150 g) yield as a white solid; m.p. 77–
1
80 °C. H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 8.6 Hz, 2 H),
7.39 (d, J = 8.6 Hz, 2 H), 7.29 (d, J = 3.3 Hz, 1 H), 7.25 (d, J =
3.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.1, 133.3,
131.5, 130.4, 124.6, 123.6, 122.1, 121.6 ppm. C10H6BrClS (273.58):
calcd. C 43.90, H 2.21; found C 43.67, H 2.40.
4-(4-Bromophenyl)-2-chlorothiophene
(4):
2-Chlorothiophene
(0.177 g, 1.5 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 4 in 66% (0.180 g) yield as a white solid; m.p. 73–
1
76 °C. H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.6 Hz, 2 H),
7.36 (d, J = 8.6 Hz, 2 H), 7.18 (d, J = 1.6 Hz, 1 H), 7.16 (d, J =
1.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.5, 134.2,
132.1, 131.3, 127.8, 125.3, 121.7, 118.9 ppm. C10H6BrClS (273.58):
calcd. C 43.90, H 2.21; found C 43.98, H 2.28.
3-Bromo-4-(4-bromophenyl)thiophene
(5):
3-Bromothiophene
(0.244 g, 1.5 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 5 in 83% (0.264 g) yield as a yellow solid; m.p. 98–
100 °C. 1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 8.6 Hz, 2
H), 7.36 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 3.3 Hz, 1 H), 7.25 (d, J
= 3.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.0,
134.2, 131.5, 130.8, 124.5, 123.8, 122.2, 110.9 ppm. C10H6Br2S
(318.03): calcd. C 37.77, H 1.90; found C 37.57, H 2.07.
Experimental Section
General: All reactions were carried out under argon atmosphere
with standard Schlenk techniques. HPLC grade 1,4-dioxane was
used and stored under argon without further purification. 1H
NMR spectra were recorded with a Bruker GPX (400 MHz) spec-
trometer. Chemical shifts (δ) were reported in parts per million rela-
tive to residual chloroform (δ = 7.26 ppm for 1H and 77.0 ppm
for 13C), constants were reported in Hertz. 1H NMR assignment
abbreviations were the following: singlet (s), doublet (d), triplet (t),
quartet (q), doublet of doublets (dd), doublet of triplets (dt), and
multiplet (m). 13C NMR spectra were recorded at 100 MHz on the
same spectrometer and reported in ppm. All reagents were weighed
and handled in air.
2-Bromo-4-(4-bromophenyl)thiophene (6):[15] 2-Bromothiophene
(0.244 g, 1.5 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 6 in 46% (0.146 g) yield. 1H NMR (400 MHz,
CDCl3): δ = 7.52 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H),
7.32 (d, J = 1.6 Hz, 1 H), 7.30 (d, J = 1.6 Hz, 1 H) ppm.
1-Benzyl-2-(4-bromophenyl)pyrrole (7):[16] 1-Benzylpyrrole (0.628,
4 mmol) and 4-bromobenzenesulfonyl chloride (0.255 g, 1 mmol)
1
affords 7 in 76% (0.237 g) yield. H NMR (400 MHz, CDCl3): δ =
7.47 (d, J = 8.2 Hz, 2 H), 7.35–7.25 (m, 3 H), 7.21 (d, J = 8.2 Hz,
2 H), 7.02 (d, J = 8.2 Hz, 2 H), 6.80 (t, J = 2.3 Hz, 1 H), 6.33–6.29
(m, 2 H), 5.15 (s, 2 H) ppm.
General Procedure: To a 25 mL oven dried Schlenk tube, hetero-
arene derivative (1 or 1.5 mmol), (poly)haloarylsulfonyl chloride (1
or 4 mmol), Li2CO3 (0.222 g, 3 mmol), 1,4-dioxane (2 mL) and 2-(3-Bromophenyl)-5-n-butylfuran (8): 2-n-Butylfuran (0.186 g,
bis(acetonitrile)dichloropalladium(II) (12.9 mg, 0.05 mmol) were 1.5 mmol) and 3-bromobenzenesulfonyl chloride (0.255 g, 1 mmol)
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New Pd-Catalysed Direct Arylation of Heteroaromatics
affords 8 in 70% (0.195 g) yield as a yellow oil. 1H NMR
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.1, 146.1, 133.3,
(400 MHz, CDCl3): δ = 7.79 (s, 1 H), 7.56 (d, J = 8.2 Hz, 1 H), 133.1, 132.0, 129.2, 127.0, 123.4, 118.6, 117.8, 31.5, 31.4, 29.7, 21.7,
7.35 (d, J = 8.2 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 6.58 (d, J =
3.2 Hz, 1 H), 6.09 (d, J = 3.2 Hz, 1 H), 2.71 (t, J = 7.4 Hz, 2 H),
1.69 (quint., J = 7.4 Hz, 2 H), 1.43 (sext., J = 7.4 Hz, 2 H), 0.98
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.4,
150.7, 133.4, 130.3, 129.6, 126.4, 123.0, 121.9, 107.2, 107.0, 30.3,
28.0, 22.4, 13.9 ppm. C14H15BrO (279.17): calcd. C 60.23, H 5.42;
found C 60.40, H 5.37.
20.3, 9.6 ppm. C16H17BrO (305.21): calcd. C 62.96, H 5.61; found
C 62.87, H 5.64.
3-(2-Bromophenyl)-4-methylthiophene (15): 3-Methylthiophene
(0.147 g, 1.5 mmol) and 2-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 15 in 41% (0.104 g) yield as a colourless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.2 Hz, 1 H), 7.33 (d,
J = 8.2 Hz, 1 H), 7.28–7.17 (m, 2 H), 7.14 (d, J = 3.2 Hz, 1 H),
7.01 (d, J = 3.2 Hz, 1 H), 2.09 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 142.1, 138.2, 137.0, 132.7, 131.6, 129.0, 127.1, 124.2,
123.8, 120.9, 14.8 ppm. C11H9BrS (253.16): calcd. C 52.19, H 3.58;
found C 52.04, H 3.69.
2-(3-Bromophenyl)-3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran (9):
Menthofuran (0.225 g, 1.5 mmol) and 3-bromobenzenesulfonyl
chloride (0.255 g, 1 mmol) affords 9 in 92% (0.280 g) yield as a
yellow solid; m.p. 70–72 °C. 1H NMR (400 MHz, CDCl3): δ = 7.76
(s, 1 H), 7.52 (d, J = 8.2 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.23
(t, J = 7.8 Hz, 1 H), 2.80–2.65 (m, 1 H), 2.50–2.10 (m, 3 H), 1.95
(s, 3 H), 2.00–1.75 (m, 2 H), 1.50–1.35 (m, 1 H), 1.11 (d, J = 7.5 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.3, 145.3, 134.5,
130.0, 128.8, 127.7, 123.3, 122.8, 120.2, 117.5, 31.5, 31.3, 29.7, 21.5,
20.1, 10.0 ppm. C16H17BrO (305.21): calcd. C 62.96, H 5.61; found
C 62.88, H 5.87.
2-(2-Bromophenyl)-1-methylpyrrole (16): 1-Methylpyrrole (0.324,
4 mmol) and 2-bromobenzenesulfonyl chloride (0.255 g, 1 mmol)
affords 16 in 79% (0.186 g) yield as a colourless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 1 H), 7.37–7.32 (m, 2
H), 7.25–7.20 (m, 1 H), 6.75–6.70 (m, 1 H), 6.23 (dd, J = 3.6,
2.8 Hz, 1 H), 6.15 (dd, J = 3.6, 1.8 Hz, 1 H), 3.47 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 135.2, 133.3, 133.1, 129.9, 127.5,
126.2, 122.7, 109.6, 107.8, 34.9 ppm. C11H10BrN (236.11): calcd. C
55.96, H 4.27; found C 55.79, H 4.18.
3-Bromo-4-(3-bromophenyl)thiophene (10): 3-Bromothiophene
(0.244 g, 1.5 mmol) and 3-bromobenzenesulfonyl chloride (0.255 g,
1 mmol) affords 10 in 28% (0.089 g) yield as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.65 (t, J = 1.7 Hz, 1 H), 7.51 (d, J =
7.7 Hz, 1 H), 7.44 (d, J = 7.7 Hz, 1 H), 7.37 (d, J = 3.5 Hz, 1 H),
7.31–7.25 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.5,
137.1, 132.0, 130.8, 129.7, 127.7, 124.4, 124.1, 122.2, 110.8 ppm.
C10H6Br2S (318.02): calcd. C 37.77, H 1.90; found C 38.00, H 1.99.
2-(4-Iodophenyl)-5-methylfuran (17): 2-Methylfuran (0.123 g,
1.5 mmol) and 4-iodobenzenesulfonyl chloride (0.302 g, 1 mmol)
affords 17 in 72% (0.204 g) yield as a yellow solid; m.p. 75–79 °C.
Due to the low boiling point of 2-methylfuran, this reaction was
1
performed in an autoclave reactor. H NMR (400 MHz, CDCl3): δ
= 7.69 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.2 Hz, 2 H), 6.57 (d, J =
3.2 Hz, 1 H), 6.08 (d, J = 3.2 Hz, 1 H), 2.38 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 152.4, 151.3, 137.6, 130.6, 125.0,
107.9, 106.6, 91.5, 13.7 ppm. C11H9IO (284.09): calcd. C 46.51, H
3.19; found C 46.30, H 3.07.
2-(3-Bromophenyl)-1-methylpyrrole (11):[17] 1-Methylpyrrole (0.324,
4 mmol) and 3-bromobenzenesulfonyl chloride (0.255 g, 1 mmol)
1
affords 11 in 81% (0.191 g) yield. H NMR (400 MHz, CDCl3): δ
= 7.58 (s, 1 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1
H), 7.28 (t, J = 7.8 Hz, 1 H), 6.75 (s, 1 H), 6.30–6.20 (m, 2 H), 3.69
(s, 3 H) ppm.
3-(4-Iodophenyl)-4-methylthiophene
(18):
3-Methylthiophene
(0.147 g, 1.5 mmol) and 4-iodobenzenesulfonyl chloride (0.302 g,
1 mmol) affords 18 in 68% (0.204 g) yield as a colourless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2 H), 7.18 (d,
J = 3.2 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 2 H), 7.03 (d, J = 3.2 Hz, 1
H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.1,
137.6, 136.7, 136.0, 130.6, 123.4, 122.5, 92.7, 15.6 ppm. C11H9IS
(300.16): calcd. C 44.02, H 3.02; found C 44.14, H 3.28.
2,5-Bis(3-bromophenyl)-1-methylpyrrole
(12):
1-Methylpyrrole
(0.081, 1 mmol) and 3-bromobenzenesulfonyl chloride (0.637 g,
2.5 mmol) affords 12 in 57% (0.223 g) yield as a red solid; m.p.
1
104–108 °C. H NMR (400 MHz, CDCl3): δ = 7.64 (s, 2 H), 7.47
(d, J = 8.2 Hz, 2 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.32 (t, J = 8.2 Hz,
2 H), 6.35 (s, 2 H), 3.63 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 136.0, 135.4, 131.6, 130.1, 130.0, 127.3, 122.7, 109.8,
34.5 ppm. C17H13Br2N (391.10): calcd. C 52.21, H 3.35; found C
52.07, H 3.10.
3-Chloro-4-(4-iodophenyl)thiophene
(19):
3-Chlorothiophene
(0.177 g, 1.5 mmol) and 4-iodobenzenesulfonyl chloride (0.302 g,
1 mmol) affords 19 in 48% (0.154 g) yield as a white solid; m.p.
1
63–66 °C. H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 2
2-(2-Bromophenyl)-5-n-butylfuran (13): 2-n-Butylfuran (0.186 g,
1.5 mmol) and 2-bromobenzenesulfonyl chloride (0.255 g, 1 mmol)
affords 13 in 75% (0.209 g) yield as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.79 (d, J = 8.2 Hz, 1 H), 7.62 (d, J =
8.2 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.09 (d, J = 3.2 Hz, 1 H),
7.07 (t, J = 7.8 Hz, 1 H), 6.11 (d, J = 3.2 Hz, 1 H), 2.69 (t, J =
7.4 Hz, 2 H), 1.69 (quint., J = 7.4 Hz, 2 H), 1.43 (sext., J = 7.4 Hz,
2 H), 0.95 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 156.7, 149.5, 134.2, 131.6, 128.4, 127.8, 127.4, 119.2, 111.6,
106.9, 30.3, 27.9, 22.4, 14.0 ppm. C14H15BrO (279.17): calcd. C
60.23, H 5.42; found C 60.39, H 5.40.
H), 7.32–7.23 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
139.4, 137.6, 134.1, 130.7, 124.7, 123.7, 121.8, 93.8 ppm. C10H6ClIS
(320.58): calcd. C 37.47, H 1.89; found C 37.24, H 2.02.
3-Bromo-4-(4-iodophenyl)thiophene
(20):
3-Bromothiophene
(0.244 g, 1.5 mmol) and 4-iodobenzenesulfonyl chloride (0.302 g,
1 mmol) affords 20 in 66% (0.241 g) yield as a white solid; m.p.
1
87–90 °C. H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.2 Hz, 2
H), 7.39 (d, J = 3.2 Hz, 1 H), 7.32–7.23 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.1, 137.5, 134.8, 131.0, 124.6, 123.8,
110.9, 93.9 ppm. C10H6BrIS (365.03): calcd. C 32.90, H 1.66; found
C 32.99, H 1.58.
2-(2-Bromophenyl)-3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran (14):
Menthofuran (0.225 g, 1.5 mmol) and 2-bromobenzenesulfonyl 1-Benzyl-2-(4-iodophenyl)pyrrole (21): 1-Benzylpyrrole (0.628,
chloride (0.255 g, 1 mmol) affords 14 in 91% (0.277 g) yield as a 4 mmol) and 4-iodobenzenesulfonyl chloride (0.302 g, 1 mmol) af-
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, fords 21 in 67% (0.240 g) yield as a white solid; m.p. 103–106 °C.
1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.18 (t, 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.2 Hz, 2 H), 7.35–
J = 7.8 Hz, 1 H), 2.80–2.65 (m, 1 H), 2.50–2.10 (m, 3 H), 1.95 (s,
7.20 (m, 3 H), 7.06 (d, J = 8.2 Hz, 2 H), 7.00 (d, J = 8.2 Hz, 2 H),
3 H), 2.00–1.75 (m, 2 H), 1.50–1.35 (m, 1 H), 1.10 (d, J = 7.5 Hz, 6.81–6.75 (m, 1 H), 6.31–6.27 (m, 2 H), 5.14 (s, 2 H) ppm. 13C
Eur. J. Org. Chem. 2015, 4428–4436
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4433

R. Ben Salem, H. Doucet et al.
FULL PAPER
NMR (75 MHz, CDCl3): δ = 138.6, 137.5, 133.7, 132.7, 130.5,
4-(4-Bromo-2-ethylphenyl)-2-methylthiophene (27): 2-Methylthio-
128.7, 127.4, 126.3, 123.6, 109.4, 108.7, 92.4, 50.7 ppm. C17H14IN phene (0.147 g, 1.5 mmol) and 4-bromo-2-ethylbenzene-1-sulfonyl
(359.20): calcd. C 56.84, H 3.93; found C 56.99, H 3.80.
chloride (0.283 g, 1 mmol) affords 27 in 60% (0.169 g) yield as a
colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J =
2.0 Hz, 1 H), 7.31 (dd, J = 8.2, 2.0 Hz, 1 H), 7.10 (d, J = 8.2 Hz,
1 H), 6.90 (d, J = 1.5 Hz, 1 H), 6.74–6.72 (m, 1 H), 2.63 (q, J =
7.6 Hz, 2 H), 2.52 (s, 3 H), 1.11 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.3, 140.8, 139.7, 135.7, 131.6, 131.5,
128.8, 127.2, 121.4, 120.6, 26.4, 15.5, 15.4 ppm. C13H13BrS
(281.21): calcd. C 55.52, H 4.66; found C 55.34, H 4.41.
2-(4-Bromo-2-fluorophenyl)-5-n-butylfuran (22): 2-n-Butylfuran
(0.186 g, 1.5 mmol) and 4-bromo-2-fluorobenzene-1-sulfonyl chlor-
ide (0.273 g, 1 mmol) affords 22 in 63% (0.187 g) yield as a yellow
1
solid; m.p. 49–52 °C. H NMR (400 MHz, CDCl3): δ = 7.63 (t, J
= 8.9 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.15 (d, J = 9.7 Hz, 1
H), 6.62 (t, J = 3.2 Hz, 1 H), 6.00 (d, J = 3.2 Hz, 1 H), 2.58 (t, J
= 7.4 Hz, 2 H), 1.57 (quint., J = 7.4 Hz, 2 H), 1.32 (sext., J =
7.4 Hz, 2 H), 0.85 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.0 (d, J = 254.7 Hz), 157.0 (d, J = 1.3 Hz), 145.4
(d, J = 3.3 Hz), 127.7 (d, J = 3.5 Hz), 126.6 (d, J = 4.2 Hz), 119.7
(d, J = 9.5 Hz), 119.6 (d, J = 24.9 Hz), 118.8 (d, J = 12.3 Hz), 111.7
(d, J = 9.7 Hz), 107.6 (d, J = 1.8 Hz), 30.3, 27.9, 22.4, 13.9 ppm.
C14H14BrFO (297.16): calcd. C 56.59, H 4.75; found C 56.41, H
4.60.
2-(4-Bromo-2-ethylphenyl)-1-methylpyrrole (28): 1-Methylpyrrole
(0.324, 4 mmol) and 4-bromo-2-ethylbenzene-1-sulfonyl chloride
(0.283 g, 1 mmol) affords 28 in 76% (0.201 g) yield as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 2.0 Hz, 1 H), 7.37
(dd, J = 8.2, 2.0 Hz, 1 H), 7.10 (d, J = 8.2 Hz, 1 H), 6.73 (t, J =
2.1 Hz, 1 H), 6.23 (t, J = 2.9 Hz, 1 H), 6.08 (dd, J = 2.9, 2.1 Hz, 1
H), 3.40 (s, 3 H), 2.51 (q, J = 7.6 Hz, 2 H), 1.11 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 146.9, 133.1, 131.6,
131.5, 131.4, 128.6, 122.4, 122.0, 109.0, 107.5, 34.2, 26.4, 15.2 ppm.
C13H14BrN (264.16): calcd. C 59.11, H 5.34; found C 59.20, H 5.50.
4-(4-Bromo-2-fluorophenyl)-2-methylthiophene (23): 2-Methylthio-
phene (0.147 g, 1.5 mmol) and 4-bromo-2-fluorobenzene-1-sulfonyl
chloride (0.273 g, 1 mmol) affords 23 in 80% (0.217 g) yield as a
colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.45–7.28 (m, 4
H), 7.08 (s, 1 H), 2.56 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.4 (d, J = 253.2 Hz), 140.0, 134.3, 130.1 (d, J = 4.2 Hz),
127.5 (d, J = 4.2 Hz), 125.3 (d, J = 2.7 Hz), 123.0 (d, J = 13.1 Hz),
121.7 (d, J = 6.9 Hz), 120.3 (d, J = 10.0 Hz), 119.7 (d, J = 26.2 Hz),
15.2 ppm. C11H8BrFS (271.15): calcd. C 48.73, H 2.97; found C
48.89, H 2.74.
2-(4-Bromo-2-methoxyphenyl)-1-methylpyrrole (29): 1-Methylpyrr-
ole (0.324, 4 mmol) and 4-bromo-2-methoxybenzene-1-sulfonyl
chloride (0.285 g, 1 mmol) affords 29 in 38% (0.101 g) yield as a
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 7.47–7.40 (m, 2 H),
6.83 (d, J = 8.2 Hz, 1 H), 6.73 (t, J = 2.1 Hz, 1 H), 6.22 (t, J =
2.9 Hz, 1 H), 6.15 (dd, J = 2.9, 2.1 Hz, 1 H), 3.80 (s, 3 H), 3.49 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.6, 134.8, 131.7,
129.7, 124.7, 123.1, 112.7, 112.5, 109.6, 107.8, 55.8, 34.7 ppm.
C12H12BrNO (266.13): calcd. C 54.16, H 4.54; found C 54.32, H
4.69.
2-(4-Bromo-2-fluorophenyl)-1-methylpyrrole (24): 1-Methylpyrrole
(0.324, 4 mmol) and 4-bromo-2-fluorobenzene-1-sulfonyl chloride
(0.273 g, 1 mmol) affords 24 in 77% (0.195 g) yield as a brown so-
lid; m.p. 37–40 °C. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.15 (m,
2 H), 7.21 (t, J = 7.9 Hz, 1 H), 6.77 (t, J = 2.2 Hz, 1 H), 6.22 (d, J
= 2.2 Hz, 2 H), 3.56 (d, J = 1.6 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.2 (d, J = 252.3 Hz), 133.1 (d, J = 3.7 Hz), 127.6
(d, J = 3.8 Hz), 127.2, 124.1, 121.6 (d, J = 9.5 Hz), 120.6 (d, J =
6.9 Hz), 119.6 (d, J = 26.0 Hz), 110.5, 108.3, 34.8 ppm. C11H9BrFN
(254.10): calcd. C 51.99, H 3.57; found C 52.19, H 3.31.
2-[4-Bromo-2-(trifluoromethyl)phenyl]-1-methylpyrrole
(30):
1-
Methylpyrrole (0.324, 4 mmol) and 4-bromo-2-trifluoromethyl-
benzene-1-sulfonyl chloride (0.323 g, 1 mmol) affords 30 in 69%
1
(0.210 g) yield as a colourless oil. H NMR (400 MHz, CDCl3): δ
= 7.90 (d, J = 2.0 Hz, 1 H), 7.70 (dd, J = 6.2, 2.0 Hz, 1 H), 7.24
(d, J = 6.2 Hz, 1 H), 6.73–6.71 (m, 1 H), 6.21–6.19 (m, 1 H), 6.16–
6.14 (m, 1 H), 3.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 135.1, 134.4, 132.6 (q, J = 30.0 Hz), 131.6, 129.5 (q, J = 5.4 Hz),
128.2, 122.8, 122.7 (q, J = 274.2 Hz), 122.3, 110.7 (q, J = 2.0 Hz),
107.6, 34.4 ppm. C12H9BrF3N (304.11): calcd. C 47.39, H 2.98;
found C 47.28, H 3.08.
2-(4-Bromo-2-ethylphenyl)-5-n-butylfuran (25): 2-n-Butylfuran
(0.186 g, 1.5 mmol) and 4-bromo-2-ethylbenzene-1-sulfonyl chlor-
ide (0.283 g, 1 mmol) affords 25 in 63% (0.193 g) yield as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 8.2 Hz, 1 H),
7.39 (s, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 6.41 (d, J = 3.0 Hz, 1 H),
6.08 (d, J = 3.0 Hz, 1 H), 2.80 (q, J = 7.6 Hz, 2 H), 2.68 (t, J =
7.6 Hz, 2 H), 1.55 (quint., J = 7.6 Hz, 2 H), 1.38 (sext., J = 7.6 Hz,
2 H), 1.24 (t, J = 7.6 Hz, 3 H), 0.95 (t, J = 7.6 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.5, 150.8, 142.8, 132.2, 129.2,
129.1, 129.0, 121.2, 109.5, 106.8, 30.4, 28.0, 27.3, 22.4, 14.9,
14.0 ppm. C16H19BrO (307.23): calcd. C 62.55, H 6.23; found C
62.34, H 6.17.
2-n-Butyl-5-(2,5-dibromophenyl)furan (31): 2-n-Butylfuran (0.186 g,
1.5 mmol) and 2,5-dibromobenzene-1-sulfonyl chloride (0.334 g,
1 mmol) affords 31 in 82% (0.293 g) yield as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.91 (d, J = 2.4 Hz, 1 H), 7.49 (d, J =
7.5 Hz, 1 H), 7.30–7.27 (m, 2 H), 6.13 (d, J = 2.4 Hz, 1 H), 2.70
(t, J = 7.6 Hz, 2 H), 1.70 (quint., J = 7.6 Hz, 2 H), 1.46 (sext., J =
7.6 Hz, 2 H), 0.97 (d, J = 7.5 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.5, 148.1, 135.6, 133.2, 130.8, 130.5, 121.5, 117.5,
112.7, 107.2, 30.3, 28.0, 22.4, 13.9 ppm. C14H14Br2O (358.07):
calcd. C 46.96, H 3.94; found C 46.80, H 4.10.
2-(4-Bromo-2-ethylphenyl)-3,6-dimethyl-4,5,6,7-tetrahydrobenzo-
furan (26): Menthofuran (0.225 g, 1.5 mmol) and 4-bromo-2-ethyl-
benzene-1-sulfonyl chloride (0.283 g, 1 mmol) affords 26 in 94%
2-(2,5-Dibromophenyl)-3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran
(32): Menthofuran (0.225 g, 1.5 mmol) and 2,5-dibromobenzene-1-
1
(0.313 g) yield as a colourless oil. H NMR (400 MHz, CDCl3): δ
sulfonyl chloride (0.334 g, 1 mmol) affords 32 in 93% (0.357 g)
1
= 7.43 (d, J = 2.0 Hz, 1 H), 7.33 (dd, J = 8.2, 2.0 Hz, 1 H), 7.12 yield as a yellow oil. H NMR (400 MHz, CDCl3): δ = 7.51 (d, J
(d, J = 8.2 Hz, 1 H), 2.70–2.55 (m, 1 H), 2.63 (q, J = 7.6 Hz, 2 H),
= 2.4 Hz, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.29 (dd, J = 7.5, 2.4 Hz,
2.45–2.05 (m, 4 H), 1.88 (s, 3 H), 1.89–1.75 (m, 1 H), 1.48–1.38 (m,
1 H), 2.75–2.65 (m, 1 H), 2.50–2.30 (m, 2 H), 2.27–2.16 (m, 1 H),
1 H), 1.15 (t, J = 7.6 Hz, 3 H), 1.10 (d, J = 7.5 Hz, 3 H) ppm. 13C 1.95 (s, 3 H), 2.00–1.75 (m, 2 H), 1.48–1.38 (m, 1 H), 1.11 (d, J =
NMR (100 MHz, CDCl3): δ = 149.7, 146.5, 146.1, 131.9, 131.8,
129.9, 128.6, 122.0, 118.6, 117.0, 31.6, 31.5, 29.9, 26.8, 21.7, 20.4,
15.2, 9.2 ppm. C18H21BrO (333.26): calcd. C 64.87, H 6.35; found
C 64.74, H 6.42.
7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.9, 144.9,
135.2, 134.7, 134.6, 132.1, 122.0, 120.8, 119.0, 118.9, 31.6, 31.4,
29.8, 21.7, 20.3, 9.8 ppm. C16H16Br2O (384.10): calcd. C 50.03, H
4.20; found C 50.24, H 4.41.
4434
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4428–4436

New Pd-Catalysed Direct Arylation of Heteroaromatics
4-(2,5-Dibromophenyl)-2-methylthiophene (33): 2-Methylthiophene
(0.147 g, 1.5 mmol) and 2,5-dibromobenzene-1-sulfonyl chloride
(0.334 g, 1 mmol) affords 33 in 89% (0.295 g) yield as a colourless
oil. 1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 2.5 Hz, 1 H),
7.49 (d, J = 7.4 Hz, 1 H), 7.28 (dd, J = 7.4, 2.5 Hz, 1 H), 7.16 (s,
1 H), 6.92 (s, 1 H), 2.53 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 139.4, 139.3, 139.2, 134.3, 133.5, 131.1, 126.4, 122.2, 120.8,
15.0 ppm. C11H8Br2S (332.05): calcd. C 39.79, H 2.43; found C
39.57, H 2.25.
[1]
[2]
A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A.
Miyafuji, T. Nakata, N. Tani, Y. Aoyagi, Heterocycles 1990, 31,
1951–1958.
a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174–238; b) T. Satoh, M. Miura, Chem. Lett. 2007, 36, 200–
205; c) L.-C. Campeau, D. R. Stuart, K. Fagnou, Aldrichim.
Acta 2007, 40, 35–41; d) I. V. Seregin, V. Gevorgyan, Chem.
Soc. Rev. 2007, 36, 1173–1193; e) B.-J. Li, S.-D. Yang, Z.-J. Shi,
Synlett 2008, 949–957; f) C. Lewis, R. G. Bergman, J. A. Ell-
man, Acc. Chem. Res. 2008, 41, 1013–1025; g) F. Bellina, R.
Rossi, Tetrahedron 2009, 65, 10269–10310; h) L. Ackermann,
R. Vicente, A. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792–
9826; Angew. Chem. 2009, 121, 9976; i) X. Chen, K. M. Engle,
D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094–
5115; Angew. Chem. 2009, 121, 5196; j) O. Daugulis, H.-Q. Do,
D. Skabashov, Acc. Chem. Res. 2009, 42, 1074–1086; k) L. Jou-
cla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673–714; l)
C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677–
685; m) L. Ackermann, Chem. Rev. 2011, 111, 1315–1345; n)
L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011,
40, 1885–1898; o) N. Kuhl, M. N. Hopkinson, J. Wencel-De-
lord, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 10236–10254;
p) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem.
Int. Ed. 2012, 51, 8960–9009; q) J. J. Mousseau, A. B. Charette,
Acc. Chem. Res. 2012, 46, 412–424; r) S. R. Neufeldt, M. S.
Sanford, Acc. Chem. Res. 2012, 45, 936–946; s) J. Wencel-De-
lord, F. Glorius, Nature Chem. 2013, 5, 369–375; t) R. Rossi,
F. Bellina, M. Lessi, C. Manzini, Adv. Synth. Catal. 2014, 356,
17–117; u) M. He, J. F. Soulé, H. Doucet, ChemCatChem 2014,
6, 1824–1859; v) M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li,
W. Su, Org. Chem. Front. 2014, 1, 843–895; w) K. Yuan, J. F.
Soulé, H. Doucet, ACS Catal. 2015, 5, 978–991.
For Pd-catalysed direct arylations of furans with aryl halides,
see: a) M. S. McClure, B. Glover, E. McSorley, A. Millar,
M. H. Osterhout, F. Roschangar, Org. Lett. 2001, 3, 1677–
1680; b) B. Glover, K. A. Harvey, B. Liu, M. J. Sharp, M. F.
Tymoschenko, Org. Lett. 2003, 5, 301–304; c) M. Parisien, D.
Valette, K. Fagnou, J. Org. Chem. 2005, 70, 7578–7584; d)
E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola,
Synthesis 2008, 136–140; e) B. Liégaut, D. Lapointe, L. Caron,
A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826–1834; f)
J. J. Dong, J. Roger, C. Verrier, T. Martin, R. Le Goff, C.
Hoarau, H. Doucet, Green Chem. 2010, 12, 2053–2063; g) V. A.
Zinovyeva, M. A. Vorotyntsev, I. Bezverkhyy, D. Chaumont,
J.-C. Hierso, Adv. Funct. Mater. 2011, 21, 1064–1075; h) T. Yan,
L. Chen, C. Bruneau, P. H. Dixneuf, H. Doucet, J. Org. Chem.
2013, 78, 4177–4183.
2-(2,5-Dibromophenyl)-1-methylpyrrole
(34):
1-Methylpyrrole
(0.324, 4 mmol) and 2,5-dibromobenzene-1-sulfonyl chloride
(0.334 g, 1 mmol) affords 34 in 73% (0.230 g) yield as a colourless
oil. 1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 7.5 Hz, 1 H),
7.50 (d, J = 2.3 Hz, 1 H), 7.36 (dd, J = 7.5, 2.3 Hz, 1 H), 6.73 (s,
1 H), 6.21 (t, J = 3.3 Hz, 1 H), 6.18–6.14 (m, 1 H), 3.48 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.7, 135.6, 134.0,
132.4, 131.5, 124.5, 122.8, 120.9, 109.7, 107.6, 34.5 ppm.
C11H9Br2N (315.00): calcd. C 41.94, H 2.88; found C 41.69, H 3.02.
2,5-Bis(2,5-dibromophenyl)-1-methylpyrrole (35): 1-Methylpyrrole
(0.081, 1 mmol) and 2,5-dibromobenzene-1-sulfonyl chloride
(0.835 g, 2.5 mmol) affords 35 in 35% (0.192 g) yield as a dark
yellow solid; m.p. 109–111 °C. 1H NMR (400 MHz, CDCl3): δ =
7.56 (d, J = 2.3 Hz, 2 H), 7.53 (d, J = 7.5 Hz, 2 H), 7.38 (dd, J =
7.5, 2.3 Hz, 2 H), 6.22 (s, 2 H), 3.25 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 135.9, 135.3, 131.4, 129.9, 129.8, 127.1,
122.5, 109.6, 34.3 ppm. C17H11Br4N (548.89): calcd. C 37.20, H
2.02; found C 37.38, H 1.87.
2-(3,4-Dibromophenyl)-1-methylpyrrole
(36):
1-Methylpyrrole
(0.324, 4 mmol) and 3,4-dibromobenzene-1-sulfonyl chloride
(0.334 g, 1 mmol) affords 36 in 74% (0.233 g) yield as a brown oil.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 2.0 Hz, 1 H), 7.62
(d, J = 8.2 Hz, 1 H), 7.19 (dd, J = 8.2, 2.0 Hz, 1 H), 6.73 (s, 1 H),
6.27–6.23 (m, 1 H), 6.20 (t, J = 3.3 Hz, 1 H), 3.66 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 134.0, 133.4, 133.2, 131.9, 128.3,
124.7, 124.6, 122.7, 109.7, 108.2, 35.1 ppm. C11H9Br2N (315.00):
calcd. C 41.94, H 2.88; found C 42.12, H 3.01.
[3]
2-n-Butyl-5-(2,4,6-tribromophenyl)furan
(37):
2-n-Butylfuran
(0.186 g, 1.5 mmol) and 2,4,6-tribromobenzene-1-sulfonyl chloride
(0.413 g, 1 mmol) affords 37 in 36% (0.157 g) yield as a colourless
oil. 1H NMR (400 MHz, CDCl3): δ = 7.77 (s, 2 H), 6.39 (d, J =
3.2 Hz, 1 H), 6.10 (d, J = 3.2 Hz, 1 H), 2.68 (t, J = 7.6 Hz, 2 H),
1.67 (quint., J = 7.6 Hz, 2 H), 1.42 (sext., J = 7.6 Hz, 2 H), 0.93
(d, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.2,
148.1, 134.6, 133.3, 126.5, 123.2, 112.2, 106.0, 30.5, 27.9, 22.3,
13.9 ppm. C14H13Br3O (436.96): calcd. C 38.48, H 3.00; found C
38.30, H 2.88.
[4]
[5]
For Pd-catalysed direct arylations of thiophenes with aryl hal-
ides, see: a) E. David, S. Pellet-Rostaing, M. Lemaire, Tetrahe-
dron 2007, 63, 8999–9006; b) H. A. Chiong, O. Daugulis, Org.
Lett. 2007, 9, 1449–1451; c) Amaladass, P. J. A. Clement, A. K.
Mohanakrishnan, Tetrahedron 2007, 63, 10363–10371; d) M.
Nakano, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10,
1-Methyl-2-(2,4,6-tribromophenyl)pyrrole (38): 1-Methylpyrrole
(0.324, 4 mmol) and 2,4,6-tribromobenzene-1-sulfonyl chloride
(0.413 g, 1 mmol) affords 38 in 85% (0.334 g) yield as a colourless
1851–1854; e) J. Roger, F. Pozgan, H. Doucet, Green Chem.
ˇ
2009, 11, 425–432; f) Liégault, B. I. Petrov, S. I. Gorlesky, K.
Fagnou, J. Org. Chem. 2010, 75, 1047–1060.
1
oil. H NMR (400 MHz, CDCl3): δ = 7.80 (s, 2 H), 6.75–6.73 (m,
For Pd-catalysed direct arylations of pyrroles with aryl halides,
see: a) B. B. Toure, B. S. Lane, D. Sames, Org. Lett. 2006, 8,
1979–1982; b) B. Liégaut, D. Lapointe, L. Caron, A. Vlassova,
K. Fagnou, J. Org. Chem. 2009, 74, 1826–1834; c) J. Roger, H.
Doucet, Adv. Synth. Catal. 2009, 351, 1977–1990; d) D. T.
Gryko, O. Vakuliuk, D. Gryko, B. Koszarna, J. Org. Chem.
2009, 74, 9517–9520; e) B. Liegault, I. Petrov, S. I. Gorelsky,
K. Fagnou, J. Org. Chem. 2010, 75, 1047–1060; f) O. Rene, K.
Fagnou, Adv. Synth. Catal. 2010, 352, 2116–2120; g) D. Roy,
S. Mom, M. Beauperin, H. Doucet, J.-C. Hierso, Angew. Chem.
Int. Ed. 2010, 49, 6650–6654; h) Nadres, E. T. A. Lazareva, O.
Daugulis, J. Org. Chem. 2011, 76, 471–483; i) O. Vakuliuk, B.
Koszarna, D. T. Gryko, Adv. Synth. Catal. 2011, 353, 925–930;
1 H), 6.24 (t, J = 3.3 Hz, 1 H), 6.09–6.07 (m, 1 H), 3.39 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.0, 134.2, 131.2,
128.2, 123.2, 122.2, 109.4, 107.6, 34.1 ppm. C11H8Br3N (393.90):
calcd. C 33.54, H 2.05; found C 33.69, H 2.24.
Acknowledgments
The authors thank the French Ministère de la Recherche for a fel-
lowship to K. Y., the Centre National de la Recherche Scientifique
(CNRS), Rennes Metropole and the Scientific Ministry of Higher
Education and Research of Tunisia for providing financial support.
Eur. J. Org. Chem. 2015, 4428–4436
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4435

R. Ben Salem, H. Doucet et al.
FULL PAPER
j) L. Florentino, F. Aznar, C. Valdes, Chem. Eur. J. 2013, 19,
10506–10510; k) P. Ehlers, A. Petrosyan, J. Baumgard, S. Jopp,
N. Steinfeld, T. V. Ghochikyan, A. S. Saghyan, C. Fischer, P.
Langer, ChemCatChem 2013, 5, 2504–2511; l) Xu, Y. L. Zhao,
Y. Li, H. Doucet, Adv. Synth. Catal. 2013, 355, 1423–1432.
[6] M. Baloch, R. J. Roy, D. Roy, K. Beydoun, H. Doucet, RSC
Adv. 2011, 1, 1527–1536.
[7] a) X. Zhao, E. Dimitrijevic, V. M. Dong, J. Am. Chem. Soc.
2009, 131, 3466–3467; b) X. Zhao, V. M. Dong, Angew. Chem.
Int. Ed. 2011, 50, 932–934; c) for sulfonylations of quinolines
using CuI as catalyst, see: Z. Wu, H. Song, X. Cui, C. Pi, W.
Du, Y. Wu, Org. Lett. 2013, 15, 1270–1273.
[8] For desulfitative couplings using Ru catalysts, see: a) N. Kami-
gata, M. Yoshikawa, T. Shimizu, J. Fluorine Chem. 1998, 87,
91–95; b) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480, [14] R. Loeser, R. Bergmann, M. Frizler, B. Mosch, L. Dombrow-
224–228.
[9] For a review on transition-metal-mediated C–S bond acti-
vation, see: L. Wang, W. He, Z. Yu, Chem. Soc. Rev. 2013, 42,
599–621.
2003, 125, 15292–15293; b) S. R. Dubbaka, P. Vogel, Org. Lett.
2004, 9, 95–98; c) S. R. Dubbaka, P. Vogel, Angew. Chem. Int.
Ed. 2005, 44, 7674–7684; Angew. Chem. 2005, 117, 7848.
[12] a) M. Zhang, S. Zhang, M. Lui, J. Cheng, Chem. Commun.
2011, 47, 11522–11524; for reactions in the presence of benz-
enesulfinic acid sodium salts, see: b) R. Chen, S. Liu, X. Liu,
L. Yang, G.-J. Deng, Org. Biomol. Chem. 2011, 9, 7675–7679;
c) Wu, M. J. Luo, F. Xiao, S. Zhang, G.-J. Deng, H.-A. Luo,
Adv. Synth. Catal. 2012, 354, 335–340; d) Miao, T. L. Wang,
Adv. Synth. Catal. 2014, 356, 429–436.
[13] a) K. Yuan, H. Doucet, Chem. Sci. 2014, 5, 392–396; b) Louko-
tova, L. K. Yuan, H. Doucet, ChemCatChem 2014, 6, 1303–
1309; c) R. Jin, K. Yuan, E. Chatelain, J.-F. Soulé, H. Doucet,
Adv. Synth. Catal. 2014, 356, 3831–3841.
ski, M. Kuchar, J. Steinbach, M. Guetschow, J. Pietzsch, Chem-
MedChem 2013, 8, 1330–1344.
[15] R. Leardini, G. Martelli, P. Spagnolo, M. Tiecco, J. Chem. Soc.
C 1970, 1464–1469.
[10] For Heck-type reaction with benzenesulfonyl chlorides, see: a)
M. Miura, H. Hashimoto, K. Itoh, M. Nomura, Tetrahedron
[16] M. Ohkubo, D. Hayashi, D. Oikawa, K. Fukuhara, S. Okam-
oto, F. Sato, Tetrahedron Lett. 2006, 47, 6209–6212.
Lett. 1989, 30, 975–976; b) M. Miura, H. Hashimoto, K. Itoh, [17] Y.-X. Liu, D. Xue, J.-D. Wang, C.-J. Zhao, Q.-Z. Zou, C. Wang,
M. Nomura, J. Chem. Soc. Perkin Trans. 1 1990, 2207–2211.
[11] For Stille, Negishi or Suzuki couplings with benzenesulfonyl
chlorides, see: a) Dubbaka, S. R. P. Vogel, J. Am. Chem. Soc.
J. Xiao, Synlett 2013, 24, 507–513.
Received: March 16, 2015
Published Online: June 9, 2015
4436
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4428–4436