Regiocontroled Pd-catalysed C5-arylation of 3-substituted thiophene derivatives using a bromo-substituent as blocking group

Article abstract of DOI:10.3762/bjoc.12.210

The use of a bromo-substituent as blocking group at the C2-position of 3-substituted thiophenes allows the regioselective introduction of aryl substituents at C5-position via Pd-catalysed direct arylation. With 1 mol % of a phosphine-free Pd catalyst, KOAc as the base and DMA as the solvent and various electron-deficient aryl bromides as aryl sources, C5-(hetero)arylated thiophenes were synthesized in moderate to high yields, without cleavage of the thienyl C-Br bond. Moreover, sequential direct thienyl C5-arylation followed by Pd-catalysed direct arylation or Suzuki coupling at the C2-position allows to prepare 2,5-di(hetero)arylated thiophenes bearing two different (hetero)aryl units in only two steps. This method provides a green access to arylated thiophene derivatives as it reduces the number of steps to prepare these compounds and also the formation of wastes.

Full text of DOI:10.3762/bjoc.12.210

Regiocontroled Pd-catalysed C5-arylation of 3-substituted
thiophene derivatives using a bromo-substituent
as blocking group
Mariem Brahim1,2, Hamed Ben Ammar*2, Jean-François Soulé*1 and Henri Doucet*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2197–2203.
1Institut des Sciences Chimiques de Rennes, UMR 6226
doi:10.3762/bjoc.12.210
CNRS-Université de Rennes "Organométalliques: Matériaux et
Catalyse", Campus de Beaulieu, 35042 Rennes, France. Tel.:
Received: 25 July 2016
0
0-33-2-23-23-63-84 and 2Laboratoire de Synthèse Organique
Accepted: 27 September 2016
Published: 17 October 2016
Asymétrique et Catalyse Homogène, (UR 11ES56) Université de
Monastir, Faculté des Sciences de Monastir, avenue de
l’environnement, Monastir 5000, Tunisia
This article is part of the Thematic Series "Green chemistry".
Guest Editor: L. Vaccaro
Email:
Hamed Ben Ammar* - hamed_benammar@yahoo.fr;
Jean-François Soulé* - jean-francois.soule@univ-rennes1.fr;
Henri Doucet* - henri.doucet@univ-rennes1.fr
© 2016 Brahim et al.; licensee Beilstein-Institut.
License and terms: see end of document.
*
Corresponding author
Keywords:
aryl bromides; C–H bond activation; catalysis; direct arylation;
palladium; thiophenes
Abstract
The use of a bromo-substituent as blocking group at the C2-position of 3-substituted thiophenes allows the regioselective introduc-
tion of aryl substituents at C5-position via Pd-catalysed direct arylation. With 1 mol % of a phosphine-free Pd catalyst, KOAc as
the base and DMA as the solvent and various electron-deficient aryl bromides as aryl sources, C5-(hetero)arylated thiophenes were
synthesized in moderate to high yields, without cleavage of the thienyl C–Br bond. Moreover, sequential direct thienyl C5-aryl-
ation followed by Pd-catalysed direct arylation or Suzuki coupling at the C2-position allows to prepare 2,5-di(hetero)arylated thio-
phenes bearing two different (hetero)aryl units in only two steps. This method provides a “green” access to arylated thiophene de-
rivatives as it reduces the number of steps to prepare these compounds and also the formation of wastes.
Introduction
Thiophene derivatives bearing aryl substituents are important Therefore, the discovery of more direct and selective proce-
structures because of their biological and/or physical properties. dures for access to 5-arylated 3-substituted thiophene deriva-
Among them, 3-substituted 5-arylthiophenes are widely used as tives is an important topic in sustainable chemistry [4]. Stille or
building blocks for the synthesis of semi-conductors [1-3]. Suzuki palladium-catalysed coupling reactions [5-10] are some
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Beilstein J. Org. Chem. 2016, 12, 2197–2203.
of the most efficient methods for the preparation of 5-arylated
-substituted thiophenes [11-14]. However, before these cou-
3
pling reactions can be performed, an organometallic compound
must be synthesized. In 1990, Ohta and co-workers described
the Pd-catalysed direct arylation of thiophene derivatives by
coupling reaction with aryl halides [15,16]. This is a highly
powerful method for a greener access to a very broad range of
arylated thiophenes [17-25]. The method is very attractive in
terms of green chemistry, because its major by-products are not
metal salts but a base associated to HX, and synthesis of an
organometallic derivative can be avoided. However, for
C3-substituted thiophenes, arylation generally occurred at the
C2-position or gave mixtures of C2- and C5-arylated products
[
26-33]. The introduction of blocking groups at C2-position on
thiophene derivatives in order to arylate regiospecifically the
C5-positions had been reported (Figure 1).
Scheme 1: Blocking groups allowing regioselective C5-arylation of
thiophenes.
C–Br bond, ii) on the reaction scope using a set of aryl bro-
mides and 2-bromo-3-substituted thiophenes, iii) conditions
allowing either the sequential C5-arylation followed by
C2-arylation or C2-heteroarylation followed by C5-arylation of
C3-substituted thiophenes.
Results and Discussion
Based on some of our previous results on Pd-catalysed direct
Figure 1: Regioselectivity of the arylation of 3-substituted thiophenes.
arylation, for this study, DMA and KOAc were selected as the
In 2010, Fagnou et al. attached a 2-chloro-substituent to the solvent and base [35]. The reaction of 2 equiv of 2-bromothio-
thiophene ring to selectively perform a Pd-catalysed direct aryl- phene with 1 equiv of 4-bromonitrobenzene using 1 mol % of
ation of 3-hexylthiophene at the C5-position (Scheme 1, top) phosphine-free Pd(OAc)2 catalyst performed at 110 °C, only
[
34]. An ester moiety as blocking group at the C2-position of afforded the desired product 1 in a trace amount, but a com-
-substituted thiophene could also direct regioselectivity of plete conversion of 2-bromothiophene was observed, revealing
3
Pd-catalysed direct arylation to the C5-position (Scheme 1, the high reactivity of the thienyl C–Br bond under these condi-
middle) [35]. Mori et al. also reported two examples of C5-aryl- tions (Table 1, entry 1). Using a lower reaction temperature of
ation of 2-bromo-3-methylthiophene with aryl iodides as aryl 80 °C, and a reaction time of 15 h, the desired C5-arylated prod-
sources with 5 mol % PdCl2(PPh3)2 catalyst and AgNO3–KF as uct 1 was formed in only 8% yield due again to the formation of
the base in DMSO (Scheme 1, bottom) [36].
several degradation products (Table 1, entry 2). Then, we exam-
ined the influence of the reaction time. After 2 or 4 h, higher
Herein, we wish to report on green conditions in terms of num- yields of 1 (55% and 48%) were obtained, respectively; where-
ber of steps, base nature, use of a phosphine-free catalyst at low as, a very short reaction time of 0.5 h led to a lower yield of
loading and a quite “atom economic” aryl source promoting 27% due to the poor conversion of 4-bromonitrobenzene (Ta-
such a C5-arylation using C3-substituted 2-bromothiophenes. ble 1, entries 3–6). The use of 0.5 mol % Pd(OAc)2 catalyst at
We report i) that only 1 mol % of air-stable Pd(OAc)2 catalyst 80 °C during 2 h also afforded 1 in a lower yield of 35%.
associated to KOAc promotes the regiospecific access to Again, a large amount of 4-bromonitrobenzene was recovered
C5-arylated 2-bromothiophenes without cleavage of the thienyl (Table 1, entry 7). When CsOAc, NaOAc or K2CO3 were em-
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Beilstein J. Org. Chem. 2016, 12, 2197–2203.
ployed as bases instead of KOAc, in the presence of 1 mol % KOAc, 80 °C, 2 h) (Schemes 2–4). First, we investigated the
Pd(OAc)2 catalyst during 2 h, a partial conversion of 4-bromo- reaction of 2-bromothiophene with 4-bromobenzonitrile,
nitrobenzene was observed and 1 was isolated in 32–40% yield 4-bromobenzaldehyde and 4-bromo-2-(trifluoromethyl)-
(
Table 1, entries 8–10). It should be noted that in the presence nitrobenzene (Scheme 2). The expected coupling products 2–4
of cyclopentyl methyl ether or diethyl carbonate as solvents, no were obtained in moderate yields. On the other hand, with
formation of 1 was observed, and 4-bromonitrobenzene was 4-bromoanisole as an electron-rich aryl bromide, the desired
recovered unreacted (Table 1, entries 11 and 12).
C5-arylated 2-bromothiophene could not be detected by
GC–MS analysis of the crude mixture, and a large amount of
unreacted 4-bromoanisole was recovered. Under these reaction
conditions, the oxidative addition of 4-bromoanisole to palla-
dium appears to be slower than the oxidative addition of
Table 1: Influence of the reaction conditions for the palladium-cata-
lysed direct C5-arylation of 2-bromothiophene with 4-bromonitro-
benzene.a
2
-bromothiophene. Therefore, this procedure is limited to the
use of electron-deficient aryl bromides. The reactivity of
-bromofuran with 4-bromonitrobenzene was also investigated.
2
Under the same reaction conditions, (1 mol % Pd(OAc)2, DMA,
KOAc, 80 °C, 2 h) no formation of the desired 2-bromo-5-aryl-
furan derivative was observed.
Entry Pd(OAc)2
mol %)
Base
Temp
(°C)
Time
(h)
Yield in 1
(%)
(
The main interest to tolerate a C–Br bond at the C2-position on
thiophene derivatives in the course of such couplings would be
the regiospecific access to C5-arylated 3-substituted thiophenes,
which cannot be obtained from 2-unsubstituted 3-substituted
thiophenes such as 3-methylthiophene. Therefore, a set of aryl
bromides was reacted with 2-bromo-3-methylthiophene, under
these conditions (Scheme 3). Its reaction with aryl bromides
para-substituted by nitro, cyano or formyl substituents gave the
desired 5-arylated thiophenes 5–7 in 60–64% yields, without
cleavage of the thienyl C–Br bond. Good yields of products 8
and 9 were also obtained from the meta-substituted aryl bro-
mides, 3-bromobenzonitrile and 3-bromonitrobenzene. Again, a
high yield of 85% of 10 was obtained with 4-bromo-2-(tri-
fluoromethyl)nitrobenzene. Then, the reactivity of a set of
ortho-substituted aryl bromides was examined. Bromobenzene
containing nitro, nitrile or formyl ortho-substituents afforded
the C5-arylated thiophenes 11–13 in 71–84% yields. Finally,
1
2
3
4
5
6
7
8
9
1
1
1
1
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
110
80
80
80
80
80
80
15
15
4
trace
8
1
1
48
55
42
27
35
35
32
40
0b
1
2
1
1
1
0.5
2
0.5
1
CsOAc 80
NaOAc 80
K2CO3 80
2
1
2
0
1
2
1
2
1
KOAc
KOAc
80
80
2
1
2
0c
aConditions: Pd(OAc)2, 2-bromothiophene (2 equiv), 4-bromonitro-
benzene (1 equiv), base (2 equiv), DMA, isolated yields. bCyclopentyl
methyl ether as solvent. cDiethyl carbonate as solvent.
Then, we studied the scope of this reaction using a set of aryl 3-bromoquinoline and 3-bromopyrimidine were reacted with
bromides and 2-bromothiophene derivatives, employing the 2-bromo-3-methylthiophene affording 14 and 15 in 63% and
most effective reaction conditions for C5-arylation of 66% yields, respectively. The higher yields obtained for the
2
-bromothiophene (Table 1, entry 4: 1 mol % Pd(OAc)2, DMA, arylation of 2-bromo-3-methylthiophene than with 2-bromo-
Scheme 2: Reactivity of 2-bromothiophene with aryl bromides.
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Beilstein J. Org. Chem. 2016, 12, 2197–2203.
Scheme 3: Reactivity of 2-bromo-3-methylthiophene with (hetero)aryl bromides.
Scheme 4: Reactivity of 3-substituted 2-bromothiophenes with aryl bromides.
thiophene are probably due to a slower oxidative addition of Then, to demonstrate the synthetic potential of the thienyl
-bromo-3-methylthiophene to palladium which reduces the bromo-substituent, product 1 was coupled with 2-methylthio-
2
formation of side-products.
phene in the presence of 1 mol % Pd(OAc)2 catalyst and KOAc
as base (Scheme 5). The desired product 19 was obtained in
The reaction is not limited to the use of 2-bromo-3-methylthio- 71% yield. Under the same conditions, a high yield of 91% in
phene. A 2-bromothiophene derivative bearing a CH2CO2Et 20 was obtained from 2 and 2-methyl-4-ethylthiazole. These
substituent at C3 also provides regioselectively the desired two reactions demonstrate that the sequential Pd-catalysed
C5-arylated thiophenes 16 and 17 in good yields; whereas, a direct di-(hetero)arylation, using 2-bromothiophene as central
lower yield of 18 was obtained for the coupling of 2-bromo-3- unit, provides a powerful and simple access to non-symmetri-
chlorothiophene with 4-bromobenzonitrile (Scheme 4).
cally 2,5-di(hetero)arylated thiophene derivatives.
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Beilstein J. Org. Chem. 2016, 12, 2197–2203.
Scheme 5: 5-Heteroarylation of 2-aryl-5-bromothiophenes.
3
-Substituted thiophene derivatives containing a heteroaryl unit
at the C2-position and an aryl at C5 can also be obtained by
direct heteroarylation at the C2-position of the C3-substituted
2
-bromothiophene, followed by direct arylation at C5
(
Scheme 6 and Scheme 7). First, we introduced imidazopy-
ridinyl or thiazolyl groups at C2-position of 2-bromo-3-
methylthiophene. In the presence of 1 mol % Pd(OAc)2 and
KOAc as base at 150 °C the products 21–23 were obtained in
Scheme 7: 5-Arylation of 2,3-disubstituted thiophenes.
7
0–88% yields. In all cases, no C2-arylation of the 2-bromo-3-
methylthiophene with itself to produce 5'-bromo-3,4'-dimethyl-
2
,2'-bithiophene was observed.
Scheme 8: 5-Arylation of 2-aryl-5-bromothiophenes.
In order to further demonstrate that a bromo-substituent at
C2-position of the thiophenes can be considered as a protecting
group, we removed it via palladium-catalysed hydrogenolysis
Scheme 6: 2-Heteroarylation of 2-bromo-3-methylthiophene.
Then, from the C2-heteroarylated 3-methylthiophenes 21–23, a (Scheme 9). Treatment of 14 with 2 mol % Pd/C (10%) and tri-
second direct arylation at position C5 allows to prepare the methylamine in ethanol under hydrogen pressure, gave the
products 24–26 in 87–91% yields (Scheme 7).
desired debrominated product 29 in almost quantitative yield.
The synthesis of 3-substituted thiophenes derivatives contain- Conclusion
ing two different aryl groups at C2 and C5 positions via Suzuki In summary, we report here that the use of a 2-bromo-substitu-
coupling in the second step was also attempted (Scheme 8). The ent on thiophenes acts as a blocking group, allowing their regio-
reaction of 5 with phenylboronic acid in the presence of only selective Pd-catalysed C5-arylation even in the presence of aryl
1
5
mol % Pd(OAc)2 catalyst and K2CO3 as base gave 3-methyl- bromides as aryl sources. Only 1 mol % of phosphine-free air
-(4-nitrophenyl)-2-phenylthiophene (27) in 60% yield. A stable Pd(OAc)2 catalyst in the presence of KOAc as base
higher yield of 80% in 28 was obtained for the coupling of 16 promotes the C5-arylation of 2-bromothiophenes containing
with phenylboronic acid. various C3-substituents with electron-deficient (hetero)aryl bro-
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Beilstein J. Org. Chem. 2016, 12, 2197–2203.
Scheme 9: Deprotection of 2-aryl-5-bromothiophene 14.
9
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