Palladium-catalysed direct regioselective C5-arylation of a thiophene bearing a cyclopropyl ketone group at C2

Article abstract of DOI:10.1016/j.catcom.2013.07.014

A thiophene bearing a cyclopropyl ketone group at C2 was successfully employed in palladium-catalysed direct arylation. The reaction proceeds regioselectively at C5 without decomposition of the cyclopropyl ketone substituent. These couplings were performed employing as little as 0.5 mol% of ligand-free Pd(OAc)₂ catalyst with electron-deficient aryl bromides. A wide variety of functional groups on the aryl bromide such as nitrile, nitro, acetyl, formyl, benzoyl, ester, trifluoromethyl, fluoro or methoxy was tolerated. 2013 Elsevier Science. All rights reserved.

Full text of DOI:10.1016/j.catcom.2013.07.014

Catalysis Communications 41 (2013) 119–122
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Palladium-catalysed direct regioselective C5-arylation of a thiophene
bearing a cyclopropyl ketone group at C2
Anissa Beladhria a,b,c, Aditya L. Gottumukkala b, Chiraz Youssef a,b, Charles Beromeo Bheeter b,
c
b,
Hamed Ben Ammar a, , Ridha Ben Salem , Henri Doucet
⁎
⁎
a
Laboratoire Laboratoire de Chimie Organique Appliquée, (UR 11ES74) Université de Gabès, Faculté des Sciences de Gabès, 6072 Gabès, Tunisia
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes “Organométalliques: Matériaux et Catalyse”, Campus de Beaulieu, 35042 Rennes, France
Laboratoire de Chimie Organique Physique, (UR 11ES74) Université de Sfax, Faculté des Sciences de Sfax, Route de la Soukra km 4, 3038 Sfax, Tunisia
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2013
Received in revised form 26 June 2013
Accepted 1 July 2013
Available online 17 July 2013
A thiophene bearing a cyclopropyl ketone group at C2 was successfully employed in palladium-catalysed direct
arylation. The reaction proceeds regioselectively at C5 without decomposition of the cyclopropyl ketone substituent.
These couplings were performed employing as little as 0.5 mol% of ligand-free Pd(OAc)2 catalyst with electron-
deficient aryl bromides. A wide variety of functional groups on the aryl bromide such as nitrile, nitro, acetyl, formyl,
benzoyl, ester, trifluoromethyl, fluoro or methoxy was tolerated. © 2013 Elsevier Science. All rights reserved.
© 2013 Elsevier B.V. All rights reserved.
Keywords:
Palladium
C\H bond functionalisation
Thiophenes
Cyclopropyl ketone
Aryl bromides
1. Introduction
thiophene have been found to allow the synthesis of a very wide variety
of thiophene derivatives (Fig. 2). Both the cyclopropyl and ketone
Thiophene derivatives are of considerable interest for pharma-
ceutical chemistry due to their biological activities. For example,
the 2-arylthiophene derivative Canagliflozin [1] is a drug for the
treatment of type 2 diabetes (Fig. 1, top). Several thiophene derivatives
containing an hydroxyalkyl group at C2 have also been found to be bio-
active. Duloxetine is employed against major depressive disorder, and
Tiemonium and Penthienate are antimuscarinics (Fig. 1, bottom).
Therefore, the development of simple and convenient processes using
readily accessible thiophene derivatives for the synthesis of arylated
thiophenes is highly desirable.
groups can be transformed. For example, the simple reduction of the
carbonyl produces the secondary alcool [27]; whereas, the addition of
nucleophiles such as ArLi or ArMgX to the carbonyl gives the tertiary
alcools [28,29]. The transformation of the carbonyl into an alkene,
via a Wittig reaction, has also been described [30]. The cyclopropyle
ring opening allows to prepare enones or sufonamides [31,32]. Recently,
Ogoshi and co-workers have reported a [3 + 2] cycloaddition reaction
of cyclopropyl 2-thienyl ketone with but-2-yne catalysed by a nickel/
R
The palladium-catalysed direct arylation of several heteroaromatics
[1–12], including thiophenes, [13–16] via a C\H bond activation using
aryl halides has led to successes in recent years. Such couplings are
very attractive compared to classical palladium-catalysed reactions
such as Stille, Suzuki or Negishi couplings,[17] as they do not require
the preliminary synthesis of organometallic derivatives. However, to
our knowledge, no examples of palladium catalysed direct arylation of
thiophenes bearing a cyclopropyl ketone group has been described
[18–24]. On the other hand, some examples of palladium-catalysed
sp3 C\H functionalisation of cyclopropanes have been reported [25,26].
The use of such reactant for direct arylation would be very attrac-
tive for synthetic organic chemists, as cyclopropyl ketone groups on
S
F
Canagliflozin
H
N
I-
Br-
N+
N+
O
S
OH
O
O
S
O
S
Duloxetine
Tiemonium
Penthienate
⁎
Corresponding authors. Tel./fax: +33 223236384.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).
Fig. 1. Examples of bioactive thiophene derivatives.
1566-7367/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2013.07.014

120
A. Beladhria et al. / Catalysis Communications 41 (2013) 119–122
dimethylaluminum chloride system which allow the synthesis of
cyclopentenes [33]. Reactions involving both ketone and cyclopropyl
groups to prepare pyrrolidine derivatives have also been described
[34]. Therefore, the tolerance to such cyclopropyl ketone substituents
on thiophene for palladium-catalysed direct arylations for a simple ac-
cess to a variety of cyclopropyl 2-thienyl ketone derivatives needed to
be studied.
O
[Pd]
O
S
Br
+
H
base
O
S
1
O
Scheme 1. Palladium-catalysed direct C5-arylation of cyclopropyl 2-thienyl ketone
with 4-bromoacetophenone.
Here, we wish to report (i) on the influence of the reaction
conditions for the coupling of cyclopropyl 2-thienyl ketone with
4-bromoacetophenone; (ii) on the access to a wide variety of
5-arylated cyclopropyl 2-thienyl ketones using substituted aryl
bromides.
nitro or cyano at C4 of bromobenzenes were also tolerated to give 5
and 6 in 90% and 93% yields, respectively (Table 2, entries 4 and 5).
On the other hand, from bromobenzenes bearing fluoro, methyl,
tert-butyl or methoxy substituents at C4, using 0.5 mol% Pd(OAc)2 cata-
lyst, conversions of 55–76% of these aryl bromides were observed and
7–10 were isolated in only 51–68% yields. With these more challenging
substrates, 2 mol% PdCl(C3H5)(dppb) catalyst had to be employed to
obtain complete conversions leading to 7–10 in slightly higher yields
(Table 2, entries 6–13). Dppb ligand certainly favours the oxidative addi-
tion of these aryl bromides to palladium.
Then, several meta-substituted aryl bromides have been employed
(Table 3). Again, the use of 0.5 mol% Pd(OAc)2 efficiently promotes
the formation of 11–16 in 86–90% yields from bromobenzenes bearing
nitrile, formyl, acetyl, nitro, trifluoromethyl or even fluoro substitu-
ents (Table 3, entries 1–6). Again, a lower yield was obtained with a
3-methyl substituted bromobenzene (Table 3, entries 7 and 8).
Then, we examined the reactivity of cyclopropyl 2-thienyl ketone
with a set of ortho-substituted aryl bromides using the same reaction
conditions (Scheme 2, Table 3). ortho-Substituents on aryl bromides
generally have an important effect on the reaction rates of palladium-
catalysed reactions due to their steric and/or coordination properties.
Very good yields in 20–24 were obtained with nitrile, formyl, nitro
trifluoromethyl or fluoro ortho-substituents on bromobenzene (Table 3,
entries 11–15). On the other hand, from (2-bromophenyl)-methanol, 25
was only obtained in 31% yield due to a partial conversion of this aryl
bromide; and 2-bromoanisole was recovered unreacted (Table 3, entries
16–18). By contrast, a clean reaction was observed in the presence of
9-bromoanthracene to give 27 in 81% yield (Table 3, entry 19).
2. Results and discussion
First, we examined the influence of the reaction conditions for the
coupling of commercially available cyclopropyl 2-thienyl ketone with
4-bromoacetophenone (Scheme 1, Table 1). Starting form a slight ex-
cess of cyclopropyl 2-thienyl ketone (1.5 eq.) with respect to the aryl
bromide, in the presence of 0.5 mol% Pd(OAc)2 as the catalyst, NaOAc
as the base, and DMA as the solvent at 120 °C, the desired product 1
was obtained in 32% yield. This moderate yield was due to a partial con-
version of the aryl bromide and not to degradation of the cyclopropyl
ketone substituent (Table 1, entry 1). The influence of a few other
bases was then examined, and both KOAc and CsOAc, led to very high
yields of 1 (Table 1, entries 2 and 3). On the other hand, no formation
of 1 was observed in the presence of carbonates as bases (Table 1,
entries 4–6). Then, we explored the influence of a few other solvents.
A high yield of 1 was obtained in NPM; whereas, xylene, cyclopentyl
methyl ether or pentan-1-ol were not suitable to promote this reaction
(Table 1, entries 7–10). The use of 0.5 mol% PdCl(C3H5)(dppb) catalyst
at 120 °C also produces 1 in good yield (Table 1, entry 12). Then, we re-
duced the catalyst loading to 0.1 mol% Pd(OAc)2 using both 120 °C and
150 °C as the reaction temperatures (Table 1, entries 13 and 14). Under
these conditions, 1 was only obtained in 76% and 73% yields, although
full conversions of 4-bromoacetophenone were observed, due to partial
degradation of the product.
Finally, the reactivity of five heteroaryl bromides for this coupling
was examined (Table 4). Pyridines or quinolines are π-electron deficient
heterocycles and therefore, their oxidative addition to palladium is, in
general, relatively easy. Using 3-bromopyridine, 3-bromoquinoline,
4-bromoisoquinoline or 5-bromopyrimidine, the desired products 28,
30–32 were obtained in good yields. It should be noted that with
We then studied the scope of the 5-arylation of cyclopropyl
2-thienyl ketone using 0.5 mol% Pd(OAc)2 catalyst, KOAc as the base
and DMA as the solvent at 120 °C (Scheme 2, Tables 2–4). First, the re-
activity or para-substituted aryl bromides were examined (Table 2).
Good yields in 2–4 were obtained from 4-bromobenzaldehyde,
4-bromobenzophenone or methyl 4-bromobenzoate (Table 2, entries
1–3). As expected, the strongly electron-withdrawing substituents,
Table 1
Influence of the reaction conditions for palladium-catalysed direct C5-arylation of
cyclopropyl 2-thienyl ketone with 4-bromoacetophenone (Scheme 1).
Entry
Pd(OAc)2
(mol%)
Solvent
Base
Conv. (%)
Yield in 1
(%)
R
nBu
Ar
HO
ArLi
R
R
N
S
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
DMA
DMA
DMA
DMA
DMA
DMA
NMP
Xylene
Cyclopentyl
methyl ether
Pentan-1-ol
DMA
DMA
DMA
DMA
NaOAc
KOAc
38
100
100
6
6
3
100
0
1
32
89
87
–
HO
S
S
CsOAc
K2CO3
Na2CO3
Cs2CO3
KOAc
NaBH4
Ar
R
nBuNH2
ArCHO
R'
–
–
R
S
R'
MgBr
but-2-yne
78
–
R
KOAc
KOAc
S
S
–
O
HO
O
Ph3PMe
ArSO2NH2
10
11
12
13
14
0.5
0.5
0.5
0.1
0.1
KOAc
KOAc
KOAc
KOAc
KOAc
1
100
100
100
100
–
ArCHO
OH
85a
84b
76
ArSO2
R
N
H
R
S
S
73c
O
Ar
R
Conditions: Pd(OAc)2, 4-bromoacetophenone (1 mmol), cyclopropyl 2-thienyl ketone
(1.5 mmol), base (2 mmol), 120 °C, 16 h, argon, conv. of 4-bromoacetophenone.
S
a
O
Cyclopropyl 2-thienyl ketone (1 mmol).
PdCl(C3H5)(dppb) as catalyst.
b
c
Fig. 2. Reactivity of cyclopropyl 2-thienyl ketones.
150 °C.

A. Beladhria et al. / Catalysis Communications 41 (2013) 119–122
121
Pd(OAc)2
0.5 mol%
Table 3
R
Palladium-catalysed 5-arylation of cyclopropyl 2-thienyl ketone with meta- or ortho-
Br
+
H
R
substituted aryl bromides (Scheme 2).
DMAc, KOAc,
120 °C, 16h
S
S
O
O
Entry Aryl bromide
1
Product
Yield (%)
86
Scheme 2. Palladium-catalysed direct 5-arylation of cyclopropyl 2-thienyl ketone with
(hetero)aryl bromides.
2
3
89
90
4-bromoisoquinoline, which is quite congested, the use of 2 mol%
PdCl(C3H5)(dppb) catalyst at 150 °C gave a better yield in 31 than
0.5 mol% Pd(OAc)2 (Table 4, entries 5 and 6). On the other hand,
2-bromopyridine was found to be unreactive (Table 4, entries 2 and 3).
This is probably due to the poisoning of the catalyst by formation of stable
palladacycles with this aryl bromide.
In summary, we have demonstrated that using as little as 0.5 mol%
of Pd(OAc)2 as the catalyst precursor, the 5-arylation via C\H bond
activation of cyclopropyl 2-thienyl ketone proceeds in moderate to
high yields. No significant decomposition of the cyclopropyl ketone
group was detected. Moreover, in all cases a completely regioselective
reaction in favour of arylation at C5 was observed. This ligand-free
procedure gave good results using electron-deficient aryl bromides.
By contrast, for electron-rich aryl bromides PdCl(C3H5)(dppb) cata-
lyst should be preferred. Several functions such as formyl, acetyl,
benzoyl, ester, nitro, nitrile, trifluoromethyl, fluoro or methoxy are
tolerated on the aryl bromide, and even a congested aryl bromide,
such as 9-bromoanthracene, gave a satisfactory result. This ligand-
free low catalyst loading procedure is economically and environ-
mentally attractive, as there is no need to eliminate phosphine
87
86
4
5
6
86
7
8
68
76a
9
82
79
10
11
Table 2
95
81
Palladium-catalysed 5-arylation of cyclopropyl 2-thienyl ketone with para-substituted
aryl bromides (Scheme 2).
Entry
1
Aryl bromide
Product
Yield (%)
91
12
13
91
2
3
94
90
14
15
93
90
4
5
16
17
28
90
93
31a
0
18
19
6
7
68
81
70a
8
9
67
68a
Conditions: Pd(OAc)2 (0.005 mmol), cyclopropyl 2-thienyl ketone (1.5 mmol), aryl bromide
(1 mmol), KOAc (2 mmol), DMA, 120 °C, 16 h.
10
11
a
PdCl(C3H5)(dppb) (0.02 mmol) as the catalyst.
58
68a
12
13
51
69a
derivatives at the end of the reaction; and as with this C\H bond activa-
tion procedure, no preparation of an organometallic derivative is re-
quired, reducing the number of steps and therefore the mass of waste
products. The major waste is the relatively non-toxic AcOH/KBr instead
Conditions: Pd(OAc)2 (0.005 mmol), cyclopropyl 2-thienyl ketone (1.5 mmol), aryl
bromide (1 mmol), KOAc (2 mmol), DMA, 120 °C, 16 h.
a
PdCl(C3H5)(dppb) (0.02 mmol) as the catalyst.

122
A. Beladhria et al. / Catalysis Communications 41 (2013) 119–122
Table 4
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Conditions: Pd(OAc)2 (0.005 mmol), cyclopropyl 2-thienyl ketone (1.5 mmol), heteroaryl
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3. Experimental
General procedure for the preparation of 1–32:
The reaction of the aryl bromide (1 mmol), cyclopropyl 2-thienyl
ketone (0.228 g, 1.5 mmol) and KOAc (0.196 g, 2 mmol) at 120 °C or
150 °C (see tables) during 16 h in DMA (4 mL) in the presence of
Pd(OAc)2 (1.12 mg, 0.005 mmol) or PdCl(C3H5)(dppb) (12.2 mg,
0.02 mmol) [35] (see tables) under argon affords the coupling product
after evaporation of the solvent and purification on silica gel.