Influence of the solvent and of the reaction concentration for palladium-catalysed direct arylation of heteroaromatics with 4-bromoacetophenone

Article abstract of DOI:10.1016/j.crci.2014.02.004

The solvent is certainly one of the main sources of wastes during palladium-catalysed direct arylation reactions. We found that such direct arylations of heteroaromatics can be performed using very high concentrations of reactants (0.5 M-5 M). However, the Pd catalyst precursor used must be adapted to both the solvent nature and the concentration of reactants. The reactions performed in DMA, NMP or DMF can be carried out in very concentrated reaction mixtures using 0.1 mol% Pd(OAc)₂ catalyst without phosphine ligand. On the other hand, the reactions in CPME, pentan-1-ol or diethylcarbonate should be performed with a palladium catalyst associated with a phosphine ligand. These reaction conditions allow us to reduce the amount of wastes formed in the course of these couplings.

Full text of DOI:10.1016/j.crci.2014.02.004

C. R. Chimie 17 (2014) 1184–1189
Contents lists available at ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
´
Full paper/Memoire
Influence of the solvent and of the reaction concentration for
palladium-catalysed direct arylation of heteroaromatics with
4-bromoacetophenone
Influence du solvant et de la concentration pour l’arylation directe
´
´ ´
catalysee au palladium d’heteroaromatiques par la
´
´
4-bromoacetophenone
*
Souhila Bensaid, Henri Doucet
Institut des sciences chimiques de Rennes, UMR 6226 CNRS–Universite´ de Rennes-1, « Catalyse et Organometalliques », campus de
Beaulieu, 35042 Rennes cedex, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The solvent is certainly one of the main sources of wastes during palladium-catalysed
direct arylation reactions. We found that such direct arylations of heteroaromatics can be
performed using very high concentrations of reactants (0.5 M–5 M). However, the Pd
catalyst precursor used must be adapted to both the solvent nature and the concentration
of reactants. The reactions performed in DMA, NMP or DMF can be carried out in very
concentrated reaction mixtures using 0.1 mol% Pd(OAc)2 catalyst without phosphine
ligand. On the other hand, the reactions in CPME, pentan-1-ol or diethylcarbonate should
be performed with a palladium catalyst associated with a phosphine ligand. These reaction
conditions allow us to reduce the amount of wastes formed in the course of these
couplings.
Received 23 January 2014
Accepted after revision 17 February 2014
Available online 7 October 2014
Keywords:
Aryl bromides
Catalysis
C–H activation
Heteroaromatics
Palladium
´
ß 2014 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Concentration
´
´
R E S U M E
´
Mots cles :
Le solvant est certainement l’une des principales sources de de´chets lors des re´actions
Bromures d’aryle
Catalyse
´ ´
´
´
d’arylation directes d’heteroaromatiques catalysees au palladium. Nous avons constate
´
ˆ
´
´
`
´
´
que ces reactions peuvent etre realisees en utilisant des concentrations tres elevees
(0,5 M–5 M). Cependant, le catalyseur de palladium utilise´ doit eˆtre adapte´ a` la fois a` la
Activation C–H
He´te´roaromatiques
Palladium
`
´
´
´
nature du solvant et a la concentration des reactifs. Les reactions effectuees dans le DMA, la
ˆ
´
´
´
´
`
´
NMP ou le DMF peuvent etre realisees dans des melanges reactionnels tres concentres, en
Concentration
utilisant 0,1 mol % de Pd(OAc)2 sans addition de ligand de type phosphine. En revanche, les
´
´
ˆ
´
reactions dans le CPME, le pentan-1-ol ou le carbonate de diethyle doivent etre effectuee
´
`
a un ligand phosphine. Ces conditions
avec un catalyseur de palladium associe
´
´
´
´
´
reactionnelles permettent de reduire la quantite de dechets formes au cours de ces
couplages.
´
´
´
´
ß 2014 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
*
Corresponding author.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).
1631-0748/$ – see front matter ß 2014 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2014.02.004

S. Bensaid, H. Doucet / C. R. Chimie 17 (2014) 1184–1189
1185
1. Introduction
pentan-1-ol, cyclopentylmethylether (CPME) and diethyl-
carbonate, which are among the ‘‘preferred’’ solvents [15].
The synthesis of arylated heteroaromatics is an
important field for research in organic synthesis due to
the physical or biological properties of these compounds.
In 1990, Ohta et al. reported that the direct arylation of
several heteroaromatics with aryl halides proceed in
moderate to good yields using Pd(PPh3)4 as the catalyst
and DMA (N,N-dimethylacetamide) as the solvent [1]. Since
these very innovative results, the Pd-catalysed direct
arylation of heteroaromatics with aryl halides or pseudo-
halides has been demonstrated to be an extremely
powerful method for the synthesis of a variety of arylated
heterocycles in a few steps [2]. This reaction provides a
cost-effective access to such compounds. Moreover, the
major wastes of the reaction are a base associated with HX
and the reaction solvent, instead of metallic salts produced
under classical cross-coupling procedures, such as Suzuki,
Negishi or Stille reactions [3]. The method avoids the
preliminary preparation of an organometallic compound,
reducing the number of steps necessary to prepare these
compounds. However, these coupling reactions are gen-
erally performed using large amounts of relatively toxic
solvents, such as DMA, DMF, NMP, or dioxane [4–6]. In
recent years, a few solvents that can be considered as
‘‘greener’’[7] according to P. Anastas’ principles have been
employed for direct arylations [8]. For example, Greaney
and Djakovitch reported that, using water as a solvent, the
direct arylation of oxazoles, thiazoles, indazoles, or indoles
The use of CPME as a solvent presents several
advantageous features, such as a high hydrophobicity.
Its limited miscibility in water allows an easy separation
and recovery from water. Another preferable characteristic
is the low formation of peroxides compared to THF or
diisopropyl ether. Moreover, CPME can be manufactured
by the addition of MeOH to cyclopentene, which produces
no apparent waste [16]. Pentan-1-ol is not considered a
hazardous air-pollutant solvent, is readily biodegradable
and practically non-toxic to fish and aquatic organisms.
Pentan-1-ol can be prepared by the reduction of 1-
valeraldehyde with hydrogen or by fermentation and is
present in cider, beer or wine to varying degrees. Therefore,
exposure to residual amounts of this alcohol is unlikely to
have any adverse health effects. Diethylcarbonate is a
polar, aprotic, non-toxic, and biodegradable solvent
[17]. Based on these properties, it also offers an envir-
onmentally friendly alternative to standard polar solvents.
Therefore, the use of CPME, pentan-1-ol or diethylcarbo-
nate as solvents is in agreement with the principles 1, 5 and
12 of ‘‘green chemistry’’ [7].
We have recently reported that the phosphine-free
Pd(OAc)2 catalyst promotes very efficiently the direct
arylation of some heteroaromatics in DMA [18]. We
initially employed this phosphine-free procedure in order
to determine the influence of the amount and nature of the
solvent for Pd-catalysed direct arylations. A first set of
reactions using thiophene 2-carbonitrile (0.75 mmol) and
4-bromoacetophenone (0.5 mmol) as the coupling part-
ners was carried out under previously reported reaction
conditions [18], but in 4, 1 or 0.5 mL of solvent with only
0.1 mol% Pd(OAc)2 catalyst (Table 1, column 3). In the
presence of polar solvents, DMA, NMP and DMF, high
conversions of 4-bromoacetophenone and yields of cou-
pling product 1 were obtained (Table 1, entries 1–3, 5–7
and 9–11 in column 3). The use of 0.1 mL of these three
solvents (concentration 5 M) and again 0.1 mol% Pd(OAc)2
catalyst led to lower conversion rates of 4-bromoaceto-
phenone of 36, 30 and 66% (Table 1, entries 4, 8 and 12 in
column 3). Then, we employed 0.1–4 mL of pentan-1-ol,
diethylcarbonate or CPME as the solvent and again
0.1 mol% Pd(OAc)2 catalyst. In all cases, poor conversions
of 4-bromoacetophenone were obtained (Table 1, entries
13–24 in column 3). The use of a higher catalyst loading of
0.5 mol% Pd(OAc)2 catalyst was found to increase the
conversion of 4-bromoacetophenone for the reactions
performed in 0.1 mL of DMA or NMP (Table 1, entries 4 and
8 in column 4), whereas it was not profitable for reactions
performed in pentan-1-ol and less profitable for reactions
performed in diethylcarbonate (Table 1, entries 14–16, 19,
and 20 in column 4). With this ligand-free catalyst, under
higher palladium concentrations, the so-called ‘‘palladium
black’’ forms more rapidly when pentan-1-ol or diethyl-
carbonate are used as the solvents. Therefore, the
concentration of active palladium species is not increased,
and the conversions of 4-bromoacetophenone are not
improved. This ligand-free procedure has to be employed
only with solvents that display coordination properties
with palladium. Therefore, in order to obtain higher yields
´
proceeds nicely [9]. Rene and Fagnou employed a mixture
of water and EtOAc for the direct arylation of thiophenes
[10a]. Polyethylene glycol (PEG 20000) has been found to
promote the direct arylation of triazoles [10b]. Carbonates,
ethers or alcohols have also been successfully employed
for the direct arylation of some heteroaromatics [11]. The
ruthenium-catalysed direct arylation of 2-arylpyridines in
carbonates or water has been reported by Fischmeister,
Dixneuf et al. [12].
Waste prevention is a major requirement in current
organic synthesis. One of the most promising approaches
to reduce the formation of wastes is solvent-free reactions
or highly concentrated reaction media [13,14]. Such
conditions make syntheses easier due to the reduction
in reactor size and to simpler work-up, as there is less
solvent to eliminate at the end of the reaction. Therefore,
the use of such conditions for Pd-catalysed direct
arylations would be environmentally attractive for the
preparation of arylated heteroarenes.
To our knowledge, the influence of the reaction
concentration using various solvents for the palladium-
catalysed direct arylation of heteroaromatics has not yet
been studied. Herein, we wish to report on the palladium-
catalysed direct arylations of a range of heteroaromatic
derivatives with an aryl bromide, using a set of solvents
under various reaction concentrations.
2. Results and discussion
For this study, six solvents were employed. DMA and
DMF, which are classified as ‘‘undesirable’’ solvents for
industrial application, NMP, which is ‘‘usable’’, and also

1186
S. Bensaid, H. Doucet / C. R. Chimie 17 (2014) 1184–1189
Table 1
Influence of the solvent nature and of the concentration on the Pd-catalysed 5-arylation of thiophene 2-carbonitrile with 4-bromoacetophenone.
O
[Pd]
NC
O
S
+
Br
NC
KOAc, 150 °C, 6h
S
1
Entry
Solvent (mL)
Pd(OAc)2
(0.1 mol%)
Conv. (%)
Pd(OAc)2
(0.5 mol%)
Conv. (%)
PdCl(C3H5)(dppb)
(0.1 mol%)
PdCl(C3H5)(dppb)
(0.5 mol%)
Conv. (%)
Conv. (%)
1
DMA (4)
DMA (1)
DMA (0.5)
DMA (0.1)
NMP (4)
100 (88)
2
100
3
100 (85)
4
36
74
63
42
54
100 (82)
5
73
6
NMP (1)
100
7
NMP (0.5)
NMP (0.1)
DMF (4)
100 (83)
8
30
9
100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DMF (1)
100
DMF (0.5)
DMF (0.1)
100 (80)
66
0
25
Pentan-1-ol (4)
Pentan-1-ol (1)
Pentan-1-ol (0.5)
Pentan-1-ol (0.1)
19
19
12
0
3
8
9
48
39
100 (76)
97
Diethylcarbonate (4)a
Diethylcarbonate (1)a
0
62
Diethylcarbonate (0.5)a
3
4
68 (56)
60
Diethylcarbonate (0.1)a
15
0
24
Cyclopentyl methyl ether (4)b
Cyclopentyl methyl ether (1)b
Cyclopentyl methyl ether (0.5)b
Cyclopentyl methyl ether (0.1)b
0
15
100 (81)
84
5
10
67
Conditions: 4-bromoacetophenone (0.5 mmol), thiophene 2-carbonitrile (0.75 mmol), KOAc (1 mmol), 6 h, 150 8C, isolated yield in parentheses.
a
Reaction temperature: 130 8C.
Reaction temperature: 125 8C.
b
Table 2
Influence of the solvent nature and of the concentration on the Pd-catalysed 5-arylation of ethyl 2-methylfuran-3-carboxylate with 4-bromoacetophenone.
EtO2C
EtO2C
O
[Pd]
O
O
+
Br
O
KOAc, 150 °C, 6h
2
Entry
Solvent (mL)
Pd(OAc)2
(0.1 mol%)
Conv. (%)
Pd(OAc)2
(0.5 mol%)
Conv. (%)
PdCl(C3H5)(dppb)
(0.1 mol%)
PdCl(C3H5)(dppb)
(0.5 mol%)
Conv. (%)
Conv. (%)
1
DMA (1)
100
2
DMA (0.5)
DMA (0.1)
NMP (1)
100 (87)
3
14
79
58
11
100
57
4
100
42
100 (82)
4
100
5
NMP (0.5)
NMP (0.1)
DMF (1)
100 (85)
100
6
7
8
DMF (0.5)
DMF (0.1)
100 (82)
47
9
100 (80)
100 (81)
10
11
12
13
14
15
16
17
18
Pentan-1-ol (1)
Pentan-1-ol (0.5)
Pentan-1-ol (0.1)
41
34
3
40
0
26
2
Diethylcarbonate (1)a
0
6
Diethylcarbonate (0.5)a
Diethylcarbonate (0.1)a
Cyclopentyl methyl ether (1)b
Cyclopentyl methyl ether (0.5)b
Cyclopentyl methyl ether (0.1)b
0
2
2
32
10
0
2
7
100 (76)
4
0
1
0
0
2
23
5
0
5
100 (84)
Conditions: 4-bromoacetophenone (0.5 mmol), ethyl 2-methylfuran-3-carboxylate (0.75 mmol), KOAc (1 mmol), 6 h, 150 8C, isolated yield in parentheses.
a
Reaction temperature: 130 8C.
Reaction temperature: 125 8C.
b

S. Bensaid, H. Doucet / C. R. Chimie 17 (2014) 1184–1189
1187
Table 3
Influence of the solvent nature and of the concentration on the Pd-catalysed 2-arylation of 1-methylpyrrole with 4-bromoacetophenone.
O
[Pd]
O
N
+
Br
N
KOAc, 150 °C, 6h
3
Entry
Solvent (mL)
Pd(OAc)2
(0.1 mol%)
Conv. (%)
Pd(OAc)2
(0.5 mol%)
Conv. (%)
PdCl(C3H5)(dppb)
(0.5 mol%)
Conv. (%)
1
DMA (1)
100
2
DMA (0.5)
100 (78)
3
DMA (0.1)
97
4
NMP (1)
100
5
NMP (0.5)
100 (75)
6
NMP (0.1)
100
7
DMF (1)
100
8
DMF (0.5)
100 (76)
9
DMF (0.1)
48
24
15
4
89
34
21
4
10
11
12
13
14
15
16
17
18
Pentan-1-ol (1)
Pentan-1-ol (0.5)
Pentan-1-ol (0.1)
Diethylcarbonate (1)a
Diethylcarbonate (0.5)a
Diethylcarbonate (0.1)a
Cyclopentyl methyl ether (1)b
88 (61)
4
3
3
3
28
6
5
100 (66)
2
0
Cyclopentyl methyl ether (0.5)b
Cyclopentyl methyl ether (0.1)b
1
3
3
4
Conditions: 4-bromoacetophenone (0.5 mmol), 1-methylpyrrole (1.5 mmol), KOAc (1 mmol), 6 h, 150 8C, isolated yield in parentheses.
a
Reaction temperature: 130 8C.
Reaction temperature: 125 8C.
b
with pentan-1-ol, diethylcarbonate or CPME solvents, we
employed 0.1 or 0.5 mol% PdCl(C3H5)(dppb) as the catalyst.
In pentan-1-ol, much better results were obtained, even in
the presence of only 0.1 mL of solvent (concentration 5 M)
(Table 1, entries 14–16 in columns 5 and 6). For reactions in
diethylcarbonate, similar conversions of 60–68% of 4-
bromoacetophenone were obtained using 1, 0.5 or 0.1 mL
of solvent and 0.5 mol% PdCl(C3H5)(dppb) (Table 1, entries
18–20 in column 6). For the reactions in CPME, the best
results were obtained using 1 or 0.5 mL of solvent (Table 1,
entries 22–24 in column 6). In summary, the phosphine-
free procedure can be employed with DMA, NMP and DMF
as the solvents, whereas the use of PdCl(C3H5)(dppb)
of 0.5 mol% PdCl(C3H5)(dppb) catalyst and 0.1 or 0.5 mL in
these solvents led to good yields of 2 (Table 2, entries 11,
15 and 18, column 6). It should be noted that, for this
reaction, with diethylcarbonate or CPME as the solvent,
better results were obtained in more concentrated reaction
mixtures (5 M or 1 M > 0.5 M).
Finally, the 2-arylation of 1-methylpyrrole with 4-
bromoacetophenone was studied using again various
amounts of the six solvents (Table 3). The use of 0.1,
0.5 or 1 mL of DMA, NMP or DMF for reaction of 0.5 mmol of
4-bromoacetophenone inthe presenceof0.1 mol%Pd(OAc)2
catalyst led to very high or complete conversions of the
starting material, in most cases (Table 3, entries 1–8). A
moderate conversion of 4-bromoacetophenone was
observed in 0.1 mL of DMF, and 0.5 mol% Pd(OAc)2 catalyst
had to been employed to obtain a high conversion of the aryl
bromide (Table 3, entry 9). As expected, the use of 0.1 or
0.5 mol% of phosphine-free Pd(OAc)2 catalyst in CPME,
pentan-1-ol or diethylcarbonate was ineffective, whereas
high or complete conversions were obtained in 0.1 mL of
pentan-1-ol or diethylcarbonate in the presence of 0.5 mol%
PdCl(C3H5)(dppb) catalyst (Table 3, entries 10–18).
catalyst
[dppb:
1,4-bis(diphenylphosphino)butane]
appears to be more reliable for reactions in pentan-1-ol,
diethylcarbonate or CPME. For most of these solvents,
reaction concentrations of 1 M can be employed.
Then, we studied the 5-arylation of a furan derivative
with these six solvents at different concentrations (Table
2). In general, furan derivatives are less reactive than
thiophenes for Pd-catalysed direct arylations [11e]. With
1 mL of DMA, NMP or DMF, 0.5 mmol of 4-bromoaceto-
phenone (concentration 0.5 M) and 0.1 mol% Pd(OAc)2
catalyst, high or complete conversions of 4-bromoaceto-
phenone were observed (Table 2, entries 1, 4 and 7, column
3). On the other hand, the use of only 0.1 mL of solvent for
0.5 mmol of aryl bromide (concentration 5 M) led to poor
conversions in these three solvents (Table 2, entries 3,
6 and 9, column 3). Again, the reactions performed in
pentan-1-ol, diethylcarbonate or CPME using Pd(OAc)2
catalyst led to low conversions of 4-bromoacetophenone
(Table 2, entries 10–18, columns 3 and 4), whereas the use
3. Conclusion
In summary, these results demonstrate that the direct
arylation of heteroaromatics can be performed with highly
concentrated reaction mixtures (up to 5 M). However, the
nature and loading of the catalyst has to be tuned
according to the solvent. For reactions in DMA, NMP or
DMF, a low loading (0.1–0.5 mol%) of a phosphine-free
catalyst promotes the coupling in high yields. On the other

1188
S. Bensaid, H. Doucet / C. R. Chimie 17 (2014) 1184–1189
hand, the palladium catalyst associated with a phosphine
ligand should be preferred for the reactions performed in
CPME, pentan-1-ol or diethylcarbonate. These results
demonstrate that most of these couplings proceed nicely
using highly concentrated reaction mixtures, even in some
solvents that are considered as ‘‘green’’. Such reactions
conditions allow industrially viable processes, as they
reduce the hazards and toxicity associated with the use of
solvents, reduce wastes costs, and simplify the separation
procedure at the end of the reaction.
Acknowledgements
We thank the CNRS and ‘‘Rennes Metropole’’ for
providing financial support.
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