Di(2-pyridyl)methylamine-palladium dichloride complex covalently anchored to a styrene-maleic anhydride co-polymer as recoverable catalyst for C-C cross-coupling reactions in water

Article abstract of DOI:10.1016/j.tet.2005.08.122

A new polymer-supported di(2-pyridyl)methylamine-palladium dichloride complex covalently anchored to a styrene-alt-maleic anhydride co-polymer is prepared. This complex catalyzes Heck, Suzuki and Sonogashira cross-coupling reactions in neat water with sim

Full text of DOI:10.1016/j.tet.2005.08.122

Tetrahedron 61 (2005) 12168–12176
Di(2-pyridyl)methylamine–palladium dichloride complex
covalently anchored to a styrene-maleic anhydride co-polymer as
recoverable catalyst for C–C cross-coupling reactions in water
Juan Gil-Molt o´ , Sofia Karlstr o¨ m and Carmen N a´ jera
*
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias and Instituto de S ´ı ntesis Org a´ nica (ISO), Universidad de Alicante, Apartado 99,
3080 Alicante, Spain
0
Received 14 July 2005; revised 4 August 2005; accepted 4 August 2005
Available online 25 October 2005
Abstract—A new polymer-supported di(2-pyridyl)methylamine–palladium dichloride complex covalently anchored to a styrene-alt-maleic
anhydride co-polymer is prepared. This complex catalyzes Heck, Suzuki and Sonogashira cross-coupling reactions in neat water with similar
4
efficiency than the monomeric complex. The turnover number (TON) of this polymer reaches up to 10 for Heck reactions, whereas for
5
Suzuki and Sonogashira couplings TONs up to 10 are achieved. There is low leaching of palladium after filtration of the polymer and the
activity remains almost constant after fourth and five reaction cycles especially in Sonogashira reactions. In the case of the Suzuki reaction Pd
nanoparticles are dispersed into the polymer after the first cycle according to TEM images and 2.4% of Pd are found by ICP-OES in the
corresponding filtrate. Alternatively, these palladium-catalyzed reactions can also be performed under microwave heating. These couplings
take place with better efficiency with polymer-supported di(2-pyridyl)methylamine–palladium dichloride complex than with the polyurea-
encapsulated Pd EnCate 40.
q 2005 Elsevier Ltd. All rights reserved.
1
from palladium–phosphine complexes, palladacycles,
4
15
1
. Introduction
1
and N-heterocyclic carbene complexes, have been used in
6
1
3
Palladium-catalyzed cross-coupling reactions have become
1
a major area of interest in organic chemistry. From the
environmental point of view several practical and economi-
cal aspects of these reactions have to be developed for their
industrialization. The use of water as solvent has important
advantages in large-scale processes due to nontoxic,
aqueous media and in neat water, mainly in Heck and
Suzuki reactions. The leaching of palladium from the solid
support and the lower reactivity in comparison with related
homogeneous catalysis are important problems when
employing these type of strategies.
2
nonflammable and inexpensive features. Additionally, the
Dipyridyl- and dipyrimidyl-based ligands 1 and 2 showed
excellent properties for palladium complexation and have
proven to beefficientcatalysts for C–C and C–N bondforming
3
recovery and recycling of the precious expensive catalyst
and its complete removal from the products constitute
1
7
4
essential problems to be solved. Several methodologies
reactions. When this type of complexes were covalently
anchored to a polymeric matrix resulting from a ROMP
polymerization, the resulting PdCl complexes 3 present
have been developed to remove and recover the catalyst
from the reaction medium, the filtration of a heterogeneous
catalyst being the most simple procedure. The palladium
2
similar or even higher catalytic activity than the monomeric
ones and no leaching of palladium being observed in organic
solvents. We have recently chosen dipyridyl-based ligands
derived from di(2-pyridyl)methylamine in order to have a
primary amino group, which could be more easily anchored to
a polymeric support than the di(2-pyridyl)amine used by
5
metal, salt or complex can be for instance encapsulated,
6
7
incarcerated, or entrapped in sol–gels, inorganic sup-
8
ports, block co-polymer matrices, dendrimers, and PEG-
9
10
1
1
resins. The preparation of covalently supported palladium
catalysts either based on polymer or on silica gel-anchored
ligands has experienced an important development in the
1
7
Buchmeiser et al. The corresponding PdCl complexes 4
2
1
2
have shown as versatile catalysts for Heck, Suzuki, and
last decade. Some of these supported catalysts, derived
1
8
Sonogashira reactions in organic and aqueous solvents.
Hereinwereportthepreparationofanovel polymer-supported
di-(2-pirydyl)methylamine-based PdCl complex covalently
Keywords: Heck reaction; Suzuki reaction; Sonogashira reaction;
Supported-catalyst; Water.
Corresponding author. Fax: C34 96 5903549; e-mail: cnajera@ua.es
2
1
9
*
anchored to a poly(styrene-alt-maleic anhydride) resin 5.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.122

J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
12169
This polymer has been widely used by our group for the
preparation of different polymer-supported N-hydroxysucci-
nimide-derived reagents presenting good mechanical stability
spectrometry (ICP-OES) revealed that resin 8 contained
an average of 1.2 mmol/g of Pd, which supposes that ca.
46% of the di-(2-pyridyl)methylamine ligand participated in
20
and solubility (Fig. 1)
the formation of the PdCl complex. The FT-IR spectra of
2
polymeric ligand 7 and complex 8 are rather similar
showing a sharp band at 1705 and 1712 cm , respectively,
for the imide carbonyls.
K1
2
2
2.2. Use of the polymer-supported palladium complex 8
in cross-coupling reactions
The systematic study of the catalytic activity of the
polymer-supported Pd-dipyridyl complex 8 for Heck,
Suzuki, and Sonogashira reactions was investigated using
water as solvent and compared with the same processes
1
8
carried out with the monomeric complex 4b. In addition,
the stability, recovery and leaching of the heterogeneous
catalyst were studied in all these processes under aqueous
conditions. Recycling experiments have been also carried
out with the commercially available polyurea-encapsulated
5
,23
[Pd EnCat 40e]
obtained with the polymeric complex 8.
in order to compare with the results
2.2.1. Heck reactions. Heck couplings were carried out
with tert-butyl acrylate or styrenes as olefinic substrates and
aryl halides. The reactions were performed in neat water as
solvent with diisopropylamine as base in the presence of
tetra-n-butylammonium bromide (TBAB, 0.5 equiv)
Figure 1.
(
Scheme 2 and Table 1). The presence of TBAB in
Pd-catalyzed cross-coupling reactions, especially in Heck
reactions, increase the conversion rate by formation and
2
. Results and discussion
2
4
stabilization of Pd colloids. The arylation of tert-butyl
acrylate and 4-chlorostyrene with 4-chloroiodobenzene in
the presence of the polymeric complex 8 gave higher yields
in similar or shorter reaction times than the monomeric 4b
2.1. Synthesis of the polymer-supported palladium
complex
The polymer-supported ligand 7 was prepared by reaction of
poly(styrene-alt-maleic anhydride) resin 5 with di-(2-
(
lowered down to 10 mol% of Pd but the temperature must
Table 1, entries 1–6). The loading of both catalyst can be
1
9
K2
1
8b,21
pyridyl)methylamine (6)
(
in a mixture of acetone–water
1/2) under reflux for 1 day (Scheme 1). Elemental analyses
be raised to 140 8C to get full conversion after more than
1
day reaction time (Table 1, entries 5 and 6). Similar
of three different batches of supported-ligand 7 showed
similar nitrogen content in the range of 10.38–11.40%,
revealing a rather high ligand loading (average 2.6 mmol/g).
For the preparation of the palladium complex 8 a 0.5 M
processes with aryl bromides must to be performed at higher
temperature and loading of catalyst (Table 1, entries 7–10).
In the coupling between 4-chlorobromobenzene and tert-
butyl acrylate quantitative yields were obtained at 160 8C
with both catalysts (Table 1, entries 7 and 8). In case of the
arylation of styrene with 4-bromoacetophenone the reaction
was faster with the monomeric catalyst 4b (Table 1, entries
methanolic solution of Na PdCl (ca. 2 equiv) was mixed
2
4
with the polymer 7 and stirred for 2 days at room
temperature. Elemental analysis of the corresponding
three different batches of complex 8 gave a 5.84–6.20% of
N content. Inductive coupled plasma-optic emission
9
1
and 10). This reaction can be performed alternatively at
00 8C under microwave heating in 10 min in good yields
(Table 1, entries 11 and 12). However, the vinylation of aryl
chlorides under this reaction conditions failed.
Scheme 2.
Recycling and leaching experiments were assayed for the
arylation of tert-butyl acrylate and 4-chlorostyrene with
4-chlorophenyl iodide using complex 8 (0.1 mol% Pd) at
Scheme 1.

1
2170
J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
complexes
a
Table 1. Heck reactions with polymeric 8 and monomeric 4b di(2-pyridyl)methylamine-based PdCl
2
b
Entry
X
Y
R
Cat. (mol% Pd)
T (8C)
t
Yield (%)
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH
CH
CH
CH
CO
CO
4-ClC
4-ClC
4-ClC
4-ClC
2
-t-Bu
-t-Bu
8 (0.1)
4b (0.1)
8 (0.1)
4b (0.1)
8 (0.01)
4b (0.01)
8 (0.1)
4b (0.1)
8 (0.5)
4b (0.5)
8 (0.1)
4b (0.1)
100
100
100
100
140
140
160
160
100
100
100 (MW)
100 (MW)
14 h
1 d
2 d
1 d
38 h
31 h
2 d
99
98
99
78
97
95
99
99
85
99
80
96
2
6
6
6
6
H
H
H
H
4
4
4
4
CO
CO
2
-t-Bu
-t-Bu
2
2 d
3
3
3
3
CO
CO
CO
CO
C
6
C
6
C
6
C
6
H
H
H
H
5
5
5
5
6.5 h
4.5 h
10 min
10 min
10
11
12
a
2 2
Reaction conditions: aryl halide (1 mmol), alkene (1.5 mmol), i-Pr NH (3 mmol), TBAB (0.5 mmol), Pd complex and H O (2 mL).
Determined by GLC using decane as internal standard.
b
8
0 8C instead under reflux in order to prevent degradation of
2.2.2. Suzuki reactions. The cross-coupling between
phenylboronic acid and aryl bromides such as 4-bromo-
acetophenone and 4-bromophenol were carried out with
K CO as base under water reflux and in aqueous MeOH
the polymer (Table 2, entries 1 and 2). The same catalyst
batch was isolated by filtration (G-5) from the reaction
medium and reused in 4 consecutive coupling reactions and
only extended reaction time was observed after the first run
in the case of tert-butyl acrylate (Table 2, entry 1). When the
2
3
either at 60 8C or at room temperature using KOH as base
(Scheme 3 and Table 3). The cross-coupling of 4-bromo-
acetophenone with phenylboronic acid under water reflux
took place with similar TON using the polymeric 8 and the
monomeric 4b catalysts either with 0.1 or 0.001 mol%
5
,23
polyurea-encapsulated [Pd EnCat 40e]
(0.1 mol% Pd)
was used as catalyst for the coupling between 4-chloro-
iodobenzene and 4-chlorostyrene, a similar behaviour than
complex 8 was observed after three cycles (Table 2,
compare entries 2 and 3). Catalytic cycles for the arylation
of tert-butyl acrylate and styrene with 4-bromoaceto-
phenone were also carried out with complex 8 (1 and
K1
5
loading of Pd and slightly higher TOF (TON!h ) of 10
K1
(h ) with the polymeric complex (Table 3, entries 1–4).
The same results were obtained with both complexes when
couplings were performed in aqueous MeOH at 60 8C
(Table 3, entries 5 and 6). In the case of the cross-coupling
of 4-bromophenol with phenylboronic acid, no differences
were observed with both complexes 8 and 4b under the three
essayed reaction conditions (Table 3, entries 7–12). When
4-chloroacetophenone was coupled with phenylboronic acid
under water reflux with K CO as base, TBAB (0.5 equiv)
0
.5 mol% of Pd, respectively) at 100 8C (Table 2, entries 4
and 5). In the case of tert-butyl acrylate the reaction time
increased after the first run and it was maintained in the next
three consecutive cycles. In all cases, yields remained
almost constant, however, in the arylation of styrene the
yield decreased after the third run. Apparently, no leaching
of Pd was observed because filtrates did not show catalytic
activity in any case. When the arylation of styrene with
2
3
was added (Table 3, entries 13–16). In this case a higher Pd
loading had to be used for the polymeric complex 8
(4.5 mol% Pd) than for the momomeric 4b (0.1 mol% Pd).
Under microwave heating 56 and 88% yield were obtained
for the same catalyst loading (0.1 mol% Pd) when the
4
-bromoacetophenone was performed under microwave
heating degradation of the polymer and leaching of
palladium was observed.
TM
Table 2. Heck reactions with polymer 8 and Pd EnCat 40 over 3 or 4 cycles
a
Entry
ArX
Alkene
Cat.
(
T
(8C)
Cycle 1
Cycle 2
Yield t (h)
Cycle 3
Yield t (h)
Cycle 4
Yield t (h)
mol% Pd)
t (h)
Yield
b
(%)
b
b
b
(
%)
(%)
99
99
91
85
91
(%)
89
99
95
88
59
c
1
2
3
4
CH
]CHCO -t-Bu
2 2
8 (0.1)
80
7
99
99
99
99
85
24
24
15
21
22
38
24
23
22
40
38
92
c
4-ClC
6
6
H
H
4
CH]CH
2
2
8 (0.1)
80
24
15
6
d
4-ClC
4
CH]CH
Pd EnCat (0.1)
100
100
100
d
CH
]CHCO -t-Bu
2 2
8 (1)
22
82
e
5
C
6
H
5
CH]CH
2
8 (0.5)
6
a
2 2
Reaction conditions: aryl halide (1 equiv), alkene (1.5 equiv), i-Pr NH (3 equiv), TBAB (0.5 equiv), Pd complex and H O (2 mL/equiv).
Determined by GLC using decane as internal standard.
Scale (3 mmol).
Scale (1 mmol).
Scale (2 mmol).
b
c
d
e

J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
12171
Scheme 3.
a
2
Table 3. Suzuki reactions with polymeric 8 and monomeric 4b di(2-pyridyl)methylamine-based PdCl complexes
Entry
X
Y
Cat.
mol% Pd)
Solvent
Base
T (8C)
t
Yield
b
(%)
(
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
CH
CH
CH
CH
CH
CH
HO
HO
HO
HO
HO
HO
3
3
3
3
3
3
CO
CO
CO
CO
CO
CO
8 (0.1)
H
H
H
H
2
2
2
2
O
O
O
O
K
K
K
K
KOH
KOH
K
K
KOH
KOH
KOH
KOH
2
2
2
2
CO
CO
CO
CO
3
3
3
3
100
100
100
100
60
1 h
30 min
1 h
75 min
1 h
30 min
30 min
40 min
30 min
30 min
6 d
5 d
7 h
6 h
5 min
5 min
99
98
99
99
99
99
88 (82)
99 (87)
94
99
86
75
99
68
56
88
4b (0.1)
8 (0.001)
4b (0.001)
8 (0.1)
4b (0.1)
8 (0.1)
4b (0.1)
8 (0.1)
4b (0.1)
8 (0.1)
4b (0.1)
8 (4.5)
4b (0.1)
8 (0.1)
4b (0.1)
c
c
MeOH/H
MeOH/H
H
H
MeOH/H
MeOH/H
MeOH/H
MeOH/H
H
H
H
H
2
O
O
2
60
2
O
O
2
CO
CO
3
3
100
100
60
2
2
c
c
c
c
2
2
2
2
O
O
O
O
1
1
1
1
1
1
1
0
1
2
3
4
5
6
60
Room temperature
Room temperature
100
100
120 (MW)
120 (MW)
d
d
d
d
CH
CH
CH
CH
3
CO
CO
CO
CO
2
O
2
O
2
O
2
O
K
K
K
K
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
a
b
c
d
2 2
Reaction conditions: aryl halide (1 mmol), PhB(OH) (1.5 mmol), base (2 mmol), Pd complex, and H O (2 mL).
Determined by GLC using decane as internal standard. In parenthesis isolated yield after flash chromatography.
Volume ratio 2/3.
TBAB (0.5 mmol) was added.
reaction was carried out with complex 8 at 100 8C and
monomeric complex 4b at 120 8C, respectively (Table 3,
entries 15 and 16).
The recovery of the polymeric complex 8 was studied for
the cross-coupling of phenylboronic acid with 4-bromo-
acetophenone and 4-bromophenol under different reaction
TM
Table 4. Suzuki cross-coupling reactions between phenylboronic acid and aryl halides with polymer 8 and Pd EnCat 40 over 2, 3, 4 or 5 cycles
a
Entry
ArX
Cat.
(
T
(8C)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
mol% Pd)
t (h)
Yield
b
t (h)
Yield
b
(%)
t (h)
Yield
b
(%)
t (h)
Yield
b
(%)
t (h)
Yield
b
(%)
(
%)
c
d
1
2
8 (0.1)
100
1.5
2
99
88
99
80
94
76
2
99
80
99
98
73
41
2.5
93
c
d
Pd EnCat (0.1)
8 (0.1)
100
2
e
3
f
60
1
1.5
7
2
99
97
93
39
2.5
7
99
94
92
49
g
4
f
8 (0.1)
60
7
7
h
f
5
8 (0.1)
60
0.5
3
2
3
3
i,j
d
6
8 (4.4)
130
14
14
15
15
47
a
2 2
Reaction conditions: aryl halide (1 equiv), PhB(OH) (1.5 equiv), base (2 equiv), Pd complex, and H O (2 mL/equiv).
b
c
d
e
f
Determined by GLC using decane as internal standard.
Scale (2 mmol).
In H
The cycles were performed in situ without filtration of the polymer 8.
In MeOH/H O and KOH as base.
2 2 3
O and K CO as base.
2
g
h
i
The catalyst was recovered by filtration from the previous cycles of entry 3 and the new 4 cycles were performed in situ without filtration of the polymer 8.
Scale (3 mmol).
Scale (1 mmol).
j
2 2 3
In H O, K CO as base and in the presence of TBAB.

12172
J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
Figure 2. TEM images of the catalyst 8 before (left) and after (right) the first cycle of the Suzuki reaction (Table 4, entry 1).
conditions (Table 4). Slight variations were observed in the
case of 4-bromoacetophenone under water reflux conditions
when the catalyst was filtered off after three catalytic cycles
2.2.3. Sonogashira reactions. For the alkynylation of aryl
iodides and bromides, a Sonogashira–Cassar–Heck copper-
free protocol, set up recently by our group using complex 4b
1
8c
(
Table 4, entry 1). However, comparative recycling studies
and PdCl as catalysts was used. The cross-coupling of
2
using Pd EnCat 40 (0.1 mol% Pd) in the cross coupling
between phenylboronic acid and 4-bromoacetophenone
under water reflux revealed lower yields, longer reaction
times, and only 30% yield being obtained in the second run
with total deactivation of the catalyst (Table 4, entry 2).
Transmission electron microscopy (TEM) analysis of the
polymer 8 before and after the 1st Suzuki coupling between
activated and deactivated iodides and bromides with
phenylacetylene and triisopropylsilylacetylene was per-
formed with pyrrolidine (2 equiv) as base and TBAB as
additive under water reflux (Scheme 4 and Table 5). For aryl
iodides 0.1 mol % of Pd was employed with the polymeric 8
and the monomeric 4b catalysts, whereas for aryl bromides
a higher loading (0.2 mol% of Pd) gave better conversions.
It is worthy to note that in general better efficiency,
concerning yield and reaction rate, was observed for the
polymeric than for the monomeric complex. In addition, the
formation of secondary products from dimerization of the
alkyne decreased when the polymer was used as catalyst.
4
-bromoacetophenone and phenylboronic acid in the
absence of TBAB (Table 4, entry 1) showed the formation
of some Pd nanoparticles (7–10 nm) in the surface of the
polymer (Fig. 2). The filtrate of this reaction was analyzed
by ICP-OES giving a low Pd leaching (2.4%).
K3
The Pd loading could be decreased to 10 mol% in the
cross-coupling of phenylacetylene and 4-chloroiodo-
benzene but longer reaction times were necessary in order
to get full conversion (Table 5, entries 1 and 3). Under these
For the recycling experiments in aqueous MeOH at 60 8C
fourth consecutive cycles were performed in the same flask
just adding all reagents with similar quantitative yields in
low Pd loading the polymer 8 showed a higher efficiency
(
1
–2.5 h (Table 4, entry 3). Then the polymer was filtered off
K1
TOF 3225 h ) than when using the monomer 4b (TOF:
and again fourth cycles were carried out in situ observing in
this case that the reaction needed longer reaction times, 7 h
in order to obtain 80–98% yield in each run (Table 4,
entry 4).
K1
30 h ) (Table 5, entries 3 and 4). Under microwave
7
heating the coupling between phenylacetylene and 4-chloro-
bromobenzene gave variable yields in the case of polymer 8
(between 13 and 47%) and lower than the monomer 4b
(
Table 5, entries 11 and 12).
The recycling experiments for the cross-coupling of
4-bromophenol and phenylboronic acid were studied using
KOH as base in aqueous MeOH at 60 8C. Under this
reaction conditions the reaction time increased from 0.5 to
3
h in the third run and remained constant for the fourth
cycle (Table 4, entry 5). The catalytic cycles in the case of
-chloroacetophenone were performed in water at 130 8C
using K CO as base and TBAB as additive to give in 3 h
4
2
3
7
6% yield. However, a lower conversion was observed in
Scheme 4.
the second cycle in a longer reaction time. Similar results,
around 39–49% yield in 14–15 h, were observed in four
consecutive cycles (Table 4, entry 6). In all recycling
experiments the filtrate showed no catalytic activity.
For the recycling studies of the polymer, alkynylation of
4-chloroiodobenzene with phenylacetylene was performed
during 5 runs without appreciable lost of catalytic activity

J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
12173
a
Table 5. Sonogashira reactions with polymeric 8 and monomeric 4b di-(2-pyridyl)methylamine-based PdCl
2
complexes
1
R X
2
b
Entry
R
Cat. (mol% Pd)
8 (0.1)
t
Yield (%)
99
1
2
3
4
5
6
7
8
9
Ph
1 h
Ph
4b (0.1)
8 (0.001)
4b (0.001)
8 (0.1)
1 h
99
Ph
31 h
4 d
1 h
99
Ph
70
Ph
96
Ph
4b (0.1)
8 (0.1)
2 h
91
TIPS
TIPS
Ph
3 h
99
4b (0.1)
8 (0.2)
6 h
94
1.5 h
2 h
99
10
11
12
13
14
15
16
Ph
4b (0.2)
8 (0.1)
86
c
Ph
10 min
47
d
Ph
4b (0.1)
8 (0.2)
10 min
66
TIPS
TIPS
Ph
14 h
22 h
1 h
99
4b (0.2)
8 (0.2)
87
92
Ph
4b (0.2)
2 h
90
a
b
c
d
Reaction conditions: aryl halide (1 mmol), alkyne (1.2 mmol), pyrrolidine (2 mmol), TBAB (0.5 mmol), Pd complex, and H
Determined by GLC using decane as internal standard.
The reaction was carried out under microwave heating at 100 8C (0.5 mmol scale).
The reaction was carried out under microwave heating at 120 8C (0.5 mmol scale)
2
O (2.5 mL) reflux.
TM
Table 6. Sonogashira reactions between phenylacetylene and aryl halides with polymer 8 and Pd EnCat 40 over 4 or 5 cycles
a
Entry
ArX
Cat. (mol% Pd) Cycle 1
t (h) Yield
Cycle 2
Cycle 3
Cycle 4
Cycle 5
t (h) Yield
(%)
t (h) Yield
(%)
t (h) Yield
(%)
t (h) Yield
(%)
b
b
b
b
b
(
%)
c
1
2
8 (0.1)
1
99
99
99
99
96
99
1
99
99
99
99
92
99
1
8
1
1
1
2
99
27
99
99
92
88
1
99
1
99
c
Pd EnCat (0.1)
1.5
1
1.5
1
d
3
c
8 (0.1)
1
99
99
94
91
1
99
99
92
93
e
4
c
8 (0.1)
1
1
1
1
c
5
8 (0.1)
1
1
1
1
f
6
8 (0.2)
1.5
1.5
2.5
2.5
a
Reaction conditions: aryl halide (1 mmol), alkyne (1.2 mmol), pyrrolidine (2 mmol), TBAB (0.5 mmol), Pd complex, and H
Determined by GLC using decane as internal standard.
Scale (3 mmol).
The cycles were performed in situ without filtration of the polymer 8.
The catalyst was recovered by filtration from the previous cycles of entry 3 and the new 5 cycles were performed in situ without filtration of the polymer 8.
Scale (2 mmol).
2
O (2.5 mL) reflux.
b
c
d
e
f

12174
J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
(
Table 6, entry 1). However, when recycling studies were
4.2. Synthesis of polymer-supported complex 8
mixture of di(2-pyridyl)methanamine (300 mg,
1.6 mmol) and poly(styrene-alt-maleic anhydride) resin
performed with Pd EnCat 40 (0.1 mol% Pd) for the same
cross-coupling under the same reaction conditions the
catalytic activity was kept only during the two first cycles
A
1
8c
(
Table 6, entry 2). In the case of 4-chloroiodobenzene the
(195 mg) was stirred under reflux during 24 h in H O/
2
coupling was performed in situ during four quantitative
cycles of 1 h by adding the reagents (except TBAB) to the
flask. Then the polymer was filtered off and four more
quantitative cycles were performed again during 1 h without
loss of the catalytic activity (Table 6, entries 3 and 4). The
alkynylation of the deactivated 4-iodoanisol with phenyl-
acetylene gave practically the same yields in 1 h after five
cycles (Table 6, entry 5). Even in the coupling of
acetone (3 mL, 2/1). The solution was cooled to room
temperature and water was added to precipitate the polymer.
The solid was filtered, washed with H O and MeOH and
2
dried under vacuum to yield 288 mg of a pale brown
precipitate of polymer 7. The average loading of amine
(2.61 mmol/g) was determined by means of the nitrogen
content from combustion analysis from three different
batches. Without further purification, the modified polymer
7 (82 mg) was stirred for 2 days in MeOH (1 mL) with a
0.5 M methanolic solution of Na PdCl (0.8 mL, 0.4 mmol).
4
-bromoacetophenone and phenylacetylene good catalytic
activity of the polymer was observed after five consecutive
runs (Table 6, entry 6).
2
4
The mixture was filtered off (G-5) and washed with MeOH.
The product was dried under reduced pressure and placed
into an oven (130 8C) overnight to yield 130 mg of a brown
solid. For the ICP-OES analysis, the resin was decomposed
3. Conclusions
with HNO giving 1.21 mmol/g of Pd.
3
In conclusion, we have found that the new polymer-
supported di(2-pyridyl)methylamine–palladium dichloride
complex covalently anchored to a styrene-alt-maleic
anhydride co-polymer showed similar catalytic activity
than the monomeric palladium complex for Heck, Suzuki
and Sonogashira reactions in water. This polymer maintains
in general their efficiency especially in Sonogashira
reactions through five recycle runs even better than the
encapsulated Pd EnCat 40. The formation of Pd nano-
particles have been detected in the surface of the polymer by
TEM analysis after a Suzuki reaction and 2.4% of Pd
leaching was detected in the corresponding filtrate. On the
other hand, the polymer cannot be recycled after microwave
heating. In general, no appreciable catalytic activity was
detected from the filtrates during recycling processes.
4
.3. General procedure for the Heck reactions
A suspension of aryl halide (1 mmol), alkene (1.5 mmol),
diisopropylamine (0.420 mL, 3 mmol), tetra-n-butyl-
ammonium bromide (161 mg, 0.5 mmol), Pd complex (see
Tables 1 and 2) and H O (2 mL) was stirred at the
2
temperature indicated on Tables 1 and 2 in air, and the
reaction progress was analyzed by GLC. After the reaction
was completed and cooled to room temperature, the mixture
was filtered off through a glass filter (G-5). The filtrate was
extracted with ethyl acetate (3!15 mL) and the organic
layer was dried over MgSO , evaporated (15 mmHg) and
4
the resulting residue purified by flash chromatography.
4
.4. General procedure for the Suzuki reactions in water
A solution of aryl halide (1 mmol), phenylboronic acid
183 mg, 1.5 mmol), potassium carbonate (276 mg,
mmol) tetra-n-butylammonium bromide (161 mg,
4. Experimental
(
2
4
.1. General
0.5 mmol, only for aryl chlorides), Pd complex (see Tables 3
and 4) in H O (2 mL) was stirred under reflux in air, and the
2
The reagents and solvents were obtained from commercial
sources and were generally used without further purifi-
cation. Flash chromatography was performed on silica gel
reaction progress was analyzed by GLC. After the reaction
was completed and cooled to room temperature, the mixture
was filtered off through a glass filter (G-5). The filtrate was
extracted with ethyl acetate (3!10 mL), the organic phases
were dried over MgSO , and evaporated (15 mmHg). The
4
subsequent residue was purified by recrystallization or by
flash chromatography on silica gel to give pure products.
6
0 (0.040–0.063 mm, Merck). Thin-layer chromatography
w
was performed on Polygram SIL G/UV254 plates. Gas
chromatographic analyses were performed on a HP-6890
instrument equipped with a WCOT HP-1 fused silica
capillary column. IR data were collected on a Nicolet
K1
Impact-400D-FT spectrophotometer in cm . ICP-OES
4.5. General procedure for the Suzuki reactions in
methanol/water
analyses were performed with a Perkin-Elmer Optima 4300.
TEM analyses were performed with a JEOL JSM-840 and
examples were dried, sonicated in hexane and supported on
a carbon-coated copper grid. Elemental analyses were
carried out by the corresponding services at the University
of Alicante. The amounts of catalysts were weighed up in an
electronic microscale (Sartorius, XM1000P) with precision
of 1 mg. Microwave reactions were performed with a CEM
Discover Synthesis Unit in glass vessels (10 mL) sealed
with a septum under magnetic stirring at the temperature
indicated on Tables 1, 3, and 5. All products have been
A mixture of aryl halide (1 mmol), phenylboronic acid
(183 mg, 1.5 mmol), potassium hydroxide (112 mg,
2 mmol), Pd complex (see Tables 3 and 4) and methanol/
water: 2/3 (2.5 mL) was stirred at room temperature or at
60 8C (see Tables 3 and 4) and the reaction progress was
analyzed by GC. After the reaction was completed and
cooled to room temperature, the mixture was filtered off
through a glass filter (G-5). When the product was not
soluble in the solvent mixture the solid was dissolved in
ethyl acetate. The filtrate was extracted with ethyl acetate
1
8
previously described.

J. Gil-Molt o´ et al. / Tetrahedron 61 (2005) 12168–12176
12175
(3!10 mL), the organic phases were dried over MgSO4,
evaporated (15 mmHg) and the crude product purified by
recrystallization (MeOH/H O:2:3) or flash chromatography
2
5. (a) Ramarao, C.; Ley, S. V.; Smith, S. C.; Shirley, I. M.;
DeAlmeida, N. Chem. Commun. 2002, 1132–1133. (b) Pears,
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on silica gel.
6. (a) Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125,
3412–3413. (b) Okamoto, K.; Akiyama, R.; Kobayashi, S.
Org. Lett. 2004, 6, 1987–1990.
4
.6. General procedure for the Sonogashira reactions
7
8
. Hamza, K.; Abu-Reziq, R.; Avnir, D.; Blum, J. Org. Lett.
2
004, 6, 925–927.
A 10 mL round-bottom flask was charged with palladium
catalyst (see Tables 5 and 6), aryl halide (1 mmol), alkyne
. (a) Ding, J. H.; Gin, D. L. Chem. Mater. 2000, 12, 22–24. (b)
Choudary, B. M.; Madhi, S.; Chowdary, N. S.; Kantam, M. L.;
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(
1.5 mmol), pyrrolidine (0.164 mL, 2 mmol), tetrabutyl-
ammonium bromide (161 mg, 0.5 mmol) and water
2.5 mL). The mixture was stirred under reflux during the
(
reaction time indicated in Tables 5 and 6. The reaction
progress was analyzed by GLC. After the reaction was
completed and cooled to room temperature, the mixture was
filtered off through a glass filter (G-5). The filtrate was
extracted with EtOAc (3!15 mL), washed with 2 M HCl,
9
. Klingelhoefer, S.; Heitz, W.; Greiner, A.; Oestreich, S.;
Foerster, S.; Antonietti, M. J. Am. Chem. Soc. 1997, 119,
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0116–10120.
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4
purified by flash chromatography on silica gel.
1
26, 1604–1605. (d) Lemo, J.; Heuze, K.; Astruc, D. Org. Lett.
005, 7, 2253–2256.
4
.7. General procedure for recycling reactions
2
1
1
1. (a) Jansson, A. M.; Grotli, M.; Halkes, K. M.; Meldal, M. Org.
Lett. 2002, 4, 2730. (b) Koellhofer, A.; Plenio, H. Chem. Eur.
J. 2003, 9, 1416–1425.
When the corresponding Heck, Suzuki or Sonogashira
reaction was finished the suspension was cooled down to
room temperature and filtered off (G-5). The polymer was
washed with water and ethyl acetate, dried under vacuum
and reused.
2. (a) Cameron, J. H. In Solid State Organometallic Chemistry;
Gielen, M., Willem, R., Eds.; Wiley: Chichester, 1999. (b)
Doerwald, F. Z. Organic Synthesis on Solid Phase; Wiley-
VCH: Weinheim, 2000. (c) Ley, S. V.; Baxendale, I. R.;
Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.;
Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3815–4195. (d) de Miguel, Y. J. Chem.
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Acknowledgements
We thank DGES of the Spanish Ministerio de Ciencia y
Tecnologia (MCyT) (project BQU2001-0724-C02-01) and
DGE of Ministerio de Educaci o´ n y Ciencia (MEC) (project
CTQ2004-00808), the Generalitat Valenciana (projects
GRUPOS03/134 and 05/011) and the University of Alicante
for financial support. J.G.M. thanks MCyT for a predoctoral
fellowship and S.K. thanks the Stiftelsen Bengt Lundquists
minne (Sweden), the Swedish Institute and the Spanish
Ministerio de Asuntos Exteriores for postdoctoral
fellowships.
(
f) Zhang, T. Y. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.;
Wiley: New York, 2002; pp 3007–3030. (g) Uozumi, Y.;
Hayashi, T. In Handbook of Combinatorial Chemistry;
Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH:
Weinheim, 2002. (h) Leadbeater, N. E.; Marco, M. Chem. Rev.
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Organopalladium Chemistry for Organic Synthesis; Negishi,
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