Microwave-assisted Suzuki-Miyaura reactions with an insoluble pyridine-aldoxime Pd-catalyst

Article abstract of DOI:10.1055/s-2004-829546

The preparation of a solid Pd(II)-precatalyst and its use in microwave-assisted Suzuki-Miyaura reactions in water is described. The precatalyst is obtained by treatment of 4-pyridine-aldoxime with Na ₂PdCl₄ and is insoluble in organic solvents as well as in water. Its robustness under microwave conditions and its insolubility allows simple reuse in 'teabags'.

Full text of DOI:10.1055/s-2004-829546

LETTER
1699
Microwave-Assisted Suzuki–Miyaura Reactions with an Insoluble Pyridine-
Aldoxime Pd-Catalyst
M
icrowave-Assiste
d
Su
l
zuki–M
a
iyaura
R
ea
d
ctions imir Solodenko,a Uwe Schön,b Josef Messinger,b Anja Glinschert,a Andreas Kirschning*a
a
Zentrum für Organische Chemie, Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: andreas.kirschning@oci.uni-hannover.de
b
Solvay Pharmaceuticals Research Laboratories, Hans-Böckler-Allee 20, 30173 Hannover, Germany
Received 28 February 2004
like an immobilized catalyst. In addition, we show that
this heterogeneous precatalyst can repeatedly be em-
ployed under microwave irradiation conditions.5
Abstract: The preparation of a solid Pd(II)-precatalyst and its use
in microwave-assisted Suzuki–Miyaura reactions in water is de-
scribed. The precatalyst is obtained by treatment of 4-pyridine-al-
doxime with Na2PdCl4 and is insoluble in organic solvents as well
as in water. Its robustness under microwave conditions and its insol-
ubility allows simple reuse in ‘teabags’.
4-Pyridine-aldoxime served as a ligand, which upon treat-
ment with sodium tetrachloropalladate, led to a precipitate
and was insoluble in most organic solvents (in DMF and
DMSO little solubility was encountered) as well as in wa-
ter (Scheme 1). Filtration and washing with methanol and
water and drying yielded a material which in contrast to
oxime palladacycles 1 did not show a Pd-C s-bond in the
1H NMR spectrum (all four hydrogen atoms of the pyri-
dine ring can be detected in deuterated DMF). This fact
found additional support by the 13C NMR spectrum and by
combustion analyses of 3. So far, the precise structure
could not be elucidated but we propose a quasi polymeric
complex in which the oxime and the pyridine nitrogen at-
oms are involved in complexation.
Key words: Suzuki–Miyaura reactions, precatalyst, pyridine-al-
doxime Pd-catalyst
Palladium-mediated cross-coupling reactions play an im-
portant role in organic synthesis. A group of new ligands
for palladium derives from aromatic oximes which have
been known since the early 1970s.1 Only in the last years
they were discovered to be efficient precatalysts for C-C
cross-coupling reactions.2 Often, these compounds are
dimeric chloro-bridged ortho-palladated complexes such
as the acetophenone oxime-based palladacycle
1
(Figure 1) utilized by Nájera et al., which is a versatile
precatalyst for several carbon-carbon coupling reactions.2
Reusable heterogeneous precatalysts3 for Suzuki–
Miyaura reactions were prepared by covalently anchoring
complex 1 via the arylether linkage to modified silica gel
yielding precatalyst 2.4
OH
OH
Na2PdCl4
N
N
proposed
structure of
precatalyst
N
N
Pd
Cl
Cl
n
3
Scheme 1
Me
Me
SiO2
The Suzuki–Miyaura cross-coupling reaction between
phenyl boronic acid (1.5 equiv) and p-bromo-acetophe-
none (1.0 equiv) (according to Scheme 2 but under ther-
mal conditions) served as a model reaction for evaluating
the activity of this new material. The reaction proceeded
in toluene at 110 °C (2 equiv K2CO3, 1 mol% 3) under air
in less than 50 minutes, a clear indication of the high ac-
tivity of complex 3. The product was isolated in 95%
yield. The particles 3 could be recollected and repeatedly
used for two additional coupling reactions, each time full
transformation was achieved within 1 hour.6 We observed
that, after an induction phase, the material turns dark and
the catalytic process is initiated. At this stage, the nature
of the active palladium species is not clear. In this context
it needs to be mentioned that de Vries and co-workers re-
cently conducted a careful study on ligand-free palladi-
um-catalyst in Heck reactions.7 They found that a low
concentration of Pd(0) is a key issue for high activity.
Higher concentrations than 0.1 mol% led to the formation
of substantial amounts of inactive Pd black. Importantly,
the authors note that palladacycles behave similarly and it
N
Pd
OH
N
Pd
OH
O
Cl
Cl
Cl
HO
Pd
2
1
N
Me
Figure 1
An alternative to anchoring homogeneous precatalysts to
a solid phase are catalysts, which are heterogeneous them-
selves. Insolubility in common reaction media allows sim-
ple removal of the catalyst at the end of the reaction. At
the same time, this approach leaves out additional reaction
steps for immobilization. Here, we report on a modified
aromatic oxime ligand for coordination to palladium(II),
which is insoluble in organic solvents and can be utilized
SYNLETT 2004, No. 10, pp 1699–1702
0
9
.08
.2
0
0
4
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829546; Art ID: G0604ST
© Georg Thieme Verlag Stuttgart · New York

1700
W. Solodenko et al.
LETTER
was concluded that they also merely serve as source for
ligand-free palladium. This interpretation cannot be ex-
cluded in the current case.
B(OH)2
R2
3, TBAB
O
+
In the next phase we tested the utility of this insoluble
complex under microwave irradiation conditions
(Table 1).8,9 Water turned out to be superior to toluene, an
observation which was supported when other substituted
aryl-boronic acids were coupled under the same condi-
tions (reaction time: 300 sec, see Table 2).
microwave
irradiation (150 °C)
300 s
R2
R1
O
Scheme 3
boronic acid with 4-bromo acetophenone under micro-
wave irradiating conditions at 120 °C (restrictions are due
to the thermal stability of the Irori kanTM, Scheme 4,
Figure 2). The reaction was terminated by removal of the
can which was washed prior to use. Even the 14th run with
the reused can give 93% of conversion within 20 minutes.
These results indicate sufficient stability and activity
(>1200 TON for all 14 runs) of the catalyst under these
microwave conditions.
B(OH)2
R
3
+
microwave
R
O
irradiation (150 °C)
Br
O
Scheme 2a
Table 1 Utility of the Insoluble Complex under Microwave Irradi-
B(OH)2
ation Conditions with Various Reaction Times
3 (inside Irori kanTM
)
+
R = H
60 s
90%
94%
120 s
79%
94%
180 s
87%
98%
240 s
98%
98%
microwave
irradiation (120 °C)
1200 s
O
Br
Toluene
Water
O
Scheme 4
Table 2 Reaction Time: 300 sa
R =
H
4-Me
79%
85%
3-CF3
62%
4-SMe
39%
4-Cl
Toluene
Water
70%
99%
69%
76%
89%
59%
a Conditions: Aryl bromide (1 mmol), boronic acid (1.5 mmol),
K2CO3 (2 mmol) and 3 (1 mol%); the degree of transformation was
analyzed by LC/MS.
Figure 2
A comparison study between the soluble Nájera precata-
lyst 1 and the new insoluble precatalysts 3 was conducted
using differently well suited reaction partners (Scheme 3,
Table 3). This investigation revealed that 1 is less active
compared to 3 in Suzuki–Miyaura reactions when moder-
ately active pairs of coupling partners are chosen while re-
active and unreactive partners behave similarly in the
presence of both precatalysts.
Under these optimized conditions (water, microwave irra-
diation 120 °C, TBAB, 1200 s) a small compound library
of biaryls was prepared. While the chosen arylboronic ac-
ids showed structural and electronic diversity, the second
reaction partner was mainly based on acetophenone with
differing halogen substituents and the triflate group, re-
spectively. Gratifyingly, also 4-chloro acetophenone
served as coupling partner in the Suzuki–Miyaura reac-
tion.10
Then, we tested the stability and recyclability of the new
catalyst. For this purpose we enclosed 3 (1 mol%) inside
an Irori kanTM and carried out the coupling of phenyl
Table 3 Comparison Study between Soluble Nájera Precatalyst 1 and the New Insoluble Precatalyst 3
R1
R2
4-Br
4-OH
2-Cl
H
4-I
4-Cl
4-Cl
4-Cl
4-I
H
4-Cl
H
Precatalyst 1
Precatalyst 3
N.r.a
N.r.
N.r.
N.r.
56%
81%
50%
87%
92%
92%
86%
84%
a N.r. = no reaction; aryl halogenide (1 mmol), boronic acid (1.5 mmol), K2CO3 (2 mmol), tetrabutylammonium bromide (TBAB; 1 mmol), 3
(1 mol%) in 3.5 mL H2O; the degree of transformation was analyzed by GC/MS.
Synlett 2004, No. 10, 1699–1702 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Suzuki–Miyaura Reactions
1701
Table 4 Small Compound Library of Biarylsa,b
B(OH)2
Br
Br
Cl
I
TfO
R
OMe
O
O
O
O
H
88%
84%
75%
87%
95%
83%
48%
100%
96%
83%
90%
95%
98%
65%
84%
75%
87%
N.d.d
79%
87%
0%
92%
N.d.d
81%
86%
96%
91%
98%
91%c
82%c
77%c
82%c
59%c
56%c
N.d.d
2-CF3
4-Cl
4-SMe
3-CF3
4-OMe
4-NH2
a Conditions: 3 (1 mol%), boronic acid (1.5 mmol), halide (1 mmol), K2CO3 (2 mmol), TBAB (1.0 mmol) in H2O (3.5 mL).
b Except for column 2 (isolated yields) yields were determined by GC; thus loss of material during workup and isolation was determined to be
less than 5%.
c Reduced and non-optimized yields due to partial degradation of triflate
d Not done.
3: IR: n = 1611 cm–1. 1H NMR (400 MHz, DMF-d7): d = 7.76 and
Finally, we checked whether the catalyst is actually re-
quired under microwave heating. Indeed, Leadbeater and
coworkers recently noted that Suzuki-type reactions can
7.81 (2 d, 2 HPy), 8.29 and 8.34 (2 s, CH=N), 8.70–9.00 (m, 2 HPy),
12.53 and 12.57 (2 s, 1 H, OH). 13C NMR (100 MHz, DMF-d7): d =
154.06, 146.3, 144.5, 122.6. Anal. Calcd for C6H6Cl2N2OPd: C,
24.07; H, 2.02; N, 9.35. Found: C, 24.08; H, 2.41; N, 9.17.
be achieved in the absence of any transition metal precat-
alyst with microwave irradiation.11 In this work it was not-
Selected spectroscopic data for the palladium-free ligand: IR:
ed that the presence of tetrabutylammonium bromide in
n = 1603 cm–1. 13C NMR (100 MHz, DMF-d7): d = 150.9, 147.4,
water is essential for successful coupling. In the present
141.4, 121.4.
case, the Suzuki–Miyaura reaction did not take place un-
der comparable conditions as described above [4-bro-
moacetophenone (1 mmol), phenylboronic acid (1.5
mmol), TBAB (1 mmol) in 3.5 mL H2O, at 150 °C in the
absence of 3].
General Procedure for the Suzuki–Miyaura Reaction under
Microwave Irradiating Conditions (Table 4). Precatalyst 3 (3
mg; 1 mol%) was inclosed inside an Irori kanTM, and was added to
a reaction mixture consisting of boronic acid (1.5 mmol), aryl halide
(1.0 mmol), tetrabutylammonium bromide (1 mmol) and K2CO3 (2
mmol) in H2O (3.5 mL). The suspension was subjected to micro-
wave irradiating conditions (EmrysTM Optimizer from Personal
Chemistry). The reaction was heated for 1200 sec at 120 °C and
then cooled. The Irori kanTM was removed and washed with EtOAc
(2 mL). The outcome of the reaction was monitored by GC- or
HLPC analysis. The reaction phase was extracted with EtOAc
(2 × 10 mL). The combined washing and extracts were concentrated
under reduced pressure and the crude product was purified by
column chromatography (silica gel; solvent mixtures consisted of
EtOAc–cyclohexane).
In summary, we developed a new insoluble Pd(II)-precat-
alyst, which is conveniently prepared by mixing of readily
available 4-pyridinealdoxime with Pd(II) salts.12 The cat-
alyst which is heterogeneous in nature is insoluble in wa-
ter as well organic solvents. Loaded inside an Irori kanTM
(‘teabag’) it repeatedly promotes the Suzuki–Miyaura re-
action under microwave irradiating conditions. The con-
cept of insoluble precatalysts without use of an additional
solid phase can be broadened towards more active and
broadly usable precatalysts, which are currently investi-
gated in our laboratories.
When the heterogeneous precatalyst 3 was directly added to the re-
action mixture (not inside the Irori kanTM) the reactions were irradi-
ated at 150 °C for 300 s. It could be recollected by filtration.
After filtration the filtrate was checked for catalytic activity by add-
ing an additional portion of phenylboronic acid and 4-bromoace-
tophenone. Under identically conducted reaction conditions, no
transformation to the biaryl derivatives was observed. However,
when the Irori kansTM were utilized as filtration aid, we found some
activity in the solution for the first three or four runs when the tea-
bag had been removed which can be rationalized by the fact that the
finest catalyst particles had left the can into solution. After the 4th
run, however, no catalytic activity was released into solution any
more while the catalyst inside the Irori kanTM still exerted catalytic
activity (see Scheme 4).
Preparation of Precatalyst 3. A solution of 4-pyridine-aldoxime
(122 mg, 1 mmol) in MeOH (1 mL) was added dropwise to the
stirred solution of sodium tetrachloropalladate(II) (294 mg, 1
mmol) in MeOH (2 mL). Gentle stirring was continued overnight,
the precipitate was filtered, washed with MeOH and H2O, and dried
in vacuum over P2O5. Precatalyst 3 was obtained as orange brown-
ish powder (288 mg, 0.96 mmol; 96%). The 1H NMR spectrum re-
veals the presence of isomers in a ratio of about 2:1. Similar
findings have been reported for other palladium catalysts with
ligands containing N-donors.13
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1702
W. Solodenko et al.
LETTER
within one week to yield the coupling product in 93%
Acknowledgment
isolated yield.
We are indebted to the Fonds der Chemischen Industrie for financi-
al support. We thank Ute Kluge and Uwe Reinecker from Solvay
Pharmaceuticals Research Laboratories for technical assistance.
(7) (a) de Vries, A. H. M.; Parlevliet, F. J.; Schmieder-van de
Vondervoort, L.; Mommers, J. H. M.; Henderickx, H. J. W.;
Walet, M. A. M.; De Vries, J. G. Adv. Synth. Catal. 2002,
344, 996. (b) de Vries, A. H. M.; Mulders, J. M. C. A.;
Mommers, J. H. M.; Henderickx, H. J. W.; De Vries, J. G.
Org. Lett. 2003, 5, 3285.
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Synlett 2004, No. 10, 1699–1702 © Thieme Stuttgart · New York