Comparison of monomode and multimode microwave equipment in Suzuki-Miyaura reactions-en route to high throughput parallel synthesis under microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2008.03.094

The microwave heated Suzuki-Miyaura cross-coupling reaction of boronic acids, boronic esters and organotrifluoroborates served as a model reaction in a singlemode equipment. The reaction conditions were optimized with respect to temperature and reaction t

Full text of DOI:10.1016/j.tetlet.2008.03.094

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3204–3207
Comparison of monomode and multimode microwave equipment
in Suzuki–Miyaura reactions—en route to high throughput
parallel synthesis under microwave conditions
a,
a
b
b
*
Uwe Schon , Josef Messinger , Simone Eichner , Andreas Kirschning
¨
a Solvay Pharmaceutical Research Laboratories, Hans-Bo¨ckler-Allee 20, D-30173 Hannover, Germany
b Institut fu¨r Organische Chemie and Zentrum fu¨r Biomolekulare Wirkstoffe (BMWZ), Leibniz Universita¨t Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany
Received 2 March 2008; revised 15 March 2008; accepted 19 March 2008
Available online 23 March 2008
Abstract
The microwave heated Suzuki–Miyaura cross-coupling reaction of boronic acids, boronic esters and organotrifluoroborates served as
a model reaction in a singlemode equipment. The reaction conditions were optimized with respect to temperature and reaction time and
were transferred to multimode equipment which is well suited for multiparallel synthesis in a larger scale. The source of the Pd species
chosen included immobilized Pd complexes and Pd particles. In fact the increased time to reach the required reaction time in multimode
chambers suitable for 48 parallel reactions has to be taken into account. The nature of the boronic acid has no impact on the efficiency of
the catalytic process. However, heterogenized Pd species perform less well in multimode chambers with larger vial volumes, which we
ascribe to diffusion phenomena.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Suzuki–Miyaura reaction; Microwave; Monomode; Multimode; Palladium precatalysts
‘Enabling technologies for organic synthesis’ such as
microwave, solid-phase assistance, new reactor design or
nonconventional solvents have changed organic chemistry
in terms of efficiency, work-up and speed. One can only
speculate when these laboratory techniques will be incorpo-
rated into industrial processes.1 Since the first reports on
the use of microwave heating for accelerating organic reac-
tions by the groups of Gedye2 and Giguere/Majetich3 in
1986, the number of publications related to microwave-
assisted organic synthesis (MAOS) has increased dramati-
cally. Clearly, this technique leads to a rate enhancement
with often excellent reproducibility, improved yields and
less side reactions compared to conventional heating.4
When comparing different reaction techniques, a significant
gain in energy efficiency using microwave irradiation has
been noted.5
With respect to parallel synthesis, compound libraries
are commonly prepared sequentially in an automated sin-
glemode instrument with full control of each reaction or
in a multimode instrument performing parallel reactions
in one irradiation experiment only. Additionally, it has
been shown that it is possible to directly scale reaction con-
ditions from singlemode small-scale to multimode larger
scale microwave reactors.6
Suzuki–Miyaura reaction has emerged as one of the
most powerful ways of preparing biaryls.7 Besides, boronic
acids and boronic esters organotrifluoroborates are becom-
ing more and more popular for these cross-coupling
reactions.8
As some limitations for these different reagents have
been discussed (e.g., purification of boronic acids, atom
economy of boronic esters or synthetic availability of
*
Corresponding author. Tel.: +49 511 857 2311; fax: +49 511 857 2195.
E-mail addresses: uwe.schoen@solvay.com (U. Scho¨n), andreas.
kirschning@oci.uni-hannover.de (A. Kirschning).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.094

U. Scho¨n et al. / Tetrahedron Letters 49 (2008) 3204–3207
3205
organofluoroborates), we initiated a research programme
for comparing the reactivity of a selected number of aryl
boronic derivatives in the microwave-assisted palladium-
catalyzed Suzuki–Miyaura cross-coupling reaction.
These studies are in line with our earlier work9 on
homogeneous and heterogeneous palladium precatalysts.
In the present study, it is our intention to investigate the
feasibility of a protocol for the rapid optimization of trans-
formations in the microwave field. Is it possible to carry
out optimization with a monomode equipment and trans-
fer the knowledge accumulated into a multimode appara-
tus for the parallel upscaled synthesis of compound
libraries? Here, we focus on the comparison of selected
Suzuki–Miyaura reactions with different Pd sources under
microwave irradiating conditions using singlemode and
multimode microwave equipment.10,11
The cross-coupling reaction between two phenyl boronic
acids and 3-bromo-naphthalene-1-carboxylic acid methyl
ester (Scheme 1) served as a model reaction. First, we inves-
tigated the temperature/time profiles under singlemode
conditions. Based on the earlier results,9 we focused on
the temperature range between 100 °C and 130 °C (Table
1). Raising the reaction time from 300 to 600 s or increas-
ing the temperature from 100 °C to 130 °C did not result in
increased yields and therefore 110 °C was chosen in the
following investigations.
multimode system (Synthos 3000) with parallel setup
(Scheme 2).
Besides the commercial Pd(OAc)2 (A) and the encapsu-
lated Pd(II)EnCatTM 40 (C), we compared a pyridine–
aldoxime derivative (B),9a palladium(0) particles immobi-
lized on an anionic exchange resin (D)12 and a Najera
precatalyst immobilized on polyvinyl pyridine (E).9c
As heating rates are reduced when processing larger
volumes compared to small volumes, the reaction time
had to be increased from 300 s to 420 s. Temperature and
power profiles for a typical Suzuki–Miyaura reaction in
the microwave field (in sealed vessel) are depicted below
(Fig. 1: monomode; Fig. 2: multimode). For a better com-
parison, the sample volume per vessel was kept constant
(5 mL each).
Obviously, for short reaction times the transfer from
mono- to multimode has to be analyzed very carefully.
While under singlemode conditions, the reaction tempera-
ture of 110 °C was reached within a few seconds, the mul-
timode conditions required more than 200 s. In this special
Pd precatalyst (A-E), K2CO3,
CO2Me
DME/H2O/EtOH (7/3/2), MW
1
+
2 or 4 or 5
3a: R = H
3b: R = OMe
3c: R = CN
R
In the following, we investigated this model Suzuki–
Miyaura reaction with different boron derivatives (acids,
esters and fluoroborates) and different palladium sources
including heterogeneous (immobilized) precatalysts in a
K
O
O
B(OH)2
B
R
5a: R = H
2a: R = H
4a: R = H
BF3
5b: R = OMe
5c: R = CN
2b: R = OMe
2c: R = CN
4b: R = OMe
4c: R = CN
R
CO2Me
R
Pd source:
Br
OH
n
Pd(OAc)2, K2CO3,
DME/H2O/EtOH (7/3/2), MW
N
NMe3 Cl
Pd(0)
CO2Me
1
+
Pd(OAc)2
A
N
Cl2Pd
N
B(OH)2
B
E
D
Cl
Pd(II)EnCatTM 40
Pd
R
N
HO
C
3a: R = H
2a: R = H
3b: R = OMe
R
2b: R = OMe
Scheme 1. Model Suzuki–Miyaura cross-coupling reactions. Reagents
and conditions: aryl bromide (0.2 mmol), boronic acid (0.4 mmol), K2CO3
(0.6 mmol), Pd(OAc)2 (0.02 mmol), DME/H2O/EtOH (7:3:2; 5 mL).
Scheme 2. Parallel setup of Suzuki-Miyaura reaction.
350
300
250
200
150
100
50
Table 1
Results of model Suzuki–Miyaura reaction (also refer to Scheme 1)
Power
Product
T (°C)
Time (s)
LC–MS Yield UVa (%)
IR-sensor
Pressure
3a
3a
3a
3a
3b
3b
3b
3b
a
100
100
110
130
100
100
110
130
600
300
300
300
600
300
300
300
90
93
90
91
81
87
86
79
0
0
50 100 150 200 250 300 350 400 450
Time [s]
Fig. 1. Microwave heating profile for singlemode irradiation
(y axis = temperature [°C], pressure [bar], power [W]); 5 mL sample
volume.10
Percentages are based on the product peak area by LC–MS (UV).

3206
U. Scho¨n et al. / Tetrahedron Letters 49 (2008) 3204–3207
Table 3
Multiwave Plot
Reagents and conditions:14,15 Aryl bromide (0.2 mmol), boronic acid
300
Pressure
1400
1200
1000
800
600
400
200
0
Temperature
T Vessel 1
T Vessel 2
T Vessel 3
T Vessel 4
T Vessel 5
T Vessel 6
T Vessel 7
T Vessel 8
T Vessel 9
T Vessel 10
T Vessel 11
T Vessel 12
T Vessel 13
T Vessel 14
T Vessel 15
T Vessel 16
Power
derivative (0.4 mmol), K2CO3 (0.6 mmol), precatalyst (0.02 mmol), DME/
H2O/EtOH (7:3:2; 5 mL)a
250
200
150
100
50
Pd precatalyst (C - F),
K2CO3, DME/H2O/EtOH (7/3/2)
MW 110 °C
CO2Me
+
1
2a
3a
Time (s)
C
D
E
F
0
180
240
300
600
900
1200
a
19
30
41
70
73
71
n.p.b
n.p.
13
18
29
n.p.
n.p.
28
47
57
67
83
90
99
n.p.
n.p.
0
200
400
600
800
1000 1200 1400
Time [s]
Fig. 2. Microwave heating profiles for multimode irradiation; rotor
48MF50; 48 Â 5 mL sample volume; top profile using the internal gas
ballon thermometer, bottom profiles with external IR-sensors.11
34
97
Percentages are based on the product peak area by LC/MS (ELSD).
Not performed.
b
case, the rapid heating and cooling profile cannot be trans-
ferred directly but had to be optimized, individually. It has
to be noted that Kappe and co-workers recently high-
lighted the importance of exact measurements of internal
and external temperatures using a dedicated reactor
setup.13
These results set the stage to simultaneously perform 45
Suzuki–Miyaura reactions with a multimode microwave
system.14,15 The results are listed in Table 2.
The data clearly reveal that all the three types of boron
derivatives behave in a similar manner irrespective of the
aromatic substitution pattern. However, the precatalysts
used, differ substantially in their performance. In general,
heterogeneous precatalysts showed low or moderate con-
versions only.
lysts at 110 °C (Table 3). These studies should reveal,
whether these differences are caused by a lower reactivity
or exclusively by diffusion phenomena. In addition, we
used precatalyst Pd(II)EnCatTM 30 (F). Based on these data,
it can be concluded that the encapsulated catalyst
Pd(II)EnCatTM 30 reacts faster and performs more effi-
ciently than Pd(II)EnCatTM 40 (C).16 With the polymer sup-
ported Najera precatalyst (E) also complete conversion is
achieved. However, the reaction times are extended,
whereas the polymeric ionic palladium source (D) only
afforded moderate results.
In conclusion the present study is a guideline for transfer-
ring reaction conditions initially identified in singlemode
equipment onto multimode equipment suitable for multi-
parallel reactions. Clearly, catalysis under homogeneous
conditions can easily be adapted. Still, only slightly longer
reaction times were encountered which is associated with
a slower heating rate present in the latter equipment.
However, for biphasic reactions using solid-phase bound
or associated Pd species the situation is more complex,
because the larger volume associated with diffusion
phenomena lead to substantially reduced reaction rates.
The studies pave the way for the rapid development of
compound libraries which includes the optimization of
reaction conditions (with monomode equipment) followed
by parallel synthesis (in 48 reactors in multimode
equipment).
Returning back to the monomode system, we performed
the model reaction with different heterogeneous precata-
Table 2
Reagents and conditions:14,15 Aryl bromide (0.2 mmol), boronic acid
derivative (0.4 mmol), K2CO3 (0.6 mmol), precatalyst (0.02 mmol), DME/
H2O/EtOH (7:3:2; 5 mL); 110 °Ca
Pd precatalyst (A-E),
K2CO3,
CO2Me
B*
CO2Me
DME/H2O/EtOH (7/3/2),
MW 420 sec
+
Br
R
1
R
3a - 3c
2a - 2c (boronic acids)
4a - 4c (boronic esters)
5a - 5c (tetrafluoroborates)
R
B*
A
B
C
D
E
Supplementary data
2a
4a
5a
2b
4b
5b
2c
4c
5c
a
H
H
H
OCH3
OCH3
OCH3
CN
CN
CN
B(OH)2
B(OR)2
BF3K
B(OH)2
B(OR)2
BF3K
B(OH)2
B(OR)2
BF3K
99
99
99
99
99
99
99
99
81
99
99
99
99
99
99
99
99
82
46
46
40
47
50
50
82
60
54
29
17
10
16
25
35
25
15
33
31
37
0
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.094.
2
30
58
14
0
References and notes
0
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