Microwave-assisted organic synthesis: Scale-up of palladium-catalyzed aminations using single-mode and multi-mode microwave equipment

Article abstract of DOI:10.1016/j.tet.2005.07.105

Batch wise scale-up of Buchwald-Hartwig aminations under microwave irradiation has been investigated for the first time. Multi-mode (microSYNTH and MARS) (several vessels irradiated in parallel per batch) as well as single-mode (Discover) (one vessel irradiated per batch) platforms can be successfully used for this purpose with trifluoromethylbenzene (benzotrifluoride: BTF) as amination solvent. The obtained yields indicate a direct scalability in BTF for all the studied aminations. The Voyager equipment (based on a Discover platform) is the most convenient system since it allows an automatic continuous batch wise production without the necessity to manually load and unload reaction vessels.

Full text of DOI:10.1016/j.tet.2005.07.105

Tetrahedron 61 (2005) 10338–10348
Microwave-assisted organic synthesis: scale-up of
palladium-catalyzed aminations using single-mode and
multi-mode microwave equipment
a
Kristof T. J. Loones, Bert U. W. Maes,
a,
a
*
Geert Rombouts, Steven Hostyn and Gaston Diels
a
b
a
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
b
Janssen Pharmaceutica, Johnson and Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
Received 23 May 2005; revised 25 July 2005; accepted 27 July 2005
Available online 8 September 2005
Dedicated to the memory of Nancy Verhaert
Abstract—Batch wise scale-up of Buchwald–Hartwig aminations under microwave irradiation has been investigated for the first time.
Multi-mode (microSYNTH and MARS) (several vessels irradiated in parallel per batch) as well as single-mode (Discover) (one vessel
irradiated per batch) platforms can be successfully used for this purpose with trifluoromethylbenzene (benzotrifluoride: BTF) as amination
solvent. The obtained yields indicate a direct scalability in BTF for all the studied aminations. The Voyager equipment (based on a Discover
platform) is the most convenient system since it allows an automatic continuous batch wise production without the necessity to manually load
and unload reaction vessels.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
on MAOS such as the ‘MAOS meeting’ in Graz and the
International Microwaves in Chemistry Conference’ in
‘
Microwave-assisted organic synthesis (MAOS) is a rapidly
growing subfield within the area of organic chemistry.
Orlando clearly support that microwave-assisted organic
synthesis has now reached a mature scientific level. The
growing interest, both from industry and academia, for such
events indicates that the real impact of microwaves on the
field of organic syntheses still has to come! Most of the
chemistry hitherto performed in a dedicated microwave
system has been executed on a small scale only. Single-
mode microwaves are standardly used for this purpose,
typically allowing the production of several hundred
milligram quantities per run. One of the major current
issues is the question whether microwave heating could be
used to scale-up these reactions to gram and kilogram scale,
preferentially without the requirement to reoptimize
reaction parameters tuned for the small scale runs. For the
scale-up purpose historically two different approaches,
1
Since the first reports in the literature on MAOS in the mid
eighties the number of annually published articles using
microwave heating has increased continuously. In the early
2
days domestic microwaves were used, often giving only a
poor reproducibility. Moreover, accidents were common
due to the lack of control. This lack of control and
reproducibility is partly responsible for the initial slow take
up of microwave heating in organic syntheses. The
introduction of dedicated equipment by Prolabo (closed
down already), CEM, Milestone, Biotage (formerly
Personal Chemistry), Plazmatronika and more recently by
Anton Paar allowing the on-line monitoring of temperature,
power and pressure had a large impact on the further
3
4
5
development of this relatively young research field. The
batch and continuous-flow, have been followed taking
into account the physical limitations inherent to microwave
latest trend is to use only microwave equipment designed
for organic synthesis and to abandon scientific results for
publication obtained using domestic microwaves. The
organisation of annual workshops and conferences focusing
1
h
equipment construction. Large batch reactors have been
developed for a multi-mode or single-mode microwave
platform. For these the most important drawback is the
limited penetration depth of microwave irradiation. Alter-
natively, multi-mode equipment supplied with a rotor with
several smaller vessels has been launched, which allows the
use of a large total volume in one microwave run without
the penetration depth issue. Besides batch approaches
Keywords: Palladium; Homogeneous catalysis; Buchwald–Hartwig amin-
ation; Aryl chlorides; Multi-mode cavity; Single-mode cavity; Microwave
irradiation.
*
Corresponding author. Tel.: C32 3 265 32 05; fax: C32 3 265 32 33;
e-mail: bert.maes@ua.ac.be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.105

K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
10339
continuous-flow systems based on single-mode and multi-
mode cavities have been used as well. The major limitation
of these continuous microwave reactors is that they are
unsuitable for heterogeneous mixtures and viscous liquids.
Interestingly, reports on scale-up using dedicated micro-
wave equipment in peer reviewed journals is hitherto rather
limited. In particular more complex chemistry, such as
6
transition metal catalyzed reactions, is hardly studied.
Based on the limited availability of more complex examples
and the background of our research group, we decided to
investigate the scale-up of Buchwald–Hartwig aminations
under microwave irradiation using dedicated multi-mode
(MicroSYNTH, MARS) and single-mode (Voyager) batch
reactors.
7
,8
2
. Description of microwave equipment used
3
2
.1. Voyager
The Voyager system (stop/flow system) of CEM is based on
the Discover single-mode platform equipped with an 80 mL
glass vessel (borosilicate), a peristaltic pump and two valves
(
Fig. 1). The system has a continuous unpulsed microwave
output ranging from 0 to 300 W. The temperature in the
vessel is controlled internally by a fiber optic probe. On-line
pressure monitoring is also provided. The Voyager
microwave is designed to automatically fill the 80 mL
vessel with reagents (two stock solutions), seal the vessel,
perform a microwave experiment, release the vessel,
remove the reaction mixture from the vessel and
subsequently clean it with solvent (even under microwave
irradiation if desired) (Fig. 2). The liquid of the cleaning
step can be collected separately via a waste line or can be
added to the product if desired. We always chose the latter.
The contents of the closed vessel can be released after a
microwave experiment at a pre-programmed temperature
and pressure (in our experiments we used 95 8C and 10 psi
as vessel release parameters), which allows a serious
increase of the throughput (number of cycles in a given
timeframe) of the system. Cooling to the set temperature
value is done using a propelled air flow. When the Voyager
platform is based on an older type of Discover microwave
an enhanced stirring device is standardly used. This device
fits in the small cavity located at the bottom of the
microwave cavity (on top of the IR sensor). It consists of a
magnet at both ends of the bar, which couples with the
magnetic stirring plate located at the bottom of the Discover
Figure 2. Add step (1), remove step (2) and clean vessel step (3) ((3a) fill
with solvent, (3b) remove solvent to waste).
Figure 1. Voyager platform (1) and 80 mL glass vessel (2).

10340
K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
unit. Two more centrally located magnets couple with the
stirring bar in the reaction vessel. The enhanced stirring
device gives access to a microwave unit with a more
powerful stirring capacity. All our experiments were done
using this special device. Recent Discover units are
equipped with electromagnetic stirring plates that deliver
more stirring power in comparison with the older type of
Discover unit. Therefore the enhanced stirring device is not
used anymore in this newer unit.
positions rotor. The system delivers a continuous power
output between 0 and 1200 W. Temperature is controlled
internally by fiber optic probe in one control reference
vessel. On-line pressure monitoring of the reference vessel
is also provided. All rotor segments are protected by a vent
nut that contains a rupture membrane. Additionally, the
system is equipped with a solvent sensor detector safety
feature. Cooling down of the rotor segments to room
temperature is done by an air flow provided by the exhaust
fan.
3
2
.2. MicroSYNTH
3
. Results
The MicroSYNTH system of Milestone is a multi-mode
platform equipped with a magnetic stirring plate and a rotor
that allows parallel processing of several vessels per batch
Recently our laboratory reported the rapid palladium-
catalyzed amination of aryl chlorides under temperature
controlled microwave heating using a CEM Discover
single-mode microwave unit.
only 10 min using a relatively low catalyst loading
1 mol%) complete conversion of starting material and a
good yield could be achieved for the coupling of both
electron rich and electron neutral aryl chlorides with all
types of amines (anilines, primary and secondary aliphatic
amines). For the coupling of anilines and secondary cyclic
aliphatic amines palladium precatalyst based on Pd(OAc)
and 2-(dicyclohexylphosphanyl)biphenyl (DCPB) ligand
(
Fig. 3). We used the high-pressure vessel assembly type
based on a rotor with 10 vessel positions (teflon (TFM)
inserts) (vessel volume 100 mL, max pressure 1450 psi,
max temperature 300 8C). The system has two magnetrons
that together deliver a maximum power output of 1000 W.
The power supply of the magnetron is pulsed. Temperature
is controlled internally by fiber optic probe in one control
reference vessel. On-line pressure monitoring of the
reference vessel is also provided. All rotor segments are
protected by a reclosing (vent and reseal) relief valve
mechanism. Additionally, the system is equipped with a
solvent sensor detector safety feature. Cooling down of the
rotor segments to room temperature is done by an air flow
provided by the exhaust fan.
7
c,7l
In a reaction time of
(
2
9
worked smoothly while for the amination reactions using
acyclic secondary and primary aliphatic amines Pd(OAc)
in combination with 2-(di-t-butylphospanyl)biphenyl
(DTPB) ligand was found to be optimal. All the reported
2
9
examples were performed on a 1 mmol scale of aryl chloride
allowing the production of hundred milligram quantities of
N-substituted anilines.
3
2
.3. MARS
First we investigated the direct scalability going from a
1
0 mL vessel to an 80 mL vessel in a Discover apparatus.
We selected the coupling of electron rich 4-chloroanisole
with morpholine, which we previously performed on a
7
l
1
mmol scale as a test case. Unfortunately, running this
reaction on a 20-fold scale (20 mmol 4-chloroanisole,
4 mmol morpholine, 28 mmol NaOt–Bu, 20 mL toluene)
using the same microwave program (initial set power
00 W, 150 8C, 10 min (total reaction time including ramp
2
Figure 3. MicroSYNTH platform (1), control vessel rotor segment (2),
high-pressure sleeve, insert and cap of a standard vessel assembly (3).
3
The MARS system of CEM is a multi-mode platform
equipped with a magnetic stirring plate and a rotor that
allows the parallel processing of several vessels per batch
time to set temperature)) as for the small scale reaction
was unsuccessful. The reaction mixture heated up
relatively slowly and the obtained final temperature after
10 min of microwave irradiation was only 128 8C, which is
substantially lower than the desired set temperature of
150 8C. Consequently, an incomplete conversion of starting
material and an isolated yield of 4-(4-methoxyphenyl)-
morpholine of only 38% was obtained (Table 1). In contrast,
(
Fig. 4). We used the HP-500 (teflon (TFA) insert) (vessel
volume 80 mL, max pressure 350 psi, max temperature
10 8C) and Greenchem (glass (borosilicate) insert) (vessel
volume 80 mL, max pressure 200 psi, max temperature
00 8C) vessel assembly types both based on a fourteen
2
2
Figure 4. MARS platform (1), control vessel rotor segment (2), Greenchem insert, cap and sleeve of a standard vessel assembly (3) and HP-500 insert, cap and
sleeve of a standard vessel assembly (4).

K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
Table 1. Scale-up of the Pd-catalyzed amination of 4-chloroanisole with morpholine
10341
a
Microwave
4-Chloroanisole
(
Vessel
Initial set power
(W)
Solvent
Yield (%)
mmol)
Volume (mL)
Type
Discover
Discover
Mars
Discover
Discover
Voyager
microSYNTH
Mars
1
10
80
80
10
80
80
100
80
Glass
Glass
Greenchem
Glass
Glass
Glass
High-Pressure
Greenchem
300
300
1200
300
300
300
600
600
Toluene
Toluene
Toluene
BTF
BTF
BTF
76
b
20
20
1
38
78
78
85
20
c
3!20
6!20
6!20
78
77
80
c
c
BTF
BTF
a
4
1
-Chloroanisole (y mmol), morpholine (1.2y mmol), NaOt-Bu (1.4y mmol), toluene or BTF (y mL).
50 8C could not be reached in 10 min.
b
c
Average yield.
for the 1 mmol scale experiment in a 10 mL vessel the set
temperature was reached in 2 min allowing a full conversion
of starting material in 10 min. Although polar reagents are
present in the reaction mixture we realized the poor
coupling characteristic of the solvent (tan d tolueneZ
whether there is a substantial difference between single and
multi-mode microwaves when solvents with low tan d are
used. Therefore, we performed power/time experiments
(temperature is slave of the power) using 20 mL of pure
toluene at full power in several commercial available
7
l
1
1
0
experiment.
.04) is responsible for the failure of the scale-up
1
microwave platforms (Discover, max power 300 W)
11
(MARS, max power 1200 W) (microSYNTH, max
0
1
1
power 1000 W) (Fig. 5). The vessels used were either
from glass (borosilicate) or teflon (PTFE or TFM). In all
Due to this failure we became interested to investigate
Figure 5. Heating profile of 20 mL of toluene in several commercial available microwave systems, irradiated in a power/time experiment at a constant
maximum power output for 10 min.

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K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
Figure 6. Heating profile of 20 mL of toluene in several commercial available microwave systems, irradiated in a power/time experiment at a constant power
of 300 W for 10 min.
cases, the temperature was measured internally using a fiber
optic probe. Interestingly, 20 mL of toluene could be heated
to 156 8C in 10 min in a Greenchem vessel in the MARS
platform. In contrast, 20 mL of toluene could only be heated
to 61 8C in a similar 80 mL glass vessel in the Discover
system. Important to mention is that even if the same
Figure 7. Heating profile of 20 mL of tetrachloromethane in several commercial available microwave systems, irradiated in a power/time experiment at a
constant power of 300 W for 10 min.

K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
10343
constant power output is used in all microwave systems the
1
final temperature of toluene is not the same (Fig. 6).
starting material and an isolate yield of 4-(4-methoxy-
phenyl)morpholine of 78% (Table 1). This is similar to the
result obtained on a 1 mmol scale in the 10 mL glass vessel
of the Discover (76%). Although we were able to
successfully perform scale-up in one glass vessel we
realized that the further scale-up making use of the
possibility to process multiple Greenchem vessels (rotor)
in one microwave run would be problematic using toluene
as solvent. Indeed, Figure 8 clearly shows that the final
temperature of toluene in power/time experiments per-
formed at 1200 W for 10 min drops each time a rotor
segment that contains a glass vessel with 20 mL of toluene
is added. This is obvious since the total volume to be heated
increases each time a rotor segment is added. Therefore we
looked for an alternative solvent for palladium-catalyzed
aminations to allow scale-up in single-mode as well as
multi-mode platforms. Possible candidates were screened
by performing power/time experiments with 20 mL of
solvent at 300 W for 10 min in each microwave system.
300 W was chosen as set power since it is the maximum
power output of the Discover. First we looked at
1
Heating the same volume of solvent in the three selected
microwaves allows a direct comparison of the heating
efficiency of these machines for that specific volume by
simply comparing the obtained final temperatures of the
1
1
heated solvent. However, one should be very careful since
the differences observed are also related to the specific
material used for the vessel construction. This can be clearly
deduced from a comparison of the heating profiles of
toluene in the Greenchem and HP-500 vessel in the MARS
1
1
at the same constant power (Fig. 6). A simple heating
experiment with 20 mL of microwave transparent tetra-
chloromethane clearly showed that the vessel material itself
(
sleeve and/or insert) is not completely microwave
transparent and is at least partially responsible for the
heating up of the irradiated solvent via conduction
1
2
Fig. 7). This process becomes more and more important
(
the more microwave transparent the irradiated solvent is.
Remarkably, toluene and tetrachloromethane can not be
heated in the high-pressure vessel of the microSYNTH at a
constant power of 300 W since the system shuts down after
a few minutes. The heating profiles of pure toluene confirm
that our failure with the scale-up of the amination of
1
0
tetrahydrofurane (tan dZ0.047), which has already been
used frequently as solvent in Buchwald–Hartwig aminations
8
f,8j
(Fig. 9).
In comparison with toluene at the same power
4
-chloroanisole with morpholine is related to the use of
(Fig. 6), tetrahydrofurane significantly increased the
obtained final temperatures in all microwave platforms
(Fig. 9) although the tan d is only slightly higher than that of
toluene. Even though the heating profile of tetrahydrofurane
is certainly a lot better, the solvent reaches a final
temperature of only 94 8C upon heating at maximum
power output for 10 min in the Discover. Therefore we
looked for other alternatives. Inspired by a lecture where
toluene as solvent in that specific microwave platform.
Importantly, the heating profiles also indicate that in the
Greenchem vessel of the MARS multi-mode microwave,
scale-up of the desired amination might be possible. Indeed,
performing the amination on a 20 mmol scale of substrate at
150 8C using an initial set power of 1200 W and for a total
reaction time of 10 min gave a complete conversion of
Figure 8. Heating profile of 1, 3, 4 and 6 Greenchem vessels, each filled with 20 mL of toluene, irradiated in the MARS system for 10 min in a power/time
experiment at a constant power of 1200 W.

10344
K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
Figure 9. Heating profile of 20 mL of tetrahydrofurane in several commercial available microwave systems, irradiated in a power/time experiment at a
constant power of 300 W for 10 min.
Figure 10. Heating profile of 20 mL of trifluoromethylbenzene (BTF) in several commercial available microwave systems, irradiated in a power/time
experiment at a constant power of 300 W for 10 min.

K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
10345
For the scale-up experiments we first evaluated the Discover
single-mode microwave of CEM. An attempt to scale-up
our test case amination of 4-chloroanisole with morpholine
with a factor 20 (20 mmol 4-chloroanisole, 24 mmol
morpholine, 28 mmol NaOt-Bu, 20 mL BTF) in an 80 mL
vessel proceeded smoothly since a complete conversion of
starting material and an isolated yield of 85% of 4-(4-
methoxyphenyl)morpholine could be achieved in the same
reaction time (10 min) as when 1 mmol of the aryl chloride
1
5
was used in BTF (Table 1). Next we looked at the
possibility to perform this experiment in a completely
automized batch wise process. For this purpose we used the
Voyager (stop/flow system) system of CEM. For our
automized scale-up experiment we made a stock solution
of catalyst (Pd(OAc) /2 DCPB) in BTF and a second
2
solution containing 4-chloroanisole, morpholine and NaOt-
Bu in BTF. The latter is a heterogeneous mixture due to the
low solubility of NaOt–Bu in BTF. Therefore this stock
solution was put on a magnetic stirring plate, which
prevented precipitation of the base at the bottom of the
bottle and, which allowed the creation of a more or less
homogeneous suspension. The whole setup can be seen in
Figure 11. When we programmed the Voyager for three
cycles of 20 mmol aryl chloride the average yield was
similar as the one obtained in the previously mentioned one
batch experiment (Table 1). Even when we performed 12
cycles the yield did not drop significantly since an average
yield of 76% for batches 10–12 was obtained. When one
takes into account that a complete cycle takes only 16 min,
the stop/flow system gives the opportunity to make 1.35 mol
Figure 11. Experimental setup for the scale-up of Pd-catalyzed aminations
using the Voyager platform.
Claisen rearrangements were executed using trifluoro-
methylbenzene (benzotrifluoride: BTF) as the solvent and
a review stating the stability of this solvent under strongly
basic conditions at high temperature we investigated the
heating profile of 20 mL of this solvent at a constant power
1
3,14
of 300 W.
Interestingly, we found that BTF heats up
very rapidly, including in the Discover system at maximum
power output, since all vessel-microwave combinations
gave a final solvent temperature equal or higher than 148 8C
(around 261 g) of 4-(4-methoxyphenyl)morpholine in one
(
Fig. 10). Since in the real experiments our vessel contains
day. Next we attempted to scale-up the most challenging
coupling we previously published namely the amination of
in addition to solvent also polar reagents that will couple
with microwaves we can expect that the required 150 8C
will certainly be reached in one to two minutes as desired.
Therefore we considered BTF as a good solvent candidate
for scale-up of Buchwald–Hartwig aminations in single-
mode as well as multi-mode platforms. Since BTF has
hitherto never been used in palladium-catalyzed reactions
we checked its potential as an amination solvent.
Rewardingly, when we coupled 4-chloroanisole with
morpholine at small scale in a 10 mL glass vessel in the
Discover we found that in the same reaction time at the same
final temperature a similar isolated yield was obtained using
this solvent as a toluene substitute (Table 1).
4-chloroanisole with N,N-dibutylamine using DTPB as
ligand for the palladium catalyst. Performing the experi-
ment on a 20 mmol scale of 4-chloroanisole in an 80 mL
glass vessel in the Discover gave the same yield as on a
1 mmol scale in a 10 mL glass vessel in toluene (Table 2).
Further scale-up in the Voyager gave an average yield of
44% over three cycles and clearly illustrates the power of
the Voyager system. Finally, we also tried to use a
heteroaromatic substrate namely 3-chloropyridine. Pd-
catalyzed amination of 3-chloropyridine (20 mmol) with
benzylamine (30 mmol) using DTPB as ligand gave a 85%
isolated yield in a one batch experiment in the 80 mL vessel
Table 2. Scale-up of the Pd-catalyzed amination of 4-chloroanisole with N,N-dibutylamine
a
Microwave
4-Chloroanisole
(
Vessel
Initial set power
(W)
Solvent
Yield (%)
mmol)
Volume (mL)
Type
Discover
Discover
Voyager
1
20
3!20
10
80
80
Glass
Glass
Glass
300
300
300
Toluene
BTF
BTF
50
45
44
b
a
4-Chloroanisole (y mmol), N,N-dibutylamine (1.2y mmol), NaOt–Bu (1.4y mmol), toluene or BTF (y mL).
Average yield.
b

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K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
Table 3. Scale-up of the Pd-catalyzed amination of 3-chloropyridine with benzylamine
a
Microwave
3-Chloropyridine
(
Vessel
Initial Set Power
(W)
Solvent
Yield (%)
mmol)
Volume (mL)
Type
Discover
Discover
Voyager
1
20
3!20
10
80
80
Glass
Glass
Glass
300
300
300
Toluene
BTF
BTF
87
85
81
b
a
3-Chloropyridine (y mmol), benzylamine (1.5y mmol), NaOt-Bu (1.4y mmol), toluene or BTF (y mL).
Average yield.
b
in the Discover, which is essentially the same as the result
obtained on a 1 mmol scale in toluene (Table 3). Running
three cycles in the Voyager also gave a similar result
microwave irradiation can be easily scaled-up without
yield decrease if trifluoromethylbenzene (BTF) is used as
solvent. Single-mode as well as multi-mode platforms can
be used for this purpose. Although similar yields could be
obtained in the Voyager, microSYNTH and MARS
equipment, we prefer the Voyager since it is a completely
automized unit that allows the continuous production of
reaction product without the necessity to manually load and
unload reaction vessels. Moreover, the Voyager allows
pumping of heterogeneous mixtures, which is problematic
in continuous-flow units.
(
average yield of 81%) (Table 3).
Secondly, we looked at the scale-up possibilities (6!
0 mmol) of the MARS (Greenchem vessels) and micro-
2
SYNTH (high-pressure vessels) multi-mode microwaves of
the companies CEM and Milestone, respectively. To get an
idea about the set power required to heat up multiple vessels
we performed power/time experiments with 6 vessels each
containing 20 mL of BTF. We decided to execute these
power/time experiments in the microSYNTH (high-pressure
vessels) since we already found that heating one Greenchem
vessel with 20 mL of BTF at a constant power of 300 W for
5. Experimental
1
0 min in the MARS system gives a higher final temperature
5
.1. General
than when a similar experiment is performed in a high-
pressure vessel in the microSYNTH (Fig. 10). Heating 6
high-pressure vessels with 20 mL of BTF at a constant
power of 300 W gave a final solvent temperature of 127 8C,
which is 21 degrees lower than when one vessel is heated at
the same constant power in the same time (Fig. 10).
Increasing the power to 600 W increased the final
temperature of the solvent for the 6 high-pressure vessels
to a similar value as with one high-pressure vessel at 300 W
and therefore 600 W was selected as the set power for the
large scale amination experiments. Irradiating a rotor with
For column chromatography Kieselgel 60 (ROCC, 0.040–
.063 mm) was used. Pd(OAc)2 (Acros), DCPB (Strem
0
Chemicals or Acros), DTPB (Strem Chemicals or Acros),
BTF (Acros) as well as all the amines and (hetero)aryl
chlorides were obtained from commercial sources and used
as such. The characterization data of 4-(4-methoxyphenyl)
morpholine, N,N-dibutyl-4-methoxyaniline and N-benzyl-
pyridin-3-amine were identical with those previously
For the microwave-assisted
7l,16
reported in the literature.
amination experiments in toluene extra dry (!30 ppm
water) toluene of Acros was used. The toluene (Acros) used
to determine the heating profiles was p.a. quality.
6
high-pressure vessels each containing 20 mmol 4-chloro-
anisole, 24 mmol morpholine, 28 mmol NaOt–Bu and
mol% Pd(OAc) /2 mol% DCPB catalyst in 20 mL BTF
1
2
to 150 8C using an initial set power of 600 W gave a
complete conversion of starting material in 10 min and an
average isolated yield of 77% of 4-(4-methoxyphenyl)-
morpholine (Table 1). A similar experiment with 6
Greenchem vessels in the MARS using the same microwave
parameters gave 80% reaction product (Table 1). Both large
scale (6!20 mmol) experiments performed in a micro-
SYNTH and MARS multi-mode system gave a similar yield
as the small scale (1 mmol) experiment in a 10 mL glass
vessel in the Discover (Table 1).
5
(
.2. Scale-up of palladium-catalyzed aminations of
hetero)aryl chlorides using the Voyager platform
5
.2.1. Preparation of the stock solutions. Stock solution
one. A 250 mL bottle (Schott) was charged with (hetero)aryl
chloride (70 mmol), amine (morpholine or N,N-dibutyl-
amine: 84 mmol) (N-benzylamine: 105 mmol) and NaOt–
Bu (9.42 g, 98 mmol) and BTF (35 mL) in air.
Subsequently, the bottle was flushed with Ar for a few
minutes under magnetic stirring. The stock solution of
reagents (including base) is heterogeneous. Therefore it was
placed on a magnetic stirring plate, which prevented
precipitation of the base at the bottom of the bottle. This
allowed the creation of a more or less homogeneous
suspension.
4. Conclusion
Rapid Pd-catalyzed amination of aryl chlorides under

K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
10347
Stock solution two. A 250 mL bottle (Schott) was charged
Acknowledgements
with Pd(OAc)2 (0.157 g, 0.70 mmol), 2-(dicyclohexyl-
phosphanyl)biphenyl (DCPB) or 2-(di-t-butylphospanyl)
biphenyl (DTPB) (1.4 mmol) and BTF (35 mL) in air.
Subsequently, the bottle was flushed with Ar for 10 min
under magnetic stirring. When DTPB was used as ligand for
the catalyst the stock solution was stirred for 16 h before
B. M. acknowledges the financial support by the ‘Fund for
Scientific Research-Flanders’ (FWO-Vlaanderen) (research
grant 1.5.088.04), the European Union and the University of
Antwerp (RAFO-RUCA). The authors wish to thank the
technical staff (ing. J. Aerts, J. Schrooten, W. Van Lierde
and ing. J. Verreydt) and Gitte Van Baelen of the research
group for their assistance. S. H. thanks the IWT-Vlaanderen
1
7
using it.
(
‘Instituut voor de Aanmoediging van Innovatie door
5
.3. Remarks
Wetenschap en Technologie in Vlaanderen’) for a
scholarship.
*
The viscosity of the stock solutions influences the
actual volume that will be pumped out of the stock
solutions in the reaction vessel of the Voyager
system in a certain timeframe. Therefore one needs
to calibrate the system first by determining the
pumping time necessary to pump in the desired
volume (#mmol of reagents and base, catalyst).
We coupled the Voyager platform to a nitrogen
cylinder (Fig. 11). In this way flushing of the tubing
during loading, unloading and cleaning of the
reaction vessel is performed with N gas instead of
2
air.
The set power for all amination experiments using
the Voyager or Discover system was 300 W, the set
temperature 150 8C. The total irradiation time
References and notes
1
. For recent reviews and books on microwave-assisted organic
synthesis: (a) Lidstr o¨ m, P.; Tierney, J.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225–9283. (b) Larhed, M.; Hallberg,
A. Drug Discovery Today 2001, 6, 406–416. (c) Kappe, C. O.
Am. Lab. 2001, 33, 13–19. (d) Larhed, M.; Moberg, C.;
Hallberg, A. Acc. Chem. Res. 2002, 35, 717–727. (e) Lew, A.;
Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem.
*
*
2
2
002, 4, 95–105. (f) Kappe, C. O. Curr. Opin. Chem. Biol.
002, 6, 314–320. (g) Hayes, B. L. Microwave Synthesis:
Chemistry at the Speed of Light; CEM: Matthews, 2002. (h)
Microwaves in Organic Synthesis; Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2002. (i) Hayes, B. L. Aldrichim.
Acta 2004, 37, 66–77. (j) Microwave-Assisted Organic
Synthesis; Lindstr o¨ m, P., Tierney, J. P., Eds.; Blackwell:
Oxford, 2004. (k) Kappe, C. O. Angew. Chem., Int. Ed. 2004,
(including the ramp time to the set temperature)
was 10 min. Crude reaction mixture was filtered
over Celite and rinsed well with dichloromethane.
The filtrate was subsequently evaporated under
reduced pressure and the residue purified by flash
column chromatography on silica gel.
43, 6250–6284.
. (a) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.;
Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279–282.
2
(
b) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945–4958.
5
4
.4. Scale-up of the palladium-catalyzed amination of
-chloranisole with morpholine using the MARS and
3
4
. http://www.cem.com/; http://www.milestonesrl.com/; http://
www.biotage.com/; http://www.plazmatronika.pl/eng/index.
html; http://www.anton-paar.com/.
microSYNTH platform
A Greenchem or high-pressure vessel was charged with
. (a) Raner, K. D.; Strauss, C. R.; Trainor, R. W.; Thorn, J. S.
J. Org. Chem. 1995, 60, 2456–2460. (b) Perio, B.; Dozias,
M.-J.; Hamelin, J. Org. Process Res. Dev. 1998, 2, 428–430.
(c) Cl e´ ophax, J.; Liagre, M.; Loupy, A.; Petit, A. Org. Process
Res. Dev. 2000, 4, 498–504.
4-chloranisole (20 mmol), morpholine (24 mmol) and
NaOt–Bu (2.69 g, 28 mmol) in air. Subsequently the vial
was flushed with Ar for one minute. Then, 20 mL of a stock
solution of catalyst was added via a syringe and the
†
resulting mixture stirred and flushed with Ar for a few
minutes. Next, the Greenchem or high-pressure vessel was
sealed. 6 Greenchem or high-pressure vessels filled in this
way were then heated to 150 8C in a MARS or
microSYNTH platform, respectively. The set power was
5
. (a) Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem.
1
994, 59, 3408–3412. (b) Kazba, K.; Chapados, B. R.;
Gestwicki, J. E.; McGrath, J. L. J. Org. Chem. 2000, 65,
210–1214. (c) Khadilkar, B. M.; Madyar, V. R. Org. Process
1
Res. Dev. 2001, 5, 452–455. (d) Esveld, E.; Chemat, F.; van
Haveren, J. Chem. Eng. Technol. 2000, 23, 279–283. (e)
Esveld, E.; Chemat, F.; van Haveren, J. Chem. Eng. Technol.
6
00 W. The total irradiation time (including the ramp time
to the set temperature) was 10 min. After the rotor was
cooled down to room temperature the vessels were opened,
the contents of the 6 vessels combined, filtered over Celite
and rinsed well with dichloromethane. The filtrate was
subsequently evaporated under reduced pressure and the
residue purified by flash column chromatography on silica
gel.
2
Tetrahedron Lett. 2002, 43, 5607–5609.
000, 23, 429–435. (f) Shieh, W.-C.; Dell, S.; Repi, O.
6
. For the scale-up of Heck and Negishi reactions in a prototype
multi-mode microwave of Anton Paar GmbH see: Stadler, A.;
Yousefi, B. H.; Dallinger, D.; Walla, P.; Van der Eycken, E.;
Kaval, N.; Kappe, C. O. Org. Process Res. Dev. 2003, 7,
7
07–716. For the scale-up of Suzuki reactions in a single-mode
†
Stock solution of catalyst, A 250 mL bottle (Schott) was charged with
microwave of CEM (Discover) using a 50 mL round-bottomed
flask see: Leadbetter, N. E.; Marco, M. J. Org. Chem. 2003, 68,
888–892.
Pd(OAc)
DCPB) (0.981 g, 2.8 mmol) and BTF (70 mL) in air. Subsequently,
the bottle was flushed with Ar for 10 min under magnetic stirring.
2
(0.314 g, 1.40 mmol), 2-(dicyclohexylphosphanyl)biphenyl
(

10348
K. T. J. Loones et al. / Tetrahedron 61 (2005) 10338–10348
7
. For small scale microwave-assisted Pd-catalyzed amination of working at the same power. The maximum power measure-
aryl halides see: (a) Sharifi, A.; Hosseinzadeh, R.; Mirzaei, M.
Monatsh. Chem. 2002, 133, 329–332. (b) Wan, Y.; Alterman,
M.; Hallberg, A. Synthesis 2002, 1597–1600. (c) Maes,
B. U. W.; Loones, K. T. J.; Lemi e` re, G. L. F.; Dommisse,
R. A. Synlett 2003, 1822–1824. (d) Wang, T.; Magnin, D. R.;
Hamann, L. G. Org. Lett. 2003, 5, 897–900. (e) Antane, S.
Synth. Commun. 2003, 33, 2145–2149. (f) Burton, G.; Cao, P.;
Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373–4376. (g) Weigand,
K.; Pelka, S. Mol. Divers. 2003, 7, 181–184. (h) McCarroll,
A. J.; Sandham, D. A.; Titcomb, L. R.; de K. Lewis, A. K.;
Cloke, F. G. N.; Davies, B. P.; de Santana, A. P.; Hiller, W.;
Caddick, S. Mol. Divers. 2003, 7, 115–123. (i) Brain, C. T.;
Steer, J. T. J. Org. Chem. 2003, 68, 6814–6816. (j) Jensen,
T. A.; Liang, X. F.; Tanner, D.; Skjaerbaek, N. J. Org. Chem.
ment method used to determine the power output of the single-
mode Discover unit (CEM) is also different so comparing
heating profiles, resulting from power/time experiments
performed at the same constant power output in a multi-
mode or single-mode platform, gives also only a rough
indication of the difference in performance of the microwave
systems. Working at the same set constant power output in
both platforms is in reality actually not working at the same
power. In addition, for all commercial microwaves (single-
mode and multi-mode) there is a ‘nominal’ power. Not all
units of a certain type produce exactly the same power so even
comparison between two units can be tricky (MARS G15%,
microSYNTH G10%, Discover G10%). Microwave power
measurement: (1) MARS (1200 W): heat 1 L of water (Tinitial
:
2
004, 69, 4936–4947. (k) Harmata, M.; Hong, X.; Ghosh, S. K.
1
8–22 8C) in a beaker for 2 min at the maximum power of the
microwave and determine the temperature difference of the
Tetrahedron Lett. 2004, 45, 5233–5236. (l) Maes, B. U. W.;
Loones, K. T. J.; Hostyn, S.; Diels, G.; Rombouts, G.
Tetrahedron 2004, 60, 11559–11564. (m) Poondra, R. R.;
Turner, N. J. Org. Lett. 2005, 7, 863–866.
water; power in WattsZ35 (TfinalKTinitial); (2) microSYNTH
(
1000 W): heat 1 L of water (Tinitial: around 10 8C) for 1 min in
a beaker at the maximum power of the microwave and
determine the temperature difference of the water; power in
WattsZ70 (TfinalKTinitial); (3) Discover (300 W): heat 50 mL
of water (Tinitial: 18–22 8C) for 30 s in a 100 mL round-
bottomed flask at the maximum power of the microwave and
determine the temperature difference of the water; Power in
WattsZ7 (TfinalKTinitial).
8
. For reviews on palladium-catalyzed amination see: (a)
Bara n˜ ano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem.
1997, 1, 287–305. (b) Frost, C. G.; Mendon c¸ a, P. J. Chem.
Soc., Perkin Trans. 1 1998, 2615–2623. (c) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2047–2067. (d) Yang, B. H.;
Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125–146. (e)
Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2000; pp 195–262. (f) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209. For
reviews containing a part on recent progress made in
palladium-catalyzed amination see: (g) Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211. (h) Prim,
D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron
1
2. For the heating profiles (IR) of quartz and glass vessels filled
with microwave transparent CCl
4
measured in a Smith
Synthesizer (Personal Chemistry) see: Garbacia, S.; Desai,
B.; Lavastre, O.; Kappe, C. O. J. Org. Chem. 2003, 68,
9
136–9139.
1
1
1
3. Lecture of N. Moorcroft presented at the ‘2nd International
Microwaves in Chemistry Conference’, Orlando (USA), 4/3–
2002, 58, 2041–2075. (i) Wolfe, J. P.; Thomas, J. S. Curr. Org.
7
/3 2004.
Chem. 2005, 9, 625–655. For a review dealing with
palladium-catalyzed aminations seen from an industrial point
of view see: (j) Schlummer, B.; Scholz, U. Adv. Synth. Catal.
4. Use of BTF as solvent in organic synthesis: Maul, J. J.;
Ostrowski, P. J.; Ublacker, G. A.; Linclau, B.; Curran, D. P.
Top. Curr. Chem. 1999, 206, 79–105.
2004, 346, 1599–1626.
5. For the amination of 4-chloroanisole with morpholine we also
attempted to scale-up with a factor 36 (36 mmol 4-chlor-
oanisole, 43.2 mmol morpholine, 50.4 mmol NaOt-Bu, 36 mL
BTF) in the 80 mL vessel of the Discover apparatus. In the
same reaction time as for the 1 mmol and 20 mmol
experiments (10 min) an isolated yield of 73% of 4-(4-
methoxyphenyl)morpholine could be obtained. This is similar
to the yield obtained on a 1 mmol scale (78%) but lower than
the isolated yield of the 20 mmol experiment (85%).
9
. For pioneering literature on Buchwald’s monodentate phos-
phine ligands based on a biphenyl backbone see: (a) Old,
D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722–9723. (b) Wolfe, J. P.; Buchwald, S. L. Angew.
Chem., Int. Ed. 1999, 38, 2413–2416. (c) Wolfe, J. P.; Tomori,
H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000,
65, 1158–1174.
1
1
0. Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.;
Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213–223.
1. The maximum power measurement method the manufacturers
1
6. (a) Trifonov, L. S.; Orahovats, A. S. Helv. Chim. Acta 1987,
7
0, 1732–1736. (b) O’Connor, S. J.; Barr, K. J.; Wang, Le.;
(
CEM, Milestone) use to determine the power output of their
Sorensen, B. K.; Tasker, A. S.; Sham, H.; Ng, S.-C.; Cohen, J.;
Devine, E.; Cherian, S.; Saeed, B.; Zhang, H.; Lee, J. Y.;
Warner, R.; Tahir, S.; Kovar, P.; Ewing, P.; Alder, J.; Mitten,
M.; Leal, J.; Marsh, K.; Bauch, J.; Hoffman, D. J.; Sebti, S. M.;
Rosenberg, S. H. J. Med. Chem. 1999, 42, 3701–3710.
multi-mode system (MARS, microSYNTH) is different. If the
IEC method is used for the MARS platform it delivers a
maximum power output of 1500 W instead of 1200 W. The
microSYNTH platform delivers a maximum power output of
1000 W following the IEC method. This means one should
take into account that the compared heating profiles, resulting
from power/time experiments performed at the same constant
power output in the MARS and microSYNTH platform, give
only a rough indication of the difference in performance of
both multi-modes. Working at the same set constant power
output in both multi-mode platforms is in reality actually not
17. Recently, Buchwald and co-workers reported that by stirring a
mixture of Pd(OAc) and DTPB in toluene for 16 h at room
temperature a palladacycle is formed. In consequence of this
report, we always stirred our stock solution of Pd(OAc) and
2
2
DTPB for at least 16 h before using it: Zim, D.; Buchwald,
S. L. Org. Lett. 2003, 5, 2413–2415.