Rapid palladium-catalyzed aminations of aryl chlorides with aliphatic amines under temperature-controlled microwave heating

Article abstract of DOI:10.1016/j.tet.2004.09.071

Rapid Buchwald-Hartwig amination of electron neutral and rich aryl chlorides and bromides have been achieved using temperature-controlled microwave heating. Primary and secondary aliphatic amines can be coupled with these substrates in good yields within a reaction time of only 10 min. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.09.071

Tetrahedron 60 (2004) 11559–11564
Rapid palladium-catalyzed aminations of aryl chlorides
with aliphatic amines under temperature-controlled
microwave heating
a,*
a
Bert U. W. Maes, Kristof T. J. Loones, Steven Hostyn, Gaston Diels and Geert Rombouts
a
b
a
a
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Janssen Pharmaceutica, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
b
Received 23 June 2004; revised 27 August 2004; accepted 17 September 2004
Available online 19 October 2004
Abstract—Rapid Buchwald–Hartwig amination of electron neutral and rich aryl chlorides and bromides have been achieved using
temperature-controlled microwave heating. Primary and secondary aliphatic amines can be coupled with these substrates in good yields
within a reaction time of only 10 min.
q 2004 Elsevier Ltd. All rights reserved.
In the last decade, the impact of homogeneous palladium
catalysis on the field of organic syntheses has increased
exponentially. Within this diverse research area the
palladium-catalyzed amination, in the mid nineties inde-
pendently discovered by Buchwald and Hartwig, has
currently established itself as the most powerful method
bond formation methodology for its use in the preparation of
biologically active compounds. However, for incorporation
in lead discovery and optimization processes the Buchwald–
Hartwig amination reaction still has the major drawback
that the reaction times are usually in the order of hours to
one day. This might be too long for high-throughput
medicinal chemistry programs in which large libraries of
2
available for the C(sp )–N bond formation as it is applicable
for both activated and non-activated aryl halogenides. This
1
8
compounds have to be made within a short period of time.
is exemplified by its use in the synthesis of several natural
products such as the alkaloids makaluvamine C, damirones
Moreover, in such programs aryl chlorides, the least reactive
substrates of the aryl halogenides, are more preferred
compounds than aryl bromides and aryl iodides because of
2
2
3
4
A and B, lavendamycin and isocryptolepine. Besides
natural products also drug analogues and drug metabolites
have been prepared by a Buchwald–Hartwig reaction. For
instance, raloxifene (launched by Eli Lilly to prevent
osteoporosis) analogues were synthesized via an alternative
1
g
their lower cost and wider availability. Recently, our
laboratory reported a procedure to perform Buchwald–
Hartwig aminations of aryl chlorides with anilines within
9
,10
10 min using temperature-controlled microwave heating.
route by Schmid and co-workers using 2-bromobenzo-
[
The ligand as well as the palladium source reported in this
short communication are air stable and commercially
available products which are important aspects when aiming
for a user-friendly protocol (without the necessity of a
glovebox) as required for chemistry in a high-throughput
program. As an extension of the published work, we now
report the more challenging rapid palladium-catalyzed
microwave-assisted amination of aryl chlorides with
5
b]thiophenes as the amination substrates. Another
example is the synthesis of hydroxyitraconazole, an active
metabolite of the antifungal drug itraconazole launched by
Janssen Pharmaceutica, in which one of the arylpiperazine
moieties is synthesized via a palladium-catalyzed C–N bond
6
formation. Norastemizole, another example of an active
metabolite, was smoothly obtained via the selective
coupling of 2-chloro-1-(4-fluorobenzyl)benzimidazole
with the primary amino group of 4-aminopiperidine. It is
9
,11
aliphatic amines.
7
First, we investigated the Buchwald–Hartwig amination
of morpholine with chlorobenzene, 4-chlorotoluene and
a metabolite of the antiallergic drug Astemizole of Janssen
Pharmaceutica which has reduced side effects. All these
examples clearly indicate the large potential of this C–N
4-chloroanisole under microwave irradiation since secon-
dary cyclic amines are known to be the easiest coupling
partners of the aliphatic amines (Table 1, entries 1–3). We
selected the same catalyst, Pd(OAc) and 2-(dicyclohexyl-
phosphanyl)biphenyl (DCPB), as we previously found to
be optimal for rapid aminations of aryl chlorides with
Keywords: Palladium; Homogeneous catalysis; Buchwald–Hartwig amin-
ation; Aryl chlorides; Aryl bromides; Microwave irradiation.
2
1
2
*
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 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.071

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B. U. W. Maes et al. / Tetrahedron 60 (2004) 11559–11564
22
Table 1. Rapid microwave-assisted Buchwald–Hartwig amination of aryl chlorides (CEM Discover apparatus)
a,b
Yield MW
(%)
a,b
Yield oil
bath (%)
Entry
1
Aryl Chloride
Amine
Ligand
1
Pd loading
(
Temp (8C)
mol%)
1
150
91
91
2
3
1
1
1
1
150
150
83
76
85
76
4
Bu
2
NH
1
1
150
15
5
6
7
8
9
Bu
Bu
Bu
Bu
Bu
2
NH
2
NH
2
NH
2
NH
2
NH
1
1
2
3
2
1
2
1
1
2
200
200
150
150
110
28
35
50
47
c
54
d
d
43
48
10
Bu
2
NH
2
1
150
70
63
e
e
11
BnNH
2
2
1
150
81
87
f
1
1
2
3
BnNH
BnNH
2
2
1
1
1
150
150
85
42
e
2
e
e
14
n-HexNH
2
2
1
150
86
85
f
1
1
5
6
n-HexNH
n-HexNH
2
2
1
1
1
150
150
87
20
e
2
a
2
Reaction conditions: Pd(OAc) (X mol%), DCPB or DTPB or DCPAB (2 X mol%), aryl chloride (1 mmol), amine (1.2 mmol), NaOt-Bu (1.4 mmol), toluene
(1 mL).
b
c
d
e
f
Yields of isolated products are an average of two runs.
Pd (dba) was used instead of Pd(OAc) , a Pd/L ratio of 1.5 was used.
The reaction time was 20 min instead of 10 min.
2
3
2
1
3
.5 mmol of amine were used instead of 1.2 mmol.
mmol of amine were used instead of 1.2 mmol.
9
anilines. Interestingly, with a catalyst loading of only
our test substrate since electron rich aryl chlorides are more
1
g
1
mol% and a temperature of 150 8C good results were
difficult substrates than electron neutral ones. This can be
explained by taking into account that the fundamental
processes oxidative addition as well as reductive elimin-
ation are disfavoured by decreasing the electrophilicity of
obtained in a reaction time of only 10 min. The isolated
yield decreased as the substrate became more electron rich
(
4
Table 1, compare entries 1–3). Nevertheless, even for
-chloroanisole (Table 1, entry 3), the most electron rich
1
c,g
the aryl group. In addition, the selectivity of reductive
elimination versus b-H elimination from a palladium amide
complex is better for electron neutral than for electron rich
aryl chloride substrate of the three used, 4-(4-methoxy-
phenyl)morpholine could be obtained in 76% yield.
1
c
substrates. As a test case, we have chosen the coupling of
4-chloroanisole with dibutylamine which is one among the
most challenging combinations. Disappointingly, only 15%
Next, we tried to couple acyclic secondary and primary
amines with aryl chlorides. We selected 4-chloroanisole as

B. U. W. Maes et al. / Tetrahedron 60 (2004) 11559–11564
11561
22
Table 2. Rapid microwave-assisted Buchwald–Hartwig amination of aryl bromides (CEM Discover apparatus)
a,b
Yield MW
(%)
a,b
Yield oil
bath (%)
Entry
Aryl bromide
Amine
Ligand
Pd loading
(
Temp (8C)
mol%)
1
1
1
150
90
91
2
3
4
5
1
1
1
1
1
1
1
1
150
150
150
150
89
87
80
87
88
83
60
Bu
2
NH
49
36
6
7
Bu
Bu
2
NH
NH
2
3
1
1
150
150
c
54
2
d
8
9
BnNH
2
2
1
2
2
1
1
1
150
150
150
61
d
87
d
93
BnNH
d
79
d
79
1
0
n-HexNH
2
a
Reaction conditions: Pd(OAc)
(1 mL).
2
(X mol%), DCPB or DTPB or DCPAB (2 X mol%), aryl bromide (1 mmol), amine (1.2 mmol), NaOt-Bu (1.4 mmol), toluene
b
c
d
Yields of isolated products are an average of two runs.
Pd (dba) was used instead of Pd(OAc) , a Pd/L ratio of 1.5 was used.
mmol of amine were used instead of 1.2 mmol.
2
3
2
3
of N,N-dibutyl-4-methoxyaniline and an incomplete reac-
tion was obtained in 10 min under the standard conditions
phosphane, gave a similar result as we obtained with DTPB
(Table 1, compare entries 7 and 8). We decided to continue
our studies with the latter since DCPAB is substantially
(1 mol% catalyst, 150 8C) (Table 1, entry 4). Neither
increasing the temperature to 200 8C (Table 1, entry 5)
1
3
more expensive than DTPB. As could be expected the
coupling of the less electron rich 4-chlorotoluene with
dibutylamine gave a higher yield than 4-chloroanisole
(Table 1, compare entries 7 and 10). Under the same
conditions as used in entry 7 (1 mol% catalyst, 150 8C,
10 min) we also tried to couple benzylamine and hexyla-
mine with 4-chloroanisole. Since primary aliphatic amines
are known to give diarylation, we used a larger excess of
amine (1.5 equiv of amine instead of 1.2 equiv) to suppress
the formation of undesired diarylated compound. Gratify-
ingly, N-benzyl-4-methoxyaniline and N-hexyl-4-methox-
yaniline could be obtained in excellent yields (81 and 86%,
respectively) (Table 1, entries 11 and 14). The use of
3 equiv of amine did not further significantly increase the
yields (Table 1, entries 12 and 15). Reinvestigation of the
ligand DCPB for the coupling of 4-chloroanisole with
nor additional increasing of the catalyst loading to 2 mol%
(Table 1, entry 6) provided us with acceptable yields and
complete conversion of starting material. Finally, we
discovered that the use of 2-(di-t-butylphosphanyl)biphenyl
(
1
2
DTPB) as the ligand instead of 2-(dicyclohexylphos-
phanyl)biphenyl (DCPB) gave an acceptable result since a
complete conversion of starting material was observed and
5
(
0% of N,N-dibutyl-4-methoxyaniline could be isolated
Table 1, entry 7). An attempt to further increase the yield
by performing the reaction at a lower temperature using a
double loading of catalyst was unsuccessful (Table 1, entry
9
get a full conversion of starting material. Interestingly, the
). In this case a reaction time of 20 min was necessary to
0
phenyl (DCPAB) another electron rich biphenyl based
use 2-dicyclohexylphosphanyl-2 -(N,N-dimethylamino)bi-
1
2

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B. U. W. Maes et al. / Tetrahedron 60 (2004) 11559–11564
benzylamine and hexylamine, respectively, showed inferior
results in comparison with DTBP as the ligand (entries 13
and 16). Interestingly, a literature search revealed that
hitherto for the synthesis of N-benzyl-4-methoxyaniline
the MW experiments the loaded vessels were immersed in a
preheated oil bath. Rapid cooling of the vessels was done in
the MW cavity using a propelled air flow. All the oil bath
experiments performed, clearly revealed a similar yield as
obtained under MW irradiation in the same reaction time
(Tables 1 and 2). These results indicate that, for this type of
reaction, no specific MW effects have to be taken into
account to explain the rapid aminations. The studied MW-
assisted reactions are only governed by thermal effects
(Arrhenius). Nevertheless, from a practical point of view,
the microwave-assisted procedure is still more convenient
than classical heating.
(
93%, 1 mol% catalyst, 4 h) and N-hexyl-4-methoxyaniline
(92%, 2 mol% catalyst, 18 h) from 4-chloroanisole only one
palladium-catalyzed amination protocol has been reported
2
3
using pentaphenylferrocenyl di-tert-butylphosphine
(
1
PPFDTBP) as the ligand for the catalyst. Although, we
4
obtained somewhat lower yields than Hartwig’s group our
protocol has the important advantage that high conversion
rates are obtained for the synthesis of N-benzyl-4-methoxy-
aniline and N-hexyl-4-methoxyaniline. For the former, we
observed a moderate speed-up by a factor 24 while the
conversion time of the latter increases more than 100 times.
Moreover, in this last mentioned case we used only 1 mol%
Pd/2 DTPB catalyst while 2 mol% Pd/2 PPFDTBP was used
in the literature procedure.
In conclusion, we have described general Pd-catalyzed
amination conditions for the high-speed coupling of
electron rich and neutral aryl chlorides with all types of
aliphatic amines under temperature-controlled MW heating
at 150 8C with DCPB (secondary cyclic aliphatic amines) or
DTBP (acyclic secondary and primary aliphatic amines) as
ligand using a low loading of catalyst in only 10 min.
Interestingly, the method developed for aryl chlorides can
also be applied for the amination of aryl bromides.
Finally, we investigated if the same protocol developed for
aryl chlorides could also be used for aryl bromides.
15,16
This
is an important aspect when aiming a generally applicable
protocol for incorporation in high-throughput medicinal
chemistry programs since aryl bromide substrates are also
easily accessible. This would seriously expand the scope of
our microwave amination method. Again electron rich
substrates (3- and 4-bromoanisole) were selected as test
substrates. First, we investigated the amination of 3- and
1. Experimental
1.1. General
1
4
-bromoanisole with N-methylaniline. Gratifyingly, we
H NMR spectra were recorded on a Varian Unity 400
found that 90% of 3-methoxy-N-methyl-N-phenylaniline
and 89% of 4-methoxy-N-methyl-N-phenylaniline were
obtained under the standard conditions used for aryl
chlorides (1 mol% Pd/2 DCPB, 150 8C, 10 min) (Table 2,
entries 1 and 2). Under these conditions also morpholine
could be efficiently coupled with 3- and 4-bromoanisole
spectrometer in the solvent indicated with TMS as the
internal standard. All chemical shifts are given in ppm and
coupling constants are given in Hz. For column chroma-
tography Kieselgel 60 (ROCC, 0.040–0.063 mm) was used.
Pd(OAc)2 (Acros), Pd (dba) (Acros), DCPB (Strem
Chemicals or Acros), DTPB (Strem Chemicals or Acros),
DCPAB (Strem Chemicals or Acros), toluene (Acros, extra
dry !30 ppm water) as well as all the amines and aryl
halides were obtained from commercial sources and used as
such.
2
3
(
Table 2, entries 3 and 4). Next, we investigated the
amination of 4-bromoanisole with dibutylamine. Interest-
ingly, in this case the DCPB ligand gave a better result than
DTPB (Table 2, entries 5 and 6), while the reverse was
observed in the related coupling starting from 4-chloroani-
sole (Table 1, entries 4 and 7). The use of DCPAB as ligand
gave a similar yield as obtained with DCPB (Table 2,
compare entries 5 and 7). We also tried to couple primary
aliphatic amines (benzylamine and hexylamine) with
1.2. General procedure for the rapid palladium-
catalyzed amination of aryl halides
A pressure vial of 10 mL was charged with aryl halide
4
-bromoanisole. As mentioned before a larger excess of
(
(
1 mmol), amine (1.2, 1.5 or 3 mmol) and NaOt-Bu
0.1345 g, 1.4 mmol) in air. Subsequently the vial was
amine is required for primary amines in order to suppress
the formation of undesired diarylated compound. For the
coupling of primary aliphatic amines with 4-bromoanisole
we immediately used 3 equiv of amine without investigating
if a smaller excess would be sufficient. Amination of
†
flushed with Ar for 1 min. Then, 1 mL of a stock solution of
catalyst was added via a syringe and the resulting mixture
†
Preparation of the stock solutions of catalyst: the stock solutions of
4
-bromoanisole with benzylamine using DTPB (87%) gave
2 2 3
catalyst (Pd/2 L or Pd/1.5 L) were prepared using Pd(OAc) or Pd (dba)
a higher yield than when DCPB (61%) was used (Table 2,
entries 9 and 8). Finally, Buchwald–Hartwig amination of
as Pd(0) source and DCPB [Z2-(dicyclohexylphosphanyl)biphenyl],
DTPB [Z2-(di-t-butylphosphanyl)biphenyl] or DCPAB [Z2-dicyclo-
hexylphosphanyl-2 -(N,N-dimethylamino)biphenyl] as ligand. The stock
0
4
-bromoanisole with hexylamine, using DTPB as ligand
for the catalyst, gave 79% of N-hexyl-4-methoxyaniline
Table 2, entry 10).
solutions were stored under an Ar atmosphere. When DTPB was used, the
19
catalyst solution was stirred for 16 h prior to its use.
(
Pd(OAc)
0.0225 g, 0.1 mmol), ligand (0.2 mmol) and toluene (10 mL) were
used. 2 mol% catalyst solution: Pd(OAc) (0.0449 g, 0.2 mmol),
ligand (0.4 mmol) and toluene (10 mL) were used.
2 2
/DCPB or DTPB. 1 mol% catalyst solution: Pd(OAc)
To investigate a possible existence of non-thermal MW
(
1
0h
effects, we executed all the coupling reactions optimized
for MW irradiation also in an oil bath at the same
temperature as the set temperature of the MW experiments.
To allow a reliable comparison the same vessels as used in
the MW runs were used. To mimic the flash heating rate of
2
Pd
Pd
2
(dba)
3
/DCPAB stock solution. 1 mol% catalyst solution:
3
(0.0458 g, 0.05 mmol), DCPAB (0.0590 g, 0.15 mmol)
2
(dba)
and toluene (10 mL) were used.

B. U. W. Maes et al. / Tetrahedron 60 (2004) 11559–11564
11563
stirred and flushed with Ar for an additional 2 min. Next, the
vial was sealed with an Al crimp cap with septum and
heated at the desired temperature (Tables 1 and 2) in a CEM
Discover microwave apparatus. The set power for all
experiments was 300 W. The total heating time for all
reactions was 10 min. After the reaction vial was cooled
down to room temperature using a propelled air flow, it was
opened and filtered over Celite and rinsed well with 100 mL
dichloromethane. The filtrate was subsequently evaporated
under reduced pressure and the residue purified by flash
column chromatography on silica gel.
CH Cl /heptane (7/3). The characterization data obtained
2 2
for N-benzyl-4-methoxyaniline are identical to those
previously reported in the literature. For comparison, we
1
4
1
report here our H NMR data: d (CDCl ): 7.38–7.31 (m,
H
3
4H), 7.27 (t, JZ7.0 Hz, 1H), 6.77 (d, JZ9.0 Hz, 2H), 6.61
(d, JZ9.0 Hz, 2H), 4.28 (s, 2H), 3.8 (br s, 1H), 3.74 (s, 3H).
1.2.7. N-Hexyl-4-methoxyaniline (Table 1, entry 14;
Table 2, entry 10). Eluent for flash column chroma-
tography: CH Cl /heptane (8/2). The characterization data
2
2
obtained for N-hexyl-4-methoxyaniline are identical to
those previously reported in the literature. For compari-
1
4
The following compounds were prepared in this manner.
1
son, we report here our H NMR data: d (CDCl ): 6.77 (d,
H
3
JZ9.0 Hz, 2H), 6.56 (d, JZ9.0 Hz, 2H), 3.74 (s, 3H), 3.3
br s, 1H), 3.06 (t, JZ7.1 Hz, 2H), 1.59 (p, JZ7.4 Hz, 2H),
.43–1.1.29 (m, 6H), 0,90 (t, JZ7.0 Hz, 3H).
1
.2.1. 4-Phenylmorpholine (Table 1, entry 1). Eluent for
flash column chromatography: CH Cl . The characteri-
(
1
2
2
zation data obtained for 4-phenylmorpholine are identical to
those previously reported in the literature. For compari-
2
0
1
son, we report here our H NMR data: d (CDCl ): 7.28 (dd,
1.2.8. 3-Methoxy-N-methyl-N-phenylaniline (Table 2,
entry 1). Eluent for flash column chromatography:
CH Cl /heptane (6/4). The characterization data obtained
H
3
JZ8.8, 7.3 Hz, 2H), 6.92 (d, JZ8.1 Hz, 2H), 6.88 (t, JZ
7
4
2
2
.3 Hz, 1H), 3.86 (br t, JZ4.7 Hz, 4H), 3.16 (br t, JZ
.7 Hz, 4H).
for 3-methoxy-N-methyl-N-phenylaniline are identical to
those previously reported in the literature. For compari-
2
1
1
son, we report here our H NMR data: d (CDCl ): 7.28 (dd,
H
3
1
.2.2. 4-(4-Methylphenyl)morpholine (Table 1, entry 2).
Eluent for flash column chromatography: CH Cl /heptane
JZ8.4, 7.3 Hz, 2H), 7.15 (t, JZ8.1 Hz, 1H), 7.06 (dd, JZ
.7, 1.1 Hz, 2H), 6.99 (tt, JZ7.3, 1.1 Hz, 1H), 6.58 (ddd,
2
2
8
(90/10). The characterization data obtained for 4-(4-
methylphenyl)morpholine are identical to those previously
JZ8.1, 2.3, 0.8 Hz, 1H), 6.53 (t, JZ2.3 Hz, 1H), 6.49 (ddd,
JZ8.1, 2.3, 0.8 Hz, 1H), 3.75 (s, 3H), 3.30 (s, 3H)
1
7
reported in the literature. For comparison, we report here
1
our H NMR data: dH (CDCl ): 7.08 (d, JZ8.3 Hz, 2H),
3
6
.83 (d, JZ8.3 Hz, 2H), 3.85 (br t, JZ4.8 Hz, 4H), 3.11 (br
1.2.9. 4-Methoxy-N-methyl-N-phenylaniline (Table 2,
entry 2). Eluent for flash column chromatography:
CH Cl /heptane (1/1). The characterization data obtained
t, JZ4.8 Hz, 4H), 2.27 (s, 3H).
2
2
1.2.3. 4-(4-Methoxyphenyl)morpholine (Table 1, entry 3;
Table 2, entry 4). Eluent for flash column chromatography:
for 4-methoxyphenyl-N-methyl-N-phenylaniline are identi-
cal to those previously reported in the literature. For
1
8
1
comparison we report here our H NMR data: d (CDCl ):
CH Cl /heptane (90/10). The characterization data obtained
2
2
H
3
for 4-(4-methoxyphenyl)morpholine are identical to those
previously reported in the literature. For comparison, we
7.19 (dd, JZ9.0, 7.2 Hz, 2H), 7.08 (d, JZ9.0 Hz, 2H), 6.88
(d, JZ9.0 Hz, 2H), 6.79 (d, JZ7.2 Hz, 2H), 6.78 (t, JZ
6.8 Hz, 1H), 3.80 (s, 3H), 3.25 (s, 3H).
1
7
1
report here our H NMR data: dH (CDCl ): 6.91–6.83
3
(
m, 4H), 3.86 (br t, JZ4.8 Hz, 4H), 3.77 (s, 3H), 3.05 (br t,
JZ4.8 Hz, 4H).
1
3
.2.10. 4-(3-Methoxyphenyl)morpholine (Table 2, entry
). Eluent for flash column chromatography: CH Cl . The
2
2
1.2.4. N,N-Dibutyl-4-methoxyaniline (Table 1, entry 7;
Table 2, entry 5). Eluent for flash column chromatography:
characterization data obtained for 4-(3-methoxyphenyl)-
morpholine are identical to those previously reported in
the literature. For comparison, we report here our
CH Cl /heptane (90/10). The characterization data obtained
2
14
2
for N,N-dibutyl-4-methoxyaniline are identical to those
previously reported in the literature. For comparison, we
report here our H NMR data: dH (CDCl ): 6.80 (d, JZ
1
H NMR data: d (CDCl ): 7.19 (t, JZ8.2 Hz, 1H), 6.53
1
4
H
3
(br d, JZ8 Hz, 1H), 6.46 (br s, 1H), 6.45 (br d, JZ8 Hz,
1
3
1
4
H), 3.85 (t, JZ4.8 Hz, 4H), 3.80 (s, 3H), 3.15 (t, JZ
.8 Hz, 4H).
9
.0 Hz, 2H), 6.65 (d, JZ9.0 Hz, 2H), 3.75 (s, 3H), 3.17 (br t,
JZ7.5 Hz, 4H), 1.51 (p, JZ7.5 Hz, 4H), 1.33 (sx, JZ
7
.4 Hz, 4H), 0.93 (t, JZ7.3 Hz, 6H).
1.2.5. N,N-Dibutyl-4-methylaniline (Table 1, entry 10).
Eluent for flash column chromatography: CH Cl /heptane
Acknowledgements
2
2
(
1/1). The characterization data obtained for N,N-dibutyl-4-
methylaniline are identical to those previously reported in
Professor Dr. B. Maes acknowledges the financial support
by the ‘Fund for Scientific Research-Flanders’ (research
grant 1.5.088.04), the European Union and the University of
Antwerp (RAFO-RUCA). Steven Hostyn thanks the
IWT-Vlaanderen (‘Instituut voor de Aanmoediging van
Innovatie door Wetenschap en Technologie in Vlaanderen’)
for a scholarship. The authors wish to thank the technical
staff (B. Acda, ing. J. Aerts, J. Schrooten, W. Van Lierde
and ing. J. Verreydt) of the research group for their
assistance.
1
the literature. For comparison, we report here our H
NMR data: d (CDCl ): 6.99 (d, JZ8.7 Hz, 2H), 6.57 (d,
7
1
H
3
JZ8.7 Hz, 2H), 3.22 (br t, JZ7.5 Hz, 4H), 2.23 (s, 3H),
.54 (p, JZ7.3 Hz, 4H), 1.33 (sx, JZ7.5 Hz, 4H), 0.94 (t,
JZ7.3 Hz, 6H).
1
1.2.6. N-Benzyl-4-methoxyaniline (Table 1, entry 11;
Table 2, entry 9). Eluent for flash column chromatography:

11564
B. U. W. Maes et al. / Tetrahedron 60 (2004) 11559–11564
Chem. 2002, 4, 95–105. (f) Kappe, C. O. Curr. Opin. Chem.
References and notes
Biol. 2002, 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.
1
. For reviews on the Buchwald–Hartwig reaction see:
a) Bara n˜ ano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem.
997, 1, 287–305. (b) Frost, C. G.; Mendon c¸ a, P. J. Chem.
(
1
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. Organometal. Chem. 1999, 576, 125–146.
11. Between the publication of our short communication (see
Ref. 9) and this manuscript Caddick and co-workers reported
microwave-assisted amination of aryl chlorides using palla-
dium-N-heterocyclic carbene complexes as catalyst:
McCarroll, A. J.; Sandham, D. A.; Titcomb, L. R.; Lewis,
A. K.; Cloke, F. G. N.; Davies, B. P.; Perez de Santana, A.;
Hiller, W.; Caddick, S. Mol. Divers. 2003, 7, 115–123.
12. For the amination of aryl chlorides under classical heating
using a palladium catalyst based on an electron rich mono-
phosphanylbiaryl ligand see: (a) Wolfe, J. P.; Buchwald, S. L.
Angew. Chem., Int. Ed. 1999, 38, 2413–2416. (b) See Ref. 8b.
(
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 recent reviews containing a chapter on the Buchwald–-
Hartwig reaction 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 2002, 58,
2
041–2075.
. Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
028–1030.
. (a) Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1984, 25,
175–3178. (b) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda,
2
3
(
c) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
1
Chem. Soc. 2003, 125, 13978–13980. (d) Zim, D.; Buchwald,
S. L. Org. Lett. 2003, 5, 2413–2415.
3. According to the ‘Strem Chemicals’ catalogue (2001–2003)
3
1
M. J. Org. Chem. 1985, 50, 5782–5789. (c) Boger, D. L.; Duff,
S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem. 1985, 50,
2
g DCPB costs 165 Euro, 2 g DTPB costs 165 Euro and 2 g
DCPAB costs 269 Euro.
5
790–5795.
1
1
4. Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553–5566.
4
. Jonckers, T. H. M.; Maes, B. U. W.; Lemi e` re, G. L. F.;
Rombouts, G.; Pieters, L.; Haemers, A.; Dommisse, R. A.
Synlett 2003, 615–618.
5. For the intermolecular microwave-assisted palladium-cata-
lyzed amination of aryl bromides see: (a) Sharifi, A.;
Hosseinzadeh, R.; Mirzaei, M. Monatsh. Chem. 2002, 133,
5
6
. Bradley, D. A.; Godfrey, A. G.; Schmid, C. R. Tetrahedron
Lett. 1999, 40, 5155–5159.
3
29–332. (b) Wan, Y.; Alterman, M.; Hallberg, A. Synthesis
002, 1597–1600. (c) Wang, T.; Magnin, D. R.; Hamann, L. G.
Org. Lett. 2003, 5, 897–900. (d) Antane, S. Synth. Commun.
. (a) Tanoury, G. J.; Senanayaka, C. H.; Hett, R.; Kuhn, A. M.;
Kessler, D. W.; Wald, S. A. Tetrahedron Lett. 1998, 39,
2
6
845–6848. (b) Tanoury, G. J.; Hett, R.; Wilkinson, H. S.;
Wald, S. A.; Senanayake, C. H. Tetrahedron: Assymmetry
003, 14, 3487–3493.
2
2
003, 33, 2145–2149. (e) Weigand, K.; Pelka, S. Mol. Divers.
003, 7, 181–184.
2
1
6. For the intramolecular microwave-assisted palladium-cata-
lyzed amination of aryl bromides see: Brain, C. T.; Steer, J. T.
J. Org. Chem. 2003, 68, 6814–6816.
7
8
. Hong, Y.; Tanoury, G. J.; Wilkinson, H. S.; Bakale, R. P.;
Wald, S. A.; Senanayaka, C. H. Tetrahedron Lett. 1997, 38,
5
607–5610.
. Recently, an interesting article appeared dealing with fast
15 min) room temperature Pd-catalyzed aminations of
1
1
7. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61,
1
133–1135.
(
8. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
activated and unactivated aryl chlorides using alkyl di-t-
butylphosphane ligated palladium(I) dimers. Unfortunately,
the scope of this exceptionally fast room-temperature
amination chemistry is narrow: (a) Stambuli, J. P.; Kuwano,
R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41, 4746–4748.
Although, also other catalysts have been used to perform
Buchwald–Hartwig aminations at room temperature the scope
is generally broader at higher temperature. Moreover, the
reaction times for couplings at room temperature are in the
order of hours to one day: (b) Wolfe, J. P.; Tomori, H.;
Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. J. Org. Chem. 2000,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5
575–5580.
9. 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
1
2
report, we always stirred our stock solution of Pd(OAc)
DTPB at least for 16 h before using it: see Ref. 12d.
2
/
2
2
2
0. Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
002, 67, 6479–6486.
1. Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43,
88–891.
2
8
65, 1158–1174. (c) Stauffer, S. R.; Lee, S.; Stambuli, J. P.;
2. In control microwave experiments the amination reactions
studied were also executed without the use of Pd-catalyst
under otherwise identical reaction conditions. The obtained
results clearly indicate that these reactions require the use of
transition metal catalyst.
Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423–1426.
. Maes, B. U. W.; Loones, K. T. J.; Lemi e` re, G. L. F.;
Dommisse, R. A. Synlett 2003, 1822–1824.
9
1
0. 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 Discov. 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. Combust.
23. It was not attempted to check whether the studied microwave-
assisted aminations were not already finished before 10
minutes. Theoretically, the possibility of a specific microwave
effect can therefore not be ruled out. Nevertheless, if there is
such a microwave effect, it is surely very small.