Study of the microwave-assisted hydrolysis of nitriles and esters and the implementation of this system in rapid microwave-assisted Pd-catalyzed amination

Article abstract of DOI:10.1016/j.tet.2008.03.028

Microwave-assisted hydrolysis of benzonitriles and methyl benzoates has been studied using a toluene/concd aq KOH two phase system in the presence and absence of phase transfer catalyst. Conditions to allow and avoid smooth hydrolysis could be identified. Based on the latter, the first microwave protocol which allows the rapid Pd-catalyzed amination of aliphatic amines with chlorobenzenes containing sensitive functional groups has been developed.

Full text of DOI:10.1016/j.tet.2008.03.028

Tetrahedron 64 (2008) 5604–5619
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study of the microwave-assisted hydrolysis of nitriles and esters
and the implementation of this system in rapid
microwave-assisted Pd-catalyzed amination
*
Gitte Van Baelen, Bert U.W. Maes
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-assisted hydrolysis of benzonitriles and methyl benzoates has been studied using a toluene/
concd aq KOH two phase system in the presence and absence of phase transfer catalyst. Conditions to
allow and avoid smooth hydrolysis could be identified. Based on the latter, the first microwave protocol
which allows the rapid Pd-catalyzed amination of aliphatic amines with chlorobenzenes containing
sensitive functional groups has been developed.
Received 22 December 2007
Received in revised form 7 March 2008
Accepted 10 March 2008
Available online 14 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Hydrolysis
Nitrile
Ester
Phase transfer catalyst
Two phase system
Microwave irradiation
Buchwald–Hartwig reaction
Aryl chlorides
Heterocycles
1. Introduction
known that one of the major advantages of microwave flash heating
is the reduction in reaction time. In one reported case, selectivity
Drugs are often synthesized via an amide or carboxylic acid
function or possess such a functional group in their final structure.
Hydrolysis of a nitrile or an ester function is a commonly used re-
action in organic synthesis to obtain carboxylic acids. The reactions
can be performed in an acidic or alkaline medium, with the use of
enzymes or, in the case of esters, with the aid of metal ions.1 Nitriles
can be hydrolyzed to amides by a whole range of reagents, for ex-
ample: concentrated H2SO4, formic acid and HCl or HBr, acetic acid
and BF3, H2O2 and OHꢀ, sodium percarbonate, dry HCl followed
by H2O.1 The use of water and certain metal ions or complexes also
gives the amide.1 The described conditions for hydrolysis are in
most cases rather harsh. Moreover, long reaction times are often
required. To speed up two phase hydrolysis reactions, in which the
used ester substrates do not dissolve in the alkaline water phase
and therefore are the organic phase, the use of a phase transfer
catalyst (PTC) is often applied.1,2 Another frequently used ‘tool’ for
esters as well as for nitriles in a one phase system is heating the
reaction mixture under microwave irradiation, since it is generally
could even be obtained under microwave irradiation by choosing
the appropriate reaction time.3
Because of the chemical relevance of hydrolysis reactions, we
decided to develop a general microwave-assisted protocol that
is simple, easy to use and mild. Short reaction times are desired and
one should be able to selectively hydrolyze nitriles to amides or
avoid hydrolysis of esters and nitriles by simple tuning of the re-
action conditions (e.g., presence or absence of PTC, higher or lower
reaction temperature). Avoided hydrolysis is interesting for two
phase Pd-catalyzed amination reactions with substrates that con-
tain hydrolysis sensitive nitrile, amide or ester groups. Two phase
Pd-catalyzed aminations under classical heating have already been
reported by Hartwig and co-workers.4 We considered a toluene/
concentrated aqueous KOH two phase system to be useful for our
purpose. KOH is of course a strong nucleophilic base, which prin-
cipally does not allow to avoid hydrolysis, but we reasoned that
when it is used in a very high concentration,5 the solubility of
aq KOH in toluene at a moderate temperature will be avoided or at
least seriously diminished. In other words, reaction conditions
which potentially avoid hydrolysis but allow Pd-catalyzed amina-
tions should be feasible. To get hydrolysis the concentration of KOH
in toluene should be increased. The addition of PTC or simple
* Corresponding author. Tel.: þ32 3 265 32 05; fax: þ32 3 265 32 33.
E-mail address: bert.maes@ua.ac.be (B.U.W. Maes).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.028

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5605
increase of the reaction temperature should fulfill this requirement.
Due to their good availability and low cost, and to the fact that they
are suitable substrates for Pd-catalyzed amination reactions,
chlorobenzonitriles and methyl chlorobenzoate esters are the
substrates of choice.
head to space volume is larger than in a 10 mL vessel allowing
a longer reaction time before the reaction needs to be stopped for
safety reasons due to the pressure increase by ammonia formation.
Clearly, the solubility of concentrated aq KOH in toluene is not high
enough to allow hydrolysis of the nitrile at 100 ꢁC but at higher
temperature (150 ꢁC) the solubility of aq KOH is sufficient allowing
the nitrile to hydrolyze. Since it seems to be possible to selectively
avoid or obtain the hydrolysis of a nitrile to a carboxylic acid by
altering the temperature, we wondered if it would also be feasible
to stop the hydrolysis reaction in the amide stage. To obtain the
benzamide and to avoid further hydrolysis, the use of a PTC at lower
temperature (100 ꢁC) was examined. Therefore, a hydrolysis ex-
periment was performed by adding 10 mol % of N-cetyl-N,N,N-tri-
methylammonium bromide. Interestingly, an isolated yield of 93%
of 4-chlorobenzamide could be obtained together with less than 5%
of 4-chlorobenzoic acid (Table 1, entry 3). The PTC brings hydroxide
anions to the toluene phase allowing hydrolysis but at 100 ꢁC only
the conversion of nitrile to amide is possible.
The hydrolysis of some other benzonitriles under microwave
irradiation was also tested. 3-Chlorobenzonitrile as substrate
showed a similar behaviour as 4-chlorobenzonitrile (Table 1, entries
5–7). 2-Chlorobenzonitrile gave at 150 ꢁC 97% of 2-chlorobenzoic
acid, while the use of N-cetyl-N,N,N-trimethylammonium bromide
at 100 ꢁC in 10 min resulted in a mixture of the corresponding
amide and carboxylic acid (Table 1, entries 8 and 9). Increasing the
time to 60 min gave 84% of 2-chlorobenzoic acid (Table 1, entry 11).
The electron withdrawing ortho chlorine atom seems to make the
hydrolysis of 2-chlorobenzamide to 2-chlorobenzoic acid easier
explaining the formation of carboxylic acid at 100 ꢁC. Nevertheless,
for the hydrolysis of 2-chlorobenzonitrile to 2-chlorobenzamide its
steric hindrance is the major factor as a slower reaction is observed
in comparison with 4-chlorobenzonitrile (Table 1, entries 3 and 9).
At 100 ꢁC, without the quaternary ammonium salt, no hydrolysis of
2-chlorobenzonitrile was observed (Table 1, entry 12). Hydrolysis of
2,6-dichlorobenzonitrile under standard conditions at 150 ꢁC for
10 min gave only 2,6-dichlorobenzamide (Table 1, entry 13). This
shows that steric hindrance of the two ortho chlorine atoms is the
determining factor in this case, not allowing the hydrolysis of 2,6-
dichlorobenzamide to 2,6-dichlorobenzoic acid. Electron rich ortho
substituted benzonitriles such as 2-methoxybenzonitrile are also
difficult substrates since hydrolysis for 2 h at 150 ꢁC gave a mixture
of 62% of 2-methoxybenzamide and 22% of 2-methoxybenzoic acid
(Table 1, entry 15). Full conversion to 2-methoxybenzoic acid could
be achieved using PTC at high temperature (Table 1, entry 17). This
experiment combines the two beneficial effects: better solubility of
the base at higher temperature and the transfer of hydroxide anions
to the toluene phase. However, 2,6-dichlorobenzonitrile could
not be converted to 2,6-dichlorobenzoic acid in a similar experi-
ment because 2,6-dichlorobenzamide was converted to 2-chloro-6-
hydroxybenzamide and 2,6-dihydroxybenzamide instead of the
aimed 2,6-dichlorobenzoic acid.
2. Results and discussion
2.1. Microwave-assisted hydrolysis based on a toluene/
concentrated aqueous KOH two phase system
The first substrate we examined was 4-chlorobenzonitrile. The
reaction conditions used were 1 mmol substrate, 250 mL 21.6 M
KOH, 0.5 mL toluene, mW (40 W).6 In the rest of the article, we will
refer to these as standard conditions. The results are summarized in
Table 1. In a reaction time of 10 min and at a reaction temperature
of 100 ꢁC, no hydrolysis product was found (Table 1, entry 2). When
the same experiment was carried out at 150 ꢁC, it had to be stopped
after 1 min and 47 s due to a serious increase in pressure (see
Section 4.5). 4-Chlorobenzoic acid (72%) and 4-chlorobenzamide
(21%) were obtained (Table 1, entry 1). The amount of 4-chlo-
robenzoic acid can be further increased (80%) (and the amount of
4-chlorobenzamide further reduced (6%)) by using an 80 mL mi-
crowave vial in the Discover unit (Table 1, entry 4). In this way, the
Table 1
Microwave-assisted hydrolysis experiments of benzonitriles in toluene/aq KOH
(21.6 M KOH) at different temperaturesa
Entry
ArCN
T
(ꢁC)
Time
(min)
PTC
Recovery
ArCN
(%)
Amide
(%)
Acid
(%)
addedb
1
150
100
100
150
1.5
10
10
6
No
No
Yes
No
d
21
d
93
6
72
d
NC
Cl
2
>90c
d
3
<5
80
4d
d
5
6
7
8
100
150
100
150
10
10
10
10
No
No
Yes
No
>90c
d
d
2
d
96
10
97
Cl
Cl
NC
d
88
2
d
9
100
100
100
100
150
10
30
60
10
10
Yes
Yes
Yes
No
No
43
45
5
5
77
84
d
CN
10
11
12
13
Traces
d
d
>90c
d
d
92e
d
Cl
Further, the hydrolysis of methyl 4-chloro-, methyl 2-chloro-
and methyl 3-chlorobenzoate was examined. Hydrolysis experi-
ments were performed under the developed standard conditions at
(a) 100 ꢁC, (b) 150 ꢁC and (c) 100 ꢁC with the addition of 10 mol %
PTC. Reaction times and yields are summarized in Table 2. As ob-
served for the chlorobenzonitriles, no hydrolysis occurred at 100 ꢁC
in 10 min (Table 2, entries 2, 8 and 11). At 150 ꢁC, as expected,
hydrolysis of methyl 4-chloro-, methyl 2-chloro- and methyl 3-
chlorobenzoate to their corresponding acids occurred in a reaction
time of 10 min (Table 2, entries 1, 7 and 10). When PTC was added,
the three esters smoothly hydrolyzed at 100 ꢁC in a reaction time of
10 min (Table 2, entries 3, 9 and 12).
14
15
16
100
10
No
97c
d
d
Cl
CN
150
100
150
120
10
No
No
Yes
d
62
d
22
d
OMe
>90c
d
CN
17
120
d
82
a
Reactions were conducted under microwave irradiation (power¼40 W) on
a 1 mmol scale in toluene (0.5 mL) and 250 mL KOH (21.6 M). The indicated isolated
yield is the average of two runs.
b
N-Cetyl-N,N,N-trimethylammonium bromide (10 mol %).
No hydrolysis product, or a trace amount that could not be isolated, was
c
observed.
For methyl 4-chlorobenzoate, we also investigated the influence
of the type of organic solvent and the concentration of the KOH
solution on hydrolysis. When toluene was substituted for dioxane
d
An 80 mL microwave vial was used and the experiment was run on a 5 mmol
scale (power¼80 W).
e
2-Chloro-6-hydroxybenzamide (2%) was formed.

5606
G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
Table 2
Table 3
Microwave-assisted hydrolysis experiments of methyl 4-chloro-, methyl 2-chloro-
and methyl 3-chlorobenzoate in toluene or dioxane/aq KOH at different
temperaturesa
Microwave-assisted hydrolysis experiments of (4-chlorophenyl)acetonitrile and
(3,4-dimethoxyphenyl)acetonitrile in toluene/aq KOH (21.6 M) at different
temperaturesa
Entry
ArCO2Me
T
Time PTC
[KOH] Solvent Recovery Acid
Entry
Nitrile
T
(ꢁC)
Time
(min)
Recovery
substrate
(%)
Amide
(%)
Acid
(%)
(ꢁC) (min) addedb (M)
ArCO2Me (%)
(%)
O
1b
2b
3
4b
5b
160
160
100
160
160
100
10
30
d
d
97
21
2
32
d
d
24
6
65
92
d
46
80
d
Cl
O
1
2
150 10
100 10
No
No
21.6
21.6
Toluene
d
94
Cl
NC
NC
MeO
Toluene >90c
d
10
3
100 10
100 10
100 10
100 10
150 10
Yes
No
No
No
No
21.6
21.6
8
Toluene
d
94
2
60
480
10
4d
5e
6g
7
Dioxane >90
O
6
99
d
Dioxane
Toluene
Toluene
d
74f
10
97
a
Reactions were conducted under microwave irradiation (power¼40 W) on
a 1 mmol scale in toluene (0.5 mL) and 250 mL KOH (21.6 M). The indicated isolated
yield is the average of two runs.
8
83
b
A set power of 50 W was used.
21.6
d
Cl
O
8
9
100 10
100 10
No
21.6
21.6
Toluene >90c
d
89f
MeO
Yes
Toluene
Toluene
d
d
carboxylic acid derivative of (4-chlorophenyl)acetonitrile. To reach
a temperature of 160 ꢁC in a reasonable ramp time, the power was
set at 50 W. After 10 min, 32% of 2-(4-chlorophenyl)acetamide
and 65% of (4-chlorophenyl)acetic acid were isolated (Table 3, entry
1). A reaction time of 30 min yielded 92% of (4-chlorophenyl)acetic
acid (Table 3, entry 2). For the hydrolysis of (3,4-dimethoxy-
phenyl)acetonitrile at 160 ꢁC and in a reaction time of 60 min, 46%
of (3,4-dimethoxyphenyl)acetic acid could be isolated together
with 21% of starting material and 24% of the corresponding amide
(Table 3, entry 4). A reaction time of 8 h yielded 80% of (3,4-
dimethoxyphenyl)acetic acid, 6% of the corresponding amide and
still 2% of the starting material (Table 3, entry 5). Interestingly,
experiments with the use of PTC at 100 ꢁC did not give the desired
amides. Instead, the ApCI-MS spectrum revealed the formation of
3-oxo-2,4-diphenylbutanenitriles (2,4-bis(4-chlorophenyl)-3-oxo-
butanenitrile and 2,4-bis(3,4-dimethoxyphenyl)-3-oxobutaneni-
trile). These products are formed via deprotonation of a benzylic
proton of the phenylacetonitrile followed by addition to the nitrile
function of another substrate molecule and subsequent hydrolysis
of the imine.
10
11
150 10
100 10
100 10
No
No
Yes
21.6
21.6
21.6
96
d
Cl
Toluene >93c
Toluene
MeO
O
12
d
91f
a
Reactions were conducted under microwave irradiation (power¼40 W) on
a 1 mmol scale in toluene (0.5 mL) and 250 mL KOH (21.6 M). The indicated isolated
yield is the average of two runs.
b
N-Cetyl-N,N,N-trimethylammonium bromide (10 mol %) was added.
No hydrolysis product, or a trace amount that could not be isolated, was
c
observed.
d
Dioxane (0.5 mL) was used.
Dioxane (0.5 mL) and 250 mL 8 M KOH were used.
No ArCO2Me, or a trace amount that could not be isolated, was observed.
8 M KOH (250 mL) was used.
e
f
g
and with otherwise standard hydrolysis conditions, only traces of
the corresponding benzenecarboxylic acid derivatives were formed
and more than 90% of the ester could be recovered while a similar
experiment with more diluted aqueous KOH (250 mL 8 M KOH,
100 ꢁC, 10 min) yielded 4-chlorobenzoic acid as the sole reaction
product with no substrate recovery (Table 2, compare entries 4 and
5). When a hydrolysis experiment was executed in toluene with
diluted aqueous KOH (8 M KOH), partial formation of 4-chloro-
benzoic acid (10%) was observed (Table 2, entry 6). These results
indicate that besides the selection of solvent, also the concentration
of base is really essential to allow (or avoid) hydrolysis. Clearly,
when the organic solvent is more polar, the solubility of aqueous
KOH can only be minimized when concentrated aqueous KOH
(21.6 M) is used.
(4-Chlorophenyl)acetonitrile and (3,4-dimethoxyphenyl)aceto-
nitrile were two other substrates which were subsequently sub-
jected to hydrolysis experiments. The challenge for these substrates
is that the cyano group is not directly attached to the arene ring, so
hydrolysis will be more difficult due to competitive a-deprotona-
tion. Moreover, the hydrolysis products are relevant from a phar-
maceutical point of view.7 (3,4-Dimethoxyphenyl)acetonitrile, for
example, can be used for the synthesis of papaverine, an alkaloid
from opium, which is used as a vasodilator and antispasmodic.8
In the papaverine synthesis, (3,4-dimethoxyphenyl)acetonitrile
is hydrolyzed to (3,4-dimethoxyphenyl)acetic acid with the aid
of H2SO4. When the benzylcyanides were subjected to our standard
hydrolysis experiment at 100 ꢁC for 10 min, a full recovery of
starting material could be achieved (Table 3, entries 3 and 6). Be-
cause the nitrile function is not directly attached to the aromatic
ring, a reaction temperature of 160 ꢁC was required to obtain the
2.2. Rapid microwave-assisted Pd-catalyzed amination of aryl
chlorides containing sensitive functional groups with
aliphatic amines based on a toluene/concentrated aqueous
KOH two phase system
The palladium-catalyzed amination of aryl halides and sulfo-
nates, pioneered by the research groups of Buchwald and Hartwig,
is the most important tool hitherto available to create C(sp2)–N
bonds.9 Recent research has mainly been devoted to the de-
velopment of new ligands that create more active catalysts for the
less reactive aryl chlorides. The interest in aryl chlorides is based on
the better availability and lower cost in comparison to the corre-
sponding bromides and iodides. Unfortunately, especially the use of
weak inorganic non-nucleophilic bases (K3PO4, K2CO3, Cs2CO3),
required for substrates that contain groups sensitive to nucleophilic
attack, still requires long reaction times (hours to 1 day) for com-
plete conversion of substrate.10 To allow fast Buchwald–Hartwig
reactions on aryl chlorides, which can be used in library design in
pharmaceutical and agrochemical research projects, our laboratory
studied the implementation of microwave irradiation. After all, one
of the major reported advantages of microwave flash heating is the
well known reduction in reaction time.11 In 2003, we described the
first microwave-assisted Pd-catalyzed aminations on aryl chlo-
rides.12 In 10 min at 150 ꢁC or 200 ꢁC under microwave irradiation,

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5607
complete conversion of substrates and good yields of arylamines
could be obtained with primary and secondary aliphatic amines as
well as anilines. The biphenyl based phosphine ligands, 2-(dicy-
clohexylphosphino)biphenyl (DCPB) and 2-(di-tert-butylphosphi-
no)biphenyl (JohnPhos), introduced by Buchwald, proved to be
ideal for this purpose and showed a good temperature stability.13
Remarkably, the protocols developed for aryl chlorides could also
be used on aryl bromide substrates without any adaptation. N-
Heterocyclic carbene based catalysts also proved to be useful
for rapid microwave-assisted Buchwald–Hartwig reactions.14 In all
these reports, strong MOt-Bu was used as a base. Unfortunately,
this base does not allow a large functional group compatibility since
the presence of esters, enolizable ketones, nitriles and nitro groups
is often incompatible. Although there are some successful examples
on the use of weak inorganic bases on aryl bromides in in-
termolecular microwave-assisted Pd-catalyzed aminations, the
applicability seems to be rather limited in amine type since only
examples on the use of anilines are described.15 Interestingly, this
limitation to anilines is also true for published examples on pseu-
dohalides such as triflates (for which Cs2CO3 was used as inorganic
base).16a Recently, also nonaflates have been used under microwave
irradiation for intermolecular couplings.16b In this case, a soluble,
non-nucleophilic organic tertiary amine based on an amidine
(DBU) or guanidine (MTBD) was selected as base. Although anilines,
heteroarylamines, imines and benzamides seem to be viable
coupling partners under the developed conditions, no examples on
reactions with aliphatic amines were shown. Interestingly, there
are only three reports on the use of aryl chlorides in combination
with a weak inorganic base in microwave-assisted intermolecular
Buchwald–Hartwig reactions.16c,d,17 In these studies only heteroaryl
chlorides or electron-deficient and some electron-neutral aryl
chlorides were successfully used. Moreover, the amine coupling
partners were very specific as only sulfonamides and sulfoximines
were used. Remarkably, all the microwave-assisted protocols
which are based on a weak base hitherto published only coupled
amines which are relatively acidic (anilines, heteroarylamines,
amides, sulfonamides, imines, sulfoximines). The limited scope
in terms of the use of the amine type for microwave-assisted
Pd-catalyzed aminations on substrates which contain a functional
group sensitive to nucleophiles, made us wonder whether our
results of Section 2.1 could be implemented for the development of
a rapid coupling protocol of aliphatic amines with aryl chlorides
while avoiding hydrolysis.
at 150 ꢁC and with a loading of 1 mol % Pd(OAc)2/2DCPB, a complete
conversion of substrate could be obtained under microwave
irradiation in 10 min reaction time. 4-(4-Methylphenyl)morpholine
was isolated in 70% yield (Table 4, entry 1). In order to achieve rapid
microwave-assisted aminations, it is crucial to take into account
the ratio of toluene and concentrated KOH solution. When 1 mL of
toluene was used instead of 0.5 mL under otherwise identical
conditions, only 9% of 4-(4-methylphenyl)morpholine could be
isolated (Table 4, entry 2). This striking difference most probably
results from a combination of two effects: (a) reduced concentra-
tion of substrate in toluene and (b) diminished contact of the two
phases.18 Our two phase system based on aqueous KOH as a base
and microwave irradiation as heating source seems to be superior
because when, with the assistance of microwave irradiation, other
weak bases were tested for the reaction of 4-chlorotoluene with
morpholine, no good results could be obtained. The use of Cs2CO3
(2 equiv) in toluene gave a low conversion in a reaction time
of 10 min at 150 ꢁC with a 1 mol % loading of Pd(OAc)2/2DCPB. This
is a striking difference with our previous study with alcoholate
base where the same coupling gave a complete conversion (iso-
lated yield: 83%) in the same reaction time at the same reaction
temperature.12b Clearly, substitution of NaOt-Bu for Cs2CO3 is
detrimental for the reaction. Unfortunately, the shape of the re-
quired 10 mL microwave vials does not allow the use of a larger
excess of Cs2CO3 in order to test a possible beneficial role of
interphase deprotonation as previously described by us for cou-
pling reactions on aryl iodides under classical heating.19 Therefore,
we tried to use a dipolar aprotic solvent (DMF), which gives
a higher solubility of the base, but still no good conversion was
obtained in 10 min at 150 ꢁC.20 Doubling the reaction time and/or
a further increase of the reaction temperature to 170 ꢁC in DMF
did not provide better results. In all cases the isolated yields were
less than 30%.
After the successful coupling of an electron-neutral chloroben-
zene also electronically rich 4-chloroanisole was tested as sub-
strate. It could be coupled with morpholine under the same
reaction conditions of entry 1, but in this case a higher loading of
catalyst (5 mol %) was required to get complete conversion in
10 min. The isolated yield (68%) is similar to the one obtained
using our MAOS protocol with strong NaOt-Bu base (76%) (Table 4,
entry 3).12b
As our real aim was the use of aryl chlorides which contain
functional groups sensitive to nucleophilic attack, we subsequently
looked at the amination of 4-chlorobenzonitrile with morpholine.
From our hydrolysis experiments, we knew that a reduction of
reaction temperature gives a reduced solubility of concentrated
aqueous KOH in toluene. In addition, we also proved that it is
important to stick to the use of aqueous KOH in the highest con-
centration to diminish its solubility in toluene at a given temper-
ature. In this way, a reaction temperature could be defined at which
As a test substrate, in order to test the feasibility of our two
phase system and to simplify the problem, we selected an electron-
neutral chlorobenzene that does not contain a functional group
which is sensitive towards nucleophilic attack: 4-chlorotoluene.
Morpholine was chosen as the amine since secondary cyclic amines
are known to be the easiest coupling partners of the aliphatic
amines. Interestingly, under our developed standard conditions
Table 4
Microwave-assisted Buchwald–Hartwig reactions of non-nucleophile sensitive aryl chlorides in a toluene/aq KOH (21.6 M) two phase systema
Entry
ArCl
Amine
Catalyst
Pd
(mol %)
T
(ꢁC)
Time
(min)
Product
Yield
(%)
1
A
A
A
1
1
5
150
150
150
10
10
10
70
9
Me
Cl
Cl
HN
O
Me
Me
N
N
N
O
O
O
2b
3c
68
MeO
HN
O
MeO
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). Amine (1.2 equiv) and 250 mL KOH (21.6 M) were used.
A¼Pd(OAc)2/2DCPB. The indicated isolated yield is the average of two runs.
b
Toluene (1.0 mL) was used.
A set power of 60 W was used.
c

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G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
no hydrolysis of the nitrile group occurs in a hydrolysis experiment,
namely 100 ꢁC. At this temperature, in the case of a Pd-catalyzed
amination reaction, a liquid–liquid interphase deprotonation might
still allow Pd-catalyzed amination reactions, while hydrolysis
sensitive substrates are not attacked. Based on the fact that we
previously found solid–liquid interphase deprotonation of Pd(II)–
amine complexes is possible, liquid–liquid interphase deprotona-
tion is certainly feasible.19 Alternatively, a low concentration of
concentrated aqueous KOH in toluene does not allow hydrolysis but
is still sufficient to allow deprotonation of Pd(II)–amine complex.
When the deprotonation step is not rate limiting in the mechanism
of the Pd-catalyzed amination reaction, the latter is certainly pos-
sible. Of course, a combination of both ways of deprotonation
cannot be excluded. Gratifyingly, when 4-chlorobenzonitrile was
coupled with morpholine under our developed standard conditions
at 100 ꢁC using Pd(OAc)2/2DCPB, no hydrolysis of nitrile was ob-
served and 76% of 4-morpholin-4-ylbenzonitrile could be isolated
(Table 5, entry 1).21 As the reaction temperature is 50 ꢁC lower
in comparison to the experiment on 4-chlorotoluene, 5 mol % of
catalyst and a reaction time of 30 min was required (see Section
4.5).
The fact that we did not need PTC for successful aminations
prompted us to see whether it is essential in the oil bath protocol
published by Hartwig (1 mol % Pd[P(t-Bu3)2, KOH (1.5 equiv),
N-cetyl-N,N,N-trimethylammonium bromide (0.5 mol %), water
(27 mL), toluene (1 mL), 90 ꢁC (oil bath)).4 Therefore, we randomly
repeated some examples underexactlythe same reaction conditions
as described by his team, only omitting PTC (Fig.1). Interestingly, for
the coupling of 4-chloroacetophenone with morpholine we
obtained 86% yield of 1-(4-morpholin-4-ylphenyl)ethanone while
Hartwig reports 84% in the presence of N-cetyl-N,N,N-trimethyl-
ammonium bromide (Fig. 1). Also for the amination of 4-chloro-
anisole with N-methylaniline (82% vs 92%) as well as for the
coupling of 4-bromoanisole with morpholine (84% vs 95%) similar
yields were obtained, indicating the addition of PTC is not essential
in these cases (Fig. 1).22 Of course, for some examples reported
by Hartwig the addition of PTC can have a beneficial effect. After
all, for the coupling of 4-chlorotoluene with dibutylamine, which
was selected as the test system for the development of the protocol,
Hartwig and co-workers clearly showed that the removal of PTC
gives a lower conversion in 24 h (23% vs 94%). Unfortunately, we
could not reproduce these previously published experiments.
Especially in cases with rate determining deprotonations and with
less acidic Pd(II)–amine complexes, the addition of PTC might be
beneficial in our opinion (as long as it does not destroy the catalyst).
However, one needs to be cautious since the higher mentioned
experiment with dibutylamine without phase transfer agent was
performed at only 70 ꢁC which anyway gives a reduced solubility
of aqueous KOH in toluene. In our opinion, one should be very
careful not to add PTC in cases where it has no substantial beneficial
effect on the Pd-catalyzed amination rate to avoid competitive
hydrolysis of sensitive functional groups. This is clearly supported
by the previously mentioned hydrolysis experiment of 4-chloro-
benzonitrile at 100 ꢁC (mW) in the presence of 10% PTC (Table 1,
entry 4), indicating that the PTC brings hydroxide anions in
the toluene phase allowing hydrolysis of the nitrile function at
100 ꢁC.
We wondered if better results could be obtained using the
Pd[P(t-Bu)3]2 catalyst described by Hartwig for amination reactions
of aryl chlorides in toluene with KOH (solid) in the presence of
water using our microwave conditions.4 For the coupling of mor-
pholine with 4-chlorobenzonitrile
a similar yield (74%) was
obtained in a reaction time of 30 min at 100 ꢁC, using 5 mol % of
Pd[P(t-Bu)3]2 (Table 5, entry 2). Importantly, Hartwig reports that
the use of PTC is essential for the transport of hydroxide anions to
the toluene phase in his protocol. Surprisingly, when we added N-
cetyl-N,N,N-trimethylammonium bromide (0.5 mol %) for the cou-
pling of 4-chlorobenzonitrile with morpholine in toluene using
Pd(OAc)2/2DCPB catalyst in the presence of 21.6 M KOH at 100 ꢁC
almost no C–N coupling occurred (Table 5, entry 3). Instead, sub-
strate and 4-chlorobenzamide could be found while the experi-
ment without PTC gave 76% of 4-morpholin-4-ylbenzonitrile.
Table 5
Microwave-assisted Buchwald–Hartwig reactions of 4-chlorobenzonitrile in toluene/aq KOH (21.6 M)a
Entry
1
Amine
Catalyst
Pd
(mol %)
T
Time
(min)
Product
Yield
(%)
(ꢁC)
A
5
100
30
76
HN
O
NC
N
O
2
B
A
A
A
5
5
5
5
100
100
100
100
30
30
30
30
74
NC
NC
NC
NC
N
N
N
N
O
O
O
3b
4c
5
Traces
70
79
HN
N
HN
NC
N
N
6
A
5
100
30
70
CH3
CH3
7
8
H2NBn
A
C
5
5
100
100
30
30
65
79
NC
NC
NHBn
NHBn
9
n-HexNH2
C
5
100
30
74
NC
N(H)n-Hex
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). Amine (1.2 equiv) and 250 mL KOH (21.6 M) were used.
A¼Pd(OAc)2/2DCPB, B¼Pd[P(t-Bu)3]2, C¼Pd(OAc)2/2JohnPhos. The indicated isolated yield is the average of two runs.
b
N-Cetyl-N,N,N-trimethylammonium bromide (0.005 equiv) was added.
Scale-up experiment: an 80 mL microwave vial was used and the experiment was run on a 4 mmol scale (power¼80 W).
c

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5609
without PTCa
86%
with PTCb
84%
Pd[P(t-Bu)3]2
O
O
KOH
+
Cl
Cl
Br
HN
HN
HN
O
N
O
Toluene/Water
6h
Me
Me
Pd[P(t-Bu)3]2
Me
N
Me
+
KOH
82%
92%
MeO
MeO
MeO
MeO
Toluene/Water
48h
Pd[P(t-Bu)3]2
KOH
84%c
95%c
+
O
N
O
Toluene/Water
3h
Figure 1. Effect of PTC on Buchwald–Hartwig reactions in toluene/concd aq KOH in an oil bath. aReactions were conducted on a 1 mmol scale in toluene (1 mL) at 90 ꢁC (oil bath).
c
ArX/amine/KOH/H2O/Pd[P(t-Bu)3]2¼100/105/150/150/1.0. Isolated yield. bN-Cetyl-N,N,N-trimethylammonium bromide (0.005 equiv) was added. ArX (1.03 mmol) and 1.03 equiv
amine were used.
After the successful implementation of the standard conditions
mentioned in Section 2.1 in the Pd-catalyzed amination of 4-
chlorobenzonitrile with morpholine, the scalability of the protocol
and the coupling of 4-chlorobenzonitrile with other aliphatic
amines were screened. When the experiment described in entry 1
of Table 5 was performed on a 4 mmol scale, 70% of 4-morpholin-
4-ylbenzonitrile could be isolated, indicating that our microwave-
assisted amination protocol is suitable for scale-up reactions.
N-Arylation of pyrrolidine gave 79% of 4-pyrrolidin-1-ylbenzonitrile
(Table 5, entry 5). 1-(3-Methylphenyl)piperazine, an amine often
used in medicinal chemistry, yielded 70% of 4-[4-(3-methyl-
phenyl)piperazin-1-yl]benzonitrile (Table 5, entry 6).23 Benzyl-
amine yielded 65% of coupled product under these reaction
conditions (Table 5, entry 7). As we previously reported for our rapid
microwave protocol based on NaOt-Bu that primary aliphatic
amines gave better results using JohnPhos as ligand, we performed
a microwave experiment by substituting DCPB for JohnPhos.12b In-
terestingly, also here a higher yield (79%) could be obtained (Table 5,
entry 8). This ligand also allowed the smooth amination of 4-
chlorobenzonitrile with hexylamine (74%) (Table 5, entry 9).
we first tested the influence of time on the hydrolysis at 100 ꢁC.
Fortunately, in 30 min no significant formation of 4-chlorobenzoic
acid was observed as more than 90% of starting material could be
recovered. Pd-catalyzed amination of methyl 4-chlorobenzoate
with morpholine using our microwave protocol optimized for
4-chlorobenzonitrile (5 mol % Pd(OAc)2/2DCPB, 0.5 mL toluene,
250 mL 21.6 M KOH, 100 ꢁC, 30 min) gave 58% of methyl 4-mor-
pholin-4-ylbenzoate (Table 6, entry 1). Piperidine, however, gave
a lower yield than morpholine (46% of methyl 4-piperidin-1-
ylbenzoate) (Table 6, entry 2). Also 1-(3-methylphenyl)piperazine
could be coupled in good yield (68%) (Table 6, entry 3). When
benzylamine and hexylamine were used as coupling partners,
respectively, 74% of methyl 4-(benzylamino)benzoate and 45% of
methyl 4-(hexylamino)benzoate were obtained (Table 6, entries 4
and 5). In these last two cases, JohnPhos was chosen as ligand as we
found it to give superior results in the corresponding coupling of
primary aliphatic amines with 4-chlorobenzonitrile.
The lower yield in the coupling reaction with piperidine is due
to hydrolysis of the substrate since approximately 20% of 4-chloro-
benzoic acid could also be isolated. Although the substrate itself,
in a mixture of toluene and 21.6 M KOH, does not give any hydro-
lysis at 100 ꢁC (Table 2, entry 2), the used amine clearly determines
the amount of hydrolysis product in the Pd-catalyzed amination
reaction. This is logical if one takes into account that the amine
modifies the polarity of the toluene phase. Consequently, the
amine can change the solubility of aqueous KOH in toluene. If there
Next, we turned our attention to methyl 4-chlorobenzoate,
another substrate sensitive towards nucleophilic attack. As no
hydrolysis occurred at 100 ꢁC in 10 min (Table 2, entry 2), this
temperature was selected for the Pd-catalyzed aminations. As for
the aminations on 4-chlorobenzonitrile 30 min proved to be a good
reaction time and since an ester function is a very sensitive group,
Table 6
Microwave-assisted Buchwald–Hartwig reactions of methyl 4-chlorobenzoate in toluene/aq KOH (21.6 M)a
Entry
Amine
Catalyst
Pd
(mol %)
T
(ꢁC)
Time
(min)
Product
Yield
(%)
O
1
2
A
A
5
5
100
100
30
30
58
N
N
O
N
HN
O
MeO
O
46b
HN
N
MeO
O
HN
N
3
4
A
B
B
5
5
5
100
100
100
30
30
30
68
74
MeO
O
CH3
CH3
H2NBn
NHBn
MeO
O
5
n-HexNH2
45c
N(H)n-Hex
MeO
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). Amine (1.2 equiv) and 250 mL KOH (21.6 M) were used.
A¼Pd(OAc)2/2DCPB, B¼Pd(OAc)2/2JohnPhos. The indicated isolated yield is the average of two runs.
b
Approximately 20% of 4-chlorobenzoic acid was also formed.
Approximately 40% of 4-(hexylamino)benzoic acid was also formed.
c

5610
G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
is a substantial increase in polarity, the hydrolysis of substrate
becomes an important competing process. Surprisingly, repeating
the coupling of methyl 4-chlorobenzoate with aniline reported by
Hartwig (1 mol % Pd[P(t-Bu3)2], KOH (1.5 equiv), N-cetyl-N,N,N-
trimethylammonium bromide (0.5 mol %), water (27 mL), toluene
(1 mL), 90 ꢁC (oil bath), 1 h) also revealed the formation of 4-
chlorobenzoic acid (33%).4 A control oil bath experiment with
methyl 4-chlorobenzoate, omitting catalyst and aniline, gave 70% of
4-chlorobenzoic acid and 25% recovery of substrate in the same
reaction time. These experiments clearly indicate that even
0.5 mol % PTC can be sufficient for a substantial competing un-
desired hydrolysis and the success of the desired process just
depends on the Pd-catalyzed amination versus hydrolysis rate. The
lower yield in the coupling reaction with hexylamine (Table 6,
entry 5) is due to hydrolysis of reaction product since approxi-
mately 40% of 4-(hexylamino)benzoic acid could be isolated. An
independent hydrolysis experiment on 1 mmol of methyl 4-(hex-
ylamino)benzoate at 100 ꢁC for 30 min revealed that almost com-
plete hydrolysis to the corresponding carboxylic acid occurred,
supporting the observation in the Pd-catalyzed amination experi-
ment. This remarkable behaviour prompted us to investigate
hydrolysis resistance of some other Buchwald–Hartwig reaction
products. Methyl 4-morpholin-4-ylbenzoate at 150 ꢁC under stan-
dard hydrolysis conditions for 60 min gave 65% recovery of
substrate and the formation of 4-morpholin-4-ylbenzoic acid. For 4-
morpholin-4-ylbenzoic acid as well as for 4-(hexylamino)benzoic
acid, it is difficult to determine the amount formed as these are
zwitterions and therefore very hard to isolate in a quantitative
hexyl chain into the toluene phase.24 By this alignment, the polar
head of the molecule, the carboxylate group, is pointed to the water
phase allowing smooth hydrolysis. Alternatively, but less probable
taking into account the structures of the other products in Table 6,
methyl 4-(hexylamino)benzoate has a certain solubility in con-
centrated aqueous KOH.
As a last challenging substrate, we investigated 4-chloro-
acetophenone. The acetyl group on itself is of course not hydrolysis
sensitive, but a competitive a-arylation of the ketone can easily
occur. Moreover, it was shown that the product of a,a-diarylation
can be hydrolyzed by hydroxide yielding 1,10-(methylenedi-4,1-
phenylene)diethanone and 4-chlorobenzoic acid.4 When 4-chloro-
acetophenone was coupled with morpholine using our microwave
protocol at 150 ꢁC, 63% of 1-(4-morpholin-4-ylphenyl)ethanone
could be obtained in 30 min reaction time (Table 7, entry 1). The
ApCI-MS spectrum clearly showed the formation of undesired 1,10-
(methylenedi-4,1-phenylene)diethanone and revealed the presence
of another side product that corresponds to 2-(4-acetylphenyl)-1-
[morpholin-4-ylphenyl]ethanone. Therefore, the temperature was
lowered to 120 ꢁC in a subsequent trial. This proved to be beneficial
since 82% of 1-(4-morpholin-4-ylphenyl)ethanone was isolated and
the ApCI-MS spectrum did not show the presence of 1,10-(methyl-
enedi-4,1-phenylene)diethanone, but 2-(4-acetylphenyl)-1-[mor-
pholin-4-ylphenyl]ethanone was still formed at this reaction
temperature (Table 7, entry 2). In a similar way, piperidine, pyrro-
lidine and 1-(3-methylphenyl)piperazine could be introduced in
a good yield, respectively, 63%, 73% and 76% (Table 7, entries 3–5).
For the reaction of 4-chloroacetophenone with benzylamine John-
Phos was again chosen as ligand. Performing the reaction at 150 ꢁC
proved to be no problem in this case since the reaction yielded
71% of 1-[4-(benzylamino)phenyl]ethanone with no indication of
1,10-(methylenedi-4,1-phenylene)diethanone formation and, as
expected, 2-(4-acetylphenyl)-1-[4-(benzylamino)phenyl]ethanone
as a side compound (Table 7, entry 6). N-Arylation of hexylamine
with 4-chloroacetophenone occurred also smoothly under the same
reaction conditions at 120 ꢁC (Table 7, entry 7).
manner.
A similar treatment of 4-morpholin-4-ylbenzonitrile
resulted in 74% recovery of substrate as well as 19% of 4-morpholin-
4-ylbenzamide. These experiments clearly reveal that the reaction
products are normally very stable towards hydrolysis since there is
a substantial solubility of aq KOH in toluene at 150 ꢁC. The ‘pro-
tection’ of the methoxycarbonyl and cyano groups in the reaction
products of the Pd-catalyzed amination reactions can be attributed
to the introduced electron releasing amino group. Based on an ar-
ticle of Tomita, the exceptionally smooth hydrolysis of methyl 4-
(hexylamino)benzoate might result from an alignment of the apolar
We also investigated the effect of X-Phos ((2-dicyclohex-
ylphosphino)-20,40,60-triisopropylbiphenyl), a new promising ligand
Table 7
Microwave-assisted Buchwald–Hartwig reactions of 4-chloroacetophenone in toluene/aq KOH (21.6 M)a
Entry
Amine
Catalyst
Pd
(mol %)
T
(ꢁC)
Time
(min)
Product
Yield
(%)
O
1
2
3
4
A
A
A
A
5
5
5
5
150
120
120
120
30
30
30
30
63
82
63
73
N
N
O
O
HN
O
Me
O
Me
O
N
HN
HN
N
Me
O
N
Me
O
HN
N
N
5
6
A
5
120
30
76
Me
O
CH3
CH3
H2NBn
B
B
5
5
150
120
30
30
71
63
NHBn
Me
O
7
n-HexNH2
N(H)n-Hex
Me
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). Amine (1.2 equiv) and 250 mL KOH (21.6 M) were used.
A¼Pd(OAc)2/2DCPB, B¼Pd(OAc)2/2JohnPhos. The indicated isolated yield is the average of two runs.

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5611
Table 8
Microwave-assisted Buchwald–Hartwig reactions of aryl chlorides in toluene/aq KOH (21.6 M) with X-Phos as ligand for the Pd-catalysta
Entry
ArCl
Amine
Pd
(mol %)
T
(ꢁC)
Time
(min)
Product
Yield
(%)
1
2
5
5
100
100
30
30
99
50
NC
O
Cl
Cl
HN
O
O
NC
N
O
O
H2NBn
NC
O
NHBn
N
3
4
5
5
5
5
100
100
120
30
30
30
24b
54
HN
MeO
MeO
O
H2NBn
NHBn
N
MeO
O
O
93
Cl
O
HN
O
Me
Me
O
6
H2NBn
5
120
30
66
NHBn
Me
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). X-Phos, amine (1.2 equiv) and 250 mL KOH (21.6 M) were
used. The indicated isolated yield is the average of two runs.
b
Approximately 20% ArCl was recovered.
whichwasintroducedbyBuchwaldin2003asanewtypeofbiphenyl
basedphosphine, ontheefficiencyofourprotocol.25,26 Ascanbeseen
in Table 8, the use of 5 mol % Pd(OAc)2/2X-Phos under otherwise
similar conditions rather exceptionally gave a better performance.
Usually equal or worse isolated yields were obtained in comparison
to DCPB and JohnPhos (compare Table 8 with Tables 5–7).
assisted coupling protocols based onweak bases have been reported
for this type of amine, we wanted to know whether our conditions
(use of our two phase system and microwave irradiation as heating
source) are also suitable. N-Methylaniline was chosen as model. The
amination of 4-chlorobenzonitrile using DCPB gave 53% of 4-
[methyl(phenyl)amino]benzonitrile (Table 9, entry 1). The use of
X-Phos gave an equal result (Table 9, entry 2). Also for the coupling
of N-methylaniline with 4-chloroacetophenone a similar yield was
As a penultimate part of this project, we also looked at the
coupling of anilines. Although, as mentioned, good microwave-
Table 9
Microwave-assisted Buchwald–Hartwig reactions of aryl chlorides with N-methylaniline in toluene/aq KOH (21.6 M)a
Entry
ArCl
Catalyst
Pd
(mol %)
T
(ꢁC)
Time
(min)
Product
Yield
(%)
Me
N
1
2
A
B
5
5
100
100
30
30
53
57
NC
Cl
Cl
NC
Me
N
NC
O
Me
N
O
3
4
5
A
B
A
5
5
5
120
120
100
30
30
30
49
45
66
Me
Me
Me
N
O
Me
O
Me
N
O
Cl
Cl
MeO
MeO
O
Me
N
6
B
A
B
5
5
5
100
150
120
30
30
30
40
28
16
MeO
MeO
Me
N
7b
8b
MeO
Me
N
MeO
MeO
Me
N
9b
C
5
120
30
61
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). N-Methylaniline (1.2 equiv) and 250 mL KOH (21.6 M) were
used. A¼Pd(OAc)2/2DCPB, B¼Pd(OAc)2/2X-Phos, C¼Pd[P(t-Bu)3]2. The indicated isolated yield is the average of two runs.
b
Power¼60 W.

5612
G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
Table 10
Microwave-assisted Buchwald–Hartwig reactions of 3-bromoquinoline and tert-butyl 5-bromo-(and chloro)-1H-indole-1-carboxylate in toluene/aq KOH (21.6 M)a
Entry
Substrate
Amine
Catalyst
Pd
(mol %)
T
(ꢁC)
Time
(min)
Product
Yield
(%)
H
N
Br
1b
A
5
5
100
100
30
30
75
H2N
H2N
H2N
CN
O
N
N
CN
H
N
2b
A
77
O
N
OEt
OEt
H
N
3b
A
A
5
5
100
100
30
30
83
70
NO2
N
NO2
Br
4
HN
N
O
N
N
Boc
N
N
O
Boc
Boc
N
HN
N
5
6
7
A
B
B
5
5
5
100
100
100
30
30
30
41
29
13
CH3
CH3
H2NBn
N
N
NHBn
Boc
Boc
n-HexNH2
N(H)n-Hex
Cl
8
A
A
5
5
100
100
30
30
72
40
HN
O
N
N
N
N
O
N
Boc
Boc
Boc
HN
N
N
9
CH3
CH3
a
Reactions were conducted under microwave irradiation (power¼40 W) on a 1 mmol scale in toluene (0.5 mL). Amine (1.2 equiv) and 250 mL KOH (21.6 M) were used.
A¼Pd(OAc)2/2DCPB, B¼Pd(OAc)2/2JohnPhos. The indicated isolated yield is the average of two runs.
b
Amine (1.05 equiv) was used.
obtained with DCPB and X-Phos (Table 9, entries 3 and 4). Using
methyl 4-chlorobenzoate as substrate, DCPB showed to be slightly
better than X-Phos (Table 9, entries 5 and 6). Generally, the yields are
rather low and it seems that our protocol is not well suited for the
introduction of anilines. In fact, also substrates with no hydrolysis
sensitive functional groups such as 4-chloroanisole also gave dis-
appointing yields in the reaction with N-methylaniline. In this case,
Pd[P(t-Bu)3]2 gave a more acceptable result as 61% of 4-methoxy-
N-methyl-N-phenylaniline was isolated (Table 9, entries 7–9).
As a last part, we investigated whether our protocol could also
successfully be used for amination reactions with heteroaromatic
substrates. In these reactions, one of the two coupling partners (the
amine or the heteroaromatic substrate) bears a functional group
sensitive to nucleophilic attack. 3-Bromoquinoline and tert-butyl
5-bromo-(and chloro)-1H-indole-1-carboxylate were chosen as
model heteroaromatic substrates. Protection of the indole nitrogen
is required, since no reaction occurred without N-protection under
our microwave reaction conditions. This is probably due to
deprotonation of the substrate followed by removal of the corre-
sponding amide from the organic phase to the aqueous phase. The
N-Boc-protected 5-halo-1H-indoles are sensitive substrate towards
nucleophilic attack. This was proven by a standard hydrolysis
experiment at 150 ꢁC (mW) in a reaction time of 30 min for tert-
butyl 5-bromo-1H-indole-1-carboxylate. The reaction yielded only
10% of N-Boc-protected substrate together with 80% of 5-bromo-1H-
indole.
3-Bromoquinoline was coupled with 4-aminobenzonitrile, ethyl
4-aminobenzoate and 4-nitroaniline under slightly altered stan-
dard conditions in, respectively, 75%, 77% and 83% (Table 10, entries
1–3). The use of 1.05 equiv amine instead of 1.2 equiv proved to be
better. It is unclear why anilines work so smoothly on this substrate.
tert-Butyl 5-bromo-1H-indole-1-carboxylate and tert-butyl 5-
chloro-1H-indole-1-carboxylate were successfully aminated with
morpholine and 1-(3-methylphenyl)piperazine (Table 10, entries 4,
5, 8 and 9). In the coupling reaction of tert-butyl 5-bromo-1H-in-
dole-1-carboxylate and tert-butyl 5-chloro-1H-indole-1-carboxyl-
ate with 1-(3-methylphenyl)piperazine, respectively, 36% and 34%
of starting material could be recovered. Reaction of tert-butyl 5-
bromo-1H-indole-1-carboxylate with benzylamine and hexyl-
amine did not proceed so fast: after 30 min reaction time only 29%
and 13% reaction product could, respectively, be isolated together
with a recovery of 53% and 74% of starting material (Table 10, en-
tries 6 and 7). Although the coupling yields in these experiments
are low (Table 10, entries 5–7), hydrolyzed substrate (5-bromo-1H-
indole) was never observed. tert-Butyl 5-bromo-1H-indole-1-car-
boxylate could be recovered, pointing out that hydrolysis of the

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5613
starting material is totally suppressed under these reaction
conditions.
Toluene (99.85%, water <50 ppm, extra dry over molecular
sieve) as well as all substrates and amines were purchased from
Acros, except hexylamine, piperidine, 2,6-dichlorobenzonitrile and
2-methoxybenzonitrile, which were obtained from Aldrich. All
compounds were used without further purification. 1-(3-Methyl-
phenyl)piperazine was liberated from its hydrochloric acid salt
using a 2 M NaOH solution. Boc-protection of 5-bromo-1H-indole
and 5-chloro-1H-indole was performed according to a literature
procedure.27 Concentrated KOH solution (21.6 M) and KOH pow-
der were prepared using KOH flakes (Acros). KOH powder was
made with a pestle and mortar and was stored under argon atmo-
sphere. N-Cetyl-N,N,N-trimethylammonium bromidewas purchased
from Merck. Pd(OAc)2 and 2-(dicyclohexylphosphino)biphenyl
(DCPB) were purchased from Acros, 2-(di-tert-butylphosphino)bi-
phenyl (JohnPhos) and 2-(dicyclohexylphosphino)-20,40,60-triiso-
propylbiphenyl (X-Phos) from Sigma–Aldrich and Pd[P(t-Bu)3]2 from
ABCR. For the reactions with Pd[P(t-Bu)3]2 as catalyst, an AtmosBag
(with zipper lock front entry, two-hand, large, Sigma–Aldrich) was
used to work under inert atmosphere. A pre-catalyst stock solution
was made for all the catalyst systems and Pd[P(t-Bu)3]2 was used as
such. Catalyst systems using DCPB or JohnPhos were stirred over-
night and X-Phos was stirred for only 10 min (we noticed that the
catalyst decomposes in a short time). Pre-catalyst formation and
storage was performed under argon atmosphere. Flash column
chromatography was performed on Kieselgel 60 (ROCC, 0.040–
0.063 mm).
3. Conclusions
In this article, we describe an easy, efficient and fast microwave-
assisted hydrolysis protocol. Substrates with nitriles and esters as
functional groups can be hydrolyzed using a two phase system
based on toluene/concd aq KOH. A range of aromatic nitriles can be
selectively hydrolyzed to the amide or carboxylic acid stage by,
respectively, adding a phase transfer catalyst or by raising the
reaction temperature. In the second part of this article, the
knowledge of the microwave-assisted hydrolysis protocol allowed
the development of a rapid Pd-catalyzed amination protocol of
aliphatic amines with aryl chlorides containing functional groups
sensitive towards nucleophilic attack. The protocol allows coupling
in only 30 min reaction time and the sensitive functional groups
remain intact. Interestingly, we found that it is generally not nec-
essary (irrespective from the heating source used) to add a phase
transfer catalyst for the deprotonation of the intermediately
formed Pd(II)–amine complex. This is in contrast with a previous
report of the Hartwig group dealing with oil bath experiments.4
Based on hydrolysis experiments, we clearly showed that adding
phase transfer catalyst makes hydrolysis of the sensitive functional
groups possible and the success of the amination reaction upon its
addition will therefore be highly dependent on the difference in
rate between coupling and hydrolysis (the reaction product is
usually not very sensitive towards hydrolysis) and the amount of
phase transfer catalyst added. When there is no rate determining
Pd(II)–amine deprotonation, the concentration of KOH in the tol-
uene phase is allowed to be very low without affecting the coupling
rate. This low concentration is, however, not enough to result in
hydrolysis of sensitive functional groups in the reaction times used.
Alternatively, the Pd-catalyzed aminations might occur via in-
terphase deprotonation. This reasoning explains the successful
implementation of the concentrated aq KOH/toluene two phase
system, presented in this article, in microwave-assisted Pd-cata-
lyzed amination reactions.
4.2. General procedures
4.2.1. General hydrolysis procedure in toluene/aq KOH (21.6 M)
under microwave irradiation (Tables 1–3)
A
10 mL microwave vial was charged with substrate
(1.0 mmol) followed by concd aq KOH (21.6 M, 250 mL). The
mixture was stirred (a triangular stir bar was used) under ni-
trogen atmosphere for 1 min. Subsequently, 0.5 mL toluene was
added via a syringe and the resulting mixture was stirred and
flushed with nitrogen for an additional 2 min. Next, the vial was
sealed with an Al crimp cap with a septum and heated at the
desired temperature in a CEM Discover microwave apparatus.
The set power was 40 W and the total heating time can be found
in the tables. After the reaction, the vial was cooled down to
room temperature using a propelled air flow, it was opened and
poured into a separating funnel. The vial was rinsed alternately
with water (100 mL) and CH2Cl2 (100 mL). After two more ex-
tractions (2ꢂ50 mL CH2Cl2), the combined organic layers were
dried over MgSO4 and subsequently evaporated under reduced
pressure, giving the first organic fraction. Then, again 100 mL
CH2Cl2 was added to the water phase. The latter was acidified
with 2 M HCl until pH¼7 and extracted. After two more extrac-
tions (2ꢂ50 mL CH2Cl2), the combined organic layers were dried
over MgSO4 and subsequently evaporated under reduced pres-
sure, giving the second organic fraction. Finally, 100 mL CH2Cl2
was added to the water phase. The water layer was now acidified
until pH w1. After two more extractions (2ꢂ50 mL CH2Cl2),
the combined organic layers were dried over MgSO4 and sub-
sequently evaporated under reduced pressure, giving the third
organic fraction. The three organic fractions were characterized
via 1H NMR.
4. Experimental
4.1. General
All melting points were determined on a Bu¨chi apparatus and
are uncorrected. The 1H and 13C NMR spectra were recorded on
a Bruker Avance 400 spectrometer in the solvent indicated with
TMS as an internal standard. All coupling constants are given in
hertz and chemical shifts are given in parts per million. For mass
spectrometric analysis, samples were dissolved in CH3OH and di-
luted to a concentration of approximately 10ꢀ5 mol/L. Injections
(10 mL) were directed to the mass spectrometer at a flow rate of
0.7 mL/min (CH3OH and 0.1% formic acid), using a Kontron HPLC
system. Mass spectrometric data were acquired on an AQA Navi-
gator mass spectrometer (ThermoQuest, Finigan) equipped with
an ApCI ionization interface. The AQAMax voltage was set to 20 V,
the corona voltage to 3.5 kV and the probe temperature to 250 ꢁC.
Nitrogen gas was used for nebulation. Mass spectra were acquired
by summing the spectra in the elution plug. In positive ion mode,
the protonated molecule [MþH]þ is recorded and in negative ion
mode the corresponding deprotonated molecule [MꢀH]ꢀ is
recorded.
When 10 mol % N-cetyl-N,N,N-trimethylammonium bromide
was added, an additional purification step was often required. To
separate the formed amide from the PTC, the first organic fraction
was purified by flash column chromatography on silica gel (eluent
CH2Cl2/MeOH (98/2)). When it was necessary to separate the
formed amide from its corresponding carboxylic acid, CH2Cl2/7 N
NH3 in MeOH (98/2) was used as eluent system.
Microwave heating was carried out with a single-mode Discover
(CEM) unit. The temperature was monitored with an infrared
sensor. Experiments were performed in sealed reaction vessels
with an Al crimp cap with septum.

5614
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4.2.2. General Pd-catalyzed amination procedures
rinsed alternately with water (100 mL) and CH2Cl2 (100 mL), and
the water layer was acidified until pH w1.28 After two more
extractions (2ꢂ50 mL CH2Cl2), the combined organic layers were
dried over MgSO4 and subsequently evaporated under reduced
pressure. Finally, the crude product was purified via column chro-
matography on silica gel to give the desired 4-methoxy-N-methyl-
N-phenylaniline.
4.2.2.1. Buchwald–Hartwig reactions of aryl halides in toluene/aq KOH
(21.6 M) under microwave irradiation, using DCPB, JohnPhos or X-Phos
as ligand for the Pd-catalyst (Tables 4–10). A 10 mL microwave vial
was charged with aryl halide (1.0 mmol) and amine (1.2 mmol) fol-
lowed by concd aq KOH (21.6 M, 250 mL). The mixture was stirred (a
triangular stir bar was used) under nitrogen atmosphere for 1 min.
Subsequently, 0.5 mL of a stock solution of the catalyst in toluene
was added via a syringe and the resulting mixture was stirred and
flushed with nitrogen for an additional 2 min. Next, the vial was
sealed with an Al crimp cap with a septum and heated at the desired
temperature in a CEM Discover microwave apparatus. The set power
and total heating time can be found in the tables. After the reaction,
the vial was cooled down to room temperature using a propelled air
flow, it was opened and poured into a separating funnel. The vial was
rinsed alternately with water (100 mL) and CH2Cl2 (100 mL). In the
case of morpholine, pyrrolidine, benzylamine, hexylamine and pi-
peridine the water layer was acidifiedy with 2 M HCl until pH¼7 and
in the case of N-methylaniline, the water layer was acidified until pH
w1.28 If 1-(3-methylphenyl)piperazine was used, no acidification
was performed. After two more extractions (2ꢂ50 mL CH2Cl2), the
combined organic layers were dried over MgSO4 and subsequently
evaporated under reduced pressure. Finally, the crude product was
purified via column chromatography on silica gel to give the desired
arylamines in the yield shown.
4.2.2.4. Buchwald–Hartwig reactions of liquid aryl halides with KOH
powder and 27 mL water under conventional heating (Fig. 1).4 In an
AtmosBag, aryl halide (1.0 mmol) and amine (1.05 mmol) were
added to a suspension of Pd[P(t-Bu)3]2 (5.1 mg, 10.0 mmol) and KOH
powder (84.0 mg, 1.5 mmol) in toluene (1.0 mL) in a microwave
vial. A stir bar was added, the vial was sealed with an Al crimp cap
with a septum and removed from the AtmosBag. Water (27 mL,
1.5 mmol) was added to the mixture by syringe. The reaction
mixture was then stirred vigorously at 90 ꢁC. After the reaction, the
vial was cooled down to room temperature, it was opened and
poured into a separating funnel. The vial was rinsed alternately
with water (100 mL) and CH2Cl2 (100 mL). In the case of morpho-
line, the water layer was acidified with 2 M HCl until pH¼7 and in
the case of N-methylaniline, the water layer was acidified until pH
w1.28 After two more extractions (2ꢂ50 mL CH2Cl2), the combined
organic layers were dried over MgSO4 and subsequently evaporated
under reduced pressure. Finally, the crude product was purified via
column chromatography on silica gel to give the desired arylamines
in the yield shown.
4.2.2.2. Microwave amination procedure for the coupling of 4-
chlorobenzonitrile with morpholine, using toluene/aq KOH (21.6 M)
and Pd[P(t-Bu)3]2 as catalyst (Table 5, entry 2). In an AtmosBag,
morpholine (104.5 mg, 1.2 mmol) was added to a suspension of
Pd[P(t-Bu)3]2 (25.6 mg, 50.0 mmol) and 4-chlorobenzonitrile
(137.6 mg, 1.0 mmol) in toluene (0.5 mL) in a microwave vial. A
triangular stir bar as well as concd aq KOH (21.6 M, 250 mL) was
added. Next, the vial was sealed with an Al crimp cap with a sep-
tum, removed from the AtmosBag and heated at the desired tem-
perature in a CEM Discover microwave apparatus. The set power
and total heating time can be found in the table. After the reaction
vial was cooled down to room temperature using a propelled air
flow, it was opened and poured into a separating funnel. The vial
was rinsed alternately with water (100 mL) and CH2Cl2 (100 mL)
and the water layer was acidified with 2 M HCl until pH¼7.28 After
two more extractions (2ꢂ50 mL CH2Cl2), the combined organic
layers were dried over MgSO4 and subsequently evaporated under
reduced pressure. Finally, the crude product was purified via col-
umn chromatography on silica gel to give the desired 4-morpholin-
4-ylbenzonitrile.
4.3. Characterization data of the hydrolysis products
4.3.1. 4-Chlorobenzamide (Table 1, entry 1)
4-Chlorobenzonitrile (137.6 mg, 1 mmol). Yield 21% (32.6 mg);
white powder; mp 177.9–178.6 ꢁC (lit. mp 179–180 ꢁC).29 The char-
acterization data are identical to those reported in the literature.30
For comparison, we report here our 1H NMR data: dH (DMSO-d6):
8.02 (br s,1H), 7.89 (d, J¼8.6 Hz, 2H), 7.52 (d, J¼8.6 Hz, 2H), 7.42 (br s,
1H); MS: [MþH]þ¼156, 158.
4.3.2. 4-Chlorobenzoic acid (Table 1, entry 1)
4-Chlorobenzonitrile (137.6 mg, 1 mmol). Yield 72% (112.7 mg);
white powder; mp 238.8–239.8 ꢁC (lit. mp 243 ꢁC).29 The charac-
terization data are identical to those reported in the literature.31 For
comparison, we report here our 1H NMR data: dH (DMSO-d6): 13.14
(br s, 1H), 7.94 (d, J¼8.6 Hz, 2H), 7.57 (d, J¼8.6 Hz, 2H); MS:
[MꢀH]ꢀ¼155, 157.
4.3.3. 3-Chlorobenzoic acid (Table 1, entry 6)
3-Chlorobenzonitrile (137.6 mg, 1 mmol). Yield 96% (150.0 mg);
white powder; mp 154.3–155.3 ꢁC (lit. mp 158 ꢁC).29 The charac-
terization data are identical to those reported in the literature.32 For
comparison, we report here our 1H NMR data: dH (DMSO-d6): 13.29
(br s, 1H), 7.92–7.88 (m, 2H), 7.70 (ddd, J¼8.0, 2.2, 1.2 Hz, 1H), 7.55
(dd, J¼8.1, 8.0 Hz, 1H); MS: [MꢀH]ꢀ¼155, 157.
4.2.2.3. Microwave amination procedure for the coupling of 4-
chloroanisole with N-methylaniline, using toluene/aq KOH (21.6 M)
and Pd[P(t-Bu)3]2 as catalyst (Table 9, entry 9). In an AtmosBag, 4-
chloroanisole (170.6 mg, 1.0 mmol) and N-methylaniline (128.6 mg,
1.2 mmol) were added to a suspension of Pd[P(t-Bu)3]2 (25.6 mg,
50.0 mmol) in toluene (0.5 mL) in a microwave vial. A triangular stir
bar as well as concd aq KOH (21.6 M, 250 mL) was added. Next, the
vial was sealed with an Al crimp cap with a septum, removed from
the AtmosBag and heated at the desired temperature in a CEM
Discover microwave apparatus. The set power and total heating
time can be found in the table. After the reaction, the vial was
cooled down to room temperature using a propelled air flow, it
was opened and poured into a separating funnel. The vial was
4.3.4. 3-Chlorobenzamide (Table 1, entry 7)
3-Chlorobenzonitrile (137.6 mg, 1 mmol). Yield 88% (136.9 mg);
white powder; mp 135.0–137 ꢁC (lit. mp 135.5–137.0 ꢁC).29 The
characterization data are identical to those reported in the litera-
ture.30 For comparison, we report here our 1H NMR data: d
H
(DMSO-d6): 8.06 (br s, 1H), 7.90 (td, J¼1.8, 0.3 Hz, 1H), 7.83 (ddd,
J¼7.7, 1.6, 1.1 Hz, 1H), 7.59 (ddd, J¼8.0, 2.2, 1.1 Hz, 1H), 7.49 (dd,
J¼8.0, 7.7 Hz, 1H), 7.48 (br s, 1H); MS: [MþH]þ¼156, 158.
4.3.5. 2-Chlorobenzoic acid (Table 1, entry 8)
y
When methyl 4-chlorobenzoate, tert-butyl 5-bromo-1H-indole-1-carboxylate
2-Chlorobenzonitrile (137.6 mg, 1 mmol). Yield 97% (151.7 mg);
or tert-butyl 5-chloro-1H-indole-1-carboxylate was used as substrate, no acidifi-
cation was performed.
white powder; mp 140.7–141.1 ꢁC (lit. mp 142 ꢁC).29 The

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5615
characterization data are identical to those reported in the litera-
ture.33 For comparison, we report here our 1H NMR data: dH
(DMSO-d6): 13.34 (br s, 1H), 7.80 (ddd, J¼7.6, 1.5, 0.6 Hz, 1H),
7.55–7.52 (m, 2H), 7.43 (ddd, J¼7.7, 5.4, 3.0 Hz, 1H); MS:
[MꢀH]ꢀ¼155, 157.
4.3.13. (3,4-Dimethoxyphenyl)acetic acid (Table 3, entry 4)
(3,4-Dimethoxyphenyl)acetonitrile (177.2 mg, 1 mmol). Yield
46% (90.3 mg); white/slightly yellow flakes; mp 96.2–97.5 ꢁC (lit.
mp 96–99 ꢁC).35 The characterization data are identical to those
reported in the literature.29 For comparison, we report here our
1H NMR data: dH (CDCl3): 7.26 (br s, 1H), 6.84–6.80 (m, 3H), 3.87
4.3.6. 2-Chlorobenzamide (Table 1, entry 9)
(s, 3H), 3.86 (s, 3H), 3.59 (s, 2H); d (DMSO-d6): 12.18 (br s, 1H),
H
2-Chlorobenzonitrile (137.6 mg, 1 mmol). Yield 45% (70.0 mg);
white powder; mp 140.0–141.0 ꢁC (lit. mp 142.4 ꢁC).29 The charac-
terization data are identical to those reported in the literature.34 For
comparison, we report here our 1H NMR data: dH (DMSO-d6): 7.83
(br s, 1H), 7.54 (br s, 1H), 7.47 (dd, J¼8.2, 1.5 Hz, 1H), 7.45–7.34 (m,
3H); MS: [MþH]þ¼156, 158.
6.87 (d, J¼8.2 Hz, 1H), 6.85 (d, J¼2.0 Hz, 1H), 6.76 (dd, J¼8.2,
2.1 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.47 (s, 2H); MS:
[MþH]ꢀ¼195.
4.4. Characterization data of the Pd-catalyzed amination
products
4.3.7. 2,6-Dichlorobenzamide (Table 1, entry 13)
2,6-Dichlorobenzonitrile (172.0 mg, 1 mmol). Yield 92%
(174.5 mg); shiny white needles; mp 200.5–201.4 ꢁC (lit. mp 196–
201 ꢁC).35 The characterization data are identical to those reported
in the literature.36 For comparison, we report here our 1H NMR
data: dH (DMSO-d6): 8.04 (br s, 1H), 7.77 (br s, 1H), 7.48 (d, J¼9.1 Hz,
1H), 7.48 (d, J¼7.0 Hz, 1H), 7.40 (dd, J¼9.0, 7.0 Hz, 1H); MS:
[MþH]þ¼190, 192, 194.
4.4.1. 4-(4-Methylphenyl)morpholine (Table 4, entry 1)
4-Chlorotoluene (126.6 mg, 1 mmol) and morpholine (104.5 mg,
1.2 mmol). Eluent for column chromatography: heptane/EtOAc (90/
10). Yield 70% (124.6 mg); light brown/yellow powder; mp 47.6–
48.2 ꢁC (lit. mp 47–48 ꢁC).10a The characterization data are identical
to those reported in the literature.4 For comparison, we report here
our 1H NMR data: d (CDCl3): 7.09 (d, J¼8.2 Hz, 2H), 6.83 (d,
H
J¼8.2 Hz, 2H), 3.86 (br t, J¼4.8 Hz, 4H), 3.11 (br t, J¼4.8 Hz, 4H), 2.28
4.3.8. 2-Methoxybenzamide (Table 1, entry 15)
(s, 3H); MS: [MþH]þ¼178.
2-Methoxybenzonitrile (133.2 mg, 1 mmol). Yield 62%
(93.6 mg); white powder; mp 127.2–128.0 ꢁC (lit. mp 129 ꢁC).29 The
characterization data are identical to those reported in the litera-
4.4.2. 4-(4-Methoxyphenyl)morpholine (Table 4, entry 3)
4-Chloroanisole (170.6 mg, 1 mmol) and morpholine (104.5 mg,
1.2 mmol). Eluent for column chromatography: first CH2Cl2 (100%),
then CH2Cl2/MeOH (99/1). Yield 68% (131.6 mg); brown solid; mp
68.8–70.0 ꢁC (lit. mp 71 ꢁC).43 The characterization data are iden-
tical to those reported in the literature.12b For comparison, we
ture.37 For comparison, we report here our 1H NMR data: d
H
(DMSO-d6): 7.80 (dd, J¼7.6, 1.9 Hz, 1H), 7.60 (br s, 1H), 7.47 (ddd,
J¼8.4, 7.3,1.9 Hz,1H), 7.46 (br s,1H), 7.13 (dd, J¼8.5, 0.8 Hz,1H), 7.02
(td, J¼7.5, 1.0 Hz, 1H), 3.89 (s, 3H); MS: [MþH]þ¼152.
report here our 1H NMR data: d (CDCl3): 6.92–6.82 (m, 4H), 3.86
H
4.3.9. 2-Methoxybenzoic acid (Table 1, entry 15)
(br t, J¼4.7 Hz, 4H), 3.77 (s, 3H), 3.06 (br t, J¼4.7 Hz, 4H); MS:
2-Methoxybenzonitrile (133.2 mg, 1 mmol). Yield 22%
(34.1 mg); white powder; mp 95.2–96.2 ꢁC (lit. mp 101 ꢁC).29 The
characterization data are identical to those reported in the litera-
ture.38 For comparison, we report here our 1H NMR data: dH
(CDCl3): 10.59 (br s, 1H), 8.20 (dd, J¼7.7, 1.8 Hz, 1H), 7.58 (ddd,
J¼8.4, 7.4, 1.9 Hz, 1H), 7.15 (ddd, J¼8.4, 7.4, 1.0 Hz, 1H), 7.07 (dd,
J¼8.4, 0.9 Hz, 1H), 4.09 (s, 3H); MS: [MꢀH]ꢀ¼151.
[MþH]þ¼194.
4.4.3. 4-Morpholin-4-ylbenzonitrile (Table 5, entry 2)
4-Chlorobenzonitrile (137.6 mg, 1 mmol) and morpholine
(104.5 mg, 1.2 mmol). Eluent for column chromatography: hep-
tane/EtOAc (70/30). Yield 74% (138.4 mg); white to pale yellow
solid; mp 81.5–82.0 ꢁC (lit. mp 85 ꢁC).10a The characterization data
are identical to those reported in the literature.44 For comparison,
we report here our 1H NMR data: dH (CDCl3): 7.52 (d, J¼9.0 Hz, 2H),
6.86 (d, J¼9.0 Hz, 2H), 3.85 (br t, J¼5.0 Hz, 4H), 3.28 (br t, J¼5.0 Hz,
4H); MS: [MþH]þ¼189.
4.3.10. 2-(4-Chlorophenyl)acetamide (Table 3, entry 1)
(4-Chlorophenyl)acetonitrile (151.6 mg, 1 mmol). Yield 32%
(54.3 mg); white to pale beige powder; mp 181.6–182.2 ꢁC (lit. mp
180–182 ꢁC).39 The characterization data are identical to those
reported in the literature.39 For comparison, we report here our 1H
NMR data: dH (CD3COOD): 7.37–7.30 (m, 4H), 3.64 (s, 2H); dH
(DMSO-d6): 7.45 (br s, 1H), 7.35 (d, J¼8.6 Hz, 2H), 7.27 (d, J¼8.5 Hz,
2H), 6.87 (br s, 1H), 3.37 (s, 2H); MS: [MþH]þ¼170, 172.
4.4.4. 4-Pyrrolidin-1-ylbenzonitrile (Table 5, entry 5)
4-Chlorobenzonitrile (137.6 mg, 1 mmol) and pyrrolidine
(85.3 mg, 1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (80/20). Yield 79% (135.3 mg); yellow solid; mp 81.3–82.8 ꢁC
(lit. mp 88–90 ꢁC).45 The characterization data are identical to
those reported in the literature.45 For comparison, we report here
4.3.11. (4-Chlorophenyl)acetic acid (Table 3, entry 1)
(4-Chlorophenyl)acetonitrile (151.6 mg, 1 mmol). Yield 65%
(110.9 mg); white powder; mp 104.8–105.5 ꢁC (lit. mp 104–
106 ꢁC).40 The characterization data are identical to those reported
in the literature.41 For comparison, we report here our 1H NMR
our 1H NMR data: d (CDCl3): 7.44 (d, J¼9.0 Hz, 2H), 6.50 (d,
H
J¼9.0 Hz, 2H), 3.35–3.30 (m, 4H), 2.08–2.00 (m, 4H); MS:
[MþH]þ¼173.
data: d (CDCl3): 9.00 (br s, 1H), 7.30 (d, J¼8.5 Hz, 2H), 7.21 (d,
4.4.5. 4-[4-(3-Methylphenyl)piperazin-1-yl]benzonitrile (Table 5,
entry 6)
H
J¼8.5 Hz, 2H), 3.62 (s, 2H). d (DMSO-d6): 12.36 (br s, 1H), 7.35 (d,
H
J¼8.6 Hz, 2H), 7.28 (d, J¼8.5 Hz, 2H), 3.58 (s, 2H); MS:
4-Chlorobenzonitrile (137.6 mg, 1 mmol) and 1-(3-methyl-
phenyl)piperazine (194.4 mg, 1.2 mmol). Eluent for column chro-
matography: heptane/EtOAc (80/20). Yield 70% (386.5 mg); pale
yellow powder; mp 132.3 ꢁC. dH (CDCl3): 7.51 (d, J¼9.1 Hz, 2H), 7.18
(t, J¼7.7 Hz, 1H), 6.90 (d, J¼9.1 Hz, 2H), 6.80–7.71 (m, 3H), 3.47 (br
[MþH]ꢀ¼169, 171.
4.3.12. 2-(3,4-Dimethoxyphenyl)acetamide (Table 3, entry 4)
(3,4-Dimethoxyphenyl)acetonitrile (177.2 mg, 1 mmol). Yield
24% (46.8 mg); white powder; mp 142.2–143.6 ꢁC (lit. mp 146–
147 ꢁC).42 dH (DMSO-d6): 7.32 (br s, 1H), 6.87 (d, J¼2.1 Hz, 1H), 6.86
(d, J¼8.1 Hz, 1H), 6.78 (br s, 1H), 6.76 (dd, J¼8.2, 2.0 Hz, 1H), 3.73 (s,
3H), 3.72 (s, 3H), 3.28 (s, 2H); MS: [MþH]þ¼196.
t, J¼5.2 Hz, 4H), 3.32 (br t, J¼5.2 Hz, 4H), 2.34 (s, 3H); d (CDCl3):
C
153.3, 150.9, 139.0, 133.5, 129.1, 121.3, 120.0, 117.2, 114.3, 113.5,
100.6, 49.1, 47.3, 21.8; MS: [MþH]þ¼278; HRMS (ESI) for C18H20N3
[MþH]þ calcd: 278.1657, found: 278.1657.

5616
G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
4.4.6. 4-(Benzylamino)benzonitrile (Table 5, entry 7)
EtOAc (90/10). Yield 45% (105.9 mg); white-pale pink crystals; mp
95.4–96.6 ꢁC (lit. mp 93–94 ꢁC).52 The characterization data are
identical to those reported in the literature.52 For comparison, we
report here our 1H NMR data: dH (CDCl3): 7.85 (d, J¼8.8 Hz, 2H),
6.53 (d, J¼8.9 Hz, 2H), 4.06 (br s, 1H), 3.84 (s, 3H), 3.16 (td, J¼7.1,
5.5 Hz, 2H), 1.63 (quintet, J¼7.3 Hz, 2H), 1.44–1.29 (m, 6H), 0.90 (t,
J¼7.1 Hz, 3H); MS: [MþH]þ¼236.
4-Chlorobenzonitrile (137.6 mg, 1 mmol) and benzylamine
(128.6 mg, 1.2 mmol). Eluent for column chromatography: hep-
tane/EtOAc (95/5). Yield 79% (164.9 mg); yellow solid; mp 74.9–
75.6 ꢁC (lit. mp 62–66 ꢁC).46 The characterization data are identical
to those reported in the literature.47 For comparison, we report
here our 1H NMR data: dH (CDCl3): 7.42 (d, J¼8.9 Hz, 2H), 7.37–7.28
(m, 5H), 6.59 (d, J¼8.9 Hz, 2H), 4.56 (br s, 1H), 4.37 (s, 2H); MS:
[MþH]þ¼209.
4.4.13. 1-(4-Morpholin-4-ylphenyl)ethanone (Table 7, entry 1)
4-Chloroacetophenone (170.6 mg, 1 mmol) and morpholine
(104.5 mg, 1.2 mmol). Eluent for column chromatography: first
heptane/EtOAc (80/20), then heptane/EtOAc (50/50). Yield 63%
(129.3 mg); shiny pale yellow powder; mp 93.0–94.4 ꢁC (lit. mp 96–
97 ꢁC).10a The characterization data are identical to those reported
in the literature.4 For comparison, we report here our 1H NMR data:
dH (CDCl3): 7.89 (d, J¼9.0 Hz, 2H), 6.87 (d, J¼9.2 Hz, 2H), 3.86 (br t,
J¼5.0 Hz, 4H), 3.31 (br t, J¼4.9 Hz, 4H), 2.53 (s, 3H); MS:
[MþH]þ¼206.
4.4.7. 4-(Hexylamino)benzonitrile (Table 5, entry 9)
4-Chlorobenzonitrile (137.6 mg, 1 mmol) and hexylamine
(121.4 mg, 1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (90/10). Yield 74% (150.4 mg); pale yellow, low melting solid;
mp 31.3–31.7 ꢁC (lit. mp 32–34 ꢁC).48 The characterization data are
identical to those previously reported in the literature.49 For com-
parison, we report here our 1H NMR data: d (CDCl3): 7.41 (d,
H
J¼8.9 Hz, 2H), 6.51 (d, J¼8.9 Hz, 2H), 4.14 (br s, 1H), 3.14 (td, J¼7.1,
5.4 Hz, 2H), 1.62 (quintet, J¼7.3 Hz, 2H), 1.45–1.28 (m, 6H), 0.90 (t,
J¼7.1 Hz, 3H); MS: [MþH]þ¼203.
4.4.14. 1-(4-Piperidin-1-ylphenyl)ethanone (Table 7, entry 3)
4-Chloroacetophenone (170.6 mg, 1 mmol) and piperidine
(102.1 mg, 1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (90/10). Yield 63% (128.4 mg); shiny white flakes/needles;
mp 87.7–88.7 ꢁC (lit. mp 87–88 ꢁC).49 The characterization data are
identical to those reported in the literature.50 For comparison, we
4.4.8. Methyl 4-morpholin-4-ylbenzoate (Table 6, entry 1)
Methyl 4-chlorobenzoate (170.6 mg, 1 mmol) and morpholine
(104.5 mg,1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (99/1). Yield 58% (127.5 mg); shiny white needles; mp 160.8–
161.7 ꢁC (lit. mp 162–163 ꢁC).10a The characterization data are
identical to those reported in the literature.10a For comparison, we
report here our 1H NMR data: d (CDCl3): 7.85 (d, J¼9.2 Hz, 2H),
H
6.85 (d, J¼9.1 Hz, 2H), 3.33–3.38 (m, 4H), 2.50 (s, 3H), 1.72–1.61 (m,
report here our 1H NMR data: d (CDCl3): 7.96 (d, J¼8.8 Hz, 2H),
6H); MS: [MþH]þ¼204.
H
6.89 (d, J¼8.9 Hz, 2H), 3.90 (s, 3H), 3.88 (br t, J¼4.9 Hz, 4H), 3.31 (br
t, J¼4.9 Hz, 4H); MS: [MþH]þ¼222.
4.4.15. 1-(4-Pyrrolidin-1-ylphenyl)ethanone (Table 7, entry 4)
4-Chloroacetophenone (170.6 mg, 1 mmol) and pyrrolidine
(85.3 mg, 1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (80/20). Yield 73% (138.4 mg); yellow/orange powder; mp
128.0–128.8 ꢁC (lit. mp 126 ꢁC).53 The characterization data are
identical to those reported in the literature.54 For comparison, we
4.4.9. Methyl 4-piperidin-1-ylbenzoate (Table 6, entry 2)
Methyl 4-chlorobenzoate (170.6 mg, 1 mmol) and piperidine
(102.1 mg, 1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (90/10). Yield 46% (101.4 mg); off-white powder; mp 92.8–
94.0 ꢁC (lit. mp 92–95 ꢁC).49 The characterization data are identical
to those reported in the literature.50 For comparison, we report
report here our 1H NMR data: d (CDCl3): 7.86 (d, J¼9.0 Hz, 2H),
H
6.51 (d, J¼9.0 Hz, 2H), 3.34–3.39 (m, 4H), 2.50 (s, 3H), 2.00–2.08
here our 1H NMR data: d (CDCl3): 7.89 (d, J¼9.2 Hz, 2H), 6.85 (d,
(m, 4H); MS: [MþH]þ¼190.
H
J¼9.1 Hz, 2H), 3.85 (s, 3H), 3.33 (br t, J¼5.4 Hz, 4H), 1.70–1.59 (m,
6H); MS: [MþH]þ¼220.
4.4.16. 1-{4-[4-(3-Methylphenyl)piperazin-1-yl]phenyl}ethanone
(Table 7, entry 5)
4.4.10. Methyl 4-[4-(3-methylphenyl)piperazin-1-yl]benzoate
(Table 6, entry 3)
4-Chloroacetophenone (170.6 mg, 1 mmol) and 1-(3-methyl-
phenyl)piperazine (211.5 mg, 1.2 mmol). Eluent for column chro-
matography: heptane/EtOAc (90/10). Yield 76% (223.9 mg); yellow
powder; mp 106.8 ꢁC. dH (CDCl3): 7.90 (d, J¼9.1 Hz, 2H), 7.18 (t,
J¼7.7 Hz, 1H), 6.91 (d, J¼9.1 Hz, 2H), 6.80–7.72 (m, 3H), 3.50 (br t,
J¼5.2 Hz, 4H), 3.32 (br t, J¼5.2 Hz, 4H), 2.53 (s, 3H), 2.34 (s, 3H); dC
(CDCl3): 196.5, 154.1, 151.0, 139.0, 130.4, 129.1, 127.9, 121.2, 117.2,
113.6, 113.5, 49.2, 47.5, 26.1, 21.8; MS: [MþH]þ¼295; HRMS (ESI) for
Methyl 4-chlorobenzoate (170.6 mg, 1 mmol) and 1-(3-meth-
ylphenyl)piperazine (211.5 mg, 1.2 mmol). Eluent for column
chromatography: heptane/EtOAc (90/10). Yield 68% (211.3 mg);
shiny pale yellow powder; mp 131.6 ꢁC. dH (CDCl3): 7.94 (d,
J¼9.1 Hz, 2H), 7.18 (td, J¼7.6, 0.6 Hz, 1H), 6.91 (d, J¼9.1 Hz, 2H),
6.80–7.72 (m, 3H), 3.87 (s, 3H), 3.48 (br t, J¼5.2 Hz, 4H), 3.33 (br t,
J¼5.2 Hz, 4H), 2.34 (s, 3H); d (CDCl3): 167.1, 154.1, 151.1, 139.0,
C
19H23N2O1 [MþH]þ calcd: 295.1810, found: 295.1806.
C
131.3, 129.1, 121.2, 120.1, 117.2, 113.8, 113.5, 51.7, 49.2, 47.7, 21.8; MS:
[MþH]þ¼311; HRMS (ESI) for C19H23N2O2 [MþH]þ calcd: 311.1760,
found: 311.1750.
4.4.17. 1-[4-(Benzylamino)phenyl]ethanone (Table 7, entry 6)
4-Chloroacetophenone (170.6 mg, 1 mmol) and benzylamine
(128.6 mg,1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (80/20). Yield 71% (160.0 mg); yellow powder; mp 76.0–
78.0 ꢁC (lit. mp 89–91 ꢁC).45 The characterization data are identical
to those reported in the literature.54 For comparison, we report
here our 1H NMR data: dH (CDCl3): 7.82 (d, J¼8.9 Hz, 2H), 7.39–7.27
(m, 5H), 6.61 (d, J¼8.9 Hz, 2H), 4.60 (br s, 1H), 4.41 (s, 2H), 2.49 (s,
3H); MS: [MþH]þ¼226.
4.4.11. Methyl 4-(benzylamino)benzoate (Table 6, entry 4)
Methyl 4-chlorobenzoate (170.6 mg, 1 mmol) and benzylamine
(128.6 mg,1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (90/10). Yield 74% (178.8 mg); pale yellow flakes; mp 119.4–
121.4 ꢁC. The characterization data are identical to those reported in
the literature.51 For comparison, we report here our 1H NMR data: d
H
(CDCl3): 7.86 (d, J¼8.9 Hz, 2H), 7.38–7.26 (m, 5H), 6.60 (d, J¼8.9 Hz,
2H), 4.49 (br s, 1H), 4.39 (s, 2H), 3.84 (s, 3H); MS: [MþH]þ¼242.
4.4.18. 1-[4-(Hexylamino)phenyl]ethanone (Table 7, entry 7)
4-Chloroacetophenone (170.6 mg, 1 mmol) and hexylamine
(121.4 mg, 1.2 mmol). Eluent for column chromatography: hep-
tane/EtOAc (90/10). Yield 63% (139.0 mg); pale yellow powder; mp
73.4–74.0 ꢁC. The characterization data are identical to those
4.4.12. Methyl 4-(hexylamino)benzoate (Table 6, entry 5)
Methyl 4-chlorobenzoate (170.6 mg, 1 mmol) and hexylamine
(121.4 mg, 1.2 mmol). Eluent for column chromatography: heptane/

G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
5617
reported in the literature.55 For comparison, we report here our 1H
NMR data: dH (CDCl3): 7.82 (d, J¼8.9 Hz, 2H), 6.54 (d, J¼8.9 Hz,
2H), 4.15 (br s, 1H), 3.17 (td, J¼7.1, 5.4 Hz, 2H), 2.49 (s, 3H), 1.63
(quintet, J¼7.3 Hz, 2H), 1.44–1.29 (m, 6H), 0.90 (t, J¼7.1 Hz, 3H);
MS: [MþH]þ¼220.
ddd, J¼8.1, 1.5, 0.4 Hz, 1H), 7.60 (ddd, J¼8.4, 6.9, 1.5 Hz, 1H), 7.52
(ddd, J¼8.2, 6.9, 1.3 Hz, 1H), 7.11 (d, J¼9.1 Hz, 2H), 6.24 (br s, 1H),
4.37 (q, J¼7.1 Hz, 2H), 1.39 (t, J¼7.1 Hz, 3H); d (CDCl3): 166.3, 146.9,
C
146.0, 144.6, 135.0, 131.6, 129.2, 128.5, 127.6, 127.4, 126.8, 122.9,
121.1, 115.4, 60.7, 14.4; MS: [MþH]þ¼293; HRMS (ESI) for
C
18H17N2O2 [MþH]þ calcd: 293.1290, found: 293.1278.
4.4.19. 4-[Methyl(phenyl)amino]benzonitrile (Table 9, entry 1)
4-Chlorobenzonitrile (137.6 mg, 1 mmol) and N-methylaniline
(128.6 mg,1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (70/30). Yield 53% (111.1 mg); yellow viscous oil. The char-
acterization data are identical to those reported in the literature.56
For comparison, we report here our 1H NMR data: dH (CDCl3): 7.45–
7.39 (m, 4H), 7.26 (tt, J¼7.4, 1.2 Hz, 1H), 7.20 (dd, J¼8.5, 1.2 Hz, 2H),
6.72 (d, J¼9.2 Hz, 2H), 3.35 (s, 3H); MS: [MþH]þ¼209.
4.4.25. N-(4-Nitrophenyl)quinolin-3-amine (Table 10, entry 3)
3-Bromoquinoline (208.1 mg, 1 mmol) and 1-amino-4-nitro-
benzene (145.0 mg,1.05 mmol). Eluentforcolumnchromatography:
CH2Cl2/EtOAc (90/10). Yield 83% (220.3 mg); bright orange powder;
mp 182.3–182.8 ꢁC. dH (CDCl3): 8.81 (d, J¼2.7 Hz, 1H), 8.19 (d,
J¼9.1 Hz, 2H), 8.10 (br ddd, J¼8.4, 1.2, 0.6 Hz, 1H), 7.97 (d, J¼2.6 Hz,
1H), 7.77 (ddt, J¼8.1,1.5, 0.5 Hz,1H), 7.67 (ddd, J¼8.5, 6.9,1.5 Hz,1H),
7.58 (ddd, J¼8.1, 6.9,1.2 Hz,1H), 7.07 (d, J¼9.1 Hz, 2H), 6.48 (br s,1H);
dC (CDCl3): 149.3, 146.5, 145.4, 140.9, 133.5, 129.3, 128.6, 128.3, 127.7,
127.0, 126.3, 124.3, 114.4; MS: [MþH]þ¼266; HRMS (ESI) for
4.4.20. 1-{4-[Methyl(phenyl)amino]phenyl}ethanone (Table 9,
entry 3)
C
15H12N3O2 [MþH]þ calcd: 266.0930, found: 266.0936.
4-Chloroacetophenone (170.6 mg,1 mmol) and N-methylaniline
(128.6 mg,1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (80/20). Yield 49% (110.0 mg); yellow flakes; mp 84.8–
85.5 ꢁC. The characterization data are identical to those reported in
the literature.57 For comparison, we report here our 1H NMR data:
dH (CDCl3): 7.82 (d, J¼9.2 Hz, 2H), 7.41 (br t, J¼7.8 Hz, 2H), 7.26–7.19
(m, 3H), 6.76 (d, J¼9.2 Hz, 2H), 3.34 (s, 3H), 2.51 (s, 3H); MS:
[MþH]þ¼226.
4.4.26. tert-Butyl 5-morpholin-4-yl-1H-indole-1-carboxylate
(Table 10, entry 4)
tert-Butyl5-bromo-1H-indole-1-carboxylate(296.2 mg,1 mmol)
and morpholine (104.5 mg, 1.2 mmol). Eluent for column chroma-
tography: first heptane/EtOAc (98/2), then heptane/EtOAc (80/20).
Yield 70% (211.7 mg); brown/red powder; mp 101.9 ꢁC. d (CDCl3):
H
8.01 (d, J¼9.0 Hz, 1H), 7.54 (d, J¼3.6 Hz, 1H), 7.05 (d, J¼2.2 Hz, 1H),
7.00 (dd, J¼9.0, 2.3 Hz, 1H), 6.48 (dd, J¼3.7, 0.6 Hz, 1H), 3.89 (br t,
J¼4.7 Hz, 4H), 3.15 (br t, J¼4.8 Hz, 4H),1.66 (s, 9H); dC (CDCl3): 149.8,
147.8,131.4,130.2,126.3,115.6,115.4,107.5,107.2, 83.4, 67.1, 51.1, 28.2;
MS: [MþH]þ¼303; HRMS (ESI) for C17H23N2O3 [MþH]þ calcd:
303.1709, found: 303.1701.
4.4.21. Methyl 4-[methyl(phenyl)amino]benzoate (Table 9, entry 5)
Methyl 4-chlorobenzoate (170.6 mg, 1 mmol) and N-methyl-
aniline (128.6 mg, 1.2 mmol). Eluent for column chromatography:
heptane/EtOAc (95/5). Yield 66% (159.5 mg); pale grey/brown
powder; mp 100.8–101.4 ꢁC. The characterization data are identical
to those reported in the literature.10b For comparison, we report
here our 1H NMR data: dH (CDCl3): 7.86 (d, J¼9.1 Hz, 2H), 7.39 (dd,
J¼8.7, 7.6 Hz, 2H), 7.23–7.18 (m, 3H), 6.76 (d, J¼9.1 Hz, 2H), 3.86 (s,
3H), 3.36 (s, 3H); MS: [MþH]þ¼242.
4.4.27. tert-Butyl 5-[4-(3-methylphenyl)piperazin-1-yl]-1H-indole-
1-carboxylate (Table 10, entry 5)
tert-Butyl
5-bromo-1H-indole-1-carboxylate
(296.2 mg,
1 mmol) and 1-(3-methylphenyl)piperazine (211.5 mg, 1.2 mmol).
Eluent for column chromatography: heptane/EtOAc (95/5). Yield
41% (160.0 mg); pale yellow powder; mp 132.5 ꢁC. dH (CDCl3): 8.02
(d, J¼8.9 Hz, 1H), 7.54 (d, J¼3.6 Hz, 1H), 7.18 (td, J¼7.7, 0.5 Hz, 1H),
7.12 (d, J¼2.2 Hz, 1H), 7.06 (dd, J¼9.0, 2.4 Hz, 1H), 6.80–6.70 (m,
3H), 6.49 (dd, J¼3.7, 0.7 Hz, 1H), 3.37 (br t, J¼6.3 Hz, 4H), 3.32 (br t,
4.4.22. 4-Methoxy-N-methyl-N-phenylaniline (Table 9, entry 9)
4-Chloroanisole (170.6 mg, 1 mmol) and N-methylaniline
(128.6 mg,1.2 mmol). Eluent for column chromatography: heptane/
EtOAc (98/2). Yield 61% (130.1 mg); colourless to pale yellow oil.
The characterization data are identical to those reported in the
literature.4 For comparison, we report here our 1H NMR data: dH
(CDCl3): 7.20 (dd, J¼8.8, 7.1 Hz, 2H), 7.09 (d, J¼9.1 Hz, 2H), 6.89 (d,
J¼9.0 Hz, 2H), 6.83–6.76 (m, 3H), 3.81 (s, 3H), 3.25 (s, 3H); MS:
[MþH]þ¼214.
J¼6.3 Hz, 4H), 2.34 (s, 3H), 1.66 (s, 9H); d (CDCl3): 151.4, 149.8,
C
147.8, 138.9, 131.4, 130.2, 129.0, 126.3, 120.9, 117.2, 116.1, 115.6,
113.5, 108.1, 107.3, 83.4, 51.2, 49.7, 28.2, 21.8; MS: [MþH]þ¼392;
HRMS (ESI) for C24H30N3O2 [MþH]þ calcd: 392.2338, found:
392.2332.
4.4.23. 4-(Quinolin-3-ylamino)benzonitrile (Table 10, entry 1)
3-Bromoquinoline (208.1 mg, 1 mmol) and 4-aminobenzo-
nitrile (124.0 mg, 1.05 mmol). Eluent for column chromatography:
CH2Cl2/EtOAc (95/5), then CH2Cl2/EtOAc (60/40). Yield 75%
4.4.28. tert-Butyl 5-(benzylamino)-1H-indole-1-carboxylate (Table
10, entry 6)
tert-Butyl 5-bromo-1H-indole-1-carboxylate (296.2 mg, 1 mmol)
and benzylamine (128.6 mg, 1.2 mmol). Eluent for column chro-
matography: first heptane/EtOAc (98/2), then heptane/EtOAc (90/
10). Yield 29% (92.5 mg); yellow solid; mp 55.6–56.4 ꢁC. dH
(CDCl3): 7.90 (d, J¼8.3 Hz, 1H), 7.50 (d, J¼3.4 Hz, 1H), 7.42–7.38 (m,
2H), 7.37–7.30 (m, 2H), 7.29–7.24 (m, 1H), 6.76 (d, J¼2.2 Hz, 1H),
6.69 (dd, J¼8.8, 2.4 Hz, 1H), 6.39 (dd, J¼3.7, 0.7 Hz, 1H), 4.37 (s,
2H), 3.96 (br s, 1H), 1.65 (s, 9H); dC (CDCl3): 149.9, 144.4, 139.8,
131.7, 128.6, 127.6, 127.2, 126.1, 115.8, 112.5, 107.1, 103.0, 83.1, 49.1,
28.3; MS: [MþH]þ¼323; HRMS (ESI) for C20H23N2O2 [MþH]þ
calcd: 323.1760, found: 323.1765.
(183.4 mg); pale yellow powder; mp 197.6–198.4 ꢁC. d (CDCl3):
H
8.77 (d, J¼2.7 Hz, 1H), 8.06 (d, J¼8.5 Hz, 1H), 7.90 (d, J¼2.6 Hz, 1H),
7.73 (dd, J¼8.1, 1.3 Hz, 1H), 7.63 (ddd, J¼8.4, 6.9, 1.5 Hz, 1H),
7.56–7.58 (dþddd, J¼8.8, 8.0, 6.8, 1.3 Hz, 3H), 7.09 (d, J¼8.8 Hz, 2H),
6.57 (br s, 1H); d (CDCl3): 147.1, 146.3, 145.0, 134.0, 129.2, 128.3,
C
128.2, 127.6, 126.9, 123.0, 122.8, 119.4, 115.6, 103.1; MS:
[MþH]þ¼246; HRMS (ESI) for C16H12N3 [MþH]þ calcd: 246.1031,
found: 246.1030.
4.4.24. Ethyl 4-(quinolin-3-ylamino)benzoate (Table 10, entry 2)
3-Bromoquinoline (208.1 mg, 1 mmol) and ethyl 4-amino-
benzoate (173.4 mg, 1.05 mmol). Eluent for column chromatogra-
phy: CH2Cl2/EtOAc (95/5). Yield 77% (224.5 mg); pale yellow flakes;
mp 134.3–135.2 ꢁC. dH (CDCl3): 8.77 (d, J¼2.7 Hz, 1H), 8.03 (br ddd,
J¼8.4 Hz, 1H), 8.00 (d, J¼8.8 Hz, 2H), 7.88 (d, J¼2.7 Hz, 1H), 7.71 (br
4.4.29. tert-Butyl 5-(hexylamino)-1H-indole-1-carboxylate (Table
10, entry 7)
tert-Butyl
5-bromo-1H-indole-1-carboxylate
(296.2 mg,
1 mmol) and hexylamine (121.4 mg, 1.2 mmol). Eluent for column

5618
G. Van Baelen, B.U.W. Maes / Tetrahedron 64 (2008) 5604–5619
chromatography: CH2Cl2/heptane (70/30). Yield 13% (41.2 mg);
yellow solid; mp 53.6–54.6 ꢁC. dH (CDCl3): 7.89 (d, J¼7.7 Hz, 1H),
7.48 (d, J¼3.3 Hz, 1H), 6.73 (d, J¼2.3 Hz, 1H), 6.64 (dd, J¼8.8,
2.3 Hz, 1H), 6.41 (d, J¼3.4 Hz, 1H), 3.48 (br s, 1H), 3.14 (t, J¼7.1 Hz,
2H), 1.68–1.59 (m, 11H), 1.46–1.29 (m, 6H), 0.90 (t, J¼6.9 Hz, 3H);
dC (CDCl3): 149.9, 144.7, 131.7, 128.5, 126.0, 115.7, 112.5, 107.0, 102.8,
83.1, 45.0, 31.7, 29.6, 28.2, 26.9, 22.7, 14.1; MS: [MþH]þ¼317;
160
140
120
100
80
HRMS (ESI) for
317.2232.
C
19H29N2O2 [MþH]þ calcd: 317.2229, found:
60
40
4.5. Additional info
20
0
4.5.1. Heating, pressure and power profile for some hydrolysis
experiments
Hydrolysis of 4-chlorobenzonitrile at a set temperature of 150 ꢁC
(Table 1, entry 1).
0
10
20
30
40
50
Time (s)
60
70
80
90
100
Temperature (°C)
Pressure (PSI)
Power (W)
160
140
120
100
80
Buchwald–Hartwig reaction of 4-chlorobenzonitrile with mor-
pholine at a set temperature of 100 ꢁC (Table 5, entry 1).
120
100
80
60
40
20
0
60
40
20
0
0
20
40
60
Time (s)
80
100
120
Temperature (°C)
Pressure (PSI)
Power (W)
0
500
1000
1500
2000
2500
Time (s)
Hydrolysis of 4-chlorobenzonitrile at a set temperature of
100 ꢁC (Table 1, entry 3)
Temperature (°C)
Pressure (PSI)
Power (W)
120
100
80
60
40
20
0
Acknowledgements
We would like to thank the Fund for Scientific Research-Flan-
ders (Belgium) (project 1.5.088.04), The Institute for the promotion
of Innovation by Science and Technology in Flanders (scholarship
for G.V.B.), the European Union, the University of Antwerp (Con-
certed action of the Special Fund for Research) and the Flemish
Government (Impulsfinanciering van de Vlaamse Overheid voor
Strategisch Basisonderzoek PFEU 2003) for financial support.
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Buchwald–Hartwig reaction of 4-chlorobenzonitrile with mor-
pholine at a set temperature of 150 ꢁC.

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