A short and efficient synthesis of N-aryl- and N-heteroaryl-N′- (arylalkyl)piperazines

Article abstract of DOI:10.1016/j.tetlet.2004.01.066

A new synthesis of N-aryl- and N-heteroaryl-N′-(arylalkyl) piperazines using palladium-catalyzed amination of aryl bromides and heteroaryl chlorides with mono N-benzyl- or N-(arylethyl)piperazines is reported. Most coupling processes proceed in high yield and good selectivity using either diadamantyl-n-butylphosphine (1), 2-(dicyclohexylphosphino)-2′-(N,N- dimethylamino)biphenyl (2), or 2-(di-tert-butylphosphino)biphenyl (3) as ligand. Applying an automated parallel synthesizer the preparation of a small library of potentially bioactive compounds is easily achieved.

Full text of DOI:10.1016/j.tetlet.2004.01.066

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2057–2061
A short and efficient synthesis of N-aryl- and N-heteroaryl-N0-
(arylalkyl)piperazines
Dirk Michalik,a Kamal Kumar,a Alexander Zapf,a Annegret Tillack,a Michael Arlt,b
Timo Heinrichb and Matthias Bellera,*
aLeibniz-Institut f€ur Organische Katalyse an der Universit€at Rostock e.V. (IfOK),Buchbinderstraße 5-6,D-18055 Rostock,Germany
bMerck KGaA,Frankfurter Str. 250,64293 Darmstadt,Germany
Received 19 December 2003; revised 16 January 2004; accepted 16 January 2004
Abstract—A new synthesis of N-aryl- and N-heteroaryl-N0-(arylalkyl)piperazines using palladium-catalyzed amination of aryl
bromides and heteroaryl chlorides with mono N-benzyl- or N-(arylethyl)piperazines is reported. Most coupling processes proceed in
high yield and good selectivity using either diadamantyl-n-butylphosphine (1), 2-(dicyclohexylphosphino)-20-(N,N-dimethyl-
amino)biphenyl (2), or 2-(di-tert-butylphosphino)biphenyl (3) as ligand. Applying an automated parallel synthesizer the preparation
of a small library of potentially bioactive compounds is easily achieved.
Ó 2004 Published by Elsevier Ltd.
R2
The synthesis of new biologically active molecules is an
important part in the development of better and inno-
vative drugs. Clearly, current drug development is
dominated by the use of stoichiometric organic trans-
formations, however, a catalytic route to a desired active
compound is often shorter in reaction steps giving the
product in a faster and more economic manner and
might be easier scaled up compared to a longer tradi-
tional route. Although in recent years catalytic reac-
N
NH
R2
n
Y
R1
N
N
+
R3
N
n
Y
R1
X
n = 0, 1
Figure 1. N-(Arylalkyl)-N0-heteroarylpiperazines.
R3
N
tions,
especially
palladium-catalyzed
coupling
reactions,1 have become more and more used by
medicinal chemists, still catalysis is somewhat under-
rated given the possibilities for unusual modifications of
a desired lead structure.
halides with piperazine derivatives. The obtained prod-
ucts are of interest for the treatment of different diseases
such as psychosis, schizophrenia, depression, neural
disorders, memory disorders, ParkinsonÕs disease,
amyotrophic lateral sclerosis, AlzheimerÕs disease, Hun-
tingtonÕs disease, eating disorders, for example, nervous
bulimia and anorexia, and premenstrual syndromes and
for positive influencing compulsive behaviors (obsessive–
compulsive disorder, OCD).5
Some time ago we started a program for the synthesis of
potentially active amphetamine analogues using base-
catalyzed hydroamination reactions.2 More recently, we
envisioned the serotonin (5-HT)-receptor subtype 2A as
an interesting target, for which N-(arylalkyl)-N0-hetero-
arylpiperazines as shown in Figure 1 are known to be
strong ligands.3 Here, we describe for the first time the
synthesis of this class of compounds by palladium-cat-
alyzed amination4 of different aryl and heteroaryl
Due to the broad pharmacological interest in piperazine
derivatives, palladium-6 and nickel-catalyzed7 coupling
reactions of piperazines with aryl halides have found
widespread interest in the past.8 In order to prepare the
potential pharmaceuticals in a faster and more efficient
way we envisioned to perform the synthesis of the
desired compounds in an automated organic synthe-
sizer. Thus, initially we studied the reaction of bromo-
benzene and N-benzylpiperazine as a model system
Keywords: Aminations; Piperazine; Palladium.
* Corresponding author. Tel.: +49-381-466930; fax: +49-381-4669324;
e-mail: matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.01.066

2058
D. Michalik et al. / Tetrahedron Letters 45 (2004) 2057–2061
using a Vantage parallel synthesizer.9 Selected results
from these screening experiments are shown in Table 1.
Table 1. Pd-catalyzed amination of bromobenzene with N-benzyl-
piperazine9
1 mol% [Pd]
ligand, NaOtBu
In general 1 mol % of a palladium precursor was applied
in the presence of 2 mol % of the corresponding ligand.
Among the five different phosphine ligands tested
diadamantyl-n-butylphosphine (1) (cataCXiumâ A),10
2-(dicyclohexylphosphino)-20-(N,N-dimethylamino) biphenyl
(2),11 and 2-(di-tert-butylphosphino)biphenyl (3) (Fig. 2)
were found to perform best with NaOtBu as base and
toluene as solvent at 110 °C.
BnN
NH Br
+
BnN
N
110 °C, toluene, 20 h
Entry
[Pd]
Ligand
Conversion [%]a Yield [%]b
1
Pd(OAc)2
1
100
100
100
100
12
9
91
93
91
96
0c
2c
93
2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
1
3
2
4
2
5
2
Next, we applied the optimized conditions using
Pd(OAc)2 in the presence of ligands 1 and 2, respec-
tively, for the synthesis of eight different N-benzyl-N0-
heteroarylpiperazines on a preparative scale (3 mmol) in
a parallel manner (Table 2). To the best of our knowl-
edge no palladium-catalyzed reactions with heteroaryl
chlorides have been described so far. Here, different
chloropyridines, 2-chloroquinoline, and 2-chloro-1,4-
pyrazine gave the aminated products in moderate to
good isolated yields. As expected the amination of 2,5-
dichloropyridine proceeded with high selectivity at the
2-position with only 9% of the other regioisomer. It is
noteworthy that the obtained products constitute
interesting piperazinyl building blocks, which might be
6
2
7
3
100
71
20
28
11
11
16
7
8
3
57
10
13
1c
1c
9
4
10
11
12
13
14
15
16
4
4
4
PCy3
PCy3
PCy3
PCy3
1
2
11
9
1c
1c
a With respect to PhBr.
b GC yield.
c Cs2CO3 instead of NaOtBu.
P
N
PCy2
P(tBu)2
N PPh2
1
2
3
4
Figure 2. Ligands for the Pd-catalyzed amination of bromobenzene with N-benzylpiperazine.
Table 2. Pd-catalyzed amination of heteroaryl chlorides with N-benzylpiperazinea
1 mol% Pd(OAc)2
ligand, NaOtBu
Y
Y
X
BnN
N
N
+
NH
BnN
110 °C, toluene, 20 h
N
R'
N
R'
Entry
1
Substrate
Ligand
Product
Yield [%]b
82
BnN
1
N
N
Cl
Cl
N
N
76
BnN
BnN
N
N
Cl
Cl
Cl
2
2
9
N
CF3
BnN
BnN
N
N
CF3
3
4
1
1
58
N
N
Cl
Cl
N
N
85

D. Michalik et al. / Tetrahedron Letters 45 (2004) 2057–2061
2059
Table 2 (continued)
Entry
Substrate
Ligand
Product
Yield [%]b
13
N
BnN
N
5
1
N
Cl
N
N
6
1
1
72
67
BnN
BnN
N
N
N
N
Cl
N
NC
NC
7c
Cl
N
CH3
CH3
a Reaction conditions: N-Benzylpiperazine (3.0 mmol), heteroaryl chloride (3.5 mmol), NaOtBu (4.0 mmol), Pd(OAc)2 (0.03 mmol, 1 mol %), ligand
(0.06 mmol, 2 mol %), toluene (anhydrous, 15 mL), 110 °C, 20 h in a 12 well Ares reactor.
b Isolated yield.
c Cs2CO3 (4.0 mmol) instead of NaOtBu.
used for further C–N coupling processes after debenz-
ylation.12
same conditions as described above in an ACT Vantage
reactor (Table 3). Most coupling products were obtained
in sufficient to good yield. Isolation was easily achieved
by column chromatography. Similar to the coupling
with N-benzylpiperazine, 2-chloroisoquinoline proved
to be the most difficult substrate and gave the desired
product in only 36% yield. Apart from N-[2-(4-fluoro-
phenyl)ethyl]piperazine also N-(2-phenylethyl)pipera-
zine was arylated in good yield.
Finally, the palladium-catalyzed coupling reactions
of two different N-(arylethyl)piperazines with eight
different aryl or heteroaryl halides were performed.
N-(Arylethyl)piperazines are easily accessible by base-
catalyzed hydroamination of styrenes with N-benzyl-
piperazine and subsequent palladium-catalyzed debenz-
ylation in >70% overall yield.12 Due to the expected
pharmacological properties in most cases N-[2-(4-fluor-
ophenyl)ethyl]piperazine was allowed to react with
selected aromatic or heteroaromatic halides under the
In summary, a facile synthesis of potential biologically
active N-(arylalkyl)-N0-heteroarylpiperazines has been
developed. The resulting compounds are of broad
Table 3. Pd-catalyzed arylation of N-(arylethyl)piperazinesa
1 mol% Pd(OA c)
2
Z
Z
ligand, NaOtBu
110 °C, toluene, 20 h
R'
N
NH
N
N
X
+
R
R
Y
R'
Y
Entry
1
(Hetero)aryl halide
Product
Yield [%]b
68
N
N
N
N
F
Br
CF3
CF3
2
3
62
64
F
F
Br
N
N
N
N
Cl
Cl
N
N
N
N
N
N
Cl
59
F
F
Cl
4
Cl
8
N
(continued on next page)

2060
D. Michalik et al. / Tetrahedron Letters 45 (2004) 2057–2061
Table 3 (continued)
Entry
(Hetero)aryl halide
Product
Yield [%]b
56
CF3
N
N
N
N
CF3
5
6
F
F
N
Cl
N
N
75
36
N
N
Cl
N
N
N
N
N
7
F
F
Cl
N
N
N
8
69
70
50
N
N
Cl
Cl
N
N
N
N
9
N
N
N
10
N
Cl
N
a Reaction conditions: N-(Arylethyl)piperazine (3.0 mmol), (hetero)aryl halide (3.5 mmol), NaOtBu (4.0 mmol), Pd(OAc)2 (0.03 mmol, 1 mol %),
ligand 2 (0.06 mmol, 2 mol %), toluene (anhydrous, 15 mL), 110 °C, 20 h in a 12 well Ares reactor.
b Isolated yield.
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