7922
K. G. Liu, A. J. Robichaud / Tetrahedron Letters 46 (2005) 7921–7922
To demonstrate the generality of this approach, a broad
range of anilines were chosen to explore the scope of this
reaction. The results are summarized in Table 1. In
general, good to excellent yields were obtained for all
aniline substrates, including those containing electron-
donating (entry 5), electron-withdrawing (entries 6–8),
and sterically hindered moieties (entry 4). N-Aryl piper-
azines with functional groups such as phenols and esters
that posed problems in the previously reported syntheses
have also been successfully assembled (entries 9 and 10).
addition of Et2O (ꢀ150 mL). The precipitate was filtered
off and washed with Et2O to provide HCl salt. The HCl
salt was further converted to free amine by treatment
with Na2CO3 solution and extracted with EtOAc (2·).
The combined organic layers were dried over Na2SO4,
and concentrated in vacuo to provide the pure free
amine product in most cases. If needed the product
was further purified by column chromatography.
In summary, we have developed a general and conve-
nient procedure for the synthesis of N-aryl piperazines
from anilines using bis(2-chloroethyl)amine hydrochlo-
ride in diethylene glycol monomethyl ether in the
absence of base and high reaction temperatures.
General procedure: In an atmosphere of dry N2, a mix-
ture of aniline (3.0 mmol), bis(2-chloroethyl)amine
hydrochloride (3.0 mmol), and diethylene glycol
monomethyl ether (0.75 mL) was heated at 150 ꢁC for
6–12 h.18 After being cooled to room temperature, the
mixture was dissolved in MeOH (ꢀ4 mL) followed by
Acknowledgments
We thank Alvin Bach, Yanxuan Cai, Bill Marathias,
and James Mattes for their routine analytical support.
Table 1. Synthesis of N-aryl piperazines from anilines
H
N
.HCl
Cl
Cl
References and notes
Ar NH2
Ar
N
NH
diethylene glycol
monomethyl ether
1. Bogeso, K. P.; Bang-Andersen, B. Textbook of Drug
Design and Discovery, 3rd ed.; Taylor & Francis Ltd.:
London, UK, 2002, p 299.
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Chem. 2001, 8, 999.
Entry
1
Ar–NH2
Product
Yield (%)a
79
NH2
N
NH
3. Prelog, V.; Driza, G. J. Collect. Czech. Chem. Commun.
1933, 5, 497.
4. Prelog, V.; Blazek, Z. Collect. Czech. Chem. Commun.
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Tetrahedron Lett. 1996, 37, 4463.
2
3
4
87
87
66
F
NH2
F
N
NH
Cl
NH2
Cl
N
NH
6. Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Anderson
Evans, C.; Goodman, A. Tetrahedron Lett. 2002, 43, 3359.
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D.; Ismaiel, A. M.; Titeler, M.; Lyon, R. A. J. Med. Chem.
1989, 32, 1921.
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McKenney, J. D. J. Med. Chem. 1986, 29, 2375.
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M.; Tulp, M. T. M. J. Med. Chem. 1988, 31, 1934.
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1997, 38, 6875.
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Synth. Commun. 1998, 28, 1175.
18. The reaction time can be significantly shortened under
microwave conditions. For example, in the case of aniline
(Table 1, entry 1) the reaction was complete within 10 min
under microwave irradiation at 180 ꢁC (unoptimized).
NH2
N
NH
MeO
F3C
MeO
F3C
5
6
95
67
NH2
N
NH
NH2
NH2
N
NH
F3C
F3C
N
NH
7
65
F3C
O2N
F3C
O2N
8
9
90
NH2
N
NH
HO
HO
87b
NH2
N
NH
EtO2C
EtO2C
10
11
90
60
NH2
N
NH
NH2
N
NH
a Isolated yields based on free amine.
b Yield based on HCl salt.