Solventless microwave assisted protocol for synthesis of arylalkylpiperazines using Cs-base

Article abstract of DOI:10.1039/b812801d

A series of some arylalkylpiperazines was prepared in good yields under microwave irradiation in dry media conditions using CsOH with high chemo- and regioselectivity.

Full text of DOI:10.1039/b812801d

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www.rsc.org/greenchem | Green Chemistry
Solventless microwave assisted protocol for synthesis of arylalkylpiperazines
using Cs-base†
Alain Gamal Giuglio-Tonolo, Thierry Terme and Patrice Vanelle
Received 4th September 2008, Accepted 19th December 2008
First published as an Advance Article on the web 6th January 2009
DOI: 10.1039/b812801d
A series of some arylalkylpiperazines was prepared in good
yields under microwave irradiation in dry media conditions
using CsOH with high chemo- and regioselectivity.
Introduction
Scheme 1
Synthesis of arylalkylpiperazines is obviously an important task
in modern medicinal chemistry. Some of them constitute an
Results and discussion
essential part of a large number of biologically active com-
pounds. For example, some derivatives, containing amidoalkyl
or amidoaryl groups, possess central nervous system depres-
sant activity, present excellent 5-HT2 receptor antagonism and
5-HT1A receptor agonism, or display D2 and 5-HT1A receptor
affinity.1
We initially studied the microwave-assisted coupling of 3,4-
(dichlorophenyl)piperazine 1 with 4-chlorobutanol 2a using a
solventless procedure (Scheme 2).
The synthetic approaches to tertiary aliphatic amines from
secondary amines include reductive amination2 and direct
N-alkylation.3 The nucleophilic attack of alkyl halides by
secondary amines in the presence of base is useful for the
preparation of tertiary amines, but the reaction requires long
reaction times and gives a mixture of secondary and ter-
tiary amines. Furthermore, reaction times of N-alkylation
of arylpiperazines with primary alkyl halides, which is an
important synthetic method to obtain the corresponding ary-
lalkylpiperazines, range between 4 and 26 h.4 In recent years,
microwave irradiation has become popular among synthetic
organic chemists both to improve classical organic reactions,
shortening reaction times and/or improving yields, as well
as promoting new reactions.5 Moreover, when carrying out a
reaction in a microwave oven, the use of a solvent can be
avoided, allowing eco-friendly synthesis and offering several
advantages, such as to reduce the risk of explosion and easier
work-up.6
Scheme 2
The first attempts to prepare 3a using 1 in slight excess (1.2 eq)
to reduce overalkylations with 2a (1 eq) were unsuccessful
(10–19%). The reactants were adsorbed on the surface of the
additive (Al2O3/base in 4:1 ratio) in large excess and a base,
such as NaHCO3, K2CO3 or KOH, was employed. As expected,
direct N-monoalkylation techniques using bases like NaHCO3
or K2CO3 and a large excess of 2a (2 eq) gave, after optimization,
moderate yields (40 and 48%, respectively) because of overalky-
lations. The volatility of 2a and the basic properties of 1 in the
reaction mixture can induce a lower yield. In the last few years,
Cs-base promoted synthetic protocols have been widely applied
to the formation of a variety of carbon-hetero atom bond
forming reactions.8–10 Recently, an elegant methodology for
direct amination reactions promoted by CsOH·H2O with the
use of DMF has been reported.8 However, this report is limited
to alkylation of primary alkyl amines which can be rapidly
converted to the secondary amine under the classical heating
method in moderate to good yields. With the aim of efficiently
synthesizing substituted arylpiperazines, SN2 alkylation using
monohydrate CsOH or Cs(CO3)2 as base under microwave
irradiation was investigated (Scheme 2, Table 1).
As a part of our program directed toward the preparation of
new derivatives with potential CNS activities,7 we developed
a method to synthesize arylalkylpiperazine moieties as syn-
thetic intermediates involving an eco-friendly method for the
chemoselective preparation of tertiary amine corresponding to
alkylsubstituted arylpiperazines (Scheme 1).
We demonstrate that arylalkylpiperazine 3a can be obtained
in good yield, using a Cs-base as base under microwave
irradiation without solvent. These conditions reaction exhibited
enhanced chemoselectivities in amine alkylation compared to
the previously reported protocols. The multimode reactor used
was an ETHOS Synth Lab station (Ethos start, Milestone Inc.).
Laboratoire de Pharmaco-Chimie Radicalaire (LPCR), Faculte´ de
Pharmacie, Universite´s d’Aix-Marseille I, II, III – CNRS UMR 6264,
Laboratoire Chimie Provence, 27 Boulevard Jean Moulin, 13385,
Marseille cedex 05, France. E-mail: patrice.vanelle@pharmacie.
univ-mrs.fr; Fax: +33(4)91794677; Tel: +33(4)91835527
† Electronic supplementary information (ESI) available: Experimental
details and experimental data. See DOI: 10.1039/b812801d
160 | Green Chem., 2009, 11, 160–162
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Table 1 Solventless N-alkylation under microwave irradiation
Entrya Base (eq)
Reaction conditions
Yieldb (3a)
1
2
3
4
CsOH·H2O (1 eq) 200 W; 50 ◦C; 2 ¥ 15 mind
64%
63%
79%
89%
Cs2CO3 (1.2 eq)
150 W; 50 ◦C; 30 min
CsOH·H2O (2 eq) 200 W; 50 ◦C; 2 ¥ 15 mind
CsOH (2 eq)c
200 W; 50 ◦C; 3 ¥ 15 mind
a All the reactions are performed using amine 1 (1 eq: 4 mmol) with
haloalkane 2a (4 eq) in the presence of 30% NaI and 0.8 g of dessicant
(MgSO4). b % Yield relative to amine 1. c CsOH·H2O was dried at 120 ◦C
for 24h. d Pulse irradiation (with 90 s intervals).
Scheme 3
derivatives. As expected, the reactions still exhibited high yields.
In order to show the advantage of the use of a microwave
reactor, we realized the preparation of compound 5b under the
same experimental conditions without microwave irradiation
but using an oil bath for heating instead. Only 21% yield
of compound 5b was isolated after 18 h versus 96% yield
after 4 ¥ 20 min, under microwave irradiation. Mono-N-
alkylation was then applicable with the use of a range of
different arylpiperazines, offering similar trends. In all entries
(Table 2), very little or no overalkylation was detected. This
chemoselectivity can be explain by analogy with the mechanism
proposed by K. W. Jung and coworkers,10 a strong affinity of the
tertiary amine for the cesium cation reduces the nucleophilicity
of the tertiary amine and produce a sterically hindered complex.
90 s intervals were needed between pulse irradiation because the
sensitivity of the products to heating. Furthermore, monohy-
drate CsOH (Table 1, entry 1 and 3) was found to be superior.
Cesium bicarbonate (Table 1, entry 2) gave lower conversions,
presumably due to decreased basicity and solubility. However,
when CsOH is strictly dried, the yield increased to 89%. More-
over, NaI is used to facilitate the reaction by a halogen exchange
activation. This methodology exhibits several advantages over
the conventional heating by reducing the reaction time, improv-
ing the reaction yield and also by eliminating the side reactions.
With this general procedure for the synthesis of 3a (Table 1,
entry 4) in hand, we then investigated direct N-monoalkylation
using a variety of arylpiperazines and haloalkanes (Table 2,
Scheme 3). In order to apply this new procedure to a series
of arylpiperazines with various haloalkanes, we have modified
some parameters, such as the power of the microwave oven,
reaction time, temperature and quantity of haloalkane (3–5 eq),
due to the physico-chemical properties of the used haloalkane.
After monitoring by TLC, the optimized yields are reported in
Table 2. For the haloalkanes 2c and 2d, the optimization seems
to be haloalkane-dependent whatever amine is used.
Conclusion
In order to obtain antipsychotic precursors, we developed
a synthetic method of arylalkylpiperazines under microwave
irradiation in “dry” media conditions including Cs(OH) as
base to promote chemo- and regioselectively the N-alkylation.
Thanks to this approach, substituted arylpiperazine derivatives
of pharmacological interest were obtained in good yields. This
simple and convenient methodology corresponds to a “green
chemistry” approach which has been widely adopted to meet
the fundamental scientific challenges of protecting human health
and the environment. Currently, efforts are underway to extend
this procedure to the synthesis of cyclic tertiary amines from
primary amines by di-N-alkylation.
As shown in Table 2, various functionalized primary chloro or
bromoalkane derivatives were efficiently coupled with various
arylpiperazines generating the corresponding tertiary amines.
This methodology can be applied with alcohol, ester or nitrile
Table 2 CsOH-promoted N-alkylation using various secondary amines and haloalkanes
X(CH2)nR2
Amine (quantity)
R1
Haloalkane (equivalent)
X
n
R2
Reaction conditions
Yielda (product)b
1 (4 mmol)
4 (4 mmol)
6 (2 mmol)
1 (2 mmol)
4 (4 mmol)
6 (2 mmol)
8 (4 mmol)
1 (2 mmol)
6 (2 mmol)
8 (2 mmol)
10 (2 mmol)
1 (2 mmol)
6 (2 mmol)
8 (2 mmol)
10 (2 mmol)
3,4-Cl
2-OCH3
4-F
3,4-Cl
2-OCH3
4-F
2,5-CH3
3,4-Cl
4-F
2,5-CH3
3-CF3·HCl
3,4-Cl
2a (4 eq)
2a (4 eq)
2a (4 eq)
2b (3 eq)
2b (3 eq)
2b (3 eq)
2b (3 eq)
2c (5 eq)d
2c (5 eq)d
2c (5 eq)d
2c (5 eq)d
2d (3 eq)
2d (3 eq)
2d (3 eq)
2d (3 eq)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Cl
Cl
Cl
Cl
4
4
4
3
3
3
3
2
2
2
2
3
3
3
3
OH
OH
OH
CN
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CO2Et
CO2Et
200 W; 60 ◦◦C; 3 ¥ 15 minc
150 W; 55 C; 4 ¥ 15 minc
200 W; 60 ◦C; 3 min
89% (3a)
90% (5a)
95% (7a)
90% (3b)
96% (5b)
86% (7b)
73% (9b)
82% (3c)
88% (7c)
74% (9c)
86% (11c)
98% (3d)
95% (7d)
97% (9d)
97% (11d)
200 W; 60 ◦◦C; 9 min
150 W; 60 C; 4 ¥ 20 minc
200 W; 60 ◦◦C; 5 min
200 W; 60 C; 3 ¥ 15 minc
100 W; 50 ◦C; 4 ¥ 5 minc
100 W; 50 ◦C; 4 ¥ 5 minc
100 W; 50 ◦C; 4 ¥ 5 minc
100 W; 50 ◦C; 4 ¥ 5 minc
150 W; 50 ◦C; 4 ¥ 4 minc
150 W; 50 ◦C; 4 ¥ 4 minc
150 W; 50 ◦C; 4 ¥ 4 minc
150 W; 50 ◦C; 4 ¥ 4 minc
4-F
2,5-CH3
3-CF3·HCl
a All the reactions are performed using 1 equivalent of arylpiperazine with corresponding haloalkane in the presence of 30% NaI and 0.8 g of dessicant
(MgSO4), promoted by dried CsOH. b NMR and mass spectra of all synthesized products are in accordance with the literature.11 c Pulse irradiation
(with 90 s intervals). d No NaI was added in the reaction mixture containing bromohaloalkane 2c.
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Experimental
General procedure
To a mixture of arylpiperazine (1 eq), sodium iodide (0.3 eq),
magnesium sulfate (0.8 g) and cesium hydroxide (2 eq) was added
4-haloalkane (3–5 eq). The reaction mixture was stirred and
irradiated in a microwave oven (Ethos start) for an appropriate
time and temperature. After being cooled down, the mixture
was then taken up in 1 N NaOH and then extracted with AcOEt
(3 ¥ 30 mL). The organic layers were washed with water (2 ¥
30 mL), with brine (30 mL) and dried over anhydrous sodium
sulfate. Concentration of the solvent under reduced pressure and
drying in a oven under reduced pressure afforded the desired
alkylarylpiperazine.
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dichlorophenyl)piperazin-1-yl]butan-1-ol
3a
NMR
1H
(200 MHz, CDCl3) 7.26 (d, J = 9.0 Hz, 1H), 6.95 (d,
J = 2.9 Hz, 1H), 6.69–6.75 (dd, J = 9.0 and 2.8 Hz, 1H),
3.64–3.56 (m, 2H), 3.47–3.41 (m, 1H), 3.27–3.22 (m, 4H),
2.74–2.69 (m, 4H), 2.50–2.55 (m, 2H), 1.72–1.63 (m, 4H);
NMR 13C (50 MHz, CDCl3) 150.7, 132.7, 130.4, 122.0, 117.1,
115.2, 70.6, 58.3, 52.8, 48.6, 27.7, 23.6; HRMS (EI): calc. for
C14H20N2OCl2 (M+) 303.1025, found 303.1023.
Acknowledgements
This work has been supported by the Centre National de la
Recherche Scientifique and the Universite´ de la Me´diterrane´e.
The authors thank V. Remusat for 1H and 13C spectra recording
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162 | Green Chem., 2009, 11, 160–162
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