Parallel synthesis of N-arylpiperazines using polymer-assisted reactions

Article abstract of DOI:10.1016/j.tetlet.2006.02.047

A series of N-arylpiperazines were prepared in a parallel fashion using palladium-catalyzed cross-coupling, or nucleophilic aromatic displacement chemistries, and polymer-assisted sequestration and purification techniques as key steps.

Full text of DOI:10.1016/j.tetlet.2006.02.047

Tetrahedron Letters 47 (2006) 2549–2552
Parallel synthesis of N-arylpiperazines using
polymer-assisted reactions
Matthew A. J. Duncton,*, Jonathan R. A. Roffey,*,à Richard J. Hamlyn
and David R. Adams
Department of Chemistry, Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh,
Wokingham RG41 5UA, UK
Received 18 December 2005; revised 30 January 2006; accepted 9 February 2006
Abstract—A series of N-arylpiperazines were prepared in a parallel fashion using palladium-catalyzed cross-coupling, or nucleo-
philic aromatic displacement chemistries, and polymer-assisted sequestration and purification techniques as key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
cross-coupling between an aryl bromide and N-tert-
butoxycarbonylpiperazine (N-Boc piperazine—Scheme
1).6,8 Excess N-Boc piperazine was removed by seques-
tration with polymer-supported isocyanate, a simple
filtration of the reaction mixture providing the protected
N-arylpiperazine 6, which was smoothly deprotected by
the use of AmberlystÒ 15 ion-exchange resin in a ‘catch-
and-release’ manner in a separate reaction step.9
Arylpiperazines are important structural elements in
many molecules possessing biological activity.1 Exam-
ples of such compounds include the 5-HT2C receptor
agonists, N-(meta-chlorophenyl)piperazine (mCPP) 1
and MK-212 2.2,3 More complex molecules, such as
the selective D3 receptor agonist piribedil 3, and the
a1-adrenoreceptor agonist prazosin 4 also contain an
N-arylpiperazine moiety.4,5 The presence of this struc-
tural motif in many substances of biological significance
has led to a number of approaches being developed to
access this chemotype, many of which have been
employed in the preparation of pharmaceutical agents.6
A high-throughput synthesis of this structural class
would therefore be of benefit in the lead discovery and
lead optimization stages of drug discovery. In this letter,
we disclose a synthesis of N-arylpiperazines which utilize
polymer-supported reagents and sequestration strategies
to facilitate production of compounds in a parallel man-
ner (Fig. 1).7
As shown in Table 1, this method was used to prepare a
range of monocyclic, bicyclic and heterocyclic N-aryl-
piperazines in good yields and purities. For example,
mCPP 1 was prepared in an overall yield of 74% and
with a purity of >95%, as judged by nuclear magnetic
resonance (NMR) and high-performance liquid chroma-
tography (HPLC) analysis.10 Other monocyclic bro-
mides furnished N-arylpiperazines in similar yields and
purities using this two-step method (compounds 8–11).
The use of bicyclic, or heterocyclic bromides was also
successful (compounds 12–14), although the purities of
final products were slightly diminished, as compared
to their monocyclic counterparts.
Our synthesis of N-arylpiperazines from ‘non-activated’
aryl halide precursors employed a palladium-catalyzed
In order to access N-arylpiperazines from ‘activated aryl
halide’ precursors, a nucleophilic aromatic displacement
reaction (SNAr) was employed under two sets of reac-
tion conditions (method A or B—Scheme 2). In method
A, the halide 15 was displaced with N-Boc piperazine
under thermal conditions and the excess piperazine re-
agent was removed with polymer-supported isocyanate.
Deprotection of the Boc group was achieved using litera-
ture ‘catch-and-release’ conditions9 to give the desired
*
Corresponding authors. E-mail addresses: mattduncton@yahoo.
com; jon.roffey@spirogen.com
Present address: Renovis Inc., Two Corporate Drive, South San
Francisco, CA 94080, USA.
à Present address: Spirogen Ltd, 29-39 Brunswick Square, London
WC1N 1AX, UK.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.047

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M. A. J. Duncton et al. / Tetrahedron Letters 47 (2006) 2549–2552
Figure 1.
was used in these studies). Thus, the activated aryl
halide 15 was allowed to react with N-Boc piperazine
in the presence of polymer-supported carbonate at
140 °C in acetonitrile for 30 min. Excess piperazine
reagent was sequestered by adding polymer-supported
isocyanate and heating for a further 5 min at 140 °C.
Significantly, it was also found that the Boc deprotec-
tion step could also be facilitated by the use of heating
under microwave irradiation.
Scheme 1. Reagents and conditions: (i) N-Boc piperazine, Pd(OAc)2,
t
tBu3P, BuONa, xylenes, 50 °C then MP-NCO, 50 °C; (ii) AmberlystÒ
15, CH2Cl2, rt then 2 M NH3/MeOH, rt. (Note: MP = macroporous.)
As shown in Table 2, a number of monocyclic and bicy-
clic N-arylpiperazines could be obtained by either of the
above methods. Yields and purities were similar between
the thermal and microwave heating protocols. For
example, MK-212 2 could be obtained in 80% yield
and >95% purity using the thermal conditions (method
A), or in 80% yield and 92% purity using the micro-
wave-assisted approach (method B). However, micro-
wave heating was found to significantly reduce
reaction times. For example, nucleophilic aromatic dis-
placement under thermal conditions was carried out at
100 °C, whereas under microwave heating, the reaction
was performed at 140 °C for 30 min. Sequestration of
excess N-Boc piperazine was also accelerated under
Table 1. Synthesis of N-arylpiperazines using palladium(0)-chemistry
Compound number
Ara
Yield % (purity %)b
1
8
3-Cl–C6H4
74 (>95)
68 (>95)
58 (90)
94 (89)
80 (92)
65 (88)
62 (84)
70 (90)
3-(CF3)–C6H4
3-CN–C6H4
4-NO2–C6H4
3,5-F2–C6H3
b-Naphthyl
9
10
11
12
13
14
Pyrimidin-5-yl
Thiophen-3-yl
a All products were derived from the corresponding aryl bromide
starting material.
b Purity established by NMR spectroscopy and HPLC analysis.
Table 2. Synthesis of N-arylpiperazines using SNAr chemistry
Compound Ara
number
Yield %
Yield %
(purity %)b,c (purity %)b,d
2
16
17
18
19
20
21e
22e
2-Cl–Pyrazin-5-yl
Pyrazin-2-yl
Pyrimidin-2-yl
Quinoxalin-2-yl
Benzothiazol-2-yl
5-(CF3)–Pyridin-2-yl 53 (91)
4-NO2–C6H4
5-Me–2-NO2–C6H3
80 (>95)
20 (90)
82 (>95)
85 (>95)
78 (92)
80 (92)
0 (0)
46 (>95)
84 (90)
68 (>95)
86 (>95)
83 (85)
65 (>95)
Scheme 2. Reagents and conditions: Method A: (i) N-Boc piperazine,
MP-CO3, DMSO, 100 °C; (ii) MP-NCO, CH2Cl2, 60 °C; (iii) MP-
SO3H, CH2Cl2, rt, filter then wash with MeOH and release with 2 M
NH3, MeOH. Method B: (i) N-Boc piperazine, MP-CO3, CH3CN,
140 °C, l-wave; (ii) MP-NCO, CH3CN, 140 °C, l-wave; (iii) MP-
SO3H, CH2Cl2, 140 °C, l-wave.
82 (>95)
91 (>95)
a Products were obtained from the aryl chloride starting material
except where noted separately.
b Purity determined by NMR spectroscopy and HPLC analysis.
c Results using method A.
product. Method B employed microwave heating to
accelerate the displacement, sequestration and deprotec-
tion steps (a CEM Explorer & DiscoverÒ microwave
d Results using method B.
e Aryl fluoride starting material employed.

M. A. J. Duncton et al. / Tetrahedron Letters 47 (2006) 2549–2552
2551
microwave heating. Thus, under thermal conditions
2. Experimental
excess N-Boc piperazine was sequestered over 24 h at
60 °C; under microwave heating the excess N-Boc piper-
azine was sequestered in 5 min at 140 °C. Deprotection
of the Boc protecting group was also found to be
accelerated under our microwave conditions. For exam-
ple, N-Boc deprotection took 24 h at room temperature,
compared to 30 min at 140 °C under microwave heating.
Parallel synthesis of N-arylpiperazines from ‘non-acti-
vated’ aryl bromides (all reactions were performed in
parallel using a Carousel from Radley’s Ltd): Tri-tert-
butylphosphine (4 mg, 0.02 mmol) was added in one
portion to a stirred solution of palladium(II) acetate
(1.2 mg, 0.005 mmol) in xylenes (mixture of isomers;
5 mL) at room temperature under argon. The mixture
was stirred for 5 min, then a solution of the aryl bromide
(1.0 mmol) in xylenes (5 mL) was added in one portion.
After another 5 min, N-Boc piperazine (0.37 g, 2 mmol)
and sodium tert-butoxide (0.14 g, 1.4 mmol) were added
separately in one portion. The mixture was heated to
50 °C and stirred overnight. Polymer-supported isocya-
nate (loading: 1 mmol/g; 2.0 g, 2 mmol) was added in
one portion and the mixture was stirred at 50 °C for
24 h, then filtered and the filter cake washed with xylenes
and MeOH.
The products from the previous chemistries could be
elaborated further to provide compounds with increased
diversity. As an example, piribedil 3 was synthesized
from 17 by reductive-alkylation with piperonal using
polymer-supported cyanoborohydride as the reductant.
Purification by ion-exchange chromatography in a
‘catch-and-release’ manner afforded 3 in an overall yield
of 73% and in 93% purity (Scheme 3). Similarly, prazo-
sin 4 was obtained in 89% yield and in 95% purity using
only polymer-supported sequestration routines and
‘catch-and-release’ purification (Scheme 4).
Concentration of the filtrate under vacuum left the
N-Boc arylpiperazine (1.0 mmol; reaction assumed to
be quantitative), which was used directly in the next
step.
In summary, we have developed a number of methods
for the parallel synthesis of N-arylpiperazines using
either nucleophilic aromatic substitution, or palladium-
catalyzed cross-coupling, in conjunction with polymer-
supported sequestration and ‘catch-and-release’ tech-
niques. As an illustration of the versatility of our ap-
proach, the biologically active substances mCPP, MK-
212, piribedil and prazosin were prepared using the
above methodology as a key step. It is envisaged that
the techniques illustrated in this letter will be of interest
to medicinal chemists when looking to prepare a series
of N-arylpiperazine derivatives in a parallel fashion.
AmberlystÒ 15 ion-exchange resin (4.5 g) was added in
one portion to a stirred solution of the N-Boc N-arylpip-
erazine (assumed to be 1.0 mmol) in CH2Cl2 (8 mL) at
room temperature under argon. The mixture was stirred
overnight, then filtered and the filter cake washed with
CH2Cl2, THF and MeOH. The filter cake was then
transferred back to an individual carousel reaction ves-
sel and 2 M NH3/MeOH added. The mixture was stirred
at room temperature for 90 min then filtered. Concen-
tration of the filtrate under vacuum gave the desired
N-arylpiperazine product (see Table 1 for yields and
purities).
Acknowledgements
Scheme 3. Reagents and conditions: (i) piperonal, CH2Cl2, AcOH, PS-
CNBH3; (ii) SCX-2, wash MeOH, release with 2 M NH3/MeOH.
We thank Ken Heatherington, Tim Haymes, Peter Clay-
ton and Graeme Harden, for performing the analysis of
final compounds described in this letter. We also thank
Nathaniel Monck, for helpful suggestions and assistance
in the preparation and production of this manuscript.
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