Application of cyclic sulfates in the synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one

Article abstract of DOI:10.1016/j.tetasy.2009.01.029

The synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one derivatives is described. These enantiomers were synthesized starting from (R)- or (S)-1-chloro-2,3-dihydroxypropane using relevant cyclic sulfates as chiral i

Full text of DOI:10.1016/j.tetasy.2009.01.029

Tetrahedron: Asymmetry 20 (2009) 322–326
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Tetrahedron: Asymmetry
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Application of cyclic sulfates in the synthesis of enantiomers of
1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one
a
b
b
a
Katarzyna Kulig a, , Agnieszka Boba , Anna Bielejewska , Magdalena Gorska , Barbara Malawska
*
a Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
b Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/56, Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one deriv-
atives is described. These enantiomers were synthesized starting from (R)- or (S)-1-chloro-2,3-dihydroxy-
propane using relevant cyclic sulfates as chiral intermediates. The enantiomeric purities of the final
compounds were in the range of 99.3–100.0%, as determined by high performance liquid chromatogra-
Received 2 December 2008
Accepted 21 January 2009
Available online 16 March 2009
phy. The final compounds were found to display moderate potency as ligands for a1-adrenoreceptors.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
with 1-chloro-2,3-epoxypropane could also lead to disubstituted
products (Fig. 3).6
Chiral aminoalcohols and their derivatives are widely used in
pharmaceuticals, for example, as adrenomimetics or b-adrenore-
ceptor antagonists, and as chiral auxiliaries in asymmetric synthe-
sis. They can be obtained in several ways,1 either by the reduction
of homochiral amino acids whose products are restricted to chiral
secondary amines with a primary hydroxyl group, or by the stereo-
specific reduction of nitrogen functionalized ketones employing
either a chemical route, using a chiral auxiliary, or an enzymatic
process, with baker’s yeast methods.2
The main industrial process leading to aminoalcohols I consists
of the preparation of a methyloxirane derivative (II) followed by its
opening by the relevant amine (Fig. 1). It is a simple and economic
process when the target product is a racemic mixture, but this
method loses its advantages in the synthesis of pure enantiomers.
Firstly, enantiopure 2-chloromethyl-oxirane is a compound that is
neither inexpensive nor easy to be obtained. Secondly, the reaction
of C1-activated 2,3-epoxypropanes with nucleophiles can proceed
by two pathways. Instead of the normal attack on the C1 carbon
atom, the nucleophile can also attack the C3 carbon atom (Fig. 2).
Due to these different substitution pathways, partial racemization
of the product is observed.3–5 Thirdly, the reaction of nucleophiles
O
C1
Nu
1
3
O
1
Cl
3
O-
C3
O
Nu-
Nu
Nu
1
3
1
3
Cl
Figure 2. Mechanism of reaction 1-chloromethyl-oxirane with nucleophiles.
In order to limit the amount of product obtained by the nucle-
ophilic attack on the C3 carbon atom of 1-chloro-2,3-epoxypro-
pane, the substitution of the chlorine atom in this molecule by
tosylate, triflate, or m-nitrobenzenosulfonate groups has been car-
ried out.3,4 The enantiomeric purity of the products synthesized
varied, although generally it was higher than when 1-chloro-2,3-
epoxypropane was used. However, the high price of the reagents
limits the application of these approaches.
OH
R1
Nu
O-
R1R2N
O
Nu-
O
N
R2
Nu
Cl
Nu
Cl
-Cl-
I
II
Figure 1. Synthesis of racemic mixture of aminoalcohols.
* Corresponding author. Tel.: +48 12 6205465; fax: +48 12 6570262.
E-mail address: mfkkulig@cyf-kr.edu.pl (K. Kulig).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.029

K. Kulig et al. / Tetrahedron: Asymmetry 20 (2009) 322–326
323
OH
Nu-
O
O
O
Nu-
Cl
Nu
+
Nu
Nu
Nu
Cl
Figure 3. Synthesis of double substituted side product.
This study is part of a project aimed at finding new 1-[3-(4-aryl-
piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one derivatives to
afforded a cyclic sulfite (R)-2 in 96% yield (Scheme 1). According
to the 1H nuclear magnetic resonance (NMR) spectra and literature
data, compounds (R)-2 are a mixture of cis- and trans-isomers (2:3)
(Table 1).19
function as
a-adrenoreceptor antagonists with antiarrhythmic
and hypotensive activity.7,8
Previously, we have reported that the enantiomers of 1-[3-(4-
phenyl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidyn-2-one and
1-{2-hydroxy-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propyl}-
pyrrolidin-2-one could be obtained by two synthetic pathways, via
either asymmetric hydrolytic kinetic resolution using water solu-
ble9 or immobilized Jacobsen salen Co(III)OAc catalyst,10 which
gave high enantiomeric purity (about 95%).
Cl
SOCl2/ CCl4
reflux
O
Cl
(R)-
OH
O
S
OH
O
1
(R)-2
Herein, we report the synthesis of the enantiomers of 1-[3-(4-
aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidyn-2-one deriva-
tives using cyclic sulfates.
Scheme 1. Synthesis of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2-oxide (R)-2.
Table 1
1H NMR data for cis- and trans-isomers of compound (R)-2
2. Results and discussion
O
O
S
S
Cyclic sulfates are at least as reactive as epoxides, if not more so,
toward various nucleophiles.11–16 Their reactivity is the result of
their ring strain which may be due to angle strain, the partial dou-
ble bond character between the ring oxygen and sulfur atom due to
2p(O)–3d(S) orbital interaction, and the 1,3 non-bonding interac-
tions between the ring oxygen and the exocyclic oxygen atoms.
The X-ray analysis of parent ethylene sulfate indicated that this
molecule exists in a puckered conformation, with an angle 20.6°
between the C4 and C5 bond and a O–S–O bond angle of 98.4°
which is substantially smaller than the strained tetrahedral angle
of 109.5°.17 In addition, application of cyclic sulfate in the synthesis
produced only the single substituted products (Fig. 4).6,18
O
O
O
O
Hc
Ha
Hc
Ha
Cl
Hd
Cl
Hd
Hb
Hb
He
He
cis-2
2
trans-
Config. Ha (dd)
Hb (dd)
Hc (m) Hd (dd)
4.71– 3.90
He (dd)
cis
4.80
4.77
Jab = 8.7 Hz,
Jbc = 6.4 Hz
3.77
Jce = 4.5 Hz,
Jde = 11.2 Hz
Jab = 8.7 Hz,
Jac = 7.5 Hz
4.75
Jcd = 4.8 Hz,
Jde = 11.2 Hz
trans
4.62
4.44
Jab = 9.0 Hz,
Jbc = 6.4 Hz
5.08– 3.65
5.16 Jcd = 4.4 Hz,
Jde = 11.6 Hz
3.53
Jce = 4.6 Hz,
Jde = 11.6 Hz
Jab = 9.0 Hz,
Jac = 5.6 Hz
R1
R2
R1
Nu
R2
R1
Nu
R2
Nu-
+
O
O
O
Cyclic sulfite (R)-2 was then oxidized further using NaIO4 and a
catalytic amount of ruthenium trichloride to furnish the corre-
sponding cyclic sulfate (R)-3 in 80% yield. The ring opening of cyclic
sulfate (R)-3 with pyrrolidin-2-one 4 was performed in tetrahydro-
furan (THF) using NaH as base. The obtained 2-sulfate ester (R)-5
(not isolated) was subsequently hydrolyzed to the 2-hydroxy com-
pound (R)-6 by treatment with concentrated sulfuric acid and
water, at a 60% yield. Finally, the alcohol (R)-6 with relevant substi-
S
OSO3H
Nu
O
Figure 4. Reaction of nucleophile with cyclic sulfates.
As a starting material for the synthesis of the enantiomers of the
title compounds, (R)-1-chloro-2,3-dihydroxypropane (R)-1 was
used; its reaction with an equimolar quantity of thionyl chloride
O
O
Cl
N
4
O
O
OSO3Na
Cl
Cl
O
H
NaIO4, RuCl3 x xH2O
MeCN, CCl4, H2O
O
S
O
N
S
O
NaH, THF
(R)-2
O
(R)-5
(R)-3
R
O
O
HN
N
OH
OH
N
H2SO4, H2O
7 a-c
N
Cl
N
N
R
TBAI, K2CO3
CH3CN
(R)-6
(S)-8a R = -H
(S)-8b R = -Cl
(S)-8c R = -OEt
Scheme 2. Synthesis of (S)-1-[3-(4-aryl-piperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one derivatives (S)-8a–c.

324
K. Kulig et al. / Tetrahedron: Asymmetry 20 (2009) 322–326
tuted N-aryl-piperazines 7a–c in the reaction of phased transfer
catalysis catalyzed by tetrabutylammonium iodide (TBAI) and
carried out in a mixture of acetonitrile/K2CO3 gave enantiomers
a dry nitrogen atmosphere. Standard vacuum techniques were
used for handling air-sensitive materials. Tetrahydrofuran (THF)
was dried, kept under nitrogen, and freshly distilled over so-
dium/benzophenone before use. Uncorrected melting points were
determined in an open capillary on a Büchi 535 melting point
apparatus (Flawil, Switzerland). Elemental analyses (C, H, and N)
were carried out on Elementar Vario EL III (Elementar Analysensys-
tem, Hanau, Germany), giving values within 0.4% of the theoretical
values. 1H NMR and 13C-spectra were recorded on a Varian Mer-
cury VX 300 MHz (Hansen Way, USA) instrument in DMSO-d6 or
CDCl3 at ambient temperature using the solvent signal as an inter-
nal standard. Thin layer chromatography was carried out on Merck
silica gel pre-coated F254 plates (0.2 mm) (Darmstadt, Germany)
using chloroform/acetone (1:1), ethyl acetate and dichlorometh-
ane/methanol (9:1), as developing systems. The plates were visual-
ized with ultraviolet (UV) light (k = 254 nm) or a mixture of 5%
(NH4)xMo7O24 and 0.2% Ce(SO4)2 in 5% H2SO4. Column chromatog-
of
1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidyn-
2-one (S)-8a–c in 80–85% yield (Scheme 2). The (R)-enantiomers
of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidyn-2-
one (R)-8a–c were obtained analogously using (S)-1-chloro-2,3-
dihydroxypropane as the starting material.
The enantiomeric excess (ee) % of the final enantiomers 8a–c was
determined by high performance liquid chromatography (HPLC)
using Chiralpak IA (enantiomer 8a) or Chiralcel OD (enantiomers
8b and 8c) columns and a mixture of n-hexane/ethanol (85:15) as
the mobile phase. It was shown that all the synthesized enantiomers
8a–c were characterized by an ee % of over 99% (Table 2).
Table 2
Retention times and ee % of enantiomers of compounds 8a–c
raphy was performed using
a Merck Kieselgel 60 (0.063–
Compound
Retention time (min)
ee %
99.6
99.8
99.6
99.0
100.0
99.3
0.200 mm) and the following solvents: chloroform/acetone (1:1),
ethyl acetate, and dichloromethane/methanol (9:1). Optical rota-
tions were determined at the sodium D line with a DIP 1000 Jusco
polarimeter (Essex, UK). HPLC analyses were performed using a
Waters (Vienna, Austria) pump Model 590, UV–vis detector Model
(R)-8a
(S)-8a
(R)-8b
(S)-8b
(R)-8c
(S)-8c
28.4
56.7
34.5
26.3
23.3
25.2
490, a 5
Chiralpak IA—amylose tris (3,5-dimethylphenylcarbamate) immo-
bilized on 5 m silica gel and Chiralcel OD—cellulose tris (3,5-dim-
ethylphenylcarbamate) coated on 10 m silica gel (all columns
ll loop Rheodyne type injector and the following columns:
l
Enantiomers 8a–c were evaluated for their in vitro activity on
l
the
a
1-adrenoreceptor by a radioreceptor assay.20,21 The binding
affinities were determined on rat cerebral cortex with [3H]prazosin
25 cm ꢀ 0.46 cm I.D. Daicel) (Chiral Technologies Europe, Illkirch,
France). Samples of compounds were dissolved in EtOH, the con-
centration of the sample being about 1 mg/ml. The mobile phase
was n-hexane/EtOH (85/15, v/v).
as a specific ligand. As depicted in Table 3, the (S)-enantiomers of
compounds 8a–c appeared to be more potent for a1AR than their
racemic mixtures or (R)-enantiomers. Moreover, the potencies of
enantiomers 8a–c were only weakly influenced by their
stereochemistry.
4.1.1. (R)- or (S)-4-Chloromethyl-[1,3,2]dioxathiolane 2-oxide
(R)-2 or (S)-2
An equimolar amount of thionyl chloride was added dropwise
via syringe to the 1 M suspension of 3-chloro-1,2-dihydroxypro-
pane (R)-1 or (S)-1 in CCl4 and the resulting mixture was refluxed
for 2 h. Then the solvent was evaporated and the resulting oil was
purified by column chromatography using ethyl acetate as solvent.
(R)-3-Chloro-1,2-dihydroxypropane (R)-1 gave 15.1 g of (R)-4-
chloromethyl-[1,3,2]dioxathiolane 2-oxide (R)-2 (yield 95%). Anal.
Calcd for C3H5O3SCl: C, 23.01; H, 3.22; S, 20.48. Found: C, 22.78;
Table 3
Affinity of compounds 8a–c toward different
a
1-AR subtypes in rat cerebral cortex
Compound
pKi a1
rac-8a
(S)-8a
(R)-8a
rac-8b
(S)-8b
(R)-8b
rac-8c
(S)-8c
(R)-8c
5.72
6.27
5.88
6.57
6.64
5.60
6.15
6.29
5.82
H, 3.06; S, 20.45. Rf (EtOAc) 0.77; ½a D20
¼ ꢂ44:65 (c 1, CH2Cl2).
ꢁ
(S)-3-Chloro-1,2-dihydroxypropane (S)-1 gave 6.9 g of (S)-4-
chloromethyl-[1,3,2]dioxathiolane 2-oxide ((S)-2) (yield 89%).
Anal. Calcd for C3H5O3SCl: C, 23.01; H, 3.22; S, 20.48. Found: C,
22.85; H, 3.12; S, 20.40. Rf (EtOAc) 0.77; ½a D20
¼ þ44:6 (c 1, CH2Cl2).
ꢁ
Inhibition constants (Ki) were calculated according to the equation of Cheng and
Prusoff.21
4.1.2. (R)- or (S)-4-Chloromethyl-[1,3,2]dioxathiolane 2,2-
dioxide (R)-3 or (S)-3
3. Conclusion
To an ice-cold solution of (R)- or (S)-4-(2-chloromethyl)-
[1,3,2]dioxathiolane-2-oxide (R)-2 or (S)-2 (3.13 g, 20 mmol) in a
mixture of acetonitrile (20 mL) and chloroform (20 mL) was added
NaIO4 (6.4167 g, 30 mmol), followed by RuCl3ꢃH2O (0.0025 g,
0.012 mmol) and water (30 mL). The resulting mixture was stirred
for 1 h, and then diluted with diethyl ether (160 mL). The organic
layer was washed with water (2 ꢀ 10 mL), saturated aqueous NaH-
CO3 (10 mL) and brine (40 mL), dried over anhydrous MgSO4, and
evaporated in a vacuum. The crude product (oil) was purified by
flash chromatography using ethyl acetate.
In conclusion, the enantiomers of compounds 8a–c were syn-
thesized by using cyclic sulfates. The above described method
could be used in the synthesis of analogues of compounds 8 and
other 2-hydroxy-amino-propyl derivatives. The final compounds
8a–c were found to be ligands for
a1-adrenoreceptor, but their
potencies were only weakly influenced by their configuration.
4. Experimental
(R)-4-Chloromethyl-[1,3,2]dioxathiolane 2-oxide (R)-2 to give
2.75 g of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (R)-
3 (yield 81%). Anal. Calcd for C3H5O4SCl: C, 20.88; H, 2.92; S,
18.58. Found: C, 20.92; H, 2.99; S, 18.65. Rf (EtOAc) 0.69;
4.1. General methods
Unless otherwise noted, the starting materials were obtained
from commercial suppliers and used without further purification.
All experiments were carried out in oven-dried glassware under
½
a 2D0
ꢁ
¼ þ4:2 (c 1, CH2Cl2); 1H NMR (CDCl3) d [ppm]: 3.75–3.90

K. Kulig et al. / Tetrahedron: Asymmetry 20 (2009) 322–326
325
(m, 2H, CH2Cl), 4.63 (dd, 1H, J = 6 Hz, J = 9 Hz, CH2), 4.83 (dd, 1H,
J = 6 Hz, J = 6 Hz, CH2), 5.05–5.13 (m, 1H, CH).
N, 13.76. 1H NMR (CDCl3) d [ppm]: 1.94–2.09 (m, 2H, CH2CH2CH2
(pirol)), 2.31–2.48 (m, 4H, CH2CO (pirol), NCH2CH), 2.50–2.62 (m,
2H, piper), 2.78–2.83 (m, 2H, piper), 3.11–3.20 (m, 4H, piper),
3.29 (s, 1H, OH), 3.52 (d, 2H, CHCH2N), 3.55–3.67 (m, 2H, CH2CH2N
(pirol)), 3.87–3.96 (m, 1H, CHOH), 7.22–7.30 (m, 5H, phenyl).
(S)-4-Chloromethyl-[1,3,2]dioxathiolane 2-oxide (S)-2 gave
2.71 g (S)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (S)-3
(yield 79%), Rf (EtOAc) 0.69. Anal. Calcd for C3H5O4SCl: C, 20.88;
H, 2.92; S, 18.58. Found: C, 20.95; H, 3.03; S, 18.68; ½a D20
¼ ꢂ4:2
ꢁ
(c 1, CH2Cl2); 1H NMR (CDCl3) d [ppm]: 3.75–3.90 (m, 2H, CH2Cl),
4.63 (dd, 1H, J = 6 Hz, J = 9 Hz, CH2), 4.83 (dd, 1H, J = 6 Hz, J = Hz,
CH2), 5.05–5.13 (m, 1H, CH).
4.1.5. (S)- or (R)-1-[3-[4-(2-Chlorophenyl)piperazin-1-yl]-2-
hydroxypropyl]pyrrolidin-2 -one (S)-8b or (R)-8b
(R)- or (S)-1-(3-Chloro-2-hydroxypropyl)-pyrrolidin-2-one
(0.89 g, 5 mmol) (R)-6 or (S)-6 and 1-(2-chloro-phenyl)-piperazine
(0.98 g, 5 mmol) were dissolved in 5 mL acetonitrile. Then anhy-
drous K2CO3 (0.69 g, 5 mmol) and TBAI (0.02 g, 0.05 mmol) were
added. The reaction mixture was stirred at room temperature for
24 h. The inorganic salt was filtered and washed with 5 mL MeOH.
The filtrate was evaporated and the oil obtained was purified by
column chromatography using an acetone/chloroform (1:1)
mixture.
4.1.3. (S)- or (R)-1-(3-Chloro-2-hydroxy-propyl)-pyrrolidin-2-
one (S)-6 or (R)-6
To an ice-cold suspension of 60% NaH (2.6 g, 65 mmol) in
130 mL THF, pyrrolidin-2-on 4 (5.5 g, 65 mmol) was added drop-
wise. The reaction mixture was stirred for 1 h then (S)- or (R)-4-
chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (S)-3 or (R)-3
(13.5 g, 75 mmol) was added and the reaction mixture was stirred
overnight. Cleavage was carried out by the addition of 3.6 mL of
H2SO4 (concd) and water (1.3 mL). After stirring for 1 h at room
temperature, the reaction mixture was acidified by adding satu-
rated NaHCO3, and washed with CHCl3 (2 ꢀ 20 mL). The organic
layers were collected, dried with anhydrous Na2SO4, and evapo-
rated. The oil obtained was purified by column chromatography
using a mixture of acetone and chloroform (1:1).
(R)-1-(3-Chloro-2-hydroxypropyl)-pyrrolidin-2-one (R)-6 gave
1.3 g of (S)-1-[3-[4-(2-chlorophenyl)piperazin-1-yl]-2-hydroxy-
propyl]pyrrolidin-2-one (S)-8b. Colorless oil (yield: 80%). Anal.
Calcd for C17H24N3O2Cl: C, 67.26; H, 8.29; N, 13.65. Found: C,
67.39; H, 8.38; N, 13.79. Rf (CH2Cl2/MeOH (9:1)) 0.46;
½
a 2D0
ꢁ
¼ ꢂ19:0 (c 1, EtOH); 1H NMR (CDCl3) d [ppm]: 1.89–2.19 (m,
2H, CH2CH2CH2(pirol)), 2.23–2.50 (m, 4H, CH2CO (pirol), NCH2CH,),
2.51 (m, 4H, CH2 (piper)), 3.07–3.47 (m, 7H, CH2, (piper), CHCH2N,
OH), 3.57–3.70 (m, 3H, CH2N, CH), 7.00–7.40 (m, 4H, phenyl).
(S)-1-(3-Chloro-2-hydroxy-propyl)-pyrrolidin-2-one (S)-6 gave
1.28 g of (R)-1-[3-[4-(2-chlorophenyl)piperazin-1-yl]-2-hydroxy-
propyl]pyrrolidin-2-one (R)-8b. Colorless oil (yield: 76%). Anal.
Calcd for C17H24N3O2Cl: C, 60.44; H, 7.16; N, 12.44. Found: C,
60.32; H, 7.09; N, 12.29. Rf (CH2Cl2/MeOH (9:1)) 0.46;
(R)-4-(2-Chloromethyl)-[1,3,2]dioxathiolane-2,2-dioxide (R)-3
gave 6.7 g (S)-1-(3-chloro-2-hydroxypropyl)-pyrrolidin-2-one (R)-
6 (yield 58%). Anal. Calcd for C7H12O2N: C, 47.33; H, 6.81; N,
7.89. Found: C, 47.54; H, 6.93; N, 7.90. Rf (acetone/CHCl3 (1:1))
0.50; ½a 2D0
ꢁ
¼ þ30:9 (c 1, MeOH); 1H NMR (CDCl3) d [ppm]: 2.05–
2.13 (m, 2H, CH2CH2CH2), 2.42 (t, 2H, CH2CO, J = 9 Hz), 3.45–3.57
(m, 6H, CH2CH, CH2Cl, CH2CH2), 3.95–4.05 (m, 1H, CH), 4.30 (s
(broad), 1H, OH).
½
a 2D0
ꢁ
¼ þ19:9 (c 1, EtOH); 1H NMR (CDCl3) d [ppm]: 1.89–2.19
(S)-4-(2-Chloro-methyl)-[1,3,2]dioxathiolane-2,2-dioxide (S)-3
gave 6.7 g (R)-1-(3-chloro-2-hydroxy-propyl)-pyrrolidin-2-one
(S)-6 (yield 58%). Anal. Calcd for C7H12O2N: C, 47.33; H, 6.81; N,
7.89. Found: C, 47.45; H, 6.89, N, 7.91. Rf (acetone/CHCl3 (1:1))
(m, 2H, CH2CH2CH2(pirol)), 2.23–2.50 (m, 4H, CH2CO (pirol),
NCH2CH,), 2.51 (m, 4H, CH2 (piper)), 3.07–3.47 (m, 7H, CH2, (piper),
CHCH2N, OH), 3.57–3.70 (m, 3H, CH2N, CH), 7.00–7.40 (m, 4H,
phenyl).
0.50; ½a 2D0
ꢁ
¼ ꢂ31:0 (c 1, MeOH); 1H NMR (CDCl3) d [ppm]: 2.05–
2.13 (m, 2H, CH2CH2CH2), 2.42 (t, 2H, CH2CO, J = 9 Hz), 3.45–3.57
(m, 6H, CH2CH, CH2Cl, CH2CH2), 3.95–4.05 (m, 1H, CH), 4.30 (s
(broad), 1H, OH).
4.1.6. (S)- or (R)-1-{3-[4-(2-Ethoxyphenyl)piperazin-1-yl]-2-
hydroxypropyl}-pyrrolidin-2-one (S)-8c or (R)-8c
(R)- or (S)-1-(3-Chloro-2-hydroxypropyl)-pyrrolidin-2-one
(0.89 g, 5 mmol) (R)-6 or (S)-6 and 1-(2-ethoxy-phenyl)-piperazine
(1.03 g, 5 mmol) were dissolved in 5 mL acetonitrile. Then anhy-
drous K2CO3 (0.69 g, 5 mmol) and TBAI (0.02 g, 0.05 mmol) were
added. The reaction mixture was stirred at room temperature for
24 h. The inorganic salt was filtered and washed with 5 mL MeOH.
The filtrate was evaporated and the oil obtained was purified by
column chromatography using an acetone: chloroform (1:1)
mixture.
4.1.4. (S)- or (R)-1-[2-Hydroxy-3-(4-phenyl-piperazin-1-yl)-
propyl]-pyrrolidin-2-one (S)-8a or (R)-8a
(R)- or (S)-1-(3-Chloro-2-hydroxy-propyl)-pyrrolidin-2-one
(0.89 g, 5 mmol) (R)-6 or (S)-6 and 1-phenylpiperazine (0.81 g,
5 mmol) were dissolved in 5 mL acetonitrile. Then anhydrous
K2CO3 (0.69 g, 5 mmol) and TBAI (0.02 g, 0.05 mmol) were added.
The reaction mixture was stirred at room temperature for 24 h.
The inorganic salt was filtered and washed with 5 mL MeOH. The
filtrate was evaporated and the oil obtained was purified by col-
umn chromatography using an acetone/chloroform (1:1) mixture.
(R)-1-(3-Chloro-2-hydroxypropyl)-pyrrolidin-2-one (R)-6 gave
1.21 g of 1-[(S)-2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-
pyrrolidin-2-one (S)-8a (yield 80%) Rf (acetone/CHCl3 (1:1)) 0.42;
(R)-1-(3-Chloro-2-hydroxy-propyl)-pyrrolidin-2-one (R)-6 gave
1.38 g of (S)-1-{3-[4-(2-ethoxyphenyl)piperazin-1-yl]-2-hydroxy-
propyl}-pyrrolidin-2-one ((S)-8c). Colorless oil (yield: 80%). Anal.
Calcd for C19H29N3O3: C, 65.68; H, 8.41; N, 12.09. Found: C,
65.25; H, 8.19; N, 12.21. TLC (CH2Cl2/MeOH (9:1)) 0.57;
½
a 2D0
ꢁ
¼ ꢂ18:4 (c 1, EtOH); 1H NMR CDCl3): d [ppm]: 1.33 (t, 3H,
½
a 2D0
ꢁ
¼ ꢂ10:3 (c 1, EtOH); mp 98–99 °C. Anal. Calcd for
CH3, J = 3.5 Hz), 1.96 (m, 2H, CH2CH2CH2 (pirol)), 2.18–2.25 (m,
4H, CH2CO, NCH2CH2), 2.61–2.72 (m, 4H, CH2 (piper)), 2.80–2.93
(m, 4H, CH2 (piper)), 3.19 (dd, 2H, CH2CH2N), 3.32 (s, 1H, OH),
3.53–3.63 (m, 3H, CH2CH2N, CH), 3.98 (qw, 2H, J = 3.5 Hz, CH2),
6.34–6.71 (m, 4H, phenyl).
C17H25N3O2: C, 67.26; H, 8.29; N, 13.65. Found: C, 67.30; H, 8.31;
N, 13.85. 1H NMR (CDCl3) d [ppm]: 1.94–2.09 (m, 2H, CH2CH2CH2
(pyrrol)), 2.31–2.48 (m, 4H, CH2CO (pirol), NCH2CH), 2.50–2.62
(m, 2H, piper), 2.78–2.83 (m, 2H, piper), 3.11–3.20 (m, 4H, piper),
3.29 (s, 1H, OH), 3.52 (d, 2H, CHCH2N), 3.55–3.67 (m, 2H, CH2CH2N
(pirol)), 3.87–3.96 (m, 1H, CHOH), 7.22–7.30 (m, 5H, phenyl).
(S)-1-(3-Chloro-2-hydroxypropyl)-pyrrolidin-2-one (S)-6 gave
1.21 g of 1-[(R)-2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-
pyrrolidin-2-one (R)-8a (yield 80%) TLC: Rf (CH2Cl2/MeOH (9:1))
(S)-1-(3-Chloro-2-hydroxy-propyl)-pyrrolidin-2-one (S)-6 gave
1.39 g of (R)-1-{3-[4-(2-ethoxyphenyl)piperazin-1-yl]-2-hydroxy-
propyl}-pyrrolidin-2-one (R)-8c. Colorless oil (yield: 81%). Anal.
Calcd for C19H29N3O3: C, 65.68; H, 8.41; N, 12.09. Found: C,
65.75; H, 8.49; N, 12.01. TLC (CH2Cl2/MeOH (9:1)) 0.57;
0.42; ½a 2D0
ꢁ
¼ þ10:3 (c 1, EtOH); mp 98–99 °C, Anal. Calcd for
½
a 2D0
ꢁ
¼ þ18:6 (c 1, EtOH); 1H NMR CDCl3): d [ppm]: 1.33 (t, 3H,
C17H25N3O2: C, 67.26; H, 8.29; N, 13.65. Found: C, 67.28; H, 8.30;
CH3, J = 3.5 Hz), 1.96 (m, 2H, CH2CH2CH2 (pirol)), 2.18–2.25 (m,

326
K. Kulig et al. / Tetrahedron: Asymmetry 20 (2009) 322–326
5. Hanson, R. M. Chem. Rev. 1991, 91, 437–475.
6. Massonneau, V.; Radisson, X.; Mulhauser, M.; Michel, N.; Bufon, A.; Botannet, B.
New J. Chem. 1992, 16, 107–112.
7. Kulig, K.; Sapa, J.; Macia˛g, D.; Filipek, B.; Malawska, B. Arch. Pharm. Chem. Life
Sci. 2007, 340, 466–475.
8. Malawska, B.; Kulig, K.; Filipek, B.; Sapa, J.; Macia˛g, D.; Zygmunt, M.;
Antkiewicz-Michaluk, L. Eur. J. Med. Chem. 2002, 37, 183–195.
9. Kulig, K.; Holzgrabe, U.; Malawska, B. Tetrahedron: Asymmetry 2001, 12, 2533–
2536.
4H, CH2CO, NCH2CH2), 2.61–2.72 (m, 4H, CH2 (piper)), 2.80–2.93
(m, 4H, CH2 (piper)), 3.19 (dd, 2H, CH2CH2N), 3.32 (s, 1H, OH),
3.53–3.63 (m, 3H, CH2CH2N, CH), 3.98 (qw, 2H, J = 3.5 Hz, CH2),
6.34–6.71(m, 4H, phenyl).
Acknowledgments
10. Kulig, K.; Nowicki, P.; Malawska, B. Polish J. Chem. 2007, 81, 179–
186.
11. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538–7539.
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13. Lohray, B. B.; Gao, Y.; Sharpless, K. B. Terahedron Lett. 1989, 30, 2623–
2626.
The authors would like to thank Prof Dr hab Gabriel Nowak and
Ms Małgorzata Dybała for implementation of radioligand studies.
The study was supported by the Polish Ministry for Science and
High Education, Grants 3 P 05 F 03622 and N204 04432/1046.
14. Lohray, B. B.; Ahuja, J. R. J. Chem. Soc., Chem. Commun. 1991, 95–97.
15. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
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