A facile synthesis of enantiomerically pure 1-(piperazin-2-yl)ethan-1-ol derivatives from (2s,3r)-threonine

Article abstract of DOI:10.1055/s-1999-3596

Starting from the proteinogenic amino acid (2S,3R)-threonine (4) a novel method for the preparation of enantiomerically pure 1-(1-benzylpiperazin-2- yl)ethan-1-ols with various substituents in position 4 (15 - 20) is described. The sequence involves as key step the LiAlH₄ reduction of the bicyclic piperazinediones 11a,b-14a,b which establishes the 1-benzyl protective group and simultaneously liberates the 1-hydroxyethyl side chain for further transformations.

Full text of DOI:10.1055/s-1999-3596

PAPER
1739
A Facile Synthesis of Enantiomerically Pure 1-(Piperazin-2-yl)ethan-1-ol
Derivatives from (2S,3R)-Threonine
Stella Soukara, Bernhard Wünsch*
Pharmazeutisches Institut der Universität Freiburg, Hermann-Herder-Str. 9, D-79104 Freiburg i. Br., Germany
Fax +(761)2036351; E-mail: wuensch@sun2.ruf.uni-freiburg.de
Received 1 April 1999; revised 11 May 1999
tion of glycine, arabinose and cyclohexyl isocyanide,8 and
hydroxyalkylation of lithiated N-nitrosopiperazines with
aldehydes.9
Abstract: Starting from the proteinogenic amino acid (2S,3R)-thre-
onine (4) a novel method for the preparation of enantiomerically
pure 1-(1-benzylpiperazin-2-yl)ethan-1-ols with various substitu-
ents in position 4 (15 – 20) is described. The sequence involves as
key step the LiAlH4 reduction of the bicyclic piperazinediones
11a,b–14a,b, which establishes the 1-benzyl protective group and
simultaneously liberates the 1-hydroxyethyl side chain for further
transformations.
Therefore, we developed a novel method for the prepara-
tion of enantiomerically pure 1-(piperazin-2-yl)ethan-1-
ol derivatives 15–20. According to our procedure, which
starts with the proteinogenic amino acid (2S,3R)-threo-
nine (4), versatile substituents (e.g. alkyl, aryl, arylalkyl,
acyl, alkoxycarbonyl) may be regioselectively introduced
in position 4 of the piperazine ring system. The N-1 ben-
zyl residue of 15 – 20 should be readily cleavable by hy-
drogenolysis opening the possibility to obtain N-1
unsubstituted (cf. 1), N-1 alkylated or acylated pipera-
zines (cf. 2, 3). In particular, the 1-hydroxyethyl residue in
position 2 of the piperazine ring should be suitable for the
introduction of pharmacophoric elements, e.g. oxygen
heterocycles like the 1,3-dioxolane ring (cf. 1), amine
substituents (cf. 2) or oxygen containing functional
groups (cf. 3).
Key words: EPC (enantiomerically pure compounds) synthesis, 1-
(piperazin-2-yl)ethan-1-ols, enantiomerically pure threonine, 1,3-
oxazolidines, alcohols, heterocycles, reductions
Various piperidines and piperazines with substituents in
position 2 are known to be potent ligands for different
central nervous system (CNS) receptors. Thus, the piperi-
dine 1 (dexoxadrol) bearing a 1,3-dioxolane ring system
in position 2 binds with high affinity to the phencyclidine
binding site of the NMDA receptor (channel blocker).1
The pyrrolidinylmethyl substituted piperazine derivative
2 belongs to the most potent and selective κ opioid recep-
tor agonists (IC50 = 0.018 nM),2 and the 1,4-diacylpipera-
zines 3 represent a novel class of substance P antagonists
(NK1 antagonists).3
Condensation of benzaldehyde with (2S,3R)-threonine
methyl ester hydrochloride, obtained by reaction of
(2S,3R)-threonine (4) with thionyl choride and metha-
nol,10 provided a mixture of the diastereomeric 1,3-oxazo-
lidines 5a, 5b and the hydroxyimine
6
(ratio
5a:5b:6 = 43:36:21).11 Since 5a, 5b and 6 are in a dynam-
ic equilibrium a separation of the three compounds was
not possible. However, after treatment of the 5a, 5b, 6
mixture with chloroacetyl chloride at –5°C the diastereo-
meric chloroacetyl derivatives 7a and 7b (75:25) could be
separated by flash chromatography (Scheme 1). Perform-
ing the acylation of the 5a, 5b, 6 mixture at room temper-
ature changed the diastereomeric ratio in favour of the
main diastereomer 7a (7a:7b = 94:6).
SN2 substitution of the separated diastereomers 7a and 7b
with NaN3 furnished the diastereomeric azides 9a and 9b,
respectively. Reduction of the azides 9a and 9b succeeded
with H2/Pd/C to afford the corresponding primary amines,
which directly cyclized to yield the bicyclic piperazinedi-
ones 11a and 11b, respectively (Scheme 2).
In the course of our work on novel ligands for CNS recep-
tors we became interested in 2 substituted piperazine de-
rivatives, which should be available by transformations of
1-(piperazin-2-yl)ethan-1-ols. In the literature the 1-(pi-
perazin-2-yl)ethan-1-ol moiety is mentioned as a part of
sleep inducing agents,4 aminoglycosides,5 and antidepres-
sants.6 However, only few methods for the synthesis of 1-
(piperazin-2-yl)ethan-1-ols have been described: cycliza-
tion of a protected glycine-threonine dipeptide,7 Ugi reac-
Alternatively, acylation of the 1,3-oxazolidine/hydroxy-
imine mixture 5a, 5b, 6 with N-Cbz protected glycine and
dicyclohexyl carbodiimide (DCC) at room temperature
stereoselectively led to the glycinamide 8a (Scheme 1). In
1
the H NMR spectrum of the unpurified product signals
for the diastereomeric dipeptide 8b could not be detected.
Again, the one-pot deprotection/cyclization of 8a suc-
ceeded by hydrogenolysis to give the bicyclic piperazine
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1740
S. Soukara, B. Wünsch
PAPER
Scheme 2
The 1-(piperazin-2-yl)ethan-1-ols 15–17 were isolated in
good yields (>74%). A somewhat lower yield (48%) was
obtained after reduction of the N-phenyl substituted deriv-
atives 14a,b. In this case reductive ring opening occurred
as side reaction due to the diminished electron releasing
activity of the aniline nitrogen atom resulting in the bu-
Scheme 1
11a (Scheme 2). For the preparation of great amounts of
11a this method was chosen as standard procedure.
Reaction of the diastereomeric chloroacetyl derivatives
7a and 7b with butylamine and benzylamine resulted in
direct formation of the N-substituted bicyclic piper-
azinediones 12a, 12b, 13a, and 13b, respectively. In con-
trast to the reaction of the aliphatic amines butylamine and
benzylamine, the aromatic amine aniline gave only the
substitution products 10a and 10b. After hydrolysis with
KOH the corresponding anilino acids were cyclized with
ethyl dimethylaminopropyl carbodiimide (EDC•HCl) to
furnish the N-phenyl substituted bicyclic piperazinedi-
ones 14a and 14b (Scheme 2).
The reduction of the bicyclic piperazinediones 11a,b–
14a,b was performed with LiAlH4 in refluxing THF.
Thereby, the lactam carbonyl groups as well as the N/O-
acetal were reduced to furnish the 1-(1-benzylpiperazin-2-
yl)ethan-1-ol derivatives 15–18 (Scheme 3). Since the ste-
reogenic centre of the N/O-acetal as destroyed during this
reduction, the a- and b-diastereomers led to the same
products, respectively. Therefore, the a- and b-diastere-
omers need not be separated and for the preparation of
large amounts of the piperazines 15–18 mixtures of a/b-
diastereomers were usually employed.
Scheme 3
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Synthesis of Enantiomerically Pure 1-(Piperazin-2-yl)ethan-1-ol Derivatives
1741
MS (CI): m/z (%) = 222 (M + H, 100), 178 (M – C2H3O, 28), 116
(M – PhCO, 17). IR (film): n = 3500–3200 (br, O–H, N–H), 1740
(s, C=O), 1642 (m, C=N), 1451, 1437 (m), 1209 (m, C–O), 759, 699
cm-1 (m, γaryl).
tane-1,3-diol 21 (26% yield). The N-4 acyl piperazines 19
and 20 were obtained by acylation of the secondary amine
15 with benzoyl chloride or (BOC)2O (Scheme 3).
In summary, the method presented opens an efficient ac-
cess to orthogonally protected, enantiomerically pure 1-
(piperazin-2-yl)ethan-1-ol derivatives from commercially
available (2S,3R)-threonine. These 1-(piperazin-2-
yl)ethan-1-ols will be used as starting material for the
preparation of novel CNS receptor ligands.
1H NMR (400 MHz, CDCl3; starred (*) δ values designate signals
of the minor diastereomer): δ = 1.22 (d, J = 6.4 Hz, 3 H, CHCH3,
6), 1.43, 1.46* (each d, J = 6.4 Hz, 3 H, CHCH3, 5a, 5b), 3.00 –
3.40 (br m, NH, OH, 5a, 5b, 6), 3.59* (d, J = 6.4 Hz, 1 H,
CHCO2CH3, 5b or 5a), 3.64 (d, J = 6.8 Hz, 1 H, CHCO2CH3, 5a or
5b), 3.74 (s, 3 H, CO2CH3, 6), 3.77 (s, 3 H, CO2CH3, 5a,b), 3.87 (d,
J = 5.1 Hz, 1 H, CHCO2CH3, 6), 4.11 (quint, J = 6.3 Hz, 1 H,
CHCH3, 5a,b), 4.29 (quint, J = 6.1 Hz, 1 H, CHCH3, 6), 5.54, 5.59*
(each s, 1 H, NCHO, 5a, 5b), 7.30–7.50 (m, 5 H, arom, 5a, 5b, and
4 H, arom, 6), 7.77 (d, J = 1.7 Hz, 1 H, arom, 6), 8.29 (s, 1 H,
CH=N, 6).
Unless otherwise noted, moisture sensitive reactions were conduct-
ed under dry N2. THF was distilled from sodium/benzophenone
ketyl prior to use. Petroleum ether used refers to the fraction boiling
at 40-60 °C. TLC: Silica gel 60 F254 plates (Merck). Flash chroma-
tography (FC):12 Silica gel 60, 0.040–0.063 mm (Merck); parenthe-
ses include diameter of the column (cm), eluent, fraction size (mL),
Rf. Melting points: Melting point apparatus Dr. Tottoli (Büchi), un-
corrected. Optical rotation: Polarimeter 241 (Perkin Elmer); 1.0 dm
tube; concentration c [g/100 mL]; temperature 20°C. Elemental
analyses: CHN elemental analyzer Rapid (Heraeus) and Elemental
Analyzer 240 (Perkin Elmer). MS: Mass spectrometer 5989A
(Hewlett Packard), MAT 312, MAT 8200, MAT 4456, and TSQ
7000 (Finnigan); EI = electron impact, CI = chemical ionization,
ESI = electron spray ionization. IR: IR spectrophotometer 1600 FT-
IR, 2000 FT-IR, and 841-IR (Perkin-Elmer) (br = broad, m = medi-
um, s = strong). 1H NMR (400 MHz), 13C NMR (100 MHz): GSX
FT NMR spectrometer (Jeol); 1H NMR (300 MHz), 13C NMR (75
MHz): Unity 300 FT NMR spectrometer (Varian), TMS as internal
standard, δ in ppm; coupling constants are given with 0.5 Hz reso-
lution; the assignments of 13C and of 1H NMR signals were support-
ed by 2D NMR techniques (COSY, DEPT); in the case of rotational
isomers, the signals of the minor rotamer are marked as mr in super-
scripts.
(2R,4S,5R)-(+)-Methyl 3-(2-Chloroacetyl)-5-methyl-2-phenyl-
1,3-oxazolidine-4-carboxylate (7a) and (2S,4S,5R)-(-)-Methyl
3-(2-Chloroacetyl)-5-methyl-2-phenyl-1,3-oxazolidine-4-car-
boxylate (7b)
A solution of chloroacetyl chloride (3.1 mL, 39 mmol) in CH2Cl2
(30 mL) was added dropwise to a stirred and cooled (–5°C) mixture
of 5a, 5b and 6 (6.95 g, obtained as described above from 3.57 g, 30
mmol of 4) and Et3N (6.3 mL, 45 mmol) in CH2Cl2 (30 mL). After
1 h, the mixture was allowed to reach r.t. and stirring was continued
for 16 h. Then Et3N•HCl was filtered off, the solvent was evaporat-
ed and the residue was dissolved in Et2O (150 mL). The solution
was washed with 0.5 N HCl (100 mL) and brine (75 mL), the com-
bined organic layers were dried (Na2SO4) and concentrated in vac-
uo. The residue was purified by FC (8 cm, petroleum ether/EtOAc,
3:1, 25 mL) to afford 7a (Rf 0.37, 4.89 g, 55% from 4) as a clear, vis-
cous oil, [α]589 +27.7 (c = 1.97, CH2Cl2), and 7b (Rf 0.45, 1.80 g,
20%) as colourless needles (i-Pr2O); mp 145°C; [α]589 –133.0
(c = 0.57, CH2Cl2).
Compound 7a
The synthesis of the 5a, 5b, 6 mixture is described in Ref.11. How-
ever, our protocol is slightly modified and improved, a new inter-
pretation of the 1H NMR spectrum as well as additional analytical
data are given.
Anal. calcd for C14H16ClNO4 (297.7): C, 56.48; H, 5.41; N, 4.70.
Found C, 55.90; H, 5.38; N, 4.61.
MS (CI): m/z (%) = 300/298 (M + H, 33/94), 262 (M – Cl, 29), 220
(M – ClCH2CO, 21), 194/192 (M – PhCO, 43/100).
IR (film): n = 1749 (s, ester C=O), 1676 (s, amide C=O), 1413 (s),
1214 (s, C–O), 760, 735, 702 cm-1 (m, C–Cl, γaryl).
(2R,4S,5R)- and (2S,4S,5R)-Methyl 5-Methyl-2-phenyl-1,3-ox-
azolidine-4-carboxylate (5a and 5b) and (2S,3R) Methyl 2-(Ben-
zylideneamino)-3-hydroxybutanoate (6)
1H NMR (300 MHz, CDCl3): δ = 1.44 (br s, 3 H, CHCH3), 3.71 (br
s, 2 H, CH2Cl), 3.80 (s, 3 H, CO2CH3), 3.87mr (br s), 3.98–4.12mr (br
m), 4.30 (br s, 2 H, CHCH3 and CHCO2CH3), 4.36–4.56mr (br m),
6.34 (br s, 1 H, NCHO), 6.47mr (br s), 7.26–7.51mr (br m), 7.41 (br
s, 3 H, arom.), 7.73 (br s, 2 H, arom).
1. (2S,3R)-Threonine Methyl Ester Hydrochloride
This compound was prepared by adding (2S,3R)-threonine (4; 10.0
g, 84 mmol) to a solution of SOCl2 (22 mL, 300 mmol) in anhyd
MeOH (100 mL) following the procedure in Ref. 10. According to
the 1H NMR data, threonine methyl ester HCl was obtained in quan-
titative yield as a colourless, viscous foam which required no further
purification. 1H NMR (400 MHz, D2O): δ = 1.33 (d, J = 6.4 Hz, 3
H, CHCH3), 3.85 (s, 3 H, CO2CH3), 4.11 (d, J = 3.9 Hz, 1 H,
CHCO2CH3), 4.43 (qd, J = 6.4, 3.9 Hz, 1 H, CHCH3).
Compound 7b
Anal. calcd for C14H16ClNO4 (297.7): C, 56.48; H, 5.41; N, 4.70.
Found C, 55.90; H, 5.38; N, 4.61.
MS (CI): m/z (%) = 300/298 (M + H, 27/81), 262 (M – Cl, 24), 220
(M – ClCH2CO, 16), 194/192 (M – PhCO, 60/100).
2. Preparation of a Mixture of 5a,b and 6
A mixture of threonine methyl ester HCl (18.55 g, prepared as de-
scribed above from 0.10 mol of 4), Et3N (16.7 mL, 0.12 mol), ben-
zaldehyde (11.2 mL, 0.11 mol), MgSO4, and anhyd MeOH (100
mL) was stirred at r.t. for 24 h. The solvent was removed in vacuo
and the residue was suspended in Et2O (300 mL). The precipitate
was filtered off and the filtrate was evaporated to dryness to yield a
mixture of 5a, 5b and 6 (ratio 43:36:21; 20.58 g, 93% from 4) as a
colourless oil, which was used without further purification. For an-
alytical purposes the traces of benzaldehyde in a small sample were
distilled off under reduced pressure.
IR (KBr): n = 1747 (s, ester C=O), 1657 (s, amide C=O), 1434 (s),
1201 (s, C–O), 764 (m, C–Cl , γaryl), 702 cm-1 (m, γaryl).
1H NMR (400 MHz, CDCl3): δ = 1.50 (d, J = 5.6 Hz, 3 H, CHCH3),
3.30 (d, J = 13.2 Hz, 1 H, CH2Cl), 3.37 (d, J = 13.2 Hz, 1 H,
CH2Cl), 3.80 (s, 3 H, CO2CH3), 4.23 (dq, J = 8.4, 5.9 Hz, 1 H,
CHCH3), 4.31 (d, J = 8.1 Hz, 1 H, CHCO2CH3), 6.15 (s, 1 H,
NCHO), 7.44 (br s, 5 H, arom).
1H NOE: After irradiation at δ = 6.15 (NCHO) a NOE was found at
δ = 4.26 (CHCH3).
Anal. calcd for C12H15NO3 (221.2): C, 65.14; H, 6.83; N, 6.33.
Found C, 65.13; H, 6.76; N, 6.55.
(2R,4S,5R)-(+)-Methyl 3-[2-(Benzyloxycarbonylamino)acetyl]-
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1742
S. Soukara, B. Wünsch
PAPER
5-methyl-2-phenyl-1,3-oxazolidine-4-carboxylate (8a)
gave 9b (67 mg, 87%) as a colourless solid; mp 88°C; [α]589 –179.6
(c = 0.82, CH2Cl2).
To a stirred and cooled (0°C) mixture of 5a, 5b and 6 (12.0 g, ob-
tained as described above from 7.14 g, 60 mmol of 4) in anhyd
CH2Cl2 (75 mL) was added slowly in succession a solution of Cbz-
glycine (13.74 g, 66 mmol) in anhyd THF (30 mL) and then a solu-
tion of dicyclohexyl carbodiimide (DCC, 18.54 g, 89 mmol) in an-
hyd CH2Cl2 (30 mL). The mixture was allowed to stir for 16 h at r.t.
The precipitate was filtered off, the solvent was removed in vacuo
and the residue was dissolved in EtOAc (300 mL). The solution was
washed with 1 N HCl (2 × 75 mL) and brine (50 mL), the combined
organic layers were dried (MgSO4) and evaporated to dryness. Pu-
rification of the residue by FC (8 cm, petroleum ether/EtOAc, 2:1,
80 mL, Rf 0.20) yielded 8a (19.1 g, 77% from 4) as a clear oil, which
solidified upon standing in the refrigerator, colourless prisms
(EtOAc); mp 111°C; [α]589 +28.4 (c = 1.49, CH2Cl2).
Anal. calcd for C14H16N4O4 (304.3): C 55.26; H, 5.30; N, 18.41.
Found C, 55.43; H, 5.31; N, 18.16.
MS (CI): m/z (%) = 305 (M + H, 22), 277 (M + H – N2, 9), 199 (M
– PhCO, 86), 91 (PhCH2, 100).
IR (KBr): n = 2113 (s, N3), 1747 (s, ester C=O), 1660 (s, amide
C=O), 1435 (s), 1283 (m), 1206 (s), 743, 704 cm-1 (m, γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.52 (d, J = 5.8 Hz, 3 H, CHCH3),
3.15 (d, J = 15.8 Hz, 1 H, CH2N3), 3.22 (d, J = 15.9 Hz, 1 H,
CH2N3), 3.84 (s, 3 H, CO2CH3), 4.25 (dq, J = 8.2, 5.9 Hz, 1 H,
CHCH3), 4.34 (d, J = 8.3 Hz, 1 H, CHCO2CH3), 6.08 (s, 1 H,
NCHO), 7.40–7.48 (m, 5 H, arom).
Anal. calcd for C22H24N2O6 (412.4): C, 64.07; H, 5.86; N, 6.79.
Found C, 64.05; H, 5.88; N, 6.76.
(2R,4S,5R)-Methyl 3-(2-Anilinoacetyl)-5-methyl-2-phenyl-1,3-
oxazolidine-4-carboxylate (10a); Typical Procedure
A solution of 7a (1.30 g, 4.37 mmol) and aniline (3.6 mL, 39 mmol)
in MeOH (30 mL) was refluxed for 72 h. The solvent was removed
in vacuo and the residue was dissolved in EtOAc (130 mL). After
washing with 1 N HCl (60 mL) and brine (25 mL), the organic layer
was dried (MgSO4) and concentrated in vacuo. Purification by FC
(4 cm, petroleum ether/EtOAc, 2:1, 30 mL, Rf 0.48) yielded 10a
(1.26 g, 81%) as a pale yellow oil.
MS (CI): m/z (%) = 413 (M + H, 4), 305 (M – PhCH2O, 100).
IR (film): n = 3331 (br, N–H), 1725 (s, ester, carbamate C=O), 1670
(s, amide C=O), 1433 (m), 1214 (s, C–O), 741, 700 cm-1 (m, γaryl).
1H NMR (300 MHz, CDCl3, ratio of rotamers, 76:24): δ = 1.42 (d,
J = 3.9 Hz, 3 H, CHCH3), 1.48mr (d, J = 5.9 Hz, 3 H, CHCH3), 3.44
(dd, J = 17.5, 3.8 Hz, 1 H, NHCH2), 3.78mr, 3.80 (each s, 3 H,
CO2CH3), 3.74–3.80mr (m, 1 H, NHCH2), 3.94 (dd, J = 17.1, 5.4 Hz,
1 H, NHCH2), 4.03–4.09mr (m, 1 H, NHCH2), 4.20–4.27 (m, 2 H and
1 Hmr, CH3CHCHCO2CH3 and CHCO2CH3mr), 4.32–4.44mr (m, 1 H,
CHCH3), 5.04, 5.09mr (each s, 2 H, CH2Ph), 5.47, 5.59mr (each br s,
1 H, NH), 6.24, 6.51mr (each s, 1 H, NCHO), 7.30, 7.39mr (each br
s, 8 H, arom), 7.48mr (br s, 2 H, arom), 7.68 (d, J = 5.8 Hz, 2 H,
arom).
13C NMR (75 MHz, CDCl3): δ = 17.6, 18.4mr (each 1 C, CHCH3),
43.0mr, 43.3 (each 1 C, NHCH2), 52.4, 52.8mr (each 1 C, CO2CH3),
63.5mr, 64.5 (each 1 C, CHCO2CH3), 66.6 (1 C, CH2Ph), 74.6,
76.6mr (each 1 C, CHCH3), 89.3, 89.9mr (each 1 C, NCHO), 126.7 –
129.5 (10 C, arom CH), 136.2–137.0 (2 C, arom C), 156.0 (1 C,
NHCO2Bn), 166.8, 167.6mr (each 1 C, NCOCH2), 169.2 (1 C,
CO2CH3).
MS (EI): m/z (%) = 354 (M, 2), 260 (M – PhNH3, 9), 220 (M –
PhNHCH2CO, 5), 106 (PhNHCH2, 100).
IR (film): n = 3384 (w, N–H), 1748 (s, ester C=O), 1669 (s, amide
C=O), 1412 (s), 1211 (s, C–O), 752, 698 cm-1 (m, γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.34 (d, J = 5.2 Hz, 3 H, CHCH3),
1.41mr (br d), 3.24mr (br d), 3.32 (d, J = 16.6 Hz, 1 H, CH2NH), 3.61
(d, J = 16.6 Hz, 1 H, CH2NH), 3.67mr (br s, 3 H, CO2CH3), 3.69 (s),
3.76 (br s), 4.08–4.15mr (br m), 4.16–4.29 (m, 2 H, CHCH3 and
CHCO2CH3), 4.30–4.57mr (br m), 6.11 (br s), 6.17 (s, 1 H, NCHO),
6.30 (d, J = 7.8 Hz, 2 H, arom), 6.43–6.52mr (br m), 6.57 (t, J = 7.5
Hz, 1 H, arom), 6.53–6.68mr (br m), 7.00 (t, J = 7.6 Hz, 2 H, arom),
7.00–7.11mr (br m), 7.18 – 7.30mr (br m), 7.29–7.38 (m, 3 H, arom),
7.40–7.49mr (br m), 7.65 (d, J = 6.6 Hz, 2 H, arom). A signal for the
proton of the NH group could not be detected.
13C NMR (75 MHz, CDCl3): δ = 17.8, 18.4mr (1 C, CHCH3), 46.3 (1
C, CH2NH), 52.5 (1 C, CO2CH3), 63.8mr, 64.6 (1 C, CHCO2CH3),
74.7 (1 C, CHCH3), 89.3, 90.2mr (1 C, NCHO), 112.8 (2 C, arom
CH), 117.7 (1 C, arom CH), 126.8mr, 127.2 (2 C, arom CH), 128.1mr,
128.8 (2 C, arom CH), 129.0 (2 C, arom CH), 129.6 (1 C, arom CH),
136.9 (1 C, arom C), 146.8 (1 C, arom C), 167.7, 169.0mr, 169.4,
170.9mr (each 1 C, C=O).
(2R,4S,5R)-(–)-Methyl 3-(2-Azidoacetyl)-5-methyl-2-phenyl-
1,3-oxazolidine-4-carboxylate (9a); Typical Procedure
A solution of 7a (1.00 g, 3.36 mmol) and NaN3 (0.54 g, 8.31 mmol)
in DMSO (25 mL) was stirred at 60°C for 24 h. H2O (100 mL) was
added and the mixture was extracted with Et2O (4 × 100 mL). The
combined organic extracts were washed with brine (50 mL), dried
(Na2SO4) and concentrated in vacuo. FC of the residue (3 cm, petro-
leum ether/EtOAc, 2:1, 20 mL, Rf 0.47) afforded 9a (0.96 g, 94%)
as a colourless oil; [α]589 –2.7 (c = 1.45, CH2Cl2).
(2S,4S,5R)-Methyl 3-(2-Anilinoacetyl)-5-methyl-2-phenyl-1,3-
oxazolidine-4-carboxylate (10b)
Anal. calcd for C14H16N4O4 (304.3): C, 55.26; H, 5.30; N, 18.41.
Found C, 55.42; H, 5.36; N, 17.88.
A solution of 7b (500 mg, 1.68 mmol) and aniline (1.5 mL, 16.5
mmol) in MeOH (10 mL) was refluxed for 72 h. The workup proce-
dure as described for 10a followed by FC (3 cm, petroleum ether/
EtOAc, 1:1, 15 mL, Rf 0.43) yielded 10b (346 mg, 58%) as a pale
yellow oil.
MS (ESI): m/z (%) = 343 (M + K, 12), 327 (M + Na, 100).
IR (film): n = 2954 (m, C–H), 2108 (s, N3 ), 1747 (s, ester C=O),
1672 (s, amide C=O), 1429, 1276, 1213 (s), 762, 702 cm-1 (m, γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.44 (br s, 3 H, CHCH3), 1.60mr
(br s), 3.46 (d, J = 15.9 Hz, 1 H, CH2N3), 3.61 (d, J = 15.6 Hz, 1 H,
CH2N3), 3.80 (br s, 3 H, CO2CH3), 4.09 – 4.48mr (br m), 4.29 (br s,
2 H, CHCH3 and CHCO2CH3), 6.16 (s, 1 H, NCHO), 6.63mr (br s,
19 H, NCHO), 7.26 – 7.53mr (br m), 7.40 (br s, 3 H, arom), 7.67 (br
s, 2 H, arom).
MS (EI): m/z (%) = 354 (M, 7), 260 (M – PhNH3, 23), 220 (M –
PhNHCH2CO, 18), 106 (PhNHCH2, 100).
IR (film): n = 3390 (w, N–H), 1747 (s, ester C=O), 1666 (s, amide
C=O), 1436 (m), 1210 (s, C–O), 739, 689 cm-1 (γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.53 (d, J = 5.9 Hz, 3 H, CHCH3),
2.90 (d, J = 16.6 Hz, 1 H, CH2NH), 3.38 (d, J = 16.9 Hz, 1 H,
CH2NH), 3.81 (s, 3 H, CO2CH3), 4.27 (dq, J = 8.0, 6.0 Hz, 1 H,
CHCH3), 4.36 (d, J = 8.0 Hz, 1 H, CHCO2CH3), 6.13 (s, 1 H,
NCHO), 6.24 (d, J = 7.6 Hz, 2 H, arom), 6.66 (t, J = 7.3 Hz, 1 H,
arom), 7.08 (t, J = 7.9 Hz, 2 H, arom), 7.46 (s, 1 H, arom), 7.49 (s,
(2S,4S,5R)-(–)-Methyl 3-(2-Azidoacetyl)-5-methyl-2-phenyl-
1,3-oxazolidine-4-carboxylate (9b)
A mixture of 7b (750 mg, 2.52 mmol), NaN3 (405 mg, 6.23 mmol),
and DMSO (15 mL) was reacted as described for 9a. Extractive
workup and FC (3 cm, petroleum ether/EtOAc, 2:1, 20 mL, Rf 0.43)
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Synthesis of Enantiomerically Pure 1-(Piperazin-2-yl)ethan-1-ol Derivatives
1743
4 H, arom). A signal for the proton of the NH group could not be
detected.
(1R,3R,8aS)-(–)-7-Butyl-1-methyl-3-phenyl-1,6,7,8a-tetra-
hydro[1,3]oxazolo[3.4-a]pyrazine-5,8-dione (12a); Typical Pro-
cedure
13C NMR (75 MHz, CDCl3): δ = 18.2 (1 C, CHCH3), 47.0 (1 C,
CH2NH), 52.5 (1 C, CO2CH3), 66.1 (1 C, CHCO2CH3), 76.9 (1 C,
CHCH3), 90.6 (1 C, NCHO), 112.6 (2 C, arom CH), 117.5 (1 C,
arom CH), 127.7 (2 C, arom CH), 128.9 (2 C, arom CH), 129.1 (2
C, arom CH), 130.5 (1 C, arom CH), 136.6 (1 C, arom C), 146.8 (1
C, arom C), 167.6, 169.4 (each 1 C, C=O).
A solution of 7a (2.0 g, 6.7 mmol) and butan-1-amine (2.7 mL, 27
mmol) in DMSO (70 mL) was stirred at 60°C for 48 h. After addi-
tion of H2O (150 mL) the mixture was extracted with Et2O (3 × 100
mL), the combined organic layers were washed with 2 N HCl
(2 × 50 mL) and brine (50 mL) and dried (Na2SO4). Removal of the
solvent in vacuo followed by FC (4 cm, petroleum ether/EtOAc,
1:1, 40 mL, Rf 0.28) gave 12a (1.66 g, 82%) as a colourless solid;
mp 83–84°C; [α]589 –13.0 (c = 0.80, CH2Cl2).
(1R,3R,8aS)-(–)-1-Methyl-3-phenyl-1,6,7,8a-tetrahydro[1,3]ox-
azolo[3.4-a]pyrazine-5,8-dione (11a)
F r o m 9 a : To a solution of 9a (450 mg, 1.48 mmol) in MeOH (10
mL) was added Pd/C (10%, 60 mg) and the suspension was stirred
under a H2 atmosphere (balloon) at r.t. for 16 h. The catalyst was fil-
tered through a pad of Celite and the filtrate was concentrated to
Anal. calcd for C17H22N2O3 (302.4): C, 67.53; H, 7.33; N, 9.26.
Found C, 67.11; H, 7.30; N, 9.06.
MS (EI): m/z (%) = 302 (M, 45), 197 (M – PhCO, 29), 105 (PhCO,
55), 42 (C3H6, 100).
yield 11a (350 mg, 96%) as a colourless solid; mp 200°C; [α]589
41.5 (c = 0.75, CH2Cl2).
–
IR (film): n = 2962, 2929 (m, C–H), 2869 (w, C–H), 1683, 1653 (s,
C=O), 1445 (m), 764, 700 cm-1 (w, γaryl).
1H NMR (300 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H,
CH2CH2CH2CH3), 1.35 (sext, J = 7.4 Hz, 2 H, CH2CH2CH2CH3),
1.54 (d, J = 5.8 Hz, 3 H, CHCH3), 1.50–1.62 (m, 2 H,
Anal. calcd for C13H14N2O3 (246.3): C, 63.40; H, 5.73; N, 11.37.
Found C, 63,63; H, 5.70; N, 11.75.
MS (EI): m/z (%) = 246 (M, 64), 169 (M – Ph, 64), 105 (PhCO,
100).
CH2CH2CH2CH3), 3.40 (dt, J = 13.9, 7.3 Hz,
CH2CH2CH2CH3), 3.51 (dt, J = 13.9, 7.3 Hz,
1
1
H,
H,
IR (KBr): n = 3320 (br, N–H), 1695 (s, C=O), 1450 (s), 760, 706
cm-1 (m, γaryl).
CH2CH2CH2CH3), 3.79 (d, J = 17.1 Hz, 1 H, COCH2), 3.89 (dd,
J = 9.0, 1.2 Hz, 1 H, COCH), 4.17 (dd, J = 17.1, 1.5 Hz, 1 H,
COCH2), 4.41 (dq, J = 9.0, 5.9 Hz, 1 H, CHCH3), 6.25 (s, 1 H,
NCHO), 7.26–7.37 (m, 5 H, arom).
1H NMR (300 MHz, CDCl3) : δ = 1.54 (d, J = 5.9 Hz, 3 H, CHCH3),
3.85 (dd, J = 17.0, 4.6 Hz, 1 H, NHCH2), 3.91 (d, J = 9.3 Hz, 1 H,
COCH), 4.06 (dd, J = 17.1, 1.5 Hz, 1 H, NHCH2), 4.40 (dq, J = 9.2,
5.9 Hz, 1 H, CHCH3), 6.29 (s, 1 H, NCHO), 7.11 (dd, J = 4.1, 1.5
Hz, 1 H, NH), 7.31–7.41 (m, 5 H, arom).
(1R,3S,8aS)-(–)-7-Butyl-1-methyl-3-phenyl-1,6,7,8a-tetrahy-
dro[1,3]oxazolo[3.4-a]pyrazine-5,8-dione (12b)
Compound 7b (1.19 g, 4.0 mmol) was reacted with butan-1-amine
(1.6 mL, 16 mmol) in DMSO (40 mL) as described for 12a. The res-
idue obtained after workup was subjected to FC (4 cm, petroleum
ether/EtOAc, 1:1, 30 mL, Rf 0.49) to afford 12b (1.07 g, 89%) as a
colourless oil; [α]589 –82.3 (c = 1.87, CH2Cl2).
13C NMR (75 MHz, CDCl3): δ = 18.1 (1 C, CH3), 46.9 (1 C, CH2),
61.8 (1 C, CHCO), 73.7 (1 C, CHCH3), 89.0 (1 C, NCHO), 126.3 (2
C, arom CH), 128.7 (2 C, arom CH), 129.3 (1 C, arom CH), 137.1
(1 C, arom C), 162.7 (1 C, NC=O), 168.2 (1 C, NC=O).
F r o m 8 a : A suspension of 8a (18.9 g, 46 mmol) and Pd/C (10%,
3.0 g) in MeOH (250 mL) was stirred under a H2 atmosphere (bal-
loon) for 8 h at r.t. After filtration through a pad of Celite and re-
moval of the solvent under reduced pressure, the residue was
subjected to FC (8 cm, EtOAc/MeOH, 85:15, 80 mL, Rf 0.60) to
yield 11a as colourless solid (9.52 g, 84%).
Anal. calcd for C17H22N2O3 (302.4): C, 67.53; H, 7.33; N, 9.26:
Found C, 67.03; H, 7.15; N, 8.97.
MS (EI): m/z (%) = 302 (M, 88), 197 (M – PhCO, 15), 105 (PhCO,
100), 45 (C2H5O, 78).
IR (film): n = 2959, 2872 (s, C–H), 1668 (s, C=O), 1450 (s), 750,
698 cm-1 (m, γaryl).
(1R,3S,8aS)-(–)-1-Methyl-3-phenyl-1,6,7,8a-tetrahydro[1,3]ox-
azolo[3.4-a]pyrazine-5,8-dione (11b)
1H NMR (300 MHz, CDCl3): δ = 0.92 (t, J = 7.3 Hz, 3 H,
CH2CH2CH2CH3), 1.31 (sext, J = 7.4 Hz, 2 H, CH2CH2CH2CH3),
1.52 (quint, J = 7.6 Hz, 2 H, CH2CH2CH2CH3), 1.67 (d, J = 5.9 Hz,
3 H, CHCH3), 3.30 (dt, J = 13.6, 7.2 Hz, 1 H, CH2CH2CH2CH3),
3.49 (dt, J = 13.7, 7.4 Hz, 1 H, CH2CH2CH2CH3), 3.75 (d, J = 16.6
Hz, 1 H, COCH2), 3.92 (dd, J = 9.1, 1.7 Hz, 1 H, COCH), 4.13 (dd,
J = 16.5, 1.7 Hz, 1 H, COCH2), 4.16 (dq, J = 9.0, 6.0 Hz, 1 H,
CHCH3), 6.27 (s, 1 H, NCHO), 7.32–7.40 (m, 3 H, arom), 7.46 –
7.52 (m, 2 H, arom).
A mixture of 9b (687 mg, 2.26 mmol), Pd/C (10%, 80 mg), and
MeOH (15 mL) was stirred under H2 (balloon) at r.t. for 16 h. After
filtration through a pad of Celite and removal of the solvent in vacuo
11b (530 mg, 95.3%) was isolated as a colourless solid; mp 211°C;
[α]589 –118.4 (c = 0.88, CH2Cl2).
Anal. calcd for C13H14N2O3 (246.3): C, 63.40; H, 5.73; N, 11.37.
Found C, 63.42; H, 5.77; N, 11.29.
MS (EI): m/z (%) = 246 (M, 42), 105 (PhCO, 100).
(1R,3R,8aS)-(+)-7-Benzyl-1-methyl-3-phenyl-1,6,7,8a-tetrahy-
dro[1,3]oxazolo[3.4-a]pyrazine-5,8-dione (13a)
IR (KBr): n = 3600–3200 (br, N–H), 1668 (s, C=O), 1455 (m), 754,
697 cm-1 (w, γaryl).
Compound 7a (1.0 g, 3.35 mmol) was reacted with benzylamine
(1.1 mL, 10 mmol) in DMSO (25 mL) as described for 12a. After
purification by FC (3 cm, petroleum ether/EtOAc, 1:2, 20 mL,
Rf 0.49) 13a (0.92 g, 82%) was obtained as colourless solid; mp
87°C; [α]589 +36.5 (c = 0.74, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.65 (d, J = 5.9 Hz, 3 H, CHCH3),
3.84 (dd, J = 16.6, 4.0 Hz, 1 H, NHCH2), 3.91 (dd, J = 9.0, 1.9 Hz,
1 H, COCH), 4.09 (dd, J = 16.6, 1.8 Hz, 1 H, NHCH2), 4.18 (dq,
J = 9.1/5.9 Hz, 1 H, CHCH3), 6.29 (s, 1 H, NCHO), 6.75 (br s, 1 H,
NH), 7.33–7.41 (m, 3 H, arom), 7.47–7.51 (m, 2 H, arom).
13C NMR (75 MHz, CDCl3): δ = 18.5 (1 C, CH3), 46.4 (1 C, CH2),
60.9 (1 C, CHCO), 76.6 (1 C, CHCH3), 88.7 (1 C, NCHO), 126.7 (2
C, arom CH), 128.4 (2 C, arom. CH), 129.3 (1 C, arom CH), 137.8
(1 C, arom C), 161.3 (1 C, NC=O), 166.4 (1 C, NC=O).
Anal. calcd for C20H20N2O3 (336.4): C, 71.41; H, 5.99; N, 8.33.
Found C, 71.22; H, 6.23; N, 8.27.
MS (CI): m/z (%) = 337 (M + H, 100), 231 (M – PhCO, 6).
IR (film): n = 1668 (s, C=O), 1454 (s), 736 (m, γaryl), 699 cm-1 (s,
γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.60 (d, J = 5.9 Hz, 3 H, CHCH3),
3.80 (d, J = 16.8 Hz, 1 H, COCH2), 3.98 (dd, J = 9.0, 1.2 Hz, 1 H,
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1744
S. Soukara, B. Wünsch
PAPER
COCH), 4.07 (dd, J = 17.1, 1.5 Hz, 1 H, COCH2), 4.49 (dq, J = 9.0,
5.8 Hz, 1 H, CHCH3), 4.61 (d, J = 14.6 Hz, 1 H, CH2Ph), 4.71 (d,
J = 14.4 Hz, 1 H, CH2Ph), 6.28 (s, 1 H, NCHO), 7.26–7.33 (m, 4 H,
arom), 7.33–7.42 (m, 6 H, arom).
Anal. calcd for C19H18N2O3 (322.4): C, 70.79; H, 5.63; N, 8.69.
Found C, 70.70; H, 5.68; N, 8.62.
MS (EI): m/z (%) = 322 (M, 58), 105 (PhCO, 100).
IR (film): n = 1657 (s, C=O), 1454 (m), 764 (w, γaryl), 703 cm-1 (m,
γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.72 (d, J = 5.9 Hz, 3 H, CHCH3),
4.12 (dd, J = 9.0, 1.5 Hz, 1 H, COCH), 4.13 (d, J = 16.0 Hz, 1 H,
COCH2), 4.34 (dq, J = 8.9, 5.9 Hz, 1 H, CHCH3), 4.58 (dd, J = 16.2,
1.2 Hz Hz, 1 H, COCH2), 6.44 (s, 1 H, NCHO), 7.23–7.46 (m, 8 H,
arom), 7.52–7.58 (m, 2 H, arom).
(1R,3S,8aS)-(–)-7-Benzyl-1-methyl-3-phenyl-1,6,7,8a-tetrahy-
dro[1,3]oxazolo[3.4-a]pyrazine-5,8-dione (13b)
As described for the preparation of 12a the chloroacetyl derivative
7b (1.0 g, 3.35 mmol) was reacted with benzylamine (1.1 mL, 10
mmol) in DMSO (25 mL). Purification by FC (3 cm, petroleum
ether/EtOAc, 1:1, 20 mL, Rf = 0.64) yielded 13b (0.89 g, 79%) as a
colourless oil; [α]589 –110.6 (c = 1.72, CH2Cl2).
Anal. calcd for C20H20N2O3 (336.4): C 71.41; H, 5.99; N, 8.33.
Found C, 71.29; H, 5.98; N, 8.23.
(1R)-(–)-1-[(2R)-1-Benzylpiperazin-2-yl]ethan-1-ol (15)
To a stirred solution of 1 M LiAlH4 in Et2O (27.5 mL, 28 mmol) and
anhyd THF (80 mL) was added dropwise a solution of 11a (845 mg,
3.45 mmol) in anhyd THF (100 ml). The mixture was refluxed for
72 h, then H2O was added cautiously. The precipitate was filtered
off, the solvent removed in vacuo, the residue dissolved in 2 N HCl
(50 mL) and the solution was washed with Et2O (2 × 80 mL). After
addition of KOH (pH 10) the aqueous layer was extracted with
CH2Cl2 (5 x 80 mL), the CH2Cl2 layer was washed with 2 N NaOH
(25 mL) and brine, dried (MgSO4), and concentrated in vacuo. Re-
crystallization (i-Pr2O) of the residue gave 15 (576 mg, 76%) as pale
yellow crystals; mp 128°C; [α]589 –2.1 (c = 0.80, CH2Cl2).
MS (CI): m/z (%) = 337 (M + H, 15), 336 (M, 100), 245 (M –
PhCH2, 78).
IR (film): n = 1667 (s, C=O), 1448 (s), 735, 700 cm-1 (each m, γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.74 (d, J = 5.9 Hz, 3 H, CHCH3),
3.77 (d, J = 16.1 Hz, 1 H, COCH2), 4.02 (d, J = 16.4 Hz, 1 H,
COCH2), 4.04 (d, J = 9.6 Hz, 1 H, COCH), 4.24 (dq, J = 9.0, 5.8 Hz,
1 H, CHCH3), 4.45 (d, J = 14.4 Hz, 1 H, CH2Ph), 4.77 (d, J = 14.4
Hz, 1 H, CH2Ph), 6.32 (s, 1 H, NCHO), 7.24–7.30 (m, 2 H, arom),
7.31–7.42 (m, 6 H, arom), 7.46–7.54 (m, 2 H, arom).
Anal. calcd for C13H20N2O (220.3): C, 70.87; H, 9.15; N, 12.71.
Found C, 70.90; H, 9.14; N, 12.68.
(1R,3R,8aS)-(–)-1-Methyl-3,7-diphenyl-1,6,7,8a-tetrahydro-
[1,3]oxazolo[3.4-a]pyrazine-5,8-dione (14a); Typical Procedure
A solution of 10a (1.12 g, 3.16 mmol) and 3 N KOH (15 mL) in
MeOH (25 mL) was allowed to stir at r.t. for 16 h. After complete
saponification (TLC control, petroleum ether/EtOAc, 1:1) the mix-
ture was concentrated in vacuo. The residue was neutralized with 2
N HCl, extracted with EtOAc (3 × 50 mL), the aqueous layer was
acidified to pH 4–5 with 2 N HCl and extracted with EtOAc (2 × 80
mL). The combined organic extracts were washed with brine (30
mL), dried (MgSO4) and concentrated in vacuo. Without purifica-
tion, the residue (1.50 g) was dissolved in anhyd CH2Cl2 (50 mL)
and N-(3-dimethylaminopropyl)-N’-ethyl carbodiimide hydrochlo-
ride (EDC, 1.00 g, 5.22 mmol) was added at 0°C. The mixture was
allowed to stir at r.t. for 24 h. Then CH2Cl2 (100 mL) was added and
the solution was washed with aq satd NaHCO3 solution (25 mL),
H2O (20 mL), 1 N HCl (2 × 25 mL) and brine (25 mL). The organic
layer was dried (MgSO4) and evaporated to dryness. FC (3 cm, pe-
troleum ether/EtOAc, 1:1, 15 mL, Rf 0.30) of the residue furnished
14a (760 mg, 75%) as a colourless solid; mp 128°C; [α]589 –17.1
(c = 1.74, CH2Cl2).
MS (CI): m/z (%) = 221 (M + H, 100), 203 (M – OH, 17), 175 (M –
C2H5O, 38).
IR (film): n = 3292 (m, O–H, N–H), 3113 (br, O–H, N–H), 2968,
2806 (s, C–H), 1452 (m), 1081 (s, C–O, C–N), 743, 696 cm-1 (m,
γaryl).
1H NMR (400 MHz, CDCl3): δ = 1.11 (d, J = 6.4 Hz, 3 H, CHCH3),
2.10–2.21 (m, 1 H, 2-H), 2.39–2.44 (m, 1 H, 6-H), 2.45 – 2.55 (m,
1 H, 5-H), 2.68 (dd, J = 13.0, 2.3 Hz, 1 H, 3-H), 2.92–3.00 (m, 2 H,
5-H and 6-H), 3.12 (dd, J = 13.2, 3.8 Hz, 1 H, 3-H), 3.83 (d,
J = 13.2 Hz, 1 H, CH2Ph), 3.87 (d, J = 13.7 Hz, 1 H, CH2Ph), 4.16
(dq, J = 8.6, 6.1 Hz, 1 H, CHCH3), 7.16–7.22 (m, 1 H, arom), 7.24–
7.28 (m, 4 H, arom). Signals for the protons of the OH and NH
groups could not be detected.
13C NMR (100 MHz, CDCl3): δ = 19.2 (1 C, CH3), 40.7 (1 C, C-5),
41.2 (1 C, C-3), 46.6 (1 C, C-6), 57.0 (1 C, CH2Ph), 63.5 (1 C, C-
2), 63.7 (1 C, CHCH3), 127.2 (1 C, arom CH), 128.3 (2 C, arom
CH), 128.7 (2 C, arom CH), 138.6 (1 C, arom C).
Anal. calcd for C19H18N2O3 (322.4): C, 70.79; H, 5.63; N, 8.69.
Found C, 70.74; h, 5.65; N, 8.64.
(1R)-(–)-1-[(2R)-1-Benzyl-4-butylpiperazin-2-yl]ethan-1-ol (16)
A solution of 12a (1.80 g, 5.95 mmol) in anhyd THF (150 mL) was
added to a stirred suspension of LiAlH4 pellets (2.19 g, 58 mmol) in
anhyd THF(150 mL) and the mixture was refluxed for 48 h. Under
N2 and with cooling (ice bath) H2O (3 mL), 3 N NaOH (3.0 ml), and
again H2O (3 mL) were successively added. The suspension was re-
fluxed for 30 min and stirring at r.t. was continued for 16 h. The pre-
cipitate was filtered off and after removal of THF under reduced
pressure aq 2 N NaOH (25 mL) was added. The solution was ex-
tracted with EtOAc (2 × 100 mL), the organic layer was washed
with brine (25 mL) and dried (MgSO4). Evaporation to dryness and
purification by FC (4 cm, EtOAc, 35 mL, Rf 0.39) provided 16 (1.43
g, 87%) as colourless viscous oil; [α]589 –6.3 (c = 1.45, CH2Cl2).
MS (EI): m/z (%) = 322 (M, 81), 245 (M – Ph, 23), 105 (PhCO,
100).
IR (film): n = 1684 (s, C=O), 1434 (m), 734 (w, γaryl), 698 cm-1 (m,
γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.59 (d, J = 5.8 Hz, 3 H, CHCH3),
4.11 (dd, J = 8.9, 1.1 Hz, 1 H, COCH), 4.21 (d, J = 16.6 Hz, 1 H,
COCH2), 4.54 (dq, J = 9.0, 5.9 Hz, 1 H, CHCH3), 4.65 (dd, J = 16.6,
1.2 Hz, 1 H, COCH2), 6.36 (s, 1 H, NCHO), 7.30–7.48 (m, 10 H,
arom).
(1R,3S,8aS)-(–)-1-Methyl-3,7-diphenyl-1,6,7,8a-tetrahydro-
[1,3]oxazolo[3.4-a]pyrazine-5,8-dione (14b)
Anal. calcd for C17H28N2O (276.4): C, 73.87; H, 10.21; N, 10.13.
Found C, 73.60; H, 10.15; N, 9.88.
As described for the preparation of 14a, hydrolysis of 10b (346 mg,
0.92 mmol) was carried out with 3 N KOH (5 mL) in MeOH (10
mL) to provide the crude amino acid (400 mg). After reaction with
EDC (269 mg, 1.40 mmol) in anhyd CH2Cl2 (7 mL), workup, and
FC purification (2 cm, petroleum ether/EtOAc, 1:1, 5 mL, Rf 0.47)
14b (126 mg, 43%) was obtained as pale yellow solid; mp 170°C;
[α]589 –104.6 (c = 1.53, CH2Cl2).
MS (CI): m/z (%) = 277 (M + H, 37), 231 (M – C2H5O, 17), 91
(PhCH2, 100).
IR (film): n = 3386 (br, O–H), 2931 (s, C–H), 2808 (m, C–H), 1667
(m), 1453 (s), 1081 (m), C–O), 739, 698 cm-1 (s, γaryl).
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Facile Synthesis of Enantiomerically Pure 1-(Piperazin-2-yl)ethan-1-ol Derivatives
1745
1H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H,
CH2CH2CH2CH3), 1.18 (d, J = 6.1 Hz, 3 H, CHCH3), 1.34 (sext,
3.95 (d, J = 13.2 Hz, 1 H, CH2Ph), 4.22 (dq, J = 9.0, 6.1 Hz, 1 H,
CHCH3), 6.86 (dt, J = 7.3, 1.0 Hz, 1 H, arom), 6.89–6.91 (m, 1 H,
arom), 6.91–6.94 (m, 1 H, arom), 7.25–7.32 (m, 3 H, arom), 7.34–
7.37 (m, 4 H, arom). A signal for the proton of the OH group could
not be detected.
13C NMR (75 MHz, CDCl3): δ = 19.7 (1 C, CH3), 43.5 (1 C, C-5),
44.3 (1 C, C-3), 45.4 (1 C, C-6), 56.8 (1 C, CH2Ph), 63.5 (1 C,
CHCH3), 64.5 (1 C, C-2), 115.9 (2 C, arom CH), 119.8 (1 C, arom
CH), 127.4 (1 C, arom CH), 128.5 (2 C, arom CH), 128.8 (2 C, arom
CH), 129.1 (2 C, arom CH), 138.3 (1 C, arom C), 151.7 (1 C, arom
C).
J = 7.3 Hz,
2 H, CH2CH2CH2CH3), 1.41–1.51 (m, 2H,
CH2CH2CH2CH3), 2.27 (t, J = 7.4 Hz, 2 H, CH2CH2CH2CH3),
2.31–2.44 (m, 3 H, 2-H and 5-H), 2.49 (dd, J = 11.8, 3.5 Hz, 1 H,
3-H), 2.52–2.62 (m, 2 H, 6-H and 3-H), 3.15 (ddd, J = 14.0, 8.4, 5.7
Hz, 1 H, 6-H), 3.85 (s, 2 H, CH2Ph), 4.08 (br s, 1 H, OH), 4.19 (dq,
J = 7.8, 6.2 Hz, 1 H, CHCH3), 7.22–7.29 (m, 1 H, arom), 7.31–7.32
(m, 4 H, arom).
13C NMR (75 MHz, CDCl3): δ = 14.0 (1 C, CH2CH2CH2CH3), 19.6
(1 C, CHCH3), 20.5 (1 C, CH2CH2CH2CH3), 28.7 (1 C,
CH2CH2CH2CH3), 46.1 (1 C, C-6), 48.2 (1 C, C-5), 48.9 (1 C, C-3),
57.2 (1 C, CH2Ph), 58.9 (1 C, CH2CH2CH2CH3), 63.9 (1 C, C-2),
65.4 (1 C, CHCH3), 127.2 (1 C, arom CH), 128.4 (2 C, arom CH),
128.8 (2 C, arom CH), 139.0 (1 C, arom C).
Compound 21
MS (CI): m/z (%) = 315 (M + H, 100), 297 (M – OH, 2).
IR (film): n = 3391 (br, O–H, N–H), 1602, 1503 (m, C=C), 734 (s,
γaryl), 696 cm-1 (m, γaryl).
(1R)-(+)-1-[(2R)-1,4-Dibenzylpiperazin-2-yl]ethan-1-ol (17)
A solution of 13a (690 mg, 2.05 mmol) in anhyd THF (50 ml) was
cautiously added to a solution of 1 M LiAlH4 in Et2O (13 mL, 13
mmol) and anhyd THF (50 ml) and the mixture was refluxed for 30
h. The mixture was worked up as described for 15 and after purifi-
cation of the residue by FC (3 cm, petroleum ether/EtOAc, 1:2, 20
mL, Rf 0.26) 17 (470 mg, 74%) was obtained as pale yellow oil;
[α]589 +18.3 (c = 1.44, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.18 (d, J = 6.1 Hz, 3 H, CHCH3),
2.63 (ddd, J = 8.9, 7.6, 4.7 Hz, 1 H, NCHCH2OH), 2.88–3.13 (m, 4
H, NCH2CH2N), 3.64–3.80 (m, 4 H, CH2OH, CHHPh and
CHCH3), 3.95 (d, J = 13.3 Hz, 1 H, CHHPh), 6.44 (br d, 2 H, o-
NHC6H5), 6.66 (tt, J = 7.3, 1.1 Hz, 1 H, p-NHC6H5), 7.10 (br t, 2 H,
m-NHC6H5), 7.23–7.37 (m, 5 H, NCH2C6H5). Signals for the pro-
tons of the NH and OH groups were not detected.
Anal. calcd for C20H26N2O (310.4): C, 77.38; H, 8.44; N, 9.02.
Found C, 77.29; H, 8.45; N, 9.00.
(+)-{(3R)-4-Benzyl-3-[(1R)-1-hydroxyethyl]piperazin-1-yl}
Phenyl Ketone (19)
As described for the preparation of 15, a solution of the bicyclic pip-
erazinedione 11a (300 mg, 1.22 mmol) in anhyd THF (50 mL) was
reduced with a solution of 1 M LiAlH4 in Et2O (11 mL, 11 mmol)
and anhyd THF (20 mL). After hydrolysis of excess LiAlH4 with
H2O, benzoyl chloride (0.14 mL, 1.22 mmol) was added to the sus-
pension. The mixture was stirred for 24 h ar r.t., filtered and the fil-
trate concentrated in vacuo. The residue was dissolved in EtOAc,
the solution was washed with 3 N NaOH (25 mL) and brine (50
mL), dried (MgSO4) and evaporated to dryness. Purification of the
residue by FC (3 cm, petroleum ether/EtOAc, 1:1, 20 mL, Rf 0.21)
provided 19 (210 mg, 53%) as a pale yellow oil; [α]589 +1.3
(c = 1.74, CH2Cl2).
MS (CI): m/z (%) = 311 (M + H, 100), 265 (M – C2H5O, 29).
IR (film): n = 3396 (br, O–H), 2930 (s, C–H), 2806 (s, C–H), 1451
(m), 1108 (s, C–O, C–N), 741, 700 cm-1 (s, γaryl).
1H NMR (300 MHz, CDCl3): δ = 1.23 (d, J = 6.1 Hz, 3 H, CHCH3),
2.46–2.59 (m, 3 H, 2-H and 6-H), 2.60–2.68 (m, 2 H, 3-H), 2.73 (dd,
J = 14.7, 2.7 Hz, 1 H, 5-H), 3.35 (ddd, J = 14.3, 9.0, 5.5 Hz, 1 H, 5-
H), 3.53 (d, J = 13.2 Hz, 1 H, CH2Ph), 3.70 (d, J = 13.1 Hz, 1 H,
CH2Ph), 3.98 (d, J = 13.2 Hz, 1 H, CH2Ph), 4.06 (d, J = 13.2 Hz, 1
H, CH2Ph), 4.36 (br s, 1 H, OH), 4.43 (qd, J = 6.0, 2.4 Hz, 1 H,
CHCH3), 7.37–7.44 (m, 2 H, arom), 7.46–7.48 (m, 8 H, arom).
13C NMR (75 MHz, CDCl3): δ = 19.4 (1 C, CH3), 45.7 (1 C, C-5),
47.8 (1 C, C-6), 48.1 (1 C, C-3), 57.1 (1 C, CH2Ph), 63.4 (1 C,
CH2Ph), 64.2 (1 C, C-2), 64.5 (1 C, CHCH3), 127.0–128.7 (10 C,
arom CH), 138.0 (1 C, arom C), 138.8 (1 C, arom C).
Anal. Calcd for C20H24N2O2 (324.4): C, 74.04; H, 7.45; N, 8.63.
Found C, 74.07; H, 7.43; N, 8.46.
MS (CI): m/z (%) = 325 (M + H, 2), 279 (M – C2H5O, 100), 188
(279 – PhCH2, 43), 105 (PhCO, 72).
(1R)-(–)-1-[(2R)-1-Benzyl-4-phenylpiperazin-2-yl]ethan-1-ol
(18) and (2R,3R)-2-[N-(2-Anilinoethyl)-N-benzylamino]butane-
1,3-diol (21)
IR (film): n = 3407 (br, O–H), 1624 (s, C=O), 1445 (m), 1285 (m),
736, 702 cm-1 (m, γaryl).
1H NMR (300 MHz, DMSO-d6, 90°C): δ = 1.07 (d, J = 6.1 Hz, 3 H,
CHCH3), 2.23 (ddd, J = 12.3, 8.9, 3.4 Hz, 1 H, 5-H), 2.44 (ddd,
J = 8.2, 5.7, 3.5 Hz, 1 H, 3-H), 2.78 (ddd, J = 12.5, 5.4, 3.4 Hz, 1 H,
5-H), 3.13 (ddd, J = 12.8, 9.1, 3.5 Hz, 1 H, 6-H), 3.20 (dd, J = 13.1,
7.8 Hz, 1 H, 2-H), 3.43 (d, J = 13.7 Hz, 1 H, CH2Ph), 3.62–3.74 (m,
1 H, 6-H), 3.91 – 3.94 (m, 1 H, 2-H), 4.00 (d, J = 13.9 Hz, 1 H,
CH2Ph), 4.12 (quint, J = 6.1 Hz, 1 H, CHCH3), 4.28 (br s, 1 H, OH),
7.19–7.25 (m, 1 H, arom), 7.30–7.34 (m, 4 H, arom), 7.35–7.38 (m,
2 H, arom), 7.39–7.44 (m, 3 H, arom).
A solution of 14a (3.14 g, 9.75 mmol) in anhyd THF (150 mL) was
slowly added to a suspension of LiAlH4 pellets (2.98 g, 62 mmol)
in anhyd THF (200 mL). After refluxing for 48 h the mixture was
worked up as described for 15 to afford a residue, which was sepa-
rated and purified by FC (5 cm, petroleum ether/EtOAc, 7:3, 40 mL,
18: Rf 0.46; 21: Rf 0.07) to yield 18 (1.40 g, 48%) as a pale yellow
solid; mp 95–96°C; [α]589 –5.0 (c = 1.50, CH2Cl2) and 21 (0.811
mg, 26%) as a pale yellow oil.
Compound 18
13C NMR (75 MHz, DMSO-d6, 70°C): δ = 17.4 (1 C, CH3), 42.8 (1
C, C-2), 43.5 (1 C, C-6), 49.1 (1 C, C-5), 56.7 (1 C, CH2Ph), 63.1
(1 C, CHCH3), 64.1 (1 C, C-3), 126.4 (1 C, arom CH), 126.5 (2 C,
arom CH), 127.8 (2 C, arom CH), 127.9 (2 C, arom CH), 128.2 (2
C, arom CH), 128.9 (1 C, arom CH), 135.8 (1 C, arom C), 138.6 (1
C, arom C), 168.7 (1 C, C=O).
Anal. calcd for C19H24N2O (296.4): C, 76.99; H, 8.16; N, 9.45.
Found C, 76.89; H, 7.99; N, 9.26.
MS (EI): m/z (%) = 296 (M, 7), 251 (M – C2H5O, 100), 91 (PhCH2,
82).
IR (film): n = 3415 (br, O–H), 1600, 1500 (m, C=C), 1454 (w), 753,
695 cm-1 (s, γaryl).
(3R)-(–)-tert-Butyl 4-Benzyl-3-[(1R)-1-hydroxyethyl]pipera-
zine-1-carboxylate (20)
As described for the preparation of 15, a solution of the bicyclic pip-
erazinedione 11a (1.50 g, 6.8 mmol) in anhyd THF (100 mL) was
1H NMR (300 MHz, CDCl3): δ = 1.25 (d, J = 6.1 Hz, 3 H, CHCH3),
2.54 (dtd, J = 8.2, 3.4, 0.7 Hz, 1 H, 2-H), 2.74 (dtd, J = 13.5, 3.1, 0.8
Hz, 1 H, 6-H), 3.08–3.14 (m, 2 H, 5-H), 3.18–3.24 (m, 1 H, 6-H),
3.27 (t, J = 3.0 Hz, 2 H, 3-H), 3.89 (d, J = 13.2 Hz, 1 H, CH2Ph),
Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1746
S. Soukara, B. Wünsch
PAPER
reduced with LiAlH4 pellets (2.30 g, 61 mmol) suspended in anhyd
THF (200 mL). The mixture was refluxed for 72 h. After hydrolysis
of excess LiAlH4 with H2O, di-tert-butyl dicarbonate (1.7 mL, 8
mmol) was added to the cooled (0 °C) resulting suspension. The
mixture was allowed to warm to r.t. and stirring was continued for
24 h. The suspension was filtered, the filtrate was concentrated in
vacuo and the residue was dissolved in EtOAc (100 mL). The solu-
tion was washed with 3 N NaOH (25 mL) and brine (50 mL), the
organic layer dried (MgSO4) and evaporated to dryness. FC purifi-
cation (4 cm, petroleum ether/EtOAc, 2:1, 40 mL, Rf 0.43) of the
residue gave 20 (1.18 g, 54%) as a clear, colourless oil; [α]589 –5.0
(c = 0.70, CH2Cl2).
nowledged. Thanks are also due to the Degussa AG for donation of
chemicals.
References
(1) Thurkauf, A.; Mattson, M. V.; Richardson, S.; Mirsadeghi, S.;
Ornstein, P. L.; Harrison, E. A.; Rice, K. C.; Jacobson, A. E.;
Monn, J. A. J. Med. Chem. 1992, 35, 1323.
(2) Naylor, A.; Judd, D. E.; Lloyd, J. E.; Scopes, D. I. C.; Hayes,
A. G.; Birch, P. J. J. Med. Chem. 1993, 36, 2075.
(3) (a) Mills, S. G.; Wu, M. T.; MacCoss, M.; Budhu, R. J.; Dorn,
C. P.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; Greenlee,
W.J. Bioorg. Med. Chem. Lett. 1993, 3, 2707.
Anal. Calcd for C18H28N2O3 (320.4): C, 67.47; H, 8.80; N, 8.74.
Found C, 67.80; H, 8.84; N, 8.36.
(b) Mills, S. G.; MacCoss, M.; Cascieri, M. A.; Sadowski, S.;
Patel, S.; Chapman, K. L.; Hutson, P. H. Bioorg. Med. Chem.
Lett. 1995, 5, 599.
MS (CI): m/z (%) = 321 (M + H, 100), 275 (M – C2H5O, 10), 265
(MH – C4H8, 30), 91 (PhCH2, 62).
(4) Van Daele, G. H. P.; Vlaeminck, F. F.; Verdonck, M. G. C.
(Janssen Pharmaceutica) Eur. Pat. 285 219, 1988; Chem.
Abstr. 1989, 110, 231 665.
IR (film): n = 3448 (br, O–H), 1694 (s, C=O), 1173 (m, C–O), 741,
699 cm-1 (w, γaryl).
1H NMR (300 MHz, DMSO-d6, 60°C): δ = 1.09 (d, J = 6.4 Hz, 3 H,
CHCH3), 1.38 [s, 9 H, C(CH3)3], 2.13 (ddd, J = 12.3, 8.7, 3.5 Hz, 1
H, 5-H), 2.31 (ddd, J = 7.4, 6.1, 3.6 Hz, 1 H, 3-H), 2.67 (ddd,
J = 12.2, 5.6, 3.4 Hz, 1 H, 5-H), 2.97–3.10 (m, 2 H, 6-H and 2-H),
3.39 (d, J = 13.7 Hz, 1 H, CH2Ph), 3.46 (dddd, J = 12.9, 5.4, 3.7, 1.1
Hz, 1 H, 6-H), 3.73 (ddd, J = 13.3, 3.5, 1.2 Hz, 1 H, 2-H), 3.96 (d,
J = 13.7 Hz, 1 H, CH2Ph), 4.08 (quint, J = 6.3 Hz, 1 H, CHCH3),
4.50 (br s, 1 H, OH), 7.20–7.40 (m, 5 H, arom).
13C NMR (75 MHz, DMSO-d6, 60°C): δ = 17.8 (1 C, CH3), 27.8 [3
C, C(CH3)3], 40.3 (1 C, C-2), 41.3 (1 C, C-6), 48.4 (1 C, C-5), 56.8
(1 C, CH2Ph), 63.4 (1 C, CHCH3), 63.8 (1 C, C-3), 78.3 [1 C,
C(CH3)3], 126.5 (1 C, arom CH), 127.8 (2 C, arom CH), 128.3 (2 C,
arom CH), 138.7 (1 C, arom C), 153.7 (1 C, C=O).
(5) Igarashi, K.; Irisawa, J.; Homma, T. (Shionogi and Co.) Eur.
Pat. 1643, 1979; Chem. Abstr. 1980, 92, 42 341.
(6) Leigh, T.; Todd, A. H. (ImperialChemical Industries) Ger.
Offen. 1 909 222, 1969; Chem. Abstr. 1969, 71, 124 494.
(7) Shin, C.; Yonezawa, Y.; Sato, Y.; Nakano, T. Heterocycles
1983, 20, 405.
(8) Polyakov, A. I.; Aseeva, N. N.; Bezrukova, V. G. Izv. Akad.
Nauk SSSR, Ser. Khim. 1974, 7, 1589; Chem. Abstr. 1974, 81,
152 601.
(9) Seebach, D.; Enders, D.; Renger, B. Chem. Ber. 1977, 110,
1852.
(10) Guttmann, S.; Boissonnas, R. A., Helv. Chim. 1958, 41, 1852.
(11) Miehling, W.; Brunner, H., Monatsh. Chem. 1984, 115, 1237.
(12) Still, W. S.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
Acknowledgement
Financial support of this work by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie is gratefully ack-
Article Identifier:
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Synthesis 1999, No. 10, 1739–1746 ISSN 0039-7881 © Thieme Stuttgart · New York