Synthesis of new homochiral 2,3-dialkylpiperazines derived from (R)-(-)-phenylglycinol

Article abstract of DOI:10.1016/S0957-4166(01)00036-2

The synthesis of four new 2,3-dialkylpiperazines in yields of 70-99% using (R)-(-)-phenylglycinol as a chiral inductor is described. The synthesis involved reduction of the oxazino-oxazine type derivatives obtained by condensation of glyoxal and phenylglycinol to give hydroxyethylenediamine precursors which were further condensed with glyoxal, butanedione and 1-phenyl-1,2-propanedione and then reduced to provide the corresponding piperazines. The stereochemical outcome is determined by the configuration of the bisoxazolidine precursors, which is in turn dictated by steric effects exerted by the substituents on the five membered ring. The structures of five derivatives were established by X-ray analysis.

Full text of DOI:10.1016/S0957-4166(01)00036-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 241–247
Synthesis of new homochiral 2,3-dialkylpiperazines derived from
(R)-(−)-phenylglycinol
V´ıctor Santes,a Elizabeth Go´mez,a Vero´nica Za´rate,a Rosa Santillan,a Norberto Farfa´na,* and
Susana Rojas-Limab
aDepartamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del IPN, Apdo. Postal 14-740,
07000 Me´xico D.F., Mexico
bCentro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Hidalgo, Unidad Universitaria,
Carretera Pachuca-Tulancingo Km 4.5, Pachuca, Hidalgo, C.P. 42076, Mexico
Received 3 November 2000; accepted 3 January 2001
Abstract—The synthesis of four new 2,3-dialkylpiperazines in yields of 70–99% using (R)-(−)-phenylglycinol as a chiral inductor
is described. The synthesis involved reduction of the oxazino–oxazine type derivatives obtained by condensation of glyoxal and
phenylglycinol to give hydroxyethylenediamine precursors which were further condensed with glyoxal, butanedione and 1-phenyl-
1,2-propanedione and then reduced to provide the corresponding piperazines. The stereochemical outcome is determined by the
configuration of the bisoxazolidine precursors, which is in turn dictated by steric effects exerted by the substituents on the five
membered ring. The structures of five derivatives were established by X-ray analysis. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
six-membered fused derivatives could not be obtained.14
The oxazino–oxazine derivatives have been shown
to provide exclusively the cis-fused products due to
the presence of a stabilising double anomeric effect.13,16
This fact is important because these heterocycles can
be reduced diastereoselectively to obtain symmetrical or
unsymmetrical hydroxyethylenediamines depending on
the a-diketone used. Moreover, the chiral ligands
could be used as catalysts in asymmetric synthesis.15
In continuation of our studies on the synthesis of
piperazines we describe herein four new 2,3-dialkyl-
piperazines where the hydroxyethylenediamine precur-
sor was obtained by reduction of oxazino–oxazine
1 prepared by condensation of phenylglycinol with
glyoxal.
In the course of our study on the synthesis of dihydro-
1,4-oxazine and bisoxazolidine type structures a new
route for preparing N,N%-substituted piperazines
diastereoselectively has been found.1–3 Although studies
concerning various aspects of the synthesis and chem-
istry of this interesting type of compounds have been
reported,4–12 to our knowledge this is the first report
describing 2,3-dialkylsubstituted piperazines with trans-
stereoselectivity.3 In a recent study13 the condensation
of phenylglycinol with several a-diketones was shown
to provide dihydro-1,4-oxazines or oxazino–oxazines
depending on the solvent, molar ratios and reaction
conditions, in contrast to a previous report where the
Scheme 1.
* Corresponding author. E-mail: jfarfan@mail.cinvestav.mx
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00036-2

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V. Santes et al. / Tetrahedron: Asymmetry 12 (2001) 241–247
2. Results and discussion
The formation of bisoxazolidines 3a–d was achieved by
condensation of 2 with the corresponding a-dicarbonyl
compound (Scheme 2). Bisoxazolidine 3a was obtained
diastereoselectively after 5 h under reflux in ethanol.
The NMR spectra showed nine 1H and eight 13C signals
consistent with the presence of a C2 axis and the X-ray
diffraction analysis allowed us to establish its structure
as well as the (R,R)- absolute configuration of the ring
fusion carbons. In contrast, no stereoselectivity was
observed in the reaction with 2,3-butanedione, which
under the same reaction conditions afforded two
The reaction of (R)-(−)-phenylglycinol with glyoxal
afforded oxazino–oxazine 1 in 70% yield which was
subsequently transformed into dihydroxyethylenedi-
amine 2 by reduction using BH3–THF, as shown in
Scheme 1. The cis stereochemistry at the ring fusion for
compound 1 is supported by X-ray diffraction analysis
(Fig. 1). The selective formation of 2 was evidenced by
1H and 13C NMR spectroscopy, and the product was
used in the next step without purification.
Figure 1. Molecular perspective views for 1, 3a, 3d, 4a and 4c.

V. Santes et al. / Tetrahedron: Asymmetry 12 (2001) 241–247
243
Scheme 2.
diastereomers (3b and 3c) in a 1:1 ratio, as determined
by NMR spectroscopy. Finally, bisoxazolidine 3d was
and 4c (Scheme 2), which were separated and purified
1
by chromatography on silica gel. The H NMR spec-
1
obtained as the only product. The H and 13C NMR
trum of 4b showed a quartet at 3.06 ppm for C-(2)H
due to coupling with the methyl group, while the same
proton in piperazine 4c appears as doublet of quartets
at 2.22 ppm (J=10.9, 5.4 Hz) due to coupling to the
methyl group and the diastereotopic C-(3)H proton.
The absence of spin coupling between C-(2)H and
C-(3)H in 4b (dihedral angle:60°) and the large spin
coupling value in 4c (dihedral angle:180°) are evidence
for trans-diaxial and trans-diequatorial arrangements
of the methyl groups in 4b and 4c, respectively. Addi-
spectra of 3d showed signals for each atom because of
the absence of molecular symmetry and were assigned
based on COSY, NOESY, HETCOR and HMBC
experiments. The NOESY experiment revealed that the
signal corresponding to the methyl group correlates
with the ortho-protons of the phenyl group attached to
C-(2), this suggests that both the methyl and phenyl
groups are on the same side. Additionally the structure
of 3d was established by single-crystal X-ray crystallo-
graphic analysis (Fig. 1) which shows that the fusion is
cis—confirming the stereochemistry suggested by NMR
and the absolute configuration with respect to C-(2)
and C-(2%) is (R,S).
1
tionally, the H NMR signal for 4b is shifted upfield by
0.84 ppm compared with the equivalent signal in 4c,
and the 13C NMR spectrum showed that the methyl
carbon signal in the spectrum of 4b appears at 11.5
ppm whereas those of 4c are shifted to 16.0 ppm.
Examination of the X-ray diffraction structure of 4c
allowed us to establish the absolute configuration of the
carbons at the 2 and 3 positions as (R,R), respectively.
Furthermore, the substituents at the nitrogen atoms
were equatorial as observed for piperazine 4a. It is
worth noting that the methyl groups of piperazine 4c
are trans-diaxial in contrast to the results found by
NMR experiments in solution and is due to the exis-
tence of hydrogen bonds between nitrogen and the
hydroxyl groups. Piperazine 4d was obtained with high
diasteroselectivity.
Piperazines 4a–d were obtained by reduction of bisoxa-
zolidines 3a–d, respectively (Scheme 2). Piperazine 4a
1
was obtained as the only product. The H NMR spec-
trum showed a broad multiplet between 2.83 and 2.34
ppm for the ring protons, whereas these carbons give
rise to a broad singlet at 49.6 ppm in the 13C NMR
spectrum. Moreover, the 13C NMR recorded at 223 K
showed two different signals at 52.3 and 45.2 ppm for
C-(2) and C-(3), which coalesced at 273 K, allowing us
to calculate a DG"=12.14 kcal/mol for the ring inter-
conversion process. The structure of 4a was further
established by X-ray diffraction analysis (Fig. 1) which
showed that in the solid state the substituents attached
to the nitrogen atoms occupy equatorial positions pre-
sumably to minimise steric effects.
3. Conclusions
The outcome of the reaction shows that the condensa-
tion of the hydroxyethylenediamine derived from
phenylglycinol with glyoxal and butanedione is stereo-
The mixture of bisoxazolidines 3b and 3c was reduced
to provide a mixture of diastereomeric piperazines 4b

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V. Santes et al. / Tetrahedron: Asymmetry 12 (2001) 241–247
selective, yielding the trans-fused bisoxazolidine. The
X-ray structure of the bisoxazolidine derived from 1-
phenyl-1,2-propanedione shows that the phenyl groups
are responsible for steric repulsion that leads to iso-
meric bisoxazolidines with cis-fusion. Reduction of
oxazine–oxazine type structures provides access to tet-
radentate ligands which could find applications as lig-
ands in chiral catalysts. The benzylic groups at the
nitrogen atoms can be removed by hydrogenation to
obtain new piperazines.
of 3293 reflections were collected from which 1698 were
unique (Rint 0.038), 1194 were considered observed,
F>4|(F), 217 parameters, final R=0.037, Rw=0.093.
4.3. Crystal data for 3d
C29H35N2O3.5, M=467.53 g/mol, orthorhombic, space
group P21212, with a=20.393(4), b=20.667(4), c=
3
,
,
5.9480(10) A, h=i=k=90°, V=2506.9 (8) A , Z=4,
d
calc=1.220 g cm−3, v=0.080 mm−1. A total of 4963
reflections were collected from which 4392 were unique
(Rint 0.037), 2889 were considered observed, F>4|(F),
292 parameters, final R=0.048, Rw=0.136.
4. Experimental
1H and 13C NMR spectra were recorded on Jeol-270,
Bruker Avance DPX-300 and Jeol Eclipse+400 spec-
trometers. Chemical shifts (ppm) are relative to
4.4. Crystal data for 4a
1
(CH3)4Si. Coupling constants (J) are quoted in Hz. H
and 13C NMR spectral assignments were supported by
2D NMR techniques (COSY, NOESY, HETCOR and
HMBC). Infrared spectra were recorded on a Perkin–
Elmer 16F spectrophotometer. Mass spectra were
obtained with a HP 5989A mass spectrometer. Optical
rotations were measured on a Perkin–Elmer 241 polar-
imeter, [h]2D5 values are given in deg cm−2 g−1. Melting
points were obtained on a Gallenkamp MFB-595
apparatus and are uncorrected. The X-ray crystallo-
graphic studies for 1, 3a, 3d and 4a were done on an
Enraf Nonius CAD4 diffractometer, u(MoKh)=0.71069
C20H26N2O2, M=326.43 g/mol, orthorhombic, space
group C2221, with a=5.744(1), b=10.468(2), c=
3
,
,
28.218(6) A, h=i=k=90°, V=1696.7 (6) A , Z=4,
d
calc=1.278 g cm−3, v=0.083 mm−1. A total of 1658
reflections were collected from which 1479 were unique
(Rint 0.028), 1126 were considered observed, F>4|(F),
109 parameters, final R=0.048, Rw=0.131
4.5. Crystal data for 4c
,
A, graphite monochromator, T=293 K, ꢀ/2q, range
C22H30N2O2, M=354.48 g/mol, orthorhombic, space
2<q<25°. The structure of 4c was determined on a
Bruker AXS Smart 6000 with CCD scan type hemi-
sphere, data reduction was done using Saint ver. 6.01.
Corrections were made for Lorentz and polarisation
effects. The structures were solved by direct methods
(SHELXS-86), all non-hydrogen atoms were refined
anisotropically by full-matrix least squares using
SHELXS-93 for 1, 3a, 3d and 4a and SHELXTL-97
ver. 5.10 for 4c. Hydrogen atoms were included in fixed
positions. Elemental microanalyses were performed by
Oneida Research Services, Whitesboro, NY. The
HRMS was determined on a Jeol 102A spectrometer at
the Instituto de Qu´ımica, UNAM.
group P212121, with a=7.8993(4), b=9.1470(5), c=
3
,
,
28.2164(13) A, h=i=k=90°, V=2038.77 (18) A , Z=
4, dcalc=1.155 g cm−3, v=0.074 mm−1. A total of 10995
reflections were collected from which 2932 were unique
(Rint 0.040), 1908 were considered observed, F>4|(F),
236 parameters, final R=0.037, Rw=0.072.
4.6. (3R,7R,4aR,8aR)-3,7-cis-Perhydro-[1,4]oxazino-
[3,2-b]-1,4-oxazine 1
To a solution of (R)-(−)-phenylglycinol (2.0 g, 14.36
mmol) in ethanol (30 mL), was added glyoxal (40% in
water, 1.04 g). The reaction mixture was stirred under
reflux for 3 h and concentrated to give a white solid
(1.48 g, 70%) which was recrystallized from chloro-
form–ethanol to afford a white crystalline product, mp
191–192°C [h]D25=−164.6 (c=0.1, CH2Cl2); 1H NMR
(399.78 MHz, CDCl3): l 7.44 (2H, d, J=7.0 Hz, H-o),
7.36 (2H, t, J=7.0 Hz, H-m), 7.30 (1H, t, J=7.0 Hz,
H-p), 4.55 (1H, s, H-4a), 4.51 (1H, dd, J=3.3, 11.0 Hz,
H-3), 3.92 (1H, dd, J=3.3, 11.0 Hz, H-2eq), 3.60 (1H,
t, J=11.0 Hz, H-2ax), 2.58 (1H, s, NH); 13C NMR
(100.54 MHz, CDCl3): l 139.9 (C-i ), 128.6 (C-o), 127.9
(C-p), 127.4 (C-m), 81.5 (C-4a), 72.4 (C-2), 52.5 (C-3);
MS, m/z (%): [M++1, 297 (2)], 265 (2), 162 (14), 161
(100), 148 (9), 136 (9), 120 (19), 104 (48), 91 (3), 70 (7);
IR wmax (KBr): 2914, 2898, 2846, 1490, 1452, 1340,
1162, 1102, 1082, 1074, 1064, 1044, 928, 784, 760, 738,
700, 530 cm−1. Anal. calcd for C18H20N2O2: C, 72.97;
H, 6.75; N, 9.45. Found: C, 72.73; H, 6.94; N, 9.37.
4.1. Crystal data for 1
C18H20N2O2, M=296.36 g/mol, monoclinic, space
group C2, with a=31.597(6), b=5.7510(10), c=
,
20.281(4) A, h=90, i=120.59(3), k=90°, V=
3
3172.5(10) A , Z=8, dcalc=1.241 g cm−3, v=0.082
,
mm−1. A total of 3147 reflections were collected from
which 3084 were unique (Rint 0.038), 1655 were consid-
ered observed, F>4|(F), 398 parameters, final R=
0.050, Rw=0.133.
4.2. Crystal data for 3a
C22H22N2O2, M=322.40 g/mol, monoclinic, space
group P21, with a=10.199(2), b=6.648(10), c=
,
12.803(3) A, h=90, i=97.31(3), k=90°, V=861.0 (3)
3
A , Z=2, dcalc=1.244 g cm−3, v=0.081 mm−1. A total
,

V. Santes et al. / Tetrahedron: Asymmetry 12 (2001) 241–247
245
4.7. (1R)-N,N%-Bis-[(2-hydroxy-1-phenyl)ethyl-ethylene-
and 2.79 (2H, AB, J=17.4 Hz, CH2-6), 2.52 (2H, m,
CH2-6), 1.50 (6H, s, CH3); 13C NMR (75.47 MHz,
CDCl3): l 140.5 and 139.8 (C-i ), 129.0, 128.9, 128.3,
128.2, 128.1, 127.0, 98.5 and 96.7 (C-2), 74.5 and 73.4
(C-5), 70.0 and 62.4 (C-4), 46.8 and 42.9 (C-6), 28.0 and
10.9 (C-7).
diamine 2
To a solution of 1 (1.0 g, 3.3 mmol) in dry THF (30
mL) was added BH3–THF (2 M, 6.7 mL, 13.4 mmol),
and the mixture stirred under reflux for 5 h. Water (20
mL) was added and the solvent was removed with a
Dean–Stark trap. The organic layer was extracted with
chloroform (3×15 mL), the organic extract was then
evaporated to afford an oil (0.98 g, 97%) which was
4.10. (2R,2%S,4R,4%R)-N,N%-Ethylene(2%-methyl-2,4,4%-
triphenyl)-2,2%-bisoxazolidine 3d
1
used in the next step without purification; H NMR
To a solution of diamine 2 (2.0 g, 6.6 mmol) in benzene
(30 mL), was added 1-phenyl-1,2-propanedione (0.942
mL, 7 mmol) and the reaction mixture heated to boiling
and stirred under reflux for 24 h. The solvent was
removed under reduced pressure and the resulting
product was washed with methanol at −78°C to afford
a white solid of 3d (1.90 g, 70%), mp 182–184°C;
(399.78 MHz, CDCl3): l 7.35–7.23 (5H, m, H-o,m,p),
3.80–3.64 (3H, m, CH2-2 and CH-1), 2.66–2.56 (2H, m,
CH2-3); 13C NMR (100.54 MHz, CDCl3): l 140.4 (C-
i ), 128.7 (C-o), 127.6 (C-p), 127.4 (C-m), 66.8 (C-2),
64.8 (C-1), 46.7 (C-3).
1
4.8. (2R,2%R,4R,4%R)-N,N%-Ethylene(4,4%-diphenyl)-2,2%-
bisoxazolidine 3a
[h]2D5=−145 (c=0.94, CH2Cl2); H NMR (399.78 MHz,
CDCl3): l 7.85 (2H, d, J=7.3 Hz, H-o%%) 7.43 (2H, t,
J=7.3 Hz, H-m%%), 7.39–7.26 (11H, m, H-arom.), 4.66
(1H, dd, J=8.4, 7.3 Hz, H-4%), 4.64 (1H, dd, J=9.9, 8.4
Hz, H-4), 4.56 (1H, t, J=7.3 Hz, Ha-5%), 4.26 (1H, dd,
J=9.9, 7.7 Hz, Ha-5), 3.90 (1H, t, J=7.7 Hz, Hb-5),
3.75 (1H, dd, J=8.4, 7.3 Hz, Hb-5%), 3.09 (1H, ddd,
J=12.8, 8.4, 4.0, Hz, Ha-6%), 3.75 (1H, ddd, J=12.8,
8.4, 4.0, Hz, Hb-6%), 2.70 (1H, ddd, J=13.9, 8.1, 4.0 Hz,
Ha-6), 2.56 (1H, ddd, J=13.9, 8.1, 4.0 Hz, Hb-6), 1.30
(s, CH3); 13C NMR (100.53 MHz, CDCl3): l 142.3,
140.3, 135.8 (C-i, C-i%, C-i%%), 128.9, 128.6, 128.5, 128.9,
127.8, 127.7, 127.6, 127.5, 127.4 (C-arom.), 103.6 (C-2),
95.3 (C-2%), 74.1 (C-5%), 66.7 (C-4%), 66.3 (C-4), 62.9
(C-5), 44.8 (C-6%), 38.2 (C-6), 27.2 (CH3); MS, m/z; (%):
[M++1, 413 (1)], [M+, 412 (2)], 250 (13), 189 (32), 188
(10), 187 (24), 162 (46), 104 (100), 91 (10), 77 (18), 56
(15), 43 (14); IR wmax (KBr): 3026, 2950, 2942, 2880,
1448, 1474, 1326, 1198, 1092, 1060, 1044, 1028, 932,
768, 758, 702, 678 cm−1. HRMS calcd for C27H29N2O2:
413.2216. Found: 413.2216, error 3.0 ppm.
To a solution of diamine 2 (0.98 g, 3.25 mmol) in
ethanol (30 mL) was added glyoxal (40% in water, 0.47
mL), and the reaction mixture stirred under reflux for 5
h. The solvent was removed under reduced pressure
and the resulting white solid was recrystallised from
chloroform/ethanol to give white crystals of 3a (0.71 g,
68%). Mp 241–243°C [h]2D5=−245.79 (c=0.107,
1
CH2Cl2); H NMR (399.78 MHz, CDCl3): l 7.39 (2H,
d, J=7.0 Hz, H-o), 7.36 (2H, t, J=7.0 Hz, H-m), 7.30
(1H, t, J=7.0 Hz, H-p), 4.32 (1H, t, J=7.0 Hz, Ha-5),
3.96 (1H, s, H-2), 3.79 (1H, t, J=7.0 Hz, H-4), 3.74
(1H, t, J=7.0 Hz, Hb-5), 2.72 (1H, d, J=7.3 Hz,
Ha-6), 2.39 (1H, d, J=7.3 Hz, Hb-6); 13C NMR
(100.54 MHz, CDCl3): l 138.6 (C-i ), 128.7 (C-m),
128.0 (C-p), 127.8 (C-o), 94.3 (C-2), 75.0 (C-5), 65.5
(C-4), 45.8 (C-6); MS, m/z (%): [M++1, 323 (5)], [M+,
322 (12)], 217 (21), 189 (21), 188 (69), 148 (14), 120 (12),
117 (15), 105 (16), 104 (100), 103 (32), 91 (19), 90 (11),
78 (16), 77 (19), 42 (10), 28 (9); IR wmax (KBr): 2956,
2942, 2884, 2850, 2822, 1492, 1356, 1292, 1278, 1268,
1212, 1156, 1108, 1082, 1072, 1056, 1010, 968, 928, 898,
758, 702, 680, 532, 492 cm−1. Anal. calcd for
C20H22N2O2: C, 74.53; H, 6.83; N, 8.62. Found: C,
74.23; H, 6.96; N, 8.66.
4.11. (1%R)-1,4-Bis-[(2%-hydroxy-1%-phenyl)ethyl]-
piperazine 4a
To a solution of bisoxazolidine 3a (0.25 g, 7.76 mmol)
in dry THF (30 mL), was added a solution of BH3–
THF (2 M, 1.55 mL, 3.10 mmol). The reaction mixture
was heated to boiling and stirred under reflux for 5 h.
After cooling to rt, water (20 mL) was added and the
solvent was removed using a Dean–Stark trap. The
organic phase was extracted with chloroform (3×10
mL). The solvent was evaporated under vacuum and
the product precipitated with ethyl ether to yield a
white solid (0.177 g, 70%), mp 129–130°C; [h]2D5=21.77
4.9. (2R,2%R,4R,4%R)- and (2S,2S,4R,4%R)-N,N%-Ethyl-
ene(2,2%-dimethyl-4,4%-diphenyl)-2,2%-bisoxazolidine 3b
and 3c
To a solution of diamine 2 (2.0 g, 6.6 mmol) in toluene
(30 mL) was added (0.61 mL, 7 mmol) of 2,3-butane-
dione. The reaction mixture was heated to boiling and
stirred under reflux for 12 h. The solvent was removed
under reduced pressure and the residue purified by
chromatography over silica gel with n-hexane/ethyl ace-
tate (95:5). The main band to elute was evaporated to
afford a white solid of the diastereomeric mixture of 3b
1
(c=0.107, CH2Cl2); H NMR (270.17 MHz, CDCl3): l
7.36–7.26 (3H, m, H-m,p), 7.14 (2H, dd, J=6.9, 1.7 Hz,
H-o), 3.90 (1H, t, J=11.0 Hz, H-2%), 3.69–3.51 (2H, m,
H-1%, 2%), 2.83–2.34 (4H, m, CH2-2); 13C NMR (67.94
MHz, CDCl3): l 135.8 (C-i ), 128.9 (C-o), 128.4 (C-m),
128.1 (C-p), 70.0 (C-1%), 60.5 (C-2%), 49.6 (s broad, C-2);
MS, m/z (%): [M++1, 327 (1)], 296 (23), 295 (100), 278
(10), 277 (22), 175 (39), 132 (26), 121 (20), 104 (12), 77
(24), 56 (29), 43 (11), 42 (15), 28 (11); IR wmax (KBr):
3198, 3178, 3152, 3144, 3128, 3122, 3102, 3094, 3088,
3056, 3044, 3026, 2938, 2890, 2874, 2840, 2822, 1128,
1
and 3c (1.94 g, 84%) which could not be separated. H
NMR (300.13 MHz, CDCl3): l 7.28–7.48 (10H, m,
H-arom.), 4.31 (1H, t, J=7.6 Hz, H-5), 4.30 (1H, dd,
J=8.6, 7.4 Hz, H-5), 4.00 (1H, dd, J=10.4, 7.2 Hz,
H-4), 3.99 (1H, t, J=7.8 Hz, H-4), 3.74 (1H, dd,
J=9.9, 8.2 Hz, H-5), 3.66 (1H, t, J=7.6 Hz, H-5), 3.03

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V. Santes et al. / Tetrahedron: Asymmetry 12 (2001) 241–247
1072, 1038, 1016, 942, 794, 756, 700, 532 cm−1. Anal.
calcd for C20H26N2O2: C, 73.61; H, 7.97; N, 8.58.
Found: C, 73.26; H, 7.95; N, 8.54.
4.15. (1%R,2S,3R)-1,4-Bis-[(2%-hydroxy-1%-phenyl)ethyl]-
2-phenyl-3-methylpiperazine 4d
To a solution of bisoxazolidine 3d (1.80 g, 4.37 mmol)
in dry THF (30 mL), was added a solution of BH3–
THF (1.2 M, 14.56 mL, 16.2 mmol) at −78°C. The
reaction mixture was stirred for 30 min at −78°C,
allowed to warm to room temperature and stirred for a
further 30 min then heated to reflux and stirred for 6 h.
After cooling, water (20 mL) was added, and the sol-
vent was removed using a Dean–Stark trap. The
aqueous phase was extracted with chloroform (3×10
mL). The solvent was evaporated under reduced pres-
sure and the resulting product was purified by chro-
matography on silica gel with n-hexane/ethyl acetate
(95:5), the main fraction to elute was evaporated to
afford an oil (1.80 g) d.e. (99%); [h]2D5=−81.1 (c=0.172,
4.12. Piperazines 4b and 4c
To a solution of the diastereomeric mixture of 3b and
3c (1.0 g, 2.85 mmol) in dry THF (30 mL), was added
a solution of BH3–THF (1.2 M, 9.5 mL, 11.4 mmol) at
−78°C. The reaction mixture was stirred for 30 min,
allowed to warm to room temperature and stirred for a
further 30 min then heated to boiling and stirred under
reflux for 6 h. After cooling to rt, water (20 mL) was
added and the solvent removed with a Dean–Stark
trap. The aqueous layer was extracted with chloroform
(3×10 mL) and dried (Na2SO4). The solvent was evapo-
rated under reduced pressure to yield a white solid of
the diastereomeric mixture of piperazines 4b and 4c,
which was separated by chromatography on silica gel
with n-hexane/ethyl acetate (9:1) for piperazine 4b and
(8:2) for piperazine 4c.
1
CHCl3); H NMR (270.17 MHz, CDCl3): l 7.44–7.09
(13H, m, H-arom.), 6.92 (2H, d, J=3.5 Hz, H-o), 4.09
(1H, dd, J=9.2, 4.5 Hz, H-2% or H-2%%), 3.98 (1H, dd,
J=10.1, 9.7 Hz, H-2% or H-2%%), 3.93 (1H, d, J=3.5 Hz,
H-2), 3.81–3.61 (3H, m, H-2% or H-2%%, H-1% or H-1%%),
3.05 (1H, dq, J=3.5, 6.7 Hz, H-3), 2.99–2.90 (2H, m,
CH2-5 and CH2-6), 2.62–2.56 and 2.28–2.20 (2H, m,
CH2-5 and CH2-6), 0.97 (3H, d, J=6.7 Hz, CH3); 13C
NMR (67.94 MHz, CDCl3): l 139.3, 138.5, 135.7 (C-i ),
130.2, 128.9, 128.7, 128.5, 128.1, 128.0, 127.9 (C-
arom.), 69.2 (C-2), 65.8 and 61.9 (C-1% and C-1%%), 61.3
and 60.9 (C-2% and C-2%%), 56.8 (C-3), 45.7 and 43.8 (C-5
and C-6), 16.2 (CH3); MS, m/z (%): [M++2, 418 (1)],
[M++1, 417 (2)], 385 (23), 296 (22), 295 (100), 175 (64),
162 (15), 103 (24), 91 (26), 77 (12), 71 (17); IR wmax
(KBr): 3408, 3058, 3026, 2929, 2850, 1492, 1452, 1370,
1140, 762, 702 cm−1; HRMS calcd for C27H33O2N2:
417.2542. Found 417.2546.
4.13. (1%R,2S)-1,4-Bis-[(2%-hydroxy-1%-phenyl)ethyl]-2,3-
dimethylpiperazine 4b
Mp 81–83°C; [h]D25=−28.2 (0.156, CHCl3); 1H NMR
(270.17 MHz, CDCl3): l 7.34–7.25 (5H, m, H-o,m,p),
3.76–3.58 (3H, m, H-1%, H-2%), 3.06 (1H, q, J=6.4 Hz,
H-2), 2.52 and 2.33 (2H, AB, J=13.4 Hz, H-5), 1.21
(3H, d, J=6.4 Hz, CH3); 13C NMR (67.94 MHz,
CDCl3): l 140.4 (C-i ), 128.7 (C-o), 128.5 (C-m), 127.7
(C-p), 67.7 (C-1%), 62.9 (C-2%), 57.9 (C-2), 42.5 (C-5),
11.5 (C-7); MS, m/z (%): [M++1, 355 (1)], 324 (25), 323
(100), 305 (18), 233 (22), 203 (15), 146 (35), 132 (17),
121 (26), 113 (99), 103 (65), 77 (40), 70 (59), 55 (53), 43
(70), 42 (36), 41 (60), 29 (42); IR wmax (KBr): 3256,
2954, 2916, 2850, 2360, 2342, 1472, 1456,1364, 1056,
1036, 708, 700 cm−1. HRMS calcd for C22H31N2O2:
355.2386. Found: 355.2391.
Acknowledgements
Financial support from CONACYT is gratefully
acknowledged. The authors wish to thank Ing. Q.
Geiser Cuellar for mass spectra.
4.14. (1%R,2R)-1,4-Bis-[(2%-hydroxy-1%-phenyl)ethyl]-2,3-
dimethylpiperazine 4c
Mp 131–133°C; [h]D25=−47.17 (c=0.106, CHCl3); 1H
NMR (270.17 MHz, CDCl3): l 7.37–7.25 (3H, m,
H-m,p), 7.16 (2H, dd, J=2.0, 7.7 Hz, H-o), 4.11 (1H,
dd, J=9.2, 5.2 Hz, H-1%), 3.88 (1H, t, J=10.4, 9.2 Hz,
H-2%), 3.59 (1H, dd, J=10.4, 5.2 Hz, H-2%), 2.82 and
2.16 (2H, AB, J=13.4, H-5), 2.22 (1H, dq, J=10.9, 5.4
Hz, H-2), 1.19 (3H, d, J=5.4 Hz, CH3); 13C NMR
(67.94 MHz, CDCl3): l 136.0 (C-i ), 128.9 (C-o), 128.4
(C-m), 128.0 (C-p), 62.3 (C-1%), 60.3 (C-2%), 57.6 (C-2),
44.4 (C-6), 16.0 (CH3); MS, m/z (%): [M++1, 355 (9)],
[M+, 354 (1)], 324 (45), 323 (100), 306 (20), 305 (32),
294 (21), 233 (42), 203 (20), 178 (17), 146 (22), 121 (18),
113 (62), 103 (47), 91 (46), 77 (26), 70 (25), 56 (19); IR
wmax (KBr): 3446, 3026, 2982, 2962, 2928, 2872, 2850,
1492, 1384, 1366, 1294, 1186, 1174, 1144, 1080, 1066,
1058, 1032, 1024, 1004, 998, 838, 772, 708 cm−1. Anal.
calcd for C22H30N2O2: C, 74.57; H, 8.47; N, 7.90.
Found: C, 74.57; H, 8.42; N, 7.90.
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