Facile deuteration of chiral N,N'-substituted piperazines

Article abstract of DOI:10.1055/s-2001-10810

The synthesis of four chiral N,N'-substituted piperazines stereoselectively labelled with deuterium atoms is described. The preparation was accomplished by reduction of norephedrine derived bisoxazolidines with LiAlD₄ or BD₃·THF to afford 2,3-d₂-piperazine and 2,3-dimethyl-2,3-d₂-piperazine, while 2,2,3,3-d₄- and 2,2,3,3,5,6-d₆-piperazine were obtained from a strategically deuterated hydroxyethylenediamine precursor using the same route. In all cases, deuteration of bisoxazolidines proceeded with trans stereoselectivity.

Full text of DOI:10.1055/s-2001-10810

PAPER
235
Facile Deuteration of Chiral N,N’-Substituted Piperazines
Víctor Santes, Elizabeth Gómez, Rosa Santillan, Norberto Farfán*
Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, 07000 México D. F., México
Fax +52(5)7477113; E-mail: jfarfan@mail.cinvestav.mx
Received 19 June 2000; revised 25 September 2000
Ph
OH HO
Ph
Ph
OH
Abstract: The synthesis of four chiral N,N’-substituted piperazines
stereoselectively labelled with deuterium atoms is described. The
preparation was accomplished by reduction of norephedrine derived
bisoxazolidines with LiAlD4 or BD3∑THF to afford 2,3-d2-pipera-
zine and 2,3-dimethyl-2,3-d2-piperazine, while 2,2,3,3-d4- and
2,2,3,3,5,6-d6-piperazine were obtained from a strategically deuter-
ated hydroxyethylenediamine precursor using the same route. In all
cases, deuteration of bisoxazolidines proceeded with trans stereose-
lectivity.
1
2
1). 1,2-dibromoethane
2). NaOH
NH
H3C
NH
CH3
H3C
NH2
3
1
R1COCOR2
HO
R1
R1
O
N
D
O
2
Ph
H3C
Ph
Ph
N
5
4
LiAlD4 or
D
2
3
N
1'
6
Ph
5
N
Key words: bisoxazolidine, N,N’-substituted piperazine, amino al-
cohols, asymmetric synthesis, condensation, reductions
CH3
R2
CH3
6R2
2'
H3C
BD3-THF
OH
2a. R1= R2= H
2b. R1= R2= CH3
3a-d2. R1= R2= H
3b-d2. R1= R2= CH3
Scheme 1
Despite the importance of piperazine-containing mole-
cules owing to their broad spectrum of pharmacological
activities1-4 only a few asymmetric routes for preparing
chiral piperazines have been described in the literature
which include the syntheses of piperazine carboxylic ac-
ids,5,6 2-substituted piperazines,7,8 2,6-methylated
piperazines9 or benzyl-a-D-arabinopyranoso[3,4-b]piper-
azines,10 all of which provide optically pure material. As
part of our research involving the synthesis and study of
heterocyclic compounds,11-13 we have recently described
a new route for the preparation of symmetrical and un-
symmetrical piperazines14 using condensation reactions in
which the stereochemical outcome is controlled by the
stereochemistry of bisoxazolidine type structures. To our
knowledge, there are no reports concerning methodolo-
gies for the construction of N,N’-substituted piperazines
strategically ring labelled with deuterium, therefore, in
this paper, the synthesis of piperazine norephedrine deriv-
atives in which the ring methylenes are stereoselectively
labelled with deuterium is reported.
singlet at 2.56 ppm for CHD-2, while the same carbons
appeared as a broad singlet at 50.8 ppm in the 13C NMR
spectrum. As expected, these molecules show dynamic
behavior due to ring inversion and the energy required for
this process was obtained by variable temperature 13C
NMR experiments. Thus upon cooling to 223 K two sin-
glets corresponding to the diastereotopic carbons at posi-
tions 5 and 6 were observed at 52.1 ppm and 49.5 ppm,
whereas CD-2 and CD-3 appeared as two broad singlets at
51.7 ppm and 49.1 ppm. The coalescence temperature was
achieved at 262 K, and a DGπ = 12.2 kcalmol-1 in agree-
ment with the value reported for the non-deuterated ana-
logue, was calculated for the interconversion process
using the Eyring equation. In the mass spectrum the
m/z = 357 ion corresponding to M+ + 1 was detected. The
1H NMR spectrum of piperazine 3b-d2 displayed signals
for a single isomer and the ring methyl group appeared as
a singlet at 1.23 ppm, indicating no coupling to the deute-
rium atom while the 13C NMR spectrum showed a triplet
shifted to 58.4 ppm (JCD = 20.8 Hz). Mass spectrometric
data revealed the m/z = 385 ion corresponding to the
M+ + 1 ion.
Compound 1 was obtained by treatment of (1S,2R)-(+)-
norephedrine with 1,2-dibromoethane in a sealed ampoule
at 130 °C. Subsequent condensation of diamine 1 with
glyoxal or butanedione led to the formation of previously
reportedbisoxazolidines 2a and 2b. Stereoselective incor-
poration of deuterium atoms into the 2- and 3-positions of
piperazines was accomplished by reduction of 2a and 2b
using LiAlD4 or BD3∑THF to yield the dideuterated piper-
azines 3a-d2 and 3b-d2 with trans stereochemistry, as
shown in Scheme 1.
The same methodology was applied for the preparation of
piperazines 7a-d4 and 7b-d6 (Scheme 2) starting from the
previously described16-18 diamide 4. Since reduction with
LiAlD4 in THF yielded a mixture of diamine 5-d4 and
starting material, the reaction was carried out in a mixture
of refluxing THF/toluene for 48 hours to yield exclusively
the diamine 5-d4. The 1H NMR spectrum of 5-d4 showed
no signals for methylene groups and the 13C spectrum
showed a quintet shifted to 46.1 ppm (JCD = 20.0 Hz).
Mass spectrometry showed the m/z = 334 and 333 ions
corresponding to M+ + 2 and M+ + 1, respectively. Treat-
Evidence for the formation of these piperazines was ob-
tained from mass spectral and NMR data. The existence of
only one diastereoisomer was confirmed by addition of
four equivalents of Pirkle’s reagent.15 The 1H NMR spec-
trum of 3a-d2 showed a broad multiplet between 2.71 ppm
and 2.57 ppm for the methylene at position 5 and a broad
Synthesis 2000, No. 2, 235–238 ISSN 0039-7881 © Thieme Stuttgart · New York

236
V. Santes et al.
PAPER
All reagents were purchased from Aldrich. BD3∑THF was prepared
from NaBD4 using the procedure described in the literature.19 1H
and 13C NMR spectra were recorded on a Jeol-270 spectrometer.
Chemical shifts (ppm) are relative to TMS. Coupling constants are
quoted in Hz. The HETCOR and COSY standard pulse sequence,
which incorporates quadrature detection in both domains was used.
Infrared spectra were recorded on a Perkin Elmer 16F spectropho-
tometer. Mass spectra were obtained with a HP 5989A mass spec-
trometer. Optical rotations were measured on a Perkin Elmer 241
polarimeter, [a]D25 values are given in deg cm-2g-1. Melting points
were obtained on a Gallenkamp MFB-595 apparatus and are uncor-
rected.
ment of diamine 5-d4 with glyoxal gave bisoxazolidine
6-d4 as a single product displaying the signal for C-6 as a
quintet at 45.2 ppm (JCD = 20.0 Hz) in the 13C NMR spec-
trum and the m/z = 355 ion which corresponds to the
M+ + 1 in mass spectrometry.
Ph
Ph
OH HO
NH NH
Ph
Ph
HO
NH
OH
NH
LiAlD4
H3C
CH3
CH3
H3C
THF/Toluene
3
D
D
D
D
O
O
5-d4
4
(1S,2R)-N,N’-Bis-[(1-hydroxy-2-methyl-1-phenyl)ethyl]ethyl-
enediamine (1)
Glyoxal
HO
A mixture of (+)-norephedrine (5.0 g, 33.0 mmol) and 1,2-dibromo-
ethane (1.42 mL, 16.5 mmol) was heated in a sealed ampoule for
8 h at 100 °C. After cooling, the solid was washed with CHCl3
yielding a white product (4.85 g, 14.3 mmol). Following addition of
aq NaOH (1.14 g, 27.74 mmol) the free amine was extracted with
CHCl3 (3 î 10 mL) to give hydroxyethylenediamine 1 (3.8 g,
70%).
H
H
O
O
Ph
Ph
H3C
R2
LiAlH4 or
D
H3C
5
Ph
2
N
4
R1
1'
6
5
D
N
N
LiAlD4
THF
N
CH3
H
Ph
2H
3
D
CH3
D
2'
D
D
6
OH
D
D
7a-d4. R1= R2= H
7b-d6. R1= R2= D
6-d4
Scheme 2
(1’R,2’S,2R,3R)-1,4-Bis-[(2’-hydroxy-1’-methyl-2’-phenyl)eth-
yl]-2,3-d2-piperazine (3a-d2)
To a solution of bisoxazolidine 2a (1.0 g, 2.85 mmol) in anhyd THF
(30 mL) was added LiAlD4 (0.47 g, 11.2 mmol) at 0 °C and the mix-
ture was refluxed for 5 h. After cooling, H2O (10 mL) was added
and the suspension was filtered through Celite, dried (Na2SO4) and
evaporated under reduced pressure to give 3a-d2 as a white solid
(0.8 g, 80%); mp 164-165 °C; [a]D25 +3.66 (c = 0.099, CH2Cl2).
MS (EI): m/z (%) = 357 (M+ + 1, 1), 251 (2), 50 (19), 249 (100), 141
(12), 115 (11), 114 (11), 113 (11), 86 (10), 85 (12), 77 (11), 57 (25),
56 (14), 43 (19), 42 (11), 29 (10).
The synthesis of piperazines 7a-d4 and 7b-d6 was
achieved by reduction of bisoxazolidine 6-d4 using
LiAlH4 or LiAlD4, respectively. The stereochemistry of
bisoxazolidine 6-d4 accounts for the stereochemical out-
come of these piperazines. For compound 7a-d4, CH2-5
gives rise to a broad AB system in the 1H NMR which is
overlapped with the doublet of quartets for H-1’. Addi-
tionally, the 13C NMR spectrum showed two broad signals
at 50.9 ppm and 49.1 ppm which correspond to C-5 and
CD2-2, the spin-spin couplings for the deuterated carbon
were not observed due to dynamic behavior. For this
compound the M+ ion was absent and the base peak at
m/z = 251 corresponding to M+ + 1 with loss of CHPhOH
fragment was detected. The 1H NMR spectrum of piper-
azine 7b-d6 exhibited a broad singlet at 2.58 ppm for
CH-5 while CD2-2 and CDH-5 appeared at 50.5 ppm in
the 13C NMR spectrum. Mass spectrometry showed the
m/z = 361 ion corresponding to M+ + 1 and the base peak
at m/z = 253 corresponding to M+ + 1 with loss of
CHPhOH fragment as observed for compound 7a-d4.
Although these compounds also show dynamic behavior,
attempts to obtain spectra at low temperature were unsuc-
cessful since they precipitate at 273 K in chloroform or
dichloromethane solution.
IR (KBr): n = 3400, 3086, 3064, 3030, 3004, 2984, 2962, 2928,
2916, 2900, 2878, 2850, 2830, 2706, 1492, 1452, 1396, 1352, 1170,
1154, 1128, 1034, 756, 736, 720, 700 cm-1.
1H NMR (270.17 MHz, CDCl3): d = 7.36-7.22 (5 H, m, H-o,p,m),
4.89 (1 H, d, J = 3.7 Hz, H-2’), 2.71-2.57 (3 H, m, H-1’, CH2-5),
2.56 (1 H, br s, CHD-2), 0.82 (3 H, d, J = 6.9 Hz, CH3-7).
13C NMR (67.94 MHz, CDCl3): d = 142.0 (C-i), 128.1 (C-o), 126.9
(C-p), 126.0 (C-m), 71.9 (C-2’), 64.3 (C-1’), 50.8 (br s, CH2-5,
CHD-2), 10.3 (C-7).
(2’S,1’R,2S,3S)-1,4-Bis-[(2’-hydroxy-1’-methyl-2’-phenyl)eth-
yl]-2,3-dimethylpiperazine-2,3-d2 (3b-d2)
To a solution of bisoxazolidine 2b (0.70 g, 1.85 mmol) in anhyd
THF (30 mL) was added BD3•THF (14.8 mL, 0.5 M) at 0 °C and the
mixture was refluxed for 5 h. After cooling, H2O (20 mL) was added
and the solvent evaporated with a Dean-Stark trap. The organic
phase was extracted with CHCl3 (3 î 10 mL) and the solvent was
evaporated under reduced pressure to give 3b-d2 (0.68 g, 95%) as a
white solid; mp 110-111 °C; [a]D25 +58.027 (c = 0.301, CHCl3).
In conclusion we have completed the stereoselective syn-
thesis of four piperazines strategically deuterated in the
ring methylenes based on the reduction of norephedrine
derived bisoxazolidines with LiAlH4, LiAlD4 or
BD3∑THF and applying the sequence previously de-
scribed. The synthesis described herein provides easily
stereocontrolled access to optically active piperazines
in good yield and the new derivatives contain two new
stereogenic carbons in the ring labelled with deuterium
atoms.
MS (EI): m/z (%) = 385 (M+ + 1,1), 278 (27), 276 (4), 171 (5), 155
(14), 107 (5), 99 (6), 79 (10), 43 (8).
IR (KBr): n = 3438, 3024, 2984, 2974, 2958, 2918, 2848, 2364,
2344, 1472, 1464, 1458, 1450, 1382, 1358, 1198, 1176, 1164, 1108,
1100, 1064, 1006, 974, 748, 744, 696, 668 cm-1.
1H NMR (270.17 MHz, CDCl3): d = 7.34-7.18 (5 H, m, arom), 4.66
(1 H, d, J = 4.5 Hz, H-2’), 2.92 (1 H, dq, J = 4.5, 6.9 Hz, H-1’), 2.65
and 2.17 (2 H, AB, J = 7.6 Hz, H-5), 1.23 (3 H, s, CH3-7), 0.85 (3
H, d, J = 6.9 Hz, CH3-8).
Synthesis 2001, No. 2, 235–238 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Facile Deuteration of Chiral N,N’-Substituted Piperazines
237
13C NMR (67.94 MHz, CDCl3): d = 141.8 (C-i), 128.0 (C-o), 127.0
(C-p), 126.2 (C-m), 73.2 (C-2’), 60.5 (C-1’), 58.4 (t, JCD = 20.8 Hz,
C-2), 41.7 (C-5), 12.4 (C-8), 11.5 (C-7).
1H NMR (270.17 MHz, CDCl3): d = 7.35-7.24 (5 H, m, H-o,m,p),
4.91 (1 H, d, J = 4.0 Hz, H-2’), 2.69 (1 H, dq, J = 4.0, 7.0 Hz, H-1’),
2.70-2.61 (2 H, br AB, CH2-5), 0.84 (3 H, d, J = 7.0 Hz, CH3-7).
13C NMR (67.94 MHz, CDCl3): d = 141.9 (C-i), 128.0 (C-o), 126.9
(C-p), 125.9 (C-m), 71.9 (C-2’), 64.3 (C-1’), 50.9 (C-5), 49.9 (br s,
CD2-2), 10.2 (C-7).
(1S,2R)-N,N’-Bis-[(1-hydroxy-2-methyl-1-phenyl)ethyl]ethyl-
ene-d4-diamine (5-d4)
To a solution of diamide 416-18 (1.0 g, 2.8 mmol) in a mixture of an-
hyd THF (15 mL) and anhyd toluene (20 mL) was added LiAlD4
(0.47 g, 11.2 mmol) at 0 °C and the mixture was refluxed for 48 h.
After cooling, H2O (10 mL) was added and the solution was filtered
through Celite, dried (Na2SO4) and evaporated under reduced pres-
sure to afford 5-d4 (0.91 g, 97%) as a white solid; mp 91-92 °C;
[a]D25 -4.03 (c = 0.322, CH2Cl2).
(2’S,1’R,5R,6R)-1,4-Bis-[(2’-hydroxy-1’-methyl-2’-phenyl)eth-
yl]-2,2,3,3,5,6-d6-piperazine (7b-d6)
To a solution of bisoxazolidine 6-d4 (0.45 g, 1.27 mmol) in anhyd
THF (30 mL) was added LiAlH4 (0.21 g, 5.08 mmol) at 0 °C and the
mixture was refluxed for 5 h. After cooling, H2O (10 mL) was add-
ed, the suspension filtered through Celite, dried (Na2SO4) and evap-
orated under reduced pressure to yield the piperazine 7b-d6 (0.321
g, 70%) as a white solid; mp 168-170 °C; [a]D25 +8.08 (c = 0.099,
CH2Cl2).
MS (EI): m/z (%) = 361 (M+ + 1, 1), 265 (3), 254 (22), 253 (100),
119 (8), 118 (9), 117 (8), 89 (10), 88 (12), 77 (20), 60 (11), 58 (15),
57 (12).
MS (EI): m/z (%) = 334 (M+ + 2, 2), 333 (M+ + 1, 6), 226 (21), 225
(100), 207 (40), 164 (24), 148 (19), 117 (10), 107 (29), 91 (10), 79
(28), 77 (24), 76 (16), 74 (12), 60 (22), 47 (14), 44 (10), 42 (10), 32
(11).
IR (KBr): n = 3150, 3086, 3068 3026, 2968, 2908, 2850, 1492,
1452, 1422, 1406, 1374, 1138, 1084, 1010, 1000, 942, 760, 708,
698, 550 cm-1.
1H NMR (270.17 MHz, CDCl3): d = 7.36-7.20 (5 H, m, H-o,m,p),
4.69 (1 H, d, J = 4.0 Hz, H-1), 2.88 (1 H, dq, J = 4.0, 6.4 Hz, H-2),
0.84 (3 H, d, J = 6.4 Hz, CH3-4).
13C NMR (67.94 MHz, CDCl3): d = 141.6 (C-i), 128.2 (C-o), 127.2
(C-p), 126.2 (C-m), 76.6 (C-1), 58.5 (C-2), 46.1 (quint, JCD = 20.0
Hz, CD2-3), 14.9 (C-4).
IR (KBr): n = 3400, 2960, 2916, 2900, 1012, 976, 748, 706, 700,
cm-1.
1H NMR (270.17 MHz, CDCl3): d = 7.35-7.22 (5 H, m, H-o,p,m),
4.91 (1 H, d, J = 3.7 Hz, H-2’), 2.68 (1 H, dq, J = 3.7, 7.0 Hz, H-1’),
2.58 (1 H, br s, CHD-5), 0.83 (3 H, d, J = 7.0 Hz, CH3-7).
13C NMR (67.94 MHz, CDCl3) d = 141.9 (C-i), 128.0 (C-o), 126.9
(C-p), 125.9 (C-m), 71.9 (C-2’), 64.3 (C-1’), 50.5 (br, CHD-5, CD2-
2), 10.2 (C-7).
(5S,5’S,4R,4’R,2R,2’R)-N,N’-Ethylene-d4-[(4,4’-dimethyl-5,5’-
diphenyl)]-2,2’-bisoxazolidine (6-d4)
A solution of diamine 5-d4 (0.91 g, 2.74 mmol) in EtOH (40 mL)
and aq glyoxal (0.39 mL, 40%) was refluxed for 12 h. After cooling,
the solvent was removed under reduced pressure to afford 6-d4
(0.68 g, 70%) as a white solid; mp 194-195 °C; [a]D25 -48.48
(c = 0.099, CH2Cl2).
Acknowledgement
The authors thank CONACYT for financial support and G. Uribe
for NMR spectra.
MS (EI): m/z (%) = 356 (M+ + 2, 5), 355(M+ + 1, 13), 354 (M+, 10),
353 (10), 326 (21), 235 (38), 208 (13), 207 (33), 148 (22), 135 (15),
134 (10), 130 (25), 119 (16), 118 (100), 105 (14), 101 (14), 91 (36),
78 (10), 77 (15), 54 (15).
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Article Identifier:
1437-210X,E;2001,0,02,0235,0238,ftx,en;M11000SS.pdf
Synthesis 2001, No. 2, 235–238 ISSN 0039-7881 © Thieme Stuttgart · New York