Synthesis of homochiral 2-(2-arylethyl)piperazines

Article abstract of DOI:10.1055/s-2007-983791

The synthesis of a series of (S)-2-(2-arylethyl)piperazines was achieved from (S)-1,4-dibenzyl-2-vinylpiperazine via a tandem hydroboration/Suzuki coupling sequence followed by cleavage of the N-benzyl protecting groups. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983791

PAPER
2307
Synthesis of Homochiral 2-(2-Arylethyl)piperazines
Synthesis
o
of
H
omochir
h
al 2-(2-Aryle
n
thyl)piperazines M. Schaus,* Joseph H. Krushinski, Kevin M. Ruley, Vincent P. Rocco
Discovery Chemistry Research and Technology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA
Fax +1(317)2767600; E-mail: schaus_john_m@Lilly.com
Received 13 March 2007
Dedicated to Professor Paul A. Wender on the 60th anniversary of his birthday
readily prepared via a palladium-mediated coupling of
N,N¢-dibenzylethylenediamine and cis-1,4-diacetoxybut-
2-ene by the method of Tsuda.3 Several research groups
have studied the effect of asymmetric ligands in this reac-
tion and a synthesis of (R)-3 with 88% ee was reported re-
cently.4 For our studies, we prepared (S)-3 in high optical
purity (ee >98%) by resolution with (R)-mandelic acid.1
Unfortunately, attempts to prepare olefin 4 (Ar = phenyl)
through Heck coupling or via olefin metathesis resulted in
low and variable yields of the desired product.
Abstract: The synthesis of a series of (S)-2-(2-arylethyl)piper-
azines was achieved from (S)-1,4-dibenzyl-2-vinylpiperazine via a
tandem hydroboration/Suzuki coupling sequence followed by
cleavage of the N-benzyl protecting groups.
Key words: Suzuki reaction, hydroboration, cross-coupling, aryl-
ation, palladium
During the course of work to identify antipsychotic agents
with improved efficacy and tolerability,1 we determined
that the 3¢-phenethyl-substituted analogue of olanzapine
(1, Ar = phenyl) possessed a desirable receptor binding
profile (Figure 1). In order to study how modification of
the pendant aromatic ring would affect the in vitro and in
vivo activity of this series, we needed to prepare a series
of analogues of structure 1 and consequently required ac-
cess to a series of arylethylpiperazines 2.
Bn
Bn
Heck coupling,
or olefin metathesis
N
N
N
N
Bn
Bn
Ar
3
4
Scheme 1
An alternative, successful route is outlined in Scheme 2.
Hydroboration of vinylpiperazine 3 with 9-borabicy-
clo[3,3,1]nonane (9-BBN) in THF regioselectively pro-
vided organoborane 5 (BR2 = 9-borabicyclo[3,3,1]nonyl)
which, without isolation, was treated with an aryl halide
and aqueous sodium hydroxide in the presence of triphe-
nylphosphine and tetrakis(triphenylphosphine)palladi-
um(0) to give 6, the product of Suzuki coupling.
Me
N
N
S
NH
N
Ar
HN
Ar
N
H
Me
1
2
Ar = aryl and heteroaryl
Bn
Figure 1 Structures of 3¢-arylethyl-substituted olanzapine and aryl-
ethylpiperazines
Bn
a
N
b
N
3
N
N
Bn
BR2
Bn
Ar
While racemic 2-phenethylpiperazine is known2 and we
have prepared the desired (S)-2-phenethylpiperazine anti-
pode from a commercially available (S)-homophenylala-
nine derivative,1 other analogues of 2 have not been
reported. Furthermore, they could not be prepared via this
route because the corresponding homophenylalanine ana-
logues are not available. Hence, we needed to develop a
general synthesis of a series of optically active (S)-2-aryl-
ethylpiperazine analogues of structure 2.
6a–s
5
Scheme 2 Reagents and conditions: (a) 9-BBN, THF; (b) ArX,
Pd(PPh3)4, PPh3, NaOH, H2O, heat.
We found that this reaction sequence was quite general
and could provide us with a range of phenethylpiperazine
analogues. The reaction scope and conditions are outlined
in Table 1. The reaction proceeded in reasonable yields
(30–84%) and tolerated substitution with either electron-
withdrawing (entries 2–10) or electron-donating (entries
11–13) substituents. The method could be used to prepare
ortho-, meta-, and para-substituted derivatives in high re-
gioisomeric purity. The bicyclic 1-and 2-naphthyl sys-
tems were also readily prepared by this method.
Furthermore, we found that we could extend this method
to the synthesis of heteroaromatic analogues (entries 16–
19) through the synthesis of the 2-, 3-, and 4-pyridyl and
the 3-thienyl analogues. While the tandem hydroboration/
An attractive approach to the chiral piperazines 2 is the
arylation of the 2-vinylpiperazine derivative 3 to provide
olefin 4 (Scheme 1). Reduction of the olefin and cleavage
of the benzyl protecting groups could provide a variety of
substituted 2-arylethylpiperazines 2. Racemic 3 was
SYNTHESIS 2007, No. 15, pp 2307–2312
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983791; Art ID: C01607SS
© Georg Thieme Verlag Stuttgart · New York

2308
J. M. Schaus et al.
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Table 1 Tandem Hydroboration/Suzuki Coupling Sequence
Table 2 Debenzylation of 2-(2-Arylethyl)piperazines
Bn
Bn
Bn
N
NH
N
N
1. 9-BBN, THF
HN
N
N
N
Ar
Bn
Bn
Ar
Bn
Ar
2. Ar-X, Pd(PPh3)4,
PPh3, NaOH, H2O
2a–s
6a–s
6a–s
3
Entry
1
Product
Ar
Method
Yield (%)
87
Entry
1
Product
6a
6b
6c
ArX
Yield (%)
84
2a
2b
2c
2d
2e
2f
Ph
B
B
B
B
C
C
C
B
A
B
B
B
B
B
B
B
B
B
C
PhI
2
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
2-OMeC6H4
3-OMeC6H4
4-OMeC6H4
1-naphthyl
2-naphthyl
2-pyridyl
3-pyridyl
4-pyridyl
3-thienyl
89
2
2-FC6H4I
3-FC6H4I
4-FC6H4I
2-ClC6H4I
3-ClC6H4I
4-ClC6H4I
2-CF3C6H4I
3-CF3C6H4I
4-CF3C6H4I
2-OMeC6H4I
3-OMeC6H4I
4-OMeC6H4I
40
3
78
3
66
4
80
4
6d
6e
66
5
75
5
31
6
63
6
6f
72
7
2g
2h
2i
34
7
6g
6h
6i
69
8
93
8
30
9
~100
93
9
73
10
11
12
13
14
15
16
17
18
19
2j
10
11
12
13
14
15
16
17
18
19
6j
37
2k
2l
87
6k
6l
65
94
79
2m
2n
2o
2p
2q
2r
2s
94
6m
6n
6o
6p
6q
6r
40
38
1-iodonaphthalene
2-bromonaphthalene
2-bromopyridine
3-iodopyridine
61
77
69
75
79
32
40
86
4-bromopyridine (HCl salt) 56
3-iodothiophene 66
27
6s
Suzuki coupling process is well recognized as a useful cleavage, particularly useful when sensitive functionality
synthetic sequence,5 the chemistry outlined in this report is present, is the modified von Braun reaction using 1-
is remarkable in that there are few other reported exam- chloroethyl chloroformate (AceCl) as the cleavage agent
ples of such a transformation in which a basic amine is and methanol to solvolyze the resulting carbamate (Meth-
present in one of the coupling partners.6
od C).8 The conditions and yields are reported in Table 2.
Three different methods were used to effect the cleavage In conclusion, a series of (S)-2-(2-arylethyl)piperazines 2
of the N-benzyl protecting groups (Scheme 3). Catalytic was prepared in two steps from the readily available 2-vi-
hydrogenolysis using palladium-on-carbon as catalyst nylpiperazine derivative 3. This transformation consists
could be performed using either standard reducing condi- of a one-pot hydroboration/Suzuki coupling sequence fol-
tions under a hydrogen atmosphere (Method A) or by lowed by cleavage of the N-benzyl protecting groups us-
transfer hydrogenation using ammonium formate as the ing either catalytic hydrogenolysis or a modified von
hydrogen source (Method B).7 An alternative method of Braun degradation. This sequence is versatile and can be
used to prepare a range of substituted phenyl and hetero-
Bn
aromatic analogues of 2.
NH
N
a, b, or c
HN
N
Ar
Bn
Ar
All reagents were used directly as obtained commercially. Melting
points were determined in capillary tubes using a Thomas–Hoover
capillary melting point apparatus and are uncorrected. Column
chromatography was carried out on Biotage silica gel columns (40–
2a–s
6a–s
Scheme 3 Reagents and conditions: (a) H2, Pd/C, EtOH; (b) ammoni-
um formate, Pd/C, MeOH; (c) 1. AceCl, ClCH2CH2Cl, 2. MeOH,
heat.
1
63 mm). H NMR spectra (300 MHz) were measured on a Bruker
Synthesis 2007, No. 15, 2307–2312 © Thieme Stuttgart · New York

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Synthesis of Homochiral 2-(2-Arylethyl)piperazines
2309
Avance 300 MHz spectrometer. Electrospray mass spectra were ob-
tained using a Waters ZQ single quadrapole mass spectrometer.
Elemental analysis data were obtained on a Exeter Analytical CEC-
440 elemental analyzer.
1H NMR (300 MHz, DMSO-d6): d = 7.41–7.16 (m, 14 H), 3.93 (d,
J = 13.6 Hz, 1 H), 3.51 (d, J = 13.1 Hz, 1 H), 3.39 (d, J = 13.1 Hz,
1 H), 3.27 (d, J = 13.6 Hz, 1 H), 2.76–2.36 (m, 4 H), 2.35–2.12 (m,
5 H), 1.97–1.71 (m, 2 H).
MS (ESI): m/z = 405 [M + H]+.
Hydroboration/Suzuki Coupling Sequence; (S)-1,4-Dibenzyl-2-
phenethylpiperazine (6a); Typical Procedure
Anal. Calcd for C26H29ClN2: C, 77.11; H, 7.22; N, 6.92. Found: C,
77.12; H, 7.13; N, 7.07.
9-Borabicyclo[3.3.1]nonane (199.6 mL, 99.78 mmol, 0.5 M in
THF) was added via cannula to a N2-purged flask containing neat
(S)-1,4-dibenzyl-2-vinylpiperazine (3; 4.9 g, 16.63 mmol). The
mixture was stirred at r.t. for 24 h and iodobenzene (5.1 g, 24.95
mmol), Ph3P (697.9 mg, 2.66 mmol), (Ph3P)4Pd (384.3 mg, 0.33
mmol), and aq 3 N NaOH (13.7 mL) were added. After stirring for
22 h at 60 °C, the mixture was diluted with EtOAc (150 mL) and
extracted with aq 1 N H2SO4 (3 × 200 mL). The pH was adjusted to
14 and the aqueous layer was extracted with EtOAc (3 × 150 mL).
The combined organic layers were washed with brine (1 × 100 mL),
dried (Na2SO4), and concentrated. This material was purified by sil-
ica gel chromatography (5–10% EtOAc–hexanes) to give 6a; white
solid; mp 86–90 °C.
(S)-1,4-Dibenzyl-2-[2-(3-chlorophenyl)ethyl]piperazine (6f)
The title compound was purified by crystallization from EtOH;
white solid; mp 56–60 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.36–7.17 (m, 13 H), 7.09 (d,
J = 7.2 Hz, 1 H), 3.89 (d, J = 13.6 Hz, 1 H), 3.50 (d, J = 13.0 Hz, 1
H), 3.38 (d, J = 13.0 Hz, 1 H), 3.27 (d, J = 13.6 Hz, 1 H), 2.68–2.34
(m, 6 H), 2.31–2.13 (m, 3 H), 1.92–1.78 (m, 2 H).
MS (ESI): m/z = 405 [M + H]+.
Anal. Calcd for C26H29ClN2: C, 77.11; H, 7.22; N, 6.92. Found: C,
77.35; H, 7.02; N, 6.90.
1H NMR (300 MHz, DMSO-d6): d = 7.37–7.19 (m, 12 H), 7.18–
7.08 (m, 3 H), 3.89 (d, J = 13.7 Hz, 1 H), 3.51 (d, J = 13.2 Hz, 1 H),
3.38 (d, J = 13.2 Hz, 1 H), 3.26 (d, J = 13.7 Hz, 1 H), 2.68–2.35 (m,
6 H), 2.33–2.12 (m, 3 H), 1.93–1.78 (m, 2 H).
(S)-1,4-Dibenzyl-2-[2-(4-chlorophenyl)ethyl]piperazine (6g)
The title compound was purified by crystallization from EtOH;
white solid; mp 87–90 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.36–7.18 (m, 12 H), 7.15 (d,
J = 8.6 Hz, 2 H), 3.88 (d, J = 13.6 Hz, 1 H), 3.50 (d, J = 13.3 Hz, 1
H), 3.38 (d, J = 13.3 Hz, 1 H), 3.26 (d, J = 13.6 Hz, 1 H), 2.68–2.33
(m, 6 H), 2.30–2.12 (m, 3 H), 1.91–1.75 (m, 2 H).
MS (ESI): m/z = 371 [M + H]+.
Anal. Calcd for C26H30N2: C, 84.28; H, 8.16; N, 7.56. Found: C,
84.31; H, 8.09; N, 7.64.
MS (ESI): m/z = 405 [M + H]+.
(S)-1,4-Dibenzyl-2-[2-(2-fluorophenyl)ethyl]piperazine (6b)
The title compound was purified by silica gel chromatography (5%
EtOAc–hexanes); solid; mp 62–66 °C.
Anal. Calcd for C26H29ClN2: C, 77.11; H, 7.22; N, 6.92. Found: C,
76.93; H, 7.06; N, 7.01.
1H NMR (300 MHz, DMSO-d6): d = 7.36–7.17 (m, 12 H), 7.15–
7.06 (m, 2 H), 3.90 (d, J = 13.4 Hz, 1 H), 3.51 (d, J = 13.2 Hz, 1 H),
3.38 (d, J = 13.2 Hz, 1 H), 3.25 (d, J = 13.4 Hz, 1 H), 2.70–2.35 (m,
6 H), 2.34–2.12 (m, 3 H), 1.99–1.72 (m, 2 H).
(S)-1,4-Dibenzyl-2-[2-(2-trifluoromethylphenyl)ethyl]piper-
azine (6h)
The title compound was purified by crystallization from EtOH;
white solid; mp 77–82 °C.
MS (ESI): m/z = 389 [M + H]+.
1H NMR (300 MHz, DMSO-d6): d = 7.83–7.53 (m, 2 H), 7.47–7.37
(m, 2 H), 7.37–7.16 (m, 10 H), 3.93 (d, J = 13.7 Hz, 1 H), 3.51 (d,
J = 13.3 Hz, 1 H), 3.40 (d, J = 13.3 Hz, 1 H), 3.27 (d, J = 13.7 Hz,
1 H), 2.79–2.36 (m, 6 H), 2.35–2.14 (m, 3 H), 2.00–1.71 (m, 2 H).
(S)-1,4-Dibenzyl-2-[2-(3-fluorophenyl)ethyl]piperazine (6c)
The title compound was purified by crystallization from EtOH;
white solid.
1H NMR (300 MHz, DMSO-d6): d = 7.36–7.18 (m, 11 H), 7.01–
6.92 (m, 3 H), 3.90 (d, J = 13.7 Hz, 1 H), 3.50 (d, J = 13.4 Hz, 1 H),
3.38 (d, J = 13.4 Hz, 1 H), 3.26 (d, J = 13.7 Hz, 1 H), 2.69–2.35 (m,
6 H), 2.31–2.12 (m, 3 H), 1.95–1.78 (m, 2 H).
MS (ESI): m/z = 439 [M + H]+.
Anal. Calcd for C27H29F3N2: C, 73.95; H, 6.67; N, 6.39. Found: C,
74.11; H, 6.68; N, 6.50.
(S)-1,4-Dibenzyl-2-[2-(3-trifluoromethylphenyl)ethyl]piper-
azine (6i)
The title compound was purified by crystallization from EtOH;
white solid.
MS (ESI): m/z = 389 [M + H]+.
Anal. Calcd for C26H29FN2: C, 80.38; H, 7.52; N, 7.21. Found: C,
80.56; H, 7.71; N, 7.27.
1H NMR (300 MHz, CDCl3): d = 7.60–7.55 (m, 2 H), 7.54–7.49 (m,
2 H), 7.47–7.43 (m, 1 H), 7.42–7.30 (m, 9 H), 4.80 (d, J = 12.6 Hz,
1 H), 4.24–4.34 (m, 1 H), 4.29 (d, J = 13.2 Hz, 1 H), 4.11 (d,
J = 12.3 Hz, 1 H), 4.10–3.97 (m, 1 H), 3.92–3.78 (m, 1 H), 3.75–
3.60 (m, 2 H), 3.51 (d, J = 11.7 Hz, 1 H), 3.22 (d, J = 13.8 Hz, 1 H),
3.09 (d, J = 13.8 Hz, 1 H), 2.87–2.76 (m, 1 H), 2.75–2.66 (m, 1 H),
2.51–2.37 (m, 2 H).
(S)-1,4-Dibenzyl-2-[2-(4-fluorophenyl)ethyl]piperazine (6d)
The title compound was purified by crystallization from EtOH;
white solid.
1H NMR (300 MHz, DMSO-d6): d = 7.37–7.10 (m, 12 H), 7.09–
7.00 (m, 2 H), 3.89 (d, J = 13.6 Hz, 1 H), 3.50 (d, J = 13.3 Hz, 1 H),
3.38 (d, J = 13.3 Hz, 1 H), 3.26 (d, J = 13.6 Hz, 1 H), 2.69–2.33 (m,
6 H), 2.32–2.10 (m, 3 H), 1.91–1.77 (m, 2 H).
MS (ESI): m/z = 439 [M + H]+.
MS (ESI): m/z = 389 [M + H]+.
(S)-1,4-Dibenzyl-2-[2-(4-trifluoromethylphenyl)ethyl]piper-
azine (6j)
The title compound was purified by crystallization from EtOH;
Anal. Calcd for C26H29FN2: C, 80.38; H, 7.52; N, 7.21. Found: C,
80.35; H, 7.71; N, 7.27.
white solid; mp 71–75 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.60 (d, J = 7.9 Hz, 2 H), 7.40–
7.16 (m, 12 H), 3.89 (d, J = 13.6 Hz, 1 H), 3.51 (d, J = 13.3 Hz, 1
(S)-1,4-Dibenzyl-2-[2-(2-chlorophenyl)ethyl]piperazine (6e)
The title compound was purified by crystallization from EtOH;
white solid.
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J. M. Schaus et al.
PAPER
H), 3.38 (d, J = 13.3 Hz, 1 H), 3.28 (d, J = 13.6 Hz, 1 H), 2.71–2.35
MS (ESI): m/z = 421 [M +H]+.
(m, 6 H), 2.32–2.14 (m, 3 H), 1.99–1.79 (m, 2 H).
(S)-1,4-Dibenzyl-2-(2-pyridin-2-ylethyl)piperazine (6p)
The title compound was purified by silica gel chromatography (aq
2 N NH3 in MeOH–CH2Cl2, 0.5–3%); yellow solid; mp 83–86 °C;
[a]D20 +47.5 (c 0.5, MeOH).
MS (ESI): m/z = 439 [M + H]+.
Anal. Calcd for C27H29F3N2: C, 73.95; H, 6.67; N, 6.39. Found: C,
74.15; H, 6.72; N, 6.52.
1H NMR (300 MHz, DMSO-d6): d = 8.45 (d, J = 4.7 Hz, 1 H), 7.65
(ddd, J = 7.7, 7.7, 1.8 Hz, 1 H), 7.35–7.13 (m, 12 H), 3.94 (d,
J = 13.6 Hz, 1 H), 3.49 (d, J = 13.2 Hz, 1 H), 3.39 (d, J = 13.2 Hz,
1 H), 3.23 (d, J = 13.6 Hz, 1 H), 2.81–2.53 (m, 4 H), 2.48–2.38 (m,
2 H), 2.27–2.11 (m, 3 H), 2.02–1.92 (m, 2 H).
(S)-1,4-Dibenzyl-2-[2-(2-methoxyphenyl)ethyl]piperazine (6k)
The title compound was purified by silica gel chromatography (5%
EtOAc–hexanes); solid; mp 58–61 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.39–7.18 (m, 10 H), 7.18–
7.11 (m, 1 H), 7.05 (dd, J = 1.8, 7.3 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1
H), 6.86–6.79 (m, 1 H), 3.96 (d, J = 13.7 Hz, 1 H), 3.70 (s, 3 H),
3.50 (d, J = 13.3 Hz, 1 H), 3.39 (d, J = 13.3 Hz, 1 H), 3.21 (d,
J = 13.7 Hz, 1 H), 2.68–2.32 (m, 6 H), 2.31–2.08 (m, 3 H), 1.89–
1.67 (m, 2 H).
MS (ESI): m/z = 372 [M + H]+.
Anal. Calcd for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C,
80.56; H, 7.60; N, 11.30.
(S)-1,4-Dibenzyl-2-(2-pyridin-3-ylethyl)piperazine (6q)
The title compound was purified by silica gel chromatography (aq
2 N NH3 in MeOH–CH2Cl2, 1–3%); yellow solid; mp 94–95.5 °C.
1H NMR (300 MHz, DMSO-d6): d = 8.36 (s, 1 H), 8.37 (dd, J = 6.2,
1.6 Hz, 1 H), 7.56 (ddd, J = 7.9, 1.9, 1.9 Hz, 1 H), 7.36–7.18 (m, 11
H), 3.90 (d, J = 13.7 Hz, 1 H), 3.51 (d, J = 13.2 Hz, 1 H), 3.38 (d,
J = 13.2 Hz, 1 H), 3.27 (d, J = 13.7 Hz, 1 H), 2.68–2.37 (m, 6 H),
2.30–2.15 (m, 3 H), 1.94–1.81 (m, 2 H).
MS (ESI): m/z = 401 [M + H]+.
Anal. Calcd for C27H32N2O: C, 80.96; H, 8.05; N, 6.99. Found: C,
81.08; H, 7.99; N, 7.10.
(S)-1,4-Dibenzyl-2-[2-(3-methoxyphenyl)ethyl]piperazine (6l)
The title compound was purified by silica gel chromatography (5%
EtOAc–hexanes); off-white solid; mp 73–75 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.37–7.11 (m, 11 H), 6.76–
6.64 (m, 3 H), 3.89 (d, J = 13.6 Hz, 1 H), 3.71 (s, 3 H), 3.51 (d,
J = 13.2 Hz, 1 H), 3.38 (d, J = 13.2 Hz, 1 H), 3.26 (d, J = 13.6 Hz,
1 H), 2.67–2.32 (m, 6 H), 2.31–2.13 (m, 3 H), 1.93–1.77 (m, 2 H).
MS (ESI): m/z = 372 [M + H]+.
Anal. Calcd for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C,
80.54; H, 7.76; N, 11.32.
MS (ESI): m/z = 401 [M + H]+.
(S)-1,4-Dibenzyl-2-(2-pyridin-4-ylethyl)piperazine (6r)
The title compound was purified by silica gel chromatography (aq
2 N NH3 in MeOH–CH2Cl2, 1–3%); yellow solid; mp 96–98 °C.
Anal. Calcd for C27H32N2O: C, 80.96; H, 8.05; N, 6.99. Found: C,
81.16; H, 8.08; N, 7.04.
1H NMR (300 MHz, DMSO-d6): d = 8.41 (dd, J = 4.4, 1.6 Hz, 2 H),
7.36–7.18 (m, 10 H), 7.15 (dd, J = 4.4, 1.6 Hz, 2 H), 3.89 (d,
J = 13.5 Hz, 1 H), 3.50 (d, J = 13.2 Hz, 1 H), 3.38 (d, J = 13.2 Hz,
1 H), 3.28 (d, J = 13.5 Hz, 1 H), 2.68–2.36 (m, 6 H), 2.29–2.15 (m,
3 H), 1.94–1.82 (m, 2 H).
(S)-1,4-Dibenzyl-2-[2-(4-methoxyphenyl)ethyl]piperazine (6m)
The title compound was purified by crystallization from EtOH;
white solid.
1H NMR (300 MHz, DMSO-d6): d = 7.37–7.16 (m, 10 H), 7.03 (d,
J = 8.7 Hz, 2 H), 6.80 (d, J = 8.7 Hz, 2 H), 3.88 (d, J = 13.4 Hz, 1
H), 3.70 (s, 3 H), 3.50 (d, J = 13.4 Hz, 1 H), 3.37 (d, J = 13.4 Hz, 1
H), 3.25 (d, J = 13.4 Hz, 1 H), 2.67–2.29 (m, 6 H), 2.29–2.12 (m, 3
H), 1.89–1.74 (m, 2 H).
MS (ESI): m/z = 372 [M + H]+.
Anal. Calcd for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C,
80.80; H, 7.99; N, 11.18.
MS (ESI): m/z = 401 [M + H]+.
(S)-1,4-Dibenzyl-2-(2-thiophen-3-ylethyl)piperazine (6s)
The title compound was purified by silica gel chromatography
(EtOAc–hexanes, 10%), then strong cation exchange (MeOH wash,
then aq 2 N NH3 in MeOH) to elute product; solid; mp 87–90 °C.
Anal. Calcd for C27H32N2O: C, 80.96; H, 8.05; N, 6.99. Found: C,
80.61; H, 7.98; N, 7.05.
(S)-1,4-Dibenzyl-2-(2-naphthalen-1-ylethyl)piperazine (6n)
The title compound was purified by crystallization as the dihydro-
chloride salt from aq 5 N HCl and MeOH; white solid; mp 211–
215 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 8.08 (d, J = 7.6 Hz, 1 H),
8.00–7.94 (m, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.65–7.52 (m, 4 H),
7.52–7.35 (m, 10 H), 4.57–4.15 (m, 4 H), 3.72–3.56 (m, 1 H), 3.49–
2.96 (m, 8 H), 2.53–2.39 (m, 1 H), 2.30–2.12 (m, 1 H).
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.40 (dd, J = 4.8, 2.9 Hz,
1 H), 7.36–7.20 (m, 10 H), 7.06–7.02 (m, 1 H), 6.94 (dd, J = 5.0, 1.2
Hz, 1 H), 3.89 (d, J = 13.5 Hz, 1 H), 3.50 (d, J = 13.2 Hz, 1 H), 3.38
(d, J = 13.2 Hz, 1 H), 3.25 (d, J = 13.5 Hz, 1 H), 2.67–2.37 (m, 6 H),
2.26–2.12 (m, 3 H), 1.92–1.80 (m, 2 H).
MS (ESI): m/z = 377 [M + H]+.
Cleavage of N-Benzyl Protecting Groups; Typical Procedures
Method A, (S)-2-[2-(3-Trifluoromethylphenyl)ethyl]piperazine (2i):
A mixture of (S)-1,4-dibenzyl-2-[2-(3-trifluoromethylphenyl)eth-
yl]piperazine (6i; 10.0 g, 22.8 mmol) and 10% Pd/C (2.5 g) in
MeOH (150 mL) was stirred under H2 (1 atm) for 18 h. The catalyst
was removed by filtration through Celite and the filtrate was then
concentrated to give (S)-2-[2-(3-trifluoromethylphenyl)ethyl]piper-
azine (2i).
MS (ESI): m/z = 421 [M + H]+.
Anal. Calcd for C30H34Cl2N2: C, 73.01; H, 6.94; N, 5.68; Cl, 14.37.
Found: C, 72.98; H, 7.27; N, 5.59; Cl, 14.06.
(S)-1,4-Dibenzyl-2-(2-naphthalen-2-ylethyl)piperazine (6o)
The title compound was purified by crystallization from EtOH; tan
crystals; mp 85–88 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.87–7.78 (m, 3 H), 7.59 (s, 1
H), 7.50–7.40 (m, 2 H), 7.36–7.17 (m, 11 H), 3.92 (d, J = 13.7 Hz,
1 H), 3.52 (d, J = 13.2 Hz, 1 H), 3.39 (d, J = 13.2 Hz, 1 H), 3.29 (d,
J = 13.7 Hz, 1 H), 2.80–2.54 (m, 4 H), 2.53–2.37 (m, 2 H), 2.34–
2.15 (m, 3 H), 2.01–1.90 (m, 2 H).
Method B, (S)-2-Phenethylpiperazine (2a): To a solution of (S)-1,4-
dibenzyl-2-phenethylpiperazine (6a; 5.15 g, 13.90 mmol) in EtOH
(100 mL) was added ammonium formate (4.38 g, 69.49 mmol) and
5% Pd/C (672.5 mg). The mixture was stirred and heated at reflux
for 3 h and cooled to r.t. The catalyst was removed by vacuum fil-
Synthesis 2007, No. 15, 2307–2312 © Thieme Stuttgart · New York

PAPER
Synthesis of Homochiral 2-(2-Arylethyl)piperazines
2311
tration through Celite. The filtrate was concentrated to residue and
(S)-2-[2-(3-Chlorophenyl)ethyl]piperazine (2f)
purified on silica gel to give (S)-2-phenethylpiperazine (2a).
The title compound was purified by silica gel chromatography (10%
2 N NH3 in MeOH–CH2Cl2); off-white solid; mp 93–97 °C.
Method C, (S)-2-[2-(2-chlorophenyl)ethyl]piperazine (2e): To a
0 °C solution of (S)-1,4-dibenzyl-2-[2-(2-chlorophenyl)ethyl]piper-
azine (6e; 2.59 g, 6.38 mmol) in DCE (30 mL) was slowly added 1-
chloroethyl chloroformate (2.74 g, 19.15 mmol). The solution was
slowly warmed to r.t. and then heated at reflux for 15 h. The solvent
was removed under vacuum and the resulting residue was dissolved
in MeOH (75 mL) and heated to reflux for 1 h. The MeOH was re-
moved under vacuum and the resulting solid was dissolved in aq 1
N NaOH (100 mL). The aqueous layer was extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were washed with brine
(1 × 100 mL), dried (Na2SO4), and concentrated. This material was
purified on silica gel to give (S)-2-[2-(2-chlorophenyl)ethyl]piper-
azine (2e).
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.36–7.11 (m, 4 H),
2.85–2.37 (m, 8 H), 2.26–2.11 (m, 1 H), 1.57–1.43 (m, 2 H).
MS (ESI): m/z = 225 [M + H]+.
Anal. Calcd for C12H17ClN2: C, 64.13; H, 7.62; N, 12.47. Found: C,
64.12; H, 7.42; N, 12.45.
(S)-2-[2-(4-Chlorophenyl)ethyl]piperazine (2g)
The title compound was purified by silica gel chromatography (10%
2 N NH3 in MeOH–CH2Cl2); off-white solid; mp 140–144 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.32 (d, J = 8.3 Hz, 2 H),
7.24 (d, J = 8.3 Hz, 2 H), 2.81–2.39 (m, 8 H), 2.18 (dd, J = 10.3,
11.4 Hz, 1 H), 1.58–1.40 (m, 2 H).
(S)-2-Phenethylpiperazine (2a)
The title compound was purified by silica gel chromatography (10%
7 N NH3 in MeOH–CH2Cl2); white solid; mp 116–119 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.30–7.10 (m, 5 H), 2.80–2.34
(m, 8 H), 2.15 (dd, J = 9.9, 11.3 Hz, 1 H), 1.98 (br s, 2 H), 1.54–1.38
(m, 2 H).
MS (ESI): m/z = 225 [M + H]+.
Anal. Calcd for C12H17ClN2: C, 64.13; H, 7.62; N, 12.47. Found: C,
64.01; H, 7.42; N, 12.33.
(S)-2-[2-(2-Trifluoromethylphenyl)ethyl]piperazine (2h)
The title compound was purified by silica gel chromatography (10%
2 N NH3 in MeOH–CH2Cl2); white solid; mp 43–47 °C.
MS (ESI): m/z = 191 [M + H]+.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.70–7.55 (m, 2 H),
7.51–7.34 (m, 2 H), 2.90–2.40 (m, 8 H), 2.18 (dd, J = 10.2, 11.4 Hz,
1 H), 1.61–1.39 (m, 2 H).
Anal. Calcd for C12H18N2: C, 75.74; H, 9.53; N, 14.72. Found: C,
75.90; H, 9.57; N, 14.59.
(S)-2-[2-(2-Fluorophenyl)ethyl]piperazine (2b)
White solid.
MS (ESI): m/z = 259 [M + H]+.
1H NMR (300 MHz, DMSO-d6): d = 7.33–7.05 (m, 4 H), 3.32 (br s,
1 H), 2.84–2.34 (m, 8 H), 2.15 (dd, J = 10.0, 11.5 Hz, 1 H), 1.95 (br
s, 1 H), 1.52–1.40 (m, 2 H).
(S)-2-[2-(3-Trifluoromethylphenyl)ethyl]piperazine (2i)
White solid.
1H NMR (300 MHz, DMSO-d6): d = 9.85 (br s, 2 H), 7.63 (s, 1 H),
7.60–7.51 (m, 3 H), 3.60–3.53 (m, 1 H), 3.49–3.37 (m, 3 H), 3.29–
3.19 (m, 2 H), 3.16–3.07 (m, 1 H), 2.92–2.77 (m, 2 H), 2.08–1.90
(m, 2 H)
MS (ESI): m/z = 209 [M + H]+.
Anal. Calcd for C12H17FN2: C, 69.20; H, 8.23; N, 13.45. Found: C,
68.91; H, 8.11; N, 13.29.
MS (ESI): m/z = 259 [M + H]+.
(S)-2-[2-(3-Fluorophenyl)ethyl]piperazine (2c)
The title compound was purified by silica gel chromatography (20%
2 N NH3 in MeOH–CH2Cl2); white solid; mp 95–99 °C.
(S)-2-[2-(4-Trifluoromethylphenyl)ethyl]piperazine (2j)
Off-white solid; mp 135–141 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.38–7.15 (m, 1 H),
7.09–6.92 (m, 3 H), 2.79–2.34 (m, 8 H), 2.22–2.09 (m, 1 H), 1.57–
1.40 (m, 2 H).
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.63 (d, J = 8.0 Hz, 2 H),
7.44 (d, J = 8.0 Hz, 2 H), 2.82–2.38 (m, 8 H), 2.18 (dd, J = 10.2,
11.5 Hz, 1 H), 1.59–1.46 (m, 2 H).
MS (ESI): m/z = 209 [M + H]+.
MS (ESI): m/z = 259 [M + H]+.
Anal. Calcd for C12H17FN2: C, 69.20; H, 8.23; N, 13.45. Found: C,
69.13; H, 8.40; N, 13.28.
(S)-2-[2-(2-Methoxyphenyl)ethyl]piperazine (2k)
The title compound was purified by silica gel chromatography (20%
2 N NH3 in MeOH–CH2Cl2); oil.
(S)-2-[2-(4-Fluorophenyl)ethyl]piperazine (2d)
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.22–7.07 (m, 2 H),
6.97–6.81 (m, 2 H), 3.77 (s, 3 H), 2.82–2.35 (m, 8 H), 2.16 (dd,
J = 10.0, 11.5 Hz, 1 H), 1.53–1.35 (m, 2 H).
The title compound was purified by silica gel chromatography (20%
2 N NH3 in MeOH–CH2Cl2); white solid; mp 112–114 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.26–7.17 (m, 2 H),
7.13–7.03 (m, 2 H), 2.79–2.36 (m, 8 H), 2.15 (dd, J = 10.3, 11.3 Hz,
1 H), 1.55–1.40 (m, 2 H).
MS (ESI): m/z = 221 [M + H]+.
MS (ESI): m/z = 209 [M + H]+.
(S)-2-[2-(3-Methoxyphenyl)ethyl]piperazine (2l)
The title compound was purified by silica gel chromatography (10%
7 N NH3 in MeOH–CH2Cl2); white solid; mp 53–57 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.23–7.13 (m, 1 H),
6.80–6.69 (m, 3 H), 3.72 (s, 3 H), 2.82–2.36 (m, 8 H), 2.24–2.09 (m,
1 H), 1.56–1.41 (m, 2 H).
Anal. Calcd for C12H17FN2: C, 69.20; H, 8.23; N, 13.45. Found: C,
68.97; H, 8.14; N, 13.21.
(S)-2-[2-(2-Chlorophenyl)ethyl]piperazine (2e)
The title compound was purified by silica gel chromatography (10%
2 N NH3 in MeOH–CH2Cl2); solid.
MS (ESI): m/z = 221 [M + H]+.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.43–7.17 (m, 4 H),
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found: C,
70.52; H, 9.06; N, 12.74.
2.87–2.39 (m, 8 H), 2.28–2.12 (m, 1 H), 1.57–1.390 (m, 2 H).
MS (ESI): m /z = 225 [M + H]+.
Synthesis 2007, No. 15, 2307–2312 © Thieme Stuttgart · New York

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J. M. Schaus et al.
PAPER
(S)-2-[2-(4-Methoxyphenyl)ethyl]piperazine (2m)
The title compound was purified by silica gel chromatography (20%
2 N NH3 in MeOH–CH2Cl2); white solid; mp 125–130 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 8.43 (dd, J = 4.4, 1.5 Hz,
2 H), 7.25 (dd, J = 4.4, 1.5 Hz, 2 H), 2.79–2.37 (m, 8 H), 2.17 (dd,
J = 11.6, 10.1 Hz, 1 H), 1.56–1.46 (m, 2 H).
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.10 (d, J = 8.7 Hz, 2 H),
6.83 (d, J = 8.7 Hz, 2 H), 3.71 (s, 3 H), 2.80–2.35 (m, 8 H), 2.16 (dd,
J = 10.1, 11.7 Hz, 1 H), 1.55–1.35 (m, 2 H).
MS (ESI): m/z = 192 [M + H]+.
Anal. Calcd for C11H17N3: C, 69.07; H, 8.96; N, 21.97. Found: C,
69.08; H, 8.77; N, 21.81.
MS (ESI): m/z = 221 [M + H]+.
(S)-2-(2-Thiophen-3-ylethyl)piperazine (2s)
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found: C,
70.58; H, 9.05; N, 12.61.
The title compound was purified by silica gel chromatography (2 N
NH3 in MeOH–CH2Cl2, 10% then 7 N NH3 in MeOH–CH2Cl2,
10%) and recrystallized from EtOAc; tan solid.
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.42 (dd, J = 4.8, 2.9 Hz,
1 H), 7.14–7.11 (m, 1 H), 6.98 (dd, J = 4.9, 1.1 Hz, 1 H), 2.78–2.38
(m, 8 H), 2.16 (dd, J = 11.4, 10.3 Hz, 1 H), 1.55–1.46 (m, 2 H).
(S)-2-(2-Naphthalen-1-ylethyl)piperazine (2n)
The title compound was purified by silica gel chromatography (2 N
NH3 in MeOH–CH2Cl2, 2.5–10%, then 7 N NH3 in MeOH–CH2Cl2,
20%); yellow oil.
1H NMR (300 MHz, DMSO-d6/D2O): d = 8.08 (dd, J = 8.0, 1.1 Hz,
1 H), 7.94–7.88 (m, 1 H), 7.76 (d, J = 7.9 Hz, 1 H), 7.59–7.47 (m, 2
H), 7.46–7.34 (m, 2 H), 3.20–3.08 (m, 1 H), 3.06–2.94 (m, 1 H),
2.89–2.68 (m, 3 H), 2.66–2.46 (m, 3 H), 2.25 (dd, J = 11.4, 10.3 Hz,
1 H), 1.66–1.56 (m, 2 H).
MS (ESI): m/z = 197 [M + H]+.
Acknowledgment
The authors thank David Dobson and Bruce Shaw for supplying
vinylpiperazine 3. John He is acknowledged for performing
examples 6i and 2i.
MS (ESI): m/z = 241 [M + H]+.
(S)-2-(2-Naphthalen-2-ylethyl)piperazine (2o)
The title compound was purified by silica gel chromatography (7 N
NH3 in MeOH–CH2Cl2, 2.5–10%); yellow solid; mp 151–154 °C.
References
1H NMR (300 MHz, DMSO-d6/D2O): d = 7.89–7.81 (m, 3 H), 7.69
(s, 1 H), 7.51–7.37 (m, 3 H), 2.86–2.42 (m, 8 H), 2.20 (dd, J = 11.6,
10.2 Hz, 1 H), 1.65–1.55 (m, 2 H).
(1) Aicher, T. D.; Chen, Z.; Chen, Y.; Faul, M. M.; Krushinski,
J. H.; LeHeurou, Y.; Pineiro-Nunez, M. M.; Rocco, V. P.;
Ruley, K. M.; Schaus, J. M.; Thompson, D. C.; Tupper, D.
E. PCT Int. Appl. WO 2003082877, 2003; Chem. Abstr.
2003, 139, 307804.
MS (ESI): m/z = 241 [M + H]+.
(2) (a) Behun, J. D.; Levine, R. J. Org. Chem. 1961, 26, 8879.
(b) Hendrix, J. A.; Strupczewski, J. T.; Bordeau, K. J.;
Brooks, S.; Hemmerle, H.; Urmann, M.; Zhao, X.; Mueller,
P. J. PCT Int. Appl. WO 2002066468, 2002; Chem. Abstr.
2002, 137, 201306.
(S)-2-(2-Pyridin-2-ylethyl)piperazine (2p)
The title compound was purified by silica gel chromatography (7 N
NH3 in MeOH–CH2Cl2, 5–15%); brown solid; mp 83–87 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 8.45 (dd, J = 4.7, 0.7 Hz,
1 H), 7.68 (ddd, J = 7.6, 7.6, 1.9 Hz, 1 H), 7.24 (d, J = 7.9 Hz, 1 H),
7.18 (ddd, J = 7.4, 4.9, 0.9 Hz, 1 H), 2.83–2.61 (m, 5 H), 2.58–2.35
(m, 3 H), 2.15 (dd, J = 11.4, 10.3 Hz, 1 H), 1.63–1.53 (m, 2 H).
(3) Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem. 1990, 55,
3388.
(4) (a) Uozumi, Y.; Tanahashi, A.; Hayashi, T. J. Org. Chem.
1993, 58, 6832. (b) Yamazaki, A.; Achiwa, K. Tetrahedron:
Asymmetry 1995, 6, 1021. (c) Nakano, H.; Yokoyama, J.;
Fujita, R.; Hongo, H. Tetrahedron Lett. 2002, 43, 7761.
(d) Ito, K.; Imahayashi, Y.; Kuroda, T.; Eno, S.; Saito, B.;
Katsuki, T. Tetrahedron Lett. 2004, 45, 7277.
(5) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(6) (a) Palani, A.; Shapiro, S.; Josien, H.; Bara, T.; Clader, J. W.;
Greenlee, W. J.; Cox, K.; Strizki, J. M.; Baroudy, B. M. J.
Med. Chem. 2002, 45, 3143. (b) Guillena, G.; Kruithof, C.
A.; Coasado, M. A.; Egmond, M. R.; van Koten, G. J.
Organomet. Chem. 2003, 668, 3.
MS (ESI): m/z = 192 [M + H]+.
Anal. Calcd for C11H17N3: C, 69.07; H, 8.96; N, 21.97. Found: C,
68.84; H, 8.85; N, 21.65.
(S)-2-(2-Pyridin-3-ylethyl)piperazine (2q)
The title compound was purified by silica gel chromatography (7 N
NH3 in MeOH–CH2Cl2, 2.5–15%); yellow solid; mp 104–110 °C.
1H NMR (300 MHz, DMSO-d6/D2O): d = 8.42 (d, J = 1.7 Hz, 1 H),
8.38 (dd, J = 4.7, 1.6 Hz, 1 H), 7.63 (ddd, J = 7.7, 1.8, 1.8 Hz, 1 H),
7.31 (ddd, J = 7.7, 4.8, 0.7 Hz, 1 H), 2.83–2.38 (m, 8 H), 2.19 (dd,
J = 11.4, 10.1 Hz, 1 H), 1.56–1.45 (m, 2 H).
MS (ESI): m/z = 192 [M + H]+.
(7) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
(8) (a) Olofson, R. A.; Martz, J. T.; Senet, J.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081. (b) For those
cases in which debenzylation was not complete, the crude
reaction product was resubjected to the reaction conditions.
(S)-2-(2-Pyridin-4-ylethyl)piperazine (2r)
The title compound was purified by silica gel chromatography (7 N
NH3 in MeOH–CH2Cl2, 5–15%); yellow solid; mp 113–116 °C.
Synthesis 2007, No. 15, 2307–2312 © Thieme Stuttgart · New York