Gram-scale synthesis of N-aryl- and N-aryl-N′-methylpiperazines on a novel, water-swellable, oxethane-linked poly(ethylene glycol) high-loading resin

Article abstract of DOI:10.1055/s-2005-918462

A new methodology for the synthesis of N-arylpiperazines was developed using a poly(ethylene glycol)-derived solid support. The reactions proceeded in up to 60% overall yield over four steps. The scope and limitations of the method are discussed, as well as the utility of ¹³C gel-phase NMR spectroscopy for reaction monitoring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918462

3456
PAPER
Gram-Scale Synthesis of N-Aryl- and N-Aryl-N¢-methylpiperazines on a
Novel, Water-Swellable, Oxethane-Linked Poly(ethylene glycol)
High-Loading Resin
S
ynthesis of
N
-
Ary
a
l- and
N
-A
n
ryl-
N
'-methy
s
lpiperazines on
C
a
N
ovel Poly(eth
h
ylene glycol)
r
Resin istian Rudbeck,a Ib Johannsen,b Ole Nielsen,a Thomas Ruhland,a Michael Bech Sommer,a David Tanner,c
Robert Dancer*a
a
H. Lundbeck A/S, Ottiliavej 7–9, 2500 Valby, Denmark
Fax +4536438256; E-mail: rda@lundbeck.com
VersaMatrix A/S, Gamle Carlsbergvej 10, 2500 Valby, Denmark
Department of Chemistry, Technical University of Denmark, Building 201, Kemitorvet, 2800 Kongens Lyngby, Denmark
b
c
Received 16 September 2005
This article is dedicated to Prof. Steven Ley on the occasion of his 60th birthday.
achieved in a total reaction time of eight hours (final load-
ing: 1.48 mmol·g–1, confirmed by chloride analysis)
(Scheme 1).
Abstract: A new methodology for the synthesis of N-arylpipera-
zines was developed using a poly(ethylene glycol)-derived solid
support. The reactions proceeded in up to 60% overall yield over
four steps. The scope and limitations of the method are discussed,
as well as the utility of 13C gel-phase NMR spectroscopy for reac-
tion monitoring.
Cl
O
O
a)
O
O
b)
Cl
OH
N
Key words: N-arylpiperazines, solid-phase synthesis, heterocycles,
cleavage, 13C gel-phase NMR spectroscopy
Cl
1
Scheme 1 Reagents and conditions: (a) COCl2 in toluene (20% w/w,
2 equiv), THF, r.t., 2 h; (b) bis(chloroethyl)amine hydrochloride (3.5
equiv), K2CO3 (6 equiv), H2O, r.t., 6 h.
The synthesis of organic molecules on solid phase holds
several advantages compared to traditional solution-phase
chemistry. Due to the high cost of commercially available
solid-phase supports, only a few examples of larger-scale
solid-phase syntheses of small molecules exist in the liter-
ature.1 We report herein a high-yielding solid-phase syn-
thesis employing a comparatively inexpensive oxethane-
linked poly(ethylene glycol)-derived resin.2,3 The main
advantage of such poly(ethylene glycol)-derived resins
over the cheaper polystyrene-based resins is their much-
improved swelling properties in water, allowing reaction
on the support in aqueous media.
This reaction was conveniently monitored by 13C gel-
phase NMR spectroscopy.7 In particular, the 13C NMR
spectroscopic shifts of the two backbone carbons closest
to the terminal hydroxy group were diagnostic of the im-
mobilization of the bis(chloroethyl)amine. The carbons
derived from the remainder of the synthesized molecule
could also be observed easily. Usually, 1024 scans were
sufficient to produce a rough picture of the extent of reac-
tion, and a longer acquisition period (13312 scans) pro-
duced a fairly clear picture of the resin-bound product
(Figure 1).
N-arylpiperazines represent a common structural motif in
many compounds of pharmaceutical interest.4 They are
commonly synthesized from bis(chloroethyl)amine and
derivatives via ring closure under weakly basic condi-
tions.5 However, this method suffers from the drawback
that the toxic bis(chloroethyl)amine must be used under
forcing conditions. A solid-phase approach where the
bis(chloroethyl)amine is first immobilized on resin under
mild, aqueous, and therefore safer, conditions is desirable.
A number of syntheses were then performed where
anilines with various substituents were added to the resin
on a 10-g scale (ca. 15 mmol of resin 1) in isobutyl methyl
ketone (MIBK) at 100 °C (Scheme 2).5c,8 These reactions
were again monitored conveniently through the use of 13C
gel-phase NMR spectroscopy (e.g., Figure 2). As expect-
ed, the electron-rich 4-methoxyaniline reacted relatively
fast with resin 1 to give the resin-bound N-arylpiperazine
2a in 28 hours, while the reaction between resin 1 and the
other, less-nucleophilic anilines required at least two days
of reaction time (Table 1). Reaction between the sterically
hindered 2,6-dimethylaniline and resin 1 only reached
25% conversion after six days, judged by 13C gel-phase
NMR spectroscopy. A similar lack of reactivity was ob-
served for 2,6-dimethoxyaniline, which implies that steric
hindrance is the dominating factor in this instance.
Bis(chloroethyl)amine was immobilized by means of a
chloroformate handle, generated from the reaction of
VersabeadsTM VO400 with a commercially available 20%
w/w solution of phosgene in toluene, a method originally
developed by Hauske and Dorff.6 Upon addition of
bis(chloroethyl)amine as the hydrochloride salt in aque-
ous solution, complete conversion into resin 1 was
SYNTHESIS 2005, No. 19, pp 3456–3462
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918462; Art ID: C08305SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of N-Aryl- and N-Aryl-N¢-methylpiperazines on a Novel Poly(ethylene glycol) Resin
3457
Figure 1 The monitoring of the on-resin immobilization of bis(chloroethyl)amine. Note the change in the position of the carbon peaks from
the carbons a (A) and b (B) to the binding site (from 61.2 to 64.5 ppm and from 72.4 to 69.0 ppm, respectively). The two carbon atoms (C) are
nonequivalent due to hindered rotation. The upper spectrum was acquired using 13312 scans, and the lower was acquired using 1024 scans.
Cl
In the case of the 1-(3,4-dichlorophenyl)-4-methylpipera-
zine 3d, a significant amount (10–15%) of the corre-
O
O
a)
N
N
N
R1
sponding 1-(4-chlorophenyl)-4-methylpiperazine was
observed in the crude product. The dechlorination of
arenes under reductive conditions is a well-known phe-
nomenon.10 Preliminary results suggest that this byprod-
uct can be avoided through the use of in situ generated
zinc borohydride as reducing agent.11,12
O
O
Cl
R2
2a–h
1
2a,2e: R1 = OCH3 R2 = H
2b,2f: R1 = H R2 = H
2c,2g: R1 = F R2 = H
2d,2h: R1 = Cl R2 = Cl
Basic cleavage of the resin-bound piperazine was
achieved using potassium tert-butoxide in refluxing 1,2-
dimethoxyethane. The free amines were isolated in 34–
46% crude overall yield (Table 1, entries 5–8) and were
purified by means of precipitation as the corresponding
oxalates.
Scheme 2 Reagents and conditions: (a) aniline derivative (5 equiv),
py (10 equiv), KI (0.2 equiv), MIBK, 100 °C.
The final products were cleaved from the resin under ei-
ther reductive or basic conditions (Scheme 3). Reductive
cleavage with lithium aluminum hydride, following a pro-
cedure developed by Ho and Kukla,9 yielded N¢-aryl-N-
methylpiperazines 3a–d in crude overall yields (for four
steps) ranging from 22–60% (based on the initial hydroxyl
loading on the VersabeadsTM VO400) with excellent to
moderate purities upon aqueous workup (Table 1, entries
1–4).
In one instance, potassium hydroxide in refluxing metha-
nol was used to cleave the N-arylpiperazine from the res-
in. Here, the methyl carbamate 4 was formed as the sole
product in reasonable yield and excellent purity (32%
overall yield, pure by C,H,N analysis) (Scheme 4). It is
known that other nucleophiles can be used in similar
Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York

3458
H. C. Rudbeck et al.
PAPER
Table 1 Reaction Times and Crude Yields from the Addition of Various Anilines to Resin 1
Entry
Compound
Number
Reaction time Crude isolated Purity of the crude Purified yield
(h)
yielda (%)
60c
productb (%)
(%)
1
2
3
4
3a
3b
3c
3d
28
100
60
H3CO
N
N
CH3
86
49
50
41
22
75–80d
99
37
21
4
N
N
CH3
N
F
N
CH3
112
ca. 60d,e
Cl
Cl
N
N
CH3
5
6
7
8
3e
3f
32
60
46
40
39
34
55f
20g
17g
23g
6g
H3CO
N
NH
ca. 70d,f
77
N
NH
3g
3h
66
F
N
NH
111
85
Cl
Cl
N
NH
a Overall yield based on 1.97 mmol·g–1 loading of Versabeads™.
b Purity obtained from HPLC.
c Pure by C,H,N analysis.
d Due to problems from overlapping peaks on the HPLC, the purity of the crude product is estimated from 1H NMR spectroscopy.
e 10–15% of 1-(4-chlorophenyl)-4-methylpiperazine was also present.
f Due to contamination of DME with MeOH, a significant amount of the corresponding methyl carbamate was formed during cleavage (entry
5: 35%, entry 6: 5–10%).
g Isolated as the oxalate.
cleavage reactions,13 which broadens the scope of this minum salts, and then examined by 13C gel-phase NMR
linking approach.
spectroscopy for traces of noncleaved material. No peaks
other than those originating from the polymer backbone
were observed. The resin was then converted into resin 1
using identical conditions to those used previously. Chlo-
ride analysis and 13C gel-phase NMR spectroscopy of this
resin showed essentially identical loading compared to
similar analyses from the first use of the resin (Cl analysis:
1.68 mmol⋅g–1, identical to resin 1). These results indicate
that the resin is capable of being reused a number of times
The cost of the resin itself is an important factor in the
synthesis of small molecules on a larger scale, i.e. 0.1 mol
or greater. In such cases, the solid support itself must be
reusable, otherwise its cost would outweigh the practical
advantages. To this end, we have examined briefly the
possibility of reusing the resin. Following the reductive
cleavage of 3c from the resin, the resin was washed with
4 M hydrogen chloride and water to remove residual alu-
3a–d
R2
R2
a)
R1
R1
N
N
N
N
CH3
H
+
+
OH
OH
O
N
N
R1
b)
O
2a–h
R2
2a,2e,3a,3e: R1 = OCH3 R2 = H
2b,2f,3b,3f: R1 = H R2 = H
2c,2g,3c,3g: R1 = F R2 = H
2d,2h,3d,3h: R1 = Cl R2 = Cl
3e–h
Scheme 3 Reagents and conditions: (a) LiAlH4 (10 equiv), THF, reflux, 19 h; (b) t-BuOK (2.2 equiv), DME, reflux, 3 h.
Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Aryl- and N-Aryl-N¢-methylpiperazines on a Novel Poly(ethylene glycol) Resin
3459
Cl
O
O
H3CO
a)
b)
N
N
N
OCH3
O
Cl
1
4
Scheme 4 Reagents and conditions: (a) 4-methoxyaniline (5 equiv),
py (5 equiv), KI (0.2 equiv), MIBK, 100 °C, 15 h; (b) KOH (10
equiv), MeOH, reflux, 3.5 h.
in Et2O prior to reaction. All reactions were run under N2. All final
compounds gave satisfactory NMR spectroscopic and, for solid
compounds, C,H,N analysis data.
Solution-phase NMR spectra were recorded on a Bruker 500 MHz
spectrometer. The 13C gel-phase NMR spectra were recorded at
62.5 MHz on a Bruker 250 MHz spectrometer. Automated flash
chromatography was performed on an Argonaut Flash Master II us-
ing Isolute Flash Si II prepacked columns. LC/MS, UV and ELSD
was run in an integrated system on a Waters Symmetry C18 column
(4.6 × 30 mm, particle diameter 0.035 mm), using a H2O/MeCN
gradient at pH 6. Mass spectra were acquired using an Applied Bio-
systems API300 triple quadrupole mass spectrometer with Atmo-
spheric Pressure Photoionization (APPI) ion source. The UV
spectra were recorded with a Shimadzu SPD10A UV detector at
254 nm and Evaporative Light Scattering Detection (ELSD) data
were recorded with a Polymer Laboratories PL-ELS 2100 ELS-de-
tector. The HPLC of crude products was taken on a Varian Star
HPLC using a LiChrosobe RP-8 column (4 × 250 mm, particle di-
ameter 0.005 mm). The eluent used was MeCN–H2O (50:50) buff-
ered to pH 3 with a Et3N–phosphate buffer. GC/MS were performed
on a Varian 2000 mass spectrometer connected to a Varian 3400
GC, equipped with a Phenomex column (15 m, 0.25 mm internal di-
ameter) and EI at 70 eV; He was used as the carrier gas. Melting
points were recorded on a Büchi B-540 melting point apparatus and
appear uncorrected.
Figure 2 A section of the 13C gel-phase NMR spectrum of the resin
after a 42-h reaction with 4-fluoroaniline. Note how peak A at 41.2
ppm (–CH2Cl) is gradually replaced by peak B at 43.2 ppm (pipera-
zine).
without loss of utility, thereby lowering the effective per-
synthesis resin cost. Work in this area is continuing.
To further demonstrate an application of the method, resin
1 (7.5 mmol) was reacted with 2-benzylaniline to yield
3% of the experimental antidepressant Sifaprazine (5)14
upon reductive cleavage (Scheme 5). Here, an excess of
potassium iodide was employed in the piperazine-forming
step as this was shown to accelerate the reaction.
Resin-Bound Bis(chloroethyl)amine 1
In summary, we have developed a safe, versatile method
for the synthesis of arylpiperazines. We have demonstrat-
ed that this linker system can be multidirectional, with
production of N-arylpiperazines plus their N¢-methyl and
methyl carbamate derivatives from a single resin-bound
intermediate. We have shown that the reactions can be
conveniently monitored by 13C gel-phase NMR spectros-
copy, and have demonstrated the scope of poly(ethylene
glycol)-based resins in gram-scale reactions.
Versabeads™ VO400 (90.0 g, 177 mmol) were suspended in THF
(900 mL). A solution of COCl2 in toluene (20% w/w, 190 mL, 355
mmol, 2.0 equiv) was slowly added and the suspension was stirred
mechanically at r.t. for 2 h. The liquid was removed and the resin
was washed successively with THF (750 mL), MeOH (2 × 500 mL),
and THF (900 mL).
Bis(chloroethyl)amine hydrochloride (110 g, 0.61 mol, 3.5 equiv)
was dissolved in H2O (450 mL) and was added to the resin. The sus-
pension was cooled on an ice–water bath and K2CO3 (147 g, 1.06
mol, 6.0 equiv) was added portionwise with mechanical stirring.
The ice–water bath was removed and the suspension was stirred for
6 h at r.t. The resin was recovered by filtration and washed succes-
sively with H2O (3 × 500 mL), THF (3 × 500 mL), MeOH (3 × 500
All solvents and chemicals were used as received except for Versa-
beads™ VO400, which were washed with THF and MeOH (10
mL·g–1) and dried before use, and aniline, 2,6-dimethylaniline, and
4-fluoroaniline, which were purified by precipitation with dry HCl
CH3
N
Cl
NH2
O
N
a)
b)
N
+
O
Cl
1
5
Scheme 5 Formation of Sifaprazine on resin. Reagents and conditions: (a) 2-benzylaniline (5 equiv), py (9.5 equiv), KI (3 equiv), MIBK, 100
°C, 67 h; (b) LiAlH4 (10 equiv), THF, reflux, 19 h.
Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York

3460
H. C. Rudbeck et al.
PAPER
mL), H2O (2 × 500 mL), THF (1 × 750 mL), and MeOH (2 × 500
mL) before drying in vacuo.
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H), 2.56 (t, J = 5.2 Hz,
4 H), 3.12 (t, J = 5.2 Hz, 4 H), 6.84–6.88 (m, 2 H), 6.92–6.98 (m, 2
H).
End weight: 123.1 g (103% of theoretical weight gain).
13C NMR (62.5 MHz, CDCl3): d = 158.5, 156.6, 148.3, 118.2,
118.1, 115.9, 115.8, 55.5, 50.5, 46.5.
Cl analysis: 11.9% Cl [1.68 mmol bis(chloroethyl)amine·g–1 resin,
113% of theoretical maximum loading].
Anal. Calcd for C11H15N2F: C, 68.01; H, 7.78; N, 14.42. Found: C,
67.89; H, 7.89; N, 14.38.
13C NMR (CDCl3): d = 155.4, 73.8, 70.2, 69.0, 66.7, 64.5, 63.2,
50.9, 50.5, 43.1, 42.3, 23.0, 20.6, 17.2, 7.5.
1-(3,4-Dichlorophenyl)-4-methylpiperazine (3d)
Resin-Bound N-Arylpiperazines 2a–h; General Procedure
Resin 1 (10.0 g, 14.8 mmol) was suspended in MIBK (75 mL) in the
presence of the aniline (74 mmol, 5 equiv) and KI (0.5 g, 3 mmol,
0.2 equiv). Then, py (12.0 mL, 0.15 mol, 10 equiv) was added and
the suspension was heated to 100 °C with mechanical stirring. After
the reaction time stated in Table 1, the solvent was removed and the
resin was washed successively with THF (3 × 100 mL), MeOH (3 ×
100 mL), H2O (3 × 100 mL), and THF (3 × 100 mL), and dried in
vacuo to give the immobilized piperazines 2a–h. The completion of
the reactions were confirmed through 13C gel-phase NMR spectros-
copy.
Byproduct 1-(4-chlorophenyl)-4-methylpiperazine was removed by
Kugelrohr distillation at 160–165 °C (1 mbar), and the residue was
purified by flash chromatography (EtOAc–heptane–Et3N).
Brown oil, which solidified upon standing; yield: 0.13 g (4%); mp
52–53 °C.
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H), 2.55 (t, J = 5.2 Hz,
4 H), 3.18 (t, J = 4.7 Hz, 4 H), 6.74 (dd, J1 = 9.0 Hz, J2 = 2.8 Hz, 1
H), 6.95 (d, J = 2.8 Hz, 1 H), 7.26 (d, J = 8 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 151.1, 133.1, 130.8, 122.4,
117.5, 115.6, 55.2, 49.0, 46.5.
N-Aryl-N¢-methylpiperazines 3a–d; General Procedure
Resin 2a–d (14.8 mmol) was suspended in THF (100 mL). Then,
LiAlH4 (5.7 g, 0.15 mol, 10 equiv) was added as pellets and the sus-
pension was refluxed for 19 h with mechanical stirring. The reaction
was cooled on an ice–water bath, quenched by the sequential addi-
tion of H2O (6 mL), NaOH soln (13% w/v, 6 mL), and H2O (17 mL).
The suspension was filtered and the resin was washed successively
with THF (3 × 100 mL), HCl (3 × 100 mL, 1 M), THF (1 × 60 mL),
and 1 M HCl (2 × 100 mL).
Anal. Calcd for C11H14N2Cl2: C, 53.89; H, 5.76; N, 11.43. Found:
C, 54.12; H, 5.97; N, 11.38.
N-Arylpiperazines 3e–h; General Procedure
Resin 2e–h (14.8 mmol) was suspended in DME (100 mL). Then, t-
BuOK (3.7 g, 33 mmol, 2.2 equiv) was added and the suspension
was refluxed for 3 h. The suspension was filtered and washed suc-
cessively with DME (3 × 100 mL), 1 M HCl (3 × 100 mL), DME
(1 × 50 mL), 1 M aq HCl (3 × 100 mL), and DME (2 × 50 mL). The
DME was removed from the filtrate under reduced pressure, and the
residual filtrate was washed with EtOAc (2 × 50 mL) and made ba-
sic with aq NH3 (25% w/v, 100 mL). The aqueous phase was ex-
tracted with toluene (6 × 100 mL). The combined organic phases
were filtered to remove impurities, washed with sat. aq NaHCO3 (50
mL), sat. aq NaCl (50 mL), and H2O (2 × 50 mL), dried (anhyd
Na2SO4), and evaporated.
The THF was removed from the filtrate under reduced pressure. The
residual filtrate was washed with EtOAc (2 × 50 mL) and made ba-
sic with aq NH3 (25% w/v, 100 mL). The resulting suspension was
shaken with toluene (100 mL) and filtered. The solid was washed
with toluene (2 × 100 mL). The filtrate was separated and the aque-
ous phase was washed with toluene (3 × 100 mL). The combined or-
ganic phases were washed with sat. aq NaHCO3 (40 mL), sat. aq
NaCl (40 mL), and H2O (2 × 40 mL), dried (anhyd Na2SO4), and
evaporated.
The crude products were dissolved in abs EtOH (10 mL) and a so-
lution of oxalic acid dihydrate (1.1 equiv) in abs EtOH (9 mL) was
added with stirring. The oxalate formed was allowed to precipitate
in the fridge overnight. In the case of 3e, the equivalents of acid
were calculated based on the HPLC purity, otherwise they were cal-
culated on the total weight of the crude product.
1-(4-methoxyphenyl)-4-methylpiperazine (3a)15
Red solid. Yield: 1.85 g (60%). Mp 63–65 °C (Lit.15a 62–64 °C).
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H), 2.57 (t, J = 4,7 Hz,
4 H), 3.10 (t, J = 5.2 Hz, 4 H), 3.76 (s, 3 H) 6.83 (ddd, J1 = 10.4 Hz,
J2 = 9.0 Hz, J3 = 2.8 Hz, 2 H), 6.90 (ddd, J1 = 10.4 Hz, J2 = 9.0 Hz,
J3 = 2.3 Hz, 2 H).
1-(4-Methoxyphenyl)piperazine Oxalate (3e)
Light-brown crystals; yield: 0.85 g (20%); mp 199–200 °C.
1H NMR (500 MHz, D2O): d = 3.30–3.40 (m, 8 H), 3.76 (s, 3 H),
6.97 (ddd, J1 = 10.8 Hz, J2 = 3.8 Hz, J3 = 2.4 Hz, 2 H), 7.08 (ddd,
J1 = 10.4 Hz, J2 = 3.8 Hz, J3 = 2.4 Hz, 2 H).
13C NMR (62.5 MHz, D2O): d = 166.4, 155.2, 143.8, 120.3, 115.3,
56.1, 48.5, 43.5.
13C NMR (62.5 MHz, CDCl3): d = 154.2, 146.1, 118.5, 114.8, 55.9,
55.7, 51.0, 46.5.
Anal. Calcd for C12H18N2O: C, 69.86; H, 8.80; N, 13.58. Found: C,
69.70; H, 8.88; N, 13.43.
1-Methyl-4-phenylpiperazine (3b)15
Purified by flash chromatography (EtOAc–heptane–Et3N). Yellow
oil; yield: 0.96 g (37%).
Anal. Calcd for C13H18N2O5: C, 55.20; H, 6.49; N, 9.91. Found: C,
55.22; H, 6.48; N, 9.80.
1H NMR (500 MHz, CDCl3): d = 2.31 (s, 3 H), 2.53 (t, J = 4.7 Hz,
4 H), 3.18 (t, J = 4.7 Hz, 4 H), 6.81–6.85 (m, 1 H), 6.88–6.92 (m, 2
H), 7.21–7.26 (m, 2 H).
13C NMR (250 MHz, CDCl3): d = 151.7, 129.5, 120.1, 116.5, 55.6,
49.5, 46.6.
1-Phenylpiperazine Oxalate (3f)
Light-brown crystals; yield: 0.64 g (17%); mp 167–169 °C.
1H NMR (500 MHz, D2O): d = 3.35–3.43 (m, 8 H), 7.03–7.07 (m, 1
H), 7.08–7.12 (m, 2 H), 7.34–7.39 (m, 2 H).
13C NMR (62.5 MHz, D2O): d = 166.5, 149.9, 130.1, 123.0, 118.2,
47.3, 43.5.
1-(4-Fluorophenyl)-4-methylpiperazine (3c)
Purified by flash chromatography (EtOAc–heptane–Et3N). Yellow
solid; yield: 0.6 g (21%); mp 42–44 °C.
Anal. Calcd for C12H16N2O4: C, 56.90; H, 6.77; N, 11.06. Found: C,
56.65; H, 6.49; N, 11.10.
Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Aryl- and N-Aryl-N¢-methylpiperazines on a Novel Poly(ethylene glycol) Resin
3461
1-(4-Fluorophenyl)piperazine Oxalate (3g)
Light-brown crystals; yield: 0.93 g (23%); mp 172–173 °C.
1H NMR (500 MHz, D2O): d = 3.32–3.40 (m, 8 H), 7.07–7.12 (m, 4
H).
13C NMR (62.5 MHz, D2O): d = 166.3, 157.8, 146.3, 120.2, 120.2,
116.4, 116.2, 48.1, 43.5.
was filtered and the resin washed successively with THF (3 × 50
mL), 1 M aq HCl (3 × 50 mL), THF (1 × 50 mL), 1 M aq HCl (3 ×
50 mL), and THF (3 × 50 mL). The filtrate was filtered through
Celite and the THF was removed under reduced pressure. The aque-
ous phase was made strongly acidic with concd aq HCl and was
washed with EtOAc (2 × 25 mL). The aqueous phase was then made
basic with aq NH3 (25% w/v, 50 mL). The resulting suspension of
salts was shaken with toluene (50 mL) and filtered. The solid was
washed with toluene (2 × 50 mL). The filtrate was separated and the
aqueous phase was washed with toluene (3 × 50 mL). The combined
organic phases were washed with sat. aq NaHCO3 (25 mL), sat. aq
NaCl (25 mL), and H2O (2 × 40 mL), dried (Na2SO4), and evaporat-
ed to give a brown oil (134 mg). Purification through automated
flash chromatography yielded 5 as a slightly yellow oil that solidi-
fied upon standing.
Anal. Calcd for C12H15N2O4F: C, 53.33; H, 5.59; N, 10.37. Found:
C, 53.35; H, 5.68; N, 10.37.
1-(3,4-Dichlorophenyl)piperazine Oxalate (3h)
Recrystallized (i-PrOH). Light-brown crystals; yield: 0.27 g (6%);
mp 230–232 °C.
1H NMR (500 MHz, D2O): d = 3.22–3.32 (m, 8 H), 6.86 (dd, J1 =
8.9 Hz, J2 = 2.8 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 7.32 (d, J = 9.0
Hz, 1 H).
Yield: 53 mg (2.7%); mp 77–79 °C.
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H), 2.39–2.74 (m, 4 H),
2.89 (t, J = 4.8 Hz, 4 H), 4.07 (s, 2 H), 7.08–7.28 (m, 9 H).
13C NMR (62.5 MHz, D2O): d = 149.7, 131.2, 119.1, 117.6, 46.7,
43.3.16
13C NMR (62.5 MHz, CDCl3): d = 152.0, 142.2, 137.0, 131.3,
129.4, 128.7, 127.5, 126.1, 124.4, 121.0, 56.1, 53.0, 46.6, 37.0.
Anal. Calcd for C12H14N2O4Cl2: C, 44.81; H, 4.39; N, 8.71. Found:
C, 45.21; H, 4.61; N, 8.58.
Anal Calcd for C18H22N2: C, 81.16; H, 8.33; N, 10.20. Found: C,
80.72; H, 8.37; N, 10.46.
Methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (4)
Resin 1 (10.0 g, 14.8 mmol) was suspended in MIBK (100 mL). 4-
Methoxyaniline (8.9 g, 75 mmol, 5 equiv) and KI (0.48 g, 3 mmol,
0.2 equiv) were added, followed by py (6 mL, 75 mmol, 5 equiv).
The mixture was heated to 100 °C for 15 h. The resin was washed
successively with THF (2 × 100 mL), MeOH (2 × 100 mL), H2O
(2 × 100 mL), THF (2 × 100 mL), and MeOH (2 × 100 mL), and
then was suspended in MeOH (100 mL). Then, KOH (8.2 g, 140
mmol, 10 equiv) was added and the suspension was refluxed for 3.5
h. The suspension was filtered and the resin was washed successive-
ly with THF (2 × 100 mL), 1 M HCl (2 × 100 mL), THF (1 × 100
mL), 1 M HCl (2 × 100 mL), and THF (1 × 100 mL). The THF was
removed by evaporation in vacuo and the remaining solution was
washed with EtOAc (2 × 50 mL). The aqueous phase was made ba-
sic with aq NH3 (25 w/v, 25 mL) and extracted with Et2O (5 × 100
mL). The combined organic phases were washed with sat. aq
NaHCO3 (50 mL), sat. aq NaCl (50 mL), and H2O (2 × 50 mL),
dried (anhyd Na2SO4), and evaporated to give compound 4 as an oil
that solidified upon standing.
Acknowledgement
We gratefully acknowledge the assistance of the Analytical Depart-
ment at H. Lundbeck A/S for invaluable help with setting up the
analysis, Mrs. Anne Marie Munk Jørgensen of the H. Lundbeck
A/S Department of Computational Chemistry for providing valua-
ble information on Sifaprazine and The Danish Ministry of Science,
Technology and Development for funding.
References
(1) (a) Raillard, S. P.; Ji, G.; Mann, A. D.; Baer, T. A. Org.
Process Res. Dev. 1999, 3, 177. (b) Meisenbach, M.;
Allmendinger, T.; Mak, C.-P. Org. Process Res. Dev. 2003,
7, 553.
(2) Price for 100 g of Versabeads™ VO400 loading 2 mol·kg–1
(as used in this article): € 739 equal to € 370 per mol. Price
for 100 g of Rapp Polymere hydroxymethyl polystyrene
loading 1.5 mol·kg–1: € 360 equal to € 240 per mol (price
for 100 g of Rapp Polymere TentaGel Standard (water
compatible), loading 0.3 mol·kg–1: € 1010 equal to € 33667
per mol)
Yield: 1.15 g (32%); mp 94–97 °C.
1H NMR (500 MHz, CDCl3): d = 3.00–3.04 (m, 4 H), 3.59–3.65 (m,
4 H), 3.73 (s, 3 H), 3.77 (s, 3 H), 6.84 (ddd, J1 = 9.4 Hz, J2 = 3.3 Hz,
J3 = 2.8 Hz, 2 H), 6.90 (ddd, J1 = 9.4 Hz, J2 = 3.3 Hz, J3 = 2.8 Hz, 2
H).
13C NMR (62.5 MHz, CDCl3): d = 156.3, 154.7, 146.0, 119.3,
114.9, 55.9, 53.0, 51.3, 44.3.
(3) (a) Rademann, J.; Grøtli, M.; Meldal, M.; Bock, K. J. Am.
Chem. Soc. 1999, 121, 5459. (b) Christensen, S. F.;
Michael, R. Chimica Oggi/Chemistry Today (Focus on
Peptides & Amino Acids) 2004, 48. (c) Christensen, S. F.;
Ramos, M.; Michael, R. PharmaChem 2004, 9, 59.
(4) (a) López-Rodriguez, M. L.; Ayala, D.; Benhamú, B.;
Morcillo, M. J.; Viso, A. Curr. Med. Chem. 2002, 9, 443.
(b) Bettinetti, L.; Schlotter, K.; Hübner, H.; Gmeiner, P. J.
Med. Chem. 2002, 45, 4594. (c) Grundt, P.; Carlson, E. E.;
Cao, J.; Bennett, C. J.; McElveen, E.; Taylor, M.; Luedke, R.
R.; Newman, A. H. J. Med. Chem. 2005, 48, 839.
(d) Toogood, P. L.; Harvey, P. J.; Repine, J. T.; Sheehan, D.
J.; VanderWel, S. N.; Zhou, H.; Keller, P. R.; McNamara, D.
J.; Sherry, D.; Zhu, T.; Brodfuehrer, J.; Choi, C.; Barvian, M.
R.; Fry, D. W. J. Med. Chem. 2005, 48, 2388. (e) López-
Rodríguez, M. L.; Morcillo, M. J.; Fernández, E.; Benhamú,
B.; Tejada, I.; Ayala, D.; Viso, A.; Campillo, M.; Pardo, L.;
Anal Calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C,
62.06; H, 7.30; N, 11.06.
Sifaprazine (5)
Resin 1 (5.1 g, 7.5 mmol) was suspended in MIBK (40 mL) with 2-
benzylaniline (6.87 g, 37 mmol, 5 equiv) and KI (3.74 g, 22.5 mmol,
3 equiv). Then, py (6 mL, 5.6 g, 71 mmol, 9.5 equiv) was added and
the suspension was heated to 100 °C for 67 h with magnetic stirring.
The resin was washed successively with NMP (3 × 50 mL), THF
(3 × 50 mL), MeOH (3 × 50 mL), H2O (3 × 50 mL), NMP (3 × 50
mL), THF (3 × 50 mL), MeOH (3 × 50 mL), and THF (3 × 50 mL),
and then dried. The resin was suspended in THF (50 mL). Pellets of
LiAlH4 (2.8 g, 75 mmol, 10 equiv) were added and the suspension
was refluxed for 19 h with magnetic stirring.17 The suspension was
cooled on ice and quenched by the sequential addition of H2O (3
mL), aq NaOH (13% w/v, 3 mL), and H2O (10 mL). The suspension
Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York

3462
H. C. Rudbeck et al.
PAPER
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Synthesis 2005, No. 19, 3456–3462 © Thieme Stuttgart · New York