First catalytic enantioselective synthesis of the cocaine abuse therapeutic agent (S)-(+)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol

Article abstract of DOI:10.1016/j.tetasy.2006.12.028

(S)-(+)-1-(4-{2-[Bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol, which is a promising candidate as a cocaine abuse therapeutic agent, is prepared in several steps. The key asymmetric step is the catalytic enantioselective addition of dimethylzinc to either 2-chloro or 2-bromoacetophenone catalyzed by the use of different chiral isoborneolsulfonamide ligands in the presence of titanium tetraisopropoxide. The synthesis of a new isoborneolsulfonamide ligand bearing a trifluromethyl substituent and its use in this addition is also presented.

Full text of DOI:10.1016/j.tetasy.2006.12.028

Tetrahedron: Asymmetry 18 (2007) 400–405
First catalytic enantioselective synthesis of the cocaine abuse
therapeutic agent (S)-(+)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}-
piperazin-1-yl)-2-phenyl-2-propanol
*
*
´
Vicente J. Forrat, Diego J. Ramon and Miguel Yus
Instituto de Sı´ntesis Orga´nica (ISO), Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Alicante,
Apdo. 99, E-03080 Alicante, Spain
Received 21 December 2006; accepted 31 December 2006
Available online 21 February 2007
Dedicated to Professor T. Hiyama on occasion of his 60th birthday
Abstract—(S)-(+)-1-(4-{2-[Bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol, which is a promising candidate as a
cocaine abuse therapeutic agent, is prepared in several steps. The key asymmetric step is the catalytic enantioselective addition of di-
methylzinc to either 2-chloro or 2-bromoacetophenone catalyzed by the use of different chiral isoborneolsulfonamide ligands in the pres-
ence of titanium tetraisopropoxide. The synthesis of a new isoborneolsulfonamide ligand bearing a trifluromethyl substituent and its use
in this addition is also presented.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
candidate as a cocaine abuse therapeutic agent. It could de-
crease the cocaine-maintained response in rhesus monkeys
at lower doses than those affecting food-maintained
responding, as other related compounds do,9 which is an
important characteristic for a potential treatment agent.
Moreover, the hydroxy substituent would allow its further
conversion to an oil-soluble prodrug and the presence of
the methyl group suggests a possible resistance to metabo-
lism, all these facts making it a good candidate for further
development. Finally, it should be pointed out that the
absolute configuration of the quaternary stereocenter has
a great impact on the DAT and SERT binding affinities,
the (S)-enantiomer giving the best results.10
The abuse of cocaine 1 continues to be a major health,
social, and economical problem in spite of much govern-
mental effort devoted toward educating the public about
the dangers of illicit drug use. The misuse of this potent
central nervous system stimulant is linked to numerous
health risks, ranging from cardiovascular complications
to chronic inflammation, and also infectious diseases.1
The euphoric and reinforcing properties of cocaine are be-
lieved to be primarily associated with a perturbation of the
dopaminergic transporter system (DAT),2 as well as with
other neuronal diseases including Parkinson, Huntington,
and schizophrenia.3 However, the level of these perturba-
tions is similar for serotonin (SERT)4 and norepinephrine
(NET)5 transporter systems.6
OH
Although, there are several treatments for cocaine abuse,7
the regulatory agencies (EMEA, FAD, etc.) have not yet
approved any specific medication among the different
candidates.8 (S)-(+)-1-(4-{2-[Bis(4-fluorophenyl)methoxy]-
ethyl}piperazin-1-yl)-2-phenyl-2-propanol 2 is a promising
N
O
N
N
OMe
F
O
O
O
*
Corresponding authors. Tel.: +35 965 90 35 48; fax: +35 965 90 35 49;
e-mail addresses: djramon@ua.es; yus@ua.es
F
1
2
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.028

V. J. Forrat et al. / Tetrahedron: Asymmetry 18 (2007) 400–405
401
Chiral compound 2 has been already obtained either by
semi-preparative chiral HPLC followed by recrystalli-
zation,10 or by diastereoselective crystallization of the
starting racemic atrolactic acid with chiral 1-phenyl-1-
ethylamine.11
selectivities among the second generation ligands due to the
beneficial possibility of a double titanium atom complexa-
tion19 (Table 1, entry 2). However, the only significant
change took place in the chemical yield, and not in the
enantioselectivity. In our previous studies with other simple
ketones, the use of the so-called third generation ligands
gave the best enantioselectivities. Therefore ligand
3c14a,15b from the third generation set was tested and, sur-
prisingly, the results were worse. This disappointing result
could be explained as a consequence of the presence of an
extra-coordinating basic functionality. We thought that
increasing the acidity of the ligand by the introduction of
an electron withdrawing group on the aromatic ring, such
as in ligand 3d, could improve the results (Table 1, entry
3). In fact, the results could be somewhat better than the
previous results with the third generation ligand 3c, but
inferior to those obtained using the second generation
one HOCSAC. These results pointed out that, although
for simple ketones increasing generations gave better re-
sults, for a particular functionalized ketone some ligand
optimization needs to be done. Finally, the reaction of di-
methylzinc with 2-bromoacetophenone catalyzed by HOC-
SAC 3b gave the related alcohol 6b with a disappointing
enantioselectivity (compare entries 2 and 5 in Table 1).
On the other hand, in our research group, as well as in
others, a new family of chiral isoborneolsulfonamide12–15
ligands 3 has been introduced as excellent chiral ligands
for catalytic enantioselective addition16 of organozinc
reagents to ketones17 in the presence of titanium alkoxides.18
In this paper, we present the first enantioselective synthesis
of compound 2 through a catalytic addition of dimethyl-
zinc 5 to 2-haloacetophenone 4 as the key asymmetric step.
2. Results and discussion
The synthesis started with the study of the asymmetric key
step (Table 1).
The enantioselective addition of dimethylzinc 5 to 2-chloro-
acetophenone 4 (X = Cl) at room temperature catalyzed
by the first generation ligand 3a12b,2c gave the expected
functionalized tertiary alcohol 6a with a moderated chem-
ical yield and good enantioselectivity (Table 1, entry 1), the
absolute configuration being assigned by correlation with
the final product 2. After this promising initial result, we
tested HOCSAC 3b,13b,15b which presented the best enantio-
Once the chiral part of prodrug 2 was prepared, the achiral
part was synthesized starting by a standard20 double addi-
tion of 4-fluorophenylmagnesium bromide 7 to ethyl for-
mate 8 at 0 ꢁC to give the corresponding diaryl methanol
921 with good yield (96%, Scheme 1).
Table 1. Catalytic enantioselective addition of dimethylzinc to ketone 4
O
OH
Ti(OPri)4 (110 mol %)
PhMe, 25 °C
+ Me2Zn
X
X
Ligand 3 (5 mol %)
4
5
6
OH
OH
SO2
NH
SO2
NH
OH
SO2
NH
NH
NH
SO2
SO2
OH
R
3c: R = Me
3d: R = CF3
3a
3b (HOCSAC)
Entry
Ligand
Time (h)
No
X
Yielda (%)
eeb (%)
1
2
3
4
5
3a
3b
3c
3d
3b
180
111
180
180
42
6a
6a
6a
6a
6b
Cl
Cl
Cl
Cl
Br
60
90
69
81
83
80
78
48
68
59
a Isolated yield based on the starting ketone 4 after column chromatography (hexane/ethyl acetate).
b Enantiomeric excess determined by HPLC using a Chiralcel OJ column.

402
V. J. Forrat et al. / Tetrahedron: Asymmetry 18 (2007) 400–405
Then, the reaction of alcohol 9 with an excess of 2-chloro-
ethanol 10 in the presence of a Brønsted acid22 (phosphoric
acid23) at room temperature gave the expected ether 119a in
excellent yield, resulting from a classical SN1 reaction. The
final step was an SN2 substitution reaction between chlori-
nated derivative 11 and piperazine 12 to yield the final achi-
ral compound 139a (Scheme 1).
of chlorinated alcohol 6a with piperazine derivative 13 gave
the expected compound 211 in 81% yield, after column
chromatography purification (Scheme 2). Surprisingly, the
enantiomeric excess of the final compound 2 was 91%,
whereas the enantiomeric excess of the initial alcohol
6a was only 78%. The enantiomeric enrichment of different
substances through their column chromatography purifica-
tion has been previously described and associated with the
formation of diastereomeric dimers of the chiral com-
pound;24 therefore, we believe that the same resolution
equilibrium occurs in our case.
MgBr
OH
O
THF
+
H
OEt
0 °C, 1 h
F
F
When the reaction was performed using the brominated
derivative 6b, the corresponding compound 2 was obtained
in 76% yield and, as in the previous case, there is an impor-
tant enantiomeric enrichment from the initial 59% ee of 6b
up to 72% ee of the final compound 2. In this last case, the
enantiomeric excess could be further improved up to 89%
simply by recrystallization of the corresponding dimaleate
salt11 from DMF–methanol and final basic extraction to
liberate the initial amine 2.
F
9 (96 %)
7
8
Cl
HO
10 (150 mol %)
H3PO4 (350 mol %)
PhMe, 25 °C, 48 h
F
F
F
F
HN
NH
3. Conclusion
12 (400 mol %)
O
O
K2CO3 (300 mol %)
The first catalytic enantioselective synthesis of a promising
candidate as a cocaine abuse therapeutic agent (S)-(+)-1-
(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-
phenyl-2-propanol was accomplished in 59% overall yield
by a five-step process, which permits its easy multigram
scale-up and avoids the economical and environmental
problems associated with the presence of other enantiomer.
The key asymmetric step was the catalytic enantioselective
addition of dimethylzinc to 2-haloacetophenone in the
presence of stoichiometric amounts of titanium tetraiso-
propoxide and substoichiometric amounts of different iso-
borneolsulfonamide ligands. The enantiomeric excess of
the initially obtained products was further increased by
spontaneous enrichment by the column chromatography
isolation.
PhMe, 110 °C, 18 h
N
Cl
HN
13 (85 %)
11 (99 %)
Scheme 1. Synthesis of compound 13.
Finally, product 2 was synthesized by a SN2 displacement
reaction in the presence of a weak base. So, the reaction
F
OH
O
+
X
N
4. Experimental
F
6a: X = Cl
6b: X = Br
HN
Melting points were obtained with a Reichert Thermovar
apparatus. [a]D were recorded at room temperature (ca.
25 ꢁC) in a DIP-1000 JASCO polarimeter. FT-IR spectra
were obtained on a Nicolet Impact 400D spectrophoto-
meter. NMR spectra were recorded on a Bruker AC-300
13
K2CO3 (300 mol %)
EtOH, 80 C, 24 h
°
1
(300 MHz for H and 75 MHz for 13C) using CDCl3 as a
OH
solvent and TMS as internal standard; chemical shifts are
given in d (parts per million) and coupling constants (J)
in Hertz. Mass spectra (EI) were obtained at 70 eV on a
Shimazdu QP-5000 spectrometer, giving fragment ions in
m/z with relative intensities (%) in parentheses. The high
resolution mass spectrum was performed by the corre-
sponding Mass Spectrometry Service at the University of
Alicante. The purity of volatile products and the chromato-
graphic analyses (GLC) were determined with a Hewlett
Packard HP-5890 instrument equipped with a flame ioniza-
tion detector and 12 m HP-1 capillary column (0.2 mm
diam, 0.33 mm film thickness, OV-1 stationary phase),
N
N
F
O
F
2 (81-76 %)
Scheme 2. Final step in the synthesis of compound 2.

V. J. Forrat et al. / Tetrahedron: Asymmetry 18 (2007) 400–405
403
using nitrogen (2 mL/min) as a carrier gas, Tinjector
=
(3.0 g, 46%). White solid, mp 80–82 ꢁC (ethyl acetate/hex-
ane); Rf = 0.56 (hexane/ethyl acetate: 1/1); [a]D = +1.0 (c
1.3, CHCl3); H NMR d = 0.86 and 1.08 [2s, 3H each;
275 ꢁC, Tdetector = 300 ꢁC, Tcolumn = 60 ꢁC (3 min) and
60–270 ꢁC (15 ꢁC/min), P = 40 kPa; tR values are given in
minutes under these conditions. The enantiomeric ratios
(er) for the calculation of enantiomeric excess of tertiary
alcohols were determined by HPLC analysis in a HP-
1100 or a Jasco P-1030 apparatus by using hexane/2-pro-
panol mixtures as solvents, and Chiralcel OD-H (ODH)
and Chiralcel OJ (OJ) as chiral columns, indicating in each
case the column and solvent ratio used. The tR (R) and tR
(S) values are given in minutes under these conditions.
Thin layer chromatography (TLC) was carried out on
Schleicher & Schuell F1400/LS 254 plates coated with a
0.2 mm layer of silica gel; detection by UV254 light, staining
with phosphomolybdic acid [25 g phosphomolybdic acid,
10 g Ce(SO4)2Æ4H2O, 60 mL concentrated H2SO4 and
940 mL H2O]; Rf values are given under these conditions.
Column chromatography was performed using silica gel
60 of 35–70 mesh. Chiral ligands 3a12c and 3b,c15b,25 were
prepared according to literature procedures. All other re-
agents were commercially available (Acros, Aldrich, Strem)
and were used as received. Solvents were dried by standard
procedures.26
1
C(CH3)2], 1.10–2.10 [m, 17H; CH(CH2)4CH and
(CH2)2CHCH2], 2.90–2.95 and 3.10–3.15 (2m, 1H each;
2 · CHN), 2.95 and 3.55 (2d, J = 13.6 Hz, 1H each;
CH2S), 3.48 (d, J = 3.8 Hz, 1H; CHO), 4.10 (s, 1H; OH),
5.08 (d, J = 8.1 Hz, 1H; NH), 5.90 (d, J = 7.6 Hz, 1H;
NH), 7.77 and 8.02 (2d, J = 8.1 Hz, 2H each; Ar); 13C
NMR d = 14.1, 19.9, 20.4, 24.4, 27.3, 30.5, 33.2, 34.65,
39.0, 44.4, 48.75, 50.5, 53.9, 57.2, 57.6, 60.4, 126.25 (2C),
126.3 (2C), 127.4, 144.6; IR (KBr): m = 3551, 3288 (NH,
OH), 1062 cmꢀ1 (C–O); MS (EI): m/z (%): 323 (14), 145
(13), 113 (64), 108 (10), 96 (100), 93 (10), 69 (10). HRMS:
calcd for C23H33F3N2O5S2–H2O: 520.1677; found:
520.1669.
4.2. General procedure for the enantioselective addition of
dimethylzinc to 2-haloacetophenone
To a solution of corresponding chiral ligand 3 (0.25 mmol,
0.05 equiv) in toluene (10 mL) was added a solution of
dimethylzinc in toluene (2.0 M, 6 mL, 12 mmol, 2.4 equiv)
under argon atmosphere. After 5 min stirring at 25 ꢁC, a
solution of Ti(OPri)4 (1.6 mL, 5.5 mmol, 1.1 equiv) was
added, followed by the corresponding 2-haloacetophenone
4 (5 mmol, 1 equiv). The reaction mixture was stirred for
several hours (see Table 1) at the same temperature and
finally quenched by successively addition of methanol
(1 mL) and a saturated solution of NH4Cl (15 mL). The
mixture was filtered through Celite and the resulting solu-
tion was extracted with ethyl acetate (3 · 40 mL). The
organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was purified by flash chro-
matography (hexane/ethyl acetate) to give chiral tertiary
alcohols 6. Yields and enantiomeric excesses are included
in Table 1. Physical and spectroscopic data, as well as liter-
ature references, follow.
4.1. Synthesis of (1S,2R,4S,10R,20R)-N-{trans-20-[2-
hydroxy-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethylsulfon-
amino]cyclohexyl}-400-trifluoromethylbenzenesulfonamide 3d
To a solution of (1R,2R)-trans-(+)-diaminocyclohexane
(1.37 g, 12 mmol, 1 equiv) in CH2Cl2 (15 mL) was added
an aqueous solution of NaOH (2 M, 15 mL) at 0 ꢁC. To
the former strongly stirred biphasic mixture was slowly
added a solution of 4-trifluoromethylbenzenesulfonyl chlo-
ride (2.94 g, 12 mmol, 1.0 equiv) in CH2Cl2 (15 mL), allow-
ing the temperature to rise to 25 ꢁC for 6 h. The reaction
was quenched by addition of a 2 M solution of HCl up
to acid pH and the organic layer was decanted. The acid
aqueous layer was basified by addition of an aqueous
6 M solution of NaOH and extracted with CH2Cl2
(4 · 50 mL). The organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated to give the expected
highly pure ketone (6.4 g, 99%). This solid was dissolved
in MeCN (25 mL) at 0 ꢁC, subsequently adding 4-DMAP
(0.73 g, 6 mmol, 0.5 equiv) and Et3N (7.6 mL, 54 mmol,
4.5 equiv). Then, a solution of (1S)-(+)-(10)-camphorsulfo-
nyl chloride (4.51 g, 18 mmol, 1.5 equiv) in MeCN (25 mL)
was slowly added to the above solution at 0 ꢁC. After 24 h
allowing the temperature to rise to 25 ꢁC, the reaction mix-
ture was quenched by addition of a 3 M aqueous solution
of NaOH (50 mL) and extracted with ethyl acetate
(4 · 40 mL). The organic layers were washed with a 2 M
solution of HCl, dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was dissolved in ethanol
(50 mL) at 0 ꢁC and NaBH4 (2.27 g, 60 mmol, 6 equiv)
was added. The reaction mixture was stirred for 24 h allow-
ing the temperature to rise to 25 ꢁC. Then, the reaction
mixture was quenched with 10 mL of a saturated solution
of NH4Cl and extracted with ethyl acetate (4 · 40 mL).
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated. The
residue was purified by flash chromatography on silica
gel (hexane/ethyl acetate) to give the title compound
4.2.1. (S)-1-Chloro-2-phenylpropan-2-ol 3a.27 Pale yellow
oil. Rf = 0.57 (hexane/ethyl acetate: 7/3); tR (GC) = 9.6;
HPLC (OJ, UV 215 nm, hexane/2-propanol: 97/3, flow
1 mL/min) tR (R) 26.9, tR (S) 28.8; [a]D = +14.9 [c 3.7,
CHCl3; er (R/S): 10.0/90.0]; 1H NMR d = 1.62 (s, 3H;
CH3), 2.71 (br s, 1H; OH), 3.77 (q, J = 11.1 Hz, 2H;
CH2), 7.25–7.45 (m, 5H; Ph); 13C NMR d = 27.2, 55.3,
73.8, 124.9 (2C), 127.5, 128.35 (2C), 144.1; IR (film):
m = 3420 (OH), 1066 cmꢀ1 (C–O); MS (EI): m/z (%): 170
[M]+ (<1), 121 (100), 91 (10), 77 (17).
4.2.2. (S)-1-Bromo-2-phenylpropan-2-ol 3b.28 Pale yellow
oil. Rf = 0.65 (hexane/ethyl acetate: 7/3); tR (GC) = 10.4;
HPLC (OJ, UV 206 nm, hexane/2-propanol: 98/2, flow
0.8 mL/min) tR (R) 36.1, tR (S) 39.3; [a]D = +15.3 [c 11.5,
CHCl3; er (R/S): 20.5/79.5]; 1H NMR d = 1.66 (s, 3H;
CH3), 2.72 (br s, 1H; OH), 3.70 (q, J = 10.4 Hz, 2H;
CH2), 7.25–7.45 (m, 5H; Ph); 13C NMR d = 27.9, 46.1,
73.1, 124.8 (2C), 127.4, 128.3 (2C), 144.1; IR (film):
m = 3451 (OH), 1067 cmꢀ1 (C–O); MS (EI): m/z (%): 214
[M]+ (<1), 121 (100), 77 (10).

404
V. J. Forrat et al. / Tetrahedron: Asymmetry 18 (2007) 400–405
4.3. Synthesis of bis(4-fluorophenyl)methanol 9
d = 2.22 (br s, 1H; NH), 2.45–2.50 and 2.85–2.90 [2 m,
4H each; N(CH2CH2)2], 2.64 (t, J = 6.0 Hz, 2H;
OCH2CH2N), 3.56 (t, J = 6.0 Hz, 2H; OCH2CH2N), 5.33
(s, 1H; CHO), 6.95–7.00 and 7.25–7.30 (2m, 4H each;
Ar); 13C NMR d = 45.95 (2C), 54.75 (2C), 58.4, 66.8,
82.5, 115.1 (2C), 115.3 (2C), 128.5 (2C), 128.6 (2C),
137.7, 137.8, 160.9, 163.3; IR (film): m = 3412 (NH), 1610,
1508 cmꢀ1 (C@C); MS (EI): m/z (%): 332 [M]+ (<1), 203
(18), 201 (11), 183 (12), 99 (100), 86 (15) 70 (10) 56 (16).
To a solution of ethyl formate (2.4 mL, 30 mmol,
1.0 equiv) in THF (60 mL) a 2 M solution of 4-fluorophen-
ylmagnesium bromide in diethyl ether (37.5 mL, 75 mmol,
2.5 equiv) was slowly added at 0 ꢁC. After 1 h allowing the
temperature to rise to 25 ꢁC, the reaction mixture was
quenched by addition of a saturated solution of NH4Cl
(40 mL). The mixture was filtered through Celite and the
resulting solution was extracted with ethyl acetate
(3 · 50 mL). The organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated to give pure title com-
pound (6.3 g, 96%):21 white needles, mp 47–49 ꢁC (ethyl
4.6. General procedure for the synthesis of (S)-(+)-1-(4-{2-
[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-
2-propanol 2
1
acetate/hexane); Rf = 0.61 (hexane/ethyl acetate: 7/3); H
NMR d = 2.64 (s, 1H; OH), 5.71 (s, 1H; CH), 6.95–7.00
and 7.25–7.30 (2m, 4H each; Ar); 13C NMR d = 74.8,
115.2 (2C), 115.5 (2C), 128.1 (2C), 128.2 (2C), 139.3,
139.35, 160.5, 163.8; IR (KBr): m = 3244 (OH), 1610,
1514 cmꢀ1 (C@C); MS (EI): m/z (%): 221 [M+H]+ (2),
220 [M]+ (18), 219 [MꢀH]+ (12), 201 (12), 125 (13), 124
(11), 123 (100), 97 (18), 96 (11), 95 (19).
A suspension of compound 13 (0.33 g, 1.1 mmol, 1 equiv),
chiral tertiary alcohol 6 (1.2 mmol, 1.1 equiv), and K2CO3
(0.46 g, 3.3 mmol, 3 equiv) in absolute ethanol (9 mL) was
heated at reflux for 24 h. The solvent was removed under
reduced pressure to afford a crude oil. Then, H2O
(10 mL) was added and the mixture was extracted with
CH2Cl2 (3 · 15 mL). The organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by flash chromatography (hexane/ethyl ace-
tate) to give the pure title compound 2.11 Yields and enan-
tiomeric excesses are included in Scheme 2 and text: pale
yellow oil. Rf = 0.67 (ethyl acetate/methanol: 9/1); tR
(GC) = 36.5; HPLC (OD-H, UV 225 nm, hexane/2-propa-
nol: 99.7/0.3, flow 0.3 mL/min) tR (S) 45.8, tR1(R) 52.7;
[a]D = +2.9 [c 7.1, CHCl3; er (R/S): 4.5/95.5]; H NMR
d = 1.45 (s, 3H; CH3), 1.63 (br s, 1H; OH), 2.30–2.40 [m,
8H; 2 · N(CH2)2], 2.58 (t, J = 6.1 Hz, 2H; OCH2CH2N),
2.61 and 2.82 (2d, J = 13.1 Hz, 1H each; NCH2CO), 3.49
(t, J = 6.1 Hz, 2H; OCH2CH2N), 5.29 (s, 1H; CHO),
6.95–7.00, 7.20–7.35, and 7.40–7.45 (3m, 4, 7, and 2H,
respectively; Ar); 13C NMR d = 29.5, 53.7 (2C), 54.5
(2C), 57.6, 66.7, 69.0, 71.5, 82.5, 115.1 (2C), 115.3 (2C),
124.6 (2C), 126.2, 128.05 (2C), 128.5 (2C), 128.55 (2C),
128.8, 137.7, 148.1, 160.9, 163.3; IR (film): m = 3417
(OH), 3062 (C@CH), 1606, 1514 (C@C), 1217 cmꢀ1 (C–
O); MS (EI): m/z (%): 448 [MꢀH2O]+ (5), 346 (22), 345
(97), 215 (26), 204 (15), 203 (100), 202 (10), 201 (15), 183
(22), 142 (15), 111 (10), 97 (10), 70 (17), 56 (10).
4.4. Synthesis of 1-bis(4-fluorophenyl)methoxy-2-chloro-
ethane 11
To a solution of bis(4-fluorophenyl)methanol 9 (5.5 g,
25 mmol, 1 equiv) and 2-chloroethanol 10 (2.5 mL,
37.5 mmol, 1.5 equiv) in toluene (50 mL) was slowly added
dropwise 5 mL of phosphoric acid (85%) at 25 ꢁC. The
mixture was strongly stirred for 48 h at the same tempera-
ture, quenched by addition of brine and extracted with
ethyl acetate (3 · 50 mL). The organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated. The
residue was purified by flash chromatography (hexane/
ethyl acetate) to give the title compound 11:9a pale yellow
oil. Rf = 0.43 (hexane/ethyl acetate: 9/1); tR (GC) = 14.8;
1H NMR d = 3.67–3.70 (m, 4H; CH2CH2), 5.39 (s, 1H;
CHO), 7.00–7.05 and 7.25–7.30 (2m, 4H each; Ar); 13C
NMR d = 43.0, 69.0, 82.6, 115.3 (2C), 115.5 (2C), 128.6
(2C), 128.65 (2C), 137.2, 137.3, 161.05, 163.5; IR (film):
m = 3077, 3043 (C@CH), 1606, 1513 cmꢀ1 (C@C); MS
(EI): m/z (%):285 [M+3H]+ (1), 284 [M+2H]+ (7), 283
[M+H]+ (4), 282 [M]+ (23), 204 (17), 203 (100), 201 (27),
187 (16), 183 (27), 123 (38), 95 (12), 63 (12).
4.5. Synthesis of 1-{2-[bis(4-fluorophenyl)-methoxy]-
ethyl}piperazine 13
Acknowledgments
This work was supported by DGI (Project CTQ2004-
To a mixture of piperazine 12 (8.0 g, 93.2 mmol, 4 equiv)
and potassium carbonate (9.7 g, 69.9 mmol, 3 equiv) in
toluene (20 mL), 1-bis(4-fluorophenyl)methoxy-2-chloro-
ethane 11 (6.6 g, 23.3 mmol, 1 equiv) was slowly added
dropwise at reflux, keeping the temperature for 18 h,
quenched with water and extracted with CH2Cl2
(3 · 40 mL). The combined organic layers were extracted
with an aqueous 3 M solution of citric acid (3 · 50 mL).
Then, the combined acid aqueous layers were basified with
a solution of ammonium hydroxide (25%) and extracted
with CH2Cl2 (3 · 80 mL). The organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated to give
the pure title compound 13:9a pale yellow oil. Rf = 0.57
´
01261) from the Spanish Ministerio de Educacion y Ciencia
and the Generalitat Valenciana (Project GV05/157). We
also thank MEDALCHEMY SL for the gift of some
chemicals.
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