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H), 1.39–1.21 (m, 9H, H3C-(CH2)3-Pip + Pip-4-H + CH2-CH2Ph), 0.85
(t, J = 6.3 Hz, 3H, CH3); MS (70 eV); m/z (%) = 317 ([MÅ]+, 2), 198
5.1.6.1. 1-[2-(3-Chlorophenoxy)ethyl]-4-piperidino-piperidine
dihydrogen oxalate (9). From 1-bromo-2-(3-chlorophenoxy)
ethane 2a (0.59 g, 2.5 mmol). Yield 16%. Mp. 223–225 °C. 1H
NMR [DMSO-d6]: d = 7.29 (t, J = 8.2 Hz, 1H, Ph-5-H), 7.03–6.92
(m, 2H, Ph-2,4-H), 6.90 (d, J = 1.5 Hz, 1H, Ph-6-H), 4.16 (t,
J = 4.9 Hz, 2H, CH2-O), 3.30–2.90 (m, 9H, Pip-CH2 + Pip-4-
H + Pip0-2,6-H + Pip-2,6-He), 2.44–2.36 (m, 2H, Pip-2,6-Ha), 2.10–
1.96 (m, 2H, Pip-3,5-He), 1.85–1.65 (m, 6H, Pip0-3,4,5-H), 1.51
(18), 154 (100), 91(27); IR (KBr) (cmꢁ1): 1114s (
m [C–O–C]).
Anal. calcd for C21H35NO ꢀ C2H2O4(Mr: 407.56): C, 67.78; H,
9.15; N, 3.44. Found: C, 67.45; H, 9.23; N, 3.39.
5.1.4.3. 4-Benzyl-1-[3-phenylpropoxy)propyl]piperidine hydro-
gen oxalate (6). From 3-(4-benzylpiperidin-1-yl)propan-1-ol
(1.17 g, 5 mmol). Heated in the microwave oven for 240 s (4ꢀ
60 s). After removing the solvent under reduced pressure, the res-
idue was purified by CC [eluent CHCl3/MeOH/MeOH saturated
with gaseous NH3; 98:2:2]. Yield: 19%. Mp 112–114 °C. 1H NMR
[CDCl3]: d = 7.32–7.21 (m, 6H, Ph-2,4,6-H + Ph-20,40,60-H), 7.21–
7.11 (m, 4H, Ph-3,5-H + Ph-30,50-H), 3.61 (br s, 2H, Ph0-CH2-Pip),
3.42 (t, J = 5.6 Hz, 2H, O-CH2), 3.38 (t, J = 6.6 Hz, 2H, CH2-O), 3.06
(t, J = 7.7 Hz, 2H, CH2-Ph), 2.67–2.58 (m, 6 H, Pip-2,6-H + Pip-
CH2), 2.01–1.90 (m, 3H, PipCH2-CH2 + Pip-4-H), 1.88–1.75 (m,
6H, Pip-3,5-H + CH2-CH2Ph); MS (70 eV); m/z (%) = 351 ([MÅ]+, 5),
(br s, 2H, Pip-3,5-Ha); IR (KBr) (cmꢁ1): 1227s (
m [C–O–C]).
Anal. calcd for C18H27N2OCl ꢀ 2C2H2O4 (Mr: 502.95): C, 52.54;
H, 6.21; N, 5.57. Found: C, 52.10; H, 6.40; N, 5.62.
5.1.6.2. 1-[2-(3-Methoxyphenoxy)ethyl]-4-piperidino-piperidine
dihydrogen oxalate (10). From 1-bromo-2-(3-methoxyphe-n-
oxy)ethane 2b (0.58 g, 2.5 mmol). Yield 30%. Mp 224–226 °C. 1H
NMR [DMSO-d6]: d = 7.16 (t, J = 8.0 Hz, 1H, Ph-5-H), 6.55–6.45 (m,
3H, Ph-2,4,6-H), 4.15 (t, J = 5.1 Hz, 2H, CH2-O), 3.71 (s, 3H, OCH3),
3.38–3.25 (m, 2H, Pip-CH2), 3.25–3.02 (m, 7H, Pip-4-H + Pip0-2,6-
H + Pip-2,6-He), 2.55–2.51 (m, 2H, Pip-2,6-Ha), 2.13–1.98 (m, 2H,
Pip-3,5-He), 1.89–1.65 (m, 6H, Pip0-3,4,5-H), 1.50 (br s, 2H, Pip-
258 (20), 188 (100), 98 (16); IR (KBr) (cmꢁ1): 1114s (
m [C–O–C]).
Anal. calcd for C24H33NO ꢀ C2H2O4(Mr: 441.58): C, 70.72; H,
7.98; N, 3.17. Found: C, 70.46; H, 7.85; N, 3.25.
3,5-Ha); IR (KBr) (cmꢁ1): 1202s (
m [C–O–C]), 1155s (m [C–O–C]).
Anal. calcd for C19H30N2O2 ꢀ 2C2H2O4(Mr: 498.51): C, 55.41; H,
5.1.4.4. 2-[3-(3-Phenylpropoxy)propyl]-1,2,3,4-tetrahydro-iso-
quinoline hydrogen oxalate (8). From 3-(3,4-dihydro-1H-iso-
quinolin-2-yl)-propan-1-ol (0.48 g, 2.5 mmol). Heated in the
microwave oven for 45 s. Washed twice H2O (20 mL). Yield: 10%.
Mp. 101–103 °C. 1H NMR [DMSO-d6]: d = 7.28–7.12 (m, 9H, Ph-
2,3,4,5,6-H + tHIQ-5,6,7,8-H), 4.22 (s, 2H, tHIQ-1-H), 3.43 (t,
J = 6.1 Hz, 2H, CH2-O), 3.38–3.25 (m, 4H, CH2O-CH2 + tHIQ-4-H),
3.07 (t, J = 8.0 Hz, 2H, tHIQ-3-H), 3.01 (t, J = 6.1 Hz, 2H, tHIQ-CH2),
2.59 (t, J = 7.2 Hz, 2H, CH2-Ph), 1.99–1.89 (m, 2H, tHIQ-CH2-CH2),
1.82–1.73 (m, 2H, CH2-CH2Ph); MS (70 eV); m/z (%) = 309 ([MÅ]+,
6.87; N, 5.62. Found: C, 55.57; H, 7.04; N, 5.66.
5.1.6.3. 1-[2-(3-Trifluoromethylphenoxy)ethyl]-4-piperidino-
piperidine dihydrogen oxalate (12). From 1-bromo-2-(3-triflu-
oromethylphenoxy)ethane 2c (0.67 g, 2.5 mmol). Yield 19%. Mp
228–230 °C. 1H NMR [DMSO-d6]: d = 7.51 (t, J = 8.2 Hz, 1H, Ph-5-
H), 7.30–7.24 (m, 3H, Ph-2,4,6-H), 4.24 (t, J = 4.9 Hz, 2H, CH2-O),
3.36–2.90 (m, 9H, Pip-CH2 + Pip-4-H + Pip0-2,6-H + Pip-2,6-He),
2.42–2.36 (m, 2H, Pip-2,6-Ha), 2.09–1.98 (m, 2H, Pip-3,5-He),
1.88–1.64 (m, 6H, Pip0-3,4,5-H), 1.50 (br s, 2H, Pip-3,5-Ha).
Anal. calcd for C19H27N2OF3 ꢀ 2C2H2O4(Mr: 536.49): C, 51.48; H,
5.82; N, 5.22. Found: C, 51.45; H, 6.04; N, 5.25.
2), 146 (100), 132 (87), 91(30); IR (KBr) (cmꢁ1): 1113s (
m [C–O–C]).
Anal. calcd for C21H27NO ꢀ C2H2O4 ꢀ 0.33 H2O (Mr: 405.36): C,
68.14; H, 7.36; N, 3.46. Found: C, 68.33; H, 7.23; N, 3.56.
5.1.6.4. 1-[2-(4-Methylphenoxy)ethyl]-4-piperidino-piperidine
dihydrogen oxalate (13). From 1-bromo-2-(4-methylphenoxy)
ethane 2d (0.54 g, 2.5 mmol). Yield 25%. Mp 202–205 °C. 1H NMR
[DMSO-d6]: d = 7.06 (d, J = 8.2 Hz, 2H, Ph-3,5-H), 6.81 (d, J = 8.7 Hz,
2H, Ph-2,6-H), 4.07 (t, J = 5.6 Hz, 2H, CH2-O),3.25–3.08 (m, 7H, Pip-
CH2 + Pip-4-H + Pip0-2,6-H), 2.90–2.85 (m, 2H, Pip-2,6-He), 2.35–2.28
(m, 2H, Pip-2,6-Ha), 2.21 (s, 3H, Ph-4-CH3), 2.07–1.94 (m, 2H, Pip-
3,5-He), 1.83–1.63 (m, 6H, Pip0-3,4,5-H), 1.50 (br s, 2H, Pip-3,5-Ha);
5.1.5. The synthesis of 2-[3-(3-phenylpropoxy)propyl]decahydro-
isoquinoline hydrogen oxalate (7)
To 10 mL DMSO, powdered KOH (1.1 g, 20 mmol) was added
and stirred for 5 min at ambient temperature. Then, 3-(octahy-
dro-isoquinolin-2-yl)propan-1-ol (0.49 g, 2.5 mmol) and 1-bro-
mo-3-phenylpropane (0.59 g, 3 mmol) were added and stirred for
1 h at the same temperature. Afterwards, the mixture was poured
into H2O (10 mL) and extracted with 10 mL CH2Cl2. The extracts
were dried over anhydrous Na2SO4 and purified by CC (eluent:
CHCl3/MeOH; 85:15). The final product was crystallized as salt of
oxalic acid from EtOH/Et2O. Yield: 27%. Mp 112–116 °C. 1H NMR
[DMSO-d6]: d = 7.33–7.23 (m, 2H, Ph-3,5-H), 7.23–7.10 (m, 3H,
Ph-2,4,6-H), 3.41 (t, J = 5.8 Hz, 2H, CH2-O), 3.36 (t, J = 6.4 Hz, 2H,
CH2O-CH2), 3.27 ( d, J = 11.1 Hz, 1H, dHIQ-1-He), 3.12–2.88 (m,
4H, dHIQ-3-H + dHIQ-CH2), 2.83 (t, J = 11.4 Hz, 1H, dHIQ-1-Ha),
2.61 (t, J = 7.5 Hz, 2H, CH2-Ph), 1.98–1.84 (m, 2H, dHIQCH2-CH2),
1.84–1.74 (m, 3H, CH2-CH2Ph + dHIQ-10-H), 1.74–0.85 (m, 11H,
dHIQ-5,6,7,8,9-H); MS (70 eV); m/z (%) = 315.5 ([MÅ]+, 4), 196
IR (KBr) (cmꢁ1): 1243s (
m [C–O–C]).
Anal. calcd for C19H30N2O ꢀ 2C2H2O4(Mr: 482.51): C, 58.11; H,
7.78; N, 6.20. Found: C, 57.25; H, 7.10; N, 5.81.
5.1.6.5. 1-[2-(4-Chlorophenoxy)ethyl]-4-piperidino-piperidine
dihydrogen oxalate (14). From 1-bromo-2-(4-chlorophenoxy)
ethane 2e (0.59 g, 2.5 mmol). Yield 35%. Mp 213–215 °C. 1H NMR
[DMSO-d6]: d = 7.30 (d, J = 8.7 Hz, 2H, Ph-3,5-H), 6.95 (d, J = 9.0 Hz,
2H, Ph-2,6-H), 4.10 (t, J = 4.9 Hz, 2H, CH2-O),3.19–2.86 (m, 7H, Pip-
CH2 + Pip-4-H + Pip0-2,6-H), 2.90–2.80 (m, 2H, Pip-2,6-He), 2.32–2.24
(m, 2H, Pip-2,6-Ha), 2.06–1.97 (m, 2H, Pip-3,5-He), 1.80–1.60 (m,
6H, Pip0-3,4,5-H), 1.51 (br s, 2H, Pip-3,5-Ha); IR (KBr) (cmꢁ1): 1243s
(18), 152 (100), 98 (6); IR (KBr) (cmꢁ1): 1117s (
m [C–O–C]).
Anal. calcd for C21H33NO ꢀ C2H2O4 ꢀ 0.25 H2O (Mr: 410.05): C,
(
m
[C–O–C]).
67.37; H, 8.73; N, 3.42. Found: C, 67.42; H, 8.56; N, 3.40.
Anal. calcd for C18H27N2OCl ꢀ 2C2H2O4(Mr: 502.95): C, 52.54; H,
6.21; N, 5.57. Found: C, 53.08; H, 6.49; N, 5.73.
5.1.6. General procedure for the preparation of ethers 9, 10, 12–14
A mixture of 4-piperidino-piperidine (0.42 g, 2.5 mmol), pheno-
xyalkyl halide (2.5 mmol), K2CO3 (0.35 g, 2.5 mmol) in 15 ml of
CH3CN was heated to reflux for 15 h. After cooling, the solid was
filtered and the solvent was evaporated under reduced pressure.
The residue was purified by CC (eluent: CH2Cl2/MeOH; 90:10).
The pure fractions were concentrated in vacuum and crystallized
as hydrogen oxalate from EtOH/Et2O.
5.1.7. General procedure for the preparation of ethers 11, 15
and 16
A mixture of 4-piperidino-piperidine (0.67 g, 4 mmol), a pheno-
xyalkyl halide (2 mmol), K2CO3 (0.83 g, 6 mmol) in 42 mL of EtOH
and 8 mL H2O with catalytic KI was heated to reflux for 8 h. After
cooling, the solid was filtered and the solvent was evaporated un-
der reduced pressure to the half of the volume. Then, 20 mL 1% HCl