2734
T. Mikꢀo et al. / Bioorg. Med. Chem. 12 (2004) 2727–2736
resulting white solid was crystallized as a salt of oxalic
acid from ethanol/diethyl ether (60%). 1H NMR
(CF3COOD): d 7.58 (d, J ¼ 7:9 Hz, 2H, Ph-2-H, Ph-6-
H), 7.48 (d, J ¼ 7:9 Hz, 2H, Ph-3-H, Ph-5-H), 7.18 (d,
J ¼ 8:6 Hz, 4H, Xyl-2-H, Xyl-3-H, Xyl-5-H, Xyl-6-H),
2-Heq, Pip-6-Heq), 2.92–3.01 (m, 2H, Pip-2-Hax, Pip-6-
Hax), 2.31 (s, 3H, CH3), 1.96–2.07 (m, 3H, Pip-3-Heq,
Pip-4-Heq, Pip-5-Heq), 1.79–1.90 (m, 2H, Pip-3-Hax, Pip-
5-Hax), 1.51–1.60 (m, 1H, Pip-4-Hax); MS (70 eV), m=z
(%) 295 (Mþꢀ, 42).
6.80 (br, 1H, N –H), 5.39 (s, 2H, CH2–O), 4.37 (d,
þ
J ¼ 5:4 Hz, 2H, CH2–N), 3.70 (d, J ¼ 11:4 Hz, 2H, Pip-
2-Heq, Pip-6-Heq), 3.00–3.09 (m, 2H, Pip-2-Hax, Pip-6-
Hax), 2.34 (s, 3H, CH3), 2.09 (d, J ¼ 14:8 Hz, 2H, Pip-3-
Heq, Pip-5-Heq), 1.99 (d, J ¼ 13:2 Hz, 1H, Pip-4-Heq),
1.82–1.92 (m, 2H, Pip-3-Hax, Pip-5-Hax), 1.54–1.64 (m,
1H, Pip-4-Hax); MS (70 eV), m=z (%) 338 (Mþꢀ, 44).
4.2.11. 1-(3-(4-Chlorophenoxymethyl)benzyl)piperidine
(16). Synthesized, as described for 15 from 4-chloro-
phenol (0.26 g, 2 mmol) (60%). 1H NMR (CF3COOD): d
7.65 (d, J ¼ 7:4 Hz, 1H, Xyl-4-H), 7.59 (t, J ¼ 7:4 Hz,
1H, Xyl-5-H), 7.54 (s, 1H, Xyl-2-H), 7.45 (d, J ¼ 7:4 Hz,
1H, Xyl-6-H), 7.30 (d, J ¼ 7:9 Hz, 2H, Ph-3-H, Ph-5-H),
7.00 (d, J ¼ 7:9 Hz, 2H, Ph-2-H, Ph-6-H), 6.79 (br, 1H,
Nþ–H), 5.29 (s, 2H, CH2–O), 4.37 (d, J ¼ 4:1 Hz, 2H,
CH2–N), 3.61 (d, J ¼ 12:0 Hz, 2H, Pip-2-Heq, Pip-6-
Heq), 2.92–3.01 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.07 (d,
J ¼ 14:9 Hz, 2H, Pip-3-Heq, Pip-5-Heq), 1.98 (d,
J ¼ 13:8 Hz, 1H, Pip-4-Heq), 1.80–1.90 (m, 2H, Pip-3-
Hax, Pip-5-Hax), 1.51–1.61 (m, 1H, Pip-4-Hax); MS
(70 eV), m=z (%) 315 (Mþꢀ, 34).
4.2.8. (4-Chlorophenyl)carbamic acid 4-piperidinometh-
ylbenzyl ester (14). Synthesized, as described for 13 from
4-chlorophenyl isocyanate (0.61 g, 4 mmol). The white
solid was directly crystallized as a salt of oxalic acid
from ethanol/diethyl ether without prior purification
1
(36%). H NMR (CF3COOD): d 7.57 (d, J ¼ 7:6 Hz,
2H, Ph-2-H, Ph-6-H), 7.48 (d, J ¼ 7:6 Hz, 2H, Ph-3-H,
Ph-5-H), 7.33 (d, J ¼ 8:7 Hz, 2H, Xyl-2-H, Xyl-6-H),
7.28 (d, J ¼ 8:7 Hz, 2H, Xyl-3-H, Xyl-5-H), 6.80 (br,
1H, Nþ–H), 5.38 (s, 2H, CH2–O), 4.37 (d, J ¼ 4:3 Hz,
2H, CH2–N), 3.69 (d, J ¼ 12:2 Hz, 2H, Pip-2-Heq, Pip-6-
Heq), 3.00–3.08 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.09 (d,
J ¼ 14:6 Hz, 2H, Pip-3-Heq, Pip-5-Heq), 1.99 (d,
J ¼ 13:6 Hz, 1H, Pip-4-Heq), 1.82–1.92 (m, 2H, Pip-3-
Hax, Pip-5-Hax), 1.57–1.64 (m, 1H, Pip-4-Hax); MS
(70 eV), m=z (%) 358 (Mþꢀ, 48).
4.2.12. (2-(Piperidinomethyl)phenyl)methanol (17a).
Synthesized, as described for 15a from phthaldialde-
hyde (3 g, 22 mmol). The product was obtained as an
orange solid (41%). Mp 72–73 C.38 1H NMR
(CF3COOD): d 7.51–7.60 (m, 3H, Xyl-3-H, Xyl-4-H,
Xyl-5-H), 7.49 (d, J ¼ 7:3 Hz, 1H, Xyl-6-H), 5.02 (s, 2H,
CH2–O), 4.3 (d, J ¼ 3:5 Hz, 2H, CH2–N), 3.64 (d,
J ¼ 12:2 Hz, 2H, Pip-2-Heq, Pip-6-Heq), 3.01–3.07 (m,
2H, Pip-2-Hax, Pip-6-Hax), 2.10 (d, J ¼ 14:8 Hz, 2H,
Pip-3-Heq, Pip-5-Heq), 1.98 (d, J ¼ 13:3 Hz, 1H, Pip-4-
Heq), 1.73–1.80 (m, 2H, Pip-3-Hax, Pip-5-Hax), 1.57–1.64
(m, 1H, Pip-4-Hax); MS (70 eV), m=z (%) 205 (Mþꢀ, 16).
Anal. (C13H19O). (Mr 205.12).
4.2.9. (3-(Piperidinomethyl)phenyl)methanol (15a). Iso-
phthaldialdehyde (3 g, 22 mmol), piperidine (1 mL,
9 mmol) and titanium(IV)-isopropoxide (2.6 mL,
9 mmol) were dissolved in 20 mL of dry ethanol and
stirred for 1 h at room temperature. NaBH4 (0.84 g,
22 mmol) was added and the mixture was additionally
stirred for 8 h. After adding 10 mL of water the solution
was filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (eluent:
EtOAc/hexane/triethylamine 1:1:0.02) and a colourless
oil was obtained (46%).38 1H NMR (CF3COOD): d 7.65
(d, J ¼ 7:7 Hz, 1H, Xyl-5-H), 7.56–7.59 (m, 2H, Xyl-4-
H, Xyl-6-H), 7.51 (d, J ¼ 7:7 Hz, 1H, Xyl-2-H), 5.51 (s,
2H, CH2–O), 4.38 (d, J ¼ 3:7 Hz, 2H, CH2–N), 3.69 (d,
J ¼ 11:9 Hz, 2H, Pip-2-Heq, Pip-6-Heq), 2.99–3.09 (m,
2H, Pip-2-Hax, Pip-6-Hax), 2.09 (d, J ¼ 14:8 Hz, 2H,
Pip-3-Heq, Pip-5-Heq), 1.99 (d, J ¼ 13:8 Hz, 1H, Pip-4-
Heq ), 1.82–1.92 (m, 2H, Pip-3-Hax, Pip-5-Hax), 1.55–
1.65 (m, 1H, Pip-4-Hax); MS (70 eV), m=z (%) 205 (Mþꢀ,
45). Anal. C13H19NO. (Mr 205.12).
4.2.13. 1-(2-p-Tolyloxymethyl)benzylpiperidine (17).
Synthesized, as described for 15 from 17a (0.41 g,
1
2 mmol) (7%). H NMR (CF3COOD): d 7.59–7.65 (m,
3H, Xyl-3-H, Xyl-4-H, Xyl-5-H), 7.52 (d, J ¼ 7:3 Hz,
1H, Xyl-6-H), 7.27 (d, J ¼ 8:5 Hz, 2H, Ph-3-H, Ph-5-H),
7.01 (d, J ¼ 8:5 Hz, 2H, Ph-2-H, Ph-6-H), 6.79 (br, 1H,
Nþ–H), 5.30 (s, 2H, CH2–O), 4.44 (d, J ¼ 5:6 Hz, 2H,
CH2–N), 3.58 (d, J ¼ 12:3 Hz, 2H, Pip-2-Heq, Pip-6-
Heq), 3.01–3.10 (m, 2H, Pip-2-Hax, Pip-6-Hax), 2.36 (s,
3H, CH3), 2.07 (d, J ¼ 12:8 Hz, 2H, Pip-3-Heq, Pip-5-
Heq), 1.98 (d, J ¼ 13:6 Hz, 1H, Pip-4-Heq), 1.55–1.70 (m,
3H, Pip-3-Hax, Pip-4-Hax, Pip-5-Hax); MS (70 eV), m=z
(%) 295 (Mþꢀ, 34).
4.2.14. 2-(4-Chlorophenoxymethyl)benzyl bromide (18a).
ortho-a,a0-Dibromoxylene (5.28 g, 20 mmol) and 4-
chlorophenol (0.65 g, 5 mmol) were dissolved in 150 mL
of ethanol and K2CO3 (1.38 g, 10 mmol) was added. The
mixture was heated for 12 h under reflux and filtered.
The filtrate was concentrated in vacuo and the residue
was purified by flash column chromatography (eluent:
dichloromethane/petrol ether 2:8) to give a colourless oil
(32%). 1H NMR (CDCl3): d 7.39–7.44 (m, 2H, Xyl-3-H,
Xyl-5-H), 7.32–7.35 (m, 2H, Xyl-4-H, Xyl-6-H), 7.25 (d,
4.2.10. 1-(3-(4-Methylphenoxymethyl)benzyl)piperidine
(15). Synthesized, as described for 4 from 15a (0.51 g,
2.5 mmol) and p-cresol (0.27 g, 2.5 mmol) (34%). 1H
NMR (CF3COOD): d 7.64 (d, J ¼ 7:8 Hz, 1H, Xyl-5-
H), 7.56–7.59 (m, 2H, Xyl-4-H, Xyl-6-H), 7.44 (d,
J ¼ 7:5 Hz, 1H, Xyl-2-H), 7.17 (d, J ¼ 8:4 Hz, 2H, Ph-3-
H, Ph-5-H), 6.96 (d, J ¼ 8:4 Hz, 2H, Ph-2-H, Ph-6-H),
6.75 (br, 1H, Nþ–H), 5.31 (s, 2H, CH2–O), 4.36 (d,
J ¼ 5:3 Hz, 2H, CH2–N), 3.61 (d, J ¼ 12:0 Hz, 2H, Pip-