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D. Zampieri et al. / Bioorg. Med. Chem. 17 (2009) 4693–4707
d 2.43 (s, 3H, CH3), 3.75 (s, 2H, CH2-Ph), 4.77 (s, 2H, N–CH2–N),
7.14–7.40 (m, 4H arom.), 7.71 (d, 2H pyr), 8.77 (d, 2H pyr). MS:
m/z 375 [MH+], 377 [MH++2]. Anal. Calcd for C16H15BrN4O2 (MW
375.22): C, 51.22: H, 4.03; N, 14.93. Found: C, 51.00; H, 3.90; N,
14.98.
5.1.4.1. 5-Phenyl-3-[(piperidin-1-yl)methyl]-1,3,4-oxadiazol-
2(3H)-one (4b). Melting point 132–134 °C; Yield 29%. I.R. (Nujol,
cmꢀ1): 1760. 1H NMR (CDCl3/TMS): d 1.32–1.70 (m, 6H, H3, H4, H5
pip.), 2.74 (t, 4H, H2, H6 pip.), 4.72 (s, 2H, CH2 exocycl.), 7.51 (m, 3H,
arom.), 7.88 (m, 2H, arom.). MS: m/z 260 [MH+]. Anal. Calcd for
C14H17N3O2 (MW 259.30): C, 64.85: H, 6.61; N, 16.20. Found: C,
64.76; H, 6.79; N, 16.40.
5.1.3.8. 3-[[(4-Bromobenzyl)-methyl-amino]methyl]-5-(pyri-
dine-4-yl)-1,3,4-oxadiazol-2(3H)-one (3i). Melting point 234–
236 °C; Yield 46%. I.R. (Nujol, cmꢀ1): 1775. 1H NMR (CDCl3/TMS):
d 2.32 (s, 3H, CH3), 3.73 (s, 2H, CH2-Ph), 4.72 (s, 2H, N–CH2–N),
7.31 (d, 2H, arom), 7.52 (d, 2H, arom.), 7.72 (d, 2H pyr), 8.77 (d,
2H pyr). MS: m/z 375 [MH+], 377 [MH++2]. Anal. Calcd for
C16H15BrN4O2 (MW 375.22): C, 51.22: H, 4.03; N, 14.93. Found: C,
51.40; H, 4.20; N, 15.18.
5.1.4.2. 3-[(2-Methyl-piperidin-1-yl)methyl]-5-phenyl-1,3,4-
oxadiazol-2(3H)-one (4c). Melting point 92–94 °C; Yield 37%. I.R.
(Nujol, cmꢀ1): 1786. 1H NMR (CDCl3/TMS): d 1.15–1.80 (m, 9H, CH3
and H3, H4, H5 pip.), 2.57–3.08 (m, 3H, H2, H6 pip.), 4.70 (d, 1H, Ha
0
0
CH2 exocycl., Ja,a = 14.65 Hz), 5.07 (d, 1H, Ha CH2 exocycl.,
0
Ja ,a = 14.65 Hz), 7.51 (m, 3H, arom.), 7.88 (m, 2H, arom.). MS: m/z
274 [MH+]. Anal. Calcd for C15H19N3O2 (MW 273.33): C, 65.91: H,
5.1.3.9. 3-[[(2-Fluorobenzyl)-methyl-amino]methyl]-5-(pyri-
dine-4-yl)-1,3,4-oxadiazol-2(3H)-one (3j). Melting point 158–
160 °C; Yield 21%. I.R. (Nujol, cmꢀ1): 1773. 1H NMR (CDCl3/TMS):
d 2.44 (s, 3H, CH3), 3.84 (s, 2H, CH2-Ph), 4.80 (s, 2H, N–CH2–N),
7.00–7.47 (m, 4H arom.), 7.71 (d, 2H pyr), 8.77 (d, 2H pyr). MS:
m/z 315 [MH+]. Anal. Calcd for C16H15FN4O2 (MW 314.31): C,
61.14: H, 4.81; N, 17.83. Found: C, 61.12; H, 4.74; N, 17.69.
7.01; N, 15.37. Found: C, 66.12; H, 7.20; N, 15.43.
5.1.4.3. 3-[(3-Methyl-piperidin-1-yl)methyl]-5-phenyl-1,3,4-
oxadiazol-2(3H)-one (4d). Melting point 112–114 °C; Yield 42%.
I.R. (Nujol, cmꢀ1): 1760. 1H NMR (CDCl3/TMS): d 0.90 (d, 3H, CH3),
1.15–1.78 (m, 5H, H3, H4, H5 pip.), 2.07–2.97 (m, 4H, H2, H6 pip.),
4.74 (s, 2H, CH2 exocycl.), 7.51 (m, 3H, arom.), 7.88 (m, 2H, arom.).
MS: m/z 274 [MH+]. Anal. Calcd for C15H19N3O2 (MW 273.33): C,
65.91: H, 7.01; N, 15.37. Found: C, 66.03; H, 7.10; N, 15.33.
5.1.3.10. 3-[[(3-Fluorobenzyl)-methyl-amino]methyl]-5-(pyr-
idine-4-yl)-1,3,4-oxadiazol-2(3H)-one (3k). Melting point 268–
270 °C; Yield 46%. I.R. (Nujol, cmꢀ1): 1750. 1H NMR (CDCl3/
TMS): d 2.48 (s, 3H, CH3), 3.82 (s, 2H, CH2-Ph), 4.85 (s, 2H, N–
CH2–N), 6.99–7.35 (m, 4H arom.), 7.75 (d, 2H pyr), 8.83 (d, 2H
pyr). MS: m/z 315 [MH+]. Anal. Calcd for C16H15FN4O2 (MW
314.31): C, 61.14: H, 4.81; N, 17.83. Found: C, 60.95; H, 4.70; N,
17.77.
5.1.4.4. 3-[(4-Methyl-piperidin-1-yl)methyl]-5-phenyl-1,3,4-
oxadiazol-2(3H)-one (4e). Melting point 104–106 °C; Yield 39%.
I.R. (Nujol, cmꢀ1): 1768. 1H NMR (CDCl3/TMS): d 0.93 (d, 3H,
CH3), 1.15–1.67 (m, 5H, H3, H4, H5 pip.), 2.47–3.03 (m, 4H, H2, H6
pip.), 4.72 (s, 2H, CH2 exocycl.), 7.50 (m, 3H, arom.), 7.88 (m, 2H,
arom.). MS: m/z 274 [MH+]. Anal. Calcd for C15H19N3O2 (MW
273.33): C, 65.91: H, 7.01; N, 15.37. Found: C, 65.84; H, 6.88; N,
15.45.
5.1.3.11. 3-[[(4-Fluorobenzyl)-methyl-amino]methyl]-5-(pyr-
idine-4-yl)-1,3,4-oxadiazol-2(3H)-one (3l). Melting point 158–
160 °C; Yield 19%. I.R. (Nujol, cmꢀ1): 1783. 1H NMR (CDCl3/TMS):
d 2.42 (s, 3H, CH3), 3.74 (s, 2H, CH2-Ph), 4.76 (s, 2H, N–CH2–N),
6.95–7.34 (m, 4H arom.), 7.70 (d, 2H pyr), 8.77 (d, 2H pyr). MS:
m/z 315 [MH+]. Anal. Calcd for C16H15FN4O2 (MW 314.31): C,
61.14: H, 4.81; N, 17.83. Found: C, 61.38; H, 4.98; N, 18.09.
5.1.4.5. 3-[(Piperidin-1-yl)methyl]-5-pyridin-2-yl-1,3,4-oxa-
diazol-2(3H)-one (4g). Melting point 102–104 °C; Yield 44%. I.R.
(Nujol, cmꢀ1): 1767. 1H NMR (CDCl3/TMS): d 1.32–1.65 (m, 6H,
H3, H4, H5 pip.), 2.74–3.10 (m, 4H, H2, H6 pip.), 4.78 (s, 2H, CH2 exo-
cycl.), 7.45 (m, 1H, H3 pyr.), 7.88 (m, 2H, H4 and H5 pyr.), 8,78 (d,
1H, H6 pyr.). MS: m/z 261 [MH+]. Anal. Calcd for C13H16N4O2 (MW
260.29): C, 65.91: H, 7.01; N, 15.37. Found: C, 65.93; H, 7.08; N,
15.43.
5.1.3.12. 3-[[(4-Methylbenzyl)-methyl-amino]methyl]-5-(pyri-
dine-4-yl)-1,3,4-oxadiazol-2(3H)-one (3m). Melting point 236–
238 °C; Yield 26%. I.R. (Nujol, cmꢀ1): 1780. 1H NMR (CDCl3/TMS):
d 2.46 (s, 3H, CH3-Ph), 2.56 (s, 3H, CH3–N), 3.90 (s, 2H, CH2-Ph),
4.94 (s, 2H, N–CH2–N), 7.27 (d, 2H arom.), 7.37 (d, 2H arom.),
7.75 (d, 2H pyr), 8.91 (d, 2H pyr). MS: m/z 311 [MH+]. Anal. Calcd
for C17H18N4O2 (MW 310.35): C, 65.79: H, 5.85; N, 18.05. Found:
C, 65.77; H, 5.80; N, 18.05.
5.1.4.6. 3-[(2-Methyl-piperidin-1-yl)methyl]-5-pyridin-2-yl-
1,3,4-oxadiazol-2(3H)-one (4h). Melting point 86–88 °C; Yield
47%. I.R. (Nujol, cmꢀ1): 1770. 1H NMR (CDCl3/TMS): d 1.03–1.80
(m, 9H, CH3 and H3, H4, H5 pip.), 2.56–3.13 (m, 3H, H2, H6 pip.),
0
0
4.72 (d, 1H, Ha CH2 exocycl., Ja,a = 14.65), 5.12 (d, 1H, Ha CH2 exo-
cycl., Ja’,a = 14.65), 7.45 (m, 1H, H3 pyr.), 7.88 (m, 2H, H4 e H5 pyr.),
8,77 (d, 1H, H6 pyr.). MS: m/z 275 [MH+]. Anal. Calcd for
C14H18N4O2 (MW 274.32): C, 61.30: H, 6.61; N, 20.42. Found: C,
61.43; H, 6.78; N, 20.55.
5.1.3.13. 3-[[(1-Naphtalen-1-yl)-methyl-amino]methyl]-5-(pyr-
idine-4-yl)-1,3,4-oxadiazol-2(3H)-one (3n). Melting point 139–
140 °C; Yield 36%. I.R. (Nujol, cmꢀ1): 1780. 1H NMR (CDCl3/TMS):
d 2.49 (s, 3H, CH3-napht.), 4.19 (s, 2H, CH2-napht.), 4.84 (s 2H,
N–CH2–N), 7.37–7.86 (m, 9H arom. + napht.), 8.87 (d, 2H pyr).
MS: m/z 347 [MH+]. Anal. Calcd for C20H18N4O2 (MW 346.38): C,
69.35: H, 5.24; N, 16.17. Found: C, 69.30; H, 5.10; N, 16.05.
5.1.4.7. 3-[(3-Methyl-piperidin-1-yl)methyl]-5-pyridin-2-yl-
1,3,4-oxadiazol-2(3H)-one (4i). Melting point 98–100 °C; Yield
37%. I.R. (Nujol, cmꢀ1): 1763. 1H NMR (CDCl3/TMS): 0.88 (d, 3H,
CH3), 1.47–1.80 (m, 5H, H3, H4 and H5 pip.), 2.08–3.00 (m, 4H,
H2, H6 pip.), 4.79 (s, 2H, CH2 exocycl.), 7.45 (m, 1H, H3 pyr.), 7.88
(m, 2H, H4 and H5 pyr.), 8,78 (d, 1H, H6 pyr.). MS: m/z 275 [MH+].
Anal. Calcd for C14H18N4O2 (MW 274.32): C, 61.30: H, 6.61; N,
20.42. Found: C, 61.56; H, 6.87; N, 20.32.
5.1.4. General procedure for the synthesis of compounds 4b–n
To an ethanolic solution of 5-aryl-3H-1,3,4-oxadiazol-2-one 3a,
4a, 4f, 4k and 4p (6.1 mmol), unsubstituted or methyl-substituted
piperidine (6.1 mmol) were added. To the stirred solution, formal-
dehyde (aq 37%, 6.1 mmol) was added dropwise. After addition, the
solution was heated under reflux for 24 h. Thereafter, the reaction
mixture was cooled at room temperature and the precipitate
formed was filtered off and recrystallized from appropriate solvent
(Table 2).
5.1.4.8. 3-[(4-Methyl-piperidin-1-yl)methyl]-5-pyridin-2-yl-
1,3,4-oxadiazol-2(3H)-one (4j). Melting point 121–122 °C; Yield
40%. I.R. (Nujol, cmꢀ1): 1766. 1H NMR (CDCl3/TMS): 0.91 (d, 3H,
CH3), 1.10–1.35 (m, 3H, H3–H4–H5 pip.), 1.66–3.05 (m, 6H, H2, H3,