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4.1.2.11. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(3,4-dimethox-
yphenyl)-1,2,4-oxadiazole (7k). White solid. Yield: 36%, m.p.
125e126 ꢀC. 1H NMR (CDCl3, 300 MHz): dH ¼ 7.85 (1H, dd, J ¼ 8.4,
2.0 Hz), 7.77 (1H, dd, J ¼ 8.4, 2.0 Hz), 7.69 (2H, dd, J ¼ 7.8, 1.9 Hz),
7.00 (2H, dd, J ¼ 10.5, 8.5 Hz), 4.97e4.91 (1H, m), 4.03 (3H, s), 4.00
(3H, s), 3.93 (3H, s), 2.01e1.85 (6H, m), 1.68e1.60 (2H, m). MS (ESI,
m/z): 419.5 (M þ Na)þ.
111.21, 68.81, 56.02, 42.26, 31.52, 31.16, 25.63, 19.19, 13.86. MS (ESI,
m/z): 332.1 (M þ H)þ.
4.1.3.4. 3-(4-Cyclopentyloxy-3-methoxyphenyl)-5-(piperidin-4-yl)-
1,2,4-oxadiazole (8d). White solid. Yield: 83%, m.p. 110e112 ꢀC. 1H
NMR (CDCl3, 200 MHz): dH ¼ 7.62 (1H, dd, J ¼ 8.00, 2.00 Hz), 7.54
(1H, d, J ¼ 2.00 Hz), 6.92 (1H, d, J ¼ 8.00 Hz), 4.86e4.78 (1H, m),
3.91 (3H, s), 3.37e3.32 (6H, m), 2.94e2.81 (2H, m), 2.17e2.00 (2H,
m), 1.97e1.62 (8H, m). 13C NMR (CDCl3, 100 MHz) dC ¼ 180.85,
168.13, 150.36, 149.98, 120.77, 118.92, 114.07, 110.42, 80.44, 56.14,
44.72, 33.99, 32.85, 29.05, 24.14. MS (ESI, m/z): 344.1 (M þ H)þ.
4.1.2.12. 5-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-1,2,4-oxa-
diazole (7l). Off white solid. Yield: 31%, m.p. 149e150 ꢀC. 1H NMR
(CDCl3, 300 MHz): dH ¼ 8.18 (2H, d, J ¼ 8.9 Hz), 7.41 (2H, d,
J ¼ 10.1 Hz), 7.05 (2H, d, J ¼ 8.9 Hz), 3.98e3.88 (12H, m). 13C NMR
(CDCl3, 100 MHz) dC ¼ 175.56, 168.64, 163.21, 153.53, 140.45, 130.10,
129.25, 124.35, 122.36, 116.79, 114.50, 104.62, 60.97, 56.31, 55.53. MS
(ESI, m/z): 365.4 (M þ Na)þ.
4.1.3.5. 5-(Piperidin-4-yl)-3-(3,4,5-trimethoxyphenyl)-1,2,4-oxadia-
zole (8e). White solid. Yield: 79%, m.p. 175e176 ꢀC. 1H NMR (CDCl3,
400 MHz): dH ¼ 9.70 (1H, s(br)), 7.33 (2H, s), 3.96 (6H, s), 3.93 (3H, s),
3.55e3.13 (4H, m), 2.44e2.05 (5H, m). MS (ESI, m/z): 320.5
(M þ H)þ.
4.1.2.13. 5-(3,4-Dimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-1,2,4-
oxadiazole (7m). White solid. Yield: 29%, m.p. 158e159 ꢀC. 1H NMR
(CDCl3, 300 MHz): dH ¼ 7.87 (1H, dd, J ¼ 8.4, 2.0 Hz), 7.70 (1H, d,
J ¼ 1.9 Hz), 7.43 (2H, s), 7.03 (1H, d, J ¼ 8.5 Hz), 4.04 (3H, s), 4.00 (9H,
s), 3.94 (3H, s). 13C NMR (CDCl3, 100 MHz) dC ¼ 175.61, 168.71, 153.55,
152.92, 149.30, 140.50, 122.29, 122.16, 116.80, 111.11, 110.50, 104.67,
60.97, 56.34, 56.22, 56.12. MS (ESI, m/z): 395.4 (M þ Na)þ.
4.1.4. Synthesis of ethyl 4-(3-(3-cyclopentyloxy-4-methoxyphenyl)-
1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (9a)
A solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-5-(piper-
idin-4-yl)-1,2,4-oxadiazole (4) (0.2 mmol) in dry dichloromethane
(5 mL) was cooled to 0 ꢀC and added triethylamine (0.25 mmol)
followed by ethyl chloroformate (0.2 mmol) under nitrogen atmo-
sphere, and the reaction mixture was stirred for 5 h at 30 ꢀC. The
reaction contents were poured into ice-cold water (5 mL) and
extracted with dichloromethane (3 ꢁ 10 mL). The combined
organic phase was washed with brine, dried over anhydrous
sodium sulfate and distilled on a rotary evaporator. The residue so
obtained was purified by flash column chromatography using ethyl
acetateehexane (0e50%) as eluent to afford pure 1,2,4-oxadiazole
9a. White solid. Yield 78%, m.p. 55e56 ꢀC. 1H NMR (CDCl3,
200 MHz): 7.62 (1H, dd, J ¼ 8.0, 2.0 Hz), 7.55 (1H, d, J ¼ 2.0 Hz), 6.92
(1H, d, J ¼ 8.0 Hz), 4.89e4.82 (1H, m), 4.20e4.09 (4H, m), 3.89 (3H,
s), 3.22e2.94 (3H, m), 2.16e1.85 (10H, m), 1.62e1.58 (2H, m), 1.27
(3H, t, J ¼ 6 Hz). MS (ESI, m/z): 416.1 (M þ H)þ.
4.1.2.14. 3,5-Bis(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole (7n). White
solid. Yield: 29%, m.p. 158e159 ꢀC. 1H NMR (CDCl3, 300 MHz):
dH ¼ 7.44 (4H, d, J ¼ 7.44 Hz), 4.02e3.98 (12H, m), 3.97 (3H, s), 3.94
(3H, s). MS (ESI, m/z): 425.4 (M þ Na)þ
4.1.3. General procedure for the synthesis of 3,5-disubstituted-1,2,4-
oxadiazoles 8aee
A solution of appropriate oxadiazole 7 (0.4 mmol) in dry DCM
(2 mL) was cooled to 0 ꢀC and added trifluoroacetic acid (2 mL). The
reaction mixture was then stirred at 25 ꢀC for 6 h. After completion
of the reaction, solvent was distilled off, basified with sodium
bicarbonate and extracted with ethyl acetate (3 ꢁ 20 mL). The
combined organic phase was washed with brine, dried over anhy-
drous sodium sulfate and distilled off on a rotary evaporator to
afford 8 in excellent yield.
4.1.5. Synthesis of 3-(3-cyclopentyloxy-4-methoxyphenyl)-5-(1-
methylsulfonylpiperidin-4-yl)-1,2,4-oxadiazole (9b)
The 1,2,4-oxadiazole 9b was prepared according to the proce-
dure described for 9a except that methanesulfonyl chloride was
used instead of ethyl chloroformate.
4.1.3.1. 3-(3,4-Dimethoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole
(8a). Off white solid. Yield: 84%, m.p. 190e192 ꢀC. 1H NMR (DMSO-
d6, 400 MHz): dH ¼ 9.70 (1H, s(br)), 7.66 (1H, dd, J ¼ 8.32, 1.40 Hz),
7.54 (1H, d, J ¼ 1.48 Hz), 6.98 (1H, d, J ¼ 8.4 Hz), 3.95 (3H, s), 3.94
(3H, s), 3.50e3.36 (3H, m), 3.16e3.01 (2H, m), 2.42e2.39 (2H, m),
2.32e2.24 (2H, m). MS (ESI, m/z): 290.1 (M þ H)þ.
White solid. Yield 72%, m.p. 78e79 ꢀC. 1H NMR (CDCl3,
200 MHz): dH ¼ 7.63 (1H, dd, J ¼ 8.0, 2.0 Hz), 7.55 (1H, d, J ¼ 2.0 Hz),
6.92 (1H, d, J ¼ 8.0 Hz), 4.90e4.82 (1H, m), 3.89 (3H, s), 3.79e3.71
(2H, m), 3.20e2.94 (3H, m), 2.81 (3H, s), 2.26e1.79 (10H, m),
1.62e1.58 (2H, m). 13C NMR (CDCl3, 100 MHz) dC ¼ 180.13, 168.20,
152.62, 147.86, 120.73, 119.04, 113.20, 111.56, 80.60, 56.04, 44.87,
35.26, 33.48, 32.80, 28.77, 24.11. MS (ESI, m/z): 422.1 (M þ H)þ.
4.1.3.2. 3-(3-Ethoxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxa-
diazole (8b). Off white solid. Yield: 78%, m.p. 137e138 ꢀC. 1H NMR
(CDCl3, 400 MHz): dH ¼ 9.70 (1H, s(br)), 7.66 (1H, dd, J ¼ 8.36,
1.88 Hz), 7.56 (1H, d, J ¼ 1.88 Hz), 6.96 (1H, d, J ¼ 8.44 Hz), 4.19 (2H,
q, J ¼ 6.96 Hz), 3.94 (3H, s), 3.52e3.47 (2H, m), 3.37e3.34 (1H, m),
3.21e3.14 (2H, m), 2.46e2.41 (2H, m), 2.36e2.30 (2H, m),1.51 (3H, t,
J ¼ 6.96 Hz). 13C NMR (CDCl3, 100 MHz) dC ¼ 178.90, 168.26, 151.94,
148.55, 120.86, 118.82, 111.26, 111.07, 64.49, 56.00, 42.26, 31.51,
25.66, 14.69. MS (ESI, m/z): 304.1 (M þ H)þ.
4.1.6. Synthesis of t-butyl 4-(2-(3-cyclopentyloxy-4-methoxybenzoyl)
hydrazinecarbonyl)piperidine-1-carboxylate (13)
To a cold (0 ꢀC) solution of 3-cyclopentyloxy-4-methoxybenzoyl
chloride [33] (4 mmol) in dry DMF (5 mL), the t-butyl 4-(hydrazi-
necarbonyl)-piperidine-1-carboxylate (12) [25] (4 mmol) was
added followed by triethylamine (8 mmol). The reaction mixture
was stirred for 5 h at 30 ꢀC and poured into ice cold water, extracted
with ethyl acetate (3 ꢁ 50 mL) and the combined organic phase was
washed with brine solution and dried over anhydrous sodium
sulfate. Ethyl acetate was distilled off and the residue thus obtained
was purified by flash column chromatography using ethyl acetate
as eluent to afford pure 13. White solid. Yield 62%, m.p. 178e179 ꢀC.
1H NMR (CDCl3, 400 MHz): dH ¼ 9.22 (1H, s), 9.08 (1H, s), 7.39e7.36
(2H, m), 6.83 (1H, d, J ¼ 8.92 Hz), 4.81e4.76 (1H, m), 4.15e4.12 (2H,
m), 3.87 (3H, s), 2.77e2.70 (2H, m), 2.48e2.42 (1H, m), 1.98e1.55
4.1.3.3. 3-(3-n-Butoxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-
oxadiazole (8c). White solid. Yield: 86%, m.p. 130e131 ꢀC. 1H NMR
(CDCl3, 400 MHz): dH ¼ 9.70 (1H, s(br)), 7.66 (1H, dd, J ¼ 8.40,
1.92 Hz), 7.55 (1H, d, J ¼ 1.88 Hz), 6.95 (1H, d, J ¼ 8.44 Hz), 4.10 (2H,
t, J ¼ 6.76 Hz), 3.92 (3H, s), 3.52e3.46 (2H, m), 3.36e3.34 (1H, m),
3.20e3.14 (2H, m), 2.46e2.41 (2H, m), 2.36e2.30 (2H, m), 1.90e1.83
(2H, m), 1.55e1.49 (2H, m), 1.00 (3H, t, J ¼ 7.4 Hz). 13C NMR (CDCl3,
100 MHz) dC ¼ 178.87, 168.28, 152.09, 148.83, 120.84, 118.80, 111.37,