Journal of Medicinal Chemistry
Article
EI-MS: m/z = 384 (M+). HRMS (EI): m/z calcd for C19H16N2O5S
384.0780, found 384.0809.
J = 6.7 Hz), 4.60 (2H, s), 6.16 (2H, s), 7.10 (1H, d, J = 8.1 Hz), 7.43
(1H, d, J = 1.6 Hz), 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.54 (2H, d,
J = 8.2 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.42 (1H, t, J = 5.7 Hz). 13C
NMR (DMSO-d6, 125 MHz): δ [ppm] = 20.2, 28.0, 35.4, 46.6, 102.1,
106.1, 109.2, 116.6, 121.8, 127.5, 128.8, 134.1, 139.8, 148.1, 150.5,
162.4, 165.1, 165.8. HPLC: 95%; tR 7.11 min. EI-MS: m/z = 411 (M+).
The following compounds 8d and 9c−e were prepared in a similar
manner to that described for 8c.
3-((5-(Pyridin-4-yl)-1,3,4-oxadiazol-2-ylthio)methyl)-
benzonitrile (7a). Yield 41%, yellow solid. 1H NMR (DMSO-d6,
500 MHz): δ [ppm] = 4.66 (2H, s), 7.58 (1H, t, J = 7.8 Hz), 7.78 (1H,
dt, J = 7.7 Hz, J = 1.3 Hz), 7.86 (1H, t, J = 1.2 Hz), 7.88 (2H, dd, J =
4.4 Hz, J = 1.6 Hz), 7.99 (1H, t, J = 1.4 Hz), 8.82 (2H, dd, J = 4.4 Hz,
J = 1.6 Hz). 13C NMR (DMSO-d6, 125 MHz): δ [ppm] = 34.8, 111.4,
118.5, 120.0, 129.8, 130.0, 131.5, 132.7, 134.0, 138.6, 150.9, 163.8,
164.4. HPLC: 96%; tR 4.51 min. EI-MS: m/z = 294 (M+).
4-((5-(Pyridin-4-yl)-1,3,4-oxadiazol-2-ylthio)methyl)-
benzonitrile (7b). Yield 77%, pale-yellow solid. 1H NMR (DMSO-d6,
500 MHz): δ [ppm] = 4.69 (2H, s), 7.71 (2H, d, J = 8.2 Hz), 7.83
(2H, d, J = 8.2 Hz), 7.88 (2H, dd, J = 4.4 Hz, J = 1.6 Hz), 8.82 (2H,
dd, J = 4.5 Hz, J = 1.5 Hz). 13C NMR (DMSO-d6, 125 MHz): δ [ppm] =
35.2, 110.5, 118.6, 120.0, 130.0, 130.1, 132.4, 142.6, 150.8, 163.9, 164.4.
HPLC: 95%; tR 4.51 min. EI-MS: m/z = 294 (M+).
4-((5-(Benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-ylthio)-
methyl)-N-(2,2-dimethoxyethyl)benzamide (8d). Yield 79%,
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light-yellow solid. H NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.27
(6H, s), 3.33 (2H, br), 4.48 (1H, t, J = 5.6 Hz), 4.61 (2H, s), 6.16 (2H,
s), 7.11 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 1.7 Hz), 7.50 (1H, dd, J =
8.1 Hz, J = 1.7 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1 Hz),
8.52 (1H, t, J = 5.7 Hz). 13C NMR (DMSO-d6, 125 MHz): δ [ppm] =
35.4, 41.1, 53.2, 101.8, 102.2, 106.2, 109.2, 116.6, 121.7, 127.5, 128.9,
133.5, 140.1, 148.1, 150.4, 162.4, 165.1, 166.0. HPLC: 95%; tR 6.07
min. EI-MS: m/z = 443 (M+).
2-(Benzylthio)-5-(pyridin-4-yl)-1,3,4-oxadiazole (7c). Yield
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79%, light-yellow solid. H NMR (DMSO-d6, 500 MHz): δ [ppm] =
4-((5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-
2-ylthio)methyl)-N-isobutyl Benzamide (9c). Yield 92%, light-
brown solid. 1H NMR (DMSO-d6, 500 MHz): δ [ppm] = 0.93 (6H, d,
J = 6.7 Hz), 1.88 (1H, n, J = 6.7 Hz), 3.12 (2H, t, J = 6.6 Hz), 4.37 (2H,
m), 4.39 (2H, m), 4.66 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.45 (1H, d,
J = 2.0 Hz), 7.48 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.60 (2H, d, J = 8.2
Hz), 7.85 (2H, d, J = 8.2 Hz), 8.46 (1H, t, J = 5.7 Hz). 13C NMR
(DMSO-d6, 125 MHz): δ [ppm] = 20.2, 28.1, 35.4, 46.6, 64.1, 64.4,
115.0, 115.8, 118.1, 119.9, 127.4, 128.8, 134.1, 139.7, 143.8, 146.7,
162.4, 164.9, 165.8. HPLC: 96%; tR 7.16 min. EI-MS: m/z = 425 (M+).
4-((5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-
2-ylthio)methyl)-N-(2,2-dimethoxy ethyl)benzamide (9d). Yield
4.62 (2H, s), 7.30 (1H, m), 7.36 (2H, m), 7.50 (2H, m), 7.90 (2H, dd,
J = 4.4 Hz, J = 1.6 Hz), 8.82 (2H, dd, J = 4.4 Hz, 1.6 Hz). 13C NMR
(DMSO-d6, 125 MHz): δ [ppm] = 35.8, 120.0, 127.8, 128.6, 129.1,
130.0, 136.4, 150.8, 163.6, 164.7. HPLC: 100%; tR 4.89 min. EI-MS:
m/z = 269 (M+).
2-(3-Iodobenzylthio)-5-(pyridin-4-yl)-1,3,4-oxadiazole (7d).
7d was used as reference. It is commercially available from Calbiochem
(361541 GSK-3β Inhibitor II; CAS number, 478482-75-6).
4-((5-(Benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-ylthio)-
methyl)benzoic Acid (8a). Methyl 4-((5-(benzo[d][1,3]dioxol-5-
yl)-1,3,4-oxadiazol-2-ylthio)methyl benzoate 5c (300 mg, 0.81 mmol)
was added in 5 mL of a 2 N lithium hydroxide−tetrahydrofuran
solution. The reaction mixture was stirred overnight at 60 °C under an
argon atmosphere. The reaction mixture was diluted with water and
neutralized with 1 N HCl. Afterward, EtOAc was added and the
organic layer was washed with water and brine, dried over MgSO4, and
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84%, beige solid. H NMR (DMSO-d6, 500 MHz): δ [ppm] = 3.28
(6H, s), 3.35 (2H, d, J = 5.7 Hz), 4.31 (2H, m), 4.34 (2H, m), 4.50
(1H, t, J = 5.6 Hz), 4.61 (2H, s), 7.05 (1H, d, J = 8.3 Hz), 7.40 (1H, d,
J = 2.0 Hz), 7.43 (1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.55 (2H, d, J = 8.2
Hz), 7.81 (2H, d, J = 8.2 Hz), 8.52 (1H, t, J = 5.8 Hz). 13C NMR
(DMSO-d6, 125 MHz): δ [ppm] = 35.4, 41.1, 53.2, 64.0, 64.4, 101.8,
115.0, 105.8, 108.2, 119.9, 127.4, 128.8, 133.5, 140.0, 143.8, 146.7,
162.4, 164.9, 165.9. HPLC: 95%; tR 6.13 min. EI-MS: m/z = 457 (M+).
N-Benzyl-4-((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-
oxadiazol-2-ylthio)methyl)benzamide (9e). Yield 89%, beige
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concentrated in vacuo to give 8a (239 mg, 83%) as a rose solid. H
NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.56 (2H, s), 6.08 (2H, s),
7.04 (1H, d, J = 8.1 Hz), 7.35 (1H, d, J = 1.6 Hz), 7.43 (1H, dd, J =
8.1 Hz, J = 1.7 Hz), 7.53 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz),
12.8 (1H, s, br). 13C NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4,
102.1, 106.1, 109.1, 116.6, 121.7, 129.1, 129.5, 130.4, 141.7, 148.1, 150.4,
162.4, 165.1, 166.9. HPLC: 99%; tR 6.15 min. EI-MS: m/z = 356 (M+).
Compound 9a was prepared in a similar manner to that described
for 8a.
Methyl 4-((5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-ox-
adiazol-2-ylthio)methyl)benzoic Acid (9a). Yield 91%, colorless
solid. 1H NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m), 4.34
(2H, m), 4.62 (2H, s), 7.05 (1H, d, J = 8.4 Hz), 7.38 (1H, d, J =
2.0 Hz), 7.43 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.59 (2H, d, J = 8.3 Hz),
7.91 (2H, d, J = 8.3 Hz), 12.95 (1H, s). 13C NMR (DMSO-d6, 125
MHz): δ [ppm] = 35.4, 64.1, 64.4, 115.1, 115.7, 118.2, 119.8, 129.3,
129.5, 130.1, 141.9, 143.8, 146.7, 162.4, 165.0, 166.8. HPLC: 96%;
tR 6.22 min. EI-MS: m/z = 370 (M+).
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solid. H NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.31 (2H, m),
4.34 (2H, m), 4.47 (2H, d, J = 5.9 Hz), 4.62 (2H, s), 7.05 (1H, d, J =
8.4 Hz), 7.23 (1H, m), 7.32 (4H, m), 7.40 (1H, d, J = 2.0 Hz), 7.43
(1H, dd, J = 8.3 Hz, J = 2.0 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.86 (2H, d,
J = 8.2 Hz), 9.01 (1H, t, J = 5.9 Hz). 13C NMR (DMSO-d6,
125 MHz): δ [ppm] = 35.4, 42.6, 64.1, 64.4, 115.1, 115.8, 118.3, 119.8,
126.7, 127.3, 127.5, 128.4, 128.8, 133.7, 139.6, 140.1, 143.8, 146.7,
162.4, 165.0, 165.8. HPLC: 95%; tR 7.66 min. EI-MS: m/z = 459 (M+).
2-(4-(1H-Tetrazol-5-yl)benzylthio)-5-(benzo[d][1,3]dioxol-5-
yl)-1,3,4-oxadiazole (8e). 4-((5-Benzo[d][1,3]dioxol-5-yl)-1,3,4-ox-
adiazol-2-ylthio)methyl)benzonitrile 5b (34 mg, 0.10 mmol), NaN3
(78 mg, 1.20 mmol), and NH4Cl (64 mg, 1.20 mmol) were added to
1 mL of DMF and stirred for 5 h at 100 °C under microwave
irradiation. After cooling to room temperature, the reaction solution
was added to water (2−3 mL), acidified with 2 N HCl, and extracted
three times with ethyl acetate. The combined organic layers were dried
over Na2SO4, filtered, and the solvent evaporated off to provide 8e
4-((5-(Benzo[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-ylthio)-
methyl)-N-isobutylbenzamide (8c). A mixture of 4-((5-(benzo-
[d][1,3]dioxol-5-yl)-1,3,4-oxadiazol-2-ylthio)methyl)benzoic acid 8a
(100 mg, 0.28 mmol) and thionyl chloride (30.5 μL, 0.42 mmol)
was refluxed in dry toluene (1 mL) for about 2 h. Excess thionyl
chloride was removed by repeated evaporation in vacuo with fresh dry
toluene (3 × 1 mL). 2-Methylpropan-1-amine (27.8 μL, 0.28 mmol)
and K2CO3 (38 mg, 0.28 mmol) were added in dry acetone (1 mL)
cooled to 0 °C and stirred for 30 min. The crude acyl chloride was
dissolved in dry acetone (0.5 mL) and added dropwise to the solution.
After the addition was complete, stirring continued for 2 h. The
reaction mixture was then diluted with water, extracted three times
with EtOAc, and successively washed with brine. The organic layer was
dried over MgSO4 and concentrated under reduced pressure. The
obtained residue was recrystallized from EtOH to give 8c (90 mg,
1
(25 mg, 67%) as a beige solid. H NMR (DMSO-d6, 500 MHz): δ
[ppm] = 4.65 (2H, s), 6.15 (2H, s), 7.11 (1H, d, J = 8.1 Hz), 7.43 (1H,
d, J = 1.6 Hz), 7.50 (1H, dd, J = 8.1 Hz, J = 1.7 Hz), 7.71 (2H, d, J =
8.3 Hz), 8.00 (2H, d, J = 8.3 Hz), NH signal was not observed. 13C
NMR (DMSO-d6, 125 MHz): δ [ppm] = 35.4, 102.1, 105.0, 106.2,
108.9, 109.1, 116.6, 119.7, 121.7, 127.1, 130.0, 148.1, 150.4, 162.4,
165.1. HPLC: 96%; tR 5.92 min. EI-MS: m/z = 380 (M+).
Compound 9f was prepared in a similar manner to that described
for 8e.
2-(4-(1H-Tetrazol-5-yl)benzylthio)-5-(2,3-dihydrobenzo[d]-
1
[1,4]dioxin-5-yl)-1,3,4-oxadiazole (9f). Yield 79%, puce solid. H
1
81%) as a beige solid. H NMR (DMSO-d6, 500 MHz): δ [ppm] =
NMR (DMSO-d6, 500 MHz): δ [ppm] = 4.35 (2H, m), 4.38 (2H, m),
4.70 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz),
0.86 (6H, d, J = 6.7 Hz), 1.81 (1H, n, J = 6.7 Hz), 3.05 (2H, t,
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dx.doi.org/10.1021/jm300309a | J. Med. Chem. 2012, 55, 4407−4424