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HETEROCYCLES, Vol. 96, No. 4, 2018
silica gel chromatography (eluent EtOAc:n-hexane, 2:98 → 40:60). IR (NaCl) cm−1: 2975, 1739, 1612,
1510, 1436, 1383, 1356. 1H-NMR (CDCl3) δ: 1.31 (6H, d, J=6.0 Hz), 1.46 (3H, s), 2.87–3.00 (3H, m),
3.56 (3H, s), 3.96–4.06 (4H, m), 4.45–4.54 (1H, m), 6.78 (2H, d, J=8.8 Hz), 7.05 (2H, d, J=8.5 Hz).
13C-NMR (CDCl3) δ: 21.7 (q), 22.1 (q×2), 33.3 (t), 51.6 (q), 56.7 (d), 64.86 (t), 64.92 (t), 69.8 (d), 109.4
(s), 115.9 (d×2), 129.6 (d×2), 131.1 (s), 156.4 (s), 172.6 (s). HRMS (ESI) m/z: 309.1705 [M+H]+ (Calcd
for C17H25O5: 309.1697).
3-[(4-Isopropoxyphenyl)methyl]-2-(2-methyl-1,3-dioxolan-2-yl)propionic acid (14). A mixture of
crude product 18 from the preceding step and a 25 w/v% aqueous solution of NaOH (14 mL, 89.7 mmol)
in MeOH (19 g) was refluxed for 7 h. After this time, the reaction mixture was concentrated under
reduced pressure, and the resulting residue was dissolved in H2O (57 g) and MTBE (95 g). Following
separation of the aqueous and organic layers, the aqueous layer was washed with MTBE (95 g), while
MTBE (95 g) and 2 M HCl (37 mL) were added to the aqueous layer, and the layers were separated once
again. The organic layer was then washed with a 10% aqueous solution of NaCl (57 g) and dried over
anhydrous MgSO4. The filtrate was concentrated under reduced pressure to provide 14 as a colorless oil
(15.2 g, 85% yield from 16). IR (NaCl) cm−1: 2977, 2936, 2893, 1737, 1711, 1611, 1508, 1448, 1383,
1334. 1H-NMR (CDCl3) δ: 1.31 (6H, d, J=6.0 Hz), 1.47 (3H, s), 2.88–3.00 (3H, m), 3.97–4.07 (4H, m),
4.45–4.54 (1H, m), 6.78 (2H, d, J=8.5 Hz), 7.08 (2H, d, J=8.5 Hz). 13C-NMR (CDCl3) δ: 21.8 (q), 22.1
(q×2), 33.0 (t), 56.6 (d), 64.89 (t), 64.94 (t), 69.8 (d), 109.3 (s), 115.9 (d×2), 129.7 (d×2), 130.8 (s), 156.5
(s), 177.3 (s). HRMS (ESI) m/z: 295.1546 [M+H]+ (Calcd for C16H23O5: 295.1540).
Nʹ-Isopropyl-3-[(4isopropoxyphenyl)methyl]-2-(2-methyl-1,3-dioxolan-2-yl)propanohydrazide (19).
Thionyl chloride (6.79 g, 57.1 mmol) was added dropwise to a mixture of imidazole (7.76 g, 114 mmol)
and pyridine (9.02 g, 114 mmol) in THF (150 g) while maintaining the temperature between 0 and 10 °C
and the reaction mixture stirred for 1 h at 5 °C. Subsequently, a solution of 14 (15.2 g, 51.6 mmol) in
THF (60 g) was added dropwise to the reaction mixture, and stirring continued for 1 h at room
temperature.
After this time, DMF (31 g), Et3N (10.5 g, 104 mmol), and isopropylhydrazine
hydrochloride (8.61 g, 77.9 mmol) were added successively to the reaction mixture, and stirring
continued for 6 h at 80 °C. The reaction mixture was then cooled to room temperature and used directly
in the next step without further purification. An analytical sample of 19 was obtained as a colorless
solid by purification using silica gel column chromatography (eluent EtOAc:n-hexane, 40:60 → 100:0).
mp 104–106 °C. IR(KBr) cm−1: 3298, 2977, 1635, 1613, 1512, 1381, 1251, 1209, 1121, 1050.
1H-NMR (CDCl3) δ: 0.85 (3H, d, J=6.2 Hz), 0.95 (3H, d, J=6.2 Hz), 1.30 (6H, d, J=6.1 Hz), 1.42 (3H, s),
2.54 (1H, dd, J=3.2, 11.6 Hz), 2.87–3.05 (3H, m), 3.94–4.05 (4H, m), 4.43–4.52 (1H, m), 6.76 (2H, d,