Synthesis of Nonanic Acid Derivative

In a 200-mL two-necked round-bottomed
flask equipped
with a magnetic stirring bar, a rubber septum and an argon balloon,
NaH (60% dispersion in mineral oil, 6.24 g, 156 mmol), and THF (30
mL) were added, respectively. The reaction mixture was stirred, and
nonane-1,9-diol (4.17 g, 26.0 mmol) in THF (30 mL) was added. The
reaction mixture was warmed to reflux and stirred for 12 h. Then,
the reaction mixture was cooled to 0 °C, and 2-bromohexanoic
acid 5a (7.63 mL, 54.6 mmol) was added slowly to this
reaction mixture. The reaction mixture was warmed to reflux and stirred
for 48 h. After the reaction, the reaction mixture was cooled to 0
°C and ice water (100 mL) was added to quench the reaction. The
whole mixture was extracted with 1 M NaOH (5 × 10 mL). Then,
the pH was adjusted to 1 with 2 M H₂SO₄ solution.
The whole mixture was extracted with diethyl ether (5 × 10 mL).
The combined organic phases were washed with H₂O (20 mL),
dried (with Na₂SO₄), and concentrated in vacuo
to give a crude product. In a 100-mL one-necked round-bottomed flask
equipped with a magnetic stirring bar and a rubber septum, crude product,
EtOH (20 mL), and MeSNa aq (15 wt %, 20 mL) were added, respectively.
The reaction mixture was warmed to 40 °C and stirred for 24 h.
After the reaction, the reaction mixture was concentrated in vacuo,
and the pH was adjusted to 1 with 2 M H₂SO₄ solution.
The whole mixture was extracted with diethyl ether (5 × 10 mL).
The combined organic phases were washed with H₂O (20 mL),
dried (with Na₂SO₄), and concentrated in vacuo
to give the crude product. The crude product was purified by flash
column chromatography on silica gel (n-hexane/ethyl
acetate/acetic acid = 7:3:0.1) to give the title compound 7d (5.41 g, 54%). Colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 11.13 (brs, 2H), 3.86 (dd, J =
4.9, 7.6 Hz, 2H), 3.66–3.58 (m, 2H), 3.39 (t, J = 7.6 Hz, 1H), 3.37 (t, J = 7.6 Hz, 1H), 1.83–1.73
(m, 4H), 1.65–1.57 (m, 4H), 1.46–1.28 (m, 18H), 0.91
(t, J = 7.2 Hz, 6H); ¹³C{¹H}
NMR (126 MHz, CDCl₃) δ 178.8, 78.6, 70.9, 32.3, 29.5,
29.3, 29.1, 27.2, 25.8, 22.2, 13.7; IR (neat) 3451, 3146, 2931, 2859,
1721, 1467, 1335, 1284, 1208, 1130, 1102, 987, 730 cm^–1; HRMS (EI) m/z: [M-CHO₂]⁺ calcd for C₂₀H₃₉O₄ 343.2848, found 343.2850.