Synthesis of Ethyl 2-(2-(2-Ethoxyethoxy)ethoxy)propanoate

In a 300-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, 6.60 g, 165 mmol) and THF (50
mL) were added, respectively. The reaction mixture was cooled to 0
°C, and 18-crown-6 (3.96 g, 15.0 mmol) in THF (20 mL) and ethyl
2-hydroxypropanoate (19 mL, 165 mmol) in THF (35 mL) were added to
this reaction mixture. The mixture was stirred for 1 h at 0 °C;
then, butane-1,4-diyl bis(4-methylbenzenesulfonate) 2a (29.9 g, 75.0 mmol) within THF (55 mL) was added to the reaction
mixture. The reaction mixture was warmed to reflux and stirred for
6 h. The pH was adjusted to 7 with 2 M H₂SO₄ solution to quench the reaction. The whole mixture was extracted
with diethyl ether (5 × 10 mL). The combined organic phases were
washed with brine (20 mL), dried (with Na₂SO₄), and concentrated in vacuo to give a crude product. The crude product
was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate = 2:1) to give the title compound 3a (7.81 g, 36%). Yellow oil; ¹H NMR (500 MHz,
CDCl₃) δ 4.25–4.17 (m, 4H), 3.99–3.89
(m, 2H), 3.63–3.57 (m, 2H), 3.44–3.36 (m, 2H), 1.73–1.67
(m, 4H), 1.41–1.37 (m, 6H), 1.32–1.27 (m, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ
173.6, 75.0, 69.9, 69.9, 60.7, 26.3, 26.3, 18.6, 14.2; IR (neat) 2984,
2939, 2906, 2873, 1746, 1448, 1372, 1269, 1197, 1147, 1122, 755 cm^–1; HRMS (EI) m/z:
[M-C₃H₅O₂]⁺ calcd for
C₁₁H₂₁O₄ 217.1440, found 217.1439.