To a dry 500 mL round-bottomed flask (equipped with a magnetic stirring bar, reflux condenser tube, and rubber septum) under nitrogen protection was added 7.09 g (60.0 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid (hydroxypivalic acid, HPA) or 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (bis-hydroxypivalic acid, BHPA), and 19.55 g ( 60.0 mmol) of dried and freshly ground cesium carbonate (Cs2CO3). Subsequently 150 mL of anhydrous dimethylformamide (DMF) was added and 0.7-1.0 equivalents (40.0-60.0 mmol) of ethyl iodide was added. The reaction mixture was heated to 50-70 °C (oil bath temperature, depending on the boiling point of the halide) overnight under nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered to remove the precipitate. After the filtrate was neutralized with 1 M hydrochloric acid (HCl) in a small amount, the aqueous phase was extracted with ethyl acetate several times. The organic phases were combined and washed with saturated aqueous sodium bicarbonate (NaHCO3). The organic phase was concentrated under reduced pressure by rotary evaporator and the residue was dissolved in methyl tertiary butyl ether (MTBE). The organic solution is washed five times sequentially with water (to remove residual DMF), washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The product is usually used in the next reaction without further purification or can be purified by subtractive pressure fractionation or silica gel column chromatography (eluent: ethyl acetate/hexane mixture). According to the above method, 4.73 g (40.0 mmol) of 3-hydroxy-2,2-dimethylpropionic acid (HPA) was reacted with 3.23 mL (6.24 g, 40.0 mmol) of ethyl iodide in the presence of 13.03 g (40.0 mmol) of Cs2CO3 in 80 mL of DMF, and after post-processing, 3.40 g (68% yield) of 2-hydroxymethyl ethyl isobutyrate (2) as a yellow liquid without further purification.1H NMR (400 MHz, CDCl3): δ=1.20 (s, 6H), 1.28 (t, J=7.2Hz, 3H), 2.50-2.55 (br.m, 1H), 3.52-3.57 (br.m, 2H), 4.16 (q, J=7.2Hz, 2H ) ppm.
