Uses
Diethyl bis(hydroxymethyl)malonate is used as a reagent for preparing 1,3-dioxanes from acetals, aldehydes and ketones. It is also used as an intermediate for the preparation of substituted malonic, acrylic and isobutyric esters, for conversion to the useful dienophiles, -bromomethylacrylic acid and its ethyl ester and to bis(bromomethyl)acetic acid and its methyl ester.
Synthesis
A 35% aqueous formaldehyde solution (16.07 mL, 187.3 mmol, 3.0 eq.) was mixed with potassium bicarbonate (0.53 g, 5.27 mmol, 0.08 eq.) in a 20 °C water bath. Diethyl malonate (10.00 g, 62.43 mmol, 1.0 eq.) was added slowly and the reaction mixture was stirred overnight. After completion of the reaction, saturated sodium sulfate solution was added and the product was extracted with ether. The organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product diethyl 2,2-bis(hydroxymethyl)malonate (13.79 g, 100%) as a clear colorless oil. The product could be used in the next reaction without further purification. Thin layer chromatography (TLC) Rf value was 0.31 (unfolding agent: 50% ethyl acetate/hexane). IR spectrum (neat, cm-1): 3433 (O-H), 2982 (C-H), 1790 (C=O), 1209, 1028. 1H NMR (300 MHz, CDCl3): δ 4.22 (q, 4H, J = 6.7 Hz, 2 × OCH2CH3), 4.09-4.04 (m, 4H, 2 × CH2OH), and 2.99 (s, 2H, 2 × OH), 1.25 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.24 (t, 3H, J = 7.1 Hz, OCH2CH3).13C NMR (75 MHz, CDCl3): δ 169.58, 63.54, 61.97, 61.21, 14.04.
References
[1] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 671 - 690
[2] Synthesis, 1997, # 11, p. 1281 - 1284
[3] Patent: WO2014/110388, 2014, A1. Location in patent: Page/Page column 21; 22
[4] Tetrahedron, 1991, vol. 47, # 6, p. 1001 - 1012
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 5, p. 1675 - 1692
