4-Oxotetrahydrofuran-3-carbonitrile synthesis

Yield: 45.2%

Reaction Conditions:

Stage #1:glycolic acid methyl ester with potassium tert-butylate in tetrahydrofuran at 0; for 0.166667 h;
Stage #2:acrylonitrile in tetrahydrofuran at 20; for 3 h;

Steps:

P108.A
Preparation of 4-oxotetrahydrofuran-3-carbonitrile: To a suspension ofKOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0 °C was added dropwise methyl 2-hydroxyacetate (675.7 μ,, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 μ, 8.881 mmol) was then added and the reaction stirred at ambient temperature. After 3 hours, the reaction was diluted with H₂0 (50 mL), then extracted with Et₂0 (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HCl (5 mL), then extracted with Et₂0 (2 x 50 mL). The combined organic phases were dried with MgS0₄, filtered, and concentrated to afford a light brown oil (446 mg, 45.2% yield). 1H NMR (CDC1₃) δ 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).

References:

ARRAY BIOPHARMA INC.;ALLEN, Shelley;ANDREWS, Steven, W.;BLAKE, James, F.;CONDROSKI, Kevin, R.;HAAS, Julia;HUANG, Lily;JIANG, Yutong;KERCHER, Timothy;KOLAKOWSKI, Gabrielle R.;SEO, Jeongbeob WO2012/158413, 2012, A2 Location in patent:Page/Page column 101