Ethyl 2-oxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate synthesis

Yield:66979-47-3 50%

Reaction Conditions:

Stage #1: cyclohexanonewith lithium diisopropyl amide in tetrahydrofuran at -78 - -5; for 2 h;
Stage #2: diethyl 2-ethoxymethylenemalonate in tetrahydrofuran at -30 - 25; for 16 h;

Steps:

24

A solution of cyclohexanone (5 g, 1 eq.) in 60 mL of dry THF was added dropwise (over a period of 30 minutes) to a -78°C solution of freshly generated lithium diisopropylamide (31 mL, 1.2 eq.) in 75 mL of dry THF under dry N₂. The resulting mixture was stirred at -78°C to -5°C over 2 hours. After the solution was cooled to -30⁰C, diethyl ethoxymethylene malonate (12.4 mL, 1.2 eq.) in 20 mL of THF was added slowly (over a period of 15 ~ 20 minutes). The mixture was stirred at -30⁰C to 25°C for 16 hours. The solution was then poured onto 100 mL of 5% aqueous HCl and extracted with CH₂CI₂ (5x30 mL). The combined extracts were dried over Na₂SO₄ and concentrated under vacuum. The crude product thus obtained was purified by silica gel column chromatography to give compound 1-28 as a white solid (5.7 g, 50%). ¹H NMR (CDCl₃) δ.7.98 (s, IH), 4.35 (q, J = 6.9 Hz, 2H), 2.60- 2.55 (m, 2H), 2.48-2.44 (m, 2H), 1.84-1.74 (m, 4H), 1.36 (t, J = 7.2 Hz, 3H). ESI-MS (M+H⁺) = 223.

References:

WO2008/95058,2008,A1 Location in patent:Page/Page column 37