Potassium Carbonate → HCID 178502978, compound

Participants

Reaction Conditions

Reaction Steps

To a slurry of methyl 3-oxy-2-dimethylphosphonoacrylate sodium salt (4.1 g, 0.017 mol) in anhydrous DMSO (25 mL) under nitrogen is added methyl iodide (4.5 g, 0.031 mol), and the reaction mixture stirred for 18 hours at ambient temperature. The mixture is poured into dilute sodium chloride solution and extracted with CH2Cl2 (6×75 mL). The extracts are washed with water (100 mL), dried (MgSO4), filtered and concentrated in vacuo to afford a brown oil (5.5 g). Partial separation by chromatography on silica gel (EtOAc) of half the crude product afforded pure E-isomer (0.27 g); a mixture of the E- and Z-isomers (0.75 g); and pure Z-isomer (0.14 g). The E- and Z-products are isolated in 52% overall yield. Methyl (E)-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (E-isomer). 1H NMR (300 MHz, CDCl3): δ 7.55 (d, JH-P=10.8 Hz, 1H), 4.06 (s, 3H), 3.78 (d, JH-P=2.7 Hz, 6H), 3.75 (s, 3H). 31P NMR (121 MHz, CDCl3) δ 20.74. Methyl (Z)-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (Z-isomer). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, JH-P=31.8 Hz, 1H), 4.03 (s, 3H), 3.78 (d, JH-P=5.1 Hz, 6H), 3.75 (s, 3H). 31P NMR (121 MHz, CDCl3) δ 15.50. A mixture of crude methyl-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (6.9 g, 0.030 mol), 4-chlorophenylhydrazine hydrochloride (5.4 g, 0.030 mol), and methanol (40 mL) is heated and held at reflux under nitrogen for one hour. TLC (EtOAc) of an aliquot shows that the methyl-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate is consumed. After cooling to 45° C., water (15 mL) is added, followed by potassium carbonate (4.1 g, 0.030 mol). This mixture is heated and held at 65° C. for one hour. TLC of an aliquot shows complete conversion to product. The reaction mixture is cooled to 25° C., and further worked up as described for Method A, to afford compound 3a as a red-amber solid (5.90 g, 65%). 1H and 31P NMR spectra indicated 90% assay product, which results in a net 58% yield.

Provenance & Evidence