Methyl3,4-dichlorophenylacetate

clear colorless liquid

A solution of triphenylphosphine (11.90 g, 45.41 mmol) and imidazole (6.18 g, 90.82 mmol) in methylene chloride (80 mL) cooled to 0° C. was slowly treated with iodine (11.53 g, 45.41 mmol) followed by the dropwise addition of a solution of (tetrahydro-furan-2-yl)-methanol (4.0 mL, 41.28 mmol) in methylene chloride (5 mL). The resulting reaction mixture was allowed to warm to 25° C., where it was stirred for 4 h. The reaction mixture was then diluted with water (25 mL), and the reaction mixture was further extracted with methylene chloride (3.x.20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 25° C. The resulting solid was washed with pentane (4.x.50 mL) and filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 pentane/ether) afforded 2-iodomethyl-tetrahydro-furan (2.09 g, 25percent) as a clear, colorless liquid: EI-HRMS m/e calcd for C5H9IO (M+) 211.9698, found 211.9708. [0133] A solution of (3, 4-dichloro-phenyl)-acetic acid (14.0 g, 0.07 mol) in methanol (71 mL) was treated with a catalytic amount of concentrated sulfuric acid. The reaction mixture was heated under reflux for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3, 4-dichloro-phenyl)-acetic acid methyl ester (15.0 g, quant.) as a white solid: mp 30-32° C.; EI-HRMS m/e calcd for C9H8Cl2O2 (M+) 217.9901, found 217.9907. [0134] A solution of diisopropylamine (0.59 mL, 4.51 mmol) in tetrahydrofuran (30 mL) was cooled to -78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (1.8 mL, 4.51 mmol). The reaction mixture was stirred at -78° C. for 15 min, after which time, a solution of (3, 4-dichloro-phenyl)-acetic acid methyl ester (825 mg, 3.76 mmol) in tetrahydrofuran (3 mL) and 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2(1H)-pyrimidinone (1 mL) was slowly added via a cannula. The bright yellow solution was allowed to stir at -78° C. for 1 h, after which time, a solution of 2-iodomethyl-tetrahydro-furan (798 mg, 3.76 mmol) in 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added via a cannula. The reaction mixture was stirred at -78° C. for 1 h and then allowed to warm to 25° C., where it was stirred for 14 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3.x.20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3, 4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (501 mg, 44percent) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2O3 (M+) 302.0477, found 302.0464. [0135] A solution of 2-(3, 4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (617 mg, 2.04 mmol), methylurea (302 mg, 4.07 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. percent, 4.63 mL, 3.06 mmol) was heated at 100° C. for 8 h. After this time, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (50 mL), and then filtered through a pad of silica gel. The organics were then concentrated in vacuo to give the crude product. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[2-(3, 4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionyl]-3-methyl-urea as a white solid: EI-HRMS m/e calcd for C15H18Cl2N2O3 (M+) 344.0694, found 344.0699.REFERENCE SYNTHETIC General procedure: Thionyl chloride (1.06 mL, 14.63 mmol) was added to dropwise the solution of phenyl aceticacid derivatives (1 g, 4.877 mmol) in methanol (10 mL) at 0 . The reaction was allowed to room temperature for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved ethyl acetate and water. The mixture was extracted with ethyl acetate and washed with sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6a-f.

Molecular Weight:219.06
XLogP3:3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:217.9901349
Monoisotopic Mass:217.9901349
Topological Polar Surface Area:26.3
Heavy Atom Count:13
Complexity:185
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes