iodomethyl benzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Title compound was prepared according to the procedure described in: Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett. 2004, 6, 3225. To a 10° C. solution of zinc (dust) (0.604 g, 9.24 mmol) in THF (1.7 mL) was added a solution of iodomethyl benzoate Part A (1.21 g, 4.62 mmol) in THF (2.1 mL) and the reaction was stirred at 10° C. 1.5 h. Reaction monitored by LCMS by observing the formation of hydrolyzed product (methyl benzoate). Material was used in the next step without purification as a 0.9 M THF solution. 1.5 h Reaction Material was used in the next step without purification as a 0.9 M THF solution

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Zinc (4.81 g, 73.6 mmol) was suspended in THF (6 mL), treated with 1,2-dibromoethane (0.313 mL, 3.63 mmol) and the resulting mixture was heated at 60° C. under argon for 30 minutes. The reaction mixture was allowed to cool to room temperature, treated with trimethylchlorosilane (0.120 mL, 0.938 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of iodomethyl benzoate (Intermediate 23, 3.15 g, 12.02 mmol) in THF (6 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. This reaction mixture was added to a solution of 4,6-dichloropyrimidine (1.075 g, 7.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.695 g, 0.601 mmol) in THF (11 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was filtered through celite, diluted with saturated ammonium chloride solution and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and isohexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow solid (394 mg); to cool to room temperature the resulting mixture was stirred at room temperature for 1 hour the resulting mixture was stirred at room temperature under argon for 18 hours The reaction mixture was filtered through celite diluted with saturated ammonium chloride solution extracted with ethyl acetate (×2) dried under magnesium sulfate evaporated under reduced pressure The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and isohexane Product containing fractions evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloromethyl benzoate (2.87 g, 16.82 mmol) was dissolved in acetonitrile (20 mL) and treated portionwise with sodium iodide (5.04 g, 33.6 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (3.15 g); extracted with ethyl acetate (×2) dried under magnesium sulfate evaporated under reduced pressure The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane Product containing fractions evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloromethyl benzoate (2.87 g, 16.82 mmol) was dissolved in acetonitrile (20 mL) and treated portionwise with sodium iodide (5.04 g, 33.6 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (3.15 g); extracted with ethyl acetate (×2) dried under magnesium sulfate evaporated under reduced pressure The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane Product containing fractions evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloromethyl benzoate (2.87 g, 16.82 mmol) was dissolved in acetonitrile (20 mL) and treated portionwise with sodium iodide (5.04 g, 33.6 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (3.15 g); extracted with ethyl acetate (×2) dried under magnesium sulfate evaporated under reduced pressure The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane Product containing fractions evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, to a suspension of zinc powder (7.5 g) in THF (50 mL) were added dibromoethane (200 μL) and trimethylsilylchloride (200 μL), and then a solution of iodomethyl benzoate (15 g) in THF (50 mL) was added thereto, followed by stirring at room temperature for 1 hour. Then, a solution of 7-chloro-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (10.9 g) in THF (50 mL) and Pd(PPh3)4 (4.25 g) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. To the residue was added a 1 M aqueous NH4Cl solution, followed by extraction with EtOAc. To the organic layer were added MgSO4 and basic silica gel, followed by stirring, filtrating, and then concentrating under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl benzoate (13.8 g). by stirring at room temperature for 15 hours The reaction mixture was filtered through Celite concentrated under reduced pressure To the residue was added a 1 M aqueous NH4Cl solution followed by extraction with EtOAc To the organic layer were added MgSO4 and basic silica gel by stirring filtrating concentrating under reduced pressure The residue was purified by silica gel column (hexane/EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of pentachlorophenyl (E)-3-[4-[bis(4-fluorobenzoyloxymethoxyphosphinyl)difluoromethyl]phenyl]-but-2-enoate (6b1 R1=4-Fluorobenzoyloxymethyl) NaOH (80 mg, 2.0 mmol) in 2 mL of H2O was added dropwise to a stirred suspension of pentachlorophenyl (E)-3-(4-phosphonyldifluoromethyphenyl) but-2-enoate (500 mg, 0.92 mmol) in 5 mL of H2O. When the mixture became clear (pH˜9), AgNO3 (510 mg, 3.0 mmol) was added. After 2 h at 4° C. the gray precipitate was collected by filtration, dried over P2O5 in vacuo, and pulverized in a mortar and pestle. The powder (400 mg) was suspended in dry toluene (10 mL) and iodomethyl 4-fluorobenzoate (290 mg, 1.03 mmol) was added and stirred for 48 h at room temperature. After filtration the solvent was removed in vacuo and the crude product was purified by silica gel column chromatography eluting with 30% EtOAc-hexanes to give colorless oil. Yield 290 mg, (61%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 5.87 (m, 4H), 6.3 (s, 1H), 7.01 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.94 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 18.3, 82.5, 82.8, 115.0, 115.7, 116.1, 124.5, 126.7, 127.9, 131.4, 132.0, 132.7, 132.9, 144.2, 161.6, 163.6, 164.7, 168.1. HRMS (M+H) calc, 844.9272; found, 844.9278. was added After 2 h at 4° C. the gray precipitate was collected by filtration dried over P2O5 in vacuo After filtration the solvent was removed in vacuo the crude product was purified by silica gel column chromatography eluting with 30% EtOAc-hexanes to give colorless oil

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Title compound was prepared according to the procedure described in: Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett. 2004, 6, 3225. To a 10° C. solution of zinc (dust) (0.604 g, 9.24 mmol) in THF (1.7 mL) was added a solution of iodomethyl benzoate Part A (1.21 g, 4.62 mmol) in THF (2.1 mL) and the reaction was stirred at 10° C. 1.5 h. Reaction monitored by LCMS by observing the formation of hydrolyzed product (methyl benzoate). Material was used in the next step without purification as a 0.9 M THF solution. 1.5 h Reaction Material was used in the next step without purification as a 0.9 M THF solution