ethyl 2-isothiocyanatoacetate

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

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

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

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

Procedure: A solution of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.0 g, 8.89 mmol) in a tetrahydrofuran/ethanol solution (1:1) is treated with ethyl isothiocyanatoacetate (1.93 g, 13.34 mmol), refluxed for 9 hours, stirred at room temperature overnight, and concentrated in vacuo to obtain an orange-brown gum. Flash column chromatography of the gum using silica gel and 25% to 30% ethyl acetate in hexanes solutions gives the title product as a white foam (2.24 g, 52% yield, mp 95-103° C.) which is identified by 1H, 13C and 19F NMR spectral analyses. refluxed for 9 hours concentrated in vacuo to obtain an orange-brown gum

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

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

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

Procedure: A mixture of ethyl 6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330 mg, 0.94 mmoles), diisopropylethylamine (324 uL, 1.87 mmoles) and ethyl isothiocyanatoacetate (139 uL, 1.12 mmoles) in chloroform (20 mL) was stirred for 7 days. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was purified by flash chromatography (hexane—20% ethyl acetate in hexane) to give the title compound as a clear oil (250 mg, 60%). The diester was dissolved in ethanol (3 mL) and treated with 1 molar sodium hydroxide (2 mL). The mixture was stirred overnight, taken up in ethyl acetate and washed with 1 molar hydrochloric acid (×2), dried and evaporated. Crystallization from acetic acid afforded the title compound (160 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1 H), 12.50 (s, 1 H), 12.03 (br s, 1 H), 4.71 (m, 1 H), 4.35 (d, J=5.05 Hz, 2 H), 3.84 (t, J=7.20 Hz, 2 H), 2.10-2.38 (m, 4 H), 1.80 (d, J=12.63 Hz, 2 H), 1.42-1.71 (m, 7 H), 1.21-1.42 (m, 4 H), 1.01-1.22 (m, 1 H). The mixture was washed with 1 molar hydrochloric acid (×2) dried evaporated The residue was purified by flash chromatography (hexane—20% ethyl acetate in hexane)

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

Procedure: A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg, 2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethyl isothiocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) was stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The solid residue was purified by flash chromatography (dichloromethane) and the fractions evaporated, dissolved in ethanol (5 mL, some heating) and treated with 1 molar sodium hydroxide (3 mL). The mixture was stirred for 30 minutes and acidified to give a solid which recrystallized from ethanol-water to give the title compound (135 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (s, 1 H), 12.54 (t, J=4.80 Hz, 1 H), 4.69 (t, J=12.00 Hz, 2 H), 4.35 (d, J=5.05 Hz, 2 H), 2.25 (q, 4 H), 1.79 (d, J=12.38 Hz, 4 H), 1.63 (d, J=12.38 Hz, 6 H), 1.29 (q, 4 H), 1.13 (q, 2 H). The mixture was washed with 1 molar hydrochloric acid (×2) dried evaporated The solid residue was purified by flash chromatography (dichloromethane) the fractions evaporated dissolved in ethanol (5 mL some heating) and treated with 1 molar sodium hydroxide (3 mL) The mixture was stirred for 30 minutes to give a solid which recrystallized from ethanol-water

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

Procedure: A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg, 2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethyl isothiocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) was stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The solid residue was purified by flash chromatography (dichloromethane) and the fractions evaporated, dissolved in ethanol (5 mL, some heating) and treated with 1 molar sodium hydroxide (3 mL). The mixture was stirred for 30 minutes and acidified to give a solid which recrystallized from ethanol-water to give the title compound (135 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (s, 1 H), 12.54 (t, J=4.80 Hz, 1 H), 4.69 (t, J=12.00 Hz, 2 H), 4.35 (d, J=5.05 Hz, 2 H), 2.25 (q, 4 H), 1.79 (d, J=12.38 Hz, 4 H), 1.63 (d, J=12.38 Hz, 6 H), 1.29 (q, 4 H), 1.13 (q, 2 H). The mixture was washed with 1 molar hydrochloric acid (×2) dried evaporated The solid residue was purified by flash chromatography (dichloromethane) the fractions evaporated dissolved in ethanol (5 mL some heating) and treated with 1 molar sodium hydroxide (3 mL) The mixture was stirred for 30 minutes to give a solid which recrystallized from ethanol-water

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

Procedure: Carbon disulfide (22.8 g., 0.3 mol.) in chloroform (40 ml.) was added over a period of one hour to a stirred suspension of glycine ethyl ester hydrochloride (41.7 g. 0.3 mol.) and triethylamine (60.7 g., 0.6 mol.) in methylene chloride (300 ml.) at -10° C. The reaction mixture was allowed to warm up to 10° C. and was stirred for 10 minutes at this temperature. The mixture was treated dropwise with ethyl chloroformate (32.6 g., 0.3 mol.) in chloroform (50 ml.) at 0°-5° C. over a period of 0.5 hour. The mixture was stirred for another 40 minutes at room temperature and triethylamine (30.4 g., 0.3 mol.) was added dropwise over a period of 15 minutes. The mixture was stirred for 1/4 hour at 0° C. and an additional 1/2 hour at room temperature and finally stored over night at 25° C. The mixture was washed with water (250 ml.), 2N hydrochloric acid (2 × 300 ml.), 5% sodium bicarbonate solution (4 × 300 ml.) and dried over anhydrous sodium sulfate. The solvent was evaporated at 40° C. (15 mm.) to yield 38.1 g. of crude isothiocyanate. Upon storage overnight, a red dye was produced. This may be eliminated by distillation of the isothiocyanate.* The mixture was stirred for another 40 minutes at room temperature The mixture was stirred for 1/4 hour at 0° C. and an additional 1/2 hour at room temperature finally stored over night at 25° C The mixture was washed with water (250 ml.), 2N hydrochloric acid (2 × 300 ml.), 5% sodium bicarbonate solution (4 × 300 ml.) dried over anhydrous sodium sulfate The solvent was evaporated at 40° C. (15 mm.) to yield 38.1 g Upon storage overnight, a red dye was produced This may be eliminated by distillation of the isothiocyanate

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

Procedure: Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), benzoyl isocyanate (0.81 ml, 6.5 mmol).

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

Procedure: Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), benzoyl isocyanate (0.81 ml, 6.5 mmol).