phenylurea

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: By the procedure of Example 4, 8.2 g (60 mmol) of phenyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 6.2 g of crystal product (m.p.=114°-116° C.) identified in Table I. washed with water dried concentrated The residue was recrystallized from methylcyclohexane

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

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

Procedure: In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with phenylurea (100 mg, 0.734 mmol, 1 equivalent), potassium phosphate (234 mg, 1.10 mmol, 1.5 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (6.7 mg, 0.00734 mmol, 0.01 equivalents) and phosphine ligand (0.029 mmol, 0.04 equivalents). Then 1,2-dimethoxyethane (1.34 mL) was syringed into the vial. After stirring the mixture for 1 hour at room temperature, 4-chlorotoluene (96 μL, 0.808 mmol, 1.1 equivalents) was added. The vial was sealed with a crimp top and placed in a heating block at 85° C. After 15 hours, the reaction vial was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with dimethylformamide (0.6 mL) and stirred for 15 minutes. The slurry was then filtered through a pad of diatomaceous earth. The vial was rinsed with dimethylformamide (0.6 mL) before passing through the filter. The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil. A 1:1 mixture of methanol:water (3.5 mL) was added dropwise to the crude concentrate, leading to the precipitation of product. The solids were collected by filtration and washed with 1:1 methanol:water (3 mL). The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg. (literature reference: Kotecki B J, et al. Org. Lett. 2009; 11: 947-950). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (t, J=22.7 Hz, 2H), 7.42 (dd, J=8.5, 1.0 Hz, 2H), 7.31 (t, J=5.4 Hz, 2H), 7.26 (dd, J=10.7, 5.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 6.95 (dd, J=10.5, 4.2 Hz, 1H), 2.24 (s, 3H). In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar The vial was sealed with a crimp top placed in a heating block at 85° C After 15 hours the reaction vial was cooled to room temperature stirred for 15 minutes The slurry was then filtered through a pad of diatomaceous earth The vial was rinsed with dimethylformamide (0.6 mL) The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil concentrate leading to the precipitation of product The solids were collected by filtration washed with 1:1 methanol The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg

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

Procedure: In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with phenylurea (100 mg, 0.734 mmol, 1 equivalent), potassium phosphate (234 mg, 1.10 mmol, 1.5 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (6.7 mg, 0.00734 mmol, 0.01 equivalents) and phosphine ligand (0.029 mmol, 0.04 equivalents). Then 1,2-dimethoxyethane (1.34 mL) was syringed into the vial. After stirring the mixture for 1 hour at room temperature, 4-chlorotoluene (96 μL, 0.808 mmol, 1.1 equivalents) was added. The vial was sealed with a crimp top and placed in a heating block at 85° C. After 15 hours, the reaction vial was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with dimethylformamide (0.6 mL) and stirred for 15 minutes. The slurry was then filtered through a pad of diatomaceous earth. The vial was rinsed with dimethylformamide (0.6 mL) before passing through the filter. The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil. A 1:1 mixture of methanol:water (3.5 mL) was added dropwise to the crude concentrate, leading to the precipitation of product. The solids were collected by filtration and washed with 1:1 methanol:water (3 mL). The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg. (literature reference: Kotecki B J, et al. Org. Lett. 2009; 11: 947-950). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (t, J=22.7 Hz, 2H), 7.42 (dd, J=8.5, 1.0 Hz, 2H), 7.31 (t, J=5.4 Hz, 2H), 7.26 (dd, J=10.7, 5.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 6.95 (dd, J=10.5, 4.2 Hz, 1H), 2.24 (s, 3H). In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar The vial was sealed with a crimp top placed in a heating block at 85° C After 15 hours the reaction vial was cooled to room temperature stirred for 15 minutes The slurry was then filtered through a pad of diatomaceous earth The vial was rinsed with dimethylformamide (0.6 mL) The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil concentrate leading to the precipitation of product The solids were collected by filtration washed with 1:1 methanol The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg

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

Procedure: A solution of 1-phenylurea (2.0 g, 14.69 mmol) and ethyl 3-bromo-2-oxopropanoate (2.16 ml, 14.69 mmol) in DMF (58 ml) was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to rt and quenched with water (300 ml)/Na2CO3-solution (50 ml). The product was extracted with EA (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude product. Purification by flash-chromatography (Silica gel 62 g, gradient: cyclohexane/EA (80 ml/min.) from 95/5 (5 min.) to 80/20 (25 min.)) afforded the title compound. HPLC (Method U): RtU=1.91 min, MS (Method D) [M+H]+=233.1. quenched with water (300 ml)/Na2CO3-solution (50 ml) The product was extracted with EA (2×) The combined organic phases were washed with brine dried over Na2SO4 filtered evaporated under reduced pressure to afford crude product Purification by flash-chromatography (Silica gel 62 g, gradient: cyclohexane/EA (80 ml/min.) from 95/5 (5 min.) to 80/20 (25 min.))

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

Procedure: A solution of 1-phenylurea (2.0 g, 14.69 mmol) and ethyl 3-bromo-2-oxopropanoate (2.16 ml, 14.69 mmol) in DMF (58 ml) was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to rt and quenched with water (300 ml)/Na2CO3-solution (50 ml). The product was extracted with EA (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude product. Purification by flash-chromatography (Silica gel 62 g, gradient: cyclohexane/EA (80 ml/min.) from 95/5 (5 min.) to 80/20 (25 min.)) afforded the title compound. HPLC (Method U): RtU=1.91 min, MS (Method D) [M+H]+=233.1. quenched with water (300 ml)/Na2CO3-solution (50 ml) The product was extracted with EA (2×) The combined organic phases were washed with brine dried over Na2SO4 filtered evaporated under reduced pressure to afford crude product Purification by flash-chromatography (Silica gel 62 g, gradient: cyclohexane/EA (80 ml/min.) from 95/5 (5 min.) to 80/20 (25 min.))

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

Procedure: In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with phenylurea (100 mg, 0.734 mmol, 1 equivalent), potassium phosphate (234 mg, 1.10 mmol, 1.5 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (6.7 mg, 0.00734 mmol, 0.01 equivalents) and phosphine ligand (0.029 mmol, 0.04 equivalents). Then 1,2-dimethoxyethane (1.34 mL) was syringed into the vial. After stirring the mixture for 1 hour at room temperature, 4-chlorotoluene (96 μL, 0.808 mmol, 1.1 equivalents) was added. The vial was sealed with a crimp top and placed in a heating block at 85° C. After 15 hours, the reaction vial was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with dimethylformamide (0.6 mL) and stirred for 15 minutes. The slurry was then filtered through a pad of diatomaceous earth. The vial was rinsed with dimethylformamide (0.6 mL) before passing through the filter. The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil. A 1:1 mixture of methanol:water (3.5 mL) was added dropwise to the crude concentrate, leading to the precipitation of product. The solids were collected by filtration and washed with 1:1 methanol:water (3 mL). The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg. (literature reference: Kotecki B J, et al. Org. Lett. 2009; 11: 947-950). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (t, J=22.7 Hz, 2H), 7.42 (dd, J=8.5, 1.0 Hz, 2H), 7.31 (t, J=5.4 Hz, 2H), 7.26 (dd, J=10.7, 5.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 6.95 (dd, J=10.5, 4.2 Hz, 1H), 2.24 (s, 3H). In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar The vial was sealed with a crimp top placed in a heating block at 85° C After 15 hours the reaction vial was cooled to room temperature stirred for 15 minutes The slurry was then filtered through a pad of diatomaceous earth The vial was rinsed with dimethylformamide (0.6 mL) The combined filtrate was concentrated on a rotary evaporator to furnish an orange oil concentrate leading to the precipitation of product The solids were collected by filtration washed with 1:1 methanol The isolated product urea was dried in a vacuum oven for 6 hours at 60° C./150 mm Hg

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

Procedure: Phenyl isocyanate (1.19 g, 0.01 mol) and N-methyl-4-methylbenzene sulfonamide (1.85 g, 0.01 mol) were dissolved in 1,2-dichlorobenzene (20 ml) and refluxed for 40 hrs. After cooling, the solvent was evaporated in vacuo to give a viscous oil that crystallized on standing to give N-methyl-N-4-methylphenyl-N*-phenyl urea mp 63–65° C. MS m/z 304. (M+ calcd for C15H16N2O3S=304). H NMR (300 Mhz, CDCl3) d 2.43 (s, 3, CH3), 2.65 (s, 3, CH3), 7.33 (m, 5, aromatic), 7.48 (m, 1, aromatic), 7.75 (m, 3, aromatic). refluxed for 40 hrs After cooling the solvent was evaporated in vacuo to give a viscous oil that crystallized

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

Procedure: Phenyl isocyanate (1.19 g, 0.01 mol) and N-methyl-4-methylbenzene sulfonamide (1.85 g, 0.01 mol) were dissolved in 1,2-dichlorobenzene (20 ml) and refluxed for 40 hrs. After cooling, the solvent was evaporated in vacuo to give a viscous oil that crystallized on standing to give N-methyl-N-4-methylphenyl-N*-phenyl urea mp 63–65° C. MS m/z 304. (M+ calcd for C15H16N2O3S=304). H NMR (300 Mhz, CDCl3) d 2.43 (s, 3, CH3), 2.65 (s, 3, CH3), 7.33 (m, 5, aromatic), 7.48 (m, 1, aromatic), 7.75 (m, 3, aromatic). refluxed for 40 hrs After cooling the solvent was evaporated in vacuo to give a viscous oil that crystallized