4-chloro-2-isothiocyanato-1-methylbenzene

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:

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 mixture of 5-chloro-2-methylphenyl-isothiocyanate (9.18 g), N-methyl aminooxy acetic acid hydrochloride (7.78 g), triethylamine (20 g) and chloroform (200 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×200 mL) then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness The residue (8 g) was dissolved in benzene (150 mL). Phosphorus pentachloride (7 g) was added in portions. The mixture was heated at reflux for one hour then evaporated to dryness. The residue was dissolved in ethyl acetate (300 mL) and washed with sodium bicarbonate saturated solution (2×200 mL) then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10-20% ethyl acetate in hexane). Crystallization from ethyl acetate/hexane afforded the title compound (2.1 g) as a solid, m.p. 119-121° C. Mass spectrum (El, M.+) m/z 282/284. 1H-NMR (CDCl3; 400 MHz) δ7.32 (d, 1H), 7.23 (d, 1H), 7.13 (s, 1H), 4.81 (ABq, 2H), 4.26 (m, 2H), 2.13 (s, 3H), and 1.40 ppm (t, 3H). was heated at reflux for one hour evaporated to dryness The residue was dissolved in ethyl acetate (400 mL) washed with 2N HCl (2×200 mL) The organic phase was dried over anhydrous magnesium sulfate evaporated to dryness The residue (8 g) was dissolved in benzene (150 mL) Phosphorus pentachloride (7 g) was added in portions The mixture was heated at reflux for one hour then evaporated to dryness The residue was dissolved in ethyl acetate (300 mL) washed with sodium bicarbonate saturated solution (2×200 mL) The organic phase was dried over anhydrous magnesium sulfate evaporated to dryness The residue was chromatographed on silica gel (10-20% ethyl acetate in hexane) Crystallization from ethyl acetate/hexane

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

Procedure: A mixture of 5-chloro-2-methylphenyl-isothiocyanate (36.7 g), N-methyl aminooxy acetic acid hydrochloride (28.3 g), triethylamine (50 g) and chloroform (300 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (700 mL) and washed with 2N HCl (3×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (48 g) of [[[[(5-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a semi solid. 1H-NMR (DMSO-d6; 300 Mhz) δ12.8 (br s, 1H), 10.15 (s, 1H), 7.35-7.20 (m, 3H), 4.62 (s, 2H), 3.56 (s, 3H), and 2.18 ppm (s, 3H). The acid (48 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (42 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10% ethyl acetate in hexane). Crystallization from ethyl acetate/hexane afforded the title compound (18 g) as a solid, m.p. 100-102° C. Mass spectrum (El, M.+) m/z 270/272. 1H-NMR (CDCl3; 400 MHz) δ7.32 (d, 1H), 7.24 (d, 1H), 7.14 (s, 1H), 4.84 (ABq, 2H), 3.74 (s, 3H), and 2.13 ppm (s, 3H). was heated at reflux for one hour evaporated to dryness The residue was dissolved in ethyl acetate (700 mL) washed with 2N HCl (3×300 mL) The organic phase was dried over anhydrous magnesium sulfate evaporated to dryness

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

Procedure: A mixture of N-allyl glycine (17.4 g), 5-chloro-2-methylphenyl-isothiocyanate (20.1 g), triethylamine (20.2 g), and methylene chloride (150 mL) was heated at reflux for 2 hours. The reaction mixture was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Recrystallization from Hexane-EtOAc afford the title compound (4.8 g) as yellow solid, m.p. 106°-109° C. Anal. Calcd. for. C13H13N2O Cl S: C, 55.61; H, 4.67; N, 9.98. Found: C, 55.45; H, 4.56; N, 9.72. Mass spectrum (EI, M.+) m/z 280. was heated at reflux for 2 hours The reaction mixture was evaporated to dryness Purification Recrystallization from Hexane-EtOAc

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

Procedure: A mixture of N-butyl glycine (12.0 g), 5-chloro-2-methylphenyl-isothiocyanate (9.15 g), triethyl amine (12.0 g) and chloroform (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was treated with diethyl ether (400 mL). The mixture was filtered. The solid was washed with diethyl ether then discarded. The filtrate was evaporated to dryness. Crystallization from ethanol afforded the title compound (6.0 g) as a tan solid, m.p. 102°-103° C. Anal. Calcd. for. C14H17Cl N2 O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.41; H, 5.97; N, 9.36. Mass spectrum (EI, M.+) m/z 296/298. was heated at reflux for 5 hours The solvent was evaporated The residue was treated with diethyl ether (400 mL) The mixture was filtered The solid was washed with diethyl ether The filtrate was evaporated to dryness Crystallization from ethanol

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

Procedure: A mixture of the crude N-isopropyl glycine (21.2 g), 5-chloro-2-methylphenyl-isothiocyanate (18.3 g), triethyl amine (21.0 g) and chloroform (300 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 2N HCl (2×300 mL), then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (15.4 g) as a peach solid, m.p. 142°-144° C. Anal. Calcd. for. C13H15Cl N2O S: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.07; H, 5.20; N, 9.82. Mass spectrum (+FAB, [M+H]+) m/z 283/285. was heated at reflux for 4 hours The solvent was evaporated The residue was dissolved in ethyl acetate (400 mL) The organic phase was washed with 2N HCl (2×300 mL) The organic phase was dried over anhydrous magnesium sulfate evaporated to dryness Crystallization from ethanol