methanethioamide

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

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

Procedure: To a stirred solution of phosphorus pentasulfide (8.6 g, 19.3 mmol) in dioxane (53 ml) was added formamide (5.2 g, 115.5 mmol), and the mixture was heated at reflux temperature for 2 hours. The mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (3.02 g, 12.98 mmol) in dioxane (50 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3) to give title compound (2.11 g, 83% yield). the mixture was heated at reflux temperature for 2 hours the solution was decanted away from solids the mixture was heated at reflux temperature for 6 hours The mixture was cooled down to room temperature The whole was extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3)

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

Procedure: To a stirred solution of phosphorus pentasulfide (4.0 g, 9.0 mmol) in dioxane (40 ml) was added formamide (4.8 g, 106 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (1.2 g, 5.15 mmol) in dioxane (14 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (864 mg, 86% yield). the mixture was heated at reflux temperature for 2 hours the solution was decanted away from solids the mixture was heated at reflux temperature for 6 hours The reaction mixture was cooled down to room temperature The whole was extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4)

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

Procedure: To a stirred solution of phosphorus pentasulfide (24.5 g, 55 mmol) in dioxane (250 ml) was added formamide (28.4 g, 630 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2,4′-dibromoacetophenone (15 g, 54 mmol) in dioxane (100 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with CH2Cl2 to give title compound (12.3 g, 95% yield). the mixture was heated at reflux temperature for 2 hours the solution was decanted away from solids the mixture was heated at reflux temperature for 6 hours The reaction mixture was cooled down to room temperature The whole was extracted with diethyl ether The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography eluting with CH2Cl2

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

Procedure: To a stirred solution of phosphorus pentasulfide (4.0 g, 9.0 mmol) in dioxane (40 ml) was added formamide (4.8 g, 106 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (1.2 g, 5.15 mmol) in dioxane (14 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-exane (1:4) to give title compound (864 mg, 86% yield). the mixture was heated at reflux temperature for 2 hours the solution was decanted away from solids the mixture was heated at reflux temperature for 6 hours The reaction mixture was cooled down to room temperature The whole was extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography eluting with ethyl acetate-exane (1:4)

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

Procedure: To a stirred solution of phosphorus pentasulfide (6.0 g, 13.5 mmol) in dioxane (60 ml) was added formamide (7.2 g, 160 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone from step 1 (2.4 g, 10.5 mmol) in dioxane (20 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (1.54 g, 77% yield). the mixture was heated at reflux temperature for 2 hours the solution was decanted away from solids the mixture was heated at reflux temperature for 6 hours The reaction mixture was cooled down to room temperature The whole was extracted with ethyl acetate The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the epimeric bromoaldehydes) (2.34 g) and thioformamide (0.3 g) in dry tetrahydrofuran (23 cc) is stirred for 3 hours at 20° and then heated for 90 minutes at 50° C. The reaction mixture is diluted with ethyl acetate (160 cc) and washed with a saturated solution of sodium bicarbonate (100 cc) and then with a semi-saturated solution of sodium chloride (100 cc). After drying of the organic layer over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue obtained is subjected to chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.8 bar (80 kPa) with a 70/30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 16 to 25, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., and the residue is triturated in isopropyl ether (50 cc). After filtration and drying, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.85 g) is obtained in the form of a cream-coloured solid. washed with a saturated solution of sodium bicarbonate (100 cc) After drying of the organic layer over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C. the residue obtained is subjected to chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.8 bar (80 kPa) with a 70/30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected Fractions 16 to 25, containing the pure product concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. the residue is triturated in isopropyl ether (50 cc) After filtration drying

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

Procedure: o-(Bromoacetyl)phenyl acetate (5.0 g, 19.5 mmol) was treated with crude thioformamide (filtrate concentrated in vacuo from reaction of P2S5 (1.1 eq.) and (25 mmol) formamide in THF (30-40° C., 5 hours)) in refluxing acetone (60 mL). After 16 hours the reaction mixture was cooled to about 10° C. and the precipitated HBr salt of 2-(thiazol-4-yl)phenol was recovered. 31%, 1.50 g, LSIMS m/z=178 (MH+). the precipitated HBr salt of 2-(thiazol-4-yl)phenol was recovered

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

Procedure: To a solution of the above compound [36a] (40.3 g, 144.1 mmol) in MeCN (160 ml) are added CaCO3 (28 g, 280 mmol, 1.9 eq) and thioformamide (HCSNH2, 14 g, 229.1 mmol, 1.6 eq) and the mixture is stirred at room temperature for 18 hours under nitrogen atmosphere. Insoluble materials are filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in dichloromethane, subsequently washed with 7% aqueous sodium bicarbonate, 1N NaOH, and water, two times each, to remove non-reacted thioformamide. The dichloromethane layer is dried over MgSO4, concentrated to dryness in vacuo, and subjected to silica gel chromatography (SiO2 : 370 g, MeCN:CH2Cl2 =1:7) to obtain (4-thiazolyl)alanine derivative [37a] (29.15 g, 71%) as an oil. Insoluble materials are filtered off the filtrate is concentrated to dryness in vacuo The residue is dissolved in dichloromethane subsequently washed with 7% aqueous sodium bicarbonate, 1N NaOH, and water, two times each, to remove non-reacted thioformamide The dichloromethane layer is dried over MgSO4 concentrated to dryness in vacuo

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

Procedure: A mixture of 1.8 g (5.2 mmol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 0.34 g (5.5 mmol) of thioformamide, and 10 ml of dimethylformamide was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was triturated with acetonitrile. The resulting precipitate was collected by filtration, washed with acetonitrile, and dried to afford 1.74 g (85%) of 2-guanidino-4-(4-thiazolyl)thiazole dihydrobromide. Th:s was dissolved in 10 ml of water, and 1 ml of saturated sodium bicarbonate solution was added. The resulting precipitate was collected by filtration, washed well with water, then acetonitrile, then dried in vacuo to afford 1.17 g of 2-guanidino-4-(4-thiazoyl)thiazole as a white solid, mp 220°-222°; nmr (DMSO-d6) (δ): 8.96 (s, 1H); 7.96 (s, 1H); 7.18 (s, 1H); 7.0 (b, 4H); calcd. for C7H7N5S2 : C, 37.32; H, 3.13; N, 31.09; found: 36.94; H, 3.52; N, 29.74. The mixture was concentrated the residue was triturated with acetonitrile The resulting precipitate was collected by filtration washed with acetonitrile dried

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

Procedure: A mixture of 1.8 g (5.2 mmol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 0.34 g (5.5 mmol) of thioformamide, and 10 ml of dimethylformamide was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was triturated with acetonitrile. The resulting precipitate was collected by filtration, washed with acetonitrile, and dried to afford 1.74 g (85%) of 2-guanidino-4-(4-thiazolyl)thiazole dihydrobromide. Th:s was dissolved in 10 ml of water, and 1 ml of saturated sodium bicarbonate solution was added. The resulting precipitate was collected by filtration, washed well with water, then acetonitrile, then dried in vacuo to afford 1.17 g of 2-guanidino-4-(4-thiazoyl)thiazole as a white solid, mp 220°-222°; nmr (DMSO-d6) (δ): 8.96 (s, 1H); 7.96 (s, 1H); 7.18 (s, 1H); 7.0 (b, 4H); calcd. for C7H7N5S2 : C, 37.32; H, 3.13; N, 31.09; found: 36.94; H, 3.52; N, 29.74. The mixture was concentrated the residue was triturated with acetonitrile The resulting precipitate was collected by filtration washed with acetonitrile dried

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

Procedure: Freshly prepared thioformamide (Helv. Chim. Acta, 31, 2065, 1948) (160 mg) was added to a solution of (α-bromoketone from Step 2 (200 mg) in THF (5 mL) and the reaction mixture was stirred at r.t. for 2 h. Ethyl acetate was then added and the organic phase was washed with saturated aqueous NH4Cl, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (65:35) afforded the title compound as a white solid. the organic phase was washed with saturated aqueous NH4Cl, H2O and brine dried (MgSO4) evaporated