dimethyloxonio(trifluoro)boranuide

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

Procedure: To a solution of sodium borohydride (0.78 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride dimethyl etherate (8.78 ml) with stirring under ice-cooling and the solution was stirred at the same temperature for 10 minutes. To this solution was added (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.53 g) and the mixture was stirred at ambient temperature for 4 hours. To the reaction mixture was added methanol (5 ml) and the mixture was filtered. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in methanol (30 ml). To the solution was added 10% hydrogen chloride-methanol solution (10 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran (30 ml) and water (15 ml). To the solution was added a solution of potassium cyanate (3.83 g) in water (10 ml) and the mixture was stirred at 50°-60° C. for 30 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-(2-ureidoethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.73 g). cooling the solution was stirred at the same temperature for 10 minutes the mixture was stirred at ambient temperature for 4 hours the mixture was filtered The filtrate was evaporated in vacuo to give a residue The reaction mixture was evaporated in vacuo to give a residue the mixture was stirred at 50°-60° C. for 30 minutes The reaction mixture was evaporated in vacuo The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 The fractions containing the desired compound were collected evaporated in vacuo

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

Procedure: To a solution of sodium borohydride (0.78 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride dimethyl etherate (8.78 ml) with stirring under ice-cooling and the solution was stirred at the same temperature for 10 minutes. To this solution was added (2S, 4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.53 g) and the mixture was stirred at ambient temperature for 4 hours. To the reaction mixture was added methanol (5 ml) and the mixture was filtered. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in methanol (30 ml). To the solution was added 10% hydrogen chloride-methanol solution (10 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran (30 ml) and water (15 ml). To the solution was added a solution of potassium cyanate (3.83 g) in water (10 ml) and the mixture was stirred at 50°-60° C. for 30 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S, 4R)-2-(2-ureidoethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.73 g). cooling the solution was stirred at the same temperature for 10 minutes the mixture was stirred at ambient temperature for 4 hours the mixture was filtered The filtrate was evaporated in vacuo to give a residue The reaction mixture was evaporated in vacuo to give a residue the mixture was stirred at 50°-60° C. for 30 minutes The reaction mixture was evaporated in vacuo The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 The fractions containing the desired compound were collected evaporated in vacuo

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

Procedure: To a solution of sodium borohydride (0.78 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride dimethyl etherate (8.78 ml) with stirring under ice-cooling and the solution was stirred at the same temperature for 10 minutes. To this solution was added (2S, 4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.53 g) and the mixture was stirred at ambient temperature for 4 hours. To the reaction mixture was added methanol (5 ml) and the mixture was filtered. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in methanol (30 ml). To the solution was added 10% hydrogen chloride-methanol solution (10 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran (30 ml) and water (15 ml). To the solution was added a solution of potassium cyanate (3.83 g) in water (10 ml) and the mixture was stirred at 50°-60° C. for 30 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S, 4R)-2-(2-ureidoethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.73 g). cooling the solution was stirred at the same temperature for 10 minutes the mixture was stirred at ambient temperature for 4 hours the mixture was filtered The filtrate was evaporated in vacuo to give a residue The reaction mixture was evaporated in vacuo to give a residue the mixture was stirred at 50°-60° C. for 30 minutes The reaction mixture was evaporated in vacuo The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 The fractions containing the desired compound were collected evaporated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-chloro-pyrazine-2-carboxylic acid (10.00 g, 63.07 mmol) in tetrahydrofuran (126 mL) was treated with a solution of tert-butyl 2,2,2-trichloroacetimidate (23 mL, 126.14 mmol) in cyclohexane (126 mL). The reaction was stirred at 25° C. for 5 min and then was treated with boron trifluoride dimethyl etherate (3.2 mL, 25.23 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h and then was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 1/9 ethyl acetate/hexanes) afforded 5-chloro-pyrazine-2-carboxylic acid tert-butyl ester (12.73 g, 94%) as a colorless oil: EI-HRMS m/e calcd for C9H11ClN2O2 (M+) 214.0502, found 214.0510. The resulting reaction mixture was stirred at 25° C. for 16 h washed with a saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL) dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of sodium borohydride (0.78 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride dimethyl etherate (8.78 ml) with stirring under ice-cooling and the solution was stirred at the same temperature for 10 minutes. To this solution was added (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.53 g) and the mixture was stirred at ambient temperature for 4 hours. To the reaction mixture was added methanol (5 ml) and the mixture was filtered. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in methanol (30 ml). To the solution was added 10% hydrogen chloride-methanol solution (10 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran (30 ml) and water (15 ml). To the solution was added a solution of potassium cyanate (3.83 g) in water (10 ml) and the mixture was stirred at 50°-60° C. for 30 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-(2-ureidoethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.73 g). cooling the solution was stirred at the same temperature for 10 minutes the mixture was stirred at ambient temperature for 4 hours the mixture was filtered The filtrate was evaporated in vacuo to give a residue The reaction mixture was evaporated in vacuo to give a residue the mixture was stirred at 50°-60° C. for 30 minutes The reaction mixture was evaporated in vacuo The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 The fractions containing the desired compound were collected evaporated in vacuo

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

Procedure: To a solution of sodium borohydride (0.78 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride dimethyl etherate (8.78 ml) with stirring under ice-cooling and the solution was stirred at the same temperature for 10 minutes. To this solution was added (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.53 g) and the mixture was stirred at ambient temperature for 4 hours. To the reaction mixture was added methanol (5 ml) and the mixture was filtered. The filtrate was evaporated in vacuo to give a residue. The residue was dissolved in methanol (30 ml). To the solution was added 10% hydrogen chloride-methanol solution (10 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of tetrahydrofuran (30 ml) and water (15 ml). To the solution was added a solution of potassium cyanate (3.83 g) in water (10 ml) and the mixture was stirred at 50°-60° C. for 30 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-(2-ureidoethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.73 g). cooling the solution was stirred at the same temperature for 10 minutes the mixture was stirred at ambient temperature for 4 hours the mixture was filtered The filtrate was evaporated in vacuo to give a residue The reaction mixture was evaporated in vacuo to give a residue the mixture was stirred at 50°-60° C. for 30 minutes The reaction mixture was evaporated in vacuo The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 The fractions containing the desired compound were collected evaporated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CuBr2.SMe2 (19.13 g, 93.1 mmol) was placed into a flame-dried flask along with THF (250 ml). The mixture was cooled to −78° C. and ethylmagnesium bromide (31 ml, 3.0 M in ether, 93.1 mmol) was added slowly. The reaction was stirred for 45 minutes under nitrogen. Boron trifluoride dimethyl etherate was added (11.7 ml, 93,1 mmol) and the mixture stirred for 5 minutes. Ethyl 1-(4-chlorophenylsulfonyl)-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate (103; 8.0 g, 23.3 mmol) was added via syringe pump over a 2 hour period while maintaining −78° C. bath temperature. The reaction was stirred for 4 hours and quenched with a 1:1 solution of 2% NH4Cl/NH4OH. An equal amount of EtOAc and water was added and the mixture was filtered to remove solids. The layers were separated and the aqueous layer was extracted with two more portions of EtOAc. The organic layers were combined and dried over Na2SO4 and concentrated to yield a colorless oil (7.74 g). The material was purified by column chromatography using EtOAc/hexanes gradients to yield 5.84 g (67%) of a mixture of cis/trans (4:96) isomers. the mixture stirred for 5 minutes while maintaining −78° C. bath temperature The reaction was stirred for 4 hours quenched with a 1:1 solution of 2% NH4Cl/NH4OH An equal amount of EtOAc and water was added the mixture was filtered to remove solids The layers were separated the aqueous layer was extracted with two more portions of EtOAc dried over Na2SO4 concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CuBr.SMe2 complex (1.49 g, 7.26 mmol) was added to 25 mL of anhydrous THF and cooled to −78° C. 4-Chlorophenylmagnesium bromide (7.26 mL, 1.0 M in THF, 7.26 mmol) was added slowly via syringe. Stirring at −78° C. for 1 hour produced an orange then green-like suspension. Boron trifluoride dimethyl etherate (0.92 mL, 7.26 mmol) was added and stirred for 5 minutes. To the newly formed complex was then added over 1 hour a solution of the compound 66 (1.0 g, 4.32 mmol) in 15 mL of anhydrous THF. After stirring 2 hours at −78° C., 16 mL of aq. 20% NH4Cl/conc. NH4OH (1:1) was added, and the mixture was allowed to warm-up to room temperature. EtOAc was used to extract (3×100 mL) and the combined organic layers were washed with brine and dried (MgSO4). Solvent was removed by rotary evaporation and the residue was purified by flash chromatography to give the product 67 as a colorless oil. produced an orange then green-like suspension stirred for 5 minutes After stirring 2 hours at −78° C. to warm-up to room temperature to extract (3×100 mL) the combined organic layers were washed with brine dried (MgSO4) Solvent was removed by rotary evaporation the residue was purified by flash chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CuBr2.SMe2 (19.13 g, 93.1 mmol) was placed into a flame-dried flask along with THF (250 ml). The mixture was cooled to −78° C. and ethylmagnesium bromide (31 ml, 3.0 M in ether, 93.1 mmol) was added slowly. The reaction was stirred for 45 minutes under nitrogen. Boron trifluoride dimethyl etherate was added (11.7 ml, 93,1 mmol) and the mixture stirred for 5 minutes. Ethyl 1-(4-chlorophenylsulfonyl)-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate (103; 8.0 g, 23.3 mmol) was added via syringe pump over a 2 hour period while maintaining −78° C. bath temperature. The reaction was stirred for 4 hours and quenched with a 1:1 solution of 2% NH4Cl/NH4OH. An equal amount of EtOAc and water was added and the mixture was filtered to remove solids. The layers were separated and the aqueous layer was extracted with two more portions of EtOAc. The organic layers were combined and dried over Na2SO4 and concentrated to yield a colorless oil (7.74 g). The material was purified by column chromatography using EtOAc/hexanes gradients to yield 5.84 g (67%) of a mixture of cis/trans (4:96) isomers. the mixture stirred for 5 minutes while maintaining −78° C. bath temperature The reaction was stirred for 4 hours quenched with a 1:1 solution of 2% NH4Cl/NH4OH An equal amount of EtOAc and water was added the mixture was filtered to remove solids The layers were separated the aqueous layer was extracted with two more portions of EtOAc dried over Na2SO4 concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CuBr.SMe2 complex (1.49 g, 7.26 mmol) was added to 25 mL of anhydrous THF and cooled to −78° C. 4-Chlorophenylmagnesium bromide (7.26 mL, 1.0 M in THF, 7.26 mmol) was added slowly via syringe. Stirring at −78° C. for 1 hour produced an orange then green-like suspension. Boron trifluoride dimethyl etherate (0.92 mL, 7.26 mmol) was added and stirred for 5 minutes. To the newly formed complex was then added over 1 hour a solution of the compound 66 (1.0 g, 4.32 mmol) in 15 mL of anhydrous THF. After stirring 2 hours at −78° C., 16 mL of aq. 20% NH4Cl/conc. NH4OH (1:1) was added, and the mixture was allowed to warm-up to room temperature. EtOAc was used to extract (3×100 mL) and the combined organic layers were washed with brine and dried (MgSO4). Solvent was removed by rotary evaporation and the residue was purified by flash chromatography to give the product 67 as a colorless oil. produced an orange then green-like suspension stirred for 5 minutes After stirring 2 hours at −78° C. to warm-up to room temperature to extract (3×100 mL) the combined organic layers were washed with brine dried (MgSO4) Solvent was removed by rotary evaporation the residue was purified by flash chromatography

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

Procedure: To a solution/suspension of 3-(4-chloro-2-methoxyphenylthio)propanoic acid (1.46 g, 5.92 mmol; see step (ii) above) in dichloromethane (50 mL) under N2(g) was added boron trifluoride dimethyl etherate (1.4 mL, 15 mmol) and trifluoroacetic anhydride (2.1 mL, 15 mmol). After 2.5 h at rt the reaction was quenched with water (2 mL), then washed with more water. The deep green colour disappeared when it was further washed with sat. aq. sodium hydrogencarbonate. Drying (MgSO4) and removal of the solvent in vacuo afforded the sub-title compound as a yellow solid. After 2.5 h at rt the reaction was quenched with water (2 mL) washed with more water was further washed with sat. aq. sodium hydrogencarbonate Drying (MgSO4) and removal of the solvent in vacuo

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

Procedure: A solution of tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A4) (5.0 g, 15.8 mmol), (S)-1-phenylethanamine (3.0 ml, 23.8 mmol) and boron trifluoride dimethyl etherate (0.5 ml, 5 mmol) in dry toluene (150 ml) was heated at 140° C. under a Dean-Stark trap for 24 hours. The solvent was distilled and the residue was cooled with an ice bath, dissolved in ethyl acetate, washed with saturated NaHCO3, and water. The organic phase was dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-(1-phenylethylimino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B1) as a gum. LC-MS analysis of the crude indicated that there is trace of starting material (A4). LC-MS: m/e=419.37 (M+H). Rt=2.24 min. The solvent was distilled the residue was cooled with an ice bath dissolved in ethyl acetate washed with saturated NaHCO3, and water The organic phase was dried over Na2SO4 filtered concentrated