8-thiabicyclo[3.2.1]octan-3-one

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

Procedure: N-Chlorosuccinimide (14.0 g, 104.9 mmol) was added in three portions with stirring over 15 min to a cooled (0° C.) solution of 8-thiabicyclo[3.2.1]octan-3-one (16.0 g, 99.9 mmol) in dry benzene (400 mL) under nitrogen. The mixture was stirred for a further 2.5 h and was then filtered. The filtrate was added dropwise with stirring under nitrogen to a cooled (0° C.) solution of isopropylmagnesium bromide (from isopropyl bromide (28.3 g, 229.7 mmol), magnesium (5.7 g, 234.7 mmol) and CuI (1.52 g, 7.9 mmol)) in dry ether (300 mL). The mixture was stirred for a further 15 h and cold (0° C.), dilute hydrochloric acid was added cautiously. The organic layer was separated and washed successively with water, saturated aqueous sodium bicarbonate, and finally with water again. The dried (Na2SO4) ether-benzene solution was evaporated, giving 13.2 g of the title compound. The mixture was stirred for a further 2.5 h was then filtered The filtrate was added dropwise with stirring under nitrogen to The mixture was stirred for a further 15 h The organic layer was separated washed successively with water, saturated aqueous sodium bicarbonate The dried (Na2SO4) ether-benzene solution was evaporated

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

Procedure: Tetrahydrothiopyran-4-one (19.1 g, 150 mmol), ethylene-1,2-diol (11.2 g. 180 mmol), toluene-p-sulfonic acid (0.5 g), and toluene (500 mL) was heated under reflux in a Dean-Stark apparatus for 1.5 h. The toluene was then removed by rotary evaporation, and the residue dissolved in ether and washed, first with 10% aqueous sodium hydroxide and then with water. The organic layer was dried (Na2SO4) and evaporated, and allowed to crystallize by standing in Et2O overnight, giving 24.4 g (93%) of the title compound. under reflux in a Dean-Stark apparatus for 1.5 h The toluene was then removed by rotary evaporation the residue dissolved in ether washed, first with 10% aqueous sodium hydroxide The organic layer was dried (Na2SO4) evaporated to crystallize

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 Å molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%). was cooled to 23° C. The reaction was stirred at 23° C. for 1.5 h quenched by the addition of saturated aqueous sodium bicarbonate The mixture was extracted with dichloromethane the combined organic extracts were dried over sodium sulfate filtered concentrated The crude product was purified by Isco Combiflash, 120 gram column eluting with 0-30% ethyl acetate in hexanes

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

Procedure: A solution of tert-BuOK (2.41 g, 21.52 mmol) in t-BuOH/DME 1:2 (24 ml) was added at 0° C. to a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.53 g, 10.75 mmol) and tosylmethyl isocyanide (2.3 g, 11.83 mmol) in DME (20 ml). The solution was stirred for 3 hours at room temperature. After addition of ether, the mixture was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated. After purification by chromatography on silica gel (hexane/AcOEt 85/15), 8-thiabicyclo[3.2.1]octane-3-carbonitrile was obtained as a colorless oil (1.03 g, 63%). the mixture was washed with a saturated aqueous NaHCO3 solution dried over MgSO4 evaporated After purification by chromatography on silica gel (hexane/AcOEt 85/15)

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

Procedure: N-Chlorosuccinimide (14.0 g, 104.9 mmol) was added in three portions with stirring over 15 min to a cooled (0° C.) solution of 8-thiabicyclo[3.2.1]octan-3-one (16.0 g, 99.9 mmol) in dry benzene (400 mL) under nitrogen. The mixture was stirred for a further 2.5 h and was then filtered. The filtrate was added dropwise with stirring under nitrogen to a cooled (0° C.) solution of isopropylmagnesium bromide (from isopropyl bromide (28.3 g, 229.7 mmol), magnesium (5.7 g, 234.7 mmol) and CuI (1.52 g, 7.9 mmol)) in dry ether (300 mL). The mixture was stirred for a further 15 h and cold (0° C.), dilute hydrochloric acid was added cautiously. The organic layer was separated and washed successively with water, saturated aqueous sodium bicarbonate, and finally with water again. The dried (Na2SO4) ether-benzene solution was evaporated, giving 13.2 g of the title compound. The mixture was stirred for a further 2.5 h was then filtered The filtrate was added dropwise with stirring under nitrogen to The mixture was stirred for a further 15 h The organic layer was separated washed successively with water, saturated aqueous sodium bicarbonate The dried (Na2SO4) ether-benzene solution was evaporated

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

Procedure: Tetrahydrothiopyran-4-one (19.1 g, 150 mmol), ethylene-1,2-diol (11.2 g. 180 mmol), toluene-p-sulfonic acid (0.5 g), and toluene (500 mL) was heated under reflux in a Dean-Stark apparatus for 1.5 h. The toluene was then removed by rotary evaporation, and the residue dissolved in ether and washed, first with 10% aqueous sodium hydroxide and then with water. The organic layer was dried (Na2SO4) and evaporated, and allowed to crystallize by standing in Et2O overnight, giving 24.4 g (93%) of the title compound. under reflux in a Dean-Stark apparatus for 1.5 h The toluene was then removed by rotary evaporation the residue dissolved in ether washed, first with 10% aqueous sodium hydroxide The organic layer was dried (Na2SO4) evaporated to crystallize

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 A molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%). was cooled to 23° C. The reaction was stirred at 23° C. for 1.5 h quenched by the addition of saturated aqueous sodium bicarbonate The mixture was extracted with dichloromethane the combined organic extracts were dried over sodium sulfate filtered concentrated The crude product was purified by Isco Combiflash, 120 gram column eluting with 0-30% ethyl acetate in hexanes

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

Procedure: N-Chlorosuccinimide (14.0 g, 104.9 mmol) was added in three portions with stirring over 15 min to a cooled (0° C.) solution of 8-thiabicyclo[3.2.1]octan-3-one (16.0 g, 99.9 mmol) in dry benzene (400 mL) under nitrogen. The mixture was stirred for a further 2.5 h and was then filtered. The filtrate was added dropwise with stirring under nitrogen to a cooled (0° C.) solution of isopropylmagnesium bromide (from isopropyl bromide (28.3 g, 229.7 mmol), magnesium (5.7 g, 234.7 mmol) and CuI (1.52 g, 7.9 mmol)) in dry ether (300 mL). The mixture was stirred for a further 15 h and cold (0° C.), dilute hydrochloric acid was added cautiously. The organic layer was separated and washed successively with water, saturated aqueous sodium bicarbonate, and finally with water again. The dried (Na2SO4) ether-benzene solution was evaporated, giving 13.2 g of the title compound. The mixture was stirred for a further 2.5 h was then filtered The filtrate was added dropwise with stirring under nitrogen to The mixture was stirred for a further 15 h The organic layer was separated washed successively with water, saturated aqueous sodium bicarbonate The dried (Na2SO4) ether-benzene solution was evaporated

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

Procedure: N-Chlorosuccinimide (14.0 g, 104.9 mmol) was added in three portions with stirring over 15 min to a cooled (0° C.) solution of 8-thiabicyclo[3.2.1]octan-3-one (16.0 g, 99.9 mmol) in dry benzene (400 mL) under nitrogen. The mixture was stirred for a further 2.5 h and was then filtered. The filtrate was added dropwise with stirring under nitrogen to a cooled (0° C.) solution of isopropylmagnesium bromide (from isopropyl bromide (28.3 g, 229.7 mmol), magnesium (5.7 g, 234.7 mmol) and CuI (1.52 g, 7.9 mmol)) in dry ether (300 mL). The mixture was stirred for a further 15 h and cold (0° C.), dilute hydrochloric acid was added cautiously. The organic layer was separated and washed successively with water, saturated aqueous sodium bicarbonate, and finally with water again. The dried (Na2SO4) ether-benzene solution was evaporated, giving 13.2 g of the title compound. The mixture was stirred for a further 2.5 h was then filtered The filtrate was added dropwise with stirring under nitrogen to The mixture was stirred for a further 15 h The organic layer was separated washed successively with water, saturated aqueous sodium bicarbonate The dried (Na2SO4) ether-benzene solution was evaporated

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

Procedure: Tetrahydrothiopyran-4-one (19.1 g, 150 mmol), ethylene-1,2-diol (11.2 g. 180 mmol), toluene-p-sulfonic acid (0.5 g), and toluene (500 mL) was heated under reflux in a Dean-Stark apparatus for 1.5 h. The toluene was then removed by rotary evaporation, and the residue dissolved in ether and washed, first with 10% aqueous sodium hydroxide and then with water. The organic layer was dried (Na2SO4) and evaporated, and allowed to crystallize by standing in Et2O overnight, giving 24.4 g (93%) of the title compound. under reflux in a Dean-Stark apparatus for 1.5 h The toluene was then removed by rotary evaporation the residue dissolved in ether washed, first with 10% aqueous sodium hydroxide The organic layer was dried (Na2SO4) evaporated to crystallize

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 Å molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%). was cooled to 23° C. The reaction was stirred at 23° C. for 1.5 h quenched by the addition of saturated aqueous sodium bicarbonate The mixture was extracted with dichloromethane the combined organic extracts were dried over sodium sulfate filtered concentrated The crude product was purified by Isco Combiflash, 120 gram column eluting with 0-30% ethyl acetate in hexanes

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 Å molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%). was cooled to 23° C. The reaction was stirred at 23° C. for 1.5 h quenched by the addition of saturated aqueous sodium bicarbonate The mixture was extracted with dichloromethane the combined organic extracts were dried over sodium sulfate filtered concentrated The crude product was purified by Isco Combiflash, 120 gram column eluting with 0-30% ethyl acetate in hexanes