2-(chloromethyl)-1,1-dioxo-1,2-benzothiazol-3-one

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

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

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) and sodium p-nitrophenoxide (2.55 g, 12.9 mmol) in THF (50 ml) was heated overnight at 50° C. and then refluxed for 45 minutes. The reaction mixture was cooled, poured into a dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution and water, dried (Na2SO4), and taken to dryness in vacuo. Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether. The resultant solid was recrystallized from ethanol to afford 0.92 g of 2-(4-nitrophenoxymethyl)-saccharin as white shiny platelets, mp 162°-164° C. 1H nmr (90 MHz, CDCl3, DMSO-d6):5.95 (2H, s). FDMS m/e 334 (M+). refluxed for 45 minutes The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with sodium bicarbonate solution and water dried (Na2SO4) Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether The resultant solid was recrystallized from ethanol

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) and sodium p-nitrophenoxide (2.55 g, 12.9 mmol) in THF (50 ml) was heated overnight at 50° C. and then refluxed for 45 minutes. The reaction mixture was cooled, poured into a dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution and water, dried (Na2SO4), and taken to dryness in vacuo. Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether. The resultant solid was recrystallized from ethanol to afford 0.92 g of 2-(4-nitrophenoxymethyl)-saccharin as white shiny platelets, mp 162°-164° C. 1H nmr (90 MHz, CDCl3, DMSO-d6):5.95 (2H, s). FDMS m/e 334 (M+). refluxed for 45 minutes The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with sodium bicarbonate solution and water dried (Na2SO4) Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether The resultant solid was recrystallized from ethanol

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) , 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 hour. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel; MDC) afforded 2 g of 2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white foam that was crystallized from hot cyclohexane, mp 103°-105° C. 1H nmr (90 MHz, CDCl3):5.65 (2H, s). FDMS: m/e 379 (M+). was heated The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with water dried (Na2SO4)

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) , 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 hour. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel; MDC) afforded 2 g of 2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white foam that was crystallized from hot cyclohexane, mp 103°-105° C. 1H nmr (90 MHz, CDCl3):5.65 (2H, s). FDMS: m/e 379 (M+). was heated The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with water dried (Na2SO4)

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

Procedure: To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (68 mg, 0.140 mmol) in acetone (2 mL) was added 2-(chloromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (32.4 mg, 0.140 mmol), potassium carbonate (19.31 mg, 0.140 mmol) and potassium iodide (23.2 mg, 0.140 mmol). The resulting mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo. The resulting solid was retaken in ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution followed by brine. The organic layer was dried over anhydrous MgSO4 filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (67.4 mg, 0.099 mmol, 71% yield). 1H NMR (400 MHz, (CD3)2SO) δ 8.37 (d, J=7.4 Hz, 1H), 8.18 (dd, J=7.4, 1.3 Hz, 1H), 8.11 (td, J=7.7, 1.3 Hz, 1H), 8.04 (t, J=7.6 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.48-7.34 (m, 3H), 7.34-7.30 (m, 2H), 7.23-7.15 (m, 2H), 6.89-6.81 (m, 2H), 6.33 (d, J=16.0 Hz, 1H), 5.90 (s, 2H), 3.13 (q, J=6.9 Hz, 1H), 1.45 (s, 9H), 1.13 (d, J=6.8 Hz, 6H). The solvent was removed in vacuo The organic layer was washed with aqueous saturated ammonium chloride solution The organic layer was dried over anhydrous MgSO4 filtered concentrated in vacuo to give the crude product, which was purified by flash chromatography (SiO2, 0-30% EtOAc/Heptane)

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) and sodium p-nitrophenoxide (2.55 g, 12.9 mmol) in THF (50 ml) was heated overnight at 50° C. and then refluxed for 45 minutes. The reaction mixture was cooled, poured into a dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution and water, dried (Na2SO4), and taken to dryness in vacuo. Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether. The resultant solid was recrystallized from ethanol to afford 0.92 g of 2-(4-nitrophenoxymethyl)-saccharin as white shiny platelets, mp 162°-164° C. 1H nmr (90 MHz, CDCl3, DMSO-d6):5.95 (2H, s). FDMS m/e 334 (M+). refluxed for 45 minutes The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with sodium bicarbonate solution and water dried (Na2SO4) Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether The resultant solid was recrystallized from ethanol

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) , 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 hour. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel; MDC) afforded 2 g of 2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white foam that was crystallized from hot cyclohexane, mp 103°-105° C. 1H nmr (90 MHz, CDCl3):5.65 (2H, s). FDMS: m/e 379 (M+). was heated The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with water dried (Na2SO4)

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

Procedure: To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (68 mg, 0.140 mmol) in acetone (2 mL) was added 2-(chloromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (32.4 mg, 0.140 mmol), potassium carbonate (19.31 mg, 0.140 mmol) and potassium iodide (23.2 mg, 0.140 mmol). The resulting mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo. The resulting solid was retaken in ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution followed by brine. The organic layer was dried over anhydrous MgSO4 filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (67.4 mg, 0.099 mmol, 71% yield). 1H NMR (400 MHz, (CD3)2SO) δ 8.37 (d, J=7.4 Hz, 1H), 8.18 (dd, J=7.4, 1.3 Hz, 1H), 8.11 (td, J=7.7, 1.3 Hz, 1H), 8.04 (t, J=7.6 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.48-7.34 (m, 3H), 7.34-7.30 (m, 2H), 7.23-7.15 (m, 2H), 6.89-6.81 (m, 2H), 6.33 (d, J=16.0 Hz, 1H), 5.90 (s, 2H), 3.13 (q, J=6.9 Hz, 1H), 1.45 (s, 9H), 1.13 (d, J=6.8 Hz, 6H). The solvent was removed in vacuo The organic layer was washed with aqueous saturated ammonium chloride solution The organic layer was dried over anhydrous MgSO4 filtered concentrated in vacuo to give the crude product, which was purified by flash chromatography (SiO2, 0-30% EtOAc/Heptane)

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) and sodium p-nitrophenoxide (2.55 g, 12.9 mmol) in THF (50 ml) was heated overnight at 50° C. and then refluxed for 45 minutes. The reaction mixture was cooled, poured into a dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution and water, dried (Na2SO4), and taken to dryness in vacuo. Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether. The resultant solid was recrystallized from ethanol to afford 0.92 g of 2-(4-nitrophenoxymethyl)-saccharin as white shiny platelets, mp 162°-164° C. 1H nmr (90 MHz, CDCl3, DMSO-d6):5.95 (2H, s). FDMS m/e 334 (M+). refluxed for 45 minutes The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with sodium bicarbonate solution and water dried (Na2SO4) Chromatography (silica gel; MDC) afforded an oil that was crystallized from hot cyclohexane/ether The resultant solid was recrystallized from ethanol

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

Procedure: A mixture of 2-(chloromethyl) saccharin (3 g, 12.9 mmol) , 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 hour. The reaction mixture was cooled, poured into dilute sodium bicarbonate/ice solution and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel; MDC) afforded 2 g of 2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white foam that was crystallized from hot cyclohexane, mp 103°-105° C. 1H nmr (90 MHz, CDCl3):5.65 (2H, s). FDMS: m/e 379 (M+). was heated The reaction mixture was cooled extracted twice with ethyl acetate The combined organic extracts were washed with water dried (Na2SO4)