669008-25-7

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: This compound was obtained in 66% yield using the procedure described for the synthesis of N-tert-Butyl-(1-methyl)cyclopropylsulfonamide except 1.2 equivalents of methyl benzoate was used as the electrophile. The compound was purified by column chromatography over SiO2 using 30% to 100% CH2Cl2 in hexane: 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.52 (m, 2H), 1.81 (m, 2H), 4.16 (bs, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 8.05 (d, J=8.5 Hz, 2H). This compound was obtained in 66% yield The compound was purified by column chromatography over SiO2 using 30% to 100% CH2Cl2 in hexane

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

Procedure: A solution of N-tert-butyl-(3-chloro)propylsulfonamide (4.3 g, 20 mmol) was dissolved in dry THF (100 mL) and cooled to −78° C. To this solution was added n-BuLi (17.6 mL, 44 mmol, 2.5 M in hexane) slowly. The dry ice bath was removed and the reaction mixture was allowed to warm to rt over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 mL, 2.5 M in hexane) was added. The reaction mixture was warmed to rt, recooled to −78° C. over a period of 2 h and a neat solution of methyl iodide (5.68 g, 40 mmol) added. The reaction mixture was allowed to warm to rt overnight, quenched with saturated NH4Cl (100 mL) at rt. It was extracted with EtOAc (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), and concentrated in vacuo to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%): 1H NMR (CDCl3) δ 0.79 (m, 2H), 1.36 (s, 9H), 1.52 (m, 2H), 1.62 (s, 3H), 4.10 (bs, 1H). The dry ice bath was removed to warm to rt over a period of 1.5 h This mixture was then cooled to −78° C. The reaction mixture was warmed to rt to warm to rt overnight quenched with saturated NH4Cl (100 mL) at rt It was extracted with EtOAc (100 mL) The organic phase was washed with brine (100 mL) dried (MgSO4) concentrated in vacuo to give a yellow oil which was crystallized from hexane

Conditions: temp:-69.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a four necked, 5 L round bottom flask was added N-(tert-butyl)-3-chloropropane-1-sulfonamide (Previously dried by azeotroping with 3×100 mL toluene) (100 g, 468 mmol) and THF (1500 mL). This was cooled to an internal temperature of −69° C. then butyl lithium (2.5M in hexanes, 412 mL, 1.02 mol) was added dropwise over a period of 55 min while keeping the internal temperature below −65° C. The ice bath was removed and the reaction mixture was warmed to rt over 1.5 h and then cooled back down to an internal temperature of −69° C. Butyl lithium (196 mL, 515 mmol) was added to the reaction mixture over a period of 25 min while keeping the internal temperature below −65° C. The reaction mixture was then warmed to rt over the course of 1.5 h. The reaction mixture was recooled to an internal temperature of −69° C. and iodomethane (58.5 mL, 936 mmol) was added dropwise over a period of 40 min while keeping the internal temperature below −65° C. The reaction mixture was then warmed to an internal temperature of −50° C. over the course of 4 h. The cold bath was removed and a solution of saturated NH4Cl (1000 mL) was added. The quenched reaction mixture was transferred to a separatory funnel along with ethyl acetate (100 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. (3×75 mL). The combined organic layers were washed with brine (700 mL), dried with MgSO4, and concentrated in vacuo to an off white solid which was dried under high vac for 30 min to yield N-(tert-butyl)-1-methylcyclopropane-1-sulfonamide as a white solid (88.5 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ 4.07 (bs, 1 H), 1.51 (s, 3 H), 1.38-1.41 (m, 2 H), 1.36 (s, 9 H), 0.77-0.80 (m, 2 H). Previously dried by azeotroping with 3×100 mL toluene) (100 g, 468 mmol) and THF (1500 mL) the internal temperature below −65° C The ice bath was removed the reaction mixture was warmed to rt over 1.5 h cooled back down to an internal temperature of −69° C the internal temperature below −65° C The reaction mixture was then warmed to rt over the course of 1.5 h was added dropwise over a period of 40 min the internal temperature below −65° C The reaction mixture was then warmed to an internal temperature of −50° C. over the course of 4 h The cold bath was removed a solution of saturated NH4Cl (1000 mL) was added The quenched reaction mixture The layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with brine (700 mL) dried with MgSO4 concentrated in vacuo to an off white solid which was dried under high vac for 30 min

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

Procedure: The intermediate 1-methylcyclopropane-1-sulfonamide was prepared based on previously reported method (Synlett 2006, 5, 725-278) (Scheme 2). N-(tert-butyl)-1-methylcyclopropane-1-sulfonamide was synthesized using a one-pot procedure from N-(tert-butyl)-3-chloropropane-1-sulfonamide through n-BuLi promoted intramolecular cyclization, lithiation and alkylation with methyl iodide. The removal of the Boc protecting group with TFA afforded 1-methylcyclopropane-1-sulfonamide. The intermediate 1-methylcyclopropane-1-sulfonamide was prepared The removal of the Boc protecting group with TFA

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

Procedure: This compound was obtained in 66% yield using the procedure described for the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.2 equivalents of methyl benzoate was used as the electrophile. The compound was purified by column chromatography over SiO2 using 30% to 100% dichloromethane in hexane: 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.52 (m, 2H), 1.81 (m, 2H), 4.16 (br s, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 8.05 (d, J=8.5 Hz, 2H). This compound was obtained in 66% yield The compound was purified by column chromatography over SiO2 using 30% to 100% dichloromethane in hexane

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

Procedure: This compound was obtained in 66% yield using the procedure described for the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.2 equivalents of methyl benzoate was used as the electrophile. The compound was purified by column chromatography over SiO2 using 30% to 100% dichloromethane in hexane: 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.52 (m, 2H), 1.81 (m, 2H), 4.16 (br s, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 8.05 (d, J=8.5 Hz, 2H). This compound was obtained in 66% yield The compound was purified by column chromatography over SiO2 using 30% to 100% dichloromethane in hexane

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

Procedure: This compound was obtained in 97% yield according to the procedure described in the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.25 equivalents of allyl bromide were used as electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.83 (m, 2H), 1.34 (s, 9H), 1.37 (m, 2H), 2.64 (d, J=7.3 Hz, 2H), 4.25 (br s, 1H), 5.07-5.10 (m, 2H), 6.70-6.85 (m, 1H). This compound was obtained in 97% yield The compound was taken directly into the next reaction without purification

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

Procedure: This compound was obtained in 60% yield using the procedure described for the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.05 equivalents of benzyl bromide were used, followed by trituration with 10% ethyl acetate in hexane: 1H NMR (CDCl3) δ 0.92 (m, 2H), 1.36 (m, 2H), 1.43 (s, 9H), 3.25 (s, 2H), 4.62 (br s, 1H), 7.29-7.36 (m, 5H). This compound was obtained in 60% yield

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

Procedure: This compound was obtained in 60% yield using the procedure described for the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.05 equivalents of benzyl bromide were used, followed by trituration with 10% ethyl acetate in hexane: 1H NMR (CDCl3) δ 0.92 (m, 2H), 1.36 (m, 2H), 1.43 (s, 9H), 3.25 (s, 2H), 4.62 (br s, 1H), 7.29-7.36 (m, 5H). This compound was obtained in 60% yield