tert-butyl 3,4-dioxopiperidine-1-carboxylate

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

Procedure: In analogy to a general literature method (Neunhoeffer and Metz, Liebigs Ann. Chem., 1476-1495 (1983)), a solution of 377 mg (1.88 mmol) of acetamidrazone hydriodide (ethanimidohydrazide hydriodide), prepared from methyl ethanimidothioate hydriodide (Singh et al., Indian J. Chem., 21B: 272-273 (1982)) according to the procedure of Zelenin et al., J. Gen. Chem. USSR, 18: 1410-1415 (1982) in 10 mL of absolute ethanol was treated with 0.36 mL (268 mg, 2.07 mmol) of N,N-diisopropylethylamine, and the solution was stirred under nitrogen at room temperature for 10 min. To this was then added dropwise a solution of 400 mg (1.88 mmol) of tert-butyl 3,4-dioxopiperidine-1-carboxylate from Step C. After being stirred initially at room temperature, the reaction mixture was heated at reflux for 4.5 h. At this time, an additional 96 mg (0.48 mmol) of the amidrazone salt was added, and stirring at reflux was continued for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 30-70% ethyl acetate/hexanes, then 95:5 dichloromethane/methanol) to give the title compound. The regiochemistry was assigned in analogy to Example 36, Step A, in which both possible regioisomers were isolated and assigned. 1H N (500 MHz, CDCl3) δ 4.93 (s, 2H), 3.82 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H, 1.52 (s, 9H). LC/MS: 195 (M+1-isobutene). After being stirred initially at room temperature the reaction mixture was heated at reflux for 4.5 h stirring at reflux was continued for 3 h The reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 30-70% ethyl acetate/hexanes

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a dried flask, a solution of 8.8 mL (9.7 g, 125 mmol) of anhydrous dimethyl sulfoxide in 400 mL of anhydrous dichloromethane was stirred under nitrogen at −60° C. as 15.9 mL (23.6 g, 113 mmol) of trifluoroacetic anhydride was added dropwise. The resultant solution was stirred at −60° C. for 20 min, at which time a solution of 8.5 g (39.1 mmol) of tert-butyl 3,4-dihydroxypiperidine-1-carboxylate from Step B in 100 mL of anhydrous dichloromethane was added via cannula. The solution was stirred at −60° C. for 1.5 h, during which time some precipitation occurred. Then 36.2 mL (26.3 g, 260 mmol) of triethylamine was added, and stirring was continued at −60° C. for an additional 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes) to yield the title compound, which may exist as a mixture of tautomers. 1H NMR (500 MHz, CDCl3) δ 7.8-7.6 (br m, <1H), 5.3 (br apparent s, ≦1H), 4.00 (m, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.57 (s, 9H). LC/MS: 214 (M+1). was added dropwise was added via cannula some precipitation stirring was continued at −60° C. for an additional 30 min The reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes)

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

Procedure: In analogy to a general literature method (Neunhoeffer and Metz, Liebigs Ann. Chem., 1476-1495 (1983)), a solution of 377 mg (1.88 mmol) of acetamidrazone hydriodide (ethanimidohydrazide hydriodide), prepared from methyl ethanimidothioate hydriodide (Singh et al., Indian J. Chem., 21B: 272-273 (1982)) according to the procedure of Zelenin et al., J. Gen. Chem. USSR, 18: 1410-1415 (1982) in 10 mL of absolute ethanol was treated with 0.36 mL (268 mg, 2.07 mmol) of N,N-diisopropylethylamine, and the solution was stirred under nitrogen at room temperature for 10 min. To this was then added dropwise a solution of 400 mg (1.88 mmol) of tert-butyl 3,4-dioxopiperidine-1-carboxylate from Step C. After being stirred initially at room temperature, the reaction mixture was heated at reflux for 4.5 h. At this time, an additional 96 mg (0.48 mmol) of the amidrazone salt was added, and stirring at reflux was continued for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 30-70% ethyl acetate/hexanes, then 95:5 dichloromethane/methanol) to give the title compound. The regiochemistry was assigned in analogy to Example 36, Step A, in which both possible regioisomers were isolated and assigned. 1H N (500 MHz, CDCl3) δ 4.93 (s, 2H), 3.82 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H, 1.52 (s, 9H). LC/MS: 195 (M+1-isobutene). After being stirred initially at room temperature the reaction mixture was heated at reflux for 4.5 h stirring at reflux was continued for 3 h The reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 30-70% ethyl acetate/hexanes

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a dried flask, a solution of 8.8 mL (9.7 g, 125 mmol) of anhydrous dimethyl sulfoxide in 400 mL of anhydrous dichloromethane was stirred under nitrogen at −60° C. as 15.9 mL (23.6 g, 113 mmol) of trifluoroacetic anhydride was added dropwise. The resultant solution was stirred at −60° C. for 20 min, at which time a solution of 8.5 g (39.1 mmol) of tert-butyl 3,4-dihydroxypiperidine-1-carboxylate from Step B in 100 mL of anhydrous dichloromethane was added via cannula. The solution was stirred at −60° C. for 1.5 h, during which time some precipitation occurred. Then 36.2 mL (26.3 g, 260 mmol) of triethylamine was added, and stirring was continued at −60° C. for an additional 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes) to yield the title compound, which may exist as a mixture of tautomers. 1H NMR (500 MHz, CDCl3) δ 7.8-7.6 (br m, <1H), 5.3 (br apparent s, ≦1H), 4.00 (m, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.57 (s, 9H). LC/MS: 214 (M+1). was added dropwise was added via cannula some precipitation stirring was continued at −60° C. for an additional 30 min The reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes)

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

Procedure: In analogy to a general literature method (Neunhoeffer and Metz, Liebigs Ann. Chem., 1476-1495 (1983)), a solution of 377 mg (1.88 mmol) of acetamidrazone hydriodide (ethanimidohydrazide hydriodide), prepared from methyl ethanimidothioate hydriodide (Singh et al., Indian J. Chem., 21B: 272-273 (1982)) according to the procedure of Zelenin et al., J. Gen. Chem. USSR, 18: 1410-1415 (1982) in 10 mL of absolute ethanol was treated with 0.36 mL (268 mg, 2.07 mmol) of N,N-diisopropylethylamine, and the solution was stirred under nitrogen at room temperature for 10 min. To this was then added dropwise a solution of 400 mg (1.88 mmol) of tert-butyl 3,4-dioxopiperidine-1-carboxylate from Step C. After being stirred initially at room temperature, the reaction mixture was heated at reflux for 4.5 h. At this time, an additional 96 mg (0.48 mmol) of the amidrazone salt was added, and stirring at reflux was continued for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 30-70% ethyl acetate/hexanes, then 95:5 dichloromethane/methanol) to give the title compound. The regiochemistry was assigned in analogy to Example 36, Step A, in which both possible regioisomers were isolated and assigned. 1H N (500 MHz, CDCl3) δ 4.93 (s, 2H), 3.82 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H, 1.52 (s, 9H). LC/MS: 195 (M+1-isobutene). After being stirred initially at room temperature the reaction mixture was heated at reflux for 4.5 h stirring at reflux was continued for 3 h The reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 30-70% ethyl acetate/hexanes

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a dried flask, a solution of 8.8 mL (9.7 g, 125 mmol) of anhydrous dimethyl sulfoxide in 400 mL of anhydrous dichloromethane was stirred under nitrogen at −60° C. as 15.9 mL (23.6 g, 113 mmol) of trifluoroacetic anhydride was added dropwise. The resultant solution was stirred at −60° C. for 20 min, at which time a solution of 8.5 g (39.1 mmol) of tert-butyl 3,4-dihydroxypiperidine-1-carboxylate from Step B in 100 mL of anhydrous dichloromethane was added via cannula. The solution was stirred at −60° C. for 1.5 h, during which time some precipitation occurred. Then 36.2 mL (26.3 g, 260 mmol) of triethylamine was added, and stirring was continued at −60° C. for an additional 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes) to yield the title compound, which may exist as a mixture of tautomers. 1H NMR (500 MHz, CDCl3) δ 7.8-7.6 (br m, <1H), 5.3 (br apparent s, ≦1H), 4.00 (m, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.57 (s, 9H). LC/MS: 214 (M+1). was added dropwise was added via cannula some precipitation stirring was continued at −60° C. for an additional 30 min The reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes)