tert-Butyl benzyloxy(4-cyanobutyl)carbamate

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: Trifluoroacetic acid (TFA, 16 mL) was added to (B) (2.59 g, 8.51 mmol), and the solution stirred at room temperature for 20 min (Drierite tube). Excess TFA was removed on the rotovap, saturated NaHCO3 (50 mL) was added and the product was extracted into ether (3×50 mL). After a brine wash (50 mL), the organic extracts were concentrated to yield 1.77 g crude product. Column chromatography with 3% EtOH/CHCl3 furnished 1.31 g of (3) (75% yield), which has been previously prepared: NMR δ1.5-1.7 (m, 4 H), 2.16-2.35 (m, 2 H), 2.78-2.98 (m, 2 H), 4.66 (s, 2 H), 5.45 (br s, 1 H), 7.28 (s, 5 H). Excess TFA was removed on the rotovap, saturated NaHCO3 (50 mL) was added the product was extracted into ether (3×50 mL) After a brine wash (50 mL) the organic extracts were concentrated to yield 1.77 g crude product

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

Procedure: Trifluoroacetic acid (TFA, 16 mL) was added to (B) (2.59 g, 8.51 mmol), and the solution stirred at room temperature for 20 min (Drierite tube). Excess TFA was removed on the rotovap, saturated NaHCO3 (50 mL) was added and the product was extracted into ether (3×50 mL). After a brine wash (50 mL), the organic extracts were concentrated to yield 1.77 g crude product. Column chromatography with 3% EtOH/CHCl3 furnished 1.31 g of (3) (75% yield), which has been previously prepared: NMR δ1.5-1.7 (m, 4 H), 2.16-2.35 (m, 2 H), 2.78-2.98 (m, 2 H), 4.66 (s, 2 H), 5.45 (br s, 1 H), 7.28 (s, 5 H). Excess TFA was removed on the rotovap, saturated NaHCO3 (50 mL) was added the product was extracted into ether (3×50 mL) After a brine wash (50 mL) the organic extracts were concentrated to yield 1.77 g crude product

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

Procedure: Sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) were added to (A) (2.68 g, 12.0 mmol) in dry DMF (40 mL). After stirring 15 min, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added, and the suspension heated at 80°-85° C. for 4 h under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of (B) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. Calcd for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11. the suspension heated at 80°-85° C. for 4 h under argon After cooling the reaction was quenched with H2O (100 mL) extracted with ether (4×75 mL) The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine concentrated to give 4.39 g crude product

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

Procedure: Sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) were added to (A) (2.68 g, 12.0 mmol) in dry DMF (40 mL). After stirring 15 min, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added, and the suspension heated at 80°-85° C. for 4 h under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of (B) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. Calcd for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11. the suspension heated at 80°-85° C. for 4 h under argon After cooling the reaction was quenched with H2O (100 mL) extracted with ether (4×75 mL) The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine concentrated to give 4.39 g crude product

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

Procedure: Tert-butyl benzyloxy(4-cyanobutyl)carbamate was dissolved in a solution of 4 M HCl in 1,4-dioxane and the mixture was stirred for 18 h at room temperature. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate and diethyl ether. A solid formed which was washed with diethyl ether, filtered and dried under high vacuum to give 1-(benzyloxy)piperidin-2-imine hydrochloride as a pale yellow solid. The solvent was removed under reduced pressure the residue was treated with ethyl acetate and diethyl ether A solid formed which was washed with diethyl ether filtered dried under high vacuum

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl benzyloxycarbamate in anhydrous dimethylformamide were added 5 mol % of sodium iodide and portionwise 1.36 eq. of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at room temperature for 15 min. before 1.05 eq. of 4-chlorovaleronitrile were added. The mixture was heated to 85° C. and stirred for 3.5 h. After cooling to room temperature the mixture was quenched with water and extracted with diethyl ether. The combined organic phases were concentrated and washed with half saturated aq. sodium thiosulfate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The oily residue was washed with petroleum ether and dried under high vacuum to yield Tert-butyl benzyloxy(4-cyanobutyl)carbamate as a light yellow oil. were added After cooling to room temperature the mixture was quenched with water extracted with diethyl ether The combined organic phases were concentrated washed with half saturated aq. sodium thiosulfate, water and brine The organic phase was dried over sodium sulfate filtered concentrated under reduced pressure The oily residue was washed with petroleum ether dried under high vacuum

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl benzyloxycarbamate in anhydrous dimethylformamide were added 5 mol % of sodium iodide and portionwise 1.36 eq. of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at room temperature for 15 min. before 1.05 eq. of 4-chlorovaleronitrile were added. The mixture was heated to 85° C. and stirred for 3.5 h. After cooling to room temperature the mixture was quenched with water and extracted with diethyl ether. The combined organic phases were concentrated and washed with half saturated aq. sodium thiosulfate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The oily residue was washed with petroleum ether and dried under high vacuum to yield Tert-butyl benzyloxy(4-cyanobutyl)carbamate as a light yellow oil. were added After cooling to room temperature the mixture was quenched with water extracted with diethyl ether The combined organic phases were concentrated washed with half saturated aq. sodium thiosulfate, water and brine The organic phase was dried over sodium sulfate filtered concentrated under reduced pressure The oily residue was washed with petroleum ether dried under high vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(5-Aminopentyl)-N-(tert-butoxycarbonyl)-O-benzylhydroxylamine (7) was prepared by adding Raney nickel (W-2 grade, 0.98 g) and concentrated NH4OH (1.6 mL) to a solution of (4) (0.57 g, 1.87 mmol) in methanol (9.5 mL) in a 250 mL Parr bottle. The suspension was cooled to 0° C. and ammonia was gently bubbled in for 10 minutes. Hydrogenation was carried out on a Parr shaker for 3.5 hours at 55-58 psi. The catalyst was filtered off (Celite) and the filtrate was concentrated to give 0.61 g crude product. Column chromatography using 5% concentrated NH4OH/CH3OH yielded 0.48 g of (7) (83% yield): NMR δ 1.25-1.72 (m, 17 H), 2.64 (t, 2 H, J=7), 3.39 (t, 2 H, J=7), 4.78 (s, 2 H), 7.31 (s, 5 H). Anal. calcd. for C17H28N2O3 : C, 66.21; H, 9.15; N, 9.08. Found: C, 66.24, H, 9.18; N, 9.05. ammonia was gently bubbled in for 10 minutes The catalyst was filtered off (Celite) the filtrate was concentrated to give 0.61 g crude product

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

Procedure: N-(tert-Butoxycarbonyl)-N-(4-cyanobutyl)-O-benzylhydroxylamine (4) was synthesized by adding sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) to O-benzyl-N-tert-butoxycarbonyl hydroxylamine (2.68 g, 12.0 mmol) in dry DMF (40 ml). After stirring for 15 minutes, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added and the suspension heated at 80°-85° C. for 4 hours under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of O-benzyl-N-(tert-butoxycarbonyl)-N-(4-cyanobutyl)hydroxylamine (4) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. calcd. for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11. the suspension heated at 80°-85° C. for 4 hours under argon After cooling the reaction was quenched with H2O (100 mL) extracted with ether (4×75 mL) The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine concentrated to give 4.39 g crude product

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

Procedure: N-(4-Cyanobutyl)-O-benzylhydroxylamine (5) was synthesized by adding trifluoroacetic acid (TFA, 16 mL) to (4) (2.59 g, 8.51 mmol), and the solution was stirred at room temperature for 20 minutes (Drierite tube). Excess TFA was removed by rotary evaporation, saturated NaHCO3 (50 mL) was added and the product was extracted into ether (3×50 mL). After a brine wash (50 mL), the organic extracts were concentrated to yield 1.77 g crude product. Column chromatography with 3% EtOH/CHCl3 furnished 1.31 g of (5) (75% yield): NMR δ 1.5-1.7 (m, 4 H), 2.16-2.35 (m, 2 H), 2.78-2.98 (m, 2 H), 4.66 (s, 2 H), 5.45 (br s, 1 H), 7.28 (s, 5 H). Anal. calcd. for C12H16N2O: C, 70.56; H, 7.90. Found: C, 70.51; H, 7.91. Excess TFA was removed by rotary evaporation, saturated NaHCO3 (50 mL) was added the product was extracted into ether (3×50 mL) After a brine wash (50 mL) the organic extracts were concentrated to yield 1.77 g crude product