tert-butyl N-(2-azidoethyl)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: A solution of (2-azidoethyl)carbamic acid t-butyl ester (1.22 g, 6.55 mmol) in methanol (60 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.22 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (60 ml) were added chloroformic acid p-nitrobenzyl ester (2.12 g, 9.8 mmol) and triethylamine (1.37 ml, 9.8 mmol) in an ice bath, and the reaction mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford (2-t-butoxycarbonylaminoethyl)carbamic acid p-nitrobenzyl ester (1.46 g, yield 66%) as a white solid. the completion of the reaction the reaction mixture was filtered the filtrate concentrated under reduced pressure To a solution of the obtained crude product in methylene chloride (60 ml) the completion of the reaction the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column

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

Procedure: To a solution of (2-hydroxyethyl)carbamic acid t-butyl ester (1.5 g, 6.2 mmol) in tetrahydrofuran (75 ml) were added diphenylphosphoryl azide (3.0 ml, 13.9 mmol), triphenylphosphine (3.7 g, 14.1 mmol), and a 40% solution of diethylazodicarboxylate in toluene (5.1 g, 13.9 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred for 4 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) as the eluant to afford (2-azidoethyl)carbamic acid t-butyl ester (1.24 g, yield 72%) as a colorless and transparent syrup. the completion of the reaction the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The obtained residue was purified by chromatography on a silica gel column

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

Procedure: HCl.H2NCH2CH2N3 (4) was synthesized by dissolving azide 3 (2.11 g, 11.33 mmol) in 4 N HCl in dioxane (100 mL) and stirring at room temperature for 1 h. The solvent was removed under reduced pressure to give a dirty white powder. (Boc)2NN(Boc)CH2CO2H (4.42 g, 11.33 mmol) was then added, and the mixture was dissolved in methylene chloride/DMF (70:45 mL). The mixture was cooled to 0° C., and PyBOP (5.9 g, 11.33 mmol) and Et3N (3.2 mL, 22.66 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred under Ar(g) for 21 h. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 50% v/v ethyl acetate in hexanes) to give (Boc)2NN(Boc)CH2CONHCH2CH2N3 as a colorless viscous oil (4.9 g, 95%). HRMS (ESI) [M+Na]+ calcd for C19H34N6O7Na, 481.2387; found, 481.2389; 1H NMR (400 MHz, CDCl3, 2 rotamers) δ 8.51 and 8.27 (bs, 1H), 4.06 and 3.99 (s, 2H), 3.49-3.40 (m, 4H), 1.56-1.44 (m, 27H); 13C NMR (100 MHz, CDCl3, 2 rotamers) δ 169.5, 169.2, 154.0, 153.5, 151.4, 151.2, 85.2, 85.1, 83.5, 82.8, 56.5, 54.8, 50.6, 38.9, 34.1, 29.9, 28.2, 28.1. The solvent was removed under reduced pressure to give a dirty white powder The mixture was cooled to 0° C. to warm to room temperature The solvent was removed under reduced pressure the residue was purified by flash chromatography (silica gel, 50% v/v ethyl acetate in hexanes)

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

Procedure: HCl.H2NCH2CH2N3 (4) was synthesized by dissolving azide 3 (2.11 g, 11.33 mmol) in 4 N HCl in dioxane (100 mL) and stirring at room temperature for 1 h. The solvent was removed under reduced pressure to give a dirty white powder. (Boc)2NN(Boc)CH2CO2H (4.42 g, 11.33 mmol) was then added, and the mixture was dissolved in methylene chloride/DMF (70:45 mL). The mixture was cooled to 0° C., and PyBOP (5.9 g, 11.33 mmol) and Et3N (3.2 mL, 22.66 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred under Ar(g) for 21 h. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 50% v/v ethyl acetate in hexanes) to give (Boc)2NN(Boc)CH2CONHCH2CH2N3 as a colorless viscous oil (4.9 g, 95%). HRMS (ESI) [M+Na]+ calcd for C19H34N6O7Na, 481.2387; found, 481.2389; 1H NMR (400 MHz, CDCl3, 2 rotamers) δ 8.51 and 8.27 (bs, 1H), 4.06 and 3.99 (s, 2H), 3.49-3.40 (m, 4H), 1.56-1.44 (m, 27H); 13C NMR (100 MHz, CDCl3, 2 rotamers) δ 169.5, 169.2, 154.0, 153.5, 151.4, 151.2, 85.2, 85.1, 83.5, 82.8, 56.5, 54.8, 50.6, 38.9, 34.1, 29.9, 28.2, 28.1. The solvent was removed under reduced pressure to give a dirty white powder The mixture was cooled to 0° C. to warm to room temperature The solvent was removed under reduced pressure the residue was purified by flash chromatography (silica gel, 50% v/v ethyl acetate in hexanes)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: BocNHCH2CH2Br (10.00 g, 44.62 mmol) was dissolved in DMF (200 mL). NaN3 (14.48 g, 223.1 mmol) was added, and the mixture was stirred at 110° C. for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in water (200 mL). The resulting aqueous solution was extracted with ethyl acetate (2×200 mL). The organic layers were combined and dried over anhydrous MgSO4(s). After filtering, the organic layer was concentrated under reduced pressure and the residue was dissolved in methylene chloride (10-20 mL) and purified by flash chromatography (silica gel, methylene chloride). BocNHCH2CH2N3 (6.60 g, 80%) was isolated as a colorless oil. HRMS (ESI) [M+Na]+ calcd for C7H14N4O2Na, 209.1014; found, 209.1010; 1H NMR (400 MHz, CDCl3) δ 4.88 (bs, 1H), 3.42 (t, J=5.3 Hz, 2H), 3.34-3.26 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.8, 79.8, 51.4, 40.2, 28.5. The solvent was removed under reduced pressure the residue was dissolved in water (200 mL) The resulting aqueous solution was extracted with ethyl acetate (2×200 mL) dried over anhydrous MgSO4(s) After filtering the organic layer was concentrated under reduced pressure the residue was dissolved in methylene chloride (10-20 mL) purified by flash chromatography (silica gel, methylene chloride)

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

Procedure: To a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(prop-2-yn-1-yl)azetidin-3-yl)(4-methoxybenzyl)carbamate (95.6 mg, 0.18 mmol) in a mixture of DMSO (1.2 mL), tert-butanol (1.2 mL) and water (1.2 mL), was added copper(II) sulfate pentahydrate (4.5 mg, 0.018 mmol), sodium L-ascorbate (35.8 mg, 0.18 mmol) and N-Boc-2-azidoethylamine (76 mg, 0.39 mmol). After stirring for 12 h, more copper(II) sulfate pentahydrate (10.6 mg, 0.23 equiv), sodium L-ascorbate (37.4 mg, 1.04 equiv) and N-Boc-2-azidoethylamine (82.1 mg, 2.44 equiv) were added. After stirring for 4 days total, the reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). Combined organic layers were washed with LiCl (5% aq), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc-Hep, 0-40%) to afford the title compound (57.2 mg, 44%). LCMS: Rt=1.06 min, m/z=715.5 (M+1) Method 2m_acidic. After stirring for 4 days total The layers were separated the aqueous layer was extracted with EtOAc (2×) Combined organic layers were washed with LiCl (5% aq), brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via silica gel chromatography (EtOAc-Hep, 0-40%)

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

Procedure: To a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(prop-2-yn-1-yl)azetidin-3-yl)(4-methoxybenzyl)carbamate (95.6 mg, 0.18 mmol) in a mixture of DMSO (1.2 mL), tert-butanol (1.2 mL) and water (1.2 mL), was added copper(II) sulfate pentahydrate (4.5 mg, 0.018 mmol), sodium L-ascorbate (35.8 mg, 0.18 mmol) and N-Boc-2-azidoethylamine (76 mg, 0.39 mmol). After stirring for 12 h, more copper(II) sulfate pentahydrate (10.6 mg, 0.23 equiv), sodium L-ascorbate (37.4 mg, 1.04 equiv) and N-Boc-2-azidoethylamine (82.1 mg, 2.44 equiv) were added. After stirring for 4 days total, the reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). Combined organic layers were washed with LiCl (5% aq), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc-Hep, 0-40%) to afford the title compound (57.2 mg, 44%). LCMS: Rt=1.06 min, m/z=715.5 (M+1) Method 2m_acidic. After stirring for 4 days total The layers were separated the aqueous layer was extracted with EtOAc (2×) Combined organic layers were washed with LiCl (5% aq), brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via silica gel chromatography (EtOAc-Hep, 0-40%)

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

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

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

Procedure: To a solution of 1,1-dimethylethyl (2-hydroxyethyl)carbamate (1.483 g, 9.2 mmol) in toluene (40 mL) cooled with an ice bath was added triethylamine (1.282 mL, 9.20 mmol) then methanesulfonyl chloride (0.717 mL, 9.20 mmol) and the resulting mixture was stirred for 5 min at this temperature then tetrabutylammonium bromide (0.297 g, 0.920 mmol) was added followed by a solution of sodium azide (5 g, 77 mmol) in water (20 mL). The resulting mixture was stirred at 60° C. for 3 h then cooled to room temperature and diluted with Et2O (150 mL). The organic layer was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 50G silica cartridge gave 1,1-dimethylethyl (2-azidoethyl)carbamate (456 mg, 2.449 mmol, 26.6% yield) as a colourless oil. then cooled to room temperature The organic layer was washed with water brine, dried over MgSO4 concentrated in vacuo Purification of the residue by SP4