[(1R)-1-isocyanatopropyl]benzene

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

Procedure: To a solution of 4(R)-(pyrimidin-2-ylsulfanyl-methyl)azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0° was added dropwise LiHMDS (1M/THF) (0.33 mL, 0.331 mmol). After the reaction mixture was stirred 15 min at 0°, then cooled to −78°, 1(R)-phenylpropyl isocyanate (example 1) (0.53M/toluene, 0.63 mL, 0.315 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane) to give 2-oxo-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxylic acid (1(R)-phenylpropyl)amide (75 mg, 67% yield) as a viscous gum. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J=4.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H) 4.71 (q, J=7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J=14.2, 3.3 Hz, 1H), 3.39 (dd, J=14.2, 8.3 Hz, 1H), 3.03 (dd, J=16.0, 5.6 Hz, 1H), 2.89 (dd, J=16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); IR (neat) υ 1758, 1692 cm−1; FAB MS m/z 357.3 (MH+); HRMS calcd. for C18H21N4O2S (MH+) 357.1385, found 357.1379. cooled to −78° stirred for 1.5 h The reaction mixture was quenched with H2O diluted with EtOAc The organic phase was washed with H2O and brine dried (MgSO4) filtered evaporated The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane)

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

Procedure: To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil. the crude solution was evaporated to dryness on a rotary evaporator triphosgene was added (11.67 g, 39.3 mmol) the resulting suspension was stirred The reaction mixture was concentrated An aliquot (170 mL) was concentrated to give a colorless oil

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

Procedure: Following the same procedure as in example 1, step F, but using 4(S)-tert-butylazetidine-2-one as starting material and 1(R)-phenylpropyl isocyanate as reactant, 4(S)-tert-butyl-2-oxoazetidine-1-carboxylic acid (1(R)-phenylpropyl)amide was obtained as a waxy solid.

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

Procedure: To a solution of 4(R)-(pyrimidin-2-ylsulfanyl-methyl)azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0° was added dropwise LiHMDS (1M/THF) (0.33 mL, 0.331 mmol). After the reaction mixture was stirred 15 min at 0°, then cooled to −78°, 1(R)-phenylpropyl isocyanate (example 1) (0.53M/toluene, 0.63 mL, 0.315 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane) to give 2-oxo-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxylic acid (1(R)-phenylpropyl)amide (75 mg, 67% yield) as a viscous gum. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J=4.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H) 4.71 (q, J=7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J=14.2, 3.3 Hz, 1H), 3.39 (dd, J=14.2, 8.3 Hz, 1H), 3.03 (dd, J=16.0, 5.6 Hz, 1H), 2.89 (dd, J=16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); IR (neat) υ 1758, 1692 cm−1; FAB MS m/z 357.3 (MH+); HRMS calcd. for C18H21N4O2S (MH+) 357.1385, found 357.1379. cooled to −78° stirred for 1.5 h The reaction mixture was quenched with H2O diluted with EtOAc The organic phase was washed with H2O and brine dried (MgSO4) filtered evaporated The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane)

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

Procedure: To a solution of 4(R)-(pyrimidin-2-ylsulfanyl-methyl)azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0° was added dropwise LiHMDS (1M/THF) (0.33 mL, 0.331 mmol). After the reaction mixture was stirred 15 min at 0°, then cooled to −78°, 1(R)-phenylpropyl isocyanate (example 1) (0.53M/toluene, 0.63 mL, 0.315 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane) to give 2-oxo-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxylic acid (1(R)-phenylpropyl)amide (75 mg, 67% yield) as a viscous gum. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J=4.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H) 4.71 (q, J=7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J=14.2, 3.3 Hz, 1H), 3.39 (dd, J=14.2, 8.3 Hz, 1H), 3.03 (dd, J=16.0, 5.6 Hz, 1H), 2.89 (dd, J=16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); IR (neat) υ 1758, 1692 cm−1; FAB MS m/z 357.3 (MH+); HRMS calcd. for C18H21N4O2S (MH+) 357.1385, found 357.1379. cooled to −78° stirred for 1.5 h The reaction mixture was quenched with H2O diluted with EtOAc The organic phase was washed with H2O and brine dried (MgSO4) filtered evaporated The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane)

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

Procedure: To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil. the crude solution was evaporated to dryness on a rotary evaporator triphosgene was added (11.67 g, 39.3 mmol) the resulting suspension was stirred The reaction mixture was concentrated An aliquot (170 mL) was concentrated to give a colorless oil

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

Procedure: To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil. the crude solution was evaporated to dryness on a rotary evaporator triphosgene was added (11.67 g, 39.3 mmol) the resulting suspension was stirred The reaction mixture was concentrated An aliquot (170 mL) was concentrated to give a colorless oil

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

Procedure: Following the same procedure as in example 1, step F, but using 4(S)-tert-butylazetidine-2-one as starting material and 1(R)-phenylpropyl isocyanate as reactant, 4(S)-tert-butyl-2-oxoazetidine-1-carboxylic acid (1(R)-phenylpropyl)amide was obtained as a waxy solid.

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

Procedure: To a solution of 4(R)-(pyrimidin-2-ylsulfanyl-methyl)azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0° was added dropwise LiHMDS (1M/THF) (0.33 mL, 0.331 mmol). After the reaction mixture was stirred 15 min at 0°, then cooled to −78°, 1(R)-phenylpropyl isocyanate (example 1) (0.53M/toluene, 0.63 mL, 0.315 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane) to give 2-oxo-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxylic acid (1(R)-phenylpropyl)amide (75 mg, 67% yield) as a viscous gum. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J=4.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H) 4.71 (q, J=7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J=14.2, 3.3 Hz, 1H), 3.39 (dd, J=14.2, 8.3 Hz, 1H), 3.03 (dd, J=16.0, 5.6 Hz, 1H), 2.89 (dd, J=16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); IR (neat) υ 1758, 1692 cm−1; FAB MS m/z 357.3 (MH+); HRMS calcd. for C18H21N4O2S (MH+) 357.1385, found 357.1379. cooled to −78° stirred for 1.5 h The reaction mixture was quenched with H2O diluted with EtOAc The organic phase was washed with H2O and brine dried (MgSO4) filtered evaporated The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane)

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

Procedure: To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil. the crude solution was evaporated to dryness on a rotary evaporator triphosgene was added (11.67 g, 39.3 mmol) the resulting suspension was stirred The reaction mixture was concentrated An aliquot (170 mL) was concentrated to give a colorless oil