ethyl 2-(dibenzylamino)acetate

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: In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.29 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (0.5 g, 1.77 mmol) in dry THF (10 mL) was added dropwise via cannula. After 15 min, trimethylacetyl chloride (0.53 mL, 3.53 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave the title compound (0.492 g, 76%) as a colorless oil. MS (ESI) m/z: 368 [M−H]+; (ESI) m/z: 366 [M−H]−. 1H NMR (DMSO-d6) δ 0.93 (s, 9H), 1.16-1.25 (m, 3H), 3.79 (d, J=13.97 Hz, 2H), 3.98 (d, J=13.96 Hz, 2H), 4.07-4.25 (m, 2H), 4.60 (s, 1H), 7.20-7.41 (m, 10H). The reaction was then quenched with H2O, and Et2O was subsequently added The organic layer was washed with brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product as an oil Purification by column chromatography eluting with Cy

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

Procedure: In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.29 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (0.5 g, 1.77 mmol) in dry THF (10 mL) was added dropwise via cannula. After 15 min, trimethylacetyl chloride (0.53 mL, 3.53 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave the title compound (0.492 g, 76%) as a colorless oil. MS (ESI) m/z: 368 [M−H]+; (ESI) m/z: 366 [M−H]−. 1H NMR (DMSO-d6) δ 0.93 (s, 9H), 1.16-1.25 (m, 3H), 3.79 (d, J=13.97 Hz, 2H), 3.98 (d, J=13.96 Hz, 2H), 4.07-4.25 (m, 2H), 4.60 (s, 1H), 7.20-7.41 (m, 10H). The reaction was then quenched with H2O, and Et2O was subsequently added The organic layer was washed with brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product as an oil Purification by column chromatography eluting with Cy

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

Procedure: In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (1.6 ml, 9.3 mmol) in dry THF (40 ml) was treated with n-BuLi (2.5 M in n-hexane, 3.4 ml, 8.5 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (2.2 g, 7.8 mmol) in dry THF (40 ml) was added dropwise via cannula. After 15 min, 2-methyl-propanoyl chloride (2.4 mL, 23.3 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a crude compound (3.2 g) as a mixture of two tautomers (ketone:enol=ca. 65:35), as a colorless oil, which was used without further purification in the following step. Ketone isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (d, J=6.73 Hz, 3H), 0.91 (d, J=7.01 Hz, 3H), 1.22 (t, J=7.11 Hz, 3H), 2.99 (hept, J=6.90 Hz, 1H), 3.78 (d, J=14.11 Hz, 2H), 3.84 (d, J=14.13 Hz, 2H), 4.10-4.24 (m, 2H), 4.29 (s, 1H), 7.17-7.48 (m, 10H). Enol isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.50 (s, 3H), 1.43 (t, J=7.09 Hz, 3H), 3.16-3.28 (m, 1H), 3.90 (d, J=12.66 Hz, 2H), 3.96 (d, J=12.66 Hz, 2H), 4.38 (q, J=7.08 Hz, 2H), 7.10-7.46 (m, 10H), 12.32 (s, 1H). The reaction was then quenched with H2O, and Et2O was subsequently added The organic layer was washed with brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product Purification by column chromatography eluting with Cy

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

Procedure: In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (1.6 ml, 9.3 mmol) in dry THF (40 ml) was treated with n-BuLi (2.5 M in n-hexane, 3.4 ml, 8.5 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (2.2 g, 7.8 mmol) in dry THF (40 ml) was added dropwise via cannula. After 15 min, 2-methyl-propanoyl chloride (2.4 mL, 23.3 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a crude compound (3.2 g) as a mixture of two tautomers (ketone:enol=ca. 65:35), as a colorless oil, which was used without further purification in the following step. Ketone isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (d, J=6.73 Hz, 3H), 0.91 (d, J=7.01 Hz, 3H), 1.22 (t, J=7.11 Hz, 3H), 2.99 (hept, J=6.90 Hz, 1H), 3.78 (d, J=14.11 Hz, 2H), 3.84 (d, J=14.13 Hz, 2H), 4.10-4.24 (m, 2H), 4.29 (s, 1H), 7.17-7.48 (m, 10H). Enol isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.50 (s, 3H), 1.43 (t, J=7.09 Hz, 3H), 3.16-3.28 (m, 1H), 3.90 (d, J=12.66 Hz, 2H), 3.96 (d, J=12.66 Hz, 2H), 4.38 (q, J=7.08 Hz, 2H), 7.10-7.46 (m, 10H), 12.32 (s, 1H). The reaction was then quenched with H2O, and Et2O was subsequently added The organic layer was washed with brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product Purification by column chromatography eluting with Cy

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

Procedure: In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.3 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate (0.5 g, 1.77 mmol) in dry THF (10 ml) was added dropwise via a cannula. After 15 min, propanoyl chloride (0.46 mL, 5.29 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a pure compound (0.6 g), as a mixture of two tautomers (ketone:enol=ca. 85:15), as a colorless oil. MS (ESI) m/z: 340 [M−H]+; (ESI) m/z: 338 [M−H]−. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.24 Hz, 3H), 1.23 (t, J=7.07 Hz, 3H), 2.53-2.61 (m, 1H), 2.69 (dq, J=7.23, 18.13 Hz, 1H), 3.72-3.88 (m, 4H), 4.12-4.22 (m, 3H), 7.11-7.47 (m, 10H) (reported data refer to the major ketone tautomer). The reaction was then quenched with H2O, and Et2O was subsequently added The organic layer was washed with brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product Purification by column chromatography eluting with Cy

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of ethyl chloroacetate (1.0 g, 8.16 mmol) in EtOH (5.0 mL), dibenzylamine (2.09 g, 10.6 mmol) was added and the mixture heated at 140° C. in a microwave reactor for 20 min. After evaporation of the solvent, the crude was dissolved in CH2Cl2 and washed with a 1.0 M KOH solution and brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (98:2), gave the title compound (1.85 g, 80%), as a white solid. MS (ESI) m/z: 284 [M−H]+[1H NMR as previously reported in literature: Synthesis, 1985, 9, 850-855]. After evaporation of the solvent the crude was dissolved in CH2Cl2 washed with a 1.0 M KOH solution and brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product Purification by column chromatography eluting with Cy

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of ethyl chloroacetate (1.0 g, 8.16 mmol) in EtOH (5.0 mL), dibenzylamine (2.09 g, 10.6 mmol) was added and the mixture heated at 140° C. in a microwave reactor for 20 min. After evaporation of the solvent, the crude was dissolved in CH2Cl2 and washed with a 1.0 M KOH solution and brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (98:2), gave the title compound (1.85 g, 80%), as a white solid. MS (ESI) m/z: 284 [M−H]+[1H NMR as previously reported in literature: Synthesis, 1985, 9, 850-855]. After evaporation of the solvent the crude was dissolved in CH2Cl2 washed with a 1.0 M KOH solution and brine dried over Na2SO4 filtered concentrated in vacuo to give a crude product Purification by column chromatography eluting with Cy

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

Procedure: Ethyl bromoacetate (19.52 mL, 176 mol) was added in a single portion to a chilled (0° C.) solution of dibenzylamine (33.84 mL, 176 mmol) and triethylamine (27 mL, 193.6 mmol) in THF. The reaction mixture was stirred overnight at ambient temperature. Additional triethylamine (30 mL) and THF (100 mL) were added and the reaction mixture was heated at 50° C. for 1.5 hours. Additional ethyl bromoacetate (13 mL) was added and the reaction mixture was heated for 1 hour and then stirred at ambient temperature overnight. About half of the THF was removed under reduced pressure. The mixture was diluted with water (300 mL) and then extracted with ethyl acetate (2×400 mL). The combined extracts were washed sequentially with water and with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (700 g of silica gel, eluting with 20% ethyl acetate in hexanes) to provide 37.12 g of ethyl dibenzylaminoacetate as a colorless oil. the reaction mixture was heated at 50° C. for 1.5 hours the reaction mixture was heated for 1 hour stirred at ambient temperature overnight About half of the THF was removed under reduced pressure The mixture was diluted with water (300 mL) extracted with ethyl acetate (2×400 mL) The combined extracts were washed sequentially with water and with brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by flash chromatography (700 g of silica gel, eluting with 20% ethyl acetate in hexanes)

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

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

Procedure: Ethyl bromoacetate (19.52 mL, 176 mol) was added in a single portion to a chilled (0° C.) solution of dibenzylamine (33.84 mL, 176 mmol) and triethylamine (27 mL, 193.6 mmol) in THF. The reaction mixture was stirred overnight at ambient temperature. Additional triethylamine (30 mL) and THF (100 mL) were added and the reaction mixture was heated at 50° C. for 1.5 hours. Additional ethyl bromoacetate (13 mL) was added and the reaction mixture was heated for 1 hour and then stirred at ambient temperature overnight. About half of the THF was removed under reduced pressure. The mixture was diluted with water (300 mL) and then extracted with ethyl acetate (2×400 mL). The combined extracts were washed sequentially with water and with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (700 g of silica gel, eluting with 20% ethyl acetate in hexanes) to provide 37.12 g of ethyl dibenzylaminoacetate as a colorless oil. the reaction mixture was heated at 50° C. for 1.5 hours the reaction mixture was heated for 1 hour stirred at ambient temperature overnight About half of the THF was removed under reduced pressure The mixture was diluted with water (300 mL) extracted with ethyl acetate (2×400 mL) The combined extracts were washed sequentially with water and with brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by flash chromatography (700 g of silica gel, eluting with 20% ethyl acetate in hexanes)