ethyl 3-cyclopropylprop-2-ynoate

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

Conditions: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.7 g, 2.23 mmol) (Example 20) in ethanol (40 mL) was added 0.462 g (3.35 mmol) of cyclopropyl-propynoic acid ethyl ester (Example 99). The reaction mixture was stirred at 82° C. for 30 minutes. The reaction mixture was concentrated and purified by chromatography on silica gel, eluting with MeOH/CH2Cl2 to afford 0.145 g of the title compound. [α]D25 −10.51 (c 0.5, CHCl3). The reaction mixture was concentrated purified by chromatography on silica gel eluting with MeOH/CH2Cl2

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), (see Example 28), in ethanol (5 mL) was added cyclopropyl-propynoic acid ethyl ester (0.377 g, 2.73 mmol) (prepared from ethynyl-cyclopropane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708). The reaction mixture was heated in a microwave oven at 170° C. for 30 min. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, 2% 7N NH3 in MeOH/CH2Cl2) to afford 0.635 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-cyclopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −13.40 (c 0.5, CHCl3) The solvent was removed under vacuum the residue purified by flash column chromatography (silica gel, 2% 7N NH3 in MeOH/CH2Cl2)

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

Procedure: To a mixture of 2 (385 mg, 2.79 mmol), 1-iodo-4-(methoxymethoxy)benzene (1.47 g, 5.57 mmol), Phenylboronic acid (680 mg, 5.58 mmol) and K2CO3 (771 mg, 5.58 mmol) in DMF (8.5 ml)-H2O (2.2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.7 mg, 0.0279 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1) gave 5 (29%). 5: colorless oil; 1H-NMR (CDCl3) δ 0.44 (2H, m), 0.79 (2H, m), 1.29 (3H, t, J=7.2 Hz), 2.30 (1H, m), 3.43 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.08 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 6.99 (2H, m), 7.03-7.09 (3H, m). the mixture was stirred at room temperature for 24 h The reaction was quenched with H2O under ice cooling the whole was extracted with Et2O The organic layer was washed with H2O, brine dried over Na2SO4 concentrated Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1)

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

Procedure: To a mixture of 2 (385 mg, 2.79 mmol), 1-iodo-4-(methoxymethoxy)benzene (1.47 g, 5.57 mmol), Phenylboronic acid (680 mg, 5.58 mmol) and K2CO3 (771 mg, 5.58 mmol) in DMF (8.5 ml)-H2O (2.2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.7 mg, 0.0279 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1) gave 5 (29%). 5: colorless oil; 1H-NMR (CDCl3) δ 0.44 (2H, m), 0.79 (2H, m), 1.29 (3H, t, J=7.2 Hz), 2.30 (1H, m), 3.43 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.08 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 6.99 (2H, m), 7.03-7.09 (3H, m). the mixture was stirred at room temperature for 24 h The reaction was quenched with H2O under ice cooling the whole was extracted with Et2O The organic layer was washed with H2O, brine dried over Na2SO4 concentrated Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1)

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

Procedure: To a solution of N-hydroxybenzenecarboximidoyl chloride (Tetrahedron Letters, 47(9), 1457-1460, 2006, 500 mg, 3.21 mmol) and cyclopropyl-propynoic acid ethyl ester (Organic Syntheses, 66, 173-179, 1988, 515 mg, 3.21 mmol) in diethyl ether (5 ml) was added dropwise over a period of 2 min at ambient temperature triethylamine (0.54 ml, 3.86 mmol) and the reaction mixture was stirred for 3 d at this temperature. The resulting suspension was diluted with tert-butylmethylether (5 ml) and water (10 ml). The aqueous layer was extracted with tert-butylmethylether (10 ml) and the organic layers were washed with water (10 ml) and brine (10 ml). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20) afforded the title compound (414 mg, 50%) as a colorless liquid. MS: m/e=258.1 [M+H]+. The aqueous layer was extracted with tert-butylmethylether (10 ml) the organic layers were washed with water (10 ml) and brine (10 ml) Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20)

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

Procedure: To a solution of N-hydroxybenzenecarboximidoyl chloride (Tetrahedron Letters, 47(9), 1457-1460, 2006, 500 mg, 3.21 mmol) and cyclopropyl-propynoic acid ethyl ester (Organic Syntheses, 66, 173-179, 1988, 515 mg, 3.21 mmol) in diethyl ether (5 ml) was added dropwise over a period of 2 min at ambient temperature triethylamine (0.54 ml, 3.86 mmol) and the reaction mixture was stirred for 3 d at this temperature. The resulting suspension was diluted with tert-butylmethylether (5 ml) and water (10 ml). The aqueous layer was extracted with tert-butylmethylether (10 ml) and the organic layers were washed with water (10 ml) and brine (10 ml). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20) afforded the title compound (414 mg, 50%) as a colorless liquid. MS: m/e=258.1 [M+H]+. The aqueous layer was extracted with tert-butylmethylether (10 ml) the organic layers were washed with water (10 ml) and brine (10 ml) Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20)

Conditions: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.7 g, 2.23 mmol) (Example 20) in ethanol (40 mL) was added 0.462 g (3.35 mmol) of cyclopropyl-propynoic acid ethyl ester (Example 99). The reaction mixture was stirred at 82° C. for 30 minutes. The reaction mixture was concentrated and purified by chromatography on silica gel, eluting with MeOH/CH2Cl2 to afford 0.145 g of the title compound. [α]D25 −10.51 (c 0.5, CHCl3). The reaction mixture was concentrated purified by chromatography on silica gel eluting with MeOH/CH2Cl2

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), (see Example 28), in ethanol (5 mL) was added cyclopropyl-propynoic acid ethyl ester (0.377 g, 2.73 mmol) (prepared from ethynyl-cyclopropane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708). The reaction mixture was heated in a microwave oven at 170° C. for 30 min. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, 2% 7N NH3 in MeOH/CH2Cl2) to afford 0.635 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-cyclopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −13.40 (c 0.5, CHCl3) The solvent was removed under vacuum the residue purified by flash column chromatography (silica gel, 2% 7N NH3 in MeOH/CH2Cl2)

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

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

Procedure: To a solution of N-hydroxybenzenecarboximidoyl chloride (Tetrahedron Letters, 47(9), 1457-1460, 2006, 500 mg, 3.21 mmol) and cyclopropyl-propynoic acid ethyl ester (Organic Syntheses, 66, 173-179, 1988, 515 mg, 3.21 mmol) in diethyl ether (5 mL) was added dropwise over a period of 2 min at ambient temperature triethylamine (0.54 ml, 3.86 mmol) and the reaction mixture was stirred for 3 d at this temperature. The resulting suspension was diluted with tert-butylmethylether (5 mL) and water (10 mL). The aqueous layer was extracted with tert-butylmethylether (10 ml) and the organic layers were washed with water (10 mL) and brine (10 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20) afforded the title compound (414 mg, 50%) as a colorless liquid. MS: m/e=258.1 [M+H]+. The aqueous layer was extracted with tert-butylmethylether (10 ml) the organic layers were washed with water (10 mL) and brine (10 mL) Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20)

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

Procedure: To a solution of N-hydroxybenzenecarboximidoyl chloride (Tetrahedron Letters, 2006, 47, 1457, 2006; 500 mg, 3.21 mmol) and cyclopropyl-propynoic acid ethyl ester (Organic Syntheses, 1988, 66, 173; 515 mg, 3.21 mmol) in diethyl ether (5 mL) was added dropwise over a period of 2 min at ambient temperature triethylamine (0.54 ml, 3.86 mmol) and the reaction mixture was stirred for 3 d at this temperature. The resulting suspension was diluted with tert-butylmethylether (5 mL) and water (10 mL). The aqueous layer was extracted with tert-butylmethylether (10 mL) and the organic layers were washed with water (10 mL) and brine (10 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20) afforded the title compound (414 mg, 50%) as a colorless liquid. MS: m/e=258.1[M+H]+. The aqueous layer was extracted with tert-butylmethylether (10 mL) the organic layers were washed with water (10 mL) and brine (10 mL) Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20)