isocyanocyclopropane

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (0-5° C.) solution of (S)-2-(dibenzylamino)pentanal in dichloromethane (210 mL) was added cyclopropylisonitrile followed by acetic acid at 0-5° C. The reaction mixture temperature was raised to 25-30° C. over 40-60 minutes, and stirred for 16-18 hours at 25-30° C. Progress of the reaction was monitored by TLC analysis. When the reaction was complete, the mixture was cooled to 0-5° C., and saturated sodium bicarbonate solution (200 mL) was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with water (1×200 mL), brine (1×200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product thus obtained was slurried in hexane (150 mL) and stirred for one hour at 25-35° C. The slurry was filtered and the solid washed with hexane and dried under reduced pressure to provide 17.0 g of (2S,3S)-1-(cyclopropylamino)-3-(dibenzylamino)-1-oxohexan-2-yl acetate as a white solid. the mixture was cooled to 0-5° C. The organic layer was separated the aqueous layer was extracted with dichloromethane twice The combined organic layers were washed with water (1×200 mL), brine (1×200 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The crude product thus obtained stirred for one hour at 25-35° C The slurry was filtered the solid washed with hexane dried under reduced pressure

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

Procedure: 5-chloropyridin-2-amine (100 mg, 778 μmol, Eq: 1.00), 3-chlorobenzaldehyde (115 mg, 93.0 μl, 817 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (44.4 mg, 233 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 10 min. To this yellow solution was added dropwise isocyanocyclopropane (52.2 mg, 47.4 μL, 778 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. The solvent was removed and the dark red oil was purified twice by flash column chromatography (ethyl acetate in hexanes) to give the product as yellow solid (45 mg, 18.2%). LC/MS (acid polar): 318.1 [M+H]+; 1H-NMR (CDCl3): δ 8.50 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H), 7.58 (d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 7.28 (d, 1H), 5.44 (s, 1H), 2.70 (m, 1H), 0.46-0.39 (m, 4H). the corresponding yellow solution was stirred for 2 h The solvent was removed the dark red oil was purified twice by flash column chromatography (ethyl acetate in hexanes)

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

Procedure: 3-Imidazol-1-yl-propylamine (1 mmol) and 2-Hydroxy-5-methyl-benzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours Trimethylsilylazide (5 mmol) and Isocyano-cyclopropane (mmol) was added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. After evaporation of the solvent the residue was purified with chromatographic methods

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

Procedure: 3-Imidazol-1-yl-propylamine (1 mmol) and 2-Hydroxy-5-methyl-benzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours Trimethylsilylazide (5 mmol) and Isocyano-cyclopropane (mmol) was added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. After evaporation of the solvent the residue was purified with chromatographic methods

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (0-5° C.) solution of (S)-2-(dibenzylamino)pentanal in dichloromethane (210 mL) was added cyclopropylisonitrile followed by acetic acid at 0-5° C. The reaction mixture temperature was raised to 25-30° C. over 40-60 minutes, and stirred for 16-18 hours at 25-30° C. Progress of the reaction was monitored by TLC analysis. When the reaction was complete, the mixture was cooled to 0-5° C., and saturated sodium bicarbonate solution (200 mL) was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with water (1×200 mL), brine (1×200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product thus obtained was slurried in hexane (150 mL) and stirred for one hour at 25-35° C. The slurry was filtered and the solid washed with hexane and dried under reduced pressure to provide 17.0 g of (2S,3S)-1-(cyclopropylamino)-3-(dibenzylamino)-1-oxohexan-2-yl acetate as a white solid. the mixture was cooled to 0-5° C. The organic layer was separated the aqueous layer was extracted with dichloromethane twice The combined organic layers were washed with water (1×200 mL), brine (1×200 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The crude product thus obtained stirred for one hour at 25-35° C The slurry was filtered the solid washed with hexane dried under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylisonitrile (1.21 g, 18 mmol), (S)-tert-butyl 1-cyclobutyl-3-oxopropan-2-ylcarbamate (2.95 g, 13 mmol) in methylene chloride(20 mL), was added acetic acid (1.56 g, 26 mmol) at 0° C. After the addition was complete, the reaction mixture was allowed to warm to 25° C. and stirred for another 4 hours. The reaction mixture was diluted with 200 mL ethyl acetate and washed with a saturated solution of sodium bicarbonate, then brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was crystallized from 50 mL of ethyl acetate and hexane (v/v=1/1) to give (3S)-3-(tert-butoxycarbonylamino)-4-cyclobutyl-1-(cyclopropylamino)-1-oxobutan-2-yl acetate (3.8 g) as a white solid. After the addition washed with a saturated solution of sodium bicarbonate brine, and dried over magnesium sulfate The solvent was removed under reduced pressure the crude product was crystallized from 50 mL of ethyl acetate and hexane (v/v=1/1)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylisonitrile (1.91 g, 28.5 mmol), (S)-tert-butyl 1-oxopentan-2-ylcarbamate (3.8 g, 19 mmol) in methylene chloride (100 mL) was added acetic acid (2.28 g, 38 mmol) at 0° C. After the addition was complete the reaction mixture was allowed to warm to 25° C. and stirred for 6 hours. The reaction mixture was diluted with ethyl acetate (200 mL), then washed with a saturated solution of sodium bicarbonate and brine (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was crystallized from 50 mL of ethyl acetate and hexane(v/v=1/1) to give tert-butyl (3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate (4.8 g) as a white solid. After the addition washed with a saturated solution of sodium bicarbonate and brine (30 mL) dried over magnesium sulfate The solvent was removed under reduced pressure the crude product was crystallized from 50 mL of ethyl acetate and hexane(v/v=1/1)

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

Procedure: 5-chloropyridin-2-amine (100 mg, 778 μmol, Eq: 1.00), 3-chlorobenzaldehyde (115 mg, 93.0 μl, 817 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (44.4 mg, 233 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 10 min. To this yellow solution was added dropwise isocyanocyclopropane (52.2 mg, 47.4 μL, 778 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. The solvent was removed and the dark red oil was purified twice by flash column chromatography (ethyl acetate in hexanes) to give the product as yellow solid (45 mg, 18.2%). LC/MS (acid polar): 318.1 [M+H]+; 1H-NMR (CDCl3): δ 8.50 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H), 7.58 (d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 7.28 (d, 1H), 5.44 (s, 1H), 2.70 (m, 1H), 0.46-0.39 (m, 4H). the corresponding yellow solution was stirred for 2 h The solvent was removed the dark red oil was purified twice by flash column chromatography (ethyl acetate in hexanes)

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

Procedure: 3-Imidazol-1-yl-propylamine (1 mmol) and 2-Hydroxy-5-methyl-benzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours Trimethylsilylazide (5 mmol) and Isocyano-cyclopropane (mmol) was added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. After evaporation of the solvent the residue was purified with chromatographic methods