1-azido-2-fluorobenzene

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 4.11g. (0.03 mole) of 2-fluorophenylazide in 81 ml. of cyclohexane was treated with 20 ml. of hydrogen fluoride. The reaction mixture was then shaken at room temperature for 24 hours, then cooled, vented, and rinsed from the bomb with two successive applications of 100 ml. of dichloromethane and then 100 ml. of water. The reaction mixture was then blown down under nitrogen, quenched in 75g. of ice, and rendered basic with KOH pellets. The reaction mixture was extracted with dichloromethane to yield 2.2g. (57%) of a brown-red fluid after drying over MgSO4. The 2,4-difluoroaniline structure of the final product was confirmed by IR, and the product had a b.p. of 90°-92° C. at 40 mm. Hg. cooled rinsed from the bomb with two successive applications of 100 ml quenched in 75g The reaction mixture was extracted with dichloromethane to yield 2.2g (57%) of a brown-red fluid after drying over MgSO4

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

Procedure: A mixture of 4.44g. (0.04 mole) of 2-fluoroaniline in 16 ml. of water and 9 ml. of concentrated HCl, kept at 0°-5° C., was treated with a solution of 2.90g. (0.04 mole) of NaNO2 in 10 ml. of water. The reaction mixture was aged for one-half hour at 0°-5° C. and there was then added slowly to the mixture a solution of 2.6g. (0.04 mole) of NaN3 in 10 ml. of water. The reaction mixture was then allowed to slowly reach room temperature, and it was noted that a gas was evolved. There was then added 40 ml. of petroleum ether, and the reaction mixture was shaken well, after which it was observed to separate into two separate layers. The yellow petroleum ether layer was separated, dried over MgSO4, and concentrated under reduced pressure at a temperature of about 30° C. There was produced 5.5g. of a yellow oil and the structure of the final product was confirmed by IR. A mixture of 4.44g kept at 0°-5° C. was treated with a solution of 2.90g The reaction mixture was aged for one-half hour at 0°-5° C. there was then added slowly to the mixture a solution of 2.6g was then allowed to slowly reach room temperature, and it There was then added 40 ml to separate into two separate layers The yellow petroleum ether layer was separated dried over MgSO4 concentrated under reduced pressure at a temperature of about 30° C There was produced 5.5g

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

Procedure: A mixture of 4.44g. (0.04 mole) of 2-fluoroaniline in 16 ml. of water and 9 ml. of concentrated HCl, kept at 0°-5° C., was treated with a solution of 2.90g. (0.04 mole) of NaNO2 in 10 ml. of water. The reaction mixture was aged for one-half hour at 0°-5° C. and there was then added slowly to the mixture a solution of 2.6g. (0.04 mole) of NaN3 in 10 ml. of water. The reaction mixture was then allowed to slowly reach room temperature, and it was noted that a gas was evolved. There was then added 40 ml. of petroleum ether, and the reaction mixture was shaken well, after which it was observed to separate into two separate layers. The yellow petroleum ether layer was separated, dried over MgSO4, and concentrated under reduced pressure at a temperature of about 30° C. There was produced 5.5g. of a yellow oil and the structure of the final product was confirmed by IR. A mixture of 4.44g kept at 0°-5° C. was treated with a solution of 2.90g The reaction mixture was aged for one-half hour at 0°-5° C. there was then added slowly to the mixture a solution of 2.6g was then allowed to slowly reach room temperature, and it There was then added 40 ml to separate into two separate layers The yellow petroleum ether layer was separated dried over MgSO4 concentrated under reduced pressure at a temperature of about 30° C There was produced 5.5g

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

Procedure: DBU (3.6 ml; 24.07 mmol; 1.10 eq.) was dissolved in DMF (45 ml) and put under nitrogen atmosphere. Ethyl isobutyrylacetate (Aldrich, 3.807 g; 24.07 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (3 g; 21.858 mmol; 1 eq.) in DMF (10 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 5 hours. Water (80 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (2×100 mL). Combined organics were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a brown oil. It was used in the next step without further purification. LC/MS (Method B): 278.2 (M+H)+. The reaction mixture was stirred at 70° C. for 5 hours The aqueous layer was extracted with EtOAc (2×100 mL) Combined organics were washed with HCl 0.1N, brine dried over MgSO4 concentrated under vacuum

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

Procedure: DBU (1.32 ml; 8.82 mmol; 1.10 eq.) was dissolved in DMF (16.5 ml) and put under nitrogen atmosphere. 3-Oxo-3-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester (Pharmacore, 1.767 g; 8.82 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.1 g; 8.02 mmol; 1 eq.) in DMF (15 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 2 hours. Water (40 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×40 mL). Combined organic layers were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 320.2 (M+H)+. The reaction mixture was stirred at 70° C. for 2 hours The aqueous layer was extracted with EtOAc (3×40 mL) Combined organic layers were washed with HCl 0.1N, brine dried over MgSO4 concentrated under vacuum

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

Procedure: DBU (1.33 ml; 8.90 mmol; 1.10 eq.) was dissolved in DMF (17 ml) and put under nitrogen atmosphere. 3-Oxo-4-phenyl-butyric acid methyl ester (Chemcollect, 1.711 g; 8.90 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.11 g; 8.10 mmol; 1 eq.) in DMF (2 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (30 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×40 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 312.1 (M+H)+. The mixture was stirred at 90° C. for 2 hours the aqueous layer was extracted with EtOAc (3×40 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium carbonate (2.419 g; 17.50 mmol; 2 eq.) was dissolved in DMSO (18 ml) and put under nitrogen atmosphere. 1-Azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.2 g; 8.75 mmol; 1 eq.) was dissolved in 10 mL of DMSO and ethyl 3-(tetrahydrofuran-2-yl)-3-oxopropanoate (Pharmacore, 1.793 mg; 9.63 mmol; 1.10 eq.) was added. This solution was added dropwise to the potassium carbonate solution at room temperature. The mixture was stirred at 70° C. for 3 hours. Water (30 mL) was added to the mixture and it was extracted with EtOAc (2×40 mL). Organics were washed with brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a brown oil. It was used in the next step without further purification. HPLC (Method A) Rt 4.14 min (Purity: 86.6%). was extracted with EtOAc (2×40 mL) Organics were washed with brine dried over MgSO4 concentrated under vacuum

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

Procedure: DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (37.5 ml) and put under nitrogen atmosphere. 3-Cyclopropyl-3-oxo-propionic acid ethyl ester (Betapharma, 3.132 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a brown oil. It was used in the next step without further purification. LC/MS (Method B): 276.1 (M+H)+. the aqueous layer was extracted with EtOAc (3×50 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

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

Procedure: DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (25 ml) and put under nitrogen atmosphere. 3-Cyclopentyl-3-oxo-propionic acid ethyl ester (Pharmacore, 3.695 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 304.2 (M+H)+. The mixture was stirred at 90° C. for 2 hours the aqueous layer was extracted with EtOAc (3×50 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

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

Procedure: A solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945 (500 mg; 3.65 mmol; 1 eq.) and methyl 4-chloroacetoacetate (823 mg; 5.47 mmol; 1.5 eq.) in morpholine (10 ml) was stirred at 50° C. overnight. The reaction mixture was evaporated. Water was added (20 mL) and was extracted with EtOAc (2×20 mL). Combined organic phases were extracted with 3 portions of HCl 1 N. Combined aqueous phases were made alkaline with NaOH 5N and were extracted with EtOAc (3×20 mL). Organic layers were dried over magnesium sulfate and evaporated, affording the title product as a dark red oil. It was used in the next step without further purification. HPLC (Method A) Rt 1.81 min. (Purity: 82.5%). The reaction mixture was evaporated Water was added (20 mL) was extracted with EtOAc (2×20 mL) Combined organic phases were extracted with 3 portions of HCl 1 N were extracted with EtOAc (3×20 mL) Organic layers were dried over magnesium sulfate evaporated

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

Procedure: DBU (3.6 ml; 24.07 mmol; 1.10 eq.) was dissolved in DMF (45 ml) and put under nitrogen atmosphere. Ethyl isobutyrylacetate (Aldrich, 3.807 g; 24.07 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (3 g; 21.858 mmol; 1 eq.) in DMF (10 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 5 hours. Water (80 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (2×100 mL). Combined organics were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a brown oil. It was used in the next step without further purification. LC/MS (Method B): 278.2 (M+H)+. The reaction mixture was stirred at 70° C. for 5 hours The aqueous layer was extracted with EtOAc (2×100 mL) Combined organics were washed with HCl 0.1N, brine dried over MgSO4 concentrated under vacuum