ethyl 7-iodoheptanoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: All reactions reported in this example were carried out in an oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar, copper iodide and a T-joint to which an argon-filled balloon had been attached. The flask was evacuated while being heated, then purged with argon from the balloon. This operation was repeated three times before addition of any reagents or solvents. To a stirred suspension of cuprous iodide (2.38 g, 12.5 mmol) in 30 mL of dried THF at ca −78° C. under argon, cyclopropylmagnesium bromide in THF solution (0.5M, 50 ml, 25 mmol) was added via syringe. After the addition had been completed, the mixture was stirred for 30 min and a solution of ethyl 7-iodoheptanoate (3.02 g, 10.63 mmol) in 10 ml of THF was added. After the addition, the reaction was allowed to warm to 0° C. and stirred for 2 h. It was allowed to warm to ambient temperature and stirred overnight. The reaction was poured into a saturated ammonium chloride solution. The organic product was extracted into an ether layer which was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a residue. 1H NMR confirmed the desired ethyl 7-cyclopropylheptanoate. GC indicated a single peak material. To the residue were added 25 mL of water and a 25 ml of a solution of NaOH (2N). The mixture was stirred at ambient temperature overnight. The alkaline solution was washed with ether. The aqueous layer was separated and subjected to in vacuo evaporation to remove any residual ether. The alkaline solution was acidified with an aqueous solution of HCl (2N) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes and then the precipitate was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with water and two-50-ml of hexane, and was dried in vacuo at room temperature for 2 days to afford 0.72 g (40%) of 7-cyclopropylheptanoic acid as a white solid. 1H NMR (400 MHz DMSO-d6) δ: 0 (m, 2H), 0.37 (m, 2H), 0.66 (m, 1H), 1.16-1.18(m, 2H), 1.34-1.50 (m, 6H), 1.78 (m, 2H), 2.20 (m, 2H), 12.0 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 4.27, 10.65, 24.50, 28.61, 29.05, 33.64, 34.01, 174.43. Anal. Calcd for C10H18O2: C, 70.22; H, 10.66. Found: C, 70.05, H, 10.34 with a Karl Fisher water content %: 0.46. equipped with a Teflon-coated magnetic stirring bar The flask was evacuated while being heated purged with argon from the balloon before addition of any reagents or solvents After the addition After the addition stirred for 2 h to warm to ambient temperature stirred overnight The organic product was extracted into an ether layer which was washed with brine dried over magnesium sulfate filtered concentrated in vacuo to yield a residue The mixture was stirred at ambient temperature overnight The alkaline solution was washed with ether The aqueous layer was separated subjected to in vacuo evaporation to remove any residual ether leading to the precipitation of a white solid Stirring was continued for an additional 30 minutes the precipitate was filtered off with suction through a sintered glass funnel The collected solid was successively washed with water and two-50-ml of hexane was dried in vacuo at room temperature for 2 days

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

Procedure: Title compound 398 (0.304 g, 1.54 mmol) was dissolved in acetonitrile (5.0 mL) and the ethyl 7-iodoheptanoate (0.613 g, 2.16 mmol) and the potassium carbonate (0.639 g, 4.62 mmol) were added. The reaction mixture was stirred at 70° C. for 60 hours. The mixture was cooled down and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 399 (201 mg, 37%). MS (m/z): 354.2 (M+H). The mixture was cooled down The organic phase was washed with water and brine dried over sodium sulfate filtered evaporated The residue was purified by flash chromatography with 10% ethyl acetate in hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: All reactions reported in this example were carried out in an oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar, copper iodide and a T-joint to which an argon-filled balloon had been attached. The flask was evacuated while being heated, then purged with argon from the balloon. This operation was repeated three times before addition of any reagents or solvents. To a stirred suspension of cuprous iodide (2.38 g, 12.5 mmol) in 30 mL of dried THF at ca −78° C. under argon, cyclopropylmagnesium bromide in THF solution (0.5M, 50 ml, 25 mmol) was added via syringe. After the addition had been completed, the mixture was stirred for 30 min and a solution of ethyl 7-iodoheptanoate (3.02 g, 10.63 mmol) in 10 ml of THF was added. After the addition, the reaction was allowed to warm to 0° C. and stirred for 2 h. It was allowed to warm to ambient temperature and stirred overnight. The reaction was poured into a saturated ammonium chloride solution. The organic product was extracted into an ether layer which was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a residue. 1H NMR confirmed the desired ethyl 7-cyclopropylheptanoate. GC indicated a single peak material. To the residue were added 25 mL of water and a 25 ml of a solution of NaOH (2N). The mixture was stirred at ambient temperature overnight. The alkaline solution was washed with ether. The aqueous layer was separated and subjected to in vacuo evaporation to remove any residual ether. The alkaline solution was acidified with an aqueous solution of HCl (2N) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes and then the precipitate was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with water and two-50-ml of hexane, and was dried in vacuo at room temperature for 2 days to afford 0.72 g (40%) of 7-cyclopropylheptanoic acid as a white solid. 1H NMR (400 MHz DMSO-d6) δ: 0 (m, 2H), 0.37 (m, 2H), 0.66 (m, 1H), 1.16-1.18(m, 2H), 1.34-1.50 (m, 6H), 1.78 (m, 2H), 2.20 (m, 2H), 12.0 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 4.27, 10.65, 24.50, 28.61, 29.05, 33.64, 34.01, 174.43. Anal. Calcd for C10H18O2: C, 70.22; H, 10.66. Found: C, 70.05, H, 10.34 with a Karl Fisher water content %: 0.46. equipped with a Teflon-coated magnetic stirring bar The flask was evacuated while being heated purged with argon from the balloon before addition of any reagents or solvents After the addition After the addition stirred for 2 h to warm to ambient temperature stirred overnight The organic product was extracted into an ether layer which was washed with brine dried over magnesium sulfate filtered concentrated in vacuo to yield a residue The mixture was stirred at ambient temperature overnight The alkaline solution was washed with ether The aqueous layer was separated subjected to in vacuo evaporation to remove any residual ether leading to the precipitation of a white solid Stirring was continued for an additional 30 minutes the precipitate was filtered off with suction through a sintered glass funnel The collected solid was successively washed with water and two-50-ml of hexane was dried in vacuo at room temperature for 2 days

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: All reactions reported in this example were carried out in an oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar, copper iodide and a T-joint to which an argon-filled balloon had been attached. The flask was evacuated while being heated, then purged with argon from the balloon. This operation was repeated three times before addition of any reagents or solvents. To a stirred suspension of cuprous iodide (2.38 g, 12.5 mmol) in 30 mL of dried THF at ca −78° C. under argon, cyclopropylmagnesium bromide in THF solution (0.5M, 50 ml, 25 mmol) was added via syringe. After the addition had been completed, the mixture was stirred for 30 min and a solution of ethyl 7-iodoheptanoate (3.02 g, 10.63 mmol) in 10 ml of THF was added. After the addition, the reaction was allowed to warm to 0° C. and stirred for 2 h. It was allowed to warm to ambient temperature and stirred overnight. The reaction was poured into a saturated ammonium chloride solution. The organic product was extracted into an ether layer which was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a residue. 1H NMR confirmed the desired ethyl 7-cyclopropylheptanoate. GC indicated a single peak material. To the residue were added 25 mL of water and a 25 ml of a solution of NaOH (2N). The mixture was stirred at ambient temperature overnight. The alkaline solution was washed with ether. The aqueous layer was separated and subjected to in vacuo evaporation to remove any residual ether. The alkaline solution was acidified with an aqueous solution of HCl (2N) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes and then the precipitate was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with water and two-50-ml of hexane, and was dried in vacuo at room temperature for 2 days to afford 0.72 g (40%) of 7-cyclopropylheptanoic acid as a white solid. 1H NMR (400 MHz DMSO-d6) δ: 0 (m, 2H), 0.37 (m, 2H), 0.66 (m, 1H), 1.16-1.18(m, 2H), 1.34-1.50 (m, 6H), 1.78 (m, 2H), 2.20 (m, 2H), 12.0 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 4.27, 10.65, 24.50, 28.61, 29.05, 33.64, 34.01, 174.43. Anal. Calcd for C10H18O2: C, 70.22; H, 10.66. Found: C, 70.05, H, 10.34 with a Karl Fisher water content %: 0.46. equipped with a Teflon-coated magnetic stirring bar The flask was evacuated while being heated purged with argon from the balloon before addition of any reagents or solvents After the addition After the addition stirred for 2 h to warm to ambient temperature stirred overnight The organic product was extracted into an ether layer which was washed with brine dried over magnesium sulfate filtered concentrated in vacuo to yield a residue The mixture was stirred at ambient temperature overnight The alkaline solution was washed with ether The aqueous layer was separated subjected to in vacuo evaporation to remove any residual ether leading to the precipitation of a white solid Stirring was continued for an additional 30 minutes the precipitate was filtered off with suction through a sintered glass funnel The collected solid was successively washed with water and two-50-ml of hexane was dried in vacuo at room temperature for 2 days

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

Procedure: Following the procedure described in Example 1, step 4, but substituting indole-2-carboxylic acid for 5, followed by Example 18, step 1, 2, 3, but substituting respectively ethyl-6-iodohexanoate for ethyl-7-iodoheptanoate and indole-2-carbonyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 112 in 35% yield. 1H NMR: (300 MHz, CDCl3) δ 7.62 (m, 2H), 7.20-7.00 (m, 3H), 2.82 (m, 2H), 2.00 (m, 2H), 1.62 (m, 2H), 1.22 (m, 4H).

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

Procedure: Following the procedure described in Example 18, step 1, 2, 3, but substituting respectively ethyl-6-iodohexanoate for ethyl-7-iodoheptanoate and 2-naphthoyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 111 in 55% yield. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 8.47 (s, 1H), 8.05-7.50 (m, 6H), 3.12 (br t, 2H), 2.15 (br t, 2H), 1.82-1.60 (m, 4H), 1.46 (m, 2H). 13C NMR (75 MHz, 20% CD30D in CDCl3): δ 23.59, 25.02, 28.36, 32.33, 38.06, 123.40, 126.56, 127.46, 128.21, 128.29, 129.29, 129.60, 132.25, 133.78, 135.37, 171.04, 201.04.

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

Procedure: Following the procedure described in Example 18, step 1, 2, 3, but substituting respectively ethyl-6-iodohexanoate for ethyl-7-iodoheptanoate and 4-methoxybenzoyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 110 in 54% yield. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 7.86 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.87 (t, J=6.6 Hz, 2H), 2.07 (br t, 2H), 1.62 (m, 4H), 1.34 (m, 2H). 13C NMR (75 MHz, 20% CD3OD in CDCl3): δ 23.68, 24.96, 28.32, 32.28, 37.63, 55.14, 113.49, 129.48, 130.13, 163.35, 171.06, 199.81.

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

Procedure: Title compound 398 (0.304 g, 1.54 mmol) was dissolved in acetonitrile (5.0 mL) and the ethyl 7-iodoheptanoate (0.613 g, 2.16 mmol) and the potassium carbonate (0.639 g, 4.62 mmol) were added. The reaction mixture was stirred at 70° C. for 60 hours. The mixture was cooled down and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 399 (201 mg, 37%). MS (m/z): 354.2 (M+H). The mixture was cooled down The organic phase was washed with water and brine dried over sodium sulfate filtered evaporated The residue was purified by flash chromatography with 10% ethyl acetate in hexanes