methyl cyanoformate

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

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

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

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

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

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

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyl lithium (2.5 M, 15.8 mL) is added dropwise via syringe to a solution of diisopropyl amine (55 mL) in anhydrous THF (20 mL) at −10° C. under an atmosphere of nitrogen. After stirring for 30 min at this temperature, the solution is cooled to −78° C. and a solution of containing 6,7-dihydro-1-benzthiophen-4(5H)one (BI.1, 5.00 g) in anhydrous THF (20 mL) is added dropwise over 15 minutes. The solution is warmed to 0° C. and stirred for one hour at that temperature. After re-cooling to −78° C., HMPA (5.7 mL) and methyl-cyanoformate (3.1 mL) are sequentially added. The solution is stirred for 10 minutes at −78° C. The reaction mixture is quickly poured into cold water (100 mL) and extracted with ether (250 mL). The organic phase is washed with brine, dried over Na2SO4, filtered, and concentrated to give a red oil. This oil is chromatographed on a Biotage column eluting with 0-30% ethyl acetate in heptane (500 mL each 10%) to give 3.87 g (56%) of the title compound as a white solid. Physical characteristics. Mp. 85-86° C.; MS (ESI+) m/z 211.0 (M+H)+; HRMS (FAB) m/z 211.0425 (C10H10O3S+H). Anal. Found: C, 57.15; H, 4.84. The solution is warmed to 0° C. stirred for one hour at that temperature After re-cooling to −78° C. The solution is stirred for 10 minutes at −78° C extracted with ether (250 mL) The organic phase is washed with brine dried over Na2SO4 filtered concentrated to give a red oil This oil is chromatographed on a Biotage column eluting with 0-30% ethyl acetate in heptane (500 mL each 10%)

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

Procedure: A solution of N-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide (1.17 g, 3.27 mmol) in THF (15 ml) was added dropwise over a 15 minute period to a stirred suspension of 80% NaH (0.30 g, 10 mmol) (Aldrich) in methyl cyanoformate (1.5 ml, 19 mmol) (Aldrich) and THF (15 ml) under nitrogen. The reaction mixture was stirred 30 minutes at room temperature then quenched with acetic acid (0.7 ml, 12 mmol). The solution was concentrated in vacuo onto silica gel (3 g) and the absorbed material purified by chromatography on silica gel (30 g) eluting with ether:hexane (1:4 to 1:3) to give methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.64 g). 1H NMR (CDCl3, 200 MHz) δ: 2.5-2.9 (m, 4H, CH2CH2), 3.93 (s, 3H, CH3), 7.10 (d, J=8 Hz, 1H, Ar), 7.32 (t, J=8 Hz, 1H, Ar), 7.39 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar), 7.82 (d, J=8 Hz, 1H, Ar), 13.35 (s, 1H, OH). Anal. Calculated for C21H15F3N2O4: C, 60.58; H, 3.63; N, 6.73. Found: C, 60.66; H, 3.66; N, 6.68. The solution was concentrated in vacuo onto silica gel (3 g) the absorbed material purified by chromatography on silica gel (30 g) eluting with ether:hexane (1:4 to 1:3)

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

Procedure: β-methoxytetralone 1 (0.254 g , 1.4 mmol in 5 ml of THF) was added to a refluxed mixture of (MeO)2CO (2.8 mmol) and sodium hydride (38 mg) in THF (20 ml). The mixture was heated at reflux during the night, cooled, water (25 ml) was added and neutralized with 5% HCL and extracted with ether. The ether was washed with a cooled satured sodium bicarbonate and water. The organic phase was dried. with anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue in THF (5 ml) was added to a mixture of sodium hydride (21 mg, 85 mmol) and RcI (CH3I, 8.5 mmol) in THF (15 ml) and HMPA (1.7 mmol). The mixture was stirred during the night, water (25 ml) was added and neutralized with 5% HCL and extracted with ether. The ether was washed with a cooled satured sodium bicarbonate and water. The organic phase was dried with anhydrous MgSO4 and the solvent was removed under reduced pressure and the compound 2 (Rc =CH3) was obtained in the yield of 80%. The action of MeOCOCN (0.1 ml, 10 min at -78° C.) on the compound 2 (Rc =CH3) (200 mg in 5 ml THF) in presence of LDA (lithium diisopropyl amine prepared from 0.13 ml diisopropyl amine and 1.6M butyl lithium (0.6 ml) at -25° C., 30 min) and HMPA (0.15 ml) yield in 83% the compound 3 (Rc =CH3). To this compound (290 mg) in THF (20 ml) was added 35% potassium hydride (119 mg, 0.72 mmol) 18-crown-6 (24 mg, 0.06 mmol) and the mixture stirred 8 h at 25° C. and then I(CH2)8OTBDMS (657 mg, 1.9 mmol) was added and the mixture heated at reflux 6 h. The extraction with ethyl acetate yield the compound 4 (n=8, Rc =CH3) (98%). The decarboalkoxylation with lithium bromide in pyridine yield the compound 5 (n=8, Rc =CH3) which was treated by the Grignard's reagent of 3-bromo-anisole followed by acidic treatment. The resulting compound 6 (n=8, Rc =CH3) was converted into amide 7 (n=8, Ra =CH3, Rb =C4H9, Rc =CH3) Thus a cooled solution compound 6 (n=8, Rc =CH3) (700 mg) in acetone (17 ml) was added Jones' reagent (8N-chromic add solution, 0.77 ml). After 30 minutes, isopropanol (5 ml) was added and the mixture was poured in water and extracted three times with ethyl acetate. The organic layer was washed twice with brine, dried over magnesium sulfate and evaporated to dryness. The crude acid was used in the next step without purification. To its solution in anhydrous methylene chloride (4 ml) at -10° C. was added, under stirring, triisobutylamine (470 μl, 1.96 mmol) and isobutylchloroformate (280 μl, 2.1 mmol). After 40 minutes, N-methylbutylamine (1.5 ml) was added and the mixture was stirred at room temperature during 1 hour. Methylene chloride (50 ml) was added. The organic solution was washed with 1N HCl, saturated sodium bicarbonate solution and water (3×), dried on magnesium sulfate and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 50 g). Elution with a mixture of hexane-ethyl acetate gave the amide 7 (n=8, Ra =CH3, Rb =C4H9, Rc =CH3) (63%) The removal of the protection into compound 8 (EM 736, n=7, Ra =CH3, Rb =C4H9, Rc =CH3) is performed with pyridine-HCl.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 6.0 g (0.03 mol) of cuprous iodide in 100 ml of THF was added 25 ml of dimethyl sulfide, and the resulting yellow solution was cooled to -78° C. and treated dropwise with a solution of 23 ml (0.06 mol) of a 3.0M solution of phenyl magnesium bromide in diethyl ether. The resulting pale yellow-orange solution was stirred at -78° C. under nitrogen for one hour and then treated with 3.02 g (0.03 mol) of 2-cyclohexenone in 10 ml of THF. The resulting mixture was allowed to warm to 0° C. over a two hour period, recooled to -78 ° C., treated with 15 ml of hexamethylphosphoramide, stirred for thirty minutes, treated with 8.0 g (0.09 mol) of methyl cyanoformate and allowed to warm to ambient temperature overnight. The reaction mixture was poured into 100 ml of 2N hydrochloric acid, and the organic phase was separated and the aqueous phase back extracted with MDC. The combined organic extracts were taken to dryness in vacuo, and the residue triturated with saturated ammonium chloride, then with water, then with brine and taken to dryness once again to give 3.2 g of methyl 2-phenylcyclohexan-6-one carboxylate as an oil. to warm to 0° C. over a two hour period recooled to -78 ° C. stirred for thirty minutes to warm to ambient temperature overnight the organic phase was separated the aqueous phase back extracted with MDC the residue triturated with saturated ammonium chloride