2-Methyl-1-tetralone

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

Procedure: An oven dried Schlenk tube equipped with a rubber septum was purged with argon. The septum was removed, and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol %) and (−)-2-(dicyclohexylphosphino)-2′-(dimethylamino)-1,1′-binaphthyl (13.6 mg, 0.028 mmol 5.5 mol %). The tube was capped with the septum, purged with argon, and toluene (2 mL) and triethylamine (5 mg, 0.05 mmol) were added through the septum. The mixture was stirred at room temperature for 3 min, then vinyl bromide (1.0 mL 1.0 mmol) and 2-methyl-1-tetralone (81 mg, 0.5 mmol) were added through the septum. The septum was removed and sodium t-butoxide (96 mg, 1.0 mmol) was added. The tube was capped with the septum and purged with argon. Additional toluene (4 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 83 mg (88%) of title compound. The ee was 9 determined to be 79% by chiral HPLC analysis. An oven dried Schlenk tube equipped with a rubber septum was purged with argon The septum was removed The tube was capped with the septum were added through the septum The septum was removed The tube was capped with the septum purged with argon Additional toluene (4 mL) was added the mixture was stirred at room temperature for 2 h The mixture was quenched with saturated aqueous ammonium chloride (5 mL) diluted with ether (20 mL) poured into a separatory funnel The layers were separated the aqueous layer was extracted with ether (20 mL) The combined organic layers were washed with brine (20 mL) dried over anhydrous magnesium sulfate filtered concentrated in vacuo The crude material was purified by flash chromatography on silica gel

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

Procedure: We found that both the yield and the enantioselectivity of the arylation of 2-methyl-α-tetralone could be brought to good levels by running the arylation using 10-20 mol % Pd(0)/12-24 mol % BINAP in toluene at 100° C.8,9 It was found that an excess of aryl bromide was necessary to ensure complete conversion of the ketone; 2-methyl-1-naphthol, biaryls, and compounds resulting from aldol condensation were formed as side-products. In some reactions, the α-phenylated ketone was also observed as a side product. Subsequent experiments demonstrated that the latter side product was a result of aryl transfer from the phosphine ligand.10 Using the conditions described above, the arylations of 2-methyl-α-tetralone proceeded with enantioselectivities up to 88% (Table 1).11 We have also briefly examined the reactions of 2-methyl-1-indanone, 1. Using 5 mol % Pd(OAc)2/12 mol % BINAP the reaction with yield at 100° C

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

Procedure: We found that both the yield and the enantioselectivity of the arylation of 2-methyl-α-tetralone could be brought to good levels by running the arylation using 10-20 mol % Pd(0)/12-24 mol % BINAP in toluene at 100° C.8,9 It was found that an excess of aryl bromide was necessary to ensure complete conversion of the ketone; 2-methyl-1-naphthol, biaryls, and compounds resulting from aldol condensation were formed as side-products. In some reactions, the α-phenylated ketone was also observed as a side product. Subsequent experiments demonstrated that the latter side product was a result of aryl transfer from the phosphine ligand.10 Using the conditions described above, the arylations of 2-methyl-α-tetralone proceeded with enantioselectivities up to 88% (Table 1).11 We have also briefly examined the reactions of 2-methyl-1-indanone, 1. Using 5 mol % Pd(OAc)2/12 mol % BINAP the reaction with yield at 100° C

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

Procedure: 0.16 milliliter diisopropylamine in 10 milliliters tetrahydrofuran were allowed to stand with 1.15 equivalents butyllithium at -25° C. The resulting solution of lithium diisopropylamine was cooled to -78° C. and 1 equivalent 2-methyl-1-tetralone in 5 milliliters tetrahydrofuran solution was dropped in. The mixture was allowed to stand at -70° C. for 100 minutes. 1.5 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 11 milliliters tetrahydrofuran were mixed rapidly with the mixture at -95° C. The mixture was quenched with 30 milliliters ammonium chloride solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered, and evaporated. 2-methyl-2-fluoro-tetralone was obtained in 50% yield. were mixed rapidly with the mixture at -95° C The mixture was quenched with 30 milliliters ammonium chloride solution extracted with dichloromethane The organic phase was dried with magnesium sulfate filtered evaporated

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

Procedure: 0.16 milliliter diisopropylamine in 10 milliliters tetrahydrofuran were allowed to stand with 1.15 equivalents butyllithium at -25° C. The resulting solution of lithium diisopropylamine was cooled to -78° C. and 1 equivalent 2-methyl-1-tetralone in 5 milliliters tetrahydrofuran solution was dropped in. The mixture was allowed to stand at -70° C. for 100 minutes. 1.5 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 11 milliliters tetrahydrofuran were mixed rapidly with the mixture at -95° C. The mixture was quenched with 30 milliliters ammonium chloride solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered, and evaporated. 2-methyl-2-fluoro-tetralone was obtained in 50% yield. were mixed rapidly with the mixture at -95° C The mixture was quenched with 30 milliliters ammonium chloride solution extracted with dichloromethane The organic phase was dried with magnesium sulfate filtered evaporated

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

Procedure: To 1.55 mL diisopropylamine in 40 mL THF is added a solution of 4.36 mL n-butyllithium (2.5M) in hexane at −78° C. After 10 min, 1.63 g 2-methyl-1-tetralone in 5 mL THF is added, and the solution is stirred for 50 min. Then, 1.60 g 6-oxo-hexanoic acid methyl ester in 5 mL THF is added dropwise, and stirring is continued for 15 min. After that, the cooling bath is removed and the mixture allowed to reach rt. Conc. ammoniachloride sol is added, and extracted with ethylacetate. After evaporation the residue is purified by column chromatography yielding 0.8 g 6-hydroxy-6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hexanoic acid methyl ester (7a). 2.5 g of this alcohol 8a is dissolved in 50 mL dichloromethane and 2.27 mL triethylamine is added. After cooling to 0° C., 2.86 g methanesulfonic acid anhydride in 20 mL dichloromethane is added dropwise. After complete addition, the cooling bath is removed and stirring continued over night. The solution is washed with 2N HCl and water, separated, dried and evaporated. The crude product and 1.6 g 1,8-diazabicyclo[5.4.0]undecen-7-en (DBU) is dissolved in 60 mL toluene an heated to reflux for 24 h. The mixture is poured on 2N HCl and extracted with dichloromethane. After evaporaton and column chromatography 0.6 g 6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hex-5-enoic acid methyl ester (7b) is obtained. 7b is converted to 7c in an analogous manner to that described for the conversion of 1c to 1d in example 1. 7c was obtained as an oil, MS (APCI): 286.1 (M−1). stirring is continued for 15 min After that, the cooling bath is removed to reach rt Conc. ammoniachloride sol is added extracted with ethylacetate After evaporation the residue is purified by column chromatography

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

Procedure: To a suspension of 0.86 g NaH in 40 mL of dry THF are added 5.0 g 2-methyl-1-tetralon in 20 mL of THF. After stirring for 30 min, 7.5 g ethyl-5-bromo-pentanoate in 20 mL of THF are added and the mixture is refluxed for 6 h. The cooled mixture is poured into water and extracted with ethylacetate. The extract is evaporated yielding crude ethyl-5-(2-Methyl-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate (6a) which is purified by column chromatography, yielding 3.6 g of pure 6a. 6a is converted to 6b in an analogous manner to that described for the conversion of 1c to 1d in example 1. 6b was obtained as an oil, MS (APCI): 274.1 (M−1). the mixture is refluxed for 6 h extracted with ethylacetate The extract is evaporated

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

Procedure: To a suspension of 0.7 g NaH in 40 mL of dry THF are added 4.0 g 2-methyl-1-tetralon in 20 mL of THF. After stirring for 30 min, 5.5 g ethyl-6-bromo-hexanoate in 10 mL of THF are added and the mixture is refluxed for 6 h. After evaporation of the solvent the residue is dissolved in a solution of 4.16 g potassium hydroxide in 50 mL of MeOH and 20 mL of H2O and heated to reflux over night. After evaporation of the MeOH, the aqueous phase is extracted with ethylacetate, acidified with 2N HCl, and extracted again with ethylacetate. This second extract is evaporated yielding 4.2 g of crude 6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-hexanoic acid (4a). In an analogous manner to that described for the conversion of 3b to 3c in example 3, 4a is converted to the title compound 4c. 4c is an oil MS (APCI): 288.1 (M−1). The enantiomers of 4c were separated by semipreparative HPLC using a Chiracel OJ-R and water/methanol as the mobile phase. Purity was determined by analytical HPLC (Chiracel OJ-R column [15 cm, 4.6 mm, particle size 5 μm] using water 40/ methanol 60 v/v at a flow rate of 0.6 ml/min, injection of 10 μl-samples). Retention time and % ee of each enantiomer was 16.75 min (100% ee) and 20.25 min (87% ee), respectively. the mixture is refluxed for 6 h After evaporation of the solvent the residue is dissolved in a solution of 4.16 g potassium hydroxide in 50 mL of MeOH and 20 mL of H2O heated to reflux over night After evaporation of the MeOH the aqueous phase is extracted with ethylacetate extracted again with ethylacetate This second extract is evaporated

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

Procedure: 0.16 milliliter diisopropylamine in 10 milliliters tetrahydrofuran were allowed to stand with 1.15 equivalents butyllithium at -25° C. The resulting solution of lithium diisopropylamine was cooled to -78° C. and 1 equivalent 2-methyl-1-tetralone in 5 milliliters tetrahydrofuran solution was dropped in. The mixture was allowed to stand at -70° C. for 100 minutes. 1.5 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 11 milliliters tetrahydrofuran were mixed rapidly with the mixture at -95° C. The mixture was quenched with 30 milliliters ammonium chloride solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered, and evaporated. 2-methyl-2-fluoro-tetralone was obtained in 50% yield. were mixed rapidly with the mixture at -95° C The mixture was quenched with 30 milliliters ammonium chloride solution extracted with dichloromethane The organic phase was dried with magnesium sulfate filtered evaporated

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

Procedure: An oven dried Schlenk tube equipped with a rubber septum was purged with argon. The septum was removed, and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol %) and (−)-2-(dicyclohexylphosphino)-2′-(dimethylamino)-1,1′-binaphthyl (13.6 mg, 0.028 mmol 5.5 mol %). The tube was capped with the septum, purged with argon, and toluene (2 mL) and triethylamine (5 mg, 0.05 mmol) were added through the septum. The mixture was stirred at room temperature for 3 min, then vinyl bromide (1.0 mL 1.0 mmol) and 2-methyl-1-tetralone (81 mg, 0.5 mmol) were added through the septum. The septum was removed and sodium t-butoxide (96 mg, 1.0 mmol) was added. The tube was capped with the septum and purged with argon. Additional toluene (4 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 83 mg (88%) of title compound. The ee was 9 determined to be 79% by chiral HPLC analysis. An oven dried Schlenk tube equipped with a rubber septum was purged with argon The septum was removed The tube was capped with the septum were added through the septum The septum was removed The tube was capped with the septum purged with argon Additional toluene (4 mL) was added the mixture was stirred at room temperature for 2 h The mixture was quenched with saturated aqueous ammonium chloride (5 mL) diluted with ether (20 mL) poured into a separatory funnel The layers were separated the aqueous layer was extracted with ether (20 mL) The combined organic layers were washed with brine (20 mL) dried over anhydrous magnesium sulfate filtered concentrated in vacuo The crude material was purified by flash chromatography on silica gel

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

Procedure: We found that both the yield and the enantioselectivity of the arylation of 2-methyl-α-tetralone could be brought to good levels by running the arylation using 10-20 mol % Pd(0)/12-24 mol % BINAP in toluene at 100° C.8,9 It was found that an excess of aryl bromide was necessary to ensure complete conversion of the ketone; 2-methyl-1-naphthol, biaryls, and compounds resulting from aldol condensation were formed as side-products. In some reactions, the α-phenylated ketone was also observed as a side product. Subsequent experiments demonstrated that the latter side product was a result of aryl transfer from the phosphine ligand.10 Using the conditions described above, the arylations of 2-methyl-α-tetralone proceeded with enantioselectivities up to 88% (Table 1).11 We have also briefly examined the reactions of 2-methyl-1-indanone, 1. Using 5 mol % Pd(OAc)2/12 mol % BINAP the reaction with yield at 100° C