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With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;
(1-(4-Bromophenyl)cyclobutyl)methanol (260 mg, 1.08 mmol), tert-butyldimethyichiorosilane (0.246 mL, 1.29 mmol) and imidazole (151 mg, 2.16 mmol) combined in dimethylformamide (6 mL) at room temperature for 18 hours. Water (20 mL) added and solution extracted with a 1:1 solution of ethyl acetate-heptane. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude purified on silica gel, eluding with a gradient from 0 to 30% ethyl acetate in heptane to give ((1-(4-bromophenyl)cyclobutyl)methoxy)(tert-butyl)dimethylsilane (323 mg, 84%) 1H NMR (400 MHz, CHLOROFORM-d) delta ppm -0.15 (s, 6H) 0.82 (s, 9H) 1.77-1.86 (m, 1H) 1.97-2.08 (m, 1H) 2.20-2.26 (m, 4H) 3.59 (s, 2H) 6.98 (d, 2H) 7.37 (d, 2H)
1-(4-bromophenyl)cyclobutane-1-carboxylic acid[ No CAS ]
[ 1227159-85-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
Bromophenyl)cyclobutanecarboxylic acid (290 mg, 1.14 mmol) in tetrahydrofuran (6 mL) was added a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (0.231 mL, 2.27 mmol) drop wise at room temperature and stirred for 24 hours. Methanol (1 mL) was slowly added to the reaction mixture and then concentrated. Water (10 mL) and 1M aqueous hydrochloric acid added and reaction extracted with a 1:1 ethyl acetate: heptane solution. Extract washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude purified on silica gel, eluting with a gradient from 20% to 80% ethyl acetate in heptane to give (1-(4-bromophenyl)cyclobutyl)methanol (265 mg, 96%).1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.81-1.92 (m, 1H) 2.01-2.11 (m, 1H) 2.16-2.31 (m, 4H) 3.71 (s, 2H) 7.00 (d, 2H) 7.43 (d, 2H)
62%
With dimethylsulfide borane complex; In 1,4-dioxane; at 0 - 20℃; for 0.166667h;
To a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (300 mg, 1.20 mmol) in 1,4-dioxane (5 mL) was added borane dimethylsulfide complex (0.24 mL, 2.4 mmol) dropwise at 0 C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with methanol (20 mL). The organic solvents were removed under reduced pressure to give a residue, which was dissolved in ethyl acetate, then washed with brine. The organic phase was concentrated to give [1-(4-bromophenyl)cyclobutyl]methanol (170 mg, 62% yield) as a yellow oil which was used directly in the next step.
Step 2: 1-Bromo-4-[1-(methoxymethyl)cyclobutyl]benzene 1.28 g (31.9 mmol) of a 60% strength suspension of sodium hydride in mineral oil were added to a solution of 7.0 g (29.0 mmol) of the compound from Example 110A/step 1 in 120 ml of anhydrous DMF at approx. 5 C. After the mixture had been stirred at this temperature for 1 h, 2.2 ml (34.8 mmol) of methyl iodide were added. The reaction mixture was allowed to warm to RT and stirring was continued for 15 h. The reaction mixture was then concentrated to a volume of approx. 20 ml on a rotary evaporator. Approx. 500 ml of water were added and the mixture was extracted three times with approx. 200 ml of diethyl ether each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and removal of the solvent on a rotary evaporator, the crude product obtained was purified by means of filtration with suction over approx. 200 g of silica gel with cyclohexane/ethyl acetate 50:1 as the mobile phase. 4.92 g (66% of th.) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, delta/ppm): 7.41 (d, 2H), 7.04 (d, 2H), 3.48 (s, 2H), 3.27 (s, 3H), 2.32-2.22 (m, 4H), 2.12-2.00 (m, 1H), 1.90-1.80 (m, 1H). MS (DCI, NH3): m/z=272/274 [M+NH4]+. GC/MS (method L, ESIpos): Rt=5.25 min, m/z=254/256 [M]+.
1.28 g (31.9 mmol) of a 60% strength suspension of sodium hydride in mineral oil were added to a solution of 7.0 g (29.0 mmol) of the compound from Example 61A/step 2 in 120 ml of anhydrous DMF at approx. 5 C. After the mixture had been stirred at this temperature for 1 h, 2.2 ml (34.8 mmol) of methyl iodide were added. The reaction mixture was allowed to warm to RT and stirring was continued for 15 h. The reaction mixture was then concentrated to a volume of approx. 20 ml on a rotary evaporator. Approx. 500 ml of water were added and the mixture was extracted three times with approx. 200 ml of diethyl ether each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After filtration and removal of the solvent on a rotary evaporator, the crude product obtained was purified by means of filtration with suction over approx. 200 g of silica gel with cyclohexane/ethyl acetate 50:1 as the mobile phase. 4.92 g (66% of th.) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 7.41 (d, 2H), 7.04 (d, 2H), 3.48 (s, 2H), 3.27 (s, 3H), 2.32-2.22 (m, 4H), 2.12-2.00 (m, 1H), 1.90-1.80 (m, 1H).MS (DCI, NH3): m/z=272/274 [M+NH4]+.GC/MS (method K, ESIpos): Rt=5.25 min, m/z=254/256 [M]+.
7.20 g (25.4 mmol) of the compound from Example 61A/step 1 were dissolved in 150 ml of anhydrous THF, and 25 ml (25 mmol) of a 1 M solution of lithium aluminium hydride in THF were added dropwise at 0 C. When the addition had ended, the ice/water bath was removed and stirring was continued at RT. After 1 h, the reaction was ended by-initially cautious-addition of approx. 450 ml of saturated aqueous ammonium chloride solution. The mixture was then extracted with ethyl acetate. After drying of the organic extract over anhydrous magnesium sulphate and subsequent filtration, the solvent was removed on a rotary evaporator. 6.04 g (88% of th., purity of 90%) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 7.43 (d, 2H), 7.02 (d, 2H), 3.72 (d, 2H), 2.33-2.20 (m, 4H), 2.13-2.01 (m, 1H), 1.93-1.83 (m, 1H).MS (DCI, NH3): m/z=258/260 [M+NH4]+.GC/MS (method K, ESIpos): Rt=5.77 min, m/z=240/242 [M]+.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h;
Step 1: [1-(4-Bromophenyl)cyclobutyl]methanol 7.20 g (25.4 mmol) of the compound from Example 109A/step 1 were dissolved in 150 ml of anhydrous THF, and 25 ml (25 mmol) of a 1 M solution of lithium aluminium hydride in THF were added dropwise at 0 C. When the addition had ended, the ice/water bath was removed and stirring was continued at RT. After 1 h, the reaction was ended by-initially cautious-addition of approx. 450 ml of saturated aqueous ammonium chloride solution. The mixture was then extracted with ethyl acetate. After drying of the organic extracts over anhydrous magnesium sulfate and subsequent filtration, the solvent was removed on a rotary evaporator. 6.04 g (88% of th., purity of approx. 90%) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, delta/ppm): 7.43 (d, 2H), 7.02 (d, 2H), 3.72 (d, 2H), 2.33-2.20 (m, 4H), 2.13-2.01 (m, 1H), 1.93-1.83 (m, 1H). MS (DCI, NH3): m/z=258/260 [M+NH4]+. GC/MS (method L, ESIpos): Rt=5.77 min, m/z=240/242 [M]+.
Step 1: [1-(4-Bromophenyl)cyclobutyl]methyl acetate 236 mul (2.50 mmol) of acetic anhydride were added to a solution of 402 mg (1.67 mmol) of the compound from Example 110A/step 1 in 6 ml of pyridine at 0 C. After the reaction mixture had been stirred at RT for 16 h, all the volatile constituents were removed on a rotary evaporator. The product was isolated from the residue obtained by means of MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 10:1). 450 mg (91% of th., purity of approx. 95%) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, delta/ppm): 7.42 (d, 2H), 7.02 (d, 2H), 4.21 (s, 2H), 2.38-2.30 (m, 2H), 2.29-2.21 (m, 2H), 2.16-2.03 (m, 1H), 1.98 (s, 3H), 1.93-1.83 (m, 1H). MS (DCI, NH3): m/z=300/302 [M+NH4]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 0.5h;Inert atmosphere;
A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (260 mg, 1.00 mmol) and N,N-dimethylformiminium chloride (250 mg, 2.00 mmol) in dry dioxane (5 mL) and DMF (1 mL) was sealed in a reaction vessel and stirred at room temperature for 10 minutes to give a white slurry. To the slurry was added 2M aqueous potassium carbonate (2.5 mL, 5.0 mmol), <strong>[1227159-85-4][1-(4-bromophenyl)cyclobutyl]methanol</strong> (240 mg, 1.00 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg). The reaction mixture was degassed with nitrogen and heated to 90 C. for 30 minutes. The reaction was quenched with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic phases were dried and concentrated in vacuo to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde (180 mg, 68% yield), which was used into next step without further purification.
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