cyclobutylboronic acid

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:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclobutylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring under reflux for 6 days, to give the desired product as a light brown foam (14%). under reflux for 6 days

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (1.8 g, 6.2 mmol), cyclobutyl boronic acid (0.78 g, 7.5 mmol), Pd(dppf)Cl2 (0.40 g, 0.5 mmol), and 2M aqueous cesium carbonate (aq) (5 mL, 9.9 mmol) in toluene (10 ml) was degassed with argon for 10 minutes and then heated to 90° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and filtered through hyflo®. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (70 mL). The organic layer was isolated, then washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was subjected to flash chromatography (Si-PPC, gradient 0% to 30%, DCM in pentane) to afford the title compound as a yellow liquid (0.504 g, 42%). 1H NMR (DMSO-d6): 8.08 (1H, t, J=8.3 Hz), 7.44 (1H, d, J=13.2 Hz), 7.28 (1H, d, J=8.5 Hz), 3.65 (1H, m), 2.33 (2H, m), 2.13 (2H, m), 1.99 (1H, m), 1.84 (1H, m). The reaction mixture was then cooled to room temperature filtered through hyflo® The reaction mixture was partitioned between ethyl acetate (70 mL) and water (70 mL) The organic layer was isolated washed with brine (50 mL) dried (MgSO4) filtered concentrated in vacuo

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

Procedure: Following the procedure as described in Example 373 Step 1 and making non-critical variations to replace tert-butyl 5-chloro-4-((1-cyanocyclohexyl)-methoxy)-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate, to replace cyclopropylboronic acid with cyclobutylboronic acid, and to replace tricyclohexylphosphine tetrafluoroborate with 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos), the title compound was obtained as a colorless syrup containing ˜25% tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluorobenzoate (1.01 g, 97%): MS (ES+) m/z 359.1 (M−55).

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

Procedure: The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclobutylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring under reflux for 6 days, to give the desired product as a light brown foam (14%). under reflux for 6 days

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

Procedure: To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (4.8 g), bis(tricyclohexylphosphine)palladium (II) dichloride (515 mg), tripotassium phosphate (16 g) and cyclobutylboronic acid (2.6 g) were added toluene (39 mL) and water (2 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg). 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg) was dissolved in chloroform (1.5 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (8 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (350 mg). the mixture was refluxed for 8 hr After cooling the mixture was extracted with ethyl acetate washed with saturated brine the solvent was evaporated The residue was purified by column chromatography (hexane:ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-iodo-5-nitrobenzotrifluoride (4.62 g), cyclobutylboronic acid (4.15 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (4.15 g), cesium carbonate (22.6 g), toluene (67.0 mL) and water (33.0 mL) was stirred in a sealed tube at 80° C. for 6 hours. After cooling the reaction mixture to room temperature, extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-94:6) to give 1-cyclobutyl-4-nitro-2-(trifluoromethyl)benzene as a pale yellow oil (1.69 g). After cooling the reaction mixture to room temperature extraction The combined organic layers were dried over anhydrous magnesium sulfate after removing the desiccant by filtration the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-94:6)