2-Di-t-butylphosphino-2'-methyl)-1,1'-biphenyl

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:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-bromo-3-methylbenzoate (1.5 g, 6.55 mmol), methyl 3-oxobutanoate (0.99 g, 8.51 mmol) and K3PO4 (4.17 g, 19.6 mmol) were mixed with Pd(OAc)2 (15 mg) and di-tert-butyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphine (39 mg), and diluted with toluene (25 ml). The resultant mixture was simply degassed via vacuum and charged with argon. Then it was heated at 90° C. for 24 h and at 110° C. for 5 hours. After aqueous work-up with EtOAc, the desired product-methyl 4-(2-ethoxy-2-oxoethyl)-3-methylbenzoate was isolated by column chromatography, eluting with EtOAc/Hexane (1/3), as oil (366 mg, 25%). The resultant mixture was simply degassed via vacuum charged with argon

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

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

Procedure: Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under an argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by Et3N (1.86 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.4 mL). The reaction mixture was stirred at 10° C. for 1 h. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions c): 1.84 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H). After cooling the reaction mixture to 10° C. The reaction mixture was stirred at 10° C. for 1 h DMF was evaporated The residue was poured into NH4Cl (sat. aq. solution) extracted with EtOAc (3×50 mL) dried over Na2SO4 filtered concentrated The residue was dissolved in MeOH filtered over a PL-Thiol cartridge The filtrate was concentrated the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) 1.84 min

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

Procedure: Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under an argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by Et3N (1.86 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.4 mL). The reaction mixture was stirred at 10° C. for 1 h. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions c): 1.84 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H). After cooling the reaction mixture to 10° C. The reaction mixture was stirred at 10° C. for 1 h DMF was evaporated The residue was poured into NH4Cl (sat. aq. solution) extracted with EtOAc (3×50 mL) dried over Na2SO4 filtered concentrated The residue was dissolved in MeOH filtered over a PL-Thiol cartridge The filtrate was concentrated the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) 1.84 min

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

Procedure: A 40 mL vial equipped with a magnetic stir bar was charged with 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (0.6695 g, 1.853 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.06363 g, 0.06948 mmol), 2-(di-t-butylphosphino)-2′-methylbiphenyl (0.08684 g, 0.2779 mmol), and cesium carbonate (0.7245 g, 2.224 mmol). The reaction vessel was capped, evacuated, and backfilled with argon three times then 1,2-dimethoxyethane (20.00 mL, 192.4 mmol) was added via syringe under argon. After the mixture was stirred vigorously for 2 min at room temperature, nitroethane (0.2795 mL, 3.891 mmol) was added and the reaction was heated overnight at 50° C. The reaction was allowed to cool to ambient temperature. The mixture was quenched with a solution of sat. aqueous ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in methylene chloride and silica gel was added. The solvent was removed and the residue was purified by flash column chromatography using 0-20% ethylacetate in hexanes to give the title compound in 58% yield. A 40 mL vial equipped with a magnetic stir bar The reaction vessel was capped evacuated the reaction was heated overnight at 50° C to cool to ambient temperature The mixture was quenched with a solution of sat. aqueous ammonium chloride The layers were separated the aqueous phase was extracted with ethyl acetate The combined organic phase was washed with water then dried with magnesium sulfate filtered concentrated under reduced pressure silica gel was added The solvent was removed the residue was purified by flash column chromatography

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

Procedure: A 40 mL vial equipped with a magnetic stir bar was charged with 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (0.6695 g, 1.853 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.06363 g, 0.06948 mmol), 2-(di-t-butylphosphino)-2′-methylbiphenyl (0.08684 g, 0.2779 mmol), and cesium carbonate (0.7245 g, 2.224 mmol). The reaction vessel was capped, evacuated, and backfilled with argon three times then 1,2-dimethoxyethane (20.00 mL, 192.4 mmol) was added via syringe under argon. After the mixture was stirred vigorously for 2 min at room temperature, nitroethane (0.2795 mL, 3.891 mmol) was added and the reaction was heated overnight at 50° C. The reaction was allowed to cool to ambient temperature. The mixture was quenched with a solution of sat. aqueous ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in methylene chloride and silica gel was added. The solvent was removed and the residue was purified by flash column chromatography using 0-20% ethylacetate in hexanes to give the title compound in 58% yield. A 40 mL vial equipped with a magnetic stir bar The reaction vessel was capped evacuated the reaction was heated overnight at 50° C to cool to ambient temperature The mixture was quenched with a solution of sat. aqueous ammonium chloride The layers were separated the aqueous phase was extracted with ethyl acetate The combined organic phase was washed with water then dried with magnesium sulfate filtered concentrated under reduced pressure silica gel was added The solvent was removed the residue was purified by flash column chromatography

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

Procedure: A 200 mL round-bottom flask containing a stir bar was charged with 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene (5.00 g, 11.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.400 g, 0.437 mmol; Strem), 2-(di-t-butylphosphino)-2′-methylbiphenyl (0.546 g, 1.75 mmol; Strem), and cesium carbonate (4.55 g, 14.0 mmol; Alfa Aesar). The reaction vessel was capped with a rubber septum, evacuated, backfilled with argon three times and 1,2-dimethoxyethane (100 mL, 1000 mmol) and 4-nitro-butyric acid methyl ester (3.02 mL, 24.4 mmol) were added via syringe under argon. After the mixture was stirred vigorously for 2 min at room temperature, the flask was equipped with a condensor and heated at 50° C. overnight. The reaction was allowed to cool to ambient temperature and quenched with a solution of sat. aqueous ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in methylene chloride and absorbed onto silica gel, then purified by flash column chromatography (0-20% hexanes in ethylacetate) to give 2.34 g of the title compound in 41% yield. A 200 mL round-bottom flask containing a stir bar The reaction vessel was capped with a rubber septum evacuated were added via syringe under argon the flask was equipped with a condensor heated at 50° C. overnight to cool to ambient temperature quenched with a solution of sat. aqueous ammonium chloride The layers were separated the aqueous phase was extracted with ethyl acetate The combined organic phase was washed with water then dried with magnesium sulfate filtered concentrated under reduced pressure The crude product was dissolved in methylene chloride absorbed onto silica gel purified by flash column chromatography (0-20% hexanes in ethylacetate)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.0 g of methyl 4-bromobenzoate, 1.3 ml of nitroethane, 172 mg of tris(dibenzylideneacetone)dipalladium(0), 232 mg of 2-(di-tert-butylphosphino)-2′-methylbiphenyl, 3.33 g of cesium carbonate, and 44 ml of 1,2-dimethoxyethane (DME) was stirred at 60° C. for 18 hours. The reaction mixture was left to be cooled to room temperature, followed by adding a saturated aqueous ammonium chloride solution and extracting with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.44 g of methyl 4-(1-nitroethyl)benzoate. The reaction mixture was left to be cooled to room temperature extracting with ethyl acetate The organic layer was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate the solvent was then evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography