3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

light brown crystalline powder

To a 500 mL three-necked flask, 3-hydroxyphenylboronic acid (10.0 g, 72.46 mmol, 1.0 eq) and methylene chloride (300 mL) were added, and pinacol (10.0 g, 84.60 mmol, 1.2 eq) was added under stirring, followed by stirring at room temperature for 48 h. The reaction solution was poured into water (400 mL). The mixed solution was poured into a separatory funnel. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (400 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The crude product was purified by column chromatography (200-300 mesh silica gel, methylene chloride/methanol mixed solvent at a volume ratio of 100/1 as eluent) to obtain 15.0 g of a white solid with a yield of 94percent and a purity of 97percent.Benzylation of 3-bromophenol 1 with benzyl chloride and potassium carbonate in DMF affords compound 2. Palladium (0)-catalyzed cross-coupling reaction of 2 with bis(pinacolato)diboron, PdCl2(dppf), and potassium carbonate in DMSO at 80 C. gives rise to compound 3 (Ishiyama, T; Murata, M; Miyaura, N. J. Org. Chem. 1995, 60, 7508). Debenzylation of 3 with Pd/C at 60 psi hydrogen in MeOH produces the target compound 4 (Pennington, T. E.; Kardiman, C; Hutton, C. A. Tetrahedron Lett. 2004, 45, 6657).To a solution of 2-bromo-1-methyl-5-nitro-1H-indole(500 mg, 1.96 mmci), 3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dicxabcrcian-2-yl)phenci (431 mg, 1.96 mmol) and K2C03(542 mg, 3.92 mmci) in dioxane (10 mL) and H20 (1 mL) was added Pd(dppf)C12 (143 mg, 0.196 mmci) . The mixture was degassed in vacuo and purged with N2 for three times and stirred at 100C for 12 h. The reaction was cooled toroom temperature. EtOAc (30 mL) and H20 (30 mL) were added and phases were separated. The aqueous phase was extracted with EtOAc (30 mL x 3) . The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under vacuum tc give theresidue. The residue was purified by cciumn chromatography (SiC2, Petroleum ether/Ethyl acetate=10:1 to 5:1 to 3:1) to give the title compound (400 mg, 1.30 mmcl, 66.2% yield) as a solid.?H NNR (400 MHz, DMSO-d, ) oe (ppm) 3.83 (s, 3H), 6.84 (s, 1H), 6.87 - 6.93 (m, 1H), 6.96 - 7.01 (m, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.72 (ci, J=9.2 Hz, 1H), 8.01-8.13 (m, 1H), 8.58 (d, J=2.0 Hz, 1H), 9.76 (s, 1H).LCMS (ES) : m/z 269 [M+H.To a solution of 3-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenol (250 mg, 1.14 mmol) in DMF (3.8 mL) was added K2CO3 (314 mg, 2.27 mmol) followed by (2821) 4-(Chloromethyl)-1-methyl-1H-pyrazole (190 mg, 1.14 mmol). The reaction mixture was heated at 65 C overnight. To the cooled mixture was added EtOAc and the mixture was then extracted with water. The organic layer was washed with water twice and brine once, dried over sodium sulfate, and concentrated in vacuo to provide 124 mg, 35%, of the product as a yellow oil. The product is used as is in the next step. MS (ES+) m/e 315 (M+H)+.General procedure: Compounds 9a-9h was combined with bis(triphenylphosphine)palladium(II)chloride (0.21g) and 1H-indazole- 4-boronic acid pinacol ester (1.68g) in 1, 2-dimethoxyethane (20mL) and 15mL of 1M potassium carbonate in water. The reaction mixture was heated to 130C for 4h and monitored by TLC. After cooling to room temperature, the reaction was quenched with saturated aqueous NaCl and then extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in reduced pressure to obtain the crude product. The crude produc was purified through a column chromatography on silica with dichloromethane/methanol as eluent to produce 11a-11h as yellow solid.General procedure: Compounds 9a-9h was combined with bis(triphenylphosphine)palladium(II)chloride (0.21g) and 1H-indazole- 4-boronic acid pinacol ester (1.68g) in 1, 2-dimethoxyethane (20mL) and 15mL of 1M potassium carbonate in water. The reaction mixture was heated to 130C for 4h and monitored by TLC. After cooling to room temperature, the reaction was quenched with saturated aqueous NaCl and then extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in reduced pressure to obtain the crude product. The crude produc was purified through a column chromatography on silica with dichloromethane/methanol as eluent to produce 11a-11h as yellow solid.General procedure: Compounds 9a-9h was combined with bis(triphenylphosphine)palladium(II)chloride (0.21g) and 1H-indazole- 4-boronic acid pinacol ester (1.68g) in 1, 2-dimethoxyethane (20mL) and 15mL of 1M potassium carbonate in water. The reaction mixture was heated to 130C for 4h and monitored by TLC. After cooling to room temperature, the reaction was quenched with saturated aqueous NaCl and then extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in reduced pressure to obtain the crude product. The crude produc was purified through a column chromatography on silica with dichloromethane/methanol as eluent to produce 11a-11h as yellow solid.General procedure: Compounds 9a-9h was combined with bis(triphenylphosphine)palladium(II)chloride (0.21g) and 1H-indazole- 4-boronic acid pinacol ester (1.68g) in 1, 2-dimethoxyethane (20mL) and 15mL of 1M potassium carbonate in water. The reaction mixture was heated to 130C for 4h and monitored by TLC. After cooling to room temperature, the reaction was quenched with saturated aqueous NaCl and then extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in reduced pressure to obtain the crude product. The crude produc was purified through a column chromatography on silica with dichloromethane/methanol as eluent to produce 11a-11h as yellow solid.General procedure: Compounds 9a-9h was combined with bis(triphenylphosphine)palladium(II)chloride (0.21g) and 1H-indazole- 4-boronic acid pinacol ester (1.68g) in 1, 2-dimethoxyethane (20mL) and 15mL of 1M potassium carbonate in water. The reaction mixture was heated to 130C for 4h and monitored by TLC. After cooling to room temperature, the reaction was quenched with saturated aqueous NaCl and then extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated in reduced pressure to obtain the crude product. The crude produc was purified through a column chromatography on silica with dichloromethane/methanol as eluent to produce 11a-11h as yellow solid.

Molecular Weight:220.07
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:220.1270746
Monoisotopic Mass:220.1270746
Topological Polar Surface Area:38.7
Heavy Atom Count:16
Complexity:249
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes