3-Bromo-5-chlorophenol

a. A flask containing (l, 5-cyclooctadiene)(methoxy)-iridium(I) dimer (84 mg, 0.13 mmol), 4, 4'-di-tert butyl-2-2'-dipyridyl (69 mg, 0.26 mmol) and bis(pinacolato)diboron (1.29 g, 5.11 mmol) was purged with Ar, then hexanes (26 mL) and l-bromo-3- chlorobenzene (1 mL, 8.51 mmol) were added sequentially. The solution was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo, re-dissolved in acetone (26 mL), then oxone (5.23 g, 8.51 mmol) in water (26 mL) added [Caution: exotherm observed]. After 10 min, the reaction mixture was diluted with DCM. The layers separated, and the aqueous layer extracted with DCM. The combined organics were washed with brine, dried and concentrated in vacuo to give the title compound (1.43 g, 81percent). LCMS (Method 3): Rt 3.74 min, m/z 205, 207 [M-H3-Bromo-5-chloro-phenol; Under an atmosphere of dry nitrogen, 103 mg 1 , 5-cyclooctadiene(H5-indenyl)iridium (I) was put in a 25 ml. Pyrex bottle. Subsequently were added 0.04 ml. 1 , 2-bis(dimethylphosphino)ethane, 0.61 ml. 3-bromochlorobenzene and 1.52 ml. pinacolborane. The mixture was stirred at 150°C for 3.5 h. After cooling to room temperature, the borane adduct was taken up in 17 ml. acetone to give a clear solution. This solution was added slowly to 17.41 ml. of a 0.30 M solution of oxone in water cooled in an ice bath. The mixture was stirred vigorously for 15 min. at room A 250 mL flask was charged with 81b (7.0 g, 41.766 mmol) and 2, 4, 6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When 81b was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (NaThe general borylation/oxidation process of the present invention was as follows. The general process for borylations was as follows. In a dry box, arene (1.0 mmol), HBPin (1.5-2.5 mmoles), (Ind)Ir(COD) (8.3 mg, 0.02 mmol, 2 mol percent), and dmpe (3.0 mg, 0.02 mmol, 2 mol percent). or dppe (8.0 mg, 0.02 mmol, 2 mol percent) were transferred into an air-free flask equipped with a stirrer bar. (In cases where cyclohexane was used as a solvent, the reagents were dissolved in 1 mL cyclohexane, and transferred to the air-free flask.) The flask was sealed and brought out of the dry box and placed in an oil bath heated to 150° C. (dmpe) or 100° C. (dppe) until the reaction was judged complete by GC-FID. At that time the reaction was allowed to cool to room temperature. If solvent was used it was removed under reduced pressure. [0069] The general process for oxidations was as follows. To the crude material from above (usually a dark orange or brown gel-like liquid or a solid) was added 3.2 mL acetone. After stirring produced a homogeneous solution, an aqueous solution of OXONE (6.15 g, 1.0 mmol in 3.2 mL) was added dropwise over 2-4 min. Upon complete addition, the reaction mixture was vigorously stirred for 7 minutes. At that time the reaction was quenched with aqueous NaHSO3. A layer of dark orange oil was observed. The reaction mixture was extracted three times with ether or CH2Cl2. The combined organics were washed with brine followed by water, and concentrated in vacuo. The crude material was dissolved in CH2Cl2 or pentane/ether and passed through a plug of silica gel. Evaporation afforded the phenol. (Note: In the cases of multiple borylations (Tables 1, Entries 15-16), periodic cooling and purging of the H2 gas formed during that step of the sequence helped to maintain an effective rate of reaction.) [0070] Experimental details for synthesizing particular phenols, their spectroscopic data, and comparisons to previous methods are provided below. [0071] 3-Bromo-5-chlorophenol (1): The general process was applied to 3-bromochlorobenzene (192 mg, 1.0 mmol). The borylation step was carried out neat with HBPin (250 mg, 1.95 mmol) and dmpe (3.0 mg, 0.02 mmol, 2 mol percent) at 150° C. for 3.5 hours. The oxidation step was then carried out as described above, after which the crude material was dissolved in CH2Cl2 and passed through a plug of silica gel. Evaporation of solvent gave 183 mg of a white solid containing 171 mg (82percent) of 1 and 12 mg of trapped acetone (by 1H NMR). Preparative GC at 160° C. afforded analytically pure 1 as a white solid; mp 66-68° C. (lit. 70). 1H NMR (300 MHz, CDCl3): delta7.08 (t, J=1.65 Hz, 1 H), 6.89 (dd, J=2.2, 1.65 Hz, 1 H), 6.78 (t, J=2.1 Hz, 1 H), 5.0-5.1 (brs, 1 H); 13C NMR (75 MHz, CDCl3) : delta156.7, 135.6, 124.0, 122.9, 117.9, 115.0; IR (neat): 3293, 1578, 1435, 914, 775 cm-1; LRMS m/e 206 (M+), 127, 99. Anal. Calcd for C6H4BrClO: C, 34.74; H, 1.94. Found C, 34.87; H 2.03. For a previous preparation of 1 see either Hodgson and Wignall, J. Chem. Soc. 2077-2079 (1926) (ten steps from 1, 3, 5-trinitrotoluene, overall yield not reported) or Kohn and Zandman, Montash. 47: 367-377 (1926) (exhaustive bromination of 3-chlorophenol, followed by partial debromination).To an airfree flask equipped with a stir bar, in a glove box, was added m-bromochlorobenzene (192 mg, 1.00 mmol), HBPin (200 mg, 1.56 mmol), (Ind)Ir(COD) (8.3 mg, 0.02 mmol), and dmpe (3.0 mg, 0.02 mmol). The flask was sealed, removed for the glove box, and stirred at 150° C. for 3 h. This material was used in next step without purification. To the crude material was added NaOH (1.5 mL of a 1.5M aqueous solution) and the resulting mixture was stirred for 5 minutes. To this was added NaHCO3 (0.73 g, 8.7 mmol) and acetone (3 mL). The mixture was cooled to 0° C. and OXONE (3.2 mL of a 0.33M aqueous solution) was added dropwise. The reaction mixture was stirred at 0° C. for 10 minutes and quenched with sodium bisulfite (2.0 g in 3 ml H2O). The grayish solution was diluted with ether (20 ml), and extracted with aq. 2 M HCl (1.x.25 ml). The aqueous layer was separated from the organic layer and extracted with ether (2.x.25 ml). Combined organic layers were washed with water (2.x.25 ml), dried with MgSO4, and solvents removed under reduced pressure. Crude material was passed through silica plug eluting with CH2Cl2 to give 163.4 mg (78.8percent) of 3-bromo-5-chlorophenol as a white solid. In a separate run under the same conditions with twice the scale, 301.2 mg (72.4percent) of desired phenol was obtained. mp=68-69° C. 1H NMR (CDCl3, 300 MHz) delta7.08 (t, J=1.65 Hz, 1H), 6.89 (dd, J=2.2, 1.65 Hz, 1H), 6.78 (dd, J=2.2, 1.65 Hz, 1H), 4.83 (s, 1H). 13C NMR (CDCl3, 125 MHz) delta156.6, 135.7, 124.1, 122.9, 117.4, 115.0. FT-IR (KBr) 3221, 3159, 3090, 3046, 2927, 2856, 2793, 2659, 2492, 1577, 1486, 1458, 1426, 1376, 1359, 1286, 1239, 1214, 1088, 913, 859, 840, 778, 666 cm-1. MS (rel. int.) m/z 208 (100), 206 (82), 127 (26), 99 (37), 63 (22). Anal. Calcd for C6H4BrClO: C, 34.74; H, 1.94; N, 0.00. Found: C, 35.08; H, 2.03; N, 0.07.The general process was as follows. [0093] Borylation: In a dry box filled with nitrogen, an air-free flask, previously dried thoroughly in oven, was charged with a stirrer bar, 1 mmol arene, 0.02 mmol (2 mol percent) Ir catalyst, 0.02 mmol (2 mol percent) dmpe, followed by 1.5 mmol HBPin (Amounts of catalyst, dmpe and HBPin vary according to substrates). The flask was tightly sealed and was put into 150° C. oil bath for selected period of time, then cooled to room temperature. [0094] Oxidation condition A was as follows. The borylation mixture in the air free flask was vigorously stirred. To this mixture was added 1.5 mL 1.5 M aqueous NaOH, followed by 5 min stirring. Then 0.73 g NaHCO3 was added followed by 4.7 ml acetone. The mixture was cooled by an ice bath, and 3.2 mL 0.33 M aqueous OXONE was added slowly. After 12-15 min of stirring, the reaction was quenched by NaHSO3. [0095] Oxidation condition B (no NaHCO3) was as follows. The borylation mixture in the air free flask was vigorously stirred. To this mixture was added 1.5 mL 1.5 M aqueous NaOH, followed by 5 min stirring. Then 4.7 ml acetone was added. The mixture was then cooled by an ice bath, and 3.2 mL 0.33 M aqueous OXONE was added slowly. After 12-15 min of stirring, the reaction was quenched by NaHSO3. [0096] Oxidation condition C (no NaOH) was as follows. The borylation mixture in the air free flask was vigorously stirred. To this mixture was added 3.0-3.5 ml acetone and 3-5 min were allowed to stir. The mixture was then cooled by an ice bath, and 3.2 mL 0.33 M aqueous OXONE was added slowly. After 12-15 min of stirring, the reaction was quenched by NaHSO3. [0097] Oxidation condition D (no ice bath) was as follows. The borylation mixture in the air free flask was vigorously stirred. To this mixture was added 3.0-3.5 ml acetone and 3-5 min were allowed to stir. Then 3.2 mL 0.33 M aqueous OXONE was added dropwise at room temperature. After 7 min of stirring, the reaction was quenched by NaHSO3. [0098] In the oxidation, the preferred acetone/water ratio is about 1:1. While other solvents can be used in the oxidation, acetone is presently the preferred solvent. [0099] The workup process was as follows. To the mixture after oxidation, dichloromethane or ether was added to extract the formed phenol with the acidification of the whole mixture. The organic layer was separated and washed with brine, dried over MgSO4, and vacuumed to remove the solvent. The residue was allowed to pass through a silica plug, and the phenol was obtained. Most phenols, especially those with an electron-poor arene ring, are trapping acetone, or ether if ether was used in the workup process. [0100] The chemistry background was as follows. Selectivity: 1, 3-disubstituted arene was borylated on the double-meta position, forming a 3, 5-disubstituted phenol. Symmetric 1, 2-disubsituted arene was borylated on 4 position, forming a 3, 4-disubstituted phenol. 1, 2, 3-trisubstituted arene was borylated on 5 position, forming a 3, 4, 5-trisubstituted phenol. Fluorine-substituted arene can be borylated on positions ortho to F. [0101] Functional group tolerances were as follows. Halide, ether, dialkyl amine, ester, alkyl groups are tolerated. Aldehyde and ketone carbonyls are reduced as well as nitrile. In some instances, acidic protons can be problematic. The results are shown in Table 3. In view of the above, a highly selective and effective process for converting an arene to its corresponding phenol has been developed. The reactions are fast and efficient.General procedure: To a solution of 4-bromo-2-chlorophenol (Compound 27A) (5.0 g, 24.1 mmol)DMF (100 mL) was added K2C03 (10.0 g, 72.5 mmol) and 2-bromopropane (7.5 g, 61.5 mmol) and stirred at 100 C for 16 hours. The mixture was diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% v/v, 300 mL x 3). The combined extracts were washed with bine (300 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether) to furnish Compound 27B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.50.0 g (238.7 mmol) of 1-bromo-3-chloro-5-fluorobenzene and N-methyl-2-pyrrolidone (NMP) were mixed, and 44.5 g (214.8 mmol) of