2-bromo-2-methylpropanamide

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: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: To a solution of 4-ethoxyphenol (511 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 2 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(4-ethoxyphenyl) -2-hydroxy-2-methylpropionamide as an off-white solid (536 mg, 2.40 mmol, 64.8% yield).: mp 146-148° C. 1H NMR (400 MHz, CDCl3) δ 8.59 (br s, 1H, N--H), 7.45 (dd, 2H, Ar--H, J=9.0, 2.2 Hz), 6.84 (dd, 2H, Ar--H, J=9.0, 2.2 Hz), 4.00 (q, 2H, CH2 -CH3, J=7.1 Hz), 2.73 (br s, 1H, O--H), 1.53 (s, 6H, C(CH3)2), 1.39 (t, 3H, CH2 -CH3, J=7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 174.0, 155.7, 130.6, 74.0, 63.7, 27.9, 14.8; IR (KBr pellet) 1604, 1647 (amide C=O stretches), 3256 (NH stretch), 3281 (OH stretch); MS (CI/CH4) 224; the resulting mixture was stirred at reflux for 16 h The resulting mixture was stirred at 150° C. for 72 h The reaction was cooled to room temp. partitioned between water (50 mL) and EtOAc (100 mL) The aqueous layer was extracted with EtOAc (100 mL) the combined organics washed with water (2×50 mL) dried (Na2SO4) concentrated to about 2 g of material The brown oil was chromatographed on silica (200 mL, 4 cm diam. column) eluting with 3:7 EtOAc/hexane

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

Procedure: To a solution of 2-hydroxydibenzofuran (682 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 18 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(2-dibenzofuranyl)-2-hydroxy-2-methylpropionamide as an off-white solid (580 mg, 2.15 mmol, 58.1% yield). This was recrystallized from toluene for an analytical sample: mp 134-137° C. 1H NMR (300 MHz, CDCl3) δ 8.83 (br s, 1H, N--H), 8.41 (d, 1H, C1 --H, J=2.34 Hz), 7.92 (m, 1H, Ar--H), 7.56-7.29 (om's, 5H, Ar--H), 2.46 (br s, 1H, O--H), 1.60 (s, 6H, C(CH3)2); 13C NMR (75 MHz, CDCl3) δ 174.2, 156.8, 152.9, 132.8, 127.3, 124.6, 124.2, 122.7, 120.8, 119.5, 112.0, 111.7, 74.3, 28.0; IR (KBr pellet) 1651, 1668 (amide C=O stretches), 3364 (NH stretch), 3383 (OH stretch); MS (EI) 269; Analysis: Calculated C 71.36 H 5.61 N 5.20 Found C 71.43 H 5.58 N 5.06. the resulting mixture was stirred at reflux for 18 h The resulting mixture was stirred at 150° C. for 72 h The reaction was cooled to room temp. partitioned between water (50 mL) and EtOAc (100 mL) The aqueous layer was extracted with EtOAc (100 mL) the combined organics washed with water (2×50 mL) dried (Na2SO4) concentrated to about 3 g of material The brown oil was chromatographed on silica (200 mL, 4 cm diam. column) eluting with 3:7 EtOAc/hexane

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

Procedure: To a solution of 2-naphthol (533 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(2-naphthyl)-2-hydroxy-2-methylpropionamide as a white solid (607 mg, 2.65 mmol, 71.6% yield).: mp 155-157° C. 1H NMR (300 MHz, DMSO) δ 9.74 (br s, 1H, N--H), 8.41 (d, 1H, C1 --H, J =2.20 Hz), 7.86-7.76(om's, 4H), 7.49-7.37 (om's, 2H), 5.80 (br s, 1H, O--H), 1.40 (s, 6H, C(CH3)2); 13C NMR (75 MHz, DMSO) δ 175.7, 136.2, 133.3, 129.8, 128.1, 127.4, 127.3, 126.3, 124.6, 120.6, 115.6, 72.5, 27.7; IR (KBr pellet) 1607, 1634, 1655 (amide C=O stretches), 3289 (NH/OH stretch); MS (CI/NH3) 247; the resulting mixture was stirred at reflux for 16 h The resulting mixture was stirred at 150° C. for 72 h The reaction was cooled to room temp. partitioned between water (50 mL) and EtOAc (100 mL) The aqueous layer was extracted with EtOAc (100 mL) the combined organics washed with water (2×50 mL) dried (Na2SO4) concentrated to about 3 g of material The brown oil was chromatographed on silica (200 mL, 4 cm diam. column) eluting with 3:7 EtOAc/hexane

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

Procedure: 8.4 g of 5,2'-dichloro-2-tosylaminobenzophenone are dissolved in 40 ml of DMF and treated with 0.7 g of 80% sodium hydride; after 15 minutes, 10 g of dimethylbromoacetamide, prepared in Example 1, are added and the mixture is stirred overnight at RT. The reaction medium is poured into water, the precipitate formed is filtered off and taken up with DCM and the solution is dried and concentrated. 9.2 g of the expected product are obtained after crystallization from isopropyl ether. are added the precipitate formed is filtered off the solution is dried concentrated

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

Procedure: 4.3 g of 5-chloro-2-tosylaminophenyl cyclohexyl ketone are placed in 20 ml of DMF in the presence of 360 mg of 80% sodium hydride, after 15 minutes at RT 5.4 g of the compound prepared in step B are added and the mixture is stirred overnight at RT. The reaction medium is poured into water and the precipitate is filtered off and then taken up with DCM, dried and concentrated. The expected product crystallizes from isopropyl ether. the precipitate is filtered off dried concentrated The expected product crystallizes from isopropyl ether

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

Procedure: 3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 133, 200 mg) and 2-bromo-2-methyl-propionamide (272 mg) in dimethyl acetamide (1 mL) were treated with sodium hydroxide (66 mg) and stirred at r.t. for 17 h. A second portion of 2-bromo-2-methyl-propionamide (272 mg) followed by sodium hydroxide (66 mg) was added and the reaction mixture further stirred for 2 h at r.t. This process was repeated a last time and the reaction mixture was diluted with ice-water (10 mL), neutralized with 1N aqueous HCl, extracted with ethyl acetate (2×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, ethyl acetate/heptane 1:2) to give the title compound as off-white waxy solid (170 mg). MS (m/e)=451.0 (MH+). was added the reaction mixture further stirred for 2 h at r.t extracted with ethyl acetate (2×) dried over MgSO4 concentrated in vacuo The residue was purified by flash chromatography (20 g silica gel, ethyl acetate/heptane 1:2)