Preparation method of 2-bromo-3-fluorophenol_Kain Industrial Additive

Background and overview[1]

2-Bromo-3-fluorophenol is a chemical intermediate.

Preparation[1]

Step 1:

Put sodium hydrogen (0.96 g, 40 mmol) into tetrahydrofuran (20 mL), and slowly add trifluorophenol (20 mmol) in tetrahydrofuran solution (5 mL) dropwise to the above system at room temperature. After stirring for two hours, A solution of N, N-dimethylcarbamoyl chloride (5.42 g, 40 mmol) in tetrahydrofuran (7 mL) was added to the above system and stirred for 8 hours. Wash with saturated brine, extract with ethyl acetate, spin to dryness and column chromatography (n-hexane/ethyl acetate) to obtain 3.54 g (84%) of the product 3-fluorophenyl N, N-diethyl carbamate. 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 1H), 6.95- 6.87 (m, 3H), 3.43 (q, J = 7.2 Hz, 2H), 3.38 (q, J = 7.2 Hz, 2H) , 1.25 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 162.8 (d, J = 247.5 Hz), 153.6, 152.5 (d, J = 10.7 Hz), 129.9 (d, J = 9.2 Hz), 117.5 (d, J = 3.8 Hz), 112.0 (d, J = 21.4 Hz), 109.8 (d, J = 23.7 Hz), 42.3, 41.9, 14.2, 13.3; EI-LRMS m/z 211 (M+, 30), 72 (100); IR (neat) 3073, 2976, 2933, 1720, 1417, 1258, 1155, 970 cm-1. HRMS calcd. for C11H14FNO2 : 211.1009. Found: 211.1002

Step 2:

Put sec-butyllithium (9.23 mL, 1.3M cyclohexane/n-hexane, 12 mmol) and TMEDA (1.81 mL, 12 mmol) into anhydrous tetrahydrofuran (40 mL) under nitrogen protection, and stir at -78°C. 3-Fluorophenyl N,N-diethylcarbamate (10 mmol) was added to the above system, and stirring was continued at -78°C for 2 h. Add 1,2-dibromotetrachloroethane (12 mmol) and continue stirring at low temperature for 30 min. Quench with water and warm to room temperature, then extract with ethyl acetate (3*25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried and subjected to column chromatography to obtain (n-hexane/ethyl acetate) 2-bromo-3-fluorophenyl N, N-diethyl carbamate (2.44 g, 84% ). Rf 0.22 (hexane/EtOAc, 10/1); 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 1H), 7.06-6.94 (m, 2H), 3.49 (q, J = 7.2 Hz, 2H) , 3.39 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 159.9 (d, J = 247.8 Hz), 152.8, 150.4 (d, J = 2.9 Hz), 128.3 (d, J = 9.3 Hz), 119.6 (d, J = 3.5 Hz), 113.2 (d, J = 22.5 Hz), 105.0 ( d, J = 22.2 Hz), 42.6, 42.2, 14.3, 13.3; EI-LRMS m/z 289 (M+, 0.3), 100 (100); IR (neat) 3083, 2977, 2935, 1725, 1468, 1419, 1264, 1233, 1151, 1049, 998 cm-1. HRMS calcd. for C11H13BrFNO2: 289.0114. Found: 289.0123

Step three:

Dissolve 2-bromo-3-fluorophenyl N,N-diethylcarbamate (5 mmol) in ethanol (50 mL) and add excess sodium hydroxide NaOH (2 g, 0.05 mol). Heat and reflux for 5-8 hours (GC-MS detects that the reaction is complete). Evaporate the ethanol under pressure, dissolve the diethyl ether, neutralize it with 1M hydrochloric acid at 0°C, extract with diethyl ether (3 * 20 mL), combine the organic phases, and saturated salt Wash with water, dry with anhydrous sodium sulfate and perform column chromatography to obtain (n-hexane/ethyl acetate) 2-bromo-3-fluorophenol (0.71 g, 75%). Rf 0.31 (n-hexane/ethyl acetate, 5/1); 1H NMR (300 MHz, CDCl3) δ 7.21-7.11 (m, 1H), 6.81 (dt, J = 8.2, 1.4 Hz, 1H), 6.70 (dt , J = 8.2, 1.4 Hz, 1H), 6.12 (brs, 1H); 13C NMR (75.4 MHz, CDCl3) δ 159.6 (d, J = 276.7 Hz), 154.2 (d, J = 2.9 Hz), 129.0 (d , J = 9.4 Hz), 111.6 (d, J = 3.2 Hz), 108.1 (d, J = 22.1 Hz), 98.2 (d, J = 23.2 Hz); EI-LRMS m/z 192 (M++2, 99), 190 (M+, 100); IR (neat) 3412, 2963, 2933, 1599, 1464, 1193, 1002, 771 cm-1. HRMS calcd. for C6H4BrFO: 188.9430. Found: 188.9425

Main reference materials

[1] Journal of Organic Chemistry, 70(16), 6548-6551; 2005