1. Suspend 2-methyl-3-nitroaniline (45.6 g, 0.3 mol) in water (200 mL) and 40% aqueous hydrobromic acid (100 mL) and heat to reflux for 10 minutes. Cool to 0°C and slowly add aqueous sodium nitrite (20.7 g, 0.3 mol) (100 mL) dropwise, controlling the temperature to no more than 5°C. Continue stirring at 0-5°C for 30 min.
2. Slowly add the above diazonium salt solution to a stirred mixture of cuprous bromide (43.1 g, 0.3 mol) in hydrobromic acid (150 mL) and water (150 mL), and after stirring at room temperature for 30 minutes, heat the reaction to 70°C for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane (400 mL x 3), the organic phases were combined, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
3. The residue was purified by column chromatography (petroleum ether as eluent) to afford 1-bromo-2-methyl-3-nitrobenzene (58 g, 89% yield) as a light yellow solid.
4. 1-Bromo-2-methyl-3-nitrobenzene (37.0 g, 0.17 mol), N-bromosuccinimide (61 g, 0.34 mol) and azobisisobutyronitrile (0.7 g, 4.2 mmol) were refluxed in carbon tetrachloride (500 mL) overnight. The filtrate was filtered and concentrated to give the red liquid crude product 1-bromo-2-(bromomethyl)-3-nitrobenzene (53 g), which was used directly in the next step.
5. The crude product 1-bromo-2-(bromomethyl)-3-nitrobenzene (53 g) was stirred with a solution of sodium acetate (32.8 g, 0.4 mol) in N,N-dimethylformamide (300 mL) at 70 °C overnight. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
6. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1) to give white solid 2-bromo-6-nitrobenzyl acetate (24.0 g, two-step overall yield 51%).
7. Under nitrogen protection, nitrogen was bubbled into a solution of 2-bromo-6-nitrobenzyl acetate (24.5 g, 0.089 mol) in 1,4-dioxane (500 mL) for 20 min, potassium acetate (38.4 g, 0.358 mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.65 g, 4.5 mmol) and bis(pinacolato) alcoholato)diboron (34.1 g, 0.13 mol) and stirred at 95 °C for 20 hours. After cooling and concentration under reduced pressure, the residue was partitioned with ethyl acetate and water, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
8. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1) to afford 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-nitrobenzenemethanol as a white solid (11.0 g, 38% yield). lC-MS (ESI) m/z 322 [M+1]+ (calculated value 321.1).
9. To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-nitrobenzenemethanol (11.0 g, 0.034 mol) in methanol (350 mL) was added an aqueous solution of 5N sodium hydroxide (17 mL, 0.085 mol) and refluxed under nitrogen protection for 24 hours. Concentrate under reduced pressure and dissolve in tetrahydrofuran (200 mL), add 5N hydrochloric acid (60 mL, 0.3 mol) and stir at 40°C for 16 hours. After cooling, it was diluted with ethyl acetate and poured into brine, the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
10. The residue was recrystallized in a mixed solvent of ethyl acetate and petroleum ether to give 4-nitrobenzo[c][1,2]oxaborol-1(3H)-ol as a yellow solid (5.0 g, 81% yield).LC-MS (ESI) m/z 180 [M+1]+ (calculated value 179.0).1H NMR (300MHz, DMSO-d6): δ 9.59 ( s, 1H), 8.33 (d, 1H), 8.14 (d, 1H), 7.71 (t, 1H), 5.37 (s, 2H).
11. A solution of 4-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (2.7 g, 0.015 mol) in methanol (150 mL) was hydrogenated by addition of palladium/carbon (1.0 g) overnight at atmospheric pressure and room temperature to afford the target product, 2-bromo-6-nitrotoluene (1.5 g, 66% yield). lc-MS (ESI) m/z 150 [M+1 ]+ (calculated value 149.1).1H NMR (300MHz, DMSO-d6): δ 8.92 (s, 1H), 7.02 (t, 1H), 6.90 (d, 1H), 6.62 (d, 1H), 4.99 (s, 2H), 4.77 (s, 2H).
