2-Bromo-5-methoxy-1,3-dimethylbenzene

General procedure: 1-Methoxy-3, 5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS, 260 mg, 1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/General procedure: 1-Methoxy-3, 5-dimethylbenzene (100mg, 0.73 mmol), N-Bromosuccinimide (NBS, 260 mg, 1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reactionwas monitored by TLC/2-Bromo-5-methoxy-1, 3-dimethylbenzene: 20 mmol of 1-methoxy-3, 5-dimethylbenzene (2.82 ml) was dissolved in 100 ml of dry acetonitrile followed by 22 mmol (3.56 g) of N-bromosuccinimide. The mixture was stirred at room temperature overnight. Then the solvent vas evaporated under reduced pressure and a solid was filtered off and washed with hexanes providing 2-bromo-5-methoxy-1, 3-dimethylbenzene (3.9 g, 92percent) as white solid. 13.6 g of 1, 3-dimethyl-5-methoxybenzene, 19.8 g of N-bromosuccinimide, 100 mL of acetonitrile was stirred under ice cooling, The mixture was further stirred at room temperature for 10 hours. Water was added to the resulting reaction solution, Extraction was carried out with ethyl acetate, By concentrating the collected organic phases, 25 g of intermediate 302A was obtained.13.6 g of 1, 3-dimethyl-5-methoxybenzene, 19.8 g of N-bromosuccinimide, and 100 mL of acetonitrile were stirred under ice cooling and was further stirred at room temperature for 10 hours. Water is added to the obtained reaction solution, the solution was extracted with ethyl acetate, and a collected organic phase was condensed. As a result, 25 g of Intermediate Product 302A was obtainedStarting fragments 1 and 2 were determined to be the key building blocks to introduce the required amino substitution in the final molecules. Fragment 1 was prepared from commercially available 4-bromo-3, 5-dimethylphenol (6). The phenolic group of 6 was alkylated with iodomethane and the resulting methyl ether was then oxidized. Carboxylic acid 8 was converted to methyl ester 9. Reduction of 9 with LiBHweighed 4-bromo-3, 5-dimethylbenzene acid (1.05g, 5mmol) was dissolved in 25ml tetrahydrofuran in an ice water bath and cool to 0° C, the reaction system was added in divided portions NaH (240mg, 6mmol), naturally to room temperature, stirring was continued for 0.5 hours, then was added methyl iodide (0. 4mL, 6mmol), the reaction was stirred at 60 ° C in an oil bath for 3 hours, until the starting material the reaction was complete. 50mL50mL3 1 percent/4a (1.06g) 99percent 50mL water was added carefully to quench the reaction, 50mL per total extracted three times with ethyl acetate, the combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product was purified by flash chromatography (1percent acetic acid acetate / petroleum ether) to give the product 4a (1.06g), yield 99percent.A mixture of commercially available 4-bromo-3, 5-dimethylphenol (a compound of Formula 4) (25.0 g, 124.3 mmol), methyl iodide (35.3 g, 248.6 mmol), and potassium carbonate (34.4 g, 248.6 mmol) in 62.5 mL of DMF was stirred for 2 hours at room temperature. The reaction mixture was diluted with 300 mL of ether and washed with 250 mL of water and 5x100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give an oil, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to give 4-bromo-3, 5-dimethylanisole (a compound of Formula 5) (26 g, 120.8 mmol, 97percent);1HNMR (CDCl3) δ 2.39 (s, 6H), 3.76 (s, 3H), 6.67 (s, 2H).A solution of 4-bromo-3, 5-dimethylphenol (1.00 g, 4.97 mmol) in acetone (40 mL) was treated with solid CsCO3 (1.17 g, 4.97 mmol) and methyl iodide (0. 310 mL, 4.97 mmol) and heated to 40 oC for 3 h. Additional methyl iodide (0.310 mL, 4.97 mmol) was added over the course of the reaction to replace that lost to evaporation. The acetone was removed in vacuo. The resulting white solid residue was partitioned between water and CH2CL2. The layers were separated and the aqueous layer was further extracted with CH2C12 (2 x 25 mL). The combined organic layers were washed with water (1 x 25 mL) and dried over MGS04. The solvent was removed in vacuo to afford the product 2-bromo-5-methoxy-1, 3-dimethyl-benzene (1.01 g, 94percent) as a colorless oil, which slowly solidified upon STANDING. 1H NMR (CDC13) : δ 6.644 (s, 2H), 3.762 (s, 3H), 2. 382 (s, 6H).Example 1.3.1

Molecular Weight:215.09
XLogP3:3.3
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:213.99933
Monoisotopic Mass:213.99933
Topological Polar Surface Area:9.2
Heavy Atom Count:11
Complexity:115
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes