2-Bromo-5-(methoxymethyl)thiophene synthesis

Yield:82830-92-0 89%

Reaction Conditions:

Stage #1: (5-bromothien-2-yl)methanolwith sodium hydride in tetrahydrofuran;hexane at 20; for 0.5 h;
Stage #2: methyl iodide in tetrahydrofuran;hexane at 20; for 16 h;

Steps:

68.1 Example 68.1. 5-(meth xymethyl)thiophene-2-carbaldehyde

To a solution of (5-bromothiophen-2-yl)methanol (460 mg, 2.38 mmol) in 5 mL anhydrous tetrahydrofuran at room temperature was added carefully hexanes-washed sodium hydride (60% in oil, 143 mg, 3.57 mmol). After stirring at room temperature for 30 minutes, methyl iodide (0.3 mL, 4.76 mmol) was added in a single portion and the reaction mixture stirred for 16 h at room temperature. The reaction mixture was poured into 20 mL of 0.2 N hydrochloric acid. Organics were extracted with 1 : 1 ether/hexanes (3 x 25 mL), washed with 30 mL each of 5% aqueous sodium bisulfite solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (2-3% ethyl acetate in hexanes) to give 2-bromo-5- (methoxymethyl)thiophene (439 mg, 89%) as an oil. Used without further characterization. To a solution of 2-bromo-5-(methoxymethyl)thiophene (439 mg, 2.12 mmol) in 6 mL of 9: 1 tetrahydrofuran hexamethylphosphoramide under argon at -78 °C was added n- butyllithium (0.93 mL , 2.5 M in hexanes) dropwise. After stirring for 2 minutes at -78 °C, dimethylformamide (0.82 mL, 10.6 mmol) was added in a single portion and the reaction mixture was allowed to warm to room temperature before being poured into 30 mL of 1 N hydrochloric acid. Organics were extracted with 1 : 1 ether/hexanes (3 30 mL), washed with water (2 ^ 30 mL, brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5- 20% ethyl acetate in hexanes) to give 5-(methoxymethyl)thiophene-2-carbaldehyde (103 mg, 31%) as an oil. Used without further characterization.

References:

WO2013/192352,2013,A1 Location in patent:Page/Page column 92