Methane, dichloromethoxy- → 4-Bromo-2-Thiophenecarbonyl Chloride

A suspension of 4-bromothiophene-2-carboxylic acid (47.0 mmol crude, from previous step) in α,α-dichloromethyl methyl ether (13.0 mL, 150 mmol) was slowly heated to reflux. As the reaction mixture was heated a pale brown solution formed, and gas evolution was evident. After stirring at a gentle reflux for 5 hours, the reaction solution was allowed to cool and was then concentrated under reduced pressure to afford 4-bromothiophene-2-carbonyl chloride as a brown liquid. This liquid was dissolved in CH2Cl2 (150 mL) and the reaction flask was cooled in an ice bath. The cold reaction solution was treated with a small amount of 4-(N,N-dimethylamino)pyridine, N,O-dimethylhydroxylamine hydrochloride (5.5 g, 56 mmol), and finally N,N-diisopropylethylamine (14 mL, 80 mmol). After stirring for 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring for 16 hours, the pale brown reaction solution was quenched by the addition of ice-cold H2O, and diluted with CH2Cl2 (500 mL). The layers were separated, and the organic layer was washed with 1 N HCl (100 mL), H2O (50 mL), and saturated aqueous NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford a brown liquid. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane on silica. The product peak was collected to afford 4-bromothiophene-2-carboxylic acid methoxymethylamide as a yellow oil. (9.9 g, 83% yield over three steps). 1H-NMR (400 MHz, CDCl3): δ 7.83 (1H, d, J=1.5 Hz), 7.45 (1H, d, J=1.5 Hz), 3.78 (3H, s), 3.37 (3H, s).

1. temperaturewas slowly heated to reflux
2. temperatureAs the reaction mixture was heated a pale brown solution
3. customformed
4. temperaturea gentle reflux for 5 hours
5. temperatureto cool
6. concentrationwas then concentrated under reduced pressure

ORD record

ord-3303567f34cd4671a29c670a33999e57

Source dataset

uspto-grants-2007_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07265131B2