4-Bromo-2-thiophenecarboxylic acid

white to light yellow crystal powder

To a flask equipped with a mechanical STIRRER was added 25 g (130 mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company), acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate dissolved in 35 ML of water. After cooling this mixture on an ice-salt bath, 15 mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium chlorite were added, and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The solvent was removed IN, vacuo, and the solid was suspended in a mixture of water (175 mL) and 1 N hydrochloric acid (4 mL) and stirred for 10 min at RT. The solid was collected on a Buchner funnel and washed with water (2 x 150 mL) to afford 26 g (97%) of 35.56 g of silver nitrate (4 equivalents) are added to a solution of 10 g of 4-bromothiophene-2-carboxaldehyde in 280 ml of ethanol, and 418 ml of 1 mol/l sodium hydroxide (8 equivalents) are added. The reaction medium is stirred at 40 C. for 3 hours, then filtered through celite and concentrated under reduced pressure. The white solid obtained is dissolved in water (300 ml). The aqueous phase is taken up in ethyl acetate (2×200 ml), acidified to pH=1 with a 1.0M hydrochloric acid solution and then extracted with ethyl acetate (2×250 ml). The organic phase is then dried over sodium sulphate, filtered and then concentrated under reduced pressure, making it possible to obtain 9.62 g of a white powder corresponding to the expected product. Yield: 93% MS: MH- 206:; 4-Bromothiophene-2-carbaldehyde (1.9 g, 10 mmol) was dissolved in 40 mL of t- BuOH and 4 mL of 2-methyl-2-butene. The reaction mixture was cooled to 0 C and NaC102 (1.1 g, 12 mmol) dissolved in 12 mL of 1M NaH2P04 was added. The reaction mixture was let warm to room temperature and stirred for 5 hours. The reaction mixture was concentrated to about half the volume, and poured into 20 mL IN NaOH and 50 mL Et20. The aqueous layer was made acidic with 6N HCl and extracted with EtOAc. This organic layer was dried over sodium sulfate and concentrated to obtain the product as a white solid, 1.75 g, 8.5 mmol, 85% yield. ¹H NMR 500 MHz (DMSO-d6) 8.02 (lH, s), 7.78 (1H, s).Reference Example 121 4-Bromo-2-thiophenecarboxylic Acid Silver nitrate (1.7 g) was dissolved in water (40 ml), and sodium hydroxide (0.44 g) in water (1 ml) was added. Precipitated silver oxide was collected by filtration and suspended in 10% aqueous sodium hydroxide (20 ml). The resulting suspension was heated at 60 to 65 C., and 4-bromo-2-thiophenecarbaldehyde (1.91 g) was added dropwise. The mixture was stirred for 30 minutes, and precipitates were removed by filtration. The filtrate was washed with diethyl ether, and 1N hydrochloric acid was added to the aqueous layer to adjust the pH to 4. The aqueous layer was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give A. To a solution of 4-bromothiophene-2-carbaldehyde (9. 1 g, 48 MMOL) in acetone (150 mL) at 0C was added Jones'reagent (20 mL of a 2.6 M solution [PREPARED FROM CRO3 (26.7 g, 270 MMOL) dissolved in H20 (40 mL), and H2SO4 (23 mL) ], 52 MMOL). After stirring for 30 minutes at 0C, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 3 hours stirring at ambient temperature, the reaction was quenched by the addition of 2-propanol. After stirring for 64 hours at ambient temperature, the reaction mixture was diluted with Et2O and filtered through a pad of Florisil. The pad was thoroughly washed with EtOAc, and the filtrate was concentrated under reduced pressure to afford a brown paste. This crude material was dissolved in hot aqueous ethanol, treated with decolorizing carbon and filtered while still hot. Upon cooling an oil separated and formed a suspension. This suspension was treated with solid NAOH (4 g, 100 MMOL) and boiled briefly to dissolve the solids. The resulting basic aqueous solution was allowed to cool, and was extracted with Et2O (75 mL). The ET20 extract was discarded. The basic aqueous solution was then acidified by the dropwise addition of concentrated HCI. The acidic aqueous phase was extracted with EtOAc (4 x 60 mL). The combined EtOAc extracts were washed with brine, and dried over NA2SO4 FOR 16 hours. The mixture was filtered and concentrated under reduced pressure to afford 4-BROMOTHIOPHENE-2-CARBOXYLIC acid as a pale brown solid, which was carried on to the next step without further PURIFICATION.'H-NMR (400 MHz, Acetone-d6) : 8 7.87 (1H, d, J = 1.5 Hz), 7.72 (1H, d, J = 1. 5 Hz).NTERMEDIATE 1 Preparation of 4- 4-Formvl-phenvl)-thiophene-2-carboxylic acid methyl ester S /C/>-/lc/, OH H2 O I O B step 1 g, -Br B (OH) 2 step 2 OHC Pd (PPh3) 4 Oh po TH F, Na2CO3 O O step 3 Step 1 The mixture of 4-bromothiophene-2-carboxaldehyde (15 g), KMn04 (13.5g), H20 (500 MI) and NaOH (5g) was stirred overnight, then filtered. The filtrate was acidified with aq. HCI and extracted with EtOAc. The organic layer was washed with water and brine, then dried over Na2SO4, and concentrated to give 4-Bromo-thiophene-2-carboxylic acid (14.2 g).(A) 4-Bromothiophene-2-carboxylic Acid Chromium (VI) oxide (20 g), and concentrated sulfuric acid (32 g) were dissolved in water (50 mL) and when dissolution was complete, the volume was made up to 100 mL with water. 55 mL of the resulting solution was added dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (19.1 g) in acetone (200 mL) stirred at 0 C. After 2 h, the solution was diluted with water and extracted with chloroform. The organic extracts were washed with water, then extracted with aqueous sodium hydroxide. The alkaline mixture was acidified by cautious addition of concentrated hydrochloric acid then extracted with chloroform. The organic layer was then dried (Mg2SO4), filtered, and evaporated. The resulting solid was recrystallized from diethyl ether/hexane to give a colourless solid; MS (ES+) 207, 209 (MH+).Step 1: Preparation of ethyl 4-bromothiophene-2-carboxylate (1015) Thionyl chloride (8.8 mL, 121 mmol) was added slowly to a solution of a) a)

Molecular Weight:207.05
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:205.90371
Monoisotopic Mass:205.90371
Topological Polar Surface Area:65.5
Heavy Atom Count:9
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes