| 83.1% |
With ammonium hydroxide; zinc; In water; at 20℃; for 6h; |
At room temperature, <strong>[2434-03-9]4,5-dibromofuran-2-carboxylic acid</strong> 22a (5.5g, 20.30 mmol), 18mL of aqueous ammonia in 63mL water, and zinc powder (1.46g, 22.33 mmol) were mixed. After addition was complete, it was stirred at room temperature for 6 hours. The reaction solution was adjusted pH = 3 with 1M hydrochloric acid. The solid precipitate was filtered. The filter cake was washed with n-hexane (15mL × 4) and dried to give the title product 4-bromofuran-2-carboxylic acid 22b (3.2g, white solid), yield: 83.1%. |
| 46% |
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Step C: 4-Bromo-2-furoic acid. 4,5-Dibromo-2-furoic acid (24.51 g, 90.8 mmol) was dissolved in a mixture of water (280 mL) and aq. NH4OH (33% NH3; 80 mL) and <n="20"/>cooled in an ice bath. The mixture was stirred rapidly as zinc dust (6.23 g, 95.3 mmol) was added in portions while keeping the internal temperature below 7 0C. The mixture was stirred at 0 0C for 30 min. An additional portion of zinc dust (0.5 g, 7.6 mmol) was added and the mixture was allowed to stir at 0 0C for 30 min. The reaction was acidified to pH 1 with cone. HCI causing precipitation of the product. The mixture was cooled to 10 0C, and the product was collected by suction filtration, washed with water, and air dried to provide 8.0 g (46%) of the desired acid. Additional product could be obtained by extraction of the filtrate with DCM and recrystallization of the crude extract from water. 1H NMR (CDCI3): 7.76 (d, J = 0.8, 1 H), 7.14 (d, J = 0.8, 1 H). |
| 46% |
With ammonia; zinc; In water; at 0 - 7℃; for 1h; |
C. 4-Bromo-2-furoic acid. ; 4,5-Dibromo-2-furoic acid (24.51 g, 90.8 mmol) was dissolved in a mixture of water (280 mL) and aq. NH4OH (33% NH3; 80 mL) and cooled in an ice bath. The mixture was stirred rapidly as zinc dust (6.23 g, 95.3 mmol) was added in portions while keeping the internal temperature below 7 C. The mixture was stirred at 0 C. for 30 min. HPLC analysis of an aliquot of the reaction mixture indicated some starting material remaining. An additional portion of zinc dust (0.5 g, 7.6 mmol) was added and the mixture was stirred at 0 C. for 30 min. HPLC analysis of an aliquot indicated only a trace of starting material as well as formation of a small amount of 2-furoic acid from over-reduction. The mixture was acidified to pH 1 with conc. HCl causing precipitation of the product. The mixture was cooled to 10 C., and the product was collected by suction filtration, washed with water, and air dried to provide 8.0 g (46%) of the desired acid. Additional product could be obtained by extraction of the filtrate with DCM and recrystallization of the crude extract from water. 1H NMR (400 MHz, CDCl3): 7.76 (d, J=0.8, 1H), 7.14 (d, J=0.8, 1H). |
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Step 1: 4-Bromo-furan-2-carboxylic Acid Amide To a cooled (using a cold water bath) solution of <strong>[2434-03-9]4,5-dibromo-furan-2-carboxylic acid</strong> (12.5 g, 46.32 mmol) in NH4OH (100 1 mL) is added zinc dust (activated, powdered (washed with 2M HCl, water, MeOH, CH2Cl2) 4.54 g, 65.39 mmol) in small portions. The reaction mixture is stirred at room temperature for 10 minutes then filtered over celite and washed with water. The filtrate is cooled to -10 C. (ice/salt bath) and acidified slowly to pH 1 using conc. HCl. The aq layer is immediately extracted with ethyl acetate (4*). The organic phase is washed with brine, dried over anhydrous MgSO4, filtrated and concentrated in vacuo to give an oil (4.96 g) which solidifies on standing to give a white solid, which is used without further purification. |
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With zinc; In water; acetic acid; at 125 - 130℃; for 1.5h;Heating / reflux; |
C. A 500 mL three-necked round-bottom flask fitted with an overhead mechanical stirrer, and reflux condenser was charged with 4,5-dibromofuran- 2-carboxylic acid (34.3 g, 127 MMOL), H20 (100 mL), and HOAC (25 mL). The third neck of the flask was stoppered and the suspension was heated to reflux with a temperature controlled heating mantle held at 125-130C. Zn dust (15.0 g, 229 MMOL) (previously ground in a mortar and pestle to break up lumps) was added portionwise over 50 minutes. Subsequent portions are added after most of the previously added portion has disappeared. After the first portions of the Zn were added, all of the 4,5- dibromofuran-2-carboxylic acid dissolved to give a pale brown solution. Near the end of the Zn addition a white solid began to appear in the reaction flask. Ten minutes after the conclusion of the zinc addition a thick white slurry had formed. HPLC analysis of the reaction slurry after 15 minutes indicated nearly complete consumption of the starting 4, 5-dibromofuran-2-carboxylic acid and conversion to the desired product. After 40 minutes, heating was discontinued, and the white slurry was allowed to cool to ambient temperature. After cooling to ambient temperature the reaction slurry was diluted with cold H20 (100 mL), cooled in an ice bath, and then filtered. The solids were rinsed with cold H2O, dried on the filter, and the resulting damp solids were dissolved in warm acetone (1.6 L). The resulting solution was filtered to remove residual zinc dust, and then concentrated under reduced pressure to afford a white solid. The resulting solid was broken up with a spatula and pumped down under high vacuum to afford an OFF-WHITE POWDER. 1H NMR analysis of the material (DMSO-D6) showed it to be quite pure but to contain H20. The solids were suspended in toluene (-1 L) and heated to reflux in a flask fitted with a condenser and a Dean-Stark trap. The suspension was heated at reflux FOR-1 hour at which time less than 1 mL of H20 had collected in the trap. The suspension was cooled, and concentrated under reduced pressure to afford 4-bromo FURAN-2-CARBOXYLIC acid as a-white powdery solid. H-NMR (400MHZ, DMSOD6) : S 7.96 (1 H, d, J = 0.8 Hz), 7.04 (1 H, d, J = 0.8 Hz). |
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Step 1: 4-Bromo-furan-2-carboxylic acid amide To a cooled (using a cold water bath) solution of <strong>[2434-03-9]4,5-dibromo-furan-2-carboxylic acid</strong> (12.5 g, 46.32 mmol) in NH4OH (100 mL) is added zinc dust [activated, powdered (washed with 2M HCl, water, MeOH, DCM) 4.54 g, 65.39 mmol] in small portions. The reaction mixture is stirred at room temperature for 10 minutes then filtered over celite and washed with water. The filtrate is cooled to -10 C. (ice/salt bath) and acidified slowly to pH 1 using conc. HCl. The aq layer is immediately extracted with ethyl acetate (4*). The organic phase is washed with brine, dried over anhydrous MgSO4, filtrated and concentrated in vacuo to give an oil (4.96 g) which solidifies on standing to give a white solid, which is used without further purification. The solid (4.93 g, 25.81 mmol) is dissolved in thionyl chloride (44.2 mL) and refluxed for 1 hour. After removing the solvent in vacuo the residue is dissolved in dichloromethane (75 mL) and a solution of 0.5 M NH3 in dioxane (52 mL) is added. The reaction mixture is stirred at room temperature for 1 hour, then 33% aq. NH3 (5 mL) is added and the reaction stirred for additional 2 hours. The solvent is removed in vacuo and the residue taken-up with a solution of sat. NaHCO3. The basic solution is extracted using ethyl acetate (3*), the combined organic layers are dried over anhydrous MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography eluting with a mixture of (50:49:1) ethyl acetate: petroleum ether: acetic acid, affords the title compound (1.2 g, 22%). |
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Example 5c: 4-bromofuran-2-carboxylic acid4,5-Dibromofuran-2-carboxylic acid (5.5 g, 20.6 mmol) was suspended in water (63mL). Ammonium hydroxide (18mL) was added and the mixture was stirred vigorously at room temperature followed by the addition of Zn powder (1.3 g, 20.6 mmol). The reaction was stirred for 3 h at room temperature, filtered through celite and the clear solution was acidified to pH 2-3 with a 1M HCl solution. The product was extracted using ethyl acetate and the combined organic layer was evaporated under vacuum to give the final product which was used without further purification |
| 665 mg |
With ammonium hydroxide; zinc; In water; at 20℃; for 3h; |
4,5-Dibromofuran-2-carboxylic acid (9, 1.00 g, 3.7 mmol) was suspended in water (11 mL) and NH4OH (3.5 mL) with vigorous stirring at ambient temperature. Powdered zinc metal (1.30 g, 20.3 mmol) was added, and the mixture was allowed to stir at ambient temperature for 3 h. The reaction mixture was filtered through a pad of Celite and acidified (pH 2) with 2 N HCl. The filtrate was extracted with EtOAc (4 * 50 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure to provide 665 mg of a white powder. To this crude intermediate dissolved in MeOH (12 mL) was added concentrated sulfuric acid (80 muL) while stirring. The resulting solution was heated to reflux and stirred overnight. The reaction mixture was allowed to cool to room temperature followed by concentration under vacuum. The resulting crude residue was then partitioned between saturated aqueous NaHCO3 and diethyl ether, and the aqueous layer was further extracted with diethyl ether (2 * 40 mL). The combined ether solutions were washed with brine (20 mL), dried (Na2SO4) and concentrated to dryness under reduced pressure to provide 652 mg (3.18 mmol, 86%) of the desired product as a clear oil. |
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Step 1 4-Bromo-furan-2-carboxyliotac acid amide[00403] To a solution of 4,5-dibromo-furan-2-carboxyhc acid (7 79g, 28 85mmol) m NH4OH(100ml) is added zinc dust (2 29g, 34 62mmol) m small portions The reaction mixture is stirred at room temperature for 7 minutes then filtered over celite and washed with water and 2M HCl The filtrate is acidified to pH 1 using cone HCl and extracted with ethyl acetate (3x) The organic phase is washed with brine, dried over MgSO4, filtrated and concentrated m vacuo to give an oil (4 96g) which solidifies on standing to give a white solid, used in the amide formation step, without further purification |
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To a solution of <strong>[2434-03-9]4,5-dibromo-furan-2-carboxylic acid</strong> {1.19%, 28.85mmol) in NH4OH(10OmL) is added zinc dust (2.29g, 34.62mmol) in small portions. The reaction mixture is stirred at room temperature for 7 minutes then filtered over celite and washed with water and 2M HCl. The filtrate is acidified to pH 1 using cone. HCl and extracted with ethyl acetate (3x). The organic phase is washed with brine, dried over MgSO4, filtrated and concentrated in vacuo to give an oil (4.96g) which solidifies on standing to give a white solid, which is used without further purification. [00359] The solid (4.93g, 25.81mmol) is dissolved in thionyl chloride (44.2mL) and refluxed for 1 hour. After removing the solvent in vacuo the residue is dissolved in dichloromethane (75mL) and a solution of 0.5 M NH3 in dioxane (52mL) is added. The reaction mixture is stirred at room temperature for 1 hour, then 33% aq. NH3 (5mL) is added and the reaction stirred for additional 2 hours. The solvent is removed in vacuo and the residue taken-up with a solution of sat. NaHCO3. The basic solution is extracted using ethyl acetate (3x), the combined organic layers are dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography eluting with a mixture of (50:49:1) ethyl acetate:petroleum ethe?acetic acid, affords the title compound (1.2g, 22%). |
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