5-BROMOTHIOPHENE-2-CARBONITRILE

Colorless liquid or semisolid

Preparation Example A+-20. 5-Bromo-thiophene-2-carbonitrile To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime described in Preparation Example A+-19 (1.3g, 6.2mmol) and tetrahydrofuran (15mL) were acetic acid (1.4mL, 25mmol) and acetic anhydride (1.5mL, 15mmol) at room temperature, then, stirred at 50°C for 2 hours, and further stirred at 70°C for 8 hours. After cooling this reaction mixture, the solution was concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (heptane : ethyl acetate = 8 : 1), and the title compound (1.0g, 5.4mmol, 88percent) was obtained as a colorless solid. In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer was added 4 mmol of 5-bromothiophene-2-carbaldehyde (1-20)), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, followed by placing the reaction flask in an oil bath preheated to 50 ° C and opening the magnetic stirrer for 15 h. The reaction solution By adding sodium thiosulfate solution, stirring, and then extracting with ether, separating the organic layer, and removing the solvent under reduced pressure, The eluate was collected with the mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as the eluent, and the eluate containing the target compound was collected. The solvent was distilled off to give 5-bromothiophene-2-carbonitrile with an isolated yield of 82percent.5-Bromo-2-thiophenecarbonitrile: A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5percent aqueous sulfuric acid (2.x.30 mL), water (2.x.30 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1 L) and allowed to crystallize. The crystals obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the subtitled compound as an off-white solid (31.5 g combined, 58percent). IR (film) cm1 2200. 1H-NMR (CDCl3) δ 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M+, 98percent) 189(M+, 100percent).EXAMPLE 8 EXAMPLE 8 General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv), (NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Åmolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50°C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml), saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3–4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50percent) as awhite solid.5-Bromo-2-thiophenecarbonitrile To a solution of the available 2-thiophenecarbonitrile (2.22 g, 20.3 [MMOL)] in a mixture of acetic acid (1.22 g, 20.3 [MMOL)] and acetic anhydride (8.3 g, 81.3 [MMOL)] was [ADDED NBS (3.62 G, 1.0 EQ. ) AND BROMINE (1.05 ML, 1.0 EQ. ) AND THE REACTION MIXTURE] was stirred at rt for 3 hours. Water and ice were added and also a saturated sodium bisulfite solution. After extraction with DCM, the organic layer was washed with a saturated [NAHC03] solution, dried over [NA2SO4] and evaporated. The title compound was obtained as a orange liquid (3.74 g, 20 [MMOL)] in a quantitative yield ; GC/MS : [M+] C5H2BrNS 188(1) Weighing 4 g 2-cyanothiophene (32.47 mmol) is dissolved in 30 ml DMF, taking 3.6 g NBS is slowly added to the mixture in stirring 15 min, all in the dark after adding the reaction under the room temperature condition 6 h. After the completion of the reaction methylene chloride and aqueous phase extraction purification, congeals the organic layer to dry column chromatography purification, the developing agent is the volume ratio of 1:3 of dichloromethane: petroleum ether mixed solvent, to obtain 4-bromo-2-cyanothiophene, the yield is 75percent.To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime described in Preparation Example A+-19 (1.3g, 6.2mmol) and tetrahydrofuran (15mL) were acetic acid (1.4mL, 25mmol) and acetic anhydride (1.5mL, 15mmol) at room temperature, then, stirred at 50°C for 2 hours, and further stirred at 70°C for 8 hours. After cooling this reaction mixture, the solution was concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (heptane : ethyl acetate = 8 : 1), and the title compound (1.0g, 5.4mmol, 88percent) was obtained as a colorless solid.

Molecular Weight:188.05
XLogP3:2.7
Hydrogen Bond Acceptor Count:2
Exact Mass:186.90913
Monoisotopic Mass:186.90913
Topological Polar Surface Area:52
Heavy Atom Count:8
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes