3-AMino-4-broMo-thiophene-2-carboxylicacidMethylester

To 3-amino-2-methoxycarbonylthiophene(10 g, 63 mmol)in acetic acid (200 mL) at room temperature was added a solution of bromine (3.25 mL, 63 mmol) in acetic acid (50mL) slowly for 5 min, and the resulting mixture was stirred for 20 h at the same temperature. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The organic layer was washed with water. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1)to give the desired product 5 (5.59 g, 37percent). Synthesis of 3-[(dimethylamino)diazenyl]-4-bromothiophene-2- carboxamide (compound 2); Step a:Methyl 3-amino-4-bromothiophene-2-carboxylate: To a solution of methyl 3- aminothiophene-2carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3 x 100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33percent), mp 58-60 Step a:Methyl 3-amino-4-bromothiophene-2-carboxylate: To a solution of methyl 3-aminothiophene-2-carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3.x.100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33percent), mp 58-60° C. A mixture of 3-amino-2-thiophenecarboxylate(500 mg, 3.2 mmol) was dissolved in acetic acid (4 mL)Bromine (180 [mu] L, 3.5 mmol) was added dropwise, At room temperature for 24 hAfter the reaction is over, The reaction solution was poured into saturated sodium thiosulfate, And then extracted with methylene chloride, Separation and purification by column chromatography, To give a yellow solid, Yield: 33.8percentCommercially available methyl 3-aminothiophene-2-carboxylate (4 g, 25.4 mmol) was dissolved in acetic acid (40 mL), and a solution of bromine (1.31 mL, 25.4 mmol) in acetic acid (4 mL) was dropped onto the mixture. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate = 95/5) to give methyl 3-amino-4-bromothiophene-2-carboxylate (1.53 g, 26 percent).General procedure: Method A: To a stirred solution of the thiophene 2 (1 mmol) in acetonitrile (0.75 mL) was added sodium nitrite (76 mg, 1.1 mmol) and 48% aq. tetrafluoroboric acid (0.65 mL, 5 mmol) at 0 oC. After 45 mins, methylsulfonylacetonitrile (119 mg, 1 mmol) was added, and the reaction was stirred at 0 oC for 45 mins. N, N-Diisopropylethylamine (0.87 mL, 5 mmol) then was added dropwise, and the reaction stirred at RT for 15 mins. The solid was collected via vacuum filtration and air-dried to yield the title compound (176 mg, 62% yield).To 3-amino-4-bromo-2-(methoxycarbonyl)thiophene (5, 3.70 g, 15.7 mmol) and (4-methoxyphenyl)boronic acid (6a, 2.60 g, 17.1 mmol) in 1, 4-dioxane(74 mL) at room temperature were added triphenylphosphine (820 mg, 3.12 mmol), palladium(II) acetate (175 mg, 0.780 mmol), and 0.53N Na2CO3 (89.0 mL, 46.8 mmol). The mixture was stirred at 80 oC for 2 h. After cooling the reaction mixture to room temperature, 1, 4-dioxane was removed in vacuo and the residue was partitioned between methylene chloride and brine. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (15:1) to give the desired product 7a (3.40 g, 83%). m.p. 112.7 oC; 1H NMR (300 MHz, CDCl3):delta=7.36 (d, J=8.8 Hz, 2H), 7.18 (s, 1H), 6.98 (d, J=8.8 Hz, 2H), 5.59 (br s, 2H), 3.86 (s, 3H), 3.85 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): delta=165.1, 159.4, 151.7, 133.1, 129.4, 128.1, 126.8, 114.6, 101.1, 55.4, 51.3 ppm; IR (ATR, neat): nu=3474, 3362, 3088, 3001, 2952, 2837, 1670 (C[dbond]O), 1591, 1546, 1457, 1436, 1304, 1284, 1240, 1078, 1029, 804 cm-1; MS(ESI): m/z: 264 [M+H+]; HRMS(EI): m/z calcd for C13H13NO3S:263.0616 [M+];found: 263.0610.

Molecular Weight:236.09
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:234.93026
Monoisotopic Mass:234.93026
Topological Polar Surface Area:80.6
Heavy Atom Count:11
Complexity:167
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes