2-AMINO-4,5,6,7-TETRAHYDRO-1-BENZOTHIOPHENE-3-CARBOXAMIDE

To the stirred solution of Compound 1 (3.0 g, 30.56 mmol), 2-cyanoacetamide (2.56 g, 30.56 mmol), sulfur powder (0.97 g, 30.56 mmol) in ethanol (40 mL) was added morpholine (5.31 mL, 61.11 mmol) and stirred the reaction mixture at room temperature for 6 h. The reaction mixture was concentrated, diluted with EtOAc and washed the organic layer with H2O (2x30 mL). The separated organic layer was dried over anhydrous Na2SO4, evaporated and purified by column chromatography to get Compound 2 (5.40 g, 90percent) as an light yellow solid. ESI-MS found 197 [M+H]+.Compound 2: 2-amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-3-carboxamide Cyclohexanone (Compound 1, 10 mL), morpholine (2 mL), elemental sulfur (3.2 g), and cyanoacetamide(8.4 g) were added to absolute ethanol (80 mL).The reaction mixture was refluxed at 50 °C for 5 h. After cooling, a yellow solid was filtered, washed with absolute ethanol, and dried at 40 °C under an infrared lamp to give Compound 2 in a yield of 79percent.To a stirred mixture of cyanoacetamide (1a; 10 g) and cyclohexanone(2a; 12.3 g), at room temperature, Sulfur was added (3a;4.139 g). Upon addition of diethylamine (11.8 ml) an exothermic reaction started and the temperature rose to 55-58 °C for 1 h. The reaction mixture was stirred at 45-50 °C for 1 h and left overnightat room temperature. The solid obtained was filtered, washed withchilled ethanol and dried. 4.1.1.1. 3-Amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-2-carboxamide (4a). 78percent yield; M.P.178 °C; IR (KBr) ν(cm-1): 3390, 3155, 2941, 1660, 1560; 1H NMR (400 MHz, DMSO-d6):δ (ppm) 6.90(br s, 2H, NH2), 6.32 (br s, 2H, NH2), 2.59e2.62 (m, 2H, CyclohexylCH2), 2.46e2.48 (m, 2H, Cyclohexyl CH2), 1.70e1.77 (m, 4H, CyclohexylCH2); LC-MS/MS (M+H)+: 197.0 (calculated 196.07); Elemental analysis (percent): Calculated (Found) for C9H12N2OS: C 55.08(55.01), H 6.16 (6.19), N 14.27 (14.31), S 16.34 (16.40).General procedure: Cyclohexanone (for 18a), 1-benzoylpiperidin-3-one (for 18b) or 1-benzoylpiperidin-4-one (for 18c) (0.42mmol), cyanoacetamide (34mg, 0.40mmol) and sulfur (16mg, 0.50mmol) were suspended in EtOH (1mL). To this was added morpholine (70mg, 0.80mmol). The resulting mixture was refluxed gently with stirring for 4h, and was allowed to cool to room temperature. Solvent was removed and the residue was purified by flash chromatography on silica gel using hexanes:EtOAc (1:2) to give compounds 18a-c as off white powder.In a 250 mL three-necked flask, 10.1 g (120 mmol) of cyanoacetamide, 3.8 g (120 mmol) of elemental sulfur, 11.8 g (120 mmol) of cyclohexanone and 38 mL of absolute ethanol, 8.8 g (5.0 mmol) of diethylamine was slowly added dropwise to the above mixture at a temperature of 40 to 50 ° C and stirred for 5 h. The crystals were cooled and filtered to give a brownish solid which was washed twice with a small amount of anhydrous ethanol. To give 11.7 g of a yellow solid powder in a yield of 49.6percent.General procedure: A mixture of the ketone (1 eq.), cyanoacetate (1 eq.), and elemental sulphur (1eq.) in ethanol were combined and heated at 40-70 °C. Morpholine or diethylamne (1 eq.) was added dropwise. The reaction was stirred at 40-70 °C for 1-4 hours, and then stirred at room temperature overnight. The resulting precipitate was typically collected by filtration and recrystallised from ethanol or toluene.A solution of aminothiophene EO (prepared as described in Example C; 500mg, 2.8 mmol) in concentrated sulphuric acid (5ml) was stirred at room temperature for 65 hours. The reaction mixture was poured cautiously into ice-cold aqueous potassium carbonate, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulphate and evaporated to dryness under reduced pressure to give the desired product (383mg, 70percent) as an off-white solid. 'H NMR 8H (400MHz, CDC13) : 6.15 (2H, br s), 4.40 (2H, b-r s), 2. 65 (2H, m), 2.50 (2H, m) and 1.80 (4H, m) ppm.General procedure: Tert-butyl cyanoacetate (10 mmol), prepared according to known procedure [6] was heated to reflux with TEA (30 mmol), sulphur (10 mmol) and freshly distilled cyclohexane (10 mmol) in 15 ml of methanol for 5 h and stirred in RT overnight. The solvent was rotatory evaporated and the residue was dissolved in chloroform and filtrated. The organic layer was washed with 0.1 M solution of hydrochloric acid and distilled water. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography (n-hexane: chloroform). Yield 72 percent as dark yellow oil that solidifies under vacuum.The reaction was carried out as for tert-butyl 2-amino-4, 5, 6, 7-tetrahydro-1-benzothiophene-3-carboxylate. Purification by column chromatography (chloroform: ethyl acetate) Yield 50percent as yellow crystals. mp 185-188 °C. IR (ATR): 3398, 3299, 3183, 2928, 2832, 1626, 1558, 1480, 1418 cm

Molecular Weight:196.27
XLogP3:1.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:196.06703418
Monoisotopic Mass:196.06703418
Topological Polar Surface Area:97.4
Heavy Atom Count:13
Complexity:222
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes