2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile

White solid

General procedure: A mixture of 1 (1 mmol), 2 (1 mmol), elemental sulfur (1 mmol)and BSA (20 mg) was added to 1 mL of DMF. The reaction was incubatedat 50 C and 200 rpm. After the required time, the BSA wasfiltered off to terminate the reaction. For the products with highyields, the solid crude products precipitated in water, and then followedby filtration and drying. For the products with low yields, the crude residues were purified by flash column chromatographyon silica gel using petroleum/ethyl acetate.The structures of the products were confirmed by IR, 1H NMRand 13C NMR. 1H (400 MHz) and 13C NMR (100 MHz) spectra wererecorded on a Bruker Avance 400 spectrometer in CDCl3 using TMS(tetramethylsilane) as internal reference. IR spectra were obtainedwith a Nicolet Nexus 470 FT-IR spectrophotometer. HPLC was carriedout using an Agilent 1100 series with an Agilent TC-C18 column(3a, 3c, 3e, 3g, 3i, 3k: methanol/water ratio = 60/40, 1.0 mL/minand 220 nm; 3b, 3d, 3f, 3h, 3g, 3l: methanol/water ratio = 60/40, 1.0 mL/min and 229 nm).For all reactions, solvents for column chromatography were distilledbefore use.2.2.1. 2-Amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3a)Yellow solid, mp 140–142 C (lit. [19] mp 144–146 C). IR (KBr):. 3447, 3329, 2198 cm−1. 1H NMR (400 MHz, CDCl3): : 4.62 (bs, 2H), 2.53–2.46 (m, 4H), 1.85–1.73 (m, 4H). 13C NMR (100 MHz, CDCl3): : 159.9, 132.4, 120.7, 115.5, 88.8, 24.5, 24.1, 23.4, 22.1.To a stirred solution of cyclohexanone (10. 4ml, 0. 10 mol) in ethanol (300ml) were added sulphur (3.52g, O. llmol), malononitrile (6.60g, 0.10 mol) and diethylamine (10. 30ml, 0. 10mol). The reaction mixture was heated at 70°C for 17 hours. The mixture was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous extracted with further ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate and evaporated to dryness under reduced pressure to give the desired product (16. 7g, 94percent) as a brown solid. 1H NMR No.H (400MHz, CDCl3): 4.60 (2H, br s), 2.50 (4H, m) and 1.80 (4H, m) ppm.Cyclohexanone (0.98 g, 10.0 mmol), malononitrile (0.66g, 10.0 mmol), elemental sulfur (0.35 g, 11.0 mmol) andK2CO3 (0.28 g, 2.0 mmol) in dry ethanol (15 mL) werestirred at reflux for 3 h. The solid catalyst was filtered off, and the solvent was removed by evaporation under reducedpressure, the crude product was washed with chilled waterand recrystallized from ethanol to give yellowish crystals in94percent yield, mp: 146 °C (Lit. [16] 147 °C).General procedure: These compounds were prepared by methods borrowed from the literature [17, 18, 23-26]. We recall here the general procedure that we used: To a mixture of 0.03 mole of ketone, 0.03 mol of malononitrile and 0.03 mole of sulfur in ethanol were added drop wise with stirring a solution of diethyl amine or morpholine(2 mL) in ethanol (5 mL). When addition was completed; the mixture was stirred at a temperature of 50 °C until complete dissolution of sulfur. The heating and stirring were still left one hour. Aminothiophene1 was precipitated by adding 100 mL of cold water. The precipitate was recovered by filtration, washed with water, dried and then recrystallizedfrom suitable solvent.General procedure: Cyclohexanone (0.0981 g, 1.0 mmol), malononitrile (0.0660 g, 1.0 mmol), elemental sulfur (0.0384 g, 1.2 mmoL) was vigorouslyshaken by HSVM for a designated time.The product was purified by chromatography on silica gel and elutedusing CH2Cl2 as the eluent to afford the desired product 2‑amino-5, 6-dihydro-4H-cyclopenta[b]-thiophene-3-carbonitrile as colourlesssolid.General procedure: For the synthesis of 4, 5-alkyl-2-aminothiophenes (2a–2j), the general procedures are the same as those of compound 2i. A mixture of N-benzyl-4-piperidone (1i, 380 mg, 2 mmol), malononitrile (132 mg, 2 mmol), sulfur (64 mg, 2 mmol), and basic ionic liquid (bmIm)OH (380 mg, 2.4 equiv.) was heated to 60°C for 2 h. The reaction mixture was cooled to room temperature and washed with diethyl ether or ethyl acetate (340 mL), and the organic layers were concentrated under vacuum to obtain an oily crude product. The crude product was dissolved in ether/hexane (3:1, 50 mL) mixture, insoluble material was decanted, and the organic layer was concentrated to 1/4 of the volume and kept in a refrigerator. The precipitate that formed was filtered and dried.General procedure: A mixture of 0.070 g 4-propylcyclohexanone (0.5 mmol), 0.030 g malononitrile (0.5 mmol), 0.019 g sulfur powder(0.6 mmol), and 0.1 cmGeneral procedure: General procedure forpreparation of2‑aminothiophenesGeneral procedure: A 50ml round-bottomed flask was charged with α-methylene carbonyl compound 10 (5 mmol), malononitrile 11 (5 mmol), and 25 ml H2O, which was stirred for 20 min under heating or ultrasoundirradiation. Subsequently, sodium polysulfide 12 (5 mmol) was added and stirred at 70Cunder conventional heating or ultrasound irradiation. The mixture became turbid at the end of thereaction, which was poured into cold water. The crude product was isolated by filtration and wasfurther purified by recrystallization with ethanol to afford pure 2-aminothiophenes. All the productswere isolated, and their isolated yields are given in Table 2. Identities of the products wereestablished by comparison of their physical and spectral data with those of reported compounds.General procedure: 10 mmol of ketone or aldehyde, 10 mmol of malonodinitrile, and 10 mmol of sulfur powder were mixed. Then, 0.02 g (2.5 molpercent) of ZnO nano-particles was added and the mixture was heated to 100 °C with good stirring for the required time. After 6 h, the reaction was stopped and the corresponding product was worked up by 10 ml of ethanol and ZnO was separated by a simple filtration. Thereafter, the reaction mixture was cooled to room temperature and poured into 150 ml of ice-water. The precipitate was filtered off, washed with cold water and dried. To further purification, the crude product was purified by silica gel column chromatography with 10:1 hexane:ethyl acetate as eluent.The reaction scheme for the synthesis of azo dye 10 is shown below. In a Gewald reaction, diethylamine (8 ml) was added to a solution of equimolar quantities of cyclohexanone (9.80 g, 0.10 mol) and malononitrile (6.60 g, 0.10 mol) in ethanol, and the mixture was refluxed for 10 minutes. Then sulfur (3.53 g, 0.11 mol) was added, and the solution was refluxed for a further 3 hours. The pale yellow precipitate that formed was filtered and washed with cooled ethanol to give 10a as a pale yellow powder (13.4 g, 75percent yield), m.p. 147-148° C.(1) elemental sulfur 1.6g, malononitrile 3.3g, cyclohexanone 5ml, placed in a round bottom flask, Add solvent ethanol 50ml, the reaction at room temperature for 10min, add morpholine 5ml, 60 ° C for 12h.After cooling, the reaction solution was poured into ice-water, a large amount of solid was precipitated, and the light brown filter cake was obtained by suction filtration. After drying, ethyl acetate: petroleum ether 1: 1Recrystallization gave 2-amino-3-nitrile-4, 5, 6, 7-tetrahydrobenzothiophene 5.4g, yield 62.8percent.General procedure: To a solution of ketone (8a-c, 10, 12e-f or 14) (25 mmol) and malononitrile (1.65 g, 25 mmol) in EtOH (50 mL), sulfur (0.88 g, 27.5 mmol) and morpholine (4.35 mL, 50 mmol) were added, and the mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature and the orange solid was collected by filtration and washed with cold EtOH.General procedure: A mixture of ketone (1.0 eq.), sulfur powder (1.0 eq.) and t-butyl cyanoacetate, ethyl cyanoacetate or malononitrile (1.0 eq.) in EtOH (2mL/mmol) was prepared before morpholine (1.0 eq.) was added dropwise, ensuring that the reaction did not heat up above 60°C during the addition. The mixture was then heated at 40°C and stirred for 4–20h.EXAMPLE 42; Synthesis of N-phenyl-N'-4-[2-(5, 6, 7, 8-tetrahydrobenzo[4, 5]thieno[2, 3-d]pyrimidin-4-ylamino)ethyl]phenylurea (Compound 42); 2-Amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophen-3-yl cyanide (step a): To a mixture of cyclohexanone (1.18 g), malononitrile (0.66 g) and sulphur (0.40 g) in absolute ethanol (3 ml) was added triethylamine (2 mL). After refluxed for 16 h, the reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (4:1), to give 2-amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophen-3-yl cyanide (0.94 g, 44percent).2-Amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophen-3-yl cyanide (step a): To a mixture of cyclohexanone (1.18 g), malononitrile (0.66 g), and sulphur (0.40 g) in absolute ethanol (3 ml) was added triethylamine (2 mL). After refluxed for 16 h, the reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (4:1), to give the title compound (0.94 g, 44percent).NaOH (2.0 mmol, 80 mg) was added to a mixture of cyclohexanone (2.0 mmol, 196 mg), malononitrile (2.0 mmol, 132 mg), and sulfur (2.0 mmol, 64 mg) in t-BuOH (4.0 mL) under an argon atmosphere. The mixture was stirred at room temperature until the disappearance of the starting materials (TLC and GC). The mixture was dissolved in EtOAc (10 mL), washed with a saturated NH4Cl solution (20 mL), and dried (Na2SO4). The volatile portion was removed under reduced pressure and the solid residue recrystallized from ethyl acetate/hexanes to yield 5.General procedure: A mixture of 0.8 g azide 1 (3.9 mmol) and 4.1 mmol ofdimethyl, diethyl, or diisopropyl phosphite (6a–6c) in15 cm3 THF was stirred at r.t. for 6–10 h (TLC) andvolatile materials were removed under vacuum. Theresulting residue was chromatographed on silica gel withn-hexane/CHCl3 (8:2, v/v) to give 2-amino-4, 5, 6, 7-tetrahydrobenzo-[b]thiophene-3-carbonitrile (9) as buff substancein 10.3 percent yield; m.p. 147 C (Ref. [26] 145 C). Elutionwith n-hexane/CHCl3 (1:1, v/v) afforded 8a–8c.General procedure: A mixture of 0.8 g azide 1 (3.9 mmol) and 4.1 mmol ofdimethyl, diethyl, or diisopropyl phosphite (6a–6c) in15 cm3 THF was stirred at r.t. for 6–10 h (TLC) andvolatile materials were removed under vacuum. Theresulting residue was chromatographed on silica gel withn-hexane/CHCl3 (8:2, v/v) to give 2-amino-4, 5, 6, 7-tetrahydrobenzo-[b]thiophene-3-carbonitrile (9) as buff substancein 10.3 percent yield; m.p. 147 C (Ref. [26] 145 C). Elutionwith n-hexane/CHCl3 (1:1, v/v) afforded 8a–8c.Dimethyl 3-cyano-4, 5, 6, 7-tetrahydrobenzo[b]thiophen-2-ylphosphoramidate (8a, C11H15N2O3PS)Colorless crystals; yield: 0.76 g (68.2 percent); m.p.: 174 C(EtOH); IR (KBr): v = 3322 (NH), 2198 (CN), 1234 (P=O, bonded), 1029 (P–O–C) cm-1; 1H NMR (500.7 MHz, CDCl3): d = 1.91, 2.45 (2 m, 4 9 2H, 4 H2C-hexyl), 3.79(d, 3JPH = 11.5 Hz, 2 9 3H, 2 Me.OP), 11.35 (br, 1H, HN) ppm; 13C NMR (125.4 MHz, CDCl3): d = 151.6 (d, 2JPC = 31.5 Hz, C-NH), 134.4, 130.2 (C = C-hexyl), 113.8 (CN), 74.3 (C–CN), 52.4 (d, 2JPC = 12.9 Hz, 2MeOP), 26.4, 26.1, 23.6, 22.3 (CH2-hexyl) ppm; 31P NMR(200.7 MHz, CDCl3): d = 17.6 ppm; MS (EI, 70 eV): m/z(percent) = 285 (53) [M?-1], 259 (34) [M?-27 (H ' CN)], 150(100) [M?-136 (H ' CN ' P(O)(OMe)2)].General procedure: A mixture of 0.8 g azide 1 (3.9 mmol) and 4.1 mmol ofdimethyl, diethyl, or diisopropyl phosphite (6a–6c) in15 cm3 THF was stirred at r.t. for 6–10 h (TLC) andvolatile materials were removed under vacuum. Theresulting residue was chromatographed on silica gel withn-hexane/CHCl3 (8:2, v/v) to give 2-amino-4, 5, 6, 7-tetrahydrobenzo-[b]thiophene-3-carbonitrile (9) as buff substancein 10.3 percent yield; m.p. 147 C (Ref. [26] 145 C). Elutionwith n-hexane/CHCl3 (1:1, v/v) afforded 8a–8c.

Molecular Weight:178.26
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:178.05646950
Monoisotopic Mass:178.05646950
Topological Polar Surface Area:78
Heavy Atom Count:12
Complexity:220
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes