* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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.
Reference：
[1] Archiv der Pharmazie, 1981, vol. 314, # 2, p. 168 - 175
[2] Patent: WO2005/44008, 2005, A2, . Location in patent: Page/Page column 105-106
[3] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 6, p. 450 - 456
2
[ 108-94-1 ]
[ 109-77-3 ]
[ 4651-91-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
With octasulfur; bovine serum albumin In N,N-dimethyl-formamide at 50℃; for 4 h;
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.
94%
With sulfur; diethylamine In ethanol at 70℃; for 17 h;
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.
94%
With sulfur; potassium carbonate In ethanol for 3 h; Reflux
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).
92%
With sulfur In ethanol at 50℃; for 1 h;
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.
88%
With sulfur; diethylamine In neat (no solvent) for 0.333333 h; Milling
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.
88%
at 60℃; for 2 h; Ionic liquid; Green chemistry
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.
88%
With sulfur; choline chloride; urea; sodium hydroxide In water at 60℃; Green chemistry
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 cm3 NaOH (4 mol dm-3 aqueoussolution) in 1 cm3 choline chloride/urea was stirred at 60°C for 2–3 h. After completion of the reaction, indicated by TLC monitoring, 5 cm3 water was added. The solid product was separated by filtration and if necessary the precipitate recrystallized from EtOH to afford the corresponding pure product
88%
With sulfur In neat (no solvent) at 60℃; for 2 h;
General procedure: General procedure forpreparation of2‑aminothiophenes
84%
Stage #1: for 0.333333 h; Sonication; Green chemistry Stage #2: With Na2S6 In water for 0.5 h; Sonication; Green chemistry
General 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.
81%
With zinc(II) oxide; sulfur In neat (no solvent) at 100℃; for 6 h;
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.
75%
Stage #1: With diethylamine In ethanol for 0.166667 h; Reflux Stage #2: With sulfur In ethanol for 3 h; Reflux
EXAMPLE 10; 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.
62.8%
Stage #1: With sulfur In ethanol at 20℃; for 0.166667 h; Stage #2: at 60℃; for 12 h;
(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.
57%
With morpholine; sulfur In ethanol for 2 h; Reflux
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.
51%
With morpholine; cyanoacetic acid tert-butyl ester; sulfur In ethanol at 40℃; for 20 h;
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.
44%
With sulfur; triethylamine In ethanol for 16 h; Reflux
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).
44%
With sulfur; triethylamine In ethanol for 16 h; Reflux
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).
94 %Chromat.
With sulfur; sodium hydroxide In <i>tert</i>-butyl alcohol at 20℃; for 0.5 h; Inert atmosphere
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.
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2013, vol. 95, p. 29 - 35
[2] Synlett, 2010, # 9, p. 1351 - 1354
[3] Synthetic Communications, 2010, vol. 40, # 14, p. 2067 - 2074
[4] Applied Organometallic Chemistry, 2018, vol. 32, # 5,
[5] Patent: WO2005/44008, 2005, A2, . Location in patent: Page/Page column 91
[6] Letters in Organic Chemistry, 2014, vol. 11, # 9, p. 700 - 705
[7] Tetrahedron Letters, 2007, vol. 48, # 18, p. 3171 - 3172
[8] Letters in Organic Chemistry, 2014, vol. 11, # 6, p. 403 - 408
[9] Heterocycles, 2014, vol. 88, # 1, p. 741 - 753
[10] Synthetic Communications, 2001, vol. 31, # 20, p. 3113 - 3117
[11] Synthetic Communications, 2012, vol. 42, # 16, p. 2367 - 2374
[12] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[13] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 2091 - 2092
[14] Synthetic Communications, 2013, vol. 43, # 13, p. 1859 - 1864
[15] Journal of Sulfur Chemistry, 2014, vol. 35, # 3, p. 261 - 269
[16] Archiv der Pharmazie, 2016, vol. 349, # 11, p. 827 - 847
[17] Journal of Chemical Research, 2014, vol. 38, # 7, p. 450 - 452
[18] Synthetic Communications, 2015, vol. 45, # 1, p. 119 - 126
[19] Monatshefte fur Chemie, 2017, vol. 148, # 4, p. 711 - 716
[20] Research on Chemical Intermediates, 2018, vol. 44, # 3, p. 2195 - 2213
[21] Tetrahedron, 2006, vol. 62, # 29, p. 7121 - 7131
[22] Journal of Sulfur Chemistry, 2013, vol. 34, # 5, p. 458 - 463
[23] Journal of Molecular Catalysis A: Chemical, 2013, vol. 368-369, p. 16 - 23
[24] Applied Organometallic Chemistry, 2018, vol. 32, # 2,
[25] Patent: US2010/81823, 2010, A1, . Location in patent: Page/Page column 7
[26] Patent: CN104945412, 2018, B, . Location in patent: Paragraph 0044; 0045
[27] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 32 - 45
[28] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 38 - 50
[29] Patent: US2009/275533, 2009, A1, . Location in patent: Page/Page column 39
[30] Patent: US2010/120805, 2010, A1, . Location in patent: Page/Page column 42-43
[31] Bioconjugate Chemistry, 2012, vol. 23, # 12, p. 2403 - 2416
[32] Medicinal Chemistry Research, 1996, vol. 6, # 3, p. 148 - 163
[33] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1296 - 1301
[34] Patent: WO2006/58600, 2006, A1, . Location in patent: Page/Page column 8-9
[35] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 3, p. 853 - 857
[36] Patent: US2008/306053, 2008, A1, . Location in patent: Page/Page column 57
[37] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 4026 - 4034
[38] Archiv der Pharmazie, 2010, vol. 343, # 10, p. 590 - 601
[39] Russian Chemical Bulletin, 2011, vol. 60, # 2, p. 352 - 360
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[55] Bulletin of the Chemical Society of Ethiopia, 2018, vol. 32, # 2, p. 259 - 270
3
[ 4354-73-8 ]
[ 4651-91-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 17, p. 2740 - 2746
[2] Synlett, 2010, # 9, p. 1351 - 1354
[3] Synthetic Communications, 2004, vol. 34, # 20, p. 3801 - 3806
[4] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 3, p. 853 - 857
[5] Turkish Journal of Chemistry, 2014, vol. 38, # 4, p. 650 - 660
4
[ 1809-20-7 ]
[ 1254693-14-5 ]
[ 4651-91-6 ]
Yield
Reaction Conditions
Operation in experiment
76.4%
at 20℃;
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.
With sodium hydroxide; In tert-butyl alcohol; at 50℃; for 3h;
To a stirred solution of 5 (2.0 mmol, 356 mg) in t-BuOH (4.0 mL), benzonitrile 3a (4.0 mmol, 412 muL) and NaOH (2.0 mmol, 80 mg) were added. The mixture was stirred at 50 C until disappearance of 5 (TLC). The reaction mixture was cooled to room temperature, the residue dissolved in EtOAc (10 mL), washed with a saturated NH4Cl solution (20 mL), and dried (Na2SO4). After removal of the volatile portion under reduced pressure, compound 4a was obtained by recrystallization of the solid residue from EtOAc.
With octasulfur; bovine serum albumin; In N,N-dimethyl-formamide; at 50℃; for 4h;Catalytic behavior;
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.
97%
With morpholine; sulfur; In ethanol; at 30℃; for 8h;
General procedure: These compounds were prepared according to literature procedures with slight modification [19, 20]. Briefly, morpholine (5 mL, 60 mmol) was slowly added to a mixture of ketone (50 mmol), malonodinitrile (3.3 g, 50 mmol), and sulphur (1.6 g, 50 mmol) in ethanol (75 mL) at 30 C. Then, the mixture was stirred for 8 h at this temperature. After completion, the reaction mixture was filtered, and the resulting filtrate was poured into cold water, and allowed to stand for 1 h. Finally, the precipitate was filtered, washed with cold aqueous ethanol (50%), and recrystallized from ethanol to give the desired Gewald product.
95%
With potassium carbonate; sulfur; In ethanol; at 85℃; under 10343.2 Torr; for 0.25h;Microwave irradiation;
Cyclohexanone (0.98 g, 10 mmol), malononitrile(0.66 g, 10 mmol), sulfur powder (0.35 g, 11.0 mmol),K2CO3 (0.28 g, 2.0 mmol) and 20 mL of dry ethanol weremixed and placed in a 50 mL pressure tube. The mixturewas subjected to microwave irradiation (CEM ExplorerHybrid, USA, 100 W, 200 psi, 85 C) for 15 min. Afterthe reaction, the insoluble material was filtered out, and thesolvent was removed through evaporation under reducedpressure. The crude product was washed with water andrecrystallized from ethanol to give yellowish crystals of1.69 g (9.50 mmol), in 95% yield; mp 146.8-148.0 C;1H NMR (400 MHz, CDCl3) d 4.61 (s, 2H), 2.59-2.39(m, 4H), 1.90-1.69 (m, 4H); 13C NMR (100 MHz, CDCl3)d 159.87, 132.37, 120.67, 115.43, 88.82, 24.52, 24.13,23.37, 22.12; IR (KBr) nu / cm-1 3444, 3327, 2907, 2193,1618, 1520; HRMS (ESI) m/z, calcd. for C9H10N2S[M + H]+: 179.0637; found: 179.0638.
94%
With sulfur; diethylamine; In ethanol; at 70℃; for 17h;
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 70C 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, 94%) 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.
94%
With sulfur; potassium carbonate; In ethanol; for 3h;Reflux;
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 in94% yield, mp: 146 C (Lit. [16] 147 C).
94.9%
With piperidine; sulfur; In methanol; at 30℃; for 1h;
In a 200 mL closed four-mouth reaction flask, add 9.8 g of cyclohexanone,6.6 g of malononitrile and 3.2 g of sulfur, adding solvent methanol 50mL and 0.5mL catalyst piperidine, stirring and controlling temperature 30 C, reaction for 60 min, the reaction is finished, filtering and recrystallizingThe standard product was 16.9 g and the molar yield was 94.9%.
92%
With sulfur; In ethanol; at 50℃; for 1h;
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.
88%
With sulfur; diethylamine; In neat (no solvent); for 0.333333h;Milling;
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.
88%
With sulfur; at 60℃; for 2h;Ionic liquid; Green chemistry;
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 60C 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.
88%
With sulfur; choline chloride; urea; sodium hydroxide; In water; at 60℃;Green chemistry;
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 cm3 NaOH (4 mol dm-3 aqueoussolution) in 1 cm3 choline chloride/urea was stirred at 60C for 2-3 h. After completion of the reaction, indicated by TLC monitoring, 5 cm3 water was added. The solid product was separated by filtration and if necessary the precipitate recrystallized from EtOH to afford the corresponding pure product
88%
With sulfur; In neat (no solvent); at 60℃; for 2h;Catalytic behavior;
General procedure: General procedure forpreparation of2-aminothiophenes
84%
General procedure: A 50ml round-bottomed flask was charged with alpha-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.
81%
With zinc(II) oxide; sulfur; In neat (no solvent); at 100℃; for 6h;
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 mol%) 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.
75%
EXAMPLE 10; 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, 75% yield), m.p. 147-148 C.
62.8%
(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 62.8%.
57%
With morpholine; sulfur; In ethanol; for 2h;Reflux;
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.
56%
Step 1: Equimolar amount (0.01 mol) of malononitrile, sulphur and cyclohexanone were taken in a round bottom flask containing 20 ml of ethanol. The mixture was stirred for 5 min then morpholine (0.012 mol) was added dropwise to the reaction mixture at 60 C with constant stirring over 30 min. Later, the reaction mixture was allowed to stir for 5 h at room temperature and left in refrigerator overnight. The crystals thus formed were collected by filtration and washed with cold ethanol. Further purification by recrystallization from ethanol afford compound 9 in 56% yield, m.p. 145 C.
51%
With morpholine; cyanoacetic acid tert-butyl ester; sulfur; In ethanol; at 40℃; for 20h;
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 60C during the addition. The mixture was then heated at 40C and stirred for 4-20h.
44%
With sulfur; triethylamine; In ethanol; for 16h;Reflux;
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, 44%).
44%
With sulfur; triethylamine; In ethanol; for 16h;Reflux;
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, 44%).
With morpholine; sulfur; In ethanol; at 0 - 20℃;
To cyclohexanone (100 mmol), malononitrile (100 mmol), sulfur (100 mmol) in ethanol (30 ml) was added morpholine (lOOmmol) slowly at 0 0C. The resulting mixture was stirred at room temperature for 4 hours. After standing overnight it was diluted with water and the solid was collected and recrystallised from ethanol. EPO <DP n="10"/> A mixture of 1 (10 mmol) and triethyl orthoformate (10 ml) was heated for 3 hours at 120 0C. The reaction mixture was allowed to cool to room temperature, water (50 ml) was added and the resulting solid was collected by filtration and purified by column chromatography (silica, petroleum ether: ethyl acetate 20:1 ).
With sulfur; triethylamine; In ethanol; for 6h;Heating / reflux;
A solution of cyclohexanone (1.96 g, 20.0 mmol), malononitrile (1.32 g, 20.0 mmol), sulfur (640 mg, 20.0 mmol), and triethylamine (2.03 g, 20 mmol) in EtOH (50 mL) was refluxed for 6 h under nitrogen. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and water. The organic layer was separated, washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluding with EtOAc/Hexanes (2:3) to give the title product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 1.79 (m, 4H), 2.50 (m, 4H), 4.59 (s, 2H). MS 179 (MH-).
With sulfur; diethylamine; In ethanol; at 20 - 70℃;
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.
94%Chromat.
With sulfur; sodium hydroxide; In tert-butyl alcohol; at 20℃; for 0.5h;Inert atmosphere;
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.
With ethanol; sulfur; triethylamine; for 0.5h;Reflux;
To a solution of cyclohexanone (9.30 g,0.10 mol) in ethanol (50 mL) containing triethylamine (1.50 mL)both of elemental sulfur (3.20 g, 0.10 mol) and malononitrile(6.60 g, 0.10 mol) were added. The whole reaction mixture washeated under reflux for 30 min. then left to cool. The formedcrystals were collected by filtration.
With hydrogen sulfide; diethylamine;
The synthesis of 2-aminothiophene-3-carbonitrile 1 was performed by cyclocondensation of cyclohexanone with malononitrile and sulfur in equimolar quantity with catalyst HNEt2 as described by Sabnis et al [30]
With morpholine; sulfur; In butan-1-ol; at 150℃; for 0.166667h;Cooling with ice; Microwave irradiation;
General procedure: Starting materials 2a-c are prepared via Gewald threecomponentreaction using n-butanol as high boiling solventinstead of ethanol, in brief, a mixture of appropriate ketones1a-c (20.0 mmol), propane dinitrile (3.39 g, 30.0 mmol), andsulfur (3.2 g 10.0 mmol) in n-butanol (15 mL) is stirred andmorpholine (2.61 g, 30.0 mmol) is added dropwise at roomtemperature with cooling in ice bath. After that, the mixtureis heated at 150C for 10 min in a M.W. reactor. The reactionmixture is subjected to cooling to room temperature. Aftercooling, petroleum ether (20 mL) is added to the mixture andthe formed brown precipitate is crystallized from ethanol andafford thiophenes 2a-c.
With morpholine; sulfur; In butan-1-ol; at 150℃; for 0.166667h;Microwave irradiation;
General procedure: starting materials 2a-c were prepared via Gewald three componentreaction using n-butanol as high boiling solvent instead of ethanol, inbrief, a mixture of appropriate ketones 1a-c (20.0 mmol), propane dinitrile(3.39 g, 30.0 mmol), and sulfur (3.2 g 10.0 mmol) in n-butanol(15 ml) was stirred and morpholine (2.61 g, 30.0 mmol) was addeddropwise at room temperature with cooling in ice bath. After that, themixture was irradiated at 150 C for 10 min in a M.W. reactor. Themixture was cool to room temperature and diluted with petroleumether (20 ml). The formed brown precipitate is crystallized from ethanoland afford thiophenes 2a-c. The structure of 2-aminothiophenes 2a-cwas confirmed by their reported physical and spectral data 2a [24], 2b[23] and 2c [25].
To a stirred solution of the appropriate aminothiophene (1 equiv. ) in 1,4-dioxane (5ml per mmol aminothiophene) was added portionwise the appropriate acyl chloride (1.15 equiv. ). The reaction mixture was stirred at room temperature for 17-65 hours. The solvent was removed under reduced pressure, the residue triturated with hexane, a hexane/ether mixture or ether, and filtered to give the desired product. Compound No. 69 of Table 14 Using the alternative general procedure 2-chloro-N- (3-cyano-4, 5,6, 7-tetrahydro- benzo [b] thiophen-2-yl) -acetamide (Compound No. 69 of Table 14) was obtained from aminothiophene EO as a pale pink solid in 91% yield. 1H NMR on (400MHz, CDC13) : 9.25 (1H, br s), 4.25 (2H, s), 2.60 (4H, m) and 1.80 (4H, m) ppm.
88%
In 1,4-dioxane; for 3h;Reflux;
To a solution of compound 1 (1.80 g, 0.01 mol) in 1,4-dioxane, chloroacetyl chloride (1.13 g, 0.01 mol) was added. The reaction mixture was heated under reflux for 3 h then poured onto ice/water, and the formed solid product was collected by filtration. Crystallized from ethanol to give white crystals, yield 2.23 g (88%), m.p.188-191C. Anal. Calculated for C11H11ClN2OS (254.74):C, 51.86; H, 4.35; Cl, 13.92; N, 11.00; S, 12.59 %. Found:C, 51.69; H, 4.57; Cl, 14.26; N, 10.85; S, 12.32 %. IR, t:3477-3321 (NH), 2220 (CN), 1702 (CO), 1623 (C=C). 1HNMR,d: 1.78-1.84 (m, 4H, 2CH2), 2.56-2.74 (m, 4H,2CH2), 5.58 (s, 2H, CH2), 8.43 (s, 1H, D2O exchangeable,NH). 13C-NMR, d: 19.8, 20.5, 21.6, 24.6 (4CH2), 45.8(CH2), 116.8 (CN), 119.0, 129.7, 134.2, 136.0 (thiopheneC), 166.9 (C=O).
80%
In 1,4-dioxane; at 0℃; for 0.5h;
A mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1.78 g,10 mmol) and chloroacetyl chloride (1.11 g, 10 mmol) in dioxane (10 mL) was stirred at0 C for 30 min. The separated solid was collected by filtration, then washed by ethanoland recrystallized from toluene to give 1 as white crystals (80%), mp 188-190 C. IR(m/cm1): 3225 (NH), 2221 (CN), 1708 (CO). 1H NMR (300 MHz, DMSO-d6) d(ppm): 1.75 (m, 4H, 2CH2), 2.49-2.59 (m, 4H, 2CH2), 4.43 (s, 2H, COCH2Cl), 11.80(br.s, 1H, NH, exchangeable with D2O). 13C NMR (DMSO-d6) d (ppm): 21.7, 22.6,23.4, 42.2, 93.7, 113.9, 127.9, 131.1, 145.8, 164.5.Anal. Calcd. for C11H11ClN2OS: C, 51.87; H, 4.35; Cl, 13.92; N, 6.28; S, 12.59.Found: C, 51.81; H, 4.30; Cl, 13.99; N, 6.32; S, 12.63.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4.25h;
General procedure: Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1 mmol) is dissolved in tetrahydrofuran. To this triethyl amine (2.2 eq) is added. The reaction is cooled to 00C and stirred for 10 minutes. While maintaining the temperature, chloroacetyl chloride (1.1 eq) suspended in dichloromethane (5 ml) is added drop wise in 15 minutes. The reaction mixture is stirred at room temperature for 4 hrs. After the completion of the reaction as monitered byTLC, the reaction mixture is poured into the ice cold water and the layers are separated. The organic layer is washed with (3 X 25) water. The organic layeris dried over anhydrous sodium sulfate, and then distilled off under reduced pressure to give crude ethyl 2-(2-chloroacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate. This crude residue is treated with hexane and/or ethyl acetate to give the pure light brown solid.
3.c (c)
(c) 2-(4-Fluoro-2-nitroanilino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-nitrile 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-nitrile (3.6 g, 0.02 mol) and 2,5-difluoronitrobenzene (3.2 g, 0.02 mol) in dry DMSO (20 ml) was stirred and heated on an oil bath. When the internal temperature reached 60° C, potassium carbonate (2.76 g, 0.02 mol) was added and the mixture then stirred at 100° C. for 5 hours. The reaction mixture was poured onto ice-water, acidified and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and the solvent removed in vacuo, m.p. 137°-139° C. (EtOAc). Similarly, the following compounds were prepared using 2-amino-5-ethyl-thiophene-3-nitrile.
In 200mL four-neck reaction flask sealed, 17.8 g of 2-amino-3-cyanocyclohexane thiophene and 9.8 g of cyclohexanone were added, Temperature 100 deg.] C with stirring, the reaction 2h, the reaction was completed, the product was filtered and recrystallized to give 24.8 g target molar yield of 96.1%
93.16%
EXAMPLE 6: l,2,3,4J,8,9,10-Ortahydrobenzo[4,5]thieno[2,3-6]quinolin-ll-amine (BN-6); 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.0065moles) was added to cyclohexanone (0.013moles) in 1:2 ratio along with anhydrous zinc chloride (0.0065moles) and the reaction mixture heated under reflux for six hours. The mixture was cooled and added to 50 ml of 40% sodium hydroxide solution in water to release the product from zinc chloride complex. The precipitate was collected by vaccum filtration and purified by passing through a column using a mixture of hexane and ethyl acetate as mobile phase.Yield (%): 1.35 grams (93.16%); mp: 218.70C; IR (KBr) : 3507 (NH2), 3325, 3189, 2910, 2832cm"1; 1H NMR (CDCl3, ppm): delta 1.84-1.92 (m, 8H, 4CH2), 2.42-2.50 (m, 2H, CH2), 2.82- 2.92(m, 4H, 2CH2), 2.98-3.05 (t, 2H, CH2) 4.44 (s, 2H, NH2, D2O exchangeable); MS (ESIMS):m/z 249 [M++l] 100% ; Elemental Analysis: CaIc. for C15H18N2S: C, 69.73; H, 7.02; N, 10.84. Found: C, 69.91; H, 6.80; N, 10.59%.
93.16%
With zinc(II) chloride; for 6h;Reflux;
Example 6 1,2,3,4,7,8,9,10-Octahydrobenzo[4,5]thieno[2,3-b]quinolin-11-amine (BN-6); 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.0065 moles) was added to cyclohexanone (0.013 moles) in 1:2 ratio along with anhydrous zinc chloride (0.0065 moles) and the reaction mixture heated under reflux for six hours. The mixture was cooled and added to 50 ml of 40% sodium hydroxide solution in water to release the product from zinc chloride complex. The precipitate was collected by vacuum filtration and purified by passing through a column using a mixture of hexane and ethyl acetate as mobile phase.Yield (%): 1.35 grams (93.16%); mp: 218.7 C.; IR (KBr): 3507 (NH2), 3325, 3189, 2910, 2832 cm-1; 1H NMR (CDCl3, ppm): delta 1.84-1.92 (m, 8H, 4-CH2), 2.42-2.50 (m, 2H, CH2), 2.82-2.92 (m, 4H, 2CH2), 2.98-3.05 (t, 2H, CH2) 4.44 (s, 2H, NH2, D2O exchangeable); MS (ESIMS):m/z 249 [M++1] 100% ; Elemental Analysis: Calc. for C15H18N2S: C, 69.73; H, 7.02; N, 10.84. Found: C, 69.91; H, 6.80; N, 10.59%.
65.4%
With aluminum (III) chloride; at 120℃; for 3h;UV-irradiation;
General procedure: To a 120 C mixture of compound 1 (1 mmol) and corresponding ketone 2 (3 mL), 1 mL fresh sodium ethoxide solution (1 mol/L) was added dropwise under stirring, and then the reaction mixture was heated for 3.0 hours with a 380 nm UV lamp irradiation. The reaction mixture was cooled to room temperature after the reaction was finished by TLC monitoring. The resulting precipitate was collected by filtration. The target product compounds 3 were obtained through washing alternately with water and methanol for several times and dried. The compounds 4 were obtained by column chromatography on silica gel (200-300 mesh silica gels) with ethyl acetate-petroleum ether (1:3, v:v) as eluent. The chemical structures of target compounds 3 were fully characterized by IR, 1H NMR, 13C NMR, and HRMS while product 3a was unequivocally confirmed by X-ray diffraction analysis (Fig. 2). Additionally, the compounds 4 were partly characterized by IR, 1HNMR, 13C NMR, and HRMS with the TLC and MS assisted detection which could show the conversion response.
Concentrated sulfuric acid (4 ml) at 0-5 C was added to a mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1) (1 g, 5.6 mmol) in formic acid (10 ml). The mixture was refluxed for 2 h and allowed to cool to room temperature (rt). The mixture was poured into ice cold water. The solid separated was filtered and purified by recrystallization with ethanol.
91%
With sulfuric acid; at 0℃; for 2h;Reflux;
General procedure: To a mixure of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1) (1 g, 5.6 mmol) in formic acid (10 mL), was added concentrated sulfuric acid (4 mL) at 0-5 C. The mixture was refluxed for 2 h and left at to room temperature. The mixture was then poured into ice cold water. The solid that separated was filtered and purified by recrystallization in ethanol.
77%
With hydrogenchloride; In water; for 16h;Reflux;
3,4,5,6,7,8-Hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (step b): To a mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl cyanide (0.9 g) and formic acid (10 mL) was added 0.1 mL HCl. After refluxed for 16 h, the reaction mixture was cooled and water (20 mL) was added. The precipitated was filtered and washed thoroughly with water and hexanes to give 3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.8 g, 77%). 1H NMR (300 MHz, CDCl3): delta 7.91 (s, 1H), 3.03-3.00 (m, 2H), 2.80-2.77 (m, 2H), 1.89-1.83 (m, 4H).
77%
With hydrogenchloride; In water; for 16h;Reflux;
3,4,5,6,7,8-Hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (step b): To a mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl cyanide (0.9 g) and formic acid (10 mL) was added 0.1 mL conc. HCl. After refluxed for 16 h, the reaction mixture was cooled and water (20 mL) was added. The precipitate was collected by filtration and washed thoroughly with water and hexanes to give the title compound (0.8 g, 77%). 1H NMR (300 MHz, CDCl3): delta 7.91 (s, 1H), 3.03-3.00 (m, 2H), 2.80-2.77 (m, 2H), 1.89-1.83 (m, 4H).
77%
With hydrogenchloride; In water; for 3h;
Step 2: To a mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-carbonitrile (9, 0.9 g) and formic acid (10 ml) was added 0.1 ml HCl. After fusion for 3 h, the reaction mixture was cooled and water (20 ml) was added. The precipitated was filtered and washed thoroughly with water and hexanes to give 5,6,7,8 tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (10, 0.8 g, 77%); m.p. 250 C; IR:3520, 2934, 2874, 1660, 1543. 1H NMR (400 MHz, DMSO-d6) delta 12.27(br. s., 1H), 7.94 (s, 1H), 2.89 (br. s., 2H), 2.76 (br. s., 2H), 1.76 (br. s.,4H).
3-trimethylsilanylpropynoic acid (3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
3- (Trimethylsilyl) propynoic acid (l. Og, 7 mmol) was dissolved in DCM (lOml) under nitrogen and cooled to 0C. Oxalyl chloride (0. 6ml, 7 mmol) was added dropwise, keeping the temperature below 5C. The solution became orange. At the end of the addition, the mixture was maintained at room temperature for one hour, then aminothiophene EO (1.25g, 7 mmol) was added as a solution in THF (10ml). The reaction mixture was stirred for 4 hours at room temperature and then treated with saturated aqueous ammonium chloride and extracted with DCM. The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. Purification of the residue by flash chromatography gave the desired product (0.25g, 15%) as an amorphous solid. 'H NMR 8H (300MHz, CDC13) : 8.55 (1H, br s), 2.6 (4H, m), 1.85 (4H, m) and 0.3 (9H, s) ppm; ni/z (-ve ion): 301 (M-H).
Stage #1: 3-cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
10
The 2-aminothiophene derivative 10a (5.0 g, 0.028 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.93 g, 0.028 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 10b was formed.Julolidine (4.85 g, 0.028 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10 M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 10b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 10 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 116-122° C., (50% yield).
EXAMPLE 5: 2,3,6,7f8,9-Hexahydro-lH-benzo[4,5]thieno[2,3-b]cyclopenta[e]pyridin- 10-amine (BN-5); 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.0065 moles) was added to cyclopentanone (0.013moles) in 1:2 ratio along with anhydrous zinc chloride (0.0065moles) and the reaction mixture heated under reflux for six hours. The mixture was cooled and added to 50 ml of 40% sodium hydroxide solution in water to release the product from zinc chloride complex. The precipitate was collected by vaccum filtration and purified by passing through a column using a mixture of hexane asnd ethyl acetate as mobile phase.Yield (%): 1.25 grams (91.24%); mp: 2210C; IR (KBr): 3504 cm'1 (NH2); 1H NMR (CDCl3, ppm): delta 1.85-1.98 (m, 4H, 2CH2), 2.12-2.22 (m, 2H, CH2), 2.70-2.85 (m, 4H, 2CH2), 2.96-3.08 (m, 4H, 2CH2), 4.35 (s, 2H, NH2, D2O exchangeable); MS (ESIMS): m/z 245 [M++l] 100% ; Elemental Analysis: CaIc. for C14H16N2S: C, 68.81; H, 6.60; N, 11.46. Found: C, 68.56; H, 6.43; N, 11.30%.
91.24%
With zinc(II) chloride; for 6h;Reflux;
Example 52,3,6,7,8,9-Hexahydro-1H-benzo[4,5]thieno[2,3-b]cyclopenta[e]pyridin-10-amine (BN-5); 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (0.0065 moles) was added to cyclopentanone (0.013 moles) in 1:2 ratio along with anhydrous zinc chloride (0.0065 moles) and the reaction mixture heated under reflux for six hours. The mixture was cooled and added to 50 ml of 40% sodium hydroxide solution in water to release the product from zinc chloride complex. The precipitate was collected by vacuum filtration and purified by passing through a column using a mixture of hexane and ethyl acetate as mobile phase.Yield (%): 1.25 grams (91.24%); mp: 221 C.; IR (KBr): 3504 cm-1 (NH2); 1H NMR (CDCl3, ppm): delta 1.85-1.98 (m, 4H, 2CH2), 2.12-2.22 (m, 2H, CH2), 2.70-2.85 (m, 4H, 2CH2), 2.96-3.08 (m, 4H, 2CH2), 4.35 (s, 2H, NH2, D2O exchangeable); MS (ESIMS): m/z 245 [M++1] 100% ; Elemental Analysis: Calc. for C14H16N2S: C, 68.81; H, 6.60; N, 11.46. Found: C, 68.56; H, 6.43; N, 11.30%.
78.3%
at 100℃; for 2h;Sealed tube;
In a 200 mL sealed four-neck reaction flask, 17.8 g of 2-amino-3-cyanocyclohexane thiophene and 8.4 g of cyclopentanone were added, and the mixture was stirred and controlled at 100 C for 2 h, the reaction was completed, and recrystallization was carried out to obtain a target. The product was 19.1 g and the molar yield was 78.3%
Stage #1: 3-cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene; chloroacetonitrile In 1,4-dioxane at 80℃; for 0.166667h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water for 6h;
1.2
(2) 1.0 g of 2-amino-3-nitrile-4,5,6,7-tetrahydrobenzothiophene and 1 ml of chloroacetonitrile,With 15ml dioxane dissolved in the reaction flask, 80 ° C for 10min after the addition of hydrochloric acid 20ml, the reaction 6h, the reaction mixture was cooled and poured into ice water,Add ammonia to slightly alkaline, a large number of solid precipitation, filtration with petroleum ether: ethyl acetate 3: 1The eluent was passed through the column to give 0.9 g of 2-chloromethyl-4-amino-5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine in a yield of 63.4%.
62.4%
Stage #1: 3-cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene; chloroacetonitrile In 1,4-dioxane at 80℃; for 0.166667h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water at 80℃; for 6h;
4,5,6,7-Tetrahydro-2-(triphenylphosphoranylidenamino)benzo<b>thiophen-3-carbonitril[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.4 g
With triethylamine; In benzene; at 50℃; for 0.333333h;
General procedure: A solution of 0.05 mol of triphenylphosphine in 100 mL of anhydrous benzenewas cooled to 5C, a solution of 0.05 mol of brominein 30 mL of anhydrous benzene was added dropwise under stirring, and the mixture was stirred for 3 h at room temperature. A solution of 0.1 mol of triethylaminein 30 mL of anhydrous benzene was added to the resulting suspension of dibromo(triphenyl)-lambda5-phosphane, a solution of 0.05 mol of nitrile 6 or ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylatein 50 mL of anhydrous benzene was added, and the mixture was stirred for 20 min at 50C. After cooling, the precipitate of triethylamine hydrobromide was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by recrystallization
2-[(5-methyl-1H-indol-3-ylmethylene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With acetic acid; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of Gewald adducts (5CN, 6CN, 7CN and 8CN) and substituted indole-carboxaldehydes in absolute ethanol with 0.5 mL of acetic acid was stirred under room temperature for 24 hs. Water was addedand the solid that precipitated out was filtered under vacuum, washed with water, dried and recrystallized from absolute ethanol (Scheme 1) according previously methodology [20].
2-[(7-methyl-1H-indol-3-ylmethylene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With acetic acid; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of Gewald adducts (5CN, 6CN, 7CN and 8CN) and substituted indole-carboxaldehydes in absolute ethanol with 0.5 mL of acetic acid was stirred under room temperature for 24 hs. Water was addedand the solid that precipitated out was filtered under vacuum, washed with water, dried and recrystallized from absolute ethanol (Scheme 1) according previously methodology [20].
2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With acetic acid; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of Gewald adducts (5CN, 6CN, 7CN and 8CN) and substituted indole-carboxaldehydes in absolute ethanol with 0.5 mL of acetic acid was stirred under room temperature for 24 hs. Water was addedand the solid that precipitated out was filtered under vacuum, washed with water, dried and recrystallized from absolute ethanol (Scheme 1) according previously methodology [20].
2-[(5-cyano-1H-indol-3-ylmethylene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With acetic acid; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of Gewald adducts (5CN, 6CN, 7CN and 8CN) and substituted indole-carboxaldehydes in absolute ethanol with 0.5 mL of acetic acid was stirred under room temperature for 24 hs. Water was addedand the solid that precipitated out was filtered under vacuum, washed with water, dried and recrystallized from absolute ethanol (Scheme 1) according previously methodology [20].
2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With hydrogenchloride In 1,4-dioxane at 20℃;
5 General procedure for the synthesis of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amines 2-8, 10-13
General procedure: The corresponding 2-aminothiophene 1 (0.0094mol), the appropriatecyano derivative RCN (0.0094mol) and 20 mL of dioxane were mixed in around flask whereat a stream of dry hydrogen chloride was passed throughthe solution for 6 h. The reaction mixture was allowed to stay for 12 h atroom temperature. It was then poured into a beaker containing crushed iceand neutralized to pH∼8 using 10% (v/v) NH4OH. The precipitate wasfiltered, washed many times with water and dried. The formed precipitate was recrystallized from pyridine and washed with MeOH. Yield: 43%; Mp. 214-215 °C; IR (KBr): ν(cm-1) 3542 (NH), 3397 (NH), 2986 (CH), 2930 (CH), 2834 (CH), 1645 (NH), 1106 (C-O); 1H NMR (DMSO-d6, δ): 1.82 (s, 4H, (CH2)2), 2.76 (s, 2H, CH2), 2.93 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 3.87 (s, 6H, 2OCH3), 6.86 (s, 2H, NH2), 7.69 (s, 2H, ArH); Analysis: Calc. for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31; O, 12.92; S, 8.63; Found: C, 61.41; H, 5.73; N, 11.28; O, 12.90; S, 8.63.
Stage #1: cis,trans-2,5-dimethoxytetrahydrofuran With acetic acid at 20℃; for 0.0833333h;
Stage #2: 3-cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene at 100℃; for 0.25h; Microwave irradiation;
Synthesis of 2-(1H-Pyrrol-1-yl)thiophene-3-carbonitriles 3a-c
General procedure: A mixture of dimethoxytetrahydrofuran (DMTHF) (0.82 g, 6.2 mmol) and glacial acetic (3 mL) is stirred for 5 min at roomtemperature, followed by the addition of thiophene-3-carbonitriles2a-c (0.62 mmol). The reaction mixture is heated at100°C for 15 min in the M.W. reactor. After cooling, the reactionmixture is diluted with H2O (20 mL) and the solid formedis crystallized from ethanol to give thiophenes 3a-c.
With acetic acid at 100℃; for 0.25h; Microwave irradiation;
2 4.1.3. Synthesis of 2-(1H-pyrrol-1-yl) thiophene-3-carbonitriles 3a-c
General procedure: A mixture of dimethoxytetrahydrofuran (DMTHF) (0.82 g,6.2 mmol) and glacial acetic (3 ml) was stirred for 5 min at room temperature,followed by the addition of thiophene-3-carbonitriles 2a-c(0.62 mmol). The reaction mixture was irradiated at 100 °C for 15 minin the M.W. reactor. After cooling, the mixture is diluted with H2O(20 ml) and the precipitate formed is crystallized from ethanol to furnishthiophenes 3a-c.
(6aR*,15aS*)-14,14-dimethyl-6a,7,9,10,11,12,14,15-octahydrobenzo[f]benzo[4,5]thieno[2,3-b]pyrrolo[2,3-d]quinolin-5(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sulfuric acid In 1,2-dichloro-ethane at 0 - 25℃; for 0.5h;
Compounds 2a-2d (general procedure).
General procedure: A solution of 0.178 g (1 mmol) of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile in 1 mL of 94% sulfuric acid was cooled to 5-10°C, and a mixture of 1 mmol of arene 1a-1d and 0.014 mL (1.5 mmol) of isobutyr-aldehyde in 0.3 mL of 1,2-dichloroethane was added dropwise with vigorous stirring. The mixture was stirred for 0.5 h at room temperature and poured into a mixture of 10 mL of 25% aqueous ammonia and 7 g of crushed ice. The mixture was thoroughly stirred and extracted with ethyl acetate (3 × 75 mL), the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrys-tallized from ethyl acetate. (6aR*,15aS*)-14,14-Dimethyl-6a,7,9,10,11,12,-14,15-octahydrobenzo[f]benzo[4,5]thieno[2,3-b]pyr-rolo[2,3-d]quinolin-5(6H)-one (2a). Yield 0.282 g (75%), yellow crystals, mp 266-267°C (decomp.), R f 0.52 (petroleum ether-EtOAc, 1 : 1). IR spectrum, ν, cm -1 : 3171, 1682, 1598. 1 H NMR spectrum, δ, ppm: 1.23 s and 1.29 s (3H each, 14-CH 3 ), 1.64-1.78 m (5H, Cy, 15-H), 1.95 d (1H, 15-H, J = 13.2 Hz), 2.35- 2.46 m (2H, Cy), 2.60-2.68 m (4H, Cy), 2.73 d.d (1H, 6-H, J = 18.1, 2.9 Hz), 2.85-2.95 m (1H, Cy), 3.02 d.d (1H, 6-H, J = 18.1, 3.1 Hz), 3.81 t (1H, 6a-H, J = 2.8 Hz), 7.01 br.d (1H, H arom , J = 7.2 Hz), 7.22 br.s (1H, NH), 7.35 t.d (1H, H arom , J = 7.6, 0.9 Hz), 7.52 t.d (1H, H arom , J = 7.6, 1.4 Hz), 7.87 d.d (1H, H arom , J = 7.8, 1.3 Hz). 13 C NMR spectrum, δ C , ppm: 21.95 (CH 2 ), 22.97 (CH 2 ), 23.74 (CH 2 ), 25.55 (CH 2 ), 29.14 (CH 3 ), 32.59 (CH 3 ), 39.59 (CH 2 ), 47.10 (CH 2 ), 56.59, 60.03 (CH), 72.28, 110.12, 118.50, 125.75 (CH), 126.89 (CH), 127.58 (CH), 131.10, 131.38, 133.63 (CH), 144.41, 153.95, 162.46, 194.64 (C=O). Mass spectrum, m/z (I rel , %): 376 (100) [M] + , 361 (63.7) [M - CH 3 ] + . Found, %: C 73.13; H 6.52; N 7.32; S 8.36. C 23 H 24 N 2 OS. Calculated, %: C 73.37; H 6.43, N 7.44; S 8.52.
(3aS*,7aR*)-2,2,5,7a-tetramethyl-2,7,7a,8,10,11,12,13-octahydrobenzo[4,5]thieno[2,3-b]pyrrolo[2,3-d]quinolin-6(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With sulfuric acid; In 1,2-dichloro-ethane; at 0 - 25℃; for 0.5h;
General procedure: A solution of 0.178 g (1 mmol) of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile in 1 mL of 94% sulfuric acid was cooled to 5-10C, and a mixture of 1 mmol of arene 1a-1d and 0.014 mL (1.5 mmol) of isobutyr-aldehyde in 0.3 mL of 1,2-dichloroethane was added dropwise with vigorous stirring. The mixture was stirred for 0.5 h at room temperature and poured into a mixture of 10 mL of 25% aqueous ammonia and 7 g of crushed ice. The mixture was thoroughly stirred and extracted with ethyl acetate (3 × 75 mL), the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrys-tallized from ethyl acetate.
(3aS*,7aR*)-2,2,5-trimethyl-2,7,7a,8,10,11,12,13-octahydrobenzo[4,5]thieno[2,3-b]pyrrolo[2,3-d]quinolin-6(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With sulfuric acid In 1,2-dichloro-ethane at 0 - 25℃; for 0.5h;
Compounds 2a-2d (general procedure).
General procedure: A solution of 0.178 g (1 mmol) of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile in 1 mL of 94% sulfuric acid was cooled to 5-10°C, and a mixture of 1 mmol of arene 1a-1d and 0.014 mL (1.5 mmol) of isobutyr-aldehyde in 0.3 mL of 1,2-dichloroethane was added dropwise with vigorous stirring. The mixture was stirred for 0.5 h at room temperature and poured into a mixture of 10 mL of 25% aqueous ammonia and 7 g of crushed ice. The mixture was thoroughly stirred and extracted with ethyl acetate (3 × 75 mL), the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrys-tallized from ethyl acetate.
Multi-step reaction with 3 steps
1: hydrogenchloride / water / 3 h
2: trichlorophosphate; triethylamine / 4.5 h / 65 °C
3: monophenylthiourea; acetic acid / 4 h / Reflux
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