* 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.
With morpholine; sulfur In ethanol at 20℃; for 6 h;
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]+.
79%
With morpholine; sulfur In ethanol at 50℃; for 5 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.
78%
at 20 - 58℃;
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).
68%
With morpholine; sulfur In ethanol for 4 h; Reflux
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.
49.6%
With sulfur; diethylamine In ethanol at 40 - 50℃; for 5 h;
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.
4.8%
With morpholine; sulfur In ethanol at 20 - 55℃; for 22 h;
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.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5556 - 5564
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4337 - 4350
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 11, p. 2367 - 2371
[4] Medicinal Chemistry, 2017, vol. 13, # 8, p. 753 - 760
[5] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1053 - 1065
[6] Synthetic Communications, 2005, vol. 35, # 10, p. 1351 - 1357
[7] European Journal of Medicinal Chemistry, 2019, p. 179 - 192
[8] Mendeleev Communications, 2012, vol. 22, # 1, p. 15 - 17
[9] European Journal of Medicinal Chemistry, 2010, vol. 45, # 1, p. 69 - 77
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5436 - 5445
[11] Patent: CN105061462, 2017, B, . Location in patent: Paragraph 0017-0018; 0021-0023
[12] Tetrahedron, 2006, vol. 62, # 29, p. 7121 - 7131
[13] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7089 - 7093
[14] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3763 - 3766
[15] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4731 - 4735
[16] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 14, p. 5336 - 5341
[17] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5753 - 5756
[18] Molecules, 2012, vol. 17, # 6, p. 7217 - 7231
[19] Letters in Organic Chemistry, 2014, vol. 11, # 5, p. 380 - 385
[20] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1306 - 1309
[21] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4462 - 4466
[22] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 568 - 576
[23] Chemical Biology and Drug Design, 2018, vol. 91, # 6, p. 1141 - 1155
[24] Main Group Metal Chemistry, 2018, vol. 41, # 1-2, p. 21 - 26
2
[ 4651-91-6 ]
[ 4815-28-5 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 20℃; for 65 h;
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
3
[ 107-91-5 ]
[ 4815-28-5 ]
Yield
Reaction Conditions
Operation in experiment
50%
With sulfur In methanol at 20℃; Reflux
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-1. 1H NMR (300 MHz, CDCl3) δ 5.56 (s, 2H), 5.42-4.81 (wm, 2H), 2.69-2.59 (m, 2H), 2.59-2.48 (m, 2H) 1.85-1.77 (m,4H).13C NMR (75 MHz, CDCl3) δ 168.6, 160.8, 129.2, 118.8, 107.7, 77.4, 27.2, 24.7, 23.1.
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 261 - 267
With morpholine; sulfur In ethanol at 20℃; for 6h;
4.1.1. Preparation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2)
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,90%) as an light yellow solid. ESI-MS found 197 [M+H]+.
81%
With morpholine; sulfur In ethanol at 60℃;
80%
With Diethyl amine; sulfur at 20 - 58℃;
79%
With morpholine; sulfur In ethanol at 50℃; for 5h;
2.2. General Procedure for Chemical Synthesis
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 79%.
78%
With sulfur; diethylamine at 20 - 58℃;
4.1.1. General procedure for synthesis of 3-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide [31] (4a)
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). 78% 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 (%): Calculated (Found) for C9H12N2OS: C 55.08(55.01), H 6.16 (6.19), N 14.27 (14.31), S 16.34 (16.40).
71%
With morpholine; aluminum oxide; sulfur for 0.166667h; microwave irradiation;
68%
With morpholine; sulfur In ethanol for 4h; Reflux;
General procedure for the synthesis of compounds 18a-c
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.
67%
With morpholine; sulfur
67%
With morpholine; sulfur In ethanol at 70℃; for 2h;
3.6.3. General Procedure for the Synthesis of 4,5,6,7-tetrahydrobenzo[b]thiophenes (4a-c)
General procedure: The cyclohexanone (0.98 g, 10 mmol) was mixed with active nitrile compounds (i.e., (a) ethyl cyanoacetate, 1.13 g; (b) cyanoacetamide, (c) 0.84 g; malononitrile, 0.66 g, 10 mmol), elemental sulfur(0.32 g, 10 mmol) and a catalytic amount of morpholine (2 mL) in ethanol (30 mL), according to the Gewald method [27]. The reaction mixture was then heated at 70 °C in a water bath (WB) for 2 h and left overnight to precipitate. The crystals of (4a-c) were collected with good yields and recrystallized from ethanol.
61%
With sulfur In ethanol at 50℃;
61%
With sulfur; diethylamine In ethanol at 20℃;
49.6%
With sulfur; diethylamine In ethanol at 40 - 50℃; for 5h;
1.A Preparation of 2-amino-4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxamide
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 49.6%.
45%
With piperidine; sulfur In ethanol at 40 - 50℃; for 7h;
4.8%
With morpholine; sulfur In ethanol at 20 - 55℃; for 22h;
Preparation of 2-aminothiophenes via Gewald reaction - General method A
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.
With morpholine; sulfur In ethanol
With morpholine; sulfur In ethanol at 60℃; for 1h;
With morpholine; sulfur In ethanol Reflux;
With sulfur; diethylamine In ethanol Reflux;
With sulfur Alkaline conditions;
With morpholine; sulfur; aluminum oxide Microwave irradiation;
With morpholine; sulfur at 20℃;
With sulfur In ethanol at 85℃; Sealed tube;
Method a)
2-Cyanoacetamide (1 eq) and sulphur flowers (1 eq) were suspended in EtOH (0.2 mmol / mL) followed by addition of cyclic ketone (1 eq) and morpholine (1 eq). The reaction was heated at 85 °C overnight in a sealed tube. The mixture was filtered and the solid phase was concentrated in vacuo to afford the crude product.
With sulfur; potassium fluoride on basic alumina In ethanol at 100℃; Inert atmosphere; Microwave irradiation;
Method A General procedure for the synthesis of 2-amino-carboxyamide thiophene by modifying an existing protocol.[2]
General procedure: A microwave vial was charged with cyclopentanone (1 g, 11.9 mmol), cyanoacetamide (1 equiv., 1 g), elemental sulfur (1 equiv., 3 g), and KF-alumina (1.3 equiv., 2.5 g), then capped and dry EtOH (18 mL) was added. The solvent was degassed by bubbling N2 through the solvent for 5-10 min before it was heated in microwave to 100°C for 5-10 min. The KF-alumina was filtered off and washed with THF, and the collected solution was added to ice-cold water (250-300 mL). If the product was crashed out from the aqueous solution, it was filtered off to afford 2-amino-3-carboxamide. Otherwise, the volatile solvents were evaporated under vacuum and the residual precipitate was collected.. The product was dried under high vacuum to afford amino carboxamide in 12-76% yields. The products were characterized by NMR and used as it is without further purification.
With morpholine; sulfur In ethanol at 5 - 10℃; for 3h;
With sulfur In ethanol for 10h; Reflux;
With sulfur In ethanol
With morpholine; sulfur In N,N-dimethyl-formamide at 50 - 60℃;
2-(3,5-dimethoxyphenyl)-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With hydrogenchloride In butan-1-ol at 80℃; for 12h;
4.1.2. General procedure for synthesis of 5,6,7,8 tetrahydro-2-arylthieno[3,2,-d] pyrimidin-4(3H)-ones [27](6a to 6m)
General procedure: 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(4a;1.5 mmol) was suspended in 10 ml butanol and benzaldehydes(5a-5m;1.0 mmol). Conc HCl (0.1 ml) was added to this reaction mixture and heated at 80 °C for 12 h or until TLC confirms the completion of reaction. The solid obtained was filtered, washedwith water and dried.
With N-ethyl-N,N-diisopropylamine In toluene at 90℃; for 4h;
1.1
Procedure 1.1. 2- (CYCLOPROPANECARBONYL-AMINO)-4, 5, 6,7-tetrahydro- benzo [B] THIOPHENE-3-CARBOXAMIDE (D1) A suspension of 196 mg (1. 00 mmol) of 2-amino-4,5, 6,7-tetrahydro- benzo [b] thiophene-3-carboxamide, 100 pi (1. 10 MMOL) of cyclopropanecarboxylic acid chloride and 218 NI (1.25 mmol) of diisopropylethylamine in 3 ML toluene was heated at 90°C for 4h. After cooling at room temperature the mixture was diluted with 20 ML EtOAc and washed with 15 mi of 0.5 M HCI-solution. The water phase was extracted twice with 15 mi EtOAc and CH2CI2. The combined organic layers were dried over NA2SO4. Evaporation of the solvent and recrystallization of the residue from ethanol gave the product as a light orange powder in 78% yield. Mp.: 216-217 °C (ethanol). Mass CALC. FORCL3HL6N202S : 264.34, found (neg. mode) 263.23.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h;
With triethylamine In dichloromethane at 0 - 20℃; for 6h;
4.1.2. General procedure for the preparation of 3a-c
General procedure: To the stirred solution of compound 2 (1.0 equiv) in CH2Cl2 at 0°C was added Et3N (2.0 equiv) followed by R1COCl (1.2 equiv) and allowed to stir at room temperature for 6 h. The reaction mixture was diluted with CH2Cl2 and washed with satd NaHCO3, H2O and dried over anhyd Na2SO4 and evaporated under vacuo to get compound 3 as an off-white solid.
7,8,9,10-tetrahydrobenzo[4’,5’]thieno[3’,2’:5,6]pyrimido[2,1-a]isoindol-6(13H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With hydrogenchloride In methanol at 20℃; for 24h;
Synthesis of 5-oxo-11, 12-dihydro-5H-isoindolo[2,1-a]quinazolin-12-ium chloride (3aHCl)
General procedure: A mixture ofanthranilamide (340 mg, 2.50 mmol), and o-phthalaldehyde(334.9 mg, 2.50 mmol) were taken in100 mL round bottom flask. Then to this reactionmixture, 30 mL MeOH and 2(N) HCl (10 mL) wereadded. This reaction mixture was stirred at roomtemperature for 24 h. Then, the precipitate appearedwas collected by filtration and washed with water toget 3aHCl (411 mg, 70%).
(E)-2-((4-amino-5-cyano-3-methyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-2-yl)azo)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h;
Stage #2: 2-amino-4-methylthiophene-3-carbonitrile With sodium acetate In ethanol at 0 - 5℃; for 2h;
3.6.4. General Procedure for Synthesis of thienopyridyl-azo-tetrahydrothiophene Derivatives (6a-c)
General procedure: Molar quantities of thiophenes 4a-c (2.25 g, 1.96 g, 1.78 g, respectively, 10 mmol) in (3 mL) conc.HCl and (5 mL) of an aqueous NaNO2 solution (10 mmol, 0.69 g) were mixed and well stirred at 0-5 °C for 30 min. The freshly prepared diazonium salts (5a-c) were added afterwards to (20 mL) of ethanolic solution for the coupling of component 2-aminothiazole 1 (2.05 g, 10 mmol) containing sodium acetate (3 g) with slow and continuous stirring at 0-5 °C for 2 h. The resulting products (6a-c) were collected,dried and recrystallized from MeOH/Dioxan.
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