* 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 for 3 h; Reflux
Synthesis of compounds 1, 2a-i and 3a-i Compound 1 was prepared through standard Gewald reaction. 14 4.4 g (0.05 mol) of morpholine was added dropwise into a stirred solution of cyclohexanone (4.91 g, 0.05 mol), methyl cyanoacetate (4.95 g, 0.05 mol) and sulfur (1.92 g, 0.06 mol) in 35 mL ethanol. On completion, the mixture was refluxed for further 3 h. After cooling to room temperature, the precipitate was separated by filtration and recrystallized from ethanol to give 1 as pale yellow powders (8.6 g, 82percent yield), mp 128.2-129.4 °C (lit. 15 128-130 °C), MS (GC-MS): m/z, 211 [M+H]+, 179, 151, 125, 91, 77, 65, 53.
70%
With sulfur; triethylamine In ethanol at 20℃; Inert atmosphere
To EtOH (37.5 mL) in an open flask was added S8 (4.68 g, 150 mmol, 1.0 eq.),cyclohexanone (23.3 mL, 225 mmol, 1.5 eq.), methyl cyanoacetate (13.3. mL, 150 mmol,1.0 eq.), and Et3N (10.4 mL, 75 mmol, 0.5 eq.), and the reaction was stirred at rt overnight.The flask was cooled to 0 °C with no stirring for 5 h followed by collection of theprecipitate by filtration. The solid was washed with ice cold EtOH then dried at rt overnight to yield 6a asan off-white solid (22.1 g, 105 mmol, 70percent)
20%
Stage #1: With diethylamine In ethanol for 0.166667 h; Reflux Stage #2: With sulfur In ethanol for 3 h; Reflux
EXAMPLE 11; The reaction scheme for the synthesis of azo dye 11 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 methyl cyanoacetate (9.90 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 11a as a pale yellow powder (4.22 g, 20percent yield), m.p. 132-133° C.
Reference：
[1] Asian Journal of Chemistry, 2010, vol. 22, # 9, p. 7399 - 7404
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 12, p. 1942 - 1956
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1866 - 1871
[4] Tetrahedron, 2006, vol. 62, # 29, p. 7121 - 7131
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1947 - 1953
[6] Chemical Biology and Drug Design, 2010, vol. 76, # 2, p. 116 - 129
[7] ChemMedChem, 2015, vol. 10, # 1, p. 69 - 82
[8] Patent: US2010/81823, 2010, A1, . Location in patent: Page/Page column 8
[9] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 2, p. 305 - 308
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3620 - 3635
[11] Transition Metal Chemistry, 2014, vol. 39, # 4, p. 431 - 442
[12] Synlett, 2014, vol. 25, # 9,
[13] Journal of Molecular Liquids, 2017, vol. 243, p. 85 - 90
[14] Patent: WO2003/101979, 2003, A1, . Location in patent: Page 19
[15] European Journal of Medicinal Chemistry, 2019, vol. 161, p. 239 - 251
2
[ 108-94-1 ]
[ 105-56-6 ]
[ 108354-78-5 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sulfur; diethylamine In ethanol at 45 - 50℃; for 1 h;
Intermediate 1. To a suspension of sulfur (11.5 g, 359 mmol) and ethyl 2- cyanoacetate (38.7 g, 342 mmol) in 50 mL of ethanol was added cyclohexan-l-one (33.6 g, 342 mmol) drop-wise at room temperature, followed by addition of diethyl amine (DEA) (25.0 g, 342 mmol), making sure the temperature was maintained below 50 °C. The resulting mixture was stirred at 45 °C for 1 h, before being cooled to 0 °C and filtered. The collected material was washed with cold ethanol and dried under vacuum to give Intermediate 1 as yellow solid (57.8 g, yield: 75percent).
Reference：
[1] Journal of Chemical Research, 2004, # 5, p. 360 - 361
5
[ 67-56-1 ]
[ 4506-71-2 ]
[ 108354-78-5 ]
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 3, p. 1018 - 1021
6
[ 108354-78-5 ]
[ 1240361-06-1 ]
Reference：
[1] Chemical Biology and Drug Design, 2010, vol. 76, # 2, p. 116 - 129
[2] Chemical Biology and Drug Design, 2010, vol. 76, # 2, p. 130 - 141
With sulfur; diethylamine; In methanol; ethanol; at 20℃;Sonication;
General procedure: Compound C was synthesized following to the procedure ofGewald et al. [22], as already reported with some minor modifications[21]. The mixture of ketone D (1 mmol), alkyl cyanoacetateE (1.1 mmol), sulfur (1.1 mmol), and diethylamine (1.1 mmol) inethanol/methanol (10 mL) was kept at room temperature in anultrasonic cleaner for 1-3 h. After completion of the reaction, thesolvent was evaporated to dryness under reduced pressure. Thecrude product was purified by flash column chromatography onsilica gel (petroleum ether/ethyl acetate elute) to provide theproduct C.
82%
With morpholine; sulfur; In ethanol; for 3h;Reflux;
Synthesis of compounds 1, 2a-i and 3a-i Compound 1 was prepared through standard Gewald reaction. 14 4.4 g (0.05 mol) of morpholine was added dropwise into a stirred solution of cyclohexanone (4.91 g, 0.05 mol), methyl cyanoacetate (4.95 g, 0.05 mol) and sulfur (1.92 g, 0.06 mol) in 35 mL ethanol. On completion, the mixture was refluxed for further 3 h. After cooling to room temperature, the precipitate was separated by filtration and recrystallized from ethanol to give 1 as pale yellow powders (8.6 g, 82% yield), mp 128.2-129.4 C (lit. 15 128-130 C), MS (GC-MS): m/z, 211 [M+H]+, 179, 151, 125, 91, 77, 65, 53.
70%
With sulfur; triethylamine; In ethanol; at 20℃;Inert atmosphere;
To EtOH (37.5 mL) in an open flask was added S8 (4.68 g, 150 mmol, 1.0 eq.),cyclohexanone (23.3 mL, 225 mmol, 1.5 eq.), methyl cyanoacetate (13.3. mL, 150 mmol,1.0 eq.), and Et3N (10.4 mL, 75 mmol, 0.5 eq.), and the reaction was stirred at rt overnight.The flask was cooled to 0 C with no stirring for 5 h followed by collection of theprecipitate by filtration. The solid was washed with ice cold EtOH then dried at rt overnight to yield 6a asan off-white solid (22.1 g, 105 mmol, 70%)
20%
EXAMPLE 11; The reaction scheme for the synthesis of azo dye 11 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 methyl cyanoacetate (9.90 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 11a as a pale yellow powder (4.22 g, 20% yield), m.p. 132-133 C.
With morpholine; sulfur; In neat (no solvent); at 75℃; for 1h;
A mixture of cyclohexanone (0.196 g,2.0 mmol), methyl cyanoacetate (0.198 g, 2.0 mmol),elemental sulfur (0.064 g, 2.0 mmol) and morpholine (0.174g, 2.0 mmol) was heated at 75 C for 1 h. After nearlycomplete conversion to the corresponding 2-aminothiophene, as was indicated by TLC monitoring, thereaction mixture was cooled to r.t. and the solid residue wasrecrystallized from EtOH to afford methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6a). Then asolution of 6a (0.211 g, 1 mmol) in benzonitrile (2 mL) washeated within a flask equipped with an air-filled balloon at200 C for 24 h in a silicone oil bath. Progress of the reactionwas monitored by TLC. After completion of the reaction, the mixture was cooled to r.t. and the excess of benzonitrile wasremoved under the reduced pressure. The crude product waspurified by column chromatography using n-hexane-EtOAc(8:1) as eluent. The solvent was evaporated under thereduced pressure and the residue was crystallized from nhexane-EtOAc (5:1) to afford the pure product 7a as paleyellow crystals. Yield: 0.188 g, 91%
With sulfur; diethylamine; In DMF (N,N-dimethyl-formamide); at 60℃; for 2h;
To methyl cyanoacetate (1.74 g, 17.6 mmol) and sulfur (0.56 g) in DMF (4 mL), diethylamine (1.4 [ML)] is added under stirring. To this solution cyclohexanone (1.73 g, 17.6 mmol) is added dropwise. The mixture is heated to [60 C] for 2 hours and it is poured into water (30 mL), which is extracted with diethyl ether (30 mL). The ethereal solution is dried with sodium sulfate and concentrated to give the desired compound as a yellow solid (0.6 g). Physical characteristics: MS (ES+) for m/z 210.
With morpholine; sulfur; In methanol;Reflux;
General procedure: A mixture of 3-hexanone (1.0?g, 10?mmol), methyl cyanoacetate (882?muL, 10?mmol), sulfur (321?mg, 10?mmol), and morpholine (872?muL, 10?mmol) in MeOH (4?mL) was refluxed overnight. After cooling, the reaction mixture was poured into ice (50?g) and the precipitate was filtered and dried under vacuum. The crude product was purified by silica gel chromatography (PE/AcOEt 9:1 as eluent) to give the title compound (230?mg, 10%) as a white solid.
methyl 2-{6-[3-(methoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino]pyridin-2-ylamino}-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate[ No CAS ]
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
General procedure: Chloroacetyl chloride (1.1 g, 0.1 mol) was added to a solution of 2-aminothiophene 11-13 (0.01 mol) and Et3N (1.0 g, 0.01 mol) in DMF (20 mL) at 20 C with stirring. The reaction mass was stirred for 30 min, poured into H2O (50 mL), extracted with chloroform (2×10 mL), dried over Na2SO4. Chloroform was evaporated, the residue was crystallized from a mixture hexane-chloroform, 10 : 1.
With triethylamine; In diethyl ether; at 20℃; for 4h;
Compound 2b (0.50 g, 2.37 mmol) is dissolved in diethyl ether (10 mL) and treated with triethyl amine (1.8 mL, 12.5 mmol). To this mixture, chloroacetyl chloride (0.29 g, 2.60 mmol) dissolved in diethyl ether (5 mL) is added dropwise at room temperature. This mixture is stirred for 4 hours at room temperature. The mixture is partitioned between water (20 mL) and ether (20 mL). The organic layer is separated, dried [(MGS04)] and concentrated. The residue is subjected to chromatography by elution with 10% ethyl acetate in heptane to give the desired product as a yellow solid (0.31 g). Physical characteristics: MS (ES-) for [?] 286 (M-H) +.
EXAMPLE 1 357 ml of cyclohexanone are added dropwise at room temperature to a suspension of 115 g of sulfur and 300 ml of methyl cyanoacetate in 500 ml of methanol. 350 ml of diethylamine are then slowly added, during which the temperature is held at a maximum of 500. The mixture is stirred for a further 12 hours and cooled to 4, and the crystals are separated off and washed with ice-cold methanol. Drying gives 580 g of methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ("AA"), m.p. 130.
31
[ 479-59-4 ]
[ 108354-78-5 ]
[ 1219458-74-8 ]
Yield
Reaction Conditions
Operation in experiment
68%
The 2-aminothiophene derivative 11a (2.96.0 g, 0.014 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 (0.97 g, 0.014 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 11b was formed.Julolidine (2.50 gm, 0.014 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5 C. The diazonium solution 11b 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 11 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. 98-103 C., (68% yield).
Intermediate 2. A suspension of intermediate 1 (7.1 g, 31.5 mmol) in formamide (25 mL) was heated to 145 C overnight. The resulting mixture was allowed to cool to room temperature and filtered. The collected material was washed with ethyl acetate to provide Intermediate 2 as a light brown solid (5.2 g, yield: 80%).
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