| 85% |
With sulphur at 60℃; for 2h; Ionic liquid; Green chemistry; |
4,5-Alkyl-2-aminothiophenes (2a-2j)
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. |
| 82% |
With sulphur; trimethyl-(2-hydroxyethyl)ammonium chloride; urea; sodium hydroxide In lithium hydroxide monohydrate at 60℃; Green chemistry; |
Typical procedure for the synthesis of 2-aminothiophene derivatives
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 |
| 81% |
With potassium carbonate; sulphur In ethanol for 3h; Reflux; |
Synthesis of 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (1):
Cyclopentanone (0.84 g, 10 mmol), malononitrile (0.66 g, 10 mmol), elemental sulfur (0.35 g, 11.0 mmol), K2CO3 (0.28 g, 2.0 mmol) and 15 mL of dry ethanol were stirred at reflux for 3 h. The insoluble material was filtered off, and the solvent was removed by evaporation under reduced pressure. The crude product was washed with water and recrystallized from ethanol to give yellowish crystals in 81% yield. Mp 152-153 °C (Lit. [21]: 151 °C). |
| 80% |
With morpholine; sulphur In ethanol at 45 - 60℃; for 18.25h; |
|
| 79% |
With sulphur; <i>L</i>-proline In N,N-dimethyl-formamide at 60℃; for 10h; |
|
| 79.94% |
With morpholine; sulphur In ethanol at 20 - 60℃; for 5.5h; |
|
| 75% |
With sulphur at 100℃; for 2h; Green chemistry; |
|
| 75% |
With sulphur at 100℃; for 0.0833333h; Green chemistry; |
|
| 71% |
With sulphur In neat (no solvent) at 60℃; for 2h; |
General procedure forpreparation of2-aminothiophenes
General procedure: General procedure forpreparation of2-aminothiophenes |
| 67.12% |
With morpholine; sulphur In ethanol at 0 - 60℃; for 2.75h; |
|
| 65% |
With sulfur; bovine serum albumine In N,N-dimethyl-formamide at 50℃; for 4h; |
2.2. General procedure for the synthesis of 2-aminothiophenes
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. |
| 63% |
Stage #1: cyclopentanone; malononitrile In lithium hydroxide monohydrate for 0.333333h; Sonication; Green chemistry;
Stage #2: With Na2S6 In lithium hydroxide monohydrate for 0.5h; Sonication; Green chemistry; |
General experimental procedure
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. |
| 57% |
With sulphur In ethanol at 100℃; for 0.133333h; microwave irradiation; |
|
| 55% |
With zinc ferrite; sulphur In neat (no solvent) at 100℃; for 4h; Green chemistry; |
|
| 49% |
With zinc oxide nanoparticles; sulphur In neat (no solvent) at 100℃; for 6h; |
4.5 General procedure for the synthesis of 2-aminothiophenes derivatives
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. |
| 47% |
With sulphur In ethanol for 4h; Reflux; |
|
| 46% |
With morpholine; cyanoacetic acid tert-butyl ester; sulphur In ethanol at 40℃; for 20h; |
4.2.1.1 Method A: preparation of 2-Amino-3-substituted thiophenes via the Gewald reaction
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. |
| 42% |
With sulphur; diethylamine In neat (no solvent) for 0.333333h; Milling; |
General procedure
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. |
| 31% |
With morpholine; sulphur In ethanol at 80℃; for 2h; |
40.a
To a stirred solution of 6.28 g (0.095 mol) malonitrile in 100 ml ethanol was added 8.00 g (0.095 mol) cyclopentanone, 3.04 g (0.095 mol) sulfur, and 8.29 ml (0.095 mol) morpholine. The mixture was heated at 80 0C for 2 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane / ethyl acetate 3:1) afforded 4.89 g (31%) 2-amino-5)6-dihydro-4H-cyclopenta[bjthiophene-3- carbonitrile as a light brown solid. ES-MS m/e (%): 165 (M+H+, 100). |
|
With sulphur; triethylamine |
|
|
With sulphur; diethylamine In ethanol at 0 - 20℃; for 3.16667h; |
12.1 3-Methyl-2-phenyl-pentanoic acid (3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-amide
Step 1: Preparation of 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene. diethylamine (2.50 ML) was added dropwise to a stirred solution of cyclopentanone (2.21 ML; 25.0 mmol), malononitrile (1.67 g; 25.0 mmol) and sulfur (0.80 g; 25.0 mmol) in absolute ethanol (10 ML) under nitrogen at 0° C. After 10 min., the mixture was allowed to warm to room temperature and stirred for 3 h.The mixture was then concentrated in vacuo and the crude residue was chromatographed (Merck silica gel 60, 230-400 mesh; Eluent: 30% ethyl acetate/hexanes) to provide 1.18 g of 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene as a light brown foam. |
|
With morpholine; sulphur In ethanol Reflux; |
|
|
With morpholine; sulphur In ethanol at 20℃; |
|
|
With morpholine; sulphur In ethanol at 20℃; |
|
|
With morpholine; sulphur In ethanol at 5 - 10℃; for 3h; |
|
|
With sulphur; potassium fluoride on 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; sulphur In ethanol at 5 - 10℃; for 3h; |
|
|
With morpholine; sulphur In ethanol at 60℃; for 24h; |
|
|
With morpholine; sulphur In ethanol |
|
|
With sulphur In ethanol for 4h; Reflux; |
|
|
With sulphur In ethanol |
|
|
With sulphur; potassium carbonate In ethanol |
|
|
With sulphur In ethanol at 60℃; |
4.2 Synthesis of compounds 4.2.1 Synthesis of compounds 2a~2k
General procedure: General method A:To a solution of cyclic ketone compounds in anhydrous ethanol (conc. 0.1M) was added sodium (6%mmol), sulfur (1.1eq) and malononitrile (1eq) or ethyl cyanoacetate (1eq) at 60°C. The reaction mixture was stirred for 4-7h. After the completion of the reaction, the reaction solution was concentrated and purified by flash column chromatography with solution of EtOAc/petroleum ether to obtain compounds. |
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