| 82% |
With morpholine; sulfur In ethanol at 120℃; for 0.333333h; Microwave irradiation; |
General procedure for the synthesis of ortho amino esters (Gewald reaction) [3, 4].
General procedure: A mixtureof the respective aldehyde or ketone (1 eq), ethylcyanoacetate (1 eq), S8 (1.1 eq), and morpholine(1.5 eq) in EtOH (5 mL) was irradiated at 120 °C for 20 min under microwave conditions. Thereaction mixture was cooled and the solution was poured onto 20 mL ice water to yield a precipitatewhich was filtered, washed with water and dried under vacuum. The crude solid was recrystallizedfrom ethanol to yield the desired product. If the solid was not precipitated from water, extract theaqueous solution with EtOAc (2 x 15 mL) and the organic solution was washed with brine, driedover sodium sulfate and filtered. The solvent was evaporated in vacuo and recrystallized fromappropriate solvent. |
| 75% |
With sulfur In ethanol at 50℃; |
|
| 70% |
With sulfur; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 120℃; for 0.333333h; Irradiation; |
3.C
To a mixture of ethyl cyanoacetate (106 xL, 1.1 eq.), phenylacetaldehyde (117 U.L, 1 eq.), sulfur (32 mg, 1 eq.), in toluene (5 mL, 0.2 M) was added DBU (150 uL, 1 eq.). The mixture was heated in a pressurized vessel under microwave irradiation at 120°C for 20 min with stirring and then poured into HC1 IN, extracted with ether,washed with brine, dried over anhydrous Na2S04, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with hexane and ethyl acetate, to afford the 2-amino-5-phenyl-thiophene-3-carboxylic acid ethyl ester (174mg, 70%) as a brown solid.2-amino-5-phenylthiophene-3-carboxylic acid ethyl ester; .H NMR (CDCI3, 500MHz) 5 (ppm): 7.44 (d, 2H, J=8Hz), 7.33 (t, 2H, J=7.6Hz), 7.24 (s, 1H), 7.20 (t, 1H, 7.5Hz), 6.00 (bs, 2H), 4.30 (q, 2H, J=7.2Hz), 1.37 (t, 3H, J=7.2Hz). |
| 64% |
With sulfur; triethylamine In ethanol at 20 - 60℃; |
|
| 64% |
With pyrrolidine; sulfur In N,N-dimethyl-formamide at 50℃; for 0.5h; Microwave irradiation; |
General procedure: A mixture of 1 (1 mmol), 2 (1.1 mmol), sulfur (1.1 mmol), corresponding base (1 mmol) and solvent (3mL) was put into a 5 mL microwave reaction vial. The vial was irradiated in the microwave reactor at50 °C for 30 min with the absorbance set to “very high”. After cooling, the reaction mixture was extractedwith EtOAc (3 × 20 mL). The combined organic phase was dried over Na2SO4 and concentrated underreduced pressure and the crude residue purified by flash chromatography on silica gel to give the products3a-3m and 4a-4r. |
| 61% |
With sulfur; diethylamine In ethanol at 70℃; for 3h; |
|
| 54% |
With morpholine; sulfur at 20℃; for 18h; |
|
| 45% |
With sulfur; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 3h; |
|
| 20% |
With octasulfur; bovine serum albumin In N,N-dimethyl-formamide at 50℃; for 12h; |
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. |
| 19% |
Stage #1: phenylacetaldehyde; ethyl 2-cyanoacetate With diethylamine In ethanol for 0.166667h; Reflux;
Stage #2: With sulfur In ethanol for 3h; Reflux; |
1
EXAMPLE 1; The reaction scheme for the synthesis of azo dye 1 is shown below. In a Gewald reaction, diethylamine (8 ml) was added to a solution of equimolar quantities of phenylacetaldehyde (12.0 g, 0.10 mol) and ethylcyanoacetate (11.4 g, 0.10 mol) in ethanol and was refluxed for 10 minutes then sulfur (3.53 g, 0.11 mol) was added, and the solution was refluxed for further 3 hours. The pale yellow precipitate formed was filtered and washed with cooled ethanol to give 1a as pale yellow powder (4.70 g, 19% yield), mp. 124-125° C. |
|
With diethylamine |
|
|
Stage #1: phenylacetaldehyde; ethyl 2-cyanoacetate With ammonium acetate; acetic acid In benzene Heating;
Stage #2: With sulfur; diethylamine In ethanol at 50℃; |
|
|
With sulfur; triethylamine In N,N-dimethyl-formamide at 50℃; |
|
|
With sulfur; triethylamine In diethyl ether at 20℃; for 12h; |
Substituted 2-aminothiophenes 1
General procedure: A mixture 108 mL (1 mol) of ethyl cyanoacetate, 32 g (1 mol) of elemental sulfur and 1 mol of corresponding ketone in 200 ml of diethyl ether was stirred at room temperature. To this mixture 80 ml of diethylamine was added for 12 h. The solid product was collected by filtration and washed with aqueous alcohol (1:1), yield 50-80%. |
|
With sulfur |
|
|
With sulfur; diethylamine In ethanol at 20℃; for 26h; |
2.3.1 Substituted 2-amino-3-carbethoxythiophene (i)
General procedure: A mixture of ethyl cyanoacetate (107 mL, 1 mol), elemental sulfur (32 g, 1 mol) and the corresponding ketone (1 mol) in ethanol (200 mL) was stirred at room temperature. To this mixture, diethylamine (80 mL) was added dropwise during 12 h with stirring. Then the reaction mixture was left on 14 h; the precipitate was filtered, washed by aqueous alcohol (1:1) and dried in air. Yield 50-88%. |
|
With sulfur; triethylamine In industrial methylated spirit at 60℃; for 2h; |
73
Synthesis 73; 5-Phenyl-thiophene-3-carboxylic acid; A mixture of phenylacetaldehyde (9.3 mL, 0.083 mol), sulfur (2.64 g, 0.083 mmol), ethyl cyanoacetate (5.73 mL, 0.054 mmol) and triethylamine (15 mL, 0.108 mol) in IMS (80 mL) was heated at 600C for 2 hours. The mixture was left to stand at room temperature and the resultant precipitate was collected by filtration and re-crystallised from hot ethanol to afford 2-amino-5-phenyl-thiophene-3-carboxylic acid ethyl ester (7.97 g). |
|
With morpholine; sulfur In ethanol at 80℃; for 16h; |
|
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