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CAS No. : | 3249-68-1 | MDL No. : | MFCD00009401 |
Formula : | C8H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KQWWVLVLVYYYDT-UHFFFAOYSA-N |
M.W : | 158.20 | Pubchem ID : | 238498 |
Synonyms : |
Ethyl 3-oxohexanoate
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.05 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.5 cm/s |
Log Po/w (iLOGP) : | 1.74 |
Log Po/w (XLOGP3) : | 1.08 |
Log Po/w (WLOGP) : | 1.31 |
Log Po/w (MLOGP) : | 0.97 |
Log Po/w (SILICOS-IT) : | 1.55 |
Consensus Log Po/w : | 1.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.11 |
Solubility : | 12.4 mg/ml ; 0.0785 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.58 |
Solubility : | 4.14 mg/ml ; 0.0261 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.9 |
Solubility : | 2.0 mg/ml ; 0.0126 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.82 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P210-P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312+P362+P364-P304+P340+P312-P370+P378-P403+P235-P501 | UN#: | N/A |
Hazard Statements: | H227-H302+H312+H332 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene anschliessend mit Butyrylchlorid, Hydrieren des Reaktionsprodukts an Palladium/Kohle in Aethylacetat und Essigsaeure und Erwaermen der Reaktionsloesung; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With trifluorormethanesulfonic acid at 0 - 25℃; for 16h; | |
99% | With ferric(III) chloride In neat (no solvent) at 70℃; for 12h; Green chemistry; | 3.2.3 Conventional heating method General procedure: A mixture of the appropriate phenol 1a-e (3.73mmol), β-ketoester 2a-c (7.46mmol) and anhydrous FeCl3 (0.373mmol, 81mg) was heated at 70°C. After completion of the reaction (TLC), ethanol (5mL) was added, and the product 3a-j crystallized upon dropwise addition of water (15mL). The solid was filtered washed with water and was recrystallized from ethanol/water. The final product was then dried under high vacuum over P2O5. |
96% | With trifluoroacetic acid at 20℃; for 20h; |
96% | With sulfuric acid at 20℃; for 2h; | 1.a Concentrated sulfuric acid (2.15 g, 21.9 mmol) was added to a suspension of phloroglucinol dihydrate (I) (3.0 g, 18.5 mmol) and ethyl butyrylacetate(3.23 g, 20.4 mmol). The reaction mixture became a homogeneous yellow solution with generation of heat and then solidified. After allowing the solid to stand at room temperature for 2 hrs., the obtained solid was thoroughly pulverized. The pulverizate was washed with water and the product was filtrated. Washing with water and filtration was repeated until the washing became pH 3. Thorough drying gave the title compound as a pale-yellow powder (3.92 g, yield 96%). mp; 227 - 229 DEG C<1>H-NMR(DMSO); delta 0.95(t, 3H, J=7.3Hz), delta 1.58(sextet, 2H, J=7.4Hz), delta 2.85(t, 2H, J=7.5Hz), delta 5.83(s, 1H), delta 6,19(d, 1H, J=2.3Hz), delta 6.27(d, 1H, J=2.3Hz), delta 10.30 (s, 1H), delta 10.59 (s, 1H)<13>C-NMR(DMSO); delta 13.82, delta 22.53, delta 37.24, delta 94.74, delta 99.17, delta 99.26, delta 101.37, delta 108.28, delta 108.32, delta 156.84, delta 157.42, delta 158.51, delta 160.18, delta 160.91MS; 221(13.8, M+1), 220(100, M+), 205(37.0), 192(73.4), 177(30.0)IR(KBr); 3204, 1649, 1622, 1591, 1561 cm-<1> |
96% | With boron trifluoride diethyl ether complex for 5h; Reflux; | |
82% | With methanesulfonic acid In neat (no solvent) for 2h; Milling; | |
78% | With scandium trifluoromethanesulphonate at 80℃; for 1h; | |
72% | With nano-BFn/cellulose In neat (no solvent) at 85℃; for 1h; Green chemistry; | General procedure for the synthesis of 7-hydroxycoumarin derivatives General procedure: A mixture of phenol (1 mmol), -keto ester (1 mmol) and a catalytic amount ofnano-BFn/cellulose (0.06 g) was stirred at 85 °C. After an appropriate time that thereaction was completed, the mixture was dissolved in hot isopropyl alcohol to separatethe insoluble catalyst by a simple filtration. After cooling the solution, some crushed ice was added to it. The solid product was appeared and collected by filtration.To find out the reusability of catalyst, the recovered catalyst was washed withchloroform, dried and used for three times under the same reaction conditions |
With sulfuric acid | ||
With sulfuric acid Yield given; | ||
With sulfuric acid at 90℃; for 2h; | ||
With trifluorormethanesulfonic acid at 20℃; for 12h; | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With perchloric acid at 20℃; | 6.2.2. General method for 4-substituted 7-hydroxycoumarins (2, 4-22) General procedure: 30 mmol of properly substituted resorcinol was dissolved in 30 ml of perchloric acid. 30 mmol of β-ketoester was added and the reaction mixture was stirred at room temperature until TLC showed that resorcinol had reacted. The mixture was poured into 250 ml of cold water and the precipitate was filtered and dried at room temperature and recrystallised from ethanol. Analytical data of compounds 2-13, 15, 16, 19 and 20 is presented in refPreviewPlaceHolderSupplementary data. |
88% | With sulfuric acid Ambient temperature; | |
81% | With ferric(III) chloride In neat (no solvent) for 0.333333h; Sonication; Green chemistry; | 3.2.1 Ultrasound method General procedure: A mixture of the appropriate phenol 1a-e (3.73mmol), β-ketoester 2a-c (7.46mmol) and anhydrous FeCl3 (0.373mmol, 81mg) was placed in a 10mL glass tube and was sonicated (20kHz, 130W nominal power) for 1-20min until completion of the reaction checked by TLC. The tube during sonication was immersed in a cooling bath set at 20°C. For compounds 3a, 3b, 3c, 3f, 3j the reaction mixture solidified upon completion of the reaction, due to product precipitation. Subsequently, ethanol (5mL) was added, and the product 3a-j crystallized upon dropwise addition of water (15mL). The solid was filtered washed with water and was recrystallized from ethanol/water. The final product was then dried under high vacuum over P2O5. |
80% | With ferric(III) chloride at 70℃; | |
79.2% | With sulfuric acid at 0 - 20℃; | |
75% | With sulfuric acid at 90℃; for 18h; | 5 4-Propyl-umbelliferone. [0053] 5 g (0.1031 mol) ethyl-propionyl-acetate and 6.93 g (0.063 mol) resorcinol were reacted with 50 ml sulfuric acidas described above (18 h at 90°C). The solution was cooled down on ice and product precipitated with 50 ml ice coldwater. After addition of 100 ml diethylether, the ether fraction was dried. For re-crystallization, water was added and thecrystals collected by filtration. The final product was white-yellow and purity was confirmed by ESI-ion trap MS (Fig. 13);final yield, 75%. |
74% | With methanesulfonic acid In neat (no solvent) for 2h; Milling; | |
55% | With oxalic acid In neat (no solvent) at 80℃; for 1.33333h; Green chemistry; | Syntheses of coumarin derivatives General procedure: A mixture of phenol (10 mmol), β-keto esters (10 mmol) and oxalic acid (10 mol%) was heated to 80°C till completion of the reaction (monitored using TLC). Then, the reaction mixture was cooled to room temperature, and it was poured in ice-water mixture and stirred for 10 min. The precipitated product was collected by filtration, washed with water and dried. The product obtained was recrystallized from appropriate solvent(like ethanol) to afford corresponding pure coumarin product. |
With sulfuric acid | ||
With sulfuric acid for 2h; Ambient temperature; | ||
With sulfuric acid | ||
at 20℃; Reflux; Acidic conditions; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: ethyl butyroyl acetate With sulfuryl dichloride In diethyl ether at 0 - 20℃; for 4h; Stage #2: With sodium hydrogencarbonate | 1.D Preparation of 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid {2-[4-(6-aminopyridin-2-yl)-piperazin-1-yl]-1-methyl-ethyl} amide (D) 3-oxo-hexanoic acid ethyl ester (29.7 g, 188 mmol) was dissolved in Et2O (400 ml). The solution was cooled to 0° C., and sulfuryl chloride (22.6 ml, 282 mmol) was added dropwise. The solution gradually warmed to RT over 4 h. The solution was neutralized to pH 7 with a solution of aqueous saturated NaHCO3. The organic layer was separated, washed with brine, and dried over sodium sulfate. Evaporation under reduced pressure yielded 2-chloro-3-oxo-hexanoic acid ethyl ester (intermediate Id, 36 g, 100%). 1H-NMR (CDCl3, ppm): 0.95 d (3H); 1.35 d (3H); 1.58 m (2H); 2.7 t (2H); 4.28(d (2H); 4.78 s (1H). |
100% | With sulfuryl dichloride In dichloromethane at 0 - 20℃; for 4h; | 1 Ethyl butyrylacetate was added to the reaction flask 15.8 g (100 mmol), Dichloromethane 200 ml, Cooling to 0 ~ 10 ° C, 16.2 g (120%) of sulfonyl chloride was added dropwise, After adding up to room temperature, Insulation reaction 4 h, TLC monitoring reaction completely converted to product (developing agent: ethyl acetate: n-hexane = 1: 3) reaction is completed, cooled to 0 ° C or so, add 150mL 1 M K3P4 aqueous solution, separated several layers, Methyl chloride 50ml extraction twice, the organic layer, washed to neutral, 20g anhydrous magnesium sulfate drying, filter off the desiccant, concentrated to no slippery incision, To give an oil of 19.2 g, 100% yield, Do not need to be used directly in the next step. |
90% | With sulfuryl dichloride In diethyl ether |
90% | With sulfuryl dichloride In dichloromethane at 20℃; for 1h; | |
64% | With sulfuryl dichloride at 20℃; for 3h; | |
62% | With hydrogenchloride; iodosylbenzene In dichloromethane at 40℃; for 0.5h; | |
With sulfuryl dichloride | ||
With sulfuryl dichloride In chloroform for 2h; Heating; | ||
With sulfuryl dichloride In diethyl ether for 1h; Ambient temperature; | ||
With sulfuryl dichloride In dichloromethane at 20℃; | ||
With sulfuryl dichloride In chloroform for 2h; Heating; | ||
With sulfuryl dichloride In dichloromethane at 25℃; Inert atmosphere; | II Step II: Synthesis of ethyl 2-chloro-3-oxohexanoateA solution of ethyl 3-oxohexanoate (2.Og, 12.6 mmol) in dichloromethane was stirred at room temperature (-25 0C) under inert atmosphere. Sulphuryl chloride (1.79g, 13.2 mmol, 1.05 equiv.) was added dropwise and stirred at room temperature (-25 0C) for about 90 min. The residue obtained after concentration was dissolved in ethyl acetate, dried over anhydrous sodium sulphate and concentrated over rotavapor to afford a viscous oil (1.5 g) that was taken as such to the next step (1.5 g).EIMS m/z 193 [M+H]+ | |
With sulfuryl dichloride In dichloromethane at 0 - 20℃; | ||
With sulfuryl dichloride In dichloromethane at 20℃; | ||
With thionyl chloride In dichloromethane | ||
1.5 g | With sulfuryl dichloride In dichloromethane at 25℃; for 0.015h; Inert atmosphere; | II Step II: Synthesis of ethyl 2-chloro-3-oxohexanoate [0434] A solution of ethyl 3-oxohexanoate (2.0 g, 12.6 mmol) in dichloromethane was stirred at room temperature (˜25° C.) under inert atmosphere. Sulphuryl chloride (1.79 g, 13.2 mmol, 1.05 equiv.) was added dropwise and stirred at room temperature (˜25° C.) for about 90 min. The residue obtained after concentration was dissolved in ethyl acetate, dried over anhydrous sodium sulphate and concentrated over rotavapor to afford a viscous oil (1.5 g) that was taken as such to the next step (1.5 g). [0435] EIMS m/z 193 [M+H]+ |
With sulfuryl dichloride In chloroform at 0 - 20℃; for 3h; Reflux; | 4.1.1. General procedure for synthesis of imidazolecarbaldehydes 8a-e General procedure: Using the synthetic procedure of 4-tert-butyl-1H-imidazole-5-carbaldehyde (8c) as an example. Sulfuryl chloride (5.3 mL, 9.0 g, 66 mmol) was added dropwise to ethyl pivaloylacetate (10.2 mL, 5.2 g, 55 mmol) in 50 mL of CHCl3 at 0 °C. The resulting mixture was allowed to warm to room temperature and was stirred for 30 min, after which it was heated under reflux for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with chloroform, washed with sodium bicarbonate, water and then brine successively. The organic phase was dried and evaporated to afford 2-chloro-4,4-dimethyl-3-oxo-pentanoic acid ethyl ester as a clear oil, of sufficient purity to be used directly in the next step (10.6 g, 92%). A solution of 2-chloro-4,4-dimethyl-3-oxopentanoic acid ethyl ester (10.6 g, 51.44 mmol) in formamide (17.8 ml, 23.2 g, 51.44 mmol) and water (1.85 ml, 102.9 mmol) was heated at 180 °C for 3.5 h. The mixture was allowed to cool to room temperature, then water (20 ml) was added and the mixture was exhaustively extracted with chloroform. The crude product was purified by flash chromatography over silica gel to give ethyl 4-(tert-butyl)-1H-imidazole-5-carboxylate (2.22 g, 22%). To a solution of 5-tert-butyl-3-imidazole-4-carboxylic acid ethyl ester (2.20 g, 11.21 mmol) in THF (60 mL) was added LiAlH4 (553 mg, 14.57 mmol) in portions under argon atmosphere at 0 °C, and then the mixture was stirred for 4 h at room temperature. To this solution was added moist Na2SO4 solid slowly at 0 °C, and the resulting precipitate was removed by Celite filtration and washed by THF several times. The solvent was removed by evaporation and the residual oil was purified by silica gel chromatography using CH2Cl2/MeOH (200:1) as eluent to give an oil of (4-(tert-butyl)-1H-imidazol-5-yl)methanol (1.23 g, 71%): To a solution of alcohol 6 (1.23 g, 7.97 mmol) in acetone (20 mL) was added active MnO2 (16.2 g, 186.2 mmol), and the mixture was stirred at room temperature for 12 h. After filtration through a pad of Celite to remove MnO2, the solvent was removed by evaporation, and the residual white powder was purified by silica gel column chromatography using CH2Cl2/MeOH (200:1) as eluent to give 958.2 mg (79%) 4-(tert-butyl)-1H-imidazole-5-carbaldehyde of off-white solid. 1H NMR (400 MHz, CDCl3) d 1.48 (s, 9H), 7.67 (s, 1H),10.06 (s, 1H). Other 4-substituted imidazolealdehydes was prepared using the same standard procedure. | |
With sulfuryl dichloride In dichloromethane at -5 - 0℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With bis(acetylacetonate)nickel(II) at 100℃; Overnight; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With ruthenium trichloride; hydrogen; (R)-(6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(diphenylphosphine) In methanol at 40 - 60℃; for 10h; Autoclave; | |
98% | With ruthenium trichloride; hydrogen; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) In ethanol at 80℃; for 24h; Inert atmosphere; optical yield given as %ee; | |
96% | Stage #1: With triethylamine In toluene at 140℃; for 4h; Stage #2: ethyl butyroyl acetate With hydrogen In methanol at 80℃; for 5h; | 4 Catalyst (1) : Combine dichloro (1, 5-cyclooctadiene) ruthenium (117 mg, 0.417 mmol), (R)-BINAP (300 mg, 0.482 mmol), and NEt3 (82.5 LL, 0.59 mmol) in anhydrous toluene (13.5 mL) under N2. Heat the reaction mixture at 140° for 4 hours, and then cool to ambient temperature. Add THF to the resulting red jell, until a solution results. Concentrate the reaction mixture in vacua, and add THF (30 mL) to the give the catalyst (1) in solution. This solution is used directly for the hydrogenation. (R)-3-Hydroxy-hexanoic acid ethyl ester: In a Fisher Porter tube, add the above catalyst (1) solution (10 mL) to a solution of ethyl butyrylacetate (25 g, 0. 158 mol) in methanol (100 mL) under N2. Pressurized with H2 (50 psig) and heat at 80°C for 5 hours. Concentrate the reaction mixture in vacuo. Purify the residue by vacuum distillation (24.45 g, 96%, 97.4 % ee). Chiral GC (30 m x 0.25 mm x 0. 25 um, BETA- Dex 225, 100°C) second eluting isomer, (18.93 minutes). |
94% | With hydrogen In ethanol at 100℃; for 2h; | |
94% | With dichloro(benzene)ruthenium(II) dimer; hydrogen; (R)-tol-BINAP at 100℃; for 1.5h; Autoclave; optical yield given as %ee; | |
92% | With hydrogen In methanol at 100℃; | |
85% | With hydrogen In methanol at 30℃; | |
83% | With hydrogen at 60℃; for 48h; | |
80% | With ruthenium trichloride; hydrogen; (R)-(6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(diphenylphosphine) In methanol at 50℃; for 72h; Autoclave; | |
70% | With baker's yeast; Sucrose In water | |
60% | In water at 27℃; for 24h; Geotrichum candidum; | |
31% | With D-glucose; dimethyl sulfoxide In hexane at 30 - 35℃; for 50h; immobilized Bakers' yeast (IBY); | |
26% | With D-Galactose; engineered yeast strain 24B(pSRG29); Tris-Cl buffer at 30℃; | |
With D-glucose In ethanol; water at 25℃; for 48h; yeast Saccharomyces cerevisiae IFO0565; Yield given; | ||
With ammonium sulfate; potassium dihydrogenphosphate; growing baker's yeast; magnesium sulfate; Sucrose for 24h; | ||
With baker's yeast; allyl alcohol; Sucrose for 19h; Ambient temperature; | ||
With hydrogen In ethanol at 50℃; | ||
With dichloro(benzene)ruthenium(II) dimer; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In ethanol; N,N-dimethyl-formamide at 85℃; | ||
With hydrogen In ethanol at 50℃; for 24h; | ||
With hydrogen; 2,3-dimethyl-1-n-propyl-imidazolium bis(trifluoromethylsulfonyl)imide In methanol at 20℃; for 22h; | ||
> 99 % ee | With hydrogen In ethanol at 50℃; for 24h; | 6.a The substrate to be hydrogenated (1 mmol) is then dissolved in 2 ml of hydrogenation solvent (of the alcohol or halogenated type, such as dichloromethane) and placed in an autoclave in the presence of the catalyst under the desired hydrogen pressure and at the desired temperature. |
> 99 % ee | With hydrogen | 8 EXAMPLE 8 TABLE 2 below shows a comparison of the results of the hydrogenation of different substrates obtained on the one hand with the ruthenium complexes according to the invention and on the other hand with complexes of the type Ru-Binap, under the same operating conditions (temperature, pressure and solvent). [0235] TABLE 2 shows a comparison of the results obtained in TABLE 1 with the complexes according to the invention and the results obtained with the corresponding complexes in which the ligand (1) according to the invention has been replaced by the ligand BINAP. |
With Kluyveromyces marxianus In ethanol at 30℃; for 24h; Reduction medium; optical yield given as %ee; enantioselective reaction; | Microorganisms, media, growth conditions, and biotransformation with free cells. Saccharomyces cerevisiae, Hansenula sp., Geotrichum candidum, Kluyveromyces marxianus, Rhodotorula rubra, Aspergillus niger, and Trichoderma harzianum belong to the collection of the ‘Departamento de Engenharia Bioquímica, Escola de Química, Universidade Federal do Rio de Janeiro (Cidade Universitária, CT Bloco E, Rio de Janeiro, Brazil, e-mail selma(at)eq.ufrj.br)’ and are freely available upon request. Cells were allowed to grow for 48 h, under 150 rpm at 30 °C in a medium containing 1% glucose, 0.5% yeast extract, 0.5% peptone, 0.1% (NH4)2SO4, and 0.1% MgSO4·7H2O. After that period, they were harvested by centrifugation, re-suspended in water, and used for the reaction. After centrifugation, the cells (4 g/L, dried weight) were added to the reduction medium containing: glucose (5%), MgCl2 (0.1%) in a final volume of 100 mL. After 30 min of addition of the microorganisms, the substrate (0.5 g diluted in 1 mL of ethanol 96%) was added to the medium. The reaction was carried out in 500 mL cotton-plugged Erlenmeyer flasks for 24 h at 30 °C and 150 rpm. After 24 h, the medium was centrifuged again to separate the cells and the liquid phase was extracted with ethyl acetate. The organic phase was dried (anhydrous Na2SO4), filtered, and concentrated under vacuum. Conversions and enantiomeric excesses were determined by (chiral) gas chromatography (GC), on column Beta Dex325 (30 m × 0.25 mm × 0.25 μm), at 90 °C (23 min). The elution order was: ethyl (S)-3-hydroxyhexanoate (tR = 18.8 min) followed by ethyl (R)-3-hydroxyhexanoate (tR = 19.3 min). Substrate was eluted at 15.3 min. The reaction product was characterized by nuclear magnetic resonance (NMR) and mass spectroscopy. | |
> 99 % ee | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); hydrogen bromide; hydrogen; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) In ethanol at 50℃; for 24h; Inert atmosphere; Autoclave; | |
With D-glucose; lyophilized cells of Escherichia coli pET28a-CpAR2-BmGDH; potassium carbonate In ethanol at 30℃; Green chemistry; enantioselective reaction; | ||
>99 % ee | With D-Glucose In water at 30℃; for 2.73333h; Flow reactor; Enzymatic reaction; enantioselective reaction; | Flow Reactor: General procedure: A solution of 5 g of glucose in 100 mL of distilled water was prepared and the β-ketoester [ethyl 3-oxohexanoate (1) or tert-butyl 3-oxobutanoate (2)] were added to the solution (0.025 mol L-1 or 4 g L-1). The starting mixture was stirred for 5 min while the instrument Asia Flow Reactor was equipped with Omnifit column (volume: 12.3 mL) containing the immobilized cells from Kluyveromyces marxianus [for the bioreduction of ethyl 3-oxohexanoate (1)] and Rhodotorula rubra [for the bioreduction of tert-butyl 3-oxobutanoate (2)]. The temperature (30 °C) was selected on the flow reactor and for each flow tested (0.2 mL min-1, 0.1 mL min-1 and 0.075 mL min-1), first only the pure solvent (glucose 5%) was pumped through the system. At this point, the reaction mixture [ethyl 3-oxohexanoate (1) ortert-butyl 3-oxobutanoate (2)] was pumped through the system and aliquots were collected in different times depending on the flow rate tested (0.2 mL min-1 = 62 min; 0.1 mL min-1 = 123 min; 0.075 mL min-1 = 164 min). The reaction mixture was extracted with ethyl acetate. The organic phase was dried (anhydrous Na2SO4), filtered, and concentrated under vacuum. Products were analyzed by (chiral) gas chromatography (GC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With triethylamine In toluene at 140℃; for 4h; Stage #2: ethyl butyroyl acetate With hydrogen In methanol at 80℃; for 5h; | 4 Catalyst (2): Combine dichloro (1, 5-cyclooctadiene) ruthenium (117 mg, 0.417 mmol), (59-BINAP (300 mg, 0.482 mmol), and NEt3 (82. 5 pL, 0.59 mmol) in anhydrous toluene (13.5 mL) under N2. Heat the reaction mixture at 140° for 4 hours, and then cool to ambient temperature. Add THF to the resulting red jell, until a solution results. Concentrate the reaction mixture in vacuo, and add THF (30 mL) to the give the catalyst (1) in solution. This solution is used directly for the hydrogenation. (S)-3-Hydroxy-hexanoic acid ethyl ester: In a Fisher Porter tube, add the above catalyst (2) solution (10 mL) to a solution of ethyl butyrylacetate (25 g, 0.158 mol) in methanol (100 mL) under N2. Pressurize with H2 (50 psig) and heat at 80°C for 5 hours. Concentrate the reaction mixture ira vacuo. Purify the residue by vacuum distillation (25.0 g, 100%, 97.4 % ee). Chiral GC (30 m x 0.25 mm x 0. 25/im, BETA- Dex 225, 100°C) first eluting isomer, (18.72 minutes). |
94% | With Ru2Cl4{2,2'-bis(diphenylphosphino)-1,1'-binaphthyl}2*N(C2H5)3; hydrogen In methanol; dichloromethane at 25℃; for 48h; | |
94% | With dichloro(benzene)ruthenium(II) dimer; hydrogen; 1,1′-binaphthalene-2,2′-diylbis[bis(4-methylphenyl)phosphine] In ethanol optical yield given as %ee; |
92% | With (S)-BINAP-Ru(II); hydrogen In methanol at 100℃; | |
87% | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); hydrogen bromide; hydrogen; (S)-[(5,6),(5’,6’)-bis(ethylenedioxy)biphenyl-2,2’ diyl]bis(diphenylphosphine) In methanol; ethanol at 50℃; for 10h; enantioselective reaction; | |
72% | With Saccharomyces cerevisiae at 30℃; for 16h; aq. buffer; optical yield given as %ee; enantioselective reaction; | |
With hydrogen In methanol at 30℃; | ||
With 1,2-bis[(R,R)-2,5-diisopropylphospholano]ethane-RuBr2; hydrogen In methanol; water at 35℃; for 20h; | ||
With dried Baker's yeast In water; Petroleum ether for 18h; Yield given; | ||
With ruthenium trichloride; hydrogen; (S)-(-)-(6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) In methanol at 50℃; for 24h; | ||
With glucose-6-phosphate dehydrogenase; α-D-glucose 6-phosphate; baker yeast YOR120w gene-pIK30 plasmid at 30℃; for 24h; | ||
With (11bS, 11'bS)-4,4'-(oxydi-2,1-phenylene)bis-dinaphtho[2,1-d:,1',2'-f][1,3,2]dioxaphosphepin; hydrogen In ethanol; dichloromethane at 60℃; for 20h; | ||
90 % Chromat. | With D-glucose; engineered yeast strain 2B(pSRG41); Tris-Cl buffer at 30℃; | |
With hydrogen | ||
97 % ee | With hydrogen In ethanol; dichloromethane at 60℃; for 20h; | [Ru(benzene)Cl2]2 (N) (16 mg, 0.032 mmol) and a diphosphonite (0.067 mmol) were introduced into a 25 ml Schlenk tube. The tube was purged three times with argon before dry dimethylformamide (DMF) (3 ml) was added. The resulting mixture was heated to 100° C. for 30 minutes and then cooled to 60° C. The solvent was removed under reduced pressure, and the catalyst was obtained as a pale green-yellow solid. This catalyst was dissolved in dry dichloromethane (8 ml) and distributed uniformly between 8 vials (in each case 1 ml), which had already been purged three times with argon. A ketone, such as a β-keto ester (III) (0.8 mmol), was introduced into each vessel, then in each case 3 ml of ethanol were added. These were then transferred to a high-pressure autoclave. Once it had been purged three times with H2, the autoclave was adjusted to a pressure 60 bar with H2, and the reactions were stirred magnetically at 60° C. over 20 h. The autoclave was subsequently cooled to room temperature and H2 was cautiously discharged. Samples were taken from each reaction solution and put through a small amount of silica gel before the GC analysis in order to determine the conversions and ee values. The absolute configuration was determined in comparison to known compounds described in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid In benzene for 6h; Reflux; Inert atmosphere; chemoselective reaction; | |
90% | In benzene for 6h; Heating / reflux; | 2.2 540g (3.42mmol) of the 3-oxohexanoyl acid ethyl ester obtained in the process (1), 2.12g (34.2mmol) of ethylene glycol, and 65mg (0.4mmol) of p-toluene sulfonic acid monohydrate were dissolved in 50mL of benzene, and the solution was circulated for six hours by a circulation device incorporating the Dean and Stark device. After cooling, the reaction liquid was washed with saturated sodium bicarbonate water, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate=6/4). As a result, 3,3-ethyleneglycosyl hexanoyl acid ethyl ester denoted by the following formula was obtained. |
88% | With toluene-4-sulfonic acid In benzene for 6h; Dean-Stark conditions; Reflux; | 1.2 (1) above, ethylene glycol (7.84 g, 126.5 mmol) and p-toluenesulfonic acid monohydrate (475 mg, 2.5 mmol) were dissolved in benzene (50 mL), and allowed to reflux using a reflux apparatus equipped with a Dean Stark device for 6 hours. After cooling, the thus-obtained organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate = 6/4) to obtain the ethyl 3,3-ethylene glycosyl hexanoate shown by the formula below. Quantity Yield: 4.48 g (22.2 mmol) Percent Yield: 88% 1H-NMR (CDCl3, 500 MHz); 0.94 ppm (t, 3H), 1.29 ppm (t, 3H), 1.45 ppm (m, 2H), 1.81 ppm (m, 2H), 2.67 ppm (s, 2H), 4.00 ppm (m, 4H), 4.20 ppm (q, 2H). |
86% | With chloro-trimethyl-silane In dichloromethane for 120h; Heating; | |
80% | With toluene-4-sulfonic acid In toluene for 12h; Heating; | |
75% | With toluene-4-sulfonic acid In benzene for 16h; Heating; | |
66% | Stage #1: ethylene glycol; ethyl butyroyl acetate In cyclohexane for 9h; Reflux; Stage #2: In cyclohexane for 6h; Reflux; | 7.1 Ethyl 3-oxohexanoate (16) (12.0 g, 78.9 mmol), ethylene glycol (9.40 g, 151 mmol), pyridinium p-toluenesulfonate (PPTS) (0.1 g) and cyclohexane (50 mL) were added to a 200 mL flask, and the mixture was refluxed for 9 h while removing the generated water. Then p-toluenesufonic acid (TsOH) (cat.) was added, followed by refluxing for 6 h, while removing the generated water. After cooling, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the organic layer was separated. The organic layer was successively washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue (14.9 g) was distilled under reduced pressure (ca. 77°C / 0.2 kPa) to give the ester (17) (10.6 g, 52.4 mmol, yield 66%). |
66% | Stage #1: ethylene glycol; ethyl butyroyl acetate In cyclohexane for 9h; Reflux; Stage #2: In cyclohexane for 6h; Reflux; | 2.1 Ethyl 3-oxohexanoate (12.0 g, 78.9 mmol), ethylene glycol (9.40 g, 151 mmol), pyridinium p-toluenesulfonate (PPTS) (0.1 g) and cyclohexane (50 mL) were added to a 200 mL flask, and the mixture was refluxed for 9 h while removing the generated water. Then p-toluenesufonic acid (TsOH) (cat.) was added, followed by refluxing for 6 h, while removing the generated water. After cooling, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the organic layer was separated. The organic layer was successively washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue (14.9 g) was distilled under reduced pressure (ca. 77°C / 0.2 kPa) to give the ester (21) (10.6 g, 52.4 mmol, yield 66%). |
15% | With toluene-4-sulfonic acid In toluene for 72h; Heating; | |
With chloro-trimethyl-silane In dichloromethane | ||
With toluene-4-sulfonic acid In benzene Heating; | ||
With toluene-4-sulfonic acid In benzene Heating / reflux; | 1 Synthesis of 3-oxo-N-hexanoyl-L-homoserine lactones entails a) preparation of a protected 3-oxo-N-alkyl component and b) the coupling of its sodium salt to (L-) homoserine lactone. Preparation of the protected 3-oxo-N-hexanoyl component was performed as follows. Into a 250 mL round-bottomed flask were added 25g (158 mmoles) of ethyl butyrylacetate, 9.69 mL (173.8 mmoles) of ethylene glycol, 60 mL of benzene , 0.025g of p-toluenesulfonic acid and a few boiling chips. A Dean-Stark apparatus and condenser were attached and refluxing continued during an overnight period. (Salmi, E. J.,Chem. Ber. 71,(1938),1803-1808.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iodosylbenzene; hydrogen fluoride In dichloromethane; water at 40℃; for 1h; | |
93% | With iodosylbenzene; hydrogen fluoride In dichloromethane; water at 40℃; for 1h; | 2-Fluoro-1,3-Dicarbonyl Compounds 2a-l; General Procedure General procedure: To a PFA test tube were added ArIO (1.2 mmol), 55% aq HF soln (0.64 mL, 10 mmol HF), and CH2Cl2 (2 mL). After stirring for 15 min at r.t., a 1,3-dicarbonyl compound 1 (1 mmol) was added and then the mixture was stirred at 40 °C for the time given in Table 2. The mixture was poured into H2O (20 mL), neutralized with NaHCO3, and extracted with CH2Cl2 (3 × 6 mL) The combined organic layers were washed with sat. NaCl and dried (anhydrous Na2SO4). After evaporation of the solvent, the product was isolated by column chromatography (silica gel, EtOAc-hexane). |
79% | With ortho-methylphenyl iodide; hydrogen fluoride; 3-chloro-benzenecarboperoxoic acid In water; 1,2-dichloro-ethane at 40℃; for 1h; |
72% | With 4-(difluoroiodo)toluene; pyridine hydrogenfluoride In dichloromethane for 3h; Ambient temperature; | |
4.1 g | With Selectfluor In acetonitrile at 100℃; for 6h; | 807 3-oxo - hexanoic acid ethyl ester (10.2 g) in acetonitrile (140 mL) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis tetrafluoroborate ( added 25.0 g) at room temperature, the reaction mixture was heated and stirred for 6 hours at 0.89 ° C..The reaction mixture was cooled to room temperature, ethyl acetate was added and the mixture was washed once with water.The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.Hexanoic acid ethyl ester (8.40 g) - 2-fluoro-3-oxo purified by; (hexane / ethyl acetate = 90 / 10-80 / 20 solvent) residue was purified by silica gel column chromatography.The resulting 2-fluoro-3-oxo - a mixture of hexane acid ethyl ester (4.1g), 3- amino-6-chloro-pyridazine (2.70g) and polyphosphoric acid (30g), 3 hours of heating at 120 It stirred.After confirmation of completion of the reaction, the reaction mixture was cooled to room temperature, water was added (200 mL).The precipitated solid was collected by filtration, washed once with water and dissolved in chloroform.After drying the resulting solution over anhydrous magnesium sulfate, filtered, and concentrated.The resulting diisopropyl ether was added to the product, collected by filtration of the solid to give the title compound (1.74g).MS (ESI) M / Z; 242, 244 [M TasuH]Tas |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium nitrite In water; acetic acid at 0 - 20℃; | |
89% | With acetic acid; sodium nitrite In water at 0 - 25℃; for 4.5h; | 6.1 4.1.6.1. Synthesis of ethyl 2-amino-3-oxohexanoate hydrochloride. A solution of ethyl 3-oxo-hexanoate 23 (4.91 g, 5 mL, 31 mmol) in acetic acid (20 mL) was cooled to 0 °C, and a solution of sodium nitrite (5.35 g, 77.5 mmol) in water (17 mL) was added dropwise, with the temperature of the reaction mixture being kept below 5 °C. The stirring mixture was maintained at 0 °C for 2 h and at room temper-ature for 2.5 h. The reaction mixture was then diluted and extracted with diethyl ether (3 * 50 mL). The combined organic layers were washed with saturated NaHCO3 solution, dried with magnesium sulfate and concentrated under reduced pressure to give the α-hydroxyimino β-ketoester 24 quantitatively (5.16 g, 89%) as a clear oil. A dry 100 ml round-bottomed flask was charged with 10% Pd/C (1.54 g, 33%), α-hydroxyimino β-ketoester 24 (4.68 g, 25 mmol) and absolute ethanol 20 ml. The mixture was degased and refilled with hydrogen. 30-40% ethanolic HCl solution 10 ml was added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature under atmospheric pressure of hydrogen for 24 h. The suspension was then filtered through a Celite pad and washed with ethanol several times. The filtrate was concentrated under reduced pressure to give the desired β-ketoester hydrochloride (5.24 g, 100%). |
With acetic acid; sodium nitrite In water at 5 - 10℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 3h; | 2 5-Bromo-8-fluoro-1-propyl-1, 3,4, 9-tetrahydropyrano [3, [4-B]] [INDOLE-1-ACETIC] Acid Ethyl Ester BF3-etherate (0. [74ML,] 0.0059mM) was added to a solution of 4-bromo-7- [FLUOROTRYPTOPHOL (L. OG,] 0.0039mM) and ethyl butyrylacetate (0. [93ML,] 0.0059mM) in dry dichloromethane (15ml). This reaction was stirred for three hours at room temperature. Saturated [NAHC03] (aq) (15ml) was added to quench the reaction. The solution was washed with DCM (2X). The organic layers were combined, dried [(MGS04),] passed through a plug [OF SIO2,] and concentrated to afford 1.02g (66% yield) of the desired product as an off-white solid. NMR [(CHC13)] [6] 0.87 (t, 3H, 7.38Hz) ; 1.44 (m, 1H) ; 1.28 (t, 3H, 7.14Hz) ; 1.39 (m, 1H) ; 1.93 (m, 1H) ; 2.03 (m, [1H)] ; 2. [91M] (m, [1H)] ; 3.06 (m [1H)] ; 3.15 (m, 2H), 3.91 (m, [1H)] ; 4.03 (m, [1H),] 4.22 (m, 2H); 6.72 (m, 1H); 7.09 (m, 1H) ; 9.50 (s, 1H). |
66% | In dichloromethane at 20℃; for 3h; | |
With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; | |
93% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; | 1 5-Bromo-8-methyl-1-propyl-1, 3,4, [9-TETRAHYDROPYRANOL3, 4-B] INDOLE-1-ACETIC] Acid Ethyl Ester To a solution of 4-bromo-7-methyl tryptophol (1.12 g, 4.41 mmol) and ethyl butyrylacetate (0.71 mL, 4.41 mmol) in [CH2CI2] (20 mL) was added [BF3OET2] (0.56 mL, 4.41 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous [NAHC03] (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and filtered through a pad of silica gel. The filter cake was washed with additional [CH2CI2] and the combined organic layer was evaporated to provide 1.62 g (93%) of title compound as a white solid. 'H NMR (CDC13) : 300 MHz [5] 9.33 (bs, 1H), 7.11 (d, [J=] 7.65 Hz, 1H), 6.76 (d, [J=] 7.65 Hz, [1H),] 4.19 (m, 2H), 4.03 [(M,] 1 H), 3.90 [(M,] 1 H), 3.15 (m, 2H), 3.03 (d, [J =] 16.6 Hz, 1H), 2.89 (d, [J=] 16.6 Hz, [1H),] 2.43 (s, [3H),] 2.08 (m, [1H),] 1.96 (m, 1H), 1.38 (m, 1H), 1.27 (t, J= 7.14 Hz, 3H), 1.18 [(M,] 1H), 0.87 (t, J= 7.29 Hz, 3H). |
93% | In dichloromethane |
Stage #1: ethyl butyroyl acetate; 4-bromo-7-methyltryptophol With boron trifluoride diethyl etherate In toluene at 10 - 15℃; for 2h; Stage #2: With sodium hydrogencarbonate In water; toluene | III Crude tryptophol (0.107 kg) was dissolved in toluene (1.81 L). The solution was cooled to 10-15° C. and ethyl butyryl acetate (0.067 kg) was added followed by boron trifluoride diethyl etherate (0.060 kg). The mixture was stirred for a minimum of 2 h until less than 1% tryptophol remains by HPLC. The reaction was quenched with a solution of sodium bicarbonate (0.022 kg) in water (0.27 L) and filtered to remove insolubles. The filtrates were separated and the organic layer washed sequentially with 8% aqueous sodium bicarbonate (0.27 L), 10% brine (2×0.21 L), water (0.21 L) and 10% brine (0.21 L). The organic layer was then dried over sodium sulfate (0.15 kg). The solution was distilled to an oil (0.18 L) to give the pyranoindole which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; | 4 [5-BROMO-6-FLUORO-8-METHYL-1-PROPYL-1,] 3,4, [9-TETRAHYDROPYRANO [3, 4-B] INDOLE-1-] acetic Acid Ethyl Ester To a solution of 4-bromo-7-methyl tryptophol (400 mg g, 1.47 mmol) and ethyl butyrylacetate (0.28 mL, 1.76 mmol) in [CH2CI2] (5 mL) was added [BF3-0ET2] (0.22 mL, 1.76 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous [NAHC03] (5 mL) and brine [(5] mL). The organic phase was dried [(NA2SO4)] and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 496 mg (82%) of title compound as a pale yellow solid. Mp = 137-138 [°C ; LH] NMR (CDCl3) : [300 MHZ 8 9.] 73 (bs, [1H),] 6.76 (d, [J =] 10.1 Hz, 1H), 4.21 (m, 2H), 4.05 (m, 1H), 3.91 [(M,] 1H), 3.05-2. 89 [(M,] 4H), 2.53 (s, 3H), 2.07 (m, 1H), 1.92 (m, 1H), 1.38 (m, 1H), 1.30 [(T,] [L=] 6.98 Hz, 3H), 1.21 (m, [1H),] 0.89 (t, J= 7.08 Hz, 3H). |
82% | In dichloromethane at 20℃; for 2h; | |
With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride In water at 60℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrazine In tetrahydrofuran; ethanol at 0 - 60℃; for 24h; Inert atmosphere; | Intermediate 1 To a solution of ethyl 3-oxohexanoate (6.74 g, 42.64 mmol) in anhydrous ethanol (100 mL) was added dropwise a solution of hydrazine (42.6 mL, 42.64 mmol) in THF (1 N) at 0 °C. The reaction was allowed to be warmed up to room temperature and stirred for 20 hrs. The mixture was further heated at 60 °C for 4 hrs. Reaction mixture was concentrated on rotavapor to dryness to provide intermediate 1 as a pale yellow solid (5.37 g, 100%).1H NMR (400 MHz, DMSO-d6) δ (ppm): 5.21 (s, 1H), 4.06 (dd, J = 7.2, 1.2 Hz, 1H), 3.52 (d, J = 1.2 Hz, 1H), 2.47-2.38 (m, 2H), 1.58-1.40 (m, 2H), 1.18-1.14 (m, 2H), 0.88-0.82 (m, 3H). MS (ESI): Calcd for C6H11N2O: 127.1, found: 127.2 (M+H)+. |
91% | With hydrazine In ethanol at 0 - 70℃; for 2h; | Method A for preparing 12a-b. General procedure: A solution of β-ketoester (10 mmol) in ethanol (15 mL) was treated at 0 °C with the appropriate hydrazine (10 mmol). The mixture was then heated to 70 °C for 2 h. After the solution had cooled to room temperature, it was filtered and washed with ethanol to get the product as a creamy white solid. |
87% | With hydrazine for 0.00833333h; |
With hydrazine In ethanol Heating; | ||
With hydrazine hydrate In ethanol for 0.0833333h; Reflux; | ||
With hydrazine hydrate In ethanol at 20℃; for 0.0833333h; | General procedure for synthesisof pyrazol-chromeno[2,3-d]pyrimidine-ones (6a-g) General procedure: A solution of salicylaldehyde (1 mmol) and barbituric acid (1 mmol) in ethanol/water (1:4) (5 mL) was stirred at 70 °C. After 2 h, PTSA (0.1 mmol) and pyrazolones (1 mmol) were added and stirred for 10 h at 70 °C (pyrazolone derivatives made of hydrazine hydrate and alkyl acetoacetate in ethanol at room temperature in 5 min).After completion of the reaction, as indicated by TLC, the precipitate was washed with ethanol and the products were obtained as a white powder. | |
With hydrazine In ethanol at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cycl-isopropylidene malonate; acetic acid; for 12h;Radiochemical reaction; | A solution of 2, 2-difluoro-1, 3-benzodioxol-4-aldehyde (2.0 g), Meldrum's acid (1.6 g), ethyl 3-keto-hexanoate (1.7 g) and ammonium acetate (0.91 g) in acetic acid (20 mL) were stirred under reflux for 12 [HRS.] The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (2.4 g). To a solution of dimethylformamide (1.9 g) in chloroform (10 [ML)] were added phosphorus oxychloride (4.0 g) and a solution of the obtained colorless crystals (2.4 g) in chloroforom (10 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (27 g) solution was added, and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8: 2) ) to give colorless crystals. To a solution of the obtained colorless crystals in pyridine (20 mL) was added hydrazine (1.0 g), and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1) ) to give the title compound (190 mg) as colorless crystals. MS [(EI)] : 391 (M+). [H-NMR] [(400MHZ, DMSO-D6) B (PPM)] : 0. [90-0. 97] (6H, m), 1. [58-] 1.64 (2H, m), 2.60-2. 64 [(1H,] m), 2. [83-2. 86 (1H,] m), 3.83 (2H, q, J=7.3Hz), 5.32 [(1H,] m), 6.86 [(1H,] d, J=7.3Hz), 7.03-7. 11 (2H, m), 7.24 [(1H,] s), 9.61 [(1H,] brs), 12.06 [(1H,] brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In methanol; | Step A: 2-Ethylthio-4-hydroxy-6-propylpyrimidine To a cooled solution (0 C.) of potassium hydroxide (973 mg) in methanol (7 mL) was added <strong>[1071-37-0]2-ethyl-2-thiopseudourea hydrobromide</strong> (2.8 g). The temperature was raised to room temperature and stirred under nitrogen for 10 min. The KBr was filtered off and the reaction mixture was cooled to 0 C. To this was added ethyl butyrylacetate (612 mg), and the reaction was stirred at room temperature for 16 h. Removal of solvent followed by purification on silica gel column (10% acetone/hexane) gave 410 mg of the title compound as a white solid. Partial 1H NMR (500 MHz, CDCl3): delta 6.07 (s, 1H); 3.21 (q, J=7.3 Hz, 2H); 2.48 (t, J=7.6 Hz, 2H); 1.70 (m, J=7.4 Hz, 2H); 1.39 (t, J=7.3 Hz, 3H); 0.97 (t, J=7.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In ethyl acetate; | EXAMPLE 1 5,7-Dihydroxy-4-propylcoumarin5 (2) Concentrated sulfuric acid (200 mL) was added into a mixture of <strong>[6099-90-7]phloroglucinol dihydrate</strong> (150 g, 0.926 mol) and ethyl butyrylacetate (161 g, 1.02 mol). The resulting mixture was stirred at 90 C. for two hours whereupon it was poured onto ice. The solid product was collected by filtration, and then dissolved in ethyl acetate. The solution was washed with brine and dried over Na2 SO4. After removal of the solvent in vacuo, the residue was triturated with hexane to provide essentially pure compound 2 (203 g) in quantitative yield, mp 233-235 C. (Lit.5 236-238 C.). 1 H-NMR5 (DMSO-d6) delta 0.95 (3H,t,J=6.9 Hz, CH3); 1.63 (2H, apparent sextet, J=7.0 Hz, CH2); 2.89 (2H,t,J=7.5 Hz, CH2); 5.85 (1H, s, H3); 6.22 (1H, d, J=2.0 Hz, H6); 6.31 (1H, d, J=2.0 Hz, H8); 10.27 (1H, s, OH); 10.58 (1H, s, OH); MS (EI); 220(100, M+); 205 (37.9, M-CH3); 192 (65.8, M-C2 H4); 177 (24.8, M-C3 H7); 164 (60.9, M-CHCO2 +1); 163 (59.6 M-CHCO2); IR (KBr): 3210 (vs and broad, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1; Anal. calcd. for C12 H24 O4: C, 65.45; H, 5.49; Found: C, 65.61; H, 5.44. | |
With sulfuric acid; In ethyl acetate; | EXAMPLE 1 5,7-Dihydroxy-4-propylcoumarin5 (2) Concentrated sulfuric acid (200 mL) was added into a mixture of <strong>[6099-90-7]phloroglucinol dihydrate</strong> (150 g, 0.926 mol) and ethyl butyrylacetate (161 g, 1.02 mol). The resulting mixture was stirred at 90 C. for two hours whereupon it was poured onto ice. The solid product was collected by filtration, and then dissolved in ethyl acetate. The solution was washed with brine and dried over Na2 SO4. After removal of the solvent in vacuo, the residue was triturated with hexane to provide essentially pure compound 2 (203 g) in quantitative yield, mp 233-235 C. (Lit.5 236-238 C.). 1 H-NMR5 (DMSO-d6) delta0.95 (3H,t,J=6.9 Hz, CH3); 1.63 (2H, apparent sextet, J=7.0 Hz, CH2); 2.89 (2H,t,J=7.5Hz,CH2); 5.85 (1H, s, H3); 6.22 (1H, d, J=2.0 Hz, H6); 6.31 (1H, d, J=2.0 Hz, H8); 10.27 (1H, s, OH); 10.58 (1H, s, OH); MS (EI); 220(100, M+); 205 (37.9, M-CH3); 192 (65.8, M-C2 H4); 177 (24.8, M-C3 H7); 164 (60.9, M-CHCO2 +1); 163 (59.6 M-CHCO2); IR (KBr): 3210 (vs and broad, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1; Anal. calcd. for C12 H24 O4: C, 65.45; H, 5.49; Found: C, 65.61; H, 5.44. | |
With sulfuric acid; In ethyl acetate; | EXAMPLE 1 5,7-Dihydroxy-4-propylcoumarin5 (2) Concentrated sulfuric acid (200 mL) was added into a mixture of <strong>[6099-90-7]phloroglucinol dihydrate</strong> (150 g, 0.926 mol) and ethyl butyrylacetate (161 g, 1.02 mol). The resulting mixture was stirred at 90C for two hours whereupon it was poured onto ice. The solid product was collected by filtration, and then dissolved in ethyl acetate. The solution was washed with brine and dried over Na2 SO4. After removal of the solvent in vacuo, the residue was triturated with hexane to provide essentially pure compound 2 (203 g) in quantitative yield, mp 233-235 C. (Lit.5 236-238 C.). 1 H-NMR5 (DMSO-d6) delta 0.95 (3H,t,J=6.9 Hz, CH3); 1.63 (2H, apparent hextet, J=7.0 Hz, CH2); 2.89 (2H,t,J=7.5 Hz,CH2); 5.85 (1H, s, H3); 6.22 (1H, d, J=2.0 Hz, H6); 6.31 (1H, d, J=2.0 Hz, H8); 10.27 (1H, s, OH); 10.58 (1H, s, OH); MS (EI); 220(100, M+); 205 (37.9, M--CH3); 192 (65.8, M--C2 H4); 177 (24.8, M--C3 H7); 164 (60.9, M--CHCO2 +1); 163 (59.6 M--CHCO2); IR (KBr): 3210 (vs and broad, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1); Anal. calcd. for C12 H24 O4: C, 65.45; H, 5.49; Found: C, 65.61; H, 5.44. |
In ethyl acetate; | EXAMPLE 1 5,7-Dihydroxy-4-propylcoumarin55 (2) Concentrated sulfric acid (200 mL) was added into a mixture of <strong>[6099-90-7]phloroglucinol dihydrate</strong> (150 g, 0.926 mol) and ethyl butyrylacetate (161 g, 1.02 mol). The resulting mixture was stirred at 90 C. for two hours whereupon it was poured onto ice. The solid product was collected by filtration, and then dissolved in ethyl acetate. The solution was washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the residue was triturated with hexane to provide essentially pure compound 2 (203 g) in quantitative yield, mp 233-235 C. (Lit.55 236-238 C.). 1H-NMR55 (DMSO-6) delta0.95 (3H, t, J=6.9 Hz, CH3); 1.63 (2H, apparent sextet, J=7.0 Hz, CH2); 2.89 (2H, t, J=7.5Hz,CH2); 5.85 (1H, s, H3); 6.22 (1H, d, J=2.0 Hz, H6); 6.31 (1H, d, J=2.0 Hz, H8); 10.27 (1H, s, OH); 10.58 (1H, s, OH); MS (EI); 220(100, M+); 205 (37.9, M-CH3); 192 (65.8, M-C2H4); 177 (24.8, M-C3H7); 164 (60.9, M-CHCO2+1); 163 (59.6 M-CHCO2); IR (KBr): 3210 (vs and broad, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1; Anal. calcd. for C12H24O4: C, 65.45; H, 5.49;.Found: C, 65.61; H, 5.44. | |
With sulfuric acid; In ethyl acetate; | EXAMPLE 1 5,7-Dihydroxy4-propylcoumarin5 (2) Concentrated sulfuric acid (200 mL) was added into a mixture of <strong>[6099-90-7]phloroglucinol dihydrate</strong> (150 g, 0.926 mol) and ethyl butyrylacetate (161 g, 1.02 mol). The resulting mixture was stirred at 90 C. for two hours whereupon it was poured onto ice. The solid product was collected by filtration, and then dissolved in ethyl acetate. The solution was washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the residue was triturated with hexane to provide essentially pure compound 2 (203 g) in quantitative yield, mp 233-235 C. (Lit.5 236-238 C.). 1H-NMR5 (DMSO-d6) delta0.95 (3H, t, J=6.9 Hz, CH3); 1.63 (2H, apparent sextet, J=7.0 Hz, CH2); 2.89 (2H, t, J=7.5Hz, CH2); 5.85 (1H, s, H3); 6.22 (1H, d, J=2.0 Hz, H6); 6.31 (1H, d, J=2.0 Hz, H8); 10.27 (1H, s, OH); 10.58 (1H, s, OH); MS (EI); 220(100, M+); 205 (37.9, M-1055 CH3); 192 (65.8, M-C2H4); 177 (24.8, M-C3H7); 164 (60.9, M-CHCO2+1); 163 (59.6 M-CHCO2); IR (KBr): 3210 (vs and broad, OH); 1649 (vs, sh); 1617 (vs, sh); 1554 (s) cm-1; Anal. calcd. for C12H24O4: C, 65.45; H, 5.49; Found: C, 65.61; H, 5.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | With trimethyl orthoformate In methanol | 4 Ethyl 3-methoxy-2(E)-hexenoate EXAMPLE 4 Ethyl 3-methoxy-2(E)-hexenoate Preparation analogous to Example 1 by reacting ethyl 3-oxohexanoate with trimethyl orthoformate in methanol with sulphuric acid as catalyst. Yield: 95.8%. B.p.=87°-89° C. (20 mbar). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With ammonium acetate In ethanol for 48h; Heating / reflux; | 7.7.B To a solution of dimedone (0.70 g, 5.0 mmole) in hot ethanol (15 ml) was added 5-phenyl-2-thiophenecarboxaldehyde (0.940 g, 5.0 mmole), ethyl propylacetoacetate (0.80 ml, 5.0 mmole) and lastly ammonium acetate (0.770 g, 10.0 mmole). The mixture was held at reflux for 48 h. No precipitate was observed. The ethanol was removed in vacuo to provide a crude viscous material which was subjected to a 100 g SiO2 flash column using 40% ethyl acetate:hexanes as eluent. The desired product (1.54 g, 68%) was obtained as a yellow amorphous solid. Rf=0.37 in 1:1 ethyl acetate:hexanes. 1H NMR (400 MHz; CDCl3) δ 7.5 (bd, 2H, J=7.0 Hz); 7.32-7.25 (m, 2H); 7.19 (at, 1H, J=7.4 Hz); 7.04 (d, 1H, J=7.4 Hz); 6.8 (d, 1H, J=3.5 Hz); 6.38 (bs, 1H); 5.41 (s, 1H); 4.22-3.90 (m, 2H); 2.90-2.80 (m, 1H); 2.72-2.63 (m, 1H); 2.35 (d, 1H, J=16.8 Hz); 2.25 (d, 1H, J=16.8 Hz); 2.3-2.2 (m, 2H); 1.74-1.62 (m, 2H); 1.25 (at, 3H, J=7.0 Hz); 1.07 (s, 3H); 1.02 (s, 3H); 1.01 (at, 3H, J=7.0 Hz); 1.05-0.95 (m, 2H). LC MS shows MH+ at 450; 2M+H at 899 and 2M+Na at 921. |
Yield | Reaction Conditions | Operation in experiment |
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81% | With copper(l) iodide; caesium carbonate In 1,4-dioxane at 80℃; for 16h; Inert atmosphere; | |
78% | Stage #1: 2-bromo-5-chlorobenzamide; ethyl butyroyl acetate With caesium carbonate In 1,4-dioxane for 0.166667h; Inert atmosphere; Green chemistry; Stage #2: In 1,4-dioxane at 80℃; for 24h; Inert atmosphere; Green chemistry; | Synthesis of isoquinolin-1(2H)-ones (3a-m); general procedure General procedure: Dioxane (3 mL), 2-bromobenzamide (100 mg, 0.5 mmol), β-keto ester (0.75 mmol), Cs2CO3 (326 mg, 1 mmol) were added to a flask with a stirbar and the mixture was stirred for 10 min under argon atmosphere. Then, MCM-41-2N-CuI (111 mg, 0.05 mmol) was added and the mixture was stirred at 80 °C for 24 h under an argon atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The MCM-41-2N-CuI complex was washed with distilled water (2 × 5 mL), ethanol (2 × 5 mL), and Et2O (2 × 5 mL) and reused in the next run. The filtrate was concentrated under reduced pressure and the residue was purifiedby flash column chromatography on silica gel (petroleum ether/ethylacetate = 3 : 1 to 1 : 1) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hafnium tetrakis(trifluoromethanesulfonate) In neat (no solvent) at 80℃; | 3.2. General Synthetic Procedure and Characterization of DHPMs 1-14 and 20 General procedure: To a mixture of aldehyde (1.0 mmol), -ketoester/diketone (1.0 mmol), and urea/thiourea(1.2 mmol) was added Hf(OTf)4 (0.01 mmol). The reaction was stirred at 80 °C for 20-30 min.Then ethanol (2 mL) was added to the reaction to dissolve the solid residue completely. Upon cooling,the solid precipitate was filtered, washed, and dried to afford pure DHPM product. For compounds9, 10, 13, 14, and 20, the crude product was directly dissolved in CH2Cl2 and purified by flashcolumn chromatography. |
72 %Chromat. | With aluminium-planted mesoporous silica M41 with Si/Al = 33 In octane at 114.84℃; for 10h; Inert atmosphere; | |
88 %Chromat. | With aluminium-planted mesoporous silica In octane at 114.84℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(II) bis(trifluoromethanesulfonate) In ethanol at 100℃; for 1h; Microwave irradiation; Inert atmosphere; | Synthesis of dihydropyrimidinones General procedure: Aldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.5 mmol), Cu(OTf)2 (0.02 mmol), and EtOH (2 mL) were added to a microwave vial equipped with a magnetic stir bar. The reaction vessel was sealed and irradiated in a microwave reactor (CEM Discover system) at a temperature of 100 °C for 1 h at a maximum power of 200 W. The reaction mixture was cooled to room temperature overnight and the resulting precipitate was filtered and washed with H2O and hexane. The identity and purity of the products were confirmed by TLC, high-resolution mass spectrometry, IR and 1H and 13C NMR spectroscopy |
74% | With aluminium-planted mesoporous silica M41 with Si/Al = 33 In octane at 114.84℃; for 10h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With copper(II) bis(trifluoromethanesulfonate) In ethanol at 100℃; for 1h; Microwave irradiation; Inert atmosphere; | Synthesis of dihydropyrimidinones General procedure: Aldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.5 mmol), Cu(OTf)2 (0.02 mmol), and EtOH (2 mL) were added to a microwave vial equipped with a magnetic stir bar. The reaction vessel was sealed and irradiated in a microwave reactor (CEM Discover system) at a temperature of 100 °C for 1 h at a maximum power of 200 W. The reaction mixture was cooled to room temperature overnight and the resulting precipitate was filtered and washed with H2O and hexane. The identity and purity of the products were confirmed by TLC, high-resolution mass spectrometry, IR and 1H and 13C NMR spectroscopy |
81% | With hexaaquaaluminium(III) tetrafluoroborate In acetonitrile for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tert.-butylhydroperoxide; iodine In N,N-dimethyl-formamide at 80℃; for 6h; | Oxazoles 3; General Procedure General procedure: To a solution of benzylamine 1 (0.7 mmol) in DMF (3 mL) were successivelyadded I2 (0.6 mmol), 1,3-dicarbonyl compound 2 (0.5mmol), MCM-41-2N-Cu(OAc)2 (86 mg, 0.05 mmol), and TBHP (1mmol). After the reaction mixture had been stirred for 3 h at 80 °C,another portion of benzylamine 1 (0.3 mmol) was added to the reactionmixture and the mixture was stirred at 80 °C for another 3 h. Afterbeing cooled to r.t., the mixture was diluted with EtOAc (15 mL)and filtered. The MCM-41-2N-Cu(OAc)2 complex was washed withacetone (2 × 5 mL), followed by drying at 60 °C under vacuum for 2 h,and reused in the next run. The filtrate was washed with water (2 ×10 mL) and dried over MgSO4. Then the organic phase was concentratedin vacuum and the residue was purified by column chromatography(silica gel, light PE/EtOAc = 2:1 to 10:1) to afford the desiredproduct 3. |
63% | With tert.-butylhydroperoxide; iodine; copper(II) acetate monohydrate In N,N-dimethyl-formamide at 20℃; | |
56% | With tert-butyl hydroxyperoxide; tetra-(n-butyl)ammonium iodide In water; ethyl acetate at 40℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tert.-butylhydroperoxide; iodine In N,N-dimethyl-formamide at 80℃; for 6h; | Oxazoles 3; General Procedure General procedure: To a solution of benzylamine 1 (0.7 mmol) in DMF (3 mL) were successivelyadded I2 (0.6 mmol), 1,3-dicarbonyl compound 2 (0.5mmol), MCM-41-2N-Cu(OAc)2 (86 mg, 0.05 mmol), and TBHP (1mmol). After the reaction mixture had been stirred for 3 h at 80 °C,another portion of benzylamine 1 (0.3 mmol) was added to the reactionmixture and the mixture was stirred at 80 °C for another 3 h. Afterbeing cooled to r.t., the mixture was diluted with EtOAc (15 mL)and filtered. The MCM-41-2N-Cu(OAc)2 complex was washed withacetone (2 × 5 mL), followed by drying at 60 °C under vacuum for 2 h,and reused in the next run. The filtrate was washed with water (2 ×10 mL) and dried over MgSO4. Then the organic phase was concentratedin vacuum and the residue was purified by column chromatography(silica gel, light PE/EtOAc = 2:1 to 10:1) to afford the desiredproduct 3. |
81% | With tert.-butylhydroperoxide; iodine; copper(II) acetate monohydrate In N,N-dimethyl-formamide at 20℃; | |
78% | With [Cu(1,10-phenanthroline)2Cl]Cl; iodine; oxygen In acetonitrile at 60℃; for 24h; Molecular sieve; | Typical procedure General procedure: Iodine (1.2 mmol), 1,3-dicarbonyl compounds (1 mmol), [Cu(o-phen)2Cl]Cl (0.2 mmol), 4 Å M.S.(0.1 g) were successively added to a solution of benzylamine (1.5 mmol) derivatives in CH3CN (5 mL). The resulting solution was stirred at 60 °C for 24 h (the progress of the reaction was monitored by TLC). Then H2O (5 mL) and EtOAc (15 mL) were added. The aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine, dried (anhyd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give ethyl 5-methyl-2-phenyloxazole-4-carboxylate (1ab); yield 182 mg (79%). |
75% | With tert-butyl hydroxyperoxide; tetra-(n-butyl)ammonium iodide In water; ethyl acetate at 40℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With copper(II) bis(trifluoromethanesulfonate) In ethanol at 100℃; for 1h; Microwave irradiation; Inert atmosphere; | Synthesis of dihydropyrimidinones General procedure: Aldehyde (1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.5 mmol), Cu(OTf)2 (0.02 mmol), and EtOH (2 mL) were added to a microwave vial equipped with a magnetic stir bar. The reaction vessel was sealed and irradiated in a microwave reactor (CEM Discover system) at a temperature of 100 °C for 1 h at a maximum power of 200 W. The reaction mixture was cooled to room temperature overnight and the resulting precipitate was filtered and washed with H2O and hexane. The identity and purity of the products were confirmed by TLC, high-resolution mass spectrometry, IR and 1H and 13C NMR spectroscopy |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example B20Preparation of Compound 102; Sulfuryl chloride (0.0055 mol) was added dropwise to a solution of 3-oxo-hexanoic acid, ethyl ester (0.0055 mol) in CH2Cl2 (q.s.). The reaction mixture was stirred for 2 hours at room temperature. The solvent was evaporated. A solution of (4-methoxyphenyl)-thiourea (0.0055 mol) in EtOH (100 ml) was added to the residue. The resultant reaction mixture was stirred and refluxed for 4 hours. A saturated aqueous NaHCO3 solution was added. This mixture was extracted with EtOAc. The separated organic layer was purified by column chromatography over silica gel. The product fractions were collected and the solvent was evaporated, yielding compound 102. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tert.-butylhydroperoxide; copper nanoparticles on black carbon In water; N,N-dimethyl-formamide at 80℃; for 5h; Inert atmosphere; | General procedure for the synthesis of compounds (1a-p) General procedure: TBHP (70 wt % in H2O) was added dropwise to a mixture of the 1,3-dicarbonyl compound (1 mmol), Cu/C (10 mg, 1.84 mol %) and N,N-dialkyl formamide (2 mL) under an argon atmosphere. The reaction temperature was increased to 80 °C and stirred for 5 h. The progress of the reaction was monitored by thin-layer chromatography. After cooling to room temperature, the mixture was extracted with EtOAc (3 × 10 mL) and dried over anhydrous Na2SO4. Removal of the solvent under vacuum afforded the crude product, which was purified by column chromatography. |
68% | With tert.-butylhydroperoxide In water at 80℃; for 4h; Inert atmosphere; stereoselective reaction; | General procedure: General procedure: TBHP (70 wt % in H2O) was added dropwise to a mixture ofthe 1,3-dicarbonyl compound (1 mmol), catalyst (20 mg, 3.7 mol %) and N,Ndialkylformamide(2 mL). The reaction temperature was increased to 80 C andthe mixture was stirred for 4 h. After cooling to rt, the mixture was extractedwith EtOAc (3 10 mL) and dried over anhydrous Na2SO4. Removal of thesolvent under vacuum afforded the crude product, which was purified bycolumn chromatography to afford the desired product. For the oxidativeesterification reactions, a slightly modified procedure was employed, whichutilized DMSO as the solvent and the reaction time was increased to 10 h,giving rise to the formation of products (2a-f). |
With tert.-butylhydroperoxide; copper(II) oxide In water at 20℃; for 4h; Sonication; | 2.3. General Procedure for the Synthesis of Enol Carbamatesunder Ultrasonic Conditions General procedure: TBHP (70 wt % in H2O) was added dropwise to a mixtureof the 1,3-dicarbonyl compound (1 mmol), CuO NPs(10 mol%) and N,N-dialkylformamide (2 mL). The mixturewas continuously irradiated for 4 h with a sonic horn at 18kHz. The mixture was extracted with EtOAc (3 × 10 mL)and dried over anhydrous Na2SO4. Removal of the solventunder vacuum afforded the crude product, which was purified purifiedby column chromatography to afford the desired product.All the synthesized products, besides product 3d, wereknown and characterized by recording their IR and 1H NMRspectra. New compound 3d was fully characterized by takingits 1H NMR and 13C-NMR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tert.-butylhydroperoxide; copper nanoparticles on black carbon; In water; N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere; | General procedure: TBHP (70 wt % in H2O) was added dropwise to a mixture of the 1,3-dicarbonyl compound (1 mmol), Cu/C (10 mg, 1.84 mol %) and N,N-dialkyl formamide (2 mL) under an argon atmosphere. The reaction temperature was increased to 80 C and stirred for 5 h. The progress of the reaction was monitored by thin-layer chromatography. After cooling to room temperature, the mixture was extracted with EtOAc (3 × 10 mL) and dried over anhydrous Na2SO4. Removal of the solvent under vacuum afforded the crude product, which was purified by column chromatography. |
65% | With tert.-butylhydroperoxide; In water; at 80℃; for 4h;Inert atmosphere; | General procedure: TBHP (70 wt % in H2O) was added dropwise to a mixture ofthe 1,3-dicarbonyl compound (1 mmol), catalyst (20 mg, 3.7 mol %) and N,Ndialkylformamide(2 mL). The reaction temperature was increased to 80 C andthe mixture was stirred for 4 h. After cooling to rt, the mixture was extractedwith EtOAc (3 10 mL) and dried over anhydrous Na2SO4. Removal of thesolvent under vacuum afforded the crude product, which was purified bycolumn chromatography to afford the desired product. For the oxidativeesterification reactions, a slightly modified procedure was employed, whichutilized DMSO as the solvent and the reaction time was increased to 10 h,giving rise to the formation of products (2a-f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With cobalt sulfide In ethanol for 0.166667h; Sonication; Green chemistry; | General procedure for the synthesisof spirooxindoles General procedure: A mixture of isatin derivatives (1 mmol), phenylhydrazineor hydrazine hydrate (1 mmol), alkyl acetoacetate(1 mmol), naphthalene amine or 2-naphthol (1 mmol), and10 mg nano-Co3S4 was sonicated at 40 W power for theappropriate times. The reaction was monitored by TLC (nhexane/ethyl acetate 8:2). After cooling, the reactionmixture was dissolved in acetone and the mixture stirredfor 2 min. The suspended solution was filtered and theheterogeneous catalyst was recovered. The acetone wasevaporated and the solid that separated out was filtered andwashed with ethanol to get pure product. |
82% | With magnetic nanoparticles Fe3O4-immobilized guanidine In ethanol for 0.55h; Reflux; | General procedure for the preparation of spirooxindoles General procedure: A mixture of isatin derivatives (1 mmol), phenylhydrazine or hydrazine hydrate (1 mmol), alkyl acetoacetate (1 mmol) and naphthalene amine or 2-naphthol (1 mmol) and MNPs-guanidine (20 mg) were heated in EtOH (10 mL) under reflux conditions. The completion of the mixture was monitored by TLC, and the catalyst was separated from reaction before work up by an external magnet field. Then, the mixture was poured into cold water, and the precipitate obtained was filtered and recrystallized twice by (EtOAc/n-hexane 3:1). Afterward, the products were characterized by 1H NMR, FT-IR and 13C NMR spectroscopy. |
81% | With toluene-4-sulfonic acid In neat (no solvent) at 80℃; for 2h; Sealed tube; | 4.2 Typical procedure for preparation of spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-dihydro-3-methyl-1-phenyl-2'-one (4a) General procedure: A mixture of isatin derivatives (1 mmol), phenylhydrazine (0.11 g, 1 mmol), alkyl acetoacetate (0.130 g, 1 mmol) and naphthalen amine (0.144 g, 1 mmol) was added to a vial containing a magnetic stirring bar. The reaction mixture was sealed and stirred at 80 °C until disappearance of the starting materials (monitored by TLC on silica gel using a 1:1 mixture of ethyl acetate/n-hexane). After completion of the reaction, the solid residue was washed with water (10 mL) and ethanol (95%, 10 mL) to obtain the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With cobalt sulfide In ethanol for 0.25h; Sonication; Green chemistry; | General procedure for the synthesisof spirooxindoles General procedure: A mixture of isatin derivatives (1 mmol), phenylhydrazineor hydrazine hydrate (1 mmol), alkyl acetoacetate(1 mmol), naphthalene amine or 2-naphthol (1 mmol), and10 mg nano-Co3S4 was sonicated at 40 W power for theappropriate times. The reaction was monitored by TLC (nhexane/ethyl acetate 8:2). After cooling, the reactionmixture was dissolved in acetone and the mixture stirredfor 2 min. The suspended solution was filtered and theheterogeneous catalyst was recovered. The acetone wasevaporated and the solid that separated out was filtered andwashed with ethanol to get pure product. |
79% | With magnetic nanoparticles Fe3O4-immobilized guanidine In ethanol for 0.583333h; Reflux; | General procedure for the preparation of spirooxindoles General procedure: A mixture of isatin derivatives (1 mmol), phenylhydrazine or hydrazine hydrate (1 mmol), alkyl acetoacetate (1 mmol) and naphthalene amine or 2-naphthol (1 mmol) and MNPs-guanidine (20 mg) were heated in EtOH (10 mL) under reflux conditions. The completion of the mixture was monitored by TLC, and the catalyst was separated from reaction before work up by an external magnet field. Then, the mixture was poured into cold water, and the precipitate obtained was filtered and recrystallized twice by (EtOAc/n-hexane 3:1). Afterward, the products were characterized by 1H NMR, FT-IR and 13C NMR spectroscopy. |
75% | With toluene-4-sulfonic acid In neat (no solvent) at 80℃; for 2.33333h; Sealed tube; | 4.2 Typical procedure for preparation of spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-dihydro-3-methyl-1-phenyl-2'-one (4a) General procedure: A mixture of isatin derivatives (1 mmol), phenylhydrazine (0.11 g, 1 mmol), alkyl acetoacetate (0.130 g, 1 mmol) and naphthalen amine (0.144 g, 1 mmol) was added to a vial containing a magnetic stirring bar. The reaction mixture was sealed and stirred at 80 °C until disappearance of the starting materials (monitored by TLC on silica gel using a 1:1 mixture of ethyl acetate/n-hexane). After completion of the reaction, the solid residue was washed with water (10 mL) and ethanol (95%, 10 mL) to obtain the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 3.5h; Sonication; regioselective reaction; | 2 2.2 General procedure for the synthesis of 1,n-bis((6-alkyl or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives (1a-l) General procedure: Benzamidine hydrochloride (1, 31.7mg, 0.203mmol), β-ketoester derivatives (2, 0.184mmol) and powdered K2CO3 (63.7mg, 0.461mmol), were dissolved in DMF (1.5mL), followed by dihaloalkane (3, 0.23mmol) in a 25mL conical flask. Then the mixture was irradiated in the water bath of an ultrasonic cleaner at r. t. for the duration as shown in Table 2; and reaction progress was monitored by TLC. Upon end of the reaction, the reaction mixture was diluted with EtOAc (10mL), and washed with sat. aq NaHCO3 (10mL) and brine (10mL). The combined aqueous phases were back-extracted with EtOAc (5mL), and the combined organic phases were dried out over Na2SO4, filtered, and concentrated in vacuum to afford the title compound as near colorless oil that maybe slowly solidified upon standing. The products were established by their 1H NMR, 13C NMR, FT-IR and elemental analysis data. |
79% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.416667h; Sonication; regioselective reaction; | 2.2 General procedure for the synthesis of 1,n-bis((6-alkyl or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives (1a-l) General procedure: Benzamidine hydrochloride (1, 31.7mg, 0.203mmol), β-ketoester derivatives (2, 0.184mmol) and powdered K2CO3 (63.7mg, 0.461mmol), were dissolved in DMF (1.5mL), followed by dihaloalkane (3, 0.23mmol) in a 25mL conical flask. Then the mixture was irradiated in the water bath of an ultrasonic cleaner at r. t. for the duration as shown in Table 2; and reaction progress was monitored by TLC. Upon end of the reaction, the reaction mixture was diluted with EtOAc (10mL), and washed with sat. aq NaHCO3 (10mL) and brine (10mL). The combined aqueous phases were back-extracted with EtOAc (5mL), and the combined organic phases were dried out over Na2SO4, filtered, and concentrated in vacuum to afford the title compound as near colorless oil that maybe slowly solidified upon standing. The products were established by their 1H NMR, 13C NMR, FT-IR and elemental analysis data. |
76% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.5h; Sonication; regioselective reaction; | 2.2 General procedure for the synthesis of 1,n-bis((6-alkyl or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives (1a-l) General procedure: Benzamidine hydrochloride (1, 31.7mg, 0.203mmol), β-ketoester derivatives (2, 0.184mmol) and powdered K2CO3 (63.7mg, 0.461mmol), were dissolved in DMF (1.5mL), followed by dihaloalkane (3, 0.23mmol) in a 25mL conical flask. Then the mixture was irradiated in the water bath of an ultrasonic cleaner at r. t. for the duration as shown in Table 2; and reaction progress was monitored by TLC. Upon end of the reaction, the reaction mixture was diluted with EtOAc (10mL), and washed with sat. aq NaHCO3 (10mL) and brine (10mL). The combined aqueous phases were back-extracted with EtOAc (5mL), and the combined organic phases were dried out over Na2SO4, filtered, and concentrated in vacuum to afford the title compound as near colorless oil that maybe slowly solidified upon standing. The products were established by their 1H NMR, 13C NMR, FT-IR and elemental analysis data. |
81% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tert.-butylhydroperoxide at 70℃; for 0.5h; | 2.6. General procedure for the synthesized of enol carbamates General procedure: b-ketoester derivative (2 mmol), formamide (54 mmol), TBHP(12 mmol) and composite (0.02 mol% of Cu) were mixed in a roundbottomflask (10 mL). The resulting mixture stirred at 70 C,exposed a Xe lamp, and the reaction monitored by thin layerchromatography (TLC). After the compilation of reaction, thereaction mixture was cooled to room temperature; the organicphase was dried over anhydrous Na2SO4 andfiltered. The crudereaction was concentrated under vacuum. The residue was purifiedby silica-gel thin layer chromatography using n-hexane/ethylacetate (10:1) as eluent to afford the pure product. |
86% | With tert.-butylhydroperoxide; nickel(II) chloride hexahydrate In water at 40℃; for 5h; | |
85% | With tert.-butylhydroperoxide at 80℃; for 2h; |
85% | With tert.-butylhydroperoxide at 80℃; for 2h; | |
62% | With tert.-butylhydroperoxide at 80℃; for 0.333333h; Green chemistry; | Enol Carbamates 2a-g General procedure: A 70% aq solution of TBHP (0.193 g, 1.5 equiv) was added dropwise to a mixture of the appropriate 1,3-dicarbonyl compound1 (1 mmol), the magnetic catalyst (10 mg), and DMF (2 mL). The mixture was heated to 80 °C, stirred for 20 min, and then cooled to r.t. The catalyst was removed by using an external magnet,and the residue was extracted with EtOAc (3 × 10 mL), dried(MgSO4), filtered, and concentrated under vacuum. The crude product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.883333h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.933333h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time.Ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) Yield 93%; brown sticky liquid; 1H NMR (400 MHz, CDCl3): δ 0.84 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H), 1.49-1.58 (m, 2H), 2.78 (t, J = 7.7 Hz, 2H), 3.88 (s, 3H), 3.94 (s, 3H), 4.19 (q, J = 7.3 Hz, 2H), 6.62 (s, 1H), 6.81 (s, 1H), 6.88 (dd, J = 2.2, J = 6.2, 1H), 6.93 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.87 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ; 14.24, 23.79, 28.02, 56.23, 59.60, 110.53, 110.64, 111.05, 119.17, 120.31, 121.59, 125.25, 130.72, 131.03, 132.00, 134.79, 142.16, 149.20, 149.29, 165.51; HRMS (ESI, m/z): calcd for C24H26BrNO4 (M+H+) 471.1045, found: 471.1047. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.916667h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.883333h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 1h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.866667h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.85h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.866667h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 1.01667h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.95h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 1.06667h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.933333h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.983333h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.966667h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 0.95h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene In neat (no solvent) at 80℃; for 1.05h; Microwave irradiation; Green chemistry; | Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 °C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene; In neat (no solvent); at 80℃; under 760.051 Torr; for 0.9h;Microwave irradiation; Green chemistry; | General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene; In neat (no solvent); at 80℃; under 760.051 Torr; for 1.1h;Microwave irradiation; Green chemistry; | General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With p-toluenesulfonic acid doped polystyrene; In neat (no solvent); at 80℃; under 760.051 Torr; for 1.03333h;Microwave irradiation; Green chemistry; | General procedure: Synthesis of ethyl 4-(4-bromophenyl)-1-(3,4-dimethoxyphenyl)-2-propyl-1H-pyrrole-3-carboxylate (5a) A mixture of ethyl 3-oxohexanoate (1, 1 mmol), 3,4-dimethoxybenzenamine (2a, 1 mmol), 4-bromobenzaldehyde (3, 1 mmol), nitromethane (4, 1 ml), and 5 mg of PS-PTSA was taken in an open vessel in CATA-4R-Scientific Microwave oven and irradiated at 80 C (140 W) at an ambient pressure for 56 min. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated and the crude product was purified by flash column chromatography on silica gel (200-300 mesh) with ethyl acetate and hexane as eluent to afford the product 5a. The PS-PTSA catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and filtration followed by drying in a vacuum oven every time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With boron trifluoride diethyl etherate In neat (no solvent) at 145℃; for 0.133333h; Microwave irradiation; Sealed tube; Green chemistry; chemoselective reaction; | Synthesis using BF3*Et2O (1-19): General procedure: A β-ketoester (2 mmol), taken in a reactor vessel with BF3*Et2O (339 mg, 2.4 mmol) was mixed thoroughly for 1 min with urea derivatives (2.6 mmol). The vessel was closed immediately and was subjected to microwave irradiation at 145 °C. The compound (1-18) was further purified by column chromatography. The time of irradiation and observed yield of the compounds are listed in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrazine In dimethyl sulfoxide at 110℃; for 0.0833333h; Microwave irradiation; | 4-[(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(5-hydroxy-3-methyl-1-phenyl-1Hpyrazol-4-yl)methyl]-3-methyl-1-phenyl-1H-pyrazol-5-ol (3a). Typical Procedure. General procedure: To a mixture of phenylhydrazine (0.197 mL, 2 mmol) and ethyl acetoacetate (0.255 mL,2 mmol) was added 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (2a, 0.220 g,1 mmol) in a5 mLmicrowave vessel. The resulting mixture was irradiated in a microwaveoven at 400 W power. The microwave was programmed to give a maximum internal temperatureof 110C. The reaction mixture was irradiated for 5 min. After the completion ofthe reaction, the mixture was cooled to room temperature, 3 mL of water was added, andthe resulting solid was collected and recrystallized from hot ethanol to afford 0.534 gr(97%) of 4-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-3-methyl-1-phenyl-1H-pyrazol-5-ol (3a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iron(III) chloride adsorbed on silica gel; In ethanol; for 2h;Reflux; | General procedure: To a solution of aromatic diamine (1.0 mmol), beta-ketoester/amide (1 mmol) in ethanol (5 mL) SiO2-FeCl3 (40 mg) was added followed by reflux for appropriate time indicated in Table 1 and Table 2. After completion of reaction (TLC), the catalyst was filtered through Whatmann 42 filter paper; residue was washed several times with dichloromethane. The combined filtrate was evaporated to dryness to obtain crude product which was re-crystalized or passing through short pad silica-gel column to get analytically pure product. Residue can be re-used after washing with ethyl acetate or methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: Activated Al2O3 (10 g) was stirred with a solution of 0.56 g (5 mmol) of t-BuOK in 10 mL of tert-butyl alcohol under argon for 20 min. The solvent was removed in a vacuum. To the dry residue was added 0.65 g (5 mmol) of ethyl acetoacetate 1b, the mixture was stirred for 1 h under an argon atmosphere. Then, 0.55 g (5 mmol) of <strong>[10061-02-6](E)-1,3-dichloropropene</strong> 2 was added to the mixture, and the mixture was stirred until the reaction completed (8-10 h, GLC monitoring). The solid was washed with ethyl acetate (150 mL) on as hort column, and the solvent was removed in avacuum. The crude product was purified by column chromatography (SiO2, hexane-ethyl acetate, 9 :1?8 : 2). Yield 0.81 g (79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sulfuric acid at 20℃; for 1h; | 4.1.2.1 General procedure General procedure: To a solution of 1 or 2 (10.0mmol) in the appropriate acetoacetic ester (10.0mmol), 32 H2SO4 (7mL) was added dropwise and the mixture was stirred at room temperature for 1h. The solution was poured into an ice/water mixture (100g) and the obtained precipitate was filtered and washed with water to give the corresponding alkyl-7-hydroxycoumarin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: ethyl butyroyl acetate With 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione In water at 70℃; for 0.333333h; Stage #2: N-benzylthiourea With 1,4-diaza-bicyclo[2.2.2]octane In water; acetonitrile at 70℃; for 0.333333h; | General procedure: To a solution of the appropriate β-keto ester (1 mmol) in H2O (5 mL)held at 70 °C was added TBCA (146 mg, 0.4 mmol) in small portions and the mixture was stirred at 70 °C for 20 min. Then, MeCN (5 mL),the respective thiourea (1 mmol), and DABCO (1 mmol) were successively added and the mixture was stirred at 70 °C for an additional 20min. After the completion of the reaction, the mixture was poured onto ice and the precipitated solid was collected by filtration to afford the corresponding pure 2-aminothiazole 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine In ethanol at 90℃; for 0.166667h; | 4.2. General Procedure for the Synthesis of Products 4 Are Represented as Follows General procedure: Typically, 2-hydroxy-1-naphthaldehyde (5 mmol), ethyl 3-oxopentanoate or ethyl 3-oxohexanoateor ethyl acetoacetate (5 mmol) and piperidine (0.5 mmol) were introduced in a 20 mL vial with ethanol(10 mL) as solution. Subsequently, the reaction vial was closed and then prestirred for 10 s. The mixture was irradiated at 90 °C for 10 min. After the completion, the reaction mixture was then cooled to room temperature and concentrated in vacuo to remove the solvent. The residue was then washed with water, filtered, dried, and the precipitate was purified by recrystallization from 95% EtOH to give the products of 4. The analytical data for represent compounds are shown below. 1H-NMR and 13C-NMR spectra of compounds 4 in Supplementary Materials.4.2.1. 2-Butyryl-3H-benzo[f]chromen-3-one (4a)Yellow solid; yield 89%; m.p.: 127-129 °C; IR (KBr): 1734, 1626, 1557, 1513, 1383, 1109, 864 cm1;1H-NMR (CDCl3, 400 MHz)δ (ppm): 9.21 (s, 1H, ArH), 8.91 (s, 1H, ArH), 8.06 (d, J = 8.8 Hz, 1H, ArH),7.83 (d, J = 8.8 Hz, 1H, ArH), 7.57-7.56 (m, 1H, ArH), 7.20 (d, J = 9.2 Hz, 1H, ArH), 7.12 (dd, J1 = 8.8 Hz,J2 = 2.0 Hz, 1H, ArH), 3.00 (t, J = 7.2 Hz, 2H, CH2), 1.63-1.58 (m, 2H, CH2), 0.93 (t, J = 7.2 Hz, 3H, CH3);13C-NMR (100 MHz, DMSO-d6) δ(ppm): 197.5, 159.1, 158.9, 156.4, 142.8, 136.6, 132.1, 131.5, 124.6, 121.9,118.6, 113.0, 111.4, 104.8, 43.9, 17.3, 14.1; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With piperidine In ethanol at 90℃; for 0.166667h; | 4.2. General Procedure for the Synthesis of Products 4 Are Represented as Follows General procedure: Typically, 2-hydroxy-1-naphthaldehyde (5 mmol), ethyl 3-oxopentanoate or ethyl 3-oxohexanoateor ethyl acetoacetate (5 mmol) and piperidine (0.5 mmol) were introduced in a 20 mL vial with ethanol(10 mL) as solution. Subsequently, the reaction vial was closed and then prestirred for 10 s. The mixture was irradiated at 90 °C for 10 min. After the completion, the reaction mixture was then cooled to room temperature and concentrated in vacuo to remove the solvent. The residue was then washed with water, filtered, dried, and the precipitate was purified by recrystallization from 95% EtOH to give the products of 4. The analytical data for represent compounds are shown below. 1H-NMR and 13C-NMR spectra of compounds 4 in Supplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With α-chymotrypsin In ethanol at 60℃; for 40h; Enzymatic reaction; | Path B: General procedure: A 10-mL stoppered bottle was filled with the required 2-aminobenzamide (0.2 mmol), dicarbonyl compound (0.6 mmol), α-chymotrypsin (2400U), 2 mL EtOH and oscillate in a constant temperature shaker at 60 °C for 40 h. |
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H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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