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CAS No. : | 10538-51-9 | MDL No. : | MFCD00004378 |
Formula : | C11H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JPQWWJZORKTMIZ-ZZXKWVIFSA-N |
M.W : | 208.21 | Pubchem ID : | 697594 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.18 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 56.1 |
TPSA : | 55.76 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) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 2.06 |
Log Po/w (XLOGP3) : | 1.78 |
Log Po/w (WLOGP) : | 1.69 |
Log Po/w (MLOGP) : | 1.3 |
Log Po/w (SILICOS-IT) : | 1.79 |
Consensus Log Po/w : | 1.72 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -2.28 |
Solubility : | 1.08 mg/ml ; 0.0052 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.57 |
Solubility : | 0.561 mg/ml ; 0.0027 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.12 |
Solubility : | 1.57 mg/ml ; 0.00753 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.2 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
99% | With palladium 10% on activated carbon; hydrogen In ethyl acetate at 23℃; for 48h; | 2,5-dimethoxyhydrocinnamic acid (13) To solution of 2,5-dimethoxycinnamic acid (50.0 g, 240.1 mmol, 1.0 eq) in dry EtOAc (500 ml, 0.48 M) was added 10% Pd/C (5.0 g, 10%wt) and treated with H2 condition at room temperature for 48 hours. The reaction mixture was filtered through a plug of celite with suction and the volatile components were removed under reduced pressure to leave pale-ivory-colored solid material 13 (50.1 g, 99%) without purification. Rf : 0.54 (EtOAc : Hexane = 1 : 1) 1H NMR (CDCl3, 400 MHz) : d 6.78-6.72 (m, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 2.93-2.90 (t, J = 7.8 Hz, 2H), 2.68-2.64 (t, J = 7.8 Hz, 2H) 13C NMR (CDCl3, 100 MHz) : d 179.8, 153.4, 151.8, 129.7, 116.4, 111.7, 111.2, 55.8, 55.7, 34.1, 26.1 IR (neat, cm-1) : 2940, 2835, 1693, 1501, 1451, 1430, 1408, 1305, 1279, 1217, 1182, 1156, 1126, 1050, 1025, 936, 914, 864, 795, 731, 716, 682 LR/MS(m/z) [M+Na+] : 233.1 |
98% | With palladium 10% on activated carbon; hydrogen In ethyl acetate | |
95% | With hydrogen |
95% | With borane-ammonia complex In methanol; water at 20℃; for 90h; chemoselective reaction; | 4.5. General procedure for chemoselectivity reduction of , -unsaturated carbonyl compounds with Cu 50 Pd 50 /mpg-C 3 N 4 General procedure: The compounds 2, 4, 6, 8, 17, 19 and 22 are known. These compounds were synthesized according to literature [ 56 , 64 ]. Cu 50 Pd 50 /mpg-C 3 N 4 catalyst (5 mg) was suspended in water (3 mL) and MeOH (7 mL) mixture and it was sonicated for 5 min in a glass pressure tube. Then, convenient , -unsaturated car- bonyl compounds, and their derivatives (1 equiv.) and NH 3 BH 3 (1 equiv.) were added to the reaction mixture, respectively. The re- action mixture was stirred for 0.5 h at room temperature and the reaction was stopped. The catalyst was removed by filtration and then the solvent was removed under vacuum. The crude product was extracted with CH 2 CI 2 (2 ×15 mL). The combined extracts were dried over Na 2 SO 4 and the solvent was removed under vac- uum. Purification was performed through thin-layer chromatogra- phy (TLC) using EtOAc/hexane eluent on silica gel. Full experimen- tal detail, copies of 1 H, HRMS and 13 C NMR spectrum of all the compounds have been provided in the Supplementary file. |
With potassium hydroxide bei der elektrolytischen Reduktion; | ||
With palladium 10% on activated carbon; hydrogen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With boron trifluoride diethyl etherate; trichlorophosphate at 25 - 28℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With boron trifluoride diethyl etherate; trichlorophosphate at 25 - 28℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With boron tribromide In 1,1-dichloroethane at 82℃; for 12h; Heating / reflux; | 46 Equip a 5-L, three-neck, round-bottom flask with a large blade mechanical stirrer, thermocouple, an addition funnel, Claisen adapter, reflux condenser, and a sodium hydroxide scrubber. Charge the flask with 2,5-dimethoxycinnamic acid (182.3 g, 865 mmol, 1.0 equiv) and dichloroethane (2.5 L). Add boron tribromide (163. 5 ML, 433.2 g, 1.73 mol, 2.0 equiv. ) dropwise over 1 h, keeping the temperature below 35 oC. Gas evolution can be monitored as the temperature of the reaction is gradually increased to reflux (82 oC). Reflux for 12 h, cool to 5 oC, and quench by the careful addition of water (1.0 L). Filter the resulting yellow-red suspension/emulsion through a glass frit and wash with dichloroethane (1.0 L) and heptane (1.0 L) to afford a brown solid. Dry the wet material in a vacuum oven (30 in. , 35 oC) for 18 h, to afford the coumarin (180.3 g, 127% theory) as a brown solid : H NMR (300 MHz, DMSO-d6) 8 7.97 (d, J = 9.6 Hz, 1H), 7. 22 (d, J = 9.9 Hz, 1H), 7.05 (m, 2H), 6.43 (d, J = 9.6 Hz, 1H). Equip a 5-L, three-neck, round-bottom flask with a mechanical stirrer, thermocouple, an addition funnel, and an inlet adapter. Charge the flask with the coumarin prepared above (360.0 g, 2.20 mol, 1.0 equiv) and N, N-dimethylformamide (2.2 L). While keeping the temperature below 30 oC, add cesium carbonate [904.2 g, 2. 78 mol, 1. 25 equiv]. Then add benzyl bromide [475.5 g, 330.2 mL, 2.78 mol, 1.25 equiv] over a period of 1 h, keeping the temperature below 35 oC during the addition. Stir the mixture at ambient temperature (25-30 oC) for 10.5 h. Pour the reaction mixture into ice water (4.5 L), filter, and dry at ambient pressure for 72 H, TRITURATE in heptane (1.5 L) with vigorous stirring, filter, and dry under reduced pressure (30 in., 35 oC) to afford preparation 46 (302.4 g, 1.20 mol, 60%) as a light brown solid : H NMR (300 MHz, DMSO-D6) 8 7.99 (d, J = 9.6 Hz, 1H), 7.50-7. 29 (m, 8H), 6.49 (d, J = 9.5 Hz, 1H), 5.15 (S, 2H) ; 13C NMR (75 MHz, DMSO-D6) 8160. 0,154. 6,147. 9, 143. 9,136. 6,128. 4,127. 9, 127.7, 119.9, 119.1, 117.3, 116.6, 111.9, 69.8 ; IR (KBr) 3052 (w), 1708 (s), 1568 (m), 1492 (w), 1444 (w), 1383 (w), 1272 (m), 1168 (w), 1110 (m), 1020 (m), 927 (w), 814 (w), 762 (w), 709 (w) cm-1 ; HPLC analysis 95.9% (AUC), Phenomenex Luna C18 (2) column; ESI MS M/Z 253 [C6HIA03 + H] + |
100% | With boron tribromide In 1,2-dichloro-ethane at 35 - 82℃; for 13h; Heating / reflux; | 46 Equip a 5-L, three-neck, round-bottom flask with a large blade mechanical stirrer, thermocouple, an addition funnel, Claisen adapter, reflux condenser, and a sodium hydroxide scrubber. Charge the flask with 2,5-dimethoxycinnamic acid (182.3 g, 865 mmol, 1.0 equiv) and dichloroethane (2.5 L). Add boron tribromide (163.5 mL, 433.2 g, 1.73 mol, 2.0 equiv.) dropwise over 1 h, keeping the temperature below 35° C. Gas evolution can be monitored as the temperature of the reaction is gradually increased to reflux (82° C.). Reflux for 12 h, cool to 5° C., and quench by the careful addition of water (1.0 L). Filter the resulting yellow-red suspension/emulsion through a glass frit and wash with dichloroethane (1.0 L) and heptane (1.0 L) to afford a brown solid. Dry the wet material in a vacuum oven (30 in., 35° C.) for 18 h, to afford the coumarin (180.3 g, 127% theory) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=9.6 Hz, 1H), 7.22 (d, J=9.9 Hz, 1H), 7.05 (m, 2H), 6.43 (d, J=9.6 Hz, 1H). |
55% | With phosphorus tribromide In dichloromethane |
With boron tribromide In 1,1-dichloroethane at 40 - 83℃; for 22.5h; Heating / reflux; | 12 Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40 oC. Rapidly stir the resulting mixture and heat gradually to 83 oC over 45 min, monitoring the temperature increase and gas evolution. Stir for 6 h at reflux then for 15 h at 76 oC. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39. 8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N, N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40 oC. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl ACETATE/HEPTANE (150 mL, 10: 90), filter and dry to afford 6- METHOXYMETHOXY coumarin 17a (25.6 g, 50%) as a white solid : H NMR (300 MHz, CDC13) 8 7. 70 (d, J=7. 8HZ, 1H), 7.30-7. 12 (M, 3H), 6.41 (d, J = 7. 8 HZ, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDC13) 8 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4 ; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) CM~L ; ESI MS m/z 207 [CLLH004 + H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With piperidine; pyridine at 50 - 85℃; for 5h; Reflux; | |
92% | With piperidine; pyridine at 50℃; for 4.5h; Reflux; | |
85% | With piperidine; pyridine |
75% | With piperidine; pyridine; hydrogenchloride In lithium hydroxide monohydrate Heating; | |
67.26% | With pyridine; ammonium acetate at 85℃; for 5h; Darkness; | 15.2 Step 2: Preparation of 2,5-dimethoxyphenylacryloylpiperazine (IX15) In a 50 mL round bottom flask with a reflux condenser, 3.98 g (0.024 mol) of 2,5-dimethoxybenzaldehyde, 4.90 g (0.047 mol) of malonic acid, and 0.18 g (0.023 mol) of ammonium acetate were sequentially added. 16 mL of pyridine was placed on an oil bath and heated to 85 ° C. The reaction was carried out under reflux for 5 h in the dark. The reaction was stopped, left to cool to room temperature, and poured into 50 mL of ice water. The pH was adjusted to about 2 with dilute hydrochloric acid, and a large amount of solid was precipitated. The solid was filtered by suction, and the solid was washed with water until it had no pyridine smell. Dry to obtain a solid product. Recrystallization using anhydrous ethanol to obtain VI15 as a white solid with a yield of 67.26% and a melting point of 147.3-147.4 ° C. |
With piperidine In ethanol for 6h; | ||
With piperidine; pyridine for 6h; Reflux; | 3.2. General Procedure for the Synthesis of I General procedure: A mixture of benzaldehyde (30 mmol), malonic acid (120 mmol), and piperidine (2 mL) in pyridine was refluxed in a 250 mL single neck round bottomed flask (SNRB) for 6 h. Upon completion, the reaction mixture was poured into a 1 L Erlenmeyer flask (EF) containing cold, dilute HCl (200 mL) and stirred for 10 min. The resulting precipitate was filtered and washed with cold water to afford I. | |
With piperidine; pyridine for 20h; Reflux; | 5.10 General procedure for the preparation of compounds 8a-n General procedure: To the mixture of substituted benzaldehydes 7a-n (2.5mmol), pyridine (20.0mL), piperidine (0.2mL), propanedioic acid (5.0mmol) was added at room temperature and the mixture was heated and refluxed for 20h and monitored by TLC. The reaction mixture was cooled to room temperature and the solution was acidified to pH=5 to yielding a precipitate. The mixture was filtered and washed with water to furnish the compounds 8a-n. | |
With pyridine; ammonium acetate at 85℃; for 5h; | ||
With piperidine; pyridine at 90℃; for 3h; | 2.1.1. General procedure for the synthesis of compound CA-1 ~ CA-18 General procedure: The substituted cinnamic acids were synthesized using DoebnerKnoevenagel modification. Substituted benzaldehydes (10 mmol)malonic acid (12 mmol), and piperidine (1.2 mmol) were dissolved inpyridine (10 mL), the reaction mixture was heated at 90 C. After stirringfor 3 h, the mixture was concentrated in vacuo to remove thepyridine. The pH was adjusted to 1 with HCl/wether 1:2 (v/v). Theprecipitate was collected by filtration, and the filter cake was washedwith water and dried to afford compounds CA-1 ~ CA-18 as solids thatrequired no further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: LiAlH4 / tetrahydrofuran 2: PBr3 / benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: LiAlH4 / tetrahydrofuran 2: PBr3 / benzene 3: ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,5-dimethoxycinnamic acid With thionyl chloride at 45℃; for 1h; Stage #2: 2-amino-benzthiazole In chloroform for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride at 45℃; for 1h; | ||
With thionyl chloride Reflux; | ||
With oxalyl dichloride In dichloromethane for 3h; | 1.2 General Procedure for the Synthesis of Substituted Cinnamoyl Chloride General procedure: Oxalyl chloride (1 ml) was added to the dichloromethane (10 ml) solutions of substituted cinnamic acid (2 mmol). The reaction mixture was stirred until the bubbling stopped (approximately 3 hours), and vaporized in vacuo. The cinnamoyl chloride was used directly without purification. |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 5.11 General procedure for the preparation of compounds 9a-n General procedure: Oxalyl chloride (2.0mmol) was added drop-wise to a stirred mixture of compounds 8a-n (1.0mmol) and DMF (0.02mmol) in dichloromethane (16mL) in room temperature for 10min, and the mixture was distilled and dissolved in dichloromethane (16mL) immediately. The solution was used for the next step without further purification. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; | ||
With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 5℃; for 1h; | 15.2 In a fume hood, add VI151.66 g (0.008 mol) to a 50 mL pear-shaped bottle, add 0.25 mL of N, N-dimethylformamide (DMF) dropwise, and cool to 0-5 ° C in an ice bath. Slowly add 2.00 mL (0.021 mol) of oxalyl chloride, and the addition is completed within 10 minutes. After dripping, the ice bath was removed, and the reaction was continued for 1 h until the solution was clear, and no gas was generated in the system. Use a rotary evaporator to evaporate the excess solvent and oxalyl chloride to obtain VII15. Add 16 mL of dichloromethane to dissolve it and seal it for later use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen bromide; sodium nitrite In water; acetonitrile at 20℃; for 4h; | Representative procedure for bromodecarboxylation of α,β-unsaturated carboxylic acid (Table 1, entry 1) General procedure: In a stirred solution of cinnamic acid (0.3 gm, 2.0 mmol) in freshly distilled acetonitrile (10 mL) 48% aqueous solution of HBr (4.0 mmol) was added. To this reaction mixture was added aqueous solution of NaNO2 (20 mL, 2.5 M). The flask was immediately covered with an air filled balloon (1 L) and the stirring was continued at room temperature. After completion of the reaction (TLC), CHCl3 (10 mL) was added. The organic layer was separated and washed with aqueous solution of NaHCO3 (2 × 20 mL), followed by water (3 × 20 mL), finally dried over anhyd Na2SO4 and was concentrated in vacuum. The remaining residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 9:1) to yield pure bromostyrene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(I) oxide; 1,10-Phenanthroline; silver(l) oxide In 1-methyl-pyrrolidin-2-one at 120℃; for 6h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfuric acid Reflux; | 5.2.1. General procedure for the synthesis of the cinnamates 10-17 and 20-23 General procedure: A mixture of the commercially available cinnamic acid (4)/substituted cinnamic acids 1-3/dihydrocinnamic acids (18/19, 5 mmol) and the corresponding commercially available alcohols 5-9, i.e. propyl (7)/isopropyl (5)/octyl (8)/phenyl (6)/benzyl alcohol (9) (25 mL) and concentrated sulfuric acid (0.2 mL) was refluxed for 4-5 h (Scheme 1 and Scheme 2). On completion of the reactions as observed from TLC examination, the reaction mixture was neutralized by the addition of 10% aqueous sodium hydrogen carbonate solution (w/v) and then extracted with chloroform (2 × 25 mL), the combined organic layer was separated and dried over anhydrous Na2SO4. The crude product obtained after evaporation of organic solvent was loaded on a small silica gel column and eluted with chloroform to obtain the pure esters in 71-99% yields. The structures of all the cinnamates 10-17 and 20-23 were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structures of the known esters 11, 16 and 17 were further confirmed by comparison of their melting points with those reported in the literature [27] and [28] (Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With polyphosphate ester at 20℃; | 5.3. Synthesis of the thiocinnamates 29-44 General procedure: A mixture of the commercially available carboxylic acids (1, 2, 4 and 18, 3 mmol), the appropriate commercially available thiol (24-28, 3.1 mmol) and polyphosphate ester (PPE, 2 mL) was stirred at room temperature for 0.5-11 h (refPreviewPlaceHolderScheme 3 and refPreviewPlaceHolderScheme 4). After completion of the reaction, the mixture was treated with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with chloroform (3 × 20 mL). The combined chloroform extract was dried over sodium sulfate and evaporated in a rotary vacuum evaporator. The crude compounds were passed through a silica-gel column, using pure petroleum ether as eluent, the desired compounds were obtained as colorless viscous oils in 92-98% yields. The structures of all the thio esters were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structure of the known esters 38-41 were further confirmed by comparison of their melting points with those reported in the literature [29], [30], [31], [32] and [33](Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With polyphosphate ester at 20℃; | 5.3. Synthesis of the thiocinnamates 29-44 General procedure: A mixture of the commercially available carboxylic acids (1, 2, 4 and 18, 3 mmol), the appropriate commercially available thiol (24-28, 3.1 mmol) and polyphosphate ester (PPE, 2 mL) was stirred at room temperature for 0.5-11 h (refPreviewPlaceHolderScheme 3 and refPreviewPlaceHolderScheme 4). After completion of the reaction, the mixture was treated with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with chloroform (3 × 20 mL). The combined chloroform extract was dried over sodium sulfate and evaporated in a rotary vacuum evaporator. The crude compounds were passed through a silica-gel column, using pure petroleum ether as eluent, the desired compounds were obtained as colorless viscous oils in 92-98% yields. The structures of all the thio esters were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structure of the known esters 38-41 were further confirmed by comparison of their melting points with those reported in the literature [29], [30], [31], [32] and [33](Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With polyphosphate ester at 20℃; | 5.3. Synthesis of the thiocinnamates 29-44 General procedure: A mixture of the commercially available carboxylic acids (1, 2, 4 and 18, 3 mmol), the appropriate commercially available thiol (24-28, 3.1 mmol) and polyphosphate ester (PPE, 2 mL) was stirred at room temperature for 0.5-11 h (refPreviewPlaceHolderScheme 3 and refPreviewPlaceHolderScheme 4). After completion of the reaction, the mixture was treated with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with chloroform (3 × 20 mL). The combined chloroform extract was dried over sodium sulfate and evaporated in a rotary vacuum evaporator. The crude compounds were passed through a silica-gel column, using pure petroleum ether as eluent, the desired compounds were obtained as colorless viscous oils in 92-98% yields. The structures of all the thio esters were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structure of the known esters 38-41 were further confirmed by comparison of their melting points with those reported in the literature [29], [30], [31], [32] and [33](Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid Reflux; | 5.2.1. General procedure for the synthesis of the cinnamates 10-17 and 20-23 General procedure: A mixture of the commercially available cinnamic acid (4)/substituted cinnamic acids 1-3/dihydrocinnamic acids (18/19, 5 mmol) and the corresponding commercially available alcohols 5-9, i.e. propyl (7)/isopropyl (5)/octyl (8)/phenyl (6)/benzyl alcohol (9) (25 mL) and concentrated sulfuric acid (0.2 mL) was refluxed for 4-5 h (Scheme 1 and Scheme 2). On completion of the reactions as observed from TLC examination, the reaction mixture was neutralized by the addition of 10% aqueous sodium hydrogen carbonate solution (w/v) and then extracted with chloroform (2 × 25 mL), the combined organic layer was separated and dried over anhydrous Na2SO4. The crude product obtained after evaporation of organic solvent was loaded on a small silica gel column and eluted with chloroform to obtain the pure esters in 71-99% yields. The structures of all the cinnamates 10-17 and 20-23 were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structures of the known esters 11, 16 and 17 were further confirmed by comparison of their melting points with those reported in the literature [27] and [28] (Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With polyphosphate ester at 20℃; | 5.3. Synthesis of the thiocinnamates 29-44 General procedure: A mixture of the commercially available carboxylic acids (1, 2, 4 and 18, 3 mmol), the appropriate commercially available thiol (24-28, 3.1 mmol) and polyphosphate ester (PPE, 2 mL) was stirred at room temperature for 0.5-11 h (refPreviewPlaceHolderScheme 3 and refPreviewPlaceHolderScheme 4). After completion of the reaction, the mixture was treated with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with chloroform (3 × 20 mL). The combined chloroform extract was dried over sodium sulfate and evaporated in a rotary vacuum evaporator. The crude compounds were passed through a silica-gel column, using pure petroleum ether as eluent, the desired compounds were obtained as colorless viscous oils in 92-98% yields. The structures of all the thio esters were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structure of the known esters 38-41 were further confirmed by comparison of their melting points with those reported in the literature [29], [30], [31], [32] and [33](Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfuric acid Reflux; | 5.2.1. General procedure for the synthesis of the cinnamates 10-17 and 20-23 General procedure: A mixture of the commercially available cinnamic acid (4)/substituted cinnamic acids 1-3/dihydrocinnamic acids (18/19, 5 mmol) and the corresponding commercially available alcohols 5-9, i.e. propyl (7)/isopropyl (5)/octyl (8)/phenyl (6)/benzyl alcohol (9) (25 mL) and concentrated sulfuric acid (0.2 mL) was refluxed for 4-5 h (Scheme 1 and Scheme 2). On completion of the reactions as observed from TLC examination, the reaction mixture was neutralized by the addition of 10% aqueous sodium hydrogen carbonate solution (w/v) and then extracted with chloroform (2 × 25 mL), the combined organic layer was separated and dried over anhydrous Na2SO4. The crude product obtained after evaporation of organic solvent was loaded on a small silica gel column and eluted with chloroform to obtain the pure esters in 71-99% yields. The structures of all the cinnamates 10-17 and 20-23 were unambiguously established on the basis of their spectral (IR, 1H NMR, 13C NMR spectra and HRMS) analysis. The structures of the known esters 11, 16 and 17 were further confirmed by comparison of their melting points with those reported in the literature [27] and [28] (Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; | 8 Example 8Synthesis of (2E)-(3aR.5aR.9bSV2.3.3a.4.5.5a.6<7.8.9b-decahvdro-3a-hvdroxv-3.5a,9- trimethyl-2-oxonaphtho[ 1 ,2-b]furan-8-yl 3 -(2, 5 -dimethoxyphenyDacrylate [compound- 16. (18)1: A solution of (3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octahydro-3a,8-dihydroxy-5a,9- dimethyl-3-methylenenaphtho[l,2-b]furan-2(9bH)-one (compound-10; 300 mg, 0.001 13 mol), 2, 5-dimethoxy cinnamic acid (280 mg, 0.013 mol), 6mL of methylene dichloride (MDC), 50 mg of dimethylaminopyridine (DMAP) was taken in a RB flask and treated slowly with a solution of 351 mg of dicyclohexylcarbodiimide (DCC) (0.0017 mol) dissolved in 4mL of MDC under stirring at 0°C. The RM was then allowed to RT and continued the stirring for 2h. The RM was then poured into ice-cold water and the mixture extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated under vacuum. The residue (600 mg) was subjected to column chromatography on silica column using acetone/hexane mixtures to obtain 120 mg of compound- 16 (18, 24%) in the fraction eluted with 25% of acetone/hexane.Compound-16: NMR (CDC13> 400MHz): δ 7.91 (1H, d, J = 16.0Hz), 7.44 (1H, d, J = 8.4Hz), 6.50 (1H, dd, J = 8.4, 2.4 Hz), 6.46 (1H, d, J = 16.0 Hz), 6.48 (1H, d, J = 2.0Hz), 5.34 (1H, d, J = 4.0Hz), 3.88 (3H, s), 3.84 (3H, s), 2.52 (1H, q, J = 7.6Hz), 2.05 (2H, m), 1.848(3H, s), 1.84 (2H, m), 1.68 (2H, m), 1.47 (1H, m), 1.138(1H, m), 1.34 (3H, d, J = 7.6Hz), 1.23 (1H, m), 1.10 (3H, s); LC/MS: 479.3 (M+Na)+ positive ion mode, 455 (M- H) 491 (M+2H20-H)" negative ion mode. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tert.-butylhydroperoxide; copper(ll) sulfate pentahydrate; Langlois reagent In dichloromethane; water at 50℃; for 8h; stereospecific reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; bis(((difluoromethyl)sulfinyl)oxy)zinc In dichloromethane; water at 50℃; for 22h; stereospecific reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Inert atmosphere; | II. Experimental Procedure General procedure: (E)-3-(4-ethylphenyl)acrylic acid (100 mg, 0.567 mmol), 3-((ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride (163 mg, 0. 851 mmol), and N,N-dimethylpyridin-4-amine (13 mg, 0.19 mmol) were dissolved in dichloromethane (10 mL). N-ethyl-N-isopropylpropan-2-amine (161 mg, 1.248 mmol) was added followed by 4,5-dihydrothiazol-2-amine (64 mg, 0.624 mmol). The reaction mixture was stirred for 12 hours at room temperature. The reaction was concentrated under vacuum. Purification by column chromatography provided (E)-N-(4,5-dihydrothiazol-2-yl)-3-(4-ethylphenyl)acrylamide as a white powder (58 mg, 40% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 2-phenylethanol With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: 2,5-dimethoxycinnamic acid In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 2068.65 Torr 2.1: thionyl chloride; N,N-dimethyl-formamide / 5 h / Reflux 2.2: 0.83 h / -5 °C | ||
Multi-step reaction with 3 steps 1: hydrogen; palladium 10% on activated carbon / ethyl acetate / 48 h / 23 °C 2: thionyl chloride; N,N-dimethyl-formamide / 2 h / 23 °C / Inert atmosphere 3: aluminum (III) chloride / dichloromethane / 0.17 h / 0 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / 760.05 Torr 2: phosphorus pentoxide; methanesulfonic acid / dichloromethane / 19 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate at 20℃; Cooling with ice; | 3.3. General Procedure for the Synthesis of II General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate at 20℃; Cooling with ice; | 3.3. General Procedure for the Synthesis of II General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate at 20℃; Cooling with ice; | 3.3. General Procedure for the Synthesis of II General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate at 20℃; Cooling with ice; | 3.3. General Procedure for the Synthesis of II General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate; at 20℃;Cooling with ice; | General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | 4.4. General procedure for preparation of 7a-g and 7h1-32 General procedure: Compound 6 was dissolved in 10 mL of dimethyl formamide and treated with EDC*HCl (1.2 equiv.), NHS (1.2 equiv.) and substitutional carboxylic acid (1.2 equiv.). The reaction mixture was stirred overnight at room temperature. TLC was used to monitor the progress of the reaction. After the reaction complete, the mixture was poured into 40 mL of water and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed by brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/petroleum ether 1:1) to afford 7a as a purple solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h; | 11 Example 11: preparaton of L8 (Compound No. 8) Round-bottomed flask were added sequentially 274.56mg (1.32mmol) 2,5-dimethoxy-cinnamic acid, 4.30 mL (1.33mmol) TMP-NH2The CH2Cl2Solution, 253mg (1.32mmol) EDCI, 528μL (3.97mmol) triethylamine; 20mL of methylene chloride was added, the reaction was stirred at room temperature 12 h.TLC [V (petroleum ether) :V (acetone) = 2] Detection reaction is essentially complete, the reaction was successively washed with water (2 × 20 mL) and saturated brine (20 mL) wash, dried over anhydrous sodium sulfate, filtered, and reduced pressure evaporated to dryness.The residue was separated by silica gel column white solid, yield: 88.5%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.7% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | General procedure for the synthesis of cinnamoyl-, haro-cinnamoyl-, NO2-cinnamoyl- and (OCH3)ncinnamoyl-decursin derivatives (5a-e, 6a-i) General procedure: The mixture of cinnamic acid (1.2 equiv), EDC (2 equiv) and 4-DMAP (0.4 equiv) was dissolved inanhydrous dichloromethane. After (+)-Decursinol (1 equiv) was added, the reaction mixture stirred to roomtemperature for 5-12 hours. The completion of reaction was juged by TLC. When a spot of (+)-decursinolwas disappeared on TLC, the reaction was finished. The mixture was concentrated in vacuo and the residuewas purified by flash silica gel column chromatography using EtOAc/Hexane system as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine In acetonitrile at 70℃; for 24h; Sealed tube; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 2,5-dimethoxycinnamic acid With Bromotrichloromethane; triphenylphosphine In dichloromethane for 5h; Reflux; Stage #2: With triethylamine In dichloromethane for 8h; Reflux; | b.8 General procedure for the preparation of carboxylic acidanhydrides General procedure: To a solution of triphenylphosphine (910 mg,3.47 mmol) in dry dichloromethane (10 mL) bromotrichloromethane(710 mg, 3.58 mmol) was added, and theresulting mixture was stirred at a rate for 30 min to give areddish-brownish solution. Thereafter, cinnamic acid (4a,451 mg, 3.05 mmol) was added, and the resulting mixturewas held at reflux for 5 h. Thereafter, cinnamic acid(451 mg, 3.05 mmol) and subsequently triethylamine(310 mg, 3.05 mmol) were added, and the reaction mixturewas held at reflux for 8 h. Then, the cooled solution wasconcentrated in vacuo, and the concentrate was subjectedto rapid column chromatography on a silica gel [CH2Cl2-hexane 2:1] to give cinnamic anhydride (9a, 605 mg, 71%)as colorless crystals; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 2,5-dimethoxycinnamic acid With Bromotrichloromethane; triphenylphosphine In dichloromethane for 0.75h; Reflux; Stage #2: 2-ethyl-N-(2-ethylhexyl)-1-hexanamine In dichloromethane for 14h; Reflux; | 2.1 N,N-Bis(2-ethylhexyl) 3-(1,4-dimethoxyphen-2-yl)propenoic acid amide To a solution of PPh3 (980 mg, 3.74 mmol) in dry CH2Cl2(12 mL) BrCCl3 (1.50 g, 7.66 mmol)was added. The resultingmixture was stirred at rt for 30 min, during which it turnedreddish-brown. Thereafter, 2,5-dimethoxycinnamic acid(4c, 700 mg, 3.37 mmol) was added, and the mixture washeated under reflux for 45 min. Thereafter, di(2-ethylhexyl)amine (1.62 g, 6.71 mmol) was added dropwise via a syringe,where the ensuing reaction is exothermic. The reactionmixture was stirred at reflux for 14 h. Then, thecooled mixture was concentrated in vacuo, and the residuewas subjected directly to column chromatography on asilica gel to give 5f (875 mg, 2.03 mmol, 60%) as a colorlessoil; nmax neat/cm1) 2961, 2877, 1660, 1622, 1506, 1489,1047, 772; dH (400 MHz, CDCl3) 1.00 (16H, m),1.48 (20H, m),1.69e1.79 (2H, m), 3.28e3.43 (4H, m), 3.77 (3H, s, OCH3),3.81 (3H, s, OCH3), 6.82 (1H, d, 3J 8.8 Hz), 6.84 (1H, d,3J 8.8 Hz), 7.00 (1H, s), 7.02 (1H, d, 3J 15.6 Hz), 7.86 (1H,d, 3J 15.6 Hz); dC (67.8 MHz, CDCl3, DEPT) 10.7 (CH3), 10.8(CH3), 14.0 (CH3), 14.1 (CH3), 23.1 (CH2, 2C), 23.7 (CH2), 24.0(CH2), 28.7 (CH2), 28.8 (CH2), 30.5 (CH2), 30.7 (CH2), 37.6 (CH), 40.0 (CH), 50.7 (CH2), 52.0 (CH2), 55.7 (OCH3), 56.0(CH3), 112.3 (CH), 114.4 (CH), 115.4 (CH), 119.6 (CH), 125.2(Cquat), 137.5 (CH), 152.8 (Cquat), 153.4 (Cquat), 167.3 (Cquat,CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 24h; | Preparation of library I and II General procedure: In each 200 μL well of a microtiter plate, a mixture of diisopropyl ethylamine (5.0 μL, 180.0mM solution in DMSO), HBTU (5 μL, 90mM solutionin DMSO), a carboxylic acid (10.0 μL, 30.0mM solution in DMSO) and a scaffold (compound 1and 2 ) (10.0μL, 30.0mM solution in DMSO) was shaken at rt for 24 h and analyzed by ESI-MS (or TLC) to verify the presence of the desired product. Each reaction mixture was diluted with H2O and transferred to another 96-well microtiter plate to make a 20 mM solution per each desired molecule (based on 100% conversion of amine) for the enzymatic assay directly without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 24h; | Preparation of library I and II General procedure: In each 200 μL well of a microtiter plate, a mixture of diisopropyl ethylamine (5.0 μL, 180.0mM solution in DMSO), HBTU (5 μL, 90mM solutionin DMSO), a carboxylic acid (10.0 μL, 30.0mM solution in DMSO) and a scaffold (compound 1and 2 ) (10.0μL, 30.0mM solution in DMSO) was shaken at rt for 24 h and analyzed by ESI-MS (or TLC) to verify the presence of the desired product. Each reaction mixture was diluted with H2O and transferred to another 96-well microtiter plate to make a 20 mM solution per each desired molecule (based on 100% conversion of amine) for the enzymatic assay directly without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.1% | Stage #1: 2,5-dimethoxycinnamic acid; enoxolone With dmap In dichloromethane at 4℃; for 0.166667h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 4 - 20℃; for 24.5h; | 7 (2,5-dimethoxy)cinnamoyl-3β-Hydroxy-11-oxoolean-12-en-30-oic acid (7a) Place 6.0mmol of 2,5-dimethoxycinnamic acid and 0.6mmol of DMAP in a 100ml round bottom flask, add 50ml of methylenechloride and stir for 10-20min. After fully dissolve, add 3.0mmol of glycyrrhetinic acid and stir for 10min. After bathing at 4°C,EDCI dichloromethane solution was slowly added dropwise. After the addition was continued for about 30 minutes at 4°C, the reaction was carried out at room temperature for 24 hours. After completion of the reaction, the solution was washed with saturated sodium bicarbonate solution and saturated brine twice, dried over anhydrous sodium sulfate, and the solvent was recovered. The resulting solid was separated by column chromatography (dichloromethane:methanol=200:1) to give whitesolids. 1.132 g of powder with a yield of 57.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1,1'-bis-(diphenylphosphino)ferrocene; bis(acetylacetonato)palladium(II); N-Methyldicyclohexylamine In N,N-dimethyl acetamide at 90℃; for 8h; Inert atmosphere; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ferulic acid decarboxylase from Saccharomyces cerevisae In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 18h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 mg | Stage #1: 2,5-dimethoxycinnamic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 0.5h; Stage #2: C24H38N2O3 In dichloromethane at 20℃; | General procedure: To a solution of corresponding cinnamic acid (1.1 equiv) in dry CH2Cl2 (3mL) were added 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (29mg, 0.15mmol) and N,N-diisopropylethylamine (DIPEA) (29mg, 0.225mmol) at room temperature. After 0.5h, the above yellow oil (77mg) was added, and the reaction mixture was stirred at room temperature for 16h. The volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc and H2O. The EtOAc layer was dried over MgSO4 and condensed to afford a crude residue. The residue was purified by silica gel column chromatography with petroleum ether/acetone (2:1) to produce the desired products 5a-5o, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2,5-dimethoxycinnamic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: 1H-imidazole In tetrahydrofuran at 20℃; Inert atmosphere; | 3 (Production Example 1) Synthesis of cinnamic acid amide-type thermal base gen General procedure: In a 300 mL 2 neck flask,trans-2-methoxycinnamic acid (2.17 g, 12.2 mmol),1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride(2.81 g, 14.6 mmol) was added, and the system was replaced with N2, and then dry THF (80 mL) was added.After stirring at room temperature for 30 minutes, imidazole (1.00 g, 14.6 mmol) was added, and the mixture was stirred at room temperature overnight.After distilling off the solvent from the obtained reaction solution under reduced pressure,The mixture was extracted with chloroform, and the obtained organic layer was further diluted with dil. HCl,NaHCO3aq. And washed.After the organic layer was dried over MgSO4, the solvent was distilled off under reduced pressure to obtain a crude product.Purified by silica gel column chromatography (chloroform / methanol, 100: 1),A thermal base generator (1) (1.42 g, 51% yield) represented by the following chemical formula was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dipotassium peroxodisulfate; palladium diacetate In 1,4-dioxane; acetic acid at 80℃; for 24h; | General procedure for the synthesis of compounds General procedure: Typical coupling procedure: Pd(OAc)2 (22 mg, 5 mol%), K2S2O8 (0.81 g 3 mmol), alkene (2 mmol), arene (15 mmol, 7.5 equiv.), acetic acid (8 mL) and cosolvent (2 mL) were placed in a 20 mL scintillation vial containing a magnetic stirrer bar. The flask was sealed with a Teflon-lined crimped cap, and the reaction solution was stirred vigorously at 80 °C 24 h (unless otherwise specified). The reaction solution was cooled to room temperature, CH2Cl2 added, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel using cyclohexane/ethyl acetate to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 2,5-dimethoxycinnamic acid; 4-methoxy-aniline With thionyl chloride for 3h; Reflux; Stage #2: With triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 4.1.5. General procedure for the preparation of compounds D-1 - D-28 General procedure: Method B for the synthesis of D-10 - D-28: compound 5 (50 mg,0.168 mmol, 1 equiv.) was dissolved in 5 mL CH2Cl2 in a vial. EDCI (1.5equiv.) and HOBT (1.0 equiv.) were added to the reaction mixture. Aseries of corresponding benzoic acids or cinnamic acids (1.1 equiv.) andEt3N (3 equiv.) were added. The reaction mixture was stirred overnightat room temperature. Upon completion of the reaction, water (10 mL)was added and the product was extracted with CH2Cl2 (3 × 10 mL). Thecombined organic layers were dried using anhydrous MgSO4, thenconcentrated under vacuum, and the residues were purified by flashcolumn chromatography using petroleum ether:acetone = 3:1 as aneluent to give the target compounds. | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 4.1.5. General procedure for the preparation of compounds D-1 - D-28 General procedure: Method B for the synthesis of D-10 - D-28: compound 5 (50 mg,0.168 mmol, 1 equiv.) was dissolved in 5 mL CH2Cl2 in a vial. EDCI (1.5equiv.) and HOBT (1.0 equiv.) were added to the reaction mixture. Aseries of corresponding benzoic acids or cinnamic acids (1.1 equiv.) andEt3N (3 equiv.) were added. The reaction mixture was stirred overnightat room temperature. Upon completion of the reaction, water (10 mL)was added and the product was extracted with CH2Cl2 (3 × 10 mL). Thecombined organic layers were dried using anhydrous MgSO4, thenconcentrated under vacuum, and the residues were purified by flashcolumn chromatography using petroleum ether:acetone = 3:1 as aneluent to give the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 4-dimethylaminopyridine; diisopropyl-carbodiimide In dichloromethane at 0℃; for 0.5h; | 2.1.2. General procedure for the synthesis of compound XJS-1 ~ XJS-18 General procedure: Compound 10 (2.0 mmol) and the substituted cinnamic acids CA-1~ CA-18 (2.4 mmol) in anhydrous CH2Cl2 (10 mL) was added withDMAP (2.4 mmol) and DIPC (4.8 mmol) at 0 C. After stirring for 30 min,the reaction mixture was allowed to warm to room temperature. Afterthe reaction was completed, as monitored by TLC, the reaction mixturewas washed with 10% NaHCO3 (2 × 20 mL), and 1 N HCl (2 × 20 mL).The combined organic layers, dried over Na2SO4, filtered, and concentratedin vacuo. The crude residue was purified by chromatography onsilica gel with DCM/MeOH to give compounds XJS-1 ~ XJS-18. |
86% | With 4-dimethylaminopyridine; diisopropyl-carbodiimide In dichloromethane at 0℃; for 0.5h; | 2.1.2. General procedure for the synthesis of compound XJS-1 ~ XJS-18 General procedure: Compound 10 (2.0 mmol) and the substituted cinnamic acids CA-1~ CA-18 (2.4 mmol) in anhydrous CH2Cl2 (10 mL) was added withDMAP (2.4 mmol) and DIPC (4.8 mmol) at 0 C. After stirring for 30 min,the reaction mixture was allowed to warm to room temperature. Afterthe reaction was completed, as monitored by TLC, the reaction mixturewas washed with 10% NaHCO3 (2 × 20 mL), and 1 N HCl (2 × 20 mL).The combined organic layers, dried over Na2SO4, filtered, and concentratedin vacuo. The crude residue was purified by chromatography onsilica gel with DCM/MeOH to give compounds XJS-1 ~ XJS-18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 0.5 h / 20 °C / Inert atmosphere; Reflux; Schlenk technique 2: (4bR,11aS)-4b,11a-dihydro-12H-benzo[d]indeno[1',2':4,5]imidazo[2,1-b]thiazole; 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium salt; tetra-n-butyl-ammonium chloride / 1,2-dichloro-ethane / 16 h / Inert atmosphere; Irradiation; Schlenk technique; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Reflux; Schlenk technique; |
Tags: 10538-51-9 synthesis path| 10538-51-9 SDS| 10538-51-9 COA| 10538-51-9 purity| 10538-51-9 application| 10538-51-9 NMR| 10538-51-9 COA| 10538-51-9 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
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 |
Sorry,this product has been discontinued.
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