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CAS No. : | 520-36-5 | MDL No. : | MFCD00006831 |
Formula : | C15H10O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KZNIFHPLKGYRTM-UHFFFAOYSA-N |
M.W : | 270.23 | Pubchem ID : | 5280443 |
Synonyms : |
4',5,7-Trihydroxyflavone;Apigenol;457Trihydroxyflavone;Spigenin;Apigenine;Versulin;Flavone;Chamomile;NSC 83244;LY 080400;C.I. Natural Yellow 1
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 73.99 |
TPSA : | 90.9 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.8 cm/s |
Log Po/w (iLOGP) : | 1.89 |
Log Po/w (XLOGP3) : | 3.02 |
Log Po/w (WLOGP) : | 2.58 |
Log Po/w (MLOGP) : | 0.52 |
Log Po/w (SILICOS-IT) : | 2.52 |
Consensus Log Po/w : | 2.11 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.94 |
Solubility : | 0.0307 mg/ml ; 0.000114 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.59 |
Solubility : | 0.00688 mg/ml ; 0.0000255 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.4 |
Solubility : | 0.0107 mg/ml ; 0.0000394 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.96 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
3.4 g | Stage #1: With aluminium(III) chloride hexahydrate In methanol at 70℃; for 15 h; Sealed tube Stage #2: With phosphoric acid In methanol for 0.5 h; Sonication |
5.0 g of 6H2O-aluminum trichloride, 100 ml of methanol,98percent wild luteolin 10g,70 sealed hydrolysis 15h, Adding phosphoric acid 6ml,Mixing,Ultrasound 30min,Adding 0.1percent phosphoric acid in 1000ml of the solution with stirring slowly, placing the mixture for 30 minutes, placing overnight, filtering and washing the filter cake to obtain a mixture of wild erosin, apigenin-7-O-glucoside and apigenin; The column was eluted with chloroform-methanol (12: 1), then apigenin was first eluted, and the ratio of chloroform to methanol was adjusted to (6: 1) to give apigenin-7-O- Glucoside 3.4g, determined by HPLC content of 98.3percent, and finally out of a small amount of wild lacquer glycosides |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 20℃; for 1h; | Methylation of apigenin[0047] A solution of apigenin in MeOH was treated with ethereal diazomethane(CH2N2-Et2O) until the yellow color persisted. The reaction solution was stirred at room temperature for 30 min. Removal of the solvent under reduced pressure furnished a residue, which was purified by silica gel column chromatography (2:1 hexanes/EtOAc) to give compound 2 [Matsuda H, Morikawa T, Toguchida I5 Yoshikawa M: Structural requirements of flavonoids and related compounds for aldose reductase inhibitory activity. Chemical & Pharmaceutical Bulletin 2002, 50(6):788-795.]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine at 70℃; for 6h; | 5.1.2 2-(4-Acetoxyphenyl)-4-oxo-4H-chromene-5,7-diyl diacetate (9) General procedure: Acetic anhydride (1mL, 10.7mmol) was added to a solution of 1 (604mg, 2mmol) in anhydrous pyridine (8mL) at room temperature. The reaction mixture was stirred for 6h at 70°C. After the completion of reaction, the resultant mixture was cooled to room temperature (rt). After concentration, the crude product was recrystallized with acetone to afford 8 as a white solid (973mg, 95% yield). |
90.8% | With pyridine at 140℃; for 8h; | 1.1 1) Preparation of Structural Compounds of Formula III Among them, in the compound of formula III, R is a methyl group.In a dry clean 150 mL three-neck round bottom flask equipped with a condenser tube was added apigenin 5.4 g in order.(20 mmol), 22 mL of acetic anhydride (d=1.08 g/ml, 233 mmol), pyridine (27 mL), heated to about 140° C., and refluxed for about 8 hours. TLC showed that the starting material had completely reacted. The heating was stopped until the temperature dropped to about 50°C to 70°C. Ethyl acetate (60 mL) was added to the mixture, which was stirred and crystallized. The mixture was filtered off with suction, and the filter cake was washed with ethyl acetate to give a white flocculent solid.5,7,4'-triacetoxyflavoneThat is, the structural compound represented by Formula III was dried to give 6.7 g with a yield of 90.8%. |
87.2% | With pyridine Reflux; | 3.1 Acylation of apigenin, luteolin, daidzein and genistein To solution of apigenin (3mmol) in acetic anhydride (6mL) was added pyridine (0.6mL). Then, the mixture was heated to reflux until apigenin consumption and was poured into ice-cold water (70mL) to afford 4 as a white solid. The crude product was recrystallized to get pure compound. Compounds 5, 12 and 13 were synthesized according to the method for 4. 4.1.3.1 4', 5, 7- O-triacetylapigenin (4) Compound 4 was recrystallized from ethyl acetate. Yield 87.2%; White solid. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 2H, J = 8.8 Hz, H-2', H-6'), 7.35 (d, 1H, J = 2.0 Hz, H-8), 7.27 (d, 2H, J = 8.8 Hz, H-3', H-5'), 6.85 (d, 1H, J = 2.0 Hz, H-6), 6.62 (s, 1H, H-3), 2.44 (s, 3H, -OCOCH3), 2.35 (s, 3H, -OCOCH3), 2.34 (s, 3H, -OCOCH3). |
80% | With pyridine | |
With sodium acetate | ||
With pyridine for 16h; Ambient temperature; Yield given; | ||
26 mg | With pyridine | |
61 mg | With sulfuric acid for 0.0833333h; | |
With pyridine for 2h; Heating; | ||
1.67 g | With pyridine; dmap at 80℃; for 6h; | 4',5,7-Triacetoxyflavone (apigenin 4',5,7-triacetate, 1a) Naringenin (2f) was prepared from 2e according to the reported procedure8. To a solution of 2f (1.36 g, 5.00 mmol) in pyridine (7.5 mL) was added iodine (1.40 g, 5.51 mmol), and the mixture was stirred for 24 h at 90oC. To the mixture were added acetic anhydride (10 mL) and catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP), and further stirred for 6 h at 80oC. After cooling, the mixture was concentrated in vacuo and the residue was diluted with water. The precipitates were collected by filtration and dissolved in CHCl3. The resulting suspension was filtered to remove insoluble materials through a pad of Celite and washed with CHCl3. The filtrate and washings were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography (50 g). Elution with hexane/CHCl3 (3:1 to 1:1) furnished 1a as a colorless solid (1.67 g, 80%). Analitical sample of 1a was obtained by the recrystallization from EtOH as colorless fine needles; mp 182.3-182.8 oC (lit., 185-186 oC19); IR 1754, 1641, 1611, 1505, 1478, 1416, 1373, 1180, 1135, 1084, 1012, 893, 840 cm-1; 1H NMR (500 MHz, CDCl3) δ: 2.35 (s, 3H), 2.36 (s, 3H), 2.44 (s,3H), 6,62 (s, 1H), 6.85 (d, J-2.2 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.35 (d, J=2.2 Hz, 1H), 7.88 ((d, J=8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ: 21.1, 21.2 (2C), 108.6, 109.0, 113.7, 114.9, 122.4 (2C), 127.6 (2C), 128.6, 150.2, 153.3, 154.0, 157.6, 161.7, 168.0, 168.9, 169.4, 176.3; HRMS (ESI) calcd for C21H16NaO8 [M+Na+] 419.0743, found 419.0739 |
With pyridine Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine hydrochloride at 140 - 200℃; for 9h; | 2.1 1) Preparation of Structural Compounds of Formula III In a 500 ml round-bottomed flask, 80 g of pyridine hydrochloride was added. After heating to about 140° C., dissolved, 10 g (37 mmol) of apigenin was added, and 70 mL of benzoyl chloride (d=1.212, 600 mmol) was slowly added while stirring, and the mixture was heated to 200° C. The reflux reaction took about 9 hours. TLC detected that the reaction was complete. When the reaction solution was cooled to about 70° C., 90 mL of ethyl acetate was added, and a large amount of white solid gradually precipitated. Stirring was continued for 1 hour and cooled to room temperature and allowed to stand overnight in the refrigerator. filter,5,7,4'-Tribenzoyloxyflavone is obtained as an off-white solid. After drying, the residue was recrystallized from ethanol to obtain the pure product of 5,7,4'-tribenzalkoxyflavone (ie, the structural compound represented by formula III) as an off-white product. The purity was above 98.0%, and the yield was 89%. . |
With potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid; iodine In dimethyl sulfoxide at 100℃; for 1.5h; | |
93% | With pyridine; iodine for 4h; Heating; | |
66% | With pyridine; iodine at 95℃; for 5h; | Apigenin: Apigenin: A solution of naringenin (5.0 g, 18 mmol) and iodine (5.0 g,19 mmol) in pyridine (50 mL) was heated to 95 °C for 5 h. The mixturewas poured into ice water. The resulting precipitate was filtered,and then washed with water, dilute hydrochloric acid and saturatedsodium thiosulfate. Recrystallisation of the dried residue from ethanolafforded apigenin: 3.20 g; 66%; m.p. 345-350 °C (lit.23 344-346 °C). |
65% | With indium(III) bromide; silica gel at 130 - 140℃; for 2h; | |
With ethanol; iodine; sodium acetate | ||
With sulfuric acid; iodine; dimethyl sulfoxide at 100℃; for 0.5h; Yield given; | ||
25.8 g | With trifluoroacetic anhydride; potassium iodide In dimethyl sulfoxide; N,N-dimethyl-formamide at 80℃; for 8h; | 1-5 Example 1 In a clean and dry 500L reaction bottle, feed naringenin (content greater than 95%) 30g, DMF 100g, stir to dissolve, add 0.2g potassium iodide, and raise the temperature to 80 C, the mixed solution of 30 g of dimethyl sulfoxide and 0.3 g of trifluoroacetic anhydride was added dropwise, and the drop was completed in about 2 hours. After the dropwise addition, the heat preservation reaction is started, and the raw material is controlled in the liquid phase for 6 hours, and the raw material is less than 2%, and the reaction is stopped. After dropping to room temperature, ammonia water was added dropwise, and the reaction was continued for 1 h. Filtration, the filtrate was recovered under reduced pressure to obtain a black oil. Add 300g of 5% hydrochloric acid solution, continue to reflux for half an hour, filter by heat, and continue to wash the filter cake with hot water until neutral, to obtain crude apigenin. DMF was added to dissolve and clarify the crude product, and the solvent was recovered to one-half. Ethanol was added to beat, cooled, filtered, and dried to obtain light yellow apigenin 25.8g, with a content of 98%. |
With pyridine; iodine at 90℃; for 24h; | 4',5,7-Triacetoxyflavone (apigenin 4',5,7-triacetate, 1a) Naringenin (2f) was prepared from 2e according to the reported procedure8. To a solution of 2f (1.36 g, 5.00 mmol) in pyridine (7.5 mL) was added iodine (1.40 g, 5.51 mmol), and the mixture was stirred for 24 h at 90oC. To the mixture were added acetic anhydride (10 mL) and catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP), and further stirred for 6 h at 80oC. After cooling, the mixture was concentrated in vacuo and the residue was diluted with water. The precipitates were collected by filtration and dissolved in CHCl3. The resulting suspension was filtered to remove insoluble materials through a pad of Celite and washed with CHCl3. The filtrate and washings were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography (50 g). Elution with hexane/CHCl3 (3:1 to 1:1) furnished 1a as a colorless solid (1.67 g, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one With sodium hydride In N,N-dimethyl-formamide for 0.166667h; Cooling with ice; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere; | 4.2.1. 5,7,4'-Trimethoxyflavone,33 3a To a solution of apigenin (50 mg, 0.19 mmol) in dry dimethylformamide (2 ml) was added NaH (20 mg, 0.5 mmol), under cooling by ice bath. After stirring for 10 min under argon, methyl iodide (0.15 ml, 2.56 mmol) was added dropwise. The reaction mixture was stirred for 20 h at room temperature and then, it was diluted by dichloromethane, washed by water, organic phases collected and dried (MgSO4), and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH) and by precipitation by hexanes from ethyl acetate to yield title product as yellow solid (40%, 30 mg): IR 1640, 1601, 1573, 1511 cm-1; 1H NMR (300 MHz,CDCl3, 25 °C) δ 7.81 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.59 (s, 1H), 6.54 (d, J=1.8 Hz, 1H), 6.35 (d, J=2.3 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3, 25 °C) δ 177.60, 163.88, 162.02, 160.89, 160.65, 159.82, 127.58 (2C), 123.85, 114.33 (2C), 109.23, 107.69, 96.06, 92.81, 56.40, 55.71, 55.45 ppm.MS (ESI) m/z: found 312.9 [M+H]+; calcd 313.1. |
With potassium carbonate In acetone for 5h; Heating; | ||
With potassium carbonate In N,N-dimethyl-formamide for 72h; |
With potassium carbonate In acetone at 60℃; | General procedure (GP2) for the preparation of methylated flavones and isoflavones 15-19 General procedure: Methyl iodide (25 mmol, 5 eq) was added to a solution of potassium carbonate (30 mmol, 6 eq) and flavones (5mmol, 1.0 equal) or isoflavones (5 mmol, 1.0 equal) in acetone (60 mL). The reaction mixture was stirred overnight at 60°C, and the solvent was then evaporated in vacuum. The residue was purified by silica gel column chromatography, eluting with a solution of 15% MeOH in dichloromethane (Scheme S2), to yield yellow solid 15-19 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine hydrochloride at 180 - 190℃; for 6h; Inert atmosphere; | |
90% | With pyridine hydrochloride at 180℃; for 6h; Inert atmosphere; | Apigenin (1): Compound 5 (1.4 g, 0.005 mol) and excess pyridinehydrochloride (5.0 g, 0.04 mol) were heated at 180 °C for 6 h under aN2 atmosphere. The mixture was cooled to room temperature and H2O(100 mL) was added. The mixture was stirred for another 30 min andcooled to below 5 °C for several hours. The precipitate was filteredoff, washed with cold ethanol and recrystallised from absoluteethanol to give compound 1 as yellow crystals (1.2 g, yield 90%); |
90% | With tribromoborane In dichloromethane at 20℃; for 24h; Inert atmosphere; |
61.5% | Stage #1: 4',5,7-trimethoxyflavone With Aluminum Chloride In toluene at 80 - 140℃; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate; toluene at 0℃; | Apigenin (7) (4',5,7-trihydroxyflavone) A mixture of4',5,7-trimethoxyflavone (5) (50 g, 0.16 mol) and toluene (500mL, 10 vol.) were added to aluminium chloride (191.8 g, 1.44mol) at 80-100 °C. After completion of the addition the temperaturewas increased slowly to 130-140 °C and stirred for 1.5 h.TLC (50 % EtOAc in hexane) showed complete absence ofstarting material. After completion of the reaction the flask iscooled in an ice-salt mixture at 0 °C. Charged dilute HCl 25 %solution (1000 mL) dropwise for 2 h. The solution was filtered,dried and then washed with hot toluene. The crude productwas dissolved in methanol (600 mL) at reflux condition for1 h and filtered to obtain the pure 4',5,7-trihydroxy flavones(apigenin) (7). The yield was 61.5 % with a purity of 98.21 %obtained. |
10 g | With hydrogen iodide In acetic anhydride at 115 - 118℃; for 6h; | |
With pyridine hydrochloride at 120℃; | 2.4; 1.4 S04: Synthesis of carvaginin 4',5,7-trihydroxyflavonoids, using pyridine hydrochloride to remove the methyl group of methyl flavonoids, pyridine hydrochloride not only acts as a solvent, but also participates in chemical reactions,The reaction temperature is 120 degrees,After demethylation,There are many phenolic hydroxyl groups on the benzene ring, which are more active.easily oxidized,The entire reaction environment needs to be sealed,And replace the air in the system with nitrogen for protection,Experiments found that when the amount of pyridine hydrochloride was 8 times that of methyl flavonoids,The raw materials are basically reacted completely, after calculation,The total yield from the aniline raw material to the carapicin product reached a maximum of 39.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2-chloro-1-(2,4,6-trihydroxyphenyl)ethan-1-one; 4-hydroxy-benzaldehyde With sodium hydroxide In ethanol; water Stage #2: With hydrogenchloride Further stages.; | |
90% | Stage #1: 4-hydroxy-benzaldehyde With potassium hydroxide In ethanol; water for 0.166667h; Inert atmosphere; Stage #2: 2-chloro-1-(2,4,6-trihydroxyphenyl)ethan-1-one In ethanol; water at 60℃; for 4h; | Apigenin (7): 4-hydroxybenzaldehyde (1.22 g, 9.97 mmol, 1.0 equiv) was added to asolution of 50% KOH (aq.) (6.72 g, 59.82 mmol, 6.0 equiv) and ethanol (3 mL) andstirred for 10 min. Then compound 9 (2.02g, 9.97 mmol, 1.0 equiv) was added to the reaction mixture and heated to 60 °C and stirred for 4 h. After cooled toroom temperature, the mixture was poured into ice water and acidified withconcentrated hydrochloric acid to pH = 3. Then the suspension was filtrated, washed and the residue was dried toafford Apigenin(7) (2.43 g, 90%) as a red solid. Data for Apigenin (7): 1H NMR (400 MHz,DMSO) δ 10.84 (s, 2H), 10.02 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 6.87 (d,J = 8.6 Hz, 2H), 6.54 (s, 1H), 6.21 (s, 1H), 6.08 (s, 1H). |
83% | With potassium hydroxide In ethanol at 20 - 60℃; for 6h; | 1.2 take 13.84g (0.25mol)Potassium hydroxide and formulated into 40% KOH solution and poured into a 100 mL round bottom flask, 10 mL of ethanol and 6.24 g (51.11 mmol) of p-hydroxybenzaldehyde were added, and finally 10.00 g (51.11 mmol)2,4,6-trihydroxybenzene-chloroacetone was stirred to room temperature and placed in an oil bath at 60 ° C for 6 h,TLC detection reaction is complete, the reaction solution into the hydrochloric acid ice bath, adjust the pH to 3-4, filter,Dried apigenin11.07 g, yield 83%. |
61% | With potassium hydroxide In methanol at 20℃; for 18h; | 1 Example 1 8-((4-(Cyclopropanecarbonyl)piperazin-1-yl)methyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-benzopyran-4 -Ketone (Compound 1) Dissolve II-1 powder (1.01g, 5mmol) in methanol (20mL) to form a solution, and put potassium hydroxide (2.52g, 15mmol) and p-hydroxybenzaldehyde (0.62g, 5.05mmol) into the above solution. The mixture was brought to room temperature and stirred for 18h. After monitoring the complete disappearance of II-1 by thin-layer chromatography, the mixture was diluted with ice-cooled water (50 mL) and acidified to pH=5 with 2M hydrochloric acid. Use a rotary evaporator to remove excess methanol. The residue was extracted three times with dichloromethane and water. Take the combined organic layer, dry over Na2SO4, and remove the solvent with a rotary evaporator. The residue was purified by silica gel column chromatography (dichloromethane and methanol, from 99:1 to 93:7) to obtain pure compound IV (0.82 g, 61%). |
52% | With potassium hydroxide In methanol at 20℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; | |
64% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 9h; Inert atmosphere; | 7.1 7.1 Preparation of 7,4'-bis (methoxymethoxy) -5-hydroxyflavone (ii) To a 250 mL three-necked flask was added 50 mL of anhydrous DMF,Room temperature stirring,Add apigenin 10g (37mmol),N, N-diisopropylethylamine (9.5 g, 74 mmol).Argon under the protection,To the reaction system was slowly added dropwise 9.25 g (74 mmol)Bromomethyl methyl ether,After the dropwise addition, the temperature was raised to 70 ° C for 9 hours.TLC monitoring reaction.After the reaction, add 50 mL of water,Adjust pH to neutral with dilute hydrochloric acid.Ethyl acetate was added (100 mL x 3).The ethyl acetate layer was washed with saturated brine,Dried over anhydrous sodium sulfate.Filtered anhydrous sodium sulfate,The solvent is distilled off,Light yellow in the crude.The crude product is mixed with silica gel,With 200-300 mesh silica gel column chromatography separation and purification,Eluent V (petroleum ether): V (ethyl acetate) = 12: 1,To give 8.6 g of a yellow solid,I.e., 74'-bis (methoxymethyloxy) -5-hydroxyflavone (ii)Yield: 64%. |
51% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 3.7 Synthesis of 7,4’-[di(methoxymethoxy)]-apigenin (8) Bromomethylmethyl ether (2 equiv) was added dropwise to a solution of apigenin (1 equiv))with anhydrous N,N-diisopropylethylamine (2 equiv))in anhydrous N,N-Dimethylformamide under an atmosphere of argon, and stirring was continued for 12 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15% ethyl acetate in hexanes gradient). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; triethylamine In N,N-dimethyl-formamide for 8h; Cooling with ice; | |
87% | With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 4.5h; Cooling with ice; | General procedure for the synthesis of perhexanoylated flavonoid (1a-7a) General procedure: Flavonoid (1 (5.40 g, 0.02 mol), 2 (5.72 g, 0.02 mmol), 3 (5.45 g, 0.02 mmol), 4 (5.69 g, 0.02 mmol), 5 (5.08 g, 0.02 mmol), 6 (5.40 g, 0.02 mmol), or 7 (6.04 g, 0.02 mmol)) was dissolved in DMF (50 mL); Et3N (for 4, 5, 6.9 mL, 0.05 mol; for 1, 3, 6, 9.7 mL, 0.07 mol; for 2, 12.4 mL, 0.09 mol; for 7, 15.3 mL, 0.11 mol) and DMAP (240 mg, 2 mmol) were added. The mixture was then cooled in an ice-bath, and hexanoyl chloride (for 4, 5, 6.9 mL, 0.05 mol; for 1, 3, 6, 9.7 mL, 0.07 mol; for 2, 12.4 mL, 0.09 mol; for 7, 15.3 mL, 0.109 mol) was added and the reaction was allowed to slowly rise to room temperature in 30 min and stirred for an additional 4 h. After complete consumption of the flavonoid starting material as shown by TLC, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed with 1 M HCl aqueous solution (100 mL), saturated aqueous NaHCO3 (100 mL * 2), brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product (oil/solid), which was further purified by crystallization (methanol). Compound 1a-3a (1a, 9.8 g, 87%, Ref. [30]; 2a, 11.5 g, 85%; 3a, 10.4 g, 92%) were obtained as a light yellow solid and 4a-7a (4a, 8.4 g, 87%; 5a, 8.6 g, 95%, Ref. [28]; 6a, 9.1 g, 81%, Ref. [43]; 7a, 13.1 g, 83%) as a white solid. Analytical data and NMR spectra see Supporting Information. |
With dmap; triethylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With palladium 10% on activated carbon; hydrogen at 20℃; | General procedure for the preparation of compounds 1-3 and 8 General procedure: To a solution of flavonoid (4 mmol) in dry tetrahydrofuran (15 mL) or N,N-dimethylformamide (15 mL) was added 20-400 mgof 10% Pd/C in a hydrogen atmosphere at room temperature. The resulted mixture was stirred for 3-6 h, and the catalyst was removed by filtration. Concentration under reduced pressure furnished a residue, which was purified over a silica gel column eluting with EtOAc-petroleum ether. |
25% | With palladium 10% on activated carbon; hydrogen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42%Chromat. | With Agrocybe aegerita peroxygenase; dihydrogen peroxide; ascorbic acid; In water; N,N-dimethyl-formamide; at 20℃; for 8h;pH 7.0;phosphate buffer; Enzymatic reaction;Kinetics; | General procedure: Typical reaction mixtures (0.2-1.5 mL) contained purified peroxygenase (1-2 U mL-1), potassium phosphate buffer (50 mM, pH 7.0 resp. pH 9.0), 20% (vol/vol) DMF, and the flavonoid substrate (1-10 mM). Ascorbic acid (4 mM) was used to inhibit further oxidation of the phenolic products that were released.[15] and [17] The reactions were started by the addition of H2O2 (0.1-2.2 mM) via single injection or continuous syringe pump supply at room temperature under vigorous stirring. The reaction mixtures were analyzed after 8 h of incubation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.1% | With potassium carbonate In acetonitrile Inert atmosphere; Reflux; | 4.1.1. General procedure for the synthesis of intermediates 5a-5c General procedure: The appropriate 1,4-dibromobutane 4 (9.0 mmol) was added toa mixture of the starting material apigenin (1), naringenin (2) andgenistein (3) (3.0 mmol), respectively, and anhydrous K2CO3(553 mg, 4.0 mmol) in CH3CN (20 mL). The reaction mixture washeated to 60-65 °C and stirred for 8-10 h under an argon atmosphere.After complete reaction, the solvent was evaporated underreduced pressure.Water (30 mL) was added to the residue, and themixture was extracted with dichloromethane (30 mL x 3). Thecombined organic phases were washed with saturated aqueoussodium chloride, dried over sodium sulfate, and filtered. The solventwas evaporated to dryness under reduced pressure. The residuewas purified on a silica gel chromatography usingdichloromethane/acetone (100:1) as eluent to obtain the intermediates5a-5c. The data of compound 5c had been obtained inour previous work [28]. |
30% | With anhydrous sodium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; | 2.2.1 General procedures for the preparation of 2 General procedure: A solution of apigenin 1 (0.37 mmol) in DMF (0.5 mL) was added dropwise to a mixture of alkyl bromide (2.22 mmol) and sodium carbonate (1.11 mmol) in DMF (1.5 mL). After stirring for 6 h at room temperature, the reaction mixture was filtered. The filtrate was diluted by 50 mL of EtOAc and washed with water (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, evaporated to dryness and the residue was purified by column chromatography. |
With potassium carbonate In acetonitrile at 65℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.9% | With anhydrous sodium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; | 2.2.1 General procedures for the preparation of 2 General procedure: A solution of apigenin 1 (0.37 mmol) in DMF (0.5 mL) was added dropwise to a mixture of alkyl bromide (2.22 mmol) and sodium carbonate (1.11 mmol) in DMF (1.5 mL). After stirring for 6 h at room temperature, the reaction mixture was filtered. The filtrate was diluted by 50 mL of EtOAc and washed with water (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, evaporated to dryness and the residue was purified by column chromatography. |
52.7% | With potassium carbonate In acetonitrile at 65℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.8% | With anhydrous sodium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; | 2.2.1 General procedures for the preparation of 2 General procedure: A solution of apigenin 1 (0.37 mmol) in DMF (0.5 mL) was added dropwise to a mixture of alkyl bromide (2.22 mmol) and sodium carbonate (1.11 mmol) in DMF (1.5 mL). After stirring for 6 h at room temperature, the reaction mixture was filtered. The filtrate was diluted by 50 mL of EtOAc and washed with water (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, evaporated to dryness and the residue was purified by column chromatography. |
With potassium carbonate In acetonitrile at 65℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 2h; | 7-(2-Bromoethoxy)-5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (2a). To a solution of 1 (1.35 g,5 mmol) in 100 mL of anhydrous DMF, 1,2-dibromoethane (23.5 g, 125 mmol) and anhydrou spotassium carbonate (0.7 g, 5 mmol) were added, followed by heating at 120 °C for 2 h. After the completion of reaction, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether/ethylacetate = 2:1) to obtain 2a in 70% yield |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; | General procedure for preparation of compounds 2a-2e General procedure: A flavonoid 1 (5 mmol) was dissolved in 30 mL of DMF, followed by addition of 1,2-dibromoethane (4.3 mL, 50 mmol) and K2CO3 (20 mmol). The resulted mixture was stirred at 70 °C for 10-15 h. Three times volume of ice-cooled water was added with vigorously stirring, which was acidified with HCl and extracted with EtOAc for three times. The combined organic layer was washed with saturated brine and then dried over MgSO4. Removal of solvent under reduced pressure yield a light yellow powder. Flash chromatography (petroleum ether/EtOAc, from 3/1 to 1/1) furnished 2 in good yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 2h; | 7-(3-Bromopropoxy)-5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (2b). To a solution of 1 (1.35 g,5 mmol) in 100 mL of anhydrous DMF, 1,3-dibromopropane (25.5 g, 125 mmol) and anhydrous potassium carbonate (0.7 g, 5 mmol) were added, followed by heating at 120 °C for 2 h. After the completion of reaction, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified using column chromatography (petroleum ether/ethylacetate = 2:1) to obtain 2b in 68% yield |
65% | With potassium carbonate In acetone for 12h; Reflux; | 1.1 step 1 Apigenin (2.7g, 10mmol), anhydrous K2CO3 (1.38g, 10mmol),10mL of 1,3-dibromopropane and 150mL of acetone were added to a 250mL round bottom flask.Heat and stir under reflux for about 12h. The reaction was then stopped and acetone was removed by rotary evaporation.The resulting mixture was washed with petroleum ether to remove 1,3-dibromopropane, and filtered under reduced pressure.Solid-liquid separation, solids were collected. Wash with plenty of distilled water to remove potassium carbonate and dry.The crude product was purified by column chromatography (eluent composition: CH2Cl2: CH3OH = 100: 1), and finally a yellow solid 2 was obtained with a yield of 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; | 4.2. General procedure for the synthesis of flavone and isoflavonederivatives (1a-7c) General procedure: The synthesis of flavone and isoflavone derivatives followed the general reaction pathway outlined in Scheme 1. The substituted dinitro-compounds (series A: 1 mmol; series B: 2 mmol) mixed with flavones or isoflavones (1 mmol) through by using t-BuOK (series A: 1 mmol; series B: 2 mmol) as catalyst in 20-30 ml DMF for 3-4 h at room temperature. The reaction was monitored by TLC. The products are extracted with ethyl acetate and saturated salt water, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography using petroleum ether and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; | General procedure: The synthesis of flavone and isoflavone derivatives followed the general reaction pathway outlined in Scheme 1. The substituted dinitro-compounds (series A: 1 mmol; series B: 2 mmol) mixed with flavones or isoflavones (1 mmol) through by using t-BuOK (series A: 1 mmol; series B: 2 mmol) as catalyst in 20-30 ml DMF for 3-4 h at room temperature. The reaction was monitored by TLC. The products are extracted with ethyl acetate and saturated salt water, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography using petroleum ether and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; | 4.2. General procedure for the synthesis of flavone and isoflavonederivatives (1a-7c) General procedure: The synthesis of flavone and isoflavone derivatives followed the general reaction pathway outlined in Scheme 1. The substituted dinitro-compounds (series A: 1 mmol; series B: 2 mmol) mixed with flavones or isoflavones (1 mmol) through by using t-BuOK (series A: 1 mmol; series B: 2 mmol) as catalyst in 20-30 ml DMF for 3-4 h at room temperature. The reaction was monitored by TLC. The products are extracted with ethyl acetate and saturated salt water, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography using petroleum ether and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide; toluene at 80℃; for 20h; Inert atmosphere; | 4.2.4. Dendrimer 3d-G2. Apigenin (7.4 mg, 0.027 mmol) was dissolved in mixture of DMF and toluene (2 ml, 1/1 v/v). Then, K2CO3 (75 mg, 0.54 mmol), 18-crown-6 (5 mg, 0.02 mmol) and 2d (154 mg, 0.19 mmol) were added. The reaction mixture was stirred at 80 °C for 20 h. Then, it was diluted by dichloromethane and washed by water. Organic phases were collected, dried (MgSO4), and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient of diethyl ether in toluene/hexane (75/25 v/v)) and precipitated by pentane from THF to yield title product (40%, 28 mg) as a colorless solid glass: IR 1641, 1592,1145, 1044 cm-1; 1H NMR (500 MHz, CDCl3, 25 °C) δ 7.73 (d, J=9.1 Hz, 2H), 7.27-7.47 (m, 60H), 7.00 (d, J=9.1 Hz, 2H), 6.93 (d, J=2.1 Hz, 2H), 6.62-6.74 (m, 15H), 6.43-6.61 (m, 12H), 6.47 (d, J=2 Hz, 1H), 5.15 (s, 2H), 4.90-5.07 (m, 40H) ppm; 13C NMR (126 MHz, CDCl3, 25 °C) δ 177.18, 162.65, 161.01, 160.54, 160.18, 160.14, 160.08, 159.63, 159.52, 143.15, 139.47, 139.15, 139.07, 139.00, 138.74, 138.11, 136.85, 136.73, 136.72, 128.57, 128.51, 128.00, 127.99, 127.90, 127.61, 127.54, 127.51, 127.29, 124.14, 115.18, 109.86, 107.82, 106.47, 106.41, 106.39, 105.28, 101.83, 101.70, 101.59, 101.56, 70.12, 70.07, 70.01, 70.00 ppm. MS (MALDI-TOF) m/z found 2448.5 [M+H]+, calcd 2449.9; found 2472.4 [M+Na]+, calcd 2471.9; found 2488.5 [M+K]+, calcd 2487.9; Anal. Calcd for C162H136O23: C, 79.39, H, 5.59. Found: C, 79.22, H, 5.47. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrachloromethane; triethylamine In tetrahydrofuran at 20℃; for 24.5h; Cooling with ice; | 4.1.2 General procedure for the synthesis of compound 3 Compound 1 (1.0mmol) was added to a solution of 20mL THF and 5mL Et3N (35.6mmol), and the mixture was stirred until dissolved. A solution of HP(O)(OEt)2 (1.1equiv. per OH; the numbers of OH were calculated one less than that of compound 1) and 5mL CCl4 (35.6mmol) was added dropwise with vigorous stirring in an ice-water bath over 30min. The reaction proceeded for 24h at room temperature. The resulting salt of triethylamine was filtered. The filtrate was evaporated in vacuo, and 10mL of water was added. The solution was extracted with EtOAc (3×30mL), washed with 1M HCl (3×15mL), saturated NaHCO3 solution (3×15mL) and brine, and dried over anhydrous Na2SO4. After removal of the solvent in vacuo, the residue was purified by column chromatography on deactivated silica gel with petroleum ether/EtOAc (1:1-1:4), CH2Cl2/MeOH (100:1-60:1) as eluant to give the corresponding product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tetrachloromethane; triethylamine In tetrahydrofuran at 20℃; for 24h; Cooling with ice; | 4.1.3 General procedure for the synthesis of compound 4 General procedure: Compound 1 (1.0mmol) was added to a solution of 20mL THF and 5mL Et3N (35.6mmol), and the mixture was stirred until dissolved. A solution of HP(O)(OMe)2 (1.1equiv. per OH; the numbers of OH were calculated one less than that of compound 1) and 5mL CCl4 (35.6mmol) was added dropwise with vigorous stirring in an ice-water bath. The reaction proceeded for 24h at room temperature. The resulting salt of triethylamine was filtered. The filtrate was evaporated in vacuo, and 10mL of water was added. The solution was extracted with EtOAc (3×30mL), washed with 1M HCl (3×15mL) until neutral, saturated NaHCO3 solution (3×15mL) and brine, and then dried over anhydrous Na2SO4. After removal of the solvent in vacuo, the residue was purified by column chromatography on deactivated silica gel CH2Cl2/MeOH (60:1-30:1) with as eluant to give the corresponding product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 4,6-bis(methoxymethyl)-2-(4-acetoxybenzoyloxy)acetophenone With potassium hydroxide In pyridine at 50℃; for 0.333333h; Stage #2: With acetic acid In pyridine; water for 0.5h; Stage #3: With hydrogenchloride In methanol Reflux; | Preparation of Flavones 4, 8 & 10 General procedure: To the esters 3 (1 mmol) in dry pyridine (1 ml) at 50 °C,powdered KOH (2 mmol) was added and reaction mixture was stirred vigorously for 20 min. The reaction mass was cooled, added to aqueous acetic acid (20 ml, 10%) and stirred for 30 min. It was extracted with diethyl ether (25 mlx 2) and washed with water (10 ml x 2), dried over anhydrous Na2SO4. On removal of solvent, diketones (containing some enol forms) were obtained as yellow solid products which gave green ferric reaction and were soluble in aq.NaOH (deep yellow solution). Compounds were identified by IR and UV spectral measurements (see Table S1 in supplementary information). The diketone/enol mixtures (200mg, without purification) were taken in methanolic HCl (20ml, 10%) and refluxed for 1-2 h till the completion of reaction(monitored by TLC solvent system, toluene 50: ethylacetate50: formic acid 10). Methanol was removed and reaction mass was poured into ice-water mixture, stirred for30 min, centrifuged; the separated flavones were purified through column chromatography using SiO2 and eluted in 2-3% methanol in chloroform. Compound 4 were crystallized from mixtures of chloroform/methanol. Yields, melting points and spectral properties are given below. Compounds were characterized by 1H NMR, UV and IR data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-Bromosuccinimide In trifluoroacetic acid at 20℃; for 5h; | 6,8-Dibromoapigenin (13): 6,8-Dibromoapigenin (13): NBS (2.88 g, 16.2 mmol) was added toa solution of apigenin (2.16 g, 8 mmol) in TFA (22 mL). The reactionmixture was stirred for 5 h at room temperature, and then poured intoice water. The resulting precipitate was filtered, washed with waterand dried under vacuum to afford a green crude solid which waschromatographed on silica gel using petroleum ether/ethyl acetate(4 : 1) as the eluent to afford 13 as a yellow solid: 3.15 g; 93%; m.p.311-313 °C; |
With N-Bromosuccinimide In acetone at 22℃; for 0.716667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.4% | With potassium carbonate In acetone for 24h; Reflux; | General procedure: Chrysin (1.3 g, 5 mmol) in 120 mL of acetone was added to anhydrous potassium carbonate (0.7 g, 5 mmol). The mixture was stirred at reflux for 30 min, bromoethane (1.2 mL, 15 mmol) was added dropwise, followed by refluxing for 24 h. The mixture was cooled to room temperature, filtered, and was concentrated in vacuo. The residue was purified with a silica gel column eluting with a mixed solvent (EtOAc/CH2Cl2 = 1:10). O4',O7-Dihexyl apigenin (10): Yellowish powder; yield: 78.4%; mp: 88.5-88.6 °C; 1H NMR (400 MHz, CDCl3): δ 12.80 (s, 1H, 5-OH), 7.82 (d, 2H, J = 8.8 Hz, aromatic H2',6'), 7.00 (d, 2H, J = 8.8 Hz, aromatic H3',5'), 6.56 (s, 1H, aromatic H8), 6.47 (s, 1H, aromatic H3), 6.35 (s, 1H, aromatic H6), 4.17-3.93 (m, 4H, -OCH2-), 2.02-1.66 (m, 4H, -CH2-), 1.42 (dd, 4H, J = 48.2, 3.8 Hz, -CH2-), 1.25 (s, 8H, -CH2CH2-), 0.92 (t, 6H, J = 6.7 Hz, -CH3); MALDI-TOF: m/z 439 ([M+H]+); Anal. calcd. for C27H34O5: C, 73.94; H, 7.81; found: C, 73.79; H, 7.79. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere; Cooling with ice; | 1.1 1.1 Preparation of 5,4'-dihydroxy-7- (1-ethoxycarbonylmethoxy) flavonoids (i-1) To a 250 mL three-necked flask was added 50 mL of anhydrous DMF,Ice bath cooling, stirring conditions,Add apigenin 1g (3.7mmol),Anhydrous potassium carbonate 0.41 g (2.96 mmol).Argon under the protection,To the reaction system was slowly added dropwise 0.67 g (3.7 mmol)2-bromoacetic acidEthyl ester,After the drop, remove the ice bath,Room temperature reaction for 6 hours.TLC monitoring reaction. After the reaction,The potassium carbonate was removed by filtration,Add 50mL of water,Adjust pH to neutral with dilute hydrochloric acid.Ethyl acetate was added (100 mL x 3).The ethyl acetate layer was washed successively with saturated sodium chloride solution,Washed with water, dried over anhydrous sodium sulfate.The anhydrous sodium sulfate was removed by filtration,The solvent was distilled off under reduced pressure,A crude yellow solid.The crude product is mixed with silica gel,With 200-300 mesh silica gel column chromatography separation and purification,Eluent V (petroleum ether): V (ethyl acetate) = 6: 1,To give 0.97 g of a yellow solid,Namely 5,4'-dihydroxy-7- (1-ethoxycarbonylmethoxy) flavone (i-1) in 68% yield. |
56% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
50% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4 5. Synthesis of ProGel-apigenin Apigenin (200 mg, 0.74mmol) was dissolved in DMF (3 mL), and then K2CO3 (102 mg, 0.74mmol) and ethyl bromoacetate (124 mg, 0.74mmol) were added. The mixture was stirred at room temperature overnight. Then the reaction was quenched with water and the solution was extracted with EA (20 mLx3). The organic phase was dried over Na2S04, filtered, concentrated, and purified by flash column chromatography (MeOH/DCM = 1:50) to give the corresponding product (130 mg, yield: 50%). 1 H NMR (400 MHz, DMSO-iL): d (ppm) = 12.96 (s, 1H), 10.39 (s, 1H), 7.95 (d, 7 = 8.75 Hz, 2H), 7.09 (d, 7 = 8.75 Hz, 2H), 6.93 (s,lH), 6.80 (d, 7 = 2.05 Hz, 1H), 6.40 (d, 7 = 2.05 Hz, 1H), 4.92 (s, 2H), 4.18 (q, 2H), 1.23 (t, 7 = 7.1 Hz, 3H). |
Stage #1: 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 60 - 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Cooling with ice; | 3.3 Synthesis of 7-(methoxymethoxy)-apigenin (4). Chloromethyl methyl ether (1 equiv) was added dropwise to asolution of apigenin (1 equiv)with anhydrous K2CO3 (1 equiv) in anhydrous N,N-Dimethylformamidein ice bath under anatmosphere of argon, and stirring was continued for 12 h at room temperature. The reaction was monitored by TLC. The product was purified by silica gel chromatography (normal phase, 30% ethyl acetate in hexanes gradient). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
30% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere; | Ethyl-2-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)acetate (7a) General procedure: To a solution of Chrysin (1.00g, 3.93mmol) in DMF (40mL) was added K2CO3 (1.09g, 7.86mmol) and compound 6a (1.31g, 7.86mmol) under Ar. The mixture was stirred at 70°C for 6h. The mixture was then diluted with EtOAc (200mL) and washed with saturated NaCl solution (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2: CH3OH=90:1) to afford compound 7a (1.08g, 81%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In N,N-dimethyl-formamide for 24h; Inert atmosphere; | 5.1.3 5,7-Diisopropoxy-2-(4-isopropoxyphenyl)-4H-chromen-4-one (4) K2CO3 (5.39g, 39mmol) and (CH3)2CHI (6.63g, 39mmol) were added to a stirred solution of Apigenin 3 (2.70g, 10mmol) in dry N, N-Dimethylformamide (DMF) (10mL). After the addition, the mixture was heated to 45°C and stirred for 24h. The reaction was cooled to room temperature, filtered and diluted with ethyl acetate (100mL) and the resulting solution was poured into aqueous HCl (1M, 100mL). The organic layer was separated, washed with saturated NaCl (3×100mL) and dried over anhydrous Na2SO4. After concentrated to dryness under reduced pressure, the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 40:1) to afford the known compound 4 (3.25g, 82%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 7.79 (d, J=8.8Hz, 2H), 6.96 (d, J=8.8Hz, 2H), 6.52 (d, J=2.4Hz, 1H), 6.50 (s, 1H), 6.35 (d, J=2.4Hz, 1H), 4.69-4.55 (m, 3H), 1.45 (d, J=6.0Hz, 6H), 1.40 (d, J=6.0Hz, 6H), 1.38 (d, J=6.0Hz, 6H); 13C NMR (100MHz, CDCl3) δ 177.4, 162.0, 160.5, 160.4, 159.9, 159.4, 127.6, 123.7, 115.8, 110.1, 107.6, 100.8, 94.5, 72.5, 70.5, 70.1, 22.0, 21.9; LRMS (ESI) m/z 397 [M+H]+. |
78% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; | 5,7-diisopropoxy-2-(4-isopropoxyphenyl)-4H-chromen-4-one (10): K2CO3 (5.39g, 39 mmol, 3.9 equiv) and(CH3)2CHI (6.63 g, 39 mmol, 3.9 equiv) were added to a stirredsolution of Apigenin (7) (2.70 g, 10mmol) in dry DMF (10 mL). After the addition, the mixture was heated to 60 °Cand stirred for 24 h. The reaction was cooled to room temperature, filtered anddiluted with ethyl acetate (100 mL) and the resulting solution was poured intoaqueous HCl (1 M, 100 mL). The organic layer was separated, washed withsaturated NaCl (3×100 mL) and dried over anhydrous Na2SO4.After concentrated to dryness under reduced pressure, the crude product waspurified by column chromatography onsilica gel (petroleum ether/ethyl acetate 40:1) to afford theknown compound 10 (3.09 g, 78%) as ayellow solid. Data for 10:1H NMR (400 MHz, CDCl3) δ 7.80 (d, J= 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.32 (d, J= 1.6 Hz, 1H), 6.09 (d, J = 1.6 Hz, 1H), 4.73 (dq, J = 12.2, 6.0Hz, 1H), 4.62 (dp, J = 12.2, 6.0 Hz, 2H), 1.43 (d, J = 6.0 Hz,6H), 1.40 (d, J = 6.0 Hz, 6H), 1.36 (d, J = 6.0 Hz, 6H). |
73% | With potassium carbonate In N,N-dimethyl-formamide | 1.3 (10 mmol) of apigenin was placed in a 100 mL pressure bottle and dissolved in 30 mL of DMF. To the stirred solution was added 25.57 g (0.185 mol)Anhydrous potassium carbonate and 31.45 g (0.185 mol)2-iodopropane, placed in 60 ° C oil bath for 24 hours,After the TLC test was complete, the reaction solution was extracted with ethyl acetate and the organic phase was washed three times with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate using the developing solvent petroleum ether: ethyl acetate = 40: 1, 200-300 mesh silica gel column chromatography purification5,7-diisopropoxy-2- (4-isopropoxyphenyl) -4H-benzopyran-4-one, 10.70 g,Yield 73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.4 g | 5.0 g of 6H2O-aluminum trichloride, 100 ml of methanol,98% wild luteolin 10g,70 sealed hydrolysis 15h, Adding phosphoric acid 6ml,Mixing,Ultrasound 30min,Adding 0.1% phosphoric acid in 1000ml of the solution with stirring slowly, placing the mixture for 30 minutes, placing overnight, filtering and washing the filter cake to obtain a mixture of wild erosin, apigenin-7-O-glucoside and apigenin; The column was eluted with chloroform-methanol (12: 1), then apigenin was first eluted, and the ratio of chloroform to methanol was adjusted to (6: 1) to give apigenin-7-O- Glucoside 3.4g, determined by HPLC content of 98.3%, and finally out of a small amount of wild lacquer glycosides |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 30h; Inert atmosphere; | 5.1.5 5-hydroxy-7-isopropoxy-2-(4-isopropoxyphenyl)-4H-chromen-4-one(6) K2CO3 (3.31g, 24mmol) and (CH3)2CHI (4.08g, 24mmol) were added to a stirred solution of Apigenin 3 (2.70g, 10mmol) in dry DMF (10mL). After the addition, the mixture was stirred at room temperature for 30h. The reaction was filtered and diluted with ethyl acetate (100mL) and the resulting solution was poured into aqueous HCl (1M, 100mL). The organic layer was separated, washed with saturated NaCl (3×100mL) and dried over anhydrous Na2SO4. After concentrated to dryness under reduced pressure, the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to afford the known compound 6 (3.36g, 95%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In dichloromethane at 20 - 90℃; for 12h; | 4.1 1) Preparation of Structural Compounds of Formula III 10 g (37 mmol) of apigenin was dissolved in a mixed solvent of 60 mL of dichloromethane and 20 mL of triethylamine, 69 mL of pivaloyl chloride (d=0.979 g/ml, 555 mmol) was slowly added while stirring at room temperature, and the mixture was heated to 90° C. to reflux for about 12 minutes. Hours, TLC detected that the reaction was complete. In a system where the low-boiling solvent was evaporated under reduced pressure at 50°C, 90 mL of ethyl acetate was added, and a large amount of white solid gradually precipitated. Stirring was continued for 1 hour and cooled to room temperature and allowed to stand overnight in the refrigerator. Filtration gave 5,7,4'-tripivaloyloxyflavone as an off-white solid. After drying, it was recrystallized from ethanol to obtain 11.7 g of a pure product of 5,7,4'-tripivaloyloxyflavone (ie, the structural compound represented by formula III). The product was white-like, and the chromatographic purity was 98.0% or more. The yield was 72%. . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 6h; Inert atmosphere; | Ethyl-2-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)acetate (7a) General procedure: To a solution of Chrysin (1.00g, 3.93mmol) in DMF (40mL) was added K2CO3 (1.09g, 7.86mmol) and compound 6a (1.31g, 7.86mmol) under Ar. The mixture was stirred at 70°C for 6h. The mixture was then diluted with EtOAc (200mL) and washed with saturated NaCl solution (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2: CH3OH=90:1) to afford compound 7a (1.08g, 81%) as a pale yellow solid. |
20% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h; | 7.1 1) Preparation of Compound (7-1) The apigenin (400.0 mg, 1.48 mmol) was dissolved in N,N-dimethylformamide (14 mL).Potassium carbonate (410 mg, 2.96 mmol), methyl 6-bromohexanoate (371 mg, 1.78 mmol) was added to the above mixture, and the system was heated to 80 ° C for 6 hours, 1N HCl (20 mL × 3), The ester was extracted (20 mL × 2), and the organic phase was washed with brine (20 mL)(light yellow solid, 600.0 mg, yield: 20%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide; acetone for 2h; Inert atmosphere; | 5,7-bis((3,5,6-Trimethylpyrazin-2-yl)methoxy)-2-(4-((3,5,6-trimethylpyrazin-2-yl)methoxy)phenyl)-4Hchromen-4-one (24). TMP-Br (7.93 mmol) and apigenin (1.85 mmol) were dissolved in dry DMF (30 mL),then K2CO3 (10.87 mmol) was added in portions. The mixture was refluxed and kept at 75 °C for2 h under a nitrogen atmosphere; the brown solution was filtered and concentrated under vacuum.The product was separated by flash chromatography with dichloromethane-acetone (8:1) as eluentand recrystallized from dichloromethane. White powder, m.p.: 180.9-181.5 °C, yield 55%. 1H-NMR(CDCl3) (ppm) δ 7.78 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 10.4 Hz, 2H), 6.51 (s, 1H),5.31 (s, 2H), 5.22 (s, 4H), 2.71 (s, 3H), 2.59 (s, 3H), 2.59 (s, 3H), 2.53 (s, 6H), 2.52 (s, 6H), 2.51 (s, 3H), 2.49(s, 3H); 13C-NMR (CDCl3) (ppm) δ 177.13, 162.59, 161.10, 160.65, 159.65, 159.55, 151.91, 151.67, 151.18,150.86, 150.08, 149.00, 148.93, 148.27, 145.43, 145.25, 144.79, 127.73, 124.48, 115.36, 110.00, 107.94, 98.59,95.18, 71.28, 70.39, 70.17, 21.86, 21.81, 21.67, 21.56, 21.44, 20.80, 20.72. MS (ESI) m/z: [M + H]+ 673.3158,calcd. for C39H40N6O5 672.3060. |
55% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 2h; Inert atmosphere; | 16 Example 16 Preparation of Derivatives of Ligustrazine and Apigenin (CH-15) Weigh 0.50g of apigenin in a 100mL round bottom flask, put TMP-Br at a molar ratio of 1: 3, add an appropriate amount of anhydrous DMF to the reaction bottle and stir to dissolve, then add an appropriate amount of K2CO3, under nitrogen protection, the reaction bottle was heated in an oil bath at 75 ° C for 2h (TLC tracking reaction). After the reaction is complete, cool and filter. The filtrate was heated in a water bath at 55 ° C, and DMF was removed using a rotary evaporator. After reconstituting with dichloromethane, adding silica gel to mix samples, silica gel column separation and purification, eluent dichloromethane / acetone = 10: 1-3: 1 elution, improved color development of potassium bismuth iodide, TLC detection, white Powdery target, namely compound CH-15. M.p .: 180.9-181.5 , yield 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.93% | With dihydrogen peroxide; nitric acid; triethylamine In ethanol at 20℃; for 20h; Darkness; | 8 Example 8 A method for synthesizing a apigenin-ruthenium complex according to the present invention, wherein: Eu2O30.3519 g, apigenin 1.6214 g, and H2O2 are added to Eu2O3 according to a molar ratio of Eu2O3 and apigenin 1:6. The Eu2O3 is completely destroyed, the liquid is evaporated to dryness, the residual solid is absorbed by nitric acid, the cerium nitrate crystals are recrystallized from the double distilled water to obtain cerium nitrate crystals, and the cerium nitrate crystals are dissolved in double distilled water to prepare an aqueous solution of cerium nitrate; The ethanol solution was dissolved, and the obtained aqueous solution of cerium nitrate was added thereto, and the mixture was stirred at room temperature in the dark, and the pH of the reaction system was adjusted to 8 with triethylamine and stirring was continued for 20 hours. After suction filtration, a yellow solid product was obtained, and the yellow solid was washed with ethanol and double distilled water. The product was recrystallized 3 to 5 times with methanol, and the recrystallized solid product was dried under vacuum at 60 ° C to obtain 1.8108 g of the apigenin-indole complex in a yield of 90.93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | In dimethyl sulfoxide; for 168h;Microbiological reaction; | General procedure: A substrate (5 mg) was dissolved in 0.5 mL dimethyl sulfoxide(DMSO) and added to the grown fungal culture. The reactions werecarried out for seven days. Appropriate controls (the substrate in sterilemedium and incubation of fungal strains without a substrate) were runalong with the above experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | In dimethyl sulfoxide; for 168h;Microbiological reaction; | General procedure: A substrate (5 mg) was dissolved in 0.5 mL dimethyl sulfoxide(DMSO) and added to the grown fungal culture. The reactions werecarried out for seven days. Appropriate controls (the substrate in sterilemedium and incubation of fungal strains without a substrate) were runalong with the above experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In dimethyl sulfoxide at 100℃; for 12h; | 2.2. Synthesis of apigenin-furfurylamine & apigenin-stearylamine basedbenzoxazine monomers The multifunctional benzoxazines monomers were synthesized from Apigenin and furfurylamine (AP-f) & Apigenin and stearylamine (AP-s) according to our previous reported procedure in Ref. 10 with some amendments as shown in Scheme 1. For the synthesis of apigenin-furfurylamine based benzoxazine monomer (AP-f), apigenin (5.40 g, 20.0 mmol) was dissolved in 100 ml of DMSO in 250 mL round-bottomed flask, followed by the addition of furfurylamine (6.02 g, 60 mmol). Then, 3.60 g of formaldehyde (180 mmol) was added dropwise and the mixture was stirred under reflux at 100 °C for 12 h. A homogeneous transparent yellow liquid was obtained. This solution was then precipitated in dilute NaOH solution. The precipitate was washed several times with deionized water and dried under vacuum at 60 °C for 24 h. Yield: 84%; m.p. 94 °C (Scheme 1). Apigenin-stearylamine based benzxoazine monomer (AP-s) was synthesized by adopting a similar procedure for AP-s, where stearylamine was used instead of furfurylamine. In case of stearylamine, viscous yellow colored resin was obtained. Yield: 79% |
70% | In dimethyl sulfoxide at 100℃; for 12h; | 2.2. Preparation of apigenin/furfurylamine-based bio-benzoxazine (AP-f) Apigenin/furfurylamine-based benzoxazine derivative (AP-f) was prepared according to the reported procedure by Kim et al. [28] with slight modification as follows: Apigenin (2.7 g, 10 mmol) was dissolved in DMSO (20 mL). Paraformaldehyde (2.1 g, 70 mmol) and furfurylamine (2.9 g, 30 mmol) were added to it. The mixture was stirred at 100 C for 12 h to obtain homogeneous and transparent solution, which was naturally cooled to room temperature and poured into 50 mL of anhydrous ethanol. The precipitate was filtered and alternately washed with deionized water and ethanol. The yellow product was obtained after drying at 50 C for 24 h in vacuum (yield ~70%). FT-IR (KBr, cm- 1 ):1648 (C=C-C=O), 1203 (C-O-C), 1133 (C-N-C), 1017, 923 (oxazine). 1 H NMR (400 MHz, DMSO-d6): δ 13.28 (br, 1H), 7.59-6.34 (m, 12H), 4.97 (br, 4H), 3.86-3.41 (m, 14H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In dimethyl sulfoxide at 100℃; for 12h; | 2.2. Synthesis of apigenin-furfurylamine & apigenin-stearylamine basedbenzoxazine monomers General procedure: The multifunctional benzoxazines monomers were synthesized from Apigenin and furfurylamine (AP-f) & Apigenin and stearylamine (AP-s) according to our previous reported procedure in Ref. 10 with some amendments as shown in Scheme 1. For the synthesis of apigenin-furfurylamine based benzoxazine monomer (AP-f), apigenin (5.40 g, 20.0 mmol) was dissolved in 100 ml of DMSO in 250 mL round-bottomed flask, followed by the addition of furfurylamine (6.02 g, 60 mmol). Then, 3.60 g of formaldehyde (180 mmol) was added dropwise and the mixture was stirred under reflux at 100 °C for 12 h. A homogeneous transparent yellow liquid was obtained. This solution was then precipitated in dilute NaOH solution. The precipitate was washed several times with deionized water and dried under vacuum at 60 °C for 24 h. Yield: 84%; m.p. 94 °C (Scheme 1). Apigenin-stearylamine based benzxoazine monomer (AP-s) was synthesized by adopting a similar procedure for AP-s, where stearylamine was used instead of furfurylamine. In case of stearylamine, viscous yellow colored resin was obtained. Yield: 79% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.3% | With potassium carbonate; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere; Sealed tube; regioselective reaction; | 2.2.3. General Procedure for the Synthesis of Target Derivatives 3a-3i, 4a-4g, 5a-5e General procedure: Chrysin 2a (127.12 mg, 0.5 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), K2CO3 (138.21 mg, 1.0 mmol),PPh3 (13.11 mg, 0.05 mmol), allene (112.13 mg, 1.0 mmol), and anhydrous DMF (5 mL) were addedto a 30 mL tube under argon, which was then sealed. The resulting mixture was stirred at 80 °C for12 h. After completion, the reaction solution was cooled down to room temperature before 80 mLwater was added, followed by the addition of 1 N HCl aqueous solution at 0 °C, until the pH value reached 7. Ethyl acetate (100 mL) was added to the reaction solution and the organic layer was washed sequentially with a large amount of water (4 x 200 mL), and then brine, before being dried overanhydrous Na2SO4. The solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether-ethylacetate, 5:1) to give 3a (78.8 mg,43% yield). Compounds 3b-3i, 4a-4g, and 5a-5e were prepared according to similar procedures in which the double-substitution is a by product. The products 4a-4g were generated in a shorter time compared with the other products (within 10 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.3% | With potassium carbonate; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere; Sealed tube; regioselective reaction; | 2.2.3. General Procedure for the Synthesis of Target Derivatives 3a-3i, 4a-4g, 5a-5e General procedure: Chrysin 2a (127.12 mg, 0.5 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), K2CO3 (138.21 mg, 1.0 mmol),PPh3 (13.11 mg, 0.05 mmol), allene (112.13 mg, 1.0 mmol), and anhydrous DMF (5 mL) were addedto a 30 mL tube under argon, which was then sealed. The resulting mixture was stirred at 80 °C for12 h. After completion, the reaction solution was cooled down to room temperature before 80 mLwater was added, followed by the addition of 1 N HCl aqueous solution at 0 °C, until the pH value reached 7. Ethyl acetate (100 mL) was added to the reaction solution and the organic layer was washed sequentially with a large amount of water (4 x 200 mL), and then brine, before being dried overanhydrous Na2SO4. The solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether-ethylacetate, 5:1) to give 3a (78.8 mg,43% yield). Compounds 3b-3i, 4a-4g, and 5a-5e were prepared according to similar procedures in which the double-substitution is a by product. The products 4a-4g were generated in a shorter time compared with the other products (within 10 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.9% | With potassium carbonate; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) In N,N-dimethyl-formamide at 80℃; for 10h; Inert atmosphere; Sealed tube; regioselective reaction; | 2.2.3. General Procedure for the Synthesis of Target Derivatives 3a-3i, 4a-4g, 5a-5e General procedure: Chrysin 2a (127.12 mg, 0.5 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), K2CO3 (138.21 mg, 1.0 mmol),PPh3 (13.11 mg, 0.05 mmol), allene (112.13 mg, 1.0 mmol), and anhydrous DMF (5 mL) were addedto a 30 mL tube under argon, which was then sealed. The resulting mixture was stirred at 80 °C for12 h. After completion, the reaction solution was cooled down to room temperature before 80 mLwater was added, followed by the addition of 1 N HCl aqueous solution at 0 °C, until the pH value reached 7. Ethyl acetate (100 mL) was added to the reaction solution and the organic layer was washed sequentially with a large amount of water (4 x 200 mL), and then brine, before being dried overanhydrous Na2SO4. The solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether-ethylacetate, 5:1) to give 3a (78.8 mg,43% yield). Compounds 3b-3i, 4a-4g, and 5a-5e were prepared according to similar procedures in which the double-substitution is a by product. The products 4a-4g were generated in a shorter time compared with the other products (within 10 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With Lawessons reagent In toluene at 110℃; for 6h; Inert atmosphere; | General procedure for the synthesis of thioxoflavonoids. General procedure: A flask was charged with a flavone (5 mmol) and Lawesson's reagent (2.5 mmol) under nitrogen atmosphere, after 5 min, 35 mL of dry methylbenzene was added by syringe and the mixture was stirred while being brought to reflux. The mixture was heated to 110℃ for 6h and then cooled to room temperature. The methylbenzene is removed and concentrated in vacuo. The residue was purified by column chromatography methods to obtain target products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With flavonoid 7-O-glucosyltransferase from Andrographis paniculata; In methanol; at 30.0℃; for 12h;Enzymatic reaction; | General procedure: All assays and incubations were performed in 100 ll of 50mM Tris-HCl (pH 8.0)containing 8 lg of purified proteins, 200 lM aglycone, and 3200 lM UDP-glucose.The reactions were incubated at 30 C for 12 h and terminated by the addition of200 ll of methanol. The products of the reactions were filtered through a 0.22-lmnylon syringe filter and analyzed using a Waters Acquity UPLC-I-Class system(Waters Corp., Milford, MA) with an Acquity UPLC BEH C18 column (1.7 mm,2.1mm 50 mm). The column temperature was set to 40 C, and the flow rate was400 lL/min. Mobile phase A was a 0.1% formic acid aqueous solution, and mobilephase B was acetonitrile. Gradient programs were used to analyze the reaction mixtures(Table 1). The total conversion rate was calculated to be one percent of the sumof the peak areas of the substrate and product(s). The experiment was performed inthe ESI (-) mode as previously described [17]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.9% | With potassium carbonate In acetonitrile for 12h; Reflux; | 3 Example 3 Add 2.0mmol of apigenin 1,5mmol 7mmol anhydrous potassium carbonateAnd 30ml acetonitrile, after stirring evenly,The reaction was stirred at reflux and heated for 12 hours (the progress of the reaction was tracked by TLC);After the reaction is over, reduceThe solvent was evaporated by pressure, 50ml deionized water was added, and the mixture was extracted three times with 100ml dichloromethane. The organic layers were combined and saturated chlorinatedWash with sodium, dry and filter over anhydrous sodium sulfate, evaporate the solvent of the celery aglycone carbamate compound (I-3) under reduced pressure, and leave the residueThe product was purified by column chromatography (dichloromethane: acetone=100:1v/v) to obtain the corresponding celery aglycone carbamate compound (I-3) The yield is 57.9%. The purity of the obtained target products was determined by HPLC to be greater than 97%. |
41.8% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. 2-(4-((Dimethylcarbamoyl)oxy)phenyl)-5-hydroxy-4-oxo-4H-chromen-7-yl dimethylcarbamate (3a). Light yellow oil, 41.8%yield, 98.0% HPLC purity. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H),7.88 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 2.0 Hz,1H), 6.69 (s, 1H), 6.59 (d, J = 2.0 Hz, 1H), 3.13 (s, 3H), 3.12 (s, 3H),3.05 (s, 6H). HR-ESI-MS: Calcd. for C21H20N2O7 [M+H]+: 413.1304,found: 413.1337. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.3% | With potassium carbonate In acetonitrile for 12h; Reflux; | 27 Example 27 Add 2.0mmol of apigenin 1, 15mmol of 20mmol of anhydrous potassium carbonate and 30ml of acetonitrile into the reaction flask, stir well, heat and reflux for 12 hours with stirring (reaction progress is tracked by TLC); after the reaction is over,The solvent was evaporated under reduced pressure, 50ml of deionized water was added, and the mixture was extracted three times with 100ml of dichloromethane. The organic layers were combined and then saturated with chlorine.Wash with sodium chloride, dry and filter with anhydrous sodium sulfate, evaporate the solvent of the celery aglycone carbamate compound (I-27) under reduced pressure, and leave the residueThe residue was purified by column chromatography (dichloromethane:acetone=100:1v/v) to obtain the corresponding celery aglycone carbamate compounds(I-27), the yield is 32.3%. The purity of the obtained target products was determined by HPLC to be greater than 97%. |
23.3% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.3% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.8% | With potassium carbonate In acetonitrile for 12h; Reflux; | 2 Example 2 Add 2.0mmol of apigenin 1, 5mmol and 7mmol of anhydrous potassium carbonate in the reaction flaskAnd 30ml acetonitrile, after stirring evenly,The reaction was stirred at reflux and heated for 12 hours (the progress of the reaction was tracked by TLC);After the reaction, the solvent was evaporated under reduced pressure, 50ml of deionized water was added, and the mixture was extracted three times with 100ml of dichloromethane. The organic layers were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. The formate compound (I-2) was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:acetone=100:1v/v) to obtain the corresponding celery aglycone carbamate compound (I-2) , The yield is 60.8%. The purity of the obtained target products was determined by HPLC to be greater than 97%. |
45.1% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.2% | With potassium carbonate; In acetonitrile; at 0 - 65℃; | General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 C. Andthen the mixture was heated to 65 C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.3% | With potassium carbonate In acetonitrile for 12h; Reflux; | 1 Example 1 Add 2.0mmol in the reaction flaskApigenin 1, 5mmol 7mmol anhydrous potassium carbonateAnd 30ml acetonitrile,After mixing well,The reaction was stirred at reflux and heated for 12 hours (the progress of the reaction was tracked by TLC);After the reaction, the solvent was evaporated under reduced pressure, 50ml of deionized water was added, and the mixture was extracted three times with 100ml of dichloromethane. The organic layers were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. The formate compound (I-1) was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:acetone=100:1v/v) to obtain the corresponding apigenin carbamate compound (I-1) , The yield is 67.3%.The purity of the obtained target products was determined by HPLC to be greater than 97%. |
50.3% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
50.3% | With potassium carbonate In acetonitrile at 65℃; Cooling with ice; | General procedures for the synthesis of 7,4’-O-modified naringenin, apigenin and genistein derivatives 3a~3k. General procedure: To a solution of the starting material 1 (naringenin 1a, apigenin 1b and genistein 1c, respectively) (1.0 mmol), and anhydrous K2CO3 (3.0 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoyl chlorides 2a-2g (4 mmol) was added dropwise in ice-water bath. The mixture was naturally heated to room temperature and then heated to 65 °C for 12-15 h. After the reaction completed, the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, which was further extracted with CH2Cl2 (2 × 30 mL). The combined organic phases were washed by saturated aqueous NaCl (60 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to dryness under reduced pressure to obtain the crude product, which was further purified on a silica gel chromatography using CH2Cl2/acetone (50:1) as eluent to afford the desired target derivatives 3a~3k. |
50.3% | With potassium carbonate In acetonitrile at 65℃; Cooling with ice; | General procedures for the synthesis of 7,4’-O-modified naringenin, apigenin and genistein derivatives 3a~3k. General procedure: To a solution of the starting material 1 (naringenin 1a, apigenin 1b and genistein 1c, respectively) (1.0 mmol), and anhydrous K2CO3 (3.0 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoyl chlorides 2a-2g (4 mmol) was added dropwise in ice-water bath. The mixture was naturally heated to room temperature and then heated to 65 °C for 12-15 h. After the reaction completed, the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, which was further extracted with CH2Cl2 (2 × 30 mL). The combined organic phases were washed by saturated aqueous NaCl (60 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to dryness under reduced pressure to obtain the crude product, which was further purified on a silica gel chromatography using CH2Cl2/acetone (50:1) as eluent to afford the desired target derivatives 3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.8% | With potassium carbonate; In acetonitrile; at 0 - 65℃; | General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 C. Andthen the mixture was heated to 65 C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.5% | With potassium carbonate; In acetonitrile; at 0 - 65℃; | General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 C. Andthen the mixture was heated to 65 C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
30.5% | With potassium carbonate; In acetonitrile; at 65℃;Cooling with ice; | General procedure: To a solution of the starting material 1 (naringenin 1a, apigenin 1b and genistein 1c, respectively) (1.0 mmol), and anhydrous K2CO3 (3.0 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoyl chlorides 2a-2g (4 mmol) was added dropwise in ice-water bath. The mixture was naturally heated to room temperature and then heated to 65 C for 12-15 h. After the reaction completed, the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, which was further extracted with CH2Cl2 (2 × 30 mL). The combined organic phases were washed by saturated aqueous NaCl (60 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to dryness under reduced pressure to obtain the crude product, which was further purified on a silica gel chromatography using CH2Cl2/acetone (50:1) as eluent to afford the desired target derivatives 3a~3k. |
30.5% | With potassium carbonate; In acetonitrile; at 65℃;Cooling with ice; | General procedure: To a solution of the starting material 1 (naringenin 1a, apigenin 1b and genistein 1c, respectively) (1.0 mmol), and anhydrous K2CO3 (3.0 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoyl chlorides 2a-2g (4 mmol) was added dropwise in ice-water bath. The mixture was naturally heated to room temperature and then heated to 65 C for 12-15 h. After the reaction completed, the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, which was further extracted with CH2Cl2 (2 × 30 mL). The combined organic phases were washed by saturated aqueous NaCl (60 mL), dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to dryness under reduced pressure to obtain the crude product, which was further purified on a silica gel chromatography using CH2Cl2/acetone (50:1) as eluent to afford the desired target derivatives 3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.5% | With potassium carbonate In acetonitrile for 12h; Reflux; | 5 In the reaction flask, add 2.0mmol of apigenin 1, 5mmol 7mmol anhydrous potassium carbonate and30ml of acetonitrile, after stirring uniformly, the reaction was heated and refluxed and stirred for 12 hours (the progress of the reaction was tracked by TLC); after the reaction, the pressure was reducedEvaporate the solvent, add 50ml deionized water, extract three times with 100ml dichloromethane, combine the organic layers and use saturated sodium chlorideWash, dry and filter over anhydrous sodium sulfate, evaporate the solvent of the celery aglycone carbamate compound (I-5) under reduced pressure, the residuePurified by column chromatography (dichloromethane:acetone=100:1v/v), the corresponding celery aglycone carbamate compound (I-5) The yield is 61.5%. The purity of the obtained target products was determined by HPLC to be greater than 97%. |
36.7% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.8% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | With potassium carbonate In acetonitrile for 12h; Reflux; | 6 Example 6 Add 2.0mmol of apigenin 1, 5mmol and 7mmol of anhydrous potassium carbonate in the reaction flaskAnd 30ml of acetonitrile, after stirring uniformly, the reaction was heated and refluxed and stirred for 12 hours (the progress of the reaction was tracked by TLC); after the reaction was completed, reduceThe solvent was evaporated by pressure, 50ml deionized water was added, and the mixture was extracted three times with 100ml dichloromethane. The organic layers were combined and saturated chlorinatedWash with sodium, dry and filter with anhydrous sodium sulfate, evaporate the solvent of celery aglycone carbamate compound (I-6) to dryness under reduced pressure, and leave the residueThe product was purified by column chromatography (dichloromethane: acetone=100:1v/v) to obtain the corresponding celery aglycone carbamate compound (I-6), the yield is 66.2%. The purity of the obtained target products was determined by HPLC to be greater than 97%. |
39.8% | With potassium carbonate In acetonitrile at 0 - 65℃; | 4.2. General procedures for the synthesis of targets compounds3a~3k General procedure: To a solution of compound 1 (1.0 mmol), and anhydrous K2CO3(5.2 mmol) in anhydrous CH3CN (10 mL), N,N-disubstituted carbamoylchlorides 2a-2f (5 mmol) was added dropwise at 0 °C. Andthen the mixture was heated to 65 °C and stirred for 6e10 h. Afterthe reaction completed, the solventwas evaporated and the residuewas extracted with water (20 ml) and dichloromethane(2 x 30 mL). The combined organic phase was evaporated to obtainthe crude product and was further purified on a silica gel chromatographyby petroleum/acetone (50:1) as eluent to obtain3a~3k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium <i>tert</i>-butylate In acetonitrile at -25℃; for 36h; Inert atmosphere; Irradiation; | 4 Under a nitrogen atmosphere, dissolve apigenin (0.1 mmol), o-methoxyiodobenzene (0.09 mmol), and potassium tert-butoxide (0.4 mmol) in acetonitrile (1 mL). After addition, the reaction The material was placed at -25 ° C, irradiated at 470 nm for 36 hours, quenched with dilute hydrochloric acid (1N), the aqueous phase was extracted three times with ethyl acetate (15 mL × 3), and the organic phases were combined, followed by water and saturation It was washed with brine, dried over anhydrous sodium sulfate, concentrated and column chromatography to obtain 3-aryl flavonoid derivative (26.3 mg, 70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 15% | With potassium carbonate In acetone at 20℃; for 1h; | 4.5 Semisynthesis of compounds 2, 4-5, 9-10, 16-19, 22, 28 and 29 General procedure: Semisynthesis of compound 8 from 7; 13 and 14 from 12; 32 and 33 from 31 were previously reported, using dimethyl sulfate (Me2SO4, 4 equiv.) and 1,8-diazobicyclo[5.4.0]undec-7-en (DBU, 2 equiv.) in dried acetone at room temperature [12]. Methylation of isolated compounds 20 and 27 to provide 22, 28 and 29 and methylation of commercially available compounds 1, 3, 6 and 15 to provide compounds 2, 4-5, 9-10, 16-19, respectively, were performed by stirring the substrate with methyl iodide (MeI, 13.5 equiv.) and potassium carbonate (K2CO3, 6.6 equiv.) in dried acetone at room temperature for 1h. The crude reaction mixtures were precipitated and washed with ice-cold water. The resulting residues were solubilized with EtOAc (10mL) and treated with 1N HCl solution (3mL). The final products were extracted with EtOAc (3x10 mL) and the organic phases were washed with saturated NaCl solution and dried over Na2SO4. After filtration, and solvent evaporation, methylated compounds were purified by silica gel chromatography, using a mixture of CH2Cl2/MeOH (99.1/0.1 to 95/5 v/v) as eluent. Identification of resulting pure compounds was confirmed by comparison of 1H, 13C NMR and MS analysis with literature data. Methylation of 50mg (0.20mmol) of 5,7-dihydroxyflavone (chrysin, 1) afforded 2 (48.5mg, yield 92%) [28]. Methylation of 50mg (0.19mmol) of 5,7,4′-trihydroxyflavone (apigenin, 3) gave 4 (31.6mg, 60%) and 5 (8.3mg, 15%) with a ratio of 4/1 [29]. Methylation of 100mg (0.35mmol) of 5,7,3′,4′-tetrahydroxyflavone (kaempferol, 6) gave 9 (71.1mg, 62%) and 10 (14.3mg, 12%) with a ratio of 5/1 [30]. Methylation of 150mg (0.5mmol) of 3,5,7,3′,4′-pentahydroxyflavone (quercetin, 15) gave 16 (15.6mg, 10%), 17 (15.6mg, 9.5%), 18 (97.8mg, 55%) and 19 (17.0, 9.2%) with a ratio of 1/1/6/1 [31-33]. Methylation of 6mg (0.017mmol) of 20 gave 22 (5.5mg, 85%) [34]. Methylation of 12mg (0.032mmol) of 27 gave 28 (7.5mg, 61%) and 29 (3.9mg, 28%) with a ratio of 2/1 [35]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In acetonitrile at 20℃; | 1 A solution of 1-cyclopropanoylpiperazine (142μL, 1mmol) dissolved in acetonitrile (10ml) was added dropwise to the solution containing paraformaldehyde (94.6mg, 1.05mmol) and compound IV-1 (0.27g) at room temperature. , 1.0mmol) in acetonitrile (5ml). The reaction mixture was stirred until the compound IV-1 completely disappeared. The reaction solvent was then removed using a rotary evaporator. The residue was purified by flash column chromatography with DCM and MeOH as eluents and silica gel as column material to obtain compound 1; |
84% | In water; acetonitrile at 20℃; for 6h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: 2,4,6-trihydroxyacetophenone; 4-hydroxy-benzaldehyde With potassium hydroxide In ethanol at 20℃; for 4h; Stage #2: With iodine In dimethyl sulfoxide at 110℃; for 8h; | 40 Example 40 1-((5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromium-8-yl)methyl)piperidine-4-carboxylic acid methyl ester (Compound 40) VI-1 (1.6g, 0.01mol) was dissolved in absolute ethanol, and potassium hydroxide solid (2.8g, 0.05mol) was added under vigorous stirring at room temperature, and the color of the reaction system gradually turned red. After 4h, adjust the PH=5 with 2M hydrochloric acid. During the process, a yellow solid was gradually precipitated. After dilution with water (200mL), the solid was filtered out and used directly after drying. The intermediate obtained in the previous reaction was dissolved in anhydrous dimethyl sulfoxide (30mL), and iodine (0.13g, 0.5mmol) was added as a catalyst, and then reacted at 110°C for 8h. After the reaction, the reaction was cooled to At room temperature, 10% sodium thiosulfate solution (50mL) was added. After 10 minutes, the mixture was extracted with ethyl acetate/water system. The organic phase was taken, dried and spin-dried. The residue was purified by silica gel chromatography to obtain VII-1 ( 1.3g, the two-step yield is 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.9% | With potassium carbonate In acetonitrile at 65℃; Cooling with ice; | General procedures for the synthesis of 4’,5,7-O-carbamate derivatives 5a-5c. General procedure: The starting material 1 (naringenin 1a, apigenin 1b and genistein 1c, respectively) (1.0 mmol) and 8.0 mmol anhydrous K2CO3 were added to 10 mL anhydrous CH3CN, and then 10.0 mmol N-ethyl-N-methylcarbamoyl chloride (2c) was added dropwise in ice-water bath. The mixture was naturally heated to room temperature and then heated to 65 °C for 16-24 h. After the reaction completed, the mixture was treated by common procedure. Finally, the crude residue was purified on a silica gel chromatography using petroleum/acetone (50:1) as eluent to get the target derivatives 5a-5c. |
26.9% | With potassium carbonate In acetonitrile at 65℃; Cooling with ice; | General procedures for the synthesis of 4’,5,7-O-carbamate derivatives 5a-5c. General procedure: The starting material 1 (naringenin 1a, apigenin 1b and genistein 1c, respectively) (1.0 mmol) and 8.0 mmol anhydrous K2CO3 were added to 10 mL anhydrous CH3CN, and then 10.0 mmol N-ethyl-N-methylcarbamoyl chloride (2c) was added dropwise in ice-water bath. The mixture was naturally heated to room temperature and then heated to 65 °C for 16-24 h. After the reaction completed, the mixture was treated by common procedure. Finally, the crude residue was purified on a silica gel chromatography using petroleum/acetone (50:1) as eluent to get the target derivatives 5a-5c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / Reflux 2: N-Bromosuccinimide; trifluoroacetic acid / 20 °C 3: copper(II) bromide; methanol / N,N-dimethyl-formamide / 1.5 h / Microwave irradiation |
Tags: 520-36-5 synthesis path| 520-36-5 SDS| 520-36-5 COA| 520-36-5 purity| 520-36-5 application| 520-36-5 NMR| 520-36-5 COA| 520-36-5 structure
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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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