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CAS No. : | 552-41-0 | MDL No. : | MFCD00008730 |
Formula : | C9H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UILPJVPSNHJFIK-UHFFFAOYSA-N |
M.W : | 166.17 | Pubchem ID : | 11092 |
Synonyms : |
2'-Hydroxy-4'-methoxyacetophenone;Peonol;NSC 401442
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 45.15 |
TPSA : | 46.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.91 cm/s |
Log Po/w (iLOGP) : | 2.06 |
Log Po/w (XLOGP3) : | 1.98 |
Log Po/w (WLOGP) : | 1.6 |
Log Po/w (MLOGP) : | 0.83 |
Log Po/w (SILICOS-IT) : | 1.68 |
Consensus Log Po/w : | 1.63 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.36 |
Solubility : | 0.733 mg/ml ; 0.00441 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.58 |
Solubility : | 0.434 mg/ml ; 0.00261 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.28 |
Solubility : | 0.876 mg/ml ; 0.00527 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P273-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335-H412 | 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 |
---|---|---|
72% | With acetylhydroxamic acid; sulfuric acid In acetonitrile at 80℃; for 0.2 h; Microwave irradiation | General procedure: 2-Hydroxy acetophenone 4a (1.0 g, 7.4 mmol), acetohydroxamic acid (0.83 g, 11.0 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a 10 ml pressure tube and subjected to microwave heating (CEM discover, 360 W, 80 °C, 25 psi) for 8 min. Next, the reaction mixture was diluted with ethyl acetate (3 ml) and to this; saturated sodium bicarbonate solution (5 ml) was added drop-wise. The mixture was extracted with ethyl acetate (2 .x. 10 ml) and the combined organic layer was washed with saturated NaCl solution, dried over anhy. Na2SO4, and concentrated under reduced pressure. Purification of the mixture by normal column chromatography (silica gel 60-120 mesh, ethyl acetate/hexane: 1:9) gave benzoxazole 5a (0.67 g, 70percent) in the form of a yellow oil and 2-hydroxy acetophenone oxime 6a (68 mg, 6percent, mp 104-107 °C) in the form of a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: at 100℃; for 0.166667 h; Stage #2: With hydrogenchloride In dichloromethane; water at 40℃; for 0.5 h; |
Example 10A 7-methoxy-4H-1-benzopyran-4-one 1-(2-Hydroxy-4-methoxyphenyl)ethanone (47 g, 283 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (47 mL, 351 mmol), and the solution was heated to >100° C. in a sand bath for 10 minutes, at which point a solid mass had formed. The flask was cooled to ambient temperature, and 200 mL of heptanes were added. The solids were broken up with a spatula and collected by filtration with a frilled funnel. The solid material was crushed with a pestle and then washed with heptanes. The solid was then dried on the filter to give about 60 g of the crude intermediate. This intermediate was dissolved in dichloromethane (1 L) and stirred with 150 mL of concentrated HCl at 40° C. for 30 minutes. The flask was cooled to ambient temperature, and about 100 mL of water was added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was then precipitated from 500 mL of 1:1 cyclopentyl methyl ether:heptanes to give the title compound (35 g, 70percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J=8.9 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.28 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS(ESI+) m/z 176.9 (M+H)+. |
70% | Stage #1: at 100℃; for 0.166667 h; Stage #2: With hydrogenchloride In dichloromethane at 40℃; for 0.5 h; |
1-(2-Hydroxy-4-methoxyphenyl)ethanone (47 g, 283 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (47 mL, 351 mmol), and the solution was heated at >100° C. in a sand bath for 10 minutes, at which point a solid mass formed. The flask was cooled to ambient temperature, and 200 mL of heptanes were added. The solids were broken up with a spatula and collected by filtration with a fritted funnel. The solid material was crushed with a pestle and washed with heptanes. The solid was dried on the filter to give about 60 g of the crude intermediate. The intermediate was dissolved in dichloromethane (1 L) and stirred with 150 mL of concentrated HCl at 40° C. for 30 minutes. The flask was cooled to ambient temperature, and about 100 mL of water was added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was taken into 500 mL of 1:1 cyclopentyl methyl ether:heptanes and the precipitate was collected to provide the title compound (35 g, 70percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J=8.9 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.28 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS(ESI+) m/z 176.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyrrolidine; iodine In dimethyl sulfoxide at 150℃; for 10 h; | General procedure: 2'-Hydroxyacetophenone (1 mmol) and substituted aromatic aldehyde (1 mmol) were mixed together along with pyrrolidine (0.5 mmol) and iodine (0.05 mmol) in DMSO solvent (10 mL). The resulting mixture was then heated at 150 °C for the given time. After completion of reaction (monitored by TLC) the reaction mass was allowed to cool and diluted with ethyl acetate (20 mL). Resulting solution was then washed with water and saturated sodium thiosulfate solution followed by drying over anhydrous sodium sulfate and concentrating under reduced pressure to furnish the crude product. The residue obtained was purified by column chromatography using petroleum ether-ethyl acetate as an eluent to afford flavones (3a–r). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; bromine; In chloroform;Cooling with ice; | In the three-neckedflask, Paeonol (1) (5 mmol) was dissolved in chloroform (120 ml), then added anhydrousAlCl3 (5 mmol) and stirring in an ice-water bath. Within 15-20 min, the bromine (3 ml) was added dropwise.The reaction was monitored by TLC. After that, the reaction solution was evaporated reduced pressuredistillation. The appropriate amount of acetone was added in the residue, and recrystallizedtwice to afford compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydroxide In ethanol; water at 20 - 50℃; | |
90% | With potassium hydroxide In methanol at 20℃; for 24h; | |
85% | With potassium hydroxide at 20℃; |
78% | Stage #1: 1-(2-hydroxy-4-methoxyphenyl)ethanone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-methoxy-benzaldehyde In methanol Inert atmosphere; | The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products. |
76% | With potassium hydroxide In ethanol; water at 0 - 20℃; | |
75% | With potassium hydroxide In water; Petroleum ether at 20℃; for 36h; | |
71% | With sodium hydroxide In ethanol at 20℃; | 4.2. General procedures for synthesis of chalcones General procedure: For synthesis of chalcones we have used 2 different methods. Chalcones 1-30 were synthesized by method A and chalcones 31-44 were synthesized by method B. For Method B we used LiOHinstead of usual base NaOH for Claisen-Schmidt synthesis and the reaction was carried out in an ultrasonic bath. The general reaction scheme is depicted in Scheme 1.Method A: 20% NaOH (5 ml) was added dropwise to a previously cooled mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 25 ml ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72 h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dilute HCl. Precipitated product was filtered by suction and washed to neutral. The solid was recrystallised from dilute ethanol to get crystalline chalcone.Method B: To a mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 50 ml round bottom flask, 20 ml methanol and 35 mmol of LiOH was added. The reaction mixture was kept in an ultrasonic bath for 1-5 h, until reaction completion was indicated by TLC. The reaction was worked up as described for method A. |
70% | With pyrrolidine In ethanol at 20℃; for 16h; | |
69% | With potassium hydroxide In methanol at 20℃; | General Procedure for the Synthesis of Chalcones (1a-1u): General procedure: A solution of 50% KOH (40 mL) was added dropwise to well-stirred equimolar quantities of different substituted acetophenones and aldehydes in MeOH at room temperature. After 2436 h, the solvent was removed under reduced pressure and 5% HCl (50-70 mL) added to the residue. After extraction with EtOAc, the organic layer was washed with brine, dried (Na2CO3), and then concentrated in vacuo. The residue was purified by using column chromatography on silica gel, eluting with EtOAc in hexanes, to afford chalcones 1a-1u. |
58% | With barium dihydroxide In ethanol for 2h; Heating; | |
56% | With sodium hydroxide In ethanol | |
55% | With potassium hydroxide In methanol at 5 - 20℃; | General procedure: A solution of substituted acetophenones (5 mM) and aromatic aldehyde (5 mM) in methanol (15 mL) was cooled to 5-10 °C in an ice bath. The cooled solution was treated with adding a small portion of pulverized KOH (10 mM). The reaction mixture was magnetically stirred for 60 min and then left overnight or longer, monitored by thin layer chromatography using developing solvent n-hexane-acetone (5-1). The resulting dark solution was diluted with ice water and carefully acidified using dilute hydrochloric acid. The chalcone which separated as a yellow solid was collected by filtration after washing with water and further purified by crystallization from methanol or by silica gel column chromatography. |
48% | With sodium hydroxide In ethanol at 20℃; | |
48% | With sodium hydroxide In ethanol; water at 20℃; | General procedure for the synthesis of (2E)-1-(2-hydroxy-phenyl)-3-phenylprop-2-en-1-ones: General procedure: An aqueous solution of NaOH (3 M, 1.6 mL) was added to a solution of aromatic ketone (1 mmol) and substituted benzaldehyde (1.2 equiv.), in EtOH (1-2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from EtOH. |
32% | With sodium hydroxide In ethanol at 20℃; for 24h; | General procedures for the preparation of compounds 5a-i General procedure: 1-(2-Hydroxy-4-methoxyphenyl)ethanone (1) (166 mg, 1 mmol) and various aryl aldehyde 7 or commercially available aldehyde (1 mmol) were dissolved in EtOH (50 mL), in which was added 10% NaOH solution (10 mL). The reaction mixture was stirred at room temperature for 24 h, and yellow solid was precipitated. The yellow precipitate was filtered and washed with appropriate amount of water, the crude products recrystallized with MeOH to afford pure products. |
20% | With sodium hydroxide In ethanol; water at 20℃; for 24h; | |
19.3% | With potassium hydroxide In ethanol at 20℃; for 23h; Inert atmosphere; | |
With potassium hydroxide; sodium ethanolate | ||
3.0 g | With potassium hydroxide In ethanol Ambient temperature; | |
With barium dihydroxide In methanol | ||
With sodium hydroxide In ethanol | ||
With aqueous KOH In ethanol | 2.a 2'-Hydroxy-4,4'-dimethoxychalcone (3) Example 2a 2'-Hydroxy-4,4'-dimethoxychalcone (3) To a stirred solution of 2-hydroxy-4-methoxy acetophenone (1) (5.24 g, 31.5 mmol) and 4-methoxy benzaldehyde (2) (3.85 mL, 31.7 mmol) in absolute ethanol (100 mL) was added 80 mL of 50% aqueous KOH. The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was acidified at 0° C. with 10% aqueous HCl and then extracted with Et2O (3*150 mL). The combined ethereal extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The resulting orange yellow solid residue was purified via column chromatography on silica gel (elution with hexane-EtOAc, 8:2) to give an orange yellow solid 5.91 g (20.8 mmol) of 3 (66%). | |
With sodium hydroxide In ethanol; water at 20℃; | ||
In ethanol at 20℃; Alkaline conditions; | ||
With sodium hydroxide In ethanol; water at 50℃; | 2.2 Preparation of chalcone ligands and complexes 2.2.1 Preparation of chalcone ligands HL1-8 General procedure: Chalcone derivatives {(E)-1-(2′-hydroxyphenyl)-3-phenylprop-2-en-1-ones} HL1-8 (Scheme 2) were prepared by the Claisen-Schmidt condensation according to the literature [34-36]. To a solution of the corresponding 2-hydroxyacetophenone derivative (3mmol) and corresponding benzaldehyde derivative (3mmol) in 40mL of ethanol, 1.4mL of 40% (w/v) aq. NaOH was slowly added and this reacting system was stirred at 50°C for 4-12h until all benzaldehyde was consumed. The consumption of benzaldehyde was monitored by thin layer chromatography (TLC) on silica gel using ethylacetate/hexane (7:3 v/v) as a mobile phase. Consequently, the reaction mixture was neutralized with 1M HCl. The precipitate, which formed upon neutralization was filtered off, washed with distilled water and recrystallized from methanol giving the appropriate chalcone derivative in 50-90% yields. The purity of the prepared chalcones was checked by elemental analysis and 1H NMR spectroscopy. | |
Stage #1: 1-(2-hydroxy-4-methoxyphenyl)ethanone With sodium hydroxide In ethanol at 35℃; for 0.5h; Stage #2: 4-methoxy-benzaldehyde In ethanol | 4.1 4.4.1. 2'-Hydroxy-4,6'-dimethoxychalcone (Ch-2) General procedure: The 2-Hydroxy-6-methoxyacetophenone (500 mg, 3.012 mmol) was dissolved in ethanol (30 mL), and sodium hydroxide (482 mg, 12.048 mmol) was added to the stirred solution at 35 °C. After stirring for 30 min, p-methoxybezaldehyde (428 μL, 3.150 mmol) was added to the solution. Overnight, the resulting mixture was acidified with dilute hydrochloric acid and water to pH = 7. Then the resulting precipitate was collected and on recrystallization from ethanol gave yellow needles (698 mg, 82%). | |
With sodium hydroxide In ethanol; water at 20℃; | 2.2. Synthesis General procedure: An aqueous solution of sodium hydroxide (30%, 8 mL) was added with stirring to a solution of a substituted 2-hydroxyacetophenone (0.1 mol) and a substituted benzaldehyde (0.1 mol) in ethanol (20 mL). The reaction mixture was stirred overnight at room temperature, by which time the reaction was shown to be complete by TLC. Ice-cold hydrochloric acid (10%, 30 mL) was added, and the solid product was collected, washed with ice-cold water (2 x 50 mL) and recrystallized twice from ethanol, see Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium hydroxide; In methanol; at 20℃; | General procedure: A solution of 50% KOH (40 mL) was added dropwise to well-stirred equimolar quantities of different substituted acetophenones and aldehydes in MeOH at room temperature. After 2436 h, the solvent was removed under reduced pressure and 5% HCl (50-70 mL) added to the residue. After extraction with EtOAc, the organic layer was washed with brine, dried (Na2CO3), and then concentrated in vacuo. The residue was purified by using column chromatography on silica gel, eluting with EtOAc in hexanes, to afford chalcones 1a-1u. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In mineral oil at 0 - 85℃; for 14h; | 4-hydroxy-7-methoxy-2H-chromen-2-one (4) Solutionof 1-(2-hydroxy-3,4-dimethylphenyl)ethanone(5g; 0.03 mol) in diethylcarbonate (35 mL) was added dropwise to asuspension of NaH (60% dispersion in mineral oil) (5 g; 0.21 mol) indiethylcarbonate (25 mL) at 0 oC. The resulting mixture was heatedat 85 oC for 14 h after which it was cooled first to rt and then to0 oC. Water was then carefully addeddropwise to quench residual NaH. The remaining diethylcarbonate was extractedinto diethyl ether (3 x 50 mL). The aqueous phase was carefully acidified to pH3 with 2N HCl (significant foaming occurred). The resulting precipitated solidwas collected by filtration, washed sequentially with water followed bypetroleum ether (40-60 oC:3 x 50 mL), and then dried in a 90 oC oven overnight to yield whitecrystals (5.67 g; 98%). 1H-NMR(DMSO-d6) (δ/ppm): 12.38(1H, bs, OH-4), 7.72 (1H, d, H-5, J=8.4Hz), 7.00-6.91 (1H, m, H-6), 6.95 (1H, s, H-8), 5.46 (1H, s, H-3), 3.85 (1H, s,OCH3). 13C-NMR (DMSO-d6) d/ppm: 166.0 (C-4), 162.9 (C-1), 162.2 (C-7),155.4 (C-10), 124.3 (C-5), 111.8 (C-6), 108.9 (C-11), 100.5 (C-8), 88.5 (C-3),55.8 (OCH3). |
95% | With sodium hydride In mineral oil at 0 - 100℃; | |
92% | With sodium hydride In toluene; mineral oil at 100℃; for 4.5h; | 4.1.6. 4-Hydroxy-7-methoxy-2H-chromen-2-one (18) To the solution of paeonol (10.0 g, 60.20 mmol) in anhydroustoluene (100 mL) was added diethyl carbonate (10.7 g,90.30 mmol), then the suspension of NaH (60% dispersion in mineraloil, 12.0 g, 300.90 mmol) in anhydrous toluene (50 mL) wasadded dropwise over a period of 30 min and was stirred in an icebath. The mixture was further stirred at 100 °C for 4 h, then it wascooled to 0 °C. The residual NaH of mixturewas quenched with coolwater in an ice bath carefully and washed with diethyl ether(50 mL 3). The aqueous phase was acidified to pH 3 with 2 M HClslowly, then the white precipitation was occurred. The resultingprecipitated solid was collected by filtration, washed with water(50 mL 3) followed by petroleum ether (20 mL 3), and thendried overnight to afford white solid (10.67 g, 92%). 1HNMR(300 MHz, DMSO-d6) d 12.36 (s, 1H), 7.72 (d, J 8.5 Hz, 1H),6.95 (dd, J 8.5, 2.4 Hz, 1H), 6.91 (d, J 2.4 Hz, 1H), 5.45 (s, 1H), 3.85(s, 3H). ESI-MS m/z: 215 [MNa]. |
92% | With sodium hydride In toluene Cooling with ice; | 1.3 (3) Synthesis of 4-hydroxy-7-methoxy-2H-benzopyran-2-one (compound 2a) 2-Hydroxy-4-methoxyacetophenone (10.0g, 60.20mmol) and diethyl carbonate (10.7g, 90.30mmol) were added to a 500mL eggplant-shaped flask, dissolved in 100mL of anhydrous toluene, sodium hydride (12.0g) , 300.90 mmol) was dissolved in 50 mL of anhydrous toluene, and added dropwise to the reaction solution with a constant pressure dropping funnel under ice bath conditions. The reaction solution was cooled to room temperature, and ice water was added dropwise in an ice bath to quench excess sodium hydride, extracted with ether (100 mL×3), the aqueous phase was collected, and the pH was adjusted to 2-3 with 2N HCl, and a large amount of white precipitates were precipitated. , filtered with suction and then dried to obtain 10.67 g of a white solid with a yield of 92%. |
86% | With sodium hydride In toluene at 100℃; for 4.5h; Cooling with ice; | Synthesis of 3a-3c General procedure: 2a-2c (23.1 mmol) and diethyl carbonate (34.7 mmol, 4.14 g) in toluene (10 mL) were added dropwise to sodium hydride (115 mmol, 4.7 g) in toluene (50 mL) in ice-water bath. The mixture was stirred at ice bath for 30 min and at 100 ℃ for 4 h. The sodium hydride was quenched with water, acidized with hydrochloric acid and then the suspension was filtered separately, and the solid collected from this filtration was washed with toluene and water for three times. The solid dried at room temperature with phosphorus pentoxide. 3a: yield 70%. HPLC purity: 96.9%.1H NMR (400 MHz, d6-DMSO): δ 5.62 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 12.51 (br s, 1H). 3b: yield 67%. HPLC purity: 96.9%. 3c: yield 86%. HPLC purity: 98.2%.1H NMR (400 MHz, d6-DMSO): δ 3.83 (s, 3H), 5.51 (s, 1H), 6.92-6.96 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 12.51 (br s, 1H). |
86% | With sodium hydride In toluene; mineral oil for 5h; Reflux; | 4-Hydroxy-7-methoxy-2H-chromen-2-one (11) Compound 11 was synthesized following a literature procedure. ADDIN EN.CITE Rao2014252042520252017Rao, Maddali L. N.Kumar, AbhijeetPd-catalyzed chemo-selective mono-arylations and bis-arylations of functionalized 4-chlorocoumarins with triarylbismuths as threefold arylating reagentsTetrahedronTetrahedronTetrahedronTetrahedron6995-700570392014Sep 300040-4020WOS:000341550600012://WOS:00034155060001210.1016/j.tet.2014.07.0594 A solution of 2-hydroxy-4-methoxyacetophenone (9 mmol, 1.5 g) in toluene (15 mL) was added dropwise to a dry three-neck round-bottom flask containing sodium hydride (60% w/w suspension, 45 mmol, 1.8 g) in toluene (10 mL). This was done under argon atmosphere at ice bath temperature. The mixture was stirred at the same temperature for 15 min and followed by the dropwise addition of diethylcarbonate (13.5 mmol, 1.6 g) in toluene (10 mL). After complete addition, the reaction mixture was stirred at room temperature for 30 min and refluxed for 10 more hours. The reaction mixture was quenched at ice bath temperature by slow addition of water (20 mL) and acidified with 10% HCl. The product obtained as a solid precipitate was filtered, washed with water, and dried under vacuum. Yield: 1.46 g (86%), white solid (mp 224-226 °C). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.72 (t, J = 6.2 Hz, 1H), 6.93 (m, 2H), 5.51 (s, 1H), 3.85 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 166.49, 163.39, 162.75, 155.87, 124.77, 112.31, 109.35, 100.95, 88.94, 56.32. |
85% | Stage #1: 1-(2-hydroxy-4-methoxyphenyl)ethanone With sodium hydride In toluene; mineral oil for 0.166667h; Inert atmosphere; Stage #2: Diethyl carbonate In toluene; mineral oil for 3.5h; Reflux; | General procedure for the preparation of compounds 4b-d (Scheme 2) General procedure: To a solution of anhydrous toluene (80mL) in a 250mL two-neck flask under N2, was added 1.56g of NaH (26mmol, 60%), followed by 13mmol of 2,4-dihydroxyacetophenone 3a. After stirring for 10min, 6mL of diethyl carbonate in anhydrous toluene (20mL) was added dropwise during 30min, and the mixture was refluxed with stirring for 3h. The reaction mixture was cooled to room temperature, and then poured into water, then extracted with diethyl ether for three times until the ether layer was colourless. The aqueous layer was acidified with 100mL of 2N hydrochloric acid, and the resulting precipitate was filtered off and recrystallized from ethanol to give a white solid. Yields for 4b, 4c, and 4d were 85%, 86%, and 82%, respectively |
83% | With sodium hydride In toluene at 0℃; for 4.5h; Reflux; | 1.2.1. General procedure for preparation of target compounds 6a-f General procedure: To a stirred mixture of 5a-f (1.15 mmol) and sodium hydride (138 mg, 5.75 mmol) in 5 ml dry toluene, a solution of the diethyl carbonate (1.15 mmol) in dry toluene was dropped. The mixture was reacted at 0°C for 30 min, then heated to reflux and reacted for another 4 h. The reaction mixture was quenched with water (20 mL) at ice bath and neutralized to pH 7 with 2 N HCl. The precipitate was filtered, washed with cold water and dried to get 6a-f. |
80% | With sodium hydride at 120℃; for 3h; Cooling with ice; Inert atmosphere; | 1.1.114-hydroxy-7-methoxy-2H-chromen-2-one(28) General procedure: 1.7 g of intermediate 26(10.29mmol) was dissolved in 40ml of diethyl carbonate and was added 2.4g NaH (102.9mmol) under an ice bath with vigorous stirring. The temperature was slowly lifted and then stirred at 120oCfor 3 hours under nitrogen atmosphere. After the completion of the reaction, the solvent was evaporated at reduced pressure and the remaining solid was poured on crushed ice. The pH was adjusted to 3 by adding 6N of hydrochloric acid. The precipitate wascollected and purified by column chromatography as white solid (80%) |
69.57% | With sodium hydride In mineral oil at 120℃; Inert atmosphere; | 3 Example 3 Preparation of 4-hydroxy-7-methoxycoumarin (4) Anhydrous operation,1 g of Intermediate 3 (6.02 mmol) and 1.44 g of NaH (60.2 mmol) were added to 15 ml of diethyl carbonate, vigorously stirred, and reacted at 120 ° C under nitrogen to determine the endpoint by TLC.25ml of ice water will be added to the reaction solution, NaH destruction, stirring 2min after the liquid,The organic phase was discarded and the aqueous phase was extracted three times with ethyl acetate. The organic phase was discarded,With 1mol / L hydrochloric acid to adjust the pH of the aqueous phase 3-4, a large number of white solid precipitation, filtration of the crude product, purified by column chromatography 0.8g white powder,The yield was 69.57%. |
60% | With sodium hydride In toluene at 115℃; Inert atmosphere; | |
57% | With natrium at 0 - 100℃; for 3.5h; | |
16% | With sodium hydride In dimethyl sulfoxide at 0 - 100℃; for 2h; | |
With natrium | ||
With natrium In Dowtherm A at 160℃; for 2h; | ||
With sodium hydride In toluene at 110℃; | ||
With sodium hydride In toluene at 105℃; for 3h; Inert atmosphere; | ||
With natrium Heating; | ||
With sodium hydride In mineral oil at 0℃; for 5h; Reflux; | ||
With sodium hydride at 100℃; for 3h; | ||
With sodium hydride In toluene | ||
With sodium hydride In toluene | ||
With sodium hydride at 0 - 200℃; for 2.5h; | ||
Stage #1: 1-(2-hydroxy-4-methoxyphenyl)ethanone With sodium hydride In toluene at 0℃; for 0.25h; Inert atmosphere; Stage #2: Diethyl carbonate In toluene Inert atmosphere; | 4.2.1. Typical procedure for the synthesis of 1 In a 250 mL two-neck round-bottom flask, 9 mmol of ohydroxyacetophenonein 15 mL toluene was slowly added to sodiumhydride (60% w/w suspension, 5 equiv, 45 mmol, 1.8 g) intoluene (10 mL) under N2 atmosphere at 0 C. After 15 min,13.5 mmol of diethyl carbonate in 10 mL toluene was added dropwise,and the mixture was stirred at room temperature for 30 minand refluxed until the reaction finished (monitored by TLC (ThinLayer Chromatography)). After the mixture cooled to room temperature,the reaction was quenched by slowly addition of 2 N hydrochloricacid. The resulting precipitate was further purified by ashort silica gel column chromatography to give a white solid. | |
With sodium hydride In toluene at 0 - 110℃; | ||
With sodium hydride In toluene at 0 - 100℃; Inert atmosphere; | ||
With sodium hydride In toluene Reflux; | ||
With sodium hydride at 0 - 100℃; for 3.5h; | 4.1.1. Procedure for synthesis of compound 1b A solution of 1-(2-hydroxy-4-methoxyphenyl)ethan-1-one(1.0equiv) in appropriate amount of diethylcarbonate was addeddropwise to a oven-dried round bottom flask containing sodiumhydride (5.0 equiv) in equal amount of diethylcarbonate at 0° C.After complete addition, the reaction mixturewas stirred at 0 C for30 min and refluxed for three more hours at 100 C. After the reactionwas over monitored by TLC,the reaction mixture was cooledto room temperature and icewater was added slowly to quench thereaction mixture. Then use a large amount of ether to wash awaydiethylcarbonate. After that, the aqueous phase was acidized to pH3e4 with diluted hydrochloric acid solution to form white solid.Finally the pure light white precipitate was collected by filtration,washed with water, and dried in vacuum to obtain 1b. 1H NMR(400 MHz, DMSO-d6) δ: 12.37 (s, 1H), 7.72 (d, J 8.6 Hz, 1H), 6.93(m, 2H), 5.47 (s, 1H), 3.86 (s, 3H). MS (ESI), m/z: 193.04 [M H]. | |
Stage #1: 1-(2-hydroxy-4-methoxyphenyl)ethanone With sodium hydride In toluene at 20℃; for 0.5h; Cooling with ice; Stage #2: Diethyl carbonate In toluene for 4h; Reflux; | ||
With sodium hydride In toluene at 100℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In tetrahydrofuran at 80℃; for 4h; | |
36% | With selenium; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 100℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With perchloric acid; dihydrogen peroxide; potassium bromide In water at 0 - 20℃; for 0.5h; | 2.6. General experiment for oxidative bromination General procedure: In a 50mL round bottom flask equipped with a magnetic stirringbar, 2-hydroxyacetophenone (10 mmol) were added. To this solution,KBr (40 mmol) dissolved in 20 mL water was added and thendissolved by stirring at ambient temperature followed by additionof a 30% H2O2 (4 mmol). To this reaction mixture, vanadium(V)complex (0.01 mmol) and 70% HClO4 (4 mmol) were added and thereaction mixture was stirred at 0 C and then after 10 min at roomtemperature. An additional 4 mmol of 70% HClO4was further addedin three equal portions after every 10 min with continuous stirring.In addition, all the reactions were monitored using thin layerchromatography. The NMR spectra of bromination products aregiven in the supporting information. |
77% | Stage #1: With copper(ll) bromide In ethyl acetate Heating / reflux; Stage #2: 1-(2-hydroxy-4-methoxyphenyl)ethanone In chloroform; ethyl acetate at 20℃; for 6.05h; Heating / reflux; | 17 Heat a suspension of copper (II) bromide (16.79 g, 75.2 mmol) in EtOAc (40 ML) to reflux under N2. Add a solution of 2'-hydroxy-4'-methoxyacetophenone (7.48 g, 45.0 mmol) in CHC13 (40 mL) to the suspension dropwise over 3 minutes. Attach a drying tube to the top of the condenser and reflux for 6 hours. Cool to room temperature and stir under N2 overnight. Filter mixture and rinse filter cake with EtOAc and CHC13, concentrate mother liquor to get 12.75 grams of a green oily solid. Adsorb on SI02 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford the crude (approx. 75% pure) title compound (8.5 g, 77%). |
62% | With copper(ll) bromide In chloroform; ethyl acetate Heating; |
62% | With copper(ll) bromide In chloroform; ethyl acetate at 90℃; for 6h; | Synthesis of 2-bromo-1-(2-hydroxy-4-methoxy-phenyl)-ethanone 4 Powdered cupric bromide (13.4 g, 60 mmol) was added into a solution of paeonol (5.0 g, 30 mmol) in chloroform (100 mL) and ethyl acetate (100 mL). The mixture was refluxed at 90 °C for 6 h until the reation was complete (monitored by TLC). After cooling, the mixture was filtered. The filtrate was washed with H2O (150 mL × 4), dried over anhydrous Na2SO4. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel column with ethyl acetate/petroleum ether as the elution. The resulting bromidated panonol 4 (4.5 g) was obtained as white powder. Yield 62%, 1H-NMR (CDCl3, 600 MHz): δ 6.75-8.15 (s, 3H), 3.95 (s, 3H), 2.59 (s, 2H) ppm. |
53% | With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 80℃; | 4.1 General procedure for the synthesis of 2-bromo-1-substituted phenylethanone 10a-10i General procedure: A modified reaction route: NBS (1.2 equiv.) was added to a solution of appropriately substitutedacetophenones 9a-9l (1.0 equiv.) in CH3CN (15 mL) with p-TSA (0.2 equiv.). The solution washeated at 80 °C for 3-5 h until all the starting materials had been consumed (TLC monitored). Thereaction mass was poured in ice-cold water and extracted with DCM (3 × 20 mL). Anhydrous Na2SO4was added to the combined organic layer, filtered and the excess solvent was removed under reducedpressure. The resultant solid/ liquid obtained were washed with hexane to yield compounds 10a-10i.4,5 |
45% | With copper(ll) bromide In chloroform; ethyl acetate for 16h; Reflux; | 2-Bromo-1-(2-hydroxy-4-methoxyphenyl)ethan-1-one (8c). To a solution of commercially available 4'-hydroxy-2'-methoxyacetophenone 7c (3.22 g, 20.0 mmol,1.0 equiv) in CHCl3 (20 mL), was added a solution of EtOAc (20 mL) with CuBr2 (7.46 g, 33.4 mmol,1.67 equiv). After stirring under reflux for 16 h, the mixture was filtrated through Celite (CH2Cl2),quenched with saturated NaHCO3 and concentrated under reduced pressure. The residue was purifiedby flash chromatography on silica gel (petroleum ether/CH2Cl2 = 70:30) to afford 2-bromo-1-(2-hydroxy-4-methylphenyl)ethanone (2.21 g, 9.06 mmol, 45%) as a yellow solid. The NMR spectramatch with the data reported in the literature.4 |
With bromine In chloroform Photolysis; | ||
With copper(ll) bromide In chloroform; ethyl acetate Heating; | ||
With copper(ll) bromide In methanol at 70℃; for 0.5h; Microwave irradiation; Inert atmosphere; | ||
With copper(ll) bromide In chloroform; ethyl acetate Reflux; regioselective reaction; | ||
With copper(ll) bromide In chloroform for 24h; Reflux; | ||
With copper(ll) bromide In chloroform; ethyl acetate at 65℃; | ||
With copper(ll) bromide In ethyl acetate at 25℃; for 10h; Reflux; Inert atmosphere; | ||
With copper(ll) bromide In chloroform; ethyl acetate at 80℃; | ||
With copper(ll) bromide In ethyl acetate for 10h; Reflux; | Skeleton 1 General procedure: CuBr2 (450 mg, 2.0 mmol) was added to a solution of commercially available, substituted o-hydroxyacetophenone (1.0 mmol) in EtOAc (30 mL) at 25 °C. The reaction mixture was stirred at reflux for 10 h. Then, the reaction mixture was cooled to 25 °C, filtered, neutralized with saturated aq NaHCO3 (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried, filtered and evaporated under reduced pressure to afford crude product. Without further purification, substituted sodium sulfinate (2.1 mmol) was added to the resulting substituted α-bromo-o-hydroxyacetophenone in a cosolvent of dioxane and water [20 mL, 1:1 (v/v)] at 25 °C. The reaction mixture was stirred at reflux for 3 h. Then, the reaction mixture was cooled to 25 °C and extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine, dried, filtered and evaporated under reduced pressure to afford crude product. Purification on silica gel (hexanes/EtOAc, 10:1-2:1) afforded skeleton 1, known compounds whose analytical data are consistent with the literature.12b | |
With copper(ll) bromide In ethyl acetate for 10h; Reflux; | ||
With N-Bromosuccinimide; toluene-4-sulfonic acid In water; acetonitrile Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide In ethanol; water at 20℃; Sonication; | General procedure for preparation of 2′-hydroxychalcone derivatives General procedure: aq KOH (40%, 15mL) was added to a stirred solution of acetophenone derivates (10mmol) and (10mmol) in absolute EtOH (30mL). The mixture was sonicated for 1h and was then stirred at room temperature overnight. The dark red solution was acidified with 2M aq HCl to form a yellow precipitate, which was filtered and rinsed with distilled water. The precipitate was purified by flash chromatography with n-hexane/EtOAc (gradient 10-60% EtOAc) and recrystallisation using absolute EtOH. |
95% | With potassium hydroxide In ethanol at 40℃; Sonication; | Synthesis of (E)-3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-4-methoxy phenyl) prop-2-en-1-one (19) KOH 40% (15 mL) was added to a stirred solution of 2-hydroxy-4-methoxyacetophenone (17) (1.66 g, 10 mmol) and 3,4-dimethoxybenzaldehyde (18) (1.66 g, 10 mmol) in absolute EtOH (30 mL). The mixture was sonicated for 60 min and was then stirred at room temperature overnight. The dark red solution was acidified with 1 M of HCl to form a yellow precipitate, which was filtered and rinsed with distilled water. The precipitate was subjected to recrystallization using absolute EtOH to afford 19 as yellow solid, yield 95%, m.p. 157-159 °C; 1H NMR (500 MHz, CDCl3) δ 13.56 (s, 1H), 7.87 (t, 2H), 7.46 (d, J = 15.4 Hz, 1H), 7.27 (dd, J = 8.3, 1.8 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 11.5, 2.5 Hz, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 3.88 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 191.95, 166.81, 166.24, 151.79, 149.50, 144.72, 131.26, 127.99, 123.44, 118.23, 114.31, 111.38, 110.51, 107.78, 101.23, 77.16, 56.17, 55.71. ESI-HRMS: (C18H18O5) calc. [M+Na+] 337.1052, found 337.1078. |
89% | With sodium hydroxide In ethanol at 20℃; | 4.2. General procedures for synthesis of chalcones General procedure: For synthesis of chalcones we have used 2 different methods. Chalcones 1-30 were synthesized by method A and chalcones 31-44 were synthesized by method B. For Method B we used LiOHinstead of usual base NaOH for Claisen-Schmidt synthesis and the reaction was carried out in an ultrasonic bath. The general reaction scheme is depicted in Scheme 1.Method A: 20% NaOH (5 ml) was added dropwise to a previously cooled mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 25 ml ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72 h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dilute HCl. Precipitated product was filtered by suction and washed to neutral. The solid was recrystallised from dilute ethanol to get crystalline chalcone.Method B: To a mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 50 ml round bottom flask, 20 ml methanol and 35 mmol of LiOH was added. The reaction mixture was kept in an ultrasonic bath for 1-5 h, until reaction completion was indicated by TLC. The reaction was worked up as described for method A. |
86% | With potassium hydroxide In methanol at 20℃; for 24h; | |
82% | With potassium hydroxide In methanol at 20℃; | General Procedure for the Synthesis of Chalcones (1a-1u): General procedure: A solution of 50% KOH (40 mL) was added dropwise to well-stirred equimolar quantities of different substituted acetophenones and aldehydes in MeOH at room temperature. After 2436 h, the solvent was removed under reduced pressure and 5% HCl (50-70 mL) added to the residue. After extraction with EtOAc, the organic layer was washed with brine, dried (Na2CO3), and then concentrated in vacuo. The residue was purified by using column chromatography on silica gel, eluting with EtOAc in hexanes, to afford chalcones 1a-1u. |
55% | With lithium hydroxide In methanol Sonication; | |
50% | With barium dihydroxide In ethanol for 2h; Heating; | |
49% | With potassium hydroxide In methanol at 5 - 20℃; | General procedure: A solution of substituted acetophenones (5 mM) and aromatic aldehyde (5 mM) in methanol (15 mL) was cooled to 5-10 °C in an ice bath. The cooled solution was treated with adding a small portion of pulverized KOH (10 mM). The reaction mixture was magnetically stirred for 60 min and then left overnight or longer, monitored by thin layer chromatography using developing solvent n-hexane-acetone (5-1). The resulting dark solution was diluted with ice water and carefully acidified using dilute hydrochloric acid. The chalcone which separated as a yellow solid was collected by filtration after washing with water and further purified by crystallization from methanol or by silica gel column chromatography. |
46% | With sodium hydroxide In ethanol at 20℃; | |
46% | With sodium hydroxide In ethanol; water at 20℃; | General procedure for the synthesis of (2E)-1-(2-hydroxy-phenyl)-3-phenylprop-2-en-1-ones: General procedure: An aqueous solution of NaOH (3 M, 1.6 mL) was added to a solution of aromatic ketone (1 mmol) and substituted benzaldehyde (1.2 equiv.), in EtOH (1-2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from EtOH. |
30% | With sodium hydroxide In ethanol | |
19% | With potassium hydroxide In methanol at 70℃; | |
13% | With potassium hydroxide In ethanol at 0 - 20℃; for 24h; Inert atmosphere; | 4.9. General procedure I: preparation of chalcone General procedure: Potassium hydroxide (3 eq.) was added to a solution of aldehyde(1.2e1.4 eq.) and ketone (1 eq.) in ethanol (7 mL) at 0 C. The reactionmixturewas stirred overnight at room temperature under aninert atmosphere. The reaction mixturewas acidified by addition ofaqueous hydrogen chloride (5%) and extracted with DCM(3 12 mL). The combined organic layers were washed with brine(10 mL), dried over MgSO4, and evaporated to dryness underreduced pressure. The products were purified by column chromatographyand crystallized if needed. |
base-catalyzed Claisen-Schmidt reaction; | ||
With potassium hydroxide In methanol; water for 0.25h; Heating; Yield given; | ||
In ethanol at 20℃; Alkaline conditions; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydroxide In ethanol; water at 20℃; | 2 4.1.1 General procedure for the synthesis of chalcones (3a-3h) General procedure: A mixture of the acetophenone (5-10mmol, 1equiv) and the corresponding aldehyde (1equiv) in EtOH (20-40mL) was stirred at room temperature and a 50% aqueous solution of NaOH (5-8mL) was added. The reaction mixture was stirred at room temperature until aldehyde consumption. After that, HCl (10%) was added until neutrality. Precipitated chalcones were generally filtered and crystallized from MeOH, although in some cases the product was purified using column chromatography. Chalcones 3a, 3c, 3e and 3f have been previously described. |
64% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride In ethanol at 80℃; for 2h; | 1.1. General procedure for condensation to generate imine (2a-b) General procedure: A stirred solution of compound 2-Hydroxy-4-substitutephenylethanone,ethoxycarbonylhydrazine(1.1 equivalents) and concentrated HCl (0.08 equivalents) inethanol was boiled for 2 h(monitoring by TLC following the consumption of the initialcompound) and left at RT overnight .The separated precipitate was filtered off, washed withethanol, and dried in air. |
85% | In propan-1-ol for 24h; Heating; | |
79% | In benzene for 48h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydroxide In methanol; water at 70℃; | 2.1.2. Synthesis of 2′ -hydroxychalcone derivatives General procedure: Chalcones were synthesised following (Kachadourian et al., 2012),with some modifications (Scheme 2). One mL of a 50% aqueous solutionof NaOH was added to a stirred solution of each acetophenone (1 mmol)and benzaldehyde (1 mmol) in MeOH (10 mL). The reaction mixture washeated for 3-5 h at 70 C (Scheme 2) and the reaction was monitored byHPLC.Upon reaction completion, the solution was neutralized with 10%HCl(aq) and extracted twice with an equal volume of CH2Cl2. Theorganic layer was dried under reduced pressure and recrystallized fromMeOH/H2O (70/30, v/v). Compounds purity was confirmed by HPLC as>98%. These recrystallized compounds were used for chemical identificationand assays |
80% | With potassium hydroxide In ethanol; water for 18h; Ambient temperature; | |
79% | With sodium hydroxide In ethanol at 20℃; | 4.2. General procedures for synthesis of chalcones General procedure: For synthesis of chalcones we have used 2 different methods. Chalcones 1-30 were synthesized by method A and chalcones 31-44 were synthesized by method B. For Method B we used LiOHinstead of usual base NaOH for Claisen-Schmidt synthesis and the reaction was carried out in an ultrasonic bath. The general reaction scheme is depicted in Scheme 1.Method A: 20% NaOH (5 ml) was added dropwise to a previously cooled mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 25 ml ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72 h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dilute HCl. Precipitated product was filtered by suction and washed to neutral. The solid was recrystallised from dilute ethanol to get crystalline chalcone.Method B: To a mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 50 ml round bottom flask, 20 ml methanol and 35 mmol of LiOH was added. The reaction mixture was kept in an ultrasonic bath for 1-5 h, until reaction completion was indicated by TLC. The reaction was worked up as described for method A. |
76% | With potassium hydroxide In methanol at 5 - 20℃; | General procedure: A solution of substituted acetophenones (5 mM) and aromatic aldehyde (5 mM) in methanol (15 mL) was cooled to 5-10 °C in an ice bath. The cooled solution was treated with adding a small portion of pulverized KOH (10 mM). The reaction mixture was magnetically stirred for 60 min and then left overnight or longer, monitored by thin layer chromatography using developing solvent n-hexane-acetone (5-1). The resulting dark solution was diluted with ice water and carefully acidified using dilute hydrochloric acid. The chalcone which separated as a yellow solid was collected by filtration after washing with water and further purified by crystallization from methanol or by silica gel column chromatography. |
72% | With barium dihydroxide In ethanol for 2h; Heating; | |
48% | With barium hydroxide octahydrate In methanol at 40℃; for 12h; | |
34% | With potassium hydroxide In methanol at 70℃; | |
1.7% | With sodium hydroxide In ethanol; water at 20℃; for 48h; Inert atmosphere; | General procedure for the synthesis of chalcone 2: 2’-Hydroxy-4’-methoxyacetophenone (7.67 mmol; 1 equiv.) and 4-chlorobenzaldehyde (1 equiv.) were dissolved in 2 mL absolute ethanol. NaOH (40% in water; 0.5 equiv.) was added drop-wise. Since 4-chlorobenzaldehyde is air sensitive the reaction was carried out in an atmosphere of nitrogen. The reaction was stirred for 48 h at room temperature and the ethanol was evaporated to yield an oily residue. The residue was purified by column chromatography using petroleum ether: ethyl acetate (95:5) as eluent. |
With potassium hydroxide In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In pyridine at 90℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium hydroxide In ethanol at 20℃; for 24h; | General procedures for the preparation of compounds 5a-i General procedure: 1-(2-Hydroxy-4-methoxyphenyl)ethanone (1) (166 mg, 1 mmol) and various aryl aldehyde 7 or commercially available aldehyde (1 mmol) were dissolved in EtOH (50 mL), in which was added 10% NaOH solution (10 mL). The reaction mixture was stirred at room temperature for 24 h, and yellow solid was precipitated. The yellow precipitate was filtered and washed with appropriate amount of water, the crude products recrystallized with MeOH to afford pure products. |
50% | With barium dihydroxide In ethanol for 2h; Heating; | |
15% | With potassium hydroxide In methanol at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 1-(2-hydroxy-4-methoxyphenyl)ethanone With sodium hydroxide In methanol at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3-methoxy-benzaldehyde In methanol Inert atmosphere; | The general method for the preparation of chalconesseries 1 and series 2 General procedure: Under N2 atmosphereand 0 OC, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (1mmol, 1 eq) or1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-one (1mmol, 1 eq) was dissolved into10 ml MeOH, followed by the addition of 10 ml aq. 40% NaOH solution, themixture was stirred for about 30 min, then benzaldehydes (1.2 mmol, 1.2eq.)were added respectively. The mixture was stirred for overnight and monitored byTLC. After the starting material 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone or 1-(2-hydroxy-4,6-dimethoxyphenyl)propan-1-onewas consumed completely, the pH value was adjusted to 3 with aq. 3 N HClsolution, a large amount of yellowish solid formed. The crude product was filtrated,recrystallized from MeOH or purified by si-gel column chromatography to affordfine desired products. |
68% | With sodium hydroxide In ethanol at 20℃; | 4.2. General procedures for synthesis of chalcones General procedure: For synthesis of chalcones we have used 2 different methods. Chalcones 1-30 were synthesized by method A and chalcones 31-44 were synthesized by method B. For Method B we used LiOHinstead of usual base NaOH for Claisen-Schmidt synthesis and the reaction was carried out in an ultrasonic bath. The general reaction scheme is depicted in Scheme 1.Method A: 20% NaOH (5 ml) was added dropwise to a previously cooled mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 25 ml ethanol under vigorous stirring. The mixture was stirred at room temperature for 24-72 h. After completion of the reaction as indicated by TLC, the mixture was poured onto crushed ice and acidified with dilute HCl. Precipitated product was filtered by suction and washed to neutral. The solid was recrystallised from dilute ethanol to get crystalline chalcone.Method B: To a mixture of 5 mmol of selected acetophenone and 5 mmol of selected benzaldehyde in 50 ml round bottom flask, 20 ml methanol and 35 mmol of LiOH was added. The reaction mixture was kept in an ultrasonic bath for 1-5 h, until reaction completion was indicated by TLC. The reaction was worked up as described for method A. |
63% | With sodium hydroxide In ethanol; water at 20℃; for 24h; |
58% | With sodium hydroxide In ethanol at 20℃; | |
58% | With sodium hydroxide In ethanol; water at 20℃; | General procedure for the synthesis of (2E)-1-(2-hydroxy-phenyl)-3-phenylprop-2-en-1-ones: General procedure: An aqueous solution of NaOH (3 M, 1.6 mL) was added to a solution of aromatic ketone (1 mmol) and substituted benzaldehyde (1.2 equiv.), in EtOH (1-2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from EtOH. |
54% | With barium dihydroxide In ethanol for 2h; Heating; | |
30% | With potassium hydroxide In methanol at 70℃; | |
20% | With sodium hydroxide In ethanol | |
With sodium hydroxide In ethanol; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; In ethanol; water; at 20℃; | General procedure: An aqueous solution of NaOH (3 M, 1.6 mL) was added to a solution of aromatic ketone (1 mmol) and substituted benzaldehyde (1.2 equiv.), in EtOH (1-2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from EtOH. |
74% | General procedure: A 50 mL flask was charged with substituted acetophenone (5 mmol) and a solution of sodium hydroxide (10 mmol) in a 4:1 (v/v) mixture of ethanol/H2O (25 mL), and the resulting mixture was stirred at room temperature for 5 min. A substituted benzaldehyde (5 mmol) was then added to the reaction, and the resulting mixture was stirred at room temperature. The reaction was then monitored byTLC using ethyl acetate/petroleum ether (1:4 or 1:2 v/v) as the solvent system. Upon completion of the reaction, the crude product was filtered off and recrystallized from a mixture of dichloromethane and ethanol or purified by column chromatography over silica gel eluting with a mixture of petroleum ether and ethyl acetate to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydride; Diethyl carbonate at 0 - 100℃; for 3.33333h; | 13 Example 13 Put NaH (1.45g, 60.2mmol) and 7.5mL of diethyl carbonate in a round-bottomed flask of appropriate size, move the reaction flask to a low-temperature reactor, stir at 0, and then add paeonol (2g, 12.04mmol) ) Dissolve it in 10mL diethyl carbonate and place it in a 25mL constant pressure ground liquid funnel, slowly drip it into the reaction flask, keep it at 0°C and continue stirring for 20 minutes, then move the reaction flask to the heating reactor Stir at 100 for 3 hours, and monitor the reaction by TLC. After the reaction is complete, stop heating, place the reaction flask at room temperature, carefully add water dropwise to quench the reaction, and then wash off excess diethyl carbonate with a large amount of ether (3×25mL) , Discard the ether layer, merge the water layer, acidify the water layer with 2N HCl to pH 3 (note: because the acidification process will produce a large amount of milk foam and precipitate a large amount of white solid, it must be acidified under stirring) , Filter, wash the filter cake with a large amount of water, and vacuum dry to obtain the target product with a yield of 69% and a white powdery solid. |
Multi-step reaction with 3 steps 1: 33 percent / PhN(Me)MgBr / diethyl ether / 3 h / 20 °C 2: 84 percent / conc. HCl / 24 h / 20 °C 3: 54 percent / KOH / methanol / 0.5 h / Heating | ||
Multi-step reaction with 2 steps 1: sodium hydride / mineral oil / Inert atmosphere; Reflux 2: barium(II) hydroxide / methanol; water / 2 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Heating / reflux; | To a solution of 1-(2-hydroxy-4-methoxy-phenyl)-ethanone (2.1 g, 12.0 mmoL) and Dyridine-4-yl-acetic acid HCI salt (2.0 g, 12.0 mmoL) in CH2CI2 (20 ml_) was added triethyl amine (3.4 ml_, 24 mmoL), DMAP (180 mg, 1.2 mmoL) and DCC (3.71 g, 8 mmoL) at room temperature. The mixture was stirred overnight and then heated to reflux for another 2 hours. The resulting solution was concentrated in vacuo and dissolved in ~ 100 ml_ ether. The solid was removed by filtration. The filtrate was then concentrated to give the crude material, which was then purified by silica gel chromatography using hexanes : ethyl acetate (3:1 to 1 :1) as eluent to give the title product as a white solid (1.85 g, 58%). 1H NMR (CDCI3, delta) 8.75 (s, 1 H), 7.58 (d, J = 6.8 Hz, 1 H), 7.25 (d, J =4.32, 2H), 6.90 (d, J = 6.8 Hz, 1 H), 6.82 (s, 1 H), 3.91 (s, 3H), 2.30 (s, 3H), MS, MH+, 267. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyrrolidine; iodine; In dimethyl sulfoxide; at 150℃; for 10h; | General procedure: 2'-Hydroxyacetophenone (1 mmol) and substituted aromatic aldehyde (1 mmol) were mixed together along with pyrrolidine (0.5 mmol) and iodine (0.05 mmol) in DMSO solvent (10 mL). The resulting mixture was then heated at 150 C for the given time. After completion of reaction (monitored by TLC) the reaction mass was allowed to cool and diluted with ethyl acetate (20 mL). Resulting solution was then washed with water and saturated sodium thiosulfate solution followed by drying over anhydrous sodium sulfate and concentrating under reduced pressure to furnish the crude product. The residue obtained was purified by column chromatography using petroleum ether-ethyl acetate as an eluent to afford flavones (3a-r). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8%; 72% | With acetylhydroxamic acid; sulfuric acid; In acetonitrile; at 80℃; under 1292.9 Torr; for 0.2h;Microwave irradiation; | General procedure: 2-Hydroxy acetophenone 4a (1.0 g, 7.4 mmol), acetohydroxamic acid (0.83 g, 11.0 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a 10 ml pressure tube and subjected to microwave heating (CEM discover, 360 W, 80 C, 25 psi) for 8 min. Next, the reaction mixture was diluted with ethyl acetate (3 ml) and to this; saturated sodium bicarbonate solution (5 ml) was added drop-wise. The mixture was extracted with ethyl acetate (2 × 10 ml) and the combined organic layer was washed with saturated NaCl solution, dried over anhy. Na2SO4, and concentrated under reduced pressure. Purification of the mixture by normal column chromatography (silica gel 60-120 mesh, ethyl acetate/hexane: 1:9) gave benzoxazole 5a (0.67 g, 70%) in the form of a yellow oil and 2-hydroxy acetophenone oxime 6a (68 mg, 6%, mp 104-107 C) in the form of a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide; In ethanol; at 20℃; | General procedure: A mixture of the acetophenone (5-10mmol, 1equiv.) and the corresponding aldehyde (1equiv.) in EtOH (20-40mL) was stirred at room temperature and a 50% aqueous solution of NaOH (5-8mL) was added. The reaction mixture was stirred at room temperature until all aldehyde had been consumed. HCl (10%) was then added until neutrality. Precipitated chalcones were generally filtered and crystallized from MeOH although in some cases the product was purified using column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate; at 20℃;Cooling with ice; | General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate; at 20℃;Cooling with ice; | General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate; at 20℃;Cooling with ice; | General procedure: Phosphoryl chloride (POCl3; 20 mmol) was added slowly to a 100 mL SNRB flask containing a mixture of I (5.5 mmol) and the appropriate 2'-hydroxyacetophenone (5 mmol) in pyridine (30 mL). The flask was placed in an ice bath and the reaction mixture was left overnight, with constant stirring at room temperature. The reaction mixture was then poured into 100 mL cold, dilute HCl in a 250 mL EF, followed by extraction with ethyl acetate (EA). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product obtained was further purified by open column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With pyrrolidine; In methanol; at 20℃; | Example 129 A methyl 7-methoxy-4-oxospiro[chroman-2, 1 '-cyclobutane]-3'-carboxylate To l-(2-hydroxy-4-methoxyphenyl)ethanone (CAS 552-41-0) (500 mg, 3.01 mmol) in methanol (10 mL) was added <strong>[695-95-4]methyl 3-oxocyclobutanecarboxylate</strong> (1157 mg, 9.03 mmol) and pyrrolidine (0.754 mL, 9.03 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was extracted with CH2CI2 and the organic layer washed with water, dried over NaS04, filtered, and concentrated. Purification by flash chromatography on silica gel, eluting with ethyl acetate in heptane (0-30%) yielded title compound (200 mg, 24 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.3% | General procedure: In a typical procedure, 1.39 mmol of 2?-hydroxyacetophenone (for 1 and 3) or 2?-hydroxy-4?-methoxyacetophenone (for 2 and 4) were dissolved in 40 ml of methanol. To this solution, 4 equivalent of potassium hydroxide were added and stirred for 15 min at room temperature. Then, 1.40 mmol of the appropriate ferrocenecarboxaldehyde derivative, (i.e. 1-ferrocenecarboxaldehyde for 1 and 2 or 1,1-ferrocenedicarboxaldehyde for 3 and 4) were added. The mixture was stirred during three days at room temperature. Then, methanol was evaporated in vacuum (rotary evaporator) and the crude reaction mixture was submitted to column chromatography (silica gel 60, Ethyl acetate: Hexane = 3:10 v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In benzene; at 90℃;Inert atmosphere; | General procedure: Substituted 2-hydroxyacetophenone (1.4 mmol) was added to anhydrous benzene (4 mL) and N, N-dimethylformamide dimethyl acetal (4.2 mmol) was added to the stirred solution under normal temperature and nitrogen atmosphere.The mixture was stirred at 90 C. overnight. After the reaction was completed and cooled to 0 ,Saturated HCl (0.85 mL) was added.The resulting mixture was stirred at 55 C. for 1 hour.After the reaction was completed, diluted with EtOAc (40 mL),Washed with H2O (3x10mL) and brine (2x15mL),It was dried over anhydrous Na 2 SO 4 and concentrated in vacuo.The crude compound was purified by column chromatography (EtOAc / Hexane = 1 / 1-2 / 1) to give pure substituted 4H-chromen-4-one. |
91% | In benzene; at 90℃;Inert atmosphere; | General procedure: Substituted 2-hydroxyacetophenone (1.4 mmol) was added to anhydrous benzene (4 mL), and N, N-dimethylformamide dimethyl acetal (4.2 mmol) was added to the stirred solution under normal temperature and nitrogen atmosphere.The mixture was stirred at 90 C overnight. After the reaction was completed, the reaction mixture was cooled to 0 C, and saturated HCl (0.85 mL) was added thereto.The resulting mixture was stirred at 55 C for 1 hour. After completion of the reaction, diluted with EtOAc (40 mL), washed with H2O (3 × 10 mL) and brine (2 × 15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.The crude compound was purified by column chromatography (EtOAc / Hexane = 1/1-2/1) to give pure substituted 4H-chromen-4-one. |
70% | Example 10A 7-methoxy-4H-1-benzopyran-4-one 1-(2-Hydroxy-4-methoxyphenyl)ethanone (47 g, 283 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (47 mL, 351 mmol), and the solution was heated to >100 C. in a sand bath for 10 minutes, at which point a solid mass had formed. The flask was cooled to ambient temperature, and 200 mL of heptanes were added. The solids were broken up with a spatula and collected by filtration with a frilled funnel. The solid material was crushed with a pestle and then washed with heptanes. The solid was then dried on the filter to give about 60 g of the crude intermediate. This intermediate was dissolved in dichloromethane (1 L) and stirred with 150 mL of concentrated HCl at 40 C. for 30 minutes. The flask was cooled to ambient temperature, and about 100 mL of water was added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was then precipitated from 500 mL of 1:1 cyclopentyl methyl ether:heptanes to give the title compound (35 g, 70% yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.11 (d, J=8.9 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.28 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS(ESI+) m/z 176.9 (M+H)+. |
70% | 1-(2-Hydroxy-4-methoxyphenyl)ethanone (47 g, 283 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (47 mL, 351 mmol), and the solution was heated at >100 C. in a sand bath for 10 minutes, at which point a solid mass formed. The flask was cooled to ambient temperature, and 200 mL of heptanes were added. The solids were broken up with a spatula and collected by filtration with a fritted funnel. The solid material was crushed with a pestle and washed with heptanes. The solid was dried on the filter to give about 60 g of the crude intermediate. The intermediate was dissolved in dichloromethane (1 L) and stirred with 150 mL of concentrated HCl at 40 C. for 30 minutes. The flask was cooled to ambient temperature, and about 100 mL of water was added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was taken into 500 mL of 1:1 cyclopentyl methyl ether:heptanes and the precipitate was collected to provide the title compound (35 g, 70% yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.11 (d, J=8.9 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.28 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS(ESI+) m/z 176.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 6h; Inert atmosphere; | General procedure General procedure: A mixture of P(O)OH compounds (0.5 mmol), alcohol (0.5 mmol), and DCC (0.55 mmol) was dissolved in dioxane under N2 atmosphere, stirred at room temperature for 6h. Removal of the solvent under a reduced pressure gave the crude product; pure product was obtained by passing the crude product through a short silica gel column using Hexane/EtOAc (1:1-5:1) as eluent. |
88% | With <i>N</i>,<i>N</i>-dimethyl-aniline; 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 12h; Inert atmosphere; | General procedure General procedure: A mixture of P(O)-OH compounds (0.5mmol), phenols (0.5mmol), CDI (0.5mmol) and PhNMe2 (0.75mmol) in CH3CN (1.0mL) was stirred at room temperature under N2 atmosphere for 12h. Removal of the solvent under reduced pressure gave the crude product; pure product was obtained by passing the crude product through a short silica gel column using Hexane/EtOAc (1:1-5:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium hydride In tetrahydrofuran at 70℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With sodium hydride In tetrahydrofuran at 70℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide In ethanol; water at 20℃; | 2 4.1.1 General procedure for the synthesis of chalcones (3a-3h) General procedure: A mixture of the acetophenone (5-10mmol, 1equiv) and the corresponding aldehyde (1equiv) in EtOH (20-40mL) was stirred at room temperature and a 50% aqueous solution of NaOH (5-8mL) was added. The reaction mixture was stirred at room temperature until aldehyde consumption. After that, HCl (10%) was added until neutrality. Precipitated chalcones were generally filtered and crystallized from MeOH, although in some cases the product was purified using column chromatography. Chalcones 3a, 3c, 3e and 3f have been previously described. |
36% | With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In ethanol; water; at 20℃; | General procedure: To a solution of the appropriate ortho-hydroxyacetophenone(1 mmol) and a substituted 2-aryl-1,3-thiazole-4-carbaldehyde(1 mmol) dissolved in ethanol (10 mL) was added dropby drop a solution of KOH (0.056 g) in water (0.112 mL).The reaction mixture was stirred at room temperaturefor 10-12 h. The reaction was monitored by TLCusing dichloromethane, dichloromethane:acetone (25:1) ordichloromethane:acetone (9:1) as mobile phases. The reactionmixture was poured on water and acidified with HCl(10% aqueous solution). In all cases, a yellow or orangeprecipitate was formed, which was filtered and washed withwater. The compounds were purified by silica gel columnchromatography with dichloromethane, dichloromethane:acetone (25:1), dichloromethane:acetone (9:1) or gradientmobile phases, as indicated for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine In dichloromethane at 90℃; for 24h; | 1 (Example 1 ) ( Synthesis of Caged Compound) A caged compound represented by the above formula (3) was synthesized. More specifically, first,2'-Hydroxy-4'-methoxyacetophenone of the formula (7) (manufactured by Tokyo Chemical Industry Co., Ltd.)500 mg (3.0 mol)589 mg (3.3 mol) of 4-nitrophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) of the formula (8)(Manufactured by Wako Pure Chemical Industries, Ltd.)In 2 ml of methylene chloride was added triethylamine(Manufactured by Wako Pure Chemical Industries, Ltd.) 1 ml was added dropwise.The reaction mixture was then heated at 90 ° C. for 24 hours,After heating to reflux and cooling to room temperature,10 ml of ether was added and the mixture was stirred for 2 hours.Then, the precipitated solid was filtered,By drying,7-methoxy-4-methyl-3- (4-nitrophenyl) coumarin represented by the formula (9)(475 mg, yield: 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium hydroxide; In ethanol; at 0 - 20℃; for 73h;Inert atmosphere; | General procedure: To a stirred solution of KOH (12.0 equiv) in absolute EtOH (100 mL) cooled to 0 C in anice-bath was added dropwise a solution of the corresponding acetophenone (1.0 equiv) and aldehyde (1.0 equiv) in EtOH (20 mL). The reaction mixture was stirred at 0 C for 1 h and then at room temperature for 72 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The resulting mixture was then poured into ice-water (100 mL) and acidified to pH 3-4 with 3 M HCl. The aqueous solution was extracted with CHCl3 (3 × 100 mL) and the combined organic layer was washed with satd NaHCO3 (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography over silica and/or recrystallized from MeOH or absolute EtOH to afford the corresponding chalcones. (E)-3-(4-Bromo-2,5-dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (79). A mixture of benaldehyde 76 (1.50 g, 6.12 mmol), acetophenone 73 (1.04 g, 6.26 mmol) and KOH (4.33 g, 77.2 mmol) in absolute EtOH (100 mL) was reacted according to GP-C. The crude residue was purified by recrystallization from MeOH to afford chalcone 79 (1.01 g, 42%) as a bright yellow powdery solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; In ethanol; water; at 20℃; | General procedure: An aqueous solution of NaOH (3M, 1.6mL) was added to a solution of aromatic ketone (1mmol) and 3-methoxybenzaldehyde (1.2 eq), in EtOH (1-2mL). The reaction was stirred at r.t for 18-24h. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from ethanol. When no precipitate occurred, the reaction mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography was then utilized to purify the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydroxide; In ethanol; water; at 20℃; | General procedure: An aqueous solution of NaOH (3M, 1.6mL) was added to a solution of aromatic ketone (1mmol) and 3-methoxybenzaldehyde (1.2 eq), in EtOH (1-2mL). The reaction was stirred at r.t for 18-24h. The reaction mixture was cooled in an ice-water bath and acidified to pH 2 with concentrated HCl (37%). The solid formed was filtered, washed with ethanol and then further purified by recrystallization from ethanol. When no precipitate occurred, the reaction mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography was then utilized to purify the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine; In dichloromethane; at 20℃; | General procedure: To a solution of paeonol/2-hydroxy acetophenone/3-methoxyphenol (1/2/3, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonyl chloride (7, 1.2 mmol) in dry dichloromethane (CH2Cl2, 10 ml) at room temperature, a solution of triethylamine (Et3N) (1.5 mmol) in dry CH2Cl2 (5 ml) was added dropwise for 10 min. When the reaction was completed by TLC analysis, the reaction mixture was diluted with water (15 ml), and extracted with CH2Cl2 (30 ml*3). Subsequently, the combined organic phasewas washed by saturated aq. brine (30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain title compounds. The data for 4a-p, 5a-p, and 6a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.02% | Mix 4.28g of 4-methanesulfonylphenylacetic acid (0.02mol) and 50mL of CH2Cl2 first, then add 300mg of 4-dimethylaminopyridine. With stirring at room temperature, add 10mL of SO2Cl2 (already dissolved in 20mL of CH2Cl2) solution, dropwise about 0.5h After completion of the reaction, the temperature was controlled at 70C and the reaction was refluxed for 3h. After the reaction was completed, SOCl2 and CH2Cl2 were distilled off under reduced pressure. After the residue was dissolved in 20mL of CH2Cl2, suction filtration was performed to obtain 3.96g of pale yellow solid with a yield of 85.34%. 2.32g paeonol (0.014mol), 40mL CH2Cl2 and 4mL triethylamine were added to the three-necked flask and mixed thoroughly. 3.96g of the above product (0.017mol) was slowly added dropwise with stirring in an ice bath. After washing with 50 ml of water and adding 3 times with CH2Cl2 for extraction, the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure and evaporated to dryness to obtain a dark yellow oil. Column chromatography isolated 2.89 g of off-white solid. Yield: 57.02%. |
Tags: 552-41-0 synthesis path| 552-41-0 SDS| 552-41-0 COA| 552-41-0 purity| 552-41-0 application| 552-41-0 NMR| 552-41-0 COA| 552-41-0 structure
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P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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