Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 642-71-7 | MDL No. : | MFCD00008389 |
Formula : | C9H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VTCDZPUMZAZMSB-UHFFFAOYSA-N |
M.W : | 184.19 | Pubchem ID : | 69505 |
Synonyms : |
3,4,5-Trimethoxyphenol;5-HYDROXY-1,2,3-TRIMETHOXYBENZENE
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.94 |
TPSA : | 47.92 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 1.95 |
Log Po/w (XLOGP3) : | 1.57 |
Log Po/w (WLOGP) : | 1.42 |
Log Po/w (MLOGP) : | 0.6 |
Log Po/w (SILICOS-IT) : | 1.36 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.11 |
Solubility : | 1.41 mg/ml ; 0.00768 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.19 |
Solubility : | 1.2 mg/ml ; 0.00651 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.21 |
Solubility : | 1.15 mg/ml ; 0.00622 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.66 |
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 |
---|---|---|
100% | With bis-[(trifluoroacetoxy)iodo]benzene In water; acetonitrile for 0.166667h; Ambient temperature; | |
96% | With tetrakis-[4-(diacetoxyiodo)phenyl]methane In acetonitrile at 20℃; for 0.5h; | |
92% | With oxygen; copper dichloride In water; ethyl acetate at 70℃; for 3h; |
61% | With dihydrogen peroxide In formic acid; water at 40℃; for 2h; | |
59.9% | With potassium peroxymonosulfate In water; acetonitrile at 20℃; for 5h; | SI-5 Reaction of 5 with 2 mol eq of Oxone(Table 1, Entry 10) The reaction was setup the same as described above for the scale up reaction of 1 with Oxone. 51 mg (277 µmol) of 5 and 344 mg (559 µmol) of Oxone in 5.6 mL of 10% (v/v) ACN in H2O were used. The workup was the same as described above. The crude organic residue was loaded on a silica column for flash chromatography. It was separated using a 5% MeOH in CHCl3 solution, gradually ramping up the percentage of MeOH. The fractions were stripped of solvent, weighed, and 1H-NMR spectra recorded for identification. The recovery of 5 was 11.2% (5.7 mg) and the yield of 6 was 59.9% (27.9 mg) as a percentage of the initial moles of starting material. This result is reported as a percent yield based on converted starting material in Table 1. |
With water; iron(III) chloride | ||
With bis-[(trifluoroacetoxy)iodo]benzene In water; acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 3,4,5-trimethoxyphenol With triethylamine In dichloromethane at 20℃; for 0.25h; Stage #2: acetic anhydride In dichloromethane at 20℃; for 6h; | {1- (6-Hydroxy-2,3,4-trimethoxyphenyl) ethanone} (Compound 14): 3,4,5-trimethoxyphenol (Compound 13) (1.55 g, 8.42 mmol)Was added to anhydrous CH 2 Cl 2 (16 mL), and Et 3 N (2.36 mL, 16.63 mmol) was added to the stirred solution, followed by stirring at room temperature for 15 minutes.Acetic anhydride (1.2 mL, 12.62 mmol) was added and stirred at room temperature for 6 hours. After the reaction was completed, diluted with CH 2 Cl 2 (80 mL),2N HCl (8 mL), H 2 O (2x20 mL),Washed with brine (20mL) and dried over anhydrous Na2SO4, Concentrated in vacuo. Acetylated colorless solid compound (1.88 g, 99%) was obtained and used in the next step without further purification. |
99% | Stage #1: 3,4,5-trimethoxyphenol With triethylamine In dichloromethane at 20℃; for 0.25h; Stage #2: acetic anhydride In dichloromethane at 20℃; for 6h; | 1-(6-Hydroxy-2,3,4-trimethoxyphenyl) ethanone {1-(6-Hydroxy-2,3,4-trimethoxyphenyl) ethanone} (Compound 14): 3,4,5-trimethoxyphenol (Compound 13) (1.55 g, 8.42 mmol) was added to anhydrous CH2Cl2 (16 mL), and Et3N (2.36 mL, 16.63 mmol) was added to the stirred solution, followed by stirring at room temperature for 15 minutes. Acetic anhydride (1.2 mL, 12.62 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction, the mixture was diluted with CH2Cl2 (80 mL), washed with 2N HCl (8 mL), H2O (2 × 20 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Acetylated colorless solid compound (1.88 g, 99%) was obtained and used in the next step without further purification. |
99% | With sodium acetate at 110℃; for 2h; | 2.1 At room temperature, 3,4,5-trimethoxyphenol, compound 11a (9.2 g, 50 mmol) and sodium acetate (8.2 g, 100 mmol) were sequentially added to acetic anhydride (47 mL, 500 mmol) and mixed, and heated at 110 ° C for 2 hours. . After the reaction was completed, the reaction system was concentrated under reduced pressure, and extracted with ethyl acetate three times. It was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain 3,4,5-trimethoxyphenethyl ester, which is compound 12a (11.2 g, 49.5 mmo). White solid, 99% yield. |
96% | With sodium acetate at 110℃; for 2h; | |
96% | With sodium acetate at 110℃; for 3h; | |
96% | With sodium acetate at 110℃; | |
96% | With sodium acetate at 110℃; for 2h; | 2.1a Experimental procedure for the preparation of 3,4,5-Trimethoxyphenyl acetate (2): A mixture of 3,4,5-trimethoxyphenol (5 g, 27 mmol) and sodium acetate (5 g, 60 mmol) in acetic anhydride (25 mL, 265 mmol) was heated at 110°C for 2 h. TLC analysis (30% ethyl acetate/ pet ether) showed completion of the reaction. Then the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with dichloromethane thrice. The combined organic layer was washed with water and dried over anhydrous Na2SO4. The solvent was evaporated and the crude product was charged on silica gel column. Elution of the column with 20% ethyl acetate/ pet ether gave the compound 2 (5.91 g, 96%) as white solid. 1H NMR (400 MHz, CDCl3): δ 6.25 (s, 2H, Ar-H), 3.82 (s, 9H,3-OCH3), 2.25 (s, 3H, OCOCH3); MS (EI) m/z 227 (M+1, 100). |
With sodium acetate | ||
With sodium acetate at 110℃; for 1h; | ||
With pyridine at 0 - 20℃; | ||
Stage #1: 3,4,5-trimethoxyphenol With triethylamine In dichloromethane at 20℃; for 0.25h; Stage #2: acetic anhydride In dichloromethane at 20℃; for 6h; | ||
With potassium carbonate In tetrahydrofuran at 20℃; for 2h; | 35 Example 35: Preparation of Intermediate 6 Place 3,4,5-trimethoxyphenol (20g, 110mmol), K2CO3(163mmol, 23g) in a 500ml eggplant-shaped bottle, add 200ml of anhydrous THF to dissolve, then add acetic anhydride (17g, 165 mmol), stirred at room temperature for two hours after the addition was completed, the reaction was monitored by TLC, water was added after the reaction was completed, stirred at room temperature for 1 h, after no solid precipitated, extracted three times with DCM, the resulting organic phase was washed with saturated NaCl solution for two Next, dry over anhydrous Na2SO4, filter under reduced pressure, and spin dry to obtain intermediate 4. | |
With potassium carbonate In tetrahydrofuran at 20℃; for 2h; | 35 Example 35: Preparation of Intermediate 6 Place 3,4,5-trimethoxyphenol (20g, 110mmol), K2CO3 (163mmol, 23g) in a 500ml eggplant-shaped bottle, add 200ml of anhydrous THF to dissolve, then add acetic anhydride (17g, 165mmol), After the addition was completed, the mixture was stirred at room temperature for two hours. The reaction was monitored by TLC. After the reaction was completed, water was added and the mixture was stirred at room temperature for 1 hour. After no solid precipitated, it was extracted three times with DCM. Dry with water Na2SO4, filter under reduced pressure and spin dry to obtain intermediate 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With boron trifluoride diethyl ether complex at 85℃; for 2.5h; Inert atmosphere; | 1-(6-Hydroxy-2,3,4-trimethoxyphenyl)ethanone (4) To a stirring solution of 3 (10 g, 54.5 mmol) in BF3*Et2O(25 mL) was added CH3COOH (15 mL). After stirring under N2 atmosphere at 85 °C for 2.5 h, the reaction mixture was allowed to warm to room temperature. Then ice water (50 mL) was added slowly. The mixture was extracted with ethyl acetate (30 mL) three times, and the organic layer was dried over Na2SO4, filtered and concentrated to afford 4 (11.27 g, 92% yield) as a yellow solid [9]. M.p. 147-148 °C. 1H-NMR (CDCl3) δ 6.28 (s, 1H, 5-H), 4.10 (s, 3H, 2-H), 3.97 (s, 3H, 3-H), 3.77 (s, 3H, 4-H), 2.81 (s, 3H,21-H); 13C-NMR (CDCl3) δ 203.5 (CO), 161.9 (C(4)), 160.7 (C(6)), 155.4 (C(2)), 134.5 (C(3)), 108.1 (C(1)),96.1 (C(5)), 61.0 (MeO-C(2,21)), 56.4 (MeO-C(3)), 31.4 (MeO-C(4)); ESI-MS: m/z 227 [M + H]+. |
84% | With boron trifluoride diethyl ether complex | |
With boron trifluoride |
With boron trifluoride diethyl ether complex for 0.25h; | ||
With boron trifluoride diethyl ether complex at 85℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 3,4,5-Trimethoxyaniline With sulfuric acid; sodium nitrite In water at 10 - 15℃; Stage #2: With sulfuric acid; copper(II) sulfate at 100℃; for 2h; | |
76% | Stage #1: 3,4,5-Trimethoxyaniline With tetrafluoroboric acid In water at 20℃; for 0.0333333h; Stage #2: With sodium nitrite In water at 0℃; for 0.5h; Stage #3: With copper(I) oxide; copper(II) sulfate In water at 0 - 20℃; for 0.5h; | Typical experimental procedure for the synthesis of phenols General procedure: Water (4 mL) and HBF4 (~48-50% aq. sol., 4 mL) was added to the aniline (0.50 mmol, 1.0 equiv.) and stirred for a couple of minutes at room temperature in an open reaction flask. NaNO2 (0.038 g,1.1 equiv.) in water (2.8 mL) was added dropwise at 0°C and stirred for 30 minutes. To the cold solution of the resulting diazonium salt was added sat. aq. copper(II)sulfate (50 mL), followed by copper(I)oxide (1.0 equiv., 0.072 g), and stirred at room temperature for 30 minutes. The reaction mixture was extracted with CH2Cl2, dried (MgSO4)and evaporated in vacuo. The crude products were purified by silica gel chromatography.Potential hazard note: Diazonium compounds can be explosive, however, the risk is greatly reduced by following several rules for precaution.[17]Additional points that render the experimental procedure reported herein safer is that the diazonium salt is prepared in situ under dilute conditions and is not isolated, the reaction is performed open to air, the reaction temperature is 0°C to ambient, HBF4-is used as the counterion in this procedure, and arene diazonium tetra-fluoroborates, in contrast to the chloride salts, are renowned in general for their enhanced thermal stability and shockin sensitivity. Nevertheless, care should always be taken when handling diazonium compounds. |
Diazotization.Kochen der Loesung mit Schwefelsaeure; |
0.95 g | With sulfuric acid; copper(II) sulfate; sodium nitrite at 20 - 60℃; for 1.25h; | |
2.3 g | Stage #1: 3,4,5-Trimethoxyaniline With tetrafluoroboric acid In tetrahydrofuran Stage #2: With sodium nitrite In tetrahydrofuran; water at -5 - 0℃; Stage #3: With sulfuric acid; water; sodium sulfate at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In acetone for 12h; Reflux; | 6.d EXAMPLE 6 Ethyl 4-(3,4,5-trimethoxyphenoxy)butanoate EXAMPLE 6 [0158] In this Example, the method for synthesizing cremastranone analog 12 is described, as diagrammed in FIG. 4. [0159] Ethyl 4-(3,4,5-trimethoxyphenoxy)butanoate. To an acetone solution (10 mL) of 3,4,5-trimethoxyphenol (500 mg, 2.7 mmol) was added K2C03 (1.5 g, 11 mmol) and ethyl 4-bromobutyrate (1.3 mL, 7.9 mmol). After refluxing for 12 hours, the reaction mixture was cooled to room temperature and then filtered via a short pad of silica gel to remove excess K2C03. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (Ethyl acetate / n-hexane = 1 : 3) to afford ethyl 4-(3,4,5-trimethoxyphenoxy)butanoate (829 mg, 92%). 1H-NMR (600 MHz, CDC13) δ 6.06 (q, 1H), 4.08-4.02 (m, 2H), 3.90-3.87 (m, 2H), 3.76- 3.73 (m, 6H), 3.70-3.67 (m, 3H), 3.40-3.35 (m, 1H), 2.44-2.38 (m, 2H), 2.09-2.04 (m, 2H), 2.01-1.96 (m, 3H); 13C-NMR (150 MHz, CDC13) δ 173.1, 155.4, 153.5, 132.1, 92.0, 66.9, 60.8, 60.4, 60.3, 55.9, 30.5, 24.5, 14.1; LRMS: (ESI) m/z 321 (M+Na). |
With potassium carbonate; potassium iodide In acetone for 60h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With zinc(II) chloride; trichlorophosphate at 60℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3 1,2,3,4-Tetrahydro-8,9,10-trimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one hydrochloride Prepared by the method described in Example 1 from 3,4,5-trimethoxyphenol (25 g, 0.14 moles) and <strong>[71486-53-8]methyl 4-oxo-3-piperidinecarboxylate hydrochloride</strong> (18.8 g, 0.097 moles). Recrystallization from dilute aqueous hydrochloric acid yielded the product (17.5 g) as the hydrochloride, mp 232°-234° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 3,4,5-trimethoxy-benzaldehyde With dibutyl ether; bis[3,5-bis(trifluoromethyl)diphenyl] diselenide In 2,2,2-trifluoroethanol at 20℃; for 0.25h; Stage #2: With potassium hydroxide In methanol for 2h; Further stages.; | |
75% | With dihydrogen peroxide In 1,2-dichloro-ethane at 80℃; | |
70% | Stage #1: 3,4,5-trimethoxy-benzaldehyde With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid In dichloromethane; water at 20℃; for 1h; Stage #2: With potassium carbonate In methanol at 20℃; for 0.5h; |
65% | With dihydrogen peroxide; toluene-4-sulfonic acid In methanol for 10h; Ambient temperature; | |
62% | Stage #1: 3,4,5-trimethoxy-benzaldehyde With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; Stage #2: With potassium hydroxide In methanol; dichloromethane at 20℃; for 3h; | Synthesis of 3,4,5-trimethxyphenol (6) To a solution of 3,4,5-trimethoxybenzaldehyde (20g, 69.9 mmol) in CH2Cl2 (150 mL) was added m-CPBA (25.83 g, 104.8 mmol) in portions. The resulting solution was stirred at room temperature overnight and then 10% KOH (aq.) (100 mL) and MeOH (100 mL) were added. The mixture was stirred at r.t. for 3 hacidified with 1 M HCl to adjust the solution pH 5-6 in ice bath, and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20:1 (v/v) as eluent) to give 6 1.01g as a white powder solid with yield: 62%, m.p.142-145oC ; 1H NMR (400 MHz, CDCl3) δ 6.09 (s, 2H, 2-H and 6-H), 3.79 (s, 6H, 3-OCH3, 5-OCH3), 3.78 (s, 3H, 4-OCH3). |
60% | With sulfuric acid; dihydrogen peroxide; boric acid In tetrahydrofuran; water at 20℃; for 18h; | |
With sodium hydroxide; sulfuric acid; dihydrogen peroxide; sodium sulfite In methanol | 3,4,5-Trimethoxyphenol (2) 3,4,5-Trimethoxyphenol (2) After adding concentrated sulfuric acid (0.54 ml, 10.2 mmol) to an MeOH solution (20.4 ml, 0.5 M) of 3,4,5-trimethoxybenzaldehyde (2.0 g, 10.2 mmol) while cooling with ice, a 30% aqueous hydrogen peroxide solution (3.5 ml, 30.6 mmol) was added slowly. After stirring for 15 minutes at room temperature, a 10% aqueous sodium hydroxide solution and sodium sulfite were added while cooling with ice to stop the reaction. After washing an organic layer extracted with AcOEt with brine, the organic layer was dried with MgSO4 followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel chromatography, and 3,4,5-trimethoxyphenol (1.08 g, 7.0 mmol, 58%) was obtained in the form of a colorless solid from a elution part of AcOEt/hexane (5:6 v/v). Colorless plate (AcOEt/hexane): mp 145-147 °C. IR (CHCl3) : 3303, 1612, 1129 cm-1. 1H-NMR (400MHz, CDCl3) δ : 6.09 (2H, s), 5.90 (1H, s), 3.79 (3H, s), 3.76 (6H, s). 13C-NMR (100 MHz, CDCl3) δ : 153.6, 152.7, 131.4,93.0,61.0,55.9. MS m/z : 184 (M+). HRMS Calcd. for C9H12O4 : 184.0736. Found : 184.0715. | |
Multi-step reaction with 2 steps 1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / Inert atmosphere 2: water; potassium hydroxide / tetrahydrofuran / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: dihydrogen peroxide / 1 h / 20 °C 1.2: -20 - -10 °C 2.1: potassium hydroxide; methanol / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran | |
62% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile for 0.5h; Inert atmosphere; | |
61% | With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile for 1h; Schlenk technique; Inert atmosphere; Glovebox; | |
46% | With aluminum tri-bromide; [bis(acetoxy)iodo]benzene In acetonitrile at 23℃; |
With N-Bromosuccinimide In tetrahydrofuran at 0℃; for 1h; | ||
2.24 g | With N-Bromosuccinimide In tetrahydrofuran at 20℃; for 2h; | 2.1 (1) In a 100 mL reaction vessel, 2.0 g (10.8 mmol) of XX-3 was dissolved in 20 ml of THF. Subsequently, 1.93 g (10.8 mmol) of N-bromosuccinimide was added, and then stirred at room temperature for 2 hours. Water was added to the reaction solution, and then a precipitate was extracted with ethyl acetate and washed with water, whereby XX-4 was obtained (2.24 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With trifluoroacetic acid for 23h; | |
90% | With trifluoroacetic acid In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0 - 20℃; for 1h; | |
85% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.25h; | |
79% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -15℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With trifluoroacetic acid In dichloromethane at 20℃; for 12h; | 3.5; 6; 13C EXAMPLE 6 EXAMPLE 6 This example provides the synthesis of 4-phenyl-5,6,7-trimethoxy coumarin (2). (Scheme of ). A mixture of 46.3 mg of 3,4,5 tri-methoxy phenol (0.25 mmol, 1 eq.), 52.2 mg of ethyl phenyl propiolate (0.3 mmol, 1.2 eq), 24.9 mg palladium triflate (0.075 mmol, 0.3 eq.), 20 μL trifluoracetic acid in 0.5 mL dichloromethane was stirred at room temperature for 12 hours under argon gas. Then the reaction mixture was diluted with dichloromethane, washed using 5% sodium bicarbonate, water and brine. The organic layer was dried using anhydrous Mg (SO4)2 and was concentrated in vaccu to give 80 mg of a crude brown solid. The crude NMR shows the desired product as a major product and some impurities. The crude brown solid was dissolved in hexane, and recrystallized. 15 mg of pure product was isolated. However, 1H-NMR confirmed that the aliquot still contains the product. H1NMR (300 MHz, CD3Cl): δ=7.25-7.45 (m, 5H), 6.70 (S, 1H), 6.05 (S, 1H), 3.93 (S, 1H), 3.75 (S, 3H), 3.25 (S, 3H). |
20% | With trifluoroacetic acid In dichloromethane | 3.1; 13B This example illustrates a catalytic electrode based cycloaddition, where an electrochemical process was used to convert catalytic Pd(II) into a non-catalytic reagent and performed site selectively on an electrode array device. In this experiment Pd(II) reagent was confined to the pre-selected electrode by putting ethyl vinyl ether in the solution above the electrode array device. In order to study the generality of these reactions and the extension of the approach to a Pd(II) catalytic reaction, a site selective Pd(II) catalyzed alkoxy-Coumarin synthesis was developed. Reaction of alkoxyphenols and alkyonates in the presence of a catalytic amount of Pd(OAc)2 in trifluoroacetic acid at room temperature was reported to give Coumarin derivatives in high yields. (FIG. 13A) Although the reaction gave a high yields the reactions conditions were modified in order to fit the electrode array device environment. The primary problem was that trifluoroacetic acid digests the agarose (hydroxylated porous matrix) coat on the electrode array device. After screening different reaction conditions the use of 30 mol % Pd(OTf)2 as catalyst in 5% TFA in dichloromethane gave acceptable yields. (FIG. 13B). Table 1 below shows the results of various reaction conditions. The optimal reaction scheme is shown in FIG. 13C. |
20% | With sodium acetate; trifluoroacetic acid In dichloromethane | 3.4; 13B This example illustrates a catalytic electrode based cycloaddition, where an electrochemical process was used to convert catalytic Pd(II) into a non-catalytic reagent and performed site selectively on an electrode array device. In this experiment Pd(II) reagent was confined to the pre-selected electrode by putting ethyl vinyl ether in the solution above the electrode array device. In order to study the generality of these reactions and the extension of the approach to a Pd(II) catalytic reaction, a site selective Pd(II) catalyzed alkoxy-Coumarin synthesis was developed. Reaction of alkoxyphenols and alkyonates in the presence of a catalytic amount of Pd(OAc)2 in trifluoroacetic acid at room temperature was reported to give Coumarin derivatives in high yields. (FIG. 13A) Although the reaction gave a high yields the reactions conditions were modified in order to fit the electrode array device environment. The primary problem was that trifluoroacetic acid digests the agarose (hydroxylated porous matrix) coat on the electrode array device. After screening different reaction conditions the use of 30 mol % Pd(OTf)2 as catalyst in 5% TFA in dichloromethane gave acceptable yields. (FIG. 13B). Table 1 below shows the results of various reaction conditions. The optimal reaction scheme is shown in FIG. 13C. |
93 % Chromat. | With palladium diacetate In trifluoroacetic acid at 20℃; for 18h; | |
93 % Chromat. | With trifluoroacetic acid at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With ammonium tetrafluoroborate In 1,2-dichloro-ethane at 60℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 3,4,5-trimethoxyphenol With titanium tetrachloride In dichloromethane at 0℃; for 1h; Inert atmosphere; Stage #2: Dichloromethyl methyl ether In dichloromethane at 0℃; for 0.75h; Inert atmosphere; regioselective reaction; | 3.2. General Formylation Procedure General procedure: The appropriate benzene derivative (3.2-10.6 mmol) was dissolved in dry DCM (10-20 mL), purged with Ar, and cooled with an ice bath to 0 °C. Next, TiCl4 (2.2 eq.) was added dropwise. The reaction mixture was stirred for 1 h. Afterwards, dichloromethyl methyl ether (1.1 eq.) was added, and the mixture was left to react for a further 45 min. As a reaction quencher, a saturated solution of NH4Cl (25 mL) was added. The mixture was then left for 2 h. The organic layer was separated and washed with 0.1 N HCl solution (3 × 50 mL) and brine (3 × 50 mL). The organic layer was dried over MgSO4 and filtered, and the solvent was evaporated under vacuum to furnish the desired aldehydes (Figure 1). The purified products were homogeneous by HPLC and were characterized and purified by using various physical techniques. |
With titanium tetrachloride In dichloromethane at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With boron trifluoride diethyl etherate at 75℃; for 0.416667h; | 1.2; 2.2; 3.2; 4.2 Step 2) Synthesis of 9-hydroxy-5,6,7,4'-tetramethoxychalcone Add 0.8 g of 3,4,5-trimethoxyphenol to 1.0 g of p-methoxycinnamoyl chloride obtained in step 1),Then slowly drop 5ml of 48% boron trifluoride-ether (BF3-Et2O) complex, and heat it in an oil bath at 75°C for 25 minutes.After cooling to room temperature, a precipitate precipitated. Excess water was added to precipitate a large amount of solid, which was filtered off with suction.After drying, the crude product is recrystallized from 80% methanol1.1g golden yellow needles9-hydroxy-5,6,7,4'-tetramethoxychalcone, the yield was 73%. |
With boron trifluoride diethyl etherate for 0.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With boron trifluoride diethyl etherate for 0.25h; Heating / reflux; | 1 Example 1; 1-(6-Hydroxy-2,3 4-Trimethoxyphenyl)-3-Phenyl-Propenone (Chalcone 1) A mixture of 3,4,5-trimethoxyphenol (3.7 g, 20 mmol) and cinnamoyl chloride (3.7 g, 22 mmol) was dissolved in BF3-Et2O complex (20 ml) and heated to reflux for 15 min, monitored by TLC (hexane:EtOAc=3:1), and then quenched with an excess of water. Filtration and recrystallization from hexane:EtOAc (3:1) procured chalcone 1 (5.6 g, 90%). Alternatively, 3,4,5-trimethoxyphenol (3.7 g, 20 mmol) was acylated with acetic acid (1.7 ml, 30 mmol) in BF3-Et2O complex (20 ml) under reflux for 15 min to give a ketone intermediate (3.8 g, 83%), which was reacted without further purification with benzaldehyde (1.8 ml, 17 mmol) in ethanol (20 ml). The mixture was added to 50% KOH (7.6 g) below 15 C. and then stirred at room temperature, preferably for 8 h under nitrogen. The reaction was quenched with an excess of ice water. The mixture was acidified with 6-N HCl and then partitioned in EtOAc and water. The organic layer was washed with brine and dried with anhydrous Na2SO4. Filtration and removal of the solvent afforded after recrystallization with hexane:EtOAc (3:1) 4.3 g (80%) of 1: mp 98-100 C. 1H-NMR (CDCl3) ?: 3.82 (3 H, s), 3.96 (3 H, s), 4.03 (3 H, s), 6.34 (1 H, s), 7.45-7.48 (3 H, m), 7.67 (2 H, d, J=9.3 Hz), 8.06 (2 H, d, J=15.5 Hz), 8.33 (2 H, d, J=15.5 Hz). IR (KBr) cm-1: 3419, 1608. MS m/z: 315 (MH+). |
86% | With boron trifluoride diethyl etherate In toluene for 2h; Inert atmosphere; Reflux; | |
With boron trifluoride diethyl etherate for 0.5h; Heating; |
With boron trifluoride diethyl etherate for 0.25h; Heating; | ||
With boron trifluoride diethyl etherate for 0.166667h; Reflux; | 2 Preparation of Compounds 2a-2m General procedure: The solution of cinnamic acid (10 mmol) and dichloromethane (DCM) (30 mL) was mixed in ice bath, and then a mixture of oxalyl chloride (1.5 mL, 17.5 mmol) and dimethylformamide (DMF) was added in the solution. The solution was stirred for 2 hours at room temperature, and the solvent was removed under reduced pressure to produce cinnamoyl chloride. The cinnamoyl chloride was mixed with 3,4,5-trimethoxyphenol (1.8 g, 10 mmol) and then dissolved in boron trifluoride etherate (BF3-Et2O)(10 mL) which was heated to reflux for 10 min. After cooling, the mixture was poured into ice water, and then the precipitate was filtered and washed with water. The precipitate was washed by hexane and then added ether to obtain the corresponding compounds 1a-1m (89-97%) in orange-yellow powders. The compounds 1a-1m could be used without further purification. A mixture of compounds 1a-m (10 mmol) and iodine (1.0 eq) in DMSO (25 mL) was heated to reflux for 3 hours. After cooling, the mixture was poured into ice water. The precipitate was filtered and washed with saturated sodium thiosulfate solution. The residue was chromatographed on a silica gel column with hexane/EtOAc (2:1) as the eluent to give pure 2a-2m in pale yellow solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
97% | With potassium phosphate In toluene at 0 - 20℃; | |
97% | With potassium phosphate In water; toluene at 0 - 20℃; |
82% | With pyridine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; | |
With potassium phosphate In toluene at 0 - 20℃; | ||
With potassium phosphate In toluene for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With boron trifluoride diethyl etherate In dichloromethane for 12h; Heating; | |
80% | With boron trifluoride diethyl etherate | |
80% | Stage #1: 3,4,5-trimethoxyphenol; isobutyryl chloride With boron trifluoride diethyl etherate In dichloroethane, 2,2- for 12h; Heating / reflux; Stage #2: With hydrogenchloride; water at 20℃; for 1h; | 1 EXAMPLE l; 1 -(6-Hydroxy-2,3 ,4-trimethoxy-phenyl)-2-methyl-proρan- 1 -one[0099] To a solution of 3,4,5-trimethoxyphenol (9.21 g, 50 mmol) in 150 niL 2,2- dichloroethane, boron trifluoride diethyl etherate (28.5 mL, 220 mmol) and isobutyryl chloride (5.9 mL, 55 mmol) were added. The resulting mixture was refluxed for 12 hours, and the solvent was removed in vacuo. To the resulting residue, 80 mL 3 M HCl was added under ice bath and the mixture was stirred for 1 hour at room temperature, then extracted with ethyl acetate, dried over Na2SO4, purified by silica gel column chromatography (hexane : ethyl acetate = 6 : 1), and product was obtained. Yield: 80%.[00100] 1H NMR (CDCl3, 300 MHz), δ 13.45 (s, IH); 6.26 (s, IH); 4.01 (s, 3H); 3.94 (s,3H); 3.87 (s, 3H); 3.80 ~ 3.70 (m, IH); 1.21 (d, J - 6.76 Hz, 6H); 13C NMR (CDCl3, 75 MHz), δ 162.00; 159.64; 154.88; 134.63; 107.35; 96.20; 61.54; 60.94; 56.01; 39.03; 19.46. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 13 N-cyclohexyl-N-cyclopentyl-3-methyl-4-(3,4,5-trimethoxyphenoxy)benzamide STR25 The reaction and workup were carried out in the same manner as described in Example 1 using 4-bromo-3-methyl benzoic acid N-cyclopentyl-N-cyclohexyl amide (983 mg, 2.7 mmol), 3,4,5-trimethoxy phenol (983 mg, 2.7 mmol) and cuprous oxide (200 mg, 1.3 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 181-182 C. Anal Calcd. for C28 H37 NO5: C, 71.92; H, 7.98; N, 3.00. Found: C, 71.79; H, 8.17; N, 2.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 36 N-cyclohexyl-N-(1,1-dimethylethyl)-4-(3,4,5-trimethoxyphenoxy)benzamide STR48 A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and p-bromobenzoic acid N-tert-butyl-N-cyclohexyl amide (1.35 g, 4.0 mmol) 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 1 N-cyclohexyl-N-(1-methylethyl)-4-(3,4,5-trimethoxyphenoxy)benzamide STR13 A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-N-isopropyl-N-cyclohexyl benzamide (1.290 g, 3.98 mmol) in 2,4,6-collidine (20 ml) was refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction was cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give 1.29 g of crude product. This material was chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate hexane, melting point 124.01 C. (DSC). Anal. Calcd. for C25 H33 NO5: C, 70.23; H, 7.78; N, 3.28. Found: 70.24; H, 8.06; N, 3.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 4 N-cyclohexyl-N-cyclopentyl-4-(3,4,5-trimethoxyphenoxy)benzamide STR16 The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-cyclopentyl-N-cyclohexyl amide (2.285 g, 6.52 mmol), 3,4,5-trimethoxy phenol (1.199 g, 6.51 mmol) and cuprous oxide (486 mg, 3.40 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 166.16 C. (DSC). Anal. Calcd. for C27 H35 NO5: C, 71.50; H, 7.78; N, 3.09. Found: C, 71.57; H, 7.77; N, 3.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 19 N-cyclohexyl-3-methoxy-N-(1-methylethyl)-4-(3,4,5-trimethoxyphenoxy)benzamide STR31 A slurry of cuprous oxide (1.00 g, 6.78 mmol) in a solution of 3,4,5-trimethoxyphenol (1.62 g, 8.53 mmol) and 4-bromo-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (2.42 g, 6.8I mmol) in 2,4,6-collidine (30 ml) was refluxed with stirring under a nitrogen atmosphere for 36 hr. Additional 3,4,5-trimethoxyphenol (0.32 g), and cuprous oxide (0.16 g) were added and reflux continued for 72 hrs. The reaction mixture was cooled, poured onto 6N HCl and extracted three times with ethyl acetate. The combined organic layers were washed twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SO4) The drying agent was filtered and the filtrate concentrated in vacuo to give 1.29 g of crude product. This material was chromatographed twice on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate hexane, m. pt. 126-128 C. Anal. Calcd. for C26 H35 NO6: C, 68.25; H, 7.71; N, 3.06. Found: C, 68.04; H, 7.88; N, 2.99. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 37 N-cyclohexyl-N-(n-hexyl)-4-(3,4,5-trimethoxyphenoxy)benzamide STR49 A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and p-bromobenzoic acid N-n-hexyl-N-cyclohexyl amide (1.47 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 43 N-cyclohexyl-3-ethoxy-N-(1-methylethyl)-4-(3,4,5-trimethoxyphenoxy)benzamid STR55 A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-3-ethoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.47 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,4,6-trimethyl-pyridine; | EXAMPLE 50 3-chloro-N-cyclohexyl-N-(1-methylethyl)-4-(3,4,5-trimethoxyphenoxy)benzamide STR62 A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-3-chloro-N-cyclohexyl-N-isopropylbenzamide (1.43 g, 4.0 mmol) in 2,4,6-collidine (20 mL) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium hexamethylsilazane In N,N-dimethyl-formamide; toluene | 11.A Compounds of Formula (W) A. To a solution of 3,4,5-trimethoxyphenol (2.8 g, 15 mmol) in DMF (60 mL) at 0° C. was added potassium hexamethyldisilazide (32 mL, 16 mmol, 0.5 M solution in toluene). The resulting mixture was stirred at 0° C. After 20 minutes, 1-(chloro)acetyl-4-(t-butoxycarbonyl)piperazine (4.6 g, 15 mmol, in 15 mL of DMF) was added and the mixture stirred at ambient temperature. After 2 hours the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 6.5 g (100% yield) of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-4-(t-butoxycarbonyl)piperazine, a compound of formula (W), as a yellow solid; NMR (CDCl3) 7.2 (m, 2), 4.6 (s,2), 3.8 (m, 9), 3.6 (m, 4), 3.4 (m, 4), 1.5 (s,9) ppm. |
100% | Stage #1: 3,4,5-trimethoxyphenol With potassium hexamethylsilazane In N,N-dimethyl-formamide; toluene at 0℃; for 0.333333h; Stage #2: tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate In N,N-dimethyl-formamide; toluene at 20℃; for 2h; | |
100% | Stage #1: 3,4,5-trimethoxyphenol With potassium hexamethylsilazane In N,N-dimethyl-formamide; toluene at 0℃; for 0.333333h; Stage #2: tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate In N,N-dimethyl-formamide; toluene at 20℃; for 2h; | 11.A To a solution of 3,4, 5-trimethoxyphenol (2.8 g, 15 mmol) in DMF (60 mL) at 0°C was added potassium hexamethyldisilazide (32 mL, 16 mmol, 0.5 M solution in toluene). The resulting mixture was stirred at 0°C. After 20 minutes, 1- (chloro) acetyl- 4- (t-butoxycarbonyl) piperazine (4.6 g, 15 mmol, in 15 mL of DMF) was added and the mixture stirred at ambient temperature. After 2 hours the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 6.5 g (100% yield) of 1- ( (3, 4,5-trimethoxyphenoxy) methyl) carbonyl-4- (t- butoxycarbonyl) piperazine, a compound of formula (W), as a yellow solid ; NMR (CDCI 3) 7.2 (m, 2), 4.6 (s, 2), 3.8 (m, 9), 3.6 (m, 4), 3.4 (m, 4), 1.5 (s, 9) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 3,4,5-trimethoxyphenol; acetic anhydride With boron trifluoride diethyl etherate at 0 - 60℃; for 3h; Stage #2: With water; triethylamine at 20℃; for 1h; | 2.a l-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone [0133] l-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone. To an acetic anhydride (2 mL) solution of 3,4,5-trimethoxyphenol (1.2 g, 6.6 mmol), BF3-Et20 (0.07 mL) was added at 0°C. After stirring at 60°C for 3 hours, the reaction mixture was diluted with ethyl acetate and the reaction mixture was cooled to ca. 0°C for 2 hours and the crystallized cake filtered with ethyl acetate. H20 (10 mL) and Et3N (1 mL) were added. After stirring for 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (Ethyl acetate / n-hexanes = 1 : 1) to afford the methyl ketone (1.4 g, 95%). |
95% | With boron trifluoride diethyl etherate at 0 - 60℃; for 3h; | 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethan-1-one (2a) BF3·Et2O (0.07 ml) was added at 0°C to a solution of acetic anhydride (2 ml) in which 3,4,5-trimethoxyphenol (1a) (1.2 g, 6.6 mmol) was dissolved. The resulting mixture was stirred at 60° C. for 3 hours. The mixture was diluted with ethyl acetate (10 ml) at 0°C, and water (10 ml) and TEA (1 ml) were added at room temperature, followed by stirring for 1 hour. The mixture was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified through flash column chromatography using silica gel (ethyl acetate:n-hexane=1:5) to obtain 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethan-1-one. (2a) (1.4 g, 95%) was obtained. |
91% | Stage #1: 3,4,5-trimethoxyphenol; acetic anhydride With zinc(II) chloride In nitromethane Stage #2: With sodium hydrogencarbonate In nitromethane Further stages.; |
89% | With boron trifluoride diethyl etherate In toluene for 2h; Reflux; Inert atmosphere; | |
86% | Stage #1: 3,4,5-trimethoxyphenol; acetic anhydride With boron trifluoride diethyl etherate In dichloromethane Reflux; Stage #2: With triethanolamine In water at 20℃; for 3h; | |
86% | With boron trifluoride diethyl etherate at 60℃; for 2h; | |
86% | With boron trifluoride diethyl etherate at 75℃; for 2h; | 2-Acetyl-4,5,6-trimethoxyphenol (3) A dry round-bottomed flaskcontaining compound 2 (92 g, 0.5 mol), acetic anhydride (150 mL) andBF3-Et2O (5 mL) was heated at 75 °C for 2 h, and then cooled to roomtemperature. Ethyl acetate (300 mL) was then added and stirred fora minute. The mixture was kept in the refrigerator for 2 h. Then, it wasfiltered to give the filter cake which was poured into a solution of H2O(400 mL) and ethanolamine (40 mL). The mixture was stirred for 1 h andthen extracted with ethyl acetate (300 mL). The extract was dried withanhydrous magnesium sulfate overnight. The solvent was evaporated toobtain compound 3 (97 g, 86%). 1H NMR (CDCl3, 500 MHz): δ 13.43 (s,1H, -OH), 6.22 (s, 1H, H-3), 3.97 (s, 3H, -OCH3), 3.87 (s, 3H, -OCH |
60% | With boron trifluoride diethyl etherate; ethanolamine Reflux; | 4.1.2 4.1.2 2-Acetyl-3,4,5-trimethoxyphenol (6) Boron trifluoride diethyl etherate (21.5 mL, 81.45 mmol) was added to a mixture of 3,4,5-trimethoxyphenol (5, 3.0 g, 16.29 mmol) and acetic anhydride (8.25 mL). The reaction mixture was refluxed overnight, and then cooled to 0 °C. The resulting precipitate was filtered. The filtrate was poured into aqueous solution of ethanolamine. The mixture was stirred for 1 h and then extracted with EtOAc. The extract was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the titled compound 6. Yield 60%. 1H NMR (CDCl3, 400 MHz) δ 13.44 (1H, s), 6.23 (1H, s), 4.00 (3H, s), 3.89 (3H, s), 3.78 (3H, s), 2.65 (3H, s). Reported compound [ 41 ]. |
Stage #1: 3,4,5-trimethoxyphenol; acetic anhydride With sodium acetate at 110℃; Stage #2: With boron trifluoride diethyl etherate; acetic acid at 110℃; for 18h; | Synthesis of 2-hydroxy-4,5,6-trimethoxy acetophenone (7) BF3.Et2O (12 mL, 94.7 mmol, 3.05 equiv) was added dropwise to a solution of 6 (7.88 g, 30.9 mmol, 1 equiv.) in toluene (150 mL), and the mixture was heated to 110°C for 18h. Then, water (100 mL) and saturated solution of NH4Cl (100 mL) was added and the aqueous phase was extracted with EtOAc (100 mL×3). The separated organic layer was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to yield a brown oil.1H NMR (400 MHz, CDCl3) δ 13.32 (s, 1H, 2-OH), 6.11 (s, 1H, 3-H), 3.88 (s, 3H, OCH3), 3.77 (s, 3H, OCH3) 3.67 (s, 3H, OCH3), 2.53 (s, 3H, COCH3). 13C NMR (100 MHz, CDCl3) δ 202.88, 161.66, 159.87, 154.90, 134.38, 107.97, 95.73, 60.57, 60.42, 55.62, 31.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; potassium iodide In acetone Reflux; | 4.5 General procedure D for the preparation of 2-phenoxy acetate/propanotes or 2-phenyl acetate/propanotes General procedure: To the solution of phenol (1 equiv) was added K2CO3 (2 equiv), ethyl 2-bromo acetate/propanoate (1.5 equiv) in freshly distilled acetone, was added a pinch of KI and refluxed overnight. After the completion of reaction, acetone was distilled off and reaction mixture was partitioned between saturated brine solution and ethyl acetate. Organic layer was collected, dried over Na2SO4, concentrated and column chromatography was performed. |
80% | With potassium carbonate In acetone at 20℃; for 24h; Reflux; Inert atmosphere; | |
Stage #1: 3,4,5-trimethoxyphenol With sodium In acetone at 20℃; Stage #2: ethyl bromoacetate In acetone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3,4,5-trimethoxyphenol With boron trifluoride diethyl etherate for 0.25h; Heating / reflux; Stage #2: benzaldehyde With potassium hydroxide In ethanol; water at 15 - 20℃; for 8h; Stage #3: With hydrogenchloride In water | 1 Example 1; 1-(6-Hydroxy-2,3 4-Trimethoxyphenyl)-3-Phenyl-Propenone (Chalcone 1) A mixture of 3,4,5-trimethoxyphenol (3.7 g, 20 mmol) and cinnamoyl chloride (3.7 g, 22 mmol) was dissolved in BF3-Et2O complex (20 ml) and heated to reflux for 15 min, monitored by TLC (hexane:EtOAc=3:1), and then quenched with an excess of water. Filtration and recrystallization from hexane:EtOAc (3:1) procured chalcone 1 (5.6 g, 90%). Alternatively, 3,4,5-trimethoxyphenol (3.7 g, 20 mmol) was acylated with acetic acid (1.7 ml, 30 mmol) in BF3-Et2O complex (20 ml) under reflux for 15 min to give a ketone intermediate (3.8 g, 83%), which was reacted without further purification with benzaldehyde (1.8 ml, 17 mmol) in ethanol (20 ml). The mixture was added to 50% KOH (7.6 g) below 15 C. and then stirred at room temperature, preferably for 8 h under nitrogen. The reaction was quenched with an excess of ice water. The mixture was acidified with 6-N HCl and then partitioned in EtOAc and water. The organic layer was washed with brine and dried with anhydrous Na2SO4. Filtration and removal of the solvent afforded after recrystallization with hexane:EtOAc (3:1) 4.3 g (80%) of 1: mp 98-100 C. 1H-NMR (CDCl3) ?: 3.82 (3 H, s), 3.96 (3 H, s), 4.03 (3 H, s), 6.34 (1 H, s), 7.45-7.48 (3 H, m), 7.67 (2 H, d, J=9.3 Hz), 8.06 (2 H, d, J=15.5 Hz), 8.33 (2 H, d, J=15.5 Hz). IR (KBr) cm-1: 3419, 1608. MS m/z: 315 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate In toluene at 20℃; for 10h; regiospecific reaction; | 23 General procedure for the synthesis of arenofurans 10, 11, and 13 General procedure: To a stirred solution of naphthol/phenol 9 (0.3 mmol) and K2CO3 (0.6 mmol, 2 equiv) in toluene (2 mL) was added MBH acetate 6 (0.4 mmol, 1.3 equiv) at room temperature. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo and the crude residue was purified by silica gel column chromatography by gradient elution with ethyl acetate/petroleum ether (1:99 to 7:93). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: formic acid ethyl ester With phosphorus pentachloride In dichloromethane for 2h; Reflux; Stage #2: 3,4,5-trimethoxyphenol With tin(IV) chloride at 20℃; for 5h; | Synthesis of polyalkoxysalicylic aldehydes 8a-d (general procedure). General procedure: (i) Synthesis of the formylation reagent (dichlorodimethyl ether). Ethyl formate (1.32 g, 17.9 mmol) was added at room temperature to a suspension of PCl5 (3.38 g, 16.28 mmol) in dry CH2Cl2 (20 ml). The resulting mixture was refluxed for 2 h with stirring. (ii) Formylation. A mixture of the formylation reagent and phenol (10.85 mmol) was added dropwise to a solution of SnCl4 (1.3 g, 43.4 mmol) in dry CH2Cl2 (20 ml) at room temperature. The reaction mixture was stirred for 5 h and diluted with ice-water, followed by extraction with CH2Cl2 (3×30 ml). The organic extract was washed with water (4×50 ml), dried and concentrated in vacuo. The residual salicylic aldehyde had the purity of about 85%, and was further purified by crystallization or column chromatography (SiO2) to afford the pure target aldehyde (20-80% yield, Rf 0.6-0.7, AcOEt : light petroleum = 1: 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide; toluene at 20℃; for 7h; Inert atmosphere; | 2.6 Representative procedure for the synthesis of O-propargylphenol 5 (5a-5o) General procedure: To a stirred solution of 3-methoxyphenol 4a (1.0 g, 8.06 mmol) in dimethylformamide (27 mL) was added potassium carbonate (2.2 g, 16.12 mmol) (using NaH as base for 5e-5g and 5l-5m) followed by 80% propargyl bromide in toluene (0.91 mL, 12.09 mmol) and the resultant mixture was stirred for 7 h at rt. Then, the reaction mixture was diluted with ethylacetate (30 mL), washed with H2O (3*20 mL). The mixture was then dried over anhydrous MgSO4, filtered and concentrated to afford the crude mixture, which was purified by column chromatography to obtain the desired product. Yellow solid (1.21 g, 5.43 mmol, quant.); mp 54-57 °C; 1H NMR (300 MHz, CDCl3): δ 6.24 (s, 2H), 4.66 (d, J=2.4 Hz, 2H), 3.84 (s, 6H), 3.79 (s, 3H), 2.54 (t, J=2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 154.4, 153.9, 133.2, 93.1, 78.8, 75.8, 61.2, 56.5, 56.3; IR (KBr) ν 3282, 2119, 1595, 1506 cm-1; HRMS (ESI) calcd for C12H14O4Na [M+Na]+ 245.0790, found 245.0785. |
95% | With potassium carbonate In acetone at 50℃; for 5h; | 1,2,3-Trimethoxy-5-prop-2-ynyloxybenzene (5) To a stirred solution of 3,4,5-trimethoxyphenol (1.0 g, 5.43 mmol) inacetone (10 mL) were added K2CO3 (0.9 g, 6.52 mmol, 1.2 equiv) and propargyl bromide (0.49 mL, 6.52 mmol, 1.2 equiv) and the reaction mixture was heated at 50 °C. After stirring at 50 °C for 5 h, the mixture was cooled down to r.t. and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, diluted with CH2Cl2(10 mL), and washed with H2O (10 mL). The aqueous layer was extractedwith CH2Cl2 (2 × 5 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes-EtOAc = 9:1) to give 5 (1.15 g, 95%) as a white solid; mp 55.4-56.6 °C. IR (ATR): 3266, 2943, 2129, 1592, 1502, 1122, 993 cm-1. 1H NMR (400 MHz, CDCl3): δ = 6.23 (s, 2 H), 4.65 (d, J = 2.3 Hz, 2 H),3.83 (s, 6 H), 3.78 (s, 3 H), 2.54 (t, J = 2.3 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 154.1, 153.6, 132.9, 92.8, 78.5, 75.6,60.9, 56.2, 56.1.HRMS (ESI-QTOF): m/z [M + H]+ calcd for C12H15O4: 223.0965; found:223.0966. |
With potassium carbonate In acetone for 10h; Reflux; | 4.3 General procedure for the preparation of propargyl ethers 5a-p General procedure: Propargyl bromide (1.2mmol) was added to a mixture of phenolic compounds 4a-p (1.0mmol) and K2CO3 (1.2mmol) in acetone (5mL) and the mixture was stirred under reflux for 10h. After completion of the reaction confirmed by TLC, the solid salts were separated by filtration and the filtrate was concentrated under reduced pressure to give corresponding pure propargyl ethers 5a-p. |
Stage #1: 3,4,5-trimethoxyphenol With potassium carbonate In acetone at 70℃; for 0.5h; Stage #2: propargyl bromide In acetone at 70℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(II) bis(trifluoromethanesulfonate) In 2,2,2-trifluoroethanol at 50℃; for 4.5h; chemoselective reaction; | |
82% | With copper(II) bis(trifluoromethanesulfonate) In 2,2,2-trifluoroethanol at 50℃; for 4.5h; | 1 Compound 24: Isobutyrlaldehyde (68.4 μ, 0.75 mmol), Cu(OTf)2 (2.2 mg, 2.5 mol ethanethiol (108 μ, 1.5 mmol) and 3,4,5- trimethoxyphenol (46 mg, 0.25 mmol) were reacted according to method A. The mixture was stirred for 4.5 h at 50 °C. The residual material was purified by column chromatography (silica gel 40-60, hexane/ehyl acetate 95:5) affording compound 24 (62 mg, 82% yield) as a white solid. Characterization data of compound 24: lH NMR (CDCl3/400 MHz): δ 7.92 (s, OH), 6.22 (s. 1H), 4.27 (d, = 9.2 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 2.37 - 2.23 (m, 2H), 2.16 - 2.07 (m, 1H), 1.14 (t, = 7.4 Hz, 3H), 1.10 (d, = 6.7 Hz, 3H), 0.81 (d, = 6.7 Hz, 3H); 13C NMR (CDCI3/100 MHz): δ 153.0, 152.5, 152.3, 135.3, 110.4, 97.3, 61.0, 60.8, 55.7, 48.2, 32.3, 25.1, 21.7, 21.4, 14.3; HRMS (ESI): m/z calcd for Ci5H2404S [M+Na]+ 323.1288, found 323.1286. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: C19H25BrN2O5 With potassium carbonate In acetonitrile at 0℃; for 0.5h; Stage #2: 3,4,5-trimethoxyphenol In acetonitrile at 80℃; for 24h; | 5 4.1.3 Procedure for the synthesis of compound 4a-4d General procedure: To as solution of compound 2 (0.45 mmol) in acetonitrile (10 mL) in a 100 mL round bottom flask was cooled to 0°C. To this cooled solution potassium carbonate (1.35 mmol) was charged and continued the stirring for another 30 min at the same temperature. Then the 3,4,5-Trimethoxyphenol (0.68mmol) was added and stirred at 80°C for 24h. The completion of the reaction was monitored with the help of TLC chromatogram. The reaction was quenched with ice water and extracted with dichloromethane and dried over Na2SO4. The removal of solvent under reduced pressure gave the crude compounds 4a-4d. The crude compounds were further purified by column chromatography using dichloromethane/Methanol ratio 70:1 to afford the pre compounds in 71-87% yields respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: C20H27BrN2O5 With potassium carbonate In acetonitrile at 0℃; for 0.5h; Stage #2: 3,4,5-trimethoxyphenol In acetonitrile at 80℃; for 24h; | 6 4.1.3 Procedure for the synthesis of compound 4a-4d General procedure: To as solution of compound 2 (0.45 mmol) in acetonitrile (10 mL) in a 100 mL round bottom flask was cooled to 0°C. To this cooled solution potassium carbonate (1.35 mmol) was charged and continued the stirring for another 30 min at the same temperature. Then the 3,4,5-Trimethoxyphenol (0.68mmol) was added and stirred at 80°C for 24h. The completion of the reaction was monitored with the help of TLC chromatogram. The reaction was quenched with ice water and extracted with dichloromethane and dried over Na2SO4. The removal of solvent under reduced pressure gave the crude compounds 4a-4d. The crude compounds were further purified by column chromatography using dichloromethane/Methanol ratio 70:1 to afford the pre compounds in 71-87% yields respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: C21H29BrN2O5 With potassium carbonate In acetonitrile at 0℃; for 0.5h; Stage #2: 3,4,5-trimethoxyphenol In acetonitrile at 80℃; for 24h; | 7 4.1.3 Procedure for the synthesis of compound 4a-4d General procedure: To as solution of compound 2 (0.45 mmol) in acetonitrile (10 mL) in a 100 mL round bottom flask was cooled to 0°C. To this cooled solution potassium carbonate (1.35 mmol) was charged and continued the stirring for another 30 min at the same temperature. Then the 3,4,5-Trimethoxyphenol (0.68mmol) was added and stirred at 80°C for 24h. The completion of the reaction was monitored with the help of TLC chromatogram. The reaction was quenched with ice water and extracted with dichloromethane and dried over Na2SO4. The removal of solvent under reduced pressure gave the crude compounds 4a-4d. The crude compounds were further purified by column chromatography using dichloromethane/Methanol ratio 70:1 to afford the pre compounds in 71-87% yields respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: C22H31BrN2O5 With potassium carbonate In acetonitrile at 0℃; for 0.5h; Stage #2: 3,4,5-trimethoxyphenol In acetonitrile at 80℃; for 24h; | 8 4.1.3 Procedure for the synthesis of compound 4a-4d General procedure: To as solution of compound 2 (0.45 mmol) in acetonitrile (10 mL) in a 100 mL round bottom flask was cooled to 0°C. To this cooled solution potassium carbonate (1.35 mmol) was charged and continued the stirring for another 30 min at the same temperature. Then the 3,4,5-Trimethoxyphenol (0.68mmol) was added and stirred at 80°C for 24h. The completion of the reaction was monitored with the help of TLC chromatogram. The reaction was quenched with ice water and extracted with dichloromethane and dried over Na2SO4. The removal of solvent under reduced pressure gave the crude compounds 4a-4d. The crude compounds were further purified by column chromatography using dichloromethane/Methanol ratio 70:1 to afford the pre compounds in 71-87% yields respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 13h;Inert atmosphere; | Under a nitrogen atmosphere, A-1 three-necked flask 1000ml (27mmol), potassium carbonate (407mmol), 3,4,5-trimethoxy phenol (A-15) (271mmol), put in DMF (150ml), 13 hours reaction is at 110 It was.Thereafter, by filtration, to remove the potassium carbonate.After evaporation of the solvent, AxisExtracted with Rorometan, washed with 10percent aqueous potassium hydroxide solution, dried over sodium sulfate.ItsAfter, the solvent was distilled off, column purification (dichloromethane: acetone = 10: 1) to be performedRi, to give compound A-16 (23mmol, 85percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(II) bis(trifluoromethanesulfonate) In 2,2,2-trifluoroethanol at 50℃; for 8h; | 1 Compound 9: Benzaldehyde (51 mg, 0.5 mmol), Cu(OTf)2 (2.2 mg, 2.5 mol %), 2- phenylpropane- 1 -thiol (152 mg, 1 mmol) and 3,4,5- trimethoxyphenol (46 mg, 0.25 mmol) were reacted according to method A. The mixture was stirred for 8 h at 50 °C. The residual material was purified by column chromatography (silica gel 40-60, hexane / ethyl acetate 93:7) to obtain compound 9 (87 mg, 82% yield) as a thick oil. Characterization data of compound 9: lH NMR (CDCl3/400 MHz): δ 8.19 (s, 1H), 7.37 - 7.15 (m, 10H), 6.36 (s, 1H), 5.86 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.68 (s, 3H), 3.06 - 2.94 (m, 2H), 2.56 (dd, J = 13.3, 9.0 Hz, 2H), 14.1 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3/100 MHz): δ 153.8, 153.1, 152.4, 145.3, 144.9, 139.2, 139.2, 135.8, 128.6, 128.5, 128.1, 128.0, 127.5, 127.0, 126.7, 126.6, 109.1, 108.8, 97.8, 61.5, 61.0, 55.8, 45.1, 44.3, 40.6, 39.5, 39.0, 21.4, 20.3; HRMS (ESI): m/z calcd for C25H2804S [M+Na]+ 447.1601, 447.1593 found 389.1316, 391.1322. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 41% 2: 39% | With Amberlyst-15 In acetonitrile at 70℃; for 8h; Molecular sieve; | 4.1.3. General coupling reaction between samin and phenolics General procedure: To a solution of samin 6 (1 equiv) in acetonitrile (1.0 mL/0.1 mmol of 6) was treated with phenolics (1.5-2 equiv), Amberlyst-15 (1 mg/0.005 mmol of 6) and a 4 Å molecular sieve. After stirring at 70 °C for 8 h, the reaction mixture was evaporated to dryness and purified by silica gel column and Preparative TLC to afford furofuran lignans 7a-7e. |
1: 30% 2: 40% | With Amberlyst-15 In acetonitrile at 70℃; for 8h; Molecular sieve; | General procedure for synthesis of furofuran lignans 5 General procedure: To a solution of samin 4 (1 equiv) in acetonitrile (1.0 mL/0.1 mmol of 4) was treated with phenolics (1.5-2 equiv),Amberlyst-15 (1 mg/0.005 mmol of 4) and a 4 Å molecularsieve. After stirring at 70 °C for 8 h, the reactionmixture was evaporated to dryness and purified by flashchromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -30 - 20℃; for 15.5h; Inert atmosphere; Molecular sieve; | 4.1.1. (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6- (3-methoxyphenoxy)tetrahydro-2H-pyran (3a) and 5-methoxy-2- ((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl) tetrahydro-2H-pyran-2-yl)phenol (4a) General procedure: To a stirring mixture of 112 (200 mg, 0.29 mmol), 3- methoxyphenol (2a, 0.025 mL, 0.8 mmol), and MS4A (150 mg) in anhydrous CH2Cl2 (1 mL) was added TMSOTf (4 mL, 0.03 mmol) in CH2Cl2 (0.5 mL). After being stirred at 30 C for 30 min, the reaction temperature was raised to room temperature. After 15 h, the reaction was quenched by the addition of sat. aq. NaHCO3. The resulting mixture was filtered through a Celite pad. The filtrate was washed with sat. aq. NaHCO3, and brine, dried (Na2SO4). After concentration in vacuo, the residue was purified by silica gel column chromatography (CHCl3: hexane: EtOAc 4/8/1) to afford 3a17 as a colorless oil (109 mg, 73%, ~1:1 mixture) and 4a12b as a colorless oil (24.0 mg, 16%), respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In acetic anhydride at 110℃; for 2h; Inert atmosphere; | 3.2. 3,4,5-Trimethoxyphenyl Acetate (4) A mixture of 3,4,5-trimethoxyphenol (3, 27 mmol) and sodium acetate (61 mmol) in aceticanhydride (265 mmol) was heated at 110 °C for 2 h. The mixture was concentrated under vacuum,diluted with water (50 mL), and extracted with dichloromethane (50 mL). The organic layer waswashed with water (50 mL), and dried over anhydrous sodium sulphate to afford product 4 as a lightbrown oil, which solidified and was further crystallized from ethanol. Yield: 98%. Spectral data werein good agreement with literature data [43]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With copper(I) triflate benzene complex; C32H27N2P; triethylamine In methanol at -20℃; for 12h; Schlenk technique; Inert atmosphere; enantioselective reaction; | |
91% | With copper(I) trifluoromethanesulfonate benzene complex; C32H27N2P; N-ethyl-N,N-diisopropylamine In methanol at -20℃; for 12h; Inert atmosphere; enantioselective reaction; | 8 Example 8 Into the reaction flask add Cu (OAc) 2. H20 (0.115mmol, 5 mol %) and chiral ligand L-2-1(0.0165mmol, 5.5mol %), under nitrogen protection add 1.0 ml anhydrous methanol, stir at room temperature for 1 hour. Propargyl propanol IV-1 (0.3mmol, lequiv), 3,4,5-trimethoxybenzoic acid III-1 (0.36mmol, 1.2 equiv) and N,N-diisopropyl ethylamine ( 0.36mmol, 1.2equiν) dissolved in 2.0ml anhydrous methanol, after that the solution is protected by nitrogen and add to the solution of the above stirred catalyst, stir at room temperature for 12h. After the reaction has been completed, evaporate under reduced pressure to approximately 0.5 ml, after separation on a silica gel column (petroleum ether/ethyl acetate = 1:1), concentration under reduced pressure and vacuum drying, obtained compound I-1, light yellow oily substance, yield 58%, 92%ee.The reaction at -20 ° C gives the product (S) -3,4,5-trimethoxy_4_(1-phenyl-2-propargyl)-2,5-cyclohexadienone 1-1.The reaction temperature in Example 7 was changed to -20 °C. The same as in Example 7, the compound 1-1 was obtained in 91% yield.99 ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 5h; Inert atmosphere; | 3.2. General Method for Synthesis of Compounds 2a-c General procedure: 4-Bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.28 mmol), piperidin-4-ylmethanol, 2-(piperazin-1-yl)ethanol and 3,4,5-trimethoxyphenol (2.28 mmol), K2CO3 (0.32 g, 2.28 mol) were mixed in DMF(10 mL) and heated at 90 °C under N2 for 5 h. After cooling, the reaction mixture was filtered toremove solid and the solvent was evaporated. The residue was dissolved in dichloromethane andwashed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue solid wasapplied on column of silica gel and then eluted with the mixed solvent of ethyl acetate and hexanes(3:1, v/v) to give the pure product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 24h; | 1 5.1.1. 5-(2-Bromoethoxy)-1,2,3-trimethoxybenzene 14 To a solution of 3,4,5-trimethoxyphenol (1.0 g, 5.43 mmol) inanhydrous DMF, K2CO3 (6.76 g, 48.90 mmol) and 1,2-dibromoethane (1.22 g, 6.38 mmol) were added. The mixture washeated to 60 °C for 24 h and then treated with a saturated solutionof NaCl and extracted three times with ethyl acetate. After dryingwith Na2SO4, the solventwas removed under reduced pressure. Thecrude product was purified by flash chromatography using cyclohexane/ethyl acetate 7:3 as eluting system. The title compound(1.15 g, 75% yield) was obtained as a colorless oil.1H NMR (CDCl3):δ 6.16 (s, 2H, arom.); 4.26 (t, J 6.0 Hz, 2H,OCH2); 3.84 (s, 6H, OCH3); 3.78 (s, 3H, OCH3); 3.62 (t, J 6.0 Hz, 2H,CH2Br) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 3,4,5-trimethoxyphenol With potassium carbonate In acetone for 0.0833333h; Stage #2: benzyl bromide In acetone at 20℃; | 4.1.1 5-(benzyloxy)-1,2,3-trimethoxybenzene (2) 3,4,5-Trimethoxy phenol (5.0g, 27.2mmol) was dissolved in acetone(100mL), and then K2CO3 (5.63g, 40.7mmol) was added. After vigorously stirring for 5min, benzyl bromide (3.4mL, 28.5mmol) was added dropwise. The reaction mixture was maintained at room temperature overnight, the solid was filtered out and the reaction solution was concentrated to remove the solvent. The residue was dissolved in ethyl acetate (100mL) and then washed with 1mol/L NaOH aqueous solution twice. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 as a white solid (6.36g, yield: 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 0.5 h / Reflux 2: sodium hydrogencarbonate / ethyl acetate / 0.5 h / 20 °C 3: hydrogen bromide / acetic acid / 2 h / Reflux 4: pyridine / 2 h / Reflux 5: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 2 h / Reflux 6: hydrogenchloride / acetone; water / 16 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 95 - 99℃; under 600.06 - 675.068 Torr; for 5.5h; | 448 g of <strong>[4687-37-0]ethyl 3,4-dimethoxybenzoylacetate</strong> and a mass of 0.818 times the amount of 3,4,5-trimethoxyphenol were uniformly mixed.Keep the vacuum at 0.08MPa-0.09MPa,The temperature is 95 C ~ 99 C,Reaction for 5.5 hours,After the reaction is completed, it is cooled to 60 C;Add 0.7 times the amount of ethanol to stir.Allow to cool to room temperature,381 grams of crude sinensetin were obtained by suction filtration; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; | 1 mmol of <strong>[89-41-8]3-nitro-4-methoxybenzoic acid</strong> was dissolved in DMF, and 1.2 mmol of TEA was added thereto, and 1.1 mmol of HOBT and 1.2 mmol of EDCI were added. DMSP was 0.02 mmol, and finally 1 mmol of 3,4,5-trimethoxyphenol was added. TLC was monitored, and after completion of the reaction, water was added to precipitate a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In dimethyl sulfoxide at 20℃; for 48h; | 3.1.2. Typical Reaction Procedure for Precursors 4 and 5 General procedure: Anhydrous potassium carbonate (414 mg, 3.00 mmol, 1.5 equiv) was added to a solution of2,3-dichloro-1,4-naphtoquinone (227 mg, 1.00 mmol, 1.0 equiv) or 6,7-dichloro-5,8-quinolinquinone(228 mg, 1.00 mmol, 1.0 equiv) and 3,4,5-trimethoxyphenol (384 mg, 2.00 mmol, 2.00 equiv) in 2.5 mLof dry DMSO, and the reaction mixture was stirred at room temperature for 48 h. The mixture wasdecanted to remove inorganic salt, and partitioned between dichloromethane/water (X3). The combinedorganic extracts were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo togive a solid that was purified by silica gel FC eluting with hexane/EtOAc (from 9:1 to 6:4 v/v) for 4, andwith dichloromethane/methanol/triethylamine (96:4:0.1 v/v) for 5.2,3-Bis(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione (4). TLC (hexane: EtOAc = 1:1 v/v): Rf = 0.50. Lightorange solid. Yield: 87%. 1H-NMR (400 MHz, CDCl3) 8.15 and 7.79 (two m, 2H each, H-5/H-8 andH-6/H-7), 6.11 (s, 4H, H-20, H-60, H-20and H-60), 3.75 (s, 6H, -OCH3), 3.72 (s, 12H, -OCH3). 13C-NMR(100 MHz, CDCl3) 180.4 (C=O), 153.7, 134.7, 134.5, 130.7, 126.5, 94.4, 60.7 (-OCH3), 56.0(-OCH3).Signicant HMBC correlations: 8.15 ppm with 180.4 ppm; 7.79 ppm with 130.7 ppm. ESI(+)-MS: m/z545 [M + Na]+. HRMS(EI) calcd. for C28H26O10, 522.15260, found 522.15248. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In dimethyl sulfoxide at 20℃; for 48h; | 3.1.2. Typical Reaction Procedure for Precursors 4 and 5 General procedure: Anhydrous potassium carbonate (414 mg, 3.00 mmol, 1.5 equiv) was added to a solution of2,3-dichloro-1,4-naphtoquinone (227 mg, 1.00 mmol, 1.0 equiv) or 6,7-dichloro-5,8-quinolinquinone(228 mg, 1.00 mmol, 1.0 equiv) and 3,4,5-trimethoxyphenol (384 mg, 2.00 mmol, 2.00 equiv) in 2.5 mLof dry DMSO, and the reaction mixture was stirred at room temperature for 48 h. The mixture wasdecanted to remove inorganic salt, and partitioned between dichloromethane/water (X3). The combinedorganic extracts were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo togive a solid that was purified by silica gel FC eluting with hexane/EtOAc (from 9:1 to 6:4 v/v) for 4, andwith dichloromethane/methanol/triethylamine (96:4:0.1 v/v) for 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium hydroxide In dimethyl sulfoxide at 100℃; for 8h; | 4.1.1. 1-(4-Methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)ethan-1-one (3) A mixture of 1-(2-fluoro-4-methoxyphenyl)ethan-1-one 1 (20 mmol), 3,4,5-trimethoxyphenol 2 (20 mmol) and KOH (40 mmol) in DMSO (30 mL) was stirred at 100 °C for 8 h. After completion of reaction, the mixture was poured into 200 mL of water, pH value is adjusted to 6-9, and extracted with 100 mL of ethyl acetate for three times. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by chromatography to give product 3 as white solid (68%). |
With potassium hydroxide In dimethyl sulfoxide at 100℃; for 8h; | 1.1; 1.2; 1.3; 1.4; 1.5; 1.6; 1.7; 1.8; 1.9; 1.10; 1.11; 1.12; 1.13 Step 1: 1- (2-fluoro-4-methoxyphenyl) ethan-1-one (1 mmol), 3,4,5-trimethoxyphenol (1 mmol),Potassium hydroxide (2 mmol), 10 ml of dimethyl sulfoxide was added, and the reaction was performed at 100 ° C for 8 hours.Cool to room temperature, pour into water, extract with ethyl acetate, spin dry, and isolate and purify by silica gel column chromatography to obtain a solid powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.7% | With aluminum (III) chloride In dichloromethane at 40℃; | 1-7 Example 7 Weigh out (10mmol, 1.84g) 3,4,5-trimethoxyphenol dissolved in (20ml) dichloromethane, and slowly add (12mmol, 1.36) chloroacetyl chloride in a constant pressure dropping funnel. Rinse the dropping funnel with 5 ml of dichloromethane, drop the residual chloroacetyl chloride on the wall into the reaction flask, and then add (12 mmol, 1.60) anhydrous aluminum chloride, install a reflux and drying device, and adjust the oil bath The temperature of the reaction solution is controlled to be 40 ° C., and the reaction is heated under closed stirring.The reaction was detected by TLC. After the reaction was completed, the reaction solution was poured into concentrated hydrochloric acid: ice water (1: 1), vigorously stirred, acidified and cooled, and the solid was precipitated by standing, suction filtered, and washed with saturated sodium chloride solution to neutrality. The filter cake is dried under vacuum to obtain 6-hydroxy-2,3,4-trimethoxy-α-chloroacetophenone.Yield: 68.7%, purity: 98.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With rongalite In ethanol; water at 20℃; for 8h; Irradiation; | General Procedure General procedure: To a clean and dry round bottom flask, phenylboronic acid (76 mg, 0.5 mmol), sodium hydroxymethane sulfinate dihydrate (Rongalite) (1.0 mmol) and 1 mL of EtOH:H2O (3:1) solvent mixture were added. The resulting mixture was stirred at room temperature under sunlight irradiation in open to air for completion. The reaction progress was monitored by TLC. After reaction completion, solvent mixture was evaporated under vacuum, the crude product was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried on anhydrous Na2SO4, solvent was evaporated under vacuum. The residue was purified by using silica gel as a stationary phase and ethyl acetate/hexanes as an eluent. All reactions kept under direct sunlight between 11 am and 4 pm and the average solar intensity was 500-600 W/m2, which was measured with Newport Optical Power meter/Energy meter (Model 842.PE). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 2-(5-chloro-2-methyl-phenylamino)-6-trifluoromethyl-nicotinic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 0.5h; Stage #2: 3,4,5-trimethoxyphenol In acetonitrile at 20℃; for 24h; | 4.1.1. General Procedure for the Synthesis of Esters (11-24) General procedure: A mixture of acid 10 (0.33 g, 1 mmol), EDCI (1.92 g, 1.1 mmol), and HOBt (0.13 g, 1 mmol) in dry MeCN (10 mL) was stirred at room temperature for 30 min and then treated with the appropriate phenol (1 mmol). The mixture was stirred at room temperature for an additional 24 h. Then the solution was evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with brine (2 x 5 mL), 5% aqueous sodium hydroxide (2 x 5 mL), and water (2 x 5 mL). The organic layer was dried over anhydrous sodium sulfate. Concentration of the dried extract yielded a residue which was triturated with di-isopropyl ether. The formed precipitate was filtered off andpurified by crystallization from the adequate solvent to give the ester derivatives 11-24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 3,4,5-trimethoxyphenol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Inert atmosphere; Stage #2: 3-chloroprop-1-ene In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | General procedure for the synthesis of 5 General procedure: To a suspension of NaH (6 mmol) in dry DMF (5 mL) at 0 oC under N2 was added phenol 3 (5 mmol). The mixture was stirred at this temperature for 20 minutes, and then allyl chloride (6 mmol) was added. The mixture was allowed to warm to room temperature. After completion indicated by TLC, the mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via column chromatography (petroleum ether and ethyl acetate mixture as eluting solvent) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine In acetonitrile at 120℃; for 8h; Microwave irradiation; | 5.2.5. General preparation of compounds 4-18 General procedure: The relevant phenol (1.5 Eq) was added to a solution of the 4-(2-oxopyrrolidin-1-yl)benzenesulfonyl chloride (36, 0.10 g) in acetonitrile(3.0 mL) in presence of triethylamine (0.16 mL, 3.0 Eq). Thereaction mixture was stirred at 120 C under microwave radiationfor 8 h. After completion of the reaction, the mixture was cooled atroom temperature and the solvent was evaporated under reducedpressure. The residue was diluted within AcOEt (10 mL) and waswashed twice with HCl 1M (10 mL), NaOH 1M (10 mL) and brine(10 mL). The resulting solution was dried over anhydrous sodiumsulfate, filtered and evaporated to dryness under reduced pressure.The residue was purified by flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere; | 2.2.1 4-(3,4,5-trimethoxyphenoxy)phthalonitrile (a), Scheme1A Compound a was synthesized as follows: a mixture of 3,4,5-trimethoxyphenol (2.13g, 11.6mmol) and 4-nitrophthalonitrile (2g, 11.6mmol), and K2CO3 (5g, 36.18mmol) was added to DMF (75mL) under N2 flow at room temperature. After 48h under constant magnetic stirring, the solution was allowed to precipitate in ice, isolated under reduced pressure, and purified with methanol. Yield: 2.69g, (65%), IR [νmax /cm-1] 2800-3 (C-H), 1493 (C=C), 1216 (Ar-O-Ar). 1H NMR (600MHz in DMSO - d6): 3.6-3.9 (m, 9H, CH3), 6.5 (s, J=6.54, 1H, Ar), 6.6 (s, J=6.67,1H, Ar), 6.8 (s, J=6.82, 1H, Ar), 6.9 (s, J=6.9, 2H, Ar), Elemental Anal. Calc. Expected: C, 65.80; H, 4.55; N, 9.03, found C, 65.39; H, 4.53; N, 8.85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3,4,5-trimethoxyphenol; 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid With dmap In dichloromethane at -10℃; for 0.05h; Inert atmosphere; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 14h; Inert atmosphere; | 14 Example 14 3,4,5-trimethoxyphenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (Compound 14) To a solution of 7-((1R,2R,3R)-3-hydroxy-2-((E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoic acid (40.0 mg, 0.113 mmol) in DCM (2.0 mL) were successively added DMAP (13.8 mg, 0.113 mmol) and 3,4,5-trimethoxyphenol (29.1 mg, 0.158 mmol) at -10° C. under Ar atmosphere. The mixture was stirred at -10° C. for 3 minutes. After addition of EDC (30.3 mg, 0.158 mmol), the reaction mixture was stirred at room temperature for 14 hours. The mixture was purified by column chromatography on SiO2 (EtOAc only) to afford 3,4,5-trimethoxyphenyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl)heptanoate (48.6 mg, 83%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 6.32 (2H, s), 5.70 (1H, dd, J=14.7, 6.4 Hz), 5.57 (1H, dd, J=14.4, 8.4 Hz), 4.16-4.05 (2H, m), 3.84 (6H, s), 3.83 (3H, s), 2.76 (1H, dd, J=18.8, 7.2 Hz), 2.67 (1H, brs), 2.53 (2H, t, J=7.6 Hz), 2.41-2.34 (1H, m), 2.23 (1H, dd, J=18.8, 10.0 Hz), 2.05-1.99 (1H, m), 1.73 (2H, qn, J=7.2 Hz), 1.61-1.25 (17H, m), 0.89 (3H, t, J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With iron(III) chloride In acetonitrile at 80℃; for 12h; Sealed tube; | 4.3. Procedure for synthesis of compound 4 General procedure: To a 25 mL glass test tube equipped a stir bar were added (substituted) styrene 1 (0.5 mmol), (substituted) electron-rich arene 2 (0.60 mmol), diaryl diselenide 3 (0.5 mmol), FeCl3 (0.1 mmol) and MeCN (4.0 mL). To avoid evaporation of the solvent, the system was then fastened with a rubber septumu nder air atmosphere. The test tube was stirred in an oil bath preheated at 80 °C. After 12 h, reaction progress was checked by TLC and confirmed reaction was completed. After cooled to room temperature, the reaction mixturewas quenched by the addition of saturated NaCl solution (10 mL). The reaction mixture was extracted with ethyl acetate (15 mL X 3). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuum on a rotary evaporator. The resulting residue was purified by silica gel flash chromatography, eluting with petroleum ether/EtOAc (20/1-5/1) to afford the corresponding products as a white/colorless/yellow/dark red viscous liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium phosphate In 1,4-dioxane at 85℃; for 30h; | Synthesis of N-aryl-4-(5-phenoxyfuran-2-yl)pyrimidin-5-mines 6- and N-aryl-4-[5-(3,4,5-trimethoxyphenoxy)furan-2-yl]pyrimidin-5-amines 9- (general procedure). General procedure: Method A. A mixture of 5-bromo-4-(5-phenoxyfuran-2-yl)pyrimidine (4a) (407 mg, 1.0 mmol), aniline (5a) (137 μL, 1.5 mmol), phosphine ligand (Xanthphos or dppf) (0.2 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), and K3PO4 (2.5 mmol) was dissolved in 1,4-dioxane (20 mL). The resulting mixture was heated at 85 °C for 15 h. The solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1 : 3). Method B. Phenol (2a) or 3,4,5-trimethoxyphenol (2b) (0.75 mmol) and K3PO4 (266 mg, 1.25 mmol) were added to a solution of 5-arylmin-4-(5-nitrofuran-2-yl)pyrimidine 8 - (0.5 mmol) in 1,4-dioxane (10 mL). The resulting mixture was heated at 85 °C for 15 h (for the reaction with 2) or 30 h (for the reaction with 2b). The solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1 : 3).Products 9b-e were additionally purified by semi-preparative HPLC.4-(5-Phenoxyfuran-2-yl)-N-phenylpyrimidin-5-amine (6a). The yield was 250 mg (76 %) (method A); 132 mg, 80 % (method B) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium phosphate In 1,4-dioxane at 85℃; for 15h; | Synthesis of 5-bromo-4-(5-aryloxyfuran-2-yl)pyrimidines 4(general procedure). General procedure: Phenol (2a) or 3,4,5-trimethoxyphenol (2b) (1.5 mmol) and K3PO4 (531 mg, 2.5 mmol) were added to a solution of 5-bromo-4-(5-nitrofuran-2-yl)pyrimidine (1) (270 mg, 1.0 mmol) in 1,4-dioxane (15 mL). The reaction mixture was heated at 85 °C for 15 h. The solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1 : 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; | 15.1 1. Preparation of oxalate 2: Under nitrogen atmosphere, dissolve 3,4,5-trimethoxyphenol (1.83g, 1.0 equivalent) and triethylamine (2.8mL, 2.0 equivalent) in dichloromethane (20mL) in a 50mL double-necked flask , add ethyl oxalyl monochloride(2.1mL, 2.0 equivalent) dropwise at 0C After the addition, the reaction was continued for 10 minutes. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was spin-dried, and the compound 2 (2.69g) was obtained by separation and purification by column chromatography (PE:EA=20:1). The yield was 95%. . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; | 22.1 1. Preparation of oxalate 9: Under a nitrogen atmosphere, dissolve 3,4,5-trimethoxyphenol (1.83g, 4.0 equivalents) and triethylamine (2.8mL, 4.0 equivalents) in dichloromethane (20mL) in a 50mL double-necked flask, Add oxalyl chloride (227μL, 1.0 equivalent) dropwise at 0C, continue the reaction for 10 minutes after the addition, monitor the reaction by thin layer chromatography, after the reaction is complete, spin dry the solvent, and pass the column chromatography (PE:EA=20:1 ) Isolation and purification gave compound 9 (971 mg) with a yield of 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With triethylamine In dichloromethane at 20℃; for 48h; | 4.2.2. General preparation of PAIB-SOs 1-48 General procedure: The relevant phenol (1.0 Eq.) was mixed with a solution of 4-(3-alkyl-2-oxoimidazolidin-1-yl)benzenesulfonyl chloride (52-54, 1.0Eq.) and triethylamine (1.0 Eq.) in dry methylene chloride. The reactionmixture was stirred for 48 h at room temperature. Then, asolution of 1 N HCl was added to the reaction mixture which wasextracted three times with methylene chloride. The organic layerwas washed successively with solutions of 1 N NaOH (1 M) andbrine, and dried over anhydrous sodium sulfate and filtered. Theorganic solutionwas evaporated to dryness under reduced pressureand the residue was purified by flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine In dichloromethane at 20℃; for 48h; | 4.2.2. General preparation of PAIB-SOs 1-48 General procedure: The relevant phenol (1.0 Eq.) was mixed with a solution of 4-(3-alkyl-2-oxoimidazolidin-1-yl)benzenesulfonyl chloride (52-54, 1.0Eq.) and triethylamine (1.0 Eq.) in dry methylene chloride. The reactionmixture was stirred for 48 h at room temperature. Then, asolution of 1 N HCl was added to the reaction mixture which wasextracted three times with methylene chloride. The organic layerwas washed successively with solutions of 1 N NaOH (1 M) andbrine, and dried over anhydrous sodium sulfate and filtered. Theorganic solutionwas evaporated to dryness under reduced pressureand the residue was purified by flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In dichloromethane at 20℃; for 48h; | 4.2.2. General preparation of PAIB-SOs 1-48 General procedure: The relevant phenol (1.0 Eq.) was mixed with a solution of 4-(3-alkyl-2-oxoimidazolidin-1-yl)benzenesulfonyl chloride (52-54, 1.0Eq.) and triethylamine (1.0 Eq.) in dry methylene chloride. The reactionmixture was stirred for 48 h at room temperature. Then, asolution of 1 N HCl was added to the reaction mixture which wasextracted three times with methylene chloride. The organic layerwas washed successively with solutions of 1 N NaOH (1 M) andbrine, and dried over anhydrous sodium sulfate and filtered. Theorganic solutionwas evaporated to dryness under reduced pressureand the residue was purified by flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.4% | With triethylamine In acetonitrile at 80℃; | General procedure for synthesis of (IXa-n). General procedure: Compound(VIIIg) (200 mg, 0.48 mmol) and different substitutedphenols (0.96 mmol) were added to 4 mL acetonitrileand triethylamine (1.44 mmol), then the temperaturewas raised to 80°C. When the reaction wascompleted, it was extracted with water and ethyl acetate, and then purified by column chromatography(PE : EA = 5 : 1) to get the target compounds (IXa-n).N-((4-Ethylphenyl)carbamoyl)-2-((4-phenoxy-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide (IXa). |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :