Structure of 31680-08-7
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CAS No. : | 31680-08-7 |
Formula : | C8H7NO4 |
M.W : | 181.15 |
SMILES Code : | COC1=C(C=C(C=O)C=C1)[N+]([O-])=O |
MDL No. : | MFCD00126498 |
Boiling Point : | No data available |
InChI Key : | YTCRQCGRYCKYNO-UHFFFAOYSA-N |
Pubchem ID : | 700608 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 47.14 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.01 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.26 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.42 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.17 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.71 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.9 |
Solubility | 2.28 mg/ml ; 0.0126 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.37 |
Solubility | 0.767 mg/ml ; 0.00423 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.85 |
Solubility | 2.54 mg/ml ; 0.014 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.51 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
3.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.79 |
* 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 |
---|---|---|
93% | With sodium nitrate; In neat (no solvent); at 20℃; for 0.1h;Green chemistry; | General procedure: A mixture of aromatic compound (1 mmol), sodium nitrate(1 mmol) and SO3H-functionalized magnetic core/shell nanocatalyst (0.1 mmol) was pulverized in a mortar at room temperature for an appropriate time. The reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, CH2Cl2 (5.0 mL) was then added to the mixture and filtered. Evaporation of the solvent followed by recrystallization or column chromatography on silicagel of the crude product gave the corresponding nitratedcompounds in good to excellent yields. The nanocatalyst was simply separated from the reaction mixture by using anexternal magnet, washed with methanol/diluted HCl solutionand then dried in an oven at 60 C. Before reusing the recycled catalyst, it was weighted in any cycle, and after that, it was reused in subsequent runs. Furthermore, fresh catalyst was added to reciprocate decreased mass loss, if it was considerable. |
87% | With sulfuric acid; nitric acid; at 0 - 20℃; for 1h; | General procedure: Nitration reactions were performed according to the methodology described by Chorev et al. with minor modifications.1 A mixture of 5 mL concentrated sulfuric acid and 10 mmol of the corresponding benzaldehyde was cooled to 0 C under vigorous stirring. Then, 1.2 equiv. of nitric acid, previously dissolved in 1 mL concentrated sulfuric acid, was slowly added. After addition is completed, the reaction mixture was then warmed to room temperature and stirred for 1 additional hour. The crude was then poured into crushed ice, the solid product was recovered by filtration, washed with cold water and recrystallized from ethanol. |
82.7% | With ammonium nitrate; trifluoroacetic anhydride; at 0 - 20℃; for 7.25h; | 4-Methoxy-benzaldehyde (1 g, 7.34 mmol) was added to a mixture of ammonium nitrate (0.58 g, 7.34 mmol) and trifluoroacetic anhydride (3.56 mL, 25.69 mmol), which was cooled to 0 C. The reaction mixture was stirred at 0 C for 15 min and then allowed to stir at room temperature for about 7 h. Ice was added and stirred for 30 min. The solid obtained was filtered, washed with cold water (3 x 5 mL) and dried. Yield: 1 .100 (82.70 %); 1 H NMR (DMSO-d6, 300 MHz): 5 9.93 (s, 1 H), 8.40 (d, 1 H), 8.17 (dd, 1 H), 7.55 (d, 1 H), 4.02 (s, 3H). |
82% | With nitric acid; at 20℃; for 8h; | General procedure: 4-Methoxybenzaldehyde (6) (5.0 g, 36 mmol) was slowly added to nitric acid (70 %, 30 mL) at room temperature and the mixture was stirred at room temperature for a further 8 h. The reaction mixture was poured into ice water (400 mL). The resultant solid was collected by filtration, washed with cold water, and washed with aq NaOH to remove the acid formed from the reaction mixture and finally purified by column chromatography using ethylacetate/hexane to afford the product as light yellow solid (5.4 g, 82%): Rf = 0.4(EtOAc:Hex-50:50); 1H NMR (300 MHz, CDCl3): = 9.91 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 2.2, 9.0 Hz, 1H), 7.23 (d, J = 9.0, 1H), 4.07 ppm (s, 3H); MS (ESI) m/z: 328 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With piperidine; pyridine; In ethanol; for 18h;Reflux; | General procedure: A stirred suspension of the appropriate benzaldehyde (10mmol), malonic acid (1.15g, 11mmol), pyridine (0.4mL) and piperidine (1.2mL, 12mmol, 1.2 equiv.) in EtOH (30mL) was heated to reflux for 18h. The solvent was removed under reduced pressure, the residue diluted with water (10mL) and acidified with hydrochloric acid in water (1N solution). The yellow precipitate obtained was filtered, washed with cold water, and dried to furnish the desired product as a solid used without further purification for the next reaction.5.1.2.1 (E)-3-(4-Methoxy-3-nitrophenyl)acrylic acid (21g) Following general procedure A, starting from <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong>, compound 21g was obtained as a yellow solid. Yield: 86%, mp: 234-236C. 1H NMR (DMSO-d6) δ: 3.96 (s, 3H), 6.56 (d, J=16.0, 1H), 7.37 (d, J=8.8Hz, 1H), 7.55 (d, J=16.0, 1H), 7.98 (dd, J=8.8 and 2.0Hz, 1H), 8.23 (d, J=2.0Hz, 1H), 12.6 (bs, 1H). MS (ESI): [M+1]+=224.3 |
86% | With piperidine; pyridine; In ethanol; for 18h;Reflux; | General procedure: A stirred suspension of the appropriate benzaldehyde (10mmol), malonic acid (1.15g, 11mmol), pyridine (0.4mL) and piperidine (1.2mL, 12mmol, 1.2 equiv.) in EtOH (30mL) was heated to reflux for 18h. The solvent was removed under reduced pressure, the residue diluted with water (10mL) and acidified with hydrochloric acid in water (1N solution). The yellow precipitate obtained was filtered, washed with cold water, and dried to furnish the desired product as a solid used without further purification for the next reaction.5.1.2.1 (E)-3-(4-Methoxy-3-nitrophenyl)acrylic acid (21g) Following general procedure A, starting from <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong>, compound 21g was obtained as a yellow solid. Yield: 86%, mp: 234-236C. 1H NMR (DMSO-d6) δ: 3.96 (s, 3H), 6.56 (d, J=16.0, 1H), 7.37 (d, J=8.8Hz, 1H), 7.55 (d, J=16.0, 1H), 7.98 (dd, J=8.8 and 2.0Hz, 1H), 8.23 (d, J=2.0Hz, 1H), 12.6 (bs, 1H). MS (ESI): [M+1]+=224.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | General procedure: The compound 3,4,5-trimethoxyphenyl acetic acid (8a) (200 mg, 0.88 mmol) was dissolved in 10 mL of Ac2O, followed by addition of substituted aldehyde 9a (136 mg, 0.88 mmol) and Et3N (1 mL). The reaction mixture was heated at 140 C for 12 h. After cooling, the reaction mixture was acidified with 35% aq HCl. The reaction mixture was left overnight and the precipitated product was filtered. The precipitate was recrystallized from absolute ethanol afford the pure compound 10a, 130 mg in 40% yield. | |
45% | With acetic anhydride; triethylamine; at 140℃; for 12h; | In a three-necked 100ml flask was added 3,4,5-trimethoxy phenyl acetic acid (2.4g, 10.6mmol), 3- nitro-4-methoxybenzaldehyde (1.92g, 10.6mmol), 2.4ml triethylamine amine and 24ml of acetic anhydride, heated with stirring to 140 , reaction 12h, heating was stopped, 14.4ml of concentrated hydrochloric acid was added dropwise, at room temperature overnight.There khaki solid precipitation, the reaction was stopped, filtered solids with about 150ml recrystallized from ethanol to give yellow needles of pure product 1.86g, yield 45.0% |
A mixture of 3,4,5-trimethoxyphenylacetic acid (8.84 mmol) and 3-nitro-4-methoxyenzaldehyde (4.4 mmol), acetic anhydride (4 mL) and triethylamine (2 mL) were heated under reflux for 3 h. After acidification with concentrated hydrochloric acid (6 mL), the resulting solid was filtered off and recrystallised from ethanol to give acrylic acid intermediate 11 as fine yellow needles. Subsequently the corresponding acrylic acid intermediate (5.56 mmol) was added to powdered copper (28.8 mmol) in quinoline (20 mL), and the resulting mixture was heated at 140 C for 2 h. Upon cooling, diethyl ether was added, and the copper was filtered off through Celite. The filtrate was washed with 1 M hydrochloric acid, and the aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium carbonate, water, brine, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (SiO2 petrol/EtOAc 7:3) and recrystallization from EtOAc and petrol afforded desired intermediate compound 12 in 52% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | NaH (1.54 g, 64.2 mmol) was added into an oven-dried round-bottom reaction flask. AnhydrousCH2Cl2 (100 mL) and 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (6.94 g, 13.3mmol) were added to the reaction flask, and the reaction mixture was stirred for 1 h. The reactionmixture was cooled to -15 C, and <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (2.01 g 11.1 mmol) wasadded to the reaction flask. The reaction mixture was stirred for 20 h while warming to ambienttemperature under N2. Water (100 mL) was slowly added to the reaction, and the product wasextracted with CH2Cl2 (3 × 100 mL). The organic phase was rinsed with brine, dried withNa2SO4, and concentrated under reduced pressure, and the residue was purified by flash columnchromatography using a pre-packed 100 g silica column [solvent A: EtOAc; solvent B: hexanes;gradient: 10%A / 90%B (1 CV), 10%A / 90%B → 70%A / 30%B (10 CV), 70%A / 30%B (5CV); flow rate: 100 mL/min; monitored at 254 and 280 nm] affording 3' CA4-nitro 46 (1.51 g,S24.34 mmol, 39% yield) as a yellow solid. | |
1.3 g | To a solution of compound 4 (4.5 g, 8.6 mmol) in dry CH2Cl2 (100 mL),NaH (1.7 g, 43.1 mmol) was added at 0 C and the mixture stirred at the sametemperature for 0.5 h, and then the compound 5 (1.6 g, 8.6 mmol) in dry CH2Cl2 (20 mL) wasadded to dropwise in reaction. The mixture reaction stirred at room temperaturefor overnight and monitored by TLC. After completion of reaction, the mixturereaction was quenched with ice water, washed with water (200 mL). The organiclayer was dried over anhydrous Na2SO4 and concentratedunder vacuum. The residue was purified on a silica gel column eluted withpetroleum ether/ethyl acetate (20:1= V:V) to give the desired product 6 (1.3 g, yield 43.7%) asa yellow solid. 1HNMR (300 MHz, CDCl3) δ 7.79 (d, J = 11.6 Hz, 1H), 7.43 (d, J= 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 12.1 Hz,1H), 6.47 - 6.42(m, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 3.71 (s, 6H). HR-MS (m/z) (ESI): calcd for C18H19NO6 [M+H]+: 346.1291; found: 346.1275. | |
1.51 g | NaH (1.54 g, 64.2 mmol) was added into an oven-dried round-bottom reaction flask. Anhydrous CH2C12 (100 ml) and 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (6.94 g, 13.3 mmol) were added to the reaction flask, and the reaction mixture was stirred for 1 h. The reaction mixture was cooled to -15 C., and <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (2.01 g 11.1 mmol) was added to the reaction flask. The reaction mixture was stirred for 20 h while warming to ambient temperature under N2. Water (100 mL) was slowly added to the reaction, and the product was extracted with CH2C12 (3×100 mL). The organic phase was rinsed with brine, dried with Na2SO4, and concentrated under reduced pressure, and the residue was purified by flash column chromatography using a pre-packed 100 g silica column [solvent A: EtOAc; solvent B: hexanes; gradient: 10% A/90% B (1 CV), 10% A/90% B→70% A/30% B (10 CV), 70% A /30% B (5 CV); flow rate: 100 mL/min; monitored at 254 and 280 nm affording 3′ CA4-nitro (1.51 g, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In ethanol; for 3h;Reflux; | General procedure: The appropriate amine (10 mmol) was heated at reflux with the appropriate aldehyde (10 mmol) in ethanol (50 mL) for 3 h. The reaction mixture was reduced in vacuo and the resulting solution was left to stand until solid product crystallised. The resulting imine was recrystallised from ethanol. |
In ethanol; at 80℃; for 6h; | General procedure: A solution of various aromatic aldehydes A1-A10 (1.0 mmol, 1.0 eq) and 3,4,5-trimethoxyaniline (1.0 mmol, 1.0 eq) were added into EtOH (20 ml) at 80 C for 6 h. When the reactions were complete, organic phases were collected to give crude the products C1-C10 without further purified with column chromatography. A solution of compounds C1-C10 (1.0 mmol,1.0 eq), benzoic acid (1.0 mmol, 1.0 eq) and NaBH4 (1.0 mmol, 1.0 eq) were added into DCM (20 ml) at 25 C for 8 h. When the reactions were complete, organic phases were collected to obtain crude products and then were purified by column chromatography to obtain compounds D1-D10. A solution of compounds D1-D10 (1.0 mmol, 1.0 eq) and acyl chloride derivatives (1.0 mmol, 1.0 eq) were added into DMF (8 ml) at 25 C for 6-8 h. Then using EA (20 ml) extracted aqueous layers for three times. Collected organic layers were washed by saturated salt water, dried over magnesium sulfate anhydrous and evaporated to get crude products. Crude products were purified by column chromatography to obtain compounds E1-E11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34%; 50% | A mixture of 3,4,5-trimethoxybenzyltriphenylphosphoniumbromide [22] (1.57 g, 3 mmol), powdered potassiumcarbonate (1.38 g, 10 mmol) and 18-crown-6 (0.01 g,0.04 mmol) in dichloromethane (20 mL) was stirred at roomtemperature for 10 min. Then, <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong>(0.54 g, 3 mmol) was added and the reaction mixturewas refluxed for 6 h (monitored by TLC). The inorganicsalts were filtered after cooling and the filtrate was concentratedunder reduced pressure to give a mixture of isomers1, 2 and triphenylphosphine oxide. Recrystallization ofthe crude reaction mixture from ethanol afforded pure Estilbene1 (0.40 g, 38 % yield). Column chromatography ofthe mother liquors (petroleum ether/acetone, 15:1 v/v) gaveZ-isomer 2 (0.35 g, 34 % yield) and 1 (0.12 g, 12 % yield). (E)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene(1)Orange crystals. Rf = 0.52. Mp: 151-153 C. 1H NMR(CDCl3, 300 MHz): δ 3.87 (s, 3H, OCH3), 3.91 (s, 6H,OCH3), 3.98 (s, 3H, OCH3), 6.72 (s, 2H, ArH), 6.91 (d, 1H,J = 16.3 Hz, = CH), 6.99 (d, 1H, J = 16.3 Hz, = CH),7.08 (d, 1H, J = 8.7 Hz, ArH), 7.64 (dd, 1H, J = 1.6 Hz,J = 8.7 Hz, ArH), 7.99 (d, 1H, J = 1.6 Hz, ArH). 13CNMR (CDCl3, 75 MHz): δ 55.9; 56.5; 60.8; 103.5; 113.6;122.9; 124.9; 129.3; 130.1; 131.6; 132.1; 138.1; 139.6;151.9; 153.3.(Z)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene(2)Yellow crystals. Rf = 0.58. Mp: 122-123 C. Lit. Mp:123-124 C [12]. 1H NMR (CDCl3, 300 MHz): δ 3.70 (s,6H, OCH3), 3.84 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),6.41-6.46 (m, 3H, ArH, = CH), 6.57 (d, 1H,J = 12.1 Hz, = CH), 6.94 (d, 1H, J = 8.7 Hz, ArH), 7.42(dd, 1H, J = 2.2 Hz, J = 8.7 Hz, ArH), 7.78 (d, 1H,J = 2.2 Hz, ArH). 13C NMR (CDCl3, 75 MHz): δ 55.9;56.5; 60.9; 105.8; 113.1; 125.9; 126.8; 129.7; 131.3; 131.7;134.6; 137.7; 139.4; 151.6; 153.8. | |
Step (i) :A solution of sodium methoxide (5.66 kg, 29.34 mol) is run into a mixture, at a temperature of 5-10 C., comprising toluene (91.1 litres), trimethoxybenzylphosphonium bromide (15.35 kg, 29.33 mol) and <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (5.06 kg, 27.93 mol). At the end of the reaction, 0.32 litre (5.59 mol) of acetic acid is run in. After the medium has been maintained at 20 C., it is filtered. The cake is washed with toluene (11.1 litres). The filtrates are washed several times with water (20.2 litres) and then concentrated under vacuum. Isopropyl alcohol (87.6 litres) is then introduced and the medium is concentrated and then cooled. The suspension is then filtered at 10 C. The isolated product is dried under vacuum (6.46 kg, 52.2%). The purity of the isolated product is of the order of 78% with respect to (Z) and 22% with respect to (E). | ||
With sodium hydride; In dichloromethane; at 0 - 20℃; | General procedure: To a stirred solution of nitrobenzaldehydes (10, 11, 19, 1 mmol) and 3,4,5-trimethoxybenzyl triphenylphosphonium bromide (9, 1.1 mmol) in anhydrous dichloromethane, sodium hydride (4 mmol) was added at 0 C. The reaction mixture was stirred at room temperature for 18 h and monitored by TLC. After completion of the reaction appropriate amount of water, until foaming stopped, was added at 0 C. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure to get crude compounds, nitro Z-and E-stilbenes isomeric mixture. The isomers were separated by using column chromatographyto give pure Z-stilbenes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 0 - 20℃; for 1.16667h; | A solution of 3,4,5-trimethoxyphenylmagnesium bromide (11, 1.5eq, 0.5M in THF) was added slowly to the aldehydes 8 and 10 (5 g, 27.6 mmol and 23.6 respectively) in dry THF (10 mL) at 0 C. The reaction mixture was warmed to room temperature, and stirring was continued for another 1 h. A saturated NH4Cl solution was slowly added at 0 C to hydrolyze the adduct and extracted with EtOAc (75 mL x 2). The combined organic extracts were dried over MgSO4 and evaporated to give crude residues 12 & 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; In tetrahydrofuran; at -10 - 0℃; for 1h; | 2-(4-Methoxy-3-nitro-phenyl)-1-(3,4,5-trimethoxy-phenyl)-ethanone (2); A round-bottom flask equipped with thermometer, condenser and gas inlet was purged and maintained under nitrogen and charged with hydroxy-(3,4,5-trimethoxy-phenyl)-methyl]-phosphonic acid dimethyl ester (1Og, 32.6 mmol), 3,4-dihydro-2H-pyran (3.57g, 42.4 mmol), toluene (100 mL) and p-toluenesolfonic acid hydrate (62.1 mg, 0.01 eq). Resulted solution was stirred at 550C for 1.5 hours. TLC (EtOAc) showed full conversion of starting material into a less polar compound. Reaction mixture was cooled to -10 0C and a solution of sodium bis(trimethylsilyl)amide in THF (1M, 33.3 mL) was added drop-wise, followed by a solution of <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (5.91 g, 32.6 mmol) in THF (20 mL). Reaction mixture was stirred at 0 0C for 1 hour before allowed to warm to room temperature. TLC (Hx: EtOAc, 2:1) showed formation of Z/E isomers of 2-[2-(4-methoxy-3-nitro-phenyI)-1-(3,4,5-trimethoxy-phenyl)-vinyloxy]-tetrahydro-pyr an and traces of starting materials remaining. Reaction was quenched with water (140 mL), diluted with EtOAc (60 mL) and transferred into separator/ funnel. Organic layer was separated, washed with water (2x50 mL), brine, and concentrated. A residue was dissolved in methanol (100 mL) with energetic mechanical stirring, and 1M aqueous solution of HCI (10 mL) was added. Precipitation of product started soon, and a resulted suspension was stirred for 1 hour. Solid was filtered out, washed EPO <DP n="223"/>with methanol (50 ml_), then with water (3x30 ml_) and dried on filter followed by vacuum-drying at 60 0C until constant weight. Crude deoxybenzoin 2, 6.81 g (58%) showed LC purity of ≥ 97% and was used in the next step without further purification. | |
With sodium hexamethyldisilazane; In tetrahydrofuran; at -10 - 0℃; for 1h; | A round-bottom flask equipped with thermometer, condenser and gas inlet was purged and maintained under nitrogen and charged with hydroxy-(3,4,5-trimethoxy-phenyl)-methyl]-phosphonic acid <n="298"/>dimethyl ester (1Og, 32.6 mmol), 3,4-dihydro-2H-pyran (3.57g, 42.4 mmol), toluene (100 mL) and p-toluenesolfonic acid hydrate (62.1 mg, O.Oleq). Resulted solution was stirred at 55 0C for 1.5 hours. TLC (EtOAc) showed full conversion of starting material into a less polar compound. Reaction mixture was cooled to -10 0C and a solution of sodium bis(trimethylsilyl)amide in THF (IM, 33.3 mL) was added drop-wise, followed by a solution of <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (5.91 g, 32.6 mmol) in THF (20 mL). Reaction mixture was stirred at 0 0C for 1 hour before allowed to warm to room temperature. TLC (Hx:EtOAc, 2:1) showed formation of Z/E isomers of2-[2-(4-methoxy-3-nitro-phenyl)-l-(3,4,5-trimethoxy-phenyl)-vinyloxy]-tetrahydro-pyran and traces of starting materials remaining. Reaction was quenched with water (140 mL), diluted with EtOAc (60 mL) and transferred into separatory funnel. Organic layer was separated, washed with water (2x50 mL), brine, and concentrated. A residue was dissolved in methanol (100 mL) with energetic mechanical stirring, and IM aqueous solution of HCl (10 mL) was added. Precipitation of product started soon, and a resulted suspension was stirred for 1 hour. Solid was filtered out, washed with methanol (50 mL), then with water (3x30 mL) and dried on filter followed by vacuum-drying at 60 0C until constant weight. Crude deoxybenzoin 2, 6.81 g (58%) showed LC purity of > 97% and was used in the next step without further purification. | |
General procedure: In a round-bottomed flask maintained under a nitrogen atmosphere, appropriate amounts of a-hydroxyphosphonate (10 mmol) and 3,4-dihydro-2H-pyran (17 mmol) as well as 1.5 mol% of p-TsOH*H2O were dissolved in dry toluene (30 mL). The resulting mixture was heated to 65 C for 2 h, and dry THF (5 mL) was then added to the mixture. Upon cooling to 55 C, 10.5 mmol of n-butyllithium (15% in hexane, 1.6 mol/L) was added dropwise to the mixture, and the contents of the flask were stirred for 1 h under a nitrogen atmosphere, after which the solvent for the appropriate benzaldehyde (10 mmol) in anhydrous THF was added dropwise and stirred for another 4 h. Upon solvent removal via rotary evaporation, the residue was dissolved in a mixture of 20 mL of MeOH and HCl aq. (3 mL, 12 M) and stirred at room temperature for 1 h. Next, the flask was stored at 10 C to allow the deoxybenzoin to precipitate as a solid. Pure product as a white solid could be obtained from this crude mixture via recrystallisation from methanol (10 mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N-methyl-acetamide; | Example 48 (3-Nitro-4-methoxy)benzaldehyde 3-Nitro-4-hydroxybenzaldehyde (1.37 g, 8.20mol) was dissolved in dimethylformamide and methyl iodide (2.55 mL, 41.0 mmol) and sodium carbonate (1.74 g, 164 mmol) were added. The reaction mixture was stirred for 20 hours at ambient temperature and then poured into water. The solid product (1.10 g, 74.0%) was filtered, mp 82 C. 1 H NMR (CDCl3): d, 9.94 (s,1H), 8.37 (d, 1H), 8.11 (dd,1H), 7.25 (d,1H), 4.07 (s,3H). MS (DCl): 182 (MH+). C8 H7 NO4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 0.5h; | Example 1 : Synthesis of (£",£)-2,6-bis(3-amino-4-methoxystyryI)pyridine (compound (Ia-I)); 200 mg of 2,6-bis(diethylphosphonomethyl)pyridine (0.53 mmol) obtained in Preparation Example 1 and 205 mg of 4-methoxy-3- nitrobenzaldehyde (compound (IHe)) (1.1 1 mmol) were dissolved in 3.5 ml of tetrahydrofuran (THF), and the mixture was cooled to 0 C . 1.1 1 ml of IM potassium tert-butoxide in THF (1.1 1 mmol) was added thereto and stirred at room temperature for 30 min. Then, a large amount of methanol was added thereto and stirred at room temperature for 30 min to induce precipitation of solids. The precipitated solids were filtered and vacuum dried to obtain 214 mg of (£,£)-2,6-bis(4-methoxy-3-nitrostyryl)pyridine as a solid (yield: 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With magnesium; In tetrahydrofuran; | Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately 3 mL of a solution of 3,4-bromoveratrole (3.5 g, 15.9 mmol) in THF (10 mL) was added to a mixture of magnesium turnings (0.4 g, 15.9 mmol) in THF (5 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,4-bromoveratrole solution was added dropwise to the solution under mild reflux. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,4-dimethoxyphenyl)magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (2.4 g, 13.3 mmol) in THF (10 mL) at 0 C. After complete addition, the solution was allowed to stir at room temperature for 1 h. The mixture was cooled to 0 C. and quenched with saturated NH4Cl solution (40 mL). The aqueous layer was extracted with EtOAc (3*20 mL). The combined organic layers were washed with water (2*30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed and residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to give (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol as an oil (2.6 g, 63%): 1H NMR (CDCl3) δ 7.89 (d, J=2 Hz, 1H), 7.54-7.49 (dd, J=2, 8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.88-6.81 (m, 3H), 5.78 (d, J=3 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.38 (d, J=3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With magnesium; | (4-Methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was prepared analogously to 3-(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using 3,5-dimethoxy-bromobenzene (5.0 g, 23.0 mmol), magnesium turning (0.6 g, 23.0 mmol) and 4-methoxy-3-nitro-benzaldehyde (3.5 g, 19.2 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 1:1) to afford (4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.7 g, 60%) as an oil: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.54-7.50 (dd, J=2, 8 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 6.38 (d, J=1 Hz, 1H), 5.72 (d, J=3 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 6H), 2.45 (d, 2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium; In tetrahydrofuran; | Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately {fraction (1/4)} of a solution of 3,5-bromoveratrole (10 g, 46.1 mmol) in anhydrous THF (60 mL) was added to a mixture of magnesium turnings (1.12 g, 46.1 mmol) in THF (10 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,5-bromoveratrole solution was added dropwise to the reaction mixture under mild reflux, over 30 min. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,5-dimethoxy-phenyl) magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (6.95 g, 38.4 mmol) in THF (60 mL) at 0 C. After complete addition, the reaction mixture was stirred at cold for 10 min and then at room temperature for 2 h. The solution was cooled to 0 C. and quenched with saturated NH4Cl solution (90 mL). The aqueous layer was extracted with ether (3*90 mL). The combined organic layers were washed with water (2*120 mL), brine (120 mL) and dried (MgSO4). Removal of solvent gave the crude (3,5-dimethoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanol, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; at -78℃; | The preparation involved a reaction sequence (overall 30-46% yield in two or three steps): (1) Wittig reaction of (4-methoxybenzyl)phosphonium bromide (scheme 1) and (2-nitro-3,4,5-trimethoxybenzyl)phosphonium bromide (scheme 2), with various substituted benzaldehydes including 2-nitro or 3-nitrobenzaldehydes yielded the corresponding Z- and E-stilbenes as an about ratio of 3/1. (2) Reduction of nitro group of Z-stilbenes by Zn/AcOH to afford the desired substituted 2-amino and 2'-aminocombretastatins derivatives. Ylide (compound B2) was synthesized from the 2-nitro-3,4,5-trimethoxybenzyl bromide (compound B1). The methoxy-substituted benzaldehydes A3-A6, and B3 are commercially available. The 2-nitrobenzaldehydes A1-A2 and 3-(tert-butyldimethylsilyl) protected isovanillin B4 were prepared in two-four steps.; Example 7; 2,3'-Diamino-3,4,4',5-tetramethoxy-(Z)-stilbene (compound 7); The title compound was obtained in 34% overall yield from 2-nito-3,4,5-(trimethoxybenzyl)triphenylphosphonium bromide (compound B2) and <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (compound B3). mp 97.3-98.1 C. 1H NMR (500 MHz, Acetone-d6) δ 3.54 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 4.01 (s, 2H), 4.25 (s, 2 H), 6.26 (d, J=12.1 Hz), 6.39 (d, J=12.1 Hz, 1H), 6.53 (s, 1H), 6.56 (dd, J=8.2, 1.7 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H). 13C NMR (125 MHz, Acetone-d6) δ 56.1, 57.1, 61.0, 61.4, 110.5, 111.2, 117.0, 120.4, 120.9, 124.9, 131.3, 132.1, 133.6, 137:3, 143.0, 143.5, 146.8, 148.8. MS (EI) m/z: 330 (M+, 100%), 315 (27%). HRMS (EI) for C18H22N2O4 (M+): calcd, 330.1578; found, 330.1570. Anal. (C18H22N2O4) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium dithionite; potassium carbonate; In dichloromethane; water; | 3-Amino-4-methoxybenzaldehyde was obtained by reduction of the corresponding nitro compound according to Tetrahedron Letters, 1993, 34(46), 7445-1446. |
With acetic acid;iron; In ethanol; water; at 75℃; for 1h; | Reference Production Example 29To a mixture of 1.2 ml of acetic acid, 51 ml of water and 79 ml of ethanol was added 10.04 g of iron powder, and 5.44 g of <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> was added thereto at 75C and stirred for 1 hour. The reaction mixture was filtered and the precipitate was washed with ethyl acetate. A saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to the filtrate to effect extraction. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 4.44 g of 3-amino-4-methoxybenzaldehyde .3-Amino-4-methoxybenzaldehyde:1H-NMR (CDCl3) <5 : 9.80 (IH, s) , 7.27 (IH, dd, J = 8.2, 2.0 Hz), 7.23 (IH, d, J = 2.0 Hz), 6.88 (IH, d, J = 8.2 Hz), 3.97 (2H, br s) , 3.94 (3H, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.4% | With n-butyllithium; In tetrahydrofuran; diethyl ether; hexane; at -130℃; | A mixture of 978 mg (5.4 mmol) of 3-nitro-4-methoxy-benzaldehyde (6) and 1.6 g (5.9 mmol, 1.1 EQ) of CFBR3 in 40 mL of Et20/THF (1: 1) was brought to T =-130C ; 3.7 mL (5.9 mmol, 1.1 eq) of a 1.6 M BuLi solution in hexane was added to the mixture in 10 minutes. The reaction was quenched with 25 mL of NH4C1 saturated solution and diluted with 20 mL of diethyl ether. The aqueous phase was back- extracted with 2X20 mL of diethyl ether, the organic fractions were collected and dried over anhydrous sodium sulfate and then purified on a silica gel column using Hexane/Ethyl Acetate 95: 5 to give 1.146 g (3.1 mmol, 57.4 %) of a yellow oil. Rf = 0.53 (Hex. /AcOEt 6: 4). MS (IS): [M-1]-= 371.8 [M+ACO]-= 431.7 1H-NMR (300 MHz, CDCI3, A) : 3.2 (bs, 1H, OH), 4.0 (s, 3H, OCHs), 5.1- 5.2 (m, 1H, CH), 7.05-7. 15 (d, 1H, CHar) 7.7-7. 8 (d, 1H, CHAR), 8.05 (s, 1H, CHar). 13C-NMR (75 MHz, CDCL3, 8) : 56.9 ; 81.5 ; 81.8 ; 98.9 ; 100.3 ; 104.6 ; 113.3 ; 126.3 ; 127.3 ; 134.3 ; 153.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; water; for 3h;Heating / reflux; | EXAMPLE 10; Synthesis of 3-(4-methoxy-3-nitrophenyl)-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinazoline-1,7-(2H)-dione; To 20 mL of dehydrated ethanol were added 3 g of the amino compound obtained in the Step 4 of Example 1 and 2.9 g of <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong>. To the resulting mixture was added 0.1 mL of concentrated hydrochloric acid, followed by heating under reflux for 3 hours. After cooling to room temperature, the precipitated crystals were separated by filtration. The crystals were washed with water and diethyl ether to obtain 4.2 g of pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 15 - 25℃; for 20h; | A stirred solution of dimethyl 3-oxo-1, 3- dihydroisobenzofuran-1-ylphosphonate (2. 42 g, 0.01 mol ; prepared in a manner similar to that described in Example 23) and <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (1. 81 g, 0.01 mol) in tetrahydrofuran (15 ml) was cooled to 15C and a solution of triethylamine (1. 01 g, 0.01 mol) in tetrahydrofuran (1.5 ml) was added dropwise at <25C. The mixture was stirred at ambient temperature for 4 hours, allowed to stand at this temperature for a further 16 hours and the resulting mixture was concentrated in vacuo. The residue was triturated with water (50 ml) and stirred at ambient temperature for 2 hours before the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3- (4-methoxy-3- nitrobenzylidene)-3H-isobenzofuran-1-one (2.53 g) as a yellow solid, m. pt. 173-181C, which was used directly in the next stage. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In methanol; at 20℃; | A mixture of 4-methoxy-3-nitro- benzaldehyde (0.00625 mol) and (2-aminoethyl)- carbamic acid, 1,1 -dimethylethyl ester (0.00625 mol) in MeOH (30 ml) was reacted for 2 hours at room temperature, then sodium tetrahydroborate (0.0069 mol) was added and the reaction mixture was stirred overnight. Water was added and the resulting mixture was extracted 3 times with toluene. The organic layer was separated, dried (MgSO4) and the solvent was evaporated, yielding intermediate 58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid;silica gel; In ethanol; ethyl acetate; | Step 1: 2.24 g of 1-(3,4,5-trimethoxyphenyl)propenone, which may be prepared according to Biorg. Med. Chem. 1998, 8(9), 1051, 1.85 g of 3-nitro-4-methoxybenzaldehyde, 2 mL of piperidine and 1 mL of acetic acid in 20 mL of ethanol were successively added to a 25 mL three-necked flask on which was mounted a Soxhlet filled with 3 Å molecular sieves. The medium was refluxed for 48 hours. After cooling, the reaction medium was concentrated under reduced pressure and then taken up in 100 mL of ethyl acetate, and the organic phase was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (70-230 mesh), eluding with a mixture of cyclohexane and ethyl acetate (80/20 by volume). 2 g of E-3-(3-nitro-4-methoxyphenyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propenone were thus obtained, containing about 5% of the Z isomer, in the form of a yellow solid with a melting point of between 45 and 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In diethyl ether; ethanol; dichloromethane; | Example 11A 1H-imidazol-4-yl(4-methoxy-3-nitrophenyl)methanol A solution of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (3.0 g, 10 mmol) in dichloromethane (40 mL) under nitrogen was treated with ethylmagnesium bromide (3.0M in diethyl ether, 3.3 mL) over 2 minutes, stirred for 30 minutes, treated with 4-methoxy-5-nitrobenzaldehyde (2.0 g, 11 mmol), stirred for 1 hour, stored at 0 C. for 16 hours, concentrated to dryness, treated with 1 M HCl(100 mL), heated to 100 C. for 16 hours, cooled to ambient temperature, neutralized with NaHCO3 and extracted with 3:1 dichloromethane:ethanol (5*). The combined extractions were dried (MgSO4), filtered and concentrated. Purification on silica gel with 10% and then 20% ethanol/ammonia-saturated dichloromethane provided the desired compound. MS (DCI/NH3) m/z 250 (M+H)+. | |
With hydrogenchloride; In diethyl ether; ethanol; dichloromethane; | EXAMPLE 11A 1H-imidazol-4-yl(4-methoxy-3-nitrophenyl)methanol A solution of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (3.0 g, 10 mmol) in dichloromethane (40 mL) under nitrogen was treated with ethylmagnesium bromide (3.0 M in diethyl ether, 3.3 mL) over 2 minutes, stirred for 30 minutes, treated with 4-methoxy-5-nitrobenzaldehyde (2.0 g, 11 mmol), stirred for 1 hour, stored at 0 C. for 16 hours, concentrated to dryness, treated with 1M HCl(100 mL), heated to 100 C. for 16 hours, cooled to ambient temperature, neutralized with NaHCO3 and extracted with 3:1 dichloromethane:ethanol (5*). The combined extractions were dried (MgSO4), filtered and concentrated. Purification on silica gel with 10% and then 20% ethanol/ammonia-saturated dichloromethane provided the desired compound. MS (DCI/NH3) m/z 250 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; water; | Step 1 Preparation of (Z)-3-(3-nitro-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile 3.0 g of 3-nitro-4-methoxybenzaldehyde, 3.4 g of <strong>[13338-63-1]3,4,5-trimethoxyphenylacetonitrile</strong>, 800 mg of sodium hydroxide and 100 mg of octylmethylammonium chloride were dissolved in 15 ml of water and 15 ml of dichloromethane and reacted for 4 hours at room temperature. Ice water was added to the reaction liquid, which was then extracted three times each with dichloromethane. The extract was dried with anhydrous sodium sulfate and concentrated. The concentrated liquid was purified by crystallization (ethyl acetate) to obtain 4.4 g of the intended compound. The yield was 72%. 1 H-NMR(CDCl3): 8.30 (1H, dd, J=2.4, J=9.0), 8.21 (1H, d, J=2.4), 7.38 (1H, s), 7.21 (1H, d, J=9.0), 6.86 (2H, s), 4.05 (3H, s), 3.94 (6H, s), 3.89 (3H, s); mass spectrum (m/z): 370 (M+); melting point 191-192 C. |
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