Structure of 6312-87-4
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| CAS No. : | 6312-87-4 |
| Formula : | C14H13NO2 |
| M.W : | 227.26 |
| SMILES Code : | CC(NC1=CC=C(OC2=CC=CC=C2)C=C1)=O |
| English Name : | N-(4-Phenoxyphenyl)acetamide |
| MDL No. : | MFCD00442086 |
| InChI Key : | JIHOMPVYRSEHKW-UHFFFAOYSA-N |
| Pubchem ID : | 80579 |
| Num. heavy atoms | 17 |
| Num. arom. heavy atoms | 12 |
| Fraction Csp3 | 0.07 |
| Num. rotatable bonds | 4 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 67.27 |
| TPSA ? Topological Polar Surface Area: Calculated from |
38.33 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.45 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.13 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.25 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.66 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.62 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.82 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-3.48 |
| Solubility | 0.0754 mg/ml ; 0.000332 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.6 |
| Solubility | 0.0565 mg/ml ; 0.000249 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.05 |
| Solubility | 0.00203 mg/ml ; 0.00000891 mol/l |
| Class? Solubility class: Log S scale |
Moderately 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 |
Yes |
| 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) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
| 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 |
-5.46 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 |
0.0 |
| 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 |
0.0 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) |
1.5 |
* 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 |
|---|---|---|
| With nitric acid; acetic acid at 80℃; | ||
| With water; nitric acid; acetic anhydride; acetic acid | ||
| With nitric acid at -15℃; for 2h; | 1.B N-(4-phenoxy-phenyl)-acetamide (1.00 g, 4.03 mmol) prepared in Step A was dissolved in fuming nitric acid (2 mL), and the mixture was stirred for 2 h at -15 °C .After completion of the reaction, the reaction mixture was poured into 100 mL of ice water, which was then extracted with ethyl acetate. The extracted organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.67 g, 2.33 mmol). |
| With nitric acid at -15℃; for 2h; | 1.B Step B: N-(2-nitro-4-phenoxy-phenyl)acetamide; N-(4-phenoxy-phenyl)-acetamide (1.00 g, 4.03 mmol) prepared in Step A was dissolved in fuming nitric acid (2 mL), and the mixture was stirred for 2 h at -15° C. After completion of the reaction, the reaction mixture was poured into 100 mL of ice water, which was then extracted with ethyl acetate. The extracted organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.67 g, 2.33 mmol). | |
| 0.67 g | With nitric acid at -15℃; for 2h; | 1.B N-(2-nitro-4-phenoxy-phenyl)acetamide N-(4-phenoxy-phenyl)-acetamide (1.00 g, 4.03 mmol) prepared in Step A was dissolved in fuming nitric acid (2 mL), and the mixture was stirred for 2 h at -15° C. After completion of the reaction, the reaction mixture was poured into 100 mL of ice water, which was then extracted with ethyl acetate. The extracted organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.67 g, 2.33 mmol). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With pyridine at 20℃; | |
| 89% | ||
| With triethylamine In dichloromethane at 0 - 20℃; for 1h; | 1.A Commercial available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetic anhydride(2.22 g, 20.8 mmol) were added in drops. The mixture was stirred for 1 h at 0°C to room temperature. After completion of the reaction, the mixture was filtered using dichloromethane and crystallized to give the title compound (4.50 g, 18.6 mmol) |
| With triethylamine In dichloromethane at 0 - 20℃; | 1.A Preparation 1: 2-Nitro-4-phenoxy-phenylamineStep A: N-(4-phenoxy-phenyl)-acetamide; Commercial available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetic anhydride (2.22 g, 20.8 mmol) were added in drops. The mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, the mixture was filtered using dichloromethane and crystallized to give the title compound (4.50 g, 18.6 mmol) | |
| In dichloromethane at 20℃; Inert atmosphere; | ||
| 4.5 g | With triethylamine In dichloromethane at 0 - 20℃; for 1h; | 1.A Step A: N-(4-phenoxy-phenyl)-acetamide Commercial available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetic anhydride (2.22 g, 20.8 mmol) were added in drops. The mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, the mixture was filtered using dichloromethane and crystallized to give the title compound (4.50 g, 18.6 mmol) |
| at 0 - 5℃; | 2.2. General procedure for preparation of N-phenylacetamides (2a-2g) General procedure: N-phenylacetamides were prepared according to the literature[30]. Acetic anhydride (1.5 mmol) was gradually added to the aromaticamines (1 mmol) in the ice bath and the mixture was stirredfor 0.5e2 h. Upon completion the reaction (monitored by TLC),water is poured to the mixture and the formed precipitate wasfiltrated, washed with water and dried to yield N-phenylacetamides2a-2g which used in the next reaction without anypurification. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With potassium hydroxide In dimethyl sulfoxide at 20℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With pyridine for 0.916667h; Cooling with ice; | |
| 68% | With pyridine; dmap at 20℃; for 16h; | |
| In dichloromethane at 20℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | With potassium phosphate; tert-butyl XPhos In toluene at 100℃; for 20h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | With 2-acetonylpyridine; caesium carbonate; copper(I) bromide In dimethyl sulfoxide at 90℃; for 18h; Inert atmosphere; chemoselective reaction; | |
| 84% | With potassium phosphate; 2-di-tert-butylphosphino-2',4',6'-tricyclohexyl-3,6-dimethoxybiphenyl In 1,2-dimethoxyethane; toluene at 100℃; for 24h; Inert atmosphere; | |
| In dimethyl sulfoxide at 120℃; for 48h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | With 2-acetonylpyridine; caesium carbonate; copper(I) bromide In dimethyl sulfoxide at 90℃; for 24h; Inert atmosphere; chemoselective reaction; | |
| 80% | With copper(l) iodide; iron(III)-acetylacetonate; potassium carbonate In N,N-dimethyl-formamide at 135℃; for 12h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 67% | Stage #1: 4-acetaminophenol With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.25h; Stage #2: Diphenyliodonium triflate In tetrahydrofuran at 40℃; for 2.5h; | |
| 67% | Stage #1: 4-acetaminophenol With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.25h; Stage #2: Diphenyliodonium triflate In tetrahydrofuran at 40℃; for 2.5h; | |
| 47% | With sodium hydride In toluene; mineral oil at 60℃; for 24h; Inert atmosphere; chemoselective reaction; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With water at 20℃; for 8h; Irradiation; | 2.4. General procedure for synthesis of N-arylacetamides General procedure: Phenylaryl diazonium tetrafluoroborate (1.0 mmol) and CBB/PCN-224 (20 mg) were added into a 50 mL reaction tube in turn, and 2 mLacetonitrile was added, and the reaction was carried out in red light foreight hours at room temperature. The reaction mixture was extractedwith ethyl acetate (3 £ 10 mL) and water (20 mL) for three times, theexcess solvent was removed by distillation under reduced pressure, andthe sample was purified by column chromatography with petroleumether/ethyl acetate as eluent. The recovered catalyst is dried for lateruse. |
| 58% | With potassium phosphate; copper(l) iodide In water at 80℃; for 12h; Schlenk technique; | 21 Preparation of N-(4-phenoxyphenyl) acetamide: N- (4-phenoxyphenyl) acetamide: A mixture of 142.5 mg (0.5 mmol) of 4-phenoxyphenyl diazonium tetrafluoroborate, 0.1 mmol of copper iodide, 0.5 mmol of phosphoric acid potassium and 1.0 mmol of water was added in a Schlenk tube under a nitrogen atmosphere, the 1 mL of acetonitrile under air conditions at 80 °C was stirred for 12 hours, the reaction yield of 58%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | Stage #1: 4-phenoxyanilin With tetrafluoroboric acid In water Inert atmosphere; Stage #2: acetonitrile With potassium phosphate; water at 80℃; for 12h; | General procedure General procedure: A mixture of aryl diazonium tetrafluoroborates compounds (0.5 mmol), nitriles (0.5 mmol), H2O (1.5 mmol) and K3PO4 (0.6 mmol) was dissolved in acetonitrile (1.0 mL) or ethyl acetate (1.0 mL) under N2 atmosphere, stirred at 80 oC for 12h. Removal of the solvent under a reduced pressure gave the crude product; pure product was obtained by passing the crude product through a short silica gel column using Hexane/EtOAc (1:1-2:1) as eluent. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | Stage #1: 4-phenyl ether acetophenone oxime With sulfuryl fluoride; triethylamine In acetonitrile at 20℃; Stage #2: With hydrogenchloride In water; acetonitrile at 20℃; | |
| 91% | With 10-methyl-9-phenylacridinium perchlorate In 1,2-dichloro-ethane at 20℃; for 5h; Irradiation; Sealed tube; | |
| 90% | With C14H19BF2N2S In dichloromethane at 25℃; for 22h; Irradiation; |
| 94 % | With 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate; triethylamine In acetonitrile at 20℃; | |
| 95 % | With 1,1,1,3',3',3'-hexafluoro-propanol; tetrabutylammonium tetrafluoroborate; 2,3-dicyano-5,6-dichloro-p-benzoquinone at 20℃; Electrolysis; | General Procedure for the Synthesis of Products General procedure: Ketoxime 1 (1.00 mmol), nBu4NBF4 (0.1 M), DDQ (0.10 mmol), and HFIP (10.0 mL) were combined and added into an undivided beaker-type electrolysis cell equipped with a magnetic stirring bar, a graphite rod (l = 100.0 mm, = 7.0 mm) as the anode, and a nickel plate (1.0 cm×1.0 cm×0.3 mm) cathode. A constant-current electrolysis with a current of 2.0 mA was performed at room temperature. These conditions were applied until the substrate was consumed (monitored by TLC), and then the electrolysis was stopped. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel with petroleum ether/ethyl acetate (9:1 to 1:1) as the eluent to give the desired amide. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 61% | With trichlorophosphate at 0 - 90℃; | 2.3. General procedure for preparation of 2-chloroquinoline-3-carbaldehydes (3a-3g) General procedure: Dimethylformamide (3 mmol) was added to N-phenylacetamides(2a-2g, 1 mmol) in an ice bath, then phosphoryl chloride(15 mmol) was added dropwise to the mixture and was stirredat ice bath for 20 min, then the reaction proceeded at temperature80e90 C for 7e10 h. After completion of the reaction, ice is addedto the mixture and was stirred, then the formed precipitate wasfiltrated and recrystallized in ethanol [31]. Compounds 3a, 3c, 3d, 3f and 6a were reported in the literatures[32e35].2.3.1. 2-Chloro-6-phenoxyquinoline-3-carbaldehyde (3b)Yellow solid; yield: 61%; mp: 110e113 C; 1H NMR (300 MHz-CDCl3) d 7.18e7.20 (d, 2H, J 6 Hz, AreH), 7.26e7.30 (t, 1H, J 6 Hz,AreH), 7.47e7.53 (m, 2H, AreH), 7.75e7.79 (m, 2H, AreH),8.08e8.11 (d, 1H, J 9 Hz, AreH), 8.92 (s, 1H, AreH), 10.37 (s, 1H,CHO). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With Co(NTf2)2; trimethylsilyl trifluoromethanesulfonate; (p-anisyl)triphos; hydrogen In n-heptane at 125℃; for 14h; Autoclave; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | With C33H28ClN3ORu In toluene for 8h; Reflux; | 2.4. General procedure for the catalytic transamidation of carboxamide with amines General procedure: Carboxamide (0.001 mol), amine (0.001 mol) and 0.3 mol% of the ruthenium complex were dissolved in toluene and the reaction mixture was refluxed for 8 h. The completion of the reaction was monitored by thin layer chromatography. The solvent was evaporated in a rotary evaporator and the resulting residue dried in vacuum. The crude product was purified by column chromatography using hexane and chloroform as eluent. |

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