Structure of 4-Methoxyacetophenone
CAS No.: 100-06-1
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Dehaloperoxidase Catalyzed Stereoselective Synthesis of Cyclopropanol Esters
Siriboe, Mary G ; Vargas, David A ; Fasan, Rudi ;
Abstract: Chiral cyclopropanols are highly desirable building blocks for medicinal chemistry, but the stereoselective synthesis of these molecules remains challenging. Here, a novel strategy is reported for the diastereo- and enantioselective synthesis of cyclopropanol derivatives via the biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl diazoacetate (EDA). A dehaloperoxidase enzyme from Amphitrite ornata was repurposed to catalyze this challenging cyclopropanation reaction, and its activity and stereoselectivity were optimized via protein engineering. Using this system, a broad range of electron-deficient vinyl esters were efficiently converted to the desired cyclopropanation products with up to 99.5:0.5 diastereomeric and enantiomeric ratios. In addition, the engineered dehaloperoxidase-based biocatalyst is able to catalyze a variety of other abiological carbene transfer reactions, including N−H/S−H carbene insertion with EDA as well as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality of this enzyme and defining it as a valuable new scaffold for the development of novel carbene transferases.
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CAS No. : | 100-06-1 |
Formula : | C9H10O2 |
M.W : | 150.17 |
SMILES Code : | CC(C1=CC=C(OC)C=C1)=O |
MDL No. : | MFCD00008745 |
InChI Key : | NTPLXRHDUXRPNE-UHFFFAOYSA-N |
Pubchem ID : | 7476 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P301+P312+P330 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.13 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.93 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.74 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.9 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.44 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.83 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.14 |
Solubility | 1.09 mg/ml ; 0.00726 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.91 |
Solubility | 1.85 mg/ml ; 0.0123 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.84 |
Solubility | 0.216 mg/ml ; 0.00144 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 |
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) |
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 |
-5.98 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 |
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) |
1.0 |
* 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 |
---|---|---|
60% | Synthesis of 1,3-diphenylpropenones (1) To a stirring solution of phenylethanone derivative (1 eq.) in dry ethanol (100 mL) KOH (1.5 eq.) was added. After the reflux of 30 min the mixture was coold to room temperature and the benzaldehyde derivative (1.2 eq.) was added dropwise. The <n="26"/>crystals that formed were filtered and recrystallized from EtOH to afford 1 ,3- diarylpropenones (1); a) 3-(2-Chlor-4-methoxyphenyl)-1-(4-methoxyphenyl)propenon1-(4-methoxyphenyl)ethanone (3.70 g, 24.64 mmol) was reacted with KOH (2.07 g, 36.96 mmol) and <strong>[54439-75-7]2-<strong>[54439-75-7]chloro-4-methoxybenzaldehyde</strong></strong> (4.62 g, 27.10 mmol) according to the general experimental procedure described above to afford 3-(2- Chlor-4-methoxyphenyl)-1-(4-methoxyphenyl)propenon.C17H15CIO3 (302.75) yellow solid, mp.: 118°CYield: 14.90 mmol (4.51 g), 60percent1H-NMR [(D6)DMSO]: delta = 8.18 (m, 3H, ArH), 7.99 (d, 1 H, J = 15.5, CH), 7.90 (d, 1 H, J = 15.5, CH), 7.17 (d, 1 H, J = 2.5, ArH), 7.10 (d, 2H, J = 8.8, ArH), 7.03 (dd, 1 H, J = 2.4, J =8.8, ArH), 3.90 (s, 3H, OCH3), 3.85 (s, 3H, OCH3)MS (El, 1000C): m/z (percent) = 302 [M]+' (5), 267 (100), 252 (4), 238 (3), 224 (4), 135 (20), 77(10)IR (KBr, cm"1): 3075 (w), 2972 (w), 2934 (w), 2840 (w), 1648 (m), 1604 (s), 1575 (m), 1494 (m), 1460 (w), 1438 (m), 1423 (m), 1401 (w), 1339 (w), 1288 (m), 1268 (s), 1234 (s),1205 (W), 1191 (m), 1109 (w), 1029 (m), 981 (m), 867 (m), 746 (m), 822 (m), 746 (w), 670(W), 636 (w), 614 (w) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In methanol; at 20℃; for 24h; | General procedure: (b) A mixture of 10 mmol of 3 and 10 mmol of substituted acetophenone (4a-h) in methanol (30 ml) was stirred at room temperature for 24 hours using 20% NaOH as a catalyst to make the solution alkaline. The reaction mixture was poured in ice cold water. The crude 3-(4-((4-fluorobenzyl)oxy)phenyl)-1-phenylprop-2-en-1-one (5a-h) was isolated and recrystallized from hot absolute ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; acetic acid; at 20℃; | General procedure: To a well-stirred solution of 5-nitro-2-(furyl/thienyl)methyldiacetate 1 (5 mmol) in 20 cm3 glacial acetic acid, substitutedacetophenone 2 (5 mmol) and 0.5 cm3 of conc. H2SO4 were added. The reaction mixture was stirred for 1 h andkept aside at room temperature. The propenone crystals 3formed were collected by filtration and washed with ethanol.The crude product 3 (5 mmol) was dissolved in 20 cm3glacial acetic acid by heating. 30% v/v bromine solution wasadded drop by drop until bromination was complete. Thereaction mixture was stirred for 2 h and kept aside overnight.The alpha,beta-dibromochalcones 6 formed were filtered, washedwith ethanol, and recrystallized from glacial acetic acid. Thedibromochalcone 4 (5 mmol) was taken in a round-bottomedflask and 25 cm3 of dry benzene was added. To this, triethylamine(6 mmol) was added and the flask was closedwith a lid. The mixture was stirred for 4 h and the separatedtriethylammonium hydrobromide filtered off. The filtratewas roto-evaporated and the solid separated was collectedby filtration and further purified by recrystallization fromethanol. The compounds were characterized by reference totheir melting point [34, 35] and the data are given in ESI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylamine; In methanol; at 20.0℃; | In these schemes, ketone (4.0 equiv.) and a catalytic amount of diethylamine (10 drops) are added to a solution of substituted isatin (1.0 equiv.) in methanol (5 mL). The mixture is stirred at room temperature until starting material (substituted isatin) disappears completely. The resulting solution is concentrated and applied to flash chromatography eluting with hexane / ethyl acetate to afford pure product in quantitative yield. Further purification is done by recrystallization with hexane / ethyl acetate. An example compound synthesized by the above scheme includes: 4,7-Dichloro-3- hydroxy-3-[2-(4-methoxyphenyl-2-oxoethyl)]-l,3-dihydroindol-2-one: white solid; mp 149- 151 °C; 1H NMR (DMSO, 400 MH 1 z) delta 10.93 (s, 1H), 7.86 (d, 2H, J = 9.2 Hz), 7.26 (d, 1H, J = 8.8 Hz), 6.98 (d, 2H, J= 8.8 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.39 (s, 1H), 4.31 (d, 1H, J= 18.0 Hz), 3.80 (s, 3H), 3.61 (d, 1H, J= 18.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; at 20℃; for 24h; | General procedure: The relevant N-methyl intermediate (3a-c, 2 mmol), acetophenonederivate (2 mmol) and potassium hydroxide (6 mmol) wasdissolved in ethanol (20 mL) and stirred for 24 h. Then the reactionmixture was filtered and washed with water and cold ethanol. Thecrude product was purified by recrystallization from ethanol anddichloromethane to give pure chalcone (4a-q) with yields of34.2-93.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium methylate; In methanol; at 0℃; | <strong>[4494-26-2]5-formyl-2'-deoxyuridine</strong> (0.256 g, 1 mmol) And p-methoxyacetophenone (0.150 g, 1 mmol) Followed by addition to methanol (5 mL) Then sodium methoxide (0.081 g, 1.5 mmol) was added, The reaction was stirred at 0 C, TLC is tracked to the end of the reaction. After removing the solvent under reduced pressure, The residue was isolated by column chromatography to give the yellow solid product e (0.314 g) Yield 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; at 20℃; for 24h; | General procedure: The relevant N-methyl intermediate (3a-c, 2 mmol), acetophenonederivate (2 mmol) and potassium hydroxide (6 mmol) wasdissolved in ethanol (20 mL) and stirred for 24 h. Then the reactionmixture was filtered and washed with water and cold ethanol. Thecrude product was purified by recrystallization from ethanol anddichloromethane to give pure chalcone (4a-q) with yields of34.2-93.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With iodine; In dimethyl sulfoxide; at 110℃; for 12h; | General procedure: DMSO (3 mL) was added to a mixture of acetophenone (1.0equiv.) and I2 (1.1 equiv.). The solutionwas stirred at 110 °C, then 2-aminobenzamide (1.0 equiv.) in 2mL DMSO was added dropwise tothe mixture during 1-2 h. After a complete disappearance of thestarting material, 50 mL water and 30 mL saturated brine wereadded to the mixture. The solution was extracted with CH2Cl2(50 mLx3). The organic layer was washed with 10percent Na2S2O3 solution, dried over anhydrous Na2SO4 and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether/EtOAc 5:1) to yield the desiredproducts 9a-9d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; at 20℃; for 24h; | 1.2 10: Add methoxyacetophenone (375.5 mg, 2.5 mmol), Compound 1 (500 mg, 2.46 mmol), ethanol (50 mL), KOH (20% in water, 15 mL) in a round bottom flask, and at room temperature After stirring for 24 hours, the reaction mixture was poured into a saturated aqueous solution of sodium chloride (10 mL), and then extracted with ethyl acetate (30mL). After that, it is dried by adding anhydrous sodium sulfate.filter. Steamed and purified through a column (silica gel, EA).Finally a red solid 10 is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; for 6h;Reflux; | General procedure: A mixture of Isatins (A) (1mmol) and Acetophenone (B) (1 mmol), was taken in a 10 mL round-bottom flask containing 5 mL Ethanol solvent and triethylamine base (0.4 mmol). The reaction mixture was heated to reflux for 6 h maintaining anhydrous condition. After complete conversion of the starting materials (monitored by TLC), ethanol was distilled out under reduced pressure and the crude product was purified by column chromatography using 100-200 mesh silica gel and petroleum ether-ethyl acetate mixture as the eluent to afford 3-hydroxy-3-(2-oxo- 2-phenylethyl)indolin-2-one (C) . Then the product C was acidified with AcOH and HCl mixture (4:1) and heated at 80 for 1 hour, after this the reaction was diluted with 50 ml cold water and extracted with EtOAc (3 × 10 mL). The organic layer was combined and washed with brine and dried over anhydrous Na2SO4. After this the crude product was purified by column chromatography using 100-200 mesh silica gel and petroleum ether-ethyl acetate mixture as the eluent to afford the desired product 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of 3,3-bis(methylsulfanyl)methylenemalononitrile 1 (1.70 g, 10 mmol) in 20 mL of DMSO, keton 2a - j (10 mmol) and powdered sodium hydroxide (0.8 20 mmol) were added, and the mixture was magnetically stirred for 4 - 5 h at room temperature. After addition of 300 mL of water to the mixture, the solution was stirred for 12 h at room temperature. The formed precipitate was collected by filtra- tion and washed several times with water. After drying under air, the formed product was recrystallized using methanol or ethanol to obtain the pure products. (2Z,4E)-2-cyano-3,5-bis(methylsulfanyl)-5-(4-methoxyphenyl)penta-2,4-dienoic acid amide (3a) This compound was recrystallized from methanol to give 0.98 g (3.1 mmol) of yellow needles in 31 % yield. Mp: 175 - 176 C. IR (KBr, cm-1): 3392 (NH), 3184 (NH), 2208 (CN), 1671 (CO), 1491, 1373. 1H NMR (CDCl3, 400 MHz): 2.38 (3H, s, SMe), 2.48 (3H, s, SMe), 3.73 (3H, s, OMe), 5.32 (1H, br, NH), 5.80 (1H, br, NH), 5.94 (1H, s, = CH), 6.84 (1H, d, J = 8.4 Hz, 3′-H), 7.00 (1H, ddd, J = 1.1, 7.5, 8.5 Hz, 5′-H), 7.32 (1H, ddd, J = 1.7, 7.5, 8.5 Hz, 4′-H), 7.54 (1H, dd, J = 1.7, 7.5 Hz, 6′-H). 13C NMR (CDCl3, 100 MHz): 16.1, 16.2, 54.8, 97.7, 110.7, 116.1, 118.1, 120.4, 120.7, 130.7, 131.5, 145.3, 155.7, 164.2, 175.1. MS m/z: 321 (M+ + 1). HRMS (FAB) calcd for C15H17N2O2S2, m/z 321.0731 (M +H+); found, m/z 321.0733. Anal. Calcd. for C15H16N2O2S2 = 320.43: C, 56.22; H, 5.03; N, 8.74. Found: C, 56.31; H, 5.04; N, 8.77. |
Tags: 100-06-1 synthesis path| 100-06-1 SDS| 100-06-1 COA| 100-06-1 purity| 100-06-1 application| 100-06-1 NMR| 100-06-1 COA| 100-06-1 structure
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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.
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