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[ CAS No. 403-42-9 ]

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Chemical Structure| 403-42-9
Chemical Structure| 403-42-9
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CAS No. :403-42-9 MDL No. :MFCD00000354
Formula : C8H7FO Boiling Point : 196.7°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :138.14 g/mol Pubchem ID :9828
Synonyms :

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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:

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[ 403-42-9 ] Synthesis Path-Upstream   1~33

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  • [ 403-29-2 ]
YieldReaction ConditionsOperation in experiment
97% With Oxone; ammonium bromide In methanol for 1.3 h; Reflux General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
94.8% With bromine In cyclohexane at 0 - 40℃; for 0.5 h; 25 g of compound 1 (p-fluoroacetophenone) (0.18 mol) was dissolved in 50 mL of cyclohexane, and 2-3 drops of bromine were added dropwise, and the temperature was raised to 40 ° C.After the color of bromine was found to fade, the temperature was lowered to 0 ° C.29 g of liquid bromine (0.18 mol) was added dropwise, and the reaction was carried out for 0.5 hour.When GC was detected without Compound 1, it was washed successively with saturated aqueous sodium carbonate solution, 5percent by mass of sodium chloride solution and water.Dispensing, drying,The toluene was distilled off under reduced pressure to give 39 g of Compound 2,The purity was 95.0percent, and the yield was 94.8percent.
90% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrileReflux; Inert atmosphere; Schlenk technique General procedure: N-bromosuccinimide (0.37 mmol) was added to the stirredsolution of acetophenone (2) (0.37 mol, 1 equiv) in acetonitrile(40 mL). The resulting reaction mixture was stirredfor 10–15 min. After that p-TsOH (0.74 mmol, 2 equiv) wasadded to the reaction mixture and refluxed for 4–5 h andmonitored by TLC. After completion of reaction, reactioncontent was brought to room temperature and washed withsaturated solution of sodium bicarbonate and extracted withethyl acetate (3 × 20 mL), organic layer was dried oversodium sulphate and concentrated under reduced pressure.The obtained residues were purified by column chromatographyusing silica 100–200 mesh size by ethyl acetate:hexane (4:96) mixture and pure compound was identified as2-bromo-1-phenyl-ethanone 3a–g.
90.8% With bromine In acetonitrile 10 g (72.4 mmol) of p-fluoroacetophenone was dissolved in 100 mL of acetonitrile, and 11.57 g (72.4 mmol)Br2 in acetonitrile, stirred overnight (8-10h). After the reaction was complete, the solvent was removed by steam under reduced pressure, the ethyl acetate was re-dissolved, washed with brineWashed three times, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by steaming under reduced pressure. The solvent was filtered through 50 mL of cyclohexane and a few drops of ether to obtainTo 14.2 g of white crystals, yield: 90.8percent.
89.2% With bromine In acetonitrile at 20℃; 20 g (144.7 mmol) of p-fluoroacetophenone was dissolved in 200 mL of acetonitrile, and 23.12 g (144.7 mmol)Br2 in 50 mL of acetonitrile was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and concentrated with ethyl acetateWashed with brine three times, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting white oil was evaporated at low temperatureCuring, with 100mL n-hexane plus 1mL ethyl acetate beating, filter white solid 28g, the yield: 89.2percent,
87% at 70℃; for 3.5 h; Green chemistry The representative example of oxidative bromination is described as follows: A mixture of 1.2 g acetophenone 1a (10 mmol) and 0.121 g Cu(NO3)2•3H2O (0.5mmol) was stirred and an oxygen balloon (about 0.5–1 L) was attached to the reaction system. Then 8mol/L aqueous solution of hydrobromic acid (1.5mL, 12mmol) was added dropwise to the mixture. The reaction mixture was then stirred at 70°C and monitored by TLC or GC. After the completion of the reaction, the mixture was extracted with CH2Cl2. The organic extract was first washed with 5percent sodium sulfite, saturated sodium bicarbonate solution, and then water and finally dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/dichloromethane 3:1) to afford the product, α-bromoacetophenone (2a) in 1.81 g, yield: 91percent.
85% Microwave irradiation General procedure: Acetophenone (0.55 mmol) and 100 mL glacial acetic acid taken in beaker. Similarly, bromine (0.125 mmol) and 100 mL glacial acetic acid taken in another beaker and it added drop by drop in the solution of acetophenone and glacial acetic acid with occasionally shaking. Reaction mixture was transferred in an Erlenmeyer flask and irradiated under microwave irradiation for 15 min with a time interval of 35 s, after the completion of reaction indicated by TLC, poured in ice water, isolated the solid and recrystallized from ethanol (Scheme-I). Physico-chemical data of the synthesized compounds are given in Table-1.
85% With hydrogen bromide; potassium iodide; sodium nitrite In water at 0 - 20℃; for 10 h; General procedure: In a RBF cooled in ice bath at 0 C, HBr(12 mmol, in 2 ml of water) was taken. To this a solution of NaNO2(5 mmol, in 5ml of water) was added drop wise. The reaction was stirred for 15min maintaining the temperature at 0 °C and KI (5 mol percent) was added. After 10 min ketone(10 mmol) was added at once. After 15 min reaction temperature was brought to room temperature slowly. Reaction was monitored by TLC (ethyl acetate: pet ether, 1:9). After completion of reaction 50 ml of CHCl3 was added and organic layer separated. Aqueous layer was extracted with 25 ml of CHCl3 and combined organic layer was washed with 10percent NaHSO3 solution (2 x 20 ml) and 10percent NaHCO3 solution (2 x 20 ml).The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Pure product was obtained after column chromatography (silica gel, 60-120, eluentethyl acetate: pet ether).
79% With bromine In diethyl ether Preparation Example 1
Preparation of 2-Bromo-4'-Fluoro-acetophenone
In 25 ml of diethyl ether was dissolved 5.00 g (36.2 mmol) of p-fluoroacetophenone and while stirring the solution on an ice bath, 5.8 g (36.2 mmol) of bromine was dropped.
After dropping, the mixture was stirred for 5 minutes and then the solvent was distilled off under reduced pressure.
The residue thus obtained was purified by silica gel column chromatography (chloroform 100percent).
The results of NMR measurement revealed that it contained the target compound, and in addition, the raw materials and a dibromo form as a side product.
Yield after adjustment was 6.21 g and percent yield was 79.0percent.
1H-NMR (CDCl3, ppm) 4.42 (s, 2 H), 7.12~8.18 (m, 4 H)
73% With N-Bromosuccinimide In ethyl acetate at 40℃; 10 mmol 4-fluoroacetophenone is added to a 100 mL round bottom flaskAnd 11mmol of N-bromosuccinimide (NBS),Dissolve 35mL of ethyl acetate and add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction was warmed to 40°C and reacted. After TLC tracks the reaction,The reaction solution was filtered to remove Amberlyst 15 ion exchange resin, and the filtrate was spin-dried.Column chromatography (eluent: petroleum ether/ethyl acetate) gave green crystals in 73percent yield.
69% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 80℃; General procedure: A modified reaction route: NBS (1.2 equiv.) was added to a solution of appropriately substitutedacetophenones 9a–9l (1.0 equiv.) in CH3CN (15 mL) with p-TSA (0.2 equiv.). The solution washeated at 80 °C for 3-5 h until all the starting materials had been consumed (TLC monitored). Thereaction mass was poured in ice-cold water and extracted with DCM (3 × 20 mL). Anhydrous Na2SO4was added to the combined organic layer, filtered and the excess solvent was removed under reducedpressure. The resultant solid/ liquid obtained were washed with hexane to yield compounds 10a–10i.4,5 2-Bromo-1-(4-fluorophenyl)ethan-1-one (10a): Light brown solid, yield 69percent. M. p. 47-49 (°C).
44.56% at 15 - 50℃; for 12.3333 h; 1-(4-Fluorophenyl)ethanone (9.00 g, 65.15 mmol, 1.00 eq) was dissolved in acetic acid (100.00 mL), liquid bromine (10.41 g, 65.15 mmol, 1.00 eq) was added at 15 °C and the mixture was stirred for 20 minutes.
The resulting mixture was then stirred at 50 °C for 12 hours, concentrated under reduced pressure, and the pH of the mixture was adjusted to 9 with a sodium carbonate solution.
The mixture was extracted with ethyl acetate (200 mL * 2).
The combined organic layers were concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 to 200 mesh silica gel, petroleum ether / ethyl acetate = 1/0) to deliver 2-bromo-1-(4-fluorophenyl)ethanone (6.30 g, 29.03 mmol, 44.56percent yield) as a white solid. LCMS (ESI) m / z: 218.8 (M + 1).
14 g With bromine In methanol at 0 - 20℃; for 2.5 h; Step 1 : Synthesis of 2-bromo-l -(4-fluorophenyl) ethan-l-one: [0234] To the stirred solution of 4-Fluoroacetophenone (10 g, 71.9 mmol) in 200 mL of MeOH at 0°C was added Bromine (3.7 mL, 23.1 mmol) (dropwise addition) and stirred for about 30 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered and washed with n-hexane then dried and proceeded for next step (wt: 14.0 g).

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  • 4
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  • [ 350-40-3 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere
Stage #2: at 20℃; for 16.5 h; Inert atmosphere
General procedure: t-BuOK (2.47 g, 22.00 mmol) was added in four portions to a solution of methyltriphenylphosphonium bromide (7.12 g, 20.00 mmol) in dry THF (70 mL) at 0 oC. The mixture was stirred at 0 oC for 2 h and then acetophenone derivatives (20 mmol) in dry THF (20 mL) was added dropwise in 30 minutes. After stirred at room temperature for another 16 h, the mixture was quenched with saturated NH4Cl (50 mL). The solution was extracted three times with petroleum ether (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography with petroleum ether (Pet) as eluent to afford the corresponding α-Methylstryrene derivatives.
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YieldReaction ConditionsOperation in experiment
100%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1 h;
Stage #2: at 0 - 20℃; for 2 h;
Potassium tert-butoxide (52.9 g, 0.47 mol) was added to the suspension of methyl triphenylphosphonium iodide (190 g, 0.47 mol) in THF (400 ml) at ice-cooled condition.
After 1 h stirring at ice-cooled condition, a solution of 4-Fluoro acetophenone (30 g, 0.199 mol) in THF (100 ml) was added dropwise.
Then the reaction mixture was stirred at room temperature for 2 h and quenched with sat. ammonium chloride solution.
THF was removed under reduced pressure and the reaction mixture was extracted with petether, washed with water, brine and dried over anh. sodium sulphate nitrated.
The sub-title compound (30 g, 100percent) was obtained as pale yellow liquid by concentration of petroleum ether layer
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  • [ 400-93-1 ]
YieldReaction ConditionsOperation in experiment
55% at -15℃; for 1.33333 h; To a stirred solution of 1 -(4-fluorophenyl)ethanone (1.10 g, 7.97 mmol) in cone.H2S04 (5 mL) was added a mixture of cone. H2S04 (2 mL) and cone. HNO3 (1.50 mL)dropwise at -15°C. The reaction mixture was stirred at -15°C for 80 minutes, then poured into ice-cold H20 (120 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with H20 (100 mL) and brine (100 mL), then separated, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by columnchromatography (silica, 100-200 mesh, 40percent EtOAc in hexanes) to afford the title compound (0.80 g, 55percent) as an off-white solid. oH (400 MHz, CDC13) 2.64 (s, 3H), 7.39 (t,J9.30 Hz, 1H), 8.20-8.26 (m, 1H), 8.57-8.66 (m, 1H).
44% at -10 - 0℃; for 8 h; Example 4; Synthesis of 4-bromo-7-fluoro-6-methoxycinnoline; [00200] Step 1. l-(4-Fluoro-3-nitrophenyl)ethanone: Into a 500 mL 3-necked round bottom flask containing cone, sulfuric acid (166 mL) was added 1 -(4-fluorophenyl)ethanone (74.6 g, 540.58 mmol) dropwise over a time period of 30 min with stirring, while maintaining the temperature between -10 and 0 0C. This was followed by the dropwise addition of a solution of nitric acid (65 percent) (43 g, 648.41 mmol) in H2SO4 (98percent) (60 mL) over a time period of 30 min, while maintaining the temperature from -10 to 0 0C. The resulting solution was stirred for 7 hr at -10 to 0 0C and the reaction progress was monitored by TLC (EtOAc/PE (1:1, v/v)). Upon completion a mixture of ice and water was added to quench and the resulting solution was extracted with 3 x 100 mL of DCM. The organic layers were combined and washed with 3 x 200 mL OfNaHCO3, brine, H2O, dried (anhydrous Na2SO4), and concentrated. The material was purified by silica gel chromatography using a gradient <n="65"/>elution going from 100:1 (v/v) to 5:1 (v/v) EtOAc/PE to provide 43 g (44percent) of l-(4-fluoro-3- nitrophenyl)ethanone as a yellow solid.
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  • [ 105-58-8 ]
  • [ 1999-00-4 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydride In tetrahydrofuran; mineral oil at 60℃; for 1 h; Reflux (step 1)
To a suspension of diethyl carbonate (47.4 mL, 391 mmol) and sodium hydride (55 wtpercent paraffin oil, 23.7 g, 543 mmol) in THF was added 4'-fluoroacetophenone (26.4 mL, 271 mmol) at 60°C.
The reaction mixture was heated under reflux for 1 hr, cooled to room temperature, and poured into acetic acid (33.6 mL, 586 mmol) and ice water (1 L).
The reaction mixture was extracted with diethyl ether (2*500 mL), the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 3-(4-fluorophenyl)-3-oxopropanoate (45.7 g, 100percent, keto form:enol form=5:1) as a yellow oil.
1H-NMR(400MHz,CDCl3), keto form:δ1.26(3H, t, J=7.2Hz), 3.97(3H, s), 4.22(2H, q, J=7.2Hz), 7.13-7.19(2H, m), 7.96-8.01(2H, m) 1H-NMR(400MHz,CDCl3), enol form:δ1.34(0.6H, t, J=7.2Hz), 4.27(0.4H, q, J=7.2Hz), 5.61(0.2H, s), 7.08-7.12(0.4H, m), 7.76-7.80(0.4H, m), 12.62(0.2H, s)
95% With sodium hydride In tetrahydrofuran; mineral oil at 70℃; for 3 h; Diethyl carbonate (130 g, 1.1 mol)was dissolved in a suspension of NaH (60percent in oil, 50.2 g, 1.3 mol) in anhydroustetrahydrofuran (1.5 L), and then compound 2 (150 g, 1.09 mol) was addeddropwise at 70 oC. Theresulting mixture was stirred at 70 oC for 3 hours. After the reaction mixture was cooled to roomtemperature and pouredinto HCl (1 N). The mixture wasextracted with EtOAc, the organic phase was dried with anhydrous NaSO4and concentrated. The residue waspurified by column chromatography (eluted with PE / EtOAc = 50 / 1) to givepure compound 3 (217 g, yield: 95percent).1H-NMR (CDCl3, 400 MHz) d 7.92~7.97 (m, 2H), 7.07~7.13 (m,2H), 4.14~4.20 (m, 2H), 3.93 (s, 2H), 1.22 (t, J = 7.2 Hz, 3H).
95% With sodium hydride In tetrahydrofuran; mineral oil at 70℃; for 3 h; Step 1-Synthesis of ethyl 3-(4-fluorophenyl)-3-oxopropanoate
Diethyl carbonate (130 g, 1.1 mol) was dissolved in a suspension of NaH (60percent in oil, 50.2 g, 1.3 mol) in anhydrous tetrahydrofuran (1.5 L), and then 1-(4-fluorophenyl)ethanone (150 g, 1.09 mol) was added dropwise at 70° C.
The resulting mixture was stirred at 70° C. for 3 hours.
After the reaction mixture was cooled to room temperature and poured into HCl (1 N).
The mixture was extracted with EtOAc, the organic phase was dried with anhydrous NaSO4 and concentrated in vacuo.
The resulting residue was purified using column chromatography (eluted with petroleum ether/EtOAc=50/1) to provide ethyl 3-(4-fluorophenyl)-3-oxopropanoate (217 g, yield: 95percent).
1H-NMR (CDCl3, 400 MHz) δ 7.92˜7.97 (m, 2H), 7.07˜7.13 (m, 2H), 4.14˜4.20 (m, 2H), 3.93 (s, 2H), 1.22 (d, J=7.2 Hz, 3H). MS (M+H)+: 211.
89%
Stage #1: With sodium hydride In ethanol at 0 - 20℃; for 2 h;
Stage #2: With hydrogenchloride In ethanol; water
To a solution of 4'-fluoroacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in diethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60percent in oil, 0.63 mol) by small portions. Because heat is gradually generated, the mixture was ice-cooled and stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to quench the reaction. Water (300 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-(4-fluorophenyl)-3-oxopropionate (71.2 g, 89percent). IR ν maxKBrcm-1: 1744, 1696, 1431, 1325, 1202, 1132, 1069, 1017, 853.1H-NMR (CDCl3)δ: 1.28 (3H .x. 0.62, t, J = 7.8 Hz), 1.37 (3H .x. 0.38, t, J = 7.8 Hz), 4.04 (2H .x. 0.62, s), 4.25 (2H .x. 0.62, q, J = 7.8 Hz) , 4.31 (2H .x. 0.38, q, J ! = 7.8 Hz) , 5.75 (1H .x. 0.38, s), 7.28 (1H .x. 0.62, s), 7.70 (2H .x. 0.38, d, J = 8.0 Hz), 7.78 (2H .x. 0.62, d, J-=-8.0 Hz), 7.90 (2H .x. 0.38, d, J = 8.0 Hz), 8.08 (2H .x. 0.62, d, J = 8.0 Hz).
83% With sodium hydride In ethanol; mineral oil at 0 - 20℃; for 3.5 h; Production of intermediates of the formula [XIV] by route (V7):Ethyl 3-(4-fluorophenyl)-3-oxopropanoate [XIV-1]To a mixture of 4-fluoroacetophenone (20.0 g, 0.145 mol), ethanol (lmL) and diethylcarbonate (100 mL) is added sodium hydride (60percent, 12.0 g, 0.29 mol) at 0 °C portionwise over a period of 30 min. Afterwards the reaction mixture is allowed to warm to room temperature and stirred for 3h. Thereafter, the reaction is quenched with aqueous 10percent HC1 and extracted with ethyl acetate (2 x lOOmL). The ethyl acetate layer is dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel (230-400 mesh) in ethyl acetate and hexane (1 :99 to 5:95) as eluent and 25g (83percent>) of ethyl 3-(4-fluorophenyl)-3-oxopropanoate are obtained as light yellow liquid.'H-NMR (300MHZ, CDCI3): δ = 7.96-8.01 (m, 1H), 7.10-7.19 (m, 2H), 5.30 (s, 1H), 4.23 (q, 2H), 1.26 (t, 3H) ppmMS (ESI): 209.1 ([M-H]+)
79%
Stage #1: With potassium <i>tert</i>-butylate In toluene at 78℃; Inert atmosphere
Stage #2: at 78℃; Inert atmosphere
Stage #3: With hydrogenchloride In water; toluene at 78℃; Inert atmosphere
Diethyl carbonate (801 mL, 6.79 mole) was added dropwise over a 30 minute period to a stirring slurry of potassium i-butoxide (609.2 g, 5.43 mole) in toluene (9.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 78 °C and 4-fluoroacetophenone (250 g, 1.81 mole) in toluene (250 mL) was added over a one hour time period. Heating of the reaction mixture was continued overnight. Then the reaction mixture was quenched with 1.5 N HCl(aq) and extracted with ethyl acetate (3>< 1 L). The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo leaving a brown liquid. The liquid was distilled to give the title compound as a colorless liquid (250 g, 79percent). MS m/z 209 (M-H)\\
77% With sodium hydride In toluene; mineral oil General procedure: The substrate b-ketoesters 10 a–n were either purchased or synthesized following published procedures. Some benzoylacetates were commercially available. Ethyl 3-oxo-3-phenyl propanoate (10a) was purchased. The reaction of benzoylacetates 10 b–n was prepared as described in previous reports. 25–27 A solution of a substituted acetophenone 8 a–n (0.05 mol) dissolved in toluene (50 mL) was added dropwise to a solution containing diethyl carbonate (9) (0.10 mol) and sodium hydride (0.15 mol 60percent dispersion in mineral oil). The mixture was stirred at room temperature, and then refluxed for 30 min. The mixture was poured into ice water,acidified with glacial acetic acid, and extracted with EtOAc (3x100 mL). The EtOAc extract was then dried over anhydrous MgSO4. After removal of the solvent in vacuo, the crude products were purified by silica gel column chromatography eluting with dichloromethane to afford benzoylacetates 10 b–n. All synthetic compounds were in agreement with 1H NMR, 13C NMR, IR and mass spectroscopic data.
55%
Stage #1: With potassium <i>tert</i>-butylate In toluene at 80℃; for 1 h;
Stage #2: at 20 - 70℃; for 18 h;
To a stirred solution of potassium-i-butoxide (323 g, 2.89 mol) in toluene (1 L) was added diethyl carbonate (533 g, 4.51 mol) at RT, and the mixture was heated to 80 °C for 1 hr. l-(4-Fluorophenyl)- ethanone (250 g, 1.80 mol) in toluene (2 L) was added to the reaction mixture slowly and stirred at 70 °C for 2 hr, then cooled to RT and stirring was continued for 16 hr. The reaction mixture was quenched with dilute HC1, then diluted with water and extracted with ethyl acetate (EtOAc; 3 X 800 mL). The combined organic layer was washed with brine, dried over Na2S04, and concentrated. The crude compound was purified by fractional distillation to give 1-2 (210 g, 55percent yield, 1 mol) as pale yellow liquid. MS = 211.2 [M+l]+.
30 g at 0 - 60℃; for 1.5 h; Inert atmosphere To a stirred solution of 4-fluoroacetophenone (20 g, 144 mmol) and diethyl carbonate (85 ml, 720 mmol), sodium hydride (6.9 g, 144 mmol) was added portion wise at temperature (0° C.-5° C.) under nitrogen atmosphere in 1 hour. The reaction mixture was heated to 60° C. and stirred for 30 minutes. The reaction mixture was cooled to 0° C. and was poured into ice cold water (150 ml) and extracted with dichloromethane (2*100 ml). The combined organic layer was dried over sodium sulphate, concentrated under vacuo to give 30 g of the titled product as brown viscous oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.18 (3H, t), 4.10-4.14 (2H, q), 4.20 (2H, s), 7.61-7.64 (2H, d), 7.94-7.97 (2H, d). m/z=211 (M+H)+

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  • 12
  • [ 60-29-7 ]
  • [ 403-42-9 ]
  • [ 1999-00-4 ]
YieldReaction ConditionsOperation in experiment
78% With potassium hydrogensulfate In ethanol; water; Diethyl carbonate A.
3-(4'-Fluorophenyl)-3-oxopropanoic acid, ethyl ester
To a suspension of sodium hydride (29.5 g of 60percent oil dispersion, washed free of oil with hexane) in diethyl carbonate (88 mL, 0.726 mol) at room temperature under argon was added dropwise over 30 minutes p-fluoroacetophenone (50.0 g, 0.362 mol).
Ethanol (0.1 mL) was added during the addition to initiate the reaction.
After 2/3 of the ketone had been added, white solid had separated and Et2 O (600 mL) was added to facilitate stirring.
When the addition was complete the mixture was refluxed for 3 hours.
The mixture was then placed in an ice bath, and the reaction was quenched by the dropwise addition of water (100 mL) and 5percent KHSO4 solution (100 mL).
The mixture was acidified with 10percent H2 SO4, the organic phase separated and washed with saturated NaHCO3 and saturated NaCl solutions, dried (MgSO4) and evaporated.
The residue was distilled in vacuo to give title compound (59.66 g, 78percent) as a colorless liquid, bp 115°-118° C. (1 mmHg).
TLC (CH2 Cl2 -hexane; 4:1) Rf =0.30.
Reference: [1] Patent: US5025000, 1991, A,
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Reference: [1] Patent: US5091378, 1992, A,
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Reference: [1] Patent: US5169857, 1992, A,
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Reference: [1] Patent: US4906624, 1990, A,
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Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 17, p. 3003 - 3007
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Reference: [1] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 4, p. 304 - 309
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  • 18
  • [ 403-42-9 ]
  • [ 95-92-1 ]
  • [ 31686-94-9 ]
YieldReaction ConditionsOperation in experiment
96% at 10℃; Synthesis of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate:In a 2L round bottom flask equipped with a reflux condenser and a CaCl2 drying tube metallic sodium (49.9 g, 2.17 mol, 3.0 equiv.) was dissolved in ethanol (1.0 L) carefully. The resulting sodium ethylate solution was cooled to about 10 °C then the mixture of l -(4-fluorophenyl)ethan-l-one (100.0 g, 0.72 mol) and diethyl oxalate (2) (295 mL, 2.17 mol, 3.0 equiv.) was poured slowly into it. The reaction mixture was stirred for about 15 minutes, and then was allowed to stand in a refrigerator overnight. The reaction mixture was poured into a mixture of cone. HC1 solution (300 mL) and ice (c.a. 1 kg). The resulting precipitate was filtered off and washed with plenty of water, finally dried in a vacuum desiccator over P2O5/KOH. Yield: 165.5 g (3) (96percent) as a light yellow .powder.
81% With sodium ethanolate In ethanol at 0 - 20℃; for 5 h; sodium ethoxide (20 mL, 2.00 eq.) was added to a solution of 1-(4-fluorophenyl)ethan-1-one (5 g, 36.20 mmol, 1.00 eq.) and diethyl oxalate (5.29 g, 36.20 mmol, 1.00 eq.) in ethanol (50 mL) at 0°C. The resulting solution was stirred for 5 hours at room temperature, diluted with 500 mL of water and thesolids were collected by filtration. This resulted in 7 g (8 1percent) of ethyl 4-(4-fluorophenyl)-2,4- dioxobutanoate as a yellow solid.
81% With sodium ethanolate In ethanol at 0 - 20℃; for 5 h; sodium ethoxide (20 mL, 2.00 eq.) was added to a solution of l-(4-fluorophenyl)ethan-l-one (5 g, 36.20 mmol, 1.00 eq.) and diethyl oxalate (5.29 g, 36.20 mmol, 1.00 eq.) in ethanol (50 mL) at 0°C. The resulting solution was stirred for 5 hours at room temperature, diluted with 500 mL of water and the solids were collected by filtration. This resulted in 7 g (81percent) of ethyl 4-(4-fluorophenyl)-2,4- dioxobutanoate as a yellow solid.
70%
Stage #1: With sodium ethanolate In ethanol at 0 - 20℃; for 0.166667 h; Inert atmosphere
Stage #2: at 20℃; for 12 h; Inert atmosphere
To a solution of sodium ethoxide (351 mL, 21percent in ethanol, 1629 mmol) was added 1-(4-fluorophenyl) ethanone (150 g, 1086 mmol) in ethanol (100 mL) at 0° C. under a nitrogen atmosphere and the resulting reaction mixture was stirred at RT for 10 min Diethyl oxalate (156 mL, 1140 mmol) in ethanol (100 mL) was added and reaction was allowed to stir at RT for 12 h.
Reaction mixture was cooled to 0° C. and acidified with 1.5 N HCl and the solid was filtered and the filtrate was diluted with water and extracted with DCM (3*750 mL).
The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 1A (180 g, 70percent) which was taken to next step without further purification. MS(ES): m/z=237 [M-H]+; 1H NMR (300 MHz, CDCl3) δ ppm 15.2 (bs, 1H), 8.00-8.09 (m, 2H), 7.15-7.25 (m, 2H), 7.05 (s, 1H), 4.42 (q, J=7.15 Hz, 2H), 1.43 (t, J=7.15 Hz, 3H).
70%
Stage #1: With sodium ethanolate In ethanol at 0 - 20℃; for 0.166667 h; Inert atmosphere
Stage #2: at 20℃; for 12 h;
To a solution of sodium ethoxide (351 mL, 21percent in ethanol, 1629 mmol) was added l-(4-fluorophenyl) ethanone (150 g, 1086 mmol) in ethanol (100 mL) at 0 °C under a nitrogen atmosphere and stirred at RT for 10 min. Diethyl oxalate (156 mL, 1140 mmol) in ethanol (100 mL) was added and reaction was allowed to stir at RT for 12 h. The reaction mixture was cooled to 0 °C and acidified with 1.5 N HCl and the solid was filtered and the filtrate was diluted with water and extracted with DCM (3 x 750 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to afford Intermediate 1A (180 g, 70percent), which was taken to next step without further purification. MS(ES): m/z = 237 [M-H]+; 1H NMR (300 MHz, CDC13) δ ppm 15.2 (bs, 1H), 8.00 - 8.09 (m, 2H), 7.15 - 7.25 (m, 2H), 7.05 (s, 1H), 4.42 (q, J = 7.15 Hz, 2H), 1.43 (t, J= 7.15 Hz, 3H)
54%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 0.75 h;
Stage #2: at -78 - 20℃; for 1.33333 h;
To a solution of diisopropyl amine (6.2mL, 44mmol) in THF (44mL) at 0°C was added n-BuLi (16.2mL, 40.5mmol). The cloudy yellow solution was stirred at 0°C for 30 min., then cooled to −78°C. 4’-fluoroacetophenone (3.2mL, 26 mmol) was added slowly along the sides of the flask and was stirred for 15 min. Diethyl oxalate (7.9mL, 58 mmol) was added and the reaction stirred at −78°C for 1 hour. The mixture was warmed to room temperature and stirred for 20 min and the reaction was quenched by the addition of 1M HCl. The organic solvent was removed by rotary evaporation. The aqueous phase was extracted with EtOAc (3× 75mL) and the combined organic layers were washed with 1M HCl (25mL), saturated aqueuos NaHCO3 (25mL), and brine (25mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography and recrystallized from EtOH to obtain 2b (3.38 g, 54percent yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ 15.83 – 15.03 (m, 1H), 8.42 – 8.09 (m, 2H), 7.50 (s, 1H), 7.42 (t, J= 8.5Hz, 2H), 4.64 (q, J= 7.1Hz, 2H), 1.65(t, J= 7.2Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 189.86, 169.33, 166.36 (d, J= 256.5Hz), 162.27, 131.50 (d, J= 2.5Hz), 130.72 (d,J= 9.5Hz) , 116.3 (d, J= 22.0Hz) , 97.96, 62.83, 14.25.

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  • 19
  • [ 403-42-9 ]
  • [ 176548-69-9 ]
  • [ 1007-15-4 ]
YieldReaction ConditionsOperation in experiment
28%
Stage #1: at 70 - 90℃; for 5.83333 h;
Stage #2: With water In tert-butylmethyl ether
EXAMPLE A5(3,5-dibromo-4-fluorophenyl)-ethanone and (3-bromo-4-fluorophenyl)-ethanone69 g (0.5 mol) of p-fluoroacetophenone were added dropwise to 200.0 g (1.5 mol) of finely powdered aluminium chloride with stirring, during which time the mixture heated up to 70° C. It was kept at 75-80° C. for another 20 minutes and then 184 g (1.15 mol) of bromine were added at this temperature within 2.5 hours. Finally, the resulting mixture was heated to 90° C. for another 3 hours. After being cooled and decolorised the mixture was divided between water and tert.butylmethyl ether. Working up the organic phase yielded 130 g of a brownish-black oil which was separated into 2 fractions on silica gel using toluene as eluant: a) 41.2 g (28percent of theoretical) of colourless crystals, m.p. 59-62° C. and Rf=0.53 (toluene), which were identified as 1-(3,5-dibromo-4-fluorophenyl)-1-ethanone by spectroscopy. IR (KBr):1685 (CO) cm-1 MS:M+ = 294/296/298 (Br2) b) 46.0 g (42percent of theoretical) of colourless crystals, m.p. 52-55° C. and Rf=0.41 (toluene), which were identified as 1-(3-bromo-4-fluorophenyl)-1-ethanone by spectroscopy. IR (KBr):1682 (CO) cm-1 MS:M+ = 216/218 (Br)
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  • [ 2105-96-6 ]
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  • 23
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[2] Chemical Communications, 2013, vol. 49, # 77, p. 8629 - 8631
  • 25
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Reference: [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 39, p. 8313 - 8325
  • 26
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Reference: [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 39, p. 8313 - 8325
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