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With aluminum (III) chloride; In dichloromethane; at 20℃; for 3h;
General procedure: To a solution of aluminum chloride (1.1 eq.) and the acid chloride (1.1 eq.) in CH2Cl2 90 mL was added anisole (1 eq.) in CH2Cl2 (10 mL). The resulting reaction mixture was stirred at rt for 3 h and then poured onto 1 N HCl 50 mL at 0 C. The quenched reaction mixture was extracted with EtOAc and washed with brine, dried over Na2SO4, and filtered. The solvent was concentrated under reduced pressure which was used for the next step without further purification. 4.1.1.1. (4-Fluorophenyl)(4-methoxyphenyl)methanone (6a).
With hydrogenchloride;aluminium trichloride; In dichloromethane; water; methoxybenzene;
Step 1 Anisole (27.5 grams), 4-fluorobenzoyl chloride (35 grams) and dichloromethane (250 mL) were combined in a reaction flask. Aluminum chloride (30.8 grams) was added to the reaction mixture slowly over 20 minutes. The reaction mixture was stirred at room temperature for two hours and then poured into a mixture of 70 mL concentrated HCl and 500 mL of water. The layers were separated and the aqueous layer was extracted with two portions of dichloromethane (300 mL each). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (400 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to yield 48.0 grams of 4-fluoro-4'-methoxybenzophenone as a white solid. This material was not purified further but was used directly in the next step.
Step 2 4-Fluoro-4'-methoxybenzophenone from Step 1 (126.7 grams) and acetylene saturated N,N-dimethylformamide (380 mL) were combined in a reaction flask. Sodium acetylide solution (9% by weight in toluene, 343 grams) was added to the reaction mixture dropwise over 45 minutes. The reaction mixture was stirred at room temperature for 1 hour and then poured into ice water (600 mL). The layers were separated and the aqueous layer was extracted with three portions of diethyl ether (200 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (200 mL), saturated aqueous sodium chloride (200 mL), and saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to an amber colored oil yielding 136.6 grams of 1-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol. This material was not purified further but was used directly in the next step.
1-(dimethoxy(4-methoxyphenyl)methyl)-4-fluorobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
trifluorormethanesulfonic acid; In acetonitrile; at 25℃; for 6h;
4-Fluoro-4'-methoxybenzophenone (2.3 g, 10 mmol), trimethyl orthofromate (10.6 g, 100 mmol), anhydrous methanol (3.2 g, 100 mmol) and triflic acid (0.17 mL, 2.0 mmol) were mixed in dry acetonitrile (16 mL). After being kept at 25 0C for 6 h, the reaction was quenched with ethyldiisopropylamine (1.7 mL) and concentrated. The residue was taken up in 2 : 8 ethyl acetate and filtered through a short path of silica gel to give the title compound.
Sodium hydride (0.088 g, 2.200 mmol) is washed three times with hexanes and dried under vacuum. It is then suspended in THF (15 mL) and cooled to 0 C. in an ice bath. (2-Cyano-ethyl)-phosphonic acid diethyl ester (0.389 g, 2.200 mmol) in 10 mL THF, is added dropwise, to the reaction over 5 min. The reaction is warmed to room temperature and stirred for 20 minutes and cooled again in an ice bath to 0 C. (4-Fluoro-phenyl)-(4-methoxy-phenyl)-methanone (0.5 g, 2.172 mmol) is added (in 10 mL of THF) dropwise to the reaction mixture over the course of 10 minutes and the reaction is stirred, at room temperature, for 3 days. It is then cooled to 0 C. and quenched by the dropwise addition of water. The reaction mixture is neutralized by the addition of saturated NH4Cl and extracted twice with 50% ether in petroleum ether. The organic layers are dried over magnesium sulfate, filtered, evaporated in vacuo and purified (flash chromatography, MeOH in dichloromethane) to give the desired product (0.175 g, 31.8%).
General procedure: n-Butyllithium (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise to a solution of 1-bromo-4-methylbenzene (342 mg 2.0 mmol) in THF (3 mL) at -78 C for 30 min. Then, 4-fluorobenzaldehyde (261 mg, 2.1 mmol) was added to the mixture at -78 C and the obtained mixture was stirred at room temperature for 1 h. Then, after removal of the solvent, I2 (812 mg,3.2 mmol), K2CO3 (829 mg, 6.0 mmol), and t-BuOH (3 mL) were added and the obtained mixture was stirred for 3 h at refluxing conditions. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide 4-fluoro-4'-methylbenzophenone in 98% yield with high purity. If necessary, the product was purified by a short flash columnchromatography (silica gel; hexane/CHCl3=1:3) to give pure 4-fluoro-4'-methylbenzophenone as a colorless solid.
With palladium diacetate; sodium carbonate; In water; at 100℃; under 760.051 Torr; for 6h;Sealed tube; Autoclave; Green chemistry;
General procedure: A 75 mL autoclave equipped with a Teflon liner and a magnetic stirrer bar was charged with Pd(OAc)2 (4.48 mg, 2.0 × 10-2 mmol), L (46.7 mg, 4.0 × 10-2 mmol) and H2O (6 mL) and the mixture was stirred at room temperatures for 0.5 h under N2. Then iodobenzene (113 muL, 1 mmol), phenylboronic acid (134 mg, 1.1 mmol), Na2CO3(106 mg, 1 mmol), and n-decane (0.1 mL, GC internal standard) were added. Once sealed, the autoclave was purged three times with CO, and pressurized to 1 atm of CO. The reaction mixture was stirred at 100 C for 2 h. After reaction, the mixture was extracted with diethyl ether (3 × 5 mL). The combined organic layer was concentrated in vacuo and the product was purified by column chromatography. In the recycling experiment, the aqueous phase containing the catalyst was subjected to a second run by charging it with the same substrates as mentioned above, and the reaction performed under the same conditions.
81%
With potassium phosphate; nickel dichloride; Trimethylacetic acid; at 80℃; under 760.051 Torr; for 3h;Green chemistry;
General procedure: Into a 25 ml reaction flask was successively added nickel chloride (0.01 mmol), R2 substituted aryl iodide (table 2) (0.5 mmol), R3 substituted arylboronic acid (0.75 mmol), potassium phosphate (1.0 mmol), pivalic acid (0.25 mmol) and polyethylene glycol 400 (2.0 g), and introduce one atmospheric pressure carbon monoxide. The reaction mixture at 80 C react until starting material reaction complete and cool to room temperature, pressure reducing evaporate the solvent column chromatography separation to obtain the product. The experimental results are set out in table 2.
With titanium tetrachloride; magnesium; In 1,2-dimethoxyethane; dichloromethane; at 0℃;
General procedure: The synthesis of skeleton 3 is similar to Yan?sprotocol (Bhorge, Y. R.; Chang, S.-H.; Chang, C.-T.; Yan, T.-H. Tetrahedron 2012, 68, 4846). Mg (243mg, 1.0 mmol) was added to a solution of skeleton 1 (1.0 mmol), CHBr3 (0.3 mL), TiCl4 (1.0 mmol, 1 mL,1.0 M in CH2Cl2) in the co-solvent of DME (1.5 mL) and CH2Cl2 (1 mL) at 0 oC. The reaction mixturewas stirred at 0 oC for 5-8 h. The reaction mixture was allowed to cool to room temperature. The reactionmixture was cooled to rt. Saturated NaHCO3 (aq) (2 mL) was added to the reaction mixture and the solventwas concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2(3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated toafford crude product. Purification on silica gel (hexanes/EtOAc = 100/1~10/1) afforded skeleton 3.
With tert.-butylnitrite; oxygen; acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 1,1,2,2-tetrachloroethane; at 130℃; for 12h;Autoclave;
General procedure: A Teflon-lines 316 L stainless steel autoclave (300 mL) equipped with magnetic stirring bar was charged with substituted diarylmethanes 1 (2 mmol), 136.2 mg DDQ (0.6 mmol, 30 mol %), 41.2 mg TBN (0.4 mmol, 20 mol %), 480 mg acetic acid (8 mmol) and 20 mL TeCA. The autoclave was closed and charged with oxygen to 0.3 MPa. Then the autoclave was placed in an oil bath, which was preheated to 130 C. The mixture was then stirred for a certain time until the reaction was completed. The autoclave was taken out from the oil bath, cooled to room temperature and carefully depressurized. The mixture was concentrated under reduced pressure and purified by column chromatography to give the desired diarylketones.
With hydrogenchloride; hydrazine hydrate; In ethanol; water; for 12h;Reflux;
General procedure: Hydrazine monohydrate (85% purity, 18.2mL, 30mmol) was added to a solution of diarylmethanone (20mmol) in ethanol (20mL). Then, aqueous HCl (36.0-38.0%, 0.5mL) was added and the mixture was heated to reflux for 12h. After cooling to room temperature, the diarylmethanone hydrazone was precipitated as white needle-shaped crystal. Filtration of the crude mixture gave pure diarylmethanone hydrazone (82-94% yield) as white solid.
General procedure: An oven-dried vial was charged with anisole 1a (0.75 mmol, 1.0 equiv), acetic anhydride 2a (1.5 mmol, 2.0 equiv) and TFA (0.8 mL). The reaction mixture was stirred at room temperature and monitored by TLC or GC-MS. The reaction typically took 1.5 h to complete. Upon completion, aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography to afford ketone product 3a. Alternatively, the product can also be obtained without workup: upon completion, the solvent was removed under reduced pressure and the residue was subjected to silica gel flash column chromatography.
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