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CAS No. : | 611-99-4 | MDL No. : | MFCD00002358 |
Formula : | C13H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RXNYJUSEXLAVNQ-UHFFFAOYSA-N |
M.W : | 214.22 | Pubchem ID : | 69150 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 60.36 |
TPSA : | 57.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.68 cm/s |
Log Po/w (iLOGP) : | 1.44 |
Log Po/w (XLOGP3) : | 2.71 |
Log Po/w (WLOGP) : | 2.33 |
Log Po/w (MLOGP) : | 1.73 |
Log Po/w (SILICOS-IT) : | 2.41 |
Consensus Log Po/w : | 2.12 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.3 |
Solubility : | 0.108 mg/ml ; 0.000503 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.57 |
Solubility : | 0.0575 mg/ml ; 0.000268 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.72 |
Solubility : | 0.0408 mg/ml ; 0.000191 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
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: |
* 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 |
---|---|---|
91.1% | With ammonia In water | EXAMPLE 5 Preparation of 4-amino-5-chloro-1-phenylpyridazin-6-one (chloridazon) using 4,4'-dihydroxybenzophenone as catalyst In a 250 ml stirring autoclave, 100 parts of water, 70 parts (1.03 mol) of 25percent strength ammonia, 12 parts (0.05 mol) of 4,5-dichloro-1-phenylpyridazin-6-one (purity: 99.7percent) and 10.7 parts (0.05 mol) of 4,4'-dihydroxybenzophenone were stirred at 130° C. for 8 hours. The pressure rose steadily to about 4.5 bar. After stirring overnight, the autoclave was depressurized to atmospheric pressure, with the excess ammonia being stripped off. After cooling to room temperature, the precipitated solid was filtered off, washed with water and dried at 50° C. in a vacuum drying oven. This gave 10.2 parts of 4-amino-5-chloro-1-phenylpyridazin-6-one having a purity of 98.9percent; this corresponds to a yield of 91.1percent of theory. The pH of the filtrate was adjusted to 1.5 using 60percent strength sulfuric acid and the precipitated 4,4'-dihydroxybenzophenone was filtered off, washed with water and dried. This gave 10.9 parts of 4,4'-dihydroxybenzophenone having a purity of 98.3percent; this corresponds to 100percent of the amount of catalyst used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In acetone Reflux; | 2.1.i (i) Synthesis of 4,4-bis(4-butoxyphenyl)methanone After mixing bis(4-hydroxyphenyl)methanone (10g, 46.68mol, 1eq), 1-bromobutane (93.4ml, 0.5M), and K2CO3 (19.35g, 140.04mmol, 3eq), acetone (93.4ml) was added. After reacting at room temperature, it was refluxed. After confirming the completion of the yellow + white solution reaction, extraction was performed with 300 ml of water and diethyl ether (100 ml x 3). The organic layer was dried over MgSO4, washed with MC, washed with hexane, and filtered to obtain a product (white solid, 13.7 g, yield 90%). |
With potassium carbonate In N,N-dimethyl-formamide Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With hydroxylamine hydrochloride In ethanol at 20℃; Inert atmosphere; | Bis(4-hydroxyphenyl)methanone oxime (12a) To a solution of bis(4-hydroxy)benzophenone (100 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine HCl (69 mg, 0.99 mmol) at ambient temperature. The reaction mixture was stirred until complete consumption of the starting material on TLC and quenched with H2O. The resulting mixture was diluted with EtOAc, and the organic phase was washed with H2O and brine, dried over MgSO4 and concentrated in vacuo Purification of the residue via flash column chromatography on silica gel (EtOAc : Hexane = 1 : 5 to 1 : 3) afforded 90 mg (84 %) of 12a as colorless liquid: 1H-NMR (400 MHz, CDCl3) δ 7.30 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 3.49 (2H, s), 0.92 (1H, s); 13C-NMR (MeOD, 125 MHz) δ 158.4, 157.8, 157.3, 131.2, 131.2, 129.4, 129.4, 128.9, 124.7, 114.7, 114.7, 114.4, 114.4; LR-MS (FAB) m/z (M+H+) 230; HR-MS (FAB) calcd for (M+H+) 230.0817; found 230.0823. |
84% | With hydroxylamine hydrochloride In ethanol at 20℃; | 1 Hydroxylamine HCl (69 mg, 0.99 mmol) was added at room temperature to a solution of bis (4-hydroxy) benzophenone (100 mg, 0.46 mmol) in EtOH (2 mL). The reaction mixture was stirred on TLC until all the starting material was consumed and quenched with H2O. The resulting mixture was diluted with EtOA and the organic phase was washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc: hexane = 1: 5 to 1: 3) to give 90 mg (84%) of colorless liquid 12a |
With ethanol; hydroxylamine hydrochloride; barium carbonate |
With ethanol; hydroxylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 2-(diethylamino)ethanethiol hydrochloride; sodium t-butanolate In N,N-dimethyl-formamide for 2h; Heating; | |
89% | With potassium carbonate; 3-mercaptopropionic acid In ISOPROPYLAMIDE at 150℃; for 18h; | 5 Example 5: Preparation of 4,4'-dihydroxybenzophenone.A mixture of 4,4'-dimethoxybenzophenone (1.21 g, 5.0 mmol), potassium carbonate (8.3 g, 60 mmol), 3-mercaptopropionic acid (4.24 g, 40 mmol) and dimethylacetamide (50 mL) is stirred at 150 °C for 18 h and the solvent is removed under reduced pressure. Water is added (30 mL), followed by 37 % hydrochloric acid (8 mL) and the product is extracted with MTBE (3 * 25 mL) and ethyl acetate (2 * 25 mL). The organic phases are combined, dried with sodium sulfate and concentrated under reduced pressure. The crude is purified by chromatography (silica gel; hexane : ethyl acetate = 50 : 50), crystallized from water and dried under reduced pressure to yield 0.95 g (89 % yield) of 4,4'-dihydroxybenzophenone. 1H NMR (DMSO-d6): δ 6.87 (m, 4H), 7.60 (m, 4H), 10.29 (s, 2H). |
89% | Stage #1: bis(p-methoxyphenyl)methanone With potassium carbonate; 3-mercaptopropionic acid In ISOPROPYLAMIDE at 150℃; for 18h; Stage #2: With hydrogenchloride In water | 5 Example 5 Example 5 Preparation of 4,4'-dihydroxybenzophenone. A mixture of 4,4'-dimethoxybenzophenone (1.21 g, 5.0 mmol), potassium carbonate (8.3 g, 60 mmol), 3-mercaptopropionic acid (4.24 g, 40 mmol) and dimethylacetamide (50 mL) is stirred at 150 °C for 18 h and the solvent is removed under reduced pressure. Water is added (30 mL), followed by 37 % hydrochloric acid (8 mL) and the product is extracted with MTBE (3 * 25 mL) and ethyl acetate (2 * 25 mL). The organic phases are combined, dried with sodium sulfate and concentrated under reduced pressure. The crude is purified by chromatography (silica gel; hexane : ethyl acetate = 50 : 50), crystallized from water and dried under reduced pressure to yield 0.95 g (89 % yield) of 4,4'-dihydroxybenzophenone. 1H NMR (DMSO-d6): δ 6.87 (m, 4H), 7.60 (m, 4H), 10.29 (s, 2H). |
With aluminum tri-bromide; benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In methanol; chloroform for 48h; Heating; | |
96.9% | With sodium hydride In N,N-dimethyl-formamide at 100℃; for 1h; | Compounds of Formula IV Bis-(4-Benzyloxyphenyl)methanone (LWO02007A) To a solution of 4,4'-dihydroxybenzophenone (5.0 g, 23.34 mmol) in anhydrous DMF (150 mL) at 0° C. was added sodium hydride (60% in mineral oil, 2.1 g, 51.35 mmol), in two portions. After stirring for 20 min at which no more evolution of hydrogen was observed, benzyl bromide (8.96 g, 51.35 mmol) was added. The resulting yellow suspension was then stirred under an atmosphere of nitrogen at 100° C. for 1 h. Upon cooling to room temperature, water (500 mL) was added to the suspension and the precipitate that formed was filtered and washed exhaustively with water. After air-drying overnight at room temperature, the white solid (10.1 g) that collected was recrystallized from hot toluene to give LWO02007A as white flaky plate crystals (8.92 g, 22.61 mmol, 96.9%); m.p. 188-190° C. |
With ethanol; sodium ethanolate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2% | With triethylamine In tetrahydrofuran at 0℃; for 3h; | 2 Synthesis of 4,4'-dibenzoyl ester benzophenone (BzO-G1) (1) 4,4'-Dihydroxybenzophenone (4.00 g, 18.7 mmol) and triethylamine (4.16 g, 41.1 mmol) were placed in a round bottom flask and dissolved in THF (200 ml).The reaction mixture was cooled in an ice bath and stirred.Benzoyl chloride (5.51 g, 39.2 mmol) was added in small portions and the reaction mixture was stirred for 3 hours.The mixture was evaporated and recrystallized from THF / MeOH to isolate 4,4'-dibenzoyloxybenzophenone (Rf = 0.50 in a solution of chloroform: ethyl acetate: hexane = 4: 1: 4). Yield: 93.2% (white powder, 7.36 g, 17.42 mmol).The product was confirmed by MALDI-TOF-MASS and 1H NMR. |
90% | With triethylamine In tetrahydrofuran for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 4,4'-Dihydroxybenzophenone; epichlorohydrin With N-benzyl-N,N,N-triethylammonium chloride at 80℃; for 12h; Stage #2: With sodium hydroxide In water for 5h; | |
25% | Stage #1: 4,4'-Dihydroxybenzophenone With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: epichlorohydrin In N,N-dimethyl-formamide at 20℃; for 44h; Inert atmosphere; Stage #3: With water In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 4 (JG-111). A round-bottomed flask was charged sequentially with NaH (205 mg, 5.13 mmol, 2.2 equiv), anhydrous dimethyl formamide (5 mL), and 4,4'- dihydroxybenzophenone (500 mg, 2.33 mmol, 1 equiv) at 0 °C, and the contents were stirred under an atmosphere of argon for 10 min. Racemic epichlorohydrin (890 μL, 9.57 mmol, 4 equiv) was added via syringe and the mixture was allowed to react at room temperature for 44 h. Then, the solution was quenched with deionized water (~ 2 mL) and the mixture was extracted with ethyl acetate (3 x 4 mL). The organic layer was washed with deionized water (2 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: dichloromethane) to provide JG-111 (186 mg, 25%) as a white solid.*H NMR (400 MHz, DMSO- 6): δ 7.70 (d, J= 8.8, 4H), 7.10 (d, J= 8.4, 4H), 4.44(dd, J= 11.6, 2.4, 2H), 3.94 (dd, J= 1 1.2, 6.4, 2H), 3.36 (m, 2H), 2.86 (t, J- 4.8, 2H), 2.73 (m,2H).13C NMR (100 MHz, DMSO-rf6): δ 193.7, 162.1, 132.4, 130.9, 114.9, 69.9, 50.2,44.4.HRMS (ESI) (w/z): calc'd for C19H19O5 [M+H]+: 327.1232,found: 327.1234.TLC (5% methanol in dichloromethane), R/i 0.55 (UV,/?-anisaldehyde). |
With sodium hydroxide |
Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 4,4'-Dihydroxybenzophenone With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 16h; | General procedure for the synthesis of allenes General procedure: Bis(4-hydroxyphenyl)methanone (1.0 g, 1.0 equiv, 4.6 mmol) was added to an oven-dried 50 mL roundbottom flask equipped with a stir bar. Dry DMF (15 mL) was added and mixture was cooled to 0 C.Sodium hydride (4.48 g, 4.00 equiv, 18.7 mmol) was slowly added and the reaction was stirred at 0 C.After 30 min, methyl iodide (870 L, 3.0 equiv, 14 mmol) was added and the reaction was stirredovernight. After the reaction was complete, water (10 mL) was added and the reaction mixture wasextracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine and dried over sodiumsulfate. The solvent was removed in vacuo to give a yellow powder. The reaction was purified on silica(15% EtOAc in hexanes) to give the aryl ether as a white solid (937 mg, 3.87 mmol, 83%). |
With sodium hydroxide | ||
With potassium carbonate In acetonitrile |
Stage #1: 4,4'-Dihydroxybenzophenone With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 7h; | 3.a (a) Synthesis of SKW166-1 To a solution of a mixture of 1 (5.00 g, 23.34 mmol, 1.0 eq.) in DMF (100 mL) was added NaH (3.72 g, 93.00 mmol, 4.0 eq.) slowly at 0°C and stirred at 0°C for 30 minutes. Then Mel (10.00 g, 70.47 mmol, 3.0 eq.) was added to the mixture, and the reaction mixture was stirred at rt for 7 h. After completion, water was added to the mixture, and the resulting reaction mixture was extracted with EtOAc (3 X 200 mL). The organic layer was separated and washed with brine, dried (Na2S04), filtered, concentrated under reduced pressure to give the crude SKW166-1 as yellow solid (5.66 g, Yield 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With methanesulfonic acid In toluene at 120℃; for 12h; | 17 Preparation of 4,4-Dihydroxybenzophenone Methane sulfonic acid (MSA, 3.8 kg), 4-hydroxybenzoic acid (0.69 kg), Phenol (0.5 kg) and Toluene (1.0 kg) were charged into a 5 liter reaction flask. The mixture was stirred for 12hrs at 120°C. After completion of the reaction, the reaction mass was diluted with water and the product and unreacted 4-Hydroxy benzoic acid was extracted using Toluene. This was followed by crystallization of 0.52 kg of 4, 4’-Dihydroxybenzophenone from the Toluene (GC purity > 99%, yield of 98% w/w on Phenol). The aqueous layer was distilled to recover 3.66 kg of MSA (purity > 98%) which was reused in subsequent batches. |
With PPA | ||
With tin(IV) chloride |
With zinc(II) chloride; trichlorophosphate at 70℃; for 2.5h; | ||
Stage #1: phenol; 4-hydroxy-benzoic acid With zinc(II) chloride; trichlorophosphate at 70℃; for 2.5h; Stage #2: With water at 4℃; for 24h; Cooling with ice; | ||
With phosphoric acid; zinc(II) chloride; phosphorus trichloride | ||
With phosphoric acid; zinc(II) chloride; phosphorus trichloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate In acetone at 55℃; for 36h; | 3.1 (1) intermediate 4, 4' - diethoxy benzophenone. The bromo ethane (8.1g, 75mmol) and 4, 4' - dihydroxy benzophenone (5.4g, 25mmol) added in three-mouth flask, add 200 ml acetone, then adding potassium carbonate (10.4g, 75mmol), then heating to 55 °C to continue stirring 36h. To be reaction stops after cooling to room temperature, filter, collecting the filtrate, rotating to evaporate the solvent to get the crude product, to the volume ratio of 40:1 mixture of petroleum ether and ethyl acetate as eluant, SiO2As stationary phase, column chromatography purification to obtain 4, 4' - diethoxy benzophenone 5.5g, yield 81%. |
69% | With sodium In ethanol for 10h; Heating; | |
55% | With potassium carbonate In acetone for 15h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetone for 3h; Heating; | |
95% | With potassium carbonate In acetone for 24h; Heating; | |
83% | With potassium carbonate In acetone for 24h; Reflux; | Synthesis of bis(4-(prop-2-yn-1-yloxy))benzophenone (2) Potassium carbonate (3.87 g, 28.0 mmol) and propargylbromide (1.50 mL) were added to a stirred solution of4,4’-dihydroxybenzophenone (1.50 g, 7.00 mmol) inacetone (50 mL). The reaction mixture was refluxed for 24 h.The reaction was then quenched with ice-water/CH2Cl2. The phases were separated and the aqueous layer was extractedwith ethyl acetate (3 × 20 mL). The extracts were combinedand the resulting organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to provide crude compound 2. Afterpurification by silica gel flash column chromatography,eluted with ethyl acetate:dichoromethane:hexane 3:1:3 v/v,compound 2 was obtained as a yellow solid with83% yield (1.68 g, 5.79 mmol). The structure ofcompound 2 was supported by the following data. TLC:Rf = 0.60 (ethyl acetate:dichoromethane:hexane 3:1:3 v/v);mp 91.3-92.2 °C; IR (attenuated total reflection (ATR))νmax / cm-1 3219, 2971, 2112, 1578, 1558, 1503, 1267;1H NMR (300 MHz, CDCl3) δ 2.57 (s, 2H), 4.77 (s, 4H),7.05 (d, 4H, J 8.3 Hz), 7.80 (d, 4H, J 8.3 Hz); 13C NMR(75 MHz, CDCl3) δ 55.9, 76.1, 76.6, 114.4, 131.3, 132.2,160.7, 194.3; HRMS [M + H]+ calculated for C19H15O3:291.1016; found: 291.1016. |
83% | With potassium carbonate In acetone for 24h; Reflux; | Synthesis of bis(4-(prop-2-yn-1-yloxy))benzophenone (2a) In a previous study,32 we reported the production of 2a.Potassium carbonate (3.87 g, 28.0 mmol) and propargylbromide (1.50 mL) were added to a stirred solution of4,4’-dihydroxybenzophenone (1.50 g, 7.00 mmol) inacetone (50 mL). The reaction mixture was refluxed for24 h. The reaction was quenched with ice-water/CH2Cl2(dichloromethane (DCM)). The phases were separated,and the aqueous layer was extracted with ethyl acetate(3 × 20 mL). The extracts were combined, and the resultingorganic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressureto provide crude compound 2a. After purification by silicagel fash column chromatography, eluted with ethyl acetate-DCM-hexane 3:1:3 v/v, compound 2a was obtained as ayellow solid with 83% yield (1.68 g, 5.79 mmol). Thestructure of compound 2a is supported by the followingdata.TLC: Rf = 0.60 (ethyl acetate-DCM-hexane 3:1:3 v/v);mp 91.3-92.2 °C; IR (ATR) / cm-1 3219, 2971, 2112,1578, 1558, 1503, 1267; 1H NMR (300 MHz, CDCl3) d 2.57(s, 2H), 4.77 (s, 4H), 7.05 (d, 4H, J 8.3 Hz), 7.80 (d, 4H,J 8.3 Hz); 13C NMR (75 MHz, CDCl3) d 55.9, 76.1, 76.6,114.4, 131.3, 132.2, 160.7, 194.3; HRMS m/z, calculatedfor C19H15O3 [M + H]+: 291.1016, found: 291.1016. |
72% | Stage #1: 4,4'-Dihydroxybenzophenone With potassium carbonate In acetone for 0.5h; Reflux; Stage #2: propargyl bromide for 20h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydride In N,N-dimethyl-formamide; paraffin 1.) rt, 20 min; 50 deg C, 50 min; 2.) rt, overnight; | |
43% | With potassium carbonate In acetone Reflux; | |
21% | Stage #1: 4,4'-Dihydroxybenzophenone With anhydrous sodium carbonate In acetone at 20℃; for 0.333333h; Stage #2: iodomethane In acetone for 1h; | Synthesis of 4-hydroxy-4’-methoxybenzophenone 5 To a solution of 4,4’-dihydroxybenzophenone(9.3 mmol) in acetone (10 mL) (Synth, Diadema, SP,Brazil) was added Na2CO3 (9.3 mmol) (FMaia Indstria eComrcio Ltda, BH, Brazil) and the mixture was stirred atroom temperature for 20 min. After this time, iodomethane(Sigma-Aldrich, Saint Louis, MO, USA) was added(9.3mmol) and the completion of the reaction was notedafter 1 h by TLC. The acetone was evaporated, and theresulting product was partitioned into 10% NaOH (FMaiaIndstria e Comrcio Ltda, BH, Brazil) solution in water(m/v) and dichloromethane (Synth, Diadema, SP, Brazil).The basic layer was acidied to pH 1, extracted withdichloromethane and this new organic layer was washedwith water, dried over anhydrous Na2SO4 (FMaia Indstriae Comrcio Ltda, BH, Brazil), and concentrated underreduced pressure. The product of interest was isolated fromthe crude product by column chromatography (hexane/ethyl acetate; Synth, Diadema, SP, Brazil), with a yield of21%. Their spectra data were coherent with literature data.28 |
With sodium hydride 1.) DMF, 2.) DMF; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 4,4'-Dihydroxybenzophenone With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: pivaloyl chloride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; | |
47% | Stage #1: 4,4'-Dihydroxybenzophenone; pivaloyl chloride With triethylamine In tetrahydrofuran at 20℃; Stage #2: With lithium hydroxide monohydrate In tetrahydrofuran; methanol at 20℃; for 1h; | 4-(4-hydroxybenzoyl)phenyl pivalate 2 Bis(4-hydroxyphenyl)methanone 1 (100 g, 0.47 mol) was dissolved in 1 L of THF and cooled to 0°C. Triethylamine (188.7 g, 1.87 mol) was added followed by the dropwise addition of PivCl (141.7g, 1.17 mol). More THF (250 mL) was added and the mixture was stirred overnight. The mixture wasquenched with 500 mL of water and extracted with ethyl acetate (2x). The combined organic layerswere washed with 1N HCl (500 mL) and brine and dried over Na2SO4. Concentration afforded 194.3g of the crude bis protected benzophenone. The material was dissolved in 750 mL of THF and 50 mLof methanol. LiOH.H2O (21.4 g, 0.5 mol) was added and the mixture was stirred for 1 hour. MoreLiOH.H2O (5 g, 0.12 mol) was added and the mixture was stirred for an additional 30 min. Themixture was concentrated. At this point a second equal batch was run and combined with the firstone. The combined batches were coated on silica and purified by means of column chromatography(silica; CH2Cl2/EtOAc 20:1→ CH2Cl2/THF 20:1) affording 4-(4-hydroxybenzoyl)phenyl pivalate as awhite solid (140 g, 47%). 1H-NMR (300 MHz, CDCl3): δ 1.38 (s, 9H) 6.41 (br s, 1H), 6.90 (d, J = 9 Hz,2H), 7.18 (d, J = 8,7 Hz, 2H), 7.75 (d, J = 8,7 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H). |
46% | Stage #1: 4,4'-Dihydroxybenzophenone; pivaloyl chloride With triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: With lithium hydroxide monohydrate In tetrahydrofuran; methanol at 20℃; for 3h; | 1.1 [0564] Step 1: Synthesis of 4-(4-hydroxybenzoyl)phenyl pivalate [0565] To a solution of bis(4-hydroxyphenyl)methanone (200 g, 0.93 mol) in 2 L No.4 THF was added No.4 Et3N (378.2 g, 3.74 mol), and then PivCl (281.7 g, 2.33 mol) was added dropwise to the mixture at 0°C. The mixture was warmed to rt and stirred overnight. TLC showed the reaction was completed. The reaction mixture was quenched with No.4 water and extracted with EtOAC. The organic layer was washed with 1N HCl and brine, dried over Na2SO4, concentrated under reduced pressure to give crude product (350 g) as a white solid. To the solution of the crude product (350 g) in THF (2 L) was added No.5 MeOH (400 mL) and LiOH.H2O (40.3 g, 0.96 mol) and the mixture was stirred at rt for 1 h. Another LiOH.H2O (9.6 g, 0.23 mol) was added and the mixture was stirred at rt for another 2 h. TLC showed the reaction was completed. The reaction mixture was concentrated under reduce pressure and purified by silica gel chromatography using (DCM:EtOAc=30:1) to give No.5 4-(4-hydroxybenzoyl)phenyl pivalate 2 (130 g, 46%) as a white solid. |
42% | With sodium hydride In tetrahydrofuran for 2h; | |
12% | With potassium carbonate In tetrahydrofuran for 4h; Heating; | |
With pyridine at 50℃; for 2h; | ||
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; | ||
In tetrahydrofuran; methanol; water | 7.A 4-((1Z))-3-bicyclo[hept-2-yl-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylprop -1-enyl)phenol Step A: Under an atmosphere of nitrogen and at room temperature, di 4-hydroxyphenyl ketone (12.4g, 58 mmol) is added to dry THF. 1.2 equivalents of sodium hydride (2.70 g, 70 mmol) are added portionwise and allowed to stir for one hour. The solution is cooled to 0° C. and 1.1 equivalents of trimethyl acetyl chloride (7.8 mls, 64 mmol) is added slowly, stirred for 30 minutes at 0° C. followed by stirring at room temperature for 3 hours. Water is added to quench the reaction and the organics are extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After evaporation of solvent, the mixture of mono-acylated and di-acylated products are separated and purified on silica gel column with an eluent of 5% methanol/methylene chloride to give 4-[(4-hydroxyphenyl)carbonyl]phenyl 2,2-dimethylpropanoate as white powder. | |
Stage #1: 4,4'-Dihydroxybenzophenone; pivaloyl chloride With triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: With lithium hydroxide In tetrahydrofuran; methanol at 20℃; | S-11.1 Step 1: Preparation of 4-(4-hydroxybenzoyl)phenyl Part 1: To a solution of bis(4-hydroxyphenyl)methanone 1 (2 g, 9.34 mmol) in 100 mL of THF was added Et3N (3.8 g, 37.36 mmol). Then PivCl (2.82 g, 23.35 mmol) was added dropwise to the mixture at 0 °C. The mixture was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were washed with 1N HCl and brine, dried over Na2SO4, concentrated under reduced pressure to get a crude product.Part 2: To a solution of the crude product (3.5 g) in THF (45 mL) and MeOH (3 mL) was added LiOH (290 mg, 12.14 mmol), the mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; | |
91% | With triethylamine In tetrahydrofuran; dichloromethane at 20℃; | 4.1.6. Synthesis of [4-[4-(2,2-dimethylpropanoyloxy)benzoyl]phenyl] 2,2-dimethylpropanoate (12) To the solution of pivaloyl chloride (19.7 g, 186 mmol) in CH2Cl2 (140 mL) and THF (40 mL) was added 4,4-hydroxybenzophenone (10 g, 46.6 mmol). Triethylamine (26 mL, 186 mmol) was added slowly to the solution. The reaction mixture was turned to suspension. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water. The mixture was transferred to a separatory funnel and CH2Cl2 was added. The layer was separated. The organic layer was washed with water, aq. NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give white solid. This crude compound was crystallized from ethyl acetate to give white solid product (16 g, 91% yield). |
91% | With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 12h; | 1.1 Step 1:Preparation of [4-[4-(2,2-dimethylpropanoyloxy)benzoyl] phenyl]-2,2-dimethylpropanoate (A-1) After dissolving 4,4-hydroxybenzophenone (10 g, 46.6 mmol) in 140 mL of dichloromethane and 40 mL of tetrahydrofuran, pivaloyl chloride (19.7 g, 186 mmol) and triethylamine (26 mL, 186 mmol) was slowly added and reacted at room temperature for 12 hours. Saturated hydrogen carbonate and dichloromethane were further added to the reaction solution to extract an organic layer. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 16 g (91%) of the desired compound A-1. |
91% | With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 12h; | 1.1 Step 1: Preparation of 5 [4-[4-(2,2-dimethylpropanoyloxy)benzoyl]phenyl]2,2-dimethylpropanoate (A-1) 4,4-Hydroxybenzophenone (10 g, 46.6 mmol) was dissolved in 140 mL of 7 dichloromethane and 40 mL of 8 tetrahydrofuran, pivaloyl chloride (19.7 g, 186 mmol) and 9 triethylamine (26 mL, 186 mmol) were slowly added thereto, and then a reaction was carried out at room temperature for 12 hours. Saturated 10 sodium hydrogen carbonate and dichloromethane were further added to the reaction solution and an organic layer was extracted. The organic layer was dried with anhydrous Na2SO4 and filtered. The solvent was distilled under reduced pressure to obtain a residue, which was purified using column chromatography, thereby obtaining 16 g of the desired compound 5 A-1 (91%). |
88% | With pyridine at 20℃; | |
86% | With triethylamine In dichloromethane at 20℃; for 16h; | 3.1 To a stirred solution of bis(4-hydroxyphenyl)methanone (50 g, 234 mmol) in CH2CI2 (1500 mL) was added Et3N (97 mL, 700 mmol) under N2 at RT, To the above solution 2,2-dimethylpropanoyl chloride (86 mL, 700 mL) was added dropwise over a period of 1 h. The resultant mixture was allowed to stir at RT for 15h and then diluted with additional CH2CI2 (2000 ml_). The reaction mixture was washed with H2O (2 x 150 ml_), brine (1 x 150 ml_) dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude material, which was recrystallized from EtOAc/ n-hexanes to afford 77 g (86 %) of the title compound 10 as a white solid. 1H NMR (400 MHz, DMSO-ofe): δ 1.31 (s, 19H), 7.30 (d, J = 9 Hz, 4H), 7.8 (d, J= 9 Hz, 4H). LCMS (ESI): m/z 383 (M + H) + |
86% | With triethylamine In dichloromethane at 20℃; for 16h; | 1.1 Stepi: (Oxomethanediyl)dibenzer»e-4,1-diyl bis(2,2-dimethylpropanoate) (D To a stirred solution of bis(4-hydroxyphenyl)methanone (50 g, 234 mtnol) in CH2CI2 (1500 mL) was added Et3N (97 ml_, 700 mmol) under N2 at RT, To the above solution 2,2-dimethylpropanoyl chloride (86 mL, 700 mL) was added dropwise over a period of 1h. The resultant mixture was allowed to stir at RT for 15h and then diluted with additional CH2CI2 (2000 mL). The reaction mixture was washed with H2O (2 x 150 mL), brine (1 x 150 mL) dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude material, which was recrystallized from EtOAc/ n-hexanes to afford 77 g (86 %) of the title compound 1 as a white solid. 1H NMR (400 MHz, DMSO- d6): δ 1.31 (s, 19H), 7.30 (d, J= 9 Hz, 4H), 7.8 (d, J= 9 Hz, 4H). LCMS (ESI): m/z 383 (M + H) +. |
With pyridine at 50℃; for 2h; | ||
In pyridine | 1.a 4,4'-dipivaloyloxybenzophenone EXAMPLE 1a 4,4'-dipivaloyloxybenzophenone A solution of 10 g of 4,4'dihydroxybenzophenone in pyridine (40 ml) was treated with trimethylacetyl chloride and refluxed for 5 hours. The resultant solution was concentrated under reduced pressure and ETOAc added. The organic layer was washed with H2 O, 5% aq. K2 CO3, 1% aq. NaOH and dried over MgSO4 and concentrated to give approximately 13 g of a beige solid which was further chromatographed using 7/93 ethyl acetate-toluene to yield 2.83 g (20%) of the monoester (a) and 3.42 g (19%) (b) of the title compound; M.P.=166°-167° C. | |
With triethylamine In tetrahydrofuran; dichloromethane at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.6% | With potassium carbonate; potassium iodide In acetone at 60℃; for 12h; | |
87% | In ethanol at 85℃; | |
66.4% | With sodium hydroxide In dichloromethane at 20℃; for 48h; | 4,4’-Dihydroxy benzophenone 1 (2.142 g, 10 mmol) and 1,4-dibromobutane (17.273 g, 80 mmol) wereadded into the mixture of dichloromethane (50 mL) and 20% NaOH (50 mL) solution,the resulting mixture was stirred at room temperature for 48 hours. Thereaction solution was subsequently extracted and concentrated, and the crudematerial was purified by flash chromatography to afford the desired product 6 as a white solid in a 66.4% yield (3.215g). Bis[4-(4-bromobutoxy)phenyl]-methanone 6(1.452 g, 3 mmol) was added to a 250 mL two-necked round-bottomed flask whichwas vacuum-evacuated and argon-filled, followed by the addition of anhydrous THF(25 mL). The resulting solution was cooled to -78 oC, and TiCl4(1.0 mL) and Zn dust (0.585 g, 9 mmol) were added. The reaction mixture was allowedto warm up to 85 oC and was stirred at the same temperature underargon. After 3 hours, the reaction solution was cooled down to room temperatureand filtered through a silica gel pad. The filtrate was concentrated and the crudematerial was subsequently purified by silica gel chromatography eluting with petroleumether. Compound TPE-C4 was obtainedas a light yellow solid in a 47.2%yield (0.663 g). Compounds TPE-C2and TPE-C6 were prepared in the samefashion. All of the three TPEderivatives have been fully characterized with 1H NMR, 13CNMR and MS analyses. |
43% | With potassium carbonate In acetone Heating; | |
With sodium hydroxide In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 18-crown-6 ether; potassium carbonate In acetone for 96h; Inert atmosphere; | |
87% | With potassium carbonate In acetone Reflux; | |
70% | With potassium carbonate In acetone for 24h; Reflux; |
70% | With potassium carbonate In acetone | 16 N,N',N",N'"-[1,2-Tetrakis(1,4-phenoxyethyl)vinyl]tetrakis(triethylammonium bromide) (N+C2-TPE-C2N+) To a mixture of DHBP (3.0 g, 14.0 mmol) and potassium carbonate (5.0 g, 36.2 mmol) in acetone (50 ml) was added 1,2-dibromoethane (4 ml, 46.4 mmol). The mixture was refluxed under stirring for 24 h. After filtration and solvent evaporation, the crude product was purified by a silica gel column using chloroform as eluent. BBEBP was obtained as white powder in 70% yield (4.20 g). Rf=0.6 (chloroform); 1H NMR (300 MHz, CDCl3, 25° C., TMS): δ=3.68 (t, 4H; BrCH2), 4.38 (t, 4H; OCH2), 6.97 (d, 4H, J 9.0 Hz; Ar), 7.78 ppm (d, 4H, J=9.0 Hz; Ar); 13C NMR (75 MHz, CDCl3, 25° C., TMS): δ=29.3, 68.6, 114.8, 115.8, 131.9, 133.0, 162.0 ppm. |
70% | With potassium carbonate In acetone for 24h; Reflux; | 22 To a mixture of DHHP (3.0 g, 14.0 mmol) and potassium carbonate (5.0 g, 36.2 mmol) in acetone (50 ml) was added 1 ,2-dibromoethane (4 ml, 46.4 mmol). The mixture was refluxed under stirring for 24 h. After filtration and solvent evaporation, the crude product was purified by a silica gelcolumn using chloroform as eluent. SHEEP was obtained as white powder in 70% yield (4.20 g). R1=0.6 (chloroform); ‘H NMR (300 MHz, CDC13, 25° C., TMS): ö8=3.68 (t, 4H; HrCH2), 4.38 (t, 4H; OCH2), 6.97 (d, 4H, J=9.0 Hz; Ar), 7.78 ppm (d, 4H, J=9.0 Hz; Ar); ‘3C NMR (75 MHz, CDC13, 25° C., TMS): ö=29.3, 68.6, 114.8, 115.8, 131.9, 133.0, 162.0 ppm. |
63% | With caesium carbonate In acetonitrile for 22h; Reflux; | 1 6.1.2. Bis(4-(2-bromoethoxy)phenyl)methanone (1d) A stirred suspension of 4,4'-dihydroxybenzophenone (1c; 1.93 g. 9 mmol), 1,2-dibromoethane (15.5 mL, 180 mmol), cesium carbonate (11.77 g, 36.1 mmol) and acetonitrile (66 mL) was heated at reflux for 22 h. The suspension was filtered and the salts washed well with dichloromethane. The combined filtrate was filtered through a small pad of flash silica gel, washing the pad well with dichloromethane. The filtrate was concentrated to a semisolid that was diluted with 2-propanol. The suspension was heated for 5 min and allowed to cool. The resulting solids were collected, washed with 2-propanol, and dried to leave 2.3 g of 1d, mp 125-127 °C. Upon standing for several days, additional product crystallized from the mother liquor and was collected to give 130 mg of 1d, mp 120-125 °C. Total yield = 2.43 g (63%). 1H NMR (400 MHz,DMSO-d6): δ 7.73-7.64 (m, 4H), 7.13-7.04 (m, 4H), 4.45-4.37 (m, 4H), 3.87-3.79 (m, 4H). MS TOFES+: m/z 427.9 (M+), 428.9 (M+H)+. |
41% | With potassium carbonate In butanone Reflux; | |
40% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 48h; Inert atmosphere; | 2 Example 2Preparation of 4,4'-bis(bromoethoxy)-benzophenone (Compound 4) 1,2-dibromoethane (35.1 g, 186.7 mmol), under argon,4,4'-dihydroxybenzophenone (10.0 g, 46.7 mmol) and K2CO3 (38.7 g, 280.1 mmol) were dissolved in DMF.The reaction was carried out at 90 °C for 48 h. The reaction solution was filtered and the organic phase was spin-dried.The crude product was chromatographed on a developer dichloromethane/petroleum ether silica gel column.A white solid (8 g, 40%) was obtained |
21.7% | With potassium carbonate In acetone for 48h; Heating; | |
With potassium carbonate In butanone for 5h; Heating; | ||
With sodium hydroxide In dichloromethane at 20℃; for 48h; | 4,4’-Dihydroxy benzophenone 1 (2.142 g, 10 mmol) and 1,4-dibromobutane (17.273 g, 80 mmol) wereadded into the mixture of dichloromethane (50 mL) and 20% NaOH (50 mL) solution,the resulting mixture was stirred at room temperature for 48 hours. Thereaction solution was subsequently extracted and concentrated, and the crudematerial was purified by flash chromatography to afford the desired product 6 as a white solid in a 66.4% yield (3.215g). Bis[4-(4-bromobutoxy)phenyl]-methanone 6(1.452 g, 3 mmol) was added to a 250 mL two-necked round-bottomed flask whichwas vacuum-evacuated and argon-filled, followed by the addition of anhydrous THF(25 mL). The resulting solution was cooled to -78 oC, and TiCl4(1.0 mL) and Zn dust (0.585 g, 9 mmol) were added. The reaction mixture was allowedto warm up to 85 oC and was stirred at the same temperature underargon. After 3 hours, the reaction solution was cooled down to room temperatureand filtered through a silica gel pad. The filtrate was concentrated and the crudematerial was subsequently purified by silica gel chromatography eluting with petroleumether. Compound TPE-C4 was obtainedas a light yellow solid in a 47.2%yield (0.663 g). Compounds TPE-C2and TPE-C6 were prepared in the samefashion. All of the three TPEderivatives have been fully characterized with 1H NMR, 13CNMR and MS analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.5% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | |
47.2% | With potassium carbonate In acetone Heating; | |
44% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.2 Synthesis of 2 A mixture of 4, 4′-dihydroxybenzophenone (4.3 g, 20 mmol), 1, 3-dibromopropane (10.0 g, 50 mmol), and K2CO3 (13.8 g, 100 mmol) in DMF (20 mL) under N2 was stirred at room temperature for 24 h. Then the resulting mixture was extracted with CH2Cl2. The CH2Cl2 extract was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by column chromatography over silica gel eluting with PE/EtOAc (20:1, v/v) to give 2 (4.06 g, 44% yield) as a white solid: CAS: 288248-49-7; mp 62–63 В°C (lit. 62–64 В°C) 8b; IR (cmв€’1): 2931, 2868, 1731, 1637, 1601, 1504, 1416, 1244, 838, 763; 1H NMR (500 MHz, CDCl3) Оґ: 7.77 (d, J = 8.5 Hz, 4H), 6.96 (d, J = 8.5 Hz, 4H), 4.18 (t, J = 5.5 Hz, 4H), 3.61 (t, J = 6.0 Hz, 4H), 2.33–2.38 (m, 4H); 13C NMR (125 MHz, CDCl3) Оґ: 194.4, 162.0, 132.3, 131.0, 114.0, 65.5, 32.2, 29.8; HRMS (ESI) m/z Calcd for C19H21O3Br2 [M+H]+ 454.9852. Found 454.9844. |
26% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 2.2.1. Synthesis of compound 1 A mixture of 4,4'-dihydroxybenzophenone (5.00 g, 23.3 mmol),1,3-dibromopropane (14.20 g, 70.0 mmol) and K2CO3 (9.50 g, 70.0 mmol) in dry DMF (50 mL) was stirred under Ar atmosphere at room temperature for 24 h. After reaction, the resulting mixture was extracted with ethyl acetate (320 mL). Then the organic phase was washed with saturated brine (20 mL) and dried over Na2SO4. After removing solvent under reduced pressure, the crude product was purified by column chromatography on silica gel using petroleum ether (60-90 °C) and EtOAc (v/v, 10/1) as eluent. A white powder of compound 1 was obtained in a yield of 26.0% (2.36 g). mp = 62.4-63.7 °C; 1H NMR (300 MHz, CDCl3), δ: 7.76 (d, J = 8.7 Hz, 4H), 6.94 (d, J = 8.7 Hz, 4H), 4.18 (t, J = 5.8 Hz, 4H), 3.61 (t, J = 6.3 Hz, 4H), 2.39-2.31 (m, 4H). 13C NMR (75 MHz, CDCl3), δ: 194.74, 161.73, 132.06, 130.79, 113.87, 65.52, 32.23, 29.74. MS (ESI) m/z: [M + Na]+ Calcd for C19H20Br2O3Na: 479.0; Found: 478.7. |
With potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | 1.1 1) Synthesis of Compound 2: 4,4'-dihydroxybenzophenone (0.43 g, 2 mmol), 1,3-dibromopropane (1.00 g, 5 mmol) and potassium carbonate (1.38 g, 10 mmol) were dissolved in 20 mL of anhydrous DMF. Stir at room temperature for 12 h under nitrogen. The mixture was extracted with methylene chloride. EtOAc (EtOAc m.The product compound 2 is obtained by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 48h; | |
57% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 48h; | 3.1 Example 3 4-[Cyclooctylidene(4-[2-(dimethylamino)ethyl]oxy}phenyl)methyl]phenol (8)Step 1 : 4-Benzyloxy-4'-hydroxybenzophenone (5); To a solution of 4,4'-dihydroxybenzophenone (2.0 g, 9.3 mmol) in dry DMF (20 ml) was added benzyl bromide (1.22 ml_, 10.2 mmol) and K2CO3 (1.4 g, 10.1 mmol). The reaction mixture was heated to 60 0C for 48 h. After cooling to room temperature and filtering off solids, the filtrate was concentrated. The resulting residue was dissolved in EtOAc, and the solution was then washed with 1 N HCI followed by brine. The solution was dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (0 to 15% EtOAc in CH2CI2 elution) to afford 5 (1.6 g, 57%) as a white solid. 1H NMR (400 MHz, CDCI3): δ 5.17 (s, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.28 - 7.48 (m, 5 H), 7.75 - 7.82 (m, 4 H). LRMS (ESI): m/z 303 (M - H) " and 305 (M + H) +. |
45% | With potassium carbonate In acetone at 60℃; for 48h; | 1 Example 1: (4-benzyloxy-phenyl)-(4-hydroxy-phenyl)-methanone [69] After 50 g (233.4 mmol) of 4,4'-hydroxybenzophenone was dissolved in 500 ml of acetone, 35 g (252.1 mmol) of potassium carbonate and 30.5 ml (252.1 mmol) of benzyl bromide were sequentially added and the resulting mixture was heated at 60°C for 48 hours with stirring. After the resulting mixture was cooled to ambient temperature, the potassium carbonate was filtered and a 1M hydrochloric acid solution was added to adjust the pH of the reaction mixture to 1 to 2. After the reaction mixture was extracted twice with 200 ml of ethyl acetate, an organic layer was washed twice with 200 ml of water, washed with 200 ml of saline, dried on anhydrous magnesium sulfate, filtered, and dried by distillation under reduced pressure. After addition of 150 ml of ethanol and 50 ml of water, the resulting mixture was heated at 60°C for 1 hour with stirring, and then cooled to ambient temperature with stirring. The obtained solid was filtered and dried under reduced pressure to obtain 32 g (45%) of (4-benzyloxy-phenyl)-(4-hydroxy-phenyl)-methanone. [70] mp 169°C; IR(cm-1) 3347, 1600, 1249; 1H NMR(400 MHz, DMSO) δ7.69(d, J = 8.0 Hz, 2H), 7.62(d, J = 8.0 Hz, 2H), 7.49-7.31(m, 5H), 7.16(d, J = 12.0 Hz, 2H), 6.89(d, J = 12.0 Hz, 2H), 5.21(s, 2H) |
25% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 60℃; for 24h; | 2.1 Step-1: Synthesis of 4-(Benzyloxyphenyl) (4-hydroxyphenyl) methanone Step-1: Synthesis of 4-(Benzyloxyphenyl) (4-hydroxyphenyl) methanone To a solution of bis (4-hydroxyphenyl)methanone (50 g, 234 mmol) in DMF (500 mL), were added potassium carbonate (35 g, 252 mmol) and benzyl bromide (43 g, 255 mmol) sequentially at 0 °C. The resulting mixture was heated at 60 °C for 24 h and the completion of the reaction monitored by TLC. The reaction mixture was cooled to room temperature, quenched by adding crushed ice (100 g) and stirred for 10 min. The precipitated solid was filtered, washed with ice cold water and dried under vacuum to afford 4- (benzyloxy)phenyl)(4-hydroxyphenyl) methanone (18 g, 25 %) as an off-white solid. |
0.93 g (33%) | With sodium methylate In methanol; ethyl acetate; acetone | 1 (1) (1) To a solution of 2.0 g (9.3 mmol) of 4,4'-dihydroxybenzophenon in 50 ml dry acetone was added 27.5 ml of 0.34M NaOMe in MeOH. After the reaction mixture had been stirred for 20 min, 1.6 g (9.3 mmol) of benzylbromide was added. The reaction was stirred at room temperature for 15 h. 250 ml EtOAc was added and then extracted with 2150 ml 0.5M HCl, 2150 ml H2 O and 50 ml saturated NaCl(aq). Drying (MgSO4), evaporation of the EtOAc and purification on silica gave 0.93 g (33%) of 4'-benzyloxy-4-hydroxy benzophenon. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Reflux; Darkness; | |
94% | With titanium tetrachloride; zinc In tetrahydrofuran Inert atmosphere; | |
91% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Heating; |
91% | Stage #1: With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 20℃; for 2h; Heating / reflux; Stage #2: 4,4'-Dihydroxybenzophenone; 1-phenyl-propan-1-one In tetrahydrofuran for 2h; Heating / reflux; dark; | For the creation of the first molecule, DY25 (which is 1,1-Bis (4-hydroxyphenyl)-2-phenylbut-1-ene, using the novel process), the following steps were carried out. To a stirred suspension of zinc powder (2.0 g, 0.031 mole) in dry THF (20 mL), TiCl4 (1.5 mL, 0.014 mol) was added dropwise under Ar, at -10° C. When the addition was complete, the mixture was warmed to room temperature and the refluxed for 2 h. To the cooled suspension of the Titanium reagent was added a solution of 4,4'-hydroxybenzophenone (0.5 g, 0.0023 mol) and propiophenone (1.0 g, 0.0074 mol) in dry THF (40 mL) at 0° C., and the mixture was refluxed in the dark for 2 h. After cooling at room temperature, the reaction mixture was quenched with 10% aqueous potassium carbonate (30 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Flash column chromatography (8:2 hexanes/EtOAc) afforded DY-25 (0.66 g, 91%) as a white solid: mp 200.6° C.; 1H NMR (CDCl3) δ 7.16-7.10 (m, 7H), 6.86(d, 2H), 6.74(d, 2H), 6.48(d, 2H), 4.64(s, 1H), 4.42(s, 1H), 2.49(q, 2H), 0.92(t, 3H): 13C NMR (CDCl3) δ 157.0, 156.2, 143.8, 141.0, 139.5, 136.0, 135.6, 132.6, 131.2, 130.5, 128.6, 126.0, 115.7, 115.0, 29.5, 13.8. Anal. Calcd for C22H2O2: C, 83.51; H, 6.37. Found: C, 83.23; H, 6.58. The structure of DY25 is: |
88% | With titanium tetrachloride; zinc In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux; | |
88.7% | Stage #1: 4,4'-Dihydroxybenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 95℃; for 2h; Inert atmosphere; Stage #2: 1-phenyl-propan-1-one In tetrahydrofuran at 0 - 95℃; for 2h; Inert atmosphere; Darkness; | |
88.7% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Inert atmosphere; Darkness; | 1.1-6 Synthesis of 4,4 '- (2-phenylbut-1-ene-1,1-diyl) diphenol In a nitrogen atmosphere, zinc powder (10.0 g) was suspended in tetrahydrofuran (80 mL), titanium tetrachloride (7.5 mL) was added dropwise at -10 ° C., and the reaction solution was heated under reflux for 2 hours.The reaction solution was cooled to 0 ° C. 4,4'-hydroxybenzophenone (7) (2.51 g) and propiophenone (5.03 g) dissolved in tetrahydrofuran (50 mL) were added and the mixture was heated under reflux for 2 hours in the dark.After returning the reaction solution to room temperature, a 10% potassium carbonate aqueous solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to give the title compound (8) (3.29 g, yield 88.7%) as a pale yellow solid Obtained. |
85% | With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 2.5h; Inert atmosphere; Reflux; | 1.1 Step-1: Synthesis of4,4'-( 2-phenylbut-l-ene-l,l-diyl)diphenol Step-1: Synthesis of4,4'-( 2-phenylbut-l-ene-l,l-diyl)diphenol To a suspension of zinc dust (36.6 g, 560 mmol) in dry THF (200 mL) at -10 °C was added TiCl4 (50.4 g, 266 mmol) under nitrogen atmosphere. The contents were stirred there for 15 min, slowly allowed to warm to room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C and a solution of bis(4-hydroxyphenyl)methanone (10 g, 46.7 mmol) and propiophenone (18.7 g, 140 mmol) in dry THF (20 mL) was added and the resulting mixture was heated at reflux for 2.5 h. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (500 mL x 3), the combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified over 230-400 mesh silica gel column chromatography using (3:7) ethyl acetate in rc-hexane to afford 4,4'-(2-phenylbut-l-ene-l,l- diyl)diphenol (12.6 g, 85%) as a brown colour solid. |
82% | With titanium tetrachloride; zinc In tetrahydrofuran at -20℃; for 12h; Inert atmosphere; Reflux; Darkness; | |
73% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Heating; | |
71% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Darkness; Reflux; | 1,1-Bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) Zinc powder (6.12 g, 0.094 mol) and dry THF (60mL) were transferred to a flame-dried flask fitted with a magnetic stirrerbar, reflux condenser, and dropping funnel, under argon gas. The reaction mixture was then cooled to 108C in a carefully maintained dry ice/acetone bath. To the cooled mixture was added TiCl4 (5.0mL, 8.65 g, 0.046 mol) drop-wise. After the addition was complete, the reaction mixture was heated at reflux for 2 h. After this time, the reaction mixture was cooled in an ice bath,and a solution of ice bath cooled 4,4'-hydroxybenzophenone(1.5 g, 0.007mol), propiophenone (3.0mL, 3.0 g, 0.022mol), and dry THF (120mL) was added using a cannula. The resulting mixture was then refluxed for a further 2 h in the dark. After being cooled to room temperature the reaction mixture was quenched with 10% aqueous potassium carbonate (90mL) and then extracted with ethyl acetate (290mL). The combined organic layers were washed with brine (90mL), dried over MgSO4,and concentrated under reduced pressure. The crude reaction mixture was then subjected to flash column chromatography(5 : 95-20 : 80 ethyl acetate/hexanes) to give 1 as a white solid (1.50 g, 71 %). The spectroscopic data for compound 1 matched that reported previously in the literature.[27] |
50% | With titanium tetrachloride; zinc In tetrahydrofuran for 12h; Heating; | |
39% | With titanium tetrachloride; zinc In tetrahydrofuran for 12h; Heating; | |
32.7% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 80℃; for 16h; | 5.1 [0580] Step 1: Synthesis of 4,4'-(2-phenylbut-1-ene-1,1-diyl)diphenol [0581] To a suspension of No.5 Zn (183.1 g, 2.80 mol, 4.00 eq) in dry No.4 THF (3.75 L) at 0°C. was added dropwise TiCl4 (265.6 g, 1.40 mol, 2.00 eq) under argon. The mixture was warmed to 20°C. and was heated to reflux for 3 h. A solution of No.4 bis(4-hydroxyphenyl)methanone (150.0 g, 700.2 mmol, 1.00 eq) and No.5 propiophenone (103.3 g, 770.2 mmol, 102.3 mL, 1.10 eq) in THF was added at 0°C., and the mixture was heated at 80°C. for 16 h. TLC (Petroleum ether: Ethyl acetate=3:1, Rf (starting material)=0.10, Rf (product)=0.20) indicated all of the starting material was consumed completely. This reaction was repeated and the two batches were combined for workup and purification. The mixture was poured into H2O (15.0 L), extracted with EtOAc (5.00 L3), the combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=5:1 to 1:1). No.10 4,4'-(2-Phenylbut-1-ene-1,1-diyl)diphenol (145.0 g, 458.2 mmol, 32.7% yield) was obtained as a white solid. 1H NMR (CDCl3 400 MHz) δ: 7.09-7.20 (m, 7H), 6.82 (d, J=8.60 Hz, 2H), 6.74 (d, J=8.60 Hz, 2H), 6.48 (d, J=8.80 Hz, 2H), 4.70 (s, 1H), 4.47 (s, 1H), 2.49 (q, J=7.36 Hz, 2H), 0.93 (t, J=7.52 Hz, 3H). |
In tetrahydrofuran; water; argon; zinc | 6 Synthesis of (E·Z)-1-[4-(3-dimethylamino-2-hydroxypropoxy)-phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene (compound 7): EXAMPLE 6 Synthesis of (E·Z)-1-[4-(3-dimethylamino-2-hydroxypropoxy)-phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene (compound 7): In a stream of argon, 16 ml of titanium tetrachloride was added dropwise to 240 ml of anhydrous tetrahydrofuran while cooling with ice. The resulting mixture was returned to room temperature, stirred for about 20 minutes and then subjected to 2 hours of reflux in the presence of 14.3 g of zinc powder. After cooling down to room temperature, the resulting reaction solution was mixed with 5.46 g of 4,4'-dihydroxybenzophenone and 3.42 g of propiophenone, and the mixture was subjected to 4 hours of reflux. After cooling, the thus obtained reaction solution was added to 200 ml of water, followed by extraction with ether. The resulting organic layer was washed with water, dried over sodium sulfate and then treated in vacuoto remove the solvent. The resulting oily residue was subjected to silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain about 8 g of crystals which was then recrystallized from toluene, thereby obtaining 6.00 g of 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene in the form of white crystals. | |
With titanium tetrachloride; zinc In tetrahydrofuran for 4h; Reflux; | ||
With titanium tetrachloride; zinc In tetrahydrofuran | ||
With titanium tetrachloride; zinc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 60h; | |
72% | With potassium carbonate In acetone at 60℃; for 24h; | 5.1 (1) intermediate 4, 4' - b is 12 oxygen radicals benzophenone. The bromo-dodecane (24.8g, 100mmol) and 4, 4' - dihydroxy benzophenone (5.4g, 25mmol) added in three-mouth flask, add 300 ml acetone, then adding potassium carbonate (13.8g, 100mmol), then heating to 60 °C to continue stirring 24h. To be reaction stops after cooling to room temperature, filter, collecting the filtrate, rotating to evaporate the solvent to get the crude product, to the volume ratio of 60:1 mixture of petroleum ether and ethyl acetate as eluant, SiO2As stationary phase, column chromatography purification to obtain 4, 4' - di-n-dodecyloxy benzophenone 9.9g, yield 72%. |
64% | With potassium carbonate In acetone for 48h; Reflux; |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; | 1 A synthesis of 4,4'-didodecyloxybenzophenone (m1) 4,4'-dihydroxybenzophenone 42.8 g (0.20 mol) is put into a 1-L eggplant flask, and DMF400mL was added and it was made to dissolve. Then, 124.9 g (0.50 mol) of potassium carbonate 69.1g1(0.50 mol)-bromododecanes were added, and 80 degrees C was agitated for 12 hours. After a reaction, water is added and a sludge is filtered. The filtration residue thing was dissolved in chloroform and methanol performed reprecipitation twice. The obtained solid was dried in vacuum and 4,4'-didodecyloxybenzophenone (m1) was obtained | |
With potassium carbonate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; for 3h; Heating / reflux; | 68.1 To a stirred suspension of zinc powder (15.0 g, 0.23 mol) in THF (300 mL) was slowly added TIC14 (12.5 mL, 0.115 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of bis (4-HYDROXYPHENYL) METHANONE (4.9 g, 0.023 mol) and cycloheptanone (7.74 g, 0.07 mol) in THF (100 mL) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into a 10% aqueous K2CO3 (1 L). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous phase was further extracted with EtOAc (4 x 250 mL). The combined organic phase was washed with brine (2 x 100 mL), dried (NA2SO4), filtered, and then concentrated under reduced pressure to give the crude product as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with hexanes: EtOAc (100: 0 to 50: 50) as an eluent to afford 6.75 g (99%) of the title compound 189 as a white solid NMR (DMSO-d6) : 8 9.21 (s, 2H), 6.84 (d, J = 6.3 Hz, 4H), 6.63 (D, J = 6. 3 Hz, 4H), 2.19 (BR S, 4H), 1.48 (BR S, 8H). LCMS (ESI) : M/Z 294 (M + H) |
99% | With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; for 3h; Heating / reflux; | 1.1 Example 14-[cycloheptylidene(4-[2-(dimethylamino)ethyl]oxy}phenyl)methyl]phenol (2)Step 1 : 4,4'-(Cycloheptylidenemethanediyl)diphenol (V); To a stirred suspension of zinc powder (15.0 g, 0.23 mol) in THF (300 ml.) was slowly added TiCI4 (12.5 ml_, 0.115 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of bis(4-hydroxyphenyl)methanone (4.9 g, 0.023 mol) and cycloheptanone (7.74 g, 0.07 mol) in THF (100 ml.) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into a 10% aqueous K2CO3 (1 L). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous phase was further extracted with EtOAc (4 x 250 ml_). The combined organic phase was washed with brine (2 x 100 ml_), dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the crude product as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 50:50) as an eluent to afford 6.75 g (99%) of the title compound 1 as a white solid. 1H NMR (DMSO-d6): δ 9.21 (s, 2 H), 6.84 (d, J = 6.3 Hz, 4 H), 6.63 (d, J = 6.3 Hz, 4 H), 2.19 (br s, 4 H), 1.48 (br s, 8 H). LCMS (ESI): m/z 294 (M + H) +. |
83% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Heating; |
83% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Inert atmosphere; Reflux; | |
With titanium tetrachloride; zinc In tetrahydrofuran for 1.5h; Reflux; | ||
With titanium tetrachloride; zinc In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With pyridine; titanium tetrachloride; zinc In tetrahydrofuran Heating; | |
58% | With titanium tetrachloride; zinc In tetrahydrofuran at -10℃; for 12.5h; Reflux; Inert atmosphere; | |
58% | With titanium tetrachloride; zinc In tetrahydrofuran at -10℃; for 12.5h; Inert atmosphere; Reflux; |
54% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 78℃; for 26h; Inert atmosphere; | 4.3.1. Synthesis of 4,4’-(2-(4-bromophenyl)-2-phenylethene-1,1-diyl)diphenol (compound A) Compound A was synthesized following the procedures reported in the literature [50] with some modifications. 4-Bromobenzophenone(3.90 g, 15 mmol), 4,40-Dihydroxybenzophenone (1.60 g, 7.50 mmol)and zinc powder (4.50 g, 70 mmol) were added to a 250-mLthree-necked round-bottom flask. The flask was vacuumed and purgedwith nitrogen for 3 times. Afterward, 100 mL of anhydrous THF wasinjected. The reaction system was cooled down to 0 C, and TiCl4 (3.40mL, 31 mmol) was added dropwise to the mixture. Then the mixture wasvigorously stirred in an ice bath for 2 h. Finally, the mixture was refluxedat 78 C for 24 h. After cooling to room temperature, hydrochloric acid(150 mL, 1 mol L 1) was added. The mixture was stirred for 15 min andthen filtered. The filtrate was extracted with DCM for 3 times, and theorganic layer was dried with anhydrous sodium sulfate. Then the solventwas removed on a rotavapor. The coarse product was separated by silicagel column chromatography with hexane/ethyl acetate (5:2, v/v) aseluent. The white solid was the final product (1.80 g, yield 54%). 1HNMR (400 MHz, DMSO-d6) 9.35 (t, J 15.2 Hz, 2H), 7.31 (d, J 8.3Hz, 2H), 7.12 (dd, J 14.7, 7.3 Hz, 3H), 6.93 (d, J 7.1 Hz, 2H), 6.85(d, J 8.3 Hz, 2H), 6.73 (t, J 8.3 Hz, 4H), 6.50 (dd, J 18.5, 8.4 Hz,4H). |
With pyridine; titanium tetrachloride; zinc | ||
3.05 g | With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 90℃; for 20.5h; Inert atmosphere; | 1.1 (1) Preparation of a compound of the formula (II) Weigh 1.82 g of 4,4-dihydroxy-benzophenone,6.5 g of 4-bromo-benzophenone and 6.53 g of zinc powder in a 250 mL round bottom flask,Add 100 mL of tetrahydrofuran to dissolve to obtain a mixed solution;Magnetic stirring under nitrogen protection, cooling to 0 ° C,Inject 5.6 ml of titanium tetrachloride and stir at -10 ° C for 30 min.The mixture was heated to reflux at 90 ° C for 20 h, cooled to room temperature and quenched by the addition of 60 ml of diluted hydrochloric acid.Purified by column chromatography, the eluent was n-hexane / ethyl acetate.3.05 g of a white solid compound of formula (II) was isolated. |
With titanium tetrachloride; zinc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With titanium tetrachloride; zinc In tetrahydrofuran at -78 - 70℃; for 23h; Inert atmosphere; | 2.2. Synthetic procedure 2.2.1. Synthesis of 4,4’-(2,2-diphenylethene-1,1-diyl)diphenol (DEDO)DEDO was synthesized by a common McMurry approach [29]. Amixture of benzophenone (4.00 g, 21.97 mmol), bis(4-hydroxyphenyl)methanone (4.70 g, 21.97 mmol), Zn power (5.70 g, 88 mmol), and150 mL anhydrous THF was mixed into a two-necked flask, and cooleddown to 78 C. Then drop-by-drop addition of 9.7 mL TiCl4 (87.8mmol) into the above mixture was performed under nitrogen atmosphere.The solution was kept at 78 C under constant stirring for 30min and further warmed to room temperature (RT) for another 8 h. Itwas continued to refilux at 70 C for an additional 15 h. After coolingdown, the reaction was quenched by the addition of a saturated K2CO3solution. The mixtures were then extracted with DCM to remove anysoluble hydrocarbons, followed by washing with 0.1 M HCl solution anddrying with Na2SO4. After the solvent was removed by rotary evaporation,the raw product was purified by column chromatography (SiO2,DCM/petroleum ether, V/V = 1:3-1:5) to render DEDO as pale yellowsolid (6.80 g, 85% yield). FTIR (KBr, cm 1): 1607, 1594, 1505, 1441(-C- -C- stretch in the aromatic region), 3311 (-OH stretch). 1H NMR(400 MHz, DMSO-d6): 9.30 (s, 2H, -OH), 7.14-7.05 (m, 6H), 6.95-6.90(m, 4H), 6.73 (d, J = 8.6 Hz, 4H), 6.48 (d, J = 8.6 Hz, 4H). 13C NMR(101 MHz, DMSO-d6): 156.34, 144.65, 141.07, 138.11, 134.56,132.51, 131.24, 128.23, 126.44, 115.03. HRMS(ESI): m/z: calcd for[M+H]+ C26H21O2: 365.1536, found: 365.1531. F = 28.25%. Tm (m.p.by DSC): 195 C. |
74% | With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice; | |
69% | With pyridine; titanium tetrachloride; zinc In tetrahydrofuran Heating; |
65% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 20℃; for 5h; Inert atmosphere; Reflux; | |
53% | With titanium tetrachloride; zinc In tetrahydrofuran Inert atmosphere; Reflux; | 1 Synthesis of compound 1 Take 30mL of redistilled tetrahydrofuran in the reaction flask, under the protection of argon, add zinc powder (5.2g, 80mmol) to redistilled tetrahydrofuran, stir under ice bath for 15min, and slowly add TiCl4(4.5mL, 40mmol)with a syringe. Heat to reflux for 2h.Dissolve benzophenone (1.82g, 10mmol) and 4,4'-dihydroxybenzophenone (2.57g, 12mmol) in 20mL redistilled tetrahydrofuran, slowly add them to the reaction flask, continue to heat and reflux overnight, the occurrence of McMurry coupling United.After thereaction, the reaction was quenchedwith saturated NaHCO3solution, the pH was adjusted to 7, and the mixture was extracted three times with 30 mL of dichloromethane. The organic phases were combined, washed with water, and dried with anhydrous Na2SO4.Separation by silica gel column chromatography (200-300 mesh column chromatography silica gel, petroleum ether:ethyl acetate/V:V=3:1) to obtain compound 1 (light white solid, 1.93 g, yield 53%). |
31% | With titanium tetrachloride; zinc In tetrahydrofuran; ethyl acetate at -10 - 75℃; for 12.5h; Inert atmosphere; | 1.1 Example 1: Preparation of TPE-diSS (tetrastyryl bissulfonic acid sodium salt) (1) Weigh 0.46g (2.5mmol) of benzophenone and 1.64g (25mmol) of zinc powder, add them to a 100mL two-necked round bottom flask equipped with a stirring magnet, and put a rubber on the mouth of the bottle. Stopper, the other bottle mouth is connected to the double-row tube, the vacuum operation is started, and nitrogen is introduced, and these two operations are repeated 3 times. Dissolve 0.54g (2.5mmol) of 4,4'-dihydroxybenzophenone in 37.5mL of anhydrous tetrahydrofuran and add it to a two-neck round-bottomed flask. Mix ethyl acetate and liquid nitrogen to create a low temperature environment. Keep the temperature at -10°C, slowly add 2.36g (12.5mmol) TiCl4 dropwise under stirring conditions, remove the ice bath, wait until the temperature rises to room temperature, react at room temperature for 0.5h, slowly increase the temperature to 75°C, reaction time For 12h. After the reaction is completed, when the temperature is lowered to room temperature, the solvent is distilled off under reduced pressure. The obtained solid is extracted with a dichloromethane/water system. The dichloromethane organic extract is collected and dried with anhydrous MgSO4 to remove excess water. Methyl chloride, the obtained crude product was purified by silica gel column chromatography, and the eluent was petroleum ether/ethyl acetate (v/v=1:1). 0.306 g (0.84 mmol) of the intermediate of formula (IV) was obtained as a yellow solid with a yield of 31%. |
With titanium tetrachloride; zinc In tetrahydrofuran Cooling with ice; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; | |
93% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 0 - 20℃; for 27.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 20℃; for 5h; Inert atmosphere; Reflux; | |
89% | With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 20℃; for 5.5h; Heating / reflux; dark; | Synthesis of DY34 The next step created DY34, which is 1,1-Bis (4-hydroxyphenyl)-2-phenylbut-3-methyl-1-ene (1b). To a stirred suspension of zinc powder (2.0 g, 0.031 mole) in dry THF (20 mL) was added TiCl4 (1.5 mL, 0.014 mol), under Ar, at -10° C. When the addition was complete, the mixture was warmed to room temperature and the refluxed for 2.5 h. To the cooled suspension of the Titanium reagent was added a solution of 4,4'-hydroxybenzophenone (0.5 g, 0.0023 mol) and isobutyrophenone (1.0 g, 0.0067 mol) in dry THF (40 mL) at 0° C., and the mixture was refluxed in the dark for 3 h. After cooling, the reaction mixture was quenched with 10% aqueous potassium carbonate (30 mL) and extracted with ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Flash column chromatography (8:2 hexanes/EtOAc) afforded 1b (0.68 g, 89%) as a white solid: mp 138.0° C.; 1H NMR (CDCl3) δ 7.26-7.17 (m, 5H), 7.11(d, 2H), 7.07(d, 2H), 6.81(d, 2H), 6.44(d, 2H), 4.70(s, 1H), 4.41(s, 1H), 3.04(m, 1H), 0.95(d, 6H): 13C NMR (CDCl3) δ 157.0, 155.9, 145.9, 141.4, 140.1, 136.1, 135.9, 132.2, 132.1, 131.3, 128.1, 126.7, 115.9, 114.8, 32.8, 22.1. Anal. Calcd for C23H22O2: C, 83.60; H, 6.71. Found: C, 83.78; H, 6.66. The structure of DY34 is: |
89% | With titanium tetrachloride; zinc In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux; | 1,1-Bis (4-hydroxyphenyl)-2-phenylbut-3-methyl-1-ene (1a) To a stirred suspension of zinc powder (2.0 g, 31 mmol) in dry THF(30 mL) was added TiCl4 (1.5 mL, 14 mmol), under Ar, at 10 C.When the addition was complete, the mixture was warmed toroom temperature and then refluxed. After titanium reagent wasrefluxed for 2.5 h, the mixture was cooled to 0 C and then a solution of 4,40-hydroxybenzophenone (0.5 g, 2.3 mmol) and isobutyrophenone(1.0 g, 6.7 mmol) in dry THF (40 mL) at 0 C wasadded to the mixture. Upon completion of addition of solution,the mixture was refluxed in the dark for 2.5 h, cooled to room temperature;and quenched with 10% aqueous potassium carbonate(50 mL) and extracted with EtOAc. The organic layer was washedwith brine, dried over MgSO4, and concentrated in vacuo. Flash columnchromatography (8:2 hexanes/EtOAc) afforded 1a (0.68 g,89%) as a white solid: mp 137.7 C; 1H NMR (600 MHz, CDCl3) d7.27-7.18 (m, 5H), 7.12 (d, 2H), 7.07 (d, 2H), 6.81 (d, 2H), 6.45(d, 2H), 4.70 (s, 1H), 4.41 (s, 1H), 3.05 (m, 1H), 0.96 (d, 6H); 13CNMR (125 MHz, CDCl3) d 157.0, 155.9, 146.0, 141.5, 140.2, 136.1,136.0, 132.3, 132.1, 131.4, 128.1, 127.0, 115.9, 114.8, 32.8, 22.2.Anal. Calcd for C23H22O2: C, 83.60; H, 6.71. Found: C, 83.78; H, 6.66. |
89% | With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 0℃; for 2.5h; Inert atmosphere; Reflux; | 2 1,1 -bis (4-hydroxyphenyl)-2-phenylbut-3-methyl-1 - ene (la) j0468] To a stirred suspension of zinc powder (2.0 g, 31 mmol) in dry THF (30 mE) was added TiC14 (1.5 mE, 14 mmol), under Ar, at -10° C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. After titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 degree C. and then a solution of 4,4’-hydroxybenzophenone (0.5 g, 2.3 mmol) and isobutyrophenone (1.0 g, 6.7 mmol) in dry THF (40 mE) at 0° C. was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature; and quenched with 10% aqueous potassium carbonate (50 mE) and extracted with EtOAc. The organic layer was washed with brine, dried over Mg504, and concentrated in vacuo. Flash column chromatography (8:2 hexanes/EtOAc) afforded la (0.68 g, 89%) as a white solid: mp 137.7° C.; 1H NMR (600 MHz, CDC13) δ 7.27-7.18 (m, 5H), 7.12 (d, 2H), 7.07 (d, 2H), 6.81 (d, 2H),6.45 (d, 2H), 4.70 (s, 1H), 4.41 (s, 1H), 3.05 (m, 1H), 0.96 (d, 6H); 13C NMR (125 MHz, CDC13) δ 157.0, 155.9, 146.0, 141.5, 140.2, 136.1, 136.0, 132.3, 132.1, 131.4, 128.1,127.0, 115.9, 114.8, 32.8, 22.2. Anal. Calcd for C23H2202:C, 83.60; H, 6.71. Found: C, 83.78; H, 6.66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide In acetone at 20℃; for 4h; | 12 0.01 Mole of 4,4'-dihydroxyl-benzophenone, 0.02 mole of NaOH and 150 mL of acetone were charged into a 250 mL three necked flask, and nitrogen gas was bubbled to remove oxygen in the flask. The mixture was allowed to react at 20° C. for 4 hrs, and a precipitate was obtained. The precipitate was filtered out under nitrogen atmosphere, washed twice with 50 mL of hot acetone, and then dried under reduced pressure at 200° C. for 3 hrs, to yield 24.2 g of bis-sodium salt of 4,4'-dihydroxyl-benzophenone. The yield was 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.1% | With ammonia; In water; | EXAMPLE 5 Preparation of 4-amino-5-chloro-1-phenylpyridazin-6-one (chloridazon) using 4,4'-dihydroxybenzophenone as catalyst In a 250 ml stirring autoclave, 100 parts of water, 70 parts (1.03 mol) of 25% strength ammonia, 12 parts (0.05 mol) of 4,5-dichloro-1-phenylpyridazin-6-one (purity: 99.7%) and 10.7 parts (0.05 mol) of 4,4'-dihydroxybenzophenone were stirred at 130 C. for 8 hours. The pressure rose steadily to about 4.5 bar. After stirring overnight, the autoclave was depressurized to atmospheric pressure, with the excess ammonia being stripped off. After cooling to room temperature, the precipitated solid was filtered off, washed with water and dried at 50 C. in a vacuum drying oven. This gave 10.2 parts of 4-amino-5-chloro-1-phenylpyridazin-6-one having a purity of 98.9%; this corresponds to a yield of 91.1% of theory. The pH of the filtrate was adjusted to 1.5 using 60% strength sulfuric acid and the precipitated 4,4'-dihydroxybenzophenone was filtered off, washed with water and dried. This gave 10.9 parts of 4,4'-dihydroxybenzophenone having a purity of 98.3%; this corresponds to 100% of the amount of catalyst used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | In water; | EXAMPLE 6 Preparation of 4-amino-5-chloro-1-phenylpyridazin-6-one (chloridazon) using recycled 4,4'-dihydroxybenzophenone as catalyst The catalyst from Example 5 was stirred at 130 C. with 100 parts of water, 70 parts (1.03 mol) of 25% strength ammonia and 12 parts (0.05 mol) of 4,5-dichloro-1-phenylpyridazin-6-one (purity: 99.7%) for 8 hours in a 250 ml stirring autoclave. A pressure of 4.3 bar was established. After stirring overnight, the autoclave was depressurized to atmospheric pressure, with the excess ammonia being stripped off. After cooling to room temperature, the precipitated solid was filtered off, washed with water and dried at 50 C. in a vacuum drying oven. This gave 10 parts of 4-amino-5-chloro-1-phenylpyridazin-6-one having a purity of 99.1%; this corresponds to a yield of 89.5% of theory. The pH of the filtrate was adjusted to 1.5 using 60% strength sulfuric acid and the precipitated 4,4'-dihydroxybenzophenone was filtered off, washed with water and dried. This gave 10.7 parts of 4,4'-dihydroxybenzophenone having a purity of 99.2%; this corresponds to 99.2% of the amount of catalyst used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In hexane; N,N-dimethyl-formamide; | EXAMPLE 1 Preparation of bis(4-(2-quinolylmethoxy)phenyl)methyliminoxyacetic acid STR10 Step 1: bis(2-quinolylmethoxyphenyl) ketone To a solution of 4-4'-dihydroxybenzophenone (4.22 g, 20 mmol) and K2 CO3 (16.5 g, 120 mmol) in DMF (75 mL) was added 2-chloromethylquinoline hydrochloride (8.56 g, 40 mmol), and the resulting solution was stirred at 60 C. for 16 hours. The reaction mixture was then poured into ice water (100 mL). The resulting solid was filtered, slurried in 20% ether/hexane, filtered, and dried in vacuo to afford bis(2-quinolylmethoxyphenyl) ketone (9.3 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In hexane; N,N-dimethyl-formamide; | EXAMPLE 25 Preparation of 1,1-bis(4-(2-quinolylmethoxy)phenyl)ethanol STR24 Step 1: bis(4-(2-quinolylmethoxy)phenyl) ketone To a solution of 4-4'-dihydroxybenzophenone (4.22 g, 20 mmol) and K2 CO3 (16.5 g, 120 mmol) in DMF (75 mnL) was added 2-chloromethylquinoline hydrochloride (8.56 g, 40 mmol) and the resulting solution was stirred at 60 C. or 16 hours. The reaction mixture was then poured into ice water (100 mL and the resulting solid was collected by filtration, slurried in 20% ether/hexane, filtered, and dried in vacuo to afford bis(4-(2-quinolylmethoxy)phenyl) ketone (9.3 g, 94%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sulfuric acid; In methanol; at 50℃; for 2h; | Aqueous potassium hydroxide (1 niL of 0.1 N5 0.1 mmol) was added to a solution of 2-(3,6-dihydroxy-9H-xanthen-9-yl)-benzoic acid [33 mg, 0.1 mmol, Cui, Y. et al., Yaoxue Tongbao, 1982, 17(9), 528] in 5 mL of ethanol and the mixture was stirred for additional 2 h at room temperature. The mixture was evaporated to dryness under reduced pressure to give 37 mg (100% yield) of the desired compound as a orange solid, mp >300C. 1H NMR (D2O5 300 MHz): £5.76 [s, H5 -CH], 6.94-6.99 [m, IH, Ar-H], 7.09-7.13 [m, 2Eta, Ar-H]5 7.26-7.31 [m, 6Eta, Ar-H]5 7.49-7.54 [m, IH5 Ar-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 4,4'-Dihydroxybenzophenone; 1-(3-bromophenyl)-1-propanone In tetrahydrofuran at 20℃; for 3h; Heating / reflux; Stage #2: | 1.1 To a stirred suspension of zinc powder (13.7 g, 0.211mol) in THF (300 ml.) was slowly added TiCI4No.2THF complex (35.Og, 0.105 mol) via a funnel at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1.0 h. A solution of bis(4-hydroxyphenyl)methanone (4.5 g, 0.021 mol), and i-(3-bromophenyl)-1-propanone (13.42 g, 0.063 mol) in THF (200 mL) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h. The reaction mixture was allowed to cool at room temperature. A standard work-up of the McMurry coupling reaction is followed. As used herein, the term "standard workup" refers generally to the standard work-up of the McMurry reaction as follows: The reaction mixture was poured into a 20% aqueous HCI (400 mL) slowly and stirred for 0.5 h. The reaction mixture was extracted with EtOAc (4 x 250 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the crude product as a gold-yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:ethyl acetate (100:0 to 3:2) as an eluent to afford a white foam. The white foam was recrystallized from acetonitrile to afford 7.960 g (96%) of the title compound 1 as a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With zinc In tetrahydrofuran at 20℃; for 3h; Heating / reflux; | 1.2 To a stirred suspension of zinc powder (3.3 g, 50 mmol) in THF (100 ml_) at room temperature under nitrogen atmosphere was slowly (drop-wise) added TiCI4 (2.7 ml_, 25 mmol). The resulting reaction mixture was heated at reflux for 1h. A mixture of bis(4- hydroxyphenyl)methanone (1.07 g, 5.0 mmol) and ketone 1 (4.0 g, 15.13 mmol) in THF (ml_) was then added followed by refluxing an additional 2h. The reaction mixture was allowed to cool at room temperature and poured into a 10% aqueous K2CO3 (300 ml_) slowly. The reaction mixture was filtered through celite and the solids washed with EtOAc. The filtrate was extracted with EtOAc (4 x 150 ml_). The combined organics were washed with brine, dried, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography over SiO2 with hexanes: ethyl acetate (100: 0 to 1 :1) to afford 1.60 g (72 %) of the title compound 2 as an off-white foam. 1H NMR (300 MHz, DMSO-αfe): δ 0.73 (t, J = 7.2 Hz, 3 H), 1.89 (m, 7H), 2.33 (br t, J = 7.6 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.70 (s, 2 H), 6.41(d, J= 8.8 Hz, 2 H), 6.60 ( (d, J= 8.4 Hz, 2 H), 6.71 (d, J= 3.0 Hz, 2 H), 6.74 (d, J= 2.4 Hz, 2 H), 6.94 (d, J= 8.4 Hz1 2 H), 6.99 (d, J= 8.4 Hz, 2 H), 9.13 (s, 1 H), 9.36 (s, 1 H). LCMS (ESI): m/z 445 (M - H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With zinc;titanium tetrachloride; In tetrahydrofuran; at 20℃; for 3h;Heating / reflux; | To a stirred suspension of zinc powder (11.2 g, 172 mmol) in THF (200 ml_) at room temperature under a nitrogen atmosphere was slowly (drop-wise) added TiCI4 (9.3 mL, 86 mmol). The resulting reaction mixture was heated at reflux for 1 h. A mixture of bis (4- hydroxyphenyl) methanone (3.69 g, 17.2 mmol) and 1-(4-bromophenyl)-1 -propanone (11.0 g, 51.62 mmol) in THF (100 mL) was then added followed by refluxing an additional 2 h. A standard work-up of the McMurry coupling reaction is followed. As used herein, the term "standard work-up" refers generally to the standard work-up of the McMurry reaction as follows: The reaction mixture was allowed to cool at room temperature and poured into a 10% aqueous K2CO3 (500 mL) slowly. The reaction mixture was filtered through celite and the solids washed with EtOAc. The filtrate was extracted with EtOAc (3 x 250 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to give the crude product as gold-yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes: ethyl acetate (100:0 to 3:2) to afford the title compound as a white foam. Recrystallization from EtOAc/hexanes yielded 5.52 g (96%) of the title compound 1 as a crystalline solid. 1H NMR (400 MHz, DMSO-d6): delta 0.82 (t, J = 7.2 Hz, 3 H), 2.37 (q, J1 = 14.4 Hz, J2= 7.2 Hz, 2 H ), 6.41 (d, J = 8.4 Hz, 2 H), 6.58 (d, J= 8.4 Hz, 2 H), 6.72 (d, J= 8.8 Hz, 2 H), 6.94 (d, J= 8.4 Hz1 2 H), 7.00 (d, J= 8.8 Hz, 2 H), 7.33 (d, J= 8.4 Hz, 2 H), 9.20 (s, 1 H), 9.41 (s, 1 H). LCMS (APCI): m/z 396 (M + H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | TiCl4; In tetrahydrofuran; | Example 5 1,1,2,2-tetrakis(4-hydroxyphenyl)ethylene (DHTPE) A suspension of 4,4'-dihydroxybenzophenone (3.0 g, 14.0 mmol), 1 equiv of TiCl4 (1.54 ml, 14.0 mmol), and 2 equiv of Zn dust (1.83 g, 28.0 mmol) in 100 ml of dry THF was refluxed for 20 h. The reaction mixture was cooled to room temperature and filtered. The filtrates were evaporated and the crude product was purified by a silica gel column using ethyl acetate (EA)(EA) as eluent. DHTPE was obtained as slight yellow powder of 83% yield. |
83% | TiCl4; In tetrahydrofuran; ethyl acetate; | Example 5 1,1,2,2-tetrakis(4-hydroxyphenyl)ethylene (DHTPE) A suspension of 4,4'-dihydroxybenzophenone (3.0 g, 14.0 mmol), 1 equiv of TiCl4 (1.54 ml, 14.0 mmol), and 2 equiv of Zn dust (1.83 g, 28.0 mmol) in 100 ml of dry THF was refluxed for 20 h. The reaction mixture was cooled to room temperature and filtered. The filtrates were evaporated and the crude product was purified by a silica gel column using ethyl acetate (EA) as eluent. DHTPE was obtained as slight yellow powder of 83% yield. |
83% | With titanium tetrachloride; zinc; In tetrahydrofuran; for 20h;Reflux; | A suspension of 4,4′-dihydroxybenzophenone (3.0 g, 14.0 mmol), 1 equiv of TiCl4 (1.54 ml, 14.0 mmol), and 2 equiv of Zn dust (1.83 g, 28.0 mmol) in 100 ml of dry THF was refluxed for 20 h. The reaction mixture was cooled to room temperature and filtered. The filtrates were evaporated and the crude product was purified by a silica gel column using ethyl acetate (EA) as eluent. DHTPE was obtained as slight yellow powder of 83% yield. Characterization data of DHTPE: 1H NMR (300 MHz, d-DMSO), δ (ppm): 9.24-8.94 (br), 7.07-7.04 (d, 4H), 6.95-6.95 (d, 4H), 6.70-6.56 (m, 4H), 6.47-6042 (t, 4H). 13C NMR (75 MHz, CDCl3), δ (ppm): MS (FAB), m/e: 391.2 ([M-4H]+, calcd. 392.1). |
76% | With titanium tetrachloride; zinc; In tetrahydrofuran; at -10℃; for 24h;Inert atmosphere; Reflux; | Zinc (2.73 g, 42.0 mmol) and anhydrous THF (80 mL) were placed in a 250-mL two-neck flask and cooled to below 10 C under a N2 at-mosphere. TiCl4 (2.34 mL, 21.5 mmol) was added slowly and then the mixture was stirred for 30 min at 10 C before heating at 70 C for 3 h with stirring, under a N2 atmosphere. A solution of 4,4 0 -dihydrox-ybenzophenone (3.00 g, 14.0 mmol) in dry THF (30 mL) was added dropwise and then the mixture was heated under reflux for 24 h. Aqueous K2CO3 (10 wt %, 50 mL) was poured into the mixture to quench the reaction. The organic phase was separated, and the aqueous phase extracted with EtOAc (3 30 mL). The combined organic phases were concentrated to afford an oily residue. Recrystallization (acetone/H2O) afforded a white powder (2.10 g, 76%). FTIR (KBr, cm 1): 3650 - 3200 (O - H stretching) and 1611 (C -- C stretching). 1H NMR (DMSO - d6, 25 C, 500 MHz): δ (ppm) 6.48 (d, J 8.4 Hz, 8H), 6.70 (d, J 8.4 Hz, 8H), 9.22 (s, 4H, OH). 13C NMR (DMSO - d6, 25 C, 500 MHz): δ (ppm) 115.12, 132.73, 135.84, 138.45, 156.26. |
72% | With pyridine; titanium tetrachloride; zinc; In tetrahydrofuran; at -5℃; for 8h;Inert atmosphere; Reflux; | A three-necked flask equipped with a magnetic stirrer was charged with zinc powder (3.1 g, 47 mmol) and 30 mL anhydrous THF under nitrogen atmosphere. The mixture was cooled to 0 to -5 C and TiCl4 (2.6 mL, 23.5 mmol) was slowly added by a syringe. The suspension was warmed to room temperature and stirred for 30 min, then heated at reflux for 2.5 h. The mixture was again cooled to 0 to -5 C, charged with pyridine (0.9 mL, 11.3 mmol) and stirred for 10 min. The solution of 4,4ʹ-dihydroxybezophenone (1 g, 4.7 mmol) in 10 mL of THF was added slowly. After addition, the reaction mixture was heated at reflux for 8 h. The reaction was quenched by addition of 10% aqueous K2CO3 solution and worked up with CHCl3. The organic layer was collected and concentrated. The crude product was purified by column chromatography using 100-200 silica gel and 2:5 ethyl acetate in petroleum ether (60-80) as an eluent to afford the desired product (3). Off-white solid, yield: 72%; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 6.48 (d, J = 8.4 Hz, 8H), 6.70 (d, J = 8.4 Hz, 8H), 9.22 (s, 4H, exchangeable); 13C NMR (75 MHz, DMSO-d6): δ (ppm) 114.9, 132.4, 135.5, 138.2, 155.8; ESI-MS: m/z 419 [M + Na]+; Anal. Calcd. for C26H20O4: C, 78.77; H, 5.09; Found: C, 78.92; H, 5.11. |
55% | With titanium tetrachloride; zinc; In tetrahydrofuran; for 24h;Inert atmosphere; Reflux; | The 1.700 g (26.5 mmol) zinc powder is added to a 50 ml water removal THF three-port in round bottomed flask stirring. The mixture using ice bath cooling to 0 C after, under the protection of nitrogen, for pipette slowly dropping 1.4 ml (13.0 mmol) of titanium tetrachloride, goes to the ice-bath withdraw the end of the dropping, stirring at room temperature 10 min, reheat reflux 2.5 h, stop heating, cooling to room temperature, then the 3.000 g (6.6 mmol) 4, 4' - dihydroxy benzophenone dissolved in water removal THF dropping, and milling to continue to heating reflux after 1 day, completion of the reaction, cooling to room temperature, slowly adding dilute hydrochloric acid aqueous solution and stirring, filtering, the ethyl acetate extract 3 × 50 ml, drying, filtering, filtrate and steaming and to remove the ethyl acetate. Obtaining pink solid crude product, acetone purification, to obtain the solid 3.142 g, yield: 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In acetone; at 0 - 50℃; for 3h; | To a solution of 4,4'-dihydroxybenzophone (500 mg,2.33 mmol) in acetone (5.0 ml) at 0C, K2CO3 (161 mg, 1.17 mmol) andpropargyl bromide (0.11 ml, 1.16 mmol) were added. The reaction mixture wasstirred at 50 C for 3 h, cooled to room temperature, and quenched with H2O (10 mL). The mixture was extracted threetimes with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered, andconcentrated. The residue was purified via Biotage (ethyl acetate / n-hexane = 1 : 2 Snap Ultra25g column). The desired fractions were collected and concentrated togive propargylatedbenzophenone (6') (240 mg, 82% BRSM). 1H-NMR (600 MHz, CD3OD)delta 7.73 (d, 2H, J = 8.4 Hz), 7.67 (d,2H, J = 8.4 Hz), 7.09 (d, 2H, J = 9.0 Hz), 6.87 (d, 2H, J = 9.0 Hz), 4.82 (s, 2H), 3.00 (t , 1H,J = 2.4 Hz); 13C-NMR (150MHz, CD3OD) delta 195.4, 162.0, 161.0, 132.3, 131.6, 131.1, 128.9,114.7, 114.7, 77.8, 75.9, 55.3; HRMS(ESI): mass calcd for C16H15O3 [M + H] +, 253.0786; found, 253.0872. |
46% | (JG-195 B). To a stirred solution of 4,4'-dihydroxybenzophenone (250 mg, 1.16 mmol, 1 equiv) in anhydrous dimethyl formamide (2 mL) at rt was added K2C03 (242 mg, 1.75 mmol, 1.5 equiv) and the mixture was stirred for 20 min under argon atmosphere. Propargyl bromide (156 mu, 1.75 mmol, 1.5 equiv) was added and the mixture was stirred for 14.5 h at rt. Deionized water (0.5 mL) was added and the mixture was extracted with ethyl acetate (3 x2 mL). The organic layer was washed with deionized water (2 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% ethyl acetate in dichloromethane) to provide JG-195 B (135 mg, 46%) as a white solid.H NMR (400 MHz, DMSO- 6): delta 10.32 (s, 1H), 7.68 (d, J= 8.8, 2H), 7.62 (d, J =8.8, 2H), 7.1 1 (d, J = 8.8, 2H), 6.88 (d, J= 8.4, 2H), 4.91 (d, J= 2.4, 2H), 3.63 (t, J= 2.0, 1H). C NMR (100 MHz, DMSO- ): delta 193.7, 162.2, 160.8, 132.8, 132.1, 131.6, 129.0,115.7, 1 15.1 , 79.4, 79.3, 56.3.HRMS (ESI) irnlz): naTLC (5% methanol in dichloromethane), Rf: 0.48 (UV, /7-anisaldehyde). | |
33% | With potassium carbonate; In acetone; for 5h;Reflux; | [0172] (4-hydroxyphenyl)(4-(prop-2-yn-l-yloxy)phenyl)methanone. To an acetone solution (5.0 mL) of 4,4'-dihydroxybenzophenone (512 mg, 2.4 mmol) were added propargyl bromide (0.21 mL, 2.4 mmol) and K2CC"3 (495 mg, 3.6 mmol). After refluxing for 5 hours, the reaction mixture was diluted with ethyl acetate and the combined organic phase was washed with water and brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Ethyl acetate / n-hexane = 1 : 2) to afford the propargylated benzophenone (197 mg, 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In acetone at 60℃; for 30h; | II.1 Compound 9 (1 g, 4.6 mmol) was dissolved in 20 mL dry acetone in a 100 mL round bottom flask fitted with a reflux condenser. To this mixture K2CO3 (3.2 g, 5 eq., 9.33 mmol), isopropylbromide (10 equiv., 46 mmol) and tetrabutylammonium bromide (TBAB) (0.5 eq.) were added. The mixture was refluxed for 30 hrs at 60° C. When the reaction was complete (monitored by TLC), acetone was removed under reduced pressure on a rotary evaporator; diluted with distilled water and extracted with ethyl acetate (25 mL×3). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent followed by column chromatographic purification of the crude material yielded compound 10 in 82% yield as a white solid.The product was characterized by the following spectral techniques. FT-IR(KBr,υmax/cm-1): 2980, 2935, 2900, 1676, 1639, 1598, 1504, 1467, 1454, 1377, 1255, 950, 848. 1H NMR (300 MHz, CDCl3): δ 7.76 (d, 4H, J=8.79 Hz), 6.93 (d, 4H, J=8.79 Hz), 4.68-4.64 (m, 2H), 1.30-1.39 (s, 12H). 13C NMR (75 MHz, CDCl3): δ 161.04, 131.95, 130.10, 114.62, 69.74, 21.67 |
82% | With tetrabutylammomium bromide; potassium carbonate In acetone at 60℃; for 30h; | Synthesis of 4,4'-Diisopropoxy Benzophenone Compound 9 (1 g, 4.6mmol) was dissolved in 20 mL dry acetone in a 100 mL round bottom flask fitted with a reflux condenser. To this mixture K2CO3 (3.2 g , 5eq., 9.33 mmol), isopropylbromide (10 equiv., 46 mmol) and tetrabutylammonium bromide (TBAB) (0.5 eq.) were added. The mixture was refluxed for 30 hrs at 60°C. When the reaction was complete (monitored by TLC), acetone was removed under reduced pressure on a rotary evaporator; diluted with distilled water and extracted with ethyl acetate (25mL x 3). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent followed by column chromatographic purification of the crude material yielded compound 10 in 82 % yield as a white solid. The product was characterized by the following spectral techniques. FT-IR(KBr,υmax/cm-1) : 2980, 2935, 2900, 1676, 1639, 1598, 1504, 1467, 1454, 1377, 1255, 950, 848. 1H NMR (300 MHz, CDCl3): δ 7.76 (d, 4H, J=8.79Hz), 6.93 (d, 4H, J=8.79Hz), 4.68 - 4.64 (m, 2H), 1.30 - 1.39 (s, 12H). 13C NMR (75 MHz, CDCl3): δ 161.04, 131.95, 130.10, 114.62, 69.74, 21.67 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Cs2CO3 (8.55g, 26.3mmol, 4.0eq.) was added to a solution of 16 4,4?-hydroxybenzophenone 10 (1.41g, 6.56mmol, 1.0eq.) in dry DMF (15mL) at room temperature. The mixture was heated to reflux and stirred for 10min, at which point the solution was cooled to room temperature and 68 N,N-dimethyl-2-chloro-N,N-dimethylethylamine hydrochloride (945mg, 6.56mmol, 1.0eq.) was added portion-wise. The reaction was then heated to 80C and stirred for 4h, whereupon it was cooled to room temperature, quenched with saturated ammonium chloride solution (10mL) and extracted with ethyl acetate (3×25mL). The crude product was purified by column chromatography eluting with 10% MeOH in CH2Cl2 to afford 70 11 as a white solid (960mg, 3.37mmol) in 51% yield. The spectroscopic data of the product is in agreement with that reported in the literature. | |
39% | Example 2 4-[(4-[2-(dimethylamino)ethyl]oxy}phenyl)(3,3,5,5- tetramethylcyclohexylidene)methyl]phenol hydrochloride (4)Step 1 : (4-[2-(dimethylamino)ethyl]oxy}phenyl)(4-hydroxyphenyl)methanone (3); To a round-bottom flask containing 4,4'-dihydroxybenzophenone (1 g, 4.67 mmol) in DMF (10 ml.) was added CS2CO3 (6 g, 18.7 mmol). After several minutes of stirring at reflux, 2-(dimethylamino)ethyl chloride hydrochloride (0.61 g, 4.20 mmol) was added to the reaction mixture and heated at reflux overnight. The reaction mixture was allowed to cool to room temperature then quenched with saturated NH4CI (45 ml.) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The crude material was purified by flash chromatography on silica gel using EtOAc:MeOH (0 to 10% MeOH) to afford 0.52 g, (39%) of the title compound as a white powder. 1H NMR (400 MHz, DMSO- ck): delta 2.20 (m, 6 H), 2.63 (t, J = 11.6 Hz, 2 H), 4.12 (t, J = 1 1.5 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.05 (d, J = 8.6 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 2 H), 10.32 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 24h; | |
99% | With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 24h; | |
99% | With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 24h; | 1 Bis(4-(allyloxy)phenyl)methanone (10) To a solution of 4,4'-dihydroxybenzophenone (5.0 g, 23.3 mmol) in DMF (50 mL) were added KOH (6.5 g, 116.7 mmol) and allyl bromide (5.1 mL, 58.4 mmol). The reaction mixture was stirred at room temperature for 24 h, quenched with H2O (10 mL) and consecutively washed with EtOAc (100 mL*3). The organic layers were combined, washed with brine (50 mL*3), dried over anhydrous MgSO4, filtered and concentrated. The desired product 10 (6.77 g, 99%) was obtained as a white crystal after purification by column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=8.9 Hz, 8H), 6.96 (d, J=8.9 Hz, 8H), 6.06 (m, 2H), 5.44 (dd, J=10.8, 1.3 Hz, 2H), 5.32 (dd, J=10.7, 1.3 Hz, 2H), 4.61 (d, J=5.1 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 194.3, 161.8, 132.6, 132.1, 130.8, 118.1, 114.1, 68.8. HRMS (EI): calcd for C19H18O3 294.1256; found 294.1259. |
75% | Stage #1: 4,4'-Dihydroxybenzophenone With potassium carbonate In acetone for 6h; Stage #2: allyl bromide In acetone for 24h; Reflux; | |
5.78 g | With potassium carbonate In tetrahydrofuran; tetrachloromethane at 60℃; for 24h; Inert atmosphere; | 3 4.9% g (50 mmol) of 4-hydroxybenzophenone,7.92 g (50 mmol) of potassium carbonate,120 ml of carbon tetrachloride was added to a 250 ml three-necked flask equipped with a magnetic stirrer and a thermometer.Passing nitrogen,Heat and stir.12.30 g (100 mmol) of 3-bromopropene,Tetrahydrofuran 144g (2mol) was uniformly mixed in a constant pressure funnel.Then slowly add the mixture to the three-necked flask.Rinse to 60 ° C for 24 h,After the reaction,Filter to remove solid impurities,Washed,Dissolve the salt three times,After the solvent is removed by steaming,Recrystallization gives a white powder crystal,5.78g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 4,4'-Dihydroxybenzophenone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 20℃; for 21h; Inert atmosphere; | 6 (JG-183). To a stirred solution of 4,4'-dihydroxybenzophenone (1000 mg, 4.66 mmol, 1 equiv) in anhydrous dimethyl formamide (5 mL) at rt was added K2C03 (1.9 g, 14 mmol, 3 equiv) and the mixture was stirred for 20 min under argon atmosphere. l -Bromo-3- chloropropane (1.4 mL, 14 mmol, 3 equiv) was added and the mixture was stirred for 21 h at rt. Deionized water (2 mL) was added and the mixture was extracted with ethyl acetate (3 x3 mL). The organic layer was washed with deionized water (3 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% ethyl acetate in dichloromethane) to provide JG-183 (1.5 g, 89%) as a white solid.H NMR (400 MHz, DMSO-c¾): δ 7.69 (d, J = 8.8, 4H), 7.08 (d, J= 8.4, 4H), 4.19(t, J= 6.0, 4H), 3.80 (t, J= 6.4, 4H), 2.20 (q, 4H).13C NMR (100 MHz, DMSO-J6) δ 193.7, 162.3, 132.5, 130.8, 114.8, 65.3, 42.5,32.2.HRMS (ESI) (m/z): calc'd for Ci9H2o03NaCl2 [M+Na] : 389.0687, found: 389.0692.TLC (5% methanol in dichloromethane), Kf. 0.82 (UV, />-anisaldehyde). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In acetone for 48h; Reflux; | |
92% | With tetrabutylammomium bromide; potassium carbonate In acetone for 48h; Reflux; | 1.4 Example 1 A total of 71 g (0.33 mol) of 4-(4-hydroxybenzoyl)phenol was put into 250 ml of acetone,Potassium carbonate 35 g (0.25 mol),1-bromohexane 116 g (0.7 mol),Tetrabutylammonium bromide 4.5 g (0.014 mol) Heating at reflux was stirred 48h,The reaction solution changes from yellow to white.Atmospheric distillation to remove solvent acetone, Washed away salt, Ethanol recrystallization, A white flaky crystalline product was obtained bis[4-(hexyloxy)phenyl]methanone. 118.4 g (0.31 mol), yield 92% |
75% | With potassium carbonate In N,N-dimethyl-formamide for 48h; Reflux; |
With potassium carbonate In N,N-dimethyl-formamide Heating; | ||
With potassium carbonate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate In acetone at 50℃; for 48h; | 4.1 (1) intermediate 4, 4' - b-octoxy benzophenone. The bromo octane (9.7g, 50mmol) and 4, 4' - dihydroxy benzophenone (5.4g, 25mmol) added in three-mouth flask, add 300 ml acetone, then adding potassium carbonate (6.9g, 50mmol), then heating to 50 °C to continue stirring 48h. To be reaction stops after cooling to room temperature, filter, collecting the filtrate, rotating to evaporate the solvent to get the crude product, to the volume ratio of 30:1 mixture of petroleum ether and ethyl acetate as eluant, SiO2As stationary phase, column chromatography purification to obtain 4, 4' - di-n-hexyloxy benzophenone 8.7g, yield 79%. |
77% | With potassium carbonate In acetone for 48h; Reflux; | |
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6.5h; | 4-1: synthesis of 4,4'-didocosoxy-benzophenone To 4,4'-dihydroxy-benzophenone (8.2 g, 38.3 mmol) and <strong>[6938-66-5]1-bromodocosane</strong> (31.3 g, 80.4 mmol) were added DMF (300 mL) and potassium carbonate (15.9 g, 115 mmol) and the mixture was stirred at 80C for 6.5 hr. After confirmation of disappearance of monoalkylated form, the reaction mixture was ice-cooled and 1N hydrochloric acid (300 mL) and water (150 mL) were slowly added with sufficient stirring. The slurry was filtered, and the obtained crystals were washed with water and methanol to give 4,4'-didocosoxy-benzophenone (28.3 g, 34.1 mmol, 89%). 1H-NMR (CDCl3/300MHz) delta= 0.88 (6H, t, J=6.6 Hz, OC22H45 C22-H) 1.1-1.6 (76H, br, OC22H45 C3-21-H) 1.81 (4H, m, OC22H45 C2-H) 2.04 (1H, s, -OH) 4.03 (4H, t, J=6.5 Hz, OC22H45 C1-H) 6.94 (4H, d, J=8.8 Hz, Ph C3,3',5,5'-H) 7.77 (4H, d, J=8.7 Hz, Ph C2,2',6,6'-H) |
With hydrogenchloride; potassium carbonate; In water; N,N-dimethyl-formamide; | (1) Synthesis of 4,4'-didocosyloxy-benzophenone To 4,4'-dihydroxy-benzophenone (8.2 g, 38.3 mmol) and <strong>[6938-66-5]1-bromodocosane</strong> (31.3 g, 80.4 mmol) were added DMF (300 mL) and potassium carbonate (15.9 g, 115 mmol), and the mixture was stirred at 80 C. for 6.5 hr. After confirmation of the disappearance of the monoalkylated compound, the reaction mixture was ice-cooled, and 1N hydrochloric acid (300 mL) and water (150 mL) were slowly added to the thoroughly-stirred mixture. The slurry was filtered, and the obtained crystals were washed with water and methanol to give the title compound (28.3 g, 34.1 mmol, 89%). 1H-NMR (CDCl3/300 MHz) delta=0.88 (6H, t, J=6.6 Hz, OC22H45 C22-H), 1.1-1.6 (76H, br, OC22H45C3-21-H), 1.81 (4H, m, OC22H45C2-H), 2.04 (1H, s, -OH), 4.03 (4H, t, J=6.5 Hz, OC22H45C1-H), 6.94 (4H, d, J=8.8 Hz, Ph C3,3',5,5'-H), 7.77 (4H, d, J=8.7 Hz, Ph C2,2',6,6'-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; | 13 Example 13 synthesis of 4,4-di(12-docosoxydodecyloxy)benzophenone To 4,4-dihydroxybenzophenone (196 mg, 915 μmol) were added DMF (20 ml), 1-(12-bromododecyloxy)docosane (1.1 g, 1.91 mmol) and potassium carbonate (379 mg, 2.74 mmol), and the mixture was stirred at 90°C overnight. The reaction mixture was cooled to room temperature, and 0.5N hydrochloric acid (20 ml) and chloroform (20 ml) were added. After stirring for a while, the aqueous layer was removed, and the organic layer was washed with water (10 ml)*2. The organic layer was evaporated under reduced pressure, and the residue was washed with methanol. The precipitate was collected by filtration to give 4,4-di(12-docosoxydodecyloxy)benzophenone (1.04 g, 867 μmol, 95%). 1H-NMR (CDCl3/300MHz) 0.88 (6H, t, J=6.9, C21H42-CH3) 1.15-1.60 (116H, br, Alkyl-H) 1.81 (4H, m, Ar-O-CH2-CH2-) 3.39 (8H, t, J=6.9, C11H22-CH2-O-CH2-C21H43) 4.03 (4H, t, J=6.6, Ar-O-CH2-C11H22) 6.94 (4H, d, J=8.7, Ph C3,5-H) 7.77 (4H, d, J=8.7, Ph C2,6-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With titanium tetrachloride; potassium carbonate; zinc In tetrahydrofuran at 0 - 90℃; for 2h; Darkness; Inert atmosphere; | 4.1 4.4.1. 2-[3-(Benzyloxy)phenyl]-1,1-bis(4-hydroxyphenyl)-1-butene (3) To a suspension of zinc powder (15.8 g, 242 mmol) in THF (30 mL) at -10 °C was added titanium(IV) chloride (12.0 mL, 109 mmol). The reaction mixture was diluted with THF (20 mL) and refluxed at 90 °C (bath temperature) for 2 h and then a mixture of 4,4'-dihydroxybenzophenone (1) (12.3 g, 57.3 mmol) and 1-[3-(benzyloxy)phenyl]propanone (2) (4.30 g, 17.9 mmol) in THF (60 mL) was added to the mixture at 0 °C. After the reaction mixture had been refluxed at 90 °C (bath temperature) for 2 h in the dark, 10% aqueous potassium carbonate was added to the mixture at 0 °C in the light. The mixture was filtered through a short pad of Celite with ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by column chromatography on silica gel (eluant; hexane/ethyl acetate = 2:1) to afford 3 (7.09 g, 94%) as a colorless solid: mp: 153-156 °C; IR (KBr): 3402, 3039, 2962, 1589, 1504, 1234 cm-1; 1H NMR (CD3OD): δ 7.36-7.26 (5H, m, Ar), 7.08-6.95 (1H, m, Ar), 7.02 (2H, d, J = 8.5 Hz, Ar), 6.76 (2H, d, J = 8.5 Hz, Ar), 6.73-6.67 (3H, m, Ar), 6.67 (2H, d, J = 9.0 Hz, Ar), 6.45 (2H, d, J = 9.0 Hz, Ar), 4.86 (2H, s, Bn), 2.46 (2H, q, J = 7.5 Hz, 3-H), 0.90 (3H, t, J = 7.5 Hz, 4-H); 13C NMR (CD3OD): δ 159.8, 157.2, 156.4, 145.6, 141.3, 140.1, 138.8 (Ar), 136.4 (1), 136.3 (2), 132.9, 131.6, 130.7, 129.8, 129.4, 128.7, 128.6, 123.5, 117.9, 116.1, 115.8, 115.2, 114.1 (Ar), 71.0 (Bn), 29.7 (3), 14.0 (4); HR MS: calcd for C29H26O3Na (M+Na+) m/z 445.1774, found 445.1780. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.5h; | A mixture of fert-butyl 3 -(methylsulfonyloxy)pyrrolidine-l -carboxylate (0.6 g, 2.26 mmol), bis(4-hydroxyphenyl)methanone (2.15 g, 10.0 mmol) and K2CO3 (313 mg, 2.26 mmol) in 12 mL DMF was heated at 100 C for 3.5 h, then quenched with water, and extracted with EtOAc. The extract was washed with water, dried, and concentrated to give a residue, to which was added CH2C12 and the white suspension thus formed removed and filtration. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether/CH2Cl2/acetone = 4/2/1) to give the desired product (400 mg, 46% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 4,4'-Dihydroxybenzophenone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 3.2. General procedure for the synthesis of 1a-u General procedure: To a solution of hydroxybenzophenone or phenol derivatives (3) (1 mmol) in anhydrous DMF (3 mL), K2CO3 (2 mmol) was added at room temperature under N2. The mixture was stirred for 10 min and the corresponding 2a-c (1 mmol) was added, respectively. The reaction mixture was heated at 80 °C for 5-15 h. Then, the mixture was poured into ice-cold H2O (30 mL) and the resulting precipitate was filtered off. The obtained solid was further washed with ice-cold water (10 mL). The crude products 1a-u were finally purified by silica column chromatography eluting with hexane/ethylacetate 5:1 to 1:1 to yield the pure compounds in 52.2%-98.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a solution of 4,4?-dihydroxybenzophenone (33.5 mg, 0.156 mmol) in DMF (1.56 mL) at 0 °C was added 55percent sodium hydride (dispersion in paraffin liquid, 54.6 mg, 1.25 mmol). The reaction mixture was stirred for 10 min at 50 °C and then <strong>[26487-67-2]N-(2-chloroethyl)hexahydro-1H-azepine hydrochloride</strong> (102 mg, 0.515 mmol) was added in portions at room temperature. After the reaction mixture had been stirred for 6 h at 50 °C, saturated aqueous ammonium chloride was added at 0 °C. The mixture was extracted with dichloromethane and the organic layer was dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by thin layer chromatography on silica (eluant; ammoniacal chloroform/methanol = 15/1) to afford RID-F-S*5 (compound 23) (61.2 mg, 85percent) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 90℃; for 5h; Inert atmosphere; Darkness; | 1,1-Bis(4-hydroxyphenyl)-2-cyclohexyl-2-phenylethene To a suspension of zinc powder (1.15 g, 17.6 mmol) in THF (8 mL) at -10 °C was added titanium(IV) chloride (d 1.726, 0.872 mL, 7.93 mmol). The reaction mixture was diluted with THF (6 mL) and refluxed at 90 °C (bath temperature) for 2 h and then a mixture of 4,4’-dihydroxybenzophenone (891 mg, 4.16 mmol) and cyclohexyl phenyl ketone (245 mg, 1.30 mmol) in THF (15 mL) was added to the mixture at 0 °C. After the reaction mixture had been refluxed at 90 °C (bath temperature) for 5 h in the dark, 10% aqueous potassium carbonate was added to the mixture at 0 °C in the light. The mixture was filtered through a short pad of Celite with ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by column chromatography on silica (eluant; hexane/ethyl acetate= 2/1) to afford 1,1-bis(4-hydroxyphenyl)-2-cyclohexyl-2-phenylethene (314 mg, 65%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 90℃; for 2h; Inert atmosphere; Darkness; | 1,1-Bis(4-hydroxyphenyl)-2-pentylhept-1-ene To a suspension of zinc powder (501 mg, 7.66 mmol) in THF (3 mL) at -10 °C was added titanium(IV) chloride (d 1.726, 0.380 mL, 3.46 mmol). The reaction mixture was diluted with THF (1 mL) and then refluxed at 90 °C (bath temperature) for 2 h and then a mixture of 4,4’-dihydroxybenzophenone (389 mg, 1.82 mmol) and 6-undecanone (d 0.830, 0.116 mL, 0.565 mmol) in THF (8 mL) was added to the mixture at 0 °C. After the reaction mixture had been refluxed at 90 °C (bath temperature) for 2 h in the dark, 10% aqueous potassium carbonate was added to the mixture at 0 °C in the light. The mixture was filtered through a short pad of Celite with ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by thin layer chromatography on silica (eluant; hexane/ethylacetate = 2/1) to afford 1,1-bis(4-hydroxyphenyl)-2-pentylhept-1-ene (185 mg, 92%) as a pale yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 90℃; for 2h; Inert atmosphere; Darkness; | 1,1-Bis(4-hydroxyphenyl)-2-hexyloct-1-ene To a suspension of zinc powder (464 mg, 7.10 mmol) in THF (3 mL) at -10 °C was added titanium(IV) chloride (d 1.726, 0.350 mL, 3.18 mmol). The reaction mixture was diluted with THF (1 mL) and then refluxed at 90 °C (bath temperature) for 2 h and then a mixture of 4,4’-dihydroxybenzophenone (360 mg, 1.68 mmol) and 7-tridecanone (104 mg, 0.524mmol) in THF (8 mL) was added to the mixture at 0 °C. After the reaction mixture had been refluxed at 90 °C (bath temperature) for 2 h in the dark, 10% aqueous potassium carbonate was added to the mixture at 0 °C in the light. The mixture was filtered through a short pad of Celite with ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by thin layer chromatography on silica (eluant; hexane/ethylacetate = 2/1) to afford 1,1-bis(4-hydroxyphenyl)-2-hexyloct-1-ene (177 mg, 89%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a solution of 4,4?-dihydroxybenzophenone (2) (262mg, 1.22mmol) in DMF (12.2mL) was added 55% sodium hydride (dispersion in paraffin liquid, 428mg, 9.81mmol). The reaction mixture was stirred for 15min at 50C and then <strong>[7250-67-1]1-(2-chloroethyl)pyrrolidine hydrochloride</strong> (688mg, 4.05mmol) was added in portions at room temperature. After the reaction mixture had been stirred for 7.5h at 50C, saturated aqueous ammonium chloride was added at 0C. The mixture was extracted with dichloromethane, and the organic layer was washed with water and brine, and dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by column chromatography on silica (eluant; ammoniacal chloroform/methanol=9/1) to afford 3 (425mg, 85%) as a pale yellow solid: Mp: 109.8-110.5C; IR (KBr): 2962, 2796, 1643, 1601, 1512, 1477, 1319, 1261, 1250cm-1; 1H NMR (CDCl3): delta 7.81-7.72 (m, 4H, Ar), 7.03-6.91 (m, 4H, Ar), 4.20 (t, J=6.0Hz, 4H, OCH2), 2.95 (t, J=6.0Hz, 4H, NCH2), 2.72-2.56 (m, 8H, pyrrolidinyl 2-H), 1.89-1.76 (m, 8H, pyrrolidinyl 3-H); 13C NMR (CDCl3): delta 194.2 (1), 161.8, 132.0, 130.7, 113.9 (Ar), 66.8 (OCH2), 54.64 (NCH2), 54.55 (pyrrolidinyl 2-C), 23.3 (pyrrolidinyl 3-C); HR MS: calcd for C25H33N2O3 (M+H+) 409.2486, found 409.2486. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.87% | With potassium carbonate at 60℃; for 36h; Inert atmosphere; | |
46% | With potassium carbonate In acetone at 60℃; for 36h; Inert atmosphere; | 1.1 (1) Synthesis of compound 2 Weigh potassium carbonate (200mmol) into the reaction vessel, vacuum and change nitrogen three times, then inject 1,6-dibromohexane (38.85mL, 240mmol) into the reaction vessel through a constant pressure dropping funnel, and then inject a small amount of acetone (40mL) ), heated to 60°C to produce reflux, the remaining acetone (100mL) was first dissolved in 4,4'-dihydroxybenzophenone (80mmol) and then slowly dropped into the reaction vessel through a constant pressure dropping funnel, after 36 hours of reaction After cooling, the mixture was first removed with dilute hydrochloric acid to remove potassium carbonate, and then extracted with DCM and water three times. The excess solvent was removed by distillation under reduced pressure and then purified by silica gel chromatography. The eluent was PE:EA by volume ratio of 8: 1. A white solid product 2 with a yield of 46% was obtained.In the synthesis of compound 2, acetonitrile can be used as a solvent instead of acetone. |
With sodium hydroxide In dichloromethane at 20℃; for 48h; | 4,4’-Dihydroxy benzophenone 1 (2.142 g, 10 mmol) and 1,4-dibromobutane (17.273 g, 80 mmol) wereadded into the mixture of dichloromethane (50 mL) and 20% NaOH (50 mL) solution,the resulting mixture was stirred at room temperature for 48 hours. Thereaction solution was subsequently extracted and concentrated, and the crudematerial was purified by flash chromatography to afford the desired product 6 as a white solid in a 66.4% yield (3.215g). Bis[4-(4-bromobutoxy)phenyl]-methanone 6(1.452 g, 3 mmol) was added to a 250 mL two-necked round-bottomed flask whichwas vacuum-evacuated and argon-filled, followed by the addition of anhydrous THF(25 mL). The resulting solution was cooled to -78 oC, and TiCl4(1.0 mL) and Zn dust (0.585 g, 9 mmol) were added. The reaction mixture was allowedto warm up to 85 oC and was stirred at the same temperature underargon. After 3 hours, the reaction solution was cooled down to room temperatureand filtered through a silica gel pad. The filtrate was concentrated and the crudematerial was subsequently purified by silica gel chromatography eluting with petroleumether. Compound TPE-C4 was obtainedas a light yellow solid in a 47.2%yield (0.663 g). Compounds TPE-C2and TPE-C6 were prepared in the samefashion. All of the three TPEderivatives have been fully characterized with 1H NMR, 13CNMR and MS analyses. |
With potassium carbonate In acetonitrile Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 90℃; for 2h; Darkness; | 4.1 4.1. 2-[3-(Benzyloxy)phenyl]-l,l-bis(4-hydroxyphenyl) -1-butene (3): To a suspension of zinc powder (15.8 g, 242 mmol) in THF (30 mL) at -10 °C was added titanium(IV) chloride (12.0 mL, 109 mmol). The reaction mixture was diluted with THF (20 mL) and refluxed at 90 °C (bath temperature) for 2 h and then a mixture of 4,4'-dihydroxybenzophenone (1) (12.3 g, 57.3 mmol) and l-[3-(benzyloxy)phenyl]propanone (2) (4.30 g, 17.9 mmol) in THF (60 mL) was added to the mixture at 0 °C. After the reaction mixture had been refluxed at 90 °C (bath temperature) for 2 h in the dark, 10% aqueous potassium carbonate was added to the mixture at 0 °C in the light. The mixture was filtered through a short pad of Celite with ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was purified by column chromatography on silica gel (eluant; hexane/ethyl acetate = 2/1) to afford compound 3 (7.09 g, 94%) as a colorless solid: mp: 153-156 °C; IR (KBr): 3402, 3039, 2962, 1589, 1504, 1234 cm"1; NMR (CD3OD): δ 7.36-7.26 (5H, m, Ar), 7.08-6.95 (1H, m, Ar), 7.02 (2H, d, J= 8.5 Hz, Ar), 6.76 (2H, d, J= 8.5 Hz, Ar), 6.73-6.67 (3H, m, Ar), 6.67 (2H, d, J= 9.0 Hz, Ar), 6.45 (2H, d, J= 9.0 Hz, Ar), 4.86 (2H, s, Bn), 2.46 (2H, q, J= 7.5 Hz, 3-H), 0.90 (3H, t, J= 7.5 Hz, 4-H); C NMR (CD3OD): δ 159.8, 157.2, 156.4, 145.6, 141.3, 140.1, 138.8 (Ar), 136.4 (1), 136.3 (2), 132.9, 131.6, 130.7, 129.8, 129.4, 128.7, 128.6, 123.5, 117.9, 116.1, 115.8, 115.2, 114.1 (Ar), 71.0 (Bn), 29.7 (3), 14.0 (4); HR MS: calcd for C29H2603Na (M + Na+) m/z 445.1774, found 445.1780. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 60℃; for 12h; Inert atmosphere; | 2.3.2 Bis (4-(6-(9H-carbazol-9-yl) hexyloxy) phenyl) methanone(2a) A solution of 9-(6-bromohexyl)-9H-carbazole (1.00 g, 3 mmol) and 4,4′-dihydroxy benzophenone (0.30 g, 1.5 mmol) in DMF (20 mL) was stirred under an argon atmosphere at 60 °C. K2CO3 (0.26 g) and NaI (0.18 g) was added and the mixture was stirred for 12 h. After filtration, the filtrate was distilled under reduced pressure, and the crude residue was recrystallized from ethanol. A white powder was obtained (0.48 g, 45% yield). Mp 91.4-92.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 4H, J=7.6Hz), 7.73 (d, 4H, J=8.8Hz), 7.43 (d, 8H, J=16.2),7.22 (d, 4H, J=3.6), 6.87 (d, 4H, J=8.8Hz), 4.32 (t, 4H, J=6.8Hz), 3.97 (s, 4H), 1.92 (d, 4H, J=14.0Hz), 1.75 (d, 4H, J=13.4Hz), 1.55-1.38 (m, 8H); MS(m/z):713([M]+calcd for C49H48N2O3, 713); Anal. Calc. for C49H48N2O3: C 82.55, H 6.76, N 3.93; Found: C 82.37, H 6.73, N 3.99%. |
45% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 60℃; for 48h; Inert atmosphere; | 2.4.2. Synthesis of compound 2 A solution of 9-(6-bromohexyl)-9H-carbazole (1.03 g, 3.1 mmol)and 4,4′-dihydroxy benzophenone (0.31 g, 1.4 mmol) in DMF (20 mL)was stirred under an argon atmosphere at 60 °C. K2CO3 (0.26 g,1.7 mmol) and NaI (0.18 g, 1.1 mmol) was added and the mixture was stirred for 48 h. After filtration, the filtrate was distilled under reduced pressure, and the crude residue was recrystallized from ethanol. Awhite powder was obtained (0.48 g, 45% yield). 1H NMR (500 MHz,CDCl3) δ 8.09 (d, J=7.6 Hz,4H),7.73 (d, J=8.8 Hz,4H), 7.43 (d,J=16.2,8H),7.22 (d, J=3.6,4H), 6.87 (d, J=8.8 Hz, 4H), 4.32 (t,J=6.8 Hz, 4H), 3.97 (s, 4H), 1.92 (d, J=14.0 Hz, 4H), 1.75 (d,J=13.4 Hz, 4H), 1.55-1.38 (m, 8H); MS (MALDI-TOF), m/z: 713.401([M+H]+ calcd for C49H48N2O3, 712.366). |
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 60℃; for 48h; Inert atmosphere; | 1.2 2) Synthesis of Compound 2: In a 100 mL three-necked flask equipped with a reflux unit and argon gas,The compound N-6-bromohexyl-9H-carbazole (1.03 g, 3.12 mmol,The formula is: 20 mL DMF, K2CO3 (0.26 g, 1.69 mmol), NaI (0.18 g, 1.08 mmol),4,4'-dihydroxybenzophenone (0.31 g, 1.42 mmol).The reaction was stirred at a temperature of 60 ° C for 48 h and then filtered.The filtrate is subjected to distillation under reduced pressure.The obtained solid was recrystallized from ethanol to give a white solid product.which is:Compound 2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With titanium tetrachloride; zinc In tetrahydrofuran at 0 - 20℃; for 5h; Inert atmosphere; Reflux; | |
79% | With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 90℃; for 3h; | 1 Titanium tetrachloride (1.30 mL, 11.8 mmol) was added dropwise at -10 ° C. to a solution of zinc (1.64 g, 25.2 mmol) in tetrahydrofuran (8.0 mL) followed by tetrahydrofuran (6.0 mL) . The temperature was raised to room temperature and then stirred at 90 ° C. for 2 hours. The reaction system was cooled with ice and a mixed solution of 4,4'-dihydroxybenzophenone (399.1mg, 1.86 mmol) and 3-pentanone (0.63 mL, 6.00 mmol) in tetrahydrofuran (14.0 mL) was added. The reaction system was shielded from light and stirred at 90 ° C. for 3 hours. The reaction was terminated by adding 10% potassium carbonate aqueous solution to the reaction system at 0° C. After filtration through Celite, diethyl ether was added to separate the layers, and the mixture was extracted with diethyl ether from the aqueous layer. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Hexane / EtOAc = 2/1) to obtain 1,1-bis (4-hydroxyphenyl) -2-ethyl-1-butene (391.6 mg , 79%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran at 0 - 20℃; for 5h; Inert atmosphere; Reflux; | |
86% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Reflux; | 81.1 Step 1: Preparation of 4,4’-(4-chloro-2-phenylbut-1-ene-1,1-diyl)biphenol (SIAIS208102) according to Scheme 18: A dry three-necked flask equiped with a reflux device was charged with Zinc powder (6.5 g, 100 mmol), evacuatedand refilled with the air three times, and then THF (80 mL) was added under Ar gas, and followed by dropping TiCl4 (9.5g, 50 mmol) at 0°C. After removing the ice bath, the reaction mixture was warmed to room temperature and heated toreflux for 2 h. After cooling to room temperature, solutions of compounds 1 (2.14 g, 10 mmol) and 2 (5.1 g, 30 mmol) inTHF (80 mL) were added, and refluxed for 3 h in the dark. After the reaction is complete, the reaction mixture was cooledand rotary-evaporated to remove most of the solvent, quenched with saturated ammonium chloride solution, and extractedwith ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried with anhydroussodium sulfate, rotary-evaporated to dryness, and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=2:1) to obtain 3 g of yellow solid product with a yield of 86%. 1H NMR (500 MHz, CDCl3) δ 7.21 -7.10 (m, 7H), 6.84 - 6.81 (m, 2H), 6.75 - 6.72 (m, 2H), 6.49 - 6.46 (m, 2H), 4.99 (s, 1H), 4.73 (s, 1H), 3.45 - 3.36 (m,2H), 2.99 - 2.91 (m, 2H). HRMS (ESI) m/z: calcd for, C22H20ClO2+ [M+H]+, 351.1146; found, 351.1138. |
86% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 3h; Inert atmosphere; Reflux; Darkness; | 1 Synthesis of 4,4'-(4-chloro-2-phenylbut-1-ene-1,1-diyl)biphenol (SIAIS 208102) A dried three-necked flask equipped with a reflux condenser was charged with Zinc powder (6.5 g, 100 mmol), followed by evacuation and refilling with argon gas for three times, and then addition of THF (80 mL) under argon. TiCl4 was added dropwise at 0° C. The mixture was warmed to r.t., and refluxed for 2 h. After the mixture was cooled to room temperature, a solution of compound 1 (2.14 g, 10 mmol) and compound 2 (5.1 g, 30 mmol) in THF (80 mL) was added, and refluxed in the dark for 3 h. After the reaction was complete, the resulting mixture was cooled down to r.t., and rotary evaporated to remove most of the solvent. The reaction was quenched with saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was then separated and purified by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate=2:1) to obtain a yellow solid product (3 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.21-7.10 (m, 7H), 6.84-6.81 (m, 2H), 6.75-6.72 (m, 2H), 6.49-6.46 (m, 2H), 4.99 (s, 1H), 4.73 (s, 1H), 3.45-3.36 (m, 2H), 2.99-2.91 (m, 2H). HRMS (ESI) m/z: calcd for C22H20ClO2+ [M+H]+, 351.1146; found, 351.1138. |
86% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 3h; Inert atmosphere; Reflux; Darkness; | 1 Synthesis of 4,4'-(4-chloro-2-phenylbut-1-ene-1,1-diyl)biphenol (SIAIS 208102) A dried three-necked flask equipped with a reflux condenser was charged with Zinc powder (6.5 g, 100 mmol), followed by evacuation and refilling with argon gas for three times, and then addition of THF (80 mL) under argon. TiCl4 was added dropwise at 0° C. The mixture was warmed to r.t., and refluxed for 2 h. After the mixture was cooled to room temperature, a solution of compound 1 (2.14 g, 10 mmol) and compound 2 (5.1 g, 30 mmol) in THF (80 mL) was added, and refluxed in the dark for 3 h. After the reaction was complete, the resulting mixture was cooled down to r.t., and rotary evaporated to remove most of the solvent. The reaction was quenched with saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was then separated and purified by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate=2:1) to obtain a yellow solid product (3 g, 86% yield). 1H NMR (500 MHz, CDCl3) δ 7.21-7.10 (m, 7H), 6.84-6.81 (m, 2H), 6.75-6.72 (m, 2H), 6.49-6.46 (m, 2H), 4.99 (s, 1H), 4.73 (s, 1H), 3.45-3.36 (m, 2H), 2.99-2.91 (m, 2H). HRMS (ESI) m/z: calcd for C22H20ClO2+ [M+H]+, 351.1146; found, 351.1138. |
70% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux; | 4.1.1. Method A. McMurry reductive coupling reaction General procedure: General procedure: To a stirred suspension of zinc powder (31 mmol) in dry THF (30 mL) was added TiCl4 (14 mmol), under Ar, at 10 C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. After titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 C and then a solution of 4,4'-hydroxybenzophenone (2.3 mmol)and substituted-phenone (6.7 mmol) in dry THF (40 mL) at 0 C was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature (25 C); and quenched with 10% aqueous potassium carbonate(50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. |
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 2h; Reflux; | 1.1.1 Synthesis of methyl 4-ene-5,5-bis-(4-hydroxyphenyl)-4-ruthenocenyl-pentanoate TiCLt (0.6 ml, 5.5 mmol) was added dropwise to a suspension of zinc powder (0.6 g, 9.2 mmol) in 8 ml of THF at 0°C. The dark grey mixture obtained was heated at reflux for 2 h. A solution of THF (8 ml) containing 4,4'-dihydroxybenzophenone (0.65 g, 3 mmol) and methyl 4-oxo-4-ruthenocenylbutanoate (0.47 g, 1.36 mmol) was added dropwise to the first solution and the resulting mixture was heated for 2 h. After cooling to room temperature, the mixture was acidified by addition of diluted HC1. The aqueous layer was extracted with EtOAc for three times. The combined organic layer was dried over MgS04 and evaporated. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc (2: 1) to give methyl 4-ene-5,5-bis- (4-hydroxyphenyl)-4-ruthenocenyl-pentanoate as a light yellow solid 613 mg, yield 85%. 1H NMR (300 MHz, Acetone-^) δ 2.45 (t, J = 7.5 Hz, 2H, CH2), 2.66 (t, J = 7.5 Hz, 2H, CH2), 3.56 (s, 3H, OCH3), 4.34 (t, J = 3.0 Hz, 2H, C5H4), 4.39 (t, J = 3.0 Hz, 2H, C5H4), 4.54 (s, 5H, C5H5), 6.67 (d, J = 8.6 Hz, 2H, C6H4), 6.79 (d, J = 8.6 Hz, 2H, C6H4), 6.86 (d, J= 8.6 Hz, 2H, C6H4), 6.99 (d, J= 8.5 Hz, 2H, C6H4), 8.21 (s, 1H, OH), 8.28 (s, 1H, OH); 13C NMR (75 MHz, Acetone-^) δ 32.4 (CH2), 35.1 (CH2), 51.5 (OCH3), 70.4 (2 CH C5H4), 71.8 (5 CH C5H5), 72.8 (2 CH C5H4), 93.4 (C C5H4), 115.9 (2 CH C6H4), 1 15.5 (2 CH C6H4), 131.9 (2 CH, C6H4), 131.1 (2 CH, C6H4), 132.3 (2 C C=C), 136.8 (C C6H4), 140.7 (C C6H4), 156.9 (C C6H4), 156.7 (C C6H4), 173.8 (C CO). |
85% | With titanium tetrachloride; zinc In tetrahydrofuran for 2h; Reflux; | 1.1.1 Synthesis of methyl 4-ene-5,5-bis-(4-hydroxyphenyl)-4-ruthenocenyl-pentanoate (W2) TiCl4 (0.6 ml, 5.5mmol) was added dropwise to a suspension of zinc powder (0.6 g, 9.2 mmol) in 8 ml of THF at 0°C. The dark grey mixture obtained was heated at reflux for 2 h. A solution of THF (8 ml) containing 4,4’-dihydroxybenzophenone (0.65 g,3 mmol) and methyl 4-oxo-4-ruthenocenylbutanoate (0.47 g, 1.36 mmol) was added dropwise to the first solution andthe resulting mixture was heated for 2 h. After cooling to room temperature, the mixture was acidified by addition ofdiluted HCl. The aqueous layer was extracted with EtOAc for three times. The combined organic layer was dried overMgSO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc (2:1)to give methyl 4-ene-5,5-bis-(4-hydroxyphenyl)-4-ruthenocenyl-pentanoate as a light yellow solid 613 mg, yield 85%.1H NMR (300 MHz, Acetone-d6) δ 2.45 (t, J= 7.5 Hz, 2H, CH2), 2.66 (t, J= 7.5 Hz, 2H, CH2), 3.56 (s, 3H, OCH3), 4.34(t, J = 3.0 Hz, 2H, C5H4), 4.39 (t, J = 3.0 Hz, 2H, C5H4), 4.54 (s, 5H, C5H5), 6.67 (d, J= 8.6 Hz, 2H, C6H4), 6.79 (d, J=8.6 Hz, 2H, C6H4), 6.86 (d, J= 8.6 Hz, 2H, C6H4), 6.99 (d, J= 8.5 Hz, 2H, C6H4), 8.21 (s, 1H, OH), 8.28 (s, 1H, OH); 13CNMR (75 MHz, Acetone-d6) δ 32.4 (CH2), 35.1 (CH2), 51.5 (OCH3), 70.4 (2 CH C5H4), 71.8 (5 CH C5H5), 72.8 (2 CHC5H4), 93.4 (C C5H4), 115.9 (2 CH C6H4), 115.5 (2 CH C6H4), 131.9 (2 CH, C6H4), 131.1 (2 CH, C6H4), 132.3 (2 CC=C), 136.8 (C C6H4), 140.7 (C C6H4), 156.9 (C C6H4), 156.7 (C C6H4), 173.8 (C CO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 2h; | Methyl 5,5-bis(4-hydroxyphenyl)-4-ferrocenylpent-4-enoate (14). General procedure: TiCl4 (3.8mL, 33mmol) was added dropwise to a suspension of zinc powder (4.5g, 66mmol) in 40mL of THF at 0°C. The dark grey mixture obtained was heated at refluxing for 2h. A solution of THF (20mL) containing 4,4'-dihydroxybenzophenone (4.91g, 22mmol) and 4-oxo-4-ferrocenylbutanoate (3.13g, 10mmol) was added dropwise to the first solution and the resulting mixture was heated for 2h. After cooling to room temperature, the mixture was acidified by addition of dilute HCl solution. The aqueous layer was extracted with EtOAc for three times. The combined organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (2:1) to give methyl 5,5-bis(4-hydroxyphenyl)-4-ferrocenylpent-4-enoate as a red solid 2.8g, yield: 58%. |
68% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran at 10℃; Reflux; | 1.1.2 5-chloro-2-ferrocenyl-1,1-bis-(4-hydroxyphenyl)-pent-1-ene, P687 General procedure: Titanium chloride was added dropwise to a suspension of zinc powder in dry THF at 10°C. The mixture washeated at reflux for 2 hours. A second solution was prepared by dissolving the corresponding ketone (equimolar) in dryTHF. This latter solution was added dropwise to the first solution and then the reflux was continued for 2 hours or more.After cooling to room temperature, the mixture was stirred with water and dichloromethane. The mixture was acidifiedwith diluted hydrochloric acid until dark color disappeared and was decanted. The aqueous layer was extracted withdichloromethane and the combination of organic layers was dried on magnesium sulphate. After concentration underreduced pressure, the crude product was chromatographed on silica gel column with a mixture of cyclohexane/ethylacetate as the eluent. Yield: 68%. 1H NMR (acetone D6): δ 1.89-2.02 (m, 2 H, CH2), 2.84 (t, J = 8.0 Hz, 2 H, CH2), 3.54 (t, J = 8.0Hz, 2 H, CH2), 4.00 (t, J = 1.9 Hz, 2 H, CH C5H4), 4.12 (t, J = 1.9 Hz, 2 H, CH C5H4), 4.17 (s, 5 H, Cp), 6.74 (d, J = 8.7Hz, 2 H, C6H4), 6.86 (d, J = 8.7 Hz, 2 H, C6H4), 6.90 (d, J = 8.7 Hz, 2 H, C6H4), 7.10 (d, J = 8.7 Hz, 2 H, C6H4), 8.29 (s,1 H, OH), 8.34 (s, 1 H, OH). 13C NMR (acetone D6): δ 33.8 (CH2), 35.1 (CH2), 46.7 (CH2Cl), 69.5 (2 CH C5H4), 70.6(5CH Cp), 70.7 (2 CH C5H4), 89.1 (C C5H4), 116.5 (2 CH C6H4), 116.7 (2 CH C6H4), 132.0 (2 CH C6H4), 132.5 (2 CHC6H4), 134.7 (C), 137.6 (C), 138.0 (C), 140.7 (C), 157.5 (C). IR (KBr, ν cm-1): 3433 (OH), 3085, 2951, 2868 (CH, CH2).MS (CI, NH3) m/z: 473 [M+H]+. HRMS (ESI, C27H25ClFeO2: [M]+) calcd: 472.0892, found: 472.0887. |
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran |
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran Reflux; | ||
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran Reflux; | 4.2. General procedure for McMurry coupling General procedure: Titanium chloride was added dropwise to a suspension of zincpowder in dry THF at 10e20 C. The mixture was heated at refluxfor 2 h. A second solution was prepared by dissolving the two ketonesin dry THF. This latter solution was added dropwise to thefirst solution and then the reflux was continued for the indicatedtime. After cooling to room temperature, the mixture was stirredwith water and dichloromethane. The mixture was acidified withdilute hydrochloric acid until the dark color disappeared and was then decanted. The aqueous layer was extracted with dichloromethaneand the combination of organic layers was dried onmagnesium sulfate. After concentration under reduced pressure,the crude product was flash chromatographed on silica gel columnwith the indicated eluent to afford the alkenes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With titanium tetrachloride; zinc; In tetrahydrofuran; for 2h;Inert atmosphere; Reflux; | General procedure: To a suspension of zinc powder (1.50 g, 23.1 mmol) in THF (15 mL) was added dropwise titanium(IV) chloride (1.20 mL, 10.9 mmol) at -10 C under Ar. The mixture was refluxed with stirring for 3 h, and a solution of 4,4'-dimethoxybenzophenone (726 mg, 3.00 mmol) and 3,3-dimethylcyclohexanone (0.420 mL, 3.03 mmol) in THF (13 mL) was added dropwise. The mixture was refluxed with stirring for 2 h. The reaction mixture was cooled to room temperature, and poured slowly into saturated aqueous NaHCO3. Et2O was added to the aqueous solution, and the heterogeneous mixture was filtered through Celite. The filtrate was extracted with Et2O, washed with brine, dried over MgSO4, and concentrated. Purification of the residue by silica gel column chromatography (eluent: n-hexane/AcOEt, 40:1) gave 22 (90%). 4.2.18 3-[Bis(4-hydroxyphenyl)methylene]cyclohexanone (26) McMurry coupling of 4,4'-dihydroxybenzophenone and <strong>[4969-01-1]1,3-cyclohexanedione mono-ethylene ketal</strong> was performed by the same method as that used for preparation of 22. Purification by silica gel column chromatography (eluent: n-hexane/AcOEt, from 3:1 to 2:1) gave the methylene product (45%). 1H NMR (CDCl3) delta 1.62-1.68 (2H, m), 1.77 (2H, t, J = 5.8 Hz), 2.25 (2H, t, J = 5.8 Hz), 2.41 (2H, s), 3.82-3.94 (4H, m), 4.79 (2H, s), 6.73 (4H, d, J = 8.7 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.05 (2H, d, J = 8.7 Hz); HRMS Calcd for C21H22O4 338.1519. Found 338.1522. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In ethanol; at 20℃;Inert atmosphere; | General procedure: To a solution of bis(4-hydroxy)benzophenone (100 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine HCl (69 mg, 0.99 mmol) at ambient temperature. The reaction mixture was stirred until complete consumption of the starting material on TLC and quenched with H2O. The resulting mixture was diluted with EtOAc, and the organic phase was washed with H2O and brine, dried over MgSO4 and concentrated in vacuo Purification of the residue via flash column chromatography on silica gel (EtOAc : Hexane = 1 : 5 to 1 : 3) afforded 90 mg (84 %) of 12a as colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol; at 20.0℃;Inert atmosphere; | General procedure: To a solution of bis(4-hydroxy)benzophenone (100 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine HCl (69 mg, 0.99 mmol) at ambient temperature. The reaction mixture was stirred until complete consumption of the starting material on TLC and quenched with H2O. The resulting mixture was diluted with EtOAc, and the organic phase was washed with H2O and brine, dried over MgSO4 and concentrated in vacuo Purification of the residue via flash column chromatography on silica gel (EtOAc : Hexane = 1 : 5 to 1 : 3) afforded 90 mg (84 %) of 12a as colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With titanium tetrachloride; zinc; In tetrahydrofuran; at -78 - 60℃;Inert atmosphere; | Under an inert atmosphere and _78 C,Equimolar amounts of 4,4 '- dihydroxybenzophenone and 4,4' - dibromobenzophenone,And 8.0 equivalents of zinc powder were added to the three-necked flask,Ar gas ventilation three times,With a syringe into anhydrous tetrahydrofuran; then Ar gas ventilation three times,With the syringe slowly into the 4.0 equivalent of titanium tetrachloride; the solution to room temperature after 30min reaction, the temperature to 60 C,The reaction was allowed to stand overnight; the reaction solution was allowed to cool to room temperature,concentrate,Then 30 mL of 10% aqueous potassium carbonate solution was added;After extraction with 30 mL of ethyl acetate three times,Combine organic phase,Dried over anhydrous sodium sulfate;Concentrated to give the crude product; purified by column chromatography to give compound 5 in 26% yield; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 0 - 60 °C 2: zinc; titanium tetrachloride / tetrahydrofuran / 2.5 h / 0 °C / Inert atmosphere; Reflux 3: potassium carbonate / acetonitrile / 24 h / 80 °C 4: methanol; water / 16 h / 80 °C / Sealed tube 5: boron tribromide / dichloromethane / 0.5 h / -78 °C | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile; water / 16 h / 80 °C / Large scale 2: titanium tetrachloride; zinc / tetrahydrofuran / 16 h / 0 - 80 °C 3: sodium iodide / tetrahydrofuran / 16 h / 70 °C / Autoclave |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In acetonitrile at 20℃; for 4h; Inert atmosphere; | 1-7-1 Synthesis of Ketone 1 In nitrogen atmosphere, Hydroxy-ketone 1(10.0 g) and triethylamine (13.2 g) were mixed with acetonitrile (50 ml). Below 20° C., Protecting agent 1 (13.7 g) was added dropwise. Stirring was continued at room temperature for 4 hours. Water (30 ml) was added to the reaction solution to quench the reaction. This was followed by ordinary aqueous workup. The product was purified by silica gel column chromatography, obtaining Ketone 1 (16.6 g, yield 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With titanium tetrachloride; zinc In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux; | 4.1.1. Method A. McMurry reductive coupling reaction General procedure: General procedure: To a stirred suspension of zinc powder (31 mmol) in dry THF (30 mL) was added TiCl4 (14 mmol), under Ar, at 10 C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. After titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 C and then a solution of 4,4'-hydroxybenzophenone (2.3 mmol)and substituted-phenone (6.7 mmol) in dry THF (40 mL) at 0 C was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature (25 C); and quenched with 10% aqueous potassium carbonate(50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. |
79% | With titanium tetrachloride; zinc In tetrahydrofuran at -10 - 0℃; for 2.5h; Inert atmosphere; Reflux; | 2 Method A. McMurry Reductive Coupling Reaction. General procedure: To a stirred suspension of zinc powder (31 mmol) in dry THF (30 mE) was added TiC14 (14 mmol), under Ar, at 10° C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. Afier titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 degree C. and then a solution of 4,4’-hydroxybenzo- phenone (2.3 mmol) and substituted-phenone (6.7 mmol) in dry THF (40 mE) at 0° C. was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature (25° C.); and quenched with 10% aqueous potassium carbonate (50 mE) and extracted with EtOAc. The organic layer was washed with brine, dried over Mg504, and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux; | 4.1.1. Method A. McMurry reductive coupling reaction General procedure: General procedure: To a stirred suspension of zinc powder (31 mmol) in dry THF (30 mL) was added TiCl4 (14 mmol), under Ar, at 10 C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. After titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 C and then a solution of 4,4'-hydroxybenzophenone (2.3 mmol)and substituted-phenone (6.7 mmol) in dry THF (40 mL) at 0 C was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature (25 C); and quenched with 10% aqueous potassium carbonate(50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. |
With titanium(IV) tetrachloride; zinc powder In tetrahydrofuran Reflux; | 4.2. General procedure for McMurry coupling General procedure: Titanium chloride was added dropwise to a suspension of zincpowder in dry THF at 10e20 C. The mixture was heated at refluxfor 2 h. A second solution was prepared by dissolving the two ketonesin dry THF. This latter solution was added dropwise to thefirst solution and then the reflux was continued for the indicatedtime. After cooling to room temperature, the mixture was stirredwith water and dichloromethane. The mixture was acidified withdilute hydrochloric acid until the dark color disappeared and was then decanted. The aqueous layer was extracted with dichloromethaneand the combination of organic layers was dried onmagnesium sulfate. After concentration under reduced pressure,the crude product was flash chromatographed on silica gel columnwith the indicated eluent to afford the alkenes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With titanium tetrachloride; zinc In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux; | 4.1.1. Method A. McMurry reductive coupling reaction General procedure: General procedure: To a stirred suspension of zinc powder (31 mmol) in dry THF (30 mL) was added TiCl4 (14 mmol), under Ar, at 10 C. When the addition was complete, the mixture was warmed to room temperature and then refluxed. After titanium reagent was refluxed for 2.5 h, the mixture was cooled to 0 C and then a solution of 4,4'-hydroxybenzophenone (2.3 mmol)and substituted-phenone (6.7 mmol) in dry THF (40 mL) at 0 C was added to the mixture. Upon completion of addition of solution, the mixture was refluxed in the dark for 2.5 h, cooled to room temperature (25 C); and quenched with 10% aqueous potassium carbonate(50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In hexane; N,N-dimethyl-formamide; | EXAMPLE 1 Preparation of bis(4-(2-quinolylmethoxy)phenyl)methyloximinoacetic acid STR11 Step 1: bis(4-(2-quinolylmethoxy)phenyl) ketone To a solution of 4-4'-dihydroxybenzophenone (4.22 g, 20 mmol) and K2 CO3 (16.5 g, 120 mmol) in DMF (75 mL) was added 2-chloromethylquinoline hydrochloride (8.56 g, 40 mmol) and the resulting solution was stirred at 60 C. or 16 hours. The reaction mixture was then poured into ice water (100 mL and the resulting solid was collected by filtration, slurried in 20% ether/hexane, filtered, and dried in vacuo to afford bis(4-(2-quinolylmethoxy)phenyl) ketone (9.3 g, 94%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With titanium tetrachloride; zinc In tetrahydrofuran at 75℃; for 4h; Inert atmosphere; | |
95% | With titanium tetrachloride; zinc In tetrahydrofuran at 75℃; for 4h; | 4,4'-((Adamantan-2-ylidene)methylene)diphenol (18). Titanium tetrachloride (11.36 mL, 0.10 mol), was added dropwise at -20 °C to a suspension of zinc (13.7 g, 20.95 mol) in THF (140 mL). After removal of the cooling, the reaction mixture was refluxed at 75 °C for 2.5 hours. After allowing the solution to cool down to rt, a mixture of 2-adamantanone (4.2 g, 27.96 mmol) and 4,4-dihydroxybenzophenone (6 g, 28.01 mmol) in THF (40 mL) was added and refluxed again for 4 hours. The heating was stopped and the reaction mixture was cooled, when a 10% K2CO3 solution (200 mL) was poured into the reaction flask and stirred overnight. The resulting emulsion was filtered through celite, extracted with Et20 (3x200 ml), washed with brine (80 ml) and dried (NaiSCL). The solvent was evaporated to afford a white solid, which was further washed with CH2CI2 to give the pure product (8.8. g, 95% yield) as a white solid. NMR (500 MHz, CD3OD): d 6.94 - 6.91 (m, 4H), 6.70 - 6.66 (m, 4H), 2.68 (br s, 2H), 2.12 - 2.00 (m, 2H), 1.86-1.72 (m, 10H), 1.62 - 1.54 (m, 2H). 13C NMR (l26 MHz, CD3OD) d 155.4, 144.6, 134.8, 130.8, 130.3, 114.4, 39.4, 37.1, 34.6, 28.5. |
With titanium tetrachloride; zinc In tetrahydrofuran for 4h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
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71% | Stage #1: thiosemicarbazide With toluene-4-sulfonic acid In methanol; water at 70℃; Stage #2: 4,4'-Dihydroxybenzophenone In methanol; water at 70℃; | 3.4. General Procedure for the Synthesis of Thiosemicarbazones (2a-j) General procedure: Thiosemicarbazide (2.75 mmol) and p-toluenesulfonic acid monohydrate catalytic were dissolvedin methanol (20 mL) and water (1 mL). The solution was refluxed for 15 min followed by the additionof benzophenone (2.75 mmol) [44]. Then the resulting precipitate was isolated by filtration andrecrystallized or purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In benzene; at 20 - 30℃; for 1h;Inert atmosphere; | In a reaction vessel equipped with a mechanical stirring and temperature control device, 36 parts of 4,4'-dihydroxybenzophenone, 420 parts of benzene and 15 parts of triethylamine were placed. After nitrogen gas was stirred for 30 min, 99 parts of diphenyl chlorophosphate was added. After the addition was completed, the mixture was stirred at 20-30 C for 1 h. The system was clarified by turbidity, and the reaction was quenched with water. The solvent was evaporated under reduced pressure and extracted three times with dichloromethane. The organic phase was washed three times with deionized water, and the methylene chloride was evaporated to dryness to give a colorless liquid, which was purified by column chromatography ( petroleum ether: ethyl acetate = 5:1, V/V) to give a white solid DHP. . |
With mechanical agitation,12 parts of 4,4'-dihydroxybenzophenone was added to the reaction vessel of the temperature control device.140 parts of solvent,5 parts of triethylamine.Passing nitrogen,After stirring at 20-30 C for 30 min, 33 parts of diphenyl chlorophosphate was added.After the addition, the mixture was stirred at 20-30 C for 1 h.The system is clarified by turbidity,Add water to quench the reaction,Evaporate the solvent under reduced pressure.Extracted 3 times with dichloromethane,The organic phase was washed 3 times with deionized water.Evaporate the dichloromethane under reduced pressure.Obtaining a colorless liquid,Separation and purification of the product by column chromatography (petroleum ether: ethyl acetate = 5:1, V/V),A white solid DHPP was obtained. | ||
.In the reaction vessel equipped with a stirring device and a temperature control device, 18 parts of 4,4'-dihydroxybenzophenone, 210 parts of xylene, and 7 parts of triethylamine are added; and the mixture is stirred under nitrogen at 20 to 30 C. After 30 minutes, 50 parts of diphenyl chlorophosphate was added. After the addition was completed,The reaction was stirred at 20~30 C for 1 h, the system was clarified by turbidity, and the reaction was quenched with water. The mixture was extracted three times with dichloromethane, and the organic phase was washed three times with deionized water, and dichloromethane was evaporated to give a colorless liquid. Column chromatography (petroleum ether: ethyl acetate = 5:1, V/V)Separate and purify the product to give a white solidDiphenyl benzophenone 4,4'-diphosphate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With C6H4MoNO7(1-)*C19H42N(1+); oxygen In water at 100℃; for 20h; Green chemistry; chemoselective reaction; | 2.3. General procedure for the catalytic oxidation of alcohols toaldehydes General procedure: A mixture of alcohol (0.75 mmol), and catalyst Mo1 (13 mg,3.0 mol%) taken in 0.5 mL of water was stirred at 100 ° C under oxygenatmosphere (O2 bladder) and the stirring was continued for16-24 h as per requirement. The progress of reaction was monitoredby TLC. After completion of the reaction, ethyl acetate was added to the mixture. The aqueous phase was extracted with ethyl acetate 2-3 times. Then the combined organic extracts were driedover anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product so obtained was purified by column chromatography using hexane-ethyl acetate as eluent. While the known products were characterized by spectroscopic techniques and compared with reported data and the new products 22b and 36b were characterized completely. The characterization detail is provided in supporting information section. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | Stage #1: Diphenylmethane With n-butyllithium In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: 4,4'-Dihydroxybenzophenone In tetrahydrofuran at 20℃; Inert atmosphere; | Synthesis of compound 2: Take a 250mL three-necked round bottom flask and add diphenylmethane (5.8g, 34.68mmol), then vacuum for 3min, slowly pour nitrogen in for 2 minutes. After the exchange cycle for 3 times, finally, under the protection of nitrogen, inject 70 mL of freshly distilled tetrahydrofuran, turn on the stirring, put the reaction solution in an ice bath to 0°C, and then use a constant pressure dropping funnel to drop 20.60 dropwise. mL n-butyllithium (33.03mmol, 2.5mol/L) solution, 0.5h was added dropwise, continue to stir at 0°C for 0.5h, then add compound 1 (8.0g, 33.0mmol) with a solid addition funnel, remove the ice bath, react overnight at room temperature. After the reaction of the raw materials is completed, 60 mL of saturated NH4Cl aqueous solution is added dropwise to quench the reaction, Separate the organic phase, extract the water layer with chloroform three times and combine with the organic phase, add anhydrous MgSO4 to dry, Then the MgSO4 solid was filtered under reduced pressure and rotary evaporated to obtain a white solid, and then recrystallized with CHCl3-CH3OH to obtain 12.3 g of a white solid with a yield of 90.7%. The yields in this reaction were all R1 = R2 = H as an example. |
Tags: 611-99-4 synthesis path| 611-99-4 SDS| 611-99-4 COA| 611-99-4 purity| 611-99-4 application| 611-99-4 NMR| 611-99-4 COA| 611-99-4 structure
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