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CAS No. : | 1501-05-9 | MDL No. : | MFCD00004411 |
Formula : | C11H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SHKWSBAVRQZYLE-UHFFFAOYSA-N |
M.W : | 192.21 | Pubchem ID : | 73914 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 52.83 |
TPSA : | 54.37 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) : | -6.41 cm/s |
Log Po/w (iLOGP) : | 1.59 |
Log Po/w (XLOGP3) : | 1.49 |
Log Po/w (WLOGP) : | 2.12 |
Log Po/w (MLOGP) : | 1.61 |
Log Po/w (SILICOS-IT) : | 2.15 |
Consensus Log Po/w : | 1.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.96 |
Solubility : | 2.12 mg/ml ; 0.011 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.24 |
Solubility : | 1.11 mg/ml ; 0.00577 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.94 |
Solubility : | 0.222 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.32 |
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 |
---|---|---|
85% | With aluminum (III) chloride; at 0℃; for 1h;Reflux; | Stirred benzene (Aa) (60 mL) and glutaric anhydride (B) (44 mmol) at 0 CTo this was added powdery anhydrous aluminum chloride (96.5 mmol), and the resulting mixture was refluxed for 1 hour.The reaction mixture was then cooled to 0 C and slowly cooled with water at the same temperature.Neutralize and extract with saturated sodium carbonate solution.Acidified with hydrochloric acid to pH 1 and the aqueous solution was concentrated,Extracted with ethyl acetate (100 mL 3). The extract was dried over anhydrous MgSO4,Concentrated in vacuo to give crude 4-benzoylbutanoic acid (1a),It was recrystallized from petroleum ether and ethyl acetate with a yield of 85%. |
83% | With aluminum (III) chloride; at 8 - 20℃; for 19.5h; | A flask was charged with AlCl3 (96.38 mmol, 12.85 g, 2.2 equiv) and dry benzene (20 ml) under calcium chloride guard tube and the formed suspension was stirred on ice bath. Subsequently, a solution of glutaric anhydride 10 (43.8 mmol, 5.00 g) in dry benzene (40 ml) was added dropwise over 30 minutes (t < 8 C). The cooling bath was removed and the resulting mixture was stirred at room temperature for 19 hours. The mixture was carefully quenched with water (95 ml) and conc. H2SO4 (10 ml), the aqueous layer was extracted with ethyl acetate (1 x 200 ml, 3 x 50 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The crude product was crystallized from ethyl acetate to yield 5-oxo-5-phenylpentanoic acid (7.00 g, 83%) as a yellow-brown powder;1 mp 124-125 C; 1H NMR (300 MHz, acetone-d6): delta = 1.99 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 7.51 (m, 2H), 7.62 (m, 1H), 8.01 (d, J = 7.8 Hz, 2H), 10.56 (bs, 1H). 5-Oxo-5-phenylpentanoic acid (26.1 mmol, 5.02 g), paraformaldehyde (78.3 mmol, 2.35 g, 3.0 equiv) and piperidine (5.3 mmol, 0.52 ml, 0.2 equiv) were dissolved/suspended in pyridine (22 ml) and stirred at 70 C for 21 hours. Afterwards, the mixture was poured into 3M H2SO4 (100 ml), the aqueous layer was extracted with ethyl acetate (3 x 100 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The residue was redissolved in CH2Cl2 (100 ml) and extracted with a mixture of half-saturated aqueous NaHCO3 (300 ml) and 2M NaOH (20 ml). The extraction was repeated with half-saturated aqueous NaHCO3 (50 ml). The combined aqueous solutions were washed with CH2Cl2 (2 x 50 ml) and afterwards acidified with conc. H2SO4 to pH = 1-2 and extracted with ethyl acetate (1 x 100 ml, 3 x 70 ml). The combined organics were dried over Na2SO4, filtered and concentrated to give 4-benzoylpent-4-enoic acid 9a (4.60 g, 86%) as a yellow solid; mp 45-46 C; 1H NMR (300 MHz, CDCl3): delta = 2.63 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 5.69 (s, 1H), 5.94 (s,1H), 7.43 (m, 2H), 7.54 (m, 1H), 7.72 (d, J = 6.9 Hz, 2H), 11.39 (bs, 1H); 13C NMR (75 MHz, CDCl3): delta = 27.2, 32.6, 127.2, 128.2, 129.4, 132.3, 137.5, 145.9, 179.0, 197.8. |
74% | With aluminum (III) chloride; In dichloromethane; at 20℃; for 1h; | Anhydrous AlCl3 (5.86 g, 44.00 mmol) was added portion-wise over 5 minutes to an oven dried 250.00 mL round bottom flask containing glutaric anhydride (2.28 g, 20.00 mmol) and benzene (2.00 mL, 22.00 mmol) in DCM (60.oo mL) and reaction mixture was stirred at room temperature until no starting material was detected by TLC (16 h). The reaction mixture was poured into 1 N HCl (pH ~2), and product was extracted with diethyl ether (2 x 200.00 mL). Combined organic portion was collected and washed with 1N HCl (3 x 50.00 mL), dried over MgSO4 and concentrated in vacuo to give a crude solid residue. Purification using flash column chromatography with ethyl acetate/hexanes (1:19 to 1:3) has afforded compound 33 as white solid (2.80 g, 74%). 1H NMR (400 MHz, CDCl3-d) deltaH 2.00 - 2.17 (m, 2 H, CH2CH2CH2) 2.51 (t, 2H, J = 7.09 Hz, CH2CH2) 3.09 (t, 2H, J = 7.09 Hz, CH2CH2) 7.42 - 7.52 (m, 2 H, ArH) 7.53 - 7.62 (m, 1 H, ArH) 7.97 (dd, 2H, J = 8.19, 0.86 Hz, ArH). |
With aluminum (III) chloride; In dichloromethane;Inert atmosphere; | General procedure: To an oven dried 250 mL round bottom flask containing succinic anhydride (3.00 g, 30.0 mmol) and the aromatic compound (1.1 equiv) in DCM (100 mL) was added aluminum chloride (2.2 equiv) portion-wise at room temperature in an atmosphere of argon over 5 minutes and allowed to stir until completion of reaction. The reaction was cooled at 0 C and quenched by carefully addition of aqueous solution of 1N HCl, extracted with THF and ethyl acetate (1:1) (2 x 200 mL), the organic layer dried under Na2SO4 and concentrated to give the product as a solid that was subsequently washed with hexanes and vacuum filtered to afford the crude product S1 used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetyl chloride at 0 - 20℃; for 15h; Inert atmosphere; | |
97% | With sulfuric acid for 1h; | |
97% | With sulfuric acid |
96% | With acetyl chloride at 0 - 20℃; | |
95% | With tert.-butylnitrite at 40℃; for 48h; | 35 Add compound 1ai (0.5 mmol, 96.2 mg) and methanol containing 40 mol% tert-butyl nitrite to the reaction tube; then react for 48 hours at 40°C in air; after the reaction, add sodium thiosulfate and stir. After quenching, using a rotary evaporator to remove the solvent, adsorbing on silica gel, and finally performing column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3ai with a yield of 95%. |
95% | With tert.-butylnitrite at 40℃; for 48h; Green chemistry; | |
92% | With sulfuric acid at 68℃; | |
90% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; | |
85% | With sulfuric acid In benzene for 3h; Heating; | |
85% | With diazomethyl-trimethyl-silane In hexane; dichloromethane at 25℃; for 16h; | 1 Weigh 1.9221g benzoylbutyric acid (0.01mol) and place it in a round bottom flask,Add 20mL dichloromethane and 10mL methanol,Stir until completely dissolved;Take 20mL of 2mol/L trimethylsilyldiazomethane in n-hexane solution,Add to the benzoyl butyric acid solution four times,Add 5mL each time, with an interval of 1h twice,Stir at room temperature (25°C) for 16h,Evaporate and concentrate, use n-hexane: ether=1:1 as the mobile phase on a silica gel column,Obtain methyl benzoylbutyrate (1.7531g, yield: 85%),It is a light yellow oil phase, and the liquid chromatogram of the product is shown in Figure 3.It can be seen from Figure 3 that the result of the liquid phase is a single peak,Without other impurity peaks,From this result, it can be considered that the purity of methyl benzoyl butyrate prepared by this method is relatively high. |
53% | With toluene-4-sulfonic acid In benzene for 18h; Reflux; | |
With hydrogenchloride | ||
With sulfuric acid | ||
With hydrogenchloride | ||
With pyridinium p-toluenesulfonate Yield given; | ||
With toluene-4-sulfonic acid In chloroform at 61℃; | ||
With thionyl chloride | ||
With sulfuric acid | ||
With sulfuric acid for 2h; Reflux; | ||
4.9 g | With acetyl chloride at 0 - 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: Method B:22 NaBH4 (227 mg, 6.00 mmol) was added at 0 C to a solution of NaOH (500 mg, 12.5 mmol) and the corresponding keto acid (5mmol) in H2O (10 mL). The reaction mixture was stirred at r.t. for more than 2 h. After completion of the reaction, concd HCl was carefully added until the pH of the resultant solution reached 2. The solution was then extracted with CH2Cl2 (3 × 15 mL), and the organic phases were combined, dried (anhyd Na2SO4), and evaporated under reduced pressure. The resultant oil or solid was directly dissolved in CH2Cl2 (18 mL) with trifluoroacetic acid (0.75 mL) and the solution was stirred at r.t. for more than 24 h. Afterwards, the solution was cooled and washed with sat. aq Na2CO3 (15 mL). Then, the solution was extracted with CH2Cl2 (3 × 15mL), and the organic phases were combined, dried (anhyd Na2SO4) and evaporated under reduced pressure. The crude product was purified by a bulb-to-bulb distillation to give the corresponding lactone. | |
73% | With 1,2-bis(dimethylsilyl)ethane; tris(pentafluorophenyl)borate; In dichloromethane; at 20℃; for 0.166667h;Inert atmosphere; | General procedure: To a solution of levulinic acid (LA) (40 mg, 0.34 mmol) and (HMe2SiCH2)2 (55mg, 0.38 mmol) in anhydrous CH2Cl2 (4 mL) under argon atmosphere was addedB(C6F5)3 (1.8 mg, 0.0035 mmol) at room temperature. The resulting mixture wasstirred at the same temperature for 10 min before quenching with H2O (2 mL) andextraction with CH2Cl2 (3 × 3 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the crudeproduct by silica gel flash column chromatography (gradient eluent: 0-3% ofEtOAc/petroleum ether) afforded GVL (29 mg, 86% yield) as a colorless oil. |
By following the same procedure, from 4-benzoylbutanoic acid, there was prepared 5-phenyl-5-pentanolide, as an oily substance. Nuclear magnetic resonance spectrum: 1.30-2.20(4H), 2.40-2.70(2H), 5.40(1H), 7.30(5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In ethanol Heating; | ||
With sodium hydroxide In acetone at 25℃; other temp., ΔΔH excit., ΔΔS excit.; | ||
With lithium hydroxide; water In methanol at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sulfuric acid; nitric acid; | A flask charged with 3 mL of concentrated H2SO4 (3 mL) was cooled to -20 C and to this was added compound 33 (1.00 g, 5.20 mmol) was added dropwise with intense stirring. After the addition was complete a thoroughly mixed solution of 0.8 mL of fuming nitric acid (0.8 mL, 18.82 mmol) and 2.4 mL of concentrated H2SO4 (2.4 mL, 45.00 mmol) was added dropwise with stirring. The nitrating reagent was added at a rate so as to maintain a temperature of -15 C. After the addition was complete, the reaction mixture was stirred at -15 C for an additional 15 min and then poured into 250.00 g of ice. The resulting precipitate was isolated by suction filtration and, was washed with H2O (2 x 100.00 mL). The solid was dissolved in 100.00 mL of diethyl ether. The organic phase was washed with 5% NaHCO3 (aq.) (2 x 50.00 mL) and H2O (50.00 mL). The organic layer was dried over MgSO4, and filtered, and the solvent was removed on a rotary evaporator to obtain title compound 34 was isolated as a pale-yellow solid (1.00 g, 81%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3-d) deltaH 2.06 - 2.20 (m, 2 H, CH2CH2CH2) 2.56 (t, 2H, J = 1.00 Hz, CH2) 3.15 (t, 2H, J = 1.00 Hz, CH2) 7.69 (t, 1H, J = 1.00 Hz, ArH) 8.31 (d, 1H, J = 1.00 Hz, ArH) 8.43 (d, 1H, J = 1.00 Hz, ArH) 8.80 (s, 1 H, ArH). |
With sulfuric acid; nitric acid; at 0℃; | To a mixture Of HNO3 (4 mL) and H2SO4 (2 mL) at OC was slowly added the above carboxylic acid (2 g, 10.4 mmol). The mixture was stirred under OC for 30 minutes. The resulting solution was poured into 20 mL of H2O at OC, and the precipitate was filtered to give compound (2 g) as a yellow solid. MS (ESI) m/e (M+H*): 238. | |
With sulfuric acid; nitric acid; at -10 - 0℃; for 1.5h; | To a well-stirred mixture of fuming nitric acid (670 mL) and concentrated sulfuric acid (335 mL) at -10 C. was added 4-benzoylbutyric acid (333 g, 1730 mmol) in portions such that the reaction temperature was held at -10-0 C. [Note: temperature control is critical as the reaction is exothermic.] Total addition time was 1.0 h. Following the addition, the reaction mixture was stirred for 0.5 h at 0 C. The mixture then was poured slowly into a vigorously stirred slurry of water-ice/water. After the ice had completely melted the resulting solids were recovered by filtration, washed twice with water, and dried to afford 298 g of the crude product, which was employed in Part B without further purification or characterization. |
2 g | With sulfuric acid; nitric acid; at 0℃; for 0.5h; | To a mixture of HNO3 (4 mL) and H2SO4 (2 mL) at 0 C. was slowly added the above carboxylic acid (2 g, 10.4 mmol). The mixture was stirred under 0 C. for 30 minutes. The resulting solution was poured into 20 mL of H2O at 0 C., and the precipitate was filtered to give compound (2 g) as a yellow solid. MS (ESI) m/e (M+H+): 238. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride; In mineral oil; at 98℃; for 9h; | Adding a concentration of 20% of 0.7 mol sodium hydride solution to the reaction flask, adding 0.13 mol of eosin and 0.1 mol of 4-(benzoyl)butyric acid while stirring, and then heating to 98 C for 9 h, using thin layer chromatography The reaction was monitored at the end of the reaction. After the reaction was cooled to room temperature, the reaction was poured into water 10 times the volume of the reactants, and the pH was adjusted to 1.7 with concentrated hydrochloric acid. A large amount of solid was precipitated and dried by suction filtration to obtain a yellow solid powder. 3-carboxyethyl-quinoline-4-carboxylic acid having the formula: C19H15NO4, molecular weight 321 and yield 85-95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In a 500-mL round-bottomed flask, 4-benzoylbutyric acid (20 g, 0.1 mol) is added to a mixture of dioxane (180 mL) and ether (60 mL). Bromine (6.55 mL, 1.25 Eq, 0.125 mol) is added dropwise, and the solution is stirred for 3 h and then poured into an aqueous 30% NaHCO3 solution (150 mL) and again stirred for 6 h. The phases are separated, and the aqueous phase is extracted with CH2Cl2 (3×75 mL). The organic phases are combined, washed with brine (150 mL), dried using anhydrous sodium sulfate, filtered and evaporated to dryness. Silica column chromatography gives the desired compound (14.64 g). Chromatography solvent: AcOEt/hexane, 30/70, Rf: 0.20 Yield: 74% White solid, MP = 91 C. {acute(1)}RMN 1H(200 MHZ, CDCl3): delta 2, 44-2, 67(m, 4H, H2 et H3); 5, 79-5, 85(m, 1H, H4); 7, 48-7, 65(m, 3H arom. meta et para); 7, 96-8, 00(m, 2H arom. ortho).{acute(1)}RMN 13C(50 MHz, CDCl3): delta 24, 92(C3); 26, 76(C2); 78, 18(C4); 128, 75(CH arom.); 128, 97(CH arom.); 133, 49(C6); 134, 29 (CH arom.); 176, 20(C1); 194, 24(C5). Key:1NMR2Meta and para Microanalysis: C % H % theoretical 69.46 5.30 actual 69.36 5.29 {acute(1)}SM(IE, 70 eV) m/e(intensite relative %): 190(M+, 38), 105[(M-PhCO)+, 100]. Key: 1Mass spectrometry 2Relative intensity % | |
63% | With oxygen; potassium carbonate; calcium iodide; In tetrahydrofuran; at 20 - 50℃; for 20h;Irradiation; | General procedure: Table 1, entry10: A solution of substrate (0.3 mmol), CaI2 (0.2 equiv) and K2CO3 (0.1 equiv) in dry THF (5 mL) in a Pyrex test tube with O2 balloon is stirred and irradiated externally with 400 W high pressure mercury lamp at room temperature for indicated time. The temperature of the reaction mixture at the final stage of this reaction was about 50 C. The product is quenched with 0.5 M aq Na2S2O3. Then the solution is acidified with 0.5 N aq HCl and extracted with EtOAc. The product is purified by PTLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tert-butylhypochlorite; silver triflate-bis(1,10-phenanthroline) complex In acetonitrile at 45℃; for 23h; Inert atmosphere; | |
With lead(IV) acetate; lithium chloride 1) benzene, 25 deg C, 1 h, 2) reflux, 2 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 70% 2: 12% | With methanol; iodine; magnesium at 40℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 25℃; for 1h;Inert atmosphere; | To a stirred solution of 5-oxo-5-phenylpentanoic acid (2.00 g, 10.4 mmol) in THF (60 mL) at 0 C was added LiAlH4 (1.58 g, 41.6 mmol) portionwise. The reaction was slowly warmed to RT over 1 h. After this time, the reaction was quenched by sequential dropwise addition of water (1.6 mL), aq. NaOH (15% w/v, 1.6 mL) and water (4.7 mL). The reaction mixture was diluted with Et2O (20 mL) and MgSO4 was added. The mixture was stirred vigorously for 30 mins then filtered and concentrated in vacuo. Purification by column chromatography (CH2Cl2:MeOH, 95:5) afforded the title compound 2p as a colourless oil (1.82 g, 97%). The spectral data matched that previously reported in the literature.14 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium carbonate; formic acid; In ethyl acetate; | To 178 g. ammonium carbonate was added, during one-half hour, 188 g. 85 percent formic acid and the mixture was cautiously heated to 165C. during a three hour period during which time water and some formic acid were removed by distillation through an 85 cm. Vigreux column. Heating was continued for 1 and 1/2 hours at 165C. after which 92 g. 4-benzoylbutyric acid was added and heating was continued for 22 hours. The mixture was cooled to room temperature, ethyl acetate was added with stirring, and the solid was collected by filtration to give after charcoal treatment and recrystallization from acetonitrile 41 g. 6-phenyl-2-piperidone; m.p. 139-141C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine; trifluoroacetic acid; In ethanol; water; | 5-Methyl-2-Phenyl-1H-Indole-3-Propanoic Acid Triethylamine (1.4 mL, 10 mmol) was added to a stirred suspension of delta-oxobenzenepentanoic acid (1.92 g, 10 mmol) and (4-methylphenyl)hydrazine hydrochloride (1.59 g, 10 mmol) in ethanol (16 mL) and the mixture was stirred at room temperature for 4 h. Ether (100 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (15 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the volume was reduced to Ca. 10 mL by evaporation under reduced pressure. The precipitate was collected and recrystallized from ether to give the title compound as a pale solid (1.51 g, 54%). 1H NMR (360 MHz, DMSO-d6) delta2.39 (3H, s), 2.50-2.58 (2H, m), 3.03-3.09 (2H, m), 6.91-6.95 (1H, m), 7.23-7.25 (1H, m), 7.34-7.40 (2H, m), 7.47-7.63 (4H, m), 11.4 (1H, br s), and 12.25 (1H, br s). n/z (ES+) 280 (M+1). |
54% | Triethylamine (1.4 mL, 10 mmol) was added to a stirred suspension of [delta]-oxobenzenepentanoic acid (1.92 g, 10 mmol) and (4-methylphenyl)hydrazine hydrochloride (1.59 g, 10 mmol) in ethanol (16 mL) and the mixture was stirred at room temperature for 4 h. Ether (100 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (15 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the volume was reduced to Ca. 10 mL by evaporation under reduced pressure. The precipitate was collected and recrystallized from ether to give the title compound as a pale solid (1.51 g, 54%). H NMR (360 MHz, DMSO-d6) [delta]2.39 (3H, s), 2.50-2.58 (2H, m), 3.03-3.09 (2H, m), 6.91-6.95 (1H, m), 7.23-7.25 (1H, m), 7.34-7.40 (2H, m), 7.47-7.63 (4H, m), 11.4 (1H, br s), and 12.25 (1H, br s). m/z (ES) 280 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With aluminium trichloride; sulfuric acid In methanol; hexane; ethyl acetate; 1,2-dichloro-ethane | R.67 Methyl 4-[3-(1-adamantyl)benzoyl]butyrate (compound ooo): Reference Example 67 Methyl 4-[3-(1-adamantyl)benzoyl]butyrate (compound ooo): 5.0 g (26.0 mmol) of 4-benzoylbutyric acid was dissolved in 100 ml of 1,2-dichloroethane, and 8.70 g (65.03 mmol) of aluminum trichloride and 5.30 (31.21 mmol) of 1-chloroadamantane were added thereto, followed by stirring the mixture at 60° C. for 6 hours. The reaction mixture was poured into hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue were added 100 ml of methanol and 5 ml of conc. sulfuric acid, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was poured into water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica-gel column chromatography (eluent: a mixture of 1% ethyl acetate and hexane) to obtain 2.13 g of the above-mentioned compound (yield 24%). NMR (CDCl3) δ (ppm): 7.98-7.20(4H, m), 3.68(3H, s), 3.06(2H, t, J=7 Hz), 2.46(2H, t, J=7 Hz), 2.17-1.64(17H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.9 g (90%) | With sulfuric acid; sodium hydrogencarbonate In methanol; water | 1.a a) a) Synthesis of methyl 5-oxo-5-phenylpentanoate A solution of 50.0 g of 5-oxo-5-phenylpentanoic acid (260 mmol) (origin: Fluka) and 70 ml of conc. H2SO4 in 1400 ml of methanol was heated under reflux for 1 h. The reaction mixture was cooled down to room temperature and added to 2 l of water and extracted with ether (2*). The organic phase was washed with water (1*), an aq. solution of NaHCO3 (10%, 2*), again with water (2*), dried (Na2SO4) and concentrated to give 47.9 g (90%) of a slightly yellow oil, which slowly crystallizes at 4° C. Analytical data: UV/Vis (hexane): 369 (sh, 2), 355 (sh, 12), 339 (sh, 33), 322 (45), 309 (sh, 41), 287 (600), 278 (800), 248 (sh, 7900), 238 (13200). IR (neat): 3061w, 3022w, 2949m, 2902w, 1730s, 1681s, 1597m, 1580m, 1447m, 1435m, 1412m, 1370m, 1315m, 1277m, 1254m, 1207s, 1174s, 1146s, 1073m, 1055m, 1013m, 1000m, 990m, 975m, 931w, 879m, 843w, 739s, 689s, 657w. 1H-NMR (360 MHz, CDCl3): 8.02-7.92 (m, 2 H); 7.59-7.52 (m, 1 H); 7.50-7.41 (m, 2 H); 3.68 (s, 3 H); 3.05 (t, J=7.1, 2 H); 2.45 (t, J=7.3, 2 H); 2.08 (quint., J=7.2, 2 H). 13C-NMR (90.6 MHz, CDCl3): 199.35 (s); 173.69 (s); 136.82 (s); 133.08 (d); 128.60 (d); 128.02 (d); 51.56 (q); 37.44 (t); 33.11 (t); 19.34(t). MS (EI): 206 (M+, 7), 175 (10), 174 (3), 147 (8), 146 (8), 133 (3), 120 (14), 106 (8), 105 (100), 78 (3), 77 (35), 59 (3), 55 (5), 51 (10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dimethyl (2R,2'R)-2,2'-((2-iodo-5-(methoxycarbonyl)-1,3-phenylene)bis(oxy))dipropionate; 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid; In 2,2,2-trifluoroethanol; at 20℃; for 24h; | General procedure: A 10 mL three-necked round-bottomed flask was equipped with a magnetic stirrer,platinum plate (1.0×1.0 cm2) electrode as the working electrode and counter electrode. Thesubstrate 1a (23 mg, 0.1 mmol), chiral iodobenzene 2b (56 mg, 0.12 mmol) and supportingelectrolyte n-Bu4NBF4 (66 mg, 0.2 mmol) were added to the solvent TFE (4 mL). The resultingmixture was allowed to stir and electrolyzed at constant current conditions (7.0 mA/cm2) atroom temperature for 1 h. The solvent was removed under vacuum and the residue was purifiedby column chromatography (Petroleum ether:EtOAc, 3:1) to give 3a as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Alkenoic acids were prepared via a Wittig reaction from the commercially available keto-acids according to the procedure reported by Hartwig et al.2 To a suspension of methyltriphenylphosphnium bromide (1.3 eq.) inTHF (c.a. 0.25M) was added sodium tert-butoxide (2.6 eq.) at 0 C.The mixture was stirred for 30 min. Keto-acid (1.0 eq.) was then added to the reaction mixture at 0 C. The mixture was allowed to warm up to room temperature and stirred for 16 h. After the mentioned time, the reaction mixture was concentrated under reduced pressure, diluted with CH2Cl2(10 mL) and NaOH (1N, 10 mL). The aqueous layer was washed with CH2Cl2 twice. The pH was adjusted to approx. 2 and the aqueous layer was extracted with CH2Cl2 twice. The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo to afford the crude product that was purified by flash column chromatography (hexane/EtOAc 1:1) to afford the corresponding alkenoic acids 3a-3g. | ||
General procedure: In an oven dried 250 mL round bottom flask was added at 0 C potassium tert-butoxide (3 equiv, 5.27 g, 47.0 mmol) in a suspension of methyltriphenylphosphonium bromide (2 equiv, 11.2 g, 31.3 mmol) in THF (70 mL) in an atmosphere of argon. The mixture was the stirred for 30 min. The acid S1 (1 equiv) was then added to the reaction mixture at 0 C. The mixture was allowed to warm to room temperature, and was then stirred for 16 h. After evaporation of THF, the crude product was diluted with 1 N NaOH (50 mL). The aqueous layers was washed with dichloromethane. The aqueous layer was treated with 12N HCl until pH=2, extracted with dichloromethane and dried under Na2SO4. The product S2 was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With caesium carbonate In acetone for 17h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 4,5,6,7-tetrafluoro-2-hydroxy-3-(2,2,2-trifluoroethoxy)-3-trifluoromethylisoindolin-1-one; oxygen; cobalt(II) acetate; manganese(III) triacetate dihydrate; In 2,2,2-trifluoroethanol; at 60℃; under 760.051 Torr; for 48h; | General procedure: To a solution of benzoate 36a (72.1 mg, 0.300 mmol) in 35(5.8 mg, 0.015 mmol), TFE (0.15 mL), Co(OAc)2 (0.53 mg,0.00300 mmol) and Mn(OAc)3·H2O (0.80 mg, 0.00300 mmol)were added. The reaction mixture was stirred for 48 h at 60Cunder O2 atmosphere. The mixture was evaporated under reducedpressure, and the residue was purified with flash columnchromatography (SiO2, n-hexane-EtOAc=9 : 1) to afford ketone37a (59.8 mg, 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tetra-N-butylammonium tribromide; dibromoisocyanuric acid; In dichloromethane; at 20℃; for 5h;UV-irradiation; | EXAMPLE 12 (0564) Bromodecarboxylation of alkanoic acids (0565) bromoisocyanurate (0566) RC02H -1 · RBr (0567) hv (0568) [00169] A mixture of alkanoic acid RC02H (2 mmol), bromoisocyanurate, additive (optionally) and solvent (12 mL) was stirred under fluorescent room light irradiation (FL). The reaction mixture washed with 1 M aq Na2S03, dried over Na2S04, filtered through short silica gel pad and concentrated in vacuo to yield crude alkyl bromide RBr. Optionally, the crude bromide was purified by chromatography on silica gel. The results are presented in Table 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With piperidine; In pyridine; at 70℃; for 21h; | A flask was charged with AlCl3 (96.38 mmol, 12.85 g, 2.2 equiv) and dry benzene (20 ml) under calcium chloride guard tube and the formed suspension was stirred on ice bath. Subsequently, a solution of glutaric anhydride 10 (43.8 mmol, 5.00 g) in dry benzene (40 ml) was added dropwise over 30 minutes (t < 8 C). The cooling bath was removed and the resulting mixture was stirred at room temperature for 19 hours. The mixture was carefully quenched with water (95 ml) and conc. H2SO4 (10 ml), the aqueous layer was extracted with ethyl acetate (1 x 200 ml, 3 x 50 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The crude product was crystallized from ethyl acetate to yield 5-oxo-5-phenylpentanoic acid (7.00 g, 83%) as a yellow-brown powder;1 mp 124-125 C; 1H NMR (300 MHz, acetone-d6): delta = 1.99 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 7.51 (m, 2H), 7.62 (m, 1H), 8.01 (d, J = 7.8 Hz, 2H), 10.56 (bs, 1H). 5-Oxo-5-phenylpentanoic acid (26.1 mmol, 5.02 g), paraformaldehyde (78.3 mmol, 2.35 g, 3.0 equiv) and piperidine (5.3 mmol, 0.52 ml, 0.2 equiv) were dissolved/suspended in pyridine (22 ml) and stirred at 70 C for 21 hours. Afterwards, the mixture was poured into 3M H2SO4 (100 ml), the aqueous layer was extracted with ethyl acetate (3 x 100 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The residue was redissolved in CH2Cl2 (100 ml) and extracted with a mixture of half-saturated aqueous NaHCO3 (300 ml) and 2M NaOH (20 ml). The extraction was repeated with half-saturated aqueous NaHCO3 (50 ml). The combined aqueous solutions were washed with CH2Cl2 (2 x 50 ml) and afterwards acidified with conc. H2SO4 to pH = 1-2 and extracted with ethyl acetate (1 x 100 ml, 3 x 70 ml). The combined organics were dried over Na2SO4, filtered and concentrated to give 4-benzoylpent-4-enoic acid 9a (4.60 g, 86%) as a yellow solid; mp 45-46 C; 1H NMR (300 MHz, CDCl3): delta = 2.63 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 5.69 (s, 1H), 5.94 (s,1H), 7.43 (m, 2H), 7.54 (m, 1H), 7.72 (d, J = 6.9 Hz, 2H), 11.39 (bs, 1H); 13C NMR (75 MHz, CDCl3): delta = 27.2, 32.6, 127.2, 128.2, 129.4, 132.3, 137.5, 145.9, 179.0, 197.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Triethylamine (1.4 mL, 10 mmol) was added to a stirred suspension of [delta]-oxobenzenepentanoic acid (1.92 g, 10 mmol) and (4-methylphenyl)hydrazine hydrochloride (1.59 g, 10 mmol) in ethanol (16 mL) and the mixture was stirred at room temperature for 4 h. Ether (100 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (15 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the volume was reduced to Ca. 10 mL by evaporation under reduced pressure. The precipitate was collected and recrystallized from ether to give the title compound as a pale solid (1.51 g, 54percent). H NMR (360 MHz, DMSO-d6) [delta]2.39 (3H, s), 2.50-2.58 (2H, m), 3.03-3.09 (2H, m), 6.91-6.95 (1H, m), 7.23-7.25 (1H, m), 7.34-7.40 (2H, m), 7.47-7.63 (4H, m), 11.4 (1H, br s), and 12.25 (1H, br s). m/z (ES) 280 (M+1); Prepared from [delta]-oxobenzenepentanoic acid and <strong>[60481-51-8](3,4-dimethylphenyl)hydrazine hydrochloride</strong> according to the method of Description 7 as a 2:1 mixture of isomers. H NMR (360 MHz, CDCl3) (Contains 29percent [delta]-oxobenzenepentanoic acid); 5,6-dimethyl-2-phenyl-1H-indole-3-propanoic acid (Major Isomer) [delta]7.85 (1H, s), 7.58-7.33 (5H, m), 7.37 (1H, s), 7.16 (1H, s), 3.25-3.20 (2H, m), 2.75-2.67 (2H, m), and 2.38 (6H, s); 4,5-dimethyl-2-phenyl-1H-indole-3-propanoic acid (Minor Isomer) [delta]7.92 (1H, s), 7.58-7.33 (5H, m), 7.12 (1H, t, J 8.2 Hz), 7.02 (1H, t, J 8.2 Hz), 3.35-3.31 (2H, m), 2.75-2.67 (2H, m), 2.64 (3H, s), and 2.39 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85%Chromat. | In water; at 180℃; for 1h;Sealed tube; | 2 mmol of 4-benzoyl butyric acid, 30 mmol of formamide and 80 mmol of water were placed in a 15 mL polytetrafluoroethylene-lined stainless steel reaction vessel. The sealed reaction kettle is placed in an oil bath that has been heated to a predetermined temperature (180 C). Reaction at 500r/min for 60min, The reaction vessel was taken out and cooled to room temperature with tap water. Add 13 mL of methanol to the reaction kettle. The yield of 6-(4-fluorophenyl)-2-piperidone was determined by GC, The conversion of 4-(4-fluorobenzoyl)butyric acid was measured by HPLC. Using naphthalene as an internal standard to make a standard curve, the yield of 6-phenyl-2-piperidone (m/z: 175.1) in the reaction mixture was determined by gas chromatography to be 85%. The conversion of 4-benzoylbutyric acid was determined by liquid chromatography to be 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 52% 2: 14% | With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In 2-methyltetrahydrofuran for 16h; Sealed tube; Darkness; Schlenk technique; chemoselective reaction; |
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