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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
p-Toluic Acid is a benzoic acid derivative commonly used as an intermediate in chemical synthesis and drug research.
Synonyms: 4-Methylbenzoic acid
4.5
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Dehaloperoxidase Catalyzed Stereoselective Synthesis of Cyclopropanol Esters
Siriboe, Mary G ; Vargas, David A ; Fasan, Rudi ;
Abstract: Chiral cyclopropanols are highly desirable building blocks for medicinal chemistry, but the stereoselective synthesis of these molecules remains challenging. Here, a novel strategy is reported for the diastereo- and enantioselective synthesis of cyclopropanol derivatives via the biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl diazoacetate (EDA). A dehaloperoxidase enzyme from Amphitrite ornata was repurposed to catalyze this challenging cyclopropanation reaction, and its activity and stereoselectivity were optimized via protein engineering. Using this system, a broad range of electron-deficient vinyl esters were efficiently converted to the desired cyclopropanation products with up to 99.5:0.5 diastereomeric and enantiomeric ratios. In addition, the engineered dehaloperoxidase-based biocatalyst is able to catalyze a variety of other abiological carbene transfer reactions, including N−H/S−H carbene insertion with EDA as well as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality of this enzyme and defining it as a valuable new scaffold for the development of novel carbene transferases.
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CAS No. : | 99-94-5 |
Formula : | C8H8O2 |
M.W : | 136.15 |
SMILES Code : | O=C(O)C1=CC=C(C)C=C1 |
Synonyms : |
4-Methylbenzoic acid
|
MDL No. : | MFCD00002565 |
InChI Key : | LPNBBFKOUUSUDB-UHFFFAOYSA-N |
Pubchem ID : | 7470 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
With cetyltrimethylammonim bromide; chlorine; In water; at 60℃; for 8h; | Add in a glass reactor equipped with a thermometer, a stirring paddle and a condenser200 g of p-toluic acid and 800 ml of water, and 2 g of cetyltrimethylammonium bromide,After heating to 60 C, chlorine gas was introduced and the reaction was monitored using a chromatogram.When the product yield is greater than 98%, the reaction is stopped and the reaction is carried out for 8 hours.The reaction solution was added to a Buchner funnel, filtered, and washed with 1500 ml of water.The obtained filter cake was vacuum dried at 80 C to a constant weight.Quantitative analysis by liquid chromatography,A purity of 98% 3-chloro-4-methylbenzoic acid was obtained.The other 2% is p-toluic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With diphosphorus tetraiodide; In acetonitrile; at 80℃;Sealed tube; Inert atmosphere; | General procedure: To amixture of ortho-substituted (-NH 2 or -SH or -OH) anilines(1 mmol) and aryl acids (1 mmol) in acetonitrile (2 mL) in asealed tube (10 mL) was added diphosphorus tetraiodide (0.2mmol) under nitrogen atmosphere. Then, the tube was cappedand the mixture heated in an oil bath at 80 C with stirringuntil the reaction was complete as monitored by TLC. Afterbeing cooled to room temperature, the reaction was quenchedwith aqueous NaHCO 3 solution and extracted with ethyl acetatethree times. The combined organic layer was washed withwater and brine and then dried over anhydrous Na 2 SO 4 . Thesolvent was removed under reduced pressure and the residuewas purified by chromatography on silica gel, eluting withpetroleum ether/ethyl acetate, to afford the correspondingproduct. The products obtained were known compounds andwere identified by melting point and 1 H NMR spectroscopy.The spectral data were compared with the literature values.2-Phenyl-1H-benzimidazole (Table-2, entry 1): m.p.:290-293 C (Lit. [21] 292-294 C); IR (KBr, ν max , cm -1 ): 3450,3045, 1620, 1580, 1458; 1 H NMR (400 MHz, DMSO-d 6 ): δ7.08-7.14 (m, 2H), 7.31-7.5 (m, 5H), 7.96 (d, 2H), 12.80 (s,1H); 13 C NMR (DMSO-d 6 , TMS): δ 116.5, 123.1, 127.4, 128.6,129.5, 130.7, 139.0, 152.7; MS (ESI) m/z: [M+H] + 195.1. |
85% | With Amberlyst-15; In water; at 90℃; for 2h;Irradiation; | General procedure: To a solution of o-phenylenediamine 1a, o-amino phenol 1b or o-amino thiophenol 1c (1.0 mmol) and aromatic acid (2, 1.2 mmol) in water (5 mL) was added Amberlyst-15 (10%, w/w) and the mixture was irradiated with ultrasound (40 KHz) continuously at 90 C till the completion of the reaction(monitored by TLC) as indicated in Table 3. The solid separated was filtered, washed with diethyl ether (2 x 5 mL), dried and treated with EtOAc (15 mL). After stirring for 10 min the mixture was filtered to remove the insoluble catalyst. The filtrate was collected and concentrated under vacuum. The solid obtained was purified by recrystallization (column chromatography infew cases) to afford the desired products 3, 4 or 5. |
84% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 100℃; for 0.166667h;Microwave irradiation; Sealed tube; | General procedure: A mixture of o-aminobenzenethiol (1 mmol), carboxylic acid (1 mmol), N,N-diisopropylethylamine (1.5 mmol) and propylphosphonic anhydride (1 mmol, 50% w/w in AcOEt) was irradiated for 10 min under microwave at 100 C in a sealed tube. It was diluted with H2O, followed by alkalinization with saturated aqueous NaHCO3 solution. The precipitate was collected by filtration and washed thoroughly with H2O to afford the respective benzothiazole. If necessary, simple recrystallization was carried out in EtOH/H2O. |
70% | 4-methylbenzoic acid (10.24 g, 75 mmol) was added portionwise to polyphosphoric acid (30 mL) at 100 C until a smooth paste was obtained. o-aminothiophenol (9.36 g, 75 mmol) was added, and the reaction mixture was heated to 185 C. After stirring at 185 C for a further 30 min, the mixture was poured into vigorously stirred H2O. The resulting solution was extracted with CH2Cl2, and washed by Na2CO3 aqueous solution and then deionized water. The concentrated residue was further purified on silica gel (CH2Cl2 as elute), providing 1 as white solid (7.91 g, 70%). 1H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 8.0 Hz,1H, NC6H4S), 7.99 (d, J = 8.0 Hz, 2H, C6H4), 7.90 (d,J = 8.0 Hz, 1H, NC6H4S), 7.50 (t, J = 7.6 Hz, 1H, NC6H4S), 7.38 (t, J = 7.6 Hz, 1H, NC6H4S), 7.31 (d,J = 8.0 Hz, 2H, C6H4), 2.43 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 168.2, 154.2, 141.4, 134.9, 131.0, 129.7, 127.5, 126.3, 125.0, 123.1, 121.6, 21.5 ppm; HRMS (EI) : m/z calc. for [M+]: 225.0612; found: 225.0612. | |
With PPA; In water; | Synthesis of 4-(benzothiazol-2-yl) toluene 125 g (1 mol) of o-aminothiophenol, 136 g (1 mol) of p-toluic acid and 600 g of polyphosphoric acid were admixed and stirred into nitrogen gas at 170-200 C. for 4 hours. After the reaction mixture was cooled to 100 C., it was poured in 5 l of water. The mixture was adjusted to pH 5 with NaOH and the resulting crystals were filtered off, whereupon 220 g of 4-(benzothiazol-2-yl) toluene was obtained as crude crystals. Recrystallization from n-hexane gave 172 g of pure product as colorless prisms melting at 84-85 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PPA; at 180℃; for 2h; | Example 144 A2-p-tolylbenzo[d]oxazole-4-carboxylic acid; 4-Methylbenzoic acid (275 g, 2 mmol) and <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> (334 mg, 2 mmol) were added to the polyphosphoric acid (2.0 g). The mixture was heated at 180 C. for 2 h, allowed to cool, poured into water, and filtered; the cake was washed with water, dried under reduced pressure at 50 C. to obtain a mixture of methyl 2-p-tolylbenzo[d]oxazole-4-carboxylate and 2-p-tolylbenzo[d]oxazole-4-carboxylic acid powders. The mixture were added to thionyl chloride (10 ml) and the mixture was stirred under reflux for 2 h. Evaporated the solvents under reduced pressure and the residue was added to methanol (20 ml), stirred at room temperature for 10 min. Then evaporated the solvents, the residue was dissolved in ethyl acetate, washed with water, the organic layer was dried with sodium sulfate, removed the solvents to obtain 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (500 mg) as a yellow solid. Yield: 93%. LC-MS (ESI) m/z: 268 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | General procedure: 2,2'-Disulfanediyldianiline 1a or 6,6'-disulfanediylbis(3-chloroaniline) 1b (0.5 mmol) and carboxylic acid (1.0 mmol, except 0.5mmol for 2k) were added to a three-neck flask under an atmosphere of Ar, and 5 mL dry toluene was added, then the mixture was stirred for 2.5 h at 70 C to allow the solid to dissolve in toluene solvent completely. After the reaction solution was cooled down to 30 C, PCl3 (1.2 mmol, 0.165 g) was added dropwise. When the PCl3 was added completely, the reaction mixture was further stirred for 4 - 6 h at 100C until no 2,2'-disulfanediyldianiline or 6,6'-disulfanediylbis(3-chloroaniline) was detected by TLC analysis. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and extracted with CH2Cl2. The collected organic layers were dried over anhydrous MgSO4. After filtered toremove the MgSO4 and the solvent was removed under reduced pressure. The crude product was purifiedby flash chromatography on silica gel using PE / EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dipotassium hydrogenphosphate; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; triphenylphosphine; In dichloromethane; water; at 20℃; for 48h;Inert atmosphere; Irradiation; | Firstly weighing (20.4 mg, 0 . 15 mmol),photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(2.3 mg, 0.002 mmol), K2HPO4(7.0 Mg, 0 . 04 mmol),and Ph3P (31.5 mg, 0.12 mmol)are added to a reaction tube, pumping air through the vacuum line three times, in the argon atmosphere, adding DCM/H2O (2.0 ml, 4:1 v/v), then carefully added (36.2 Mg, 0.1 mmol),then put into 5W blue LEDs lamp irradiation, react at room temperature for 48 h.Add 20 ml water, and the DCM extraction (3x 10 ml) the aqueous phase, combined with the organic phase. The organic phase by absolute Na2SO4 after drying and steaming and to remove the solvent, dry sample, column chromatography (300 - 400 item of chromatographic analysis silica gel) (petroleum ether - ethyl acetate) to obtain the product 34.2 mg, Yield 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With dipotassium hydrogenphosphate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; triphenylphosphine; In dichloromethane; water; at 20℃;Inert atmosphere; Irradiation; | Firstly weighing (27.2 mg, 0.2 mmol),photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(2.3 mg, 0.002 mmol), K2HPO4(7.0 mg, 0.04 mmol), and Ph3P (62.9 mg, 0.24 mmol) are added to a reaction tube, pumping air through the vacuum line three times, in the argon atmosphere, adding DCM/H2O (2.0 ml, 4:1 v/v), then carefully added (31.5 mg, 0.3 mmol), hen put into 5 W blue LEDs lamp irradiation, react at room temperature for 36 - 60 h. Add 20 ml water, and the DCM extraction (3x 10 ml) the aqueous phase, combined with the organic phase. The organic phase by absolute Na2SO4 after drying and steaming and to remove the solvent, dry sample, column chromatography (300 - 400 item of chromatographic analysis silica gel) (petroleum ether - ethyl acetate) to obtain the product 30.6 mg, Yield 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1H-imidazole; copper ammonium sulphate hexahydrate; lithium tert-butoxide; In N,N-dimethyl-formamide; isopropyl alcohol; for 72h;Irradiation; | Step 1: Weigh out 85 mg (0.5 mmol) of <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong>, respectively.Imidazole 34 mg (0.5 mmol), copper ammonium sulphate (hexahydrate) 24 mg (12 mmolpercent),Rose red 11mg (2mmolpercent),Lithium tert-butoxide lithium t-BuOli 72 mg (0.9 mmol) was placed in a quartz reaction tube.1.5 ml of each of isopropyl alcohol and DMF was added as a solvent.Step 2: The quartz reaction tube was exposed to ultraviolet light at 254 nm under air for 72 hours. The reaction formula is as follows:Step 3: The product was isolated by column chromatography after completion of the reaction in a yield of 85percent. The resulting product was p-toluic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chlorine; In water; at 60℃; for 53h; | Add 30g to the glass reactor equipped with thermometer, stirring paddle and condenserAfter p-methylbenzoic acid and 120 ml of water, the temperature was raised to 60 C, and chlorine gas was introduced.The reaction was monitored using a chromatogram, and when the yield was greater than 90%, the reaction was stopped.The reaction was carried out for 53 h, and the reaction solution was added to a Buchner funnel to filter.After filtration, wash with 700 ml of water.The obtained filter cake was vacuum dried at 80 C to a constant weight.Quantitative analysis by liquid chromatography,Obtaining 3,5-dichloro-4-methylbenzoic acid with a purity of 90%,Another 8% is 3-chloro-4-methylbenzoic acid.2% is p-toluic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With palladium diacetate; caesium carbonate; sodium sulfate; In N,N-dimethyl-formamide; at 150℃; for 12h;Inert atmosphere; | 513 mg (3 mmol) of p-methylbromobenzene 1a, 408 mg (3 mmol) were added to a 25 mL round bottom flask at room temperature.p-Methylbenzoic acid 3b and 511 mg (3.6 mmol) of sodium sulfate 2,Then, 10 mL of DMF, 135 mg (0.6 mmol) of palladium acetate and 1956 mg (6 mmol) of cesium carbonate were successively added, and the mixture was stirred at 150 C for 12 hours, and the reaction was carried out under a nitrogen atmosphere. After cooling10 mL of saturated NaCl aqueous solution was added to the system, and extracted with ethyl acetate three times, each time 10 mL, the organic phase was combined, and driedAfter Na2SO4 is dried, the solvent is distilled off.200-300 mesh silica gel column chromatography to obtain 228 mg of di-p-methyldiphenyl sulfone 4b pure product, yield 85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | General procedure: The appropriate carboxylic acid (1.2 equiv.) and dichlorotriphenylphosphorane (1.5-2.4 equiv.) were suspended in chloroform (0.1-0.2M) and stirred for 15minat RT before addition of the appropriate aniline (1.0 equiv.), and the mixture was irradiated at 100C for 1-2h. Removal of the solvent in vacuo followed by column chromatography isolated the target compound. |
Tags: p-Toluic acid | 4-Methylbenzoic acid | Carboxylic Acids | Fluorinated Building Blocks | Aryls | Organic Building Blocks | 99-94-5
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Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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