Benzoic acid, 4-cyano-, ethyl ester

white to light yellow crystalline powder

General procedure: Arylaldehyde (25 mmol) and [bmim]N3 (75 mmol) and alcohol (75 mmol) were mixed thoroughly and stirred at 50–60 C. The completion of reaction was monitored by TLC using (EtOAc/petroleum ether 1:7) as eluent and the product was isolated via preparative chromatography from EtOAc/petroleum ether as eluent.General procedure: In a typical experiment, a J. Young Teflon sealed NMR tube was charged with the desired amount of the catalyst from a stock solution of CTo a stirred solution of 4-cyanobenzoic acid (XXII; 10 g; 68 mmol) in ethanol (150 mL) was added a catalytic quantity of sulfuric acid (1 mL). The reaction mixture was heated to a reflux for 12 hours. The reaction mixture was cooled, concentrated at reduced pressure and dilutedwith water. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed sequentially with sodium bicarbonate and brine, then dried over Na2SO4, filtered and concentrated under vacuum to afford ethyl 4-cyanobenzoate as a white solid (XXIII; 10 g, 84percent yield). ‘H NMR (400 MHz, DMSO-d6) ö 8.10-8.08 (d, J = 8.4 Hz, 2H), 8.01-7.99 (d, J = 8.4 Hz, 2H), 4.37-4.32 (q, J = 7.2 Hz, 2H), 1.35-1.3 1 (t, J = 7.2 Hz, 3H).Example 22; 2-chloro-4-((1R, 2S)-1-(5-(4-cyanophenyl)-1, 3, 4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile; Intermediate 22a; Ethyl 4-cyanobenzoate; To a 250 mL round bottom flask charged with 4-cyanobenzoic acid (19.36 g, 0.13 mol) in abs. ethanol (100 mL) was added concentrated sulfuric acid (3 mL). This mixture was heated to reflux for a period of 28 h, then allowed to cool to room temperature overnight. The solvent was removed via rotary evaporation and the resulting off-white residue was taken up in diethyl ether (500 mL). This was then washed with saturated sodium bicarbonate/water solution (5.x.100 mL), then brine (1.x.100 mL), and dried over magnesium sulfate. Filtration and concentration yielded an off-white solid. Recrystallization from 95percent ethanol (50 mL) yielded product as white crystals (16.85 g, 73percent). General procedure: A mixture of acid (0.2 mmol), alcohol (0.6 mmol) and GO (50 wtpercent, calculated with the mass of acid) in ethyl alcohol or DCE (1 mL) was placed in a test tube equipped with a magnetic stirring bar. The mixture was stirred at 100 °C for 24 h. After the reaction was finished, filtered the GO, solvent was removed, and the residue was separated by column chromatography to give the pure sample.General procedure: To a flask containing dried LiCl (0.35 g, 8.24 mmol) was added iPrMgCl (2 M in THF, 4.1 mL) and THF (5 mL) at 15° C. After beingstirred for 15 min, 3-bromo-1-benzonitrile (1.46 g, 8.03 mmol) inTHF (1 mL) was added to the reaction mixture and the obtainedmixture was stirred for 15 min. Then, DMF (1.3 mL, 12 mmol) wasadded at 0° C and the mixture was stirred for 2 h. Then, aq NH3 (7 mL, 28-30percent) and I2 (4.06 g, 16 mmol) were added to the reaction mixture. After being stirred for 2 h at room temperature, the reactionmixture was poured into satd aq Na2SO3 solution and was extracted with CHCl3 (3∗30 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue waspurified by short column chromatography on silica gel (eluent:hexane/ethyl acetate=9:1, v/v) to provide pure 1, 3-dicyanobenzene (0.73 g) in 71percent yield. Most nitriles mentioned in this work are commercially availableand were identified by comparison with the authentic samples.General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1, 11.9mg), dppf (0.06mmol, 33.3mg), Zn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn(CN)2 (0.8mmol) , 93.9mg), p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88percent, and 1H NMR purity was greater than 98percent.General procedure: A mixture of diaryliodonium salt (0.5 mmol), K4[Fe(CN)6] (184.2 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), K2CO3 (138.2 mg, 1 mmol), and DMF (1 mL) was taken in a 10 ml reaction tube and heated at 130 °C for 2 h under vigorous stirring. After completion of the reaction (observed on TLC or GC), the mass was cooled to room temperature, and 5 ml of water was added. The mixture was stirred for 10 min and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated under reduced pressure and the residue was purified on silica gel column by using petroleum ether and ethyl acetate as eluent to obtain the pure product. All the compounds were analyzed by 1H NMR, 13C NMR, and mass spectra.#10;General procedure: To a mixture of benzyl alcohol (108 mg, 1.0 mmol) and TBHP(180 mg, 2.0 mmol) in water (3 ml), the catalyst TBAI (73.8 mg, 0.2 mmol), imidazole (136 mg, 2.0 mmol), and MeOH (2 ml)were added, and the mixture was stirred at 80 °C for 8 h. Theprogress of the reaction was monitored by TLC. After completionof reaction, the reaction mixture was cooled to room temperature.Then MeOH was distilled out, and the organic productwas extracted with ethyl acetate (3 × 10 ml), repeatedly washedwith distilled water (4 × 5 ml) to remove the unreacted TBHP, dried with anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to afford methyl benzoate (112mg, yield 82percent).General procedure: Under Oxygen, a reaction tube was charged with p-iodoanisole (46.3 mg, 0.2 mmol), urea (48.0 mg, 0.8 mmol), CuFGeneral procedure: Under Ar atmosphere in a dry Schlenk tube, a mixture of NaH (6.0 mmol) and trifluoroacetate (6.0 mmol) was stirred in THF (5 mL) at room temperature for 10 min. To this mixture enolizable ketones (5.0 mmol) in THF (5 mL) was added dropwise at 0 °C under Ar atmosphere. After stirring for 2–6 h at reaction temperature, the reaction solution was cooled to 0 °C again and quenched with 6 mL of 1 mol/L HCl. After stirring for additional 15 min, the mixture was neutralized with saturated NaHCO3 solution. After usual workup, the residue was purified by chromatography on silica gel to afford the trifluoromethyl alkyl ketone products.#10;General procedure: An oven-dried Schlenk-tube (10 mL) was charged with Pd source (1 mol percent), and ethyl potassium oxalate (0.75 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). After that, iodobenzene (0.5 mmol) and NMP (1.0 mL) were added by syringe under a counter flow of argon at room temperature. The reaction vessel was closed and then placed under stirring in a preheated oil bath. The reaction mixture was stirred for 24 h. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate, and analyzed by gas chromatography.General procedure: n-BuLi (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise into a solution of p-bromochlorobenzene (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, ethyl formate (1.6 mL, 20 mmol) was added to the mixture and the obtained mixture was stirred at -78 °C. After 3 h at the same temperature, IGeneral procedure: General procedure: A mixture of the aryl halide (1.0 mmol), alcohol (5.0 equiv), Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv) and palladacycle 1 (1 mol percent Pd) was heated in a pressure tube at 130 °C under microwave irradiation. The reaction was monitored by TLC. When the reaction has completed, the reaction mixture was cooled to room temperature and the alcohol was removed. The crude mixture was subjected to F-SPE to remove palladacycle 1 (see general procedure for the recycling of palladacycle 1) and the solution of crude product was concentrated, diluted with EtOAc (20 mL) and washed successively with 2 M HCl (210 mL) and water (10 mL). The organic layer was driedover anhydrous MgSO4, filtered and concentrated to give pure 6.General procedure: Aryl halide (0.5 mmol), α-Iminonitrile (0.6 mmol), Cu(TFA)2 (1.0 mmol), Pd(OAc)2(0.1 mmol) and 2ml DMF were added into a 15 ml sealed tube with a magneticstirring bar. Stirred under air at 120°C for 24 h. Monitor the reaction by TLC. Themixture was poured into water (10 ml) and extracted by ethyl acetate (3×10 ml).Dried by Na2SO4 and evaporated. Finally, pure the mixture by silica gel column.General procedure: Example 37 Example 38 Under a nitrogen atmosphere, copper acetylacetonate (20 molpercent, 6.6 mg) and magnets were added to a previously baked 10 mL glass pressure tube. Subsequently, N, N-dimethylformamide (0.5 mL), ethyl 4-iodobenzoate (0.125 mmol, 1.0 equiv., 34.5 mg) and phenylsilane (3.0 equiv., 40.6 mg) were added. The pressure tube was sealed, the tube air was removed and charged with carbon dioxide (0.67 mmol, 5.0 equiv., 15 mL) and ammonia gas (0.67 mmol, 5.0 equiv., 15 mL). After the addition, the glass pressure tube was placed in a metal module that had been preheated to 160°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature and pressure was slowly released. Using dodecane as an internal standard, the yield of the gas chromatography was determined to be 78percent.

Molecular Weight:175.18
XLogP3:2.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:175.063328530
Monoisotopic Mass:175.063328530
Topological Polar Surface Area:50.1
Heavy Atom Count:13
Complexity:220
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes