5-Cyanophthalide

White to Pale Yellow Crystalline Solid

In the reaction flask, 5-cyanophthalide(0.4 mmol) was added.Potassium hydroxide (0.48 mmol), Phenylsilane (1.6 mmol) and tetrahydrofuran (4 mL) were reacted at 66 ° C for 6 h.Stop the reaction and add a small amount of alcohol to quench the reaction.After separation, o-(4-cyanobenzene)dimethanol 49 mg was obtained.The yield was 75percent.General procedure: Isobenzofuran-1(3H)-one (0.4 mmol), KOH (0.4 mmol), PhSiH3 (1.2 mmol), dried THF (2 mL) were charged in a Schlenk tube(15 mL) under N2 atmosphere. The mixture was refluxed for 4 h. After cooling to rt, the reaction was quenched with EtOH(0.5-1 mL). Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel with petroleum ether-ethyl acetate as the eluent to afford the desired product.i-oxo-1, 3-dihydroisohenzofuran-5-carhonitrile (0.2 g, 1.257 mmoi) was taken in tolune (8 ml), 2-methyl-i-phenylpropan-2-oi (0.245 g, 1, 634 mmol) was added followed by H2S04 (1.340 ml, 25.1 mmol) dropwise at 0 °C. Reaction mixture was allowed to stir at RT for overnight. Reaction mixture was neutralized by sodium bicarbonate and extracted with ethyl acetate. organic portion was washed with brine, dried with anhydrous sodium sulfate and evaporated to give crude which was purified by Reverse phase Prep.HJL.C to give pure5-(3, 3-dimethyi-3.4-dihvdroisoquinoiin.-i-yi)isobenzofurani(3H)one (300 mg, 1030 mmoi, 32 percent).5-cyanophthalide (31.8 g, 1.0 equiv.), tetrahydrofuran (300 ml), and a certain amount of metal salt MAXB were added. The reactants were cooled to '5° C., and the reaction was carried out under stirring for 0.5 hour. At a temperature controlled at '5 to 0° C., 300 ml of a solution of p-fluorophenyl magnesium bromide in tetrahydrofuran (0.8 mmol/ml, 1.2 equiv.) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 1 hour while maintaining the temperature. The temperature was raised to 5° C. and controlled between 5 to 10° C. 260 ml solution of N, N-dimethylaminopropyl magnesium chloride in tetrahydrofuran (1.0 mmol/ml, 1.3 equivalent) was slowly added dropwise. After the addition, the reaction was carried out under stirring for 0.5 hour while maintaining the temperature. The reaction solution was added into 500 mL of saturated aqueous solution of ammonium chloride, and stirred for 2 hours. The organic layer was separated. The aqueous layer was extracted twice with toluene 200 ml×2. The organic layers were combined, washed twice with water 200 ml×2, and concentrated to dry. A sample was taken and tested with HPLC for the conversion rate of the reaction and the purity of the main product in the reaction solution. 400 ml of toluene was added to the dry product. The mixture was heated to 50° C., and stirred till clear. 100 ml of water was added to the mixture. The aqueous layer was adjusted with concentrated hydrochloric acid to a pH of 4.0-5.0, and separated. The toluene layer was further extracted once with 50 ml of water. The aqueous layers were combined, and cooled to 5° C. A large amount of solid was precipitated. The mixture was stirred for 60 minutes while maintaining the temperature, and filtered. The filter cake was dried under vacuum at 50° C. to give citalopram diol hydrochloride. The yield was calculated. Different equivalents and types of metal salt MAXB, and different organic solvents are used for performing the above experiment. The results are shown in the following table:General procedure: A 10'mL Pyrex tube equipped with a magnetic stir bar wascharged with 1, 4'DCB (25.6 mg, 0.2 mmol), fac'Ir(ppy)3 (2.6mg, 2 molpercent) and DMSO (2 mL). The Pyrex tube was sealed with rubber plug and then deaerated by bubbling Ar for 15 min, then benzaldehyde (30.5 muL, 0.3 mmol) and DIPEA (52.4 muL, 0.3mmol) were added. The reaction system was irradiated with blue LEDs (lambda = 450 ± 10 nm) for 12 h at RT. When the reaction was complete, the aqueous solution was extracted with ethyl acetate (5 mL × 3). The organic extracts were combined, washed with brine and dried over anhydrous sodium sulfate.The solvent was removed under vacuum and the residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to afford the desired product.

5-Cyanophthalide is a useful synthetic intermediate.

Molecular Weight:159.14
XLogP3:0.5
Hydrogen Bond Acceptor Count:3
Exact Mass:159.032028402
Monoisotopic Mass:159.032028402
Topological Polar Surface Area:50.1
Heavy Atom Count:12
Complexity:253
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes