4-(HYDROXYMETHYL)BENZONITRILE

4-cyanobenzyl alcohol is an aromatic primary alcohol. It derives from a benzyl alcohol.

8A. 4-Hydroxymethyl-benzonitrile Boron trifluoride diethyl etherate (0.85 mL, 6.8 mmol) was added to a solution of 4-cyanobenzoic acid (1.0 g, 6.8 mmol) and THF (10 mL). At room temperature, borane-tetrahydrofuran complex (1.0 M, 13.6 mL) was added to the reaction mixture drop-wise with no observed exotherm. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The resulting residue was taken up in ethyl acetate (50 mL), washed with saturated NaHCOInto a 3000 mL four-necked flask, 138 g of potassium carbonate, 151.5 g of 4-chloromethylbenzonitrile, and 2300 g of water were placed.Heat to 80°C, react for 10 hours, sample for HPLC detection, It was confirmed that the hydrolysis reaction of 4-chloromethylbenzonitrile was complete. Dichloromethane extraction was performed in the hydrolysis reaction solution (800 mL each time, and extracted 3 times at room temperature).The extract was distilled to remove the extraction solvent to obtain 128 g of 4-cyanobenzyl alcohol with a purity of 96-98percent and a yield of 96.2percent.Transfer hydrogenation in a biphasic system with formate salts as hydride donor on aldehyde substrates The selected aldehyde (2.5 mmol), HCOONHGeneral procedure: To a solution of [CpRu(PPhGeneral procedure: A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with dicarbonyl compound (1.0 mmol) and 10 mL THF. After cooling to 0°C, PDBBA (1.3 mmol) was added dropwise and stirred for 1h at same temperature. The reaction was stopped by the aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSOGeneral procedure: In a glovebox, aldehydes (0.25 mmol) and the Hantzsch ester 1 (95 mg, 0.38 mmol) were added to asolution of tris[3, 5-bis(trifluoromethy)phenyl]borane (9) (8.1 mg, 12.5 μmol) in 1 mL of anhydrous1, 4-dioxane. The reaction mixture was stirred at 25 or 100 C for 12 h. An internal standard (biphenylor mesitylene) was added to the reaction mixture and filtrated through a cotton plug. The resultingsolution was analyzed with gas chromatography.Step A General procedure: The reaction procedure was as follows: glucose (18 mg), glucose dehydrogenase (0.35 U), NAD (2 mg), 7α-hydroxysteroid dehydrogenase (1.1 U) and benzaldehyde (0.02 mmol, dissolved in 10 μL of DMSO) were mixed in 1 mL of potassium phosphate buffer (100 mM, pH 7.0). The mixture was shaken for 12 h at 30 °C, and was then extracted with methyl tert-butyl ether (800 μL). The organic extract was dried over anhydrous sodium sulfate and subjected to HPLC analysis to measure the conversion. The products were identified by comparison with authentic samples in HPLC analysis.To a solution of 4-formyl-benzonitrile (1.51 g, 11.5 mmoL) in MeOH(15 mL)was added NaBH4 (0.51 g, 13.4 mmoL) at 0 °C. Then the mixture was stirred at this temperature for 1.5 hrs. The reaction was quenched with H20 (7.5 mL) and the resulting mixture was concentrated to remove most of the MeOH. Then the residue was poured into H20 (20 mL) and extracted with EtOAc (30 nJ*2) The combined EtOAc extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated to give 4-hydroxymethyl-benzonitrile (1.26 g, yield: 82percent) as colorless oil.General procedure: To a 25 mL Schlenk tube containing a solution of 1 in 2 mL of THF was added an aldehyde (1.0 mmol) and (EtO)3 SiH (0.20 g, 1.2 mmol). The reaction mixture was stirred at 50–55 °C until there was no aldehyde left (monitored by TLC and GC–MS). The reaction was then quenched byMeOH (2mL) and a 10percent aqueous solution of NaOH (5 mL) with vigorous stirring at 60 °C for about 24 h.The organic product was extracted with diethyl ether (10 mL × 3), dried over anhydrous MgSO4, and concentrated under vacuum. The alcohol product was further purified using flash column chromatography (elute with 5–10percent ethyl acetate in petroleum ether). The 1H NMR and 13C NMR spectra of the alcohol products are providedin Supporting information.General procedure: Knölker iron complex 2a (3 mol percent, 12.6 mg), paraformaldehyde (300 mg, 10 mmol), and Na2CO3 (106 mg, 1 mmol, 1.0 equiv) and a stirring bar were charged in a pressure tube and flushed withargon. DMSO (1.0 mL), degassed water (1.0 mL), and benzaldehyde (1 mmol)were added under an argon atmosphere to the pressure tube with a syringe.The pressure tube was placed in oil and heated at 120 C for 24 h, then cooledto room temperature. The reaction mixture was neutralized with HCl (1M) andstirred for 30 min. After extraction with EtOAc for 3 times, the combinedorganic layers were dried over MgSO4. The crude product was purified bycolumn chromatography (Heptane/EtOAc: 70:30). The reaction was cooled toroom temperature and hexadecane (100 lL) was added as a GC internalstandard.Sodium borohydride (289.0 mg, 7.6 mmol) and Dowex 50 (1.4 g) were addedsuccessively to a solution of 4-cyanobenzaldehyde 27 (1.0 g, 7.6 mmol) in THF (20 mL) at icebath temperature under argon atmosphere. The reaction mixture was stirred at room temperaturefor 15 minutes and quenched with water. The layers were separated; aqueous layer was extractedwith DCM (2 × 30 mL). The combined organic layer was dried (MgSO4) and concentrated to getdesired product as a colorless solid. Yield: 990.0 mg, quant.General procedure: Aryl iodide (0.7 mmol, 1 equiv), tert-butyl isocyanide (2.1 mmol, 237 μL, 3 equiv), Pd(OAc)Hydrogenation of 1 mmol of hexyl hexanoate under 20 bar at 100°C in toluene, resulted in 99percent yield of hexanol (Entry 1). Under the same conditions ethyl butyrate was hydrogenated to give 98percent yield of butanol and 91 percent yield of ethanol after 50 hours (Entry 2). When the reaction was performed at shorter reaction time (22 hours, Entry 2bis), small amounts of ethyl acetate and butyl butanoate were also formed, attributed to a transesterification reaction with the formed ethanol and butanol. Cyclohexylmethyl acetate gave 99percent yield of cyclohexylmethanol and 60percent yield of ethanol (Entry 3), and no transesterification products were observed. Hydrogenation of the secondary aliphatic ester heptan-2-yl acetate resulted in 98percent yield of heptane-2-ol and 57percent yield of ethanol (Entry 4). Ethyl 3-phenylpropanoate was smoothly hydrogenated, rendering 99percent yield of 3-phenylpropan-l-ol and 70percent yield of ethanol after 21 hours (Entry 5). Similarly, ethyl 3- phenylpropanoate gave 99percent yield of phenyknethanol and 74percent yield of butanol after 22 hours (Entry 6). In order to get full hydrogenation of benzyl benzoate longer reaction time was needed (43 hours, 99percent yield benzyl alcohol, Entry 7). Similarly, methyl benzoate gave 96percent yield of benzyl alcohol and 63 percent of methanol after 50 hours (Entry 8). ε-Caprolactone was smoothly and quantitatively hydrogenated to 1 , 6-hexanediol (99percent yield, Entry 9). The activated benzyl trifluoroacetate gave 99percent yield of benzyl alcohol and 78percent of 2, 2, 2- trifluoroethanol (Entry 10), and no secondary products where observed. Gratifyingly, allyl trifluoroacetate gave 97percent yield of 2, 2, 2-trifluoroethanol and 96percent of allyl alcohol (Entry 1 1), showing high chemoselectivity to ester hydrogenation over C=C hydrogenation. Hydrogenation of ethyl 4-isocyano-benzoate required an increase of precatalyst loading to 3percent, probably due to competing nitrile coordination, and resulted in 61 percent yield of (4-isocyanophenyl)methanol and 66percent yield of ethanol, with no hydrogenation of the nitrile group detected (Entry 12).Example 3

Molecular Weight:133.15
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:133.052763847
Monoisotopic Mass:133.052763847
Topological Polar Surface Area:44
Heavy Atom Count:10
Complexity:139
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes