3-CHLOROBENZOYLACETONITRILE

To a stirred solution of ethyl 3-chlorobenzoate (5 g, 27.16 mmol) and sodium methoxide (2.02g, 40.75mmol) in acetonitrile (50 mL) and reaction was heated to reflux for 3 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion the reaction was filtered and solid dissolved in water. The residue was acidified with 3M HC1 solution and extracted with DCM. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain a crude compound. The crude product was purified by washing with DCM and ether to afford the mixture of two isomers compound (1.2 g, 49.7%)General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketoamides 1a-p, white solid compounds in 45% - 85% yields.General procedure: The enzymatic reaction was performed biotransformations at 25mL-scale, using an enzyme-coupled system (glucose and glucose dehydrogenase from Bacillus megaterium) for cofactor recycling. Biotransformations were carried out by addition of 10mM substrate dissolved in 250muL of DMSO, 0.1mM NADP+, KRED1-Pglu (20mU/mL), GDH (1U/mL), glucose 40mM in Tris/HCl buffer pH 8.0 (0.05M, 25mL) at 30C. Biotransformations of 1k-n were also performed also in acetate buffer (NaAB 0.1M, pH 5.0). The reaction mixture was kept under stirring at 30C until completion and then extracted with 20mL of EtOAc; the aqueous phase was extracted twice more with 15mL of EtOAc. The organic phases were collected and dried over Na2SO4 and the solvent was evaporated. The crude residue was purified by flash chromatography.General procedure: A typical procedure was as follows. For enantioselective reduction of alpha-cyanoacetophenones or alpha-nitroacetophenones, catalyst 5 (8.70 mg, 2.0 mumol of Ir, based on ICP analysis), acetophenones (0.80 mmol), and an aqueous solution of formic acid (5.0 equiv. 1.0 M formate solution, 0.2 M overall concentration, for X = CN, pH = 3.5; for X = NO2, pH = 2.0) were added sequentially to a 10.0 mL round-bottom flask. The mixture was then stirred at room temperature (25 C) for 5-20 h. [For enantioselective reduction of beta-ketoesters, catalyst 6 (8.0 mg, 2.0 mumol of Ir, based on ICP analysis), beta-ketoesters (0.80 mmol), and an aqueous sodium formate solution (5.0 equiv. 1.0 M formate solution, 0.2 M overall concentration, pH = 8.0) were added to a 10.0 mL roundbottom flask in turn. The mixture was then stirred at 4 C for 6-8 h.] During this period, the reaction was monitored constantly by TLC. After the completion of the reaction, the catalyst was separated by centrifugation (10, 000 rpm) for the recycling experiment. The aqueous solution was extracted with ethyl ether (3 x 3.0 mL). The combined ethyl ether extracts were washed with brine twice and then dehydrated with Na2SO4. After evaporation of ethyl ether, the residue was purified by silica gel flash column chromatography to afford the desired product. The conversion was calculated through the external standard method, and the ee value was determined by a HPLC analysis using a UV-Vis detector and a Daicel OJ-H chiralcel column (Phi 0.46 x 25 cm).General procedure: A typical procedure was as follows. For enantioselective reductionof alpha-cyanoacetophenones or alpha-nitroacetophenones, catalyst 5(8.70 mg, 2.0 lmol of Ir, based on ICP analysis), acetophenones(0.80 mmol), and an aqueous solution of formic acid (5.0 equiv. 1.0 M formate solution, 0.2 M overall concentration, for X = CN, pH = 3.5; for X = NO2, pH = 2.0) were added sequentially to a10.0 mL round-bottom flask. The mixture was then stirred at roomtemperature (25 C) for 5-20 h. [For enantioselective reduction of beta-ketoesters, catalyst 6 (8.0 mg, 2.0 lmol of Ir, based on ICP analysis), beta-ketoesters (0.80 mmol), and an aqueous sodium formate solution(5.0 equiv. 1.0 M formate solution, 0.2 M overall concentration, pH = 8.0) were added to a 10.0 mL roundbottom flask in turn. Themixture was then stirred at 4 C for 6-8 h.] During this period, the reaction was monitored constantly by TLC. After the completionof the reaction, the catalyst was separated by centrifugation(10, 000 rpm) for the recycling experiment. The aqueous solutionwas extracted with ethyl ether (3 3.0 mL). The combined ethylether extracts were washed with brine twice and then dehydratedwith Na2SO4. After evaporation of ethyl ether, the residue waspurified by silica gel flash column chromatography to afford thedesired product. The conversion was calculated through the externalstandard method, and the ee value was determined by a HPLCanalysis using a UV-Vis detector and a Daicel OJ-H chiralcel column(U 0.46 25 cm).General procedure: Fresh cells and lyophilised cells of Rhodotorula rubra MIM147 were used 20gL-1 dry weight re-suspended in phosphate buffer or in tap water with 50gL-1 of glucose; then the substrates 1, 3-10 were dissolved in DMSO and added at 2gL-1 concentration. For substrate 1, biotransformations were also carried out at 4, 6 or 10gL-1 concentration.3-[1-(3-chloro-phenyl)-1, 4-dihydro-[1]-benzothiopyrano[4, 3-c]pyrazol-3-yl]-3-oxo-propanenitrile, m.p. 187-188 C.;General procedure: The corresponding ester prepared above (1 equiv.) in tetrahydrofuran (0.9 M) and acetonitiile (1 equiv.) was added dropwise to a stirred solution of sodium hydride (1.5 equiv.) in tetrahydrofuran (0.65M). The resulting reaction mixture was stirred at 70 C for 16 h. After completion of starting material, the reaction mixture was quenched with ice cold water and acdified to pH 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed brine, dried over sodium sulphate and concentrated under vacuum to give the desired product.

Molecular Weight:179.60
XLogP3:2.4
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:179.0137915
Monoisotopic Mass:179.0137915
Topological Polar Surface Area:40.9
Heavy Atom Count:12
Complexity:218
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes