* 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.
With n-butyllithium; acetic acid; diisopropylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; hexane; water
EXAMPLE 112 2-Fluoro-5-cyano-benzaldehyde To a stirred, cooled solution (0° C.) of diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (200 mL) n-butyllithium (40 mL of 2.5M in hexane, 0.11 mol) was added from a dropping funnel over a period of 30 min. under argon. The mixture was stirred at that temperature for 30 min. and then cooled to -78° C. A solution of 4-fluoro-benzonitrile (12.1g, 0.1 mol) in dry THF (50 mL) was then added dropwise over 15 min. via syringe and stirred for 1 hour at -78° C. Dimethylformamide (8 mL) was added dropwise from a syringe and the stirring was continued for another 20 min. The reaction was quenched by the rapid addition of acetic acid (20 mL) followed by water (500 mL) and the product was extracted with diethyl ether (2*500 mL). The combined organic layers were washed with 1N HCl, water, saturated sodium chloride and then dried over anhydrous magnesium sulfate, and evaporated to give 2-fluoro-5-cyano-benzaldehyde (11.8 g, 79percent yield) as a light yellow solid. 1H NMR (CDCl3): δ10.32 (s, 1H), 8.18 (dd, 1H, J=6.5, 2.5 Hz), 7.88 (m, 1H), 7.33 (t, 1H, J=9.5 Hz).
74.6%
With acetic acid; diisopropylamine In <i>N</i>-methyl-acetamide; ethyl acetate
A. 4-Fluoro-3-Formylbenzenecarbonitrile Lithium diisopropyi amide (LDA) (22 mL, 49.56 mmol, 2.0 N commercial solution in heptanes) was added to tetrahydrofliran (50 mL), cooled to 78° C. and under nitrogen. 4-Fluorobenzonitrile was weighed out (5.0 g, 41.3 imnol), placed under nitrogen and dissolved in 25 mL of dry tetrahydrofliran. This solution was added dropwise to the solution of LDA. The resulting solution was stirred at -78° C. for one hour before quenching with 4 mL of dimethylformamide. The temperature was maintained for 10 min before adding 8 mL of acetic acid and 20 mL of distilled water. The crude product was extracted with ethyl acetate. Purification by column chromatography (SiO2, 20percent ethyl acetate in hexanes) afforded 4.6 g of pure product as a white solid (74.6percent yield). -A second batch of the title compound (3.5 g, 56.8 percent/yield) was prepared 20 using 5 g of benzonitrile (41.3 mmol): 1H NMR (CDCl3) δ 10.3 (s, 1H), 8.21 (dd, 1H), 7.91 (d of q, 1H), 7.35 (t, 1H); ES-MS M+was not detected.
A mixture of 74 (1.82 g, 9 mmol) and copper (I) cyanide (1.4 g, 15.7 mmol) in DMF (14.0 mL) was stirred at reflux overnight. After completion, the reaction mixture was cooled to rt and poured into a solution of water (10 mL) and NH4OH (10 ml) followed by extraction with EtOAc (3 x 25 mL). The organic layer was sequentially washed with brine (2 x 15 mL), dried over anhydrous Na2S04, and concentrated in vacuo to give 757a (0.80 g, 60 percent).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8582 - 8591
[2] Patent: WO2013/56003, 2013, A2, . Location in patent: Page/Page column 63
With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In water; acetonitrile at 0 - 20℃; for 1 h;
NaH2PO4 (87 mg, 0.724 mmol) in water (3.5 mL) was added to a solution of 5-cyano-2-fluorobenzaldehyde (500 mg, 3.35 mmol) in acetonitrile (7 mL), followed by 30percent H2O2 (0.31 mL). Sodium chlorite (434 mg, 4.8 mmol) in water (3.5 mL) was added dropwise to this reaction mixture at 0 °C. The mixture was stirred at room temperature for 1 h, quenched with aqueous sodium sulfite solution at 0 °C and then acidified with 1.5N HCl solution. The aqueous solution was extracted with EtOAc and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-cyano-2-fluorobenzoic acid (500 mg, yield 90percent). 1H NMR (300 MHz, DMSO-d6) δ 13.79 (br s, 1H), 8.30 - 8.27 (dd, J = 6.6 Hz, 2.2 Hz, 1 H), 8.17 - 8.12 (ddd, J = 8.6 Hz, 4.4 Hz, 2.3 Hz, 1 H), 7.60 - 7.53 (dd, J = 10.5 Hz, 8.8 Hz, 1 H). MS (ESI) m/z: Calculated for C8H4FNO2: 165.02; found: 163.6 (M-H)-.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
A mixture of 1.00 g of 2-fluoro-5-cyanobenzaldehyde, 855 mg of methyl thioglycolate, 1.02 g of potassiumcarbonate, and 15 ml of N,N-dimethylformamide was stirred for 2 hours at 60°C. The reaction mixture was cooled toroom temperature. Water was added to the reaction mixture, and extraction was performed three times by using ethylacetate. The collected organic layer was with water and saturated saline, dried over magnesium sulfate, and thenconcentrated under reduced pressure, thereby obtaining 1.18 g of methyl 5-cyanobenzo[b]thiophene-2-carboxylate.
A 1 L four-necked flask was fitted with a constant pressure dropping funnel and mechanical agitation.N2 is replaced three times, and N2 is protected by flow. Turn on mechanical agitation,Add 400 ml of THF and 182 ml of LDA (2 mol/L);40 g of p-fluorobenzonitrile (formula IV, 0.33 mol) was dissolved in 200 ml of THF.Transfer to a constant pressure dropping funnel and start to cool down.Temperature control at -75 ° C ~ -85 ° C dropwise addition of p-fluorobenzonitrile in THF solution; after the end of the addition,The temperature is controlled at -75 ° C ~ -85 ° C for 1 h,At the same time, 26.6 g of DMF was diluted with 30 ml of THF and transferred to a constant pressure dropping funnel. Temperature control at -75 ° C ~ -85 ° C dropwise addition of DMF in THF solution, after the end of the addition,The temperature control was stirred at -75 ° C ~ -85 ° C for 1 h until the reaction with p-fluorobenzonitrile was complete.After the reaction was completed, it was quickly added to 64 ml of acetic acid and quenched, and 400 g of water was added.The layers were separated and the aqueous extracted with EtOAc EtOAc. The organic phase was combined, washed with 400 ml of diluted HCl (1 mol/L), and the organic layer was washed with 400 ml of brine, and the organic39 g of the compound of formula III are obtained as a bright yellow solid
4-(4-[5-(<i>N</i>-hydroxycarbamimidoyl)-benzo[<i>b</i>]thiophen-2-ylmethyl]-methanesulfonyl-amino}-phenoxy)-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
4-{4-[(5-cyano-benzo[<i>b</i>]thiophen-2-ylmethyl)-ethoxycarbonylmethanesulfonyl-amino]-phenoxy}-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
4-(4-{ethoxycarbonylmethanesulfonyl-[5-(<i>N</i>-hydroxycarbamimidoyl)-benzo[<i>b</i>]thiophen-2-ylmethyl]-amino}-phenoxy)-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
To a solution of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (688 mg, 4.6 mmol Tetrahedron Lett., 1992, 7499-7502) in tetrahydrofurane (15 ml) was added phenethyl magnesium bromide (15 ml, 0.3 M solution in tetrahydrofurane) dropwise at -78° C. under nitrogen atmosphere. The mixture was stirred at room temperature overnight. To the mixture were added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml*2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=8:1/4:1 as eluent) to afford the titled compound as a colorless oil. (463 mg, 39percent) 1H-NMR (CDCl3) delta:7.87 (dd, J=2.2 Hz, 6.8 Hz, 1H), 7.53-7.59 (m, 1H), 7.08-7.32 (m, 6H), 5.05 (q, J=5.5 Hz, 1H), 2.72-2.84 (m, 2H), 2.02-2.12 (m, 2H) ppm.
cyclopropane carboxyimidamide hydrochloride[ No CAS ]
[ 146137-79-3 ]
[ 648423-80-7 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; for 144h;Molecular sieve; Heating / reflux;
Into 60 ml of acetonitrile were suspended 1.5 g of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong>, 2.0 g of potassium carbonate, 2.3 g of molecular sieves 4A, and 1.7 g of cyclopropanecarboxyimidamide hydrochloride, followed by 6 days of heating under refluxing. Insoluble matter was separated by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 220 mg of the title compound from an eluate eluted with hexane-ethyl acetate (8:2, v/v). FABMASS 196 [M+H]+
With hydrogenchloride; iron(III) chloride; In water; N,N-dimethyl-formamide;
Step A 5-Cyano-2-fluorobenzaldehyde To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190 ° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65 ° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10percent sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product: 1H NMR (CDCl3) delta 10.34 (m, 1H), 8.21 (m, 1H), 7.90 (m, 1H), 7.35 (m, 1H).
With hydrogenchloride; iron(III) chloride; In water; N,N-dimethyl-formamide;
Step A 5-Cyano-2-fluorobenzaldehyde To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10percent sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product: 1H NMR (CDCl3) delta 10.34 (m, 1H), 8.21 (m, 1H), 7.90 (m, 1H), 7.35 (m, 1H).
PREPARATION 88(1) To a solution of 5-bromo-2-fluorobenzaldehyde (10 g) in dimethylformamide (60 mL) were added zinc cyanide (6.92 g) and tetrakis(triphenylphosphine)palladium(O) (2.28 g), and the mixture was stirred at 80° C. for 6 hours. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluding with a mixture of hexane and ethyl acetate (3:1) to give 5-cyano-2-fluorobenzaldehyde (5.3 g) as a solid substance. NMR (DMSO-d6, delta): 7.35 (1H, t, J=9 Hz), 7.91 (1H, m), 8.22 (1H, dd, J=2, 7 Hz), 10.36 (1H, s); Mass m/z: 150 (M++1).
With n-butyllithium; acetic acid; diisopropylamine; In tetrahydrofuran; N-methyl-acetamide; hexane; water;
EXAMPLE 112 2-Fluoro-5-cyano-benzaldehyde To a stirred, cooled solution (0° C.) of diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (200 mL) n-butyllithium (40 mL of 2.5M in hexane, 0.11 mol) was added from a dropping funnel over a period of 30 min. under argon. The mixture was stirred at that temperature for 30 min. and then cooled to -78° C. A solution of 4-fluoro-benzonitrile (12.1g, 0.1 mol) in dry THF (50 mL) was then added dropwise over 15 min. via syringe and stirred for 1 hour at -78° C. Dimethylformamide (8 mL) was added dropwise from a syringe and the stirring was continued for another 20 min. The reaction was quenched by the rapid addition of acetic acid (20 mL) followed by water (500 mL) and the product was extracted with diethyl ether (2*500 mL). The combined organic layers were washed with 1N HCl, water, saturated sodium chloride and then dried over anhydrous magnesium sulfate, and evaporated to give 2-fluoro-5-cyano-benzaldehyde (11.8 g, 79percent yield) as a light yellow solid. 1H NMR (CDCl3): delta10.32 (s, 1H), 8.18 (dd, 1H, J=6.5, 2.5 Hz), 7.88 (m, 1H), 7.33 (t, 1H, J=9.5 Hz).
74.6%
With acetic acid; diisopropylamine;SiO2; In N-methyl-acetamide; ethyl acetate;
A. 4-Fluoro-3-Formylbenzenecarbonitrile Lithium diisopropyi amide (LDA) (22 mL, 49.56 mmol, 2.0 N commercial solution in heptanes) was added to tetrahydrofliran (50 mL), cooled to 78° C. and under nitrogen. 4-Fluorobenzonitrile was weighed out (5.0 g, 41.3 imnol), placed under nitrogen and dissolved in 25 mL of dry tetrahydrofliran. This solution was added dropwise to the solution of LDA. The resulting solution was stirred at -78° C. for one hour before quenching with 4 mL of dimethylformamide. The temperature was maintained for 10 min before adding 8 mL of acetic acid and 20 mL of distilled water. The crude product was extracted with ethyl acetate. Purification by column chromatography (SiO2, 20percent ethyl acetate in hexanes) afforded 4.6 g of pure product as a white solid (74.6percent yield). -A second batch of the title compound (3.5 g, 56.8 percent/yield) was prepared 20 using 5 g of benzonitrile (41.3 mmol): 1H NMR (CDCl3) delta 10.3 (s, 1H), 8.21 (dd, 1H), 7.91 (d of q, 1H), 7.35 (t, 1H); ES-MS M+was not detected.
With acetic acid; diisopropylamine; lithium diisopropyl amide;SiO2; In tetrahydrofuran; N-methyl-acetamide; ethyl acetate;
A. 4-Fluoro-3-formylbenzenecarbonitrile Lithium diisopropyl amide (LDA) (22 mL, 49.56 mmol, 2.0 N commercial solution in heptanes) was added to tetrahydrofuran (50 mL), cooled to 78° C. and under nitrogen. 4-Fluorobenzonitrile was weighed out (5.0 g, 41.3 mmol), placed under nitrogen and dissolved in 25 mL of dry tetrahydrofuran. This solution was added dropwise to the solution of LDA. The resulting solution was stirred at -78° C. for one hour before quenching with 4 mL of dimethylformamide. The temperature was maintained for 10 min before adding 8 mL of acetic acid and 20 mL of distilled water. The crude product was extracted with ethyl acetate. Purification by column chromatography (SiO2, 20percent ethyl acetate in hexanes) afforded 4.6 g of pure product as a white solid (74.6percent yield). A second batch of the title compound (3.5 g, 56.8percent yield) was prepared 20 using 5 g of benzonitrile (41.3 mmol): 1H NMR (CDCl3) delta 10.3 (s, 1H), 8.21 (dd, 1H), 7.91 (d of q, 1H), 7.35 (t, 1H); ES-MS M+ was not detected.
With acetic acid; diisopropylamine; lithium diisopropyl amide;SiO2; In tetrahydrofuran; N-methyl-acetamide; ethyl acetate;
A. 4-Fluoro-3-formylbenzenecarbonitrile Lithium diisopropyl amide (LDA) (22 mL, 49.56 mmol, 2.0 N commercial solution in heptanes) was added to tetrahydrofuran (50 mL), cooled to 78° C. and under nitrogen. 4-Fluorobenzonitrile was weighed out (5.0 g, 41.3 mmol), placed under nitrogen and dissolved in 25 mL of dry tetrahydrofuran. This solution was added dropwise to the solution of LDA. The resulting solution was stirred at -78° C. for one hour before quenching with 4 mL of dimethylformamide. The temperature was maintained for 10 min before adding 8 mL of acetic acid and 20 mL of distilled water. The crude product was extracted with ethyl acetate. Purification by column chromatography (SiO2, 20percent ethyl acetate in hexanes) afforded 4.6 g of pure product as a white solid (74.6percent yield). A second batch of the title compound (3.5 g, 56.8percent yield) was prepared 20 using 5 g of benzonitrile (41.3 mmol): 1H NMR (CDCl3) delta 10.3 (s, 1H), 8.21 (dd, 1H), 7.91 (d of q, 1H), 7.35 (t, 1H); ES-MS M+was not detected.
With dihydrogen peroxide; sodium sulfite; In water; acetonitrile;
PREPARATION 88(2) To a solution of <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (145 mg) in acetonitrile (2 mL) were added a sodium dihydrogenphosphate aqueous solution (23 mg in 1 mL water) and 30percent hydrogen peroxide (0.09 mL). To the resulting mixture was added dropwise a sodium chlorite aqueous solution (126mg in 1 mL water) for an hour at 0° C. The mixture was stirred for an hour at ambient temperature, then a small amount of sodium sulfite was added. The mixture was diluted with ethyl acetate and washed successively with 1N-hydrochloric acid and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-cyano-2-fluorobenzoic acid (137 mg) as a solid substance. NMR (DMSO-d6, delta): 7.29 (1H, t, J=9 Hz), 7.83 (1H, m), 8.32 (1H, dd, J=2, 7 Hz); Mass m/z: 164 (M+-1).
Step A 5-Cyano-1-methylindazole To a solution of <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (0.50 g, 3.35 mmol) in ether (5 mL) was added methyl hydrazine (0.178 muL, 3.35 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give the hydrazone as a yellow solid. This solid was fused at 230° C. for 10 min, cooled to rt, dissolved in CH2Cl2 and purified by filtration through a pad of silica (eluant CH2Cl2:MeOH; 19:1) to afford the title compound as a light yellow solid: 1H NMR (DMSO) delta 8.38 (s, 1H), 8.23 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 4.09 (s, 3H).
In dichloromethane;
Step A 5-Cyano-1-methylindazole To a solution of <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (0.50 g, 3.35 mmol) in ether (5 mL) was added methyl hydrazine (0.178 muL, 3.35 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give the hydrazone as a yellow solid. This solid was fused at 230° C. for 10 min, cooled to rt, dissolved in CH2Cl2 and purified by filtration through a pad of silica (eluant CH2Cl2:MeOH; 19:1) to afford the title compound as a light yellow solid: 1H NMR (DMSO) delta 8.38 (s, 1H), 8.23 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 4.09 (s, 3H).
With ammonium chloride; methyllithium; In tetrahydrofuran;
Step A 4-Fluoro-3-(1-hydroxyethyl)benzonitrile To a solution of <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (1.50 g, 10.06 mmol) in THF (15 mL) cooled to 0° C. was added methyllithium (7.90 mL, 11.06 mmol). The mixture was stirred at room temperature for 2 h and quenched by the addition of saturated NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (50 mL) and water (20 mL), the organic was washed with water (20 mL), dried over magnesium sulfate and concentrated in vacuo to provide a residue. Purification via flash column chromatography (30*150 mm column; elution with EtOAc: Hex, 1:2) afforded pure compound: 1H NMR (CDCl3) delta 7.89 (dd, J=2.2; 6.7 Hz, 1H), 7.57 (m, 1H), 7.12 (t, J=9.1 Hz, 1H), 5.22 (m, 1H), 1.93 (d, J=4.4 Hz, 1H), 1.51 (d, J=6.4 Hz, 3H).
Benzo[b]thiophene-5-carboxamidine hydrochloride 4-Fluorobenzonitrile was formylated with LDA and DMF in THF at -78° C. under the usual conditions to give 4-fluoro-3-formylbenzonitrile in 77percent yield. This was annulated under the usual conditions with NaH and methyl thioglycollate to give methyl 5-cyanobenzo[b]thiophene-2-carboxylate in 64percent yield.
36
methylthioglycollate[ No CAS ]
[ 146137-79-3 ]
[ 146137-93-1 ]
Yield
Reaction Conditions
Operation in experiment
86.4%
With potassium tert-butylate; In tetrahydrofuran; ice-water; chloroform;
EXAMPLE 113 Methyl 5-cyano-benzthiophene-2-carboxylate Methylthioglycollate was added to t-BuOK (43 mL, 1M in THF) in a flame dried flask cooled in ice-water bath. An additional 100 mL of dry THF was added and the mixture was stirred at room temperature for 30 min. A solution of <strong>[146137-79-3]2-fluoro-5-cyano-benzaldehyde</strong> from Example 112 (6g, 0.04 mol) in 100 mL of dry THF was added dropwise via a syringe over a period of 30 min. The reaction was exothermic and a considerable darkening of the reaction mixture was observed. The reaction mixture was stirred for another 30 min. at room temperature. The mixture was carefully added to an ice-water mixture and the precipitated was removed by filtration. The precipitate was dissolved in chloroform and dried over magnesium sulfate. The solution was filtered and evaporated to give methyl 5-cyano-benzthiophene-2-carboxylate (7.5 g, 86.4percent yield). 1H NMR (CDCl3): d 8.16 (s, 1H), 8.04 (s, 1H), 7.92 (d, 1H, J=8.5 Hz), 7.62 (d, 1H, J=8.5 Hz).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 20℃; for 6h;
To a solution of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (300 mg) in dichloromethane (7 ml) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-lambda4-sulfanyl)ethanamine (757 mg) at room temperature, followed by stirring for 6 hours, and addition of a saturated aqueous NaHCO3 solution (15 ml). After extraction with chloroform (30 ml), the organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain 3-(difluoromethyl)-4-fluorobenzonitrile (174 mg) as a colorless liquid.
To a solution of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (1 eq) in DMF (0.32 M) was added p- tolylhydrazine hydrochloride (1.05 eq) and the suspension was irradiated in a microwave oven at 80 0C for 5 min. K2CO3 (2 eq) and DMF (up to 0.16 M concentration) were added and the suspension was irradiated in a microwave oven at 160 0C for 20 min. The mixture was then partitioned between EtOAc and brine, dried (Na2SO4), filtered and evaporated. The residue was purified by SCX cartridge, eluting with methanol. Evaporation of the solvent afforded compound Bl.MS (ES) Ci5HnN3 requires: 233, found: 234 (M+H)+.1H-NMR (300 MHz, OMSO-d6, 300K) delta: 8.52 (s, IH); 7.95 (s, IH); 7.98-7.86 (m, IH); 7.83-7.75 (m, IH); 7.64 (d, J= 8.2 Hz, 2H); 7.42 (d, J= 8.2 Hz, 2H); 2.40 (s, 3H).
With potassium carbonate; In acetonitrile; at 80℃; for 0.0833333h;Sealed tube;
3-formyl-4-(lH-l,2,4-triazol-l-yl)benzonitrile In sealed microwave reactors, <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (850 mg, 5.7 mmol) was dissolved in acetonitrile (15 mL), lH-l,2,4-triazol (590 mg, 8.55 mmol, 1.5eq) and K2C03 (1575 mg, 11.39 mmol, 2 eq) were added to give a colorless suspension. Then the reaction mixture was stirred and heated at 80°C for 5min. The reaction mixture was poured into 20 mL of water, extracted with 2x 20 mL of EtOAc. The combined organic layers were washed with lx 20 mL of water, lx 20 mL of brine, dried over Na2S04, filtered and concentrated in vacuo to give an orange solid, m= 983mg. The solid was triturated with dichloromethane and petroleum ether, filtered and dried in vacuo at 45 °C overnight to give 493 mg of a brown powder (Yield : 43percent) APCI-MS: (M+H)+ =199 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.01 (s, 1H), 9.33 (s, 1H), 8.46 - 8.29 (m, 3H), 8.05 (d, J = 9.0 Hz, 1H). 4-(lH-l,2,4-triazol-l-yl)nicotinaldehvde Aspect of the product: yellow solid (Yield: 49percent) APCI-MS: (M+H)+ =175 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.20 (s, 1H), 9.39 (s, 1H), 8.99 - 8.91 (m, 2H), 8.39 (s, 1H), 7.90 (d, J = 5.5 Hz, 1H).
With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃;Microwave irradiation;
To a solution of <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (200 mg, 1.34 mmol) in DMSO (8 mL) are added 1,2,4-triazole (139 mg, 2.01 mmol) and K2CO3 (370 mg, 2.7 mmol) at room temperature. The solution is heated to 80 °C for 5 minutes in a microwave reactor and then cooled down and washed with H20 (20 mL). The solution is extracted with EtOAc (3 x 15 mL). The combined organic layer is dried (MgS04), filtered and concentrated. The residue (120 mg, 45percent) is used in the next step of the synthesis without further purification.
With Oxone; In water; N,N-dimethyl-formamide; at 20℃; for 3h;
To a solution of 4-(2-amino-pyrimidin-5-yl)-N -ieri-butyl-benzene-l,2-diamine (2 g, 0.008 mol) in DMF (20 mL) is added <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (1.4 g, 0.009 mol) at room temperature. Oxone (4.9 g, 0.008 mol) in H20 (5 mL) is added and the solution is stirred at the same temperature for 3 hours. Saturated sodium thiosulfate solution (15 mL) is added and the mixture is extracted with EtOAc (3 x 15 mL) and H20 (20 mL). The combined organic layer is dried with MgS04 (1 g) and is filtered. The filtrate is concentrated and the residue is re-dissolved in AcCN (10 mL). The solid that precipitates out from the solution is collected by filtration. The resulting white solid is dried under vacuum and is used in the next step of the synthesis without further purification.
With potassium carbonate; In dimethyl sulfoxide; at 50℃; for 4h;
A mixture of 75 (0.8 g, 5.4 mmol), 2,5-dichlorophenol (0.98 g, 6.0 mmol) in DMSO (10.0 mL) and anhydrous K2C03 (1.12 g, 8.1 mmol) was heated at 50 °C for 4 h. The mixture was poured into ice water extracted with EtOAc (3 x 50 mL). The organic layer was sequentially washed with brine (2 x 75 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by column chromatography to give 70 (1.40 g, 100percent). 1H NMR (500 MHz, CDC13) delta 10.30 (s, 1H), 8.40 (d, J= 2.7 Hz, 1H), 8.12 (d, J= 7.9 Hz, 1H), 7.74 (m, 2H), 7.30 (d, J= 8.7, 1H), 7.24 (s, 1H). HR-MS (ES) calcd for C14H7C12N02 [M+l]+ 293.0100, found 293.0102.
A mixture of 74 (1.82 g, 9 mmol) and copper (I) cyanide (1.4 g, 15.7 mmol) in DMF (14.0 mL) was stirred at reflux overnight. After completion, the reaction mixture was cooled to rt and poured into a solution of water (10 mL) and NH4OH (10 ml) followed by extraction with EtOAc (3 x 25 mL). The organic layer was sequentially washed with brine (2 x 15 mL), dried over anhydrous Na2S04, and concentrated in vacuo to give 757a (0.80 g, 60 percent).
With caesium carbonate; In acetonitrile; for 3h;Reflux;
Example 125(1)3-Formyl-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (125a)Compound (100a) (2.0 g), cesium carbonate (3.41 g), and <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (1.25 g) were suspended in acetonitrile (23 mL), followed by reflux for 3 hr. The reaction solution was distributed between chloroform and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (125a) (2.00 g, 67percent) as a white solid.1H-NMR (DMSO-d6) delta: 9.93 (1H, s), 8.30-8.24 (3H, m), 8.20 (1H, d, J=4.88 Hz), 7.96 (1H, d, J=4.88 Hz), 3.95 (1H, tt, J=6.83, 6.83 Hz), 1.44 (6H, d, J=6.83 Hz); LRMS (ESI) m/z 417 [M+H]+.
3- formyl-4-methox benzonitrile In a 10 mL reactor flask, <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (900 mg, 6.04 mmol) was dissolved under argon in 2 mL of methanol. Sodium methoxide (1.232 mL, 6.64 mmol) was added and the reaction mixture was heated at reflux for 2h. TLC showed no more starting material. The reaction mixture was poured into 10 mL of water. The resulting solid was filtered, washed with water, DIPE and dried in vacuo. The residue was purified by flash chromatography, eluted with a gradient from pretroleum ether to MTBE give 587 mg of a grey solid (Yield :59percent) LC-MS: 98percent 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.28 (s, 1H), 8.12 (dd, J = 8.8, 2.2 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 18h;
3-formyl-4-(4-fluorophenylthio)benzonitrile In a 50 mL round-bottomed flask, <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (900 mg, 5.73 mmol) and potassium carbonate (872 mg, 6.31 mmol) were suspended in DMF (10 mL) to give a yellow suspension. Then 4-fluorobenzenethiol (0.654 mL, 6.02 mmol) was added and the reaction mixture heated at 70°C for 18h. The reaction mixture was poured into water. The solid was filtered, washed with water and with a few amount of DIPE then dried in vacuo to give 1.44g of a pale yellow solid (Yield : 97percent) APCI-MS: (M+H)+ =257 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.12 (s, 1H), 8.49 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.5, 2.0 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.43 (ddd, J = 10.9, 6.0, 2.6 Hz, 2H), 6.80 (d, J = 8.5 Hz, 1H).
(E)-ethyl α-cyano-2-(pyrrolidin-1-yl)-5-cyanocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
In ethanol; at 78℃; for 2h;
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield.
(E)-ethyl α-cyano-2-(morpholin-4-yl)-5-cyanocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In ethanol; at 78℃; for 2h;
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield.
(E)-ethyl α-cyano-2-(4-methylpiperazine)-5-cyanocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
In ethanol; at 78℃; for 1.75h;
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield.
(E)-ethyl α-cyano-2-(methyl isonipecotat-1-yl)-5-cyanocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In ethanol; at 78℃; for 1h;
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield.
(E)-ethyl α-cyano-2-(piperidin-1-yl)-5-cyanocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
In ethanol; at 78℃; for 1.16667h;
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield.
ethyl (E)-3-(5-cyano-2-(pyrrolidin-1-yl)phenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydroxide; In water; for 8h;Inert atmosphere; Reflux; Green chemistry;
General procedure: To a 25 mL three-necked round-bottomed flask was added 4-fluoro-3-nitrobenzaldehyde (2b, 0.1691 g, 1.0 mmol), NaOH(0.0600 g, 1.5 mmol), (2-ethoxy-2-oxoethyl)triphenylphosphoniumbromide (4a, 0.6440 g, 1.5 mmol), piperidine (3b, 0.2968mL, 3.0 mmol), and H2O (5 mL), then heated to 50 °C. The reactionprogress was carefully monitored by TLC. After 10 min, thesolvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography.
4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 2h;Inert atmosphere;
A mixture of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (14.2 g, 96.0 mmol), 4-bromo-3-hydroxymethylphenol (19.4 g, 96 mmol), and potassium carbonate (15.2 g, 110 mmol) in N,N-dimethylformamide (200 mL) was stirred at 70° C. under nitrogen atmosphere for 2 h. The mixture was poured into ethyl acetate/water. The organic layer was washed with water twice and with brine, then dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (3:1 to 7:3 hexane/ethyl acetate) to give 4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile (26.0 g, 82percent).
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