* 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 hydroxylamine; sodium hydroxide In water for 14 h; Inert atmosphere; Reflux
General procedure: Ketonitrile 5 (100 mmol) was added to 15percent aqueous NaOH solution(100 mL) followed by hydroxylamine (200 mmol). The resulting mixture was heated at reflux for 14 h, cooled down to r.t., theresulting precipitate was isolated by filtration and crystallized from isopropyl alcohol.
19.8%
With sodium hydroxide; hydroxyammonium sulfate In ethanol; water at 20 - 80℃; for 24 h;
Example 145; N-(3-Phenylisoxazol-5-yl)-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide; (1) 3-Phenylisoxazole-5-amine; A mixture of 3-oxo-3-phenylpropanenitrile (5.00 g, 34.4 mmol), hydroxylamine sulfate (3.10 g, 18.9 mmol), ethanol (35 ml) and an aqueous solution (35 ml) of sodium hydroxide (1.66 g, 41.4 mmol) was stirred at 80°C for 24 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=11 by addition of an aqueous 8N sodium hydroxide solution and then extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 1) to obtain the desired product (1.09 g, 19.8percent) as a solid. 1H-NMR (CDCl3) δ; 4.00 (2H, br s), 6.09 (1H, s), 7.41 - 7.46 (3H, m), 7.70 - 7.73 (2H, m).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 6, p. 1914 - 1925
[2] Organic Letters, 2017, vol. 19, # 4, p. 934 - 937
[3] Organic Letters, 2018, vol. 20, # 9, p. 2774 - 2777
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1082 - 1105
[5] Patent: EP1813606, 2007, A1, . Location in patent: Page/Page column 81
[6] Justus Liebigs Annalen der Chemie, 1891, vol. 266, p. 329
[7] Heterocycles, 1991, vol. 32, # 6, p. 1153 - 1158
2
[ 614-16-4 ]
[ 14208-52-7 ]
Reference：
[1] Patent: US2013/131040, 2013, A1,
3
[ 614-16-4 ]
[ 621-03-4 ]
Reference：
[1] Gazzetta Chimica Italiana, 1951, vol. 81, p. 511,521
4
[ 24424-99-5 ]
[ 614-16-4 ]
[ 257892-43-6 ]
Yield
Reaction Conditions
Operation in experiment
62.9%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 60℃; for 2.25 h; Cooling with ice Stage #2: With water; sodium hydroxide In tetrahydrofuran at 20℃; for 0.333333 h; Cooling with ice
A solution of 3-oxo-3-phenylpropanenitrile (7.26 g, 50 mmol) in tetrahydrofuran (100 mL) was added, over 15 minutes, to an ice cooled solution of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (100 mL). The mixture was stirred for 15 minutes at room temperature, then at 60° C. for 2 hours. The mixture was cooled in an ice bath and quenched by the dropwise addition of water (3.8 mL), followed by the dropwise addition of 4 M sodium hydroxide solution (3.8 mL), followed by the dropwise addition of water (11.4 mL). The mixture was stirred at room temperature for an additional 20 minutes, and the solids were then removed by suction filtration, rinsing the solids with tetrahydrofuran. The mixture was stirred overnight with BOC-anhydride (13 g, 59.6 mmol), concentrated under reduced pressure, and the residue purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (70:30) to give racemic (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 7.9 g, 62.9percent).
With hydroxylamine; sodium hydroxide; In water; for 14h;Inert atmosphere; Reflux;
General procedure: Ketonitrile 5 (100 mmol) was added to 15% aqueous NaOH solution(100 mL) followed by hydroxylamine (200 mmol). The resulting mixture was heated at reflux for 14 h, cooled down to r.t., theresulting precipitate was isolated by filtration and crystallized from isopropyl alcohol.
19.8%
With sodium hydroxide; hydroxyammonium sulfate; In ethanol; water; at 20 - 80℃; for 24h;pH 11.0;
Example 145; N-(3-Phenylisoxazol-5-yl)-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide; (1) 3-Phenylisoxazole-5-amine; A mixture of 3-oxo-3-phenylpropanenitrile (5.00 g, 34.4 mmol), hydroxylamine sulfate (3.10 g, 18.9 mmol), ethanol (35 ml) and an aqueous solution (35 ml) of sodium hydroxide (1.66 g, 41.4 mmol) was stirred at 80C for 24 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=11 by addition of an aqueous 8N sodium hydroxide solution and then extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 1) to obtain the desired product (1.09 g, 19.8%) as a solid. 1H-NMR (CDCl3) delta; 4.00 (2H, br s), 6.09 (1H, s), 7.41 - 7.46 (3H, m), 7.70 - 7.73 (2H, m).
With acetic acid; at 150℃; for 0.0833333h;Microwave irradiation;
EXAMPLE 1:; 2-phenylpyrazolori,5-alphalquinazolin-5(4//)-one; A solution (0.66 M) of <strong>[33906-30-8]2-hydrazinobenzoic acid hydrochloride</strong> (from Aldrich) in AcOH was treated with benzoylnitrile (1 eq.). The reaction mixture was heated at 1500C under microwave irradiation for 5 min. The resulting precipitate was filtered, washed with Et2O and dried to afford(69%) the title compound as a solid.1U NMR (400 MHz, DMSO-de, 300K) delta 6.38 (s, IH), 7.40 (t, J 7.6 Hz, IH), 7.48 (t, J 7.6 Hz,2H), 7.51 (t, J7.6 Hz, IH), 7.91 (t, J7.6 Hz, IH), 7.97 (d, J7.6 Hz, 2H), 8.17-8.14 (m, 2H),12.31 (s, IH). MS (ES+) Ci6HnN3O requires: 261, found: 262 (M+H)+.
With triethylamine; In ethanol; at 20℃; for 4h;Heating / reflux;
2.9 g of alpha-cyanoacetophenone and 3.9 g of <strong>[20570-96-1]benzyl hydrazine dihydrochloride</strong> were suspended in 50 mL of ethanol. The reaction solution was added with 6.0 ml of triethylamine at room temperature, and heated under reflux for 4 hours. The solvent was evaporated, and the residue was added with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified and separated by silica gel column chromatography (ethyl acetate :n-hexane=1:4), to afford 4.1 g of the title compound as a yellow needle powder.1H-NMR (400 MHz, CDCl3) delta 3.40 (2H, bs), 5.28 (2H, s), 5.92 (1H, s), 7.22 (2H, d, J = 8.0 Hz), 7.28 (2H, t, J = 8.0 Hz), 7.32-7.37 (2H, m), 7.38 (2H, t, J = 8.0 Hz), 7.77 (2H, d, J = 8.0 Hz).
1-ethyl-6-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine; at 110℃; for 48h;
EXAMPLE 104; A mixture of benzoylacetonitrile (365 mg), tetrahydropyran-4-carbaldehyde (287 mg), 5-amino-1-methylpyrazole (289 mg) in pyridine (7.3 ml) was stirred for 2 days at 110 C. The solvent was removed under reduced pressure. The residue was purified with silica gel column chromatography to give pure 1-ethyl-6-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (359 mg). 1H-NMR (CDCl3) delta 1.56 (3H, t, J=6.6 Hz), 1.94 (2H, d, J=12.2 Hz), 2.25-2.42 (2H, m), 3.62-3.79 (3H, m), 4.16-4.24 (2H, m), 4.62 (2H, q, J=6.6 Hz), 7.51-7.58 (3H, m), 7.85-7.93 (2H, m), 8.35 (1H, s)
A solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) in EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochloride (2.6 g, 20.7 mmol) in EtOH (35 mL) and the solution was heated to reflux with stirring for 18 h. The solution was cooled, concentrated and the residue was partitioned between sat. aq NaHCO3 (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO4), and the solvent removed in vacuo to give 6e as a pale yellow solid; yield: 2.2 g (97%); mp 100-102 C.
83%
To a slurry of TERT-BUTYLHYDRAZINE HYDROCHLORIDE (12.8 g, 102.9 MMOL) in 350 mL of EtOH was added sodium hydroxide (3.5 g, 88.2 MMOL). After 1 hr of stirring, a solution of 3-oxo-3-phenyl-propionitrile (10.6 g, 73.5 mmol, in 50 mL of ETOH) was added and the resulting slurry was heated to reflux. After 12 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting solid was washed with hexanes and dried under reduced pressure to give the title compound (13.1 g, 83% yield) as yellow-colored solid, which was used without further purification. LRMS m/z (APCI) 216 (M+1); 500 MHz 1H NMR (CD30D) 8 7.67 (d, J = 7.5 Hz, 2H), 7.35-7. 29 (m, 2H), 7.25-7. 20 (m, 1H), 5.86 (s, 1 H), 1.65 (S, 9H).
45%
With triethylamine; In ethanol; for 2h;Heating / reflux;
Step 2 - Preparation of Intermediate Compound BB EPO <DP n="86"/>To a solution of benzoylacetonitrile (2.18 g, 15.0 mmol) and tert- butylhydrazine hydrochloride (2.12 g, 17.0 mmol) in ethanol (20 mL), was added triethylamine (3.5 mL, 25 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 2 hours. The reaction mixture was then cooled to room temperature and quenched with 5% aqueous NaOH. The resulting solution was extracted using ethyl acetate and the ethyl acetate was washed sequentially with water and brine, then dried over MgSO4 and concentrated in vacuo to provide a crude residue. The crude residue was recrystallized from CH2Cb to provide Compound B as a yellow solid (1.46 g, 45% yield). 1H NMR (400 MHz, (CD3)2SO) delta 7.64-7.58 (m, 2 H), 7.34-7.26 (m, 2 H), 7.22-7.16 (m, 1 H), 5.75 (s, 1 H), 4.94 (s, 2H), 1.55 (s, 9H).
A solution of 3-oxo-3-phenylpropanenitrile (7.26 g, 50 mmol) in tetrahydrofuran (100 mL) was added, over 15 minutes, to an ice cooled solution of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (100 mL). The mixture was stirred for 15 minutes at room temperature, then at 60 C. for 2 hours. The mixture was cooled in an ice bath and quenched by the dropwise addition of water (3.8 mL), followed by the dropwise addition of 4 M sodium hydroxide solution (3.8 mL), followed by the dropwise addition of water (11.4 mL). The mixture was stirred at room temperature for an additional 20 minutes, and the solids were then removed by suction filtration, rinsing the solids with tetrahydrofuran. The mixture was stirred overnight with BOC-anhydride (13 g, 59.6 mmol), concentrated under reduced pressure, and the residue purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (70:30) to give racemic (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 7.9 g, 62.9%).
3-(cyanomethyl)thiophene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.65%
Benzoyl acetonitrile (73.8 g, 0.508 mol) was added to a cooled solution of sodium ethoxide (prepared from sodium 19.5 g, 0.847 mol. and ethanol, 1125 ml). 3-Bromo-2- thiophene-2-carboxylic acid (75.0 g, 0.362 mol) was added and the mixture was stirred at room temperature for 2 hr. 4.5 g (0.0247 mol) Of copper (II) acetate anhydrous wasadded and the mixture was boiled under reflux for 2 hours. 4.5 g (0.0247 mol) of copper(II) acetate anhydrous was added and the mixture was boiled under reflux for 8 hr.Mixture was cooled to room temperature and filtered the mass. Ethanol was removed bydistillation under vacuum at a temperature 60C. The reaction mixture was diluted with750 ml of water while maintaining at 25-30C by cooling and the solution was acidifiedwith hydrochloric acid, and extracted with two 750 ml portions of ethyl acetate. The ethyl acetate extracts were combined and extracted with two times with 750 ml portions of 5% sodium carbonate solution. The aqueous sodium carbonate extracts were combined, the solution was acidified with hydrochloric acid and extracted with two 325 ml portions of ethyl acetate. The ethyl acetate was removed by distillation under vacuum, to give acrude product and recrystallization of a crude product from isopropyl ether to give 34.8 g (56.65 %) as a-yellow solid, melting point 102C to 106C, with 97.1 % purity by HPLC. ?HNMR (400 MHz, DMSO-d6) 3- Value (ppm): 4.25 [s, CH2 (2H)], 7.24 (d, 1H), 7.88(d, lH), 13.44[s, (broad), OH, lH]. 13 CNMR (400 MHz, DMSO-d6) 3- Value (ppm):17.72 (1C), 118.5 (iC), 129.5(1C), 130.6 (1C), 132.46(1C), 137.0 (1C), 162.9 (1C). Mass:167.0 [M], 166.0 [M-1]
With hydrogenchloride; In ethanol; water; for 0.333333h;Reflux;
General procedure: The solution of 0.145 g 3-phenyl-3-oxopropanenitrile (6e 1.0 mmol) in 25 mL of ethanol and 0.165 g benzothiazolylhydrazine (5a, 1 mmol) was refluxed for 20 minutes in the presence of conc. HCl. The progress of the reaction was monitored by TLC (ethyl acetate/n-hexane: 1/4). After complete consumption of reactants, the reaction mixture was added with 0.225 g 3-(4-bromophenyl)-3-oxopropanenitrile (6a, 1 mmol) and 0.044 g acetaldehyde (8b, 1 mmol). The reaction mixture was heated again to reflux for another 20 minutes till solid product separates out in the reaction mixture. The reaction mixture was filtered at the vacuum pump and washed well with hot ethanol to afford the pure 7j. Compounds (7k-r) were synthesized using the same procedure with sequential addition of appropriate reactants.
2-phenyl-5-p-bromophenylpyrazolo[1,5-a]pyrimidin-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
General procedure: To the 1 mol eq. of 3-aryl-3-oxopropanonitrile (2) was added1 mol eq. of hydrazine hydrate (1) in Toluene/EtOH (9:1) and thereaction mixture was refluxed for 30 min then another 1 mol eq. ofdifferent 3-aryl-3-oxopropanonitrile (2) and catalytic amount ofPTSA (0.01 mol eq.) was added. Again reaction mixture wasrefluxed up to 4 h. On completion of the reaction, excess solvent was distilled off. The solid so obtained was filtered and washedwith cold ethanol. Solid was neutralised with aq. sodium bicarbonatesolution and again filtered. Compound thus obtained wasair dried and recrystallized from ethanol.
With triethylamine; In N,N-dimethyl-formamide; at 90.0℃; for 16.0h;
General procedure: 1H-Pyrazol-5-amine 1 (1 equiv.), 3-oxopropanenitrile 2 (1 equiv.), benzaldehyde 3 (1 equiv.), and Et3N (2 equiv.) were stirred in DMF (1 M) at 90 C for 16 h. The volatiles were removed under reduced pressure (or positive N2 (g) pressure). Sodium nitrite (3 equiv.) and acetic acid (134 equiv.) were added to the crude material, and the reaction mixture was stirred for 10 min. The volatiles were removed under reduced pressure (or positive N2 (g) pressure), and the crude reaction mixture was subjected to silica gel column chromatography with ethyl acetate in hexanes.
ethyl 2-(5-amino-3-(phenyl)-1H-pyrazol-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In ethanol; for 2h;Reflux;
A mixture of benzoylacetonitrile (7A, 44 g, 304 mmol) and ethyl hydrazinoacetate hydrochloride (47 g, 304 mmol) in ethanol (400 mL) is heated to reflux for 2 h. The reaction mixture is concentrated in vacuo. The crude reaction mixture is partitioned between CH2Cl2 (400 mL) and saturated NaHCO3 (aq). The aqueous phase is extracted with CH2Cl2 and the organic phases are combined, dried over MgSO4, filtered and evaporated to give compound 8A as a solid (70 g, 95% yield).1H NMR (400 MHz, CDCl3) (ppm) 7.73 (m, 2H), 7.38 (m, 2H), 7.26 (m, 1H), 5.96 (s, 1H), 4.86 (s, 2H), 4.25 (m, 2H), 3.7 (s, 2H), 1.28 (s, 3H).
10-chloro-4-(4-hydroxyphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine; In ethanol; at 80℃;
General procedure: The mixture of aromatic aldehyde (1 mmol), 1H-indazol-3-amine (<strong>[20925-60-4]4-chloro-1H-indazol-3-amine</strong>) (1 mmol), and 3-(1H-indol-3-yl)-3-oxopropanenitrile or 3-oxo-3-arylpropanenitrile (1 mmol), 95% EtOH (8 mL), Et3N (0.2 mmol) was put in a reaction flask under 80 C about 3-5 h (monitored by TLC). After the completion of the reaction, the reaction mixture was cooled to room temperature and the products could be precipitated out from solvent. Then, compound 4 and 6 were recrystallized from DMF or EtOH.
10-chloro-2-phenyl-4-(p-tolyl)pyrimido[1,2-b]indazole-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With triethylamine; In ethanol; at 80℃;
General procedure: The mixture of aromatic aldehyde (1 mmol), 1H-indazol-3-amine (<strong>[20925-60-4]4-chloro-1H-indazol-3-amine</strong>) (1 mmol), and 3-(1H-indol-3-yl)-3-oxopropanenitrile or 3-oxo-3-arylpropanenitrile (1 mmol), 95% EtOH (8 mL), Et3N (0.2 mmol) was put in a reaction flask under 80 C about 3-5 h (monitored by TLC). After the completion of the reaction, the reaction mixture was cooled to room temperature and the products could be precipitated out from solvent. Then, compound 4 and 6 were recrystallized from DMF or EtOH.
10-chloro-4-(4-methoxyphenyl)-2-phenylpyrimido[1,2-b]indazole-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In ethanol; at 80℃;
General procedure: The mixture of aromatic aldehyde (1 mmol), 1H-indazol-3-amine (<strong>[20925-60-4]4-chloro-1H-indazol-3-amine</strong>) (1 mmol), and 3-(1H-indol-3-yl)-3-oxopropanenitrile or 3-oxo-3-arylpropanenitrile (1 mmol), 95% EtOH (8 mL), Et3N (0.2 mmol) was put in a reaction flask under 80 C about 3-5 h (monitored by TLC). After the completion of the reaction, the reaction mixture was cooled to room temperature and the products could be precipitated out from solvent. Then, compound 4 and 6 were recrystallized from DMF or EtOH.
With sulfonic acid-functionalized mesoporous MCM-41; In neat (no solvent); at 80℃; for 0.333333h;Green chemistry;
General procedure: For the synthesis of spiro-1H-pyrazolo-[3,4-b]pyridines,a mixture of isatin or ninhydrin (1 mmol), 3-oxo-3-phenylpropanenitrile (1 mmol), 1H-pyrazol-5-amine(1 mmol) and PTPSAMCM-41 (10 mg) was stirred at80 C under solvent-free conditions for 20 min (monitoredby TLC, eluent: n-hexane/ethyl acetate, 6:1). The workup was performed as mentioned above to give the pure product.
With sulfonic acid-functionalized mesoporous MCM-41; In neat (no solvent); at 80℃; for 0.333333h;Green chemistry;
General procedure: A mixture of aldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile(1 mmol), 1H-pyrazol-5-amine (1 mmol) andPTPSAMCM-41 (10 mg) was stirred at 80 C under solvent-free conditions. After completion of the reaction(monitored by TLC, eluent: n-hexane/ethyl acetate, 6:1),acetone (10 mL) was added; the catalyst was filtered and washed with acetone. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from EtOH to give the pure product.
With sulfonic acid-functionalized mesoporous MCM-41; In neat (no solvent); at 80℃; for 0.333333h;Green chemistry;
General procedure: A mixture of aldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile(1 mmol), 1H-pyrazol-5-amine (1 mmol) andPTPSAMCM-41 (10 mg) was stirred at 80 C under solvent-free conditions. After completion of the reaction(monitored by TLC, eluent: n-hexane/ethyl acetate, 6:1),acetone (10 mL) was added; the catalyst was filtered and washed with acetone. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from EtOH to give the pure product.
With sulfonic acid-functionalized mesoporous MCM-41; In neat (no solvent); at 80℃; for 0.333333h;Green chemistry;
General procedure: A mixture of aldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile(1 mmol), 1H-pyrazol-5-amine (1 mmol) andPTPSAMCM-41 (10 mg) was stirred at 80 C under solvent-free conditions. After completion of the reaction(monitored by TLC, eluent: n-hexane/ethyl acetate, 6:1),acetone (10 mL) was added; the catalyst was filtered and washed with acetone. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from EtOH to give the pure product.
tetraphenylphosphonium 2-(acetonitrilium)nonahydro-closo-decaborate(1-)[ No CAS ]
[ 614-16-4 ]
[ 2001-45-8 ]
2C24H20P(1+)*C11H18B10N2O(2-)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
General procedure: 4.3.1 Preparation of (Ph4P)2[1-6] A solution of nBuLi in hexane (250mumol; 100 muL) was dropwisely added to a stirred solution of any one of the CH-acid (malonodinitrile, benzoylacetonitrile, or ethyl benzoylacetate) in dry CH2Cl2 at RT under dinitrogen. After stirring for 10min, a solution of (Ph4P)[C1-2] (250mumol) in dry CH2Cl2 (1 mL) was added to the mixture and a resulted solution was kept upon stirring for 1h at RT. Next, a solution of (Ph4P)Cl (500mumol) in CH2Cl2 (1 mL) was added to the mixture, which was kept on stirring for 30min at RT. The solvent was evaporated at RT in vacuo and the resulted oily residue was subjected to column chromatography (eluent: MeCN:CH2Cl2=1:8, v/v). The first fraction was collected and the eluent was evaporated at RT in vacuo. The oily residue was crystallized under Et2O at RT and the powder formed was dried at RT in air. Ph4P)2[1]. Yield 90% (203mg).
General procedure: 4.3.1 Preparation of (Ph4P)2[1-6] A solution of nBuLi in hexane (250mumol; 100 muL) was dropwisely added to a stirred solution of any one of the CH-acid (malonodinitrile, benzoylacetonitrile, or ethyl benzoylacetate) in dry CH2Cl2 at RT under dinitrogen. After stirring for 10min, a solution of (Ph4P)[C1-2] (250mumol) in dry CH2Cl2 (1 mL) was added to the mixture and a resulted solution was kept upon stirring for 1h at RT. Next, a solution of (Ph4P)Cl (500mumol) in CH2Cl2 (1 mL) was added to the mixture, which was kept on stirring for 30min at RT. The solvent was evaporated at RT in vacuo and the resulted oily residue was subjected to column chromatography (eluent: MeCN:CH2Cl2=1:8, v/v). The first fraction was collected and the eluent was evaporated at RT in vacuo. The oily residue was crystallized under Et2O at RT and the powder formed was dried at RT in air. Ph4P)2[1]. Yield 90% (203mg).
4-(benzo[b]thiophen-3-yl)-2-methyl-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With acetic acid; In isopropyl alcohol; at 100℃; for 16h;
A mixture of thianaphthene-3-carboxaldehyde (0.104 g, 0.64 mmol), 3-aminocrotonitrile (0.052 g, 0.64 mmol), benzoylacetonitrile (0.0897 g, 0.62 mmol) and acetic acid (0.035 mL, 0.64 mmol) in isopropyl alcohol (3.5 mL) was heated to 100C and left to stir for 16 hours. The mixture was allowed to cool to RT and concentrated. The residue was basified with aq. sodium bicarbonate, and the resulting solid was filtered off and purified by column chromatography (3:1 Hexane: Ethyl acetate) rendering a light-yellow solid (0.0162 g, 7 %). 1H-NMR (400 MHz, DMSO-d6) delta = 2.12 (s, 3H), 5.17 (s, 1H), 7.39-7.49 (m, 2H), 7.50-7.59 (m 5H), 7.78 (s, 1H), 8.01 (dd, 1H), 8.06 (dd, 1H), 9.92 (s, 1H). HPLC-MS: Rt 4.329 min, m/z 354.1 (MH+). The following examples were synthesized according to Method F.
5-hydroxy-2-phenyl-5-(trifluoromethyl)-4,5-dihydrofuran-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium acetate; In 1,4-dioxane; at 20℃; for 8h;
In a 25 mL reaction tube with a Teflon magnetic stir bar,Add 0.5 mmol benzoylacetonitrile, 0.5 mmol <strong>[431-35-6]3-bromo-1,1,1-trifluoroacetone</strong>, 0.5 mmol sodium acetate,Finally, 58 mmol of 1,4-dioxane was added, and the reaction was stirred at room temperature for 8 hours.Add 15 mL of water, extract three times with 10 mL of ether, and combine the organic phases.Washing with saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and then removing the organic solvent by rotary evaporation;The obtained crude product was eluted with n-pentane and ethyl acetate (10:1, v/v).5-Hydroxy-2-phenyl-5-(trifluoromethyl)-4,5-dihydrofuran-3-carbonitrile was isolated by silica gel column chromatography(Isolation yield 90%).
(2-amino-5-(trifluoromethyl)furan-3-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium carbonate; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;
Under a nitrogen atmosphere, in a 25 mL reaction tube with a Teflon magnetic stirrer,Add 0.5 mmol of benzoylacetonitrile, 0.5 mmol of <strong>[431-35-6]3-bromo-1,1,1-trifluoroacetone</strong>, 0.5 mmol of sodium carbonate,Finally, 58 mmol of 1,4-dioxane was added, and the reaction was stirred in a closed system for 12 hours under an oil bath at 80 C, and then cooled to room temperature.Add 15 mL of water, extract three times with 10 mL of ethyl acetate, and combine the organic phases.Washing with saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and then removing the organic solvent by rotary evaporation;The obtained crude product was eluted with n-pentane and ethyl acetate (10:1, v/v).2-Amino-5-(trifluoromethyl)furan-3-yl(phenyl)methanone was isolated by silica gel column chromatography (yield 86%).
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