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CAS No. : | 2338-75-2 | MDL No. : | MFCD00001921 |
Formula : | C9H6F3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QNKOCFJZJWOXDE-UHFFFAOYSA-N |
M.W : | 185.15 | Pubchem ID : | 75359 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.97 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.87 cm/s |
Log Po/w (iLOGP) : | 1.78 |
Log Po/w (XLOGP3) : | 2.19 |
Log Po/w (WLOGP) : | 3.92 |
Log Po/w (MLOGP) : | 2.82 |
Log Po/w (SILICOS-IT) : | 3.15 |
Consensus Log Po/w : | 2.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.58 |
Solubility : | 0.49 mg/ml ; 0.00265 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.32 |
Solubility : | 0.879 mg/ml ; 0.00475 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.77 |
Solubility : | 0.0311 mg/ml ; 0.000168 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.21 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.89% | With ammonia; hydrogen In methanol | (4-Trifluoromethyl-phenyl)-acetonitrile (2g, 10.81mmol) in methanolic ammonia (50mL) was added to Raney nickel (400mg) in methanol taken in a parr hydrogenator. The flask was stirred at 50 PSI overnight. The reaction was monitored by TLC (10percent methanol in CHC13). The reaction mixture was filtered through celite bed and the filtrate was dried under reduced pressure to afford 2g of the product (97.89percent yield).LCMS purity: 98.73percent, m/z = 190.0 (M+l) |
97.89% | With ammonia; hydrogen In methanol | Step 1: Preparation of Intermediate 2-(4-Trifluoromethyl-phenyl)-ethylamine (I-16a) (4-Trifluoromethyl-phenyl)-acetonitrile (2 g, 10.81 mmol) in methanolic ammonia (50 mL) was added to Raney nickel (400 mg) in methanol taken in a parr hydrogenator. The flask was stirred at 50 PSI overnight. The reaction was monitored by TLC (10percent methanol in CHCl3). The reaction mixture was filtered through celite bed and the filtrate was dried under reduced pressure to afford 2 g of the product (97.89percent yield). LCMS purity: 98.73percent, m/z=190.0 (M+1) |
95% | With ammonia; hydrogen In methanol | To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2 N NH3/MeOH (400 mL) was added Raney Ni (-4. 0 g). The reaction mixture was placed in a Parr Apparatus and hydrogentated under 50 lb pressure of H2 overnight. The solution was filtered through celite and concentrated IN VACUO to yield the desired amine (38 g, 95percent). ESI-MS calc. For CGHIOF3N : 189; Found: 190 (M+H) |
95% | With ammonia; hydrogen In methanol | To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni (~4. 0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95percent). ESI-MS calc. For C9HlOF3N : 189; Found: 190 (M+H). |
95% | With ammonia In methanol | INTERMEDIATE 13; To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni (-4. 0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated iM vacuo to yield the desired amine (38 g, 95percent). |
95% | With ammonia In methanol | To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni (4.0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95percent). ESI-MS calc. For C9H10F3N: 189; Found: 190 (M+M). |
95% | With ammonia; hydrogen In methanol | EXAMPLES INTERMEDIATE 1 Step A; To a solution of 4- trifluoromethyl phenylacetonitrile (40 g, 220 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni ((at)4.0 g). The reaction mixture was placed in a par-shaker and shook under 50 1b pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95percent). ESI-MS calc. For C9H10F3N: 189; Found: 190 (M+H). |
95% | With ammonia In methanol | To a solution of 4- trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni ((at)4.0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95percent). ESI-MS calc. For C9H10F3N: 189; Found: 190 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.6% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 0℃; for 1h; | 88.1 Synthesis of 1-(4-(trifluoromethyl)phenyl)cyclobutane-1-carbonitrile 2-(4-(trifluoromethyl)phenyl)acetonitrile (3.000 g, 16.203 mmol) and sodium hydride (60.00%, 1.426 g, 35.647 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0 °C for 5 minutes After addition of 1,3-dibromopropane (1.645 mL, 16.203 mmol) and further stirring at the same temperature for 1 hour, at 0 °C Water (10 mL) was added to the mixture and the reaction was terminated by stirring for 10 minutes. The solvent was removed from the reaction mixture under reduced pressure, the obtained concentrate was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and water was removed with anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 10%) and concentrated to give the title compound (2.430 g, 66.6%) as a colorless oil. |
61% | With sodium hydride In diethyl ether; dimethyl sulfoxide at 0 - 20℃; for 4h; | 205A Example 205A Example 205A 1-(4-(trifluoromethyl)phenyl)cyclobutanecarbonitrile To a suspension of NaH (0.95 g, 23.7 mmol) in DMSO (15 mL) was added dropwise a solution of 4-(trifluoromethyl)phenyl acetonitrile (2.0 g, 10.8 mmol) and 1,3-dibromopropane (2.37 g, 11.9 mmol) in ether (40 mL) at 0° C. The mixture was stirred for 4 hours at room temperature. After addition of water (15 mL), the mixture was extracted with diethyl ether (100 mL*2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=10/1) to obtain Example 205A (1.5 g, yield 61%) as a solid. LC-MS: 226 [M+H]. |
61% | With sodium hydride In diethyl ether; dimethyl sulfoxide at 0 - 20℃; for 4h; | 205A 1 -(4-(trifluoromethyl)phenyl)cyclobutanecarbonitrile 1 -(4-(trifluoromethyl)phenyl)cyclobutanecarbonitrile[401] To a suspension of aH (0.95 g, 23.7 mmol) in DMSO (15 mL) was added dropwise a solution of 4-(trifluoromethyl)phenyl acetonitrile (2.0 g, 10.8 mmol) and 1,3- dibromopropane (2.37 g, 11.9 mmol) in ether (40 mL) at 0 °C. The mixture was stirred for 4 hours at room temperature. After addition of water (15 mL), the mixture was extracted with diethyl ether (100 mL x 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc =10/1) to obtain Example 205A (1.5 g, yield 61%) as a solid. LC-MS: 226 [M+H]. |
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 50 - 60℃; for 16.5h; | 1.1 Step 1. 1 -(4.-(Trifluoromethyl)phenyl)cyciobutanecarbonitriie A solution of 244.(rifluoromethyl)phenyl1acetonitrile (200 g. 1.08 mol), I ,3 .dibromopropane (164mL, 1.62 moi), and benzyi triethyi ammomun chloride (5.00 g, 0.02 mol) was heated to 50 °C.Sodium hydroxide (260 g, 6.4 mol) in DI water (400 mL) was added at 50 °C slowly over 30 mm(exothenn observed 10 °C), and the mixture stirred for 16 h at 60 °C. After TLC analysis, thereaction mixture was diluted with water (1.0 L) and 2 M HCI (1.6 L), and extracted with CHCi (2.0L). The separated aqueous layer was washed with CH2C12 (1.0 L). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (petroleum ether/EtOAc, 9:1) to afford the title compound as an oil. ‘H NMR (400 MHz, CDC13)) 7.67 (d. J = 8.4 Hz, 2H), 7,56 (d, J = 8.4 Hz, 2H), 2.91-2.86 (i:n, 21-i),2.85-2.60 (m, 2H), 2.54-2.17 (in, 1H), 2.16-2.12 (m, IH). | |
With sodium hydride | ||
With potassium hydroxide In dimethyl sulfoxide at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere; | 119.1 Step 1. Synthesis of 2-methyl-2-(4-(trifluoromethyl)phenyl)propionitrile 60% NaH (519 mg, 13.0 mmol) was added to a solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (1.00 g, 5.40 mmol) in DMF (10 mL) under nitrogen and at 0°C, and then CH3I (1.99 g, 14.0 mmol) was added. The mixture was warmed to room temperature and stirred for 4 hours. The mixture was quenched with water (15 mL), and extracted with EtOAc (15 mL*3). The combined organic layer was washed with brine (10 mL), and dried over anhydrous Na2SO4 to obtain the desired compound (1.12 g, yield 68%) as a colorless oil. 1HNMR (400 MHz, DMSO-d6): δ 7.67-7.62 (m, 4H), 1.76 (s, 6H). |
With sodium hydride | ||
With sodium hydride In N,N-dimethyl-formamide at 0 - 80℃; for 3h; | 1.20 (4-Trifluoromethyl-phenyl)-acetonitrile (lg, 5.4010mmol) in DMF (8.1mL) was added to a stirred mixture of NaH (518.49mg, 21.604mmol) in DMF (8. ImL) at 0°C. This was followed by the addition of methyl iodide (3.3mL, 54.0102mmol) and the resulting mixture was heated to 80°C for 3 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was diluted with cold water and extracted with diethyl ether. The organic layer was washed with brine solution, dried over Na2S04 and concentrated to afford 1.2g of the crude product which was used in the next step without further purification. NMR (CDC13, 300 MHz): δ 7.80-7.49 (m, 4H), 1.8 (s, 6H) |
Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; Stage #2: iodomethane In N,N-dimethyl-formamide at 80℃; for 3h; | 20.1 Preparation of Intermediate 2-Methyl-2-(4-trifluoromethyl-phenyl)-propionitrile (I-20a) Step 1: Preparation of Intermediate 2-Methyl-2-(4-trifluoromethyl-phenyl)-propionitrile (I-20a) (4-Trifluoromethyl-phenyl)-acetonitrile (1 g, 5.4010 mmol) in DMF (8.1 mL) was added to a stirred mixture of NaH (518.49 mg, 21.604 mmol) in DMF (8.1 mL) at 0° C. This was followed by the addition of methyl iodide (3.3 mL, 54.0102 mmol) and the resulting mixture was heated to 80° C. for 3 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was diluted with cold water and extracted with diethyl ether. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 1.2 g of the crude product which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.80-7.49 (m, 4H), 1.8 (s, 6H) | |
Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at 0 - 20℃; for 13h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.89% | With ammonia; hydrogen; In methanol; under 2585.81 Torr; | (4-Trifluoromethyl-phenyl)-acetonitrile (2g, 10.81mmol) in methanolic ammonia (50mL) was added to Raney nickel (400mg) in methanol taken in a parr hydrogenator. The flask was stirred at 50 PSI overnight. The reaction was monitored by TLC (10% methanol in CHC13). The reaction mixture was filtered through celite bed and the filtrate was dried under reduced pressure to afford 2g of the product (97.89% yield).LCMS purity: 98.73%, m/z = 190.0 (M+l) |
97.89% | With ammonia; hydrogen; In methanol; under 2585.81 Torr; | Step 1: Preparation of Intermediate 2-(4-Trifluoromethyl-phenyl)-ethylamine (I-16a) (4-Trifluoromethyl-phenyl)-acetonitrile (2 g, 10.81 mmol) in methanolic ammonia (50 mL) was added to Raney nickel (400 mg) in methanol taken in a parr hydrogenator. The flask was stirred at 50 PSI overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was filtered through celite bed and the filtrate was dried under reduced pressure to afford 2 g of the product (97.89% yield). LCMS purity: 98.73%, m/z=190.0 (M+1) |
95% | With ammonia; hydrogen;nickel; In methanol; | To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2 N NH3/MeOH (400 mL) was added Raney Ni (-4. 0 g). The reaction mixture was placed in a Parr Apparatus and hydrogentated under 50 lb pressure of H2 overnight. The solution was filtered through celite and concentrated IN VACUO to yield the desired amine (38 g, 95%). ESI-MS calc. For CGHIOF3N : 189; Found: 190 (M+H) |
95% | With ammonia; hydrogen;nickel; In methanol; | To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni (~4. 0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95%). ESI-MS calc. For C9HlOF3N : 189; Found: 190 (M+H). |
95% | With ammonia;nickel; In methanol; | INTERMEDIATE 13; To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni (-4. 0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated iM vacuo to yield the desired amine (38 g, 95%). |
95% | With ammonia;Raney Ni; In methanol; | To a solution of 4-trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni (4.0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95%). ESI-MS calc. For C9H10F3N: 189; Found: 190 (M+M). |
95% | With ammonia; hydrogen;nickel; In methanol; under 37503.8 Torr; | EXAMPLES INTERMEDIATE 1 Step A; To a solution of 4- trifluoromethyl phenylacetonitrile (40 g, 220 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni ((at)4.0 g). The reaction mixture was placed in a par-shaker and shook under 50 1b pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95%). ESI-MS calc. For C9H10F3N: 189; Found: 190 (M+H). |
95% | With ammonia;nickel; In methanol;Product distribution / selectivity; | To a solution of 4- trifluoromethyl phenylacetonitrile (40 g, 215 mmol) in 2N NH3/MeOH (400 mL) was added Raney Ni ((at)4.0 g). The reaction mixture was placed in a par-shaker and shook under 50 Lb pressure overnight. The solution was filtered through celite and concentrated in vacuo to yield the desired amine (38 g, 95%). ESI-MS calc. For C9H10F3N: 189; Found: 190 (M+H). |
With ammonia; hydrogen;nickel; In ethanol; water; for 16h; | INTERMEDIATE 1; Step A; A solution of 4-trifluoromethylphenylacetonitrile (10 g, 49 mmol) in a mixture of ethanol (100 mL) and ammonium hydroxide (20 mL of a 29.3% aqueous solution) was hydrogenated over Raney nickel (1 g) for 16 h. The catalyst was removed by filtration through celite and the filtrate evaporated to dryness. The neat residue was added in a dropwise manner to trifluoroacetic anhydride (25 mL, 180 mmol) cooled at 0 C. and the resulting mixture stirred at 0 C. for 30 minutes. The reaction mixture was poured onto ice (250 mL) and the resulting mixture stirred for 30 minutes after which the precipitate was removed by filtration and air dried to give the product as a white solid (13.4 g, 90%). | |
With ammonia; hydrogen;nickel; In methanol; under 2585.81 Torr; for 20h; | [4-(Trifluoromethyl)phenyl]acetonitrile (10.0 g, 54 mmol) was dissolved in a 2.00 M solution of ammonia in methanol (100 mL) in a Parr flask. To it was added Raney Nickel (approx. 1 g). The mixture was shaken under hydrogen (50 psi) for 20 h and filtered through celite which was then washed with methylene chloride several times. The filtrate was concentrated to afford the title compound as a solid. MS calculated for C9H10F3N: (M+H)+190; found 173.1 (M+H-NH3)+ | |
With ammonia; hydrogen;nickel; In methanol; under 2585.81 Torr; for 18h;Product distribution / selectivity; | A solution of 5.0 g (27 mmol) of 4-(trifluoromethyl)phenylacetonitrile in 60 mL 2 M MeOH / NH3 was treated with 0.7 g of Raney Nickel. The mixture was then shaken on a Parr Apparatus under 50 psi of hydrogen for 18 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo to afford 4.62 g of the product amine as brown oil. ¹H NMR (CDC13, 400 MHz) 8:7.56-7.58, (d, 2H), 7.32- 7.34 (d, 2H), 3.00 (t, 2H), 2.8 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With piperidine In water at 50℃; for 5h; Ionic liquid; Sealed tube; | |
With piperidine In ethanol at 75℃; for 14h; | ||
In water Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With piperidine In ethanol at 75℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; hydroxylamine hydrochloride In ethanol for 48h; Heating; | ||
With hydroxylamine hydrochloride; potassium carbonate In methanol at 20℃; | 22.1 Step lN'-hydroxy- -i^trifluoromethy pheny acetimidamide Hydroxylamine hydrochioride (1.126 g, 16.20 mmol) was added at room temperature to a mixture of 4-trifluorobenzyl nitriie (1 g, 5.4 mmol) and potassium carbonate (4.48 g, 32.4 mmol) in MeOH (25 mL) and the mixture was stirred at room temperature overnight. TLC showed that a small amount starting material was left. The mixture was diluted with dichloromethane (100 mL), washed with water (2 x 20 mL), dried ( gS04), filtered and the solvent was evaporated under reduced pressure to give 22A as a brown yellow syrup. | |
With hydroxylamine hydrochloride; potassium carbonate In methanol for 2h; Inert atmosphere; Reflux; |
With hydroxylamine hydrochloride; potassium carbonate In methanol for 8h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With iodine In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: With sodium methylate In methanol; water at -78 - 20℃; for 10h; Inert atmosphere; | 1 Preparation of 3,4-bis (4-trifluoromethylphenyl) maleimide To a solution of 3 g (0.0165 mol)Of 4-trifluoromethyl benzene acetonitrile were added 4.31g (0 · 017mol)Of iodine and 35 ml of distilled water,After the reactants were dissolved and cooled to _78 ° C,Slowly added dropwise a fresh 35ml of 2.4M sodium methoxide in methanol,After the addition was completed, the reaction was allowed to proceed for 10 hours at room temperature, Adding distilled water to terminate the reaction;With 1M hydrochloric acid to neutral,Extraction with dichloromethane,Washed with saturated saline three times,Drying over anhydrous magnesium sulfate, filtration, rotary evaporation and column chromatography gave 3.4-bis (4-trifluoromethylphenyl) maleimide in 66% yield |
Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With iodine; sodium methylate In tetrahydrofuran; methanol at -78 - -25℃; for 16h; Stage #2: With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With allyl(cyclopentadiene)palladium(II); 1,3-bis(dicyclohexylphosphine)propane In 1,2-dimethoxyethane at 80℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tris(dibenzylideneacetone)dipalladium (0); zinc(II) fluoride; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 90℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.75h; Stage #2: ethyl iodide In tetrahydrofuran; hexane at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium hydroxide at 100℃; for 13h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol for 4h; Heating / reflux; | 74.A A suspension of [4-(trifluoromethyl)phenyl]acetonitrile (1.0 g, 5.4 mmoles), hydroxylamine hydrochloride (0.41 g, 5.9 mmoles) and NaHCO3 (0.50 g, 5.9 mmoles) in MeOH (15 ml) was refluxed for 4 hours. The reaction mixture was then concentrated to remove the solvent methanol. The residue was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated to afford the desired product (1.0 g, 84.9%) as white solid. LCMS calculated for C9H10F3N2O (M+H): 219.1; found: 219.1. |
48% | With hydroxylamine hydrochloride; potassium carbonate In ethanol at 20℃; for 7h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Glyoxilic acid; 4-(Trifluoromethyl)phenylacetonitrile With potassium carbonate In methanol at 20℃; for 15h; Stage #2: With formic acid; sulfuric acid at 110℃; for 3h; | 59 Description 59: 3, PVRIDAZINE 4-Trifluoromethylphenylacetonitrile (38.9 g, 210 mmol) was dissolved in dry methanol under nitrogen. Glyoxylic acid monohydrate (29 g, 315 mmol) was added followed by potassium carbonate (74 g, 535 mmol) and the resulting mixture was stirred for 15 hours at room temperature. The resulting solid was filtered, washed with dichloromethane and dried on the sinter to yield an off white solid which was added at room temperature to a solution of CONC. sulfuric acid (30 ml) and formic acid (400 ml). The resulting mixture was then heated with stirring at 110 °C for 3 hours, allowed to cool to room temperature and concentrated under vacuum to 2/3 of the initial volume. It was then poured ice-water (1000 ml) and the resulting solid was filtered off, washed with water and dried on the sinter to yield 35 g of 3- (4- trifluoromethylphenyl) maleic anhydride as an off white solid. The crude anhydride (35 g) was suspended in water (290 ml) and glacial acetic acid (145 ml) was added followed by a solution of hydrazine hydrate (7 ml, 144 mmol) in water (21 ml). After thorough mixing CONC. sulfuric acid was added in small portions with external water cooling and the mixture was heated while stirring at 125 °C for 3 hours. After cooling to room temperature the solid was filtered off, washed with water until the pH was neutral and dried on the sinter to yield a grey solid. Phosphorous oxychloride (200 ml, 2.1 mol) was added to the solid and the mixture was heated at 120 °C for 2 hours. After cooling to room temperature the homogeneous dark solution was concentrated under reduced pressure to half of its original volume and poured into water (800 ml) while stirring vigorously. The resulting solid was filtered off, washed with water and dried on the sinter to yield a grey solid which was recrystallised from toluene/iso-hexane (1: 1) to yield the title compound as a yellow solid (8.2 g, 13 %). | |
Stage #1: Glyoxilic acid; 4-(Trifluoromethyl)phenylacetonitrile With potassium carbonate In methanol at 20℃; for 15h; Stage #2: With formic acid; sulfuric acid at 20 - 110℃; for 3h; | 5 Description 5; 6-CHLORO-3-HYDRAZINO-5-(4-TRIRUOROMETHPHENSL) PVRIDAZINE Description 5 6-CHLORO-3-HYDRAZINO-5-(4-TRIRUOROMETHPHENSL) PVRIDAZINE 4-TRIFLUOROMETHYLPHENYLACETONITRILE (38.9 g, 210 mmol) was dissolved in dry methanol under nitrogen. Glyoxylic acid monohydrate (29 g, 315 mmol) was added followed by potassium carbonate (74 g, 535 mmol) and the resulting mixture was stirred for 15 h at room temperature. The resulting solid was filtered, washed with dichloromethane and dried on the sinter to yield an off- white solid which was added at room temperature to a solution of cone. sulfuric acid (30 ml) and formic acid (400 ml). The resulting mixture was then heated with stirring at 110 C for 3 h, allowed to cool to room temperature and concentrated under vacuum to 2/3 of the initial volume. It was then poured ice- water (1000 ml) and the resulting solid was filtered off, washed with water and dried on the sinter to yield 35 g of 3- (4-trifluoromethylphenyl) maleic anhydride as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water | 6.A Step A Step A Synthesis of 4-trifluoromethylphenylacetonitrile as an intermediate A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile. | |
With magnesium sulfate In ethanol; water | 17.A Step A Step A Synthesis of 4-trifluoromethylphenylacetonitrile as an intermediate A stirred solution of 250.0 grams (1.05 moles) of 4-trifluoromethylphenylmethyl bromide in 1000 mL of ethanol was heated to about 80° C., and a solution of 109.0 grams (1.67 moles) of potassium cyanide in about 275 mL of water was added. Upon completion of addition, the reaction mixture was stirred at 80° C. for about 1.75 hours. After this time the reaction mixture was cooled to ambient temperature and extracted with three portions of diethyl ether. The combined extracts were washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was added with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 197 grams of 4-trifluoromethylphenylacetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran; diethyl ether; water | 6.B Step B Step B Synthesis of 2-methyl-2-(4-trifluoromethylphenyl)propanenitrile as an intermediate A stirred solution of 101.3 grams (0.55 mole) of 4-trifluoromethylphenylacetonitrile in 300 mL of tetrahydrofuran was cooled in an ice-bath, and a solution of 194.1 grams (1.37 moles) of iodomethane in 100 mL of tetrahydrofuran was added. Upon completion of addition, a solution of 153.5 grams (1.37 moles) of potassium tert.-butoxide in 900 mL of tetrahydrofuran was then added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was stirred with about 400 mL of water, then aqueous 1N hydrochloric acid was added until the color of the reaction mixture changed from red to yellow. Water was then added to the reaction mixture to cause an oily residue to separate from the mixture. The water was decanted from the oil, and the oil was dissolved in diethyl ether. The ether solution was washed with two portions of water and two portions of an aqueous solution saturated with sodium chloride. The ether solution was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 119.8 grams of 2-methyl-2-(4-trifluoromethylphenyl)propanenitrile. The NMR spectrum was consistent with the proposed structure. | |
With hydrogenchloride In tetrahydrofuran; diethyl ether; water | 17.B Step B Step B Synthesis of 2-methyl-2-(4-trifluoromethylphenyl)propanenitrile as an intermediate A stirred solution of 101.3 grams (0.55 mole) of 4-trifluoromethylphenylacetonitrile in 300 mL of tetrahydrofuran was cooled in an ice-bath, and a solution of 194.1 grams (1.37 moles) of iodomethane in 100 mL of tetrahydrofuran was added. Upon completion of addition, a solution of 153.5 grams (1.37 moles) of potassium tert.-butoxide in 900 mL of tetrahydrofuran was then added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was stirred with about 400 mL of water, then aqueous 1N hydrochloric acid was added until the color of the reaction mixture changed from red to yellow. Water was then added to the reaction mixture to cause an oily residue to separate from the mixture. The water was decanted from the oil, and the oil was dissolved in diethyl ether. The ether solution was washed with two portions of water and two portions of an aqueous solution saturated with sodium chloride. The ether solution was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 119.8 grams of 2-methyl-2-(4-trifluoromethylphenyl)propanenitrile. The NMR spectrum was consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.1 Synthesis of 1-benzyl-4-(4-trifluoromethyl-phenyl)-4-cyano-piperidine Prepare by the method of example 76.1 using 4-trifluoromethylphenyl-acetonitrile (1.5 g, 8.1 mmol) and <strong>[10429-82-0]N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride</strong> (1.9 g, 8.1 mmol) to give the title compound. | ||
78.1 Synthesis of 1-benzyl-4-(4-trifluoromethyl-phenyl)-4-cyano-piperidine Prepare by the method of example 76.1 using 4-trifluoromethyl-phenyl-acetonitrile (1.5 g, 8.1 mmol) and <strong>[10429-82-0]N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride</strong> (1.9 g, 8.1 mmol) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 50℃; for 16h; Inert atmosphere; | 8 1-[4-(trifluoromethyl)phenyl]cyclopropane carbonitrile (2): A mixture of benzyl triethylammonium chloride (137mg, 0.58mmol), 1-bromo-2-chloroethane (3.65mL, 43.75mmol), 1 (5.40g, 29.17mmol) and NaOH (7.00g, 175mmol) in 7ml of water was stirred at 50°C under a nitrogen atmosphere. Additional water was added to facilitate stirring if needed. After 16h TLC (10% EtOAc in PE (40-60)) indicated complete consumption of the starting material. The reaction mixture was diluted with EtOAc and washed twice with water. The combined aqueous layers were extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and evaporated to give 2 (6.21 g, 29.17mmol, 100%) as a red liquid which crystalizes on standing. 1H NMR (400 MHz, CDCl3) δ ppm 7.62 (d, 2H), 7.40 (d, 2H), 1.69-1.97 (m, 2H), 1.33-1.53 (m, 2H). |
86% | With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 50℃; | |
86% | With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In water at 50℃; for 16h; | This compound was prepared following the procedure described by Jonczyk et al. (see Org. Prep. Proc. Int, 1995, 27(3): 355-359). To a 25 mL round-bottom flask equipped with a condenser was added 2-(4-(trifluoromethyl)phenyl)acetonitrile (0.75 g, 4.05 mmol, 1.0 eq.), 1-bromo-2-chloroethane (0.50 mL, 6.08 mmol, 1.5 eq.), and triethylbenzyl ammonium chloride (0.018 g, 0.08 mmol, 0.02 eq.). The resulting mixture was heated to 50° C. and sodium hydroxide (0.97 g, 24.0 mmol, 6.0 eq. dissolved in 1.0 mL of water) was added dropwise. The mixture was allowed to stir at 50° C. for 16 hours. It was cooled to room temperature and poured into 50 mL of water. This suspension was extracted with three 25 mL-portions of methylene chloride and the combined organic layers washed with three 50 mL-portions of 1.2 N HCl aqueous solution, three 50 mL-portions of water, and 50 ml of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography (Biotage Flash 40, 10% ethyl acetate/hexanes) to give the desired product as a light yellow oil (intermediate 19, 0.74 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 1.41-1.53 (m, 2H), 1.78-1.87 (m, 2H), 7.40 (d, J=8.34 Hz, 2H), 7.62 (d, J=8.34 Hz, 2H). |
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 50℃; for 12h; | ||
With lithium hexamethyldisilazane In tetrahydrofuran at -50 - 20℃; for 2.5h; | 34 Example 34 (R)-1-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)cyclopropane-1-carboxyamide 2-(4-(Trifluoromethyl)phenyl)acetonitrile (1.00 g, 5.40 mmol) was dissolved in THF (8.0 mL), subsequently the solution was stirred for a while at -50°C, a THF solution of lithium bis(trimethylsilyl)amide (1.3 M) (4.15 mL, 5.40 mmol) was added thereto, and then 1-bromo-2-chloroethane was added thereto. Subsequently, a THF solution of lithium bis(trimethylsilyl)amide (1.3 M) (4.15 mL, 5.40 mmol) was added thereto again, the mixture was stirred for 30 minutes, and then the mixture was stirred for 2 hours at room temperature. Water was added to the reaction liquid, the mixture was extracted with ethyl acetate, an organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of 1-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (pale yellow powder, 219 mg) was obtained. | |
With lithium hexamethyldisilazane In tetrahydrofuran at -50℃; for 2.5h; | 34 Example 34 (R)-1-(4-(trifluoromethyl)phenyl)-N-(1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)cyclopropane-1-carboxyamide 2-(4-(Trifluoromethyl)phenyl)acetonitrile (1.00g, 5.40 mmol) was dissolved in THF (8.0 mL), subsequently thesolution was stirred for a while at -50°C, a THF solution of lithium bis(trimethylsilyl)amide (1.3M) (4.15 mL, 5.40 mmol)was added thereto, and then 1-bromo-2-chloroethane was added thereto. Subsequently, a THF solution of lithiumbis(trimethylsilyl)amide (1.3M) (4.15 mL, 5.40 mmol) was added thereto again, the mixture was stirred for 30 minutes,and then the mixture was stirred for 2 hours at room temperature. Water was added to the reaction liquid, the mixturewas extracted with ethyl acetate, an organic layer thus separated was dried over anhydrous sodium sulfate, insolublematerials were filtered, subsequently the solvent was distilled off under reduced pressure, and thereby a crude form of1-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (pale yellow powder, 219 mg) was obtained. The crude form of1-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (219 mg) was dissolved in THF (3.0 mL), subsequently a 4Naqueous solution of sodium hydroxide (3.0 mL) was added thereto, the mixture was stirred for 16 hours at 100°C, andthe solvent was distilled off under reduced pressure. Water was added thereto to obtain an aqueous solution, subsequentlythe aqueous solution was washed with ethyl acetate, a 2N aqueous solution of hydrochloric acid was added thereto toneutralize the aqueous solution, and the aqueous layer was extracted with a mixed liquid of chloroform and methanol.An organic layer thus separated was dried over anhydrous sodium sulfate, insoluble materials were filtered, subsequentlythe solvent was distilled off under reduced pressure, and thereby a crude form of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (yellow crystals, 42 mg) was obtained. According to a technique similar to Example 1, the titlecompound (white amorphous, 43 mg, 1.8%) was obtained using the crude form of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (42 mg) and (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-amine (42 mg, 0.18 mmol) synthesizedin Reference Example 1-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With ammonium acetate;palladium 10% on activated carbon; In methanol; at 20℃; for 72h; | Step 1: 5-[2-(4-Trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-benzoimidazol-2-one A solution of 3.0 mmol (4-trifluoromethyl-phenyl)-acetonitrile and 2.0 mmol <strong>[95-23-8]5-amino-1,3-dihydro-benzoimidazol-2-one</strong> in MeOH (10 ml) was treated with NH4OAc (12.00 mmol) and 10% Pd/C (200 mg) and stirred at rt for 72 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (73%) and was used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With potassium <i>tert</i>-butylate In methanol; dimethyl sulfoxide at 20℃; Stage #2: 2,6-di-tert-butyl-4-(4-methoxybenzylidene)-cyclohexa-2,5-dienone In methanol; dimethyl sulfoxide at 20℃; for 1h; Stage #3: With acetic acid In methanol; water; dimethyl sulfoxide at 20℃; optical yield given as %de; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With potassium <i>tert</i>-butylate In methanol; dimethyl sulfoxide at 20℃; Stage #2: 2,6-di-tert-butyl-4-(4-dimethylaminobenzylidene)-cyclohexa-2,5-dienone In methanol; dimethyl sulfoxide at 20℃; for 1h; Stage #3: With acetic acid In methanol; water; dimethyl sulfoxide at 20℃; optical yield given as %de; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With potassium <i>tert</i>-butylate In methanol; dimethyl sulfoxide at 20℃; Stage #2: 2,6-di-<i>tert</i>-butyl-4-(2,3,6,7-tetrahydro-1<i>H</i>,5<i>H</i>-pyrido[3,2,1-<i>ij</i>]quinolin-9-ylmethylene)-cyclohexa-2,5-dienone In methanol; dimethyl sulfoxide at 20℃; for 1h; Stage #3: With acetic acid In methanol; water; dimethyl sulfoxide at 20℃; optical yield given as %de; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 59% 2: 18% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer In ethyl-cyclohexane at 160℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With ammonium formate;palladium 10% on activated carbon; In methanol; at 80℃; for 2h; | A solution of 10.4 mmol 4-(trifluoromethyl)phenylacetonitrile (commercially available) and 3.5 eq. aminoquinoline in MeOH (10 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (100 mg) and stirred at 80 C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, CH2Cl2/MeOH) afforded the title compound (73%) as a yellow oil. MS m/e: 317.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With hydrogen; ammonium hydroxide In ethanol for 16h; Stage #2: trifluoroacetic anhydride at 0℃; for 0.5h; | A A solution of 4-trifluoromethylphenylacetonitrile (10 g, 49 mmol) in a mixture of ethanol (100 mL) and ammonium hydroxide (20 mL of a 29.3% aqueous solution) was hydrogenated over Raney nickel (1 g) for 16 h. The catalyst was removed by filtration through celite and the filtrate evaporated to dryness. The neat residue was added in a dropwise manner to trifluoroacetic anhydride (25 mL, 180 mmol) cooled at 0° C. and the resulting mixture stirred at 0° C. for 30 minutes. The reaction mixture was poured onto ice (250 mL) and the resulting mixture stirred for 30 minutes after which the precipitate was removed by filtration and air dried to give the product as a white solid (13.4 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: carbon disulfide; 4-(Trifluoromethyl)phenylacetonitrile With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃; | N4.A A solution of 4-(trifTuoromethyl)phenylacetonitrile (2.0 g, 10.8 mmol) and carbon disulfide (714 μL, 11.8 mmol) in tetrahydrofuran (30 rnL) is added dropwise to a solution of sodium hydride (950 mg, 24 mmol) in tetrahydrofuran (20 mL) at 0 0C and stirred at room temperature for 3h. The mixture is cooled to 0 0C, and methyl iodide (1.5 mL, 24 mmol) is added slowly and stirred at room temperature for 12h. The mixture is poured into water and extracted with dichloromethane (2 x 60 mL). The organic layers are combined, washed with brine, dried (MgSO4), concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide 3,3-bis(methylthio)-2-(4-(trifluoromethyl)phenyl)acrylonitrile N4a. ESIMS calcd. for CI2HHF3NS2 ([M+H]+) 290.0, found 290.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With hydrogenchloride In water at 65 - 70℃; for 2h; Inert atmosphere; | |
35% | With Os(hydride)6(triisopropylphosphine)2; water In tetrahydrofuran-d8 at 100℃; for 48h; Inert atmosphere; | |
With sulfuric acid at 0℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; O,O-Diethyl hydrogen phosphorodithioate In 1,4-dioxane at 20℃; for 18h; | 204.204-A A mixture of [3-(trifluoromethyl)phenyl]acetonitrile (20.0 g, 108 mmol), O,O-diethyl dithiophosphate (18.2 mL, 119 mmol) and 4M hydrogen chloride-dioxane solution (216 mL, 864 mmol) was stirred at room temperature for 18 hr. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed successively with water (100 mL), 0.2M aqueous sodium hydroxide solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was treated with hexane (200 mL) in an ice bath to allow solidification. The solid was collected by filtration and washed with hexane to give the title compound (21.3 g) as a white solid (yield 90%). 1H NMR (400 MHz, CDCl3) δ 4.17 (2H, s), 6.61 (1H, brs), 7.46 (2H, d, J = 6.8 Hz), 7.52 (1H, brs), 7.67 (2H, d, J = 7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.9% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile With sodium ethanolate In ethanol at 20℃; for 0.5h; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In ethanol at 20℃; for 4h; | 51.1 Intermediate (51 .1 ) tert-butyl 4-(cyano(4- (trifluoromethyl)phenyl)methylene)piperidine- 1 -carboxylate Intermediate (51 .1 ) tert-butyl 4-(cyano(4- (trifluoromethyl)phenyl)methylene)piperidine- 1 -carboxylateTo the solution of 4-(trifluoromethyl)phenylacetonitrile (2560.9 mg; 1 3.83 mmol; 1 .06 eq.) in ethanol (50 mL), 21 % sodium ethoxide (5.70 ml; 15.27 mmol; 1 .17 eq.) in ethanol was added dropwise at RT. After stirred for 30 min, a solution of 1 -boc-4- piperidone (2600.00 mg; 13.05 mmol; 1 .00 eq.) in ethanol (10 mL) was added slowly. The reaction mixture was stirred at room teperature for 4h. The reaction was quenched with 50mL of saturated aqueous NH4CI and concentrated to half volume. The aqueous solution was extracted with ether three times. The combined organic extracts were washed with brine, dried and then concentrated to give the crude product, which was purified by Biotage chromatography with EtOAc/Hexane (5-30%) to yield the desired product as light yellow solid (3200.00 mg, yield 66.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 70℃; for 16h; | A solution of 4-trifluoromethylbenzyl cyanide (0.92 g, 5.0 mmol) and bis(2-bromoethyl)ether (2.3 mL, 18 mmol) in DMF (10 mL) at room temperature was treated portion wise with sodium hydride (60% in mineral oil, 0.6 g, 15 mmol) over a period of 10 mins followed by stirring at the same temperature for 1 h. The mixture was then stirred at 70 C. for 16 h. Then cooled to room temperature and the reaction mixture was quenched with slow addition of methanol. Water (100 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water and brine and dried over sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography using a gradient of 5% EtOAc in hexanes to 30% EtOAc in hexanes to give the title compound (1.11 g, yield: 87%). 1H NMR (CDCl3 300 MHz): deltappm 7.75 (d, 2H), 7.65 (d, 2H), 4.20-4.09 (m, 2H), 4.00-3.85 (m, 2H), 2.27-2.05 (m, 4H). |
83% | Step 1 Preparation of 4-(4-(trifluoromethyl) phenyl)-tetrahydro-2H-pyran-4-carbonitrile To a stirred solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (2.0 g, 10.8 mmol) in DMF (10 mL) was slowly added a suspension of NaH (60%, 0.95 g, 23.7 mmol) in DMF (10 mL) at 0 C. under N2 atmosphere over 10 min, the reaction was allowed to warm to room temperature and stirred for 0.5 h. Then the reaction was cooled to 0 C. and 2,2'-dibromodiethyl ether (1.5 mL, 11.8 mmol) in DMF (20 mL) was added dropwise over 60 min. The reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL*3). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified with column chromatography on silica gel (petroleum ether:EtOAc=100:1) to afford 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonitrile (2.30 g, 83%) as red oil. GC-MS: [M]+ 255; tR=10.39 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 4-trifluoromethylbenzoic acid With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane; iodine In chloroform at 60℃; Inert atmosphere; Stage #2: trimethylsilyl cyanide With tetrabutyl ammonium fluoride In tetrahydrofuran; chloroform at 60℃; for 5h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydride In diethyl ether; dimethyl sulfoxide at 0℃; for 2h; | 248 Preparation of (237) 1-(4-Trifluoromethyl-phenyl)-cyclopentanecarbonitrile To a suspension of NaH (8.18 g, 135.13 mmol, 60%) in dimethyl sulfoxide (100 mL) were added dropwise a mixture of (4-trifluoromethyl-phenyl)-acetonitrile (236) (25 g, 135.13 mmol) and 1,4-dibromobutane (16 mL, 135.13 mmol) dissolved in dimethyl sulfoxide:ether (1:1) (300 mL) at 0° C. and the reaction mixture was stirred at this temperature for 2 h. After completion of the reaction, water (100 mL) and 10% HCl solution (50 mL) were added to the mixture and extracted with ethyl acetate (2×400 ml). The organic layer was dried over Na2SO4, concentrated and purified by 100-200 silica column chromatography using hexane as the eluent to give 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237) (21 g, 65%) as a colorless liquid. [0908] GC-MS: 239 (M/H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With piperidine; In neat (no solvent); at 20℃; for 0.333333h;Sealed tube; | General procedure: The general procedure for synthesizing 1,1?-ferrocenyldiacrylonitriles was developed from that described by Imrie et al. [15]. Compound 1 (1 eq.) and substituted phenylacetonitriles (2.2 eq.) were mixed in a Pyrex tube fitted with a ground-glass joint. The compounds were thoroughly ground with a glass rod. One to two drops of piperidine was added into the Pyrex tube and the mixture was further ground at RT until a melt was formed. The Pyrex tube was sealed and placed in a shaker for approximately 20 min. To evaporate the remaining piperidine (boiling point 106 C) and water formed as a by-product, the samples were first dried in open air, and thereafter under a vacuum line. The products were further purified by silica gel chromatography. The formation of the products was determined using IR or NMR spectroscopy (1H and 13C). In solid-state IR spectra, formation of the products was characterized by the disappearance of the sharp carbonyl absorption at approximately 1650 cm-1 and the appearance of a strong nitrile absorption at approximately 2200 cm-1. 1H and 13C NMR spectra showed the disappearance of the carbonyl resonance and the appearance of alkene resonance peaks. Pure compounds were further analyzed by mass spectrometry, microanalysis, and X-ray diffraction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 100℃; for 0.5h; | 4-Trifluoromethylphenylacetonitrile I-6a (18.4 g, 100 mmol) is dissolved in N,N-dimethylformamide dimethyl acetal (20 mL, 151 mmol) and stirred at 100 °C for 30 min. Cooling and concentration yields 3-(dimethylamino)-2-(4-(trifluoromethyl)phenyl)-acrylonitrile I-6b as an orange-brown solid: 1H NMR (400 MHz, CDCl3) δ = 7.52 (d, J = 8.3Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.01 (s, 1H), 3.28 (s, 6H); 19F NMR (376.47 MHz, CDCl3)δ = - 62.15; ESI-MS calcd. for C12H12F3N2 ([M+H]+) 241.1, found 241.1. The product is used without further purification. | |
With triethylamine In N,N-dimethyl-formamide at 120℃; for 0.333333h; Microwave irradiation; | General Procedure A General procedure: A solution of aryl acetonitrile 2 (50 mg), and triethylamine (1.1 equiv.) in dimethylformamide dimethyl acetal (0.5 mL, 3.76 mmol) was heated in a microwave reactor at 120 °C for 20 minutes. The mixture was cooled to RT, and solvents were then evaporated. To the resulting crude product 3 was added hydrazine mono-hydrobromide (3.0 equiv.), 200 proof EtOH (1.0 mL), and H2O (0.3 mL). The mixture was heated in a microwave reactor at 120 °C for 20 minutes. The mixture was cooled to RT and concentrated in vacuo. The resulting residue was subjected to liquid-liquid extraction using saturated NaHCO3 (aq) and CH2Cl2. The organic layer was collected, dried over anhydrous MgSO4, filtered and removed under vacuum to afford 4.The resulting crude product 4 and 2-arylsubstitutedmalondialdehydes or 1,1,3,3tetramethoxypropane (1.0 equiv.) were dissolved in glacial AcOH (1.0 mL) and 200 proof EtOH (1.5 mL). The mixture was heated in a microwave reactor at 120 °C for 20 minutes. After cooling on ice, the precipitate was collected on a fine scintered-glass frit and washed with icecold EtOH (2 x 1.0 mL). The resulting crystals 5-32 were dried and collected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h; | A solution of Intermediate 6a (2.0 g, 10.8 mmol) and carbon disulfide (0.71 mL, 11.8 mmol) in tetrahydrofuran (30 mL) is added dropwise to an ice cold solution of sodium hydride (950 mg of 60 % suspension in oil, 24 mmol) in tetrahydrofuran and stirred at room temperature for 3 hours. The mixture is cooled to 0 °C, then methyl iodide (1.5 mL, 24 mmol) is added dropwise and stirred at room temperature for 12 hours. The mixture is poured into water andextracted with dichloromethane (2 x). The organic layers are combined, washed with brine, dried over MgSO4, filtered, concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford 3,3-bis(methylthio)-2-(4-(trifluoromethyl) phenyl)acrylonitrile I-14a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium fluoride In water; N,N-dimethyl-formamide at 125℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate In 1,4-dioxane; water at 100℃; for 12h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium phosphate; dicyclohexyl-({2-[2-(dicyclohexylphosphanyl)phenyl]-phenyl})-phosphane; palladium diacetate In 1,4-dioxane at 100℃; for 12h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With caesium carbonate In water; dimethyl sulfoxide at 25℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With piperidine; In melt; at 20℃; for 0.0833333h;Milling; | General procedure: The general procedure for the synthesis and characterization of 1,1?-ferrocenyl-diacrylonitriles is displayed in Scheme 1 and has been previously reported [20]. In brief, 1,1?-ferrocenedicarboxaldehyde and substituted phenylacetonitriles (2.2 Eq.) were mixed in a Pyrex tube fitted with a ground glass joint. The compounds were thoroughly ground in the open air with a glass rod in the presence of 1-2 drops of piperidine to form a melt. The melt was first dried in open air, followed by drying under a vacuum line. The dry products were purified by means of silica gel chromatography. Formation of the products was determined by use of IR or NMR spectroscopy (1H- and 13C-NMR). In the solid-state IR spectra, the formation of the products was characterized by the disappearance of the sharp carbonyl absorption band at approximately 1650cm-1 and the appearance of a strong nitrile absorption band at approximately 2200cm-1. The 1H- and 13C-NMR spectra showed the disappearance of the carbonyl resonance (?10ppm) and the appearance of alkene resonance peaks (?7.4ppm). Pure compounds were further analyzed by melting point determination (DSC), mass spectrometry, microanalysis, and X-ray diffraction. 4.2.3 1,1?-Ferrocenyldi[-2(4-{trifluoromethyl}phenyl)acrylonitrile] (para-CF3 catalyst)T he general procedure for synthesis of this catalyst is described in Section 4.2 and involves the use of 1,1?-ferrocenyldicarboxaldehyde (145.0 mg, 0.60 mmol) and 4-(trifluoromethyl)phenylacetonitrile (244.0 mg, 1.32 mmol). Upon grinding a deep red paste was formed, which was dried to obtain a red solid. The reaction completion was monitored by use of preparative TLC plates with a solvent system of hexane/diethyl ether (1:1) and the product was then purified by means of column chromatography with a solvent system of hexane/diethyl ether (1:1) to obtain red crystals as the product (268.0 mg, 78%) and 31.0 mg of the recovered starting 1,1?-ferrocenedicarboxaldehyde. Product m.p. 252 C; IR (cm-1) 3059, 2924, 2216, 1617, 1593, 1456, 1421, 1324, 1255, 1157, 1111, 1070, 1000, 925, 824, 729, 667, 642, 621, 584, 477, 421; 1H-NMR spectra (CDCl3) 7.40 (8H, q, J 5 Hz, ArH), 7.31 (2H, s, CH), 5.12 (4H, s, C5H4), 4.62 (4H, s, C5H4); 13C-NMR spectra (CDCl3) 141.4, 125.9, 124.8, 107.3, 79.1, 77.2, 73.1, 72.9; HR-MS (C30H18F6FeN2) ES: [M]+ m/z calc. 576.0724, found 576.0717. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium methylate; copper diacetate In dimethyl sulfoxide at 100℃; for 15h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine; sodium ethanolate In ethanol for 3h; Reflux; Schlenk technique; | 1 Experimental procedure for the synthesis of 2,5-difluoro-1,4-phenylene-3,30-bis{2-[(4-trifluoromethyl)phenyl]acrylonitrile} 3 In a first Schlenk vessel 2,5-difluoro-1,4-benzenedicarbaldehyde 1 (680 mg, 0.40 mmol) and (4-trifluoromethyl)phenylacetonitrile 2 (1.48 g, 0.80 mmol) were taken in absolute ethanol (50 mL). In a second Schlenk vessel, sodium ethoxide (0.400 g, 5.76 mmol) and freshly distilled dry pyridine (4.96 mmol, 0.40 mL) were taken in absolute ethanol (50 mL). Under protection from air, the two solutions were mixed and heated to reflux for 3 h.;Then, pyridine and volatiles were removed under reduced pressure. Under protection from air, the residue was repeatedly extracted with small portions (15 mL) of dichloromethane. The organic layer was washed with water, dried over anhydrous MgSO4, and then, filtered through a syringe filter. The extract was evaporated under reduced pressure to leave the residue affording 2,5-difluoro-1,4-phenylene-3,3'-bis{2-[(4-trifluoromethyl)phenyl]acrylonitrile} 3 in 90% yield. Pale-green solid, M.p: 259-261 °C; 1H NMR (400 MHz, CDCl3) 7.76 (d, phenyl, 4 H, J = 8.2 Hz), 7.83 (s, 2 H, ethenyl-H), 7.85 (d, 4 H, phenyl, J = 8.2 Hz), 8.21 (t, 2H, phenyl, J = 8.4 Hz). EI-MS (MH+): 503. Elemental analysis calculated for C26H12F8N2: C, 61.91%; H, 2.40%; N, 5.55%. Found: C, 61.80%; H, 2.55%; N, 5.64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile; 2,3,4-trimethoxybenzaldehyde In ethanol at 70℃; for 0.5h; Stage #2: With sodium hydroxide In ethanol at 70℃; | General methods for 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitrile derivatives (2-9) General procedure: Absolute ethyl alcohol (100 mL), substituted benzylcyanide (5.4 mmol), and 2,3,4-trimethoxybenzaldehyde (5.4 mmol) were added to three-necked reaction flask with a mechanical stirrer. The reaction mixture was stirred for 0.5 h at 70 °C. Then, a sodium hydroxide (20 %) solution was added dropwise until a precipitate formed. The reaction was cooled to room temperature and the mixture was poured into ice-water. The residue was filtered and washed with hot water to pH 7. The crude product was dried under vacuum and then recrystallized in ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(I) oxide; oxygen; ammonium chloride; sodium hydroxide In acetonitrile at 120℃; for 30h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium azide; triethylamine hydrochloride In toluene at 110℃; for 16h; Inert atmosphere; | |
68.9% | With hydrogenchloride; sodium azide; triethylamine In toluene at 110℃; | General procedure for preparation of 5-substituted1-H-tetrazoles (2a-2m) General procedure: Nitriles (1 mmol) were added to a solution of NaN3 (3 mmol), PhMe (50 mL), and Et3N.HCl (3 mmol) in around-bottomed flask. The reaction mixture was stirred at 110 °C. After completion of the reaction (as indicated byTLC), the product was cooled and extracted with water. Next, 36% HCl was added dropwise to the aqueous layer to precipitate the tetrazoles. After filtration, the solid wasdried under reduced pressure and recrystallized fromEtOAc/Et2O to yield the 5-substituted-1-H-tetrazoles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium methylate In methanol for 1.5h; Reflux; | 4.1.2.5. General Method for Knoevenagel condensation.4.1.2.5.1. Method A. General procedure: To a stirred solution of MeONa in MeOH (5%,1.5 mL) was added 3a (ca. 122 mg, 0.5 mmol, 1 eq), immediatelyfollowed by cyano derivative (1.1 eq) at room temperature. Thereaction mixture was heated under reflux for 1.5 h. After coolingfor 1 h in ice bath, the solid was filtered and washed with a minimumof cold MeOH. If not pure, crude product was purified by columnchromatography on silica gel with CH2Cl2/MeOH: 99:1?90:10 as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 21℃; for 12h; | General Procedure B: for aryl / heteroaryl acetonitriles substrate’s cyclopropanation General procedure: To a 5 mL Schlenk tube were added aryl / heteroaryl acetonitriles 1 (1.0 mmol, 1.0 equiv.), vinyl diphenylsulfonium triflate (434.4 mg, 1.2 mmol, 1.2 equiv.), and DMSO (5 mL). The mixture was stirred at room temperature for 2 min and to the mixture DBU (456 mg, 3 mmol, 3.0 equiv.) was added. The mixture was stirred for 12 hours at room temperature, and then to the mixture was added saturated ammonium chloride solution (25 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with H2O (2 x 30 mL), dried with anhydrous sodium sulfate. After concentration, product 2 was purified using silica gel column chromatography using an appropriate eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tert.-butylnitrite; potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-(Trifluoromethyl)phenylacetonitrile at 100℃; for 2h; Microwave irradiation; Stage #2: With hydrazine hydro-chloride In ethanol; water at 80℃; | 5.d Step d: Synthesis of intermediate 5: Add 8.88 g (48 mmol) of 4-trifluorophenylacetonitrile to a 10 mL microwave tube, N,N-dimethylacetamide dimethyl acetal 5.32 g (40 mmol) was added. Microwave reaction was carried out at 100 °C for 2 h. Take hydrazine hydrochloride 4.11g (60mmol) was added to a 25mL round bottom flask, followed by EtOH 8mL, H2O 5mL was added, wherein the microwave reaction solution was added. The mixture was reflux at 80 °C overnight, the reaction was cooled to room temperature after completion of the reaction solution, ΕΑ (20mLx 3) was basified and extracted with saturated NaHCO3, and the combined EA phases were washed with saturated brine, dried over anhydrous MgSO4, filtered and rotary evaporation, and EA with PE to give a pale yellow solid was recrystallized. Yield of two steps is 87.75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | Synthesis of 11, 12 General procedure: To a solution of 10 (1.0 mmol, 1.0 equiv.) and substituted benzyl cyanate (1.2 mmol, 1.2 equiv.)in 5 mL of anhydrous DMF was added NaH 60% in mineral oil (66 mg, 2.0 mmol, 2.0 equiv.) at0°C. The reaction mixture was allowed to warm to room temperature overnight, and was quenchedwith saturated NH4Cl and extracted with ethyl acetate (3 x 30 mL). The combined organic phaseswere washed with brine, dried over anhydrous MgSO4, filtered and concentrated to yield the crudeproduct. The product was purified via combi-flash on silica gel using 20% EtOAc in hexanes togive the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium ethanolate; In ethanol; for 3h;Reflux; | In a round bottom flask 1,3,5-Benzenetricarbaldehyde 1 (0.5 g,3.1 mmol) and trifluoromethyl substituted phenylacetonitrile 2(9.7 mmol) were taken in absolute ethanol (300 mL). Sodium ethoxide(0.80 g, 11.6 mmol) was added drop wise to the above solution.Under protection from air, the solution was heated to reflux for 3 h. Then, volatiles were removed under reduced pressure. Under protection from air, 200 ml of water was added to the residue. The mixture was repeatedly extracted with small portions (30 mL) of dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum condition to leave the residue. The resulting residue was chromatographed on silica gel (Wako C-300) using dichloromethane/hexane (1:1) mixed solvent as an eluent to give the desired compound(1.9 g, 90% for 3a, 2.4 g, 88% for 3b) as pale yellow solids.Compound 3a, pale yellow solid, M.p. 231-232 C; 1H NMR(400 MHz, CDCl3) 7.72 (s, 3H, aryl H), 7.76 (d, 6H, aryl H, J = 7.3 Hz),7.86 (d, 6H, aryl H, J = 7.3 Hz), 8.48 (s, 3H, ethenyl H). EI-MS (75eV):m/z 663 (M+). Elemental analysis calculated for C36H18F9N3: C,65.16%; H, 2.73%; N, 6.33%. Found: C, 65.30%; H, 2.55%; N, 6.49%.Compound 3b, pale yellow solid, M.p. 249-251 C; 1H NMR(400 MHz, CDCl3) 7.79 (s, 3H, aryl H), 7.99 (s, 3H, aryl H), 8.16 (s, 6H,aryl H), 8.51 (s, 3H, ethenyl H).EI-MS (75eV): m/z 867 (M+).Elemental analysis calculated for C39H15F18N3: C, 53.99%; H, 1.74%;N, 4.84%. Found: C, 53.81%; H,1.85%; N, 4.64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.9% | With sodium hydroxide In ethanol for 3h; Reflux; | 2.16 Compound 10b To 50 mL of anhydrous ethnol was added NaOH (160 mg,4 mmol), 2-formyl pyrrole (380.4 mg, 4 mmol) and 4-trifluoromethyl benzyl cyanide (624 μL, 4 mmol). The reaction was heated to reflux with stirring for 3 h. After cooled to room temperature, the reaction solution was evaporated in vacuum. The residue was purified by silica gel column (hexane:ethyl actate = 40: 1) to give 10b as yellow solid ( 596 mg, 56.9%). 1H NMR (400MHz, CDCl3), δ 9.82 (s, 1H), 7.70-7.65 (m, 4H), 7.48 (s, 1H), 7.12-7.11 (dd, J = 4.0, 2.7Hz, 1H), 6.77-6.76 (m, 1H), 6.40-6.37 (dt, J = 3.7, 2.5 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium methylate In ethanol for 6h; Inert atmosphere; Reflux; | 2.2.2. (2Z,2′Z)-3,3'-(4,4″-bis(diphenylamino)-[1,1':3′,1″-terphenyl]-4′,6′-diyl)bis(2-(p-tolyl)acrylonitrile) (MDCS-TPA) General procedure: Compound 3 (0.85 g, 1.37 mmol) and 2-(p-tolyl)acetonitrile (0.45 g,3.43 mmol) were added into dry ethanol (75 mL), and then CH3ONa(0.19 g, 3.52 mmol) was added quickly. The mixture was refluxed withstirring for 6 h under an atmosphere of nitrogen. After cooling to roomtemperature, the resulting precipitate was collected by filtration, anddried under vacuum. The crude product was purified by column chromatography(silica gel, CH2Cl2/petroleum ether, v/v=3/1), affordinga yellow-green solid (1.03 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium methylate In ethanol for 6h; Inert atmosphere; Reflux; | 2.2.2. (2Z,2′Z)-3,3'-(4,4″-bis(1,2,2-triphenylvinyl)-[1,1':3′,1″-terphenyl]-4′,6′-diyl)bis(2-(4-methoxyphenyl)acrylonitrile) (MODCS-TPE) General procedure: Compound 3 (1.00 g, 1.26 mmol) and 2-(4-methoxyphenyl)acetonitrile(0.50 g, 3.40 mmol) were added into dry ethanol (50 mL), andthen CH3ONa (0.20 g, 3.70 mmol) was added quickly. Then the mixture was refluxed with stirring for 6 h under an atmosphere of nitrogen.After the reaction is complete, the mixture was cooled to room temperature,the resulting precipitate was collected by filtration, and thendried under vacuum. The crude product was purified by column chromatography(silica gel, CH2Cl2), affording a bright yellowish-greensolid (0.90 g). Yield 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium methylate In tetrahydrofuran; ethanol for 6h; Inert atmosphere; Reflux; | 2.2.1.1. (2Z,20 Z)-3,3’-(2,5-bis(10-ethyl-9,9-dimethyl-9,10-dihydroacridin-2-yl)-1,4-phenylene)bis(2-(4-(triflluoromethyl)phenyl)acrylonitrile)(DMTCS-AC). Compound 3 (1.00 g, 1.65 mmol) and 2-(4-(trifiluoromethyl)phenyl)acetonitrile (0.76 g, 4.10 mmol) were addedinto dry ethanol (50 mL) and dry THF (10 mL), and then CH3ONa(0.22 g, 4.08 mmol) was added quickly. The mixture was refluxed for 6 hunder an atmosphere of nitrogen. When the reaction was finished, themixture was cooled to room temperature. Then the resulting precipitatewas collected by filtration, and dried under vacuum. The crude productwas purified by column chromatography (silica gel, CH2Cl2/petroleumether, v/v 2/3), affording a bright orange solid (1.12 g). Yield 72%.Mp: 310-312 C. 1H NMR (400 MHz, CDCl3) 8.36 (s, 2H), 7.77 (d,J 4.4 Hz, 6H), 7.67 (d, J 8.0 Hz, 4H), 7.58 (s, 2H), 7.41 (t, J 7.6 Hz,J 7.2 Hz, 4H), 7.26 (d, J 7.6 Hz, 2H), 7.13 (d, J 8.4 Hz, 2H), 7.07(d, J 8.0 Hz, 2H), 7.02 (t, J 7.6 Hz, J 7.2 Hz, 2H), 4.15-4.10 (m,4H), 1.50 (t, J 9.2 Hz, J 7.2 Hz, 18H) (Figs. S9 and S10); 13C NMR(100 MHz, CDCl3) 143.95, 141.29, 140.51, 139.68, 137.35, 133.05,132.43, 131.84, 130.39, 130.11, 128.48, 127.04, 126.87, 126.27,126.12, 126.09, 124.74, 120.91, 117.70, 112.56, 112.01, 40.50, 36.21,29.30, 26.92, 11.81 (Fig. S11). IR (KBr, cm 1): 611, 619, 746, 789, 841,863, 951, 997, 1068, 1121, 1138, 1164, 12621326, 1385, 1417, 1452,1467, 1478, 1616, 1637. HRMS (MALDI-TOF) m/z: [M] Calcd forC60H48F6N4 938.3783; Found 938.3769 (Figs. S12 and S13). Anal. Calcd(%) for C60H48F6N4: C 76.74, H 5.15, N 5.97; Found: C 76.82, H 5.26, N5.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium amide In dichloromethane at 60℃; for 6h; Sealed tube; | General procedure for the syntheses of the products c General procedure: To a 10 mL sealed tube equipped with a stir bar was added substituted acetonitrile b (0.24 mmol), NaNH2 (0.30 mmol, 11.7 mg) and CH2Cl2 (1.0 mL), then the solution of monocyclic 1,2,3-triazine a (0.20 mmol) in CH2Cl2 (1.0 mL) was slowly added, the tube was sealed and stirred at 60 °C for 6.0 h. After that, the reaction system was cooled to room temperature and quenched with aqueous NH4Cl. The resulting mixture was extracted three times with CH2Cl2, the combined organic layer was dried overwith anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified through column chromatography on silica gel with PE/EA as the eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With lithium tert-butoxide In dimethyl sulfoxide at 80℃; for 12h; Inert atmosphere; | 10 Example 10 Under a nitrogen atmosphere, add 0.2 mmol to a 25 mL reaction flask equipped with a reflux condenser p-trifluoromethyl phenylacetonitrile,0.6 mmol of lithium tert-butoxide, 0.6 mmol of α-trifluoromethylstyrene, 4 ml of dimethyl sulfoxide, the reaction system was stirred at 80°C for 12 hours,Stop heating and stirring, cool to room temperature, add water to quench the reaction, add ethyl acetate to extract the reaction solution,The ethyl acetate layer was subjected to rotary evaporation under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the target product,The column chromatography eluent used was a petroleum ether: ethyl acetate mixed solvent with a volume ratio of 30:1; the yield of the product was 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 5,5’-(2,7-dioctyl-1,3,6,8-tetraoxo-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline-4,9-diyl)bis(thiophene-2-carbaldehyde); 4-(Trifluoromethyl)phenylacetonitrile With piperidine In dichloromethane; acetonitrile for 0.25h; Stage #2: In dichloromethane; acetonitrile at 70℃; for 12h; Inert atmosphere; | 2.2.1. Synthesis (2Z,2=Z)-3,3=-(5,5=-(2,7-dioctyl-1,3,6,8-tetraoxo-1,2,3,6,7,8-hexahydrobenzo [lmn][3,8]phenanthroline-4,9-diyl)bis(thiophene-5,2-diyl))bis(2-(4-(trifuoromethyl) phenyl)acrylonitrile) (F1) A mixture of 5,56-(2,7-dioctyl-1,3,6,8-tetraoxo-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenan throline-4,9-diyl)bis(thiophene-2-carbaldehyde)compound 1 (400 mg, 0.5633 mmol), 4-trifluoromethyl phenylacetonitrile2 (206 mg, 1.239 mmol) and catalytic amount ofpiperidine were added in 20 mL dry ACN:DCM (1:1, v/v). Resultingmixture was stirred for 15 min. Further, the reaction mixture was heatedat 70 °C under nitrogen atmosphere with constant stirring The progress of reaction was monitored by TLC. After completion ofreaction, the reaction mixture was cooled and the solvent was evaporatedusing rotary evaporation. Obtained solid was washed with methanol(3 × 5 mL). The crude product was purified by column chromatography(hexane: ethylacetate: dichloromethane = 8.5:1.3:0.2, v/vratio). The obtained compound was precipitated in hexane to give F1(412 mg) as a red powder in 70 % yield. FT- IR (KBr), v (cm-1): 2923,2852, 2214, 1710, 1673, 1583, 1441, 1324, 1172, 1120, 1074, 818,590, 545; 1H NMR (500 MHz, CDCl3): B ppm = 8.77 (s, 2 H),7.79-7.77(m, 8 H), 7.73- 7.71 (d, J =8.39 Hz,4 H), 7.33-7.32 (d, J=3.8 Hz, 2 H), 4.13-4.10 (t, J =7.47 Hz, 4 H), 1.71-1.65 (q, 2 H),1.39-1.25 (m, 20 H), 0.87-0.84 (t, J =6.82 Hz, 6 H); 13CNMR (100MHz, CDCl3): B ppm = 162, 161.9, 146.4, 139.7, 139.3, 137.5, 136.5,135.9, 134.2, 129,127.9, 126.4, 126.3, 125.9, 124.3, 117.9, 107.7,41.6, 32, 29.5, 29.4, 28.2, 27.3, 22.9, 14.3. MALDI-TOF = Calculatedmass for C58H50F6N404S2: 1045.16; found: 1045.6838 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With iodine; sodium In methanol; diethyl ether at 20℃; Cooling with ice; Inert atmosphere; | 2.2.1. General procedure for the synthesis of 1-6 General procedure: Phenylacetonitrile derivatives (1 mmol) and iodine (0.25 g, 1 mmol)were dissolved in 5 mL of dry diethyl ether. Sodium methoxide solutionnewly prepared from sodium (0.05 g, 2.1 mmol) and 5 mL of methanolwas added slowly (over a period of 30 min) into the reaction solution atdry ice temperature under a nitrogen atmosphere. The reaction solutionwas allowed to warm by replacing the dry ice bath with an ice-water bath before the temperature rose to above 0 °C. The reaction solutionwas stirred for another 3-4 h at room temperature, and then the reactionwas quenched with 3-6% hydrochloric acid at less than 10 °C, andfiltered to isolate the solid which was rinsed with cold methanol-watersolution to wash away ionic substances. The reaction mixture was extractedwith ethyl acetate, washed by saturated brine and then over anhydrous MgSO4. After the solvent was removed under reducedpressure, the crude product was purified by column chromatography orrecrystallization to give the pure product. 2.2.1.1. 2,3-Bis(4-(trifuoromethyl)phenyl)fumaronitrile (1). powder; Yield 74%; mp 228.3 °C; 1H NMR (CDCl3, 400 MHz) R 7.98(d, J=8.34 Hz, 4H), 7.84 (d, J=8.4 Hz, 4H); 13C NMR (CDCl3,100 MHz) R 134.70, 133.99, 133.66, 129.27, 126.50, 125.86, 115.68;HRMS (ESI) m/z [M+H]+ calcd 367.0670, found 367.0673. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 4-(Trifluoromethyl)phenylacetonitrile; methyl iodide With sodium hydride In tetrahydrofuran at 0 - 20℃; for 18h; Inert atmosphere; Stage #2: With diisobutylaluminium hydride In toluene at -78℃; for 4h; Inert atmosphere; Stage #3: diethyl p-nitrobenzylphosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With copper(I) oxide; [2,2]bipyridinyl; di-tert-butyl peroxide In chlorobenzene at 130℃; for 13h; | 4.2 Typical procedure for preparation of targeted molecules General procedure: Under N2, a mixture of arylacetonitrile 2 (0.4mmol), 1 (4.0mL), Cu2O (10mmol%), Bpy (20mmol%) and DTBP (3.0 equiv.) in PhCl (2.0mL) was stirred at 130°C for indicated time. After the mixture was cooled down to the room temperature, the mixture was passed through a short silica gel column with EtOAc as eluent. The filtrate was concentrated under reduced pressure and the residue was further purified by column chromatography on silica gel to obtain the product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetra(n-butyl)ammonium hydroxide In ethanol for 2h; Reflux; | 4.1.5.4-((Z)-1-cyano-2-(4-((E)-2-(10-ethyl-10H-phenothiazin-3-yl)vinyl)phenyl)vinyl)benzonitrile (PCVCN). General procedure: Compound 4 (0.2 g, 0.56 mmol), 4-cyanoacetonitrile (0.08 g, 0.56mmol) were dispersed in EtOH (25 mL). The mixture was heated torefilux and then pyrrolidine (0.1 mL) was added. After 2 h, the solutionwas cooled to room temperature, and a large amount of deep red solids appeared. Rude product was obtained after filtration and washing withethanol. Pure product was achieved by column chromatography (silicagel, CH2Cl2/petroleum ether (V/V = 1:5). Yield: 71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol at 60℃; | 4.2.5 General procedure for synthesis of hybrids 21a-e General procedure: To a solution of 50% glyoxylic acid (0.95mmol, 0.95eq), the corresponding benzeneacetonitrile (1mmol, 1eq) and K2CO3 (1.5mmol, 1.5eq) in methanol (10ml) was stirred at 60°C for 5-8h until TLC showed the reaction was completed. Then filtered, the filter cake was washed three times with CH2Cl2 Afterwards the filter cake was dissolved in water and using hydrochloric acid to adjust pH to 4. The aqueous phase was extracted with ethyl acetate three times. The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to obtain hybrids 21a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dichloro bis(acetonitrile) palladium(II); cesium hydroxide; potassium acetate In cyclohexane; toluene at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 2-amino-benzenethiol; 4-(Trifluoromethyl)phenylacetonitrile With aluminum (III) chloride at 90℃; for 0.166667h; Schlenk technique; Stage #2: With potassium phosphate; iodine; potassium iodide In N,N-dimethyl-formamide at 90℃; for 12h; Schlenk technique; | General procedure for the synthesis of 2-acylbenzothiazoles General procedure: A 25 mL schlenk-flask was equipped with a magnetic stir bar and charged with substituted 2-aminobenzenethiols 1 (0.5 mmol, 1.0 equiv.), aryl-substituted acetonitriles 2 (1.5 mmol), AlCl3 (0.6 mmol) at 90 °C for 10 minutes, and then added I2 (0.6 mmol), KI (0.75 mmol), K3PO4 (0.5 mmol) and DMF (2 mL), stirred for 12 h. Then the reaction was quenched with 5% aqueous Na2S2O3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated. The residue was purified by column chromatography using a mixture of EtOAc and petroleum ether as the eluent to afford product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 4-chloro-2-aminobenzenethiol; 4-(Trifluoromethyl)phenylacetonitrile With aluminum (III) chloride at 90℃; for 0.166667h; Schlenk technique; Stage #2: With potassium phosphate; iodine; potassium iodide In N,N-dimethyl-formamide at 90℃; for 12h; Schlenk technique; | General procedure for the synthesis of 2-acylbenzothiazoles General procedure: A 25 mL schlenk-flask was equipped with a magnetic stir bar and charged with substituted 2-aminobenzenethiols 1 (0.5 mmol, 1.0 equiv.), aryl-substituted acetonitriles 2 (1.5 mmol), AlCl3 (0.6 mmol) at 90 °C for 10 minutes, and then added I2 (0.6 mmol), KI (0.75 mmol), K3PO4 (0.5 mmol) and DMF (2 mL), stirred for 12 h. Then the reaction was quenched with 5% aqueous Na2S2O3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated. The residue was purified by column chromatography using a mixture of EtOAc and petroleum ether as the eluent to afford product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 2,2′-bis(dipyrrolylphosphinooxy)-1,1′-(±)-biphenyl; dicarbonyl(acetylacotonato)rhodium(I); hydrogen; potassium hydroxide In toluene at 80℃; for 4h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With chlorobis(ethylene)rhodium(I) dimer; hydrogen; C44H28F4N4O2P2; potassium hydroxide In tetrahydrofuran at 120℃; for 2h; Autoclave; | 9 The preparation steps are as follows: in the air,Add the rhodium precursor chlorobis(ethylene) rhodium(I) dimer [RhCl(CH2=CH2)2]2 (1.8mmol%) into the autoclave,Phosphine ligand (2mmol%) as shown in formula (L10),P-Trifluoromethylbenzeneacetonitrile (1mmol),1-hexene (2mmol),KOH (1.5mmol%) and solvent tetrahydrofuran (3mL),Fill with CO and H2 for a total of 2MPa.The reaction was stirred at 120°C for 2h.After the reaction was completed, it was cooled to room temperature.After separation, a colorless and transparent liquid was obtained with a yield of 74% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With ammonium hydroxide In acetonitrile at 60℃; for 24h; Sealed tube; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With [carbonylchlorohydrido{bis[2-(diphenylphosphinomethyl)ethyl]amino}ethylamino] ruthenium(II); potassium carbonate In toluene at 75℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 3,5,3'-Trijodothyronin (T3) | 119.1 Step 1. Step 1. Synthesis of 2-methyl-2-(4-(trifluoromethyl)phenyl)propionitrile 60% NaH (519 mg, 13.0 mmol) was added to a solution of 2-(4-(trifluoromethyl)phenyl)acetonitrile (1.00 g, 5.40 mmol) in DMF (10 mL) under nitrogen and at 0°C, and then CH3I (1.99 g, 14.0 mmol) was added. The mixture was warmed to room temperature and stirred for 4 hours. The mixture was quenched with water (15 mL), and extracted with EtOAc (15 mL*3). The combined organic layer was washed with brine (10 mL), and dried over anhydrous Na2SO4 to obtain the desired compound (1.12 g, yield 68%) as a colorless oil. 1HNMR (400 MHz, DMSO-d6): δ 7.67-7.62 (m, 4H), 1.76 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | Stage #1: 3,3-bis(methylsulfanyl)-1-pyridin-2-ylprop-2-en-1-one; 4-(Trifluoromethyl)phenylacetonitrile With sodium hydroxide In dimethyl sulfoxide at 20℃; for 2h; Stage #2: With ammonium hydroxide for 1h; Reflux; | 3.2. Synthesis of 4-(Methylsulfanyl)-5-Phenyl-[2,2'-Bipyridin]-6-Amine (3) General procedure: To a solution of 3,3-bis(methylsulfanyl)-2-(phenylsulfonyl)acrylonitrile (1) (560 mg,2.5 mmol) and 2-phenylacetonitrile (2a) (439 mg, 3.8 mmol) in DMSO (20 mL), powderedsodium hydroxide (200 mg, 5.0 mmol) was added, and the mixture was stirred for 2 h atroom temperature. The reaction solution was poured into 200 mL of ice water and neutralizedwith a 10% hydrochloric acid solution. The mixture was extracted with chloroform (3 50 mL), washed with brine (50 mL), and dried over anhydrous sodium sulfate. Afterconcentration under reduced pressure conditions, a mixture of the residue and 150 mL of28% aqueous ammonia was refluxed for 1 h. After the evaporation of the ammonia andwater, the residue was chromatographed on a silica gel column using toluene as an eluentto obtain 205 mg (0.7 mmol, 28%) of 3 as colorless needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium <i>tert</i>-butylate; cobalt(II) chloride; 1,2-bis-[(2,6-diisopropylphenyl)imino]acenaphthene In toluene at 150℃; for 36h; Green chemistry; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium <i>tert</i>-butylate; cobalt(II) chloride; 1,2-bis-[(2,6-diisopropylphenyl)imino]acenaphthene In toluene at 150℃; for 36h; Green chemistry; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 2-methoxyisophthalaldehyde; 4-(Trifluoromethyl)phenylacetonitrile In tetrahydrofuran; ethanol at 50℃; for 1h; Inert atmosphere; Stage #2: With tetra(n-butyl)ammonium hydroxide In tetrahydrofuran; ethanol at 50℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.8% | Stage #1: 2-hydroxybenzene-1,3-dicarboxaldehyde; 4-(Trifluoromethyl)phenylacetonitrile In tetrahydrofuran; ethanol at 50℃; for 1h; Inert atmosphere; Stage #2: With tetra(n-butyl)ammonium hydroxide; potassium etoxide In tetrahydrofuran; ethanol at 50℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine In ethanol Reflux; | 2.2.1. Synthesis of dye HBTN General procedure: To a solution of compound 1 (269 mg, 1 mmol) and p-nitrobenzeneacetonitrile(194 mg, 1.2 mmol) in 15 mL of absolute ethanol, 3drops of piperidine was added, the mixture was stirred and heated torefilux. After reacting overnight, the reaction mixture was cooled andfiltered to obtain the crude product, which was recrystallized fromethanol to give HBTN (320 mg, 77%). |
Tags: 2338-75-2 synthesis path| 2338-75-2 SDS| 2338-75-2 COA| 2338-75-2 purity| 2338-75-2 application| 2338-75-2 NMR| 2338-75-2 COA| 2338-75-2 structure
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