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CAS No. : | 1813-33-8 | MDL No. : | MFCD00084939 |
Formula : | C8H3ClF3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GEHMLBFNZKJDQM-UHFFFAOYSA-N |
M.W : | 205.56 | Pubchem ID : | 2736476 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
With triethylamine;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; copper(l) iodide; DavePhos; at 65℃; for 2h; | Example IA. 2-(3.3 -dimethylbut-1-ynyl)-4-(trifluoromethyl)benzonitrile .Pd2dba3:CHCl3 (0.439 g, 0.424 mmol, 1.5%), dicyclohexylphosrhohino-2'-(N,N- dimethylamino)biphenyl (0.640 g, 1.63 mmol, 6%), and CuI (0.155 g, 0.816 mmol, 3%) were placed in a flask and purged with N2. triethylamine (16 mL) was added and the mixture was stirred for 5 minutes followed by the addition of <strong>[1813-33-8]3-chloro-4-cyanobenzotrifluoride</strong> (4.00 mL, 27.0 mmol) and 3,3-dimethylbutyne (4.00 mmol, 1.2 eq). The mixture was heated under N2 at 65 0C for 2 hours, cooled to ambient temperature and diluted with ethyl acetate (~300 mL). The mixture was washed sequentially with ~2% aqueous NH4OH (120 mL) and saturated aqueous NH4CI (10OmL). The organic layer was dried (Na2SO4), filtered, concentrated, and filtered through SiO2 (~90 mL) with 4% diethyl ether/Hex to provide the title compound. 1H- NMR (CDCl3) delta 7.71-7.75 (m, 2H), 7.58 (dd, IH), 1.37 (s, 9H). | |
With copper(l) iodide; triethylamine;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; at 65℃; for 4h;Inert atmosphere; | To a flask was added Pd2dba3 (0.405 g), DavePhos (0.6884 g, 1.75 mmol), and CuI (0.1655 g). This was purged with nitrogen and degassed; triethylamine (100 mL) was then added. <n="43"/>Benzonitrile (XVII) (36.2 g, 176 mmol) was then added, and the mixture was heated to 65 0C. 3,3-dimethylbutyne (23.7 g, 288 mmol) was then slowly added over 2 hours. The mixture was heated an additional 2 hours, and the heat removed. The mixture was diluted with isopropyl acetate (150 mL) and washed twice with water (150 mL) and twice with 10% aqueous citric acid (150 mL). The organics were diluted with methanol (40 mL), and the volume reduced in vacuo to 60 mL. This was repeated twice with 190 mL methanol, the residual material diluted to 250 g with methanol and used in the next step as a solution. An analytical sample was obtained by removing all the solvent in vacuo.1H NMR (CDCl3, 400 mHz) 7.75 - 7.70 (m, 2H), 7.60-7.55 (m, IH), 1.37 (s, 9H); 13C NMR (CDCl3, 100MHz) 132.6, 128.7, 128.6, 123.8, 123.7, 116.24, 107.96, 75.06, 30.73, 28.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2A. (2-isobutyl-4-(trifluoromethyl)phenyl)methanamine. A solution of 2-methylpropenylmagnesium bromide (0.5 M in THF, 6.0 mL, 3.0 mmol) was added to a solution of ZnCh (1 -0 M in diethyl ether, 3.0 mL, 3.0 mmol) at 00C. The mixture was stirred for 10 minutes cold, and an additional 30 min after removing the cooling bath. 2-chloro-4-trifluoromethyI-benzonitrile (0.35mL, 2.4 mmol) was added, followed by a solution containing Pd2dba3.CHCl3 (48.5 mg, 0.047 mmol) and 2- dicyclohexylphophino-2'-(N,N-dimethylamino)biphenyl (56.3 mg, 0.14 mmol) in THF (1 mL). The mixture was stirred at 60 0C for 3 hours, diluted with ethyl acetate and the resulting mixture washed sequentially with 0.1 N aqueous HCl (2x) and brine (Ix). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure, and purified by flash chromatography (5% diethyl ether/hexane) to provide 0.264 g of the nitrile as a clear oil which was used without further purification. The oil was dissolved in 4:1 methanol: ethyl acetate (25 mL), shaken in the presence of 10% Pd/C and Ra Ni (catalytic amounts) under H2 (60 psi) overnight. The mixture was filtered and concentrated under reduced pressure, and the residue purified by flash chromatography (20-100% ethyl acetate in dichloromethane as a gradient elution) to provide the title compound. 1H NMR (CDCl3) delta 7.43-7.52 (m, 2H), 7.37 (brs, IH), 3.94 (brs, 2H), 2.57 (d, 2H), 1.87 (m, IH), 1.49 (brs, 2H), 0.94 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; toluene; for 18h;Heating / reflux; | Example 4A. 2-isopropyl-4-(trifluoromethyl)benzonitrile. To a solution of <strong>[1813-33-8]2-chloro-4-trifluoromethyl-benzonitril</strong>e (0.67mL, 4.5 mmol) and [1,1 '-bisfdiphenylphosphinojferroceneldichloropalladiumtll) (110 mg, 0.14 mmol) in 15 mL of dioxane was added Zn(iso-Propyl)2 (IN in toluene, 9 mmol). The mixture was heated to reflux for 18 hours, cooled to ambient temperature and diluted with methanol. The mixture was further diluted with ether and washed sequentially with IN HCl, water and brine. The organic layer was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by flash column chromatography (0% to 10% ethyl acetate/hexane) to provide the title compound. 1H NMR (CDCl3) delta 7.73 (d, IH), 7.63 (s, IH), 7.55 (d, IH), 3.45 (sept, IH), 1.36 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 246A 2-chloro-4-(trifluoromethyl)benzylamine The title compound was prepared using the procedure described in Example 244A using <strong>[1813-33-8]2-chloro-4-(trifluoromethyl)benzonitrile</strong> instead of 4-bromo-3-methylbenzonitrile. MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) delta 3.97 (s, 2H), 7.50-7.70 (m, 3H). | ||
Example 246A 2-chloro-4-(trifluoromethyl)benzylamine The title compound was prepared using the procedure described in Example 244A using <strong>[1813-33-8]2-chloro-4-(trifluoromethyl)benzonitrile</strong> instead of 4-bromo-3-methylbenzonitrile. MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) delta 3.97 (s, 2H), 7.50-7.70 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrahydrofuran; tetrahydrofuran, ethyl bromide; | EXAMPLE 17 1'-[4-[1-(4-Fluorophenyl)-5-trifluoromethylindazol-3-yl]-1-butyl]spiro]isobenzofuran-1(3H),4'-piperidine], 17a. To a suspension of magnesium turnings (135 g) in 300 ml of dry tetrahydrofuran, ethyl bromide (140 g) dissolved in 500 ml of dry tetrahydrofuran was slowly added followed by reflux for 20 min. A solution of 4-chloro-1-butanol (274 g) in 500 ml of tetrahydrofuran was added dropwise at reflux temperature. After stirring for 20 min, the Grignard solution was filtered and added portionwise to a solution of <strong>[1813-33-8]2-chloro-4-trifluoromethyl-benzonitril</strong> (200 g) in 600 ml of dry tetrahydrofuran. The reaction mixture was stirred for 16 h at room temperature followed by addition af 2N hydrochloric acid and ice. Extraction with ether, drying of the ether phase over magnesium sulfate and removal of solvent in vacuo left a viscous oil which was applied to a silica gel column (eluent:dichloromethane/ether=3:1) giving 4-(2-chloro-5-trifluoromethylbenzoyl)-1-butanol (101 g) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.8% | 2-Chloro-4-(trifluoromethyl)benzonitrile (500 mg, 2.43 mmol) was diluted with toluene (3 mL), placed under nitrogen and cooled to -78C. DIBAL-H (4865 muL, 4.86 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 00C and acetic acid (2 mL) was added followed by 10 mL of water. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was purified using a biotage 25 cartridge running a gradient, 100%hexanes to 20%DCM/hexanes to yield 2-chloro-4-(trifluoromethyl)benzaldehyde (400 mg, 1.92 mmol, 78.8 % yield) as a clear oil. | |
30% | Dissolve <strong>[1813-33-8]2-chloro-4-trifluoromethylbenzonitrile</strong> (405 mg, 1.97 mmol) in anhydrous toluene (7 mL) and cool in a dry ice/ethanol bath. Add diisobutylaluminum EPO <DP n="62"/>hydride (DIBAL) (3.94 niL, 3.94 mmol, 1.0 M in toluene) slowly. Stir 30 min. Warm to room temperature, add acetic acid (2 mL) and water (10 rnL) and stir for 2 hours. Extract the aqueous layer with ethyl acetate twice. Wash the organic layer with potassium sodium tartrate solution (Rochelle salt) twice. Dry (magnesium sulfate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel eluting with a gradient of 100:0 to 1:1 hexanes:dichloromethane to give 2-chloro-4- trifluoromethylbenzaldehyde (123 mg, 30%). 1H NMR (400 MHz, CDCl3) delta 10.52 (s, IH), 8.05 (d, IH5 J = 8.0 Hz), 7.75 (s, IH), 7.66 (d, IH, J = 8.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | at 80℃; | To commercially available <strong>[1813-33-8]2-chloro-4-trifluoromethylbenzonitrile</strong> 13 (1 ml, 7.2 mmol) was added piperidine (4equiv., 2.8ml) and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 1 g of a yellow oil. Yield = 56% 'HNMR (DMSO, 200 MHz) delta 1.60 (6H, m), 3.20 (4H, m), 7.34 (2H, m), 7.89 (1H, dd, J = 8.6 Hz, J' = 0.4 Hz) |
56% | at 80℃; | Preparation of 4-(trifluoromethyl)-2-(piperidin-1-yl)benzonitrile 14c (scheme 7) To commercially available 2-chloro-4-benzonitrile (1 ml, 7.2 mmol) was added piperidine (4equiv., 2.8ml) and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 1 g of a yellow oil. Yield = 56% 1HNMR (DMSO, 200 MHz) delta 1.60 (6H, m), 3.20 (4H, m), 7.34 (2H, m), 7.89 (1H, dd, J = 8.6 Hz, J' = 0.4 Hz) |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; at 50℃; for 12h; | General procedure: A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate amine (NR2, 2.00 mmol),and DBU (2.5 mmol) were dissolved in 1,4-dioxane (8 ml). Themixture was stirred for 12 h at 50 C. The reaction was quenched with water and extracted with EtOAc twice. The combined organicextracts were dried over MgSO4, filtered, and concentrated invacuo. The residue was purified by flash column chromatographyon silica gel using EtOAc/hexane (1:7-1:10) eluant condition.(NR2 = 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloridefor 17). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | at 80℃; | To commercially available <strong>[1813-33-8]2-chloro-4-trifluoromethylbenzonitrile</strong> 13 (4 ml, 29 mmol) morpholine (4equiv., 10 ml) was added and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 6.19 g of a yellow oil. Yield = 83% 'HNMR (DMSO, 200 MHz) delta 3.24 (4H, m), 3.75 (4H, m), 7.94 (1H, m), 8.23 (1H, m). |
83% | at 80℃; | Preparation of 4-(trifluoromethyl)-2-morpholinobenzonitrile 14d (scheme 7) To commercially available 2-chloro-4-benzonitrile (4 ml, 29 mmol) morpholine (4equiv., 10 ml) was added and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 6.19 g of a yellow oil. Yield = 83% 1HNMR (DMSO, 200 MHz) delta 3.24 (4H, m), 3.75 (4H, m), 7.94 (1H, m), 8.23 (1H, m). |
In N,N-dimethyl-formamide; at 120℃; for 6h; | General procedure: A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate amine (NR2, 2.00 mmol)were dissolved in DMF (8 ml). The mixture was stirred for 6 h at120 C. The reaction was quenched with water and extracted withEtOAc twice. The combined organic extracts were dried overMgSO4, filtered, and concentrated in vacuo. The residue was purifiedby flash column chromatography on silica gel using EtOAc/hexane (1:7) eluant condition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | at 80℃; | To commercially available <strong>[1813-33-8]2-chloro-4-trifluoromethylbenzonitrile</strong> 13 (lml, 7.2 mmol) pyrrolidine (4equiv., 2.38 ml) was added and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 940mg of a yellow solid. Yield = 54% 'HNMR (DMSO, 200 MHz) delta 1.95 (4H, m), 3.58 (4H, m), 6.94 (2H, m), 7.73 (1H, dd, J = 8 Hz, J'= 0.8 Hz). |
54% | at 80℃; | Preparation of 4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzonitrile 14b (scheme 8) To commercially available 2-chloro-4-benzonitrile (1ml, 7.2 mmol) pyrrolidine (4equiv., 2.38 ml) was added and the solution was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 940mg of a yellow solid. Yield = 54% 1HNMR (DMSO, 200 MHz) delta 1.95 (4H, m), 3.58 (4H, m), 6.94 (2H, m), 7.73 (1H, dd, J = 8 Hz, J' = 0.8 Hz) |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; at 50℃; for 12h; | General procedure: A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate amine (NR2, 2.00 mmol),and DBU (2.5 mmol) were dissolved in 1,4-dioxane (8 ml). Themixture was stirred for 12 h at 50 C. The reaction was quenched with water and extracted with EtOAc twice. The combined organicextracts were dried over MgSO4, filtered, and concentrated invacuo. The residue was purified by flash column chromatographyon silica gel using EtOAc/hexane (1:7-1:10) eluant condition.(NR2 = 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloridefor 17). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | at 80℃;closed vessel; | To commercially available <strong>[1813-33-8]2-chloro-4-trifluoromethylbenzonitrile</strong> 13 (0.5 ml, 3.6 mmol) dimethylamine (4equiv., 0.95 ml) was added and the solution was heated in closed vessel at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 730 mg of a pale yellow oil. Yield = 94% 'HNMR (CDC13, 200 MHz) delta 3.13 (6H, s), 7.05 (1H, bs), 7.59 (1H, dd, J = 8.4 Hz, J' = 0.6 Hz), 7.99 (1H, bs) |
94% | In ethyl acetate; at 80℃;Sealed vessel; | Example 4: 1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea (scheme 1) Preparation of 2-(dimethylamino)-4-(trifluoromethyl)benzonitrile 14a (scheme 7) To commercially available 2-chloro-4-benzonitrile (0.5 ml, 3.6 mmol) dimethylamine (4equiv., 0.95 ml) was added and the solution was heated in closed vessel at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 730 mg of a pale yellow oil. Yield = 94% 1HNMR (CDCI3, 200 MHz) delta 3.13 (6H, s), 7.05 (1H, bs), 7.59 (1H, dd, J = 8.4 Hz, J' = 0.6 Hz), 7.99 (1H, bs) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | To a suspension of NaH 60% (0.09g, 3.97 mmol) in DMF (20 mL) at 0C was added in one portion lH-imidazole (2.5 mol eq, 0.61g). After 10 min 2-chloro- 4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.61 mmol) was added and the reaction mixture was heated at 100C for 2h. The reaction was cooled at room temperature, water was added and the aqueous solution was extracted with EtOAc (3x25 mL). The recombined organic phases were dried over sodium sulfate and evaporated to dryness to give the 2-imidazol-l-yl-4-(trifluoromethyl)benzonitrile as pale yellow oil (0.63g, 73% Yield) used for the reduction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 80℃; | To commercially available <strong>[1813-33-8]2-chloro-4-trifluoromethylbenzonitrile</strong> 13(lml, 7.2 mmol) in DMF 1 equiv. of NaH and 1 ,2,4-tetrazole (4equiv., 1.98 g) were added and the mixture was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 900mg of a yellow solid. Yield = 53% 'HNMR (DMSO, 200 MHz) delta 8.08 (1H, dd, J = 7.6 Hz, J' = 1 Hz), 8.33 (3H, m), 9.29 (1H, s). |
53% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 80℃; | Preparation of 4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile 14e (scheme7) To commercially available 2-chloro-4-benzonitrile (1ml, 7.2 mmol) in DMF 1 equiv. of NaH and 1,2,4-tetrazole (4equiv., 1.98 g) were added and the mixture was heated at 80C overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 900mg of a yellow solid. Yield = 53% 1HNMR (DMSO, 200 MHz) delta 8.08 (1H, dd, J = 7.6 Hz, J' = 1 Hz), 8.33 (3H, m), 9.29 (1H, s). |
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