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Photocatalytic α-arylation of cyclic ketones
Md Mubarak Hossain ; Aslam C. Shaikh ; Jules Moutet , et al. Nat. Synth.,2022,1(2):147-157.
Abstract: The direct α-arylation of carbonyl compounds using aryl halides represents a powerful method to synthesize critical building blocks for diverse useful compounds. Numerous synthetic methods exist to forge C(sp2)–C(sp3) bonds although mild and metal-free direct α-arylation of ketones remains a challenging transformation. Here we report a green-light-mediated α-arylation of ketones from readily available aryl halides via activation of a C(sp2)–X bond (X = I, Br, Cl) and an α-carbonyl C(sp3)–H bond in a single photocatalytic cycle. This approach is characterized by its mild reaction conditions, operational simplicity and wide functional group tolerance. Importantly, the impressive outcome of the multigram photocatalytic reaction underpins the strength of this method as a potentially practical and attractive approach for scale-up industrial purposes. The utility and scope of this reaction were further demonstrated by formal syntheses of several feedstock chemicals that are commercially expensive but critical for synthesizing numerous pharmaceutical agents.
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CAS No. : | 3058-39-7 |
Formula : | C7H4IN |
Linear Structure Formula : | NC(C6H4I) |
M.W : | 229.02 |
SMILES Code : | N#CC1=CC=C(I)C=C1 |
MDL No. : | MFCD00051310 |
InChI Key : | XOKDXPVXJWTSRM-UHFFFAOYSA-N |
Pubchem ID : | 76467 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.87 |
TPSA ? Topological Polar Surface Area: Calculated from | 23.79 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.89 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 2.74 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 2.16 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 2.37 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.79 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 2.39 |
Log S (ESOL):? ESOL: Topological method implemented from | -3.48 |
Solubility | 0.0759 mg/ml ; 0.000332 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.89 |
Solubility | 0.292 mg/ml ; 0.00128 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.44 |
Solubility | 0.083 mg/ml ; 0.000362 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -5.75 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.98 |
* 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 |
---|---|---|
100% | With N,N-dimethylglycine hydrochoride; caesium carbonate;copper(l) iodide; In 1,4-dioxane; at 90℃; for 88h; | To phenol (1.23 g, 13.10 mmol), copper(l) iodide (333 mg, 1.75 mmol), cesium carbonate (5.69 g, 17.47 mmol), 4-iodobenzonithle (2.00 g, 8.73 mmol) and N,N-dimethylglycine hydrochloride (366 mg, 2.62 mmol) under nitrogen was added degassed 1 ,4- dioxane (10.0 ml_). The whole mixture was heated at 90 0C for 88 hours. The cooled mixture was partitioned between ethyl acetate (100 ml_) and water (100 ml_). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 ml_). The organic layers were combined and washed with brine (100 ml_) and dried with Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography EtOAc/ Hex (1 :12 ? 1 :8) to give the pure product as a white solid (quantative yield). 1H NMR (300 MHz, CDCL3) d(ppm): 7.00 (2H, d, J = 9.1 Hz), 7.06 (2H, d, J = 7.6 Hz), 7.23 (1 H, t, J = 7.2 Hz), 7.41 (2H, t, J = 8.1 Hz), 7.59 (2H, d, J = 9.1 Hz). 13C NMR (75 MHz, CDCL3) d(ppm): 105.9, 118.0 (CH), 119.0, 120.5 (CH), 125.3 (CH), 130.4 (CH), 134.2 (CH), 154.9, 161.8. MS (FAB+): 196 (MH+). HRMS for Ci3H9NO (MH+): calculated: 196.0762; found 196.0780. |
100% | With caesium carbonate;copper(l) iodide; N,N-dimethylglycine hydrochoride; In 1,4-dioxane; at 90℃; for 88h;Inert atmosphere; | To phenol (1.23 g, 13.10 mmol), copper(I) iodide (333 mg, 1.75 mmol), cesium carbonate (5.69 g, 17.47 mmol), 4-iodobenzonitrile (2.00 g, 8.73 mmol) and N,N-dimethylglycine hydrochloride (366 mg, 2.62 mmol) under nitrogen was added degassed 1,4-dioxane (10.0 mL). The whole mixture was heated at 90 C. for 88 hours. The cooled mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with brine (100 mL) and dried with Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography EtOAc/Hex (1:12→1:8) to give the pure product as a white solid (quantitative yield). 1H NMR (300 MHz, CDCL3) δ(ppm): 7.00 (2H, d, J=9.1 Hz), 7.06 (2H, d, J=7.6 Hz), 7.23 (1H, t, J=7.2Hz), 7.41 (2H, t, J=8.1 Hz), 7.59 (2H, d, J=9.1 Hz). 13C NMR (75 MHz, CDCL3) δ(ppm): 105.9, 118.0 (CH), 119.0, 120.5 (CH), 125.3 (CH), 130.4 (CH), 134.2 (CH), 154.9, 161.8. MS (FAB+): 196 (MH+). HRMS for C13H9NO (MH+): calculated: 196.0762; found 196.0780. |
96% | With copper(l) iodide; potassium carbonate; dimethylbiguanide; In acetonitrile; at 20 - 60℃; for 10.1667h; | General procedure: To a 25 mL flask containing a mixture of CuI (19.2 mg,0.1 mmol), metformin (0.1 mmol), phenol (1.0 mmol), and K2CO3(2 mmol, 276 mg) in CH3CN (5 mL) was added an aryl halide(1.1 mmol). The mixture was stirred for 10 min at room temperature, and then heated to 60∘C for the appropriate amount of time(see Table 4). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product. |
95% | With tetrabutylammomium bromide; caesium carbonate; In dimethyl sulfoxide; at 120℃; for 10h; | General procedure: Polymer supported Cu(II) catalyst (0.05 g, 0.0098 mmol) in DMSO (5 mL) was taken in a 100 ml R.B flask and stirred at room temperature for 10 min. Then aryl halide (1 mmol), phenol(1 mmol), tetrabutylammonium bromide (tBu4NBr) (0.1 mmol),Cs2CO3 (1 mmol) and DMSO (5 mL) were added to it. The final reaction mixture was refluxed at 120 C under an open air condition.The reaction mixtures were collected at different time intervals and identified by GCMS and quantified by GC. After the completion of the reaction, the catalyst was filtered off and washed with water followed by acetone and dried in oven. The filtrate was extracted with ethyl acetate (3 x 20 ml) and the combined organic layers were dried with anhydrous Na2SO4 by vacuum. The filtrate was concentrated by vacuum and the resulting residue was purified by column chromatography on silica gel to provide the desired product. |
95% | With copper(I) oxide; caesium carbonate; imidazole-4-carboxylic acid; In acetonitrile; at 80℃; for 24h; | General procedure: To a screw-capped vial (4-mL) were added Cs2CO3 (1.0 mmol, 325 mg), Cu2O (0.005 mmol, 0.7 mg), 1H-imidazole-4-carboxylic acid (0.01 mmol, 1.1 mg) and acetonitrile (0.25 mL). The vial was sealed with septum and allowed to stir for a while; the iodoarene (0.5 mmol) and phenol (0.6 mmol) were then injected into the reaction mixture via a syringe. The septum was removed, and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 oC for 24 h. The crude reaction mixture was diluted with CH2Cl2, filtered through a thin Celite pad, and concentrated in vacuo. The residue was isolated through a column chromatography by using hexane and ethyl acetate as eluent to give the pure product. Products 3a-v were obtained according to this procedure. The known structures were characterized by the 1H NMR and 13C NMR of reported literatures.1-3 Spectral data, 1H NMR and 13C NMR spectra for all the new compounds are listed below. |
85% | With copper(l) iodide; 2-(2-benzoylhydrazine-1-carbonyl)-1-benzylpyrrolidine 1-oxide; caesium carbonate; In acetonitrile; at 80℃; for 12h;Inert atmosphere; Sealed tube; | General procedure: CuI (19.2 mg, 0.1 mmol, 10 mol%), Cs2CO3 (650 mg, 2.0 mmol) and L2 (34 mg, 0.1 mmol, 10 mol%) were added to a re-sealable 25 mL test tubes with Teflon septa. The tube was evacuated and backfilled three times with nitrogen. Add the corresponding solvent (EtOH or CH3CN, 1 mL) via syringe under countercurrent nitrogenflow, continue adding halides (1.5 mmol) and nucleophile (1.0 mmol), seal the test tube. The reaction mixture was heated at 80 C for 12 h, and then allowed to cool to room temperature. After the reaction mixture was diluted with CH2Cl2, the precipitate was removed by filtration and washed with water. After extraction, the organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by column chromatography. |
83% | With caesium carbonate; In dimethyl sulfoxide; at 20 - 80℃; for 10h; | The compound 4-cyanoiodobenzene 1a (0.023 g, 0.10 mmol, 1.0 eqv.) was added to the reactor in that order.DMSO (0.3 ml), Cs2CO3 (0.065 g, 0.20 mmol, 2.0 eq.).Phenol 2a (0.0113 g, 0.12 mmol, 1.2 eq.) was stirred at room temperature for 10 minutes.Then placed in an 80 C oil bath, reacted under light for 10 h,After the TLC detection reaction is completed, the reaction solution is subjected to filtration, extraction and column chromatography.The target product 3a was obtained in a yield of 83%. |
79% | With caesium carbonate; In dimethyl sulfoxide; at 20 - 80℃; for 10.1667h;Irradiation; | The compound 4-cyanoiodobenzene 1a (1.0 mmol), DMSO (5 ml), Cs2CO3 (2.0 mmol), and phenol 2a (1.2 mmol) were added to the mixture, and the mixture was stirred at room temperature for 10 minutes. Then placed in an 80 C oil bath, reacted under lightAfter 10 h, after TLC detection reaction, the reaction solution was filtered, extracted and subjected to column chromatography to obtain the target product 4a, yield 79%. |
79% | With caesium carbonate; In dimethyl sulfoxide; at 20 - 80℃; for 10.1h;Irradiation; | The compound 4-cyanoiodobenzene 1a (1.0 mmol) was added to the reactor in that order.DMSO (5 ml), Cs2CO3 (2.0 mmol), phenol 2a (1.2 mmol) was stirred at room temperature for 6 min.Then, it was placed in an oil bath at 80 C, and reacted for 10 hours under light. After the TLC detection reaction was completed, the reaction solution was subjected to filtration, extraction and column chromatography to obtain the objective product 4a, yield 79%. |
55% | With sodium hydroxide; In neat (no solvent); at 90℃; for 8h;Green chemistry; | General procedure: A round bottom glass tube was charged by phenol (1mmol,0.094g), iodobenzene (1mmol, 0.203g), NaOH (3mmol,0.12g), and Fe3O4AMCA-MIL53(Al)-NH2-CoII NPs(VI)(1.08mol%, 0.04g). The reaction mixture was stirred at 90C under solvent free conditions. Thin layer chromatography(TLC) or gas chromatography (GC) were used to monitor the progress of the reaction. After completion of the reaction (6h), the reaction mixture was quenched by additionof 2mL ethyl acetate. The nanostructured catalyst was separated using an external magnetic field, washed with ethanol and water before drying in an oven at 50C overnight for the next run use. The obtained crude product was purified by thin layer chromatography using n-hexane/ethyl acetate(50:1) to aford the pure diphenyl ether (0.161g, 95% yield). |
36% | With L-valine; cobalt(II) diacetate tetrahydrate; caesium carbonate; zinc; In acetonitrile; at 135℃; for 48h;Inert atmosphere; Green chemistry; | General procedure: An oven-dried sealed tube equipped with a magneticstirring bar was charged with aryl iodide (0.65 mmol),Co(OAc)24H2O (15 mol%), l-valine (30 mol%), cesiumcarbonate (2 equiv.), and phenol (0.78 mmol). Acetonitrilesolvent (2.5 cm3) was added and the sealed tube wasevacuated using a vacuum pump, filled with nitrogen,and tightly sealed. It was then stirred in a pre-heated oil bath for 24-48 h. After the completion of the reaction, thereaction mixture was extracted with 15 cm3 of EtOAc andthe EtOAc layer was separated and washed with water.The aqueous layer was collected and further extractedtwo more times with EtOAc (2 × 15 cm3). The combinedorganic layers were dried over anhydrous Na2SO4andevaporated using a rotatory evaporator. The residue waslater purified by column chromatography (silica 100-200mesh) using hexane-EtOAc mixture as the eluent. |
With caesium carbonate; In dimethyl sulfoxide; at 20 - 80℃; for 10.6667h; | The compound 4-cyanoiodobenzene 1a (0.023 g, 0.10 mmol, 1.0 eq.), DMSO (0.3 ml), Cs2CO3 (0.065 g 0.20 mmol, 2.0 eq.), phenol 2a (0.0113 g, 0.12 mmol, 1.2 eq., and stirred at room temperature for 40 minutes. Then, it was placed in an oil bath at 80 C, and reacted for 10 hours under light. After the TLC detection reaction was completed, the reaction solution was subjected to filtration, extraction and column chromatography to obtain the objective product 3a, yield 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; water; toluene; for 16h;Inert atmosphere; Reflux; | Step-1 :- Preparation of 4'-bromo-[ 1,1 '-biphenyl] -4-carbonitrile To a solution of 4-iodobenzonitrile (1.0 g, 4.365 mmol) in MeOH /toluene (1 : 1 ratio, 20 mL) was added (4-bromophenyl)boronic acid (0.964 g, 4.824 mmol). The reaction mixture was de-gassed under vacuum for 10 mins, followed by addition of tetrakis(triphenylphosphine)Pd(0) (49.0 mg, 0.043 mmol) and aq. Na2C03 (0.683 g, 6.45 mmol) under nitrogen atmosphere. The reaction mixture was heated at reflux for 16 h. Then the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc. The organic layer was washed with water, brine and the organic portion was separated, dried, concentrated and further purified by column chromatography to afford 1.1 g of title product. 1H NMR (300 MHz, CDC13 ): δ 7.75 (d, 2H), 7.72- 7.60 (m, 4H) , 7.47- 7.44(d, = 8.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; potassium carbonate; triphenylphosphine; In benzene; at 150℃; for 24h;Sealed tube; | General procedure: In a 30-mL sealed tube, <strong>[2622-63-1]1-methyl-2-phenylbenzimidazole</strong> (1, 0.25mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), Ph3P (0.075 mmol),K2CO3 (0.50 mmol), and iodoarene (0.25 mmol) were combined inanhydrous benzene (2 mL) under air. The mixture was then stirredat 150 °C for 24 h. The mixture was cooled to r.t., diluted with EtOAc, and filtered through a small pad of Celite. The filtrate was concentrated in vacuo and purified by flash chromatography (silicagel, EtOAc?hexane) to give the analytically pure 2-(biphenyl-2-yl)benzimidazoles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Synthesis of 4-(6-Bromo-2-methyl-indol-1-yl)-benzonitrile (CXXXIV): To a solution of CXXXIII (1.0 g, 4.70 mmol) in 1,4-dioxane (50 mL) was added potassium phosphate (2.98 g, 0.044 mol) and 4-iodo-benzonitrile (2.1 g, 0.010 mol). The mixture was sparged with nitrogen gas for 0.5 h at room temperature. Then copper(I) iodide (0.44 g, 0.230 mmol) and 20 trans-(+/-)-1,2-diaminocyclohexane (0.054 g, 0.470 mmol) were added to the flask. The resultant reaction mixture was heated at 130 C for 48 h. After cooling to room temperature, the reaction mixture was filtered through a bed of celite and the filter pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the remaining crude 197 of 363 {//-- DRAFT --//4069/3020WO/00228726/v2} 4069.3020 WO product mixture was purified by column chromatography on (100-200 mesh) silica gel, using 5% ethyl aceate in hexanes to afford CXXXIV (0.65 g, 44%) as an off-white solid.1H NMR (400 MHz, CDCl3): delta 7.85 (d, J= 8.3 Hz, 2H), 7.4-7.45 (m, 2H), 7.42-7.39 (m, 1H), 7.24-7.22 (m, 2H), 6.41 (s, 1H), 2.29 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.4 g | Synth es is of 4-(2-Meth yl-pyrrolo[3,2-b]pyridin-1-yl)-benzonitrile (XXI): In a s ealed tube, a mixture of copper (I) iodide (43 mg, 0.226 mmol), compound X X (0.600 g, 4.53 mmol) and potass ium phosphate (1.60 g, 7.70 mmol) in 1 ,4-dioxane (20 mL) w as sparged with nitrogen gas for 0.5 h. Then trans-(+/-)-1 ,2-cyclohexanediamine (26 mg, 0.226 mmol) and 4-iodo- benzonitrile (1.00 g, 4.53 mmol) where then added to the flask at room temperature and the 30 resulting reaction mixture was heated at 110 oC for 38 h. After cooling to room temperature, the reaction mixture was filtered through celite and the filter pad w as washed with ethyl acetate. The filtrate was concentrated to afford the crude product mixture. The crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate in hexane as the eluant to obtain product XXI (0.4 g) as an off-white solid. 1H NMR (400 MHz, 114 of 363 {//-- DRAFT --//4069/3020WO/00228726/v2} 4069.3020 WO CDCl3): delta 8.45 (dd, J= 5.2, 1 Hz, 1H), 7.93 (d, J= 8.6 Hz, 2H), 7.60 (d, J= 8.2 Hz, 1H), 7.52 (d, J= 8.5 Hz, 2H), 7.21 (dd, J= 8.3, 5.2 Hz, 1H), 6.94 (s, 1H), 2.43 (s, 3H), MS (ESI, positive mode) m/z 234 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With copper(l) iodide; cesium fluoride; In tetrahydrofuran; at 20℃; for 24h;Sealed tube; | A sealed tube was charged with 4-iodobenzonitrile (1.0 g, 4.4 mmol), <strong>[1192-07-0]isoxazolidin-3-one</strong> (1 .2 equiv.; 0.46 g, 5.2 mmol), dimethylethylenediamine (0.1 equiv., 0.47 mL, 0.44 mmol), cesium fluoride (2.5 equiv., 1.66 g, 10.9 mmol), copper iodide (0.05 equiv., 0.04 g, 0.20 mmol), tetrahydrofuran (8 imL) and the reaction contents were stirred at room temperature for 24 hours. The reaction contents were diluted with ethyl acetate and a saturated aqueous ammonium chloride solution. The layers were separated and the organic fraction was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography over silica gel (cyclohexane:EtOAc eluent gradient 9:1 to 1 :9) to afford 0.82 g (50% yield) of the title compound as an amorphous brown solid. (0614) LC/MS (Method A) retention time = 0.72 minutes, 188 (M+H)+. (0615) NMR (400 MHz, CDCIs) delta ppm: 7.83 (d, 2H), 7.65 (d, 2H), 4.59 (t, 2H), 3.07 (t, 2H), 3.30 (0616) (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) dichloromethane; caesium carbonate; at 100℃; for 16h;Inert atmosphere; | (0667) A mixture of 4-iodobenzonitrile (300 mg, 1.31 mmol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (346 mg, 1.96 mmol), cesium carbonate (1.28 g, 3.93 mmol) and chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) dichloromethane adduct (176 mg, 0.262 mmol) in tert-amyl alcohol (5 mL) was stirred at 100 °C for 16 h under N2. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give a residue, which was diluted with H2O (10 mL). The water layer was extracted with EtOAc (20 mL x 2). The collected organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 065percent EA/PE gradient (at) 40 mL/min) to give 4-(4-methyl-2- phenylpiperazin-1-yl)benzonitrile as an oil. ESI-MS m/z [M+H]+: 277.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N,N'-diethylurea; at 120℃; for 24h;Schlenk technique; Sealed tube; Inert atmosphere; | General procedure: Aryl iodides (0.2 mmol) t-BuOK (0.6 mmol, 3.0 equiv), and U6 (0.02 mmol, 10 mol%) were added in dried Schlenk tubes. Benzene (2 mL) were added into tubes by syringe. The septum-sealed tube was evacuated and refilled with nitrogen three times. The mixture was stirred under a nitrogen atmosphere in sealed Schlenk tubes at 120 C for 24 h. The reaction was cooled down to room temperature. The mixture was filtered through a short plug of silica gel, washed with a copious amount of ethyl acetate. The combined organic phase was concentrated under vacuum. The product was purified through flash column chromatography on 300-400 mesh silica gel with hexane/ethyl acetate as eluent. Solvent was removed under vacuum to give the pure product. |
Tags: 3058-39-7 synthesis path| 3058-39-7 SDS| 3058-39-7 COA| 3058-39-7 purity| 3058-39-7 application| 3058-39-7 NMR| 3058-39-7 COA| 3058-39-7 structure
A143295 [1227311-09-2]
4-Iodo-3,5-dimethylbenzonitrile
Similarity: 0.89
A143295 [1227311-09-2]
4-Iodo-3,5-dimethylbenzonitrile
Similarity: 0.89
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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