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CAS No. : | 4421-08-3 | MDL No. : | MFCD00001820 |
Formula : | C8H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QJRWLNLUIAJTAD-UHFFFAOYSA-N |
M.W : | 149.15 | Pubchem ID : | 78135 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.67 |
TPSA : | 53.25 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.83 cm/s |
Log Po/w (iLOGP) : | 1.69 |
Log Po/w (XLOGP3) : | 0.54 |
Log Po/w (WLOGP) : | 1.27 |
Log Po/w (MLOGP) : | 0.51 |
Log Po/w (SILICOS-IT) : | 1.31 |
Consensus Log Po/w : | 1.06 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.44 |
Solubility : | 5.38 mg/ml ; 0.0361 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.23 |
Solubility : | 8.79 mg/ml ; 0.0589 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.02 |
Solubility : | 1.43 mg/ml ; 0.00962 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.4 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
98% | With iron(III) chloride; hydroxylamine hydrochloride; In N,N-dimethyl-formamide; for 3h;Reflux; | General procedure: Aldehyde(1 mmol) and hydroxylamine hydrochloride (1.2 mmol) were added successively toa solution of anhydrous ferric chloride (0.5 mmol) in 5 ml dry DMF. The mixturewas reflux for appropriate time (Table 2). The progress of the reaction wasmonitored by TLC. After completion of the reaction, the solution was pouredinto 100 ml water and extract with ethyl acetate washed several times withwater. The combined organic mixture was dried over anhydrous Na2SO4,concentrated and the residue was purified by column chromatography on silicagel 60-120 mesh using petroleum ether/ethyl acetate (96:4) as eluent to affordthe pure nitrile. All the products were characterized by IR, 1H NMRand 13C NMR. |
98% | With copper(II) oxide; hydroxylamine hydrochloride; In neat (no solvent); for 0.0194444h;Microwave irradiation; Green chemistry;Mechanism; | General procedure: A mixture of aldehyde (2 mmol), hydroxylamine hydrochloride (3 mmol), and copper oxide NPs (5 mol%) was placed in a Pyrex cylindrical tube and then homogenized and irradiated at 250 W in a MILESTONE microwave reactor. After irradiation (1-2 min), the mixture was cooled to 25 C and extracted with dichloromethane (5 ml x 2). The solvent was filtered under vacuum and the organic layer dried over fused calcium chloride. The crude product was then subjected to short-column silica gel chromatography using light petrol as an eluent to produce pure product. |
98% | With hydroxylamine hydrochloride; dimethyl sulfoxide; for 0.0208333h;Heating; Microwave irradiation; Green chemistry; | General procedure: Hydroxylamine hydrochloride, 0.55 g (0.72 mmol)was added to a solution of 0.5 g (0.66 mmol) aldehyde1 in 3 mL of DMSO. The reaction mixture wassubjected to microwave irradiation at 180 W (with 15-sintervals) for 60-120 s. Reaction progress was monoredby TLC on aluminum coated silica gel (ethylacetate:hexane, 1 : 4). After the reaction had beencomplete, the reaction mixture was cooled to roomtemperature and poured on crushed ice, the reactionproduct was extracted in ethyl acetate, the extract wasdried over Na2SO4 and concentrated in a vacuum, andthe residue was recrystallized. |
96% | With hydroxylamine hydrochloride; In N,N-dimethyl-formamide; for 1h;Reflux; | General procedure: Aldehyde (0.5 mmol) and hydroxylamine hydrochloride (0.75 mmol) were added successively to a solution of Fe3O4-CTAB NPs (5.7 mg) i.e Fe3O4 (1.8 mol%) in 5 ml dry DMF. The mixture was refluxed for appropriate time (table 3). The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was poured into 100 ml water and extract with ethyl acetate, washed several times with water. The combined organic mixture was dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography on silica gel 60-120 mesh using petroleum ether/ethyl acetate (95:5) as eluent to afford the pure nitrile. All the products were characterized by IR, 1H NMR and 13C NMR. |
95% | With hydroxylamine hydrochloride; In DMF (N,N-dimethyl-formamide); at 25 - 140℃; for 1h; | Example 1a Preparation of 3-methoxy-4-hydroxy Benzonitrile To a 3-necked 500 ML round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxy benzoaldehyde (50.2 g, 0.33 mole), hydroxylamine hydrochloride (25.5 g, 0.37 mole), and N,N'-dimethylformamide (40 ML) were successively added at 25 C., followed by heating in an oil bath at 140 C. for 1 hour.The reaction mixture was allowed to cool to 85 C., and water (250 ML) was added to yield 3-methoxy-4-hydroxybenzonitrile.The reaction mixture was further cooled to 10 C. for a complete precipitation, and the resulting solid was then isolated by filtration and dried under reduced pressure to yield a product as an off-white solid with a yield of 95% and a purity of higher than 99% as indicated by HPLC analysis. |
95.1% | With hydroxylamine hydrochloride; In N,N-dimethyl-formamide; at 50 - 110℃; for 6h; | In a 500 ml four-necked flask, 152.0 g of vanillin and 125.1 g of hydroxylamine hydrochloride were successively added.304 ml of N,N-dimethylformamide, stirring and mixing; the oil bath is slowly heated to an internal temperature of about 50 C. and incubated for 4 hours; slightly heated, the internal temperature rises to 110 C.,The reaction was further incubated for 2 hours; at the end of the reaction, the reaction mixture was slowly poured into 1000 ml of water, and the mixture was stirred and crystallized until complete; the mixture was filtered and dried to give 141.69 g of a white powder of vanillin as a white crystalline powder. Yield: 95.1.%, melting point: 87.5 to 88.0C, purity: 99.30%. |
94% | With bismuth(lll) trifluoromethanesulfonate; acetylhydroxamic acid; In acetonitrile; for 15h;Reflux; | General procedure: 4-Isopropylbenzaldehyde 1a (0.50 g, 3.37 mmol), acetohydroxamic acid (0.30 g, 4.05 mmol), acetonitrile (5 ml), and Bi(OTf)3 (0.11 g, 0.17 mmol) were taken into a 25 ml round-bottomed flask fitted with a condenser and calcium chloride guard tube. The mixture was refluxed for 14 h and after completion of the reaction (GC, 10% SE-30 on Chromosorb, 10' × 1/8 column), the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product obtained was purified by normal column chromatography(silica gel 100-200 mesh, ethyl acetate/hexane = 1:20) to obtain 4-isopropylbenzonitrile 3a (0.47 g, 97%). |
89% | With trifluorormethanesulfonic acid; trimethylsilylazide; In acetonitrile; at 20℃; for 0.5h;Sealed tube; Inert atmosphere; | General procedure: To a solution of an aromatic aldehyde 1 (0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,2.0 equiv) in a premixed HFIP/ACN mixture (2.0 mL, 1:1) in a nitrogen-flushed two dram vial wasadded triflic acid (TfOH; 17.7 L, 0.200 mmol, 0.40 equiv) (exotherm and brisk effervescence due tonitrogen gas evolution was immediately observed). The vial was capped and the reaction mixture wasallowed to stir at rt for 20-75 min. The reaction mixture was concentrated under nitrogen. The residueobtained was suspended in CH2Cl2/hexanes mixture and loaded on a silica gel in a 5 g samplecartridge. Purification using a normal phase silica flash column on a CombiFlash purification systemafforded a corresponding aromatic nitrile 2 upon concentration of appropriate fractions. |
86% | With sodium azide; silica gel; toluene-4-sulfonic acid; at 120℃; for 3.5h;Green chemistry; | General procedure: Aldehyde (1 mmol) , sodium azide (2 mmol) and p-toluene sulphonic acid (3 mmole) were finely mixed with silica gel 60-120 mesh (1g) in mortar and pestle. The resultant solid mixture was poured into a round-bottom flask (50ml) and allowed to stir on magnetic stirrer at 120 for an appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was poured into 100 ml water and extract with ethyl acetate, washed several times with water. The combined organic mixture was dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography on silica gel 60-120 mesh using petroleum ether/ethyl acetate as eluent to afford the pure nitrile. All the products were characterized by IR, 1H NMR and 13C NMR. |
80% | With hydroxylamine hydrochloride; acetic acid; at 110℃; for 2h; | Vanillin (750 mg, 5 mmol) was dissolved in acetic acid (15 mL). NH2OH*HCl (520 mg, 7.5 mmol) was added and the mixture was stirred and warmed at 110 C for 2 h. The reaction was stopped by adding H2O; the organic product extracted using CH2Cl2, dried and purified by flash chromatography (Ethyl acetate/cyclohexane 3/7). Yield: 80%. 1H NMR (400 MHz, DMSO, delta (ppm): delta 7.34 (1H, s, Ar), 7.27 (d, 1H Ar), 6.88 (d, 1H Ar) 3.81 (s, OCH3). 13C NMR (400 MHz, DMSO, delta (pm)) delta 151.79 (Ar-C), 148.41 (Ar-C), 126.92 (Ar-C), 120.06 (CN), 116.68 (Ar-C), 115.56 (Ar-C); 101.1 (Ar-C) 1, 56.39 (OCH3). |
With hydroxylamine hydrochloride; In N,N-dimethyl-formamide; for 2h;Reflux; High pressure; | In the reactor R0101 were first added vanillin, hydroxylamine hydrochloride, DMF was added with stirring to dissolve the raw materials,Access to high pressure steam S601001 to the reactor R0101 heating, raw materials in the reactor R0101 stirred at reflux for 2h, detected at the test port 01001 material composition, the reactor stopped heating reaction;Then the condensate CWS01002 was introduced into the reactor R0101, until the temperature of the reaction solution dropped to about 85 ,The reaction solution was transferred to a crystallizer C0101, and in the crystallizer C0101 was added industrial water PW01002,After stirring and crystallization completely, the reaction material is transferred to the filter F0101 through the material pump P0101,The filter cake obtained after filtration was washed with pure water PW01003, the filtrate into the waste water recovery tank V0101,The filter cake was transferred to a desiccator D0101 and dried to obtain the product 3-methoxy-4-hydroxybenzonitrile,3-Methoxy-4-hydroxybenzonitrile was transferred to reactor R0201. | |
With hydroxylamine hydrochloride; acetic acid; at 110℃; for 2h; | 750 mg (5 mmol) of 10 vanillin were dissolved in 15 mL of 11 acetic acid. 520 mg of 12 NH2OH.HCl (7.5 mmol) are added and the mixture was stirred and warmed at 110 C. for 2 h. The reaction was stopped by adding 13 H2O, the organic product extracted using 14 CH2Cl2, dried and purified by flash chromatography (Ethyl acetate/cyclohexane 3/7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 40℃; for 16h; | To a stirred solution of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (5.0 g, 33.5 mmol) in N,Ndimethylformamide (50 mL) was added iodoethane (6.27 g, 40.2 mmol, 3.22 mL) and potassium carbonate (9.27 g, 67.0 mmol) at 0 C, then the reaction was warmed and stirred at 40 C for 16 h. The reaction mixture was quenched by addition of water (50 mL) then the mixture was extracted with ethylacetate (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-ethoxy-3- methoxybenzonitrile (5.80 g, 32.7 mmol, 98 %) as a white solid. 1 NMR (400 MHz, ODd3) O 7.20-7.16 (m, 1 H), 7.00 (d, J 1.9 Hz, 1 H), 6.81 (d, J 8.4 Hz, 1 H), 4.07 (q, J 6.9 Hz, 2H), 3.82 (s, 3H), 1.45-1.39 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron(III) chloride; silica gel; In neat (no solvent); at 110℃; for 1.5h;Green chemistry;Catalytic behavior; | General procedure: Aldoxime (1.0 mmol) and anhydrous FeCl3 (1.0 mmol) were intimately mixed with silica gel 60-120 mesh (1.0 g) in mortar and pestle. The resulting solid mixture was poured into a round-bottom flask (50 ml) and allowed to stir on magnetic stirrer at 110 C for an appropriate time (Table 2). The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was extracted with ethyl acetate (3 15 ml) and washed several times with water. The combined organic mixture was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography on silica gel 60-120 mesh using petroleum ether/ethyl acetate as eluent to afford pure nitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 57 % Chromat. 2: 43 % Chromat. | With hydroxylamine hydrochloride In toluene for 6h; Heating; | |
With hydroxylamine hydrochloride; titanium(IV) oxide for 0.00833333h; Microwave irradiation; Neat (no solvent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 100% | With sodium azide; zinc dibromide; In water; isopropyl alcohol; at 80℃; for 24h; | (a) 5-[4-(tert-Butyldimethylsilyloxy)-3-methoxyphenyl]-2H-tetrazole (3b): To a solution of vanillonitrile (2, 1.00g, 6.7mmol), in isopropanol-water (1:2, 15mL), NaN3 (524mg, 8.04mmol, 2molequiv) and ZnBr2 (20mg, cat.) were added. After stirring at 80C for 24h, the reaction was cooled to room temp, and worked up by the addition of 2N H2SO4, extraction with EtOAc, and washing with brine. The organic phase was dried (Na2SO4) and evaporated, and the crude product was washed with petroleum ether to obtain a white solid (1.1g, ca. quantitative yield). A portion of this (780mg, 4.1mmol) was dissolved in dry dichloromethane (10mL), and triethylamine (1.69mL, 12.2mmol, 3molequiv) and tert-butyldimethylsilyl chloride (1M in CH2Cl2, 4.06mL, 1molequiv) were sequentially added. After stirring at RT for 4h, the reaction was quenched by the addition of 2N H2SO4 and dilution with CH2Cl2. The organic phase was washed with brine, dried, and evaporated, to afford 1.205g (97%) of white solid, that was directly used for the next steps. 1H NMR (300MHz, CDCl3): delta 7.72 (1H, d, J=1.5Hz), 7.66 (1H, dd, J=8.3, 1.5Hz), 6.93 (1H, d, J=8.3Hz), 3.85 (3H, s), 0.97 (9H, s), 0.15 (6H, s); 13C NMR (75MHz, CDCl3): delta 156.08, 151.83, 148.54, 121.66, 120.83, 116.67, 111.21, 55.84, 46.74, 25.71, -4.53. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; at 20 - 25℃; | 24 ml (141 mmol) of trifluoromethanesulfonic anhydride are slowly added dropwise to a solution of 20 g (134 mmol) of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> in pyridine (80 ml), keeping the reaction temperature below 25 C. with the aid of an ice bath. The suspension is then stirred at RT for 1 h. Ice water (400 ml) is added, and the suspension is stirred further until room temperature is reached. It is then filtered, the solid is dissolved in ethyl acetate, and the solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. 37.13 g (92% of theory) of the title compound are obtained as a white solid.LC-MS (Method 1): Rt=2.54 min; MS (Elpos): m/z=282 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): delta=3.97 (s, 3H), 7.60 (dd, 1H), 7.71 (d, 1H), 7.92 (d, 1H). |
92% | With pyridine; at 20 - 25℃; for 1h; | While maintaining the reaction temperature using an ice bath to less than 25 , 24 ml trifluoromethanesulfonic acid anhydride, 4- hydroxy-3-methoxy benzonitrile 20 g (134 mmol) of (141mmol) of pyridine (80 ml) It was slowly added dropwise to the solution. Thereafter, the suspension was stirred for 1 hour at room temperature. It was added to ice water (400 ml), and the mixture was stirred until the suspension to room temperature. Then, filtered and the solid was dissolved in ethyl acetate and the solution was washed with a saturated aqueous sodium chloride solution. Dried and concentrated the organic phase over magnesium sulfate. The title compound was 37.13 g (92% of theory) of the back It was obtained as a colored solid. |
89% | 3-methoxy-4-O-trifluoromethylsulfonylbenzonitrile (60d). Triethylamine (15.7 g, 155 mmol) was added to a stirred solution of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (20.0 g, 134 mmol) in dry CH2Cl2 maintained below 0 C. Triflic anhydride (47.4 g, 168 mmol) was added dropwise over 45 min such that the temperature of the reaction mixture did not exceed 5 C. The reaction mixture was maintained for 1 h, poured into ice water, and extracted into EtOAc. Column chromatography [hexane/EtOAc (9:1)], afforded colorless crystals (33.4 g, 89%): mp 51-53 C (hexanes/EtOAC); 1H NMR delta 7.92 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.4 and 1.9 Hz, 1H), 3.97 (s, 3H); HPLC (Method B) tR 6.89 min (100 area % at 230 nm). Anal. (C9H6F3NO4S) C, H, N, F, S. |
76% | With pyridine; In ethyl acetate; at 0℃; for 1h; | To a solution of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (10.9 g, 73.1 mmol) in ethyl acetate (75 ml) were added pyridine (13.0 ml, 161 mmol) and trifluoromethanesulfonic anhydride (22.7 g, 80.4 mmol) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was combined with ice water, and extracted twice with ethyl acetate. The combined organic layer was washed with 1 M hydrochloric acid, 1 M aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure, and crystallized from ethyl acetate-hexane to give the title compound (15.7 g, yield 76%). 1H NMR (CDCl3) delta 3.98 (3H, s), 7.30-7.35 (3H, m). |
With pyridine; In dichloromethane; at 0 - 20℃; for 0.5h; | Reference Example 11 3-Methoxy-4-phenylbenzonitrile 4-Hydroxy-3-methoxybenzonitrile (14.9g) and pyridine (24mL) were dissolved in dichloromethane (150mL). To the stirred mixture was added dropwise trifluoromethanesulfonic anhydride (19.4mL) under ice-cooling. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dilute hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the trifluoromethanesulfonic acid ester. The obtained trifluoromethanesulfonic acid ester, phenylboronic acid (14.7g), tetrabutylammonium bromide (1.6g), sodium carbonate (21.2g), tetrakis(triphenylphosphine)palladium (5.7g) and water (24mL) were suspended in toluene (150mL), and the mixture was stirred at 80C for 12 hours. The insoluble material was removed by filtration through celite, and the solvent of filtrate was removed under reduced pressure. To the residue was added dropwise water, and then added brine, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent:ethyl acetate/hexane=1/5) to give the title compound (18.0g). 1H―NMR (CDCl3) delta ppm: 3.84 (3H, s), 7.15-7.60 (8H, m) | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78℃; for 1h; | EXAMPLE 133-methoxy-4-ethyl-benzonitrile (13-2)To a solution of <strong>[4421-08-3]3-methoxy-4-hydroxybenzonitrile</strong> (13-1, 2.0 g, 13.4 mmol) in DCM (67 mL) at -78 C was added diisopropylethylamine (3.0 mL, 17.4 mmol) followed by triflic anhydride (2.7 mL, 16.0 mmol) and stirred at -78 C for Ih. The mixture was poured into a separatory funnel containing a few pieces of ice and then partitioned between ice water and ether. The organic phase was washed with IN HCl and then 10% Na2CO3, dried over Na2SO4, filtered and concentrated to yield a pale yellow oil. To a solution of this oil (2.7 g, 9.60 mmol) in DMF (96.0 mL) was added tetraethyl tin (3.80 mL, 19.2 mmol), bis(tri-t-butylphosphine) palladium(O) (0.491 g, 0.960 mmol) and LiCl (1.22g, 28.8 mmol) and the system was heated to 80 C for Ih in an oil bath. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the desired compound (13-2) as a pale yellow crystalline solid. ESI+ MS [M+H]+ Ci0Hi iNO: 162.1 found, 162.2 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: iron (III)-chloride; water; sodium peroxo disulfate / Erhitzen des Reaktionsprodukts mit Acetanhydrid 2: aq. NaOH solution |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With aluminium(III) iodide; diisopropyl-carbodiimide; In acetonitrile; at 80℃; for 18h; | General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid |
95% | With aluminium(III) iodide; calcium oxide; In acetonitrile; at 80℃; for 18h; | To a 100 ml eggplant flask was added aluminum triiodide (2.242 g, 5.5 mmol), acetonitrile (40 ml),CaO (0.422 g, 7.5 mmol) and <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (0.746 g, 5.0 mmol) were heated to 80 C,After 18 hours of reaction, stirring was stopped. After cooling to room temperature, 2 mol/L dilute hydrochloric acid (10 ml) was acidified in an eggplant-shaped flask.Extract with ethyl acetate (50ml x 3) and combine the organic phases and wash first with saturated aqueous sodium thiosulfate (10ml).It was washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator.The residue was purified by flash chromatography (eluent: ethyl acetate / petroleum ether = 1:1, volume ratio).0.645 g of 3,4-dihydroxybenzonitrile (white solid, yield 95%) was obtained. |
95% | With aluminium(III) iodide; In dimethyl sulfoxide; acetonitrile; at 80℃; for 18h; | Add aluminum triiodide (2·240 g, 5 · 5 mmol), acetonitrile (40 ml) and DMSO (0.430 g, 5.5 mmol) to a 100 ml eggplant-shaped flask, and heat to 80 C with stirring, and stir for 0.5 hour. Then, <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (0.746 g, 5.0 mmol) was added, and the reaction was further stirred (80 C), the reaction was stopped after 18 hours, and after cooling to room temperature, 2 mol was added to the eggplant-shaped flask. /L of dilute hydrochloric acid (10 ml), EtOAc (EtOAc (EtOAc) (EtOAc) Dry over magnesium sulfate, filter, and evaporate the filtrate with a rotary evaporator. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:4, volume ratio) to give 0.642 g 3,4 Hydroxybenzonitrile (white solid, yield 95%). |
95% | With aluminium(III) iodide; dimethyl sulfoxide; In acetonitrile; at 80℃; for 18h; | General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in MeCN was added anhyd DMSO (0.430 g, 5.5 mmol, 1.1 equiv). After stirring for 0.5 h at 80 C, the selected substrate (5 mmol) was added in one portion. The mixture was stirred overnight (18 h) at that temperature before quenching with aq 2 M HCl (10 mL). After extraction with EtOAc (3 50 mL), the organic phases were combined, washed with sat. aq Na2S2O3 and brine, and dried (MgSO4). The solvents were removed on a rotary evaporator, and the residue was purified by column chromatography to give the relevant catechol or phenol. |
94% | With aluminium(III) iodide; diisopropyl-carbodiimide; In acetonitrile; at 80℃; for 18h; | To a 100 ml eggplant flask were added aluminum triiodide (2.253 g), acetonitrile (40 ml), DIC (0.378 g) and <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (0.742 g) was added and heated to 80 C. After stirring for 18 hours, the mixture was stirred, cooled to room temperature and acidified with 2 mol / L dilute hydrochloric acid (10 ml) Extracted with ethyl acetate (50 ml X) The combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml) Washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness with a rotary evaporator, The residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether = 3: 7, volume ratio) To give 0.636 g of 4-cyano catechol (white solid in 94% yield). |
89.27% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 30 - 135℃; for 8h; | In a 1000 ml four-neck flask, 120 g of vanillin, 82.3 g of hydroxylamine hydrochloride, and 420 ml of N,N-dimethylformamide were added.Stir and mix; heat to an internal temperature of 55C for 2 hours; continue heating to an internal temperature of 90C for about 2 hours; cool down to an internal temperature of 60C, and distill off under reduced pressure to distill off about 80 ml of aqueous N,N-bisMethyl carboxamide solvent; then cooled to 30 C, slowly added 121.2g anhydrous aluminum trichloride, after the addition, stirring at 30 C for 2 hours; oil bath slowly heated to an internal temperature of 135 C, heat preservation reaction6 hours; constant water cooling, to an internal temperature of about 60 C; the reaction solution was slowly added to the dilute hydrochloric acid solution for hydrolysis; extracted with ethyl acetate several times, combined ethyl acetate extract, washed with water pH weak acid; organic layer minusThe mixture was concentrated under pressure, and the ethyl acetate was recovered; the residue was decolored and recrystallized from dilute alcohol water to obtain 95.14 g of 3,4-dihydroxybenzonitrile as a white crystalline solid powder. Yield: 89.27%, melting point: 155.50-156.0.C, purity: 99.3% |
88% | With pyridine; aluminium(III) iodide; In acetonitrile; at 80℃; for 18h; | General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99%). |
88% | To a 100 ml eggplant flask were added iodine (2.109 g), aluminum powder (0.412 g) and acetonitrile (50 ml)Heated to reflux, stirring for 2 hours to the purple red of iodine disappears.Further, pyridine (1.860 g) and <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (0.746 g)The reaction was continued for 18 hours. The mixture was stirred and cooled to room temperature. The reaction solution was acidified with 2 mol / L dilute hydrochloric acid (10 ml) and extracted with ethyl acetate (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate.The filtrate was evaporated to dryness on a rotary evaporator and the residue was purified by flash column chromatography (mobile phase ethyl acetate:Petroleum ether = 1: 4, volume ratio) to give 4-cyanocatechol (white solid, 0.598 g, yield 88%). | |
70.6% | To a 3-necked 250 mL round bottom flask equipped with a mechanical stirrer and a condenser, <strong>[4421-08-3]3-methoxy-4-hydroxybenzonitrile</strong> (13.4 g, 89.9 mmole), lithium chloride (7.6 g, 179.2 mmole), and N,N'-dimethylformamide (60 mL) were added successively at 25 C., followed by heating in an oil bath at 180 C. for 20 hours. The reaction mixture was allowed to cool to 85 C. Water (285 mL) was then added, and upon cooling to 25 C., treatment with concentrated hydrochloric acid proceed. The resulting mixture was extracted with ethyl acetate (300 mL×2). The extract was concentrated under reduced pressure to give a pale brown solid. Water (430 mL) was added and the mixture was then heated till the mixture became homogeneous. After the reaction mixture was cooled down to approximately 40 C., 3,4-Dihydroxybenzonitrile was precipitated out and the reaction mixture was further cooled to 10 C. so as to ensure complete precipitation. The resulting solid was isolated by filtration and dried under reduced pressure. 3,4-Dihydroxybenzonitrile was obtained as a white solid with a yield of 70.6% and a purity of greater than 99% as indicated by HPLC analysis. | |
67% | Example 2a Preparation of 3,4-dihydroxybenzonitrile from <strong>[4421-08-3]3-methoxy-4-hydroxybenzonitrile</strong> To a 4-necked 1 L round bottom flask equipped with a mechanical stirrer and a condenser, <strong>[4421-08-3]3-methoxy-4-hydroxybenzonitrile</strong> 2a (2a (70.7 g, 0.47 mole), lithium bromide (81.3 g, 0.94 mole), and N,N'-dimethylformamide (220 ML) were added successively at 25 C., followed by heating in an oil bath at 180 C. for 10 hours.The reaction mixture was allowed to cool to 85 C. water (285 ML) was then added, and upon cooling to 25 C., and treatment with concentrated hydrochloric acid proceed.The resulting mixture was extracted with ethyl acetate (300 ML*2).The extract was concentrated under reduced pressure to give a pale brown solid.Water (430 ML) was added and the mixture was then heated till the mixture became homogeneous.After the reaction mixture was cooled down to approximately 40 C., 3,4-Dihydroxybenzonitrile was precipitated out and the reaction mixture was further cooled to 10 C. so as to ensure complete precipitation.The resulting solid was isolated by filtration and dried under reduced pressure. 3,4-Dihydroxybenzonitrile (42.5 g) was obtained as a white solid with a yield of 67% and a purity of greater than 99% as indicated by HPLC analysis. | |
With pyridine; aluminum (III) chloride; N-benzyl-N,N,N-triethylammonium chloride; In ethyl acetate; at 0 - 65℃; for 9h; | Ethyl acetate was added to the reactor R0201,<strong>[4421-08-3]3-methoxy-4-hydroxybenzonitrile</strong> synthesized in the first stage was completely dissolved under full stirring,The reactor R0201 cooled to 0 C, and then were added anhydrous aluminum chloride, pyridine and TEBA,After the raw materials are fully dissolved, the temperature is raised to 65 DEG C, the reaction is continued for 9 hours, and the sample is taken from the sampling port 02001,After the reaction of the raw material is completed, the reaction is stopped; then 12 mol / L of concentrated hydrochloric acid is added, and while stirring, the pH is adjusted to 2,The reaction liquid enters the extraction vessel R0202A through the material pump P0201, and the suitable amount of ethyl acetate is introduced into the extraction vessel R0202A,After fully stirring 30min, standing 1h, stratification, the lower liquid through the material pump P0202 into the extraction vessel R0202B,The upper organic layer into the vacuum dryer D0201; in the extraction vessel R0202B pass through a suitable amount of ethyl acetate,Stir 30min, let stand 1h, stratification, the lower liquid into the extraction vessel R0202A by the material pump P0203,The upper organic layer into the vacuum dryer D0201; extraction cycle several times,Sampling port 02002 or sampling port 02003 sampling test, stop the extraction operation;Into the vacuum dryer D0201 material, the solvent was dried under vacuum ethyl acetate recovery,Recover the ethyl acetate into the ethyl acetate recovery tank V02001,The recovered ethyl acetate can enter the extraction kettle R0202A again through the material pump P0204 to participate in the extraction operation,After the ethyl acetate was recovered, the product 3,4-dihydroxybenzonitrile and the product 3,4-dihydroxybenzonitrile came out of the vacuum dryer D0201. |
Yield | Reaction Conditions | Operation in experiment |
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92% | With tributylphosphine; In tetrahydrofuran; | EXAMPLE 106 To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (317 mg), 4-cyano-2-methoxyphenol (300 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1'-(azodicarbonyl)dipiperidine (400 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and crystals of 4-(4-chlorophenyl)-5-[3-(4-cyano-2-methoxyphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole (413 mg, 92%) were obtained from an ethyl acetate-hexane (2:3, v/v)-eluted fraction. |
Yield | Reaction Conditions | Operation in experiment |
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95.7% | 8.1 g of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (Compound 1) and 8.3 g of potassium carbonate were added to 100 mL of acetonitrile and stirred at room temperature for 10 min.After the stirring is completed, 7 mL of benzyl chloride is added.Heating and refluxing for 5 h,The reaction was monitored by TLC; after completion of the reaction, it was cooled to room temperature, filtered, and evaporated to give a crude product.A small amount of methanol was rinsed to obtain 12.2 g of the target product.The yield was 95.7%. | |
88% | With potassium carbonate; In acetone; | Example 3 To <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (20.0 g, 134 mmol) in acetone (200 ml) were added K2CO3 (55.6 g, 402 mmol) and benzyl chloride (23.2 ml, 201 mmol). The resulting reaction mixture was refluxed overnight. After cooling to room temperature, acetone was removed by evaporation under reduced pressure and the residue was recrystallized to obtain 4-benzyloxy-3-methoxy-benzonitrile(28.5 g, 88%). Then, according to the similar procedure of Example 1, 7-(4-Benzyloxy-3-methoxy-phenyl)-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine was prepared. |
Yield | Reaction Conditions | Operation in experiment |
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87% | With triethylamine; In tetrahydrofuran; at -10℃; for 1h; | Reference Example 19; 5-Cyano-2-trifluoromethylsulfonyloxyanisole (Reference Compound No.19-1) A mixture of 5-cyano-2-hydroxyanisole (600 mg, 4.02 mmol) and triethylamine (1.40 mL, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under argon atomosphere. Trifluoromethanesulfonyl chloride (642 muL, 6.03 mmol) were added thereto at -10C, and stirred at the same temperature for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (979 mg) as a colorless solid. (Yield 87%) |
Yield | Reaction Conditions | Operation in experiment |
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91% | Sodium hydride (60% in oil, 2.81 g, 10 mmol) was added to a solution of 4-hydroxy-3-methoxy-benzonitrile (10 g, 67 mmol) in DMF (100 mL) at 0 C. Mixture was allowed to stir at ambient temperature for 30 min. Bromomethylmethyl ether (6.4 mL, 70 mmol) was added to the resultant solution, and the solution was stirred at rt for 2 h. The solution was poured into ice water (400 mL). The product, 3-Methoxy-4-methoxymethoxy-benzonitrile, was collected by filtration, washed generously with water, and allowed to air dry to give the product as a colorless solid 11.75 g (91%). The purity of the product was estimated to be (95% by HPLC and H NMR, and the product was used without further purification in the subsequent step). 1H NMR (CDCl3): delta 3.51 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.12 (d, J=1.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H) and 7.25 (d of d, J=8.4 & 1.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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59% | With tetrabutylammomium bromide; copper(II) acetate monohydrate In water at 20 - 140℃; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
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86% | With tetrabutylammomium bromide; copper(II) acetate monohydrate In water at 180℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
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100% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | 4-Hydroxy-3-methoxybenzonitrile (3.4 g, 22.8 mmol) was dissolved in DMF (45 mL), potassium carbonate (4.73 g, 34.2 mmol) was added slowly, followed by benzyl bromide (3.0 mL, 25.1 mmol). The reaction mixture was stirred overnight at ambient temperature then brine (50 mL) solution was added. The precipitate was collected affording the title compound as a white solid (5.45 g, 100%). Mp: 81-83 C (lit 81-83 C 6); 1H NMR (500 MHz, CDCl3) delta: 3.91 (s, 3H, OCH3), 5.21 (s, 2H, Ar-CH2), 6.92 (d, 1H, ArH, J = 8.3 Hz), 7.11 (d, 1H, ArH, J = 1.9 Hz), 7.22 (dd, 1H, ArH, J = 1.9, 8.3 Hz), 7.30-7.46 (m, 5H, ArH). 13C NMR (125 MHz, CDCl3) delta: 56.20, 70.89, 104.18, 113.32, 114.40, 119.23, 126.27, 127.25, 128.77, 128.80, 135.81, 149.68, 152.00. HRMS (ESI, m/z): calc?d for C15H14NO2 [M+H]+ 240.1019 found: 240.1017 |
96.8% | 8.1 g of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (Compound 1) and 8.3 g of potassium carbonate were added to 100 mL of acetonitrile, and stirred at room temperature for 10 min. After stirring, 7 mL of benzyl bromide was added, and the mixture was heated under reflux for 5 h, TLC Monitor the progress of the reaction; end of the reaction After cooling to room temperature, filter,The solvent is distilled off to give a crude product.Rinse with a small amount of methanol to give a white solid product 12.5 g.The yield is 96.8%. | |
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> (10.0 g, 67.11 mmol) and potassium carbonate (19 g, 134 mmol) were taken in DryDMF (20 mL) at 0C. And then benzyl bromide (9.0 mL, 80.5 mmol) was added to the reaction mixture very slowly. The reaction mixture was stirred 12 h at room temperature, and brine solution (100 mL) was added. The resulting precipitate was collected, washed with water and dried to provide 4-benzyloxy-3-methoxybenzonitrileas a white solid (13.9 g, 89% yield). 1H NMR (300MHz, CDCl3) delta 3.88 (s, 3H), 5.18 (s, 2H),6.88 (d, J=8.4 Hz, 1H),7.03 (s, 1H),7.21 (dd, J=8.4, 2.0 Hz, 1H),7.32-7.42 (m, 5H). ESI [M+Na]+: 262.25). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | EXAMPLE 94The synthesis of 6-methoxy-7-(3-morpholinopropoxy)-4-(3-chloro-4-fluoro anilino)-benzo[d][1,2,3]triazine; Step A: General procedure for the synthesis of 3-methoxy-4-chloropropoxybenzonitrile 2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a round bottom flask. The solution was stirred and cooled in a water bath. Several batches of anhydrous K2CO3 (0.347 g, 2.50 mmol) were added to the solution and the mixture was stirred at 20 C. to react for 1 h. 1-chloro-3-bromopropane (0.23 ml, 2.14 mmol) was added, and the mixture was stirred at room temperature (25 C.) to react overnight. The mixture was heated to 37 C. to react for 6 h and then poured into a mixture of ice/H2O (25 mL). After stirring for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield white solid product (0.388 g) with a recovery rate of 90%, | |
82% | To 74.5 gms (0.5mol) of 4-Hydroxy-3-methoxybenzonitrile in 450ml. of acetone was added 136gms (1 mole) of potassium carbonate and the resultant reaction mixture was stirred at about 25-30C for about 5min. To the reaction suspension 1 10 gms (0.7mol) of 3-Chloro-l- bromo propane was added drop-wise at about 25-35C for about 30mins. The resultant reaction mixture was refluxed for about 12hrs. The undissolved inorganic salts was filtered off and washed with acetone. The solvent was distilled completely under vacuum and the residue was re-crystallised from 300ml of isopropyl alcohol to afford the title compound as white crystalline solid. Yield: 92.5gms (% Yield : 82%). | |
Step A: General procedure for the synthesis of 3-methoxy-4-chloropropoxybenzonitrile 2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a round bottom flask. The soltuion was stirred and cooled in a water bath. Sevearl batches of anhydrous K2CO3 (0.347 g, 2.50 mmol) were added to the solution and the mixture was stirred at 20C to react for 1 h. 1-chloro-3-bromopropane (0.23 ml,2.14 mmol) was added, and the mixture was stirred at room temperature (25C) to react overnight. The mixture was heated to 37C to react for 6 h and then poured into a mixture of ice/H2O (25 mL). After stirring for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield white solid product (0.388 g) with a recovery rate of 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | EXAMPLE 11The synthesis of 6-methoxy-7-butoxy-4-anilino-benzo[d][1,2,3]triazineStep A: General Procedure for the synthesis of 3-methoxy-4-butoxybenzonitrile; 2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a flask, then cooled in a water bath while stirring. Several batches of K2CO3 (0.347 g, 2.50 mmol) were added to the mixture and stirred at 20 C. to react for 1 h. n-butyl bromine (0.23 ml, 2.14 mmol) was added into the mixture, which was stirred at room temperature overnight, then heated at 37 C. to react for 6 h. Poured the solution into a mixture of ice/H2O (25 mL), then stirred for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield 0.361 g of white solid product with a recovery rate of 92%. | |
Step A: General Procedure for the synthesis of 3-methoxy-4-butoxybenzonitrile 2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a flask, then cooled in a water bath while stirring. Several batches of K2CO3 (0.347 g, 2.50 mmol) were added to the mixture and stirred at 20C to react for 1 h. n-butyl bromine(0.23 ml,2.14 mmol) was added into the mixture, which was stirred at room temperature overnight, then heated at 37C to react for 6 h. Poured the solution into a mixture of ice/H2O (25 mL), then stirred for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield 0.361 g of white solid product with a recovery rate of 92%. |
Yield | Reaction Conditions | Operation in experiment |
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81% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 48.5h; | Synthesis of 3-Methoxy-4-(tetrahydro-pyran-4-yloxy)-benzonitrile (4.14) (for Example 59, 60, 63-65)4.148 g 3-Methoxy-4-hydroxy-benzonitrile, 28.1 g triphenylphosphine and 5.48 g tetrahydro-4H- pyran-4-o l wa s s u s pe n d ed i n 1 L tetra h yd rofu ra n at 0 C befo re 24.7 g d i-tert- butylazodicarboxylate (DBAD) was added over 30 min. The reaction was warmed to ambient temperature and stirred for 2 d. After this time, the reaction was diluted with water and ethyl acetate. The organic phase was separated and then it was washed with 1 N sodium hydroxide, water and saturated sodium chloride, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel chromatography (Si02: heptane /ethyl acetate 8:2 to 7:3) to provide the title compound.Yield: 10.2 g (81 % of theory)Analysis: HPLC-MS (Method C): Rt: 1 .72 min, (M+H)+: 234. |
81% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 48.5h; | 8 g 3-Methoxy-4-hydroxy-benzonitrile, 28.1 g triphenylphosphine and 5.48 g tetrahydro-4H-pyran-4-ol was suspended in 1 L tetrahydrofuran at 0 C. before 24.7 g di-tert-butylazodicarboxylate (DBAD) was added over 30 min. The reaction was warmed to ambient temperature and stirred for 2 d. After this time, the reaction was diluted with water and ethyl acetate. The organic phase was separated and then it was washed with 1N sodium hydroxide, water and saturated sodium chloride, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel chromatography (SiO2: heptane/ethyl acetate 8:2 to 7:3) to provide the title compound. Yield: 10.2 g (81% of theory) Analysis: HPLC-MS (Method C): Rt: 1.72 min, (M+H)+: 234. |
Yield | Reaction Conditions | Operation in experiment |
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73% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | Synthesis of 3-Methoxy-4-(1 -methyl-piperidine-4-yloxy)-benzonitrile (For Example 104)4.432.04 g 4-Hydroxy-3-methoxy-benzonitrile, 1 .57 g 1 -methyl-piperidine-4-o l a n d 7. 1 7 g triphenylphosphine were placed in 125 mL tetrahydrofuran at 0C before 6.30 g di-tert- butylazodicarboxylate (DBAD) as a solution in 125 mL tetrahydrofuran was added over 15 min. The reaction was stirred for 5 min at 0C and then warmed to ambient temperature where it was maintained overnight. After this time additional 0.31 g 1 -methyl-piperidine-4-ol, 1 .79 g triphenylphosphine and 1 .58 g di-tert-butylazodicarboxylate (DBAD) were added and the reaction was stirred for a further 3 h at ambient temperature. The mixture was then diluted with ethyl acetate and water and the organic phase was separated, washed with 1 N sodium hydroxide (x2), water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The material that remained was dissolved in tert-butyl dimethyl ether and washed with 3N hydrochloric acid . The aqueous phase was then made basic with 5N sodium hydroxide and extracted with ethyl acetate (x3). The combined organic fractions were washed water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel chromatography (Si02: dichloromethane/methanol 5% then dichloromethane/7N ammonia in methanol 5%) provided the title compound.Yield: 2.48 g (73% of theory)Analysis: HPLC-MS (Method B): Rt: 1 .1 1 min. (M+H)+ = 247 |
73% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | 2.04 g 4-Hydroxy-3-methoxy-benzonitrile, 1.57 g 1-methyl-piperidine-4-ol and 7.17 g triphenylphosphine were placed in 125 mL tetrahydrofuran at 0 C. before 6.30 g di-tert-butylazodicarboxylate (DBAD) as a solution in 125 mL tetrahydrofuran was added over 15 min. The reaction was stirred for 5 min at 0 C. and then warmed to ambient temperature where it was maintained overnight. After this time additional 0.31 g 1-methyl-piperidine-4-ol, 1.79 g triphenylphosphine and 1.58 g di-tert-butylazodicarboxylate (DBAD) were added and the reaction was stirred for a further 3 h at ambient temperature. The mixture was then diluted with ethyl acetate and water and the organic phase was separated, washed with 1N sodium hydroxide (*2), water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The material that remained was dissolved in tert-butyl dimethyl ether and washed with 3N hydrochloric acid. The aqueous phase was then made basic with 5N sodium hydroxide and extracted with ethyl acetate (*3). The combined organic fractions were washed water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel chromatography (SiO2: dichloromethane/methanol 5% then dichloromethane/7N ammonia in methanol 5%) provided the title compound. Yield: 2.48 g (73% of theory) Analysis: HPLC-MS (Method B): Rt: 1.11 min. (M+H)+=247 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate; In acetone;Reflux; | Synthesis of 3-Methoxy-4-(tetrahydro-pyran-4-ylmethoxy)-benzonitrile (For Example1 .0 g 4-Hydroxy-3-methoxybenzonitrile, 1.1 g potassium carbonate and 2.0 g 4-(iodomethyl)- tetrahydropyran were placed in 20 mL acetone and heated to reflux overnight. After this time,1 .1 g potassium carbonate was added and the reaction was heated at reflux for a further 2 h before more 0.93 g potassium carbonate was introduced and reflux was continued for a further 3 h. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between diethyl ether and water and the aqueous phase was removed and extracted with additional diethyl ether. The combined organic fractions were dried, filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (Si02: ethyl acetate/heptanes: 10% to 30%) provided the title compound. Yield: 307 mg (19% of theory)Analysis: HPLC-MS (Method B): Rt: 1 .85 min. |
19% | With potassium carbonate; In acetone;Reflux; | 1.0 g 4-Hydroxy-3-methoxybenzonitrile, 1.1 g potassium carbonate and 2.0 g 4-(iodomethyl)-tetrahydropyran were placed in 20 mL acetone and heated to reflux overnight. After this time, 1.1 g potassium carbonate was added and the reaction was heated at reflux for a further 2 h before more 0.93 g potassium carbonate was introduced and reflux was continued for a further 3 h. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between diethyl ether and water and the aqueous phase was removed and extracted with additional diethyl ether. The combined organic fractions were dried, filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (SiO2: ethyl acetate/heptanes: 10% to 30%) provided the title compound. Yield: 307 mg (19% of theory) Analysis: HPLC-MS (Method B): Rt: 1.85 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In N,N-dimethyl acetamide; at 120℃; for 3h; | Step 15 g 4-(4-Hydroxy-cyclohexyl)-1-methyl-piperazine-2-one was dissolved in 50 mL acetonitrile and concentrated by approximately 50%. The suspension was diluted with 25 mL tetrahydrofuran, cooled to 0C and 6.16 mL of triethylamine and 1.87 mL methanesulfonylchloride was added dropwise. The mixture was stirred for 2 h at ambient temperature. The precipitate was filtered and the filtrate was stirred at reflux for 4 h. After cooling the precipitate was removed by filtration, washed with ethyl acetate, dried and concentrated.Yield: 4.15 g of 1.1 (71% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In ISOPROPYLAMIDE; at 120℃; for 3h; | 2 g 4-Hydroxy-3-methoxy-benzonitrile, 4.15 g intermediate 1.1 and 2.8 g potassium carbonate was suspended in 20 mL dimethylacetamide and stirred at 120 C. for 3 h. After cooling the mixture was diluted with dichloromethane, washed with water and the organic phase was dried over magnesium sulfate and concentrated.Yield: 4.54 g (95% content, 94% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 115℃; for 3h; | N,N-bis(2-chloroethyl)-N-methylamine hydrochloride (0.96 g; 5 mmol), <strong>[4421-08-3]3-methoxy-4-hydroxybenzonitrile</strong> (1.49 g; 10 mmol), anhydrous K2CO3 (4.14 g; 30 mmol) and N-methyl-2-pyrrolidone (20 ml) was stirred together at 115 C for 3 h (progress of the reaction was followed by TLC) and then poured into ice water (200 ml). The precipitated solid was filtered, washed with water, and dried to obtain 1.86 g (Yield: 98%) of a white solid of 2a. M.p. = 84.5-88 C. 1H NMR (299.86 MHz, CDCl3) delta in ppm: 2.56 (s; 3H; H-11), 3.09 (t; J = 5.7 Hz; 4H; H-9, H-9'), 3.85 (s; 6H; H-10, H-10'), 4.23 (t; J = 5.7 Hz; 4H; H-8, H-8'), 6.92 (d; J = 8.4 Hz; 2H; H-6, H-6'), 7.07 (d; J = 1.5 Hz; 2H; H-3, H-3'), 7.25 (dd; J1 = 8.4 Hz J2 = 1.5 Hz; 2H; H-5, H-5'). 13C NMR (75.40 MHz, CDCl3) delta in ppm: 43.73 (C-11), 56.3 (C-10, C-10'), 56.3 (C-9, C-9'), 67.2 (C-8, C-8'), 104.5 (C-4, C-4'), 112.9 (C-6, C-6'), 114.5 (C-3, C-3'), 119.3 (C-7, C-7'), 126.5 (C-5, C-5'), 149.7 (C-2, C-2'), 151.2 (C-1, C-1'). C21H23N3O4 (381.44 g/mol): calcd (%): C = 66.13; H = 6.08; N = 11.02; found (%): C = 65.87; H = 6.24; N = 10.91. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 3h; | To a solution of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> 1.49 g (10 mmol) in N-methyl-2-pyrrolidone (15 ml) with anhydrous K2CO3 2.76 g (20 mmol), 0.72 g (5 mmol) of bis(2-chloroethyl)ether was added and stirred at 130 C for 3 h (progress of the reaction was followed by TLC). The hot reaction mixture was poured into ice water (300 ml), and the precipitated solid was filtered, washed with water and dried at 60 C. Recrystalisation from ethanol gave 1.64 g (Yield: 89%) of a white solid of 7a. M.p. = 137-139 C. 1H NMR (400.13 MHz, CDCl3) delta in ppm: 3.86 (s; 6H; H-10, H-10'), 3.98 (t; J = 4.7 Hz; 4H; H-8, H-8'), 4.24 (t; J = 4.7 Hz; 4H; H-9, H-9'), 6.93 (d; J = 8.4 Hz; 2H; H-6, H-6'), 7.08 (broad s; 2H; H-3, H-3'), 7.24 (dd; J1 = 1.2 Hz J2 = 8.4 Hz; 2H; H-5, H-5'). 13C NMR (100.61 MHz, DMSO-d6) delta in ppm: 56.3 (C-10, C-10'), 68.8 (C-9, C-9'), 69.9 (C-8, C-8'), 104.5 (C-4, C-4'), 113.2 (C-6, C-6'), 114.6 (C-3, C-3'), 119.4 (C-7, C-7'), 126.5 (C-5, C-5'), 149.8 (C-2, C-2'), 152.4 (C-1, C-1'). C20H20N2O5 (368.39 g/mol): calcd. (%): C = 65.21, H = 5.47, N = 7.60; found (%): C = 65.38, H = 5.52, N = 7.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 0.08 h / 25 - 30 °C 1.2: 12.5 h / 25 - 30 °C / Reflux 2.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 9 h / 30 - 90 °C 3.1: copper(l) chloride / toluene; diethyl ether / 2 h / Reflux 3.2: 2 h / 25 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methoxy-4-hydroxybenzonitrile With hydrogenchloride In 1,4-dioxane; ethanol at 20℃; Stage #2: With ammonium carbonate In ethanol at 20℃; | 41.1 To 3-methoxy-4-hydroxybenzonitrile (2.0 g, 13.4 mmol) were added ethanol (3 mL) and 4N hydrochloric acid/1,4-dioxane (27 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (50 mL). Ammonium carbonate (6.4 g, 67 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added and the mixture was freeze-dried to give the title compound (1.82 g). 1H-NMR(400MHz, DMSO-d6) δ 9.40-8.70(5H, br s), 7.46(1H, d, J=2.4Hz), 7.40(1H, dd, J=8.4, 2.4Hz), 6.97(1H, d, J=8.4Hz), 3.86(3H, s). MS(ESI) m/z 167(M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate; In N,N-dimethyl-formamide; at 95℃; for 16h;Inert atmosphere; | To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (1.79 g, 12.0 mmol) in dry DMF (24 mL) was added <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (1.90 g, 12.0 mmol, 1.0 eq) followed by the addition of Cs2CO3 (6.92 g, 21.2 mmol, 1.77 eq). The reaction mixture was stirred at 95 C for 16 h under Ar atmosphere before cooling to room temperature. The mixture was diluted with EtOAc and poured onto water. The product was extracted with EtOAc (3 ? 100 mL), and the combined organic phases washed with water (3 ? 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was subsequently purified by flash chromatography on silica with Hex-EtOAc (Hex, then Hex-EtOAc 4:1 to 3:2) to give the desired product as pale-yellow solid (2.50 g, 72%). 1H NMR (DMSO) delta 9.92 (s, 1H), 8.10 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H); 13C NMR (DMSO) delta 190.8, 156.5, 151.0, 146.3, 132.5, 131.8, 130.0, 126.2, 123.1, 122.1, 118.4, 117.4, 117.3, 108.9, 56.5; HPLC purity 97.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 10h;Schlenk technique; | General procedure: A mixture of the aryl halide (1.0 mmol), K4Fe(CN)6 (0.22 mmol), Cs2CO3 (1.0 mmol), Pd-zeolite (0.025 mmol Pd) and 5 mL of solvent (DMF) was placed in a Schlenk tube (25 mL), and was vigorously stirred for 10 h at 130 C. Upon completion, the mixture was cooled to room temperature, and diluted with ether and water. Organic layer was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure using rotary evaporator to give the crude product. The residue was purified by recrystallisation using ethanol and water. The purity of the compounds was checked by 1H NMR and yields are based on aryl halide. All the products are known and the spectroscopic data (FT-IR and NMR) and melting points were consistent with those reported in the literature.4-19,38,39 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With ammonium hydroxide; oxygen In tert-Amyl alcohol at 110℃; for 15h; Autoclave; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 145℃; for 6h; | 3-Methoxy-4-hydroxybenzonitrile (1.49 g, 10 mmol) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (1.48 g, 5 mmol) in NMP (20 mL) were stirred at 145 C together with anhydrous K2CO3 (2.76 g, 20 mmol) (progress of the reaction was followed by TLC). After 6 h the reaction mixture was poured into ice water (300 mL). The obtained solid was filtered, washed with water and dried. The crude product was dissolved in hot EtOH and filtered hot. The precipitate was purified by column chromatography (Merck Silica gel 60, 230-400 mesh ASTM, eluent CH2Cl2:MeOH-98:2) to afford 1.31 g of 15a (yield 50%), mp 177-179 C. 1H NMR (400.13 MHz, CDCl3) delta: 2.34 (s, 3H, 11-CH3), 3.61 (t, J = 6.0 Hz, 4H, 9- and 9'-CH2), 3.69 (s, 6H, 10- and 10'-OCH3), 4.24 (t, J = 6.0 Hz, 4H, 8- and 8'-CH2), 6.82 (d, J = 8.4 Hz, 2H, H-5,-5'), 6.98 (d, J = 2 Hz, 2H, H-2,-2'), 7.16-7.21 (m, 4H, H-6,-6',-3",-5"), 7.64-7.66 (m, 2H, H-2",-6"). For C27H27N3O6S (521.60 g/mol) calcd: C, 62.17; H, 5.22; N, 8.06; S, 6.15; found: C, 62.03; H, 5.47; N, 7.86; S, 6.32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With laccase from Trametes versicolor; oxygen; In acetone; at 20℃; for 24h;pH 5.0;Green chemistry; Enzymatic reaction; | 4-Hydroxy-3-methoxybenzonitrile dimer (2): MW = 296 g/mol, yield: 95%. 1H NMR (400 MHz, CDCl3, delta (ppm)): delta 9.91 (s, 2H, HO), 7.57(s, 2H, Ar), 7.42 (s, 2H, Ar), 3,93 (s, 6H, OCH3). 13C NMR (400 MHz, CDCl3, delta (ppm)): delta 148.63 Ar-C), 147.85 (Ar-C), 128.05 (Ar-C), 124.56 (Ar-C), 119.45 (Ar-C), 114.03 (Ar-C), 100.30 (CN), 56.15 (OCH3). |
95% | With laccase from Trametes versicolor; oxygen; In acetone; at 20℃; for 24h;pH 5.0;Enzymatic reaction; | A solution of 1.5 g of compound of <strong>[4421-08-3]4-hydroxy-3-methoxybenzonitrile</strong> in 20 mL of acetone was added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The solution was saturated in O2 for 5 min. Laccase from Trametes versicolor (20 U, 12.4 mg) was added and the reaction was stirred at room temperature for 24 hours. The precipitate was filtered, washed with water and dried under vacuum (at 100 C. overnight). Analyses: Mass: 296.1 (100%), 297.1 (18%), 298.1 (2%); 1H NMR: delta 9.91 (s, 2H, HO), 7.57 (s, 2H, Ar), 7.42 (s, 2H, Ar), 3.93 (s, 6H, OCH3); 13C NMR: delta 148.63 (Ar-C), 147.85 (Ar-C), 128.05 (Ar-C), 124.56 (Ar-C), 119.45 (Ar-C), 114.03 (Ar-C), 100.30 (CN), 56.15 (OCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: aluminum (III) chloride; pyridine; N-benzyl-N,N,N-triethylammonium chloride / ethyl acetate / 9 h / 0 - 65 °C 2: potassium iodide; potassium carbonate / acetone / 9 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; pyridine; N-benzyl-N,N,N-triethylammonium chloride / ethyl acetate / 9 h / 0 - 65 °C 2.1: potassium iodide; potassium carbonate / acetone / 9 h / Reflux 3.1: acetic acid / 20 °C 3.2: 5 - 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a stirred solution of substituted phenol (1 mmol) in DMF(4 mL), K2CO3 (3 mmol) was added. Furthermore 2-(chloromethyl)-5-aryl-1,3,4-oxadiazole derivatives (6a-6e) and KI (0.5 mmol) wasadded. The reaction mixture was stirred at RT for 1-2 h. Aftercompletion of the reaction, the reaction mixture was washed withcold water. The solid product was collected by filtration and driedunder the vacuum. It had been further crystallized in ethyl acetate/petroleum ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium tetrahydroborate; copper ferrite In water for 0.0833333h; Reflux; Green chemistry; chemoselective reaction; | General procedure for the reduction of nitriles to primary amines General procedure: As a representative example, in a round-bottom flask (15 mL) equipped with a magnetic stirrer, benzonitrile (1 mmol, 0.103 g) was dissolved in H2O (2 mL). Afterward, CuFe2O4 (0.2 mmol, 0.048 g) was added and the mixture was stirred. Then, NaBH4 (2 mmol, 0.076 g) was also added, and the resulting mixture continued to stir at reflux for 5 min. Upon completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, and the catalyst was separated by an external magnet. The reaction mixture was extracted with ethyl acetate (EtOAc) (2 x 4 mL). The organic layers were combined together and dried over anhydrous sodium sulfate (Na2SO4). The solvent was evaporated under reduced pressure. The pure colorless liquid benzylamine was obtained in 95% yield. |
81% | With sodium tetrahydroborate; nickel(II) acetate tetrahydrate In water at 50℃; for 0.2h; | 3.2. General procedure for the reduction of arynitriles to corresponding primary amines General procedure: As a representative example, in a round-bottom flask (10 mL) equipped with a magnetic stirrer, benzonitrile (1 mmol) was dissolved in H2O (2 mL). Afterward, Ni(OAc)2•4H2O (50 mol%) was added, and the mixture was stirred. Then, NaBH4 (2 mmol) was added, and the resulting mixture was continued to stirring at 50 C for 12 min. Upon completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, and then 5 mL of water was added to the reaction mixture and was stirred at room temperature for about 5-10 min. The reaction mixture was extracted with ethyl acetate (EtOAc) (2 × 4 mL). The organic layers were combined and dried over anhydrous sodium sulfate (Na2SO4). Next, the solvent was evaporated under reduced pressure, and subsequently, the pure colorless liquid benzylamine was obtained in 89% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; potassium iodide; In 1-methyl-pyrrolidin-2-one; at 65℃; for 24h; | General procedure: A mixture of corresponding hydroxybenzonitrile 1a,c-i (1 mol),finely divided K2CO3 (5 mol), KI (0.01 mol), 5-chloro-1-pentyne(1.5 mol) and N-methylpyrrolidone-2 was heated at 65 C for24 h. The cooled reaction mixture was treated by cold water andstirred for 3e4 h. The solid was collected and recrystallized fromthe corresponding solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
402 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2.5h; | i) 4-Hydroxy-3-methoxybenzonitrile (250 mg), 2-fluoro-5-(trifluoromethyl)benzaldehyde (322 mg) and K2CO3(463 mg) were suspended in DMF (8mL) and stirred at 90C for 2,5 hours. The reaction was cooled to room temperature and partitioned between water and EtOAc. The water layer was extracted twice more with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified on silica column, using a gradient of 0 to 30% EtOAc in heptane, to obtain 4-[2-formyl-4-(trifluoromethyl)phenoxy]-3-methoxy-benzonitrile (402 mg). |
Tags: 4421-08-3 synthesis path| 4421-08-3 SDS| 4421-08-3 COA| 4421-08-3 purity| 4421-08-3 application| 4421-08-3 NMR| 4421-08-3 COA| 4421-08-3 structure
[ 173900-47-5 ]
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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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